Showing papers by "University of Alberta published in 2011"

Apixaban versus Warfarin in Patients with Atrial Fibrillation

Abstract: A b s t r ac t Background Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. Methods In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic em - bolism. The trial was designed to test for noninferiority, with key secondary objec - tives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. Results The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the war - farin group (hazard ratio with apixaban, 0.79; 95% confidence interval (CI), 0.66 to 0.95; P<0.001 for noninferiority; P = 0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P = 0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ra - tio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P = 0.42). Conclusions In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.)

Definition and classification of cancer cachexia: an international consensus

Abstract: Summary To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] 2 ) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages—precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management.

Institutional Complexity and Organizational Responses

Abstract: Organizations face institutional complexity whenever they confront incompatible prescriptions from multiple institutional logics. Our interest is in how plural institutional logics, refracted through field-level structures and processes, are experienced within organizations and how organizations respond to such complexity. We draw on a variety of cognate literatures to discuss the field-level structural characteristics and organizational attributes that shape institutional complexity. We then explore the repertoire of strategies and structures that organizations deploy to cope with multiple, competing demands. The analytical framework developed herein is presented to guide future scholarship in the systematic analysis of institutional complexity. We conclude by suggesting avenues for future research.

Manganese oxide-based materials as electrochemical supercapacitor electrodes

Abstract: Electrochemical supercapacitors (ECs), characteristic of high power and reasonably high energy densities, have become a versatile solution to various emerging energy applications. This critical review describes some materials science aspects on manganese oxide-based materials for these applications, primarily including the strategic design and fabrication of these electrode materials. Nanostructurization, chemical modification and incorporation with high surface area, conductive nanoarchitectures are the three major strategies in the development of high-performance manganese oxide-based electrodes for EC applications. Numerous works reviewed herein have shown enhanced electrochemical performance in the manganese oxide-based electrode materials. However, many fundamental questions remain unanswered, particularly with respect to characterization and understanding of electron transfer and atomic transport of the electrochemical interface processes within the manganese oxide-based electrodes. In order to fully exploit the potential of manganese oxide-based electrode materials, an unambiguous appreciation of these basic questions and optimization of synthesis parameters and material properties are critical for the further development of EC devices (233 references).

Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry

Abstract: Metabolism has an essential role in biological systems. Identification and quantitation of the compounds in the metabolome is defined as metabolic profiling, and it is applied to define metabolic changes related to genetic differences, environmental influences and disease or drug perturbations. Chromatography-mass spectrometry (MS) platforms are frequently used to provide the sensitive and reproducible detection of hundreds to thousands of metabolites in a single biofluid or tissue sample. Here we describe the experimental workflow for long-term and large-scale metabolomic studies involving thousands of human samples with data acquired for multiple analytical batches over many months and years. Protocols for serum- and plasma-based metabolic profiling applying gas chromatography-MS (GC-MS) and ultraperformance liquid chromatography-MS (UPLC-MS) are described. These include biofluid collection, sample preparation, data acquisition, data pre-processing and quality assurance. Methods for quality control-based robust LOESS signal correction to provide signal correction and integration of data from multiple analytical batches are also described.

Antibiotic resistance is ancient

Abstract: The discovery of antibiotics more than 70 years ago initiated a period of drug innovation and implementation in human and animal health and agriculture. These discoveries were tempered in all cases by the emergence of resistant microbes. This history has been interpreted to mean that antibiotic resistance in pathogenic bacteria is a modern phenomenon; this view is reinforced by the fact that collections of microbes that predate the antibiotic era are highly susceptible to antibiotics. Here we report targeted metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics. Structure and function studies on the complete vancomycin resistance element VanA confirmed its similarity to modern variants. These results show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.

PHAST: A Fast Phage Search Tool

Abstract: PHAge Search Tool (PHAST) is a web server designed to rapidly and accurately identify, annotate and graphically display prophage sequences within bacterial genomes or plasmids. It accepts either raw DNA sequence data or partially annotated GenBank formatted data and rapidly performs a number of database comparisons as well as phage ‘cornerstone’ feature identification steps to locate, annotate and display prophage sequences and prophage features. Relative to other prophage identification tools, PHAST is up to 40 times faster and up to 15% more sensitive. It is also able to process and annotate both raw DNA sequence data and Genbank files, provide richly annotated tables on prophage features and prophage ‘quality’ and distinguish between intact and incomplete prophage. PHAST also generates downloadable, high quality, interactive graphics that display all identified prophage components in both circular and linear genomic views. PHAST is available at (http://phast.wishartlab.com).

DrugBank 3.0: a comprehensive resource for ‘Omics’ research on drugs

Abstract: DrugBank (http://www.drugbank.ca) is a richly annotated database of drug and drug target information. It contains extensive data on the nomenclature, ontology, chemistry, structure, function, action, pharmacology, pharmacokinetics, metabolism and pharmaceutical properties of both small molecule and large molecule (biotech) drugs. It also contains comprehensive information on the target diseases, proteins, genes and organisms on which these drugs act. First released in 2006, DrugBank has become widely used by pharmacists, medicinal chemists, pharmaceutical researchers, clinicians, educators and the general public. Since its last update in 2008, DrugBank has been greatly expanded through the addition of new drugs, new targets and the inclusion of more than 40 new data fields per drug entry (a 40% increase in data ‘depth’). These data field additions include illustrated drug-action pathways, drug transporter data, drug metabolite data, pharmacogenomic data, adverse drug response data, ADMET data, pharmacokinetic data, computed property data and chemical classification data. DrugBank 3.0 also offers expanded database links, improved search tools for drug–drug and food–drug interaction, new resources for querying and viewing drug pathways and hundreds of new drug entries with detailed patent, pricing and manufacturer data. These additions have been complemented by enhancements to the quality and quantity of existing data, particularly with regard to drug target, drug description and drug action data. DrugBank 3.0 represents the result of 2 years of manual annotation work aimed at making the database much more useful for a wide range of ‘omics’ (i.e. pharmacogenomic, pharmacoproteomic, pharmacometabolomic and even pharmacoeconomic) applications.

Does Corporate Social Responsibility Affect the Cost of Capital

Abstract: We examine the effect of corporate social responsibility (CSR) on the cost of equity capital for a large sample of US firms. Using several approaches to estimate firms’ ex ante cost of equity, we find that firms with better CSR scores exhibit cheaper equity financing. In particular, our findings suggest that investment in improving responsible employee relations, environmental policies, and product strategies contributes substantially to reducing firms’ cost of equity. Our results also show that participation in two “sin” industries, namely, tobacco and nuclear power, increases firms’ cost of equity. These findings support arguments in the literature that firms with socially responsible practices have higher valuation and lower risk.

Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group

Abstract: Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice.

The Human Serum Metabolome

Abstract: Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca.

Improved Algorithms for Linear Stochastic Bandits

Abstract: We improve the theoretical analysis and empirical performance of algorithms for the stochastic multi-armed bandit problem and the linear stochastic multi-armed bandit problem. In particular, we show that a simple modification of Auer's UCB algorithm (Auer, 2002) achieves with high probability constant regret. More importantly, we modify and, consequently, improve the analysis of the algorithm for the for linear stochastic bandit problem studied by Auer (2002), Dani et al. (2008), Rusmevichientong and Tsitsiklis (2010), Li et al. (2010). Our modification improves the regret bound by a logarithmic factor, though experiments show a vast improvement. In both cases, the improvement stems from the construction of smaller confidence sets. For their construction we use a novel tail inequality for vector-valued martingales.

Indication of Electron Neutrino Appearance from an Accelerator-produced Off-axis Muon Neutrino Beam

Abstract: The T2K experiment observes indications of nu(mu) -> nu(mu) e appearance in data accumulated with 1.43 x 10(20) protons on target. Six events pass all selection criteria at the far detector. In a three-flavor neutrino oscillation scenario with |Delta m(23)(2)| = 2.4 x 10(-3) eV(2), sin(2)2 theta(23) = 1 and sin(2)2 theta(13) = 0, the expected number of such events is 1.5 +/- 0.3(syst). Under this hypothesis, the probability to observe six or more candidate events is 7 x 10(-3), equivalent to 2.5 sigma significance. At 90% C.L., the data are consistent with 0.03(0.04) < sin(2)2 theta(13) < 0.28(0.34) for delta(CP) = 0 and a normal (inverted) hierarchy.

Heavy quarkonium: progress, puzzles, and opportunities

Abstract: A golden age for heavy-quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the B-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations at BESIII, the LHC, RHIC, FAIR, the Super Flavor and/or Tau-Charm factories, JLab, the ILC, and beyond. The list of newly found conventional states expanded to include h(c)(1P), chi(c2)(2P), B-c(+), and eta(b)(1S). In addition, the unexpected and still-fascinating X(3872) has been joined by more than a dozen other charmonium- and bottomonium-like "XYZ" states that appear to lie outside the quark model. Many of these still need experimental confirmation. The plethora of new states unleashed a flood of theoretical investigations into new forms of matter such as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of c (c) over bar, b (b) over bar, and b (c) over bar bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. Lattice QCD has grown from a tool with computational possibilities to an industrial-strength effort now dependent more on insight and innovation than pure computational power. New effective field theories for the description of quarkonium in different regimes have been developed and brought to a high degree of sophistication, thus enabling precise and solid theoretical predictions. Many expected decays and transitions have either been measured with precision or for the first time, but the confusing patterns of decays, both above and below open-flavor thresholds, endure and have deepened. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark-gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.

Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study.

Abstract: The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD. METHODS: A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician. RESULTS: A total of 18.7% of the infants developed ASD. Infant gender and the presence of 1 older affected sibling were significant predic- tors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was 1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sib- ling, and other demographic factors did not predict ASD outcome. CONCLUSIONS: The sibling recurrence rate of ASD is higher than sug- gested by previous estimates. The size of the current sample and pro- spective nature of data collection minimized many limitations of previ- ous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed. Pediatrics 2011;128:e000

Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia

Abstract: Objective. To develop a fibromyalgia (FM) survey questionnaire for epidemiologic and clinical studies using a modification of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010). We also created a new FM symptom scale to further characterize FM severity. Methods. The ACR 2010 consists of 2 scales, the Widespread Pain Index (WPI) and the Symptom Severity (SS) scale. We modified these ACR 2010 criteria by eliminating the physician’s estimate of the extent of somatic symptoms and substituting the sum of 3 specific self-reported symptoms. We also created a 0–31 FM Symptom scale (FS) by adding the WPI to the modified SS scale. We administered the questionnaire to 729 patients previously diagnosed with FM, 845 with osteoarthritis (OA) or with other noninflammatory rheumatic conditions, 439 with systemic lupus erythematosus (SLE), and 5210 with rheumatoid arthritis (RA). Results. The modified ACR 2010 criteria were satisfied by 60% with a prior diagnosis of FM, 21.1% with RA, 16.8% with OA, and 36.7% with SLE. The criteria properly identified diagnostic groups based on FM severity variables. An FS score ≥ 13 best separated criteria+ and criteria− patients, classifying 93.0% correctly, with a sensitivity of 96.6% and a specificity of 91.8% in the study population. Conclusion. A modification to the ACR 2010 criteria will allow their use in epidemiologic and clinical studies without the requirement for an examiner. The criteria are simple to use and administer, but they are not to be used for self-diagnosis. The FS may have wide utility beyond the bounds of FM, including substitution for widespread pain in epidemiological studies.

An Expanded Palette of Genetically Encoded Ca2+ Indicators

Abstract: Engineered fluorescent protein (FP) chimeras that modulate their fluorescence in response to changes in calcium ion (Ca2+) concentration are powerful tools for visualizing intracellular signaling activity. However, despite a decade of availability, the palette of single FP-based Ca2+ indicators has remained limited to a single green hue. We have expanded this palette by developing blue, improved green, and red intensiometric indicators, as well as an emission ratiometric indicator with an 11,000% ratio change. This series enables improved single-color Ca2+ imaging in neurons and transgenic Caenorhabditis elegans. In HeLa cells, Ca2+ was imaged in three subcellular compartments, and, in conjunction with a cyan FP–yellow FP–based indicator, Ca2+ and adenosine 5′-triphosphate were simultaneously imaged. This palette of indicators paints the way to a colorful new era of Ca2+ imaging.

Shrub expansion in tundra ecosystems: dynamics, impacts and research priorities

Abstract: Recent research using repeat photography, long-term ecological monitoring and dendrochronology has documented shrub expansion in arctic, high-latitude and alpine tundra

A Tale of Two Cities: Competing Logics and Practice Variation In the Professionalizing of Mutual Funds

Abstract: This paper examines practice diffusion in an environment where competing logics exist, focusing on how organizational and practice variations are institutionally shaped. Empirically, I study how trustee and performance logics in the mutual fund industry that were rooted in different geographic locations (Boston and New York) led to variation in how mutual funds established contracts with independent professional money management firms. This focus on competing logics redirects institutional research away from isomorphism and the segregation of institutional and technical forces, and towards an appreciation of how multiple forms of rationality provide a foundation for ongoing struggle and change in organizational fields. Implications for the dominant two-stage institutional model of diffusion as well as research on institutions, organizations, and professions are discussed.

Effect of nesiritide in patients with acute decompensated heart failure.

Abstract: A b s t r ac t Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, −0.4 percentage points; 95% CI, −1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.)

Longitudinal Development of Human Brain Wiring Continues from Childhood into Adulthood

Abstract: Healthy human brain development is a complex process that continues during childhood and adolescence, as demonstrated by many cross-sectional and several longitudinal studies. However, whether these changes end in adolescence is not clear. We examined longitudinal white matter maturation using diffusion tensor tractography in 103 healthy subjects aged 5–32 years; each volunteer was scanned at least twice, with 221 total scans. Fractional anisotropy (FA) and mean diffusivity (MD), parameters indicative of factors including myelination and axon density, were assessed in 10 major white matter tracts. All tracts showed significant nonlinear development trajectories for FA and MD. Significant within-subject changes occurred in the vast majority of children and early adolescents, and these changes were mostly complete by late adolescence for projection and commissural tracts. However, association tracts demonstrated postadolescent within-subject maturation of both FA and MD. Diffusion parameter changes were due primarily to decreasing perpendicular diffusivity, although increasing parallel diffusivity contributed to the prolonged increases of FA in association tracts. Volume increased significantly with age for most tracts, and longitudinal measures also demonstrated postadolescent volume increases in several association tracts. As volume increases were not directly associated with either elevated FA or reduced MD between scans, the observed diffusion parameter changes likely reflect microstructural maturation of brain white matter tracts rather than just gross anatomy.

Web-based inference of biological patterns, functions and pathways from metabolomic data using MetaboAnalyst

Abstract: MetaboAnalyst is an integrated web-based platform for comprehensive analysis of quantitative metabolomic data. It is designed to be used by biologists (with little or no background in statistics) to perform a variety of complex metabolomic data analysis tasks. These include data processing, data normalization, statistical analysis and high-level functional interpretation. This protocol provides a step-wise description on how to format and upload data to MetaboAnalyst, how to process and normalize data, how to identify significant features and patterns through univariate and multivariate statistical methods and, finally, how to use metabolite set enrichment analysis and metabolic pathway analysis to help elucidate possible biological mechanisms. The complete protocol can be executed in approximately 45 min.

Institutional Work: Refocusing Institutional Studies of Organization

Abstract: In this paper, we discuss an alternative focus for institutional studies of organization - the study of institutional work. Research on institutional work examines the practices of individual and collective actors aimed at creating, maintaining, and disrupting institutions. Our focus in this paper is on the distinctiveness of institutional work as a field of study and the potential it provides for the examination of new questions. We argue that research on institutional work can contribute to bringing the individual back into institutional theory, help to re-examine the relationship between agency and institutions, and provide a bridge between critical and institutional views of organization.

How many steps/day are enough? For older adults and special populations

Abstract: Older adults and special populations (living with disability and/or chronic illness that may limit mobility and/or physical endurance) can benefit from practicing a more physically active lifestyle, typically by increasing ambulatory activity. Step counting devices (accelerometers and pedometers) offer an opportunity to monitor daily ambulatory activity; however, an appropriate translation of public health guidelines in terms of steps/day is unknown. Therefore this review was conducted to translate public health recommendations in terms of steps/day. Normative data indicates that 1) healthy older adults average 2,000-9,000 steps/day, and 2) special populations average 1,200-8,800 steps/day. Pedometer-based interventions in older adults and special populations elicit a weighted increase of approximately 775 steps/day (or an effect size of 0.26) and 2,215 steps/day (or an effect size of 0.67), respectively. There is no evidence to inform a moderate intensity cadence (i.e., steps/minute) in older adults at this time. However, using the adult cadence of 100 steps/minute to demark the lower end of an absolutely-defined moderate intensity (i.e., 3 METs), and multiplying this by 30 minutes produces a reasonable heuristic (i.e., guiding) value of 3,000 steps. However, this cadence may be unattainable in some frail/diseased populations. Regardless, to truly translate public health guidelines, these steps should be taken over and above activities performed in the course of daily living, be of at least moderate intensity accumulated in minimally 10 minute bouts, and add up to at least 150 minutes over the week. Considering a daily background of 5,000 steps/day (which may actually be too high for some older adults and/or special populations), a computed translation approximates 8,000 steps on days that include a target of achieving 30 minutes of moderate-to-vigorous physical activity (MVPA), and approximately 7,100 steps/day if averaged over a week. Measured directly and including these background activities, the evidence suggests that 30 minutes of daily MVPA accumulated in addition to habitual daily activities in healthy older adults is equivalent to taking approximately 7,000-10,000 steps/day. Those living with disability and/or chronic illness (that limits mobility and or/physical endurance) display lower levels of background daily activity, and this will affect whole-day estimates of recommended physical activity.

Myalgic encephalomyelitis: International Consensus Criteria

Abstract: 12 FatigueConsultationClinic,SaltLake RegionalMedicalCenter; 13 InternalMedicine,FamilyPractice,UniversityofUtah,SaltLakeCity,UT,USA; 14 ME ⁄CFSCenter,OsloUniversity HospitalHF,Norway; 15 DepartmentofPaediatrics,StateUniversityofNewYork,Buffalo,NY,USA; 16 Independent,Pavia,Italy; 17 Harbor-UCLA MedicalCenter,UniversityofCalifornia,LosAngeles,CA; 18 EVMedResearch,Lomita,CA,USA; 19 UniversityofLimerick,Limerick,Ireland; 20 Pain Clinic,KonyangUniversityHospital,Daejeon,Korea; 21 DonvaleSpecialistMedicalCentre,Donvale,Victoria,Australia; 22 Departmentsof Anesthesiology,NeurobiologyandAnatomy,UniversityofUtah,SaltLakeCity,UT,USA; 23 DepartmentofMedicinaNuclear,ClinicaLasCondes, Santiago,Chile; 24 WhittemorePetersonInstitute,UniversityofNevada,Reno,NV,USA; 25 MiwaNaikaClinic,Toyama,Japan; 26 A.Kirchenstein InstituteofMicrobiologyandVirology,RigaStradinsUniversity,Riga,Latvia; 27 DepartmentofBiochemistryBand 28 DepartmentofSportsSciences,UniversityofthePacific,Stockton,CAUSA

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

How many steps/day are enough? for adults

Abstract: Physical activity guidelines from around the world are typically expressed in terms of frequency, duration, and intensity parameters. Objective monitoring using pedometers and accelerometers offers a new opportunity to measure and communicate physical activity in terms of steps/day. Various step-based versions or translations of physical activity guidelines are emerging, reflecting public interest in such guidance. However, there appears to be a wide discrepancy in the exact values that are being communicated. It makes sense that step-based recommendations should be harmonious with existing evidence-based public health guidelines that recognize that "some physical activity is better than none" while maintaining a focus on time spent in moderate-to-vigorous physical activity (MVPA). Thus, the purpose of this review was to update our existing knowledge of "How many steps/day are enough?", and to inform step-based recommendations consistent with current physical activity guidelines. Normative data indicate that healthy adults typically take between 4,000 and 18,000 steps/day, and that 10,000 steps/day is reasonable for this population, although there are notable "low active populations." Interventions demonstrate incremental increases on the order of 2,000-2,500 steps/day. The results of seven different controlled studies demonstrate that there is a strong relationship between cadence and intensity. Further, despite some inter-individual variation, 100 steps/minute represents a reasonable floor value indicative of moderate intensity walking. Multiplying this cadence by 30 minutes (i.e., typical of a daily recommendation) produces a minimum of 3,000 steps that is best used as a heuristic (i.e., guiding) value, but these steps must be taken over and above habitual activity levels to be a true expression of free-living steps/day that also includes recommendations for minimal amounts of time in MVPA. Computed steps/day translations of time in MVPA that also include estimates of habitual activity levels equate to 7,100 to 11,000 steps/day. A direct estimate of minimal amounts of MVPA accumulated in the course of objectively monitored free-living behaviour is 7,000-8,000 steps/day. A scale that spans a wide range of incremental increases in steps/day and is congruent with public health recognition that "some physical activity is better than none," yet still incorporates step-based translations of recommended amounts of time in MVPA may be useful in research and practice. The full range of users (researchers to practitioners to the general public) of objective monitoring instruments that provide step-based outputs require good reference data and evidence-based recommendations to be able to design effective health messages congruent with public health physical activity guidelines, guide behaviour change, and ultimately measure, track, and interpret steps/day.