Pharmacokinetics of anti-TB drugs in Malawian children: reconsidering the role of ethambutol

Background Current guidelines for dosing of anti-TB drugs in children advocate higher doses for rifampicin and isoniazid despite limited availability of paediatric data on the pharmacokinetics of these drugs, especially from Africa, where the burden of childhood disease remains high. Methods Thirty children aged 6 months to 15 years underwent intensive pharmacokinetic sampling for first-line anti-TB drugs at Queen Elizabeth Central Hospital, Blantyre, Malawi. Rifampicin, isoniazid, pyrazinamide and ethambutol were dosed at 10, 5, 25 and 20 mg/kg, respectively. Plasma drug concentrations were determined using sensitive, validated bioanalytical methods and summary pharmacokinetic parameters were estimated using non-compartmental analysis. Results The median (IQR) Cmax was 2.90 (2.08–3.43), 3.37 (2.55–4.59), 34.60 (32.30–40.90) and 1.20 (0.85–1.68) mg/L while the median (IQR) AUC0–∞ was 16.92 (11.10–22.74), 11.48 (7.35–18.93), 333.50 (279.50–487.2) and 8.65 (5.96–11.47) mg·h/L for rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. For all drugs, pharmacokinetic parameters relating to drug absorption and exposure were lower than those published for adults, though similar to existing paediatric data from sub-Saharan Africa. Weight and/or dose predicted at least one measure of exposure for all drugs. Age-related decreases in CL/F for rifampicin and pyrazinamide and a biphasic elimination pattern of isoniazid were observed. Predicted AUC0–∞ for rifampicin dosed at 15 mg/kg was comparable to that of adults while the dose required to achieve ethambutol exposure similar to that in adults was 55 mg/kg or higher. Conclusions These data support recently revised WHO recommendations for dosing of anti-TB drugs in children, but dosing of ethambutol in children also appears inadequate by comparison with adult pharmacokinetic data

On representations of super coalgebras

The general structure of the representation theory of a $Z_2$-graded coalgebra is discussed. The result contains the structure of Fourier analysis on compact supergroups and quantisations thereof as a special case. The general linear supergroups serve as an explicit illustration and the simplest example is carried out in detail.Comment: 18 pages, LaTeX, KCL-TH-94-

Is the Shroud of Turin in Relation to the Old Jerusalem Historical Earthquake?

Phillips and Hedges suggested, in the scientific magazine Nature (1989), that neutron radiation could be liable of a wrong radiocarbon dating, while proton radiation could be responsible of the Shroud body image formation. On the other hand, no plausible physical reason has been proposed so far to explain the radiation source origin, and its effects on the linen fibres. However, some recent studies, carried out by the first author and his Team at the Laboratory of Fracture Mechanics of the Politecnico di Torino, found that it is possible to generate neutron emissions from very brittle rock specimens in compression through piezonuclear fission reactions. Analogously, neutron flux increments, in correspondence to seismic activity, should be a result of the same reactions. A group of Russian scientists measured a neutron flux exceeding the background level by three orders of magnitude in correspondence to rather appreciable earthquakes (4th degree in Richter Scale). The authors consider the possibility that neutron emissions by earthquakes could have induced the image formation on Shroud linen fibres, trough thermal neutron capture by Nitrogen nuclei, and provided a wrong radiocarbon dating due to an increment in C(14,6)content. Let us consider that, although the calculated integral flux of 10^13 neutrons per square centimetre is 10 times greater than the cancer therapy dose, nevertheless it is100 times smaller than the lethal dose.Comment: 13 pages, 1 figur

A network approach to understanding distance learners’ experience of stress and mental distress whilst studying

Research has shown that learners’ stress and mental distress are linked to poorer academic outcomes. A better understanding of stress and mental distress experiences during study could foster more nuanced course and intervention design which additionally teaches learners how to navigate through to protect their academic performance. The current study draws on data collected via validated self-reported questionnaires completed by final year undergraduate students (n = 318) at a large distance education university. We examined how common features of stress, depression and anxiety link to each other using a network analysis of reported symptoms. The results included findings demonstrating the symptoms with the greatest relative importance to the network. Specifically, these included the stress symptom ‘I found it difficult to relax’ and the depression symptom ‘I was unable to become enthusiastic about anything’. The findings could help institutions design interventions that directly correspond to common features of students’ stress and distress experiences

Pan-genome analysis highlights the role of structural variation in the evolution and environmental adaptation of Asian honeybees.

The Asian honeybee, Apis cerana, is an ecologically and economically important pollinator. Mapping its genetic variation is key to understanding population-level health, histories and potential capacities to respond to environmental changes. However, most efforts to date were focused on single nucleotide polymorphisms (SNPs) based on a single reference genome, thereby ignoring larger scale genomic variation. We employed long-read sequencing technologies to generate a chromosome-scale reference genome for the ancestral group of A. cerana. Integrating this with 525 resequencing data sets, we constructed the first pan-genome of A. cerana, encompassing almost the entire gene content. We found that 31.32% of genes in the pan-genome were variably present across populations, providing a broad gene pool for environmental adaptation. We identified and characterized structural variations (SVs) and found that they were not closely linked with SNP distributions; however, the formation of SVs was closely associated with transposable elements. Furthermore, phylogenetic analysis using SVs revealed a novel A. cerana ecological group not recoverable from the SNP data. Performing environmental association analysis identified a total of 44 SVs likely to be associated with environmental adaptation. Verification and analysis of one of these, a 330 bp deletion in the Atpalpha gene, indicated that this SV may promote the cold adaptation of A. cerana by altering gene expression. Taken together, our study demonstrates the feasibility and utility of applying pan-genome approaches to map and explore genetic feature variations of honeybee populations, and in particular to examine the role of SVs in the evolution and environmental adaptation of A. cerana

Alignment of Biological Sequences with Jalview

In this chapter, we introduce core functionality of the Jalview interactive platform for the creation, analysis, and publication of multiple sequence alignments. A workflow is described based on Jalview's core functions: from data import to figure generation, including import of alignment reliability scores from T-Coffee and use of Jalview from the command line. The accompanying notes provide background information on the underlying methods and discuss additional options for working with Jalview to perform multiple sequence alignment, functional site analysis, and publication of alignments on the web

Tannakian duality for Anderson-Drinfeld motives and algebraic independence of Carlitz logarithms

We develop a theory of Tannakian Galois groups for t-motives and relate this to the theory of Frobenius semilinear difference equations. We show that the transcendence degree of the period matrix associated to a given t-motive is equal to the dimension of its Galois group. Using this result we prove that Carlitz logarithms of algebraic functions that are linearly independent over the rational function field are algebraically independent.Comment: 39 page

How to obtain division algebras used for fast-decodable space-time block codes

We present families of unital algebras obtained through a doubling process from a cyclic central simple algebra D, employing a K-automorphism tau and an invertible element d in D. These algebras appear in the construction of iterated space-time block codes. We give conditions when these iterated algebras are division which can be used to construct fully diverse iterated codes. We also briefly look at algebras (and codes) obtained from variations of this method