Communications Biophysics

Contains reports on four research projects.National Institutes of Health (Grant 1 P01 GM-14940-02)Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DA 28-043-AMC-02536(E)National Institutes of Health (Grant 5 TO1 GM-01555-02

Increased UV transmission by improving the manufacturing process for FS

ABSTRACT Optical designers have been designing ultraviolet (UV) systems at wavelengths in the UV region for many years. With increasing demand for deep UV applications, special considerations that are not applicable to traditional visible optics must be taken to produce the optics. Specifically as the wavelength of incident light decreases, the importance of very smooth surfaces increases. The intent of this project is to increase the performance of UV optics in a four-phase project. The first phase consists of characterizing sub-surface damage using destructive methods to enable process control, the second phase (presented here) focuses on polishing methods, the third phase will include cleaning and possible etching protocols and the fourth phase will be improving thin film coating performance. Keywords: Ultraviolet, fused silica, polishing, coating INTRODUCTION As trends in UV optical system design shift to shorter UV wavelengths, optical manufacturing has to be more conscious of the effect that subsurface damage, surface features, residual contamination from polishing and cleaning and coating have on the residual performance of the optics in their systems. For many years, researchers have tackled partial aspects of these problems. For example, Bloembergen 1 stated that cracks and pores on an optical surface will lead to laser damage (LD) when incident with a laser beam. Neauport et al. 2 spoke to two of the main damage initiators of LD, sub-surface damage (SSD) and nano-absorbing centers, focusing mainly on the latter. They used fused silica optics in high power laser applications at 351nm. Higher cerium concentration on the surfaces strongly correlated with increased damage density. Aluminum, copper and iron did not have similar correlations. Neauport et al. also tried to correlate the presence of cerium with damage morphology but the results were inconclusive. Yoshiyama et al. 3 studied the effects of polishing, etching, cleaving and water leaching on the UV damage of fused silica. The surfaces were all exposed to a Nd:YAG laser at 355nm. Micropits were found on the polished surface. Their analysis found high concentrations of Al, B, Ce and Zr. The concentrations of the Al, B and Zr all decreased rapidly to less than 10% of the maximum value at a depth of 50nm, but the Ce required ~100nm before decreasing to less than 10% of its maximum value. A second sample etched with a buffered HF solution had a lower pit density than the polished surface. The pit density decreased exponentially with the etched layer thickness indicating that the cerium is a precursor to laser damage. Micropits found on the cleaved surface indicated that cerium contamination is not the only cause of damage. It is hypothesized that damage initiated because of residual stresses and permanent mechanical damage from the cleaving process. Hydrolyzed cleaved surfaces were found to decrease the laser damage threshold. Camp et al. 4 determined that the zirconia conventionally polished surfaces have a higher laser damage threshold at 355nm compared to ceria polished surfaces. They also observed that damage typically centered around scratches or digs on the surface of the parts. Néauport et al

Communications Biophysics

Contains research objectives and reports on two research projects.National Institutes of Health (Grant 2 PO1 GM-14941-01)Joint Services Electronics Programs (U. S. Army, U.S. Navy, and U.S. Air Force) under Contract DA 28-043-AMC-02536(E)National Aeronautics and Space Administration (Grant NsG-496)National Institutes of Health (Grant 2 RO1 NB-05462-04)National Institutes of Health (Grant 1 TO1 GM-01555-01

Communications Biophysics

Contains research objectives, summary of research and reports on two research projects.National Institutes of Health (Grant 5 PO1 GM-14940-02)Joint Services Electronics Programs (U. S. Army, U.S. Navy, and U. S. Air Force) under Contract DA 28-043-AMC-02536(E)National Aeronautics and Space Administration (Grant NGL 22-009-304)National Institutes of Health (Grant 5 TO1 GM-01555-02)National Institutes of Health (Grant NB-08082-01

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients

Introduction: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. Methods: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Results: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. Conclusion: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. Trial registration: ClinicalTrials.gov NCT02058316. Registered 20 January 2014

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin.

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs

Inhaled Voriconazole for Prevention of Invasive Pulmonary Aspergillosis▿

Targeted airway delivery of antifungals as prophylaxis against invasive aspergillosis may lead to high lung drug concentrations while avoiding toxicities associated with systemically administered agents. We evaluated the effectiveness of aerosolizing the intravenous formulation of voriconazole as prophylaxis against invasive pulmonary aspergillosis caused by Aspergillus fumigatus in an established murine model. Inhaled voriconazole significantly improved survival and limited the extent of invasive disease, as assessed by histopathology, compared to control and amphotericin B treatments

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs