An intact signal peptide on dengue virus E protein enhances immunogenicity for CD8+ T cells and antibody when expressed from modified vaccinia Ankara

Dengue is a global public health concern and this is aggravated by a lack of vaccines or antiviral therapies. Despite the well-known role of CD8(+) T cells in the immunopathogenesis of Dengue virus (DENV), only recent studies have highlighted the importance of this arm of the immune response in protection against the disease. Thus, the majority of DENV vaccine candidates are designed to achieve protective titers of neutralizing antibodies, with less regard for cellular responses. Here, we used a mouse model to investigate CD8(+) T cell and humoral responses to a set of potential DENV vaccines based on recombinant modified vaccinia virus Ankara (rMVA). To enable this study, we identified two CD8(+) T cell epitopes in the DENV-3 E protein in C57BL/6 mice. Using these we found that all the rMVA vaccines elicited DENV-specific CD8(+) T cells that were cytotoxic in vivo and polyfunctional in vitro. Moreover, vaccines expressing the E protein with an intact signal peptide sequence elicited more DENV-specific CD8(+) T cells than those expressing E proteins in the cytoplasm. Significantly, it was these same ER-targeted E protein vaccines that elicited antibody responses. Our results support the further development of rMVA vaccines expressing DENV E proteins and add to the tools available for dengue vaccine development.Parts of this work were supported by the InstitutoNacional de Ciência e Tecnologia de Vacinas–INCTV (National Insti-tute of Science and Technology of Vaccines) and by a FAPEMIGPPM grant (CBB, PPM-00461-11). BRQ was a CAPES/PDSE fellow-ship recipient (8815-11-9). FGF is a CNPq fellowship recipient. DCTis an ARC Future Fellow (FT110100310)

Technology for large-scale translation of clinical practice guidelines : a pilot study of the performance of a hybrid human and computer-assisted approach

Background: The construction of EBMPracticeNet, a national electronic point-of-care information platform in Belgium, was initiated in 2011 to optimize quality of care by promoting evidence-based decision-making. The project involved, among other tasks, the translation of 940 EBM Guidelines of Duodecim Medical Publications from English into Dutch and French. Considering the scale of the translation process, it was decided to make use of computer-aided translation performed by certificated translators with limited expertise in medical translation. Our consortium used a hybrid approach, involving a human translator supported by a translation memory (using SDL Trados Studio), terminology recognition (using SDL Multiterm termbases) from medical termbases and support from online machine translation. This has resulted in a validated translation memory which is now in use for the translation of new and updated guidelines. Objective: The objective of this study was to evaluate the performance of the hybrid human and computer-assisted approach in comparison with translation unsupported by translation memory and terminology recognition. A comparison was also made with the translation efficiency of an expert medical translator. Methods: We conducted a pilot trial in which two sets of 30 new and 30 updated guidelines were randomized to one of three groups. Comparable guidelines were translated (a) by certificated junior translators without medical specialization using the hybrid method (b) by an experienced medical translator without this support and (c) by the same junior translators without the support of the validated translation memory. A medical proofreader who was blinded for the translation procedure, evaluated the translated guidelines for acceptability and adequacy. Translation speed was measured by recording translation and post-editing time. The Human Translation Edit Rate was calculated as a metric to evaluate the quality of the translation. A further evaluation was made of translation acceptability and adequacy. Results: The average number of words per guideline was 1,195 and the mean total translation time was 100.2 min/1,000 words. No meaningful differences were found in the translation speed for new guidelines. The translation of updated guidelines was 59 min/1,000 words faster (95% CI 2-115; P=.044) in the computer-aided group. Revisions due to terminology accounted for one third of the overall revisions by the medical proofreader. Conclusions: Use of the hybrid human and computer-aided translation by a non-expert translator makes the translation of updates of clinical practice guidelines faster and cheaper because of the benefits of translation memory. For the translation of new guidelines there was no apparent benefit in comparison with the efficiency of translation unsupported by translation memory (whether by an expert or non-expert translator

Health Literacy and Patient Reported Outcomes in Orthopaedic Surgery Patients

Background: Health literacy may be an important factor in patient health outcomes, however, prior research has primarily focused on primary care patients with research in orthopaedic specific populations lacking. Questions/purposes: The purpose of this study was to examine the relationship between health literacy and patient reported outcomes in an orthopaedic patient population. Patients and Methods: 183 patients \u3e18 years of age who presented to our institution’s sports orthopaedic surgery clinic with shoulder or knee complaints were analyzed. The primary outcomes were physical function recorded using Patient-Reported Outcomes Measurement Information System (PROMIS) physical function and Single Assessment Numerical Evaluation (SANE) scores. Health literacy was determined utilizing Health LiTT, a self-administered multimedia touchscreen test based on item response theory that provides a numerical score of 0-100 with a score \u3e50 suggestive of health literacy. In addition, demographic data including age, race, gender, highest level of education, injury location, and surgery status were collected. Results: Bivariate analysis revealed that low health literacy (Health LiTT score Conclusions: Our data showed that PROMIS scores are less reliant on health literacy and more dependent on age, employment status, having surgery and low education level achieved. Adaptations to clinical practice may be necessary to better guide these select populations and improve patient-reported physical function. Furthermore, PROMIS measures can be administered successfully to patients regardless of health literacy. Level of Evidence: Level I

Perfect-information games with lower-semicontinuous payoffs

We prove that every multiplayer perfect-information game with bounded and lower-semicontinuous payoffs admits a subgame-perfect epsilon-equilibrium in pure strategies. This result complements Example 3 in Solan and Vieille [Solan, E., N. Vieille. 2003. Deterministic multi-player Dynkin games. J. Math. Econom. 39 911-929], which shows that a subgame-perfect epsilon-equilibrium in pure strategies need not exist when the payoffs are not lower-semicontinuous. In addition, if the range of payoffs is finite, we characterize in the form of a Folk Theorem the set of all plays and payoffs that are induced by subgame-perfect 0-equilibria in pure strategies

Pharmacokinetics of Pamidronate in Patients With Bone Metastases

Background: Pamidronate is a secondgeneration bisphosphonate used in the treatment of tumor-induced hypercalcemia and in the management of bone metastases from breast cancer, myeloma, or prostate cancer. The pharmacokinetics of pamidronate is unknown in cancer patients. Purpose: To determine the influence of the rate of administration and of bone metabolism, we studied the pharmacokinetics of pamidronate at three different infusion rates in 37 patients with bone metastases. Methods: Three groups of 11-14 patients were given 60 mg pamidronate as an intravenous infusion over a period of 1, 4, or 24 hours. Urine samples were collected in the three groups of patients. Plasma samples were obtained only in the 1-hour infusion group. The assay of pamidronate in plasma and urine was performed by high-performance liquid chromatography with fluorescence detection after the derivatization of pamidronate with fluorescamine. Results: The body retention (BR) at 0-24 hours of pamidronate represented 60%-70% of the administered dose and was not significantly modified by the infusion rate. In particular, the BR at 0-24 hours was not reduced at the fastest infusion rate. Among patients, a threefold variability in BR at 0-24 hours occurred, which was related directly to the number of bone metastases and, to some extent, to creatinine clearance. At 60 mg/hour, the plasma kinetics followed a multiexponential course characterized by a short distribution phase. The mean (±SD) half-life of the distribution phase was 0.8 hour (±0.3), the mean (±SD) of the area under the curve for drug concentration in plasma × time at 0-24 hours was 22.0 × 8.8 μmol/L × hours, and the mean (±SD) of the maximum plasma concentration was 9.7 μmol/L (±3.2). Pharmacokinetic variables remained unchanged after repeated infusions applied to four patients. Clinically, the three infusion rates were equally well tolerated without significant toxicity. Conclusions: The 1-hour infusion rate could be proposed as kinetically appropriate for the administration of pamidronate to patients with metastatic bone diseases. [J Natl Cancer Inst 84: 788-792, 1992

Electronic Structure Calculations with LDA+DMFT

The LDA+DMFT method is a very powerful tool for gaining insight into the physics of strongly correlated materials. It combines traditional ab-initio density-functional techniques with the dynamical mean-field theory. The core aspects of the method are (i) building material-specific Hubbard-like many-body models and (ii) solving them in the dynamical mean-field approximation. Step (i) requires the construction of a localized one-electron basis, typically a set of Wannier functions. It also involves a number of approximations, such as the choice of the degrees of freedom for which many-body effects are explicitly taken into account, the scheme to account for screening effects, or the form of the double-counting correction. Step (ii) requires the dynamical mean-field solution of multi-orbital generalized Hubbard models. Here central is the quantum-impurity solver, which is also the computationally most demanding part of the full LDA+DMFT approach. In this chapter I will introduce the core aspects of the LDA+DMFT method and present a prototypical application.Comment: 21 pages, 7 figures. Chapter of "Many-Electron Approaches in Physics, Chemistry and Mathematics: A Multidisciplinary View", eds. V. Bach and L. Delle Site, Springer 201

NGC 3628: Ejection Activity Associated with Quasars

NGC3628 is a well-studied starburst/low level AGN galaxy in the Leo Triplet noted for its extensive outgassed plumes of neutral hydrogen. QSOs are shown to be concentrated around NGC3628 and aligned with the HI plumes. The closest high redshift quasar has z=2.15 and is at the tip of an X-ray filament emerging along the minor axis HI plume. Location at this point has an accidental probability of ~2x10^-4. In addition a coincident chain of optical objects coming out along the minor axis ends on this quasar. More recent measures on a pair of strong X-ray sources situated at 3.2 and 5.4 arcmin on either side of NGC3628 along its minor axis, reveal that they have nearly identical redshifts of z=0.995 and 0.981. The closer quasar lies directly in the same X-ray filament which extends from the nucleus out 4.1 arcmin to end on the quasar of z=2.15. The chain of objects SW along the minor axis of NGC3628 has been imaged in four colors with the VLT. Images and spectra of individual objects within the filament are reported. It is suggested that material in various physical states and differing intrinsic redshifts is ejected out along the minor axis of this active, disturbed galaxy.Comment: 8 pages, 5 figures. Accepted for publication in A&A. Postscript file including full resolution figures at http://www.eso.org/~fpatat/ngc3628/paper_ngc3628.ps.g

Moderate Champagne consumption promotes an acute improvement in acute endothelial-independent vascular function in healthy human volunteers

Epidemiological studies have suggested an inverse correlation between red wine consumption and the incidence of CVD. However, Champagne wine has not been fully investigated for its cardioprotective potential. In order to assess whether acute and moderate Champagne wine consumption is capable of modulating vascular function, we performed a randomised, placebo-controlled, cross-over intervention trial. We show that consumption of Champagne wine, but not a control matched for alcohol, carbohydrate and fruit-derived acid content, induced an acute change in endothelium-independent vasodilatation at 4 and 8 h post-consumption. Although both Champagne wine and the control also induced an increase in endothelium-dependent vascular reactivity at 4 h, there was no significant difference between the vascular effects induced by Champagne or the control at any time point. These effects were accompanied by an acute decrease in the concentration of matrix metalloproteinase (MMP-9), a significant decrease in plasma levels of oxidising species and an increase in urinary excretion of a number of phenolic metabolites. In particular, the mean total excretion of hippuric acid, protocatechuic acid and isoferulic acid were all significantly greater following the Champagne wine intervention compared with the control intervention. Our data suggest that a daily moderate consumption of Champagne wine may improve vascular performance via the delivery of phenolic constituents capable of improving NO bioavailability and reducing matrix metalloproteinase activity

Correlation of Fermi-LAT sources with the AT20GHz radio survey

We cross correlate the Fermi 11 months survey catalogue (1FGL) with the 20 GHz Australia Telescope Compact Array radio survey catalogue (AT20G) composed by 5890 sources at declination <0 deg. Among the 738 Fermi sources distributed in the southern sky we find 230 highly probable candidate counterparts in the AT20G survey. Of these, 222 are already classified as blazars (176 of known type and 46 of unknown optical class) in the Fermi 1-year LAT AGN Catalogue (1LAC) and 8 are new associations. By studying the gamma-ray and radio properties of these associations we find a strong correlation between the gamma-ray flux (above 100 MeV) and the 20 GHz flux density. This correlation is more than 3 sigma statistically significant both for the population of BL Lacs and of FSRQ considered separately. We also find that the radio counterparts associated to the Fermi sources have on average flat radio spectra between 5 and 20 GHz and that Fermi gamma-ray sources are not preferentially associated with "ultra inverted spectrum" radio sources. For 2 of the 8 new associations we build the broad band spectral energy distribution combining Fermi, Swift and radio observations. One of these two sources is identified with the high redshift FSRQ Swift J1656.3-3302 (z=2.4) and we classify the other source as a candidate new FSRQ. We also study the brightest radio source of the 46 associations without an optical classification and classify it as a new BL Lac candidate "twin" of the prototypical BL Lac OJ 287 if its redshift is somewhat larger, z~0.4.Comment: 12 pages, 10 figures, 3 tables. Submitted to MNRAS on the 22nd March 2010

Nonadiabatic Dynamics of Ultracold Fermions in Optical Superlattices

We study the time-dependent dynamical properties of two-component ultracold fermions in a one-dimensional optical superlattice by applying the adaptive time-dependent density matrix renormalization group to a repulsive Hubbard model with an alternating superlattice potential. We clarify how the time evolution of local quantities occurs when the superlattice potential is suddenly changed to a normal one. For a Mott-type insulating state at quarter filling, the time evolution exhibits a profile similar to that expected for bosonic atoms, where correlation effects are less important. On the other hand, for a band-type insulating state at half filling, the strong repulsive interaction induces an unusual pairing of fermions, resulting in some striking properties in time evolution, such as a paired fermion co-tunneling process and the suppression of local spin moments. We further address the effect of a confining potential, which causes spatial confinement of the paired fermions.Comment: 4 pages, 5 figure