Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study

Background Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens. Methods REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18–90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5–21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7–10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643. Findings Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6–94·7] of 154 patients) and best available therapy (135 [91%; 85·9–95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam. Interpretation These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa. Funding AstraZeneca

A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia

Ceftazidime/avibactam comprises the broad-spectrum cephalosporin ceftazidime and the non-β-lactam β-lactamase inhibitor avibactam. This phase 3, randomised, double-blind study (NCT01726023) assessed the efficacy and safety of ceftazidime/avibactam plus metronidazole compared with meropenem in patients with complicated intra-abdominal infection (cIAI) in Asian countries. Subjects aged 18–90 years and hospitalised with cIAI requiring surgical intervention were randomised 1:1 to receive every 8 h either: ceftazidime/avibactam (2000/500 mg, 2-h infusion) followed by metronidazole (500 mg, 60-min infusion); or meropenem (1000 mg, 30-min infusion). Non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was concluded if the lower limit of the 95% confidence interval (CI) for the between-group difference in clinical cure rate was greater than −12.5% at the test-of-cure (TOC) visit (28–35 days after randomisation) in the clinically evaluable (CE) population. Safety was also evaluated. Of 441 subjects randomised, 432 received at least one dose of study medication (ceftazidime/avibactam plus metronidazole, n = 215; meropenem, n = 217). In the CE population at the TOC visit, non-inferiority of ceftazidime/avibactam plus metronidazole to meropenem was demonstrated, with clinical cure reported for 93.8% (166/177) and 94.0% (173/184) of subjects, respectively (between-group difference, −0.2, 95% CI −5.53 to 4.97). The clinical cure rate with ceftazidime/avibactam plus metronidazole was comparable in subjects with ceftazidime-non-susceptible and ceftazidime-susceptible isolates (95.7% vs. 92.1%, respectively). Adverse events were similar between the study groups. Ceftazidime/avibactam plus metronidazole was non-inferior to meropenem in the treatment of cIAIs in Asian populations and was effective against ceftazidime-non-susceptible pathogens. No new safety concerns were identified

Tight-binding g-Factor Calculations of CdSe Nanostructures

The Lande g-factors for CdSe quantum dots and rods are investigated within the framework of the semiempirical tight-binding method. We describe methods for treating both the n-doped and neutral nanostructures, and then apply these to a selection of nanocrystals of variable size and shape, focusing on approximately spherical dots and rods of differing aspect ratio. For the negatively charged n-doped systems, we observe that the g-factors for near-spherical CdSe dots are approximately independent of size, but show strong shape dependence as one axis of the quantum dot is extended to form rod-like structures. In particular, there is a discontinuity in the magnitude of g-factor and a transition from anisotropic to isotropic g-factor tensor at aspect ratio ~1.3. For the neutral systems, we analyze the electron g-factor of both the conduction and valence band electrons. We find that the behavior of the electron g-factor in the neutral nanocrystals is generally similar to that in the n-doped case, showing the same strong shape dependence and discontinuity in magnitude and anisotropy. In smaller systems the g-factor value is dependent on the details of the surface model. Comparison with recent measurements of g-factors for CdSe nanocrystals suggests that the shape dependent transition may be responsible for the observations of anomalous numbers of g-factors at certain nanocrystal sizes.Comment: 15 pages, 6 figures. Fixed typos to match published versio

Asymptotic expansions for renewal measures in the plane

Let P be a distribution in the plane and define the renewal measure R=ΣP *n where * denotes convolution. The main results of this paper are three term asymptotic expansions for R far from the origin. As an application, expansions are obtained for distributions in linear boundary crossing problems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47655/1/440_2004_Article_BF00348749.pd

Isospin Asymmetry in Nuclei and Neutron Stars

The roles of isospin asymmetry in nuclei and neutron stars are investigated using a range of potential and field-theoretical models of nucleonic matter. The parameters of these models are fixed by fitting the properties of homogeneous bulk matter and closed-shell nuclei. We discuss and unravel the causes of correlations among the neutron skin thickness in heavy nuclei, the pressure of beta-equilibrated matter at a density of 0.1 fm$^{-3}$, the derivative of the nuclear symmetry energy at the same density and the radii of moderate mass neutron stars. Constraints on the symmetry properties of nuclear matter from the binding energies of nuclei are examined. The extent to which forthcoming neutron skin measurements will further delimit the symmetry properties is investigated. The impact of symmetry energy constraints for the mass and moment of inertia contained within neutron star crusts and the threshold density for the nucleon direct Urca process, all of which are potentially measurable, is explored. We also comment on the minimum neutron star radius, assuming that only nucleonic matter exists within the star.Comment: 49 pages, 17 figures, Phys. Rep. (in press); made improvements to "RAPR" and corrected transition densitie

A Case-Based Approach to Cross Domain Sentiment Classification

This paper considers the task of sentiment classification of subjective text across many domains, in particular on scenarios where no in-domain data is available. Motivated by the more general applicability of such methods, we propose an extensible approach to sentiment classification that leverages sentiment lexicons and out-of-domain data to build a case-based system where solutions to past cases are reused to predict the sentiment of new documents from an unknown domain. In our approach the case representation uses a set of features based on document statistics, while the case solution stores sentiment lexicons employed on past predictions allowing for later retrieval and reuse on similar documents. The case-based nature of our approach also allows for future improvements since new lexicons and classification methods can be added to the case base as they become available. On a cross domain experiment our method has shown robust results when compared to a baseline single-lexicon classifier where the lexicon has to be pre-selected for the domain in question

Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial

Background: Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE). Methods: Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7-14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21-25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than -12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96). Findings: Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference -4·2% [95% CI -10·8 to 2·5] ). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference -0·7% [95% CI -7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related. Interpretation: Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens. Funding: AstraZeneca

An Evaluation Framework and Adaptive Architecture for Automated Sentiment Detection

Analysts are often interested in how sentiment towards an organization, a product or a particular technology changes over time. Popular methods that process unstructured textual material to automatically detect sentiment based on tagged dictionaries are not capable of fulfilling this task, even when coupled with part-of-speech tagging, a standard component of most text processing toolkits that distinguishes grammatical categories such as article, noun, verb, and adverb. Small corpus size, ambiguity and subtle incremental change of tonal expressions between different versions of a document complicate sentiment detection. Parsing grammatical structures, by contrast, outperforms dictionary-based approaches in terms of reliability, but usually suffers from poor scalability due to its computational complexity. This work provides an overview of different dictionary- and machine-learning-based sentiment detection methods and evaluates them on several Web corpora. After identifying the shortcomings of these methods, the paper proposes an approach based on automatically building Tagged Linguistic Unit (TLU) databases to overcome the restrictions of dictionaries with a limited set of tagged tokens

Cetacean <i>Morbillivirus</i>: Current knowledge and future directions

We review the molecular and epidemiological characteristics of cetacean morbillivirus (CeMV) and the diagnosis and pathogenesis of associated disease, with six different strains detected in cetaceans worldwide. CeMV has caused epidemics with high mortality in odontocetes in Europe, the USA and Australia. It represents a distinct species within the Morbillivirus genus. Although most CeMV strains are phylogenetically closely related, recent data indicate that morbilliviruses recovered from Indo-Pacific bottlenose dolphins (Tursiops aduncus), from Western Australia, and a Guiana dolphin (Sotalia guianensis), from Brazil, are divergent. The signaling lymphocyte activation molecule (SLAM) cell receptor for CeMV has been characterized in cetaceans. It shares higher amino acid identity with the ruminant SLAM than with the receptors of carnivores or humans, reflecting the evolutionary history of these mammalian taxa. In Delphinidae, three amino acid substitutions may result in a higher affinity for the virus. Infection is diagnosed by histology, immunohistochemistry, virus isolation, RT-PCR, and serology. Classical CeMV-associated lesions include bronchointerstitial pneumonia, encephalitis, syncytia, and lymphoid depletion associated with immunosuppression. Cetaceans that survive the acute disease may develop fatal secondary infections and chronic encephalitis. Endemically infected, gregarious odontocetes probably serve as reservoirs and vectors. Transmission likely occurs through the inhalation of aerosolized virus but mother to fetus transmission was also reported