Myanmar Oxford Clinical Research Unit

BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

BACKGROUND: Antimicrobial resistance (AMR) is widely acknowledged as a global problem, yet in many parts of the world its magnitude is still not well understood. This review, using a public health focused approach, aimed to understand and describe the current status of AMR in Africa in relation to common causes of infections and drugs recommended in WHO treatment guidelines. METHODS: PubMed, EMBASE and other relevant databases were searched for recent articles (2013-2016) in accordance with the PRISMA guidelines. Article retrieval and screening were done using a structured search string and strict inclusion/exclusion criteria. Median and interquartile ranges of percent resistance were calculated for each antibiotic-bacterium combination. RESULTS: AMR data was not available for 42.6% of the countries in the African continent. A total of 144 articles were included in the final analysis. 13 Gram negative and 5 Gram positive bacteria were tested against 37 different antibiotics. Penicillin resistance in Streptococcus pneumoniae was reported in 14/144studies (median resistance (MR): 26.7%). Further 18/53 (34.0%) of Haemophilus influenza isolates were resistant to amoxicillin. MR of Escherichia coli to amoxicillin, trimethoprim and gentamicin was 88.1%, 80.7% and 29.8% respectively. Ciprofloxacin resistance in Salmonella Typhi was rare. No documented ceftriaxone resistance in Neisseria gonorrhoeae was reported, while the MR for quinolone was 37.5%. Carbapenem resistance was common in Acinetobacter spp. and Pseudomonas aeruginosa but uncommon in Enterobacteriaceae. CONCLUSION: Our review highlights three important findings. First, recent AMR data is not available for more than 40% of the countries. Second, the level of resistance to commonly prescribed antibiotics was significant. Third, the quality of microbiological data is of serious concern. Our findings underline that to conserve our current arsenal of antibiotics it is imperative to address the gaps in AMR diagnostic standardization and reporting and use available information to optimize treatment guidelines.

Inflammatory bowel disease (IBD) represents a group of idiopathic, chronic, inflammatory intestinal conditions. Its two main disease categories are: Crohn's disease (CD) and ulcerative colitis (UC), which feature both overlapping and distinct clinical and pathological features. While these diseases have, in the past, been most evident in the developed world, their prevalence in the developing world has been gradually increasing in recent decades. This poses unique issues in diagnosis and management which have been scarcely addressed in the literature or in extant guidelines. Depending on the nature of the complaints, investigations to diagnose either form of IBD or to assess disease activity will vary and will also be influenced by geographic variations in other conditions that might mimic IBD. Similarly, therapy varies depending on the phenotype of the disease being treated and available resources. The World Gastroenterology Organization has, accordingly, developed guidelines for diagnosing and treating IBD using a cascade approach to account for variability in resources in countries around the world.

BACKGROUND: Women across the world are mistreated during childbirth. We aimed to develop and implement evidence-informed, validated tools to measure mistreatment during childbirth, and report results from a cross-sectional study in four low-income and middle-income countries. METHODS: We prospectively recruited women aged at least 15 years in twelve health facilities (three per country) in Ghana, Guinea, Myanmar, and Nigeria between Sept 19, 2016, and Jan 18, 2018. Continuous observations of labour and childbirth were done from admission up to 2 h post partum. Surveys were administered by interviewers in the community to women up to 8 weeks post partum. Labour observations were not done in Myanmar. Data were collected on sociodemographics, obstetric history, and experiences of mistreatment. FINDINGS: 2016 labour observations and 2672 surveys were done. 838 (41·6%) of 2016 observed women and 945 (35·4%) of 2672 surveyed women experienced physical or verbal abuse, or stigma or discrimination. Physical and verbal abuse peaked 30 min before birth until 15 min after birth (observation). Many women did not consent for episiotomy (observation: 190 [75·1%] of 253; survey: 295 [56·1%] of 526) or caesarean section (observation: 35 [13·4%] of 261; survey: 52 [10·8%] of 483), despite receiving these procedures. 133 (5·0%) of 2672 women or their babies were detained in the facility because they were unable to pay the bill (survey). Younger age (15-19 years) and lack of education were the primary determinants of mistreatment (survey). For example, younger women with no education (odds ratio [OR] 3·6, 95% CI 1·6-8·0) and younger women with some education (OR 1·6, 1·1-2·3) were more likely to experience verbal abuse, compared with older women (≥30 years), adjusting for marital status and parity. INTERPRETATION: More than a third of women experienced mistreatment and were particularly vulnerable around the time of birth. Women who were younger and less educated were most at risk, suggesting inequalities in how women are treated during childbirth. Understanding drivers and structural dimensions of mistreatment, including gender and social inequalities, is essential to ensure that interventions adequately account for the broader context. FUNDING: United States Agency for International Development and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, WHO.

BACKGROUND: Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion. METHODS: In this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance). We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria. We used microsatellite genotyping to assess genetic relatedness. FINDINGS: As part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates. In 2014-15, a single long PfKelch13 C580Y haplotype (-50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep. Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand. C580Y mutated parasites from Myanmar had a different genetic origin. INTERPRETATION: Our results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective. FUNDING: The Wellcome Trust and the Bill and Melinda Gates Foundation.

Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain-carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion.

BACKGROUND: The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. METHODS: P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. RESULTS: The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. CONCLUSIONS: K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.

BACKGROUND: Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. METHODS: We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. FINDINGS: Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. INTERPRETATION: Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. FUNDING: Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.

BACKGROUND: There has been an impressive recent reduction in the global incidence of malaria, but the development of artemisinin resistance in the Greater Mekong Region threatens this progress. Increasing artemisinin resistance is particularly important in Myanmar, as it is the country in the Greater Mekong Region with the greatest malaria burden. If malaria is to be eliminated in the region, it is essential to define the spatial and temporal epidemiology of the disease in Myanmar to inform control strategies optimally. RESULTS: Between the years 2005 and 2014 there was an 81.1 % decline in the reported annual incidence of malaria in Myanmar (1341.8 cases per 100,000 population to 253.3 cases per 100,000 population). In the same period, there was a 93.5 % decline in reported annual mortality from malaria (3.79 deaths per 100,000 population to 0.25 deaths per 100,000 population) and a 87.2 % decline in the proportion of hospitalizations due to malaria (7.8 to 1.0 %). Chin State had the highest reported malaria incidence and mortality at the end of the study period, although socio-economic and geographical factors appear a more likely explanation for this finding than artemisinin resistance. The reduced malaria burden coincided with significant upscaling of disease control measures by the national government with support from international partners. These programmes included the training and deployment of over 40,000 community health care workers, the coverage of over 60 % of the at-risk population with insecticide-treated bed nets and significant efforts to improve access to artemesinin-based combination treatment. Beyond these malaria-specific programmes, increased general investment in the health sector, changing population demographics and deforestation are also likely to have contributed to the decline in malaria incidence seen over this time. CONCLUSIONS: There has been a dramatic fall in the burden of malaria in Myanmar since 2005. However, with the rise of artemisinin resistance, continued political, financial and scientific commitment is required if the ambitious goal of malaria elimination in the country is to be realized.

Introduction Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM. Methods MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies. Results 156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I 2 =99.90%) and 31.55% (95% CI 17.12% to 50.70%, I 2 =97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I 2 =100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2–F4), while 14.95% (95% CI 11.03% to 19.95%, I 2 =99.00%) had advanced fibrosis (F3–F4). Conclusion This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD. PROSPERO registration number CRD42022360251.

BACKGROUND: The reported case-fatality rate associated with severe malaria varies widely. Whether age is an independent risk factor is uncertain. METHODS: In a large, multicenter treatment trial conducted in Asia, the presenting manifestations and outcome of severe malaria were analyzed in relation to age. RESULTS: Among 1050 patients with severe malaria, the mortality increased stepwise, from 6.1% in children (age, <10 years) to 36.5% in patients aged >50 years (P<0.001). Compared with adults aged 21-50 years, the decreased risk of death among children (adjusted odds ratio, 0.06; 95% confidence interval, 0.01-0.23; P<0.001) and the increased risk of death among patients aged >50 years (adjusted odds ratio, 1.88; 95% confidence interval, 1.01-3.52; P<0.001) was independent of the variation in presenting manifestations. The incidence of anemia and convulsions decreased with age, whereas the incidence of hyperparasitemia, jaundice, and renal insufficiency increased with age. Coma and metabolic acidosis did not vary with age and were the strongest predictors of a fatal outcome. The number of severity signs at hospital admission also had a strong prognostic value. CONCLUSION: Presenting syndromes in severe malaria depend on age, although the incidence and the strong prognostic significance of coma and acidosis are similar at all ages. Age is an independent risk factor for a fatal outcome of the disease.

BACKGROUND: Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. METHODS: In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2-65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. FINDINGS: Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin-piperaquine (183 [17%]), dihydroartemisinin-piperaquine plus mefloquine (269 [24%]), artesunate-mefloquine (73 [7%]), artemether-lumefantrine (289 [26%]), or artemether-lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin-piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin-piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin-piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate-mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI -6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether-lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI -1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin-piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether-lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether-lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether-lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin-piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin-piperaquine plus mefloquine; p=0·50). INTERPRETATION: Dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. FUNDING: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Abstract Since 2000, aquaculture became well‐integrated into the global food system. Aquaculture systems are highly diverse, producing globally equal amounts of fed and extractive species. In Asia and Africa, inland aquaculture provides the bulk of aquaculture production, while in the Americas, Europe, and Oceania, marine aquaculture dominates. The realized growth of annual production since 2000 is due to intensification, the use of more and better feeds, improved production management, and increased attention to biosecurity. Fed and extractive aquaculture, both need to pay more attention to scaling, site selection, and the health of the wider production environment. In terms of land use, aquaculture is more efficient than terrestrial animal production. Still, water use remains a challenge. More attention should be given to water recycling in land‐based systems, reducing water consumption and facilitating nutrient recovery and reuse. Future development should focus on making aquaculture climate neutral and on reducing environmental impacts, both inland and at sea. More attention must be given to making aquaculture an important part of local food systems on all continents, as is the case in Asia today. Integration of aquaculture into local nutrition‐sensitive, circular, and sustainable food systems should become the major driver for future aquaculture system development.

The four genetically divergent dengue virus (DENV) types are traditionally classified as serotypes. Antigenic and genetic differences among the DENV types influence disease outcome, vaccine-induced protection, epidemic magnitude, and viral evolution. We characterized antigenic diversity in the DENV types by antigenic maps constructed from neutralizing antibody titers obtained from African green monkeys and after human vaccination and natural infections. Genetically, geographically, and temporally, diverse DENV isolates clustered loosely by type, but we found that many are as similar antigenically to a virus of a different type as to some viruses of the same type. Primary infection antisera did not neutralize all viruses of the same DENV type any better than other types did up to 2 years after infection and did not show improved neutralization to homologous type isolates. That the canonical DENV types are not antigenically homogeneous has implications for vaccination and research on the dynamics of immunity, disease, and the evolution of DENV.

In 2001, dengue virus type 1 (DENV-1) populations in humans and mosquitoes from Myanmar acquired a stop-codon mutation in the surface envelope (E) protein gene. Within a year, this stop-codon strain had spread to all individuals sampled. The presence of truncated E protein species within individual viral populations, along with a general relaxation in selective constraint, indicated that the stop-codon strain represents a defective lineage of DENV-1. We propose that such long-term transmission of defective RNA viruses in nature was achieved through complementation by coinfection of host cells with functional viruses.

OBJECTIVE: To assess the prevalence of counterfeit antimalarial drugs in Southeast (SE) Asia. DESIGN: Cross-sectional survey. SETTING: Pharmacies and shops selling antimalarial drugs in Myanmar (Burma), Lao PDR, Vietnam, Cambodia and Thailand. MAIN OUTCOME MEASURES: Proportion of artemisinin derivatives or mefloquine containing drugs of substandard quality. RESULTS: Of the 188 tablet packs purchased which were labelled as 'artesunate' 53% did not contain any artesunate. All counterfeit artesunate tablets were labelled as manufactured by 'Guilin Pharma', and refinements of the fake blisterpacks made them often hard to distinguish from their genuine counterparts. No other artemisinin derivatives were found to be counterfeited. Of the 44 mefloquine samples, 9% contained <10% of the expected amount of active ingredient. CONCLUSIONS: An alarmingly high proportion of antimalarial drugs bought in pharmacies and shops in mainland SE Asia are counterfeit, and the problem has increased significantly compared with our previous survey in 1999-2000. This is a serious threat to public health in the region.

OBJECTIVE: To study dengue vector breeding patterns under a variety of conditions in public and private spaces; to explore the ecological, biological and social (eco-bio-social) factors involved in vector breeding and viral transmission, and to define the main implications for vector control. METHODS: In each of six Asian cities or periurban areas, a team randomly selected urban clusters for conducting standardized household surveys, neighbourhood background surveys and entomological surveys. They collected information on vector breeding sites, people's knowledge, attitudes and practices surrounding dengue, and the characteristics of the study areas. All premises were inspected; larval indices were used to quantify vector breeding sites, and pupal counts were used to identify productive water container types and as a proxy measure for adult vector abundance. FINDINGS: The most productive vector breeding sites were outdoor water containers, particularly if uncovered, beneath shrubbery and unused for at least one week. Peridomestic and intradomestic areas were much more important for pupal production than commercial and public spaces other than schools and religious facilities. A complex but non-significant association was found between water supply and pupal counts, and lack of waste disposal services was associated with higher vector abundance in only one site. Greater knowledge about dengue and its transmission was associated with lower mosquito breeding and production. Vector control measures (mainly larviciding in one site) substantially reduced larval and pupal counts and "pushed" mosquito breeding to alternative containers. CONCLUSION: Vector breeding and the production of adult Aedes aegypti are influenced by a complex interplay of factors. Thus, to achieve effective vector management, a public health response beyond routine larviciding or focal spraying is essential.

The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.

BACKGROUND: Accurate diagnosis is essential for prompt and appropriate treatment of malaria. While rapid diagnostic tests (RDTs) offer great potential to improve malaria diagnosis, the sensitivity of RDTs has been reported to be highly variable. One possible factor contributing to variable test performance is the diversity of parasite antigens. This is of particular concern for Plasmodium falciparum histidine-rich protein 2 (PfHRP2)-detecting RDTs since PfHRP2 has been reported to be highly variable in isolates of the Asia-Pacific region. METHODS: The pfhrp2 exon 2 fragment from 458 isolates of P. falciparum collected from 38 countries was amplified and sequenced. For a subset of 80 isolates, the exon 2 fragment of histidine-rich protein 3 (pfhrp3) was also amplified and sequenced. DNA sequence and statistical analysis of the variation observed in these genes was conducted. The potential impact of the pfhrp2 variation on RDT detection rates was examined by analysing the relationship between sequence characteristics of this gene and the results of the WHO product testing of malaria RDTs: Round 1 (2008), for 34 PfHRP2-detecting RDTs. RESULTS: Sequence analysis revealed extensive variations in the number and arrangement of various repeats encoded by the genes in parasite populations world-wide. However, no statistically robust correlation between gene structure and RDT detection rate for P. falciparum parasites at 200 parasites per microlitre was identified. CONCLUSIONS: The results suggest that despite extreme sequence variation, diversity of PfHRP2 does not appear to be a major cause of RDT sensitivity variation.

BACKGROUND: A community-based malaria intervention was introduced through fixed and mobile clinics in rural Myanmar. This study attempted to identify treatment-seeking behaviour of caregivers for children under five and the determinants of appropriate treatment-seeking behaviour in mobile clinic villages (MV) and non-mobile clinic villages (NMV) in malaria-endemic rural areas in Myanmar. METHODS: A cross-sectional study was conducted in 23 MV and 25 NMV in Ingapu Township, Myanmar. Appropriate treatment-seeking behaviour was operationally defined as seeking treatment from trained personnel or at a health facility within 24 hours after the onset of fever. Multiple logistic regression analyses were conducted to identify the determinants of appropriate treatment-seeking behaviour. RESULTS: Among the 597 participants in both types of villages, 166 (35.3%) caregivers sought appropriate treatment. No significant difference in appropriate treatment-seeking behaviour was found between the two types of villages (adjusted odds ratio (AOR), 0.80; 95% confidence interval (CI), 0.51-1.24). Determinants of behaviour include proximity to public health facilities (AOR, 5.86; 95% CI, 3.43-10.02), knowledge of malaria (AOR, 1.90; 95% CI, 1.14-3.17), malaria prevention behaviour (AOR, 1.76; 95% CI, 1.13-2.76), treatment at home (AOR, 0.26; 95% CI, 0.15-0.45), and treatment and transportation costs (AOR, 0.52; 95% CI, 0.33-0.83). CONCLUSIONS: Caregivers' treatment-seeking behaviour was poor for fever cases among children under age five, and did not differ significantly between MV and NMV. It is necessary to educate caregivers, particularly for early treatment seeking and appropriate use of health care options for fever, and catering to their medical needs. These findings can help promote awareness and prevention, and improve the quality of interventions at the community level.