Combating poor-quality anti-malarial medicines: a call to action

The circulation of poor-quality medicines continues to undermine the fight against many life-threatening diseases. Anti-malarial medicines appear to have been particularly compromised and present a major public health threat in malaria-endemic countries, negatively affecting individuals and their communities. Concerted collaborative efforts are required from global, regional and national organizations, involving the public and private sectors, to address the problem. While many initiatives are underway, a number of unmet needs deserve urgent and increased multisector attention. At the global level, there is a need for an international public health legal framework or treaty on poor-quality medicines, with statutes suitable for integration into national laws. In addition, increased international efforts are required to strengthen the governance of global supply chains and enhance cooperation between national medicine regulation authorities and law enforcement bodies. Increased investment is needed in innovative technologies that will enable healthcare teams to detect poor-quality medicines at all levels of the supply chain. At the regional level, a number of initiatives would be beneficial-key areas are standardization, simplification, and reciprocal recognition of registration processes and development of quality control capacity in regional centres of excellence that are better aligned with public health needs; improved surveillance methods and creation of a framework for compulsory and transparent reporting of poor-quality medicines; additional support for national medicine regulation authorities and other national partner authorities; and an increase in support for regional laboratories to boost their capabilities in detecting poor-quality medicines. It is vital that all stakeholders involved in efforts against poor-quality anti-malarial medicines extend and strengthen their actions in these critical areas and thus effectively support global health development and malaria elimination programmes

Cohomology Groups of Deformations of Line Bundles on Complex Tori

The cohomology groups of line bundles over complex tori (or abelian varieties) are classically studied invariants of these spaces. In this article, we compute the cohomology groups of line bundles over various holomorphic, non-commutative deformations of complex tori. Our analysis interpolates between two extreme cases. The first case is a calculation of the space of (cohomological) theta functions for line bundles over constant, commutative deformations. The second case is a calculation of the cohomologies of non-commutative deformations of degree-zero line bundles.Comment: 24 pages, exposition improved, typos fixe

Calibrated cycles and T-duality

For Hitchin's generalised geometries we introduce and analyse the concept of a structured submanifold which encapsulates the classical notion of a calibrated submanifold. Under a suitable integrability condition on the ambient geometry, these generalised calibrated cycles minimise a functional occurring as D-brane energy in type II string theories, involving both so-called NS-NS- and R-R-fields. Further, we investigate the behaviour of calibrated cycles under T-duality and construct non-trivial examples.Comment: 43 pages. v4: formalism and T-duality part considerably expande

Electrochemical performances and post-operational characterization of a segmented sofc operated under load for 15k hours

In the frame of the ENDURANCE FCH-JU-FP7 project (2014-2017) a segmented cell (20 segments regularly distributed from fuel inlet to fuel outlet) was operated for 15k hours in co-flow at 750\ub0C (average temperature) in hydrogen under load. Each segment was carefully monitored during operation by periodically acquiring the impedance spectra and constantly checking the voltage under current load. After 15k hours of operation the test was stopped and the cell used for further investigations in order to compare the cell evolution with the segment degradation. The overall observation in cross section of the cell has shown a good stability, however some differences were observed in the electrodes that might be related to the local operating conditions: temperature, H2 /H2O ratio in the fuel stream. The gathered results will contribute to increase the understanding the evolution of a SOFC in real operating conditions. Evidences of the effect of temperature, time and fuel pollutants were found

Key Knowledge Gaps for Plasmodium vivax Control and Elimination

There is inadequate understanding of the biology, pathology, transmission, and control of Plasmodium vivax, the geographically most widespread cause of human malaria. During the last decades, study of this species was neglected, in part due to the erroneous belief that it is intrinsically benign. In addition, many technical challenges in culturing the parasite also hampered understanding its fundamental biology and molecular and cellular responses to chemotherapeutics. Research on vivax malaria needs to be substantially expanded over the next decade to accelerate its elimination and eradication. This article summarizes key knowledge gaps identified by researchers, national malaria control programs, and other stakeholders assembled by the World Health Organization to develop strategies for controlling and eliminating vivax malaria. The priorities presented in this article emerged in these technical discussions, and were adopted by expert consensus of the authors. All involved understood the priority placed upon pragmatism in this research agenda, that is, focus upon tools delivering better prevention, diagnosis, treatment, and surveillance of P. vivax

Fredholm Modules on P.C.F. Self-Similar Fractals and their Conformal Geometry

The aim of the present work is to show how, using the differential calculus associated to Dirichlet forms, it is possible to construct Fredholm modules on post critically finite fractals by regular harmonic structures. The modules are d-summable, the summability exponent d coinciding with the spectral dimension of the generalized laplacian operator associated with the regular harmonic structures. The characteristic tools of the noncommutative infinitesimal calculus allow to define a d-energy functional which is shown to be a self-similar conformal invariant.Comment: 16 page

Mirror duality and noncommutative tori

In this paper, we study a mirror duality on a generalized complex torus and a noncommutative complex torus. First, we derive a symplectic version of Riemann condition using mirror duality on ordinary complex tori. Based on this we will find a mirror correspondence on generalized complex tori and generalize the mirror duality on complex tori to the case of noncommutative complex tori.Comment: 22pages, no figure

Strategies for Understanding and Reducing the Plasmodium vivax and Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised Placebo-Controlled Trial and Mathematical Model

The undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge for malaria control and elimination in endemic countries. This study aims to directly determine the contribution of relapses to the burden of P. vivax and P. ovale infection, illness, and transmission in Papua New Guinean children.; From 17 August 2009 to 20 May 2010, 524 children aged 5-10 y from East Sepik Province in Papua New Guinea (PNG) participated in a randomised double-blind placebo-controlled trial of blood- plus liver-stage drugs (chloroquine [CQ], 3 d; artemether-lumefantrine [AL], 3 d; and primaquine [PQ], 20 d, 10 mg/kg total dose) (261 children) or blood-stage drugs only (CQ, 3 d; AL, 3 d; and placebo [PL], 20 d) (263 children). Participants, study staff, and investigators were blinded to the treatment allocation. Twenty children were excluded during the treatment phase (PQ arm: 14, PL arm: 6), and 504 were followed actively for 9 mo. During the follow-up time, 18 children (PQ arm: 7, PL arm: 11) were lost to follow-up. Main primary and secondary outcome measures were time to first P. vivax infection (by qPCR), time to first clinical episode, force of infection, gametocyte positivity, and time to first P. ovale infection (by PCR). A basic stochastic transmission model was developed to estimate the potential effect of mass drug administration (MDA) for the prevention of recurrent P. vivax infections. Targeting hypnozoites through PQ treatment reduced the risk of having at least one qPCR-detectable P. vivax or P. ovale infection during 8 mo of follow-up (P. vivax: PQ arm 0.63/y versus PL arm 2.62/y, HR = 0.18 [95% CI 0.14, 0.25], p < 0.001; P. ovale: 0.06 versus 0.14, HR = 0.31 [95% CI 0.13, 0.77], p = 0.011) and the risk of having at least one clinical P. vivax episode (HR = 0.25 [95% CI 0.11, 0.61], p = 0.002). PQ also reduced the molecular force of P. vivax blood-stage infection in the first 3 mo of follow-up (PQ arm 1.90/y versus PL arm 7.75/y, incidence rate ratio [IRR] = 0.21 [95% CI 0.15, 0.28], p < 0.001). Children who received PQ were less likely to carry P. vivax gametocytes (IRR = 0.27 [95% CI 0.19, 0.38], p < 0.001). PQ had a comparable effect irrespective of the presence of P. vivax blood-stage infection at the time of treatment (p = 0.14). Modelling revealed that mass screening and treatment with highly sensitive quantitative real-time PCR, or MDA with blood-stage treatment alone, would have only a transient effect on P. vivax transmission levels, while MDA that includes liver-stage treatment is predicted to be a highly effective strategy for P. vivax elimination. The inclusion of a directly observed 20-d treatment regime maximises the efficiency of hypnozoite clearance but limits the generalisability of results to real-world MDA programmes.; These results suggest that relapses cause approximately four of every five P. vivax infections and at least three of every five P. ovale infections in PNG children and are important in sustaining transmission. MDA campaigns combining blood- and liver-stage treatment are predicted to be a highly efficacious intervention for reducing P. vivax and P. ovale transmission.; ClinicalTrials.gov NCT02143934

A prospective cohort study to assess the micro-epidemiology of Plasmodium falciparum clinical malaria in Ilha Josina Machel (Manhiça, Mozambique)

Background: After the decrease in clinical malaria incidence observed in Mozambique until 2009, a steady resurgence of cases per year has been reported nationally, reaching alarming levels in 2014. However, little is known about the clinical profile of the cases presented, or the possible epidemiological factors contributing to the resurgence of cases. Methods: An analysis of surveillance data collected between July 2003 and June 2013 in the high malaria-transmission area of Ilha Josina Machel (Southern Mozambique) through a paediatric outpatient morbidity surveillance system was conducted to calculate hospital-based clinical malaria rates, slide-positivity rates, and minimum community-based incidence rates (MCBIRs) and incidence rate ratios per malaria season in children younger than 15 years of age. Clinical malaria was defined as a fever ≥37.5 °C or a reported fever in the previous 24 h with a positive blood smear. Yearly mean age, geometric mean parasitaemia (GMP) and mean packed cell volume (PCV) were also described for all clinical malaria cases and compared between seasons using DID analysis or ANOVA tests. Results: During the study period, the percentage of outpatient visits presenting with confirmed clinical malaria decreased from 51 % in the 2003–2004 season to 23 % in 2008–2009, followed by an increase back to 51 % in 2012–2013. The yearly mean age of cases significantly increased from 2.9 (95 % CI 2.8–3.0) in 2003–2004 to 5.7 (95 % CI 5.6–5.7) in 2012–2013, compared to non-malaria cases. An increase in mean PCV levels was also observed (p < 0.001), as well as in GMPs: from 5778 parasites/µL in 2002–2003 to 17,316 parasites/µL in 2012–2013 (p < 0.001) mainly driven by an increase in GMP in children older than 1 year of age. MCBIRs in infants decreased by 70 % (RR = 0.3, p < 0.001) between 2003–2004 and 2012–2013. Incidence diminished by a third among children 1- to 4-years between 2003 and 2007, although such drop was unsustained as observed in 2012–2013 (RR = 1.0, 95 % CI 0.9–1.0). Finally, the incidence among children 5–14 years was 3.8 (95 % CI 3.4–4.3) times higher in 2012–2013 compared to 2003–2004. Conclusion: Since 2003, Ilha Josina Machel observed a significant reduction of clinical malaria cases which was followed by an upsurge, following the national trend. A shift in the age distribution towards older children was observed, indicating that the changes in the transmission intensity patterns resulted in a slower acquisition of the naturally acquired immunity to malaria in children