Efficacy and Safety of Meropenem\u2013Vaborbactam Versus Best Available Therapy for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Patients Without Prior Antimicrobial Failure: A Post Hoc Analysis

open5siIntroduction: Infections due to Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are associated with increased morbidity and high mortality. Meropenem–vaborbactam (MV) is a novel β-lactam/β-lactamase inhibitor combination active against KPC-producing Enterobacteriaceae. The aim of this post hoc analysis of the TANGO-II randomized controlled trial was to assess the efficacy of MV versus best available therapy (BAT) in the subgroup of patients without prior antimicrobial failure. Methods: The primary outcome measure was clinical cure at the test of cure (TOC). Secondary outcome measures included (1) clinical cure at the end of therapy (EOT), (2) microbiological cure at TOC, (3) microbiological cure at EOT, and (4) 28-day all-cause mortality. Results: First-line MV was associated with a 42.9% absolute increase in clinical cure rate at TOC (95% confidence intervals [CI] 13.7–72.1) in comparison with first-line BAT. A 49.3% absolute increase in clinical cure rate at EOT (95% CI 20.8–77.7), a 42.6% absolute increase in microbiological cure rate at EOT (95% CI 13.4–71.8), and a 36.2% absolute increase in microbiologic cure rate at TOC (95% CI 5.9–66.6) were also observed, in addition to a 29.0% absolute reduction in mortality (95% CI − 54.3 to − 3.7). Overall, fewer adverse events were observed in the MV group than in the BAT group. Conclusion: MV was superior to BAT in the subgroup of patients with serious carbapenem-resistant Enterobacteriaceae (CRE) infections and no prior antimicrobial failure, with very high rates of clinical success, and was well tolerated. Post approval and real-world studies remain essential to clearly define the most appropriate population for early, empirical MV coverage, in accordance with antimicrobial stewardship principles. Funding: The Medicines Company.openBassetti M.; Giacobbe D.R.; Patel N.; Tillotson G.; Massey J.Bassetti, M.; Giacobbe, D. R.; Patel, N.; Tillotson, G.; Massey, J

Processing Irradiated Beryllium For Disposal

The purpose of this research was to develop a process for decontaminating irradiated beryllium that will allow it to be disposed of through normal radwaste channels. Thus, the primary objectives of this ongoing study are to remove the transuranic (TRU) isotopes to less than 100 nCi/g and remove {sup 60}Co, and {sup 137}Cs, to levels that will allow the beryllium to be contact handled. One possible approach that appears to have the most promise is aqueous dissolution and separation of the isotopes by selected solvent extraction followed by precipitation, resulting in a granular form for the beryllium that may be fixed to prevent it from becoming respirable and therefore hazardous. Beryllium metal was dissolved in nitric and fluorboric acids. Isotopes of {sup 241}Am, {sup 239}Pu, {sup 85}Sr, and {sup 137}Cs were then added to make a surrogate beryllium waste solution. A series of batch contacts was performed with the spiked simulant using chlorinated cobalt dicarbollide (CCD) and polyethylene glycol diluted with sulfone to extract the isotopes of Cs and Sr. Another series of batch contacts was performed using a combination of octyl (phenyl)-N,N-diisobutylcarbamoylmethylphosphine oxide (CMPO) in tributyl phosphate (TBP) diluted with dodecane for extracting the isotopes of Pu and Am. The results indicate that greater than 99.9% removal can be achieved for each isotope with only three contact stages

Foods advertised in US weekly supermarket sales circulars over one year: a content analysis

BACKGROUND: The nutritional content of Americans’ shopping carts is suboptimal despite federal dietary guidance, in this case, the MyPlate consumer icon which displays desired proportions of vegetables, fruits, dairy, grains and protein foods for consumption. Consumers mention print advertising—such as weekly sales circulars—frequently as influencing their grocery shopping decisions. METHODS: To examine and describe the relative proportions of advertised foods aggregated into the MyPlate food grouping system, a content analysis of 9 209 foods advertised in 52 weekly supermarket newspaper sales inserts in 2009 from a local grocery chain was conducted in a Midwestern community. RESULTS: Overall, the protein foods group was most often represented in sales circulars (25% of total items), followed by grains (18%); dairy (10%); vegetables (8%) and fruits (7%). Less than 3% of sales advertisements were for dark green and red & orange vegetables. Over twice as much whole fruit versus 100% fruit juice was advertised (70% vs. 30%, respectively; P < 0.001). Significantly fewer protein foods and more grains than expected were advertised in the fall, and slightly more dark green vegetables were advertised in winter and spring than in summer and fall (P = 0.05). CONCLUSIONS: The average American diet, including underconsumption of fruits and vegetables but overconsumption of protein foods, was reflected in the relative frequency of food groups advertised in weekly sales circulars. Modifying sales circulars to represent healthier food groups may preserve retail profits (considering these groups’ higher profit margin) while promoting adherence to federal dietary guidance

Actinide partitioning studies using dihexyl-N,N-diethycarbamolymehtyl phosphonate and dissolved zirconium calcine

A baseline flowsheet capable of partitioning the transuranic (TRU) elements from dissolved zirconium calcines has been developed. The goal of the TRU partitioning process is to remove the TRUs from solutions of dissolved zirconium calcines to below the 10 CFR 61.55 Class A waste limit of 10 nCi/g. Extraction, scrub, strip, and wash distribution coefficients for several elements, including the actinides, were measured in the laboratory by performing equal volume batch contacts. A solvent containing diheyl-N, N- diethylcarbamoylmethyl phosphonate (CMP), tributylphosphate (TBP), and a branched chain hydrocarbon as the diluent were used to develop this process. A non-radioactive zirconium pilot-plant calcine was spiked with the TRUs, U, Tc, or a radioactive isotope of zirconium to simulate the behavior of these elements in actual dissolved zirconium calcine feed. Distribution coefficient data obtained from laboratory testing were used to recommend: (1) solvent composition, (2) scrub solutions capable of selectively removing extracted zirconium while minimizing actinide recycle, (3) optimized strip solutions which quantitatively recover extracted actinides, and (4) feed adjustments necessary for flowsheet efficiency. Laboratory distribution coefficients were used in conjunction with the Generic TRUEX Model (GTM) to develop and recommend a flowsheet for testing in the 5.5-cm Centrifugal Contractor Mockup. GTM results indicate that the recommended flowsheet should remove the actinides from dissolved zirconium calcine feed to below the Class A waste limit of 10 nCi/g. Less than 0.01 wt% of the extracted zirconium will report to the high- activity waste (HAW) fraction using the 0.05 M H{sub 2}C{sub 2}O{sub 4} in 3.0 M HNO{sub 3} scrub, and greater than 99% of the extracted actinides are recovered with 0.001 M HEDPA

Separation of Minor Actinides from Lanthanides by Dithiophosphinic Acid Extractants

The selective extraction of the minor actinides (Am(III) and Cm(III)) from the lanthanides is an important part of advanced reprocessing of spent nuclear fuel. This separation would allow the Am/Cm to be fabricated into targets and recycled to a reactor and the lanthanides to be dispositioned. This separation is difficult to accomplish due to the similarities in the chemical properties of the trivalent actinides and lanthanides. Research efforts at the Idaho National Laboratory have identified an innovative synthetic pathway yielding new regiospecific dithiophosphinic acid (DPAH) extractants. The synthesis provides DPAH derivatives that can address the issues concerning minor actinide separation and extractant stability. For this work, two new symmetric DPAH extractants have been prepared. The use of these extractants for the separation of minor actinides from lanthanides will be discussed

DIAMIDE DERIVATIVES OF DIPICOLINIC ACID AS ACTINIDE AND LANTHANIDE EXTRACTANTS IN A VARIATION OF THE UNEX PROCESS

The Universal Extraction (UNEX) process has been developed for simultaneous extraction of cesium, strontium, and actinides from acidic solutions. This process utilizes an extractant consisting of 0.08 M chlorinated cobalt dicarbollide (HCCD), 0.007-0.02 M polyethylene glycol (PEG-400), and 0.02 M diphenyl-N,N-di-n-butylcarbamoylmethylphosphine oxide (Ph2CMPO) in the diluent trifluoromethylphenyl sulfone (CF3C6H5SO2, designated FS-13) and provides simultaneous extraction of Cs, Sr, actinides, and lanthanides from HNO3 solutions. The UNEX process is of limited utility for processing acidic solutions containing large quantities of lanthanides and/or actinides, such as dissolved spent nuclear fuel solutions. These constraints are primarily attributed to the limited concentrations of CMPO (a maximum of ~0.02 M) in the organic phase and limited solubility of the CMPO-metal complexes. As a result, alternative actinide and lanthanide extractants are being investigated for use with HCCD as an improvement for waste processing and for applications where higher concentrations of the metals are present. Our preliminary results indicate that diamide derivatives of dipicolinic acid may function as efficient actinide and lanthanide extractants. The results to be presented indicate that, of the numerous diamides studied to date, the tetrabutyldiamide of dipicolinic acid, TBDPA, shows the most promise as an alternative actinide/lanthanide extractant in the UNEX process

PI3K-δ and PI3K-γ Inhibition by IPI-145 Abrogates Immune Responses and Suppresses Activity in Autoimmune and Inflammatory Disease Models

SummaryPhosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases