Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy

There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 108 CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 108 to 109 CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae. In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates

The SED Machine: a robotic spectrograph for fast transient classification

Current time domain facilities are finding several hundreds of transient astronomical events a year. The discovery rate is expected to increase in the future as soon as new surveys such as the Zwicky Transient Facility (ZTF) and the Large Synoptic Sky Survey (LSST) come on line. At the present time, the rate at which transients are classified is approximately one order or magnitude lower than the discovery rate, leading to an increasing "follow-up drought". Existing telescopes with moderate aperture can help address this deficit when equipped with spectrographs optimized for spectral classification. Here, we provide an overview of the design, operations and first results of the Spectral Energy Distribution Machine (SEDM), operating on the Palomar 60-inch telescope (P60). The instrument is optimized for classification and high observing efficiency. It combines a low-resolution (R$\sim$100) integral field unit (IFU) spectrograph with "Rainbow Camera" (RC), a multi-band field acquisition camera which also serves as multi-band (ugri) photometer. The SEDM was commissioned during the operation of the intermediate Palomar Transient Factory (iPTF) and has already proved lived up to its promise. The success of the SEDM demonstrates the value of spectrographs optimized to spectral classification. Introduction of similar spectrographs on existing telescopes will help alleviate the follow-up drought and thereby accelerate the rate of discoveries.Comment: 21 pages, 20 figure

Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.

Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis

Building the Positive Language Classroom: A Four Strands Approach

articl

The PTF Orion Project: a Possible Planet Transiting a T-Tauri Star

We report observations of a possible young transiting planet orbiting a previously known weak-lined T-Tauri star in the 7-10 Myr old Orion-OB1a/25-Ori region. The candidate was found as part of the Palomar Transient Factory (PTF) Orion project. It has a photometric transit period of 0.448413 +- 0.000040 days, and appears in both 2009 and 2010 PTF data. Follow-up low-precision radial velocity (RV) observations and adaptive optics imaging suggest that the star is not an eclipsing binary, and that it is unlikely that a background source is blended with the target and mimicking the observed transit. RV observations with the Hobby-Eberly and Keck telescopes yield an RV that has the same period as the photometric event, but is offset in phase from the transit center by approximately -0.22 periods. The amplitude (half range) of the RV variations is 2.4 km/s and is comparable with the expected RV amplitude that stellar spots could induce. The RV curve is likely dominated by stellar spot modulation and provides an upper limit to the projected companion mass of M_p sin i_orb < 4.8 +- 1.2 M_Jup; when combined with the orbital inclination, i orb, of the candidate planet from modeling of the transit light curve, we find an upper limit on the mass of the planetary candidate of M_p < 5.5 +- 1.4 M_Jup. This limit implies that the planet is orbiting close to, if not inside, its Roche limiting orbital radius, so that it may be undergoing active mass loss and evaporation.Comment: Corrected typos, minor clarifications; minor updates/corrections to affiliations and bibliography. 35 pages, 10 figures, 3 tables. Accepted to Ap

A Rationale for a Positive Psychology-Informed Approach to Content and Language Integrated Learning

This article provides a brief introduction to the relatively new field of positive psychology and discusses its potential compatibility with a number of content topics common to language courses. The relevance of Seligman’s (2010) PERMA framework to content topics commonly found in EFL classrooms illustrates that a positive psychology-informed approach need not disrupt existing curricula and can be achieved non-controversially. Lyubomirsky’s (2005) “happiness inventory,” abridged by Helgesen (2016), provides classes of all levels a shared vocabulary to discuss behaviors shown to support well-being. The article also presents the results of successful studies examining the association between learner well-being and factors essential to academic success. Teachers are invited to experiment with the concepts of positive psychology in their classes by considering familiar content topics from the perspective of happiness research

IPAC Image Processing and Data Archiving for the Palomar Transient Factory

The Palomar Transient Factory (PTF) is a multiepochal robotic survey of the northern sky that acquires data for the scientific study of transient and variable astrophysical phenomena. The camera and telescope provide for wide-field imaging in optical bands. In the five years of operation since first light on 2008 December 13, images taken with Mould-R and SDSS-g′ camera filters have been routinely acquired on a nightly basis (weather permitting), and two different Hα filters were installed in 2011 May (656 and 663 nm). The PTF image-processing and data-archival program at the Infrared Processing and Analysis Center (IPAC) is tailored to receive and reduce the data, and, from it, generate and preserve astrometrically and photometrically calibrated images, extracted source catalogs, and co-added reference images. Relational databases have been deployed to track these products in operations and the data archive. The fully automated system has benefited by lessons learned from past IPAC projects and comprises advantageous features that are potentially incorporable into other ground-based observatories. Both off-the-shelf and in-house software have been utilized for economy and rapid development. The PTF data archive is curated by the NASA/IPAC Infrared Science Archive (IRSA). A state-of-the-art custom Web interface has been deployed for downloading the raw images, processed images, and source catalogs from IRSA. Access to PTF data products is currently limited to an initial public data release (M81, M44, M42, SDSS Stripe 82, and the Kepler Survey Field). It is the intent of the PTF collaboration to release the full PTF data archive when sufficient funding becomes available

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy