Publications by authors named "Elizabeth A Ashley"

119 Publications

High burden of infections caused by ESBL-producing MDR in paediatric patients, Yangon, Myanmar.

JAC Antimicrob Resist 2021 Mar 14;3(1):dlab011. Epub 2021 Feb 14.

University of Medicine 2, Yangon, Myanmar.

Background: There is mounting evidence of a high burden of antimicrobial-resistant infections in children in low- and middle-income countries (LMICs).

Objectives: To detect the frequency of ESBL-producing in clinical specimens from paediatric patients attending Yangon Children's Hospital in Myanmar.

Methods: All children attending Yangon Children's Hospital who had clinical specimens submitted to the hospital diagnostic microbiology laboratory from June 2019 to December 2019 were included in the study. Specimens were processed routinely using standard methods with BD Phoenix used for pathogen identification and susceptibility testing. Presence of ESBLs was determined using the cephalosporin/clavulanate combination disc method with confirmation by PCR.

Results: From 3462 specimens submitted to the Microbiology Laboratory, a total of 123 were isolated. Among them, 100 isolates were phenotypically ESBL producers, 94 (76.4%) of which were confirmed by PCR [82/94 (87%) CTX-M, 72/94 (77%) TEM, 1/94 (1%) SHV]. Most of the ESBL-producing were isolated from urine samples (52.1%, 49/94) and the majority were from the surgical unit (61.7%, 58/94). Only 34/94 (36%) isolates were susceptible to meropenem.

Conclusions: This study confirms a high proportion of infections caused by ESBL-producing and MDR in children hospitalized in Yangon, where access to effective second-line antimicrobials is limited.
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http://dx.doi.org/10.1093/jacamr/dlab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882151PMC
March 2021

Impact of delays to incubation and storage temperature on blood culture results: a multi-centre study.

BMC Infect Dis 2021 Feb 12;21(1):173. Epub 2021 Feb 12.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Background: Blood cultures are one of the most important tests performed by microbiology laboratories. Many hospitals, particularly in low and middle-income countries, lack either microbiology services or staff to provide 24 h services resulting in delays to blood culture incubation. There is insufficient guidance on how to transport/store blood cultures if delays before incubation are unavoidable, particularly if ambient temperatures are high. This study set out to address this knowledge gap.

Methods: In three South East Asian countries, four different blood culture systems (two manual and two automated) were used to test blood cultures spiked with five common bacterial pathogens. Prior to incubation the spiked blood culture bottles were stored at different temperatures (25 °C, in a cool-box at ambient temperature, or at 40 °C) for different lengths of time (0 h, 6 h, 12 h or 24 h). The impacts of these different storage conditions on positive blood culture yield and on time to positivity were examined.

Results: There was no significant loss in yield when blood cultures were stored < 24 h at 25 °C, however, storage for 24 h at 40 °C decreased yields and longer storage times increased times to detection.

Conclusion: Blood cultures should be incubated with minimal delay to maximize pathogen recovery and timely result reporting, however, this study provides some reassurance that unavoidable delays can be managed to minimize negative impacts. If delays to incubation ≥ 12 h are unavoidable, transportation at a temperature not exceeding 25 °C, and blind sub-cultures prior to incubation should be considered.
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http://dx.doi.org/10.1186/s12879-021-05872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881545PMC
February 2021

Inter-prescriber variability in the decision to prescribe antibiotics to febrile patients attending primary care in Myanmar.

JAC Antimicrob Resist 2021 Mar 19;3(1):dlaa118. Epub 2021 Jan 19.

Myanmar Oxford Clinical Research Unit, Yangon, Myanmar (MOCRU), Yangon, Myanmar.

Background: Most antibiotic prescribing occurs in primary care. Even within the same health facility, there may be differences between prescribers in their tendency to prescribe antibiotics, which may be masked by summary data. We aimed to quantify prescriber variability in antibiotic prescription to patients with acute fever in primary care clinics in Myanmar.

Methods: We conducted a secondary analysis of prescribing data from 1090 patient consultations with 40 prescribing doctors from a trial investigating the effect of point-of-care C-reactive protein (CRP) tests on antibiotic prescription for acute fever. We used multilevel logistic regression models to assess inter-prescriber variability in the decision to prescribe antibiotics.

Results: The median odds ratio (MOR) in the unadjusted model was 1.82 (95% CI: 1.47-2.56) indicating that when two prescribers from this population are randomly selected then in half of these pairs the odds of prescription will be greater than 1.82-fold higher in one prescriber than the other. The estimated variability from this sample of prescribers corresponds to a population of prescribers where the top 25% of prescribers will prescribe antibiotics to over 41% of patients while the bottom 25% will prescribe antibiotics to less than 23% of patients. Inter-prescriber variation in antibiotic prescribing remained after adjustment for patient characteristics and CRP information (<0.001).

Conclusions: Despite sharing the same management guidelines, there was substantial inter-prescriber variation in antibiotic prescription to patients with acute fever. This variation should be considered when designing trials and stewardship programmes aiming to reduce inappropriate antibiotic prescribing.
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http://dx.doi.org/10.1093/jacamr/dlaa118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814214PMC
March 2021

Prediction of disease severity in young children presenting with acute febrile illness in resource-limited settings: a protocol for a prospective observational study.

BMJ Open 2021 Jan 25;11(1):e045826. Epub 2021 Jan 25.

Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, Oxfordshire, UK.

Introduction: In rural and difficult-to-access settings, early and accurate recognition of febrile children at risk of progressing to serious illness could contribute to improved patient outcomes and better resource allocation. This study aims to develop a prognostic clinical prediction tool to assist community healthcare providers identify febrile children who might benefit from referral or admission for facility-based medical care.

Methods And Analysis: This prospective observational study will recruit at least 4900 paediatric inpatients and outpatients under the age of 5 years presenting with an acute febrile illness to seven hospitals in six countries across Asia. A venous blood sample and nasopharyngeal swab is collected from each participant and detailed clinical data recorded at presentation, and each day for the first 48 hours of admission for inpatients. Multianalyte assays are performed at reference laboratories to measure a panel of host biomarkers, as well as targeted aetiological investigations for common bacterial and viral pathogens. Clinical outcome is ascertained on day 2 and day 28.Presenting syndromes, clinical outcomes and aetiology of acute febrile illness will be described and compared across sites. Following the latest guidance in prediction model building, a prognostic clinical prediction model, combining simple clinical features and measurements of host biomarkers, will be derived and geographically externally validated. The performance of the model will be evaluated in specific presenting clinical syndromes and fever aetiologies.

Ethics And Dissemination: The study has received approval from all relevant international, national and institutional ethics committees. Written informed consent is provided by the caretaker of all participants. Results will be shared with local and national stakeholders, and disseminated via peer-reviewed open-access journals and scientific meetings.

Trial Registration Number: NCT04285021.
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http://dx.doi.org/10.1136/bmjopen-2020-045826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839891PMC
January 2021

Serological evidence indicates widespread distribution of rickettsioses in Myanmar.

Int J Infect Dis 2021 Feb 11;103:494-501. Epub 2020 Dec 11.

Myanmar Oxford Clinical Research Unit, Yangon, Myanmar; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao Democratic People's Republic. Electronic address:

Background: Little research has been published on the prevalence of rickettsial infections in Myanmar. This study determined the seroprevalence of immunoglobulin G (IgG) antibodies to rickettsial species in different regions of Myanmar.

Methods: Seven hundred leftover blood samples from patients of all ages in primary care clinics and hospitals in seven regions of Myanmar were collected. Samples were screened for scrub typhus group (STG), typhus group (TG) and spotted fever group (SFG) IgG antibodies using enzyme-linked immunosorbent assays (ELISA). Immunofluorescence assays were performed for the same rickettsial groups to confirm seropositivity if ELISA optical density ≥0.5.

Results: Overall IgG seroprevalence was 19% [95% confidence interval (CI) 16-22%] for STG, 5% (95% CI 3-7%) for TG and 3% (95% CI: 2-5%) for SFG. The seroprevalence of STG was particularly high in northern and central Myanmar (59% and 19-33%, respectively). Increasing age was associated with higher odds of STG and TG seropositivity [per 10-year increase, adjusted odds ratio estimate 1.68 (p < 0.01) and 1.24 (p = 0.03), respectively].

Conclusion: Rickettsial infections are widespread in Myanmar, with particularly high seroprevalence of STG IgG antibodies in central and northern regions. Healthcare workers should consider rickettsial infections as common causes of fever in Myanmar.
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http://dx.doi.org/10.1016/j.ijid.2020.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862081PMC
February 2021

Seasonal malaria chemoprevention: closing the know-do gap.

Lancet 2020 12;396(10265):1778-1779

College of Health Sciences, Makerere University, Kampala, Uganda; Infectious Diseases Research Collaboration, Kampala, Uganda.

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http://dx.doi.org/10.1016/S0140-6736(20)32525-3DOI Listing
December 2020

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

PLoS Med 2020 11 19;17(11):e1003393. Epub 2020 Nov 19.

WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom.

Background: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial.

Methods And Findings: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high.

Conclusions: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.
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http://dx.doi.org/10.1371/journal.pmed.1003393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676739PMC
November 2020

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: Application to a dose-finding trial for a novel Russell's viper antivenom in Myanmar.

PLoS Negl Trop Dis 2020 11 16;14(11):e0008109. Epub 2020 Nov 16.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. fewer than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined 'optimal dose'. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation. We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell's viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Daboia siamensis envenoming, efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified '3+3' design). The model based design can identify an optimal dose after fewer patients relative to the rule based design. Open source code for the simulations is made available in order to determine adequate sample sizes for future adaptive snakebite trials. Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar.
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http://dx.doi.org/10.1371/journal.pntd.0008109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704047PMC
November 2020

A cautionary note on the use of unsupervised machine learning algorithms to characterise malaria parasite population structure from genetic distance matrices.

PLoS Genet 2020 10 9;16(10):e1009037. Epub 2020 Oct 9.

Department of Statistics, University of Oxford, Oxford, United Kingdom.

Genetic surveillance of malaria parasites supports malaria control programmes, treatment guidelines and elimination strategies. Surveillance studies often pose questions about malaria parasite ancestry (e.g. how antimalarial resistance has spread) and employ statistical methods that characterise parasite population structure. Many of the methods used to characterise structure are unsupervised machine learning algorithms which depend on a genetic distance matrix, notably principal coordinates analysis (PCoA) and hierarchical agglomerative clustering (HAC). PCoA and HAC are sensitive to both the definition of genetic distance and algorithmic specification. Importantly, neither algorithm infers malaria parasite ancestry. As such, PCoA and HAC can inform (e.g. via exploratory data visualisation and hypothesis generation), but not answer comprehensively, key questions about malaria parasite ancestry. We illustrate the sensitivity of PCoA and HAC using 393 Plasmodium falciparum whole genome sequences collected from Cambodia and neighbouring regions (where antimalarial resistance has emerged and spread recently) and we provide tentative guidance for the use and interpretation of PCoA and HAC in malaria parasite genetic epidemiology. This guidance includes a call for fully transparent and reproducible analysis pipelines that feature (i) a clearly outlined scientific question; (ii) a clear justification of analytical methods used to answer the scientific question along with discussion of any inferential limitations; (iii) publicly available genetic distance matrices when downstream analyses depend on them; and (iv) sensitivity analyses. To bridge the inferential disconnect between the output of non-inferential unsupervised learning algorithms and the scientific questions of interest, tailor-made statistical models are needed to infer malaria parasite ancestry. In the absence of such models speculative reasoning should feature only as discussion but not as results.
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http://dx.doi.org/10.1371/journal.pgen.1009037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577480PMC
October 2020

Myanmar Burkholderia pseudomallei strains are genetically diverse and originate from Asia with phylogenetic evidence of reintroductions from neighbouring countries.

Sci Rep 2020 10 1;10(1):16260. Epub 2020 Oct 1.

Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus, Oxford, UK.

Melioidosis was first identified in Myanmar in 1911 but for the last century it has remained largely unreported there. Burkholderia pseudomallei was first isolated from the environment of Myanmar in 2016, confirming continuing endemicity. Recent genomic studies showed that B. pseudomallei originated in Australia and spread to Asia, with phylogenetic evidence of repeated reintroduction of B. pseudomallei across countries bordered by the Mekong River and the Malay Peninsula. We present the first whole-genome sequences of B. pseudomallei isolates from Myanmar: nine clinical and seven environmental isolates. We used large-scale comparative genomics to assess the genetic diversity, phylogeography and potential origins of B. pseudomallei in Myanmar. Global phylogenetics demonstrated that Myanmar isolates group in two distantly related clades that reside in a more ancestral Asian clade with high amounts of genetic diversity. The diversity of B. pseudomallei from Myanmar and divergence within our global phylogeny suggest that the original introduction of B. pseudomallei to Myanmar was not a recent event. Our study provides new insights into global patterns of B. pseudomallei dissemination, most notably the dynamic nature of movement of B. pseudomallei within densely populated Southeast Asia. The role of anthropogenic influences in both ancient and more recent dissemination of B. pseudomallei to Myanmar and elsewhere in Southeast Asia and globally requires further study.
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http://dx.doi.org/10.1038/s41598-020-73545-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530998PMC
October 2020

Non-malarial febrile illness: a systematic review of published aetiological studies and case reports from Africa, 1980-2015.

BMC Med 2020 09 21;18(1):279. Epub 2020 Sep 21.

Infectious Diseases Data Observatory, University of Oxford, New Richards Building,Old Road Campus,Headington, Oxford, OX3 7LG, UK.

Background: The availability of reliable point-of-care tests for malaria has heralded a paradigm shift in the management of febrile illnesses away from presumptive antimalarial therapy. In the absence of a definitive diagnosis, health care providers are more likely to prescribe empirical antimicrobials to those who test negative for malaria. To improve management and guide further test development, better understanding is needed of the true causative agents and their geographic variability.

Methods: A systematic review of published literature was undertaken to characterise the spectrum of pathogens causing non-malaria febrile illness in Africa (1980-2015). Literature searches were conducted in English and French languages in six databases: MEDLINE, EMBASE, Global Health (CABI), WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. A number of published articles (rather than incidence or prevalence) reporting a given pathogen were presented.

Results: A total of 16,523 records from 48 African countries were screened, of which 1065 (6.4%) met selection criteria. Bacterial infections were reported in 564 (53.0%) records, viral infections in 374 (35.1%), parasitic infections in 47 (4.4%), fungal infections in nine (0.8%), and 71 (6.7%) publications reported more than one pathogen group. Age range of the study population was not specified in 233 (21.9%) publications. Staphylococcus aureus (18.2%), non-typhoidal Salmonella (17.3%), and Escherichia coli (15.4%) were the commonly reported bacterial infections whereas Rift Valley fever virus (7.4%), yellow fever virus (7.0%), and Ebola virus (6.7%) were the most commonly reported viral infections. Dengue virus infection, previously not thought to be widespread in Africa, was reported in 54 (5.1%) of articles.

Conclusions: This review summarises the published reports of non-malaria pathogens that may cause febrile illness in Africa. As the threat of antimicrobial resistance looms, knowledge of the distribution of infectious agents causing fever should facilitate priority setting in the development of new diagnostic tools and improved antimicrobial stewardship.

Trial Registration: PROSPERO, CRD42016049281.
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http://dx.doi.org/10.1186/s12916-020-01744-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504660PMC
September 2020

Non-malarial febrile illness: a systematic review of published aetiological studies and case reports from Southern Asia and South-eastern Asia, 1980-2015.

BMC Med 2020 09 21;18(1):299. Epub 2020 Sep 21.

Infectious Diseases Data Observatory (IDDO), University of Oxford, NDMRB, Old Road Campus, Oxford, OX3 7FZ, UK.

Background: In the absence of definitive diagnosis, healthcare providers are likely to prescribe empirical antibacterials to those who test negative for malaria. This problem is of critical importance in Southern Asia (SA) and South-eastern Asia (SEA) where high levels of antimicrobial consumption and high prevalence of antimicrobial resistance have been reported. To improve management and guide further diagnostic test development, better understanding is needed of the true causative agents of fever and their geographical variability.

Methods: We conducted a systematic review of published literature (1980-2015) to characterise the spectrum of pathogens causing non-malarial febrile illness in SA and SEA. We searched six databases in English and French languages: MEDLINE, EMBASE, Global Health (CABI) database, WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection.

Results: A total of 29,558 records from 19 countries in SA and SEA were screened, of which 2410 (8.1%) met the selection criteria. Bacterial aetiologies were reported in 1235 (51.2%) articles, viral in 846 (35.1%), parasitic in 132 (5.5%), and fungal in 54 (2.2%), and 143 (6.0%) articles reported more than one pathogen group. In descending order of frequency, Salmonella Typhi, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and coagulase negative Staphylococcus were the commonly reported bacteria, while dengue virus, chikungunya virus, Japanese encephalitis virus, hepatitis B virus, and hepatitis C virus were common viral pathogens reported. Reports of rarely reported or emerging pathogens included a case report of Borrelia burgdorferi (Lyme disease) in India in 2010 and reports of Nipah virus in Singapore and India.

Conclusions: This review summarises the reported non-malaria pathogens that may cause febrile illness in SA and SEA. The findings emphasise the need of standardising the reporting of aetiological studies to develop effective, evidence-based fever management and improved surveillance. Research and development of diagnostic tools would benefit from up-to-date epidemiological reporting of the regional diversities of non-malaria fever aetiologies.

Trial Registration: PROSPERO registration, CRD42016049281.
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http://dx.doi.org/10.1186/s12916-020-01745-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504862PMC
September 2020

Treatment and prevention of malaria in children.

Lancet Child Adolesc Health 2020 10;4(10):775-789

Timika Research Facility, Papuan Health and Community Development Foundation, Timika, Indonesia; Department of Child Health, Faculty of Medicine, Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia.

Malaria disproportionately affects children younger than 5 years. Falciparum malaria is responsible for more than 200 000 child deaths per year in Africa and vivax malaria is well documented as a cause of severe anaemia and excess mortality in children in Asia and Oceania. For the treatment of malaria in children, paediatric dosing recommendations for several agents, including parenteral artesunate and dihydroartemisinin-piperaquine, have belatedly been shown to be suboptimal. Worsening antimalarial resistance in Plasmodium falciparum in the Greater Mekong Subregion threatens to undermine global efforts to control malaria. Triple antimalarial combination therapies are being evaluated to try to impede this threat. The RTS,S/AS01 vaccine gives partial protection against falciparum malaria and is being evaluated in large, pilot studies in Ghana, Malawi, and Kenya as a complementary tool to other preventive measures. Seasonal malaria chemoprevention in west Africa has resulted in declines in malaria incidence and deaths and there is interest in scaling up efforts by expanding the age range of eligible recipients. Preventing relapse in Plasmodium vivax infection with primaquine is challenging because treating children who have G6PD deficiency with primaquine can cause acute haemolytic anaemia. The safety of escalating dose regimens for primaquine is being studied to mitigate this risk.
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http://dx.doi.org/10.1016/S2352-4642(20)30127-9DOI Listing
October 2020

Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study.

Lancet Infect Dis 2020 12 14;20(12):1470-1480. Epub 2020 Jul 14.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Background: The Greater Mekong subregion is a recurrent source of antimalarial drug resistance in Plasmodium falciparum malaria. This study aimed to characterise the extent and spread of resistance across this entire region between 2007 and 2018.

Methods: P falciparum isolates from Myanmar, Thailand, Laos, and Cambodia were obtained from clinical trials and epidemiological studies done between Jan 1, 2007, and Dec 31, 2018, and were genotyped for molecular markers (pfkelch, pfcrt, pfplasmepsin2, and pfmdr1) of antimalarial drug resistance. Genetic relatedness was assessed using microsatellite and single nucleotide polymorphism typing of flanking sequences around target genes.

Findings: 10 632 isolates were genotyped. A single long pfkelch Cys580Tyr haplotype (from -50 kb to +31·5 kb) conferring artemisinin resistance (PfPailin) now dominates across the eastern Greater Mekong subregion. Piperaquine resistance associated with pfplasmepsin2 gene amplification and mutations in pfcrt downstream of the Lys76Thr chloroquine resistance locus has also developed. On the Thailand-Myanmar border a different pfkelch Cys580Tyr lineage rose to high frequencies before it was eliminated. Elsewhere in Myanmar the Cys580Tyr allele remains widespread at low allele frequencies. Meanwhile a single artemisinin-resistant pfkelch Phe446Ile haplotype has spread across Myanmar. Despite intense use of dihydroartemisinin-piperaquine in Kayin state, eastern Myanmar, both in treatment and mass drug administrations, no selection of piperaquine resistance markers was observed. pfmdr1 amplification, a marker of resistance to mefloquine, remains at low prevalence across the entire region.

Interpretation: Artemisinin resistance in P falciparum is now prevalent across the Greater Mekong subregion. In the eastern Greater Mekong subregion a multidrug resistant P falciparum lineage (PfPailin) dominates. In Myanmar a long pfkelch Phe446Ile haplotype has spread widely but, by contrast with the eastern Greater Mekong subregion, there is no indication of artemisinin combination therapy (ACT) partner drug resistance from genotyping known markers, and no evidence of spread of ACT resistant P falciparum from the east to the west. There is still a window of opportunity to prevent global spread of ACT resistance.

Funding: Thailand Science Research and Innovation, Initiative 5%, Expertise France, Wellcome Trust.
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http://dx.doi.org/10.1016/S1473-3099(20)30228-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689289PMC
December 2020

Evaluation of the forum theatre approach for public engagement around antibiotic use in Myanmar.

PLoS One 2020 9;15(7):e0235625. Epub 2020 Jul 9.

Nuffield Department of Clinical Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.

Introduction: The risk of emergence and spread of antibiotic resistance is high in Southeast Asian countries and various strategies are being used to raise awareness about appropriate antibiotic use and antibiotic resistance within communities. Public engagement in science has not been widely practised in Myanmar. We describe the use of a forum theatre to engage with the community about antibiotic use.

Methods: The engagement activities took place in a peri-urban township in Yangon, Myanmar. Five preliminary story gathering workshops with the community were carried out to develop scripts and songs for the forum theatre. After that, we organised forum theatre plays between September and October 2018. Following each play we provided four simple key messages based on WHO's world antibiotic awareness week advocacy materials; 1) Antibiotics are medicines used to treat bacterial infections 2) Antibiotics are not useful for coughs and colds 3) Never use leftover antibiotics or share antibiotics with others 4) Prevent infections by regularly washing hands, preparing food hygienically, avoiding close contact with sick people, and keeping vaccinations up to date. We evaluated the engagement activities by conducting focus group discussions (FGD) with audience members.

Results: Ten forum theatre plays were performed on two topics; "Fever and antibiotics" and "Mixed medicines", reaching 1175 community members. Four themes emerged from our thematic analysis: 1) Knowledge dissemination, 2) Enjoyment and fun, 3) Willingness to support and recommendations for future engagement activities and 4) Preference over traditional methods of health education. We found improvement of antibiotic related knowledge and enjoyment among audience who were also willing to support future engagement activities and preferred forum theatre approach over formal health talks.

Conclusions: We conclude that forum theatre is an effective innovative approach to engage and disseminate knowledge on appropriate use of antibiotics with the community in a participatory way.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235625PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347174PMC
September 2020

Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis.

Lancet Infect Dis 2020 08 29;20(8):943-952. Epub 2020 Apr 29.

WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK; Infectious Diseases Data Observatory (IDDO), Oxford, UK; Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. Electronic address:

Background: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women.

Methods: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013.

Findings: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57-14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14-0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34-0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18-0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29-23·82).

Interpretation: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.

Funding: The Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.
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http://dx.doi.org/10.1016/S1473-3099(20)30064-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391007PMC
August 2020

ACORN (A Clinically-Oriented Antimicrobial Resistance Surveillance Network): a pilot protocol for case based antimicrobial resistance surveillance.

Wellcome Open Res 2020 1;5:13. Epub 2020 Jun 1.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

: Antimicrobial resistance (AMR) / drug resistant infections (DRIs) are a major global health priority. Surveillance data is critical to inform infection treatment guidelines, monitor trends, and to assess interventions. However, most existing AMR / DRI surveillance systems are passive and pathogen-based with many potential biases. Addition of clinical and patient outcome data would provide considerable added value to pathogen-based surveillance. : The aim of the ACORN project is to develop an efficient clinically-oriented AMR surveillance system, implemented alongside routine clinical care in hospitals in low- and middle-income country settings. In an initial pilot phase, clinical and microbiology data will be collected from patients presenting with clinically suspected meningitis, pneumonia, or sepsis. Community-acquired infections will be identified by daily review of new admissions, and hospital-acquired infections will be enrolled during weekly point prevalence surveys, on surveillance wards. Clinical variables will be collected at enrolment, hospital discharge, and at day 28 post-enrolment using an electronic questionnaire on a mobile device. These data will be merged with laboratory data onsite using a flexible automated computer script. Specific target pathogens will be spp and . A bespoke browser-based app will provide sites with fully interactive data visualisation, analysis, and reporting tools. : ACORN will generate data on the burden of DRI which can be used to inform local treatment guidelines / national policy and serve as indicators to measure the impact of interventions. Following development, testing and iteration of the surveillance tools during an initial six-month pilot phase, a wider rollout is planned.
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http://dx.doi.org/10.12688/wellcomeopenres.15681.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250055PMC
June 2020

Setting priorities for patient-centered surveillance of drug-resistant infections.

Int J Infect Dis 2020 Aug 2;97:60-65. Epub 2020 Jun 2.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Cambodia Oxford Medical Research Unit, Angkor Hospital for Children, Siem Reap, Cambodia.

Methods: A priority-setting process (PSP) was launched to define priorities for patient-centered antimicrobial resistance (AMR) surveillance and research in low- and middle-income countries (LMICs). A list of uncertainties related to AMR surveillance in human health was generated using an online survey of stakeholders in LMICs, which asked for unanswered questions about diagnosis, treatment, or prevention of antibiotic resistance.

Results: A total of 445 respondents generated 1076 questions that were mapped to a final shortlist of 107 questions. The most common theme was the treatment of drug-resistant infections, followed by diagnosis, then prevention, and requests for local AMR data. The most asked question was a request for local AMR data, revealing the lack of basic information in many LMICs to guide actions to tackle AMR. The steering group recommended three research areas to be prioritized for funding in the next five years: infection prevention and control in LMICs, improved electronic patient records, starting with laboratory information management systems, and sustainable behavior change among doctors and other health care professionals with a focus on diagnostic stewardship.
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http://dx.doi.org/10.1016/j.ijid.2020.05.121DOI Listing
August 2020

Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BMC Med 2020 06 2;18(1):138. Epub 2020 Jun 2.

WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK.

Background: Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection.

Methods: A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and < 37.0 weeks), small for gestational age (SGA, birthweight of < 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013.

Results: Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p < 0.001).

Conclusions: The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.
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http://dx.doi.org/10.1186/s12916-020-01592-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263905PMC
June 2020

Case-based surveillance of antimicrobial resistance in the ACORN (A Clinically Oriented Antimicrobial Resistance Surveillance Network) study.

JAC Antimicrob Resist 2020 Mar 12;2(1):dlaa018. Epub 2020 Mar 12.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1093/jacamr/dlaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134533PMC
March 2020

Plasmodium falciparum ATP4 inhibitors to treat malaria: worthy successors to artemisinin?

Lancet Infect Dis 2020 08 8;20(8):883-885. Epub 2020 Apr 8.

Myanmar Oxford Clinical Research Unit, Yangon, Myanmar.

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http://dx.doi.org/10.1016/S1473-3099(20)30139-0DOI Listing
August 2020

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

PLoS Med 2020 03 5;17(3):e1003040. Epub 2020 Mar 5.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

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.
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http://dx.doi.org/10.1371/journal.pmed.1003040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058280PMC
March 2020

Standardising the reporting of microbiology and antimicrobial susceptibility data.

Lancet Infect Dis 2019 11;19(11):1163-1164

Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Laos; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1016/S1473-3099(19)30561-4DOI Listing
November 2019

Trace Element Concentrations in Livers of Pacific Harbor Seals () from San Juan County, Washington, USA.

J Wildl Dis 2020 04 17;56(2):429-436. Epub 2019 Oct 17.

SeaDoc Society, University of California, Davis Karen C. Drayer Wildlife Health Center-Orcas Island Office, 942 Deer Harbor Road, Eastsound, Washington 98245, USA.

Approximately 5,000 Pacific harbor seals () reside year-round in San Juan County (SJC), Washington (US) in the center of the binational Salish Sea. We retrospectively analyzed total cadmium (Cd), copper (Cu), iron (Fe), mercury (Hg), magnesium (Mg), manganese (Mn), lead (Pb), selenium (Se), and zinc (Zn) in livers of dead stranded harbor seals (=57) collected in SJC between 2009 and 2012 to identify age-related and regional patterns of trace element exposure. Consistent with prior studies of contaminants in pinnipeds, Hg, Cd, and Se concentrations increased with age, and Se:Hg molar ratios approached 1:1 in adult seals. Concentrations of Cd and Hg were below putative marine mammal toxicity thresholds. Mercury concentrations were comparable among Salish Sea populations. Although SJC is less urbanized with fewer industrial inputs than South Puget Sound (SPS), SJC nonpups had greater concentrations of Cd, Cu, and Zn, and pups had greater concentrations of Zn compared to SPS seals. We hypothesize these regional differences could be due to prey preference and availability or to natural geochemical processes. Reported concentrations inform future sampling protocols and can assist in tracking long-term temporal and spatial trends of trace elements in marine organisms.
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April 2020

Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.

Lancet Infect Dis 2019 09 22;19(9):952-961. Epub 2019 Jul 22.

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. Electronic address:

Background: The emergence and spread of resistance in Plasmodium falciparum malaria to artemisinin combination therapies in the Greater Mekong subregion poses a major threat to malaria control and elimination. The current study is part of a multi-country, open-label, randomised clinical trial (TRACII, 2015-18) evaluating the efficacy, safety, and tolerability of triple artemisinin combination therapies. A very high rate of treatment failure after treatment with dihydroartemisinin-piperaquine was observed in Thailand, Cambodia, and Vietnam. The immediate public health importance of our findings prompted us to report the efficacy data on dihydroartemisinin-piperaquine and its determinants ahead of the results of the overall trial, which will be published later this year.

Methods: Patients aged between 2 and 65 years presenting with uncomplicated P falciparum or mixed species malaria at seven sites in Thailand, Cambodia, and Vietnam were randomly assigned to receive dihydroartemisinin-piperaquine with or without mefloquine, as part of the TRACII trial. The primary outcome was the PCR-corrected efficacy at day 42. Next-generation sequencing was used to assess the prevalence of molecular markers associated with artemisinin resistance (kelch13 mutations, in particular Cys580Tyr) and piperaquine resistance (plasmepsin-2 and plasmepsin-3 amplifications and crt mutations). This study is registered with ClinicalTrials.gov, number NCT02453308.

Findings: Between Sept 28, 2015, and Jan 18, 2018, 539 patients with acute P falciparum malaria were screened for eligibility, 292 were enrolled, and 140 received dihydroartemisinin-piperaquine. The overall Kaplan-Meier estimate of PCR-corrected efficacy of dihydroartemisinin-piperaquine at day 42 was 50·0% (95% CI 41·1-58·3). PCR-corrected efficacies for individual sites were 12·7% (2·2-33·0) in northeastern Thailand, 38·2% (15·9-60·5) in western Cambodia, 73·4% (57·0-84·3) in Ratanakiri (northeastern Cambodia), and 47·1% (33·5-59·6) in Binh Phuoc (southwestern Vietnam). Treatment failure was associated independently with plasmepsin2/3 amplification status and four mutations in the crt gene (Thr93Ser, His97Tyr, Phe145Ile, and Ile218Phe). Compared with the results of our previous TRACI trial in 2011-13, the prevalence of molecular markers of artemisinin resistance (kelch13 Cys580Tyr mutations) and piperaquine resistance (plasmepsin2/3 amplifications and crt mutations) has increased substantially in the Greater Mekong subregion in the past decade.

Interpretation: Dihydroartemisinin-piperaquine is not treating malaria effectively across the eastern Greater Mekong subregion. A highly drug-resistant P falciparum co-lineage is evolving, acquiring new resistance mechanisms, and spreading. Accelerated elimination of P falciparum malaria in this region is needed urgently, to prevent further spread and avoid a potential global health emergency.

Funding: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, and National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(19)30391-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715822PMC
September 2019

The effect of dose on the antimalarial efficacy of artesunate-mefloquine against malaria: a protocol for systematic review and individual patient data (IPD) meta-analysis.

BMJ Open 2019 06 27;9(6):e027738. Epub 2019 Jun 27.

WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK.

Introduction: Antimalarial posology based on weight bands leaves patients at the margins vulnerable to receiving either lower or higher weight-adjusted (mg/kg) dosages. This article aims to describe the protocol for systematic review and individual patient meta-analysis (MA) for a study of the distribution of artesunate and mefloquine dosage administered in patients with uncomplicated malaria treated with an artesunate-mefloquine (AS-MQ) regimen. Relationship between mg/kg dose and therapeutic outcomes will be assessed through a one-stage individual participant data (IPD) MA.

Methods And Analysis: Therapeutic efficacy studies with the AS-MQ regimen will be identified by searching the following databases: PUBMED, EMBASE and Web of Science. The corresponding authors of the relevant studies will be requested to share the IPD for the purpose of this MA to a secured repository. All available studies will be standardised using a common data management protocol and pooled into a single database. The relationship between mg/kg dosage and treatment failures will be assessed using a Cox regression model with study sites considered as a shared frailty term. Safety parameters will be explored where available.

Ethics And Dissemination: This IPD MA met the criteria for waiver of ethical review as defined by the Oxford Tropical Research Ethics Committee as the research consisted of secondary analysis of existing anonymous data. The results of this analysis will be disseminated at conferences, WorldWide Antimalarial Resistance Network website and any peer-reviewed publication arising will be made open source.

Prospero Registration Number: CRD42018103776.
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http://dx.doi.org/10.1136/bmjopen-2018-027738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609048PMC
June 2019

Genomic structure and diversity of Plasmodium falciparum in Southeast Asia reveal recent parasite migration patterns.

Nat Commun 2019 06 17;10(1):2665. Epub 2019 Jun 17.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

Estimates of Plasmodium falciparum migration may inform strategies for malaria elimination. Here we elucidate fine-scale parasite population structure and infer recent migration across Southeast Asia using identity-by-descent (IBD) approaches based on genome-wide single nucleotide polymorphisms called in 1722 samples from 54 districts. IBD estimates are consistent with isolation-by-distance. We observe greater sharing of larger IBD segments between artemisinin-resistant parasites versus sensitive parasites, which is consistent with the recent spread of drug resistance. Our IBD analyses reveal actionable patterns, including isolated parasite populations, which may be prioritized for malaria elimination, as well as asymmetrical migration identifying potential sources and sinks of migrating parasites.
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http://dx.doi.org/10.1038/s41467-019-10121-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572796PMC
June 2019

Contribution of Functional Antimalarial Immunity to Measures of Parasite Clearance in Therapeutic Efficacy Studies of Artemisinin Derivatives.

J Infect Dis 2019 08;220(7):1178-1187

Burnet Institute, Melbourne, Australia.

Background: Antibodies to the blood stages of malaria parasites enhance parasite clearance and antimalarial efficacy. The antibody subclass and functions that contribute to parasite clearance during antimalarial treatment and their relationship to malaria transmission intensity have not been characterized.

Methods: Levels of immunoglobulin G (IgG) subclasses and C1q fixation in response to Plasmodium falciparum merozoite antigens (erythrocyte-binding antigen [EBA] 175RIII-V, merozoite surface protein 2 [MSP-2], and MSP-142) and opsonic phagocytosis of merozoites were measured in a multinational trial assessing the efficacy of artesunate therapy across 11 Southeast Asian sites. Regression analyses assessed the effects of antibody seropositivity on the parasite clearance half-life (PC½), having a PC½ of ≥5 hours, and having parasitemia 3 days after treatment.

Results: IgG3, followed by IgG1, was the predominant IgG subclass detected (seroprevalence range, 5%-35% for IgG1 and 27%-41% for IgG3), varied across study sites, and was lowest in study sites with the lowest transmission intensity and slowest mean PC½. IgG3, C1q fixation, and opsonic-phagocytosis seropositivity were associated with a faster PC½ (range of the mean reduction in PC½, 0.47-1.16 hours; P range, .001-.03) and a reduced odds of having a PC½ of ≥5 hours and having parasitemia 3 days after treatment.

Conclusions: The prevalence of IgG3, complement-fixing antibodies, and merozoite phagocytosis vary according to transmission intensity, are associated with faster parasite clearance, and may be sensitive surrogates of an augmented clearance capacity of infected erythrocytes. Determining the functional immune mechanisms associated with parasite clearance will improve characterization of artemisinin resistance.
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http://dx.doi.org/10.1093/infdis/jiz247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735958PMC
August 2019

Measuring Mosquito-borne Viral Suitability in Myanmar and Implications for Local Zika Virus Transmission.

PLoS Curr 2018 Sep 28;10. Epub 2018 Sep 28.

Department of Zoology, University of Oxford, Oxford, UK.

Introduction: In South East Asia, mosquito-borne viruses (MBVs) have long been a cause of high disease burden and significant economic costs. While in some SEA countries the epidemiology of MBVs is spatio-temporally well characterised and understood, in others such as Myanmar our understanding is largely incomplete.

Materials And Methods: Here, we use a simple mathematical approach to estimate a climate-driven suitability index aiming to better characterise the intrinsic, spatio-temporal potential of MBVs in Myanmar.

Results: Results show that the timing and amplitude of the natural oscillations of our suitability index are highly informative for the temporal patterns of DENV case counts at the country level, and a mosquito-abundance measure at a city level. When projected at fine spatial scales, the suitability index suggests that the time period of highest MBV transmission potential is between June and October independently of geographical location. Higher potential is nonetheless found along the middle axis of the country and in particular in the southern corridor of international borders with Thailand.

Discussion: This research complements and expands our current understanding of MBV transmission potential in Myanmar, by identifying key spatial heterogeneities and temporal windows of importance for surveillance and control. We discuss our findings in the context of Zika virus given its recent worldwide emergence, public health impact, and current lack of information on its epidemiology and transmission potential in Myanmar. The proposed suitability index here demonstrated is applicable to other regions of the world for which surveillance data is missing, either due to lack of resources or absence of an MBV of interest.
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http://dx.doi.org/10.1371/currents.outbreaks.7a6c64436a3085ebba37e5329ba169e6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472868PMC
September 2018

Microbiology Investigation Criteria for Reporting Objectively (MICRO): a framework for the reporting and interpretation of clinical microbiology data.

BMC Med 2019 03 29;17(1):70. Epub 2019 Mar 29.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Background: There is a pressing need to understand better the extent and distribution of antimicrobial resistance on a global scale, to inform development of effective interventions. Collation of datasets for meta-analysis, mathematical modelling and temporo-spatial analysis is hampered by the considerable variability in clinical sampling, variable quality in laboratory practice and inconsistencies in antimicrobial susceptibility testing and reporting.

Methods: The Microbiology Investigation Criteria for Reporting Objectively (MICRO) checklist was developed by an international working group of clinical and laboratory microbiologists, infectious disease physicians, epidemiologists and mathematical modellers.

Results: In keeping with the STROBE checklist, but applicable to all study designs, MICRO defines items to be included in reports of studies involving human clinical microbiology data. It provides a concise and comprehensive reference for clinicians, researchers, reviewers and journals working on, critically appraising, and publishing clinical microbiology datasets.

Conclusions: Implementation of the MICRO checklist will enhance the quality and scientific reporting of clinical microbiology data, increasing data utility and comparability to improve surveillance, grade data quality, facilitate meta-analyses and inform policy and interventions from local to global levels.
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http://dx.doi.org/10.1186/s12916-019-1301-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440102PMC
March 2019