Publications

Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine (CQ), is widely used in the treatment of rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis) and is being studied for the treatment and prevention of COVID-19. Here, we investigate through mathematical modelling the safety profile of HCQ, CQ and other QT-prolonging anti-infective agents to determine their risk categories for Torsade de Pointes (TdP) arrhythmia. We performed safety modelling with uncertainty quantification using a risk classifier based on the qNet torsade metric score, a measure of the net charge carried by major currents during the action potential under inhibition of multiple ion channels by a compound. Modelling results for HCQ at a maximum free therapeutic plasma concentration (free C max) of approximately 1.2 µM (malaria dosing) indicated it is most likely to be in the high-intermediate-risk category for TdP, whereas CQ at a free C max of approximately 0.7 µM was predicted to most likely lie in the intermediate-risk category. Combining HCQ with the antibacterial moxifloxacin or the anti-malarial halofantrine (HAL) increased the degree of human ventricular action potential duration prolongation at some or all concentrations investigated, and was predicted to increase risk compared to HCQ alone. The combination of HCQ/HAL was predicted to be the riskiest for the free C max values investigated, whereas azithromycin administered individually was predicted to pose the lowest risk. Our simulation approach highlights that the torsadogenic potentials of HCQ, CQ and other QT-prolonging anti-infectives used in COVID-19 prevention and treatment increase with concentration and in combination with other QT-prolonging drugs.

1. Mineral homoeostasis was investigated in 172 Thai adults with acute falciparum malaria at presentation (87 males, 85 females; mean age 30 years), and prospectively in a subgroup of 10 severely ill patients. 2. Mild, asymptomatic hypocalcaemia (corrected plasma calcium concentration 1.79–2.11 mmol/l) was found in 61 cross-sectional study patients (35.5%), with no difference between those with uncomplicated (2.16 ± 0.10 mmol/l, mean ± sd, n = 89) and severe (2.18 ± 0.15 mmol/l, n = 83, P = 0.36) infections. Six prospectively studied patients were hypocalcaemic during treatment; simultaneous serum intact parathormone concentrations were inappropriately low (< 5.0 pmol/l), but rose in three patients to high levels (11.8–16.4 pmol/l) on the fifth day. 3. Plasma phosphate concentration was decreased (< 0.80 mmol/l) on admission in 74 patients (43.0%) and increased (> 1.45 mmol/l) in 15 (8.7%). Severe phosphate depletion (plasma phosphate concentration < 0.30 mmol/l) occurred in 14 patients, of whom 11 had severe infections. Serum phosphate concentrations in the prospective study patients on admission (0.59 ± 0.23 mmol/l) correlated significantly with the simultaneous renal threshold phosphate concentration (0.68 ± 0.33 mmol/l; r = 0.607, P < 0.025) and both parameters rose in parallel during treatment. 4. Plasma magnesium concentrations were normal (0.75–1.05 mmol/l) in 108 patients (62.8%); 45 cases (26.1%) had hypermagnesaemia and 19 (11.0%) had hypomagnesaemia. 5. These data suggest that mild hypocalcaemia is common in malaria regardless of disease severity; a depressed parathormone response may contribute. Despite malaria-associated haemolysis, hypophosphataemia is also common, but can be severe. Phosphate replacement should therefore be considered where strict monitoring of plasma phosphate concentrations is feasible.

The qinghaosu (artemisinin) group of drugs is the most important new class of antimalarials developed in the last fifty years. Although there has been no clinical evidence of neurotoxicity, an unusual pattern of damage to specific brain-stem nuclei has been reported in experimental animals receiving high doses of arteether or artemether. Detailed clinical examinations, audiometry, and brain stem auditory evoked potentials (BSAEPs) were assessed in 242 Vietnamese subjects who had previously received up to 21 antimalarial treatment courses of artemisinin or artesunate alone and 108 controls from the same location who had not received these drugs. There was no evidence of a drug effect on the clinical or neurophysiological parameters assessed. In this population there was no clinical or neurophysiological evidence of brain-stem toxicity that could be attributed to exposure to artemisinin or artesunate.

Red blood cells infected by mature stages of Plasmodium ovale obtained from a 56-year-old Thai patient formed rosettes readily with uninfected erythrocytes. Ex vivo, the ring stage-infected erythrocytes matured well under the in vitro conditions used for P. falciparum culture, and the infected erythrocytes formed rosettes when the parasites became mature trophozoites. These rosettes were stable and remained intact until completion of schizogony. Plasmodium ovale rosettes were similar to those formed by P. falciparum- and P. vivax-infected erythrocytes. Rosette formation appears to be a common property of three species of human plasmodia.

No abstract is provided for this article.

Administration of a loading dose of quinine in severe malaria may be dangerous if therapeutic blood concentrations are already present because of previous treatment. To assess the reliability of the history of pretreatment we conducted a prospective study of 379 adult patients with acute falciparum malaria admitted to a hospital in western Thailand. Admission plasma concentrations of quinine were measured by high performance liquid chromatography (HPLC), and compared with the patients' history of previous quinine treatment. The sensitivity of the history was 59% (95% confidence interval [CI] 49–69%), the specificity was 79% (95% CI 74–84%), the positive predictive value was 53%, and the negative predictive value 82%. A rapid (10 min) semi-quantitative estimate of plasma quinine concentrations, based on a simple ‘dipstick’ method using a quinine-specific monoclonal antibody, proved considerably more sensitive and specific. The correlation between the dipstick estimate and the subsequent HPLC measurement of plasma quinine concentration was 0.85 (n = 404; P < 0.0001). In 404 admission samples, the negative predictive value of the dipstick estimate for plasma quinine concentrations >1 μg/mL was 100%. In Thailand the history of previous quinine treatment given by the patients or their relatives was unreliable but the quinine dipstick provided a simple and rapid means of assessment of quinine pre-treatment in acute falciparum malaria.

Summary. Nine Thai adults with P. vivax malaria were investigated. Light and electron microscope studies of marrow aspirates revealed morphological evidence of dyserythro‐poiesis in six of them, Dyserythropoiesis was most marked in the four most anaemic patients. In these four patients the electron microscope also revealed the presence of erythro‐blasts at various stages of degradation within the cytoplasm of macrophages. Neither the dyserythropoiesis nor the ineffective erythropoiesis could be attributed to a deficiency of vitamin B 12 , folate or iron. The abnormalities of erythropoiesis seemed to result from the P. vivax infection itself. Other bone marrow reactions seen in this infection included macrophage hyperplasia, plasmacytosis and increased eosinophil granulocytopoiesis. Unlike in severe P. falciparum malaria, the microvasculature of the marrow was not obstructed by parasitized red cells.

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential. Methods: Open label randomized controlled trial. Participants received standard care – amphotericin combined with fluconazole for the first 2 weeks – or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) – the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031 . Results: Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (−0.48log10 colony-forming units/mL/CSF control arm versus −0.49 tamoxifen arm, difference −0.005log10CFU/ml/day, 95% CI: −0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation. Conclusions: High-dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed. Funding: The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.

This paper introduces a Theme Issue presenting the latest developments in research on the interplay between flexibility and constraint in social behaviour, using comparative datasets, long-term field studies and experimental data from both field and laboratory studies of mammals. We first explain our focus on mammals and outline the main components of their social systems, focusing on variation within- and among-species in numerous aspects of social organization, mating system and social structure. We then review the current state of primarily ultimate explanations of this diversity in social behaviour. We approach the question of how and why the balance between behavioural flexibility and continuity is achieved by discussing the genetic, developmental, ecological and social constraints on hypothetically unlimited behavioural flexibility. We introduce the other contributions to this Theme Issue against this background and conclude that constraints are often crucial to the evolution and expression of behavioural flexibility. In exploring these issues, the enduring relevance of Tinbergen's seminal paper ‘On aims and methods in ethology’, with its advocacy of an integrative, four-pronged approach to studying behaviour becomes apparent: an exceptionally fitting tribute on the 50th anniversary of its publication.

Paul Newton and colleagues propose that clinical trial guidelines should include a requirement to assess and state the quality of the drugs and other medical products used

Journal Article Susceptibility of Pseudomonas pseudomallei to some newer β-lactam antibiotics and antibiotic combinations using time-kill studies Get access M. D. Smith, M. D. Smith aFaculty of Tropical Medicine, Mahidol University42016 Rajvithi Road, Bangkok 10400, ThailandbNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of OxfordOxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar V. Wuthiekanuna, V. Wuthiekanuna aFaculty of Tropical Medicine, Mahidol University42016 Rajvithi Road, Bangkok 10400, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar A. L. Walsh, A. L. Walsh aFaculty of Tropical Medicine, Mahidol University42016 Rajvithi Road, Bangkok 10400, ThailandbNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of OxfordOxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar N. J. White N. J. White aFaculty of Tropical Medicine, Mahidol University42016 Rajvithi Road, Bangkok 10400, ThailandbNuffield Department of Clinical Medicine, John Radcliffe Hospital, University of OxfordOxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Antimicrobial Chemotherapy, Volume 33, Issue 1, January 1994, Pages 145–149, https://doi.org/10.1093/jac/33.1.145 Published: 01 January 1994 Article history Received: 22 March 1993 Accepted: 22 July 1993 Published: 01 January 1994

Derivation of time series model.

Plasmodium vivax threatens nearly half the world’s population and is a significant impediment to achievement of the millennium development goals. It is an important, but incompletely understood, cause of anaemia. This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia. Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent. Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells. Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion. Anaemia can be averted by early and effective anti-malarial treatment.

The elimination of Plasmodium vivax is challenged by dormant liver stages (hypnozoites) that can reactivate months after initial infection resulting in relapses that enhance transmission. Relapsing infections confound antimalarial clinical efficacy trials due to the inability to distinguish between recurrences arising from blood-stage treatment failure (recrudescence), reinfection or relapse. Genetic relatedness of paired parasite isolates, measured by identity-by-descent (IBD), can provide important information on whether individuals have had single or multiple mosquito inoculations, thus informing on recurrence origin. We developed a high-throughput amplicon sequencing assay comprising 93 multi-SNP (microhaplotype) P. vivax markers to determine IBD between P. vivax clinical isolates. The assay was evaluated in 659 independent infections from the Asia-Pacific and Horn of Africa, including 108 pairs of infections from a randomized controlled trial (RCT). A bioinformatics pipeline (vivaxGEN-MicroHaps) was established to support data processing. Simulations using paneljudge demonstrated low error in pairwise IBD estimation in all countries assessed (all RMSE &lt;0.12) and IBD-based networks illustrated strong clustering by geography. IBD analysis in the RCT demonstrated a higher frequency of suspected relapses or recrudescence in patients treated with primaquine regimens (0.84) compared to those without primaquine (0.60). Our results demonstrate the potential to derive information on P. vivax IBD using amplicon sequencing, that informs policy-relevant treatment and transmission dynamics.