Publications

No abstract is provided for this article.

BackgroundEmergence 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.MethodsWe 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.FindingsOverall, 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.InterpretationArtemisinin 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.FundingWellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.

This randomized, controlled trial shows that acetaminophen reduces kidney dysfunction and risk of developing acute kidney injury, particularly in severe malaria patients who present with high plasma hemoglobin, supporting the hypothesis that acetaminophen inhibits cell-free hemoglobin-mediated renal tubular oxidative damage.

Background There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infection. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has significant antiviral activity in vivo is uncertain. Methods In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. Viral clearance rates were derived from daily duplicate oropharyngeal quantitative PCR measurements. This ongoing trial is registered at ClinicalTrials.gov ( NCT05041907 ). Results Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Compared with the no study drug arm, the mean estimated SARS-CoV-2 viral clearance following ivermectin was 9.1% slower [95%CI -27.2% to +11.8%; n=45 versus n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41]. Conclusions High dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Measured in this way viral clearance rate is a valuable pharmacodynamic measure in assessing antiviral COVID-19 therapeutics in vivo . Funding “Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)” is funded by the Wellcome Therapeutics Accelerator (223195/Z/21/Z). Impact Rate of viral clearance determined from daily duplicate oropharyngeal swabs over one week is an efficient measure of antiviral efficacy in early COVID-19 infection. High dose ivermectin did not demonstrate measurable antiviral activity in early symptomatic COVID-19 infection.

Background Malaria and hypertensive disorders of pregnancy (HDoP) affect millions of pregnancies worldwide, particularly those of young, first-time mothers. Small case-control studies suggest a positive association between falciparum malaria and risk of pre-eclampsia but large prospective analyses are lacking. Methods We characterized the relationship between malaria in pregnancy and the development of HDoP in a large, prospectively followed cohort. Pregnant women living along the Thailand-Myanmar border, an area of low seasonal malaria transmission, were followed at antenatal clinics between 1986 and 2016. The relationships between falciparum and vivax malaria during pregnancy and the odds of gestational hypertension, pre-eclampsia, or eclampsia were examined using logistic regression amongst all women and then stratified by gravidity. Results There were 23,262 singleton pregnancies in women who presented during the first trimester and were followed fortnightly. Falciparum malaria was associated with gestational hypertension amongst multigravidae (adjusted odds ratio (AOR) 2.59, 95%CI 1.59–4.23), whereas amongst primigravidae, it was associated with the combined outcome of pre-eclampsia/eclampsia (AOR 2.61, 95%CI 1.01–6.79). In contrast, there was no association between vivax malaria and HDoP. Conclusions Falciparum but not vivax malaria during pregnancy is associated with hypertensive disorders of pregnancy.

Relapses arising from dormant liver-stage Plasmodium vivax parasites (hypnozoites) are a major cause of vivax malaria. However, in endemic areas, a recurrent blood-stage infection following treatment can be hypnozoite-derived (relapse), a blood-stage treatment failure (recrudescence), or a newly acquired infection (reinfection). Each of these requires a different prevention strategy, but it was not previously possible to distinguish between them reliably. We show that individual vivax malaria recurrences can be characterised probabilistically by combined modelling of time-to-event and genetic data within a framework incorporating identity-by-descent. Analysis of pooled patient data on 1441 recurrent P. vivax infections in 1299 patients on the Thailand–Myanmar border observed over 1000 patient follow-up years shows that, without primaquine radical curative treatment, 3 in 4 patients relapse. In contrast, after supervised high-dose primaquine only 1 in 40 relapse. In this region of frequent relapsing P. vivax , failure rates after supervised high-dose primaquine are significantly lower (∼3%) than estimated previously.

Background. Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria. Methods. African children (<15 years) with severe malaria participated in a randomized comparison of parenteral artesunate and parenteral quinine in 9 African countries. Detailed clinical assessment was performed on admission. Parasite densities were assessed in a reference laboratory. Predictors of death were examined using a multivariate logistic regression model. Results. Twenty indicators of disease severity were assessed, out of which 5 (base deficit, impaired consciousness, convulsions, elevated blood urea, and underlying chronic illness) were associated independently with death. Tachypnea, respiratory distress, deep breathing, shock, prostration, low pH, hyperparasitemia, severe anemia, and jaundice were statistically significant indicators of death in the univariate analysis but not in the multivariate model. Age, glucose levels, axillary temperature, parasite density, heart rate, blood pressure, and blackwater fever were not related to death in univariate models. Conclusions. Acidosis, cerebral involvement, renal impairment, and chronic illness are key independent predictors for a poor outcome in African children with severe malaria. Mortality is markedly increased in cerebral malaria combined with acidosis. Clinical Trial Registration. ISRCTN50258054.

No abstract is provided for this article.

Chronic infection is often accompanied by a wasting process, the metabolic basis of which is not fully understood. The aims of the present study were to measure protein and energy metabolism in patients with melioidosis (a serious and antibiotic-refractory Gram-negative bacterial infection which is endemic in South-East Asia) in order to define the metabolic abnormalities that might contribute to wasting. Whole-body protein turnover was measured using the [13C]leucine technique, both in the fasted state and while consuming a high-energy meal. Resting energy expenditure was measured by indirect calorimetry, and total energy expenditure by the bicarbonate/urea method. Results were normalized for fat-free mass, as estimated from skinfold thickness. Protein turnover was increased in melioidosis patients compared with healthy controls during fasting (170.9 compared with 124.1 µmol·kg-1·h-1; P = 0.04), but the net rate of catabolism (22.2 compared with 20.5 µmol·kg-1·h-1; P = 0.77) and the anabolic response to feeding were similar in the two groups. Resting energy expenditure was higher in melioidosis patients compared with controls (191.4 and 157.3 kJ·kg-1·day-1 respectively; P = 0.04), but total energy expenditure (measured in a separate group of eight patients with melioidosis) was low (192.1 kJ·kg-1·day-1). In conclusion, this study found no evidence of metabolic causative factors, such as accelerated net protein catabolism during fasting, a blunted anabolic response to feeding or increased daily energy expenditure, and therefore suggests that reduced energy intake is the prime cause of wasting. The observed normal response to feeding should encourage nutritional approaches to prevent wasting.

No abstract is provided for this article.

Global Nation? Australia and the Politics of Globalisation by John Wiseman (Cambridge: Cambridge University Press, 1998, pp.viii + 202, £40 hb, £14.95 pb). Collaborative Federalism: Economic Reform in Australia in the 1990s by Martin Painter (Cambridge: Cambridge University Press, 1998, pp.ix + 207, £40 hb). Lionel Murphy: A Political Biography by Jenny Hocking (Cambridge: Cambridge University Press, 1997, pp.359, £40 hb). The French‐Canadian Idea of Confederation by A.I. Silver (Toronto: University of Toronto Press, 2nd edn, 1997, pp.xv + 283, £14 pb). Divide and Quit: An Eyewitness Account of the Partition of India by Penderel Moon (Delhi: Oxford India Paperbacks, 1998, pp.xxiii + 324, Rs. 345 pb). India: Fifty Years of Democracy and Development edited by Yogendra K. Malik and Ashok Kapur (New Delhi: APH Publishing, 1998, pp.xli + 489, Rs. 1,000 hb). Gandhi: Struggling for Autonomy by Ronald J. Terchek (Lanham: Rowman and Littlefield, 1998, pp.x + 265, $58 hb, $19.95 pb). Irrigation Agriculture and the Raj: Punjab, 1887–1947 by M. Mufakkharul Islam (New Delhi: Manohar, 1997, pp.180, 400rs hb). South Africa Reborn: Building a New Democracy by Heather Deegan (London: UCL Press, 1999, pp.xxi + 225, £12.95 pb). South Africa, Limits to Change: The Political Economy of Transition by Hein Marais (London: Zed/Cape Town: UCT Press, 1998, pp.xii + 290, 79.95 SA Rand). Beyond Control: Immigration and Human Rights in a Democratic South Africa edited by Jonathan Crush (Cape Town, IDASA, 1998, pp.v + 189, 54.95 SA Rand). Labour and Democracy in Namiba, 1971–1996 by Gretchen Bauer (Athens, OH, and London: Ohio University Press and James Currey Publishers, 1998, pp.229, £14.95 pb; £40 hb). Developing Uganda edited by Holger Bernt Hansen and Michael Twaddle (Oxford, Kampala, Athens, Nairobi: James Currey, Fountain Publishers, Ohio University Press, E.A.E.P, 1998, pp.ix + 293, £14.95 pb; £40 hb). Democracy and Decentralisation in South Asia and West Africa by Richard C. Crook and James Manor (Cambridge: Cambridge University Press, 1998, pp.xvi + 335, £15.95pb; £45 hb). Elections and Conflict Management in Africa edited by Timothy D. Sisk and Andrew Reynolds (Washington, DC: United States Institute of Peace Press, 1998, pp.viii + 224, $14.95/£11.75pb). Africa Works: Disorder as Political Instrument by Patrick Chabal and Jean‐Pascal Daloz (Oxford and Bloomington, IN: James Currey and Indiana University Press, 1999 pp.xxi + 170; £9.95 pb). The Power of Babel: Language and Governance in the African Experience by Ali A. Mazrui and Alamin M. Mazrui (Oxford: James Currey, 1998, pp.228, £40 hb, £12.95 pb). African Foreign Policies edited by Stephen Wright (Boulder, CO: Westview Press, 1999, pp.xi + 260, no price given). Comparative Government and Politics: An Introduction by R. Hague, M. Harrop and S. Breslin (Basingstoke: Macmillan, 4th edn. 1998, pp.xv + 317, £47.50 hb, £15.50 pb). Comparative Politics: Theory and Methods by B. Guy Peters (Basingstoke: Macmillan, 1998, pp.x + 262, £45 hb, £14.50 pb). Britain, Southeast Asia and the Onset of the Cold War, 1945–1950 by Nicholas Tarling (Cambridge: Cambridge University Press, 1998, pp.xii + 488, £45 hb). Problem Representation in Foreign Policy Decision Making edited by Donald Sylvan and James Voss (Cambridge: Cambridge University Press, 1998, pp.347, £37.50 hb).

<ns4:p><ns4:bold>Background</ns4:bold><ns4:bold>:</ns4:bold> Natural <ns4:italic>Wolbachia </ns4:italic>infections in malaria mosquitoes were recently reported in Africa, and negatively correlated with the development of <ns4:italic>Plasmodium falciparum</ns4:italic> in the vectors. The occurrence and effects of <ns4:italic>Wolbachia </ns4:italic>infections outside Africa have not been described and may have been underestimated.</ns4:p><ns4:p> <ns4:bold>Methods</ns4:bold><ns4:bold>:</ns4:bold> Mosquitoes were collected by human-landing catch during May and June 2017 in ten villages in Kayin state, Myanmar. Closely related species of malaria vectors were identified with molecular assays. <ns4:italic>Wolbachia</ns4:italic> infection rates were assessed with quantitative real-time PCR.</ns4:p><ns4:p> <ns4:bold>Results:</ns4:bold> Low titer of <ns4:italic>Wolbachia </ns4:italic>DNA was detected in 13/370 samples in six malaria vector species. Phylogenetic analysis based on 16S rRNA sequences revealed a high diversity of <ns4:italic>Wolbachia </ns4:italic>strains and identified lineages different from those described in the African malaria mosquitoes.</ns4:p><ns4:p> <ns4:bold>Conclusion:</ns4:bold> These low-density genetically diverse natural <ns4:italic>Wolbachia </ns4:italic>infections question the ecology and biology of <ns4:italic>Wolbachia</ns4:italic>-<ns4:italic>Anopheles</ns4:italic> interactions<ns4:italic> </ns4:italic>in Southeast Asia. Their effects on malaria transmission and mosquito vectors are yet to be determined.</ns4:p>