Reduced in vitro susceptibility to artemisinin derivatives associated with multi-resistance in a traveller returning from South-East Asia

Decreased in vitro susceptibility to dihydroartemisinin (21.2 nM) and artesunate (16.3 nM) associated with decreased susceptibility or resistance to quinine (1131 nM), mefloquine (166 nM), lumefantrine (114 nM), pyronaridine (70.5 nM) and piperaquine (91.1 nM) is reported in a patient returning from South-East Asia after trekking along the Mekong from the south of Laos to the north of Thailand. Decreased in vitro susceptibility to artemisinin derivatives did not appear to be mediated by the number of copies of pfmdr1 or pfATPase6, pfcrt, pfmdr1 or pfmrp polymorphism. The high IC50 to mefloquine of this Asian isolate was not associated with pfmdr1 copy number. Pfnhe-1 microsatellite ms4760 showed a profile 7 (ms4760-7) with three repeats of DNNND and one repeat of DDDNHNDNHNN, which is associated with high quinine reduced susceptibility. The patient recovered in three days without relapse after treatment with the association of quinine and doxycycline. Decreased in vitro susceptibility to quinine and the delayed effect of doxycycline may both have contributed to the delayed parasite clearance time, D4 (0.5%) and D7 (0.004%). The in vitro data, with IC50 for dihydroartemisinin and artesunate were up to ten times those of the reference clone W2, which suggests that this isolate may be resistant to artemisinin derivatives, associated with a decreased susceptibility to quinine

A heterotic sigma model with novel target geometry

We construct a (1,2) heterotic sigma model whose target space geometry consists of a transitive Lie algebroid with complex structure on a Kaehler manifold. We show that, under certain geometrical and topological conditions, there are two distinguished topological half--twists of the heterotic sigma model leading to A and B type half--topological models. Each of these models is characterized by the usual topological BRST operator, stemming from the heterotic (0,2) supersymmetry, and a second BRST operator anticommuting with the former, originating from the (1,0) supersymmetry. These BRST operators combined in a certain way provide each half--topological model with two inequivalent BRST structures and, correspondingly, two distinct perturbative chiral algebras and chiral rings. The latter are studied in detail and characterized geometrically in terms of Lie algebroid cohomology in the quasiclassical limit.Comment: 83 pages, no figures, 2 references adde

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

Background: ‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. / Methods: Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. / Findings: Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation. / Interpretation: Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. / Funding: Axcella Therapeutics

Autonomous stochastic resonance in fully frustrated Josephson-junction ladders

We investigate autonomous stochastic resonance in fully frustrated Josephson-junction ladders, which are driven by uniform constant currents. At zero temperature large currents induce oscillations between the two ground states, while for small currents the lattice potential forces the system to remain in one of the two states. At finite temperatures, on the other hand, oscillations between the two states develop even below the critical current; the signal-to-noise ratio is found to display array-enhanced stochastic resonance. It is suggested that such behavior may be observed experimentally through the measurement of the staggered voltage.Comment: 6 pages, 11 figures, to be published in Phys. Rev.

Absence of association between pyronaridine in vitro responses and polymorphisms in genes involved in quinoline resistance in Plasmodium falciparum

<p>Abstract</p> <p>Background</p> <p>The aim of the present work was to assess the <it>in vitro </it>cross-resistance of pyronaridine with other quinoline drugs, artesunate and several other commonly used anti-malarials and to evaluate whether decreased susceptibility to pyronaridine could be associated with genetic polymorphisms in genes involved in reduced quinoline susceptibility, such as <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>and <it>pfnhe</it>.</p> <p>Methods</p> <p>The <it>in vitro </it>chemosusceptibility profiles of 23 strains of <it>Plasmodium falciparum </it>were analysed by the standard 42-hour ³H-hypoxanthine uptake inhibition method for pyronaridine, artesunate, chloroquine, monodesethylamodiaquine, quinine, mefloquine, lumefantrine, atovaquone, pyrimethamine and doxycycline. Genotypes were assessed for <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfnhe-1 </it>and <it>pfmrp </it>genes.</p> <p>Results</p> <p>The IC₅₀values for pyronaridine ranged from 15 to 49 nM (geometric mean = 23.1 nM). A significant positive correlation was found between responses to pyronaridine and responses to artesunate (<it>r²</it>= 0.20; <it>P </it>= 0.0317) but too low to suggest cross-resistance. No significant correlation was found between pyronaridine IC₅₀and responses to other anti-malarials. Significant associations were not found between pyronaridine IC₅₀and polymorphisms in <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>or <it>pfnhe-1</it>.</p> <p>Conclusion</p> <p>There was an absence of cross-resistance between pyronaridine and quinolines, and the IC₅₀values for pyronaridine were found to be unrelated to mutations in the transport protein genes <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfmrp </it>or <it>pfnhe-1</it>, known to be involved in quinoline resistance. These results confirm the interest and the efficacy of the use of a combination of pyronaridine and artesunate in areas in which parasites are resistant to quinolines.</p

Geophysical Survey in Sub-Saharan Africa: magnetic and Electromagnetic Investigation of the UNESCO World Heritage Site of Songo Mnara, Tanzania

Magnetometry and Slingram electromagnetic surveys were conducted at the UNESCO World Heritage Site of Songo Mnara, Tanzania, as part of a multi-national programme of investigation to examine the uses of space within and outside of this stonetown. The town was a major Islamic trading port during the 14th and 15th centuries.The surveys detected significant evidence for the containment of activities within the town walls, and previously unknown anthropogenic activity was revealed between the existing coral rag buildings, as well as within the open areas inside the town. Over 40 areas of magnetic disturbance were identified that corresponded directly with areas of high magnetic susceptibility in the Slingram electromagnetic in-phase responses.On excavation many of these anomalies were found to correlate with wattle and daub structures, indicating a hitherto unidentified population, and the location of the anomalies also suggests a potentially deliberate delineation of space within the open areas of the stonetown. The combined results of the three geophysical data sets indicate that there are clear delineations in the use of space within Songo Mnara. This coupled with the presence of industrial activities and evidence of more ephemeral occupation, neither of which had previously been recorded at the site, indicates that the pre-existing town plan is in need of significant reappraisal. The current plan, based upon the remains of extant and collapsed coral buildings, can now be updated to incorporate the more ephemeral aspects of Swahili sites including activity areas, and notably, the homes of the ‘hidden majority’of the population.The results establish the benefit of a combined approach at these sites, and demonstrate that further invasive and non-invasive exploration is required in order to fully exploit the significance of the role of geophysical techniques in understanding Swahili towns

Jacobi structures revisited

Jacobi algebroids, that is graded Lie brackets on the Grassmann algebra associated with a vector bundle which satisfy a property similar to that of the Jacobi brackets, are introduced. They turn out to be equivalent to generalized Lie algebroids in the sense of Iglesias and Marrero and can be viewed also as odd Jacobi brackets on the supermanifolds associated with the vector bundles. Jacobi bialgebroids are defined in the same manner. A lifting procedure of elements of this Grassmann algebra to multivector fields on the total space of the vector bundle which preserves the corresponding brackets is developed. This gives the possibility of associating canonically a Lie algebroid with any local Lie algebra in the sense of Kirillov.Comment: 20 page

The Tulczyjew triple for classical fields

The geometrical structure known as the Tulczyjew triple has proved to be very useful in describing mechanical systems, even those with singular Lagrangians or subject to constraints. Starting from basic concepts of variational calculus, we construct the Tulczyjew triple for first-order Field Theory. The important feature of our approach is that we do not postulate {\it ad hoc} the ingredients of the theory, but obtain them as unavoidable consequences of the variational calculus. This picture of Field Theory is covariant and complete, containing not only the Lagrangian formalism and Euler-Lagrange equations but also the phase space, the phase dynamics and the Hamiltonian formalism. Since the configuration space turns out to be an affine bundle, we have to use affine geometry, in particular the notion of the affine duality. In our formulation, the two maps $\alpha$ and $\beta$ which constitute the Tulczyjew triple are morphisms of double structures of affine-vector bundles. We discuss also the Legendre transformation, i.e. the transition between the Lagrangian and the Hamiltonian formulation of the first-order field theor

A complete lift for semisprays

In this paper, we define a complete lift for semisprays. If $S$ is a semispray on a manifold $M$, its complete lift is a new semispray $S^c$ on $TM$. The motivation for this lift is two-fold: First, geodesics for $S^c$ correspond to the Jacobi fields for $S$, and second, this complete lift generalizes and unifies previously known complete lifts for Riemannian metrics, affine connections, and regular Lagrangians. When $S$ is a spray, we prove that the projective geometry of $S^c$ uniquely determines $S$. We also study how symmetries and constants of motions for $S$ lift into symmetries and constants of motions for $S^c$

Geometric least squares means ratios for the analysis of Plasmodium falciparum in vitro susceptibility to antimalarial drugs

<p>Abstract</p> <p>Background</p> <p>The susceptibility of microbes such as <it>Plasmodium falciparum </it>to drugs is measured in vitro as the concentration of the drug achieving 50% of maximum effect (IC₅₀); values from a population are summarized as geometric means. For antimalarial drugs, as well as for antibiotics, assessing changes in microbe susceptibility over time under drug pressure would help inform treatment policy decisions, but no standard statistical method exists as yet.</p> <p>Methods</p> <p>A mixed model was generated on log_e-transformed IC₅₀values and calculated geometric least squares means (GLSM) with 90% confidence intervals (CIs). In order to compare IC₅₀s between years, GLSM ratios (GLSMR) with 90%CIs were calculated and, when both limits of the 90%CIs were below or above 100%, the difference was considered statistically significant. Results were compared to those obtained from ANOVA and a generalized linear model (GLM).</p> <p>Results</p> <p>GLSMRs were more conservative than ANOVA and resulted in lower levels of statistical significance. The GLSMRs approach allowed for random effect and adjustment for multiple comparisons. GLM was limited in the number of year-to-year comparisons by the need for a single reference year. The three analyses yielded generally consistent results.</p> <p>Conclusion</p> <p>A robust analytical method can palliate inherent limitations of in vitro sensitivity testing. The random effects GLSMRs with adjustment for multiple comparisons and 90%CIs require only assumptions on the mixed model to be applied. Results are easy to display graphically and to interpret. The GLMSRs should be considered as an option for monitoring changes in drug susceptibility of <it>P. falciparum </it>malaria and other microbes.</p