189 research outputs found
Systematic review of economic evaluations and cost analyses of guideline implementation strategies
Objectives To appraise the quality of economic studies undertaken as part of evaluations of guideline implementation strategies; determine their resources use; and recommend methods to improve future studies. Methods Systematic review of economic studies undertaken alongside robust study designs of clinical guideline implementation strategies published (1966-1998). Studies assessed against the BMJ economic evaluations guidelines for each stage of the guideline process (guideline development, implementation and treatment). Results 235 studies were identified, 63 reported some information on cost. Only 3 studies provided evidence that their guideline was effective and efficient. 38 reported the treatment costs only, 12 implementation and treatment costs, 11 implementation costs alone, and two guideline development, implementation and treatment costs. No study gave reasonably complete information on costs. Conclusions Very few satisfactory economic evaluations of guideline implementation strategies have been performed. Current evaluations have numerous methodological defects and rarely consider all relevant costs and benefits. Future evaluations should focus on evaluating the implementation of evidence based guidelines. Keywords: Cost-effectiveness analysis, physician (or health care professional) behaviour, practice guidelines, quality improvement, systematic review.Peer reviewedAuthor versio
Extreme genetic fragility of the HIV-1 capsid
Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies
Saving the world’s terrestrial megafauna
From the late Pleistocene to the Holocene, and now the so called Anthropocene, humans have been driving an ongoing series of species declines and extinctions (Dirzo et al. 2014). Large-bodied mammals are typically at a higher risk of extinction than smaller ones (Cardillo et al. 2005). However, in some circumstances terrestrial megafauna populations have been able to recover some of their lost numbers due to strong conservation and political commitment, and human cultural changes (Chapron et al. 2014). Indeed many would be in considerably worse predicaments in the absence of conservation action (Hoffmann et al. 2015). Nevertheless, most mammalian megafauna face dramatic range contractions and population declines. In fact, 59% of the world’s largest carnivores (≥ 15 kg, n = 27) and 60% of the world’s largest herbivores (≥ 100 kg, n = 74) are classified as threatened with extinction on the International Union for the Conservation of Nature (IUCN) Red List (supplemental table S1 and S2). This situation is particularly dire in sub-Saharan Africa and Southeast Asia, home to the greatest diversity of extant megafauna (figure 1). Species at risk of extinction include some of the world’s most iconic animals—such as gorillas, rhinos, and big cats (figure 2 top row)—and, unfortunately, they are vanishing just as science is discovering their essential ecological roles (Estes et al. 2011). Here, our objectives are to raise awareness of how these megafauna are imperiled (species in supplemental table S1 and S2) and to stimulate broad interest in developing specific recommendations and concerted action to conserve them
The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III
The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with
new instrumentation and new surveys focused on Galactic structure and chemical
evolution, measurements of the baryon oscillation feature in the clustering of
galaxies and the quasar Ly alpha forest, and a radial velocity search for
planets around ~8000 stars. This paper describes the first data release of
SDSS-III (and the eighth counting from the beginning of the SDSS). The release
includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap,
bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a
third of the Celestial Sphere. All the imaging data have been reprocessed with
an improved sky-subtraction algorithm and a final, self-consistent photometric
recalibration and flat-field determination. This release also includes all data
from the second phase of the Sloan Extension for Galactic Understanding and
Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars
at both high and low Galactic latitudes. All the more than half a million
stellar spectra obtained with the SDSS spectrograph have been reprocessed
through an improved stellar parameters pipeline, which has better determination
of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from
submitted version
The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey
The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic
data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data
release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median
z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar
spectra, along with the data presented in previous data releases. These spectra
were obtained with the new BOSS spectrograph and were taken between 2009
December and 2011 July. In addition, the stellar parameters pipeline, which
determines radial velocities, surface temperatures, surface gravities, and
metallicities of stars, has been updated and refined with improvements in
temperature estimates for stars with T_eff<5000 K and in metallicity estimates
for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars
presented in DR8, including stars from SDSS-I and II, as well as those observed
as part of the SDSS-III Sloan Extension for Galactic Understanding and
Exploration-2 (SEGUE-2).
The astrometry error introduced in the DR8 imaging catalogs has been
corrected in the DR9 data products. The next data release for SDSS-III will be
in Summer 2013, which will present the first data from the Apache Point
Observatory Galactic Evolution Experiment (APOGEE) along with another year of
data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at
http://www.sdss3.org/dr
The state of the Martian climate
60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes
Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context
Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts
Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas
Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing
molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin
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