Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children.

OBJECTIVES: The objectives of this study were to investigate the population pharmacokinetics of posaconazole in immunocompromised children, evaluate the influence of patient characteristics on posaconazole exposure and perform simulations to recommend optimal starting doses. METHODS: Posaconazole plasma concentrations from paediatric patients undergoing therapeutic drug monitoring were extracted from a tertiary paediatric hospital database. These were merged with covariates collected from electronic sources and case-note reviews. An allometrically scaled population-pharmacokinetic model was developed to investigate the effect of tablet and suspension relative bioavailability, nonlinear bioavailability of suspension, followed by a step-wise covariate model building exercise to identify other important sources of variability. RESULTS: A total of 338 posaconazole plasma concentrations samples were taken from 117 children aged 5 months to 18 years. A one-compartment model was used, with tablet apparent clearance standardised to a 70-kg individual of 15 L/h. Suspension was found to have decreasing bioavailability with increasing dose; the estimated suspension dose to yield half the tablet bioavailability was 99 mg/m2. Diarrhoea and proton pump inhibitors were also associated with reduced suspension bioavailability. CONCLUSIONS: In the largest population-pharmacokinetic study to date in children, we have found similar covariate effects to those seen in adults, but low bioavailability of suspension in patients with diarrhoea or those taking concurrent proton pump inhibitors, which may in particular limit the use of posaconazole in these patients

Narrating China’s Belt and Road Initiative

This article studies the formation process of China's belt and road initiative (BRI) – the most important Chinese foreign policy initiative under Xi Jinping. It argues that the BRI was put forward as a broad policy idea that was subsequently developed with relatively concrete content. During this process, the shifting international landscapes have gradually driven the BRI from a periphery strategy into a global initiative. By examining the case of Jiangsu Province, this article also shows how Chinese local governments have actively deployed their preferred narratives to influence and (re‐)interpret the BRI guidelines of the central government in order to advance their own interests. As a result, this produces a variety of competing, ambiguous and contradictory policy narratives of the BRI within China, which undermines the Chinese central government's monopoly on the BRI narratives. This leaves the BRI as a very vague and broad policy slogan that is subject to change and open to interpretation. In this regard, the existing analyses – that consider the BRI as Beijing's masterplan to achieve its geopolitical goals – pay insufficient attention to the BRI's domestic contestation and overstate the BRI's geopolitical implications

An Empirical Analysis of Overlap Publication in Chinese Language and English Research Manuscripts

BACKGROUND: There are a number of sound justifications for publishing nearly identical information in Chinese and English medical journals, assuming several conditions are met. Although overlap publication is perceived as undesirable and ethically questionable in Europe and North America, it may serve an important function in some regions where English is not the native tongue. There is no empirical data on the nature and degree of overlap publication in English and Chinese language journals. METHODS/PRINCIPAL FINDINGS: A random sample of 100 English manuscripts from Chinese institutions was selected from PubMed. Key words and institutions were searched in the China National Knowledge Infrastructure, a comprehensive Chinese language research database. Unacknowledged overlap was a priori defined according to International Committee of Medical Journal Editor (ICMJE) guidelines following examination by two individuals. 19% (95% CI 11-27) of English manuscripts from Chinese institutions were found to have substantial overlap with Chinese published work based on full text examination. None of the manuscripts met all of the criteria established by the ICMJE for an acknowledged overlap publication. Individual-level, journal-level, and institutional factors seem to influence overlap publication. Manuscripts associated with an institution outside of China and with more than one institution were significantly less likely to have substantial overlap (p<0.05). CONCLUSIONS/SIGNIFICANCE: Overlap publication was common in this context, but instances of standard ICMJE notations to acknowledge this practice were rare. This research did not cite the identified overlap manuscripts with the hope that these empirical data will inform journal policy changes and structural initiatives to promote clearer policies and manuscripts

Rasch analysis of the Patient and Observer Scar Assessment Scale (POSAS) in burn scars

The Patient and Observer Scar Assessment Scale (POSAS) is a questionnaire that was developed to assess scar quality. It consists of two separate six-item scales (Observer Scale and Patient Scale), both of which are scored on a 10-point rating scale. After many years of experience with this scale in burn scar assessment, it is appropriate to examine its psychometric properties using Rasch analysis. Cross-sectional data collection from seven clinical trials resulted in a data set of 1,629 observer scores and 1,427 patient scores of burn scars. We examined the person-item map, item fit statistics, reliability, response category ordering, and dimensionality of the POSAS. The POSAS showed an adequate fit to the Rasch model, except for the item surface area. Person reliability of the Observer Scale and Patient Scale was 0.82 and 0.77, respectively. Dimensionality analysis revealed that the unexplained variance by the first contrast of both scales was 1.7 units. Spearman correlation between the Observer Scale Rasch measure and the overall opinion of the clinician was 0.75. The Rasch model demonstrated that the POSAS is a reliable and valid scale that measures the single-construct scar qualit

Co-operative inhibitory effects of hydrogen peroxide and iodine against bacterial and yeast species.

BACKGROUND: Hydrogen peroxide and iodine are powerful antimicrobials widely used as antiseptics and disinfectants. Their antimicrobial properties are known to be enhanced by combining them with other compounds. We studied co-operative inhibitory activities (synergism, additive effects and modes of growth inhibition) of hydrogen peroxide and iodine used concurrently against 3 bacterial and 16 yeast species. RESULTS: Synergistic or additive inhibitory effects were shown for hydrogen peroxide and iodine mixtures against all 19 species used in the study. Both biocides were mostly cidal individually and in mixtures against Pseudomonas aeruginosa and Staphylococcus aureus. Both compounds manifested static inhibitory effects individually, but their mixtures were synergistically cidal for Saccharomyces cerevisiae and Escherihia coli. Cells of S. cerevisiae treated with hydrogen peroxide and iodine-hydrogen peroxide mixture produced increased numbers of respiratory deficient mutants indicating genotoxic effects. CONCLUSION: Iodine and hydrogen peroxide used concurrently interact synergistically or additively against a range of prokaryotic and eukaryotic microorganisms. The study provides an insight as to how these traditional antimicrobials could be used more effectively for disinfection and antisepsis. In addition, a simple approach is proposed for scoring genotoxicity of different biocides by using the budding yeast system

Protein design with l- and d-alpha-amino acid structures as the alphabet

Summarizing the implications of homochiral structures in interpeptide interactions, not only in the topology but also possibly in the physics of protein folding, this Account provides an overview of the concept of shape-specific protein design using D- and L-(alpha)amino acid structures as the alphabet. The molecular shapes accessible in de novo protein design are stereochemically defined. Indeed, the defining consideration for shape specificity in proteins to be alpha-helix/beta-sheet composites is the L configuration of the alpha-amino acid structures. The stereospecificity in shapes implies that protein shapes may be diversifiable stereochemically, that is, designable de novo, using D and L structures as the alphabet. Indeed, augmented with D enantiomers, Nature's alphabet will expand greatly in the diversity of polypeptide stereoisomers, for example, from 1(30) to 2(30)-that is, from one to ca. one billion-for a modestly sized 30-residue polypeptide. Furthermore, with each isomer having conformers sterecispecific to its structure, molecular folds of specific shapes may be approachable sequentially when D and L structures are used as the alphabet. illustrating the promise, 14-20-residue bracelet-, boat-, canoe-, and cup-shaped molecular folds were designed stereochemically or implemented as specific sequence plans in the D- and L-alpha-amino acid alphabet. In practical terms, canonical poly-L peptide folds were modified to the desired shapes via stereochemical mutations invoking enantiomer symmetries in the Ramachandran phi,psi space as the logic. For example, in designing the boat-shaped fold, the canonical beta-hairpin was reengineered in its flat planar structure via multiple coordinated L-to-D mutations in its position specific cross-strand neighbor residues, upturning its ends enclosing six side chains in a molecular cleft. While affirming the generality of the approach, the 20-residue molecular canoe and the 14-residue molecular cup are also presented as examples of the scope of functional design. The canoe, possessing alkali cation-specific catgrips in its main chain, and the cup, featuring an organic cation-specific aromatic triad in its side chains, do indeed display desired specificities in their ligand binding. Stereochemistry is, therefore, the crucial specifier of protein shapes and valuable as the tool for shape-specific protein design. Proteins in general, whether poly-L or mixed-D,L, require sequence effects of amino acid side chain structures for their stability, if not also for specifying them conformationally. The principles underlying these phenomena remain a puzzle, but studies invoking a stereochemical mutation approach to the problem have suggested that the poly-L structure may be crucial to the principles of sequential encoding of protein structures in amino acid side chains as the alphabet