Showing papers by "University of Toronto published in 2006"

Reducing the Dimensionality of Data with Neural Networks

Abstract: High-dimensional data can be converted to low-dimensional codes by training a multilayer neural network with a small central layer to reconstruct high-dimensional input vectors. Gradient descent can be used for fine-tuning the weights in such "autoencoder" networks, but this works well only if the initial weights are close to a good solution. We describe an effective way of initializing the weights that allows deep autoencoder networks to learn low-dimensional codes that work much better than principal components analysis as a tool to reduce the dimensionality of data.

A fast learning algorithm for deep belief nets

Abstract: We show how to use "complementary priors" to eliminate the explaining-away effects that make inference difficult in densely connected belief nets that have many hidden layers. Using complementary priors, we derive a fast, greedy algorithm that can learn deep, directed belief networks one layer at a time, provided the top two layers form an undirected associative memory. The fast, greedy algorithm is used to initialize a slower learning procedure that fine-tunes the weights using a contrastive version of the wake-sleep algorithm. After fine-tuning, a network with three hidden layers forms a very good generative model of the joint distribution of handwritten digit images and their labels. This generative model gives better digit classification than the best discriminative learning algorithms. The low-dimensional manifolds on which the digits lie are modeled by long ravines in the free-energy landscape of the top-level associative memory, and it is easy to explore these ravines by using the directed connections to display what the associative memory has in mind.

Wilkinson Microwave Anisotropy Probe (WMAP) three year results: implications for cosmology

Abstract: A simple cosmological model with only six parameters (matter density, Omega_m h^2, baryon density, Omega_b h^2, Hubble Constant, H_0, amplitude of fluctuations, sigma_8, optical depth, tau, and a slope for the scalar perturbation spectrum, n_s) fits not only the three year WMAP temperature and polarization data, but also small scale CMB data, light element abundances, large-scale structure observations, and the supernova luminosity/distance relationship. Using WMAP data only, the best fit values for cosmological parameters for the power-law flat LCDM model are (Omega_m h^2, Omega_b h^2, h, n_s, tau, sigma_8) = 0.1277+0.0080-0.0079, 0.02229+-0.00073, 0.732+0.031-0.032, 0.958+-0.016, 0.089+-0.030, 0.761+0.049-0.048). The three year data dramatically shrink the allowed volume in this six dimensional parameter space. Assuming that the primordial fluctuations are adiabatic with a power law spectrum, the WMAP data_alone_ require dark matter, and favor a spectral index that is significantly less than the Harrison-Zel'dovich-Peebles scale-invariant spectrum (n_s=1, r=0). Models that suppress large-scale power through a running spectral index or a large-scale cut-off in the power spectrum are a better fit to the WMAP and small scale CMB data than the power-law LCDM model: however, the improvement in the fit to the WMAP data is only Delta chi^2 = 3 for 1 extra degree of freedom. The combination of WMAP and other astronomical data yields significant constraints on the geometry of the universe, the equation of state of the dark energy, the gravitational wave energy density, and neutrino properties. Consistent with the predictions of simple inflationary theories, we detect no significant deviations from Gaussianity in the CMB maps.

Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells.

Abstract: We investigated the intracellular uptake of different sized and shaped colloidal gold nanoparticles. We showed that kinetics and saturation concentrations are highly dependent upon the physical dimensions of the nanoparticles (e.g., uptake half-life of 14, 50, and 74 nm nanoparticles is 2.10, 1.90, and 2.24 h, respectively). The findings from this study will have implications in the chemical design of nanostructures for biomedical applications (e.g., tuning intracellular delivery rates and amounts by nanoscale dimensions and engineering complex, multifunctional nanostructures for imaging and therapeutics).

Global variation in copy number in the human genome

Abstract: Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.

Antecedents and consequences of employee engagement

Abstract: Purpose – Employee engagement has become a hot topic in recent years among consulting firms and in the popular business press. However, employee engagement has rarely been studied in the academic literature and relatively little is known about its antecedents and consequences. The purpose of this study was to test a model of the antecedents and consequences of job and organization engagements based on social exchange theory.Design/methodology/approach – A survey was completed by 102 employees working in a variety of jobs and organizations. The average age was 34 and 60 percent were female. Participants had been in their current job for an average of four years, in their organization an average of five years, and had on average 12 years of work experience. The survey included measures of job and organization engagement as well as the antecedents and consequences of engagement.Findings – Results indicate that there is a meaningful difference between job and organization engagements and that perceived organi...

The genome of black cottonwood, Populus trichocarpa (Torr. & Gray)

Abstract: We report the draft genome of the black cottonwood tree, Populus trichocarpa. Integration of shotgun sequence assembly with genetic mapping enabled chromosome-scale reconstruction of the genome. More than 45,000 putative protein-coding genes were identified. Analysis of the assembled genome revealed a whole-genome duplication event; about 8000 pairs of duplicated genes from that event survived in the Populus genome. A second, older duplication event is indistinguishably coincident with the divergence of the Populus and Arabidopsis lineages. Nucleotide substitution, tandem gene duplication, and gross chromosomal rearrangement appear to proceed substantially more slowly in Populus than in Arabidopsis. Populus has more protein-coding genes than Arabidopsis, ranging on average from 1.4 to 1.6 putative Populus homologs for each Arabidopsis gene. However, the relative frequency of protein domains in the two genomes is similar. Overrepresented exceptions in Populus include genes associated with lignocellulosic wall biosynthesis, meristem development, disease resistance, and metabolite transport.

Lost in knowledge translation: time for a map?

Abstract: There is confusion and misunderstanding about the concepts of knowledge translation, knowledge transfer, knowledge exchange, research utilization, implementation, diffusion, and dissemination. We review the terms and definitions used to describe the concept of moving knowledge into action. We also offer a conceptual framework for thinking about the process and integrate the roles of knowledge creation and knowledge application. The implications of knowledge translation for continuing education in the health professions include the need to base continuing education on the best available knowledge, the use of educational and other transfer strategies that are known to be effective, and the value of learning about plannedaction theories to be better able to understand and influence change in practice settings.

Global landscape of protein complexes in the yeast Saccharomyces cerevisiae

Abstract: Identification of protein-protein interactions often provides insight into protein function, and many cellular processes are performed by stable protein complexes. We used tandem affinity purification to process 4,562 different tagged proteins of the yeast Saccharomyces cerevisiae. Each preparation was analysed by both matrix-assisted laser desorption/ionization-time of flight mass spectrometry and liquid chromatography tandem mass spectrometry to increase coverage and accuracy. Machine learning was used to integrate the mass spectrometry scores and assign probabilities to the protein-protein interactions. Among 4,087 different proteins identified with high confidence by mass spectrometry from 2,357 successful purifications, our core data set (median precision of 0.69) comprises 7,123 protein-protein interactions involving 2,708 proteins. A Markov clustering algorithm organized these interactions into 547 protein complexes averaging 4.9 subunits per complex, about half of them absent from the MIPS database, as well as 429 additional interactions between pairs of complexes. The data (all of which are available online) will help future studies on individual proteins as well as functional genomics and systems biology.

A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene

Abstract: The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Racism Without Racists: Color-Blind Racism and the Persistence of Racial Inequality in the United States. Eduardo Bonilla-Silva

Abstract: Preface for Third Edition of Racism without Racists Chapter 1: The Strange Enigma of Race in Contemporary America Chapter 2: The Central Frames of Color-Blind Racism Chapter 3: The Style of Color Blindness: How to Talk Nasty about Minorities without Sounding Racist Chapter 4: \"I Didn't Get That Job Because of a Black Man\": Color-Blind Racism's Racial Stories Chapter 5: Peeking Inside the (White) House of Color Blindness: The Significance of Whites' Segregation Chapter 6: Are All Whites Refined Archie Bunkers? An Examination of White Racial Progressives Chapter 7: Are Blacks Color Blind, Too? Chapter 8: E Pluribus Unum or the Same Old Perfume in a New Bottle? On the Future of Racial Stratification in the United States Chapter 9: Will Racism Disappear in Obamerica? The Sweet (but Deadly) Enchantment of Colorblindness in Black Face Conclusion

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.

Abstract: Background The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. Methods We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and β-cell function. Results Kaplan–Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for...

Classification criteria for psoriatic arthritis: Development of new criteria from a large international study

Abstract: Objective To compare the accuracy of existing classification criteria for the diagnosis of psoriatic arthritis (PsA) and to construct new criteria from observed data. Methods Data were collected prospectively from consecutive clinic attendees with PsA and other inflammatory arthropathies. Subjects were classified by each of 7 criteria. Sensitivity and specificity were compared using conditional logistic regression analysis. Latent class analysis was used to calculate criteria accuracy in order to confirm the validity of clinical diagnosis as the gold standard definition of “case”-ness. Classification and Regression Trees methodology and logistic regression were used to identify items for new criteria, which were then constructed using a receiver operating characteristic curve. Results Data were collected on 588 cases and 536 controls with rheumatoid arthritis (n = 384), ankylosing spondylitis (n = 72), undifferentiated arthritis (n = 38), connective tissue disorders (n = 14), and other diseases (n = 28). The specificity of each set of criteria was high. The sensitivity of the Vasey and Espinoza method (0.97) was similar to that of the method of McGonagle et al (0.98) and greater than that of the methods of Bennett (0.44), Moll and Wright (0.91), the European Spondylarthropathy Study Group (0.74), and Gladman et al (0.91). The CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria consisted of established inflammatory articular disease with at least 3 points from the following features: current psoriasis (assigned a score of 2; all other features were assigned a score of 1), a history of psoriasis (unless current psoriasis was present), a family history of psoriasis (unless current psoriasis was present or there was a history of psoriasis), dactylitis, juxtaarticular new bone formation, rheumatoid factor negativity, and nail dystrophy. These criteria were more specific (0.987 versus 0.960) but less sensitive (0.914 versus 0.972) than those of Vasey and Espinoza. Conclusion The CASPAR criteria are simple and highly specific but less sensitive than the Vasey and Espinoza criteria.

Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events

Abstract: Background Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. Methods We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Results The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P = 0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P = 0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P = 0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P = 0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P = 0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P = 0.046). Conclusions In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.)

Drug penetration in solid tumours

Abstract: To be most effective anticancer drugs must penetrate tissue efficiently, reaching all the cancer cells that comprise the target population in a concentration sufficient to exert a therapeutic effect. Most research into the resistance of cancers to chemotherapy has concentrated on molecular mechanisms of resistance, whereas the role of limited drug distribution within tumours has been neglected. We summarize the evidence that indicates that the distribution of many anticancer drugs in tumour tissue is incomplete, and we suggest strategies that might be used either to improve drug penetration through tumour tissue or to select compounds based on their abilities to penetrate tissue, thereby increasing the therapeutic index.

The Supernova Legacy Survey: Measurement of Omega_M, Omega_Lambda,and w from the First Year Data Set

Abstract: We present distance measurements to 71 high redshift type Ia supernovae discovered during the first year of the 5-year Supernova Legacy Survey (SNLS). These events were detected and their multi-color light-curves measured using the MegaPrime/MegaCam instrument at the Canada-France-Hawaii Telescope (CFHT), by repeatedly imaging four one-square degree fields in four bands. Follow-up spectroscopy was performed at the VLT, Gemini and Keck telescopes to confirm the nature of the supernovae and to measure their redshift. With this data set, we have built a Hubble diagram extending to z = 1, with all distance measurements involving at least two bands. Systematic uncertainties are evaluated making use of the multiband photometry obtained at CFHT. Cosmological fits to this first year SNLS Hubble diagram give the following results: {Omega}{sub M} = 0.263 {+-} 0.042 (stat) {+-} 0.032 (sys) for a flat {Lambda}CDM model; and w = -1.023 {+-} 0.090 (stat) {+-} 0.054 (sys) for a flat cosmology with constant equation of state w when combined with the constraint from the recent Sloan Digital Sky Survey measurement of baryon acoustic oscillations.

Accuracy of Physician Self-assessment Compared With Observed Measures of Competence: A Systematic Review

Abstract: ContextCore physician activities of lifelong learning, continuing medical education credit, relicensure, specialty recertification, and clinical competence are linked to the abilities of physicians to assess their own learning needs and choose educational activities that meet these needs.ObjectiveTo determine how accurately physicians self-assess compared with external observations of their competence.Data SourcesThe electronic databases MEDLINE (1966-July 2006), EMBASE (1980-July 2006), CINAHL (1982-July 2006), PsycINFO (1967-July 2006), the Research and Development Resource Base in CME (1978-July 2006), and proprietary search engines were searched using terms related to self-directed learning, self-assessment, and self-reflection.Study SelectionStudies were included if they compared physicians' self-rated assessments with external observations, used quantifiable and replicable measures, included a study population of at least 50% practicing physicians, residents, or similar health professionals, and were conducted in the United Kingdom, Canada, United States, Australia, or New Zealand. Studies were excluded if they were comparisons of self-reports, studies of medical students, assessed physician beliefs about patient status, described the development of self-assessment measures, or were self-assessment programs of specialty societies. Studies conducted in the context of an educational or quality improvement intervention were included only if comparative data were obtained before the intervention.Data ExtractionStudy population, content area and self-assessment domain of the study, methods used to measure the self-assessment of study participants and those used to measure their competence or performance, existence and use of statistical tests, study outcomes, and explanatory comparative data were extracted.Data SynthesisThe search yielded 725 articles, of which 17 met all inclusion criteria. The studies included a wide range of domains, comparisons, measures, and methodological rigor. Of the 20 comparisons between self- and external assessment, 13 demonstrated little, no, or an inverse relationship and 7 demonstrated positive associations. A number of studies found the worst accuracy in self-assessment among physicians who were the least skilled and those who were the most confident. These results are consistent with those found in other professions.ConclusionsWhile suboptimal in quality, the preponderance of evidence suggests that physicians have a limited ability to accurately self-assess. The processes currently used to undertake professional development and evaluate competence may need to focus more on external assessment.

Revisiting the Relation Between Environmental Performance and Environmental Disclosure: An Empirical Analysis

Abstract: Previous empirical evidence provided mixed results on the relationship between corporate environmental performance and environmental disclosures. We revisit this relation by testing economics based theories of voluntary disclosure using a more rigorous research design. In particular, we improve on the prior literature by focusing on purely voluntary environmental disclosures and by developing two reliable environmental performance measures using actual toxic emissions and waste management data. We also develop a content analysis index based on the Global Reporting Initiative sustainability reporting guidelines to assess the extent of discretionary disclosures in environmental and social responsibility reports. This index better captures firm disclosures related to its commitment to protect the environment than the indices employed by prior studies. Using a sample of 191 firms from the five most polluting industries in the U.S., we find a positive association between environmental performance and the extent of discretionary environmental disclosures. The result is consistent with the predictions of the economics based voluntary disclosure theory.

Removing camera shake from a single photograph

Abstract: Camera shake during exposure leads to objectionable image blur and ruins many photographs. Conventional blind deconvolution methods typically assume frequency-domain constraints on images, or overly simplified parametric forms for the motion path during camera shake. Real camera motions can follow convoluted paths, and a spatial domain prior can better maintain visually salient image characteristics. We introduce a method to remove the effects of camera shake from seriously blurred images. The method assumes a uniform camera blur over the image and negligible in-plane camera rotation. In order to estimate the blur from the camera shake, the user must specify an image region without saturation effects. We show results for a variety of digital photographs taken from personal photo collections.

Outcome of heart failure with preserved ejection fraction in a population-based study.

Abstract: Thirty-one percent of the patients had an ejection fraction of more than 50 percent. Patients with heart failure with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation. The presenting history and clinical examination findings were similar for the two groups. The unadjusted mortality rates for patients with an ejection fraction of more than 50 percent were not significantly different from those for patients with an ejection fraction of less than 40 percent at 30 days (5 percent vs. 7 percent, P = 0.08) and at 1 year (22 percent vs. 26 percent, P = 0.07); the adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; 95 percent confidence interval, 0.94 to 1.36; P = 0.18). The rates of readmission for heart failure and of in-hospital complications did not differ between the two groups. Conclusions Among patients presenting with new-onset heart failure, a substantial proportion had an ejection fraction of more than 50 percent. The survival of patients with heart failure with preserved ejection fraction was similar to that of patients with reduced ejection fraction.

GFDL's CM2 global coupled climate models. Part I: Formulation and simulation characteristics

Abstract: The formulation and simulation characteristics of two new global coupled climate models developed at NOAA's Geophysical Fluid Dynamics Laboratory (GFDL) are described. The models were designed to simulate atmospheric and oceanic climate and variability from the diurnal time scale through multicentury climate change, given our computational constraints. In particular, an important goal was to use the same model for both experimental seasonal to interannual forecasting and the study of multicentury global climate change, and this goal has been achieved. Two versions of the coupled model are described, called CM2.0 and CM2.1. The versions differ primarily in the dynamical core used in the atmospheric component, along with the cloud tuning and some details of the land and ocean components. For both coupled models, the resolution of the land and atmospheric components is 2° latitude × 2.5° longitude; the atmospheric model has 24 vertical levels. The ocean resolution is 1° in latitude and longitude, wi...

Ultrasensitive solution-cast quantum dot photodetectors

Abstract: Solution-processed electronic and optoelectronic devices offer low cost, large device area, physical flexibility and convenient materials integration compared to conventional epitaxially grown, lattice-matched, crystalline semiconductor devices. Although the electronic or optoelectronic performance of these solution-processed devices is typically inferior to that of those fabricated by conventional routes, this can be tolerated for some applications in view of the other benefits. Here we report the fabrication of solution-processed infrared photodetectors that are superior in their normalized detectivity (D*, the figure of merit for detector sensitivity) to the best epitaxially grown devices operating at room temperature. We produced the devices in a single solution-processing step, overcoating a prefabricated planar electrode array with an unpatterned layer of PbS colloidal quantum dot nanocrystals. The devices showed large photoconductive gains with responsivities greater than 10(3) A W(-1). The best devices exhibited a normalized detectivity D* of 1.8 x 10(13) jones (1 jones = 1 cm Hz(1/2) W(-1)) at 1.3 microm at room temperature: today's highest performance infrared photodetectors are photovoltaic devices made from epitaxially grown InGaAs that exhibit peak D* in the 10(12) jones range at room temperature, whereas the previous record for D* from a photoconductive detector lies at 10(11) jones. The tailored selection of absorption onset energy through the quantum size effect, combined with deliberate engineering of the sequence of nanoparticle fusing and surface trap functionalization, underlie the superior performance achieved in this readily fabricated family of devices.

Dual methods for nonconvex spectrum optimization of multicarrier systems

Abstract: The design and optimization of multicarrier communications systems often involve a maximization of the total throughput subject to system resource constraints. The optimization problem is numerically difficult to solve when the problem does not have a convexity structure. This paper makes progress toward solving optimization problems of this type by showing that under a certain condition called the time-sharing condition, the duality gap of the optimization problem is always zero, regardless of the convexity of the objective function. Further, we show that the time-sharing condition is satisfied for practical multiuser spectrum optimization problems in multicarrier systems in the limit as the number of carriers goes to infinity. This result leads to efficient numerical algorithms that solve the nonconvex problem in the dual domain. We show that the recently proposed optimal spectrum balancing algorithm for digital subscriber lines can be interpreted as a dual algorithm. This new interpretation gives rise to more efficient dual update methods. It also suggests ways in which the dual objective may be evaluated approximately, further improving the numerical efficiency of the algorithm. We propose a low-complexity iterative spectrum balancing algorithm based on these ideas, and show that the new algorithm achieves near-optimal performance in many practical situations

Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy : Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks

Abstract: Objective To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti–tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population. Methods We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks. Results Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group. Conclusion At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies.

Molecular components of the mammalian circadian clock

Abstract: Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested.