Treatment of invasive fungal infections in clinical practice: a multi-centre survey on customary dosing, treatment indications, efficacy and safety of voriconazole

Invasive fungal infections are frequent and often deadly complications in patients with malignant hematological diseases. Voriconazole is a third generation triazole antifungal with broad activity against most clinically relevant fungal pathogens. Clinical practice often deviates from insights gained from controlled randomized trials. We conducted a multi-centre survey to evaluate efficacy, safety, treatment indications and dosing of voriconazole outside clinical trials. Patients receiving voriconazole were documented via electronic data capturing. An analysis was conducted after submission of 100 episodes from September 2004 to November 2005. Voriconazole was administered for suspected or proven invasive fungal infection (IFI) (57%), as empirical treatment in patients with fever of unknown origin (21%) and secondary (19%) as well as primary (3%) prophylaxis of IFI. Investigators’ assessment of fungal infection often diverted from EORTC/MSG 2002 criteria. A favorable response was reported in 61.4% for suspected or proven IFI and 52.4% for empirical treatment. Mortality was 15%, 26.7% of which was attributable to IFI. Breakthrough fungal infections occurred in four (21.1%) patients with voriconazole as secondary prophylaxis. Toxicity and adverse events comprised elevated liver enzymes and visual disturbances. Although indications frequently deviated from clinical evidence and legal approval, voriconazole showed efficacy and safety, comparable to major controlled clinical trials. Data from this survey demonstrate the difficulty of putting drugs to their approved use in IFI

MRI atlas of a lizard brain

Magnetic resonance imaging (MRI) is an established technique for neuroanatomical analysis, being particularly useful in the medical sciences. However, the application of MRI to evolutionary neuroscience is still in its infancy. Few magnetic resonance brain atlases exist outside the standard model organisms in neuroscience and no magnetic resonance atlas has been produced for any reptile brain. A detailed understanding of reptilian brain anatomy is necessary to elucidate the evolutionary origin of enigmatic brain structures such as the cerebral cortex. Here, we present a magnetic resonance atlas for the brain of a representative squamate reptile, the Australian tawny dragon (Agamidae: Ctenophorus decresii), which has been the subject of numerous ecological and behavioral studies. We used a high-field 11.74T magnet, a paramagnetic contrasting-enhancing agent and minimum-deformation modeling of the brains of thirteen adult male individuals. From this, we created a high-resolution three-dimensional model of a lizard brain. The 3D-MRI model can be freely downloaded and allows a better comprehension of brain areas, nuclei, and fiber tracts, facilitating comparison with other species and setting the basis for future comparative evolution imaging studies. The MRI model and atlas of a tawny dragon brain (Ctenophorus decresii) can be viewed online and downloaded using the Wiley Biolucida Server at wiley.biolucida.net.Government of Australia, Grant/Award Numbers: APA#31/2011, IPRS#1182/2010; National Science and Engineering Research Council of Canada, Grant/Award Number: PGSD3-415253-2012; Quebec Nature and Technology Research Fund, Grant/AwardNumber: 208332; National Imaging Facility of Australia; Spanish Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional, Grant/Award Number:BFU2015-68537-

Observation-based modeling of ozone chemistry in the Seoul metropolitan area during the Korea-United States Air Quality Study (KORUS-AQ)

The Seoul Metropolitan Area (SMA) has a population of 24 million and frequently experiences unhealthy levels of ozone (O3). In this work, measurements taken during the Korea-United States Air Quality Study (KORUS-AQ, 2016) are used to explore regional gradients in O3 and its chemical precursors, and an observationally-constrained 0-D photochemical box model is used to quantify key aspects of O3 production including its sensitivity to precursor gases. Box model performance was evaluated by comparing modeled concentrations of select secondary species to airborne measurements. These comparisons indicate that the steady state assumption used in 0-D box models cannot describe select intermediate species, highlighting the importance of having a broad suite of trace gases as model constraints. When fully constrained, aggregated statistics of modeled O3 production rates agreed with observed changes in O3, indicating that the box model was able to represent the majority of O3 chemistry. Comparison of airborne observations between urban Seoul and a downwind receptor site reveal a positive gradient in O3 coinciding with a negative gradient in NOx, no gradient in CH2O, and a slight positive gradient in modeled rates of O3 production. Together, these observations indicate a radical-limited (VOC-limited) O3 production environment in the SMA. Zero-out simulations identified C7+ aromatics as the dominant VOC contributors to O3 production, with isoprene and anthropogenic alkenes making smaller but appreciable contributions. Simulations of model sensitivity to decreases in NOx produced results that were not spatially uniform, with large increases in O3 production predicted for urban Seoul and decreases in O3 production predicted for far-outlying areas. The policy implications of this work are clear: Effective O3 mitigation strategies in the SMA must focus on reducing local emissions of C7+ aromatics, while reductions in NOx emissions may increase O3 in some areas but generally decrease the regional extent of O3 exposure

Atmospheric Acetaldehyde: Importance of Air-Sea Exchange and a Missing Source in the Remote Troposphere.

We report airborne measurements of acetaldehyde (CH3CHO) during the first and second deployments of the National Aeronautics and Space Administration (NASA) Atmospheric Tomography Mission (ATom). The budget of CH3CHO is examined using the Community Atmospheric Model with chemistry (CAM-chem), with a newly-developed online air-sea exchange module. The upper limit of the global ocean net emission of CH3CHO is estimated to be 34 Tg a-1 (42 Tg a-1 if considering bubble-mediated transfer), and the ocean impacts on tropospheric CH3CHO are mostly confined to the marine boundary layer. Our analysis suggests that there is an unaccounted CH3CHO source in the remote troposphere and that organic aerosols can only provide a fraction of this missing source. We propose that peroxyacetic acid (PAA) is an ideal indicator of the rapid CH3CHO production in the remote troposphere. The higher-than-expected CH3CHO measurements represent a missing sink of hydroxyl radicals (and halogen radical) in current chemistry-climate models

Plasma-photonic spatiotemporal synchronization of relativistic electron and laser beams

Modern particle accelerators and their applications increasingly rely on precisely coordinated interactions of intense charged particle and laser beams. Femtosecond-scale synchronization alongside micrometre-scale spatial precision are essential e.g. for pump-probe experiments, seeding and diagnostics of advanced light sources and for plasma-based accelerators. State-of-the-art temporal or spatial diagnostics typically operate with low-intensity beams to avoid material damage at high intensity. As such, we present a plasma-based approach, which allows measurement of both temporal and spatial overlap of high-intensity beams directly at their interaction point. It exploits amplification of plasma afterglow arising from the passage of an electron beam through a laser-generated plasma filament. The corresponding photon yield carries the spatiotemporal signature of the femtosecond-scale dynamics, yet can be observed as a visible light signal on microsecond-millimetre scales

Segmentation of the C57BL/6J mouse cerebellum in magnetic resonance images

The C57BL mouse is the centerpiece of efforts to use gene-targeting technology to understand cerebellar pathology, thus creating a need for a detailed magnetic resonance imaging (MRI) atlas of the cerebellum of this strain. In this study we present a methodology for systematic delineation of the vermal and hemispheric lobules of the C57BL/6J mouse cerebellum in magnetic resonance images. We have successfully delineated 38 cerebellar and cerebellar-related structures. The higher signal-to-noise ratio achieved by group averaging facilitated the identification of anatomical structures. In addition, we have calculated average region volumes and created probabilistic maps for each structure. The segmentation method and the probabilistic maps we have created will provide a foundation for future studies of cerebellar disorders using transgenic mouse models

Comparative Analysis of Inflammatory Cytokine Release and Alveolar Epithelial Barrier Invasion in a Transwell® Bilayer Model of Mucormycosis

Understanding the mechanisms of early invasion and epithelial defense in opportunistic mold infections is crucial for the evaluation of diagnostic biomarkers and novel treatment strategies. Recent studies revealed unique characteristics of the immunopathology of mucormycoses. We therefore adapted an alveolar Transwell® A549/HPAEC bilayer model for the assessment of epithelial barrier integrity and cytokine response to Rhizopus arrhizus, Rhizomucor pusillus, and Cunninghamella bertholletiae. Hyphal penetration of the alveolar barrier was validated by 18S ribosomal DNA detection in the endothelial compartment. Addition of dendritic cells (moDCs) to the alveolar compartment led to reduced fungal invasion and strongly enhanced pro-inflammatory cytokine response, whereas epithelial CCL2 and CCL5 release was reduced. Despite their phenotypic heterogeneity, the studied Mucorales species elicited the release of similar cytokine patterns by epithelial and dendritic cells. There were significantly elevated lactate dehydrogenase concentrations in the alveolar compartment and epithelial barrier permeability for dextran blue of different molecular weights in Mucorales-infected samples compared to Aspergillus fumigatus infection. Addition of monocyte-derived dendritic cells further aggravated LDH release and epithelial barrier permeability, highlighting the influence of the inflammatory response in mucormycosis-associated tissue damage. An important focus of this study was the evaluation of the reproducibility of readout parameters in independent experimental runs. Our results revealed consistently low coefficients of variation for cytokine concentrations and transcriptional levels of cytokine genes and cell integrity markers. As additional means of model validation, we confirmed that our bilayer model captures key principles of Mucorales biology such as accelerated growth in a hyperglycemic or ketoacidotic environment or reduced epithelial barrier invasion upon epithelial growth factor receptor blockade by gefitinib. Our findings indicate that the Transwell® bilayer model provides a reliable and reproducible tool for assessing host response in mucormycosis

An Observationally Constrained Evaluation of the Oxidative Capacity in the Tropical Western Pacific Troposphere

Hydroxyl radical (OH) is the main daytime oxidant in the troposphere and determines the atmospheric lifetimes of many compounds. We use aircraft measurements of O3, H2O, NO, and other species from the Convective Transport of Active Species in the Tropics (CONTRAST) field campaign, which occurred in the tropical western Pacific (TWP) during January–February 2014, to constrain a photochemical box model and estimate concentrations of OH throughout the troposphere. We find that tropospheric column OH (OHCOL) inferred from CONTRAST observations is 12 to 40% higher than found in chemical transport models (CTMs), including CAM-chem-SD run with 2014 meteorology as well as eight models that participated in POLMIP (2008 meteorology). Part of this discrepancy is due to a clear-sky sampling bias that affects CONTRAST observations; accounting for this bias and also for a small difference in chemical mechanism results in our empirically based value of OHCOL being 0 to 20% larger than found within global models. While these global models simulate observed O3 reasonably well, they underestimate NOx (NO + NO2) by a factor of two, resulting in OHCOL ~30% lower than box model simulations constrained by observed NO. Underestimations by CTMs of observed CH3CHO throughout the troposphere and of HCHO in the upper troposphere further contribute to differences between our constrained estimates of OH and those calculated by CTMs. Finally, our calculations do not support the prior suggestion of the existence of a tropospheric OH minimum in the TWP, because during January–February 2014 observed levels of O3 and NO were considerably larger than previously reported values in the TWP