Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study

Background

Therapeutic drug monitoring (TDM) aims to minimize the clinical impact of posaconazole and voriconazole pharmacokinetic variability. However, its benefits on clinical outcomes are still being defined. Additionally, TDM data are limited for posaconazole IV and delayed-release tablet formulations among specific patient populations, including critically ill. The aim of this study was to determine the percentage of therapeutic posaconazole and voriconazole drug levels across all formulations in a real-world clinical setting and elucidate factors affecting attainment of target concentrations.

Methods

This study was a retrospective cohort study conducted at the University of Colorado Hospital between September 2006 and June 2015 that evaluated patients who received posaconazole or voriconazole TDM as part of routine care.

Results

Voriconazole (n = 250) and posaconazole (n = 100) levels were analyzed from 151 patients. Of these, 54% of voriconazole and 69% of posaconazole levels were therapeutic. For posaconazole, 14/38 (37%), 28/29 (97%) and 27/33 (82%) levels were therapeutic for the oral suspension, IV, and delayed-release tablet, respectively. Intravenous and delayed-release tablet posaconazole were 20 fold (p < 0.01) and sevenfold (p = 0.002) more likely than the oral suspension to achieve a therapeutic level. Subsequent levels were more likely to be therapeutic after dose adjustments (OR 3.31; 95% CI 1.3–8.6; p = 0.02), regardless of timing of initial non-therapeutic level. In a multivariable logistic regression analysis, no characteristics were independently predictive of therapeutic voriconazole levels and only absence of H2RA/PPI use was independently predictive of therapeutic posaconazole levels. There was no correlation between survival and therapeutic drug levels for either voriconazole (p = 0.67) or posaconazole (p = 0.50).

Conclusions

A high percentage of drug levels did not achieve TDM targets for voriconazole and posaconazole oral suspension, supporting the need for routine TDM for those formulations. The utility of TDM for the IV and delayed-release tablet formulations of posaconazole is less apparent.

     

Local and landscape scale determinants of macroinvertebrate assemblages and their conservation value in ponds across an urban land-use gradient

Urbanisation represents a growing threat to natural communities across the globe. Small aquatic habitats such as ponds are especially vulnerable and are often poorly protected by legislation. Many ponds are threatened by development and pollution from the surrounding landscape, yet their biodiversity and conservation value remain poorly described. Here we report the results of a survey of 30 ponds along an urban land-use gradient in the West Midlands, UK. We outline the environmental conditions of these urban ponds to identify which local and landscape scale environmental variables determine the biodiversity and conservation value of the macroinvertebrate assemblages in the ponds. Cluster analysis identified four groups of ponds with contrasting macroinvertebrate assemblages reflecting differences in macrophyte cover, nutrient status, riparian shading, the nature of the pond edge, surrounding land-use and the availability of other wetland habitats. Pond conservation status varied markedly across the sites. The richest macroinvertebrate assemblages with high conservation value were found in ponds with complex macrophyte stands and floating vegetation with low nutrient concentrations and little surrounding urban land. The most impoverished assemblages were found in highly urban ponds with hard-engineered edges, heavy shading and nutrient rich waters. A random forest classification model revealed that local factors usually had primacy over landscape scale factors in determining pond conservation value, and constitute a priority focus for management.     

Pseudo-nitzschia pungens (Bacillariophyceae): A cosmopolitan diatom species?

Genetic, reproductive and morphological variation were studied in 193 global strains of the marine diatom species Pseudo-nitzschia pungens (Grunow ex Cleve) Hasle to assess potential intraspecific variation and biogeographic distribution patterns. Genetic differentiation between allo- and sympatric strains was investigated using the ITS1–5.8S–ITS2 rDNA region. Three ITS clades were found. Clones of opposite mating type were sexually compatible within clades I or II, and viable F1 hybrid offspring were produced in crosses between them. The molecular differences between these clades were correlated with slight but consistent morphological differences. At present, nothing can be said about morphology and mating behavior for clade III clones because only ITS data were available. The three ITS clades showed different geographic distributions. Clade II was restricted to the NE Pacific, whereas clones belonging to clade III originated from geographically widely separated areas (Vietnam, China and Mexico). ITS clade I was recovered in all locations studied: the North Sea (Belgium, The Netherlands, France), the eastern and western N Atlantic (Spain, Canada), the NW and S Pacific (Japan, New Zealand) and the NE Pacific (Washington State). Clade I thus appears to be globally distributed in temperate coastal areas and provides the first strong evidence to date for the global distribution of a biologically, genetically and morphologically defined diatom species.     

Mechanisms for aggregation in animals: rule success depends on ecological variables

Under the threat of predation, animals often group tightly together,with all group members benefiting from a reduction in predationrisk through various mechanisms, including the dilution, encounter-dilution,and predator confusion effects. Additionally, the selfish herdhypothesis was first put forward by Hamilton (1971). He proposedthat in order to reduce its risk of predation, an individualshould approach its nearest neighbor, reducing its risk at theexpense of those around it. Despite extensive empirical support,the selfish herd hypothesis has been criticized on theoreticalgrounds: approaching the nearest neighbor does not result inthe observed dense aggregations, and the nearest neighbor inspace is not necessarily the one that can be reached fastest.Increasingly complex movement rules have been proposed, successfullyproducing dense aggregations of individuals. However, no studyto date has made a full comparison of the different proposedmovement rules within the same modeling environment. Further,ecologically relevant parameters, such as the size and densityof a population or group and the time it takes a predator toattack, have thus far been ignored. Here, we investigate thereduction in risk for animals aggregating using different strategiesand demonstrate the importance of ecological parameters on riskreduction in group-living animals. We find that complex rulesare most successful at reducing risk in small, compact populations,whereas simpler rules are most successful in larger, low-densitypopulations, and when predators attack quickly after being detectedby their prey.     

Early interactions with adults mediate the development of predator defenses in guppies

Antipredator defenses in many species have been shown to exhibitphenotypic plasticity in response to variable predation risk.Some evidence suggests that in certain species adults act asproxy predators, triggering the development of adaptive defensesin juveniles where interaction with a predator is unlikely tooccur. However, almost nothing is known about how adult/juvenileinteractions mediate plasticity. Here, we examine the natureof the antipredator defenses that develop in Trinidadian guppiesas a function of early social experience and investigate theimportance of different types of cue (physical, visual, andolfactory) by rearing juveniles under 3 different social conditions.In the first, only juveniles are present; in the second, onlyvisual and olfactory interaction occurs between adults and juveniles;and in the third, adults physically interact with juveniles.Our analyses show that juveniles reared in the physical presenceof adults spend significantly less time shoaling with adultsthan fish from other treatments in an adult versus juvenileshoal-choice trial. Further, we show that juveniles with experienceof adult aggression have a decreased response latency to a simulatedavian predation attempt and travel a greater distance in thefirst 5 frames of movement after the simulated strike. Finally,juveniles reared with physical experience of adults developedrelatively deeper bodies and were significantly shorter in standardlength than guppies reared without physical experience of adults.     

Cytokine responses to acute and chronic exercise in multiple sclerosis.

Regular exercise reduces functional loss associated with multiple sclerosis (MS). However, the impact of exercise on inflammatory mediators associated with disease activity remains relatively unexplored. The purpose of this study was to determine whether ambulatory MS subjects would respond similarly to aerobic cycle training compared with matched controls on circulating immune variables, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Eleven MS and 11 non-MS control subjects (8 women and 3 men in both groups) matched in age, height, body mass, body fat, and peak O(2) uptake completed the study. Subjects completed 30 min of cycle ergometry at 60% of peak O(2) uptake, 3 day/wk for 8 wk. Plasma cytokine concentrations were determined before and after exercise at weeks 0, 4, and 8. MS and control subjects showed a similar cytokine responses to exercise. IL-6 at rest tended to decrease (P = 0.08) with training in both groups. Resting plasma TNF-alpha tended to be higher in MS compared with controls throughout the study (P = 0.08). MS subjects showed elevated resting TNF-alpha in MS at the end of the 8-wk program (P = 0.04), whereas resting TNF-alpha remained unchanged in controls (P > 0.05). Resting plasma IFN-gamma at rest was elevated in MS subjects (P = 0.008) and unchanged in controls at the end of the intervention (P > 0.05). The response of plasma IL-6, TNF-alpha, and IFN-gamma after a single bout of exercise was similar between MS and control subjects (P > 0.05). Additional research to understand the impact of exercise on immune variables in MS is warranted.     

The role of Polycomb-group response elements in regulation of engrailed transcription in Drosophila

Polycomb group proteins are required for long-term repression of many genes in Drosophila and all metazoans. In Drosophila, DNA fragments called Polycomb-group response elements (PREs) have been identified that mediate the action of Polycomb-group proteins. Previous studies have shown that a 2 kb fragment located from -2.4 kb to -395 bp upstream of the Drosophila engrailed promoter contains a multipartite PRE that can mediate mini-white silencing and act as a PRE in an Ubx-reporter construct. Here, we study the role of this 2 kb fragment in the regulation of the engrailed gene itself. Our results show that within this 2 kb fragment, there are two subfragments that can act as PREs in embryos. In addition to their role in gene silencing, these two adjacent PRE fragments can facilitate the activation of the engrailed promoter by distant enhancers. The repressive action of the engrailed PRE can also act over a distance. A 181 bp subfragment can act as a PRE and also mediate positive effects in an enhancer-detector construct. Finally, a deletion of 530 bp of the 2 kb PRE fragment within the endogenous engrailed gene causes a loss-of-function phenotype, showing the importance of the positive regulatory effects of this PRE-containing fragment. Our data are consistent with the model that engrailed PREs bring chromatin together, allowing both positive and negative regulatory interactions between distantly located DNA fragments.     

4-(Phenoxy)pyridin-3-yl]methylamines: a new class of selective noradrenaline reuptake inhibitors

[4-(Phenoxy)pyridine-3-yl]methylamines are disclosed as a new series of selective noradrenaline reuptake inhibitors (NRI). Structure-activity relationships established that potent NRI activity could be achieved by appropriate substitution at the 2-position of the phenoxy ring. Compound 31 demonstrated potent NRI activity combined with good selectivity over serotonin and dopamine reuptake and no significant off-target pharmacology.     

Structure and ligand binding of the soluble domain of a Thermotoga maritima membrane protein of unknown function TM1634

As a part of the Joint Center for Structural Genomics (JCSG) biological targets, the structures of soluble domains of membrane proteins from Thermotoga maritima were pursued. Here, we report the crystal structure of the soluble domain of TM1634, a putative membrane protein of 128 residues (15.1 kDa) and unknown function. The soluble domain of TM1634 is an alpha-helical dimer that contains a single tetratrico peptide repeat (TPR) motif in each monomer where each motif is similar to that found in Tom20. The overall fold, however, is unique and a DALI search does not identify similar folds beyond the 38-residue TPR motif. Two different putative ligand binding sites, in which PEG200 and Co(2+) were located, were identified using crystallography and NMR, respectively.