The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus ...process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.
The VLT Survey Telescope ATLAS Shanks, T; Metcalfe, N; Chehade, B ...
Monthly notices of the Royal Astronomical Society,
08/2015, Volume:
451, Issue:
4
Journal Article
Peer reviewed
Open access
The VLT Survey Telescope ATLAS survey is an optical ugriz survey aiming to cover ≈4700 deg2 of the southern sky to similar depths as the Sloan Digital Sky Survey (SDSS). From reduced images and ...object catalogues provided by the Cambridge Astronomical Surveys Unit, we first find that the median seeing ranges from 0.8 arcsec FWHM (full width at half-maximum) in i to 1.0 arcsec in u, significantly better than the 1.2–1.5 arcsec seeing for SDSS. The 5σ mag limit for stellar sources is r
AB
= 22.7 and in all bands these limits are at least as faint as SDSS. SDSS and ATLAS are more equivalent for galaxy photometry except in the z band where ATLAS has significantly higher throughput. We have improved the original ESO magnitude zero-points by comparing m < 16 star magnitudes with the AAVSO Photometric All-Sky Survey in gri, also extrapolating into u and z, resulting in zero-points accurate to ≈ ± 0.02 mag. We finally compare star and galaxy number counts in a 250 deg2 area with SDSS and other count data and find good agreement. ATLAS data products can be retrieved from the ESO Science Archive, while support for survey science analyses is provided by the OmegaCAM Science Archive, operated by the Wide-Field Astronomy Unit in Edinburgh.
Reactome, located at http://www.reactome.org is a curated, peer-reviewed resource of human biological processes. Given the genetic makeup of an organism, the complete set of possible reactions ...constitutes its reactome. The basic unit of the Reactome database is a reaction; reactions are then grouped into causal chains to form pathways. The Reactome data model allows us to represent many diverse processes in the human system, including the pathways of intermediary metabolism, regulatory pathways, and signal transduction, and high-level processes, such as the cell cycle. Reactome provides a qualitative framework, on which quantitative data can be superimposed. Tools have been developed to facilitate custom data entry and annotation by expert biologists, and to allow visualization and exploration of the finished dataset as an interactive process map. Although our primary curational domain is pathways from Homo sapiens, we regularly create electronic projections of human pathways onto other organisms via putative orthologs, thus making Reactome relevant to model organism research communities. The database is publicly available under open source terms, which allows both its content and its software infrastructure to be freely used and redistributed.
Chemiosmotic coupling is universal: practically all cells harness electrochemical proton gradients across membranes to drive ATP synthesis, powering biochemistry. Autotrophic cells, including ...phototrophs and chemolithotrophs, also use proton gradients to power carbon fixation directly. The universality of chemiosmotic coupling suggests that it arose very early in evolution, but its origins are obscure. Alkaline hydrothermal systems sustain natural proton gradients across the thin inorganic barriers of interconnected micropores within deep-sea vents. In Hadean oceans, these inorganic barriers should have contained catalytic Fe(Ni)S minerals similar in structure to cofactors in modern metabolic enzymes, suggesting a possible abiotic origin of chemiosmotic coupling. The continuous supply of H
2
and CO
2
from vent fluids and early oceans, respectively, offers further parallels with the biochemistry of ancient autotrophic cells, notably the acetyl CoA pathway in archaea and bacteria. However, the precise mechanisms by which natural proton gradients, H
2
, CO
2
and metal sulphides could have driven organic synthesis are uncertain, and theoretical ideas lack empirical support. We have built a simple electrochemical reactor to simulate conditions in alkaline hydrothermal vents, allowing investigation of the possibility that abiotic vent chemistry could prefigure the origins of biochemistry. We discuss the construction and testing of the reactor, describing the precipitation of thin-walled, inorganic structures containing nickel-doped mackinawite, a catalytic Fe(Ni)S mineral, under prebiotic ocean conditions. These simulated vent structures appear to generate low yields of simple organics. Synthetic microporous matrices can concentrate organics by thermophoresis over several orders of magnitude under continuous open-flow vent conditions.
Studying quasars at the highest redshifts can constrain models of galaxy and black hole formation, and it also probes the intergalactic medium in the early universe. Optical surveys have to date ...discovered more than 60 quasars up to z Asymptotically = to 6.4, a limit set by the use of the z-band and CCD detectors. Only one z gap 6.4 quasar has been discovered, namely the z = 7.08 quasar ULAS J1120+0641, using near-infrared imaging. Here we report the discovery of three new z gap 6.4 quasars in 332 deg super(2) of the Visible and Infrared Survey Telescope for Astronomy Kilo-degree Infrared Galaxy (VIKING) survey, thus extending the number from 1 to 4. The newly discovered quasars have redshifts of z = 6.60, 6.75, and 6.89. The absolute magnitudes are between -26.0 and -25.5, 0.6-1.1 mag fainter than ULAS J1120+0641. Near-infrared spectroscopy revealed the Mg II emission line in all three objects. The quasars are powered by black holes with masses of ~(1-2) x 10 super(9) M sub(middot in circle). In our probed redshift range of 6.44 < z < 7.44 we can set a lower limit on the space density of supermassive black holes of rho(M sub(BH) > 10 super(9) M sub(middot in circle)) > 1.1 x 10 super(-9) Mpc super(-3). The discovery of three quasars in our survey area is consistent with the z = 6 quasar luminosity function when extrapolated to z ~ 7. We do not find evidence for a steeper decline in the space density of quasars with increasing redshift from z = 6 to z = 7.
Summary Background MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse ...safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma. Methods We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov , number NCT00687622. Findings 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0–7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%). Interpretation Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future. Funding GlaxoSmithKline.
The pattern of atrial fibrillation (AF) occurrence-paroxysmal, persistent, or permanent-is associated with progressive stages of atrial dysfunction and structural changes and may therefore be ...associated with progressively higher stroke risk. However, previous studies have not consistently shown AF pattern to predict stroke but have been hampered by methodological shortcomings of low power, variable event ascertainment, and variable anticoagulant use.
We analysed the rates of stroke and systemic embolism in 6563 aspirin-treated patients with AF from the ACTIVE-A/AVERROES databases. There was thorough searching for events and adjudication. Multivariable analyses were performed with the adjustment for known risk factors for stroke. Mean age of patients with paroxysmal, persistent, and permanent AF was 69.0 ± 9.9, 68.6 ± 10.2, and 71.9 ± 9.8 years (P < 0.001). The CHA2DS2-VASc score was similar in patients with paroxysmal and persistent AF (3.1 ± 1.4), but was higher in patients with permanent AF (3.6 ± 1.5, P < 0.001). Yearly ischaemic stroke rates were 2.1, 3.0, and 4.2% for paroxysmal, persistent, and permanent AF, respectively, with adjusted hazard ratio of 1.83 (P < 0.001) for permanent vs. paroxysmal and 1.44 (P = 0.02) for persistent vs. paroxysmal. Multivariable analysis identified age ≥ 75 year, sex, history of stroke or TIA, and AF pattern as independent predictors of stroke, with AF pattern being the second strongest predictor after prior stroke or TIA.
In a large population of non-anticoagulated AF patients, pattern of AF was a strong independent predictor of stroke risk and may be helpful to assess the risk/benefit for anticoagulant therapy, especially in lower risk patients.
Objective
To document pregnancy outcome in homozygous sickle cell (SS) disease and in age‐matched controls with a normal haemoglobin genotype followed from birth for up to 45 years.
Methods
A total ...of 100 000 consecutive non‐operative deliveries screened for sickle cell disease at the main Government maternity hospital in Kingston, Jamaica between 1973 and 1981 detected 311 (149 female) babies with SS disease who were matched by age and gender with 250 (129 female) controls with an AA haemoglobin phenotype. These individuals have been followed from birth with prospective assessment of menarche and detailed documentation of all pregnancies.
Results
There were 177 pregnancies in 71 SS patients and 226 pregnancies in 74 AA controls. Mothers with SS disease had more spontaneous abortions (adjusted relative risk aRR 3.2, 95% CI 1.6–6.1), fewer live births (aRR 0.7, 95% CI 0.6–0.9) and their offspring were more likely to have a gestational age <37 weeks (aRR 2.1, 95% CI 1.1–3.7) and low birthweight <2.5 kg (aRR 3.0, 95% CI 1.6–5.3). They were more prone to acute chest syndrome (aRR 13.7, 95% CI 4.1–45.5), urinary tract infection (aRR 12.8, 95% CI 1.3–125.9), pre‐eclampsia/eclampsia (aRR 3.1, 95% CI 1.1–8.8), retained placenta (aRR 10.1, 95% CI 1.1–90.3), sepsis (Fisher's Exact test 0.04) and pregnancy‐related deaths (Fisher's Exact test 0.02). Four of five deaths were attributable to acute chest syndrome. There was no genotypic difference in pregnancy‐induced hypertension or postpartum haemorrhage.
Conclusion
Pregnancy in SS disease carries risks for both mother and child. The variable characteristics of pregnancy‐related deaths complicate their prevention.
Tweetable
Pregnancy in SS disease compared with controls showed increased abortions and stillbirths, fewer live births and maternal deaths in 7% patients.
Tweetable
Pregnancy in SS disease compared with controls showed increased abortions and stillbirths, fewer live births and maternal deaths in 7% patients.
The Gaia-ESO Survey was designed to target all major Galactic components (i.e. bulge, thin and thick discs, halo and clusters), with the goal of constraining the chemical and dynamical evolution of ...the Milky Way. This paper presents the methodology and considerations that drive the selection of the targeted, allocated and successfully observed Milky Way field stars. The detailed understanding of the survey construction, specifically the influence of target selection criteria on observed Milky Way field stars is required in order to analyse and interpret the survey data correctly. We present the target selection process for the Milky Way field stars observed with Very Large Telescope/Fibre Large Array Multi Element Spectrograph and provide the weights that characterize the survey target selection. The weights can be used to account for the selection effects in the Gaia-ESO Survey data for scientific studies. We provide a couple of simple examples to highlight the necessity of including such information in studies of the stellar populations in the Milky Way.
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