N-Terminal Pro–B-Type Natriuretic Peptide in the Emergency Department: The ICON-RELOADED Study

Background Contemporary reconsideration of diagnostic N-terminal pro–B-type natriuretic peptide (NT-proBNP) cutoffs for diagnosis of heart failure (HF) is needed. Objectives This study sought to evaluate the diagnostic performance of NT-proBNP for acute HF in patients with dyspnea in the emergency department (ED) setting. Methods Dyspneic patients presenting to 19 EDs in North America were enrolled and had blood drawn for subsequent NT-proBNP measurement. Primary endpoints were positive predictive values of age-stratified cutoffs (450, 900, and 1,800 pg/ml) for diagnosis of acute HF and negative predictive value of the rule-out cutoff to exclude acute HF. Secondary endpoints included sensitivity, specificity, and positive (+) and negative (−) likelihood ratios (LRs) for acute HF. Results Of 1,461 subjects, 277 (19%) were adjudicated as having acute HF. The area under the receiver-operating characteristic curve for diagnosis of acute HF was 0.91 (95% confidence interval [CI]: 0.90 to 0.93; p < 0.001). Sensitivity for age stratified cutoffs of 450, 900, and 1,800 pg/ml was 85.7%, 79.3%, and 75.9%, respectively; specificity was 93.9%, 84.0%, and 75.0%, respectively. Positive predictive values were 53.6%, 58.4%, and 62.0%, respectively. Overall LR+ across age-dependent cutoffs was 5.99 (95% CI: 5.05 to 6.93); individual LR+ for age-dependent cutoffs was 14.08, 4.95, and 3.03, respectively. The sensitivity and negative predictive value for the rule-out cutoff of 300 pg/ml were 93.9% and 98.0%, respectively; LR− was 0.09 (95% CI: 0.05 to 0.13). Conclusions In acutely dyspneic patients seen in the ED setting, age-stratified NT-proBNP cutpoints may aid in the diagnosis of acute HF. An NT-proBNP <300 pg/ml strongly excludes the presence of acute HF

Subtropical mode water variability in a climatologically forced model in the northwestern Pacific Ocean

Author Posting. © American Meteorological Society, 2012. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 42 (2012): 126–140, doi:10.1175/2011JPO4513.1.A climatologically forced high-resolution model is used to examine variability of subtropical mode water (STMW) in the northwestern Pacific Ocean. Despite the use of annually repeating atmospheric forcing, significant interannual to decadal variability is evident in the volume, temperature, and age of STMW formed in the region. This long time-scale variability is intrinsic to the ocean. The formation and characteristics of STMW are comparable to those observed in nature. STMW is found to be cooler, denser, and shallower in the east than in the west, but time variations in these properties are generally correlated across the full water mass. Formation is found to occur south of the Kuroshio Extension, and after formation STMW is advected westward, as shown by the transport streamfunction. The ideal age and chlorofluorocarbon tracers are used to analyze the life cycle of STMW. Over the full model run, the average age of STMW is found to be 4.1 yr, but there is strong geographical variation in this, from an average age of 3.0 yr in the east to 4.9 yr in the west. This is further evidence that STMW is formed in the east and travels to the west. This is qualitatively confirmed through simulated dye experiments known as transit-time distributions. Changes in STMW formation are correlated with a large meander in the path of the Kuroshio south of Japan. In the model, the large meander inhibits STMW formation just south of Japan, but the export of water with low potential vorticity leads to formation of STMW in the east and an overall increase in volume. This is correlated with an increase in the outcrop area of STMW. Mixed layer depth, on the other hand, is found to be uncorrelated with the volume of STMW.E.M.D. acknowledges support of the Doherty Foundation and National Science Foundation (OCE-0849808). S.R.J was sponsored by the National Science Foundation (OCE-0849808). Participation of S.P. and F.B. was supported by the National Science Foundation by its sponsorship of the National Center for Atmospheric Research.2012-07-0

Testing the Cosmic Coincidence Problem and the Nature of Dark Energy

Dark energy models which alter the relative scaling behavior of dark energy and matter could provide a natural solution to the cosmic coincidence problem - why the densities of dark energy and dark matter are comparable today. A generalized class of dark energy models is introduced which allows non-canonical scaling of the ratio of dark matter and dark energy with the Robertson-Walker scale factor a(t). Upcoming observations, such as a high redshift supernova survey, application of the Alcock-Paczynski test to quasar pairs, and cluster evolution, will strongly constrain the relative scaling of dark matter and dark energy as well as the equation of state of the dark energy. Thus, whether there actually is a coincidence problem, and the extent of cosmic coincidence in the universe's recent past can be answered observationally in the near future. Determining whether today is a special time in the history of the universe will be a SNAP.Comment: 5 pages, 3 figures, revtex4, submitted to PR

Sankey diagrams can clarify 'evidence attrition': A systematic review and meta-analysis of the effectiveness of rapid diagnostic tests for antimicrobial resistance.

OBJECTIVES: To demonstrate, using the example of a new systematic review of rapid diagnostic tests, how Sankey diagrams, alongside the PRISMA guidelines, can (i) facilitate reporting of the quality of the evidence base and (ii) help assess evidence syntheses when studies use heterogeneous outcomes. METHODS: Systematic review and meta-analysis of experimental and observational studies which included at least one prescribing or clinical outcome of RDTs in hospital in-patients. Sub-group analysis was used to assess heterogeneity in summary effect estimates. A Sankey diagram was then used to show the pattern and quality of evidence on RDT outcomes. RESULTS: 57 studies from 14 countries were included. The introduction of RDTs did not significantly reduce in-hospital mortality (RR 0.83, 95% CI 0.60 - 1.15) or length of stay (weighted mean difference = -0.36, 95% CI -1.67 to 0.96). There was high heterogeneity in outcomes. CONCLUSION: There is no clear evidence that the routine use of RDTs for bacterial identification and antibiotic susceptibility testing improves clinical outcomes in hospital in-patients. Sankey diagrams may be a useful further way succinctly to present the pattern and quality of evidence in systematic reviews, especially when it is heterogeneous and not easily amenable to meta-analysis

Disease modifying and antiangiogenic activity of 2-Methoxyestradiol in a murine model of rheumatoid arthritis

<p>Abstract</p> <p>Background</p> <p>A critical component of disease progression in rheumatoid arthritis (RA) involves neovascularization associated with pannus formation. 2-methoxyestradiol (2ME2) is a naturally occurring molecule with no known physiologic function, although at pharmacologic concentrations it has antiproliferative and antiangiogenic activities. We investigated the impact of orally administered 2ME2 on the initiation and development of proliferative synovitis using the anti-collagen monoclonal antibodies (CAIA) model.</p> <p>Methods</p> <p>Severe polyarticular arthritis was induced in Balb/c female mice by administration of 2 mg of a monoclonal antibody cocktail intravenously into the tail vein of mice. Twenty-four hours following monoclonal antibody administration, mice were injected with 25 μg of LPS (<it>E. coli </it>strain 0111:B4) via the intraperitoneal route. Treatment with 2ME2 (100, 75, 50, 25, 10, 1 mg/kg, p.o., daily), or vehicle control began 24 hrs following LPS challenge and continued to day 21. Hind limbs were harvested, sectioned and evaluated for DMARD activity and general histopathology by histomorphometric analysis and immunohistochemistry (vWF staining). In a separate study, different dosing regimens of 2ME2 (100 mg/kg; q.d. <it>vs </it>q.w. <it>vs </it>q.w. × 2) were evaluated. The effect of treatment with 2ME2 on gene expression of inflammatory cytokines and angiogenic growth factors in the joint space was evaluated 5 and 14 days after the induction of arthritis.</p> <p>Results</p> <p>Mice treated with 2ME2 beginning 24 hours post anti-collagen monoclonal antibody injection, showed a dose-dependent inhibition in mean arthritic scores. At study termination (day 21), blinded histomorphometric assessments of sectioned hind limbs demonstrated decreases in synovial inflammation, articular cartilage degradation, pannus formation, osteoclast activity and bone resorption. At the maximal efficacious dosing regimen (100 mg/kg/day), administration of 2ME2 resulted in total inhibition of the study parameters and prevented neovascularization into the joint. Examination of gene expression on dissected hind limbs from mice treated for 5 or 14 days with 2ME2 showed inhibition of inflammatory cytokine message for IL-1β, TNF-α, IL-6 and IL-17, as well as the angiogenic cytokines, VEGF and FGF-2.</p> <p>Conclusion</p> <p>These data demonstrate that in the CAIA mouse model of RA, 2ME2 has disease modifying activity that is at least partially attributable to the inhibition of neovascular development. Further, the data suggests new mechanistic points of intervention for 2ME2 in RA, specifically inhibition of inflammatory mediators and osteoclast activity.</p

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

A warm Jet in a cold ocean

Unprecedented quantities of heat are entering the Pacific sector of the Arctic Ocean through Bering Strait, particularly during summer months. Though some heat is lost to the atmosphere during autumn cooling, a significant fraction of the incoming warm, salty water subducts (dives beneath) below a cooler fresher layer of near-surface water, subsequently extending hundreds of kilometers into the Beaufort Gyre. Upward turbulent mixing of these sub-surface pockets of heat is likely accelerating sea ice melt in the region. This Pacific-origin water brings both heat and unique biogeochemical properties, contributing to a changing Arctic ecosystem. However, our ability to understand or forecast the role of this incoming water mass has been hampered by lack of understanding of the physical processes controlling subduction and evolution of this this warm water. Crucially, the processes seen here occur at small horizontal scales not resolved by regional forecast models or climate simulations; new parameterizations must be developed that accurately represent the physics. Here we present novel high resolution observations showing the detailed process of subduction and initial evolution of warm Pacific-origin water in the southern Beaufort Gyre

What are the toxicological effects of mercury in Arctic biota?

This review critically evaluates the available mercury (Hg) data in Arctic marine biota and the Inuit population against toxicity threshold values. In particular marine top predators exhibit concentrations of mercury in their tissues and organs that are believed to exceed thresholds for biological effects. Species whose concentrations exceed threshold values include the polar bears (Ursus maritimus), beluga whale (Delphinapterus leucas), pilot whale (Globicephala melas), hooded seal (Cystophora cristata), a few seabird species, and landlocked Arctic char (Salvelinus alpinus). Toothed whales appear to be one of the most vulnerable groups, with high concentrations of mercury recorded in brain tissue with associated signs of neurochemical effects. Evidence of increasing concentrations in mercury in some biota in Arctic Canada and Greenland is therefore a concern with respect to ecosystem health

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

Framing rights and responsibilities: accounts of women with a history of AIDS activism

<p>Abstract</p> <p>Background</p> <p>In South Africa, policy with respect to HIV/AIDS has had a strong rights-based framing in line with international trends and in keeping with the constitutional overhaul in the post-Apartheid era. There have also been considerable advances since 1994 towards legal enshrinement of sexual and reproductive health rights and in the provision of related services. Since HIV in this setting has heavily affected women of reproductive age, there has been discussion about the particular needs of this subgroup, especially in the context of service integration. This paper is concerned with the way in which HIV positive women conceptualise these rights and whether they wish and are able to actualise them in their daily lives.</p> <p>Methods</p> <p>In 2003 a group of women involved with the Treatment Action Campaign and Medicines Sans Frontières participated in an initiative to ‘map’ their bodies as affected by the virus. A book containing the maps and narratives was published and used as a political tool to pressure the government of the day to roll out antiretroviral therapy (ART) to the population. In 2008, the authors coordinated an initiative that involved conducting follow-up in-depth interviews in which five of these women reflected on those body maps and on how their lives had changed in the intervening five years since gaining the right to treatment through the public sector.</p> <p>Results</p> <p>Drawing upon this qualitative data and published sources, these new accounts are analysed in order to reflect the perspectives of these women living with chronic HIV with respect to their sexual relations and fertility desires. The paper reveals difficulties faced by these women in negotiating sexual relationships and disclosure of their HIV positive status. It focuses on how they perceive relative responsibilities in terms of taking preventative measures in sexual encounters. Women adopt tactics within a context characterised by various inequalities in order to ‘make do’, such as by remaining silent about their status. Concerns about childbearing can be addressed by information and support from a health care worker.</p> <p>Conclusions</p> <p>Women’s experience of HIV as a chronic illness and the need to adhere to ART, is linked to the way in which the language of responsibility can come to counter-balance a language of rights in treatment programmes.</p