Posaconazole Tablet Pharmacokinetics: Lack of Effect of Concomitant Medications Altering Gastric pH and Gastric Motility in Healthy Subjects.

Posaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and 2 g of magnesium hydroxide), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was a ≥10-day washout between treatment periods. Posaconazole exposure, time to maximum concentration of drug in serum (Tmax), and apparent terminal half-life (t1/2) were similar when posaconazole was administered alone or with medications affecting gastric pH and gastric motility. Geometric mean ratios (90% confidence intervals [CIs]) of the area under the concentration-time curve from time zero to infinity (AUC0-inf) (posaconazole with medications affecting gastric pH and gastric motility versus posaconazole alone) were 1.03 (0.88-1.20) with antacid, 0.97 (0.84-1.12) with ranitidine, 1.01 (0.87-1.17) with esomeprazole, and 0.93 (0.79-1.09) with metoclopramide. Geometric mean ratios (90% CIs) of the maximum concentration of drug in serum (Cmax) were 1.06 (0.90-1.26) with antacid, 1.04 (0.88-1.23) with ranitidine, 1.05 (0.89-1.24) with esomeprazole, and 0.86 (0.73-1.02) with metoclopramide. In summary, in healthy volunteers, the pharmacokinetics of a single 400-mg dose of posaconazole tablets was not altered to a clinically meaningful extent when posaconazole was administered alone or with medications affecting gastric pH or gastric motility

Body mass index at diagnosis of a childhood brain tumor; a reflection of hypothalamic-pituitary dysfunction or lifestyle?

Purpose: Childhood brain tumor survivors (CBTS) are at risk of becoming overweight, which has been shown to be associated with hypothalamic-pituitary (HP) dysfunction during follow-up. Body mass index (BMI) at diagnosis is related to BMI at follow-up. It is uncertain, however, whether aberrant BMI at brain tumor diagnosis reflects early hypothalamic dysfunction or rather reflects genetic and sociodemographic characteristics. We aimed to examine whether BMI at childhood brain tumor diagnosis is associated with HP dysfunction at diagnosis or its development during follow-up. Methods: The association of BMI at diagnosis of a childhood brain tumor to HP dysfunction at diagnosis or during follow-up was examined in a Dutch cohort of 685 CBTS, excluding children with craniopharyngioma or a pituitary tumor. Individual patient data were retrospectively extracted from patient charts. Results: Of 685 CTBS, 4.7% were underweight, 14.2% were overweight, and 3.8% were obese at diagnosis. Being overweight or obese at diagnosis was not associated with anterior pituitary deficiency or diabetes insipidus at diagnosis or during follow-up. In children with suprasellar tumors, being obese at diagnosis was associated with central precocious puberty. Conclusion: Overweight or obesity at diagnosis of a childhood brain tumor seems not to be associated with pituitary deficiencies. These results suggest that genetics and lifestyle may be more important etiologic factors for higher BMI at diagnosis in these children than hypothalamic dysfunction. To improve the long-term outcome of CBTS with regards to overweight and obesity, more attention should be given to lifestyle already at the time of brain tumor treatment

Folding and unfolding phylogenetic trees and networks

Phylogenetic networks are rooted, labelled directed acyclic graphs which are commonly used to represent reticulate evolution. There is a close relationship between phylogenetic networks and multi-labelled trees (MUL-trees). Indeed, any phylogenetic network $N$ can be "unfolded" to obtain a MUL-tree $U(N)$ and, conversely, a MUL-tree $T$ can in certain circumstances be "folded" to obtain a phylogenetic network $F(T)$ that exhibits $T$. In this paper, we study properties of the operations $U$ and $F$ in more detail. In particular, we introduce the class of stable networks, phylogenetic networks $N$ for which $F(U(N))$ is isomorphic to $N$, characterise such networks, and show that they are related to the well-known class of tree-sibling networks.We also explore how the concept of displaying a tree in a network $N$ can be related to displaying the tree in the MUL-tree $U(N)$. To do this, we develop a phylogenetic analogue of graph fibrations. This allows us to view $U(N)$ as the analogue of the universal cover of a digraph, and to establish a close connection between displaying trees in $U(N)$ and reconcilingphylogenetic trees with networks

Bioinformatics for the NuGO proof of principle study: analysis of gene expression in muscle of ApoE3*Leiden mice on a high-fat diet using PathVisio

Insulin resistance is a characteristic of type-2 diabetes and its development is associated with an increased fat consumption. Muscle is one of the tissues that becomes insulin resistant after high fat (HF) feeding. The aim of the present study is to identify processes involved in the development of HF-induced insulin resistance in muscle of ApOE3*Leiden mice by using microarrays. These mice are known to become insulin resistant on a HF diet. Differential gene expression was measured in muscle using the Affymetrix mouse plus 2.0 array. To get more insight in the processes, affected pathway analysis was performed with a new tool, PathVisio. PathVisio is a pathway editor customized with plug-ins (1) to visualize microarray data on pathways and (2) to perform statistical analysis to select pathways of interest. The present study demonstrated that with pathway analysis, using PathVisio, a large variety of processes can be investigated. The significantly regulated genes in muscle of ApOE3*Leiden mice after 12 weeks of HF feeding were involved in several biological pathways including fatty acid beta oxidation, fatty acid biosynthesis, insulin signaling, oxidative stress and inflammation

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks : an international rare cancers initiative (IRCI) ocular melanoma study

Background: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. Methods: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. Results: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus = 3 cm versus Conclusion: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.Peer reviewe

Patterns of recurrence following definitive chemoradiation for patients with proximal esophageal cancer

Introduction: The aim of this retrospective study was to determine the patterns of recurrence and overall survival (OS) in patients achieving clinical complete response after treatment with definitive chemoradiation (CRT) for proximal esophageal cancer. Materials and methods: Patients with proximal esophageal cancer treated with CRT between 2004 and 2014 in 11 centers in the Netherlands were included. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Cumulative incidence of first recurrence (locoregional or distant) and locoregional recurrence (LRR) were assessed using competing risk analyses. Results: In 197 of the 200 identified patients, response was evaluated, 133 (68%) showed a complete response. In complete responders, median OS, three-year OS, and PFS were 45.0 months (95% CI 34.8-61.5 months), 58% (95% CI 48-66), and 49% (95% CI 40-57), respectively. Three- and five-year risk of recurrence were respectively 40% (95% CI 31-48), and 45% (95% CI 36-54). Three- and five-year risk of LRR were 26% (95% CI 19-33), and 30% (95% CI 22-38). Eight of 32 patients with an isolated LRR underwent salvage surgery, with a median OS of 32.0 months (95% CI 6.8-not reached). Conclusion: In patients with a complete response after definitive CRT for proximal esophageal cancer, most recurrences were locoregional and developed within the first three years after CRT. These findings suggest to shorten locoregional follow-up from five to three years. (C) 2021 The Authors. Published by Elsevier Ltd

Beyond representing orthology relations by trees

Reconstructing the evolutionary past of a family of genes is an important aspect of many genomic studies. To help with this, simple relations on a set of sequences called orthology relations may be employed. In addition to being interesting from a practical point of view they are also attractive from a theoretical perspective in that e.\,g.\,a characterization is known for when such a relation is representable by a certain type of phylogenetic tree. For an orthology relation inferred from real biological data it is however generally too much to hope for that it satisfies that characterization. Rather than trying to correct the data in some way or another which has its own drawbacks, as an alternative, we propose to represent an orthology relation $\delta$ in terms of a structure more general than a phylogenetic tree called a phylogenetic network. To compute such a network in the form of a level-1 representation for $\delta$, we formalize an orthology relation in terms of the novel concept of a symbolic 3- dissimilarity which is motivated by the biological concept of a ``cluster of orthologous groups'', or COG for short. For such maps which assign symbols rather that real values to elements, we introduce the novel {\sc Network-Popping} algorithm which has several attractive properties. In addition, we characterize an orthology relation $\delta$ on some set $X$ that has a level-1 representation in terms of eight natural properties for $\delta$ as well as in terms of level-1 representations of orthology relations on certain subsets of $X$

Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON)

Item does not contain fulltextBACKGROUND: In lung cancer CT screening, participants often have an indeterminate screening result at baseline requiring a follow-up CT. In subjects with either an indeterminate or a negative result after screening, we investigated whether health-related quality of life (HRQoL) changed over time and differed between groups in the short term. METHODS: A total of 733 participants in the NELSON trial received four questionnaires: T0, before randomisation; T1, 1 week before the baseline screening; T2, 1 day after the screening; and T3, 2 months after the screening results but before the 3-month follow-up CT. HRQoL was measured as generic HRQoL (the 12-item Short Form, SF-12; the EuroQol questionnaire, EQ-5D), anxiety (the Spielberger State-Trait Anxiety Inventory, STAI-6), and lung-cancer-specific distress (the Impact of Event Scale, IES). For analyses, repeated-measures analysis of variance was used, adjusted for covariates. RESULTS: Response to each questionnaire was 88% or higher. Scores on SF-12, EQ-5D, and STAI-6 showed no clinically relevant changes over time. At T3, IES scores that were clinically relevant increased after an indeterminate result, whereas these scores showed a significant decrease after a negative result. At T3, differences in IES scores between the two baseline result groups were both significant and clinically relevant (P<0.01). CONCLUSION: This longitudinal study among participants of a lung cancer screening programme showed that in the short term recipients of an indeterminate result experienced increased lung-cancer-specific distress, whereas the HRQoL changes after a negative baseline screening result may be interpreted as a relief

Banana as adjunct in beer production: applicability and performance of fermentative parameters

Traditionally, the raw materials for beer production are barley, hops, water, and yeast, but most brewers use also different adjuncts. During the alcoholic fermentation, the contribution of aroma compounds from other ingredients to the final beer flavor depends on the wort composition, on the yeast strain, and mainly on the process conditions. In this context, banana can also be a raw material favorable to alcoholic fermentation being rich in carbohydrates and minerals and providing low acidity. In this work, the objective was to evaluate the performance of wort adjusted with banana juice in different concentrations. For this, static fermentations were conducted at 15 °C at pilot scale (140 L of medium). The addition of banana that changed the concentration of all-malt wort from 10 °P to 12 and 15 °P were evaluated (°P is the weight of the extract or the sugar equivalent in 100 g solution, at 20 °C). The results showed an increase in ethanol production, with approximately 0.4 g/g ethanol yield and 0.6 g/L h volumetric productivity after 84 h of processing when concentrated wort was used. Thus, it was concluded that banana can be used as an adjunct in brewing methods, helping in the development of new products as well as in obtaining concentrated worts.Fundação para a Ciência e a Tecnologia (FCT)EMATER-MGJohnson-DiverseyFapesp (Fundação de Amparo à Pesquisa do Estado de São Paulo/Brasil)Wallerstein Industrial & CommercialNovozymesCAPES (Coordenação para Aperfeiçoamento do Ensino Superior/ Brasil)Malteria do ValeGRICES (Gabinete de Relações Internacionais da Ciência e do Ensino Superior/Portugal

Cognitive loading affects motor awareness and movement kinematics but not locomotor trajectories during goal-directed walking in a virtual reality environment.

The primary purpose of this study was to investigate the effects of cognitive loading on movement kinematics and trajectory formation during goal-directed walking in a virtual reality (VR) environment. The secondary objective was to measure how participants corrected their trajectories for perturbed feedback and how participants' awareness of such perturbations changed under cognitive loading. We asked 14 healthy young adults to walk towards four different target locations in a VR environment while their movements were tracked and played back in real-time on a large projection screen. In 75% of all trials we introduced angular deviations of ±5° to ±30° between the veridical walking trajectory and the visual feedback. Participants performed a second experimental block under cognitive load (serial-7 subtraction, counter-balanced across participants). We measured walking kinematics (joint-angles, velocity profiles) and motor performance (end-point-compensation, trajectory-deviations). Motor awareness was determined by asking participants to rate the veracity of the feedback after every trial. In-line with previous findings in natural settings, participants displayed stereotypical walking trajectories in a VR environment. Our results extend these findings as they demonstrate that taxing cognitive resources did not affect trajectory formation and deviations although it interfered with the participants' movement kinematics, in particular walking velocity. Additionally, we report that motor awareness was selectively impaired by the secondary task in trials with high perceptual uncertainty. Compared with data on eye and arm movements our findings lend support to the hypothesis that the central nervous system (CNS) uses common mechanisms to govern goal-directed movements, including locomotion. We discuss our results with respect to the use of VR methods in gait control and rehabilitation