IGNITE4 : Results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections

Funding Information: Financial support. This work was supported by Tetraphase Pharmaceuticals Inc. Funding Information: Potential conflicts of interest. J. S. S. has received support from Tetraphase Pharmaceuticals Inc. during the production of this manuscript and has served as a consultant to Merck, Pfizer, GlaxoSmithKline, and Melinta outside of the submitted work. A. S received support from Tetraphase Pharmaceuticals Inc. during the production of this manuscript. J. G. received research funding from Tetraphase Pharmaceuticals Inc. for his role as principal investigator of this study. K. L. and L. T. are employed by Tetraphase Pharmaceuticals Inc. D. E. reports grants from Tetraphase Pharmaceuticals Inc. during the conduct of the study and grants from Merck outside of the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Publisher Copyright: © 2018 The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.Background: Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae. Methods: IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated. Results: Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively. Conclusions: Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens. Clinical Trials Registration: NCT01844856.publishersversionPeer reviewe

Трупоспалення чернелів-руського черняхівського могильника

Розглянуто матеріали комплексів із кремаціями чернелів-руського могильника черняхівської культури.В статье рассмотрены материалы комплексов с кремациями чернелив-русского могильника черняховской культуры (Западное Подолье), который относится к категории могильников с доминированием ингумаций, что выделяет его среди биритуальных могильников черняховской культуры. Из 288 исследованных погребений черняховской культуры — только две кремации (погребения 44 и 240), что составляет менее 1 % погребений могильника. Кроме того, в могильнике выявлены ритуально нарушенные ингумации, в заполнении могильных ям которых зафиксированы остатки кремаций, что, возможно, связано с сожжением эксгумированных частей этих ингумаций.The article views the materials from the assemblages with cremations in the burial ground Cherneliv-Rus of Chernyakhivska culture (Western Podillya). Cherneliv-Rus burial ground belongs to the category of burial grounds with inhumation prevailed and stands out against the biritual burial grounds of Chernyakhivska culture. There are only two cremations among 288 excavated burials of Chernyakhivska culture (burials 44 and 240). It comprises less than 1% of burials on the burial ground. The latter includes also ritually disturbed inhumations with the remains of cremations in the fi ll of burial pits, which could be related with the burning of exhumated parts of these inhumations

Altering the Expression in Mice of Genes by Modifying Their 3′ Regions

Polymorphic differences altering expression of genes without changing their products probably underlie human quantitative traits affecting risks of serious diseases, but methods for investigating such quantitative differences in animals are limited. Accordingly, we have developed a procedure for changing the expression in mice of chosen genes over a 100-fold range while retaining their chromosomal location and transcriptional controls. To develop the procedure, we first dissected the effects in embryonic stem (ES) cells of elements within and downstream of the 3' untranslated region (UTR) of a single copy transgene at the Hprt locus. As expected, protein expression varied with the steady-state level and half-life of the mRNA. The rank order of expression with various tested 3' regions is the same in ES cells, and in cardiomyocytes and trophoblastocytes derived from them. In mice having two functionally different native genes with modified 3'UTRs, the desired expression was obtained

Early-stage Fundraising of University Spin-offs: A Study through Demand-site Perspectives

University spin-offs have increasingly received attention from academia, governments and policy-makers. However, there are only a limited number of studies which fully understand the contribution made by the founding team to fundraising, specifically how they use their social networks and capabilities, especially within the university spin-off context. Employing a resource-based view theory and social networks approach, this paper examines whether a founding team exploits its social networks and capabilities to signal the value of a university spin-off. Capabilities are analysed through a set of constructs - technology, strategy, human capital, organizational viability and commercial resource - that have been derived from previous literature. The contribution made by social networks is evaluated using three dimensions - structure, governance and content - which form the construct of relationships within a network. Based on data from 181 university spin-offs in Spain, this paper empirically demonstrates that by exploiting social networks a founding team can improve its capabilities which, in turn, enhance its fundraising ability

Compositional analysis of extracellular aggregates in the eyes of patients with exfoliation syndrome and exfoliation glaucoma

Purpose: Exfoliation syndrome (XFS) is a condition characterized by the production of insoluble fibrillar aggregates (exfoliation material; XFM) in the eye and elsewhere. Many patients with XFS progress to exfoliation glaucoma (XFG), a significant cause of global blindness. We used quantitative mass spectrometry to analyze the composition of XFM in lens capsule specimens and in aqueous humor (AH) samples from patients with XFS, patients with XFG and unaffected individuals. Methods: Pieces of lens capsule and samples of AH were obtained with consent from patients undergoing cataract surgery. Tryptic digests of capsule or AH were analyzed by high-performance liquid chromatography-mass spectrometry and relative differences between samples were quantified using the tandem mass tag technique. The distribution of XFM on the capsular surface was visualized by SEM and super-resolution light microscopy. Results: A small set of proteins was consistently upregulated in capsule samples from patients with XFS and patients with XFG, including microfibril components fibrillin-1, latent transforming growth factor-β-binding protein-2 and latent transforming growth factor-β-binding protein-3. Lysyl oxidase-like 1, a cross-linking enzyme associated with XFS in genetic studies, was an abundant XFM constituent. Ligands of the transforming growth factor-β superfamily were prominent, including LEFTY2, a protein best known for its role in establishing the embryonic body axis. Elevated levels of LEFTY2 were also detected in AH from patients with XFG, a finding confirmed subsequently by ELISA. Conclusions: This analysis verified the presence of suspected XFM proteins and identified novel components. Quantitative comparisons between patient samples revealed a consistent XFM proteome characterized by strong expression of fibrillin-1, lysyl oxidase-like-1, and LEFTY2. Elevated levels of LEFTY2 in the AH of patients with XFG may serve as a biomarker for the disease

The Wide-field Infrared Survey Explorer (WISE): Mission Description and Initial On-orbit Performance

The all sky surveys done by the Palomar Observatory Schmidt, the European Southern Observatory Schmidt, and the United Kingdom Schmidt, the InfraRed Astronomical Satellite and the 2 Micron All Sky Survey have proven to be extremely useful tools for astronomy with value that lasts for decades. The Wide-field Infrared Survey Explorer is mapping the whole sky following its launch on 14 December 2009. WISE began surveying the sky on 14 Jan 2010 and completed its first full coverage of the sky on July 17. The survey will continue to cover the sky a second time until the cryogen is exhausted (anticipated in November 2010). WISE is achieving 5 sigma point source sensitivities better than 0.08, 0.11, 1 and 6 mJy in unconfused regions on the ecliptic in bands centered at wavelengths of 3.4, 4.6, 12 and 22 microns. Sensitivity improves toward the ecliptic poles due to denser coverage and lower zodiacal background. The angular resolution is 6.1, 6.4, 6.5 and 12.0 arc-seconds at 3.4, 4.6, 12 and 22 microns, and the astrometric precision for high SNR sources is better than 0.15 arc-seconds.Comment: 22 pages with 19 included figures. Updated to better match the accepted version in the A

Enzymatic Primer-Extension with Glycerol-Nucleoside Triphosphates on DNA Templates

selection. Template-dependent GNA synthesis is essential to any GNA-based selection system.In this study, we investigated the ability of various DNA polymerases to use glycerol-nucleoside triphosphates (gNTPs) as substrates for GNA synthesis on DNA templates. Therminator DNA polymerase catalyzes quantitative primer-extension by the incorporation of two glyceronucleotides, with much less efficient extension up to five glyceronucleotides. Steady-state kinetic experiments suggested that GNA synthesis by Therminator was affected by both decreased catalytic rates and weakened substrate binding, especially for pyrimidines. In an attempt to improve pyrimidine incorporation by providing additional stacking interactions, we synthesized two new gNTP analogs with 5-propynyl substituted pyrimidine nucleobases. This led to more efficient incorporation of gC, but not gT.We suggest that directed evolution of Therminator might lead to mutants with improved substrate binding and catalytic efficiency

Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28