Search tips
Search criteria

Results 1-25 (116)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
more »
1.  Quality of intrapartum care by skilled birth attendants in a refugee clinic on the Thai-Myanmar border: a survey using WHO Safe Motherhood Needs Assessment 
Increasing the number of women birthing with skilled birth attendants (SBAs) as one of the strategies to reduce maternal mortality and morbidity must be partnered with a minimum standard of care. This manuscript describes the quality of intrapartum care provided by SBAs in Mae La camp, a low resource, protracted refugee context on the Thai-Myanmar border.
In the obstetric department of Shoklo Malaria Research Unit (SMRU) the standardized WHO Safe Motherhood Needs Assessment tool was adapted to the setting and used: to assess the facility; interview SBAs; collect data from maternal records during a one year period (August 2007 – 2008); and observe practice during labour and childbirth.
The facility assessment recorded no ‘out of stock’ or ‘out of date’ drugs and supplies, equipment was in operating order and necessary infrastructure e.g. a stand-by emergency car, was present. Syphilis testing was not available. SBA interviews established that danger signs and symptoms were recognized except for sepsis and endometritis. All SBAs acknowledged receiving theoretical and ‘hands-on’ training and regularly attended deliveries. Scores for the essential elements of antenatal care from maternal records were high (>90%) e.g. providing supplements, recording risk factors as well as regular and correct partogram use. Observed good clinical practice included: presence of a support person; active management of third stage; post-partum monitoring; and immediate and correct neonatal care. Observed incorrect practice included: improper controlled cord traction; inadequate hand washing; an episiotomy rate in nulliparous women 49% (34/70) and low rates 30% (6/20) of newborn monitoring in the first hours following birth. Overall observed complications during labour and birth were low with post-partum haemorrhage being the most common in which case the SBAs followed the protocol but were slow to recognize severity and take action.
In the clinic of SMRU in Mae La refugee camp, SBAs were able to comply with evidence-based guidelines but support to improve quality of care in specific areas is required. The structure of the WHO Safe Motherhood Needs Assessment allowed significant insights into the quality of intrapartum care particularly through direct observation, identifying a clear pathway for quality improvement.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-015-0444-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4332741  PMID: 25652646
Skilled birth attendant; Health care quality assessment; Pregnancy and childbirth care; Safe motherhood; Refugee setting
2.  Spiroindolone KAE609 for Falciparum and Vivax Malaria 
The New England journal of medicine  2014;371(5):403-410.
KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum.
We conducted a phase 2, open-label study at three centers in Thailand to assess the antimalarial efficacy, safety, and adverse-event profile of KAE609, at a dose of 30 mg per day for 3 days, in two sequential cohorts of adults with uncomplicated P. vivax malaria (10 patients) or P. falciparum malaria (11). The primary end point was the parasite clearance time.
The median parasite clearance time was 12 hours in each cohort (interquartile range, 8 to 16 hours in patients with P. vivax malaria and 10 to 16 hours in those with P. falciparum malaria). The median half-lives for parasite clearance were 0.95 hours (range, 0.68 to 2.01; interquartile range, 0.85 to 1.14) in the patients with P. vivax malaria and 0.90 hours (range, 0.68 to 1.64; interquartile range, 0.78 to 1.07) in those with P. falciparum malaria. By comparison, only 19 of 5076 patients with P. falciparum malaria (<1%) who were treated with oral artesunate in Southeast Asia had a parasite clearance half-life of less than 1 hour. Adverse events were reported in 14 patients (67%), with nausea being the most common. The adverse events were generally mild and did not lead to any discontinuations of the drug. The mean terminal half-life for the elimination of KAE609 was 20.8 hours (range, 11.3 to 37.6), supporting a once-daily oral dosing regimen.
KAE609, at dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; number, NCT01524341.)
PMCID: PMC4143746  PMID: 25075833
3.  Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso 
Seasonal malaria chemoprevention (SMC), with regular use of amodiaquine plus sulfadoxine-pyrimethamine (AQ/SP) during the transmission season, is now a standard malaria control measure in the Sahel subregion of Africa. Another strategy under study is SMC with dihydroartemisinin plus piperaquine (DP). Plasmodium falciparum single nucleotide polymorphisms (SNPs) in P. falciparum crt (pfcrt), pfmdr1, pfdhfr, and pfdhps are associated with decreased response to aminoquinoline and antifolate antimalarials and are selected by use of these drugs. To characterize selection by SMC of key polymorphisms, we assessed 13 SNPs in P. falciparum isolated from children aged 3 to 59 months living in southwestern Burkina Faso and randomized to receive monthly DP or AQ/SP for 3 months in 2009. We compared SNP prevalence before the onset of SMC and 1 month after the third treatment in P. falciparum PCR-positive samples from 120 randomly selected children from each treatment arm and an additional 120 randomly selected children from a control group that did not receive SMC. The prevalence of relevant mutations was increased after SMC with AQ/SP. Significant selection was seen for pfcrt 76T (68.5% to 83.0%, P = 0.04), pfdhfr 59R (54.8% to 83.3%, P = 0.0002), and pfdhfr 108N (55.0% to 87.2%, P = 0.0001), with trends toward selection of pfmdr1 86Y, pfdhfr 51I, and pfdhps 437G. After SMC with DP, only borderline selection of wild-type pfmdr1 D1246 (mutant; 7.7% to 0%, P = 0.05) was seen. In contrast to AQ/SP, SMC with DP did not clearly select for known resistance-mediating polymorphisms. SMC with AQ/SP, but not DP, may hasten the development of resistance to components of this regimen. (This study has been registered at under registration no. NCT00941785.)
PMCID: PMC4068591  PMID: 24733476
4.  Characterization of G6PD Genotypes and Phenotypes on the Northwestern Thailand-Myanmar Border 
PLoS ONE  2014;9(12):e116063.
Mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene result in red blood cells with increased susceptibility to oxidative damage. Significant haemolysis can be caused by primaquine and other 8-aminoquinoline antimalarials used for the radical treatment of Plasmodium vivax malaria. The distribution and phenotypes of mutations causing G6PD deficiency in the male population of migrants and refugees in a malaria endemic region on the Thailand-Myanmar border were characterized. Blood samples for G6PD fluorescent spot test (FST), G6PD genotyping, and malaria testing were taken from 504 unrelated males of Karen and Burman ethnicities presenting to the outpatient clinics. The overall frequency of G6PD deficiency by the FST was 13.7%. Among the deficient subjects, almost 90% had the Mahidol variant (487G>A) genotype. The remaining subjects had Chinese-4 (392G>T), Viangchan (871G>A), Açores (595A>G), Seattle (844G>C) and Mediterranean (563C>T) variants. Quantification of G6PD activity was performed using a modification of the standard spectrophotometric assay on a subset of 24 samples with Mahidol, Viangchan, Seattle and Chinese-4 mutations; all samples showed a residual enzymatic activity below 10% of normal and were diagnosed correctly by the FST. Further studies are needed to characterise the haemolytic risk of using 8-aminoquinolines in patients with these genotypes.
PMCID: PMC4275285  PMID: 25536053
5.  Pregnancy Outcome in Relation to Treatment of Murine Typhus and Scrub Typhus Infection: A Fever Cohort and a Case Series Analysis 
There is a paucity of published reports on pregnancy outcome following scrub and murine typhus despite these infections being leading causes of undifferentiated fever in Asia. This study aimed to relate pregnancy outcome with treatment of typhus.
Methodology/Principal Findings
Data were analyzed from: i) pregnant women with a diagnosis of scrub and/or murine typhus from a fever cohort studies; ii) case series of published studies in PubMed using the search terms “scrub typhus” (ST), “murine typhus” (MT), “Orientia tsutsugamushi”, “Rickettsia tsutsugamushi”, “Rickettsia typhi”, “rickettsiae”, “typhus”, or “rickettsiosis”; and “pregnancy”, until February 2014 and iii) an unpublished case series. Fever clearance time (FCT) and pregnancy outcome (miscarriage and delivery) were compared to treatment. Poor neonatal outcome was a composite measure for pregnancies sustained to 28 weeks or more of gestation ending in stillbirth, preterm birth, or delivery of a growth restricted or low birth weight newborn.
There were 26 women in the fever cohort. MT and ST were clinically indistinguishable apart from two ST patients with eschars. FCTs (median [range] hours) were 25 [16–42] for azithromycin (n = 5), 34 [20–53] for antimalarials (n = 5) and 92 [6–260] for other antibiotics/supportive therapy (n = 16). There were 36.4% (8/22) with a poor neonatal outcome.
In 18 years, 97 pregnancies were collated, 82 with known outcomes, including two maternal deaths. Proportions of miscarriage 17.3% (14/81) and poor neonatal outcomes 41.8% (28/67) were high, increasing with longer FCTs (p = 0.050, linear trend). Use of azithromycin was not significantly associated with improved neonatal outcomes (p = 0.610)
The published ST and MT world literature amounts to less than 100 pregnancies due to under recognition and under diagnosis. Evidence supporting the most commonly used treatment, azithromycin, is weak. Collaborative, prospective clinical trials in pregnant women are urgently required to reduce the burden of adverse maternal and newborn outcomes and to determine the safety and efficacy of antimicrobial treatment.
Author Summary
Typhus is an under-recognised and under-studied public health problem in Asia. In rural areas of Southeast Asia murine and scrub typhus are probably the most common treatable cause of fever. The estimated number of scrub typhus cases in Southeast Asia, more than 1 million yearly, results in approximately 50–80,000 deaths per year. Treatment delays due to lack of appropriate diagnostics and lack of awareness lead to a substantial health and economic impact in the one of the world's most densely populated regions. Only 97 cases in pregnancy are available from the published world literature over the past 18 years. Only 82 of these had known outcomes, including two maternal deaths. The proportion of poor neonatal outcome including stillbirth, prematurity and low birth weight was high occurring in more than 40% of pregnancies, and higher when the fever clearance time was longer. While poor neonatal outcomes were observed with all antibiotics prescribed, azithromycin appeared to be associated with shorter fever clearance times but this was not statistically significant. Evidence to support the use of azithromycin is weak. The correct antimicrobial or combination for undifferentiated fever in pregnant women in Southeast Asia is unknown.
PMCID: PMC4238995  PMID: 25412503
6.  Characterization of the Commercially-Available Fluorescent Chloroquine-BODIPY Conjugate, LynxTag-CQGREEN, as a Marker for Chloroquine Resistance and Uptake in a 96-Well Plate Assay 
PLoS ONE  2014;9(10):e110800.
Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than in the resistant strains 7G8 and K1. Microplate reader measurements indicated suppression of LynxTag-CQGREEN efflux after pretreatment of parasites with known reversal agents. Microsomes carrying either sensitive- or resistant-type PfCRT were assayed for uptake; resistant-type PfCRT exhibited increased accumulation of LynxTag-CQGREEN, which was suppressed by pretreatment with known chemosensitizers. Eight laboratory strains and twelve clinical isolates were sequenced for PfCRT and Pgh1 haplotypes previously reported to contribute to drug resistance, and pfmdr1 copy number and chloroquine IC50s were determined. These data were compared with LynxTag-CQGREEN uptake/fluorescence by multiple linear regression to identify genetic correlates of uptake. Uptake of the compound correlated with the logIC50 of chloroquine and, more weakly, a mutation in Pgh1, F1226Y.
PMCID: PMC4208776  PMID: 25343249
7.  Efficacy and Day 7 Plasma Piperaquine Concentrations in African Children Treated for Uncomplicated Malaria with Dihydroartemisinin-Piperaquine 
PLoS ONE  2014;9(8):e103200.
One promising new Artemisinin-based combination therapies (ACTs) is dihydroartemisinin-piperaquine (DHA-PQ). However, the pharmacokinetics of piperaquine and the relationship between drug levels and clinical efficacy are incompletely characterized, particularly in children.
We performed a single-arm open-label trial in Bobo-Dioulasso, Burkina Faso. A total of 379 participants aged 6 months or more with uncomplicated falciparum malaria were enrolled. Each participant received daily dose of DHA-PQ for three days and followed for 42 days. Parasitological efficacy was analyzed, considering rates of recrudescence and overall recurrence. PK was an exploratory endpoint and a priori, no sample size had been determined. Day 7 capillary and venous plasma concentrations of piperaquine were measured in children aged 2–10 years.
Of the 379 participants, 365 (96.3%) completed 42 days of follow-up. The median daily dose of PQ was 18.5 mg/kg [6.5–24]. Treatment with DHA-PQ was well tolerated with fever and parasitemia resolution within 48 hours in nearly all children. Recurrent malaria within 42 days of follow-up occurred in 31.3% (10/34) of children less than 2 years old, 16.0% (16/106) of those aged 2–5 years, 9.4% (15/160) of those aged 5–10 years, and none (0/68) of those over 10 years old. After genotyping, 3 of 41 recurrent episodes were recrudescence. An exploratory analysis shows that children with successful treatment outcomes had significantly higher median plasma concentrations of PQ compared to those with recurrent malaria within 42 days after therapy, considering either capillary samples (68 ng/ml [50–85] compared to 48 ng/ml [36–55], p<0.001) or venous samples (42 ng/ml [29–59] compared to 25 ng/ml [19–44], p<0.001).
DHA-PQ was effective for uncomplicated P. falciparum malaria treatment and offers an alternative to other ACTs. Recurrent malaria was mainly due to new infections after treatment and was correlated with low day 7 PQ concentration in the youngest patients.
Trial Registration ISRCTN59761234
PMCID: PMC4136730  PMID: 25133389
8.  An Integrated Lab-on-Chip for Rapid Identification and Simultaneous Differentiation of Tropical Pathogens 
Tropical pathogens often cause febrile illnesses in humans and are responsible for considerable morbidity and mortality. The similarities in clinical symptoms provoked by these pathogens make diagnosis difficult. Thus, early, rapid and accurate diagnosis will be crucial in patient management and in the control of these diseases. In this study, a microfluidic lab-on-chip integrating multiplex molecular amplification and DNA microarray hybridization was developed for simultaneous detection and species differentiation of 26 globally important tropical pathogens. The analytical performance of the lab-on-chip for each pathogen ranged from 102 to 103 DNA or RNA copies. Assay performance was further verified with human whole blood spiked with Plasmodium falciparum and Chikungunya virus that yielded a range of detection from 200 to 4×105 parasites, and from 250 to 4×107 PFU respectively. This lab-on-chip was subsequently assessed and evaluated using 170 retrospective patient specimens in Singapore and Thailand. The lab-on-chip had a detection sensitivity of 83.1% and a specificity of 100% for P. falciparum; a sensitivity of 91.3% and a specificity of 99.3% for P. vivax; a positive 90.0% agreement and a specificity of 100% for Chikungunya virus; and a positive 85.0% agreement and a specificity of 100% for Dengue virus serotype 3 with reference methods conducted on the samples. Results suggested the practicality of an amplification microarray-based approach in a field setting for high-throughput detection and identification of tropical pathogens.
Author Summary
Tropical diseases consist of a group of debilitating and fatal infections that occur primarily in rural and urban settings of tropical and subtropical countries. While the primary indices of an infection are mostly the presentation of clinical signs and symptoms, outcomes due to an infection with tropical pathogens are often unspecific. Accurate diagnosis is crucial for timely intervention, appropriate and adequate treatments, and patient management to prevent development of sequelae and transmission. Although, multiplex assays are available for the simultaneous detection of tropical pathogens, they are generally of low throughput. Performing parallel assays to cover the detection for a comprehensive scope of tropical infections that include protozoan, bacterial and viral infections is undoubtedly labor-intensive and time consuming. We present an integrated lab-on-chip using microfluidics technology coupled with reverse transcription (RT), PCR amplification, and microarray hybridization for the simultaneous identification and differentiation of 26 tropical pathogens that cause 14 globally important tropical diseases. Such diagnostics capacity would facilitate evidence-based management of patients, improve the specificity of treatment and, in some cases, even allow contact tracing and other disease-control measures.
PMCID: PMC4117454  PMID: 25078474
9.  A High-Content Phenotypic Screen Reveals the Disruptive Potency of Quinacrine and 3′,4′-Dichlorobenzamil on the Digestive Vacuole of Plasmodium falciparum 
Plasmodium falciparum is the etiological agent of malignant malaria and has been shown to exhibit features resembling programmed cell death. This is triggered upon treatment with low micromolar doses of chloroquine or other lysosomotrophic compounds and is associated with leakage of the digestive vacuole contents. In order to exploit this cell death pathway, we developed a high-content screening method to select compounds that can disrupt the parasite vacuole, as measured by the leakage of intravacuolar Ca2+. This assay uses the ImageStream 100, an imaging-capable flow cytometer, to assess the distribution of the fluorescent calcium probe Fluo-4. We obtained two hits from a small library of 25 test compounds, quinacrine and 3′,4′-dichlorobenzamil. The ability of these compounds to permeabilize the digestive vacuole in laboratory strains and clinical isolates was validated by confocal microscopy. The hits could induce programmed cell death features in both chloroquine-sensitive and -resistant laboratory strains. Quinacrine was effective at inhibiting field isolates in a 48-h reinvasion assay regardless of artemisinin clearance status. We therefore present as proof of concept a phenotypic screening method with the potential to provide mechanistic insights to the activity of antimalarial drugs.
PMCID: PMC3910761  PMID: 24217693
10.  Quantifying Low Birth Weight, Preterm Birth and Small-for-Gestational-Age Effects of Malaria in Pregnancy: A Population Cohort Study 
PLoS ONE  2014;9(7):e100247.
The association between malaria during pregnancy and low birth weight (LBW) is well described. This manuscript aims to quantify the relative contribution of malaria to small-for-gestational-age (SGA) infants and preterm birth (PTB) in pregnancies accurately dated by ultrasound on the Thai-Myanmar border at the Shoklo Malaria Research Unit.
Methods and Findings
From 2001 to 2010 in a population cohort of prospectively followed pregnancies, we analyzed all singleton newborns who were live born, normal, weighed in the first hour of life and with a gestational age (GA) between 28+0 and 41+6 weeks. Fractional polynomial regression was used to determine the mean birthweight and standard deviation as functions of GA. Risk differences and factors of LBW and SGA were studied across the range of GA for malaria and non-malaria pregnancies. From 10,264 newborns records, population centiles were created.
Women were screened for malaria by microscopy a median of 22 [range 1–38] times and it was detected and treated in 12.6% (1,292) of pregnancies. Malaria was associated with LBW, PTB, and SGA compared to those without malaria. Nearly two-thirds of PTB were classified as LBW (68% (539/789)), most of which 83% (447/539) were not SGA. After GA 39 weeks, 5% (298/5,966) of non-LBW births were identified as SGA. Low body mass index, primigravida, hypertension, smoking and female sex of the newborn were also significantly and independently associated with LBW and SGA consistent with previous publications.
Treated malaria in pregnancy was associated with an increased risk for LBW, PTB, and SGA, of which the latter are most important for infant survival. Using LBW as an endpoint without adjusting for GA incorrectly estimated the effects of malaria in pregnancy. Ultrasound should be used for dating pregnancies and birth weights should be expressed as a function (or adjusted for GA) of GA in future malaria in pregnancy studies.
PMCID: PMC4077658  PMID: 24983755
11.  Population pharmacokinetics of quinine in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda 
Journal of Antimicrobial Chemotherapy  2014;69(11):3033-3040.
Oral quinine is used for the treatment of uncomplicated malaria during pregnancy, but few pharmacokinetic data are available for this population. Previous studies have reported a substantial effect of malaria on the pharmacokinetics of quinine resulting from increased α-1-acid glycoprotein levels and decreased cytochrome P450 3A4 activity. The aim of this study was to investigate the pharmacokinetic properties of oral quinine in pregnant women with uncomplicated malaria in Uganda using a population approach.
Data from 22 women in the second and third trimesters of pregnancy with uncomplicated Plasmodium falciparum malaria were analysed. Patients received quinine sulphate (10 mg of salt/kg) three times daily (0, 8 and 16 h) for 7 days. Plasma samples were collected daily and at frequent intervals after the first and last doses. A population pharmacokinetic model for quinine was developed accounting for different disposition, absorption, error and covariate models.
Parasitaemia, as a time-varying covariate affecting relative bioavailability, and body temperature on admission as a covariate on elimination clearance, explained the higher exposure to quinine during acute malaria compared with the convalescent phase. Neither the estimated gestational age nor the trimester influenced the pharmacokinetic properties of quinine significantly.
A population model was developed that adequately characterized quinine pharmacokinetics in pregnant Ugandan women with acute malaria. Quinine exposure was lower than previously reported in patients who were not pregnant. The measurement of free quinine concentration will be necessary to determine the therapeutic relevance of these observations.
PMCID: PMC4195470  PMID: 24970740
population models; P. falciparum; NONMEM
12.  Uncomplicated Plasmodium vivax malaria in pregnancy associated with mortality from acute respiratory distress syndrome 
Malaria Journal  2014;13:191.
The association between severe malaria and Plasmodium vivax species is contentious. On the Thai-Myanmar border, all pregnant women are followed systematically with active weekly malaria screening. Over a 27-year period of providing antenatal care, 48,983 have been prospectively followed until pregnancy outcome (miscarriage or delivery) and 4,298 women have had P. vivax detected at least once. Reported here is the first known P. vivax-associated death amongst these women. The initial patient presentation was of uncomplicated P. vivax (0.5% parasitaemia) in a term, multigravida woman who responded rapidly to oral artesunate and mefloquine treatment, clearing her blood stage parasites within 48 hours. The patient appeared well, was ambulatory and due to be discharged but became unwell with acute respiratory distress syndrome (ARDS) requiring ventilation three days (67 hours) into treatment. Despite induction and delivery of a stillborn foetus, ventilatory requirements increased and the patient died on day 7. The patient had a low body mass index. Sensitive detection with nested PCR confirmed only the presence of P. vivax species and concomitant infections such as tuberculosis and human immunodeficiency virus (HIV) were also ruled out. The contemporaneous treatment of acute uncomplicated P. vivax and the onset of ARDS on day 3 in this patient implies a possible but unconfirmed association with death in this patient. Assuming this death was caused by P. vivax, the risk of ARDS-related maternal mortality in this setting did not differ significantly between Plasmodium falciparum and P. vivax (0.24 per 1,000 (1/4,158) versus 0.23 per 1,000 (1/4,298), contrary to the increased risk of maternal mortality from P. falciparum compared to P. vivax, 2.89 per 1,000 (12/4,158) versus 0.23 per 1,000 (1/4,298), P = 0.003.
PMCID: PMC4046059  PMID: 24886559
Acute respiratory distress syndrome; Maternal mortality; Plasmodium vivax; Severe malaria
13.  Population Pharmacokinetic Assessment of the Effect of Food on Piperaquine Bioavailability in Patients with Uncomplicated Malaria 
Previously published literature reports various impacts of food on the oral bioavailability of piperaquine. The aim of this study was to use a population modeling approach to investigate the impact of concomitant intake of a small amount of food on piperaquine pharmacokinetics. This was an open, randomized comparison of piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for 3 days with (n = 15) and without (n = 15) concomitant food to patients with uncomplicated Plasmodium falciparum malaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacokinetics of piperaquine and the influence of concomitant food intake. A modified Monte Carlo mapped power approach was applied to evaluate the relationship between statistical power and various degrees of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25% increase in relative bioavailability per dose occasion during recovery from malaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modified Monte Carlo mapped power approach may be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect piperaquine absorption significantly in acute malaria.
PMCID: PMC4023753  PMID: 24449770
14.  Two fatal cases of melioidosis on the Thai-Myanmar border 
F1000Research  2014;3:4.
Melioidosis is endemic in areas of Southeast Asia, however, there are no published reports from the Thai-Myanmar border. We report the first two documented cases of fatal melioidosis in this region. This is of great public health importance and highlights the need to both increase clinical awareness of melioidosis on the Thai-Myanmar border, and to assess the true burden of disease in the area through improved case detection and Burkholderia pseudomallei prevalence studies.
PMCID: PMC3976102  PMID: 24715973
15.  Clinical audit to enhance safe practice of skilled birth attendants for the fetus with nuchal cord: evidence from a refugee and migrant cohort 
Current evidence for optimal management of fetal nuchal cord detected after the head has birthed supports techniques that avoid ligation of the umbilical cord circulation. Routine audit found frequent unsafe management of nuchal cord by skilled birth attendants (SBAs) in migrant and refugee birth centres on the Thai-Burmese border.
The audit cycle was used to enhance safe practice by SBA for the fetus with nuchal cord. In the three birth centres the action phase of the audit cycle was initially carried out by the doctor responsible for the site. Six months later a registered midwife, present six days per week for three months in one birth facility, encouraged SBAs to facilitate birth with an intact umbilical circulation for nuchal cord. Rates of cord ligation before birth were recorded over a 24 month period (1-July-2011 to 30-June-2013) and in-depth interviews and a knowledge survey of the SBAs took place three months after the registered midwife departure.
The proportion of births with nuchal cord ligation declined significantly over the four six monthly quarters from 15.9% (178/1123) before the action phase of the audit cycle; to 11.1% (107/966) during the action phase of the audit cycle with the doctors; to 2.4% (28/1182) with the registered midwife; to 0.9% (9/999) from three to nine months after the departure of the registered midwife, (p < 0.001, linear trend). Significant improvements in safe practice were observed at all three SMRU birth facilities. Knowledge of fetal nuchal cord amongst SBAs was sub-optimal and associated with fear and worry despite improved practice. The support of a registered midwife increased confidence of SBAs.
The audit cycle and registered midwife interprofessional learning for SBAs led to a significant improvement in safe practice for the fetus with nuchal cord. The authors would encourage this type of learning in organizations with birth facilities on the Thai-Burmese border and in other similar resource limited settings with SBAs.
PMCID: PMC3943506  PMID: 24552462
Audit cycle; Interprofessional learning; Nuchal cord; Quality improvement; Registered midwife; Skilled birth attendant
16.  Two fatal cases of melioidosis on the Thai-Myanmar border 
F1000Research  2014;3:4.
Melioidosis is endemic in areas of Southeast Asia, however, there are no published reports from the Thai-Myanmar border.  We report the first two cases of fatal melioidosis in this region. This is of great public health importance and highlights the need to increase clinical awareness of melioidosis on the Thai-Myanmar border and to assess the true burden of disease in the area through improved case detection and Burkholderia pseudomallei prevalence studies.
PMCID: PMC3976102  PMID: 24715973
17.  Population genetic correlates of declining transmission in a human pathogen 
Molecular ecology  2012;22(2):273-285.
Pathogen control programs provide a valuable, but rarely exploited, opportunity to directly examine the relationship between population decline and population genetics. We investigated the impact of an ~12-fold decline in transmission on the population genetics of Plasmodium falciparum infections (n = 1731) sampled from four clinics on the Thai-Burma border over 10 years, and genotyped using 96 genome-wide SNPs. The most striking associated genetic change was a reduction in the frequency of infections containing multiple parasite genotypes from 63% in 2001 to 14% in 2010 (p = 3×10−15). Two measures of the clonal composition of populations (genotypic richness and the β-parameter of the Pareto distribution) declined over time as more people were infected by parasites with identical multilocus genotypes, consistent with increased selfing and a reduction in the rate at which multilocus genotypes are broken apart by recombination. We predicted that the reduction in transmission, multiple clone carriage, and outbreeding would be mirrored by an increased influence of genetic drift. However, geographical differentiation and expected heterozygosity remained stable across the sampling period. Furthermore, Ne estimates derived from allele frequencies fluctuation between years remained high (582 to ∞) and showed no downward trend. These results demonstrate how genetic data can compliment epidemiological assessments of infectious disease control programs. The temporal changes in a single declining population parallel those seen in comparisons of parasite genetics in regions of differing endemicity, strongly supporting the notion that reduced opportunity for outbreeding is the key driver of these patterns.
PMCID: PMC3537863  PMID: 23121253
18.  High-Throughput Analysis of Antimalarial Susceptibility Data by the WorldWide Antimalarial Resistance Network (WWARN) In Vitro Analysis and Reporting Tool 
Assessment of in vitro susceptibility is a fundamental component of antimalarial surveillance studies, but wide variations in the measurement of parasite growth and the calculation of inhibitory constants make comparisons of data from different laboratories difficult. Here we describe a Web-based, high-throughput in vitro analysis and reporting tool (IVART) generating inhibitory constants for large data sets. Fourteen primary data sets examining laboratory-determined susceptibility to artemisinin derivatives and artemisinin combination therapy partner drugs were collated from 11 laboratories. Drug concentrations associated with half-maximal inhibition of growth (IC50s) were determined by a modified sigmoid Emax model-fitting algorithm, allowing standardized analysis of 7,350 concentration-inhibition assays involving 1,592 isolates. Examination of concentration-inhibition data revealed evidence of apparent paradoxical growth at high concentrations of nonartemisinin drugs, supporting amendment of the method for calculating the maximal drug effect in each assay. Criteria for defining more-reliable IC50s based on estimated confidence intervals and growth ratios improved correlation coefficients for the drug pairs mefloquine-quinine and chloroquine-desethylamodiaquine in 9 of 11 and 8 of 8 data sets, respectively. Further analysis showed that maximal drug inhibition was higher for artemisinins than for other drugs, particularly in ELISA (enzyme-linked immunosorbent assay)-based assays, a finding consistent with the earlier onset of action of these drugs in the parasite life cycle. This is the first high-throughput analytical approach to apply consistent constraints and reliability criteria to large, diverse antimalarial susceptibility data sets. The data also illustrate the distinct biological properties of artemisinins and underline the need to apply more sensitive approaches to assessing in vitro susceptibility to these drugs.
PMCID: PMC3697366  PMID: 23612201
19.  A three year descriptive study of early onset neonatal sepsis in a refugee population on the Thailand Myanmar border 
BMC Infectious Diseases  2013;13:601.
Each year an estimated four million neonates die, the majority in the first week of life. One of the major causes of death is sepsis. Proving the incidence and aetiology of neonatal sepsis is difficult, particularly in resource poor settings where the majority of the deaths occur.
We conducted a three year observational study of clinically diagnosed early onset (<7 days of age) neonatal sepsis (EONS) in infants born to mothers following antenatal care at the Shoklo Malaria Research Unit clinic in Maela camp for displaced persons on the Thailand-Myanmar border. Episodes of EONS were identified using a clinical case definition. Conventional and molecular microbiological techniques were employed in order to determine underlying aetiology.
From April 2009 until April 2012, 187 infants had clinical signs of EONS, giving an incidence rate of 44.8 per 1000 live births (95% CI 38.7-51.5). One blood culture was positive for Escherichia coli, E. coli was detected in the cerebrospinal fluid specimen in this infant, and in an additional two infants, by PCR. Therefore, the incidence of bacteriologically proven EONS was 0.7 per 1000 live births (95% CI 0.1 – 2.1). No infants enrolled in study died as a direct result of EONS.
A low incidence of bacteriologically proven EONS was seen in this study, despite a high incidence of clinically diagnosed EONS. The use of molecular diagnostics and nonspecific markers of infection need to be studied in resource poor settings to improve the diagnosis of EONS and rationalise antibiotic use.
PMCID: PMC3879187  PMID: 24359288
20.  Neonatal Intensive Care in a Karen Refugee Camp: A 4 Year Descriptive Study 
PLoS ONE  2013;8(8):e72721.
A third of all deaths in children aged <5 years occur in the neonatal period. Neonatal intensive care is often considered too complex and expensive to be implemented in resource poor settings. Consequently the reductions that have been made in infant mortality in the poorest countries have not been made in the neonatal period. This manuscript describes the activities surrounding the introduction of special care baby unit (SCBU) in a refugee setting and the resulting population impact.
A SCBU was developed in Maela refugee camp on the Thailand-Myanmar border. This unit comprised of a dedicated area, basic equipment, drugs and staff training. Training was built around neonatal guidelines, comprising six clinical steps: recognition, resuscitation, examination, supportive medical care, specialised medical care, and counselling of parents with sick newborns.
From January 2008 until December 2011, 952 infants were admitted to SCBU. The main admission diagnoses were early onset neonatal sepsis, jaundice and prematurity. Early prematurity (<34 weeks) carried the highest risk of mortality (OR 9.5, 95% CI 5.4–16.5, p<0.001). There was a significant decrease in mortality from 19.3% (2008) to 4.8% (2011) among the infants admitted for prematurity (p=0.03). The neonatal mortality in Maela camp as a whole declined by 51% from 21.8 to 10.7 deaths per 1000 live births over the corresponding period (p=0.04). Staff expressed more confidence in their ability to take care of neonates and there was a more positive attitude towards premature infants.
Neonatal mortality can be reduced in a resource poor setting by introduction of a simple low cost unit specialising in care of sick neonates and run by local health workers following adequate training. Training in recognition and provision of simple interventions at a high standard can increase staff confidence and reduce fatalistic attitudes towards premature neonates.
PMCID: PMC3749980  PMID: 23991145
21.  A Prospective Evaluation of Real-Time PCR Assays for the Detection of Orientia tsutsugamushi and Rickettsia spp. for Early Diagnosis of Rickettsial Infections during the Acute Phase of Undifferentiated Febrile Illness 
One hundred and eighty febrile patients were analyzed in a prospective evaluation of Orientia tsutsugamushi and Rickettsia spp. real-time polymerase chain reaction (PCR) assays for early diagnosis of rickettsial infections. By paired serology, 3.9% (7 of 180) and 6.1% (11 of 180) of patients were confirmed to have acute scrub or murine typhus, respectively. The PCR assays for the detection of O. tsutsugamushi and Rickettsia spp. had high specificity (99.4% [95% confidence interval (CI): 96.8–100] and 100% [95% CI: 97.8–100], respectively). The PCR results were also compared with immunoglobulin M (IgM) immunofluorescence assay (IFA) on acute sera. For O. tsutsugamushi, PCR sensitivity was twice that of acute specimen IgM IFA (28.6% versus 14.3%; McNemar's P = 0.3). For Rickettsia spp., PCR was four times as sensitive as acute specimen IgM IFA (36.4% versus 9.1%; P = 0.08), although this was not statistically significant. Whole blood and buffy coat, but not serum, were acceptable specimens for these PCRs. Further evaluation of these assays in a larger prospective study is warranted.
PMCID: PMC3741253  PMID: 23732256
22.  Changes in the body weight of term infants, born in the tropics, during the first seven days of life 
BMC Pediatrics  2013;13:93.
Identifying unwell neonates, particularly in the first week of life, is often subjective. If normal values are known, calculating the weight lost or gained from birth weight can be a useful adjunct in the evaluation of the health of a neonate.
Serial body weights of well, term, breast fed infants who were attending for routine follow up, were recorded at the Shoklo Malaria Research Unit clinic in Maela Camp for displaced persons on the Thailand Myanmar border. Newborn examination was routine. Weight loss, expressed as percent weight lost from birth weight, and weight gain, expressed as a velocity (g/kg/day), was calculated for the first seven days of life. The results from normal birth weight infants, low birth weight infants (<2.5 kg) and small for gestational age infants (SGA) were examined.
In the first week of life there were no significant differences in weight gained or lost across the three study groups. The maximum weight lost was 4.4% (95% CI 4.1 – 4.6%), which occurred on day three. Weight gain ranged from 13 g/kg/day [95% CI 10 – 16] on day four to 18 g/kg/day [95% CI 15 – 20] on days six and seven.
Use of these normal values for weight gain and loss, allows infants falling outside of the expected range (95% CI) to be easily identified and subsequently highlighted as needing further medical review.
PMCID: PMC3686593  PMID: 23768173
Neonate; Weight loss; Weight gain; Weight velocity
23.  Made in Europe: will artemisinin resistance emerge in French Guiana? 
Malaria Journal  2013;12:152.
Resistance to artemisinin casts a shadow on the fight against malaria. The importance of illegal gold miners and of malaria in isolated regions of French Guiana constitutes a threat that endangers the fight against malaria in the Amazon. The hurdles of French laws and the remoteness of the territory from France make it impossible for the system to adapt to the problem of total inaccessibility of an important part of the malaria problem. Transmission is high in these areas and gold miners self-medicate with erratic regimens of artemisinin combinations, thus creating perfect conditions for the emergence of resistance. What needs to be done is being done, but within the limits of national law, with some results. However, facing the same difficult problem, Suriname shows more flexibility and is doing much better than French Guiana despite having lower resources. Local authorities in French Guiana cannot overrule the laws that block appropriate malaria care from reaching a third of malaria-exposed persons. Thus the health authorities in France should take immediate calibrated legislative and financial measures to avoid a predictable disaster.
PMCID: PMC3649934  PMID: 23641802
24.  Genetic Evaluation of the Performance of Malaria Parasite Clearance Rate Metrics 
The Journal of Infectious Diseases  2013;208(2):346-350.
Accurate measurement of malaria parasite clearance rates (CRs) following artemisinin (ART) treatment is critical for resistance surveillance and research, and various CR metrics are currently used. We measured 13 CR metrics in 1472 ART-treated hyperparasitemia infections for which 6-hour parasite counts and parasite genotypes (93 single nucleotide polymorphisms [SNPs]) were available. We used heritability to evaluate the performance of each metric. Heritability ranged from 0.06 ± 0.06 (SD) for 50% parasite clearance times to 0.67 ± 0.04 (SD) for clearance half-lives estimated from 6-hour parasite counts. These results identify the measures that should be avoided and show that reliable clearance measures can be obtained with abbreviated monitoring protocols.
PMCID: PMC3685230  PMID: 23592863
heritability; clearance rate; half-life; artemisinin; Plasmodium falciparum; single nucleotide polymorphism

Results 1-25 (116)