| 1. |
- Kloprogge, F., et al.
(author)
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Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis
- 2018
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In: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 15:6
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Journal article (peer-reviewed)abstract
- Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. A search in PubMed, Embase, ClinicalTrials. gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing < 15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.
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| 2. |
- Brotons-Gisbert, Mauro, et al.
(author)
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Coulomb blockade in an atomically thin quantum dot coupled to a tunable Fermi reservoir
- 2019
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In: Nature Nanotechnology. - : NATURE PUBLISHING GROUP. - 1748-3387 .- 1748-3395. ; 14:5, s. 442-446
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Journal article (peer-reviewed)abstract
- Gate-tunable quantum-mechanical tunnelling of particles between a quantum confined state and a nearby Fermi reservoir of delocalized states has underpinned many advances in spintronics and solid-state quantum optics. The prototypical example is a semiconductor quantum dot separated from a gated contact by a tunnel barrier. This enables Coulomb blockade, the phenomenon whereby electrons or holes can be loaded one-by-one into a quantum dot(1,2). Depending on the tunnel-coupling strength(3,4), this capability facilitates single spin quantum bits(1,2,5) or coherent many-body interactions between the confined spin and the Fermi reservoirs(6,7). Van der Waals (vdW) heterostructures, in which a wide range of unique atomic layers can easily be combined, offer novel prospects to engineer coherent quantum confined spins(8,9), tunnel barriers down to the atomic limit(10) or a Fermi reservoir beyond the conventional flat density of states(11). However, gate-control of vdW nanostructuresu(12-16) at the single particle level is needed to unlock their potential. Here we report Coulomb blockade in a vdW heterostructure consisting of a transition metal dichalcogenide quantum dot coupled to a graphene contact through an atomically thin hexagonal boron nitride (hBN) tunnel barrier. Thanks to a tunable Fermi reservoir, we can deterministically load either a single electron or a single hole into the quantum dot. We observe hybrid excitons, composed of localized quantum dot states and delocalized continuum states, arising from ultra-strong spin-conserving tunnel coupling through the atomically thin tunnel barrier. Probing the charged excitons in applied magnetic fields, we observe large gyromagnetic ratios (similar to 8). Our results establish a foundation for engineering next-generation devices to investigate either novel regimes of Kondo physics or isolated quantum bits in a vdW heterostructure platform.
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| 3. |
- Wolfe, Kenneth H., et al.
(author)
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Clade- and species-specific features of genome evolution in the Saccharomycetaceae
- 2015
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In: FEMS yeast research (Print). - : Oxford University Press (OUP). - 1567-1356 .- 1567-1364. ; 15:5
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Research review (peer-reviewed)abstract
- Many aspects of the genomes of yeast species in the family Saccharomycetaceae have been well conserved during evolution. They have similar genome sizes, genome contents, and extensive collinearity of gene order along chromosomes. Gene functions can often be inferred reliably by using information from Saccharomyces cerevisiae. Beyond this conservative picture however, there are many instances where a species or a clade diverges substantially from the S. cerevisiae paradigm-for example, by the amplification of a gene family, or by the absence of a biochemical pathway or a protein complex. Here, we review clade-specific features, focusing on genomes sequenced in our laboratory from the post-WGD genera Naumovozyma, Kazachstania and Tetrapisispora, and from the non-WGD species Torulaspora delbrueckii. Examples include the loss of the pathway for histidine synthesis in the cockroach-associated species Tetrapisispora blattae; the presence of a large telomeric GAL gene cluster in To. delbrueckii; losses of the dynein and dynactin complexes in several independent yeast lineages; fragmentation of the MAT locus and loss of the HO gene in Kazachstania africana; and the patchy phylogenetic distribution of RNAi pathway components.
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