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There has been impressive progress in malaria control and treatment over the past two decades. One of the most important factors in the decline of malaria-related mortality has been the development and deployment of highly effective treatment in the form of artemisinin-based combination therapies (ACTs). However, recent reports suggest that these gains stand the risk of being reversed due to the emergence of ACT resistance in the Greater Mekong Subregion and the threat of this resistance spreading to Africa, where the majority of the world’s malaria cases occur, with catastrophic consequences. This chapter provides an overview of strategies proposed by malaria experts to tackle artemisinin-resistant malaria, and some of the most important practical ethical issues presented by each of these interventions. The proposed strategies include mass antimalarial drug administrations in selected populations, and mandatory screening of possibly infected individuals prior to entering an area free of artemisinin-resistant malaria. We discuss ethical issues such as tensions between the wishes of individuals versus the broader goal of malaria elimination, and the risks of harm to interventional populations, and conclude by proposing a set of recommendations.

Additional file2: Antimicrobial Resistance (AMR) Surveillance Report. Antimicrobial Resistance (AMR) Surveillance Report of the study site generated by AMASS

Additional file 1. Topic guide.

Additional file 1: Table S1. Households with and without registered household numbers (Survey at M0).

Following publication of the original article [1], it was brought to the authors' attention that one of the names in the author list had been provided with the incorrect spelling. Namely, Mehul Dhorda had been incorrectly spelled as Mehul Dorda. The error has since been corrected in the original article. The authors apologize for any inconvenience caused.

Additional file 5. Summary of point mutations in pmcrt and pmmdr1 and sampling times.

Additional file 3. The equivalence position of pmmdr1 gene compared with pfmdr1 and pvmdr1.

Additional file 3. The equivalence position of pmmdr1 gene compared with pfmdr1 and pvmdr1.

Additional file 4. Summary of point mutations in pmcrt and pmmdr1 and mixed P. malariae infections.

Additional file 4. Summary of point mutations in pmcrt and pmmdr1 and mixed P. malariae infections.

Additional file 2. The PCR primers and condition for amplification of pmmdr1 gene.

Additional file 1. The PCR primers and condition for amplification of pmcrt gene.

Additional file 5. Summary of point mutations in pmcrt and pmmdr1 and sampling times.

Additional file 2. The PCR primers and condition for amplification of pmmdr1 gene.

International audience; Background: Sample size calculations for cluster randomized trials are a recognized methodological challenge for malaria research in pre-elimination settings. Positively correlated responses from the participants in the same cluster are a key feature in the estimated sample size required for a cluster randomized trial. The degree of correlation is measured by the intracluster correlation coefficient (ICC) where a higher coefficient suggests a closer correlation hence less heterogeneity within clusters but more heterogeneity between clusters. Methods: Data on uPCR-detected Plasmodium falciparum and Plasmodium vivax infections from a recent cluster randomized trial which aimed at interrupting malaria transmission through mass drug administrations were used to calculate the ICCs for prevalence and incidence of Plasmodium infections. The trial was conducted in four countries in the Greater Mekong Subregion, Laos, Myanmar, Vietnam and Cambodia. Exact and simulation approaches were used to estimate ICC values for both the prevalence and the incidence of parasitaemia. In addition, the latent variable approach to estimate ICCs for the prevalence was utilized. Results: The ICCs for prevalence ranged between 0.001 and 0.082 for all countries. The ICC from the combined 16 villages in the Greater Mekong Subregion were 0.26 and 0.21 for P. falciparum and P. vivax respectively. The ICCs for incidence of parasitaemia ranged between 0.002 and 0.075 for Myanmar, Cambodia and Vietnam. There were very high ICCs for incidence in the range of 0.701 to 0.806 in Laos during follow-up. Conclusion: ICC estimates can help researchers when designing malaria cluster randomized trials. A high variability in ICCs and hence sample size requirements between study sites was observed. Realistic sample size estimates for cluster randomized malaria trials in the Greater Mekong Subregion have to assume high between cluster heterogene-ity and ICCs. This work focused on uPCR-detected infections; there remains a need to develop more ICC references © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

Background Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (, Joel Tarning and colleagues combine individual participant data from clinical trials to develop a pharmacokinetic model and derive an optimized dose regimen for malaria treatment in children., Author Summary Why Was This Study Done? Despite expansion of malaria prevention and treatment in the last decade, malaria still kills around 1,200 people each day, mostly children below the age of five. Reduced drug exposure to one of the commonly used antimalarial drug combinations, dihydroartemisinin-piperaquine, has been reported in small children. It is crucial to develop an optimised dose regimen that achieves similar drug exposure in all patient groups, in order to give all patients an equal chance of cure. What Did the Researchers Do and Find? Drug concentration–time data (8,776 piperaquine concentration measurements) from 728 individuals in 11 separate clinical trials were collated and pooled for an individual participant data meta-analysis. A pharmacokinetic model was developed to describe the pharmacological properties of piperaquine, the expected variability between patients, and the influence of biologically important covariates. Small children had a substantially lower piperaquine exposure after recommended dosing regimens. The developed pharmacokinetic model was used to derive a new optimised dose regimen. What Do These Findings Mean? The proposed improved dose regimen of dihydroartemisinin-piperaquine is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. An optimised dose regimen should prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development.

Economic evaluation using dynamic transmission models is important for capturing the indirect effects of infectious disease interventions. We examine the use of these methods in low‐ and middle‐income countries, where infectious diseases constitute a major burden. This review is comprised of two parts: (1) a summary of dynamic transmission economic evaluations across all disease areas published between 2011 and mid‐2014 and (2) an in‐depth review of mosquito‐borne disease studies focusing on health economic methods and reporting. Studies were identified through a systematic search of the MEDLINE database and supplemented by reference list screening. Fifty‐seven studies were eligible for inclusion in the all‐disease review. The most common subject disease was HIV/AIDS, followed by malaria. A diverse range of modelling methods, outcome metrics and sensitivity analyses were used, indicating little standardisation. Seventeen studies were included in the mosquito‐borne disease review. With notable exceptions, most studies did not employ economic evaluation methods beyond calculating a cost‐effectiveness ratio or net benefit. Many did not adhere to health care economic evaluations reporting guidelines, particularly with respect to full model reporting and uncertainty analysis. We present a summary of the state‐of‐the‐art and offer recommendations for improved implementation and reporting of health economic methods in this crossover discipline. © 2016 The Authors. Health Economics published by John Wiley & Sons Ltd.

Background In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria. Methods and Findings We measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falciparum malaria of varying severity hospitalised on the Thai–Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 × 1011 (95% confidence interval [CI] 5.8 × 1011 to 8.5 × 1011) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 × 1012, 95% CI 1.3 × 1012 to 2.3 × 1012) than in patients hospitalised without signs of severity (geometric mean 2.8 × 1011, 95% CI 2.3 × 1011 to 3.5 × 1011; p < 0.001). Parasite burden was highest in patients who died (geometric mean 3.4 × 1012, 95% CI 1.9 × 1012 to 6.3 × 1012; p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony—but in severe malaria is unrelated to stage of parasite development. Conclusion Plasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes., Measuring sequestered parasites using plasma PfHRP2 concentrations may provide a more accurate estimate of total parasite mass and hence severity in falciparum malaria.

Additional file 1: Table S1. Orientia tsutsugamushi PCR positivity by organ type and small mammal species. Table S2. Habitat classification scheme. Table S3. List of the most common plants identified at the study sites (1 = Ban Thoet Thai, 2 = Ban Song Kwair, 3 = Ban Mae Mon). Figure S1. Spatial distribution over time of all trap positions and O. tsutsugamushi-positive chigger pools, individual chiggers and small mammals for Ban Thoet Thai. This is the major town of the sub-district of Mae Fahluang district. Population: approx. 5,000; elevation: 550 m a.s.l.; mixed hill tribe ethnicities. Study site is located along a small river, encompassing rice fields, vegetable/fruit gardens, patches of fallow areas, degraded secondary forest and a few homes. Figure S2. Spatial distribution over time of all trap positions and O. tsutsugamushi-positive chigger pools, individual chiggers and small mammals for Ban Song Kwair. Home of human case is shown with star. This is an isolated small village in Mae Yao sub-district. Population: approx. 150; elevation: 650 m a.s.l.; Akha hilltribe village, predominantly with traditional wooden stilt homes. Study site is located beside a fast-flowing stream, at the head of the valley; it is surrounded by mixed secondary forest, teak plantation, fallow areas and bamboo groves, and there are patches of dry rice, corn and pineapple plantations. Figure S3. Spatial distribution over time of all trap positions and O. tsutsugamushi-positive chigger pools, individual chiggers and small mammals for Ban Mae Mon. Home of human case shown with star. The village is located in Huay Chomphu sub-district. Population: approx. 1500; elevation: 1200 m a.s.l.; mixed village of Akha and Lisu hill tribe people, predominantly concrete constructed homes. The village located on the steep slope of a ridge, surrounded by coffee, fruit and vegetable plantations, fallow areas and a small secondary forest. Figure S4. Non-quantitative nestedness matrix, bipartitie network, sub-community modules and unipartite network models for O. tsutsugamushi-positive chigger/small mammal and habitat interactions. The modules are shown by different colours. The most centrally located node has an Eigenvector score closest to 1. Figure S5. Matrix of Goodman and Kruskal’s τ test for categorical variables describing small mammal and chigger species and the environment.

Additional file 1: Table S1. Orientia tsutsugamushi PCR positivity by organ type and small mammal species. Table S2. Habitat classification scheme. Table S3. List of the most common plants identified at the study sites (1 = Ban Thoet Thai, 2 = Ban Song Kwair, 3 = Ban Mae Mon). Figure S1. Spatial distribution over time of all trap positions and O. tsutsugamushi-positive chigger pools, individual chiggers and small mammals for Ban Thoet Thai. This is the major town of the sub-district of Mae Fahluang district. Population: approx. 5,000; elevation: 550 m a.s.l.; mixed hill tribe ethnicities. Study site is located along a small river, encompassing rice fields, vegetable/fruit gardens, patches of fallow areas, degraded secondary forest and a few homes. Figure S2. Spatial distribution over time of all trap positions and O. tsutsugamushi-positive chigger pools, individual chiggers and small mammals for Ban Song Kwair. Home of human case is shown with star. This is an isolated small village in Mae Yao sub-district. Population: approx. 150; elevation: 650 m a.s.l.; Akha hilltribe village, predominantly with traditional wooden stilt homes. Study site is located beside a fast-flowing stream, at the head of the valley; it is surrounded by mixed secondary forest, teak plantation, fallow areas and bamboo groves, and there are patches of dry rice, corn and pineapple plantations. Figure S3. Spatial distribution over time of all trap positions and O. tsutsugamushi-positive chigger pools, individual chiggers and small mammals for Ban Mae Mon. Home of human case shown with star. The village is located in Huay Chomphu sub-district. Population: approx. 1500; elevation: 1200 m a.s.l.; mixed village of Akha and Lisu hill tribe people, predominantly concrete constructed homes. The village located on the steep slope of a ridge, surrounded by coffee, fruit and vegetable plantations, fallow areas and a small secondary forest. Figure S4. Non-quantitative nestedness matrix, bipartitie network, sub-community modules and unipartite network models for O. tsutsugamushi-positive chigger/small mammal and habitat interactions. The modules are shown by different colours. The most centrally located node has an Eigenvector score closest to 1. Figure S5. Matrix of Goodman and Kruskal’s τ test for categorical variables describing small mammal and chigger species and the environment.

Background: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. Methods and findings: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (−61.77 milliseconds; 95% credible interval [CI]: −80.71 to −42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (−110.89 milliseconds; 95% CI: −140.38 to −81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: −3.17 to −2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. Conclusions: Adjustment for malaria and fever-recovery–related QT lengthening is necessary to avoid misattributing malaria-disease–related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval–prolonging medications are important therapeutic options.

Funder: Thailand National Science and Technology Development Agency (FDA-CO-2562-8764-TH) and Thailand Science Research and Innovation fund (MRG6280226), Funder: Food Standards Agency Fellow and is supported by the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent projects BBS/E/F/000PR10348 (Theme 1, Epidemiology and Evolution of Pathogens in the Food Chain) and BBS/E/F/000PR10351 (Theme 3, Microbial Communities in the Food Chain), The environmental bacterium Burkholderia pseudomallei causes melioidosis, an important endemic human disease in tropical and sub-tropical countries. This bacterium occupies broad ecological niches including soil, contaminated water, single-cell microbes, plants and infection in a range of animal species. Here, we performed genome-wide association studies for genetic determinants of environmental and human adaptation using a combined dataset of 1,010 whole genome sequences of B. pseudomallei from Northeast Thailand and Australia, representing two major disease hotspots. With these data, we identified 47 genes from 26 distinct loci associated with clinical or environmental isolates from Thailand and replicated 12 genes in an independent Australian cohort. We next outlined the selective pressures on the genetic loci (dN/dS) and the frequency at which they had been gained or lost throughout their evolutionary history, reflecting the bacterial adaptability to a wide range of ecological niches. Finally, we highlighted loci likely implicated in human disease.

Background:National notifiable diseases surveillance system (NNDSS) data in developing countries are usually incomplete, yet the total number of fatal cases reported is commonly used in national priority-setting. Melioidosis, an infectious disease caused by Burkholderia pseudomallei, is largely underrecognized by policy-makers due to the underreporting of fatal cases via the NNDSS. Methods:Collaborating with the Epidemiology Division (ED), Ministry of Public Health (MoPH), we conducted a retrospective study to determine the incidence and mortality of melioidosis cases already identified by clinical microbiology laboratories nationwide. A case of melioidosis was defined as a patient with any clinical specimen culture positive for B. pseudomallei. Routinely available microbiology and hospital databases of secondary care and tertiary care hospitals, the national death registry, and NNDSS data were obtained for analysis. Results:A total of 7126 culture-confirmed melioidosis patients were identified from 2012 to 2015 in 60 hospitals countrywide. The total number of cases diagnosed in Northeast, Central, South, East, North, and West Thailand were 5475, 536, 374, 364, 358, and 19 cases, respectively. The overall 30-day mortality was 39% (2805/7126). Only 126 (4%) deaths were reported to the NNDSS. Age, presentation with bacteremia and pneumonia, prevalence of diabetes, and 30-day mortality differed by geographical region (all P < .001). The ED at MoPH has agreed to include the findings of our study in the next annual report of the NNDSS. Conclusions:Melioidosis is an important cause of death in Thailand nationwide, and its clinical epidemiology may be different by region. In developing countries, NNDSS data can be supplemented by integrating information from readily available routine data sets.

Background Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. Methods and findings We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (−61.77 milliseconds; 95% credible interval [CI]: −80.71 to −42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (−110.89 milliseconds; 95% CI: −140.38 to −81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: −3.17 to −2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. Conclusions Adjustment for malaria and fever-recovery–related QT lengthening is necessary to avoid misattributing malaria-disease–related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval–prolonging medications are important therapeutic options., Xin Hui Chan and co-workers report an individual patient data meta-analysis on disease-specific heart rhythm alterations in malaria., Author summary Why was this study done? Prolongation of the electrocardiographic (ECG) QT interval is a widely used marker of the risk of developing abnormal heart rhythms, which can cause sudden death. Several antimalarial drugs are associated with QT interval prolongation, motivating systematic ECG safety monitoring in many malaria clinical studies. Malaria illness itself may also affect the heart and QT interval, but these disease effects are not well-understood. Interpretation of ECG changes after antimalarial treatment is complicated by the coincidence of peak antimalarial drug concentrations with malaria recovery. What did the researchers do and find? We performed a systematic review and meta-analysis of individual patient data to investigate the effect of malaria disease factors on the ECG QT interval. We included pretreatment data from 10,452 individuals (9,778 malaria patients and 674 healthy participants) from 43 studies in 20 countries. Malaria was associated with QT interval shortening and increased sensitivity of the QT interval to heart rate changes, and these effects increased with malaria severity. Body temperature increase (fever) was associated independently with clinically significant QT shortening. What do these findings mean? To improve cardiac safety assessments of antimalarial medicines, adjustment for malaria recovery- and defervescence-related QT interval prolongation is needed to avoid misattributing QT changes solely to drugs. These findings are relevant to drug developers, healthcare providers, clinical trialists, and policymakers who use QT interval safety data to decide which antimalarials to develop and use and at what dose. Further study of the QT interval in other infections and inflammatory disorders that cause fever and are treated with QT-prolonging medicines is recommended in order to understand the role of disease factors in QT interval changes.

2021 Annual Report for the MORU Tropical Health Network, Mahidol Oxford Tropical Medicine Research Unit