PK-guided switch between standard half-life and extended half-life factor VII products

P117 Introduction: Extended half-life (EHL) factor VIII (FVIII) requires improvements in half-life (t1/2) & area under the curve (AUC) of 1.3 & 1.25 times compared to standard half-life (SHL) products. The aim of this study is compare pharmacokinetics (PK) after the switch from SHL to EHL in patients with hemophilia A (HA). Methods: Multicenter comparative, cross-sectional, prospective study analyzing PK differences after switch from SHL to EHL (ef-moroctocog alfa [rFVIII-Fc] & rurioctocog alfa pegol [PEG-rFVIII]). WAPPS- Hemo® was used to analyze PK parameters with 2-3 samples: t1/2; AUC, peak level (PL); trough level at 24, 48 & 72 hours (TL24, TL48, TL72); & time to reach FVIII levels of 1, 2, 5% (T1%, T2%, T5%). Ratio of t1/2 & AUC, the number of weekly doses & the dose/kg/week before & after the switch were compared. Wilcoxon & Kruskal-Wallis tests (SPSS®) were used to compare the PK parameters. Results: Eightythree patients from 8 Spanish hospitals were analyzed (62 rFVIII-Fc; 21 PEG-rFVIII), 79 had severe HA & 4 moderate HA. Median age was 30 years (range = 3-64) & no differences in weight were observed between both periods.Dose/kg/week & weekly infusion frequency were reduced after the switch to EHL, & significant improvements were observed in all PK parameters after the change from SHL to EHL (Table 1). The median ratios of t1/2 & AUC were 1.3 (IQR:1.2-1.6) and 1.6 (IQR:1.3-2.2) in the entire cohort. In patients with =12 years ratios of t1/2 & AUC were 1.4 (IQR:1.3-1.6) & 1.7 (IQR:1.3-2.3), and in the cohort of 16 patients <12 years treated with rFVIII-Fc were 1.3 (IQR:0.9-1.5) and 1.4 (IQR:1.1- 2.1).After the switch to EHL, median weekly dose frequency (30%, IQR:0-33.3%) & dose/kg/week (16.9%, IQR:8.7-32.8%) were reduced. In a small subset of 15 younger patients the dose/kg/week was increased a median of 28.6% (IQR:11.7-40-7%). No differences were observed in any of the PK parameters & median ratios of t1/2 & AUC in patients aged =12 years treated with rFVIII-Fc vs. PEG-rFVIII (46 rFVIII-Fc; 21 PEG-rFVIII). Discussion/Conclusion: EHL FVIII have shown significant PK improvements in clinical real practice, allowing to reduce weekly infusion number & dose/kg/week. Outside the clinical trial setting, we have observed an increase in t1/2 & AUC ratios accordingly to EHL definition. Comparisons regarding clinical outcomes (bleeding rate after switch) will be performed after a follow-up of 1 year with EHL for the full cohort

MAGIC observations of very high energy gamma-rays from HESS J1813-178

Recently, the HESS collaboration has reported the detection of gamma-ray emission above a few hundred GeV from eight new sources located close to the Galactic Plane. The source HESS J1813-178 has sparked particular interest, as subsequent radio observations imply an association with SNR G12.82-0.02. Triggered by the detection in VHE gamma-rays, a positionally coincident source has also been found in INTEGRAL and ASCA data. In this Letter we present MAGIC observations of HESS J1813-178, resulting in the detection of a differential gamma-ray flux consistent with a hard-slope power law, described as dN/(dA dt dE) = (3.3+/-0.5)*10^{-12} (E/TeV)^{-2.1+/-0.2} cm^(-2)s^(-1)TeV^(-1). We briefly discuss the observational technique used, the procedure implemented for the data analysis, and put this detection in the perspective of multifrequency observations.Comment: Accepted by ApJ Letter

Discovery of Very High Energy gamma-rays from 1ES 1011+496 at z=0.212

We report on the discovery of Very High Energy (VHE) gamma-ray emission from the BL Lacertae object 1ES1011+496. The observation was triggered by an optical outburst in March 2007 and the source was observed with the MAGIC telescope from March to May 2007. Observing for 18.7 hr we find an excess of 6.2 sigma with an integrated flux above 200 GeV of (1.58$\pm0.32) 10^{-11}$ photons cm$^{-2}$ s$^{-1}$. The VHE gamma-ray flux is >40% higher than in March-April 2006 (reported elsewhere), indicating that the VHE emission state may be related to the optical emission state. We have also determined the redshift of 1ES1011+496 based on an optical spectrum that reveals the absorption lines of the host galaxy. The redshift of z=0.212 makes 1ES1011+496 the most distant source observed to emit VHE gamma-rays up to date.Comment: 4 pages, 6 figures, minor changes to fit the ApJ versio

Discovery of Very High Energy γ\gamma-Rays from Markarian~180 Triggered by an Optical Outburst

The high-frequency-peaked BL Lacertae object Markarian~180 (Mrk~180) was observed to have an optical outburst in 2006 March, triggering a Target of Opportunity observation with the MAGIC telescope. The source was observed for 12.4 hr and very high energy $\gamma$-ray emission was detected with a significance of 5.5 $\sigma$. An integral flux above 200 GeV of $(2.3\pm0.7)\times10^{-11} {cm}^{-2} {s}^{-1}$ was measured, corresponding to 11% of the Crab Nebula flux. A rather soft spectrum with a photon index of $-3.3\pm0.7$ has been determined. No significant flux variation was found.Comment: Accepted by ApJ Letters, minor revision

Purification of artichoke polyphenols by using membrane filtration and polymeric resins

The present study aimed at evaluating the potential of an integrated process based on the use of membrane technology and adsorbent resins for the recovery, concentration and purification of phenolic compounds from artichoke wastewaters. In particular, artichoke wastewaters coming from the blanching step were pre-treated by ultrafiltration (UF) in order to remove suspended solids and macromolecular compounds. The UF permeate was submitted to a nanofiltration (NF) process producing a concentrated fraction enriched in phenolic and sugar compounds. Three different macroporous resins were tested through adsorption/desorption methods to produce purified phenolic fractions with high antioxidant activity. Samples produced in UF, NF and adsorption desorption tests were assayed for phenolic composition (chlorogenic acid and apigenin 7-O-glucoside), sugar composition (fructose, glucose and sucrose) and antioxidant activity. Among the three different tested resins, the S 7968 offered the best performance in terms of adsorption/desorption ratio for chlorogenic acid, with a total adsorption/desorption yield (TADY) of 63.39%; for the apigenin 7-O-glucoside the S 7968 and the S 2328 resins showed a TADY in the range 68.31-78.45%. (c) 2015 Elsevier B.V. All rights reserved.Authors acknowledge the Vicerrectorado de Investigacion of the "Universitat Politecnica de Valencia" for the financial support (project 1965) from the call "Proyectos de Nuevas Lineas de Investigacion Mul-tidisciplinares (PAID05-11)".Conidi, C.; Rodríguez López, AD.; Garcia-Castello, EM.; Cassano, A. (2015). Purification of artichoke polyphenols by using membrane filtration and polymeric resins. Separation and Purification Technology. 144(1):153-161. https://doi.org/10.1016/j.seppur.2015.02.025S153161144

Distinguishing between lepton number violating scalars at the LHC

Scalars with lepton number violating interactions decaying into lepton pairs, as those mediating the see-saw of type II, always include doubly-charged components. If these are observed at the LHC, their electroweak quantum numbers can be determined through their leptonic decays in pair and single production.This work has been supported in part by the Ministry of Economy and Competitiveness (MINECO), under the grant numbers FPA2006-05294, FPA2010-17915 and FPA2011- 23897, by the Junta de Andalucía grants FQM 101 and FQM 6552, by the “Generalitat Valenciana” grant PROMETEO/2009/128, and by the U.S. Department of Energy grant No. DE-FG03-94ER40837. M.C. is supported by the MINECO under the FPU program

International lower limb collaborative (INTELLECT) study: a multicentre, international retrospective audit of lower extremity open fractures

Trauma remains a major cause of mortality and disability across the world1, with a higher burden in developing nations2. Open lower extremity injuries are devastating events from a physical3, mental health4, and socioeconomic5 standpoint. The potential sequelae, including risk of chronic infection and amputation, can lead to delayed recovery and major disability6. This international study aimed to describe global disparities, timely intervention, guideline-directed care, and economic aspects of open lower limb injuries

Stem cell‐derived enteroid cultures as a tool for dissecting host‐parasite interactions in the small intestinal epithelium.

Toxoplasma gondii and Cryptosporidium spp. can cause devastating pathological effects in humans and livestock, and in particular to young or immunocompromised individuals. The current treatment plans for these enteric parasites are limited due to long drug courses, severe side effects, or simply a lack of efficacy. The study of the early interactions between the parasites and the site of infection in the small intestinal epithelium has been thwarted by the lack of accessible, physiologically relevant, and species-specific models. Increasingly, 3D stem cell-derived enteroid models are being refined and developed into sophisticated models of infectious disease. In this review we shall illustrate the use of enteroids to spearhead research into enteric parasitic infections, bridging the gap between cell line cultures and in vivo experiments

Biogenesis and Dynamics of Mitochondria during the Cell Cycle: Significance of 3′UTRs

Nowadays, we are facing a renaissance of mitochondria in cancer biology. However, our knowledge of the basic cell biology and on the timing and mechanisms that control the biosynthesis of mitochondrial constituents during progression through the cell cycle of mammalian cells remain largely unknown. Herein, we document the in vivo changes on mitochondrial morphology and dynamics that accompany cellular mitosis, and illustrate the following key points of the biogenesis of mitochondria during progression of liver cells through the cycle: (i) the replication of nuclear and mitochondrial genomes is synchronized during cellular proliferation, (ii) the accretion of OXPHOS proteins is asynchronously regulated during proliferation being the synthesis of β-F1-ATPase and Hsp60 carried out also at G2/M and, (iii) the biosynthesis of cardiolipin is achieved during the S phase, although full development of the mitochondrial membrane potential (ΔΨm) is attained at G2/M. Furthermore, we demonstrate using reporter constructs that the mechanism regulating the accretion of β-F1-ATPase during cellular proliferation is controlled at the level of mRNA translation by the 3′UTR of the transcript. The 3′UTR-driven synthesis of the protein at G2/M is essential for conferring to the daughter cells the original phenotype of the parental cell. Our findings suggest that alterations on this process may promote deregulated β-F1-ATPase expression in human cancer