Role and Interpretation of Antifungal Susceptibility Testing for the Management of Invasive Fungal Infections.

Invasive fungal infections (IFIs) are associated with high mortality rates and timely appropriate antifungal therapy is essential for good outcomes. Emerging antifungal resistance among Candida and Aspergillus spp., the major causes of IFI, is concerning and has led to the increasing incorporation of in vitro antifungal susceptibility testing (AST) to guide clinical decisions. However, the interpretation of AST results and their contribution to management of IFIs remains a matter of debate. Specifically, the utility of AST is limited by the delay in obtaining results and the lack of pharmacodynamic correlation between minimal inhibitory concentration (MIC) values and clinical outcome, particularly for molds. Clinical breakpoints for Candida spp. have been substantially revised over time and appear to be reliable for the detection of azole and echinocandin resistance and for outcome prediction, especially for non-neutropenic patients with candidemia. However, data are lacking for neutropenic patients with invasive candidiasis and some non-albicans Candida spp. (notably emerging Candida auris). For Aspergillus spp., AST is not routinely performed, but may be indicated according to the epidemiological context in the setting of emerging azole resistance among A. fumigatus. For non-Aspergillus molds (e.g., Mucorales, Fusarium or Scedosporium spp.), AST is not routinely recommended as interpretive criteria are lacking and many confounders, mainly host factors, seem to play a predominant role in responses to antifungal therapy. This review provides an overview of the pre-clinical and clinical pharmacodynamic data, which constitute the rationale for the use and interpretation of AST testing of yeasts and molds in clinical practice

Complexity Results for Modal Dependence Logic

Modal dependence logic was introduced recently by V\"a\"an\"anen. It enhances the basic modal language by an operator =(). For propositional variables p_1,...,p_n, =(p_1,...,p_(n-1);p_n) intuitively states that the value of p_n is determined by those of p_1,...,p_(n-1). Sevenster (J. Logic and Computation, 2009) showed that satisfiability for modal dependence logic is complete for nondeterministic exponential time. In this paper we consider fragments of modal dependence logic obtained by restricting the set of allowed propositional connectives. We show that satisfibility for poor man's dependence logic, the language consisting of formulas built from literals and dependence atoms using conjunction, necessity and possibility (i.e., disallowing disjunction), remains NEXPTIME-complete. If we only allow monotone formulas (without negation, but with disjunction), the complexity drops to PSPACE-completeness. We also extend V\"a\"an\"anen's language by allowing classical disjunction besides dependence disjunction and show that the satisfiability problem remains NEXPTIME-complete. If we then disallow both negation and dependence disjunction, satistiability is complete for the second level of the polynomial hierarchy. In this way we completely classify the computational complexity of the satisfiability problem for all restrictions of propositional and dependence operators considered by V\"a\"an\"anen and Sevenster.Comment: 22 pages, full version of CSL 2010 pape

Voriconazole-associated zygomycosis: a significant consequence of evolving antifungal prophylaxis and immunosuppression practices?

AbstractMucormycosis (zygomycosis) is an uncommon infection that afflicts severely immunocompromised patients and those with poorly controlled diabetes mellitus. A recent increase in the incidence of mucormycosis at many transplant centres has been linked to the introduction and widespread use of voriconazole prophylaxis in these high-risk populations. However, it is not known if this association reflects a true epidemiological link or represents a marker of changing immunosuppression occurring in parallel with the evolution of transplant practices and immunosuppression strategies

Alloparental care in a solitary bee

Research into the evolutionary origins of sociality in insect colonies is changing emphasis from understanding how eusociality is maintained to how insects transition from solitary to social lifestyles. The pygmy carpenter bees (Ceratina spp.) offer an excellent model for investigating such factors as they have been historically thought of as solitary but have recently been shown to be socially polymorphic, which may indicate that they are currently in a transitive phase. By utilizing behavioural observation and experimental removal protocols, I show that extended parental care, as well as sibling care in Ceratina calcarata plays an important role in offspring development. I found, upon removal of the mother, that specifically produced ‘dwarf’ female offspring take over parental care roles in the nest. The existence of alloparental care and generational overlap suggests that although they are classified as solitary bees, C. calcarata possess the prerequisite behavioural repertoire for sociality

ENGINEERING AN OLEOGINOUS YEAST FOR THE PRODUCTION OF BIODIESEL

poster abstractThere are economic and social interests in replacing the current energy dependence we have on petroleum-based oleochemicals. Yarrowia lipolytica, an oleaginous yeast, has the ability to metabolize unique carbon sources, particularly hydrocarbons and to accumulate large amounts of lipids which could be developed into a source of biodiesel. The ability of Y. lipolytica to accumulate triacylglycerols in lipid droplets and the complete sequencing of its genome make Y. lipolytica a viable organism to genetically engineer for the production of large quantities of biodiesel precursors. The purpose of this project is to genetically modify Y. lipolytica to further increase its production of triacylglycerols by knocking out genes that encode enzymes involved in the β-oxidation of fatty acids. This genetic modification will be accomplished by using homologous recombination to disrupt the genes POX3-5 and POT1. The 5’ and 3’ untranslated regions of POX3-5 and POT1 were amplified by polymerase chain reaction and cloned to allow a drug resistance gene to be introduced between them. Following cloning, these genes will be knocked out from the Y. lipolytica genome using drug resistance as a marker. The disruption of these genes is expected to increase the accumulation of triacylglycerols in Y. lipolytica lipid droplets versus the wild-type. Progress towards the goals of this project will be reported

Clinical Pharmacokinetics, Pharmacodynamics, Safety and Efficacy of Liposomal Amphotericin B

Item does not contain fulltextSince its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its clinical efficacy. Since then, numerous clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preclinical and clinical setting. Nevertheless, insights into the pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound's safety. In this article, we review the clinical pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further clinical research

A study on wear evaluation of railway wheels based on multibody dynamics and wear computation

The wear evolution of railway wheels is a very important issue in railway engineering. In the past, the reprofiling intervals of railway vehicle steel wheels have been scheduled according to designers' experience. Today, more reliable and accurate tools in predicting wheel wear evolution and wheelset lifetime can be used in order to achieve economical and safety benefits. In this work, a computational tool that is able to predict the evolution of the wheel profiles for a given railway system, as a function of the distance run, is presented. The strategy adopted consists of using a commercial multibody software to study the railway dynamic problem and a purpose-built code for managing its pre- and post-processing data in order to compute the wear. The tool is applied here to realistic operation scenarios in order to assess the effect of some service conditions on the wheel wear progression

EXAMINATION OF 304 STAINLESS STEEL CLADDING FROM COLD-SWAGED AND ROLLED FUEL RODS

Samples of 304 stainless steel cladding from unirradiated fuel rods fabricated by cold swaging and tandem rolling were investigated to determine the effects of cold working. These fabrication techniques were found to produce a structure containing a large amount of slip bands. Results of tensile tests and fracture behavior observations indicate that this cladding should be adequate for boiling reactor fuel rods. (J.R.D.

A clock and wavefront mechanism for somite formation

Somitogenesis, the sequential formation of a periodic pattern along the antero-posterior axis of vertebrate embryos, is one of the most obvious examples of the segmental patterning processes that take place during embryogenesis and also one of the major unresolved events in developmental biology. In this article, we develop a mathematical formulation of a new version of the Clock and Wavefront model proposed by Pourquié and co-workers (Dubrulle, J., McGrew, M.J., Pourquié, O., 2001. FGF signalling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell 106, 219–232). Dynamic expression of FGF8 in the presomitic mesoderm constitutes the wavefront of determination which sweeps along the body axis interacting as it moves with the segmentation clock to gate cells into somites. We also show that the model can mimic the anomalies formed when progression of the wavefront is disturbed and make some experimental predictions that can be used to test the hypotheses underlying the model