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Showing papers by "University of Pittsburgh published in 2010"


Journal ArticleDOI
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


Journal ArticleDOI
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


Proceedings ArticleDOI
13 Jun 2010
TL;DR: The Cohn-Kanade (CK+) database is presented, with baseline results using Active Appearance Models (AAMs) and a linear support vector machine (SVM) classifier using a leave-one-out subject cross-validation for both AU and emotion detection for the posed data.
Abstract: In 2000, the Cohn-Kanade (CK) database was released for the purpose of promoting research into automatically detecting individual facial expressions. Since then, the CK database has become one of the most widely used test-beds for algorithm development and evaluation. During this period, three limitations have become apparent: 1) While AU codes are well validated, emotion labels are not, as they refer to what was requested rather than what was actually performed, 2) The lack of a common performance metric against which to evaluate new algorithms, and 3) Standard protocols for common databases have not emerged. As a consequence, the CK database has been used for both AU and emotion detection (even though labels for the latter have not been validated), comparison with benchmark algorithms is missing, and use of random subsets of the original database makes meta-analyses difficult. To address these and other concerns, we present the Extended Cohn-Kanade (CK+) database. The number of sequences is increased by 22% and the number of subjects by 27%. The target expression for each sequence is fully FACS coded and emotion labels have been revised and validated. In addition to this, non-posed sequences for several types of smiles and their associated metadata have been added. We present baseline results using Active Appearance Models (AAMs) and a linear support vector machine (SVM) classifier using a leave-one-out subject cross-validation for both AU and emotion detection for the posed data. The emotion and AU labels, along with the extended image data and tracked landmarks will be made available July 2010.

3,439 citations



Journal ArticleDOI
TL;DR: The 1000 Functional Connectomes Project (Fcon_1000) as discussed by the authors is a large-scale collection of functional connectome data from 1,414 volunteers collected independently at 35 international centers.
Abstract: Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.

2,787 citations


Journal ArticleDOI
Andre Franke1, Dermot P.B. McGovern2, Jeffrey C. Barrett3, Kai Wang4, Graham L. Radford-Smith5, Tariq Ahmad6, Charlie W. Lees7, Tobias Balschun1, James Lee8, Rebecca L. Roberts9, Carl A. Anderson3, Joshua C. Bis10, Suzanne Bumpstead3, David Ellinghaus1, Eleonora M. Festen11, Michel Georges12, Todd Green13, Talin Haritunians2, Luke Jostins3, Anna Latiano14, Christopher G. Mathew15, Grant W. Montgomery5, Natalie J. Prescott15, Soumya Raychaudhuri13, Jerome I. Rotter2, Philip Schumm16, Yashoda Sharma17, Lisa A. Simms5, Kent D. Taylor2, David C. Whiteman5, Cisca Wijmenga11, Robert N. Baldassano4, Murray L. Barclay9, Theodore M. Bayless18, Stephan Brand19, Carsten Büning20, Albert Cohen21, Jean Frederick Colombel22, Mario Cottone, Laura Stronati, Ted Denson23, Martine De Vos24, Renata D'Incà, Marla Dubinsky2, Cathryn Edwards25, Timothy H. Florin26, Denis Franchimont27, Richard B. Gearry9, Jürgen Glas28, Jürgen Glas19, Jürgen Glas22, André Van Gossum27, Stephen L. Guthery29, Jonas Halfvarson30, Hein W. Verspaget31, Jean-Pierre Hugot32, Amir Karban33, Debby Laukens24, Ian C. Lawrance34, Marc Lémann32, Arie Levine35, Cécile Libioulle12, Edouard Louis12, Craig Mowat36, William G. Newman37, Julián Panés, Anne M. Phillips36, Deborah D. Proctor17, Miguel Regueiro38, Richard K Russell39, Paul Rutgeerts40, Jeremy D. Sanderson41, Miquel Sans, Frank Seibold42, A. Hillary Steinhart43, Pieter C. F. Stokkers44, Leif Törkvist45, Gerd A. Kullak-Ublick46, David C. Wilson7, Thomas D. Walters43, Stephan R. Targan2, Steven R. Brant18, John D. Rioux47, Mauro D'Amato45, Rinse K. Weersma11, Subra Kugathasan48, Anne M. Griffiths43, John C. Mansfield49, Severine Vermeire40, Richard H. Duerr38, Mark S. Silverberg43, Jack Satsangi7, Stefan Schreiber1, Judy H. Cho17, Vito Annese14, Hakon Hakonarson4, Mark J. Daly13, Miles Parkes8 
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

2,482 citations


Journal ArticleDOI
TL;DR: Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas.
Abstract: Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

2,109 citations


Journal ArticleDOI
Dalila Pinto1, Alistair T. Pagnamenta2, Lambertus Klei3, Richard Anney4  +178 moreInstitutions (46)
15 Jul 2010-Nature
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Abstract: The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

1,919 citations


Journal ArticleDOI
TL;DR: In this article, the authors discuss three components to boundary objects: interpretive flexibility, the structure of informatic and work process needs and arrangements, and the dynamic between ill-structured and more tailored uses of the objects.
Abstract: There are three components to boundary objects as outlined in the original 1989 article. Interpretive flexibility, the structure of informatic and work process needs and arrangements, and, finally, the dynamic between ill-structured and more tailored uses of the objects. Much of the use of the concept has concentrated on the aspect of interpretive flexibility and has often mistaken or conflated this flexibility with the process of tacking back-and-forth between the ill-structured and well-structured aspects of the arrangements. Boundary objects are not useful at just any level of scale or without full consideration of the entire model. The article discusses these aspects of the architecture of boundary objects and includes a discussion of one of the ways that boundary objects appeared as a concept in earlier work done by Star. It concludes with methodological considerations about how to study the system of boundary objects and infrastructure.

1,655 citations



Journal ArticleDOI
TL;DR: Women with depression during pregnancy are at increased risk for PTB and LBW, although the magnitude of the effect varies as a function of depression measurement, country location, and US socioeconomic status.
Abstract: Context Maternal depressive symptoms during pregnancy have been reported in some, but not all, studies to be associated with an increased risk of preterm birth (PTB), low birth weight (LBW), and intrauterine growth restriction (IUGR). Objective To estimate the risk of PTB, LBW, and IUGR associated with antenatal depression. Data Sources and Study Selection We searched for English-language and non–English-language articles via the MEDLINE, PsycINFO, CINAHL, Social Work Abstracts, Social Services Abstracts, and Dissertation Abstracts International databases (January 1980 through December 2009). We aimed to include prospective studies reporting data on antenatal depression and at least 1 adverse birth outcome: PTB ( Data Extraction Information was extracted on study characteristics, antenatal depression measurement, and other biopsychosocial risk factors and was reviewed twice to minimize error. Data Synthesis Pooled relative risks (RRs) for the effect of antenatal depression on each birth outcome were calculated using random-effects methods. In studies of PTB, LBW, and IUGR that used a categorical depression measure, pooled effect sizes were significantly larger (pooled RR [95% confidence interval] = 1.39 [1.19-1.61], 1.49 [1.25-1.77], and 1.45 [1.05-2.02], respectively) compared with studies that used a continuous depression measure (1.03 [1.00-1.06], 1.04 [0.99-1.09], and 1.02 [1.00-1.04], respectively). The estimates of risk for categorically defined antenatal depression and PTB and LBW remained significant when the trim-and-fill procedure was used to correct for publication bias. The risk of LBW associated with antenatal depression was significantly larger in developing countries (RR = 2.05; 95% confidence interval, 1.43-2.93) compared with the United States (RR = 1.10; 95% confidence interval, 1.01-1.21) or European social democracies (RR = 1.16; 95% confidence interval, 0.92-1.47). Categorically defined antenatal depression tended to be associated with an increased risk of PTB among women of lower socioeconomic status in the United States. Conclusions Women with depression during pregnancy are at increased risk for PTB and LBW, although the magnitude of the effect varies as a function of depression measurement, country location, and US socioeconomic status. An important implication of these findings is that antenatal depression should be identified through universal screening and treated.

Journal ArticleDOI
TL;DR: Overall survival, disease-free survival, and regional control were statistically equivalent between groups, and outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available.
Abstract: Summary Background Sentinel-lymph-node (SLN) surgery was designed to minimise the side-effects of lymph-node surgery but still offer outcomes equivalent to axillary-lymph-node dissection (ALND). The aims of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 were to establish whether SLN resection in patients with breast cancer achieves the same survival and regional control as ALND, but with fewer side-effects. Methods NSABP B-32 was a randomised controlled phase 3 trial done at 80 centres in Canada and the USA between May 1, 1999, and Feb 29, 2004. Women with invasive breast cancer were randomly assigned to either SLN resection plus ALND (group 1) or to SLN resection alone with ALND only if the SLNs were positive (group 2). Random assignment was done at the NSABP Biostatistical Center (Pittsburgh, PA, USA) with a biased coin minimisation approach in an allocation ratio of 1:1. Stratification variables were age at entry (≤49 years, ≥50 years), clinical tumour size (≤2·0 cm, 2·1–4·0 cm, ≥4·1 cm), and surgical plan (lumpectomy, mastectomy). SLN resection was done with a blue dye and radioactive tracer. Outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available. The primary endpoint was overall survival. Analyses were done on an intention-to-treat basis. All deaths, irrespective of cause, were included. The mean time on study for the SLN-negative patients with follow-up information was 95·6 months (range 70·1–126·7). This study is registered with ClinicalTrials.gov, number NCT00003830. Findings 5611 women were randomly assigned to the treatment groups, 3989 had pathologically negative SLN. 309 deaths were reported in the 3986 SLN-negative patients with follow-up information: 140 of 1975 patients in group 1 and 169 of 2011 in group 2. Log-rank comparison of overall survival in groups 1 and 2 yielded an unadjusted hazard ratio (HR) of 1·20 (95% CI 0·96–1·50; p=0·12). 8-year Kaplan-Meier estimates for overall survival were 91·8% (95% CI 90·4–93·3) in group 1 and 90·3% (88·8–91·8) in group 2. Treatment comparisons for disease-free survival yielded an unadjusted HR of 1·05 (95% CI 0·90–1·22; p=0·54). 8-year Kaplan-Meier estimates for disease-free survival were 82·4% (80·5–84·4) in group 1 and 81·5% (79·6–83·4) in group 2. There were eight regional-node recurrences as first events in group 1 and 14 in group 2 (p=0·22). Patients are continuing follow-up for longer-term assessment of survival and regional control. The most common adverse events were allergic reactions, mostly related to the administration of the blue dye. Interpretation Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes. Funding US Public Health Service, National Cancer Institute, and Department of Health and Human Services.

Journal ArticleDOI
TL;DR: Kowalski et al. as mentioned in this paper reported on work to increase the number of well-measured Type Ia supernovae (SNe Ia) at high redshifts.
Abstract: We report on work to increase the number of well-measured Type Ia supernovae (SNe Ia) at high redshifts. Light curves, including high signal-to-noise HST data, and spectra of six SNe Ia that were discovered during 2001 are presented. Additionally, for the two SNe with z > 1, we present groundbased J-band photometry from Gemini and the VLT. These are among the most distant SNe Ia for which ground based near-IR observations have been obtained. We add these six SNe Ia together with other data sets that have recently become available in the literature to the Union compilation (Kowalski et al. 2008). We have made a number of refinements to the Union analysis chain, the most important ones being the refitting of all light curves with the SALT2 fitter and an improved handling of systematic errors. We call this new compilation, consisting of 557 supernovae, the Union2

Journal ArticleDOI
10 Dec 2010-Science
TL;DR: Because lithiation-induced volume expansion, plasticity, and pulverization of electrode materials are the major mechanical effects that plague the performance and lifetime of high-capacity anodes in lithium-ion batteries, these observations provide important mechanistic insight for the design of advanced batteries.
Abstract: We report the creation of a nanoscale electrochemical device inside a transmission electron microscope--consisting of a single tin dioxide (SnO(2)) nanowire anode, an ionic liquid electrolyte, and a bulk lithium cobalt dioxide (LiCoO(2)) cathode--and the in situ observation of the lithiation of the SnO(2) nanowire during electrochemical charging. Upon charging, a reaction front propagated progressively along the nanowire, causing the nanowire to swell, elongate, and spiral. The reaction front is a "Medusa zone" containing a high density of mobile dislocations, which are continuously nucleated and absorbed at the moving front. This dislocation cloud indicates large in-plane misfit stresses and is a structural precursor to electrochemically driven solid-state amorphization. Because lithiation-induced volume expansion, plasticity, and pulverization of electrode materials are the major mechanical effects that plague the performance and lifetime of high-capacity anodes in lithium-ion batteries, our observations provide important mechanistic insight for the design of advanced batteries.

Journal ArticleDOI
TL;DR: This review focuses specifically on the links between stress‐related processes embedded within the social environment and embodied within the brain, which is viewed as the central mediator and target of allostasis and allostatic load.
Abstract: The brain is the key organ of stress reactivity, coping, and recovery processes. Within the brain, a distributed neural circuitry determines what is threatening and thus stressful to the individual. Instrumental brain systems of this circuitry include the hippocampus, amygdala, and areas of the prefrontal cortex. Together, these systems regulate physiological and behavioral stress processes, which can be adaptive in the short-term and maladaptive in the long-term. Importantly, such stress processes arise from bidirectional patterns of communication between the brain and the autonomic, cardiovascular, and immune systems via neural and endocrine mechanisms underpinning cognition, experience, and behavior. In one respect, these bidirectional stress mechanisms are protective in that they promote short-term adaptation (allostasis). In another respect, however, these stress mechanisms can lead to a long-term dysregulation of allostasis in that they promote maladaptive wear-and-tear on the body and brain under chronically stressful conditions (allostatic load), compromising stress resiliency and health. This review focuses specifically on the links between stress-related processes embedded within the social environment and embodied within the brain, which is viewed as the central mediator and target of allostasis and allostatic load.

Journal ArticleDOI
Thomas J. Wang1, Feng Zhang2, J. Brent Richards, Bryan Kestenbaum3, Joyce B. J. van Meurs4, Diane J. Berry5, Douglas P. Kiel, Elizabeth A. Streeten6, Claes Ohlsson7, Daniel L. Koller8, Leena Peltonen9, Leena Peltonen10, Jason D. Cooper2, Paul F. O'Reilly11, Denise K. Houston12, Nicole L. Glazer3, Liesbeth Vandenput7, Munro Peacock8, Julia Shi6, Fernando Rivadeneira4, Mark I. McCarthy13, Mark I. McCarthy14, Mark I. McCarthy15, Pouta Anneli, Ian H. de Boer3, Massimo Mangino2, Bernet S. Kato2, Deborah J. Smyth7, Sarah L. Booth16, Paul F. Jacques16, Greg L. Burke12, Mark O. Goodarzi17, Ching-Lung Cheung18, Myles Wolf19, Kenneth Rice3, David Goltzman2, Nick Hidiroglou20, Martin Ladouceur, Nicholas J. Wareham7, Lynne J. Hocking16, Deborah J. Hart2, Nigel K Arden14, Cyrus Cooper14, Suneil Malik21, William D. Fraser22, Anna Liisa Hartikainen2, Guangju Zhai2, Helen M. Macdonald2, Nita G. Forouhi23, Ruth J. F. Loos23, David M. Reid24, Alan Hakim, Elaine M. Dennison25, Yongmei Liu10, Chris Power5, Helen Stevens2, Laitinen Jaana21, Ramachandran S. Vasan26, Nicole Soranzo9, Nicole Soranzo27, Jörg Bojunga28, Bruce M. Psaty3, Mattias Lorentzon7, Tatiana Foroud8, Tamara B. Harris10, Albert Hofman4, John-Olov Jansson11, Jane A. Cauley29, André G. Uitterlinden, Quince Gibson, Marjo-Riitta Järvelin, David Karasik, David S. Siscovick3, Michael J. Econs8, Stephen B. Kritchevsky22, Jose C. Florez, John A. Todd7, Josée Dupuis26, Elina Hyppönen5, Tim D. Spector27 
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.

Journal ArticleDOI
TL;DR: A systematic review of studies that focused on food access and food desert research in the United States finds findings from other countries offer insight into ways, in which future research, policy development and program implementation in the U.S. may continue to be explored.

Journal ArticleDOI
TL;DR: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Starlings R: University of Chicago, Chicago, Illinois,USA; Chan M: university of Alberta, Edmonton, Alberta, Canada ; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA.
Abstract: Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.

Journal ArticleDOI
04 Mar 2010-Nature
TL;DR: It is demonstrated that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting and acetylation is identified as a novel regulatory mechanism for mitochondrial fatty- acid oxidation.
Abstract: Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.

Journal ArticleDOI
TL;DR: This paper introduces the database, describes the recording procedure, and presents results from baseline experiments using PCA and LDA classifiers to highlight similarities and differences between PIE and Multi-PIE.

Journal ArticleDOI
TL;DR: The Surviving Sepsis Campaign was associated with sustained, continuous quality improvement in sepsis care and a reduction in reported hospital mortality rates wasassociated with participation.
Abstract: Objective The Surviving Sepsis Campaign (SSC or “the Campaign”) developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations on process improvement and patient outcomes.

Journal ArticleDOI
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...

Journal ArticleDOI
01 Nov 2010
TL;DR: This article explores the roadblocks and solutions to providing a trustworthy cloud computing environment and suggests a number of approaches that could be considered.
Abstract: Cloud computing is an evolving paradigm with tremendous momentum, but its unique aspects exacerbate security and privacy challenges. This article explores the roadblocks and solutions to providing a trustworthy cloud computing environment.

PatentDOI
15 Jun 2010-Langmuir
TL;DR: N nanoparticle-polymer composites are used to demonstrate the anti-icing capability of superhydrophobic surfaces and report direct experimental evidence that such surfaces are able to prevent ice formation upon impact of supercooled water both in laboratory conditions and in natural environments.
Abstract: Superhydrophobic coating compositions are provided. The compositions comprise nanoparticles between 5-100 nm in size and a polymeric binder. The compositions are effective in preventing ice formation on the surface of various substrates.

Journal ArticleDOI
TL;DR: Although quality of research into both prevention and treatment has improved, high-quality multicentre trials with long-term follow-up are needed and approaches to increase energy expenditure and decrease intake should continue.

Journal ArticleDOI
TL;DR: The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence scores, as well as overall survival and breast-cancer-specific survival.
Abstract: Summary Background The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. Methods The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. Findings There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0·006; hazard ratio [HR] 2·64, 95% CI 1·33–5·27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score Interpretation The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. Funding National Cancer Institute and Genomic Health.

Journal ArticleDOI
TL;DR: The authors presented a comprehensive account of their Motivational Theory of Life-Span Development, which integrated the model of optimization in primary and secondary control and the action-phase model of developmental regulation with their original life-span theory of control to present a comprehensive theory of development.
Abstract: This article had four goals. First, the authors identified a set of general challenges and questions that a life-span theory of development should address. Second, they presented a comprehensive account of their Motivational Theory of Life-Span Development. They integrated the model of optimization in primary and secondary control and the action-phase model of developmental regulation with their original life-span theory of control to present a comprehensive theory of development. Third, they reviewed the relevant empirical literature testing key propositions of the Motivational Theory of Life-Span Development. Finally, because the conceptual reach of their theory goes far beyond the current empirical base, they pointed out areas that deserve further and more focused empirical inquiry.

Journal ArticleDOI
TL;DR: Intensive lifestyle intervention can produce sustained weight loss and improvements in fitness, glycemic control, and CVD risk factors in individuals with type 2 diabetes.
Abstract: BACKGROUND Lifestyle interventions produce short-term improvements in glycemia and cardiovascular disease (CVD) risk factors in individuals with type 2 diabetes mellitus, but no long-term data are available. We examined the effects of lifestyle intervention on changes in weight, fitness, and CVD risk factors during a 4-year study. METHODS The Look AHEAD (Action for Health in Diabetes) trial is a multicenter randomized clinical trial comparing the effects of an intensive lifestyle intervention (ILI) and diabetes support and education (DSE; the control group) on the incidence of major CVD events in 5145 overweight or obese individuals (59.5% female; mean age, 58.7 years) with type 2 diabetes mellitus. More than 93% of participants provided outcomes data at each annual assessment. RESULTS Averaged across 4 years, ILI participants had a greater percentage of weight loss than DSE participants (-6.15% vs -0.88%; P < .001) and greater improvements in treadmill fitness (12.74% vs 1.96%; P < .001), hemoglobin A(1c) level (-0.36% vs -0.09%; P < .001), systolic (-5.33 vs -2.97 mm Hg; P < .001) and diastolic (-2.92 vs -2.48 mm Hg; P = .01) blood pressure, and levels of high-density lipoprotein cholesterol (3.67 vs 1.97 mg/dL; P < .001) and triglycerides (-25.56 vs -19.75 mg/dL; P < .001). Reductions in low-density lipoprotein cholesterol levels were greater in DSE than ILI participants (-11.27 vs -12.84 mg/dL; P = .009) owing to greater use of medications to lower lipid levels in the DSE group. At 4 years, ILI participants maintained greater improvements than DSE participants in weight, fitness, hemoglobin A(1c) levels, systolic blood pressure, and high-density lipoprotein cholesterol levels. CONCLUSIONS Intensive lifestyle intervention can produce sustained weight loss and improvements in fitness, glycemic control, and CVD risk factors in individuals with type 2 diabetes. Whether these differences in risk factors translate to reduction in CVD events will ultimately be addressed by the Look AHEAD trial. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00017953.

Journal ArticleDOI
TL;DR: These findings support the use of Tim-3–Tim-3L blockade together with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.
Abstract: The paradoxical coexistence of spontaneous tumor antigen–specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1–specific CD8+ T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1–specific CD8+ T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1+ NY-ESO-1–specific CD8+ T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3+PD-1+ NY-ESO-1–specific CD8+ T cells are more dysfunctional than Tim-3−PD-1+ and Tim-3−PD-1− NY-ESO-1–specific CD8+ T cells, producing less IFN-γ, TNF, and IL-2. Tim-3–Tim-3L blockade enhanced cytokine production by NY-ESO-1–specific CD8+ T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3–Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1–specific CD8+ T cells upon prolonged antigen stimulation and acted in synergy with PD-1–PD-L1 blockade. Collectively, our findings support the use of Tim-3–Tim-3L blockade together with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

Journal ArticleDOI
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.