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      Community engagement, social context and coverage of mass anti-malarial administration: Comparative findings from multi-site research in the Greater Mekong sub-Region

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          Abstract

          Background

          Between 2013 and 2017, targeted malaria elimination (TME), a package of interventions that includes mass drug administration (MDA)–was piloted in communities with reservoirs of asymptomatic P. falciparum across the Greater Mekong sub-Region (GMS). Coverage in target communities is a key determinant of the effectiveness of MDA. Drawing on mixed methods research conducted alongside TME pilot studies, this article examines the impact of the community engagement, local social context and study design on MDA coverage.

          Methods and findings

          Qualitative and quantitative data were collected using questionnaire-based surveys, semi-structured and in-depth interviews, focus group discussions, informal conversations, and observations of study activities. Over 1500 respondents were interviewed in Myanmar, Vietnam, Cambodia and Laos. Interview topics included attitudes to malaria and experiences of MDA. Overall coverage of mass anti-malarial administration was high, particularly participation in at least a single round (85%). Familiarity with and concern about malaria prompted participation in MDA; as did awareness of MDA and familiarity with the aim of eliminating malaria. Fear of adverse events and blood draws discouraged people. Hence, community engagement activities sought to address these concerns but their impact was mediated by the trust relationships that study staff could engender in communities. In contexts of weak healthcare infrastructure and (cash) poverty, communities valued the study’s ancillary care and the financial compensation. However, coverage did not necessarily decrease in the absence of cash compensation. Community dynamics, affected by politics, village conformity, and household decision-making also affected coverage.

          Conclusions

          The experimental nature of TME presented particular challenges to achieving high coverage. Nonetheless, the findings reflect those from studies of MDA under implementation conditions and offer useful guidance for potential regional roll-out of MDA: it is key to understand target communities and provide appropriate information in tailored ways, using community engagement that engenders trust.

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            A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

            Artemisinins are the corner stone of anti-malarial drugs 1 . Emergence and spread of resistance to them 2–4 raises risk of wiping out recent gains achieved in reducing world-wide malaria burden and threatens future malaria control and elimination on a global level. Genome wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance 5–10 . However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase as well as its lipid product phosphatidylinositol 3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signaling, where transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.
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              Review of Mass Drug Administration for Malaria and Its Operational Challenges

              Mass drug administration (MDA) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. Recently, however, there has been renewed interest in the role of MDA as an elimination tool. Following a 2013 Cochrane Review that focused on the quantitative effects of malaria MDA, we have conducted a systematic, qualitative review of published, unpublished, and gray literature documenting past MDA experiences. We have also consulted with field experts, using their historical experience to provide an informed, contextual perspective on the role of MDA in malaria elimination. Substantial knowledge gaps remain and more research is necessary, particularly on optimal target population size, methods to improve coverage, and primaquine safety. Despite these gaps, MDA has been used successfully to control and eliminate Plasmodium falciparum and P. vivax malaria in the past, and should be considered as part of a comprehensive malaria elimination strategy in specific settings.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: Writing – review & editing
                Role: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: Writing – review & editing
                Role: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                25 March 2019
                2019
                : 14
                : 3
                : e0214280
                Affiliations
                [1 ] Amsterdam Institute for Global Health and Development (AIGHD), Amsterdam, The Netherlands
                [2 ] Centre for Social Science and Global Health, University of Amsterdam, Amsterdam, The Netherlands
                [3 ] Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
                [4 ] Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
                [5 ] Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
                [6 ] Sorbonne Universités, UPMC Univ Paris 06, UPMC UMRS CR7, Paris, France
                [7 ] Ethox Centre and Wellcome Centre for Ethics and Humanities, Nuffield Department of Population Health, Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom
                [8 ] Medical Action Myanmar, Yangon, Myanmar
                [9 ] Myanmar Oxford Clinical Research Unit, Yangon, Myanmar
                [10 ] Oxford University Clinical Research Unit, Wellcome Trust Asia Programme, Ho Chi Minh City, Vietnam
                [11 ] National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
                [12 ] Savannakhet Provincial Health Department, Savannakhet Province, Laos
                [13 ] Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Vientiane, Lao PDR
                [14 ] Institute of Research and Educational Development, University of Health Sciences, Vientiane, Lao PDR
                Makerere University, UGANDA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9405-5851
                http://orcid.org/0000-0001-8981-3910
                http://orcid.org/0000-0002-7951-0745
                http://orcid.org/0000-0001-5948-5581
                http://orcid.org/0000-0002-3281-9702
                http://orcid.org/0000-0002-1897-1978
                http://orcid.org/0000-0002-0282-6469
                Article
                PONE-D-18-24841
                10.1371/journal.pone.0214280
                6433231
                30908523
                e8cb2af3-11bb-45f4-878d-6a380304fc97
                © 2019 Pell et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 August 2018
                : 11 March 2019
                Page count
                Figures: 2, Tables: 6, Pages: 28
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100010269, Wellcome Trust;
                Award Recipient :
                The TME pilots studies and the ancillary social science research is funded by the Bill and Melinda Gates Foundation (BMGF OPP1081420 - https://www.gatesfoundation.org/) (AD) and the Wellcome Trust (101148/Z/13/Z; https://wellcome.ac.uk/home) (AD, LvS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Parasitic Diseases
                Malaria
                Medicine and Health Sciences
                Tropical Diseases
                Malaria
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimalarials
                People and Places
                Geographical Locations
                Asia
                Myanmar
                People and Places
                Geographical Locations
                Asia
                Cambodia
                People and Places
                Geographical Locations
                Asia
                Laos
                Research and Analysis Methods
                Research Design
                Pilot Studies
                Biology and Life Sciences
                Parasitology
                Parasite Groups
                Apicomplexa
                Plasmodium
                Medicine and Health Sciences
                Pharmacology
                Adverse Reactions
                Custom metadata
                Data cannot be shared publicly because the informed consent that was obtained from respondents did not specify that data would be made publicly available and the public availability of data would compromise the privacy of respondents. The data are available upon request to the Mahidol Oxford Tropical Medicine Research Unit Data Access Committee ( http://www.tropmedres.ac/data-sharing) complying with the data access policy ( http://www.tropmedres.ac/_asset/file/data-sharing-policy-v1-0.pdf) for researchers who meet the criteria for access to confidential data.

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                Uncategorized

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