Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Is the Fate of Clinical Candidate Arry-520 Already Sealed? Predicting Resistance in Eg5–Inhibitor Complexes

Arry-520 is an advanced drug candidate from the Eg5 inhibitor class undergoing clinical evaluation in patients with relapsed or refractory multiple myeloma. Here we show by structural analysis that Arry-520 binds stoichiometrically to the motor domain of Eg5 in the conventional allosteric loop L5 pocket in a complex that suggests the same structural mechanism as other Eg5 inhibitors. We have previously shown that acquired resistance through mutations in the allosteric binding site located at loop L5 in the Eg5 structure appears to be independent of the inhibitors' scaffold, which suggests that Arry-520 will ultimately have the same fate. When Arry-520 was assessed in two cell lines selected for the expression of either Eg5(D130A) or Eg5(L214A) STLC-resistant alleles, mutations previously shown to convey resistance to this class of inhibitors, it was inactive in both. Surprisingly, when the cells were challenged with ispinesib, another Eg5 inhibitor, the Eg5(D130A) cells were resistant, but those expressing Eg5(L214A) were strikingly sensitive. Molecular dynamics simulations suggest that subtle differences in ligand binding and flexibility in both compound and protein may alter allosteric transmission from the loop L5 site that do not necessarily result in reduced inhibitory activity in mutated Eg5 structures. Whilst we predict that cells challenged with Arry-520 in the clinical setting are likely to acquire resistance through point mutations in the Eg5 binding site, the data for ispinesib suggests that this resistance mechanism is not scaffold independent as previously thought, and new inhibitors can be designed that retain inhibitory activity in these resistant cells

Effects of river water and salinity on the toxicity of deltamethrin to freshwater shrimp, cladoceran, and fish

Deltamethrin is a pyrethroid insecticide used extensively to control invertebrate pests on cotton and other crops. It is acutely toxic to nontarget aquatic organisms, but existing toxicity data are mostly from toxicity tests using purified laboratory water that differs greatly from the turbid, high-conductivity rivers in the cotton-growing regions of Australia. The aim of this study was to determine whether the water quality variables conductivity, suspended particles, and dissolved organic matter alter the toxicity of deltamethrin to freshwater crustaceans and a fish. We tested three Australian native species: a cladoceran (Ceriodaphnia cf. dubia), a freshwater shrimp (Paratya australiensis), and larvae of the eastern rainbow fish (Melanotaenia duboulayi). Conductivity of the test solutions ranged from 200 to 750 μS/cm, but such changes did not modify the toxicity of deltamethrin to any of the test species. However, the toxicity of deltamethrin to C. cf. dubia and P. australiensis in river water was significantly decreased (1.8-fold to 6.3-fold reduction) compared to that in laboratory water. Variability in the toxicity data limited our ability to detect differences between laboratory and river water for M. duboulayi. Despite reductions in toxicity in natural waters, deltamethrin remained highly toxic [all L(E)C50 values <0.26 μg/L] to all organisms tested; thus, further investigation of the hazard of deltamethrin is warranted. © 2008 Springer Science+Business Media, LLC

Radiomic markers of intracerebral hemorrhage expansion on non-contrast CT: independent validation and comparison with visual markers

Objective: To devise and validate radiomic signatures of impending hematoma expansion (HE) based on admission non-contrast head computed tomography (CT) of patients with intracerebral hemorrhage (ICH). Methods: Utilizing a large multicentric clinical trial dataset of hypertensive patients with spontaneous supratentorial ICH, we developed signatures predictive of HE in a discovery cohort (n = 449) and confirmed their performance in an independent validation cohort (n = 448). In addition to n = 1,130 radiomic features, n = 6 clinical variables associated with HE, n = 8 previously defined visual markers of HE, the BAT score, and combinations thereof served as candidate variable sets for signatures. The area under the receiver operating characteristic curve (AUC) quantified signatures’ performance. Results: A signature combining select radiomic features and clinical variables attained the highest AUC (95% confidence interval) of 0.67 (0.61–0.72) and 0.64 (0.59–0.70) in the discovery and independent validation cohort, respectively, significantly outperforming the clinical (pdiscovery = 0.02, pvalidation = 0.01) and visual signature (pdiscovery = 0.03, pvalidation = 0.01) as well as the BAT score (pdiscovery < 0.001, pvalidation < 0.001). Adding visual markers to radiomic features failed to improve prediction performance. All signatures were significantly (p < 0.001) correlated with functional outcome at 3-months, underlining their prognostic relevance. Conclusion: Radiomic features of ICH on admission non-contrast head CT can predict impending HE with stable generalizability; and combining radiomic with clinical predictors yielded the highest predictive value. By enabling selective anti-expansion treatment of patients at elevated risk of HE in future clinical trials, the proposed markers may increase therapeutic efficacy, and ultimately improve outcomes

The coronal plane maximum diameter of deep intracerebral hemorrhage predicts functional outcome more accurately than hematoma volume

Background: Among prognostic imaging variables, the hematoma volume on admission computed tomography (CT) has long been considered the strongest predictor of outcome and mortality in intracerebral hemorrhage. Aims: To examine whether different features of hematoma shape are associated with functional outcome in deep intracerebral hemorrhage. Methods: We analyzed 790 patients from the ATACH-2 trial, and 14 shape features were quantified. We calculated Spearman’s Rho to assess the correlation between shape features and three-month modified Rankin scale (mRS) score, and the area under the receiver operating characteristic curve (AUC) to quantify the association between shape features and poor outcome defined as mRS>2 as well as mRS > 3. Results: Among 14 shape features, the maximum intracerebral hemorrhage diameter in the coronal plane was the strongest predictor of functional outcome, with a maximum coronal diameter >∼3.5 cm indicating higher three-month mRS scores. The maximum coronal diameter versus hematoma volume yielded a Rho of 0.40 versus 0.35 (p = 0.006), an AUC[mRS>2] of 0.71 versus 0.68 (p = 0.004), and an AUC[mRS>3] of 0.71 versus 0.69 (p = 0.029). In multiple regression analysis adjusted for known outcome predictors, the maximum coronal diameter was independently associated with three-month mRS (p < 0.001). Conclusions: A coronal-plane maximum diameter measurement offers greater prognostic value in deep intracerebral hemorrhage than hematoma volume. This simple shape metric may expedite assessment of admission head CTs, offer a potential biomarker for hematoma size eligibility criteria in clinical trials, and may substitute volume in prognostic intracerebral hemorrhage scoring systems

Nr2e3 is a Genetic Modifier That Rescues Retinal Degeneration and Promotes Homeostasis in Multiple Models of Retinitis Pigmentosa

Recent advances in viral vector engineering, as well as an increased understanding of the cellular and molecular mechanism of retinal diseases, have led to the development of novel gene therapy approaches. Furthermore, ease of accessibility and ocular immune privilege makes the retina an ideal target for gene therapies. In this study, the nuclear hormone receptor gene Nr2e3 was evaluated for efficacy as broad-spectrum therapy to attenuate early to intermediate stages of retinal degeneration in five unique mouse models of retinitis pigmentosa (RP). RP is a group of heterogenic inherited retinal diseases associated with over 150 gene mutations, affecting over 1.5 million individuals worldwide. RP varies in age of onset, severity, and rate of progression. In addition, ~40% of RP patients cannot be genetically diagnosed, confounding the ability to develop personalized RP therapies. Remarkably, Nr2e3 administered therapy resulted in reduced retinal degeneration as observed by increase in photoreceptor cells, improved electroretinogram, and a dramatic molecular reset of key transcription factors and associated gene networks. These therapeutic effects improved retinal homeostasis in diseased tissue. Results of this study provide evidence that Nr2e3 can serve as a broad-spectrum therapy to treat multiple forms of RP

Quantifying the potential for bluetongue virus transmission in Danish cattle farms

We used a mechanistic transmission model to estimate the number of infectious bites (IBs) generated per bluetongue virus (BTV) infected host (cattle) using estimated hourly microclimatic temperatures at 22,004 Danish cattle farms for the period 2000–2016, and Culicoides midge abundance based on 1,453 light-trap collections during 2007–2016. We used a range of published estimates of the duration of the hosts’ infectious period and equations for the relationship between temperature and four key transmission parameters: extrinsic incubation period, daily vector survival rate, daily vector biting rate and host-to-vector transmission rate resulting in 147,456 combinations of daily IBs. More than 82% combinations of the parameter values predicted > 1 IBs per host. The mean IBs (10–90th percentiles) for BTV per infectious host were 59 (0–73) during the transmission period. We estimated a maximum of 14,954 IBs per infectious host at some farms, while a best-case scenario suggested transmission was never possible at some farms. The use of different equations for the vector survival rate and host-to-vector transmission rates resulted in large uncertainty in the predictions. If BTV is introduced in Denmark, local transmission is very likely to occur. Vectors infected as late as mid-September (early autumn) can successfully transmit BTV to a new host until mid-November (late autumn)

Risk practices for animal and human anthrax in Bangladesh: an exploratory study

From August 2009 to October 2010, International Centre for Diarrheal Disease Research, Bangladesh and the Institute of Epidemiology, Disease Control and Research together investigated 14 outbreaks of anthrax which included 140 animal and 273 human cases in 14 anthrax-affected villages. Our investigation objectives were to explore the context in which these outbreaks occurred, including livestock rearing practices, human handling of sick and dead animals, and the anthrax vaccination program

A realist synthesis of randomised control trials involving use of community health workers for delivering child health interventions in low and middle income countries

<p>Abstract</p> <p>Background</p> <p>A key constraint to saturating coverage of interventions for reducing the burden of childhood illnesses in Low and Middle Income Countries (LMIC) is the lack of human resources. Community health workers (CHW) are potentially important actors in bridging this gap. Evidence exists on effectiveness of CHW in management of some childhood illnesses (IMCI). However, we need to know how and when this comes to be. We examine evidence from randomized control trials (RCT) on CHW interventions in IMCI in LMIC from a realist perspective with the aim to see if they can yield insight into the working of the interventions, when examined from a different perspective.</p> <p>Methods</p> <p>The realist approach involves educing the mechanisms through which an intervention produced an outcome in a particular context. 'Mechanisms' are reactions, triggered by the interaction of the intervention and a certain context, which lead to change. These are often only implicit and are actually hypothesized by the reviewer. This review is limited to unravelling these from the RCTs; it is thus a hypothesis generating exercise.</p> <p>Results</p> <p>Interventions to improve CHW performance included 'Skills based training of CHW', 'Supervision and referral support from public health services', 'Positioning of CHW in the community'. When interventions were applied in context of CHW programs embedded in local health services, with beneficiaries who valued services and had unmet needs, the interventions worked if following mechanisms were triggered: anticipation of being valued by the community; perception of improvement in social status; sense of relatedness with beneficiaries and public services; increase in self esteem; sense of self efficacy and enactive mastery of tasks; sense of credibility, legitimacy and assurance that there was a system for back-up support. Studies also showed that if context differed, even with similar interventions, negative mechanisms could be triggered, compromising CHW performance.</p> <p>Conclusion</p> <p>The aim of this review was to explore if RCTs could yield insight into the working of the interventions, when examined from a different, a realist perspective. We found that RCTs did yield some insight, but the hypotheses generated were very general and not well refined. These hypotheses need to be tested and refined in further studies.</p