Publications

Melioidosis: A Major Cause of Community-Acquired Septicemia in Northeastern Thailand

Journal Article Melioidosis: A Major Cause of Community-Acquired Septicemia in Northeastern Thailand Get access Wipada Chaowagul, Wipada Chaowagul Search for other works by this author on: Oxford Academic PubMed Google Scholar Nicholas J. White, Nicholas J. White Please address requests for reprints to Dr. Nicholas J. White, Faculty 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 David A. B. Dance, David A. B. Dance Search for other works by this author on: Oxford Academic PubMed Google Scholar Yupaporn Wattanagoon, Yupaporn Wattanagoon Search for other works by this author on: Oxford Academic PubMed Google Scholar Pimjai Naigowit, Pimjai Naigowit Search for other works by this author on: Oxford Academic PubMed Google Scholar Timothy M. E. Davis, Timothy M. E. Davis Search for other works by this author on: Oxford Academic PubMed Google Scholar Sornchai Looareesuwan, Sornchai Looareesuwan Search for other works by this author on: Oxford Academic PubMed Google Scholar Nirun Pitakwatchara Nirun Pitakwatchara Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 159, Issue 5, May 1989, Pages 890–899, https://doi.org/10.1093/infdis/159.5.890 Published: 01 May 1989 Article history Received: 06 September 1988 Revision received: 02 December 1988 Published: 01 May 1989

The prevention and treatment of Plasmodium vivax malaria

points• The worldwide burden of Plasmodium vivax malaria has more than halved from an estimated 17.3 to 6.5 million cases between 2010 and 2019.This resulted from increased deployment of conventional malaria control measures (rapid diagnostic tests, effective antimalarial treatment, vector control) and significant global investment in malaria elimination.There is no generally available P. vivax vaccine, nor is there likely to be one in the near future.• The latest-generation RDTs used for P. vivax diagnosis have sensitivities comparable to microscopy.Ultrasensitive PCR methods which can detect parasite densities as low as 28/ml have revealed a much higher prevalence of asymptomatic P. vivax infection in malaria endemic regions than previously estimated.• Chloroquine remains an effective schizonticide for vivax malaria, except in Indonesia, Sabah and Papua New Guinea where there is high-level chloroquine resistance.Artemisinin combination therapies are effective alternative schizonticides that unify the treatment of all malarias.Relapses contribute significantly to the burden of P. vivax infections.Prevention of relapse requires "radical cure" with an 8-aminoquinoline (primaquine daily for 7 to 14 days, or single-dose tafenoquine).These drugs cause oxidant haemolysis in G6PD deficiency, so safe use requires G6PD testing.Overall, the risks of primaquine haemolysis have been overemphasised and the benefits of relapse prevention underappreciated.• Qualitative screening tests for G6PD deficiency (detecting <30% normal enzyme activity) are adequate for screening before giving primaquine for radical cure, but a quantitative point of care G6PD test to detect <70% normal enzyme activity is needed for tafenoquine.• Radical curative efficacy depends on the total 8-aminoquinoline dose given; higher primaquine doses (7 mg base/kg rather than 3.5 mg base/kg) are required in parts of Southeast Asia and Oceania.The currently recommended dose of tafenoquine (300 mg) is sub-optimal.In low transmission settings, elimination of vivax malaria is possible with current tools.

Advances and roadblocks in the Treatment of Malaria

The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery, and reduced treatment failure rates and transmission from the treated infection. These drugs remain highly effective against falciparum malaria in most malaria endemic areas but significant resistance has emerged in the Greater Mekong subregion of Southeast Asia. Resistance to artemisinin was followed by resistance in the ACT partner drugs, and fit multidrug resistant parasite lineages have now spread widely across the region. ACTs are highly effective against P. vivax and the other malaria species. Recent studies show that radical curative regimens of primaquine (to prevent relapse) can be shortened to seven days, and that the newly introduced single dose tafenoquine is an alternative, although the currently recommended dose is insufficient in Southeast Asia and Oceania. Targeted malaria elimination using focal mass treatments with dihydroartemisinin-piperaquine have proved safe and effective malaria elimination accelerators, but progress overall towards malaria elimination is very slow. Indeed since 2015 overall malaria case numbers globally have risen.

Coalition in the archives

The papers of Liberal activist Frances Josephy are used to examine the attitudes of ordinary Liberals to coalitions in the 1920s and 1930s.

DHFR MUTATIONS IN PLASMODIUM KNOWLESI DO NOT APPEAR LINKED TO SELECTIVE DRUG PRESSURE FROM PUTATIVE HUMAN-TO-HUMAN TRANSMISSION IN SABAH, MALAYSIA

No abstract is provided for this article.

Antimalarial dosing regimens and drug resistance

The contribution of underdosing to antimalarial treatment failure has been underappreciated. Most recommended dosage regimens are based on studies in non-pregnant adult patients. Young children and pregnant women, who bear the heaviest malaria burden, have the highest treatment failure rates. This has been attributed previously to lower immunity, although blood concentrations of many antimalarial drugs are significantly lower in pregnant women and young children than in non-pregnant adults. Nevertheless, there have been no studies of higher dosages. Sub-therapeutic concentrations will certainly contribute to poorer responses to treatment and will fuel the emergence and spread of antimalarial drug resistance. There is an urgent need for studies to optimise antimalarial dosage regimens in infants, young children and pregnant women, both to improve cure rates and to prolong the useful therapeutic lives of antimalarial drugs.

Natural History of Recurrent Urinary Tract Infections in Women

Natural History of Recurrent Urinary Tract Infections in Women Get access Walter E. Stamm, Walter E. Stamm Department of Medicine, University of Washington School of Medicine, Seattle, Washington Please address requests for reprints to Dr. Walter E. Stamm, Department of Medicine, Harborview Medical Center, 325 9th Avenue, Seattle, Washington 98104 Search for other works by this author on: Oxford Academic PubMed Google Scholar Mary McKevitt, Mary McKevitt Department of Medicine, University of Washington School of Medicine, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar Pacita L. Roberts, Pacita L. Roberts Department of Medicine, University of Washington School of Medicine, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar Nicholas J. White Nicholas J. White Department of Medicine, University of Washington School of Medicine, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar Reviews of Infectious Diseases, Volume 13, Issue 1, January 1991, Pages 77–84, https://doi.org/10.1093/clinids/13.1.77 Published: 01 January 1990 Article history Published: 01 January 1990 Received: 10 January 1990 Revision received: 03 May 1990

The William J. Pape Memorial Lecture: Shipping and Globalisation in the Post-World War Two Era (with special reference to containerisation and decolonisation)

Diphtheria

Diphtheria is a vaccine-preventable life-threatening disease. It is caused by toxins released by the bacteria Corynebacterium diphtheria, some strains of C. ulcerans, and very rarely C. pseudotuberculosis. The disease is caused by the local effects of destructive infection (usually in the nasopharynx) and the distal effects of diphtheria toxin on the heart, peripheral nerves, and kidneys. Death results from airways obstruction, myocarditis, or polyneuritis. Diphtheria has declined dramatically in wealthier countries over the past 80 years, but it remains an important disease in many parts of the tropics and there have been resurgences of the disease in some countries. Recently, there have been outbreaks in Yemen, Bangladesh, Venezuela, and Haiti associated with civil unrest, privation, forced migration, and disasters. C. diphtheriae infections result from person-to-person spread via respiratory droplets and close contact. C. ulcerans infections are usually acquired from raw milk and/or contact with farms and farm animals or close contact with companion animals and pets (cows, goats, cats, and dogs). Death can occur in up to 10% of clinical cases despite antibiotics and the use of antisera. Diphtheria is transmitted mainly by droplet spread. It is preventable by vaccination and the coverage in the population must be maintained above 95%.

Proinflammatory Cytokines and Chemokines in Humans with Japanese Encephalitis

Japanese encephalitis virus (JEV), the mosquito-borne flavivirus, annually causes an estimated 35,000-50,000 encephalitis cases and 10,000-15,000 deaths in Asia, and there is no antiviral treatment. The role played by the immune response in determining the outcome of human infection with JEV is poorly understood, although, in animal models of flavivirus encephalitis, unregulated proinflammatory cytokine responses can be detrimental.We studied the innate, cellular, and humoral immune responses in 118 patients infected with JEV, of whom 13 (11%) died.Levels of interferon (IFN)- alpha , the proinflammatory cytokine interleukin (IL)-6, and the chemokine IL-8 were all higher in the cerebrospinal fluid (CSF) of the nonsurvivors than of the survivors (P=.04, P=.006, and P=.04, respectively), as were both the IL-6 : IL-4 ratio in CSF (a marker of the balance of pro- and anti-inflammatory cytokines) and the level of the chemokine RANTES (regulated on activation, normally T cell expressed and secreted) in plasma (P=.03). In contrast, levels of immunoglobulin (Ig) M and IgG in CSF and of IgM in plasma were higher in the survivors (P=.035, P=.003, and P=.009, respectively). Levels of IFN- gamma and nitric oxide did not vary with outcome.During JEV infection, elevated levels of proinflammatory cytokines and chemokines are associated with a poor outcome, but whether they are simply a correlate of severe disease or contribute to pathogenesis remains to be determined.

Characterization of an in vivo concentration-effect relationship for piperaquine in malaria chemoprevention

An in vivo concentration-effect relationship for the malaria drug piperaquine can be used for translational simulations of expected therapeutic outcomes in vulnerable populations.

Genomic epidemiology of the current wave of artemisinin resistant malaria

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.

Weekly primaquine for radical cure of patients with Plasmodium vivax malaria and glucose-6-phosphate dehydrogenase deficiency

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).

Contrasting genetic structure in Plasmodium vivax populations from Asia and South America

Populations of Plasmodium falciparum show striking differences in linkage disequilibrium, population differentiation and diversity, but only fragmentary data exists on the genetic structure of Plasmodium vivax. We genotyped nine tandem repeat loci bearing 2–8bp motifs from 345 P. vivax infections collected from three Asian countries and from five locations in Colombia. We observed 9–37 alleles per locus and high diversity (H e =0.72–0.79, mean=0.75) in all countries. Numbers of multiple clone infections varied considerably: these were rare in Colombia and India, but > 60% of isolates carried multiple alleles in at least one locus in Thailand and Laos. However, only one or two of the nine loci show >1 allele in many samples, suggesting that mutation within infections may result in overestimation of true multiple carriage rates. Identical nine-locus genotypes were frequently found in Colombian populations, contributing to strong linkage disequilibrium. These identical genotypes were strongly clustered in time, consistent with epidemic transmission of clones and subsequent breakdown of allelic associations, suggesting high rates of inbreeding and low effective recombination rates in this country. In contrast, identical genotypes were rare and loci were randomly associated in all three Asian populations, consistent with higher rates of outcrossing and recombination. We observed low but significant differentiation between different Asian countries (standardized F ST =0.13–0.45). In comparison, we see greater differentiation between collection locations within Colombia (standardized F ST =0.4–0.7), and strong differentiation between continents (standardized F ST =0.48–0.79). The observed heterogeneity in multiple clone carriage rates, linkage disequilibrium and population differentiation are similar in some, but not all, respects to those observed in P. falciparum, and have important implications for the design of association mapping studies, and interpretation of P. vivax epidemiology.

World Antimalarial Resistance Network (WARN) IV: Clinical pharmacology

A World Antimalarial Resistance Network (WARN) database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any) studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics). By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered) individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject) characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD) studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component of the WARN database can play a pivotal role in monitoring accurately for true antimalarial drug resistance and promptly correcting sub-optimal dosage regimens to prevent these contributing to the emergence and spread of antimalarial resistance.

Spatial aspects of concretionary growth in the Upper Lias of Northeast England

Spatial distribution, size and orientation measurements on 143 concretions from the Jet Rock (Upper Lias) of northeast England are reported. The distribution of concretions conforms to a Poisson or random model at the scale sampled. Approximately 30% of the Jet Rock concretions are sufficiently asymmetrical in bedding plane section for a major axis orientation to be recorded. Orientations cluster in the range 10–30°, possibly indicating a preferred direction of pore water transport in the bedding plane during compactional expulsion.

Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross‐sectional survey on the prevalence of fake antimalarials

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

The relationship between capillary and venous concentrations of the antimalarial drug lumefantrine (benflumetol)

Journal Article The relationship between capillary and venous concentrations of the antimalarial drug lumefantrine (benflumetol) Get access M. van Vugt, M. van Vugt 1Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand2Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand3Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar F. Ezzet, F. Ezzet 4Novartis Pharma AG, Basel, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar L. Phaipun, L. Phaipun 1Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar F. Nosten, F. Nosten 1Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand2Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand5Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar N.J. White N.J. White 2Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand5Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK Address for correspondence: Professor N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand; phone + 66 2 246 0832, fax +66 2 246 7795. Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 92, Issue 5, September-October 1998, Pages 564–565, https://doi.org/10.1016/S0035-9203(98)90917-8 Published: 01 September 1998 Article history Received: 24 March 1998 Revision received: 26 June 1998 Accepted: 30 June 1998 Published: 01 September 1998