Antifungal drug resistance: does it matter?

AbstractThe objectives of this review are: to review the modes of action of currently available antifungal drugs; to define drug resistance and discuss the mechanisms by which fungi can develop resistance to antifungal drugs; to consider the epidemiological and host factors that contribute to the outcome of antifungal therapy and whether the available in vitro susceptibility test methods can reliably predict clinical response; and to assess the overall relevance of drug resistance to the outcome of fungal infections. The incidence of antifungal drug resistance among pathogens causing invasive fungal infections appears to be increasing. In the case of Candida spp., this may in part be a consequence of selective pressure brought about by more intensive antifungal use leading to a ‘pathogen shift’. Non-albicans Candida spp. are more likely to demonstrate reduced susceptibility to fluconazole compared to C. albicans. Susceptibility breakpoints developed by the National Committee for Clinical Laboratory Standards to test azoles and flucytosine against Candida spp. are helpful in guiding therapy. Antifungal drug resistance in yeasts is of clinical importance. Increasingly reliable methods of in vitro susceptibility testing can help predict clinical response to therapy, but other considerations, including host- and drug-related factors, can also have an important bearing on the ultimate outcome of treatment

Joint repair methods for cast iron natural gas distribution mains and the preliminary development of an alternative joint seal.

Approximately 10 percent of the natural gas pumped into distribution systems is unaccounted for. A significant portion of this amount is leakage from joints in 50 to 100 year old cast iron main. Because of the cumulative effects of many small leaks, these leaks must be repaired even though the repair expense is not always justified by the value of the gas conserved.Part One identifies and evaluates leak sealing techniques of the past and present by compiling available test data. A major task was to review all documented test results in journals and technical reports. This study followed-up on published articles by contacting all the individuals and organizations concerned. Recommendations for future development of an alternate sealing system are made.Part Two discusses preliminary criteria for the design of an alternative system to seal main joints from within the main without service interruption. Experiments were performed showing that very soft elastomers pressed against the rough pipe wall could prohibit leakage. Potential cleaning methods were tested. Wire and abrasive wheels, and water-jets were recommended for further development. Based on time-dependent characteristics and resistance to aging and to chemicals found in mains, fluorocarbon was recommended for use as the seal material. Preliminary design of the seal verified its feasibility. Several innovative concepts for the seal are presented. Considerations for the cleaning and sealing device and for the overal'. system are discussed

Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial

Objective To determine the efficacy of a probiotic drink containing Lactobacillus for the prevention of any diarrhoea associated with antibiotic use and that caused by Clostridium difficile. Design Randomised double blind placebo controlled study. Participants 135 hospital patients (mean age 74) taking antibiotics. Exclusions included diarrhoea on admission, bowel pathology that could result in diarrhoea, antibiotic use in the previous four weeks, severe illness, immunosuppression, bowel surgery, artificial heart valves, and history of rheumatic heart disease or infective endocarditis. Intervention Consumption of a 100 g (97 ml) drink containing Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus twice a day during a course of antibiotics and for one week after the course finished. The placebo group received a longlife sterile milkshake. Main outcome measures Primary outcome: occurrence of antibiotic associated diarrhoea. Secondary outcome: presence of C difficile toxin and diarrhoea. Results 7/57 (12%) of the probiotic group developed diarrhoea associated with antibiotic use compared with 19/56 (34%) in the placebo group (P=0.007). Logistic regression to control for other factors gave an odds ratio 0.25 (95% confidence interval 0.07 to 0.85) for use of the probiotic, with low albumin and sodium also increasing the risk of diarrhoea. The absolute risk reduction was 21.6% (6.6% to 36.6%), and the number needed to treat was 5 (3 to 15). No one in the probiotic group and 9/53 (17%) in the placebo group had diarrhoea caused by C difficile (P=0.001). The absolute risk reduction was 17% (7% to 27%), and the number needed to treat was 6 (4 to 14). Conclusion Consumption of a probiotic drink containing L casei, L bulgaricus, and S thermophilus reduce the incidence of antibiotic associated diarrhoea and C difficile associated diarrhoea. This has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50

Heterogeneous Quantal Response Equilibrium and Cognitive Hierarchies

We explore an equilibrium model of games where players’ choice behavior is given by logit response functions, but their payoff responsiveness is heterogeneous. We extend the definition of quantal response equilibrium to this setting, calling it heterogeneous quantal response equilibrium (HQRE), and prove existence under weak conditions. We generalize HQRE to allow for limited insight, in which players can only imagine others with low responsiveness. We identify a formal connection between this new equilibrium concept, called truncated quantal response equilibrium (TQRE), and the Cognitive Hierarchy (CH) model. We show that CH can be approximated arbitrarily closely by TQRE. We report a series of experiments comparing the performance of QRE, HQRE, TQRE and CH. A surprise is that the fi of the models are quite close across a variety of matrix and dominance-solvable asymmetric information betting games. The key link is that in the QRE approaches, strategies with higher expected payoffs are chosen more often than strategies with lower expected payoff. In CH this property is not built into the model, but generally holds true in the experimental data

Polarization and Charge Transfer in the Hydration of Chloride Ions

A theoretical study of the structural and electronic properties of the chloride ion and water molecules in the first hydration shell is presented. The calculations are performed on an ensemble of configurations obtained from molecular dynamics simulations of a single chloride ion in bulk water. The simulations utilize the polarizable AMOEBA force field for trajectory generation, and MP2-level calculations are performed to examine the electronic structure properties of the ions and surrounding waters in the external field of more distant waters. The ChelpG method is employed to explore the effective charges and dipoles on the chloride ions and first-shell waters. The Quantum Theory of Atoms in Molecules (QTAIM) is further utilized to examine charge transfer from the anion to surrounding water molecules. From the QTAIM analysis, 0.2 elementary charges are transferred from the ion to the first-shell water molecules. The default AMOEBA model overestimates the average dipole moment magnitude of the ion compared with the estimated quantum mechanical value. The average magnitude of the dipole moment of the water molecules in the first shell treated at the MP2 level, with the more distant waters handled with an AMOEBA effective charge model, is 2.67 D. This value is close to the AMOEBA result for first-shell waters (2.72 D) and is slightly reduced from the bulk AMOEBA value (2.78 D). The magnitude of the dipole moment of the water molecules in the first solvation shell is most strongly affected by the local water-water interactions and hydrogen bonds with the second solvation shell, rather than by interactions with the ion.Comment: Slight revision, in press at J. Chem. Phy

Precise Particle Tracking Against a Complicated Background: Polynomial Fitting with Gaussian Weight

We present a new particle tracking software algorithm designed to accurately track the motion of low-contrast particles against a background with large variations in light levels. The method is based on a polynomial fit of the intensity around each feature point, weighted by a Gaussian function of the distance from the centre, and is especially suitable for tracking endogeneous particles in the cell, imaged with bright field, phase contrast or fluorescence optical microscopy. Furthermore, the method can simultaneously track particles of all different sizes, and allows significant freedom in their shape. The algorithm is evaluated using the quantitative measures of accuracy and precision of previous authors, using simulated images at variable signal-to-noise ratios. To these we add a new test of the error due to a non-uniform background. Finally the tracking of particles in real cell images is demonstrated. The method is made freely available for non-commencial use as a software package with a graphical user-inferface, which can be run within the Matlab programming environment

Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design

In apparent contrast to its invasive potential Staphylococcus aureus colonizes the anterior nares of 20–80% of the human population. The relationship between host and microbe appears particularly individualized and colonization status seems somehow predetermined. After decolonization, persistent carriers often become re-colonized with their prior S. aureus strain, whereas non-carriers resist experimental colonization. Efforts to identify factors facilitating colonization have thus far largely focused on the microorganism rather than on the human host. The host responds to S. aureus nasal colonization via local expression of anti-microbial peptides, lipids, and cytokines. Interplay with the co-existing microbiota also influences colonization and immune regulation. Transient or persistent S. aureus colonization induces specific systemic immune responses. Humoral responses are the most studied of these and little is known of cellular responses induced by colonization. Intriguingly, colonized patients who develop bacteremia may have a lower S. aureus-attributable mortality than their non-colonized counterparts. This could imply a staphylococcal-specific immune “priming” or immunomodulation occurring as a consequence of colonization and impacting on the outcome of infection. This has yet to be fully explored. An effective vaccine remains elusive. Anti-S. aureus vaccine strategies may need to drive both humoral and cellular immune responses to confer efficient protection. Understanding the influence of colonization on adaptive response is essential to intelligent vaccine design, and may determine the efficacy of vaccine-mediated immunity. Clinical trials should consider colonization status and the resulting impact of this on individual patient responses. We urgently need an increased appreciation of colonization and its modulation of host immunity

The Effect of Walking an Unfamiliar Versus Companion Dog on Mood, Exercise Enjoyment, and Heart Rate: A Pilot Field Study

Topics in Exercise Science and Kinesiology Volume 2: Issue 1, Article 3, 2021. Background: Walking unfamiliar dogs, such as therapy dogs, has been shown to improve physiological exercise responses and exercise adherence, but whether walking a companion dog results in superior benefits is currently unknown. The purpose of the current pilot field study was to elucidate preliminary evidence of how walking an unfamiliar or companion dog influences mood, exercise enjoyment, and heart rate during a 1.5-mile walk. Methods: Participants (n=8) walked 1.5-miles at their own pace with an unfamiliar or companion dog while mood, exercise enjoyment, and heart rate were measured. Point of application #1: Walking an unfamiliar dog resulted in improved pre- to post- exercise mood changes compared to walking their own companion dog. Point of application #2: Enjoyment of exercise was higher while walking the unfamiliar dog compared to the companion dog. Point of application #3: Mean exercise heart rate was significantly higher while walking the unfamiliar versus companion dog although time to completion of the 1.5-miles was unaffected