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Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

Introduction Malaria is widespread in countries located in tropical and sub-tropical regions, where an estimated 3.2 billion people, nearly half of the world ’s population, are at risk of infection [ 79 ]. Among the five species of Plasmodium that infect humans, Plasmodium falciparum is the most virulent, with the highest rates of complications and mortality as well as the most frequent incidence of red blood cell disorders worldwide [ 12 ]. Of the estimated 216 million cases in 2016, falciparum malaria accounted for 99% of cases in Africa, 77% of cases in the Western Paci fic Region, 66% of cases in Southeast Asia, 58% of cases in the Eastern Mediterranean Region, and 36% of cases in America [ 79 ]. Over 91% of the estimated 445 000 global deaths from malaria in 2016 occurred in Sub-Saharan Africa, primarily among children less than five years of age [ 13 , 79 ]. Over the last 17 years, important measures have been put in place to prevent malaria, leading to a 60% reduction in its worldwide death toll. A decrease of 18% in the incidence of malaria cases was also reported from 2010 to 2016 [ 79 ]. This signi ficant decrease in malaria incidence is the result of both preventive measures, such as the massive distribution of insecticide-treated nets, vector control strategies, and rapid diagnostic tests, as well as the use of artemisinin-based combination therapies (ACTs) in curative therapy. ACTs, recommended by the World Health Organization (WHO), are currently used as the first-line antimalarial treatment worldwide [ 79 ]. However, the current efforts to reduce the global burden of malaria are threatened by the rapid emergence and spread of P. falciparum resistance to ACTs including artemisinin derivatives and their partner drugs.
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Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in rural health facilities in southern Cameroon

Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in rural health facilities in southern Cameroon

Conclusion: The present study indicates that AS/AQ was not available in the public health facilities at the time of the study, and health practitioners were not informed about the new treatment guidelines. Results of qualitative analysis suggest that prescribers should be involved as soon as possible in projects related to the optimization of treatment guidelines and comply with new drugs. Adapted formulations should be made available at the international level and implemented locally before new drugs and treatments are proposed through a national control programme. This baseline information will be useful to monitor progresses in the implementation of artemisinin- based combination therapy in Cameroon.
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en fr Between financial capitalism and humanitarian concerns: value, price and profits of hepatitis C antivirals and artemisinin-based combinations therapies for malaria Entre capitalisme financier et préoccupations humanitaires : valeur, prix et profit des antiviraux contre l’hépatite C et des combinaisons à base d’artémisinine contre le paludisme

I will now look at the development, appropriation, production and distribution of an artemisinin-based combination, ASAQ, used primarily in malaria endemic regions in Africa to treat the simplest forms of malaria that are resistant to former treatments (chloroquine, sulfadoxine-pyriméthamine). This was a therapeutic innovation put on the market by Sanofi in 2008, when it also obtained a WHO pre-qualification. Unlike sofosbuvir, which had involved considerable capital investments, ASAQ was noteworthy for its low capital inputs. This frugal capitalistic regime is explained by the history and economics of its invention, and especially the types of capital involved, the appropriation regime adopted, the low-income populations targeted, and the governance of this economy by a humanitarian organization: MSF/DNDI 40 . While the (Duke University Press, 2006), K.S. Rajan pointed out this disconnection between speculative and industrial capital with regard to the biotech sector and the pharmaceutical sector in the US. I discussed this issue in Actual Marx in 2003 : Cassier M., L’expansion du capitalisme dans le domaine du vivant : droits de propriété intellectuelle et marchés de la science, de la matière biologique et de la santé (Capitalism’s Expansion into the Realm of the Biosphere),
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Molecular monitoring of plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaoundé, Cameroon: Implications for the future

Molecular monitoring of plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaoundé, Cameroon: Implications for the future

Abstract Background: Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ), previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ) monotherapy. Then, artemisinin-based combination therapy (ACT), notably artesunate-amodiaquine (AS-AQ) or artemether-lumefantrine (AL), was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaoundé, a highly urbanized Cameroonian city.
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Repeated Artemisinin-Based Combination Therapies in a Malaria Hyperendemic Area of Mali: Efficacy, Safety, and Public Health Impact

Repeated Artemisinin-Based Combination Therapies in a Malaria Hyperendemic Area of Mali: Efficacy, Safety, and Public Health Impact

Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, University of Bamako, Bamako, Mali; Aix-Marseille University, Marseille, France Abstract. Artemisinin-based combination therapies (ACTs) are the first-line treatment of uncomplicated malaria. The public health benefit and safety of repeated administration of a given ACT are poorly studied. We conducted a randomized trial comparing artemether-lumefantrine, artesunate plus amodiaquine (AS+AQ) and artesunate plus sulfadoxine-pyrimethamine (AS+SP) in patients 6 months of age and older with uncomplicated malaria in Mali from July 2005 to July 2007. The patient received the same initial treatment of each subsequent uncomplicated malaria episode except for treatment failures where quinine was used. Overall, 780 patients were included. Patients in the AS+AQ and AS+SP arms had significantly less risk of having malaria episodes; risk ratio (RR) = 0.84 (P = 0.002) and RR = 0.80 (P = 0.001), respectively. The treatment efficacy was similar and above 95% in all arms. Although all drugs were highly efficacious and well tolerated, AS+AQ and AS+SP were associated with less episodes of malaria.
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Low use of artemisinin-based combination therapy for febrile children under five and barriers to correct fever management in Benin: a decade after WHO recommendation

Low use of artemisinin-based combination therapy for febrile children under five and barriers to correct fever management in Benin: a decade after WHO recommendation

Background According to the World Health Organization (WHO), children under five years of age are the most vulnerable group affected by malaria. In 2015, an estimated 429,000 malaria deaths occurred globally in the world and 70% of those deaths were by children under five. Amongst 23 African countries, a large proportion of febrile children (36%) are not taken to a health facility to receive care [1]. When prevention fails, effective malaria case management is the key for malaria control. Severe cases and death attributed to malaria can be avoided if families, especially caregivers, know the symptoms of malaria and can provide appropriate treatment as quickly as possible. Artemisinin-based combination ther- apy (ACT) is used for the treatment of malaria cases in areas where Plasmodium species are resistant to certain anti-malarial drugs. The decreasing cost of ACT, espe- cially in the public sector with subsidies from the Global Fund (GF) and other funders, has led to its adoption by many endemic countries. In settings where parasito- logical diagnosis is not possible, anti-malarial treatment must be provided based on the likelihood that the illness is malaria [2]. A large proportion of fever cases, espe- cially in Africa, are treated as cases of malaria without parasitological confirmation (50 to 90%) [1, 3–5] and most febrile children under five years of age are taken care of at home [6]. Care-seeking at health centres (HC) was not immediate and typically occurred with delay [7]. In certain sub-Saharan countries, Integrated Manage- ment of Childhood Illness (IMCI) was introduced into the community case management of fever instead of treatment at HC. The IMCI strategy focuses on malaria, diarrhoea, pneumonia, and malnutrition diagnosis and treatment [8]. This approach requires malaria parasito- logical diagnosis before treatment with ACT [9].
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China and the circulation of artemisinin-based malaria treatment in the Comoros Union

China and the circulation of artemisinin-based malaria treatment in the Comoros Union

The Nobel Prize in Medicine delivered for the discovery of artemisinin (青蒿素) to Tu Youyou in October 2015 was remarkable in at least two ways: first, never before has a development emerging from traditional Chinese medicine been recognized with such an important award, and second, this was the first time any researcher working in China has been selected for this prize. Artemisinin-based treatment for malaria has changed the face of disease treatment in sub-Saharan Africa, reducing deaths and provoking new regulations to control the medication’s use and availability.
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Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in urban health facilities in Yaoundé, central province, Cameroon

Treatment of malaria from monotherapy to artemisinin-based combination therapy by health professionals in urban health facilities in Yaoundé, central province, Cameroon

Recently, WHO proposed modifications of endemic countries guidelines, changing from monotherapy to artemisinin-based combination therapy (ACT). In view of this, and after a scientific consensus meeting held in Janu- ary 2004, the National Malaria Control Programme of Cameroon announced that amodiaquine will be replaced by the combination artesunate-amodiaquine (AS/AQ) (artesunate 4 mg/kg/day, amodiaquine 10 mg/kg/day). This combination will be used as first-line therapy for three days for the treatment of uncomplicated malaria [3,4]. These guidelines clearly stated that (i) injectable quinine or injectable artemether would be administered only in case of drug failure or severe malaria, and (ii) artemisinin derivatives should not be given to pregnant women during the first trimester of gestation and quinine remained the recommended treatment for any malaria cases during pregnancy. The new treatment guidelines are based on a clinical (fever) and laboratory (thick blood smear) diagnosis procedure and recommend an evalua- tion of treatment efficacy by health professionals, four days post-treatment [4].
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Lack of artemisinin resistance in Plasmodium falciparum in northwest Benin after 10 years of use of artemisinin-based combination therapy

Lack of artemisinin resistance in Plasmodium falciparum in northwest Benin after 10 years of use of artemisinin-based combination therapy

Centre de santé de la Commune de Cobly, BP 40 Tanguiéta, Bénin Received 26 March 2016, Accepted 28 June 2016, Published online 21 July 2016 Abstract – Aim: In Benin, artemisinin-based combination therapy (ACT) has been recommended as the first-line treatment for uncomplicated Plasmodium falciparum malaria since 2004. The emergence in Southeast Asia of para- sites that are resistant to artemisinins poses a serious threat to global control of this disease. The presence of artemi- sinin resistance genotypes in parasite populations in Benin is currently unknown. The present study investigated the prevalence of relevant K13-propeller gene polymorphisms in parasite isolates from the north-western region of Benin. Method: Plasmodium falciparum isolates were collected from children with a confirmed diagnosis of malaria aged 6 months to 5 years in two towns, Cobly and Djougou, in the north-western part of Benin. The study was conducted during the rainy season from July to November 2014 in local health facilities. The K13-propeller gene was amplified in parasite isolates using nested PCR and subsequently sequenced. Results: A total of 108 children were recruited into the study. The efficiency of amplification reactions was 72% (78/108). The propeller domain of the K13 gene was successfully sequenced in 78 P. falciparum isolates; all of them were wild type with no polymorphisms detectable. Conclusion: The absence of mutations in the K13 gene indicates that P. falciparum parasite populations in the study area are still fully susceptible to artemisinins.
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A new geography of pharmaceuticals : Trajectories of artemisinin-based medicines

A new geography of pharmaceuticals : Trajectories of artemisinin-based medicines

The TDR archives show that WHO has been funding the initial research projects in China since 1979. Concerned about the rise in treatment resistance, WHO supports the work of Chinese researchers to speed the development of technologies for two promising artemisinin derivatives: artesunate and artemether. 10 Chinese institutions have already industrialized several artemisinin-based drugs that are registered in China, so WHO’s goal is to bring Chinese laboratories and factories in line with international standards. Wallace Peters, who headed the CHEMAL committee on anti-malaria drugs, points out the gap between the standards applied by China and international standards: “from the western regulatory point of view, there were big gaps in the Chinese toxicity and efficacy studies… but China wanted the drug sold and used, and was uncomfortable about TDR taking over this development work.” 11 ” In march 1982, TDR notes the non-respect of GMP standards: “the plant that is used to lyophilize the artesunate preparations does not conform to GMP. 12 ” TDR’s collaborative research agreement specifically targets the “development of a standardized formulation of artesunate and artemether” (June 1982). 13 The account published by the Chinese inventors on the WHO collaboration emphasizes the work of bringing Chinese factories up to standards (p 88–89). Between 1979 and 1986, TDR financed several collaborative research agreements at the Shanghai Institute of Materia Medica, the Beijing Institute of Materia Medica, and the Shanghai Research Institute of Pharmaceutical Industry. The funding covered the purchase of scientific equipment, the
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High-level artemisinin-resistance with quinine co-resistance emerges in P. falciparum malaria under in vivo artesunate pressure

High-level artemisinin-resistance with quinine co-resistance emerges in P. falciparum malaria under in vivo artesunate pressure

Rajeev K. Tyagi 1,2,7 † , Patrick J. Gleeson 1,2,8 † , Ludovic Arnold 1,2 † , Rachida Tahar 3,4 , Eric Prieur 1,2 , Laurent Decosterd 5 , Jean-Louis Pérignon 1,2,9 , Piero Olliaro 6 and Pierre Druilhe 1,2* Abstract Background: Humanity has become largely dependent on artemisinin derivatives for both the treatment and control of malaria, with few alternatives available. A Plasmodium falciparum phenotype with delayed parasite clearance during artemisinin-based combination therapy has established in Southeast Asia, and is emerging elsewhere. Therefore, we must know how fast, and by how much, artemisinin-resistance can strengthen. Methods: P. falciparum was subjected to discontinuous in vivo artemisinin drug pressure by capitalizing on a novel model that allows for long-lasting, high-parasite loads. Intravenous artesunate was administered, using either single flash-doses or a 2-day regimen, to P. falciparum-infected humanized NOD/SCID IL-2R γ −/
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Design, Synthesis and Efficacy of Hybrid Triclosan‐gold Based Molecules on Artemisinin‐resistant Plasmodium falciparum and Leishmania infantum Parasites

Design, Synthesis and Efficacy of Hybrid Triclosan‐gold Based Molecules on Artemisinin‐resistant Plasmodium falciparum and Leishmania infantum Parasites

The introduction of artemisinin and its derivatives contributed to the notable decrease of malaria mortality for the 20 last years. To reduce the risk of falciparum malaria drug resistance, the WHO recommended in 2001 to use ACTs (Artemisinin-based Combination Therapies) combining artemisinin derivatives with one or two other antimalarial drugs having different mode of action and pharmacokinetic properties. [2] However, the efficacy of these drug combinations declined in South- East Asia since 2006, due to the emergence and rapid spread of P. falciparum resistance to artemisinins and partner drugs. [3] This situation is increasingly alarming because, today, the most commonly used ACT in Asia, dihydroartemisinin-piperaquine, is no longer active on artemisinin- resistant parasites. [4,5] According to the countries, the ACTs failure rate is now up to 10% for one ACT, for two ACTs and even for the 5 ACTs. [6]
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Constraint-based reachability

Constraint-based reachability

Several authors have advocated the usage of constraints to represent an infinite set of states and the usage of constraint solvers to efficiently address reachability problems [6, 13, 16, 4]. In automated program verification problems, the goal is to find a state of the program which violates a given safety property, i.e., an unsafe state. Two distinct strategies have been investigated to explore programs with constraints, namely the forward analysis and the backward analysis strategies. In forward analysis, a set of reachable states is explored by computing the transition from the initial states of a program to the next states in forward way. If an unsafe state is detected to belong to the set of reachable states during this exploration then a property violation is reported. In backward analysis, states are computed from an hypotetical unsafe state in a backward way with the hope to discover that one of those is actually an initial state. One advantage of backward analysis over forward analysis is its usage of the targeted unsafe state to refine the state search space. However, both strategies are quite powerful and have been implemented into several software model checkers based on constraint solving [25, 16] and automated test case generators [29, 18, 17, 8, 3].
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Template Based MDE

Template Based MDE

Repository Figure 2: Template Based Model Engineering In this modeling space, designers of model templates are mainly concerned with “design for reuse” and the constitution of libraries (“o↵-the-shelf models”). For this purpose, they have to identify candidate model of functionnalities and represent them as model templates for enabling their reuse. Several activities (see Fig.2) are of interest for this engineering task :

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Making artemisinin

Making artemisinin

/ La version de cette publication peut être l’une des suivantes : la version prépublication de l’auteur, la version acceptée du manuscrit ou la version de l’éditeur. For the publisher’[r]

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DTM-based Filtrations

DTM-based Filtrations

Contributions. In this paper, we introduce and study a new family of filtrations based on the notion of DTM. Our contributions are the following: Given a set X ⊂ R d , a weight function f defined on X and p ∈ [1, +∞], we introduce the weighted Čech and Rips filtrations that extend the notion of sublevel set filtration of power distances of [3]. Using classical results, we show that these filtrations are stable with respect to perturbations of X in the Hausdorff metric and perturbations of f with respect to the sup norm (Propositions 3 and 4).

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Bio-based paints

Bio-based paints

Additives are compounds used in low concentrations (a few percent), whose function is to either promote or prevent some developments of the product. For example, surfactants improve the homogeneity of the dispersion. Some additives protect the film against mold or ultraviolet radiation, or against the formation of free radicals under the action of sunlight. Since the end of the 18 th century most of those paints are petroleum-based. But the near disappearance of the petroleum causes a renewed interest in bio-based preparations. In this communication, we present the bio-based alternatives that can replace petroleum-based products.
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Property Based Coordination

Property Based Coordination

The latter embeds the non-agent entities. With the observable properties, the entities composing the environment can be clustered into agent categories, messages typology etc. which can be available as meta-information in the system. The environment is re- sponsible of the aggregation of the filters to determine who perceives what (e.g. by a rule-based engine) and can restrict the interaction possibilities thanks to filters. In fu- ture works, we propose to investigate a formal model of actions in a system based on PBC and its dynamics. Applications from the transportation domain are implemented, in which we experiment new heuristics to solve the scheduling and routing problems, these heuristics are discovered thanks to the retained model of the environment. References
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A Motion-Based Feature for Event-Based Pattern Recognition

A Motion-Based Feature for Event-Based Pattern Recognition

Indeed the method in Clady et al. (2015) requires to memorize the stream of the visual motion events (see Equation 2) and spatiotemporal extrapolations of them (called “normal events”) and operates quite complex computations between them. In the approach presented in this article, the visual motion events are integrated directly in the neighboring features, and corner detection related computations are operated only using the feature at the spatiotemporal location of the current event. We have measured important differences in terms of computation time between their different implementations; e.g., for the event stream used for the above evaluations, the feature-based approaches are ∼10 times faster. Table 1 presents the distribution of mean computation times obtained with the different approaches and over 10 repetitions (for 1500 detections). But as the method in Clady et al. (2015) has been only implemented on Matlab (Matlab2015b), they should be taken with caution; it is indeed known that memory can be poorly managed on Matlab. Measuring the computation time without code lines dedicated to memory management (which is a crucial part of the method in Clady et al., 2015 ), the gain is still around 40%. While the geometric-based method is only envisioned in
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Query-based Comparison of Mappings in Ontology-based Data Access

Query-based Comparison of Mappings in Ontology-based Data Access

In addition, the OBDA specification plays a major role in query answering, since its form may affect the system per- formance in answering queries: different, yet semantically equivalent specifications may give rise to very different exe- cution times for the same query. Thus, the study of notions of equivalence and formal comparison of OBDA specifications is also important for optimizing query processing in OBDA systems. Indeed, some systems already implement forms of optimization based on such transformations (see, e.g., (Rodriguez-Muro, Kontchakov, and Zakharyaschev 2013)).

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