Publications

Background Thiamine deficiency (beriberi) is common in some parts of southeast Asia. Acute thiamine deficiency can mimic many complications of malaria, such as encephalopathy and lactic acidosis. We examined the incidence of thiamine deficiency in adults admitted to hospital with malaria in Thailand. Methods For this prospective study, we recruited consecutive patients with malaria or other febrile illness who presented to Paholpolpayuhasena Hospital, Kanchanaburi, Thailand, between May and July, 1992. We used the activation coefficient (α) for transketolase activity in erythrocytes to measure thiamine deficiency (defined as α>1·31) in patients with severe and uncomplicated malaria and in controls (patients” relatives and healthy volunteers). To exclude the possibility of interference in the assays, transketolase activity was also measured in erythrocytes used to culture parasites. Findings 12 (52%) of 23 patients with severe malaria and ten (19%) of 54 patients with uncomplicated malaria had α values above the normal range (p<0·0001 and p=0·0014, respectively, compared with controls), which indicated severe thiamine deficiency. Thiamine deficiency was more severe in patients with cerebral malaria than in those with uncomplicated malaria and the controls (p=0·008). Interpretation In adults admitted to hospital in Thailand, thiamine deficiency commonly complicates acute falciparum malaria, particularly in severe infections, and could contribute to dysfunction of the central nervous system.

In group-living mammals, the eviction of subordinate females from breeding groups by dominants may serve to reduce feeding competition or to reduce breeding competition. Here, we combined both correlational and experimental approaches to investigate whether increases in food intake by dominant females reduces their tendency to evict subordinate females in wild meerkats ( Suricata suricatta ). We used 20 years of long-term data to examine the association between foraging success and eviction rate, and provisioned dominant females during the second half of their pregnancy, when they most commonly evict subordinates. We show that rather than reducing the tendency for dominants to evict subordinates, foraging success of dominant females is positively associated with the probability that pregnant dominant females will evict subordinate females and that experimental feeding increased their rates of eviction. Our results suggest that it is unlikely that the eviction of subordinate females serves to reduce feeding competition and that its principal function may be to reduce reproductive competition. The increase in eviction rates following experimental feeding also suggests that rather than feeding competition, energetic constraints may normally constrain eviction rates.

Journal Article Antifungal susceptibilities of Cryptococcus neoformans in north-east Thailand Get access V. Wuthiekanun, V. Wuthiekanun 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar P.A. Howe, P.A. Howe 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A.J.H. Simpson, A.J.H. Simpson 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar M.D. Smith, M.D. Smith 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A.L. Walsh, A.L. Walsh 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar B.J. Angus, B.J. Angus 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Rajchanuwong, A. Rajchanuwong 3Department of Medicine, Sappasitprasong Hospital, Ubon Ratchathani, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar N.J. White N.J. White 1Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DU, UK Address for correspondence: Professor N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand; phone +662 246 0832, fax +66 2 246 7795. fnnjw@diamond.mahidol.ac.th Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 93, Issue 1, January-February 1999, Pages 96–97, https://doi.org/10.1016/S0035-9203(99)90195-5 Published: 01 January 1999 Article history Received: 17 August 1998 Revision received: 24 September 1998 Accepted: 08 October 1998 Published: 01 January 1999

Background: Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance.Methods: Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use.Findings: In countries with 1% P. falciparum prevalence, immediate adoption of TACTs would result in substantially lower frequency of artemisinin-resistant alleles 10 years later. Median estimates were 70%, 33%, and 18% lower allele frequency for countries currently deploying dihydroartemisinin-piperaquine, artesunate-amodiaquine, or artemether-lumefantrine, respectively. Corresponding median treatment failure rate decreases are 74%, 34%, and 17%. Delaying TACT introduction increases future resistance frequencies and treatment failure rates. The most significant threat to the success of TACTs is the emergence of a triple-resistant genotype. which if above 0.01 frequency may undermine elimination efforts in low-prevalence regions.Interpretation: Introduction of TACTs could delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs and improving the chances of malaria elimination. Immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.Funding: This research falls under the auspices of the Development of Triple Artemisinin-based Combination Therapies (DeTACT) project funded by UK Aid and the UK Government’s Foreign, Commonwealth and Development Office. Funding from Wellcome Trust (220211) is also acknowledged. MFB, TDN, TN-AT acknowledge funding from the National Institutes of Health grant NIAID R01AI153355 and The Bill and Melinda Gates Foundation INV-005517 grant awarded to Pennsylvania State University. RA acknowledges funding from the Bill and Melinda Gates Foundation (OPP1193472).Declaration of Interest: None to declare.

A stenogamous colony of Anopheles cracens (A. dirus B) established 20 years ago in a Thai insectary proved susceptible to Plasmodium vivax. However, routine sporozoite production by feeding on field-collected blood samples has not been described. The setting-up of an A. cracens colony in an insectary on the Thai-Myanmar border and the process of using P. vivax field samples for the production of infectious sporozoites are described.

Summary Rapid malaria diagnosis, a key component of malaria control strategies, is hampered by the expense and training requirements of reliable microscopy. Rapid malaria antigen tests may improve the diagnosis of malaria in the rural tropics. After 1 h training 64 village health volunteers (VHVs) from rural Laos, with no previous laboratory experience, performed two malaria rapid diagnostic tests (ParacheckPf TM and OptiMAL TM ) accurately. The reliability of six VHVs was assessed longitudinally, over 10 months with different frequencies of retraining. Compared with microscopy, error rates in dipstick interpretation were low (&lt;2%) for both tests and were not associated with retraining frequency ( P &gt; 0.2). Previously untrained Lao VHVs performed malaria rapid tests reliably with high sensitivity and specificity after minimal training.

Background Most malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability. Methods In Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7–30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662. Results Mortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2·5% vs 3·0%, p=0·1). Two versus 13 (0·03% vs 0·22%, p=0·0020) were permanently disabled; total dead or disabled: 156 versus 190 (2·6% vs 3·2%, p=0·0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 [1·6%] vs 82/4426 [1·9%], risk ratio 0·86 [95% CI 0·63–1·18], p=0·35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 [1·9%] vs 57/1519 [3·8%], risk ratio 0·49 [95% CI 0·32–0·77], p=0·0013). Interpretation If patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability. Funding UNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); Sall Family Foundation; the European Union (QLRT-2000-01430); the UK Medical Research Council; USAID; Irish Aid; the Karolinska Institute; and the University of Oxford Clinical Trial Service Unit (CTSU).

Recurrent melioidosis occurs in approximately 6% of patients in the first year following the initial presentation. A recent study revealed that 25% of patients with recurrence had reinfection rather than a relapse resulting from a failure to cure. The aim of this study was to reevaluate these 2 patient groups to define their individual risk factors.All adult patients who presented to Sappasithiprasong Hospital (Ubon Ratchathani, in northeast Thailand) with culture-confirmed melioidosis during the period 1986-2004 and who survived to receive oral antimicrobial therapy were observed until July 2005. Clinical factors and antimicrobial treatment of patients with recurrent disease due to relapse or reinfection, as confirmed by bacterial genotyping, were compared using a time-varying Cox proportional hazard model.Of 889 patients who survived and underwent follow-up, 86 patients (9.7%) presented with relapse, and 30 patients (3.4%) became reinfected. There was no difference in acute outcome between the relapse and reinfection groups. No risk factors for reinfection were identified. Multivariate analyses identified choice and duration of oral antimicrobial therapy as the most important determinants of relapse, followed by positive blood culture result (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.18-2.92) and multifocal distribution (HR, 1.95; 95% CI, 1.03-3.67). Patients treated with an appropriate oral antibiotic regimen for 12-16 weeks had a 90% decreased risk of relapse (HR, 0.10; 95% CI, 0.02-0.44), compared with patients who were treated for < or = 8 weeks. Trimethoprim-sulfamethoxazole plus doxycycline was an effective oral therapy.This study highlights clinical factors associated with an increased likelihood of relapse and provides evidence for optimal oral antimicrobial therapy.

Infections with Tuberculosis (TB)-causing agents of the Mycobacterium tuberculosis complex threaten human, livestock, and wildlife health globally due to the high capacity to cross trans-species boundaries. Tuberculosis is a cryptic disease characterized by prolonged, sometimes lifelong subclinical infections, complicating disease monitoring. Consequently, our understanding of infection risk, disease progression, and mortality across species affected by TB remains limited. The TB agent Mycobacterium suricattae was first recorded in the late 1990s in a wild population of meerkats inhabiting the Kalahari in South Africa and has since spread considerably, becoming a common cause of meerkat mortality. This offers an opportunity to document the epidemiology of naturally spreading TB in a wild population. Here, we synthesize more than 25 years-worth of TB reporting and social interaction data across 3,420 individuals to track disease spread, and quantify rates of TB social exposure, progression, and mortality. We found that most meerkats had been exposed to the pathogen within eight years of first detection in the study area, with exposure reaching up to 95% of the population. Approximately one quarter of exposed individuals progressed to clinical TB stages, followed by physical deterioration and death within a few months. Since emergence, 11.6% of deaths were attributed to TB, although the true toll of TB-related mortality is likely higher. Lastly, we observed marked variation in disease progression among individuals, suggesting inter-individual differences in both TB susceptibility and resistance. Our results highlight that TB prevalence and mortality could be higher than previously reported, particularly in species or populations with complex social group dynamics. Long-term studies, such as the present one, allow us to assess temporal variation in disease prevalence and progression and quantify exposure, which is rarely measured in wildlife. Long-term studies are highly valuable tools to explore disease emergence and ecology, and study host-pathogen co-evolutionary dynamics in general, and its impact on social mammals.

The solid state spectrometer on the HEAO-2 X-ray observatory observed the X-ray spectrum of Tycho's SNR. The observations show a relative excess of line emission from Si, S, and Ar by or = 6 compared to that expected from a plasma of solar composition in collisional equilibrium and by a factor of or = 3 compared to Cas A. Similar excesses are not found for line emission from Mg and Fe. The data suggest that the SN observed by Tycho in 1572 produced significant amounts of Si group elements but did not eject large amounts of Fe as predicted by some models of Type I SN events.

Artemisinin combination therapy (ACT) is now the recommended first-line treatment for falciparum malaria throughout the world. Initiatives to eliminate malaria are critically dependent on its efficacy. There is recent worrying evidence that artemisinin resistance has arisen on the Thai-Cambodian border. Urgent containment interventions are planned and about to be executed. Mathematical modeling approaches to intervention design are now integrated into the field of malaria epidemiology and control. The use of such an approach to investigate the likely effectiveness of different containment measures with the ultimate aim of eliminating artemisinin-resistant malaria is described. A population dynamic mathematical modeling framework was developed to explore the relative effectiveness of a variety of containment interventions in eliminating artemisinin-resistant malaria in western Cambodia. The most effective intervention to eliminate artemisinin-resistant malaria was a switch of treatment from artemisinin monotherapy to ACT (mean time to elimination 3.42 years (95% CI 3.32–3.60 years). However, with this approach it is predicted that elimination of artemisinin-resistant malaria using ACT can be achieved only by elimination of all malaria. This is because the various forms of ACT are more effective against infections with artemisinin-sensitive parasites, leaving the more resistant infections as an increasing proportion of the dwindling parasite population. Containment of artemisinin-resistant malaria can be achieved by elimination of malaria from western Cambodia using ACT. The "last man standing" is the most resistant and thus this strategy must be sustained until elimination is truly achieved.

Artemisinin resistant Plasmodium falciparum is advancing across Southeast Asia in a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of standing variation that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions.

The World Health Organization recommends that primaquine should be given once weekly for 8-weeks to patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase (G6PD) deficiency, but data on its antirelapse efficacy and safety are limited.Within the context of a multicentre, randomised clinical trial of two primaquine regimens in P. vivax malaria, patients with G6PD deficiency were excluded and enrolled into a separate 12-month observational study. They were treated with a weekly dose of 0.75 mg/kg primaquine for 8 weeks (PQ8W) plus dihydroartemisinin piperaquine (Indonesia) or chloroquine (Afghanistan, Ethiopia, Vietnam). G6PD status was diagnosed using the fluorescent spot test and confirmed by genotyping for locally prevalent G6PD variants. The risk of P. vivax recurrence following PQ8W and the consequent haematological recovery were characterized in all patients and in patients with genotypically confirmed G6PD variants, and compared with the patients enrolled in the main randomised control trial.Between July 2014 and November 2017, 42 male and 8 female patients were enrolled in Afghanistan (6), Ethiopia (5), Indonesia (19), and Vietnam (20). G6PD deficiency was confirmed by genotyping in 31 patients: Viangchan (14), Mediterranean (4), 357A-G (3), Canton (2), Kaiping (2), and one each for A-, Chatham, Gaohe, Ludhiana, Orissa, and Vanua Lava. Two patients had recurrent P. vivax parasitaemia (days 68 and 207). The overall 12-month cumulative risk of recurrent P. vivax malaria was 5.1% (95% CI: 1.3-18.9) and the incidence rate of recurrence was 46.8 per 1000 person-years (95% CI: 11.7-187.1). The risk of P. vivax recurrence was lower in G6PD deficient patients treated with PQ8W compared to G6PD normal patients in all treatment arms of the randomised controlled trial. Two of the 26 confirmed hemizygous males had a significant fall in haemoglobin (>5g/dl) after the first dose but were able to complete their 8 week regimen.PQ8W was highly effective in preventing P. vivax recurrences. Whilst PQ8W was well tolerated in most patients across a range of different G6PD variants, significant falls in haemoglobin may occur after the first dose and require clinical monitoring.This trial is registered at ClinicalTrials.gov (NCT01814683).

One-hundred thirteen men (mean age, 23 years) who presented with inguinal buboes to a government-operated hospital for sexually transmitted diseases (STDs) in Bangkok were studied between February 1987 and February 1989. The median duration of preceding symptoms was 7 days (range, 1–62 days). The majority of patients (74; 65%) had received treatment previously; 31 (27%) were febrile, 13 (12%) had extrainguinallymphadenopathy, and 31 (27%) had concurrent active genital ulcers. There was no history of genital ulceration in 66 (58%) of the patients. Pus was obtained from 51 of the 110 buboes aspirated for culture; 21 (41%) of these cultures yielded Haemophilus ducreyi, and 2 (3.9%) were positive for Chlamydia trachomatis on immunofluorescence microscopy. Saline (1 mL) was injected and reaspirated from the buboes of 35 of the other 59 patients; 3 buboes yielded H. ducreyi and 9 were positive for C. trachomatis. All cultures for other aerobic and anaerobic bacteria and viruses in intact buboes were negative. Syphilis serology was positive in only one case. Patients attending STD clinics in this region who have large, fluctuant, edematous inguinal buboes containing pus should receive presumptive treatment for chancroid. If there is no pus, then the bubo is more likely to be caused by lymphogranuloma venereum.