Showing papers by "Université de Montréal published in 2007"

A second generation human haplotype map of over 3.1 million SNPs

Abstract: We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

School Readiness and Later Achievement

Abstract: Using 6 longitudinal data sets, the authors estimate links between three key elements of school readiness--school-entry academic, attention, and socioemotional skills--and later school reading and math achievement In an effort to isolate the effects of these school-entry skills, the authors ensured that most of their regression models control for cognitive, attention, and socioemotional skills measured prior to school entry, as well as a host of family background measures Across all 6 studies, the strongest predictors of later achievement are school-entry math, reading, and attention skills A meta-analysis of the results shows that early math skills have the greatest predictive power, followed by reading and then attention skills By contrast, measures of socioemotional behaviors, including internalizing and externalizing problems and social skills, were generally insignificant predictors of later academic performance, even among children with relatively high levels of problem behavior Patterns of association were similar for boys and girls and for children from high and low socioeconomic backgrounds

Optimal Medical Therapy with or without PCI for Stable Coronary Disease

Abstract: We conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, we assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6). Results There were 211 primary events in the PCI group and 202 events in the medicaltherapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P = 0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P = 0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P = 0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P = 0.33). Conclusions As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. (ClinicalTrials.gov number, NCT00007657.)

A genome-wide association study identifies novel risk loci for type 2 diabetes

Abstract: Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants wa ...

Effects of Torcetrapib in Patients at High Risk for Coronary Events

Abstract: Background Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. Methods We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. Results At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both compari...

Genome-wide detection and characterization of positive selection in human populations

Abstract: With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

Abstract: We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents

Abstract: A b s t r ac t Results The 4-year rates of stent thrombosis were 1.2% in the sirolimus-stent group versus 0.6% in the bare-metal-stent group (P = 0.20) and 1.3% in the paclitaxel-stent group versus 0.9% in the bare-metal-stent group (P = 0.30). However, after 1 year, there were five episodes of stent thrombosis in patients with sirolimus-eluting stents versus none in patients with bare-metal stents (P = 0.025) and nine episodes in patients with paclitaxel-eluting stents versus two in patients with bare-metal stents (P = 0.028). The 4-year rates of target-lesion revascularization were markedly reduced in both the sirolimus-stent group and the paclitaxel-stent group, as compared with the bare-metal-stent groups. The rates of death or myocardial infarction did not differ significantly between the groups with drug-eluting stents and those with bare-metal stents. Conclusions Stent thrombosis after 1 year was more common with both sirolimus-eluting stents and paclitaxel-eluting stents than with bare-metal stents. Both drug-eluting stents were associated with a marked reduction in target-lesion revascularization. There were no significant differences in the cumulative rates of death or myocardial infarction at 4 years.

Risk alleles for multiple sclerosis identified by a genomewide study.

Abstract: �Background Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. Methods We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. Results A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1×10 −4 ); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor α gene (IL2RA) were strongly associated with multiple sclerosis (P = 2.96×10 −8 ), as were a nonsynonymous SNP in the interleukin-7 receptor α gene (IL7RA) (P = 2.94×10 −7 ) and multiple SNPs in the HLA-DRA locus (P = 8.94×10 −81 ).

Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation.

Abstract: T(H)17 lymphocytes appear to be essential in the pathogenesis of numerous inflammatory diseases. We demonstrate here the expression of IL-17 and IL-22 receptors on blood-brain barrier endothelial cells (BBB-ECs) in multiple sclerosis lesions, and show that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo. Furthermore, T(H)17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote central nervous system inflammation through CD4+ lymphocyte recruitment.

An overview of bilevel optimization

Abstract: This paper is devoted to bilevel optimization, a branch of mathematical programming of both practical and theoretical interest. Starting with a simple example, we proceed towards a general formulation. We then present fields of application, focus on solution approaches, and make the connection with MPECs (Mathematical Programs with Equilibrium Constraints).

Evolutionary and biomedical insights from the rhesus macaque genome

Abstract: The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species.

An empirical evaluation of deep architectures on problems with many factors of variation

Abstract: Recently, several learning algorithms relying on models with deep architectures have been proposed. Though they have demonstrated impressive performance, to date, they have only been evaluated on relatively simple problems such as digit recognition in a controlled environment, for which many machine learning algorithms already report reasonable results. Here, we present a series of experiments which indicate that these models show promise in solving harder learning problems that exhibit many factors of variation. These models are compared with well-established algorithms such as Support Vector Machines and single hidden-layer feed-forward neural networks.

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

Abstract: The Ras-dependent extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase pathway plays a central role in cell proliferation control. In normal cells, sustained activation of ERK1/ERK2 is necessary for G1- to S-phase progression and is associated with induction of positive regulators of the cell cycle and inactivation of antiproliferative genes. In cells expressing activated Ras or Raf mutants, hyperactivation of the ERK1/2 pathway elicits cell cycle arrest by inducing the accumulation of cyclin-dependent kinase inhibitors. In this review, we discuss the mechanisms by which activated ERK1/ERK2 regulate growth and cell cycle progression of mammalian somatic cells. We also highlight the findings obtained from gene disruption studies.

Frailty: An Emerging Research and Clinical Paradigm—Issues and Controversies

Abstract: Clinicians and researchers have shown increasing interest in frailty. Yet, there is still considerable uncertainty regarding the concept and its definition. In this article, we present perspectives on key issues and controversies discussed by scientists from 13 different countries, representing a diverse range of disciplines, at the 2006 Second International Working Meeting on Frailty and Aging. The following fundamental questions are discussed: What is the distinction, if any, between frailty and aging? What is its relationship with chronic disease? Is frailty a syndrome or a series of age-related impairments that predict adverse outcomes? What are the critical domains in its operational definition? Is frailty a useful concept? The implications of different models and approaches are examined. Although consensus has yet to be attained, work accomplished to date has opened exciting new horizons. The article concludes with suggested directions for future research.

TestU01: A C library for empirical testing of random number generators

Abstract: We introduce TestU01, a software library implemented in the ANSI C language, and offering a collection of utilities for the empirical statistical testing of uniform random number generators (RNGs). It provides general implementations of the classical statistical tests for RNGs, as well as several others tests proposed in the literature, and some original ones. Predefined tests suites for sequences of uniform random numbers over the interval (0, 1) and for bit sequences are available. Tools are also offered to perform systematic studies of the interaction between a specific test and the structure of the point sets produced by a given family of RNGs. That is, for a given kind of test and a given class of RNGs, to determine how large should be the sample size of the test, as a function of the generator's period length, before the generator starts to fail the test systematically. Finally, the library provides various types of generators implemented in generic form, as well as many specific generators proposed in the literature or found in widely used software. The tests can be applied to instances of the generators predefined in the library, or to user-defined generators, or to streams of random numbers produced by any kind of device or stored in files. Besides introducing TestU01, the article provides a survey and a classification of statistical tests for RNGs. It also applies batteries of tests to a long list of widely used RNGs.

Transfusion Strategies for Patients in Pediatric Intensive Care Units

Abstract: Hemoglobin concentrations were maintained at a mean (±SD) level that was 2.1±0.2 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group (lowest average levels, 8.7±0.4 and 10.8±0.5 g per deciliter, respectively; P<0.001). Patients in the restrictive-strategy group received 44% fewer transfusions; 174 patients (54%) in that group did not receive any transfusions, as compared with 7 patients (2%) in the liberal-strategy group (P<0.001). New or progressive multiple-organ dysfunction syndrome (the primary outcome) developed in 38 patients in the restrictive-strategy group, as compared with 39 in the liberal-strategy group (12% in both groups) (absolute risk reduction with the restrictive strategy, 0.4%; 95% confidence interval, –4.6 to 5.4). There were 14 deaths in each group within 28 days after randomization. No significant differences were found in other outcomes, including adverse events. Conclusions In stable, critically ill children a hemoglobin threshold of 7 g per deciliter for red-cell transfusion can decrease transfusion requirements without increasing adverse outcomes. (Controlled-trials.com number, ISRCTN37246456.)

Effect of Torcetrapib on the Progression of Coronary Atherosclerosis

Abstract: Background Levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, increases HDL cholesterol levels, but the functional effects associated with this mechanism remain uncertain. Methods A total of 1188 patients with coronary disease underwent intravascular ultrasonography. After treatment with atorvastatin to reduce levels of low-density lipoprotein (LDL) cholesterol to less than 100 mg per deciliter (2.59 mmol per liter), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily. After 24 months, disease progression was measured by repeated intravascular ultrasonography in 910 patients (77%). Results After 24 months, as compared with atorvastatin monotherapy, the effect of torcetrapib–atorvastatin therapy was an approximate 61% relative increase in HDL cholesterol and a 20% relative decrease in LDL cholesterol, reaching a ratio of L...

Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial

Abstract: Summary Background The goals of axillary-lymph-node dissection (ALND) are to maximise survival, provide regional control, and stage the patient. However, this technique has substantial side-effects. The purpose of the B-32 trial is to establish whether sentinel-lymph-node (SLN) resection can achieve the same therapeutic goals as conventional ALND but with decreased side-effects. The aim of this paper is to report the technical success and accuracy of SLN resection plus ALND versus SLN resection alone. Methods 5611 women with invasive breast cancer were randomly assigned to receive either SLN resection followed by immediate conventional ALND (n=2807; group 1) or SLN resection without ALND if SLNs were negative on intraoperative cytology and histological examination (n=2804; group 2) in the B-32 trial. Patients in group 2 underwent ALND if no SLNs were identified or if one or more SLNs were positive on intraoperative cytology or subsequent histological examination. Primary endpoints, including survival, regional control, and morbidity, will be reported later. Secondary endpoints are accuracy and technical success and are reported here. This trial is registered with the Clinical Trial registry, number NCT00003830. Findings Data for technical success were available for 5536 of 5611 patients; 75 declined protocol treatment, had no SLNs removed, or had no SLN resection done. SLNs were successfully removed in 97·2% of patients (5379 of 5536) in both groups combined. Identification of a preincision hot spot was associated with greater SLN removal (98·9% [5072 of 5128]). Only 1·4% (189 of 13171) of SLN specimens were outside of axillary levels I and II. 65·1% (8571 of 13 171) of SLN specimens were both radioactive and blue; a small percentage was identified by palpation only (3·9% [515 of 13 171]). The overall accuracy of SLN resection in patients in group 1 was 97·1% (2544 of 2619; 95% CI 96·4–97·7), with a false-negative rate of 9·8% (75 of 766; 95% CI 7·8–12·2). Differences in tumour location, type of biopsy, and number of SLNs removed significantly affected the false-negative rate. Allergic reactions related to blue dye occurred in 0·7% (37 of 5588) of patients with data on toxic effects. Interpretation The findings reported here indicate excellent balance in clinical patient characteristics between the two randomised groups and that the success of SLN resection was high. These findings are important because the B-32 trial is the only trial of sufficient size to provide definitive information related to the primary outcome measures of survival and regional control. Removal of more than one SLN and avoidance of excisional biopsy are important variables in reducing the false-negative rate.

Incidence, risk factors and consequences of ICU delirium.

Abstract: Delirium in the critically ill is reported in 11–80% of patients. We estimated the incidence of delirium using a validated scale in a large cohort of ICU patients and determined the associated risk factors and outcomes. Prospective study in a 16-bed medical-surgical intensive care unit (ICU). 820 consecutive patients admitted to ICU for more than 24 h. Tools used were: the Intensive Care Delirium Screening Checklist for delirium, Richmond Agitation and Sedation Scale for sedation, and Numerical Rating Scale for pain. Risk factors were evaluated with univariate and multivariate analysis, and factors influencing mortality were determined using Cox regression. Delirium occurred in 31.8% of 764 patients. Risk of delirium was independently associated with a history of hypertension (OR 1.88, 95% CI 1.3–2.6), alcoholism (2.03, 1.2–3.2), and severity of illness (1.25, 1.03–1.07 per 5-point increment in APACHE II score) but not with age or corticosteroid use. Sedatives and analgesics increased the risk of delirium when used to induce coma (OR 3.2, 95% CI 1.5–6.8), and not otherwise. Delirium was linked to longer ICU stay (11.5 ± 11.5 vs. 4.4 ± 3.9 days), longer hospital stay (18.2 ± 15.7 vs. 13.2 ± 19.4 days), higher ICU mortality (19.7% vs. 10.3%), and higher hospital mortality (26.7% vs. 21.4%). Delirium is associated with a history of hypertension and alcoholism, higher APACHE II score, and with clinical effects of sedative and analgesic drugs.

Cortical mechanisms of action selection: the affordance competition hypothesis.

Abstract: At every moment, the natural world presents animals with two fundamental pragmatic problems: selection between actions that are currently possible and specification of the parameters or metrics of those actions. It is commonly suggested that the brain addresses these by first constructing representations of the world on which to build knowledge and make a decision, and then by computing and executing an action plan. However, neurophysiological data argue against this serial viewpoint. In contrast, it is proposed here that the brain processes sensory information to specify, in parallel, several potential actions that are currently available. These potential actions compete against each other for further processing, while information is collected to bias this competition until a single response is selected. The hypothesis suggests that the dorsal visual system specifies actions which compete against each other within the fronto-parietal cortex, while a variety of biasing influences are provided by prefrontal regions and the basal ganglia. A computational model is described, which illustrates how this competition may take place in the cerebral cortex. Simulations of the model capture qualitative features of neurophysiological data and reproduce various behavioural phenomena.

Role of Intermolecular Coupling in the Photophysics of Disordered Organic Semiconductors: Aggregate Emission in Regioregular Polythiophene

Abstract: We address the role of excitonic coupling on the nature of photoexcitations in the conjugated polymer regioregular poly(3-hexylthiophene). By means of temperature-dependent absorption and photoluminescence spectroscopy, we show that optical emission is overwhelmingly dominated by weakly coupled H aggregates. The relative absorbance of the 0-0 and 0-1 vibronic peaks provides a powerfully simple means to extract the magnitude of the intermolecular coupling energy, of approximately 5 and 30 meV for films spun from isodurene and chloroform solutions, respectively.

FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment

Abstract: Pluripotent embryonic stem (ES) cells must select between alternative fates of self-replication and lineage commitment during continuous proliferation. Here, we delineate the role of autocrine production of fibroblast growth factor 4 (Fgf4) and associated activation of the Erk1/2 (Mapk3/1) signalling cascade. Fgf4 is the major stimulus activating Erk in mouse ES cells. Interference with FGF or Erk activity using chemical inhibitors or genetic ablations does not impede propagation of undifferentiated ES cells. Instead, such manipulations restrict the ability of ES cells to commit to differentiation. ES cells lacking Fgf4 or treated with FGF receptor inhibitors resist neural and mesodermal induction, and are refractory to BMP-induced non-neural differentiation. Lineage commitment potential of Fgf4-null cells is restored by provision of FGF protein. Thus, FGF enables rather than antagonises the differentiation activity of BMP. The key downstream role of Erk signalling is revealed by examination of Erk2-null ES cells, which fail to undergo either neural or mesodermal differentiation in adherent culture, and retain expression of pluripotency markers Oct4, Nanog and Rex1. These findings establish that Fgf4 stimulation of Erk1/2 is an autoinductive stimulus for naive ES cells to exit the self-renewal programme. We propose that the Erk cascade directs transition to a state that is responsive to inductive cues for germ layer segregation. Consideration of Erk signalling as a primary trigger that potentiates lineage commitment provides a context for reconciling disparate views on the contribution of FGF and BMP pathways during germ layer specification in vertebrate embryos.

Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

Abstract: Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

A New Algorithm for Point-Spread Function Subtraction in High-Contrast Imaging: A Demonstration with Angular Differential Imaging

Abstract: Direct imaging of exoplanets is limited by bright quasi-static speckles in the point-spread function (PSF) of the central star. This limitation can be reduced by subtraction of reference PSF images. We have developed an algorithm to construct an optimized reference PSF image from a set of reference images. This image is built as a linear combination of the reference images available, and the coefficients of the combination are optimized inside multiple subsections of the image independently to minimize the residual noise within each subsection. The algorithm developed can be used with many high-contrast imaging observing strategies relying on PSF subtraction, such as angular differential imaging (ADI), roll subtraction, spectral differential imaging, and reference star observations. The performance of the algorithm is demonstrated for ADI data. It is shown that for this type of data the new algorithm provides a gain in sensitivity by up to a factor of 3 at small separation over the algorithm previously used by Marois and colleagues.

Effects of Citalopram and Interpersonal Psychotherapy on Depression in Patients With Coronary Artery Disease: The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) Trial

Abstract: ContextFew randomized controlled trials have evaluated the efficacy of treatments for major depression in patients with coronary artery disease (CAD). None have simultaneously evaluated an antidepressant and short-term psychotherapy.ObjectiveTo document the short-term efficacy of a selective serotonin reuptake inhibitor (citalopram) and interpersonal psychotherapy (IPT) in reducing depressive symptoms in patients with CAD and major depression.Design, Setting, and ParticipantsThe Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy, a randomized, controlled, 12-week, parallel-group, 2 × 2 factorial trial conducted May 1, 2002, to March 20, 2006, among 284 patients with CAD from 9 Canadian academic centers. All patients met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for diagnosis of major depression of 4 weeks' duration or longer and had baseline 24-item Hamilton Depression Rating Scale (HAM-D) scores of 20 or higher.InterventionsParticipants underwent 2 separate randomizations: (1) to receive 12 weekly sessions of IPT plus clinical management (n = 142) or clinical management only (n = 142) and (2) to receive 12 weeks of citalopram, 20 to 40 mg/d (n = 142), or matching placebo (n = 142).Main Outcome MeasuresThe primary outcome measure was change between baseline and 12 weeks on the 24-item HAM-D, administered blindly during centralized telephone interviews (tested at α = .033); the secondary outcome measure was self-reported Beck Depression Inventory II (BDI-II) score (tested at α = .017).ResultsCitalopram was superior to placebo in reducing 12-week HAM-D scores (mean difference, 3.3 points; 96.7% confidence interval [CI], 0.80-5.85; P = .005), with a small to medium effect size of 0.33. Mean HAM-D response (52.8% vs 40.1%; P = .03) and remission rates (35.9% vs 22.5%; P = .01) and the reduction in BDI-II scores (difference, 3.6 points; 98.3% CI, 0.58-6.64; P = .005; effect size = 0.33) also favored citalopram. There was no evidence of a benefit of IPT over clinical management, with the mean HAM-D difference favoring clinical management (−2.26 points; 96.7% CI, −4.78 to 0.27; P = .06; effect size, 0.23). The difference on the BDI-II did not favor clinical management (1.13 points; 98.3% CI, −1.90 to 4.16; P = .37; effect size = 0.11).ConclusionsThis trial documents the efficacy of citalopram administered in conjunction with weekly clinical management for major depression among patients with CAD and found no evidence of added value of IPT over clinical management. Based on these results and those of previous trials, citalopram or sertraline plus clinical management should be considered as a first-step treatment for patients with CAD and major depression.Trial Registrationisrctn.org Identifier: ISRCTN15858091

Contemporary carbon balance and late Holocene carbon accumulation in a northern peatland

Abstract: Northern peatlands contain up to 25% of the world’s soil carbon (C) and have an estimated annual exchange of CO2-C with the atmosphere of 0.1–0.5 Pg yr � 1 and of CH4-C of 10–25 Tg yr � 1 . Despite this overall importance to the global C cycle, there have been few, if any, complete multiyear annual C balances for these ecosystems. We report a 6-year balance computed from continuous net ecosystem CO2 exchange (NEE), regular instantaneous measurements of methane (CH4) emissions, and export of dissolved organic C (DOC) from a northern ombrotrophic bog. From these observations, we have constructed complete seasonal and annual C balances, examined their seasonal and interannual variability, and compared the mean 6-year contemporary C exchange with the apparent C accumulation for the last 3000 years obtained from C density and agedepth profiles from two peat cores. The 6-year mean NEE-C and CH4-C exchange, and net DOC loss are � 40.2 � 40.5 (� 1 SD), 3.7 � 0.5, and 14.9 � 3.1 g m � 2 yr � 1 , giving a 6-year mean balance of � 21.5 � 39.0 g m � 2 yr � 1 (where positive exchange is a loss of C from the ecosystem). NEE had the largest magnitude and variability of the components of the C balance, but DOC and CH4 had similar proportional variabilities and their inclusion is essential to resolve the C balance. There are large interseasonal and interannual ranges to the exchanges due to variations in climatic conditions. We estimate from the largest and smallest seasonal exchanges, quasi-maximum limits of the annual C balance between 50 and � 105 g m � 2 yr � 1 . The net C accumulation rate obtained from the two peatland cores for the interval 400–3000 BP (samples from the anoxic layer only) were 21.9 � 2.8 and 14.0 � 37.6 g m � 2 yr � 1 , which are not significantly different from the 6-year mean con