Mass drug administration for the acceleration of malaria elimination in a region of Myanmar with artemisinin-resistant falciparum malaria: a cluster-randomised trial

Background: To contain multidrug-resistant Plasmodium falciparum, malaria elimination in the Greater Mekong subregion needs to be accelerated while current antimalarials remain effective. We evaluated the safety, effectiveness, and potential resistance selection of dihydroartemisinin–piperaquine mass drug administration (MDA) in a region with artemisinin resistance in Myanmar. Methods: We did a cluster-randomised controlled trial in rural community clusters in Kayin (Karen) state in southeast Myanmar. Malaria prevalence was assessed using ultrasensitive quantitative PCR (uPCR) in villages that were operationally suitable for MDA (villages with community willingness, no other malaria control campaigns, and a population of 50–1200). Villages were eligible to participate if the prevalence of malaria (all species) in adults was greater than 30% or P falciparum prevalence was greater than 10% (or both). Contiguous villages were combined into clusters. Eligible clusters were paired based on P falciparum prevalence (estimates within 10%) and proximity. Community health workers provided routine malaria case management and distributed long-lasting insecticidal bed-nets (LLINs) in all clusters. Randomisation of clusters (1:1) to the MDA intervention group or control group was by public coin-flip. Group allocations were not concealed. Three MDA rounds (3 days of supervised dihydroartemisinin–piperaquine [target total dose 7 mg/kg dihydroartemisinin and 55 mg/kg piperaquine] and single low-dose primaquine [target dose 0·25 mg base per kg]) were delivered to intervention clusters. Parasitaemia prevalence was assessed at 3, 5, 10, 15, 21, 27, and 33 months. The primary outcomes were P falciparum prevalence at months 3 and 10. All clusters were included in the primary analysis. Adverse events were monitored from the first MDA dose until 1 month after the final dose, or until resolution of any adverse event occurring during follow-up. This trial is registered with ClinicalTrials.gov, NCT01872702. Findings: Baseline uPCR malaria surveys were done in January, 2015, in 43 villages that were operationally suitable for MDA (2671 individuals). 18 villages met the eligibility criteria. Three villages in close proximity were combined into one cluster because a border between them could not be defined. This gave a total of 16 clusters in eight pairs. In the intervention clusters, MDA was delivered from March 4 to March 17, from March 30 to April 10, and from April 27 to May 10, 2015. The weighted mean absolute difference in P falciparum prevalence in the MDA group relative to the control group was −10·6% (95% CI −15·1 to −6·1; p=0·0008) at month 3 and −4·5% (−10·9 to 1·9; p=0·14) at month 10. At month 3, the weighted P falciparum prevalence was 1·4% (0·6 to 3·6; 12 of 747) in the MDA group and 10·6% (7·0 to 15·6; 56 of 485) in the control group. Corresponding prevalences at month 10 were 3·2% (1·5 to 6·8; 34 of 1013) and 5·8% (2·5 to 12·9; 33 of 515). Adverse events were reported for 151 (3·6%) of 4173 treated individuals. The most common adverse events were dizziness (n=109) and rash or itching (n=20). No treatment-related deaths occurred. Interpretation: In this low-transmission setting, the substantial reduction in P falciparum prevalence resulting from support of community case management was accelerated by MDA. In addition to supporting community health worker case management and LLIN distribution, malaria elimination programmes should consider using MDA to reduce P falciparum prevalence rapidly in foci of higher transmission. Funding: The Global Fund to Fight AIDS, Tuberculosis and Malaria

Project-based learning module on creativity and entrepreneurship products subject: Validity and empirical effect

The learning process for Creativity and Entrepreneurship Products subjects in Vocational High Schools still uses printed books which are verbal in nature so this will make it difficult for students to learn the learning material. Apart from that, the learning method used the lecture method which is certainly less effective in supporting students' understanding of the material so that learning is more teacher-centred. Meanwhile, the demand for the current ‘Merdeka’ curriculum is that learning must be student-centered. This research aimed at developing learning tools of PjBL (Project Based Learning) based teaching modules on the Product Creativity and Entrepreneurship subjects. This research was a type of research and development using the ADDIE development model. There were 12 experts who validate this module from 3 aspects, namely material, media and model, and language aspects and there were 30 students for limited trials. The results of this research showed that this module was valid and has a positive effect in supporting the learning process for the Product Creativity and Entrepreneurship subjects. This research had implications for the effectiveness of Creativity and Entrepreneurship Products learning and being one method that can be used by teachers in this learning

Presence of Burkholderia pseudomallei in the 'Granary of Myanmar'.

Melioidosis is a frequently fatal infectious disease caused by the Gram negative bacillus Burkholderia pseudomallei. Although it was originally discovered in Myanmar, the disease disappeared from sight for many decades. This study focuses on detection of B. pseudomallei in soil in selected sampling sites in an attempt to start to fill the gaps in the current status of our knowledge of the geographical distribution of B. pseudomallei in soil in Myanmar. This cross-sectional study consists of 400 soil samples from 10 selected study townships from two major paddy growing regions. Bacterial isolation was done using a simplified method for the isolation of Burkholderia pseudomallei from soil. In this study, only 1% (4/400) of soil samples were found to be positive; two of four were found at 90 cm depth and another two positive samples were found at 30 cm and 60 cm. This survey has confirmed the presence of environmental B. pseudomallei in Myanmar indicating that the conditions are in place for melioidosis acquisition

Fully-automated patient-level malaria assessment on field-prepared thin blood film microscopy images, including Supplementary Information

Malaria is a life-threatening disease affecting millions. Microscopy-based assessment of thin blood films is a standard method to (i) determine malaria species and (ii) quantitate high-parasitemia infections. Full automation of malaria microscopy by machine learning (ML) is a challenging task because field-prepared slides vary widely in quality and presentation, and artifacts often heavily outnumber relatively rare parasites. In this work, we describe a complete, fully-automated framework for thin film malaria analysis that applies ML methods, including convolutional neural nets (CNNs), trained on a large and diverse dataset of field-prepared thin blood films. Quantitation and species identification results are close to sufficiently accurate for the concrete needs of drug resistance monitoring and clinical use-cases on field-prepared samples. We focus our methods and our performance metrics on the field use-case requirements. We discuss key issues and important metrics for the application of ML methods to malaria microscopy.Comment: 16 pages, 13 figure

Observational study of adult respiratory infections in primary care clinics in Myanmar: understanding the burden of melioidosis, tuberculosis and other infections not covered by empirical treatment regimes.

BACKGROUND: Lower respiratory infections constitute a major disease burden worldwide. Treatment is usually empiric and targeted towards typical bacterial pathogens. Understanding the prevalence of pathogens not covered by empirical treatment is important to improve diagnostic and treatment algorithms. METHODS: A prospective observational study in peri-urban communities of Yangon, Myanmar was conducted between July 2018 and April 2019. Sputum specimens of 299 adults presenting with fever and productive cough were tested for Mycobacterium tuberculosis (microscopy and GeneXpert MTB/RIF [Mycobacterium tuberculosis/resistance to rifampicin]) and Burkholderia pseudomallei (Active Melioidosis Detect Lateral Flow Assay and culture). Nasopharyngeal swabs underwent respiratory virus (influenza A, B, respiratory syncytial virus) polymerase chain reaction testing. RESULTS: Among 299 patients, 32% (95% confidence interval [CI] 26 to 37) were diagnosed with tuberculosis (TB), including 9 rifampicin-resistant cases. TB patients presented with a longer duration of fever (median 14 d) and productive cough (median 30 d) than non-TB patients (median fever duration 6 d, cough 7 d). One case of melioidosis pneumonia was detected by rapid test and confirmed by culture. Respiratory viruses were detected in 16% (95% CI 12 to 21) of patients. CONCLUSIONS: TB was very common in this population, suggesting that microscopy and GeneXpert MTB/RIF on all sputum samples should be routinely included in diagnostic algorithms for fever and cough. Melioidosis was uncommon in this population

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

Artemisinin resistant falciparum malaria in Myanmar

Artemisinin-based combination therapy (ACT) is first-line treatment for Plasmodium falciparum malaria globally but artemisinin resistance is now prevalent across Southeast Asia. Myanmar has the highest malaria burden in the region, and determining the prevalence of artemisinin resistance and current therapeutic efficacy of first-line antimalarial drugs is critical for both clinicians and policy makers planning malaria control and elimination programmes. The aim of this research was to study the geographical extent, prevalence, degree and optimum treatment of artemisinin-resistant falciparum malaria in Myanmar through a countrywide molecular survey and two multicentre clinical trials supported by parasitological and pharmacological investigations. In a molecular survey of clinical falciparum malaria cases carried out in 55 sites across 10 administrative regions and border sites in neighbouring countries 39% of cases (371/940) were associated with parasites carrying a kelch13 propeller mutation. Kelch13 mutation prevalence exceeded 10% in much of the east and north of the country and was 47% in an area 25 km from the border with India. In a trial conducted in central and northern Myanmar treatment efficacy of dihydroartemisinin-piperaquine (DP) was 100% but there was delayed parasite clearance associated with the kelch13 mutation F446I (median clearance half-life 4.7 hours, IQR, 3.7 to 6.2). In a randomised controlled trial of 3-days versus 5-days artemether-lumefantrine (AL) treatment efficacy was 100% (95%CI, 94.9-100) and 97% (95%CI, 90-99.7) respectively and the two arms showed equal clearance rates (measured by an ultrasensitive quantitative polymerase chain reaction assay, uqPCR)..There was no association between the presence of kelch13 propeller mutations and residual parasite density at day 21, measured using uqPCR. Gametocyte carriage rates were high reinforcing the need to implement single low-dose primaquine (0.25 mg/kg) with ACTs to kill gametocytes in this area of artemisinin resistance. In conclusion, artemisinin resistant falciparum malaria is widespread in Myanmar. While DP and AL remain efficacious, the partner drugs are vulnerable and if resistance develops treatment efficacy is likely to decline rapidly. Greater efforts are urgently needed to monitor treatment efficacy of first-line antimalarial drugs and develop alternative treatment regimens.</p

Artemisinin resistant falciparum malaria in Myanmar

Artemisinin-based combination therapy (ACT) is first-line treatment for Plasmodium falciparum malaria globally but artemisinin resistance is now prevalent across Southeast Asia. Myanmar has the highest malaria burden in the region, and determining the prevalence of artemisinin resistance and current therapeutic efficacy of first-line antimalarial drugs is critical for both clinicians and policy makers planning malaria control and elimination programmes. The aim of this research was to study the geographical extent, prevalence, degree and optimum treatment of artemisinin-resistant falciparum malaria in Myanmar through a countrywide molecular survey and two multicentre clinical trials supported by parasitological and pharmacological investigations. In a molecular survey of clinical falciparum malaria cases carried out in 55 sites across 10 administrative regions and border sites in neighbouring countries 39&percnt; of cases (371/940) were associated with parasites carrying a kelch13 propeller mutation. Kelch13 mutation prevalence exceeded 10&percnt; in much of the east and north of the country and was 47&percnt; in an area 25 km from the border with India. In a trial conducted in central and northern Myanmar treatment efficacy of dihydroartemisinin-piperaquine (DP) was 100&percnt; but there was delayed parasite clearance associated with the kelch13 mutation F446I (median clearance half-life 4.7 hours, IQR, 3.7 to 6.2). In a randomised controlled trial of 3-days versus 5-days artemether-lumefantrine (AL) treatment efficacy was 100&percnt; (95&percnt;CI, 94.9-100) and 97&percnt; (95&percnt;CI, 90-99.7) respectively and the two arms showed equal clearance rates (measured by an ultrasensitive quantitative polymerase chain reaction assay, uqPCR)..There was no association between the presence of kelch13 propeller mutations and residual parasite density at day 21, measured using uqPCR. Gametocyte carriage rates were high reinforcing the need to implement single low-dose primaquine (0.25 mg/kg) with ACTs to kill gametocytes in this area of artemisinin resistance. In conclusion, artemisinin resistant falciparum malaria is widespread in Myanmar. While DP and AL remain efficacious, the partner drugs are vulnerable and if resistance develops treatment efficacy is likely to decline rapidly. Greater efforts are urgently needed to monitor treatment efficacy of first-line antimalarial drugs and develop alternative treatment regimens.</p