Clinicians and trialists have difficulty with identifying which patients are highest risk for cardiovascular events. Prior ischemic events, polyvascular disease, and diabetes mellitus have all been ...identified as predictors of ischemic events, but their comparative contributions to future risk remain unclear.
To categorize the risk of cardiovascular events in stable outpatients with various initial manifestations of atherothrombosis using simple clinical descriptors.
Outpatients with coronary artery disease, cerebrovascular disease, or peripheral arterial disease or with multiple risk factors for atherothrombosis were enrolled in the global Reduction of Atherothrombosis for Continued Health (REACH) Registry and were followed up for as long as 4 years. Patients from 3647 centers in 29 countries were enrolled between 2003 and 2004 and followed up until 2008. Final database lock was in April 2009.
Rates of cardiovascular death, myocardial infarction, and stroke.
A total of 45,227 patients with baseline data were included in this 4-year analysis. During the follow-up period, a total of 5481 patients experienced at least 1 event, including 2315 with cardiovascular death, 1228 with myocardial infarction, 1898 with stroke, and 40 with both a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, those with a prior history of ischemic events at baseline (n = 21,890) had the highest rate of subsequent ischemic events (18.3%; 95% confidence interval CI, 17.4%-19.1%); patients with stable coronary, cerebrovascular, or peripheral artery disease (n = 15,264) had a lower risk (12.2%; 95% CI, 11.4%-12.9%); and patients without established atherothrombosis but with risk factors only (n = 8073) had the lowest risk (9.1%; 95% CI, 8.3%-9.9%) (P < .001 for all comparisons). In addition, in multivariable modeling, the presence of diabetes (hazard ratio HR, 1.44; 95% CI, 1.36-1.53; P < .001), an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57-1.85; P < .001), and polyvascular disease (HR, 1.99; 95% CI, 1.78-2.24; P < .001) each were associated with a significantly higher risk of the primary end point.
Clinical descriptors can assist clinicians in identifying high-risk patients within the broad range of risk for outpatients with atherothrombosis.
Summary Background Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose ...fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. Methods We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00080912. Findings Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 56% of 358 assessable patients who received 8 Gy vs 229 66% of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 23% of 357 vs 108 31% of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio OR 1·54, 95% CI 0·85–2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73–17·15; p=0·094). Interpretation In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. Funding Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.
Abstract
We present the first interferometric detections of fast radio bursts (FRBs), an enigmatic new class of astrophysical transient. In a 180-d survey of the Southern sky, we discovered three ...FRBs at 843 MHz with the UTMOST array, as a part of commissioning science during a major ongoing upgrade. The wide field of view of UTMOST (≈9 deg2) is well suited to FRB searches. The primary beam is covered by 352 partially overlapping fan-beams, each of which is searched for FRBs in real time with pulse widths in the range 0.655–42 ms, and dispersion measures ≤2000 pc cm−3. Detections of FRBs with the UTMOST array place a lower limit on their distances of ≈104 km (limit of the telescope near-field) supporting the case for an astronomical origin. Repeating FRBs at UTMOST or an FRB detected simultaneously with the Parkes radio telescope and UTMOST would allow a few arcsec localization, thereby providing an excellent means of identifying FRB host galaxies, if present. Up to 100 h of followup for each FRB has been carried out with the UTMOST, with no repeating bursts seen. From the detected position, we present 3σ error ellipses of 15 arcsec × 8
${^{\circ}_{.}}$
4 on the sky for the point of origin for the FRBs. We estimate an all-sky FRB rate at 843 MHz above a fluence
$\cal F_\mathrm{lim}$
of 11 Jy ms of ∼78 events sky−1 d−1 at the 95 per cent confidence level. The measured rate of FRBs at 843 MHz is two times higher than we had expected, scaling from the FRB rate at the Parkes radio telescope, assuming that FRBs have a flat spectral index and a uniform distribution in Euclidean space. We examine how this can be explained by FRBs having a steeper spectral index and/or a flatter logN–log
$\mathcal {F}$
distribution than expected for a Euclidean Universe.
The landforms of northern Gale crater on Mars expose thick sequences of sedimentary rocks. Based on images obtained by the Curiosity rover, we interpret these outcrops as evidence for past fluvial, ...deltaic, and lacustrine environments. Degradation of the crater wall and rim probably supplied these sediments, which advanced inward from the wall, infilling both the crater and an internal lake basin to a thickness of at least 75 meters. This intracrater lake system probably existed intermittently for thousands to millions of years, implying a relatively wet climate that supplied moisture to the crater rim and transported sediment via streams into the lake basin. The deposits in Gale crater were then exhumed, probably by wind-driven erosion, creating Aeolis Mons (Mount Sharp).
Cyclic dinucleotides are an expanding class of signaling molecules that control many aspects of bacterial physiology. A synthase for cyclic AMP-GMP (cAG, also referenced as 3′-5′, 3′-5′ cGAMP) called ...DncV is associated with hyperinfectivity of Vibrio cholerae but has not been found in many bacteria, raising questions about the prevalence and function of cAG signaling. We have discovered that the environmental bacterium Geobacter sulfurreducens produces cAG and uses a subset of GEMM-I class riboswitches (GEMM-Ib, Genes for the Environment, Membranes, and Motility) as specific receptors for cAG. GEMM-Ib riboswitches regulate genes associated with extracellular electron transfer; thus cAG signaling may control aspects of bacterial electrophysiology. These findings expand the role of cAG beyond organisms that harbor DncV and beyond pathogenesis to microbial geochemistry, which is important to environmental remediation and microbial fuel cell development. Finally, we have developed an RNA-based fluorescent biosensor for live-cell imaging of cAG. This selective, genetically encodable biosensor will be useful to probe the biochemistry and cell biology of cAG signaling in diverse bacteria.
Significance Bacteria are hidden forces of nature. For example, Geobacter bacteria play important roles in geochemistry by reducing metals in the environment. Scientists also are exploring the application of these bacteria toward toxic metal remediation and as “living batteries” that can generate electricity from biowaste. However, there is limited understanding of the signaling pathways that regulate this extracellular metal-reducing activity. Here we have discovered that Geobacter sulfurreducens use riboswitch sensors for a signaling molecule called cAG to regulate this process, which is an unexpected finding because cAG was previously associated only with pathogenic bacteria. Furthermore, we have adapted the riboswitch to generate a fluorescent biosensor that can be used to visualize cAG signaling in live bacteria.
Heparan sulfate is a highly modified O-linked glycan that performs diverse physiological roles in animal tissues. Though quickly modified, it is initially synthesised as a polysaccharide of ...alternating β-D-glucuronosyl and N-acetyl-α-D-glucosaminyl residues by exostosins. These enzymes generally possess two glycosyltransferase domains (GT47 and GT64)-each thought to add one type of monosaccharide unit to the backbone. Although previous structures of murine exostosin-like 2 (EXTL2) provide insight into the GT64 domain, the rest of the bi-domain architecture is yet to be characterised; hence, how the two domains co-operate is unknown. Here, we report the structure of human exostosin-like 3 (EXTL3) in apo and UDP-bound forms. We explain the ineffectiveness of EXTL3's GT47 domain to transfer β-D-glucuronosyl units, and we observe that, in general, the bi-domain architecture would preclude a processive mechanism of backbone extension. We therefore propose that heparan sulfate backbone polymerisation occurs by a simple dissociative mechanism.
This is the first nationwide survey of emerging contaminants in Brazilian waters. One hundred drinking water samples were investigated in 22 Brazilian state capitals. In addition, seven source water ...samples from two of the most populous regions of the country were evaluated. Samples were collected from June to September of 2011 and again during the same period in 2012. The study covered emerging contaminants of different classes, including hormones, plasticizers, herbicides, triclosan and caffeine. The analytical method for the determination of the compounds was based on solid-phase extraction followed by analysis via liquid chromatography electrospray triple-quadrupole mass spectrometry (LC-MS/MS). Caffeine, triclosan, atrazine, phenolphthalein and bisphenol A were found in at least one of the samples collected in the two sampling campaigns. Caffeine and atrazine were the most frequently detected substances in both drinking and source water. Caffeine concentrations in drinking water ranged from 1.8ngL−1 to values above 2.0μgL−1 while source-water concentrations varied from 40ngL−1 to about 19μgL−1. For atrazine, concentrations were found in the range from 2.0 to 6.0ngL−1 in drinking water and at concentrations of up to 15ngL−1 in source water. The widespread presence of caffeine in samples of treated water is an indication of the presence of domestic sewage in the source water, considering that caffeine is a compound of anthropogenic origin.
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•First national survey of emerging contaminants in Brazil•Caffeine detected in 93% of samples•Strong indication of the presence of domestic sewage in source waters
Delays in peer reviewed publication may have consequences for both assessment of scientific prowess in academics as well as communication of important information to the knowledge receptor community. ...We present an analysis on the perspectives of authors publishing in conservation biology journals regarding their opinions on the importance of speed in peer-review as well as how to improve review times. Authors were invited to take part in an online questionnaire, of which the data was subjected to both qualitative (open coding, categorizing) and quantitative analyses (generalized linear models). We received 637 responses to a total of 6,547 e-mail invitations sent. Peer-review speed was generally perceived as slow, with authors experiencing a typical turnaround time of 14 weeks while their perceived optimal review time is six weeks. Male and younger respondents seem to have higher expectations of review speed than females and older respondents. Majority of participants attributed lengthy review times to the 'stress' on the peer-review system (i.e., reviewer and editor fatigue), while editor persistence and journal prestige were believed to speed up the review process. Negative consequences of lengthy review times appear to be greater for early career researchers and can also have impact on author morale (e.g. motivation or frustration). Competition among colleagues were also of concern to respondents. Incentivizing peer review was among the top suggested alterations to the system along with training graduate students in peer review, increased editorial persistence, and changes to the norms of peer-review such as opening the peer-review process to the public. It is clear that authors surveyed in this study view the peer-review system as under stress and we encourage scientists and publishers to push the envelope for new peer review models.
The Messinian salinity crisis is widely regarded as one of the most dramatic episodes of oceanic change of the past 20 or so million years (refs 1-3). Earliest explanations were that extremely thick ...evaporites were deposited in a deep and desiccated Mediterranean basin that had been repeatedly isolated from the Atlantic Ocean,, but elucidation of the causes of the isolation - whether driven largely by glacio-eustatic or tectonic processes - have been hampered by the absence of an accurate time frame. Here we present an astronomically calibrated chronology for the Mediterranean Messinian age based on an integrated high-resolution stratigraphy and 'tuning' of sedimentary cycle patterns to variations in the Earth's orbital parameters. We show that the onset of the Messinian salinity crisis is synchronous over the entire Mediterranean basin, dated at 5.96 ± 0.02 million years ago. Isolation from the Atlantic Ocean was established between 5.59 and 5.33 million years ago, causing a large fall in Mediterranean water level followed by erosion (5.59-5.50 million years ago) and deposition (5.50-5.33 million years ago) of non-marine sediments in a large 'Lago Mare' (Lake Sea) basin. Cyclic evaporite deposition is almost entirely related to circum-Mediterranean climate changes driven by changes in the Earth's precession, and not to obliquity-induced glacio-eustatic sea-level changes. We argue in favour of a dominantly tectonic origin for the Messinian salinity crisis, although its exact timing may well have been controlled by the ∼400-kyr component of the Earth's eccentricity cycle.
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