ORCID Profile
0000-0002-7951-0745
Current Organisations
Université Pierre et Marie Curie
,
University of Oxford
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Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.PREGHY.2022.09.005
Abstract: The prediction of preecl sia in pregnancy has resulted in a plethora of prognostic models. Yet, very few make it past the development stage and most fail to influence clinical practice. The timely identification of high-risk pregnant women could deliver a tailored antenatal care regimen, particularly in low-resource settings. This study externally validated and calibrated previously published models that predicted the risk of preecl sia, based on blood pressure (BP) at multiple time points in pregnancy, in a geographically erse population. The prospective INTERBIO-21st Fetal Study included 3,391 singleton pregnancies from Brazil, Kenya, Pakistan, South Africa, Thailand and the UK, 2012-2018. Preecl sia prediction was based on baseline characteristics, BP and deviation from the expected BP trajectory at multiple time points in pregnancy. The prediction rules from the Avon Longitudinal Study of Parents and Children (ALSPAC) were implemented in the INTERBIO-21st cohort. Model discrimination was similar to the development cohort. Performance was best with baseline characteristics and a BP measurement at 34 weeks' gestation (AUC 0.85, 95 % CI 0.80-0.90). The ALSPAC models largely overestimated the true risk of preecl sia incidence in the INTERBIO-21st cohort. After recalibration, these prediction models could potentially serve as a risk stratifying tool to help identify women who might benefit from increased surveillance during pregnancy.
Publisher: Springer Science and Business Media LLC
Date: 08-2011
DOI: 10.1038/NATURE10306
Publisher: Public Library of Science (PLoS)
Date: 10-01-2017
Publisher: Springer Science and Business Media LLC
Date: 08-2016
Publisher: Springer Science and Business Media LLC
Date: 11-04-2008
Abstract: The treatment options for acute Plasmodium falciparum malaria are based on the clinician classifying the patient as uncomplicated or severe according to the clinical and parasitological findings. This process is not always straightforward. An adult male presented to a clinic on the western border of Thailand with a physical examination and P. falciparum trophozoite count (1.2% of infected red blood cells, IRBC) from malaria blood smear, consistent with a diagnosis of uncomplicated P. falciparum infection. However, the physician on duty treated the patient for severe malaria based on the reported P. falciparum schizont count, which was very high (0.3% IRBC), noticeably in relation to the trophozoite count and schizont:trophozoite ratio 0.25:1. On intravenous artesunate, the patient deteriorated clinically in the first 24 hours. The trophozoite count increased from 1.2% IRBC at baseline to 20.5% IRBC 18 hours following the start of treatment. By day three, the patient recovered and was discharged on day seven having completed a seven-day treatment with artesunate and mefloquine. The malaria blood smear provides only a guide to the overall parasite biomass in the body, due to the ability of P. falciparum to sequester in the microvasculature. In severe malaria, high schizont counts are associated with worse prognosis. In low transmission areas or in non-immune travelers the presence of schizonts in the peripheral circulation is an indication for close patient supervision. In this case, an unusually high schizont count in a clinically uncomplicated patient was indicative of potential deterioration. Prompt treatment with intravenous artesunate is likely to have been responsible for the good clinical outcome in this case.
Publisher: Wiley
Date: 28-04-2016
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.VACCINE.2017.03.023
Abstract: Plasmodium vivax is the most widely distributed malaria species and the most prevalent species of malaria in America and Asia. Vaccine development against P. vivax is considered a priority in the global program for the eradication of malaria. Earlier studies have characterized the Apical Membrane Antigen 1 (AMA-1) ectodomain and the C-terminal region (19kDa) of the Merozoite Surface Protein 1 (MSP-1) of P. vivax as immunodominant antigens. Based on this characterization, we designed a chimeric recombinant protein containing both merozoite immunodominant domains (PvAMA1
Publisher: Public Library of Science (PLoS)
Date: 12-06-2018
Publisher: Springer Science and Business Media LLC
Date: 25-08-2016
DOI: 10.1038/SREP32159
Abstract: During pregnancy a variety of immunological changes occur to accommodate the fetus. It is unknown whether these changes continue to affect humoral immunity postpartum or how quickly they resolve. IgG levels were measured to P. falciparum and P. vivax antigens in 201 postpartum and 201 controls over 12 weeks. Linear mixed-effects models assessed antibody maintenance over time and the effect of microscopically confirmed Plasmodium spp. infection on antibody levels, and whether this was different in postpartum women compared with control women. Postpartum women had reduced Plasmodium spp. antibody levels compared to controls at baseline. Over 12 weeks, mean antibody levels in postpartum women increased to levels observed in control women. Microscopically confirmed P. falciparum and P. vivax infections during follow-up were associated with an increase in species-specific antibodies with similar magnitudes of boosting observed in postpartum and control women. Antibodies specific for pregnancy-associated, VAR2CSA-expressing parasites did not rapidly decline postpartum and did not boost in response to infection in either postpartum or control women. After pregnancy, levels of malaria-specific antibodies were reduced, but recovered to levels seen in control women. There was no evidence of an impaired ability to mount a boosting response in postpartum women.
Publisher: Informa UK Limited
Date: 2019
Publisher: Wiley
Date: 11-1996
DOI: 10.1111/J.1365-2125.1996.TB00115.X
Abstract: 1. The pharmacokinetic and effect kinetic properties of oral (p.o.), intramuscular (i.m.), and intrarectal (i.r.) artemether (5 mg kg-1) were compared in a crossover study in eight healthy adult volunteers. Plasma concentrations of artemether (AM) and its active metabolite dihydroartemisinin (DHA) were measured by high performance liquid chromatography with reductive mode electrochemical detection (h.p.l.c.-ECD), and plasma antimalarial activity in vitro (effect) was assessed on the same s les by a sensitive bioassay (BA). 2. Artemether was absorbed rapidly after oral administration with a mean (95% CI) Cmax for the parent compound of 406 (249 to 561) nmol l-1 and for DHA of 1009 (639 to 1379) nmol l-1 with tmax values of 1.7 (1.2 to 2.2) and 1.8 (1.4 to 2.2) h respectively. The mean (95% CI) elimination half-life of AM was 2.6 (1.8 to 3.4) h and for DHA was 1.9 (1.4 to 2.4) h. Plasma concentration and effect profiles with h.p.l.c.-ECD and BA were similar suggesting that other unidentified bioactive metabolites contributed little to antimalarial activity in vivo. 3. Absorption was slower, more variable, and DHA concentrations were lower following the i.m. and i.r. routes of administration. The mean (95% CI) relative bioavailability compared with oral artemether in the 6 h following administration AUC (0.6h) was 25 (9 to 41)% following i.m. and 35 (10 to 60)% following i.r. artemether. 4. These data demonstrate that oral artemether undergoes extensive first pass metabolism to the more active metabolite DHA. Plasma antimalarial activity following oral administration is significantly greater than following i.m. administration. The i.r. route of administration provided similar bioavailability to i.m. injection but there was considerable variability in absorption following both routes. Further studies are needed to determine whether i.r. artemether would be an effective treatment of severe malaria in the rural tropics in situations where oral or parenteral administration is not possible.
Publisher: Elsevier BV
Date: 06-2010
Publisher: Oxford University Press (OUP)
Date: 09-1998
Publisher: Oxford University Press (OUP)
Date: 12-2019
DOI: 10.1093/OFID/OFZ518
Abstract: Vaccination remains the mainstay of prevention of hepatitis B virus (HBV) including birth dose and hepatitis B immunoglobulins (HBIGs). National estimates of vaccination coverage exclude migrants. The objective of this study is to investigate documentation practices of HBV-related infant vaccinations in Northern Thailand including migrants. This is a retrospective review of hospital records of women who birthed infants in 2015 at Maharaj Nakorn Hospital, Chiang Mai (CM) or on the Thailand-Myanmar border, Tak. Of 2522 women, 987 were from CM (861 Thai nationals, 126 migrants) and 1535 were from Tak (651 Thai residence and 884 Myanmar residence). In CM, documentation for the birth dose vaccine (999 of 999, 100%) and HBIG was complete. In Tak, documentation was 1441 of 1549 (93%) for birth dose and 26 of 34 (76.5%) for HBIG, with missed opportunities including home delivery, delay in obtaining hepatitis B e-antigen status, and limitations of the records. Expanded Program of Immunization (EPI) documentation of 3 follow-up vaccinations dwindled with subsequent doses and distance, and complete documentation of 3 HBV EPI vaccines at the hospital of birth was low, 41.5% (1056 of 2547), but equitable for Thai or migrant status. This review provides strong support for excellent documentation of HBIG and birth dose vaccination in urban and rural settings, and in migrants, consistent with Thailand’s vaccination policy and practice. Documentation of the 3 HBV EPI at the hospital of birth decreases with sequential doses, especially in families further away. Innovative data linkage is required to prove coverage and identify gaps.
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/S0140-6736(96)91488-9
Abstract: On the western border of Thailand the efficacy of mefloquine in the treatment of falciparum malaria has declined while gametocyte carriage rates have increased, which suggests increased transmissibility of these resistant infections. We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine, quinine, and the artemisinin derivatives. Between 1990 and 1995 we assessed gametocytaemia in a series of prospective studies of antimalarial drug treatment in 5193 adults and children with acute uncomplicated falciparum malaria in an area of malarious hill forest on the western border of Thailand. Weekly parasite counts from thick and thin blood films were done during the 4-week (1990-93) or 9-week (1993-95) follow-up period. Gametocyte positivity rates and person gametocyte week (PGW) rates were calculated to measure gametocyte carriage and transmission potential. In primary P falciparum infections the gametocyte carriage rate was significantly higher after treatment with mefloquine than after treatment with the artemisinin derivatives (PGW 34.1 [95% CI 25.2-42.9] vs 3.9 [1.9-5.9] per 1000 person weeks relative risk 8.0 [4.1-15.6] p<0.0001). Recrudescent infections were associated with increased gametocyte carrier rates (relative risk 2.2 [1.6-3.0] p<0.0001), but retreatment with artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [3.5-98] compared with mefloquine retreatment and 6.8 fold (3.1-15.1) compared with quinine retreatment (p<0.001). The introduction of the artemisinin derivatives in routine treatment at this study site in mid 1994 was associated with a reduction in the subsequent incidence of falciparum malaria of 47 (25-69)% Although environmental changes affect vector numbers, and hence malaria incidence, artemisinin derivatives were found to reduce the transmission potential of falciparum malaria. Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance.
Publisher: Oxford University Press (OUP)
Date: 09-1997
DOI: 10.1016/S0035-9203(97)90032-8
Abstract: On the western border of Thailand, in an area endemic for multi-drug resistant Plasmodium falciparum malaria, therapeutic responses were assessed in 1967 patients with uncomplicated falciparum malaria treated with 3 d of artesunate (total dose 12 mg/kg) plus mefloquine (total dose 25 mg/kg). The regimen was well tolerated and resulted in a rapid clinical response within 48 h, 96% of patients were aparasitaemic and 94% were afebrile. After correcting for reinfections, the cure rate by day 42 was 89% (95% confidence interval [95% CI] 87-91%). Three independent factors were found to predict recrudescence: age 40,000/microL (AHR = 1.6, 95%, CI 1.2-2.2), and pure P. falciparum infections (AHR = 1.8, 95% CI 1.3-2.7). These 3 factors combined accounted for 62% of all treatment failures. Patients who received mefloquine on admission with a high admission parasitaemia (> 40,000/microL) had a three-fold (95% CI 1.3-7) risk of subsequent recrudescence compared with those who received their mefloquine on the second or third day (P = 0.01). There has been no decline in the efficacy of the 3 d artesunate plus mefloquine regimen since it was introduced in 1992. This regimen is safe, well tolerated, and highly effective in the treatment of multi-drug resistant falciparum malaria.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2020
DOI: 10.1186/S12936-020-3123-1
Abstract: The Sustainable Development Goals (SDG) call for increased gender equity and reduction in malaria-related mortality and morbidity. Plasmodium vivax infections in pregnancy are associated with maternal anaemia and increased adverse perinatal outcomes. Providing radical cure for women with 8-aminoquinolines (e.g., primaquine) is hindered by gender-specific complexities. A symptomatic episode of vivax malaria at 18 weeks of gestation in a primigravid woman was associated with maternal anaemia, a recurrent asymptomatic P. vivax episode, severe intra-uterine growth restriction with no other identifiable cause and induction to reduce the risk of stillbirth. At 5 months postpartum a qualitative glucose-6-phosphate dehydrogenase (G6PD) point-of-care test was normal and radical cure with primaquine was prescribed to the mother. A 33% fractional decrease in haematocrit on day 7 of primaquine led to further testing which showed intermediate phenotypic G6PD activity the G6PD genotype could not be identified. Her infant daughter was well throughout maternal treatment and found to be heterozygous for Mahidol variant. Adverse effects of vivax malaria in pregnancy, ineligibility of radical cure for pregnant and postpartum women, and difficulties in diagnosing intermediate levels of G6PD activity multiplied morbidity in this woman. Steps towards meeting the SDG include prevention of malaria in pregnancy, reducing unnecessary exclusion of women from radical cure, and accessible quantitative G6PD screening in P. vivax -endemic settings.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 04-1999
DOI: 10.4269/AJTMH.1999.60.547
Abstract: In prospective studies of acute uncomplicated, multidrug-resistant falciparum malaria on the western border of Thailand, the oral artemisinin derivatives were used alone in the treatment of 836 patients (artesunate 630, artemether 206), were combined with mefloquine (15-25 mg base/kg) in 2,826 patients, and mefloquine alone was used in 1,303 patients. The combined regimens of mefloquine plus an artemisinin derivative were associated with more side effects than those with an artemisinin derivative alone acute nausea (31% versus 16%), vomiting (24% versus 11%), anorexia (51% versus 34%), and dizziness (47% versus 15%) (P < 0.001). Oral artesunate and artemether alone were very well tolerated. There was no difference in the incidence of possible adverse effects between the two drugs, and no evidence that either derivative caused allergic reactions, neurologic or psychiatric reactions, or cardiovascular or dermatologic toxicity. Blackwater fever occurred in three patients treated with mefloquine plus artesunate regimens. Oral artesunate and artemether are safe and well tolerated antimalarial drugs.
Publisher: Frontiers Media SA
Date: 04-03-2021
DOI: 10.3389/FCIMB.2021.639665
Abstract: Preterm birth (PTB) is the most common cause of neonatal morbidity and mortality worldwide. Approximately half of PTBs is linked with microbial etiologies, including pathologic changes to the vaginal microbiota, which vary according to ethnicity. Globally more than 50% of PTBs occur in Asia, but studies of the vaginal microbiome and its association with pregnancy outcomes in Asian women are lacking. This study aimed to longitudinally analyzed the vaginal microbiome and cytokine environment of 18 Karen and Burman pregnant women who delivered preterm and 36 matched controls delivering at full term. Using 16S ribosomal RNA gene sequencing we identified a predictive vaginal microbiota signature for PTB that was detectable as early as the first trimester of pregnancy, characterized by higher levels of Prevotella buccalis , and lower levels of Lactobacillus crispatus and Finegoldia , accompanied by decreased levels of cytokines including IFNγ, IL-4, and TNFα. Differences in the vaginal microbial ersity and local vaginal immune environment were associated with greater risk of preterm birth. Our findings highlight new opportunities to predict PTB in Asian women in low-resource settings who are at highest risk of adverse outcomes from unexpected PTB, as well as in Burman/Karen ethnic minority groups in high-resource regions.
Publisher: Oxford University Press (OUP)
Date: 03-1998
DOI: 10.1016/S0035-9203(98)90750-7
Abstract: Oral artesunate is the most effective treatment for uncomplicated hyperparasitaemia in falciparum malaria. To assess the contribution of mefloquine to therapeutic efficacy in an area endemic for mefloquine-resistant Plasmodium falciparum, an open randomized comparison of a 5 d course of oral artesunate (total dose 12 mg/kg) with and without a single dose of mefloquine (25 base mg/kg) was conducted in 100 adults and children with uncomplicated hyperparasitaemia (> 4% parasitized red blood cells). Both regimens were well tolerated and gave equally rapid clinical responses (84% of patients were aparasitaemic and 96% were afebrile within 48 h), but the recrudescence rate assessed at day 42 was 6% in those receiving artesunate with mefloquine compared to 36% in those receiving artesunate alone (adjusted hazard ratio 7, 95% confidence interval [95% CI] 2-32 P < 0.01). In addition, the efficacy of a 7 d course of artesunate, with and without the addition of mefloquine, was monitored in 178 patients who were not part of the randomized comparison. The failure rate was again lower in those receiving artesunate and mefloquine--7% (95% CI 2-13) compared with 26% (95% CI 8-44) in patients treated with artesunate alone. An oral regimen of 5 d or more of artesunate, together with mefloquine (25 mg/kg) given on day 2, is an effective treatment for uncomplicated hyperparasitaemic falciparum malaria in this area of high level multidrug resistance.
Publisher: Public Library of Science (PLoS)
Date: 24-07-2020
Publisher: Public Library of Science (PLoS)
Date: 23-02-2009
Publisher: Springer Science and Business Media LLC
Date: 18-09-2015
Publisher: American Society of Tropical Medicine and Hygiene
Date: 10-2001
DOI: 10.4269/AJTMH.2001.65.285
Abstract: The safety of daily application of N, N-diethyl-m-toluamide (DEET) (1.7 g of DEET/day) in the second and third trimesters of pregnancy was assessed as part of a double-blind, randomized, therapeutic trial of insect repellents for the prevention of malaria in pregnancy (n = 897). No adverse neurologic, gastrointestinal, or dermatologic effects were observed for women who applied a median total dose of 214.2 g of DEET per pregnancy (range = 0-345.1 g). DEET crossed the placenta and was detected in 8% (95% confidence interval = 2.6-18.2) of cord blood s les from a randomly selected subgroup of DEET users (n = 50). No adverse effects on survival, growth, or development at birth, or at one year, were found. This is the first study to document the safety of DEET applied regularly in the second and third trimesters of pregnancy. The results suggest that the risk of DEET accumulating in the fetus is low and that DEET is safe to use in later pregnancy.
Publisher: SAGE Publications
Date: 04-2005
Publisher: Oxford University Press (OUP)
Date: 09-2003
DOI: 10.1016/S0035-9203(03)80040-8
Abstract: Pregnant women are particularly vulnerable to malaria infections. Multidrug resistance in Plasmodium falciparum seriously compromises treatment in some endemic areas. Between April 1999 and October 2001, we treated and prospectively followed 27 Karen pregnant women with multiple recrudescent P. falciparum infections who were resistant to all other antimalarials with a triple combination of artesunate-atovaquone-proguanil. The treatment was well tolerated and we found no evidence of toxicity for the mothers and the fetus. All but 1 woman were cured (cure rate 96%, 95% CI 89-100). The triple combination of artesunate (4 mg/kg/d), atovaquone (20 mg/kg/d), and proguanil (8 mg/kg/d) may provide a much needed, albeit expensive, 3-d rescue treatment for pregnant women exposed to multidrug- resistant P. falciparum malaria.
Publisher: Oxford University Press (OUP)
Date: 10-09-2012
Publisher: F1000 Research Ltd
Date: 18-05-2023
DOI: 10.12688/WELLCOMEOPENRES.19396.1
Abstract: Background: Prematurity is the highest risk for under-five mortality globally. The aim of the study was to assess the effect of antenatal dexamethasone on neonatal mortality in early preterm in a resource-constrained setting without assisted ventilation. Methods: This retrospective (2008-2013) cohort study in clinics for refugees/migrants on the Thai-Myanmar border included infants born weeks gestation at home, in, or on the way to the clinic. Dexamethasone, 24 mg (three 8 mg intramuscular doses, every 8 hours), was prescribed to women at risk of preterm birth (28 to weeks). Appropriate newborn care was available: including oxygen but not assisted ventilation. Mortality and maternal fever were compared by number of doses (complete: three, incomplete: one or two, or no dose). A sub-cohort participated to neurodevelopmental testing at one year. Results: Of 15,285 singleton births, 240 were included: 96 did not receive dexamethasone and 144 received one, two or three doses (56, 13 and 75, respectively). Of live born infants (n=233), early neonatal and neonatal mortality/ 1,000 livebirths (95%CI) with complete dosing was 141 (78–240) and 304 (191–448) compared to 292 (210–389) and 521 (407–633) with no dose. Compared to complete dosing, both incomplete and no dexamethasone were associated with elevated adjusted ORs 4.09 (1.39 to 12.00) and 3.13 (1.14 to 8.63), for early neonatal death. By contrast, for neonatal death, while there was clear evidence that no dosing was associated with higher mortality, adjusted OR 3.82 (1.42 to 10.27), the benefit of incomplete dosing was uncertain adjusted OR 1.75 (0.63 to 4.81). No adverse impact of dexamethasone on maternal fever or neurodevelopmental scores was observed. Conclusions: Neonatal mortality reduction is possible with complete dexamethasone dosing in pregnancies at risk of preterm birth in settings without capacity to provide assisted ventilation.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.EJMECH.2016.04.058
Abstract: Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2011
Publisher: Oxford University Press (OUP)
Date: 15-01-2011
Publisher: BMJ
Date: 09-2020
DOI: 10.1136/BMJOPEN-2020-038123
Abstract: Hepatitis B virus (HBV) remains a public health threat and the main route of transmission is from mother to child (MTCT). Tenofovir disoproxil fumarate (TDF) treatment can reduce MTCT of HBV although the optimal timing to attain undetectable HBV DNA concentrations at delivery is unknown. This protocol describes the procedures following early initiation of maternal TDF prior to 20 weeks gestation to determine efficacy, safety and feasibility of this approach in a limited-resource setting. One hundred and seventy pregnant women from the Thailand–Myanmar border between 12 and weeks gestational age will be enrolled into a one-arm, open-label, TDF treatment study with cessation of TDF 1 month after delivery. S ling occurs monthly prenatal, at birth and at 1, 2, 4 and 6 months post partum. Measurement of tenofovir concentrations in maternal and cord plasma is anticipated in 10–15 women who have detectable HBV DNA at delivery and matched to 20–30 women with no detectable HBV DNA. Infant HBsAg status will be determined at 2 months of age and HBV DNA confirmed in HBsAg positive cases. Adverse events including risk of flare and adherence, based on pill count and questionnaire, will be monitored. Infants will receive HBV vaccinations at birth, 2, 4 and 6 months and hepatitis B immunoglobulin at birth if the mother is hepatitis B e antigen positive. Infant growth and neurodevelopment at 6 months will be compared with established local norms. This study has ethical approval by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University (FTM ECF-019-06), Johns Hopkins University (IRB no: 00007432), Chiang Mai University (FAM-2559-04227), Oxford Tropical Research Ethics Committee (OxTREC Reference: 49-16) and by the local Tak Community Advisory Board (TCAB-02/REV/2016). The article will be published as an open-access publication. NCT02995005 , Pre-results.
Publisher: Springer Science and Business Media LLC
Date: 12-2013
Publisher: Cambridge University Press (CUP)
Date: 03-1995
DOI: 10.1017/S0031182000001463
Abstract: Several years ago the Walter Reed Army Institute of Research (WRAIR) initiated an independent analysis of the candidate malaria blood stage vaccine SPf66. WRAIR contracted for the synthesis and formulation of SPf66 in United States Food and Drug Administration (FDA) inspected laboratories within the U.S., and in 1992, filed an Investigational New Drug (IND) application with the FDA. Preclinical studies indicated that the vaccine could be synthesized to meet its release specifications, and when adjuvanted with alum, was essentially equivalent to Colombian produced SPf66 in regards to immunogenicity in preclinical studies of rodents and primates, and in human volunteers in Phase I studies. The goal of these efforts was ultimately to conduct a Phase IIb field trial to determine the safety and efficacy of SPf66 produced under current Good Manufacturing Practices (cGMP). Such a trial is currently underway in a malaria endemic refugee c along the Thai–Burmese border. Here we briefly describe the study and present the formal analytic plan that was submitted to regulatory authorities in the United States for analysis of the study results. We believe such independent confirmatory studies are an essential part of the vaccine development process and are required to provide important data regarding the safety and efficacy of candidate vaccines in erse geographical regions, and as a means to assess their role in the context of broader malaria control programmes.
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.EXPPARA.2006.02.006
Abstract: In vitro susceptibility tests provide information on the intrinsic response of Plasmodium vivax to antimalarials, free from confounding factors such as host immunity or relapse. This study examined the utility of radioisotope and PicoGreen assays as alternatives to the traditional microscopic examination for assessing response of P. vivax to antimalarial drugs. There was no significant difference in the mean chloroquine IC(50) of P. vivax (n=40) as determined by the microscopic (33.4 ng/ml), isotopic (33.6 ng/ml), and PicoGreen (39.1 ng/ml) assays, respectively (F=0.239, df=2, 51, and p=0.788). However measurement of IC(50)s by the microscopic method was slightly more successful in producing valid assays (57%), compared to the isotopic (32.5%) and PicoGreen (45.5%) methods. In a paired comparison of 20 fresh and cryopreserved isolates as examined by the microscopic method, there were no significant differences between the mean IC(50) responses (T=1.58, df=15, and p=0.34). Detailed methodologies for the short time culture of field and cryopreserved P. vivax are described. Although the microscopic in vitro assay provides a useful method for characterizing the drug susceptibility phenotype of P. vivax isolates, its utility is limited by a laborious methodology and need for highly skilled microscopists. Future efforts should focus on further development of high throughput assays such as the PicoGreen assay as described in this study.
Publisher: American Society for Microbiology
Date: 05-2010
DOI: 10.1128/AAC.01572-09
Abstract: The novel organometallic chloroquine analog ferroquine (SSR 97193) is effective against chloroquine-resistant Plasmodium falciparum . The ex vivo efficacy of ferroquine against Plasmodium vivax isolates was tested. Ferroquine has a potent ex vivo effect on P . vivax schizont maturation (median 50% inhibitory concentration, 15 nM n = 42). No significant cross-sensitivity between ferroquine and other antimalarials was detected. This drug may be a suitable replacement for chloroquine in the treatment of drug-resistant P . vivax malaria.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Wiley
Date: 05-2010
DOI: 10.1002/DDR.20369
Publisher: Elsevier BV
Date: 2012
Publisher: Cold Spring Harbor Laboratory
Date: 19-08-2018
DOI: 10.1101/393843
Abstract: The global malaria burden has decreased over the last decade and many nations are attempting elimination. Asymptomatic infections aren’t normally diagnosed or treated, posing a major hurdle for elimination efforts. One solution to this problem is mass drug administration (MDA), which is dependent on adequate population participation to disrupt transmission. There is little empirical evidence regarding the necessary threshold level of participation. Here we present a detailed spatiotemporal analysis of malaria episodes and asymptomatic infections in four villages undergoing MDA in Myanmar. In iduals from neighborhoods with high MDA adherence had 90% decreased odds of having a malaria episode post-MDA, regardless of in idual participation, suggesting a strong herd effect. High mosquito biting rates, living in a house with someone else with malaria, or having an asymptomatic malaria infection were also predictors of clinical episodes. Spatial clustering of non-adherence to MDA, even in villages with high overall participation, can frustrate elimination efforts.
Publisher: Oxford University Press (OUP)
Date: 09-1995
DOI: 10.1016/0035-9203(95)90094-2
Abstract: To compare the therapeutic efficacy of oral artesunate and artemether in combination with mefloquine for the treatment of multidrug resistant malaria, a trial was conducted in 540 adults and children on the Thai-Myanmar border. Three regimens were compared: artesunate (4 mg/kg/d for 3 d), artemether (4 mg/kg/d for 3 d), both in combination with mefloquine (25 mg/kg), and a single dose of mefloquine (25 mg/kg). The artesunate and artemether regimens gave very similar clinical and parasitological responses, and were both very well tolerated. There was no significant adverse effect attributable to the artemisinin derivatives. Fever and parasite clearance times with mefloquine alone were significantly longer (P < 0.001). After adjusting for reinfections the failure rates were 13.9% for the artesunate combination, 12.3% for the artemether combination and 49.2% for mefloquine alone (P < 0.0001 relative risk 3.8 [95% confidence interval 2.6-5.4]). Mefloquine should no longer be used alone for the treatment of multidrug resistant falciparum malaria in this area. Three-day combination regimens with artesunate or artemether are well tolerated and more effective.
Publisher: SAGE Publications
Date: 12-2008
Abstract: Refugee and migrant populations are considered to be at high risk from sexually transmitted infection (STI) and HIV. Cross-sectional surveys for syphilis and HIV were conducted in antenatal clinics (ANCs) on the Thai-Burmese border. In Mae La refugee c , the seroprevalence of HIV and syphilis were 0.2% (one of 500) (95% CI 0–1.1) and 0% (0 of 404) (95% CI 0–0.9) in 1997 and 0.4% (two of 500) (95% CI 0.1–1.4) and 0.4% (three of 741) (95% CI 0.1–1.2) in 2005, respectively syphilis seroprevalence in migrant women in 2005 was 0 (0 of 234) (95% CI 0–1.6). The seroprevalence was lower than that reported from surrounding ANCs for Thai or Burmese women. Focus group discussions with HIV-negative and -positive pregnant refugee women established that aspects of Karen culture and isolation (geographical and political) had a significant protective role from HIV and STI. This survey has resulted in programmatic changes in services to pregnant women in this area.
Publisher: MDPI AG
Date: 26-01-2016
DOI: 10.3390/NU8020066
Publisher: Public Library of Science (PLoS)
Date: 20-11-2014
Publisher: American Society for Microbiology
Date: 09-2011
DOI: 10.1128/AAC.00154-11
Abstract: In order to study the pharmacokinetic properties of amodiaquine and desethylamodiaquine during pregnancy, 24 pregnant women in the second and third trimesters of pregnancy and with Plasmodium vivax malaria were treated with amodiaquine (10 mg/kg of body weight/day) for 3 days. The same women were studied again at 3 months postpartum. Plasma was analyzed for amodiaquine and desethylamodiaquine by use of a liquid chromatography-tandem mass spectrometry method. In idual concentration-time data were evaluated using noncompartmental analysis. There were no clinically relevant differences in the pharmacokinetics of amodiaquine and desethylamodiaquine between pregnant ( n = 24) and postpartum ( n = 18) women. The results suggest that the current amodiaquine dosing regimen is adequate for the treatment of P. vivax infections during pregnancy.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 10-2014
Publisher: American Society for Microbiology
Date: 10-2015
DOI: 10.1128/AAC.00267-15
Abstract: Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma s les from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an E max model, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].)
Publisher: Cold Spring Harbor Laboratory
Date: 13-12-2022
DOI: 10.1101/2022.12.11.22282391
Abstract: Screening for G6PD deficiency can inform disease management including malaria. Treatment with the antimalarial drugs primaquine and tafenoquine can be guided by point-of-care testing for G6PD deficiency. Data from similar clinical studies evaluating the performance of the STANDARD ™ G6PD Test (SD Biosensor, South Korea) conducted in Bangladesh, Brazil, Ethiopia, India, Thailand, the United Kingdom, and the United States were pooled. Test performance was assessed in a retrospective analysis on capillary and venous specimens. All study sites used spectrophotometry for reference G6PD testing, and either the HemoCue or complete blood count for reference hemoglobin measurement. The sensitivity of the STANDARD ™ G6PD Test using the manufacturer thresholds for G6PD deficient and intermediate cases in capillary specimens from 4212 study participants was 100% (95% Confidence Interval (CI): 97.5%–100%) for G6PD deficient cases with % activity and 77% (95% CI 66.8%– 85.4%) for females with intermediate activity between 30%–70%. Specificity was 98.1% (95% CI 97.6%–98.5%) and 92.8% (95% CI 91.6%–93.9%) for G6PD deficient in iduals and intermediate females, respectively. The majority (12/20) of G6PD intermediate females with false normal results had activity levels % on the reference assay. Negative predictive values for females with G6PD activity % was 99.6% (95% CI 99.1%–99.8%) on capillary specimens. Test sensitivity among 396 P. vivax malaria cases was 100% (69.2%–100.0%) for both deficient and intermediate cases. In the study population, a high proportion of those classified as G6PD deficient or intermediate resulted from true normal cases. Despite this, the majority cases would receive the correct medication and no true G6PD deficient cases would be treated inappropriately. The STANDARD G6PD Test enables safe access to drugs which are contraindicated for in iduals with G6PD deficiency. Operational considerations will inform test uptake in specific settings.
Publisher: Springer Science and Business Media LLC
Date: 02-09-2009
Abstract: Mefloquine and artesunate combination therapy is the recommended first-line treatment for uncomplicated malaria throughout much of south-east Asia. Concerns have been raised about the potential central nervous system (CNS) effects of both drug components and there are no detailed reports in very young children. Children, aged between three months and five years, with acute uncomplicated Plasmodium falciparum malaria were randomized to either 7 days of artesunate monotherapy or the same schedule of artesunate plus mefloquine on day 7 and 8. Neurological testing targeting coordination and behaviour was carried out at day 0, 7, 9, 10, 14 and 28. Non-febrile healthy control children from the same population were tested on days 0, 7, 14 and 28. From December 1994 to July 1997, 91 children with uncomplicated P. falciparum , 45 treated with artesunate monotherapy, 46 treated with mefloquine and artesunate combination therapy and 36 non-febrile controls, underwent neurological testing. Malaria and fever had a significant negative impact on testing performance. By contrast, the anti-malarial treatments were not associated with worsening performances in the various components of the test. Artesunate and mefloquine do not appear to have a significant influence on coordination and behaviour. Children treated with mefloquine were significantly less likely to suffer recurrent malaria infection during follow-up compared to those treated with artesunate alone (P = 0.033). In keeping with the results of randomized controlled trials in adults, mefloquine was not associated with a decrease in specific items of neurological performance. Likewise, children treated with artesunate did not perform significantly differently to control children. This study does not exclude subtle or rare treatment CNS effects of artesunate or mefloquine. Treatment of acute uncomplicated malaria results in a significant improvement on items of neurological performance.
Publisher: Public Library of Science (PLoS)
Date: 06-06-2006
Publisher: Oxford University Press (OUP)
Date: 03-1996
DOI: 10.1016/S0035-9203(96)90102-9
Abstract: From November 1991 to November 1992 a prospective, descriptive study of malaria epidemiology was conducted in a Karen population on the western border of Thailand. Two study groups were selected at random and more than 80% of the subjects were followed for one year. In Group 1, comprising 249 schoolchildren (aged 4-15 years), daily surveillance for illness was combined with fortnightly malaria surveys. These children experienced 1.5 parasitaemic infections per child-year (95% confidence interval [CI] 1.3-1.7), of which 68% (193/285) were symptomatic (Plasmodium falciparum 84%, P. vivax 57%). The estimated pyrogenic densities were 1460/microL for P. falciparum and 181/microL for P. vivax. In Group 2, comprising subjects of all age from 428 households, malaria was diagnosed during two-monthly surveys, at weekly home visits, and otherwise by passive case detection. Malaria and splenomegaly prevalence rates were low in all age groups (spleen index 2-9% P. falciparum prevalence rate 1-4% P. vivax 1-6%). Group 2 subjects had 1.0 infections per person-year (95% CI 0.9-1.1), most of which were symptomatic (312/357 87%). Malaria infections clustered in households. Overall, P. vivax caused 53% and P. falciparum 37% of the infections (10% were mixed), but whereas P. vivax was most common in young children, with a decline in incidence with increasing age, P. falciparum incidence rates rose with age to a peak incidence between 20 and 29 years, although the risk of developing a severe malaria decreased with increasing age. There was no death from malaria during the study. P. falciparum infections were more common in males, subjects with a history of malaria before the study, and in those who had travelled outside their village. These findings suggest a higher transmission rate for P. vivax than P. falciparum, although adults still suffered symptomatic malaria due to both species. The 2 malaria parasites found in this area contribute approximately 50% of infections each, but their clinical epidemiology is very different.
Publisher: F1000 Research Ltd
Date: 14-04-2022
DOI: 10.12688/WELLCOMEOPENRES.17795.1
Abstract: This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 s les of Plasmodium vivax collected at 88 worldwide locations between 2001 and 2017. It includes 1,370 new s les contributed by MalariaGEN and VivaxGEN partner studies in addition to previously published s les from these and other sources. We provide genotype calls at over 4.5 million variable positions including over 3 million single nucleotide polymorphisms (SNPs), as well as short indels and tandem duplications. This enlarged dataset highlights major compartments of parasite population structure, with clear differentiation between Africa, Latin America, Oceania, Western Asia and different parts of Southeast Asia. Each s le has been classified for drug resistance to sulfadoxine, pyrimethamine and mefloquine based on known markers at the dhfr , dhps and mdr1 loci. The prevalence of all of these resistance markers was much higher in Southeast Asia and Oceania than elsewhere. This open resource of analysis-ready genome variation data from the MalariaGEN and VivaxGEN networks is driven by our collective goal to advance research into the complex biology of P. vivax and to accelerate genomic surveillance for malaria control and elimination.
Publisher: Oxford University Press (OUP)
Date: 19-06-2012
DOI: 10.1093/CID/CIS568
Publisher: American Society of Tropical Medicine and Hygiene
Date: 02-08-2018
Publisher: Cambridge University Press (CUP)
Date: 26-06-2019
DOI: 10.1017/S0007114519000758
Abstract: The objective of the present study is to summarise trends in under- and over-nutrition in pregnant women on the Thailand–Myanmar border. Refugees contributed data from 1986 to 2016 and migrants from 1999 to 2016 for weight at first antenatal consultation. BMI and gestational weight gain (GWG) data were available during 2004–2016 when height was routinely measured. Risk factors for low and high BMI were analysed for ·5 kg/m 2 or ≥23 kg/m 2 , respectively. A total of 48 062 pregnancies over 30 years were available for weight analysis and 14 646 pregnancies over 13 years (2004–2016) had BMI measured in first trimester ( weeks’ gestational age). Mean weight at first antenatal consultation in any trimester increased over the 30-year period by 2·0 to 5·2 kg for all women. First trimester BMI has been increasing on average by 0·5 kg/m 2 for refugees and 0·6 kg/m 2 for migrants, every 5 years. The proportion of women with low BMI in the first trimester decreased from 16·7 to 12·7 % for refugees and 23·1 to 20·2 % for migrants, whereas high BMI increased markedly from 16·9 to 33·2 % for refugees and 12·3 to 28·4 % for migrants. Multivariate analysis demonstrated low BMI as positively associated with being Burman, Muslim, primigravid, having malaria during pregnancy and smoking, and negatively associated with refugee as opposed to migrant status. High BMI was positively associated with being Muslim and literate, and negatively associated with age, primigravida, malaria, anaemia and smoking. Mean GWG was 10·0 ( sd 3·4), 9·5 ( sd 3·6) and 8·3 ( sd 4·3) kg, for low, normal and high WHO BMI categories for Asians, respectively.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2018
DOI: 10.1038/S41467-018-07588-X
Abstract: The predisposition of parasites acquiring artemisinin resistance still remains unclear beyond the mutations in Pfk13 gene and modulation of the unfolded protein response pathway. To explore the chain of casualty underlying artemisinin resistance, we reanalyze 773 P. falciparum isolates from TRACI-study integrating TWAS, GWAS, and eQTL analyses. We find the majority of P. falciparum parasites are transcriptomically converged within each geographic site with two broader physiological profiles across the Greater Mekong Subregion (GMS). We report 8720 SNP-expression linkages in the eastern GMS parasites and 4537 in the western. The minimal overlap between them suggests differential gene regulatory networks facilitating parasite adaptations to their unique host environments. Finally, we identify two genetic and physiological backgrounds associating with artemisinin resistance in the GMS, together with a farnesyltransferase protein and a thioredoxin-like protein which may act as vital intermediators linking the Pfk13 C580Y mutation to the prolonged parasite clearance time.
Publisher: F1000 Research Ltd
Date: 10-03-2022
DOI: 10.12688/WELLCOMEOPENRES.16393.2
Abstract: In rural areas of South and Southeast Asia malaria is declining but febrile illnesses still account for substantial morbidity and mortality. Village health workers (VHWs) are often the first point of contact with the formal health system, and for patients with febrile illnesses they can provide early diagnosis and treatment of malaria. However, for the majority of febrile patients, VHWs lack the training, support and resources to provide further care. Consequently, treatable bacterial illnesses are missed, antibiotics are overused and poorly targeted, and patient attendance wanes along with declining malaria. This Open Letter announces the start of a new initiative, the Rural Febrile Illness (RFI) project, the first in a series of projects to be implemented as part of the South and Southeast Asian Community-based Trials Network (SEACTN) research programme. This multi-country, multi-site project will run in Bangladesh, Cambodia, Lao PDR, Thailand, and Myanmar. It will define the epidemiological baseline of febrile illness in nine remote and underserved areas of Asia where malaria endemicity is declining and access to health services is limited. The RFI project aims to determine the incidence, causes and outcomes of febrile illness understand the opportunities, barriers and appetite for adjustment of the role of VHWs to include management of non-malarial febrile illnesses and establish a network of community healthcare providers and facilities capable of implementing interventions designed to triage, diagnose and treat patients presenting with febrile illnesses within these communities in the future.
Publisher: F1000 Research Ltd
Date: 26-03-2021
DOI: 10.12688/WELLCOMEOPENRES.16393.1
Abstract: In rural areas of South and Southeast Asia malaria is declining but febrile illnesses still account for substantial morbidity and mortality. Village health workers (VHWs) are often the first point of contact with the formal health system, and for patients with febrile illnesses they can provide early diagnosis and treatment of malaria. However, for the majority of febrile patients, VHWs lack the training, support and resources to provide further care. Consequently, treatable bacterial illnesses are missed, antibiotics are overused and poorly targeted, and patient attendance wanes along with declining malaria. This Open Letter announces the start of a new initiative, the Rural Febrile Illness (RFI) project, the first in a series of projects to be implemented as part of the South and Southeast Asian Community-based Trials Network (SEACTN) research programme. This multi-country, multi-site project will begin in Bangladesh, Cambodia, Lao PDR, and Myanmar and will define the epidemiological baseline of febrile illness in five remote and underserved areas of Asia where malaria endemicity is declining and access to health services is limited. The RFI project aims to determine the incidence, causes and outcomes of febrile illness understand the opportunities, barriers and appetite for adjustment of the role of VHWs to include management of non-malarial febrile illnesses and establish a network of community healthcare providers and facilities capable of implementing interventions designed to triage, diagnose and treat patients presenting with febrile illnesses within these communities in the future.
Publisher: American Society for Microbiology
Date: 03-4008
DOI: 10.1128/AAC.00955-07
Abstract: The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interin idual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUC day 0-63 ]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUC day 3-20 ) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2016
DOI: 10.1038/SREP20498
Abstract: Historically seen as a benign disease, it is now becoming clear that Plasmodium vivax can cause significant morbidity. Effective control strategies targeting P. vivax malaria is hindered by our limited understanding of vivax biology. Here we established the P. vivax transcriptome of the Intraerythrocytic Developmental Cycle (IDC) of two clinical isolates in high resolution by Illumina HiSeq platform. The detailed map of transcriptome generates new insights into regulatory mechanisms of in idual genes and reveals their intimate relationship with specific biological functions. A transcriptional hotspot of vir genes observed on chromosome 2 suggests a potential active site modulating immune evasion of the Plasmodium parasite across patients. Compared to other eukaryotes, P. vivax genes tend to have unusually long 5′ untranslated regions and also present multiple transcription start sites. In contrast, alternative splicing is rare in P. vivax but its association with the late schizont stage suggests some of its significance for gene function. The newly identified transcripts, including up to 179 vir like genes and 3018 noncoding RNAs suggest an important role of these gene/transcript classes in strain specific transcriptional regulation.
Publisher: Springer Science and Business Media LLC
Date: 25-04-2013
DOI: 10.1038/SREP01734
Publisher: Elsevier BV
Date: 07-2004
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-04-2012
Abstract: Knowing that antimalarial drug resistance is characterized by selective sweeps and reduced ersity around resistance mutations, Cheeseman et al. (p. 79 ) looked for signatures of selection in a modified genome-wide association study in parasite populations from Cambodia, Laos, and Thailand. Thirty-three regions showed evidence of selection and enrichment of known antimalarial resistance genes. Fine-mapping of parasite s les taken during the past decade narrowed the association down to a 35-kb region of seven genes on chromosome 13 that seemed to explain at least 35% of the observed reduction in parasite clearance rate. However, the absence of strong candidate mutations suggests the involvement of noncoding regulatory mutations.
Publisher: Wiley
Date: 23-01-2007
DOI: 10.1111/J.1365-3156.2006.01778.X
Abstract: To assess the safety of chloroquine (CQ) as prophylaxis against Plasmodium vivax infection during pregnancy. One thousand pregnant Karen women were enrolled in a randomized, double-blind, placebo-controlled trial of chemoprophylaxis with chloroquine (500 mg phosphate (or 300 mg base) weekly). Women received a median (range) chloroquine phosphate total dose of 9500 (1500-17 500) mg. The mothers were actively followed from inclusion to delivery and their infants until 12 months of age. Chloroquine prophylaxis completely prevented P. vivax episodes 10.1% (95%CI: 7.3-14.5) of women in the placebo group experienced at least one episode of vivax malaria but no episode occurred in women in the CQ group. By contrast, the numbers of P. falciparum episodes were similar in each group: 7.4% (95%CI: 3.7-11.1) and 5.6% (95%CI: 3.3-7.9) in the placebo and CQ groups respectively (P = 0.56). Chloroquine prophylaxis was well tolerated and there was no difference in the proportions of reported side effects between CQ treated and placebo groups except for the duration of palpitations and sleeping disorders which were more frequent in those who had received CQ. Chloroquine prophylaxis had no impact on maternal anaemia, birth weight, gestational age, development of newborns or on growth, neurological development or visual acuity in infants at 1 year of age. Chloroquine is safe and effective as prophylaxis against P. vivax during pregnancy in this population.
Publisher: Wiley
Date: 09-12-2009
DOI: 10.1002/DDR.20348
Publisher: Springer Science and Business Media LLC
Date: 24-05-2017
DOI: 10.1038/S41598-017-02440-6
Abstract: Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type ) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance. Here, we evaluate the in vitro drug sensitivity profile of normally-developing P. falciparum ring stages and DHA-pretreated dormant rings (DP-rings) using a panel of antimalarial drugs, including the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. We report that while KDU691 shows no activity against rings, it is highly inhibitory against DP-rings a drug effect opposite to that of ART. Moreover, we provide evidence that KDU691 also kills DP-rings of P. falciparum ART-resistant strains expressing mutant K13.
Publisher: Springer Science and Business Media LLC
Date: 09-05-2018
DOI: 10.1038/S41467-018-04221-9
Abstract: Malaria liver stages represent an ideal therapeutic target with a bottleneck in parasite load and reduced clinical symptoms however, current in vitro pre-erythrocytic (PE) models for Plasmodium vivax and P . falciparum lack the efficiency necessary for rapid identification and effective evaluation of new vaccines and drugs, especially targeting late liver-stage development and hypnozoites. Herein we report the development of a 384-well plate culture system using commercially available materials, including cryopreserved primary human hepatocytes. Hepatocyte physiology is maintained for at least 30 days and supports development of P . vivax hypnozoites and complete maturation of P . vivax and P . falciparum schizonts. Our multimodal analysis in antimalarial therapeutic research identifies important PE inhibition mechanisms: immune antibodies against sporozoite surface proteins functionally inhibit liver stage development and ion homeostasis is essential for schizont and hypnozoite viability. This model can be implemented in laboratories in disease-endemic areas to accelerate vaccine and drug discovery research.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2016
Publisher: American Society of Tropical Medicine and Hygiene
Date: 05-1997
DOI: 10.4269/AJTMH.1997.56.526
Abstract: In preparation for a recently reported, independent field trial of SPf66 malaria vaccine efficacy in Thailand, we first established the safety and immunogenicity of two clinical lots of U.S. manufactured lots of SPf66 in a series of overlapping Phase I studies. The vaccine was produced in approved laboratories using good manufacturing practices. Two clinical lots of alum-adsorbed SPf66 were evaluated in a combined, open-label, Phase I clinical trial involving 50 healthy, malaria-experienced Karen adults and children. Volunteers were grouped by age and immunized sequentially. Group 1 had 30 adults. Group 2 had 10 children 8-15 years of age, and Group 3 had 10 children 2-6 years of age. The SPf66 vaccine was well tolerated in this malaria-experienced population. The most common side effects were erythema, induration, warmth, and tenderness at the site of injection, which typically resolved within 24-48 hr. One adult volunteer developed an acute urticarial rash following the third dose. Among adults, and to a lesser extent older children females had more local reactions than their male counterparts. Seroconversion to SPf66 by enzyme-linked immunosorbent assay occurred in 76% of volunteers receiving two or three doses. This vaccine was safe and immunogenic in malaria-experienced Karen adults and children. This study establishes the comparability of U.S.-manufactured SPf66 with that of Colombian origin, and is important for interpreting the efficacy results of U.S.-manufactured SPf66 in the same study population.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2017
Publisher: American Society for Microbiology
Date: 10-2013
DOI: 10.1128/AAC.00682-13
Abstract: Ex vivo antimalarial sensitivity testing in human malaria parasites has largely depended on microscopic determination of schizont maturation. While this microscopic method is sensitive, it suffers from poor precision and is laborious. The recent development of portable, low-cost cytometers has allowed us to develop and validate a simple, field-optimized protocol using SYBR green and dihydroethidium for the accurate and objective determination of antimalarial drug sensitivity in freshly isolated Plasmodium vivax and Plasmodium falciparum .
Publisher: Springer Science and Business Media LLC
Date: 16-11-2017
Publisher: Springer Science and Business Media LLC
Date: 04-01-2014
Publisher: Public Library of Science (PLoS)
Date: 31-10-2007
Publisher: Springer Science and Business Media LLC
Date: 12-08-2019
DOI: 10.1038/S41467-019-11332-4
Abstract: The ability to culture pathogenic organisms substantially enhances the quest for fundamental knowledge and the development of vaccines and drugs. Thus, the elaboration of a protocol for the in vitro cultivation of the erythrocytic stages of Plasmodium falciparum revolutionized research on this important parasite. However, for P. vivax , the most widely distributed and difficult to treat malaria parasite, a strict preference for reticulocytes thwarts efforts to maintain it in vitro. Cultivation of P. cynomolgi , a macaque-infecting species phylogenetically close to P. vivax , was briefly reported in the early 1980s, but not pursued further. Here, we define the conditions under which P. cynomolgi can be adapted to long term in vitro culture to yield parasites that share many of the morphological and phenotypic features of P. vivax . We further validate the potential of this culture system for high-throughput screening to prime and accelerate anti- P. vivax drug discovery efforts.
Publisher: American Medical Association (AMA)
Date: 05-2021
Publisher: Public Library of Science (PLoS)
Date: 24-10-2014
Publisher: Elsevier BV
Date: 09-1996
DOI: 10.1016/S0140-6736(96)04465-0
Abstract: Previous efficacy trials of SPf66 malaria vaccine have produced conflicting results in different populations. We report a randomised double-blind trial of the SPf66 vaccine conducted in Karen children aged 2-15 living in a malarious region of northwestern Thailand. Recombinant hepatitis B vaccine was used as a comparator. The study had a power of 90% to detect an efficacy of 30%, defined as a reduction in the incidence of first cases of symptomatic falciparum malaria after three doses of vaccine. 1221 children received three immunisations and were eligible for the primary efficacy analysis. Intense active and passive case detection continued over 15 months of follow-up. The SPf66 vaccine was well tolerated, although 26 children had mild or moderately severe local or systemic allergic reactions, compared with none in the comparator group. The vaccine was immunogenic after three doses, 73% of recipients had seroconverted. There were no deaths due to malaria during the study. During the 15-month period of evaluation there were 379 first cases of symptomatic falciparum malaria (195 in the SPf66 recipients, 184 in the comparator group) an SPf66 efficacy of -9% (95% CI -33 to 14, p = 0.41). No significant differences between the two study groups in parasite density or any other measure of malaria-related morbidity were detected. These findings are consistent with a recent study showing lack of efficacy of SPf66 among Gambian infants and differ from earlier positive reports from South America and evidence of borderline efficacy from Tanzania. We conclude that SPf66 does not protect against clinical falciparum malaria and that further efficacy trials are not warranted.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 02-2004
Publisher: American Society of Tropical Medicine and Hygiene
Date: 08-11-2017
Publisher: Public Library of Science (PLoS)
Date: 09-03-2020
Publisher: Oxford University Press (OUP)
Date: 11-2002
DOI: 10.1016/S0035-9203(02)90339-1
Abstract: Both Plasmodium vivax and P. falciparum malaria can cause the delivery of low birthweight babies. In this report, we have quantitated haemozoin levels in placentas from women living on the Thai-Burmese border in a region of low transmission for both P. falciparum and P. vivax malaria from June 1995 to January 2000. P. falciparum malaria infections during pregnancy lead to the accumulation of haemozoin (malaria pigment) in the placenta, especially in infections near term and in primigravid pregnancies. Haemozoin concentration was not associated with adverse birth outcomes. Women with P. vivax infections during pregnancy do not have measurable levels of placental haemozoin suggesting that P. vivax-infected erythrocytes do not accumulate in the placenta as much as P. falciparum-infected ones.
Publisher: Oxford University Press (OUP)
Date: 07-1998
DOI: 10.1016/S0035-9203(98)91081-1
Abstract: An artemisinin derivative (artesunate or artemether) was used for the treatment of multidrug-resistant Plasmodium falciparum malaria in 83 Karen pregnant women in Thailand 55 women were treated for recrudescent infection following quinine or mefloquine, 12 for uncomplicated hyperparasitaemic episodes, and 16 had not declared their pregnancy when treated. The women were followed weekly until delivery. Artesunate and artemether were well tolerated and there was no drug-related adverse effect. Recrudescence within 42 d occurred in 16% of the treated episodes. Overall 73 pregnancies (88%) resulted in live births, 3 (4%) in abortions and 2 (3%) in still births, and 5 women were lost to follow-up before delivery. There was no congenital abnormality in any of the newborn children, and the 46 children followed for more than one year all developed normally.
Publisher: Public Library of Science (PLoS)
Date: 29-06-2012
Publisher: Oxford University Press (OUP)
Date: 13-09-2012
DOI: 10.1093/BIOINFORMATICS/BTS557
Abstract: Summary: There is an immediate need for tools to both analyse and visualize in real-time single-nucleotide polymorphisms, insertions and deletions, and other structural variants from new sequence file formats. We have developed VarB software that can be used to visualize variant call format files in real time, as well as identify regions under balancing selection and informative markers to differentiate user-defined groups (e.g. populations). We demonstrate its utility using sequence data from 50 Plasmodium falciparum isolates comprising two different continents and confirm known signals from genomic regions that contain important antigenic and anti-malarial drug-resistance genes. Availability and implementation: The C++-based software VarB and user manual are available from arb. Contact: taane.clark@lshtm.ac.uk
Publisher: American Society of Tropical Medicine and Hygiene
Date: 04-2004
Publisher: Elsevier BV
Date: 06-2015
Publisher: Cold Spring Harbor Laboratory
Date: 05-01-2021
DOI: 10.1101/2021.01.05.425445
Abstract: The emergence of artemisinin (ART) resistance in Plasmodium falciparum parasites has led to increasing rates of treatment failure with first-line ART-based combination therapies (ACTs) in Southeast Asia. In this region, select mutations in K13 can result in delayed parasite clearance rates in vivo and enhanced survival in the ring-stage survival assay (RSA) in vitro . Our genotyping of 3,299 P. falciparum isolates across 11 sub-Saharan countries reveals the continuing dominance of wild-type K13 and confirms the emergence of a K13 R561H variant in Rwanda. Using gene editing, we provide definitive evidence that this mutation, along with M579I and C580Y, can confer variable degrees of in vitro ART resistance in African P. falciparum strains. C580Y and M579I were both associated with substantial fitness costs in African parasites, which may counter-select against their dissemination in high-transmission settings. We also report the impact of multiple K13 mutations, including the predominant variant C580Y, on RSA survival rates and fitness in multiple Southeast Asian strains. No change in ART susceptibility was observed upon editing point mutations in ferrodoxin or mdr2, earlier associated with ART resistance in Southeast Asia. These data point to the lack of an evident biological barrier to mutant K13 mediating ART resistance in Africa, while identifying their detrimental impact on parasite growth.
Publisher: Oxford University Press (OUP)
Date: 09-2012
Publisher: Springer Science and Business Media LLC
Date: 27-06-2016
DOI: 10.1038/NG.3599
Publisher: American Society for Microbiology
Date: 2019
DOI: 10.1128/JCM.00948-18
Abstract: Malaria rapid diagnostic tests (RDTs) primarily detect Plasmodium falciparum antigen histidine-rich protein 2 (HRP2) and the malaria-conserved antigen lactate dehydrogenase (LDH) for P. vivax and other malaria species. The performance of RDTs and their utility is dependent on circulating antigen concentration distributions in infected in iduals in a population in which malaria is endemic and on the limit of detection of the RDT for the antigens.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2013
Publisher: The Royal Society
Date: 17-08-2011
Abstract: Many women in resource-poor settings lack access to reliable gestational age assessment because they do not know their last menstrual period there is no ultrasound (US) and methods of newborn gestational age dating are not practised by birth attendants. A bespoke multiple-measures model was developed to predict the expected date of delivery determined by US. The results are compared with both a linear and a nonlinear model. Prospectively collected early US and serial symphysis-pubis fundal height (SFH) data were used in the models. The data were collected from Karen and Burmese women attending antenatal care on the Thai–Burmese border. The multiple-measures model performed best, resulting in a range of accuracy depending on the number of SFH measures recorded per mother (for ex le six SFH measurements resulted in a prediction accuracy of ±2 weeks). SFH remains the proxy for gestational age in much of the resource-poor world. While more accurate measures should be encouraged, we demonstrate that a formula that incorporates at least three SFH measures from an in idual mother and the slopes between them provide a significant increase in the accuracy of prediction compared with the linear and nonlinear formulae also using multiple SFH measures.
Publisher: Oxford University Press (OUP)
Date: 15-11-2004
DOI: 10.1086/425015
Abstract: Dihydroartemisinin-piperaquine (DP) is a new and relatively inexpensive artemisinin-containing fixed-combination antimalarial treatment. An adult treatment course contained 6.4 mg/kg dihydroartemisinin (DHA), which is >40% lower than the level in most artemisinin-containing combinations. This raised the possibility that the efficacy of the current coformulation may not be optimal in the treatment of multidrug-resistant falciparum malaria. In 2 large randomized, controlled studies in Thailand, the recommended dose of DP was compared with a regimen with additional artemisinin derivative (12 mg/kg DP+) and with mefloquine plus artesunate (MAS3). A total of 731 patients were included: 201 in a hospital-based study and 530 in a community study. Day-28 cure rates in the hospital-based study were 100% (95% confidence interval [CI], 93.9%-100%) in the MAS3 and DP+ groups and 98.3% (95% CI, 91%-99.7%) in the DP group, with a single recrudescence on day 21. In the community study, polymerase chain reaction genotyping-adjusted cure rates on day 63 were 96.1% (95% CI, 92.6%-99.7%) in the DP group, 98.3% (95% CI, 96.1%-100%) in the DP+ group, and 94.9% (95% CI, 91.2%-98.6%) in the MAS3 group (P=.2). Adverse events were few, with an excess of mild abdominal pain in the DP group. The current dosage of DP (6.4 mg/kg DHA and 51.2 mg/kg piperaquine phosphate) given over the course of 48 h is highly effective, safe, and well tolerated for the treatment of multidrug-resistant falciparum malaria, and its efficacy is not improved by the addition of more DHA.
Publisher: American Society of Hematology
Date: 19-02-2015
DOI: 10.1182/BLOOD-2014-08-596015
Abstract: Plasmodium vivax merozoites preferentially infect a subgroup of reticulocytes generally restricted to the bone marrow. Accelerated “maturation” of infected reticulocytes.
Publisher: Oxford University Press (OUP)
Date: 20-10-2016
Publisher: Oxford University Press (OUP)
Date: 15-12-2002
DOI: 10.1086/344901
Abstract: In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone-proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria.
Publisher: Oxford University Press (OUP)
Date: 11-1999
DOI: 10.1016/S0035-9203(99)90057-3
Abstract: Genetic characterization of Plasmodium falciparum infections in north-western Thailand, a region of low transmission intensity (1 infection erson each year), has found a comparable number of parasite genotypes per infected person to regions with hyperendemic malaria. Clone multiplicity and parasite ersity were found to be homogeneous across 129 infected in iduals comprising a range of age-groups (1.32 parasite genotypes n = 98), patients (aged 2-16 years) with recrudescent infections (1.54 n = 13), and pregnant women (1.61 n = 18). In iduals belonging to groups with a high risk of infection, as deduced by clinical epidemiology, did not harbour a higher number of clones per infection, nor greater parasite ersity than low-risk groups. In fact, multiple genotype infections were as common in low-risk groups, suggesting that there is frequent transmission of polyclonal infections from a single inoculum, rather than superinfection. Such a polyclonal transmission system would enable generation of extensive parasite ersity by recombination, despite the low level of transmission. However, co-infection with P. vivax was associated with fewer P. falciparum genotypes per infection.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2021
DOI: 10.1038/S41598-021-99152-9
Abstract: Improved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro . By developing an extended assay, we show both drugs are in idually hypnozonticidal and made more potent when partnered with chloroquine, similar to clinically relevant combinations. Post-hoc analyses of screening data revealed excellent performance of ionophore controls and the high quality of single point assays, demonstrating a platform able to support screening of greater compound numbers. A comparison of P. vivax liver stage activity data with that of the P. cynomolgi blood, P. falciparum blood, and P. berghei liver stages reveals overlap in schizonticidal but not hypnozonticidal activity, indicating that the delivery of new radical curative agents killing P. vivax hypnozoites requires an independent and focused drug development test cascade.
Publisher: Elsevier BV
Date: 06-2015
Publisher: Oxford University Press (OUP)
Date: 10-05-2019
Abstract: Antibodies to the blood stages of malaria parasites enhance parasite clearance and antimalarial efficacy. The antibody subclass and functions that contribute to parasite clearance during antimalarial treatment and their relationship to malaria transmission intensity have not been characterized. Levels of immunoglobulin G (IgG) subclasses and C1q fixation in response to Plasmodium falciparum merozoite antigens (erythrocyte-binding antigen [EBA] 175RIII-V, merozoite surface protein 2 [MSP-2], and MSP-142) and opsonic phagocytosis of merozoites were measured in a multinational trial assessing the efficacy of artesunate therapy across 11 Southeast Asian sites. Regression analyses assessed the effects of antibody seropositivity on the parasite clearance half-life (PC½), having a PC½ of ≥5 hours, and having parasitemia 3 days after treatment. IgG3, followed by IgG1, was the predominant IgG subclass detected (seroprevalence range, 5%–35% for IgG1 and 27%–41% for IgG3), varied across study sites, and was lowest in study sites with the lowest transmission intensity and slowest mean PC½. IgG3, C1q fixation, and opsonic-phagocytosis seropositivity were associated with a faster PC½ (range of the mean reduction in PC½, 0.47–1.16 hours P range, .001–.03) and a reduced odds of having a PC½ of ≥5 hours and having parasitemia 3 days after treatment. The prevalence of IgG3, complement-fixing antibodies, and merozoite phagocytosis vary according to transmission intensity, are associated with faster parasite clearance, and may be sensitive surrogates of an augmented clearance capacity of infected erythrocytes. Determining the functional immune mechanisms associated with parasite clearance will improve characterization of artemisinin resistance.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Informa UK Limited
Date: 23-10-2018
DOI: 10.1080/14740338.2018.1535593
Abstract: Malaria in pregnancy and postpartum cause maternal mortality and adverse fetal outcomes. Efficacious and safe antimalarials are needed to treat and prevent such serious consequences. However, because of the lack of evidence on fetal safety, quinine, an old and less efficacious drug has long been recommended for pregnant women. Uncertainty about safety in relation to breastfeeding leads to withholding of efficacious treatments postpartum or cessation of breastfeeding. Areas covered: A search identified literature on humans in three databases (MEDLINE, Embase and Global health) using pregnancy or lactation, and the names of antimalarial drugs as search terms. Adverse reactions to the mother, fetus or breastfed infant were summarized together with efficacies. Expert opinion: Artemisinins are more efficacious and well-tolerated than quinine in pregnancy. Furthermore, the risks of miscarriage, stillbirth or congenital abnormality were not higher in pregnancies exposed to artemisinin derivatives for treatment of malaria than in pregnancies exposed to quinine or in the comparable background population unexposed to any antimalarials, and this was true for treatment in any trimester. Assessment of safety and efficacy of antimalarials including dose optimization for pregnant women is incomplete. Resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum and long unprotected intervals between intermittent treatment doses begs reconsideration of current preventative recommendations in pregnancy. Data remain limited on antimalarials during breastfeeding while most first-line drugs appear safe, further research is needed.
Publisher: BMJ
Date: 05-2020
DOI: 10.1136/BMJPO-2020-000641
Abstract: To describe neonatal survival and long-term neurological outcome in neonatal hyperbilirubinaemia (NH) with extreme serum bilirubin (SBR) values. Retrospective chart review, a one-off neurodevelopmental evaluation. Special care baby unit in a refugee c and clinics for migrant populations at the Thailand–Myanmar border with phototherapy facilities but limited access to exchange transfusion (ET). Neonates ≥28 weeks of gestational age with extreme SBR values and/or acute neurological symptoms, neurodevelopment evaluation conducted at 23–97 months of age. Neonatal mortality rate, prevalence of acute bilirubin encephalopathy (ABE) signs, prevalence of delayed development scores based on the Griffiths Mental Development Scale (GMDS). From 2009 to 2014, 1946 neonates were diagnosed with jaundice 129 (6.6%) had extreme SBR values during NH (extreme NH). In this group, the median peak SBR was 430 (IQR 371–487) µmol/L and the prevalence of ABE was 28.2%. Extreme NH-related mortality was 10.9% (14/129). Median percentile GMDS general score of 37 survivors of extreme NH was poor: 11 (2–42). ‘Performance’, ‘practical reasoning’ and ‘hearing and language’ domains were most affected. Four (10.8%) extreme NH survivors had normal development scores (≥50th centile). Two (5.4%) developed the most severe form of kernicterus spectrum disorders. In this limited-resource setting, poor neonatal survival and neurodevelopmental outcomes, after extreme NH, were high. Early identification and adequate treatment of NH where ET is not readily available are key to minimising the risk of extreme SBR values or neurological symptoms.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2011
Publisher: Informa UK Limited
Date: 04-2014
Publisher: Public Library of Science (PLoS)
Date: 10-08-2016
Publisher: Cold Spring Harbor Laboratory
Date: 07-11-2019
DOI: 10.1101/824730
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: American Society for Microbiology
Date: 10-2015
DOI: 10.1128/JCM.01226-15
Abstract: Flow cytometry is an objective method for conducting in vitro antimalarial sensitivity assays with increasing potential for application in field sites. We examined in vitro susceptibility to seven anti-malarial drugs for 40 fresh P. falciparum field isolates via a flow cytometry method (FCM), a colorimetric LDH-based ELISA ( DELI), and standard microscopic slide analysis of growth. For FCM, 184/280 (66%) assays met analytical acceptance criteria, compared to 166/280 (59%) for DELI. There was good agreement between FCM and microscopy, while DELI tended to produce higher half-maximal inhibition constants (IC 50 s) than FCM, with an overall bias of 2.2-fold (Bland-Altman comparison). Values for artesunate and dihydroartemisinin were most affected. Paradoxical increases in signal at very high concentrations of mefloquine and related compounds were more marked with the DELI assay, suggesting that off-target effects on LDH production may be responsible. Loss of FCM signal due to reinvasion or slow growth was observed in a small number of s les. These results extend previous work on use of flow cytometry to determine antimalarial susceptibility in terms of the number of s les, range of drugs, and comparison with other methods.
Publisher: Public Library of Science (PLoS)
Date: 14-06-2016
Publisher: Springer Science and Business Media LLC
Date: 04-09-2020
DOI: 10.1186/S12936-020-03352-Z
Abstract: Microscopy performed on stained films of peripheral blood for detection, identification and quantification of malaria parasites is an essential reference standard for clinical trials of drugs, vaccines and diagnostic tests for malaria. The value of data from such research is greatly enhanced if this reference standard is consistent across time and geography. Adherence to common standards and practices is a prerequisite to achieve this. The rationale for proposed research standards and procedures for the preparation, staining and microscopic examination of blood films for malaria parasites is presented here with the aim of improving the consistency and reliability of malaria microscopy performed in such studies. These standards constitute the core of a quality management system for clinical research studies employing microscopy as a reference standard. They can be used as the basis for the design of training and proficiency testing programmes as well as for procedures and quality assurance of malaria microscopy in clinical research.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 05-09-2012
Publisher: Elsevier BV
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 02-07-2008
DOI: 10.1007/S00228-008-0500-Z
Abstract: We compared the pharmacokinetics of chloroquine in pregnant and nonpregnant women treated for Plasmodium vivax malaria. Twelve pregnant women and 15 nonpregnant women of child-bearing age with acute P. vivax malaria were treated with 25 mg chloroquine base/kg over 3 days on the northwestern border of Thailand. Blood concentrations of chloroquine and desethylchloroquine were measured using hydrophilic interaction liquid chromatography coupled with fluorescence detection. Twenty-five women completed the pharmacokinetic study. Although increasing gestational age was associated with reduced chloroquine AUC0-->infinity, there was no significant difference overall in the pharmacokinetics of chloroquine between pregnant and nonpregnant women. Fever was associated with lower chloroquine AUC0-->infinity values. Desethylchloroquine area under the curve (AUC) values were not significantly affected by pregnancy. Pregnancy did not significantly affect blood concentrations of chloroquine or its metabolite, desethylchloroquine, in women with P. vivax malaria.
Publisher: Oxford University Press (OUP)
Date: 10-2000
DOI: 10.1093/OXFORDJOURNALS.MOLBEV.A026247
Abstract: Multilocus genotyping of microbial pathogens has revealed a range of population structures, with some bacteria showing extensive recombination and others showing almost complete clonality. The population structure of the protozoan parasite Plasmodium falciparum has been harder to evaluate, since most studies have used a limited number of antigen-encoding loci that are known to be under strong selection. We describe length variation at 12 microsatellite loci in 465 infections collected from 9 locations worldwide. These data reveal dramatic differences in parasite population structure in different locations. Strong linkage disequilibrium (LD) was observed in six of nine populations. Significant LD occurred in all locations with prevalence <1% and in only two of five of the populations from regions with higher transmission intensities. Where present, LD results largely from the presence of identical multilocus genotypes within populations, suggesting high levels of self-fertilization in populations with low levels of transmission. We also observed dramatic variation in ersity and geographical differentiation in different regions. Mean heterozygosities in South American countries (0.3-0.4) were less than half those observed in African locations (0. 76-0.8), with intermediate heterozygosities in the Southeast Asia/Pacific s les (0.51-0.65). Furthermore, variation was distributed among locations in South America (F:(ST) = 0.364) and within locations in Africa (F:(ST) = 0.007). The intraspecific patterns of ersity and genetic differentiation observed in P. falciparum are strikingly similar to those seen in interspecific comparisons of plants and animals with differing levels of outcrossing, suggesting that similar processes may be involved. The differences observed may also reflect the recent colonization of non-African populations from an African source, and the relative influences of epidemiology and population history are difficult to disentangle. These data reveal a range of population structures within a single pathogen species and suggest intimate links between patterns of epidemiology and genetic structure in this organism.
Publisher: American Society for Microbiology
Date: 09-2014
DOI: 10.1128/AAC.02727-13
Abstract: Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo . Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
Publisher: F1000 Research Ltd
Date: 24-08-2017
DOI: 10.12688/WELLCOMEOPENRES.12338.1
Abstract: Background: Inherited red blood cell disorders are prevalent in populations living in malaria endemic areas G6PD deficiency is associated with oxidant-induced hemolysis and abnormal hemoglobin variants may cause chronic anemia. In pregnant women, microcytic anemia caused by hemoglobinopathies mimics iron deficiency, complicating diagnosis and treatment. Anemia during pregnancy is associated with morbidity and mortality. The aim of this study was to characterize the prevalence of G6PD deficiency, hemoglobinopathies, ABO and Rhesus blood groups among the pregnant population living along the Thailand-Myanmar border. Pregnant women attending antenatal clinics in this area belong to several distinct ethnic groups. Methods: Data was available for 13,520 women attending antenatal care between July 2012 and September 2016. Screening for G6PD deficiency was done by fluorescent spot test routinely. G6PD genotyping and quantitative phenotyping by spectrophotometry were analyzed in a subs le of women. Hemoglobin variants were diagnosed by HPLC or capillary electrophoresis and molecular methods. Blood groups were diagnosed by agglutination test. The prevalence and distribution of inherited red blood cell disorders and blood groups was analyzed with respect to ethnicity. Results: G6PD deficiency was common, especially in the Sgaw Karen ethnic group, in whom the G6PD Mahidol variant allele frequency was 20.7%. Quantitative G6PD phenotyping showed that 60.5% of heterozygote women have an intermediate enzymatic activity between 30% and 70% of the population median. HbE, beta-thalassemia trait and alpha-thalassemia trait were found in 31.2% of women. Only 0.15% of women were Rhesus negative. Conclusions: Distribution of G6PD and hemoglobin variants varied among the different ethnic groups, but the prevalence was generally high throughout the cohort. These findings encourage the implementation of an extended program of information and genetic counseling to women of reproductive age and will help inform future studies and current clinical management of anemia in the pregnant population in this region.
Publisher: Springer Science and Business Media LLC
Date: 10-2003
DOI: 10.1007/S00228-003-0651-X
Abstract: To determine the effects of late pregnancy and also oestrogen supplementation on the CYP2C19-mediated biotransformation of proguanil (PG) to its active antifol triazine metabolite cycloguanil (CG). Case control study conducted on the NW border of Thailand a single dose of PG (4 mg/kg) was administered to Karen women in late pregnancy and a single blood and urine s le taken 6 h later. Women were studied in late pregnancy (>36 weeks) and restudied 2 months after delivery. A separate cohort of Karen women newly attending a birth-control clinic were studied before and 3 weeks into their first course of oral contraceptives (OCP: levonorgestrel 0.15 mg and ethinyloestradiol 0.03 mg). Forty-five pregnant women and forty-two healthy OCP users were studied. The results were similar in both groups pregnancy and OCP use were both associated with reduced formation of cycloguanil (CG). Impaired PG biotransformation was seen in women with the "extensive metaboliser" phenotype (urine PG/CG ratio <10). CG levels, adjusted for dose, were a median (range) 73% (-59 to 420%) higher following the pregnancy than during the pregnancy in women characterised as extensive metabolisers ( P<0.001). CG levels in women characterised as extensive metabolisers were 34% (-54 to 323%) higher before than while taking the OCP ( P<0.01). Late pregnancy and OCP use impair biotransformation of the active antimalarial metabolite CG from the parent PG. This may be mediated by oestrogen inhibition of CYP2C19 activity. The dose of PG should be increased by 50% in these groups.
Publisher: Cold Spring Harbor Laboratory
Date: 05-07-2022
DOI: 10.1101/2022.07.03.22277173
Abstract: New point-of-care (POC) quantitative G6PD testing devices developed to provide safe radical cure for P. vivax malaria may be used to diagnose G6PD deficiency in newborns at risk of severe neonatal hyperbilirubinaemia, improving clinical care, and preventing related morbidity and mortality. Methods: We conducted a mixed-methods study analyzing technical performance and usability of the “STANDARD G6PD” Biosensor when used by trained midwives on cord blood s les at two rural clinics on the Thailand-Myanmar border. In 307 cord blood s les, the Biosensor had a sensitivity of 1.000 (95%CI 0.859-1.000) and a specificity of 0.993 (95% CI 0.971-0.999) as compared to gold standard spectrophotometry to diagnose G6PD deficient newborns using a receiving operator characteristic (ROC) analysis-derived threshold of ≤4.8IU/gHb. The Biosensor had a sensitivity of 0.727 (95%CI: 0.498-0.893) and specificity of 0.933 (95%CI: 0.876-0.969) for 30-70% activity range in females using ROC analysis-derived range of 4.9 to 9.9IU/gHb. These thresholds allowed identification of all G6PD deficient neonates and 80% of female neonates with intermediate phenotypes. Need of phototherapy treatment for neonatal hyperbilirubinaemia was higher in neonates with deficient and intermediate phenotypes as diagnosed by either reference spectrophotometry or Biosensor. Focus group discussions found high levels of learnability, willingness, satisfaction, and suitability for the Biosensor in this setting. The staff valued the capacity of the Biosensor to identify newborns with G6PD deficiency early (“We can know that early, we can counsel the parents about the chances of their children getting jaundice”) and at the POC, including in more rural settings (“Because we can know the right result of the G6PD deficiency in a short time. Especially for the clinic which does not have a lab”). Conclusions: The Biosensor is a suitable tool in this resource-constrained setting to identify newborns with abnormal G6PD phenotypes at increased risk of neonatal hyperbilirubinaemia.
Publisher: Wiley
Date: 22-07-2015
DOI: 10.1111/BCP.12660
Publisher: F1000 Research Ltd
Date: 07-04-2022
DOI: 10.12688/WELLCOMEOPENRES.17743.1
Abstract: Background: Gestational diabetes mellitus (GDM) contributes significantly to maternal and neonatal morbidity, but data from marginalized populations remains scarce. This study aims to compare risk-factor-based screening to universal testing for GDM among migrants along the Thailand-Myanmar border. Methods: From the prospective cohort (September 2016, February 2019), 374 healthy pregnant women completed a 75g oral glucose tolerance test (OGTT) at 24-32 weeks gestation. Fasting, one hour and two hour cut-offs were based on Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO trial) criteria and cases were treated. The sensitivity and specificity of risk-factor-based screening criteria was calculated using OGTT as the gold standard. Risk factors included at least one positive finding among 10 criteria, e.g., obesity (body mass index (BMI) ≥27.5kg/m 2 ), 1 st degree relative with diabetes etc. Adverse maternal and neonatal outcomes were compared by GDM status, and risk factors for GDM were explored. Results: GDM prevalence was 13.4% (50/374) (95% CI: 10.3-17.2). Risk-factors alone correctly identified 74.0% (37/50) OGTT positive cases: sensitivity 74.0% (59.7-85.4) and specificity 27.8% (3.0-33.0). Burman women accounted for 29.1% of the cohort population, but 38.0% of GDM cases. Percentiles for birthweight (p=0.004), head circumference (p=0.005), and weight-length ratio (p=0.010) were higher in newborns of GDM mothers compared with non-GDM, yet 21.7% (75/346) of newborns in the cohort were small-for-gestational age. In Burman women, overweight/obese BMI was associated with a significantly increased adjusted odds ratio 5.03 (95% CI: 1.43-17.64) for GDM compared to normal weight, whereas underweight and overweight/obese in Karen women were both associated with similarly elevated adjusted odds, approximately 2.4-fold (non-significant) for GDM. GDM diagnosis by OGTT was highest prior to peak rainfall. Conclusions: Risk-factor-based screening was not sufficiently sensitive or specific to be useful to diagnose GDM in this setting among a cohort of low-risk pregnant women. A two-step universal screening program has thus been implemented.
Publisher: Public Library of Science (PLoS)
Date: 13-04-2012
Publisher: BMJ
Date: 2019
DOI: 10.1136/BMJOPEN-2018-023417
Abstract: Preterm birth (PTB) results from heterogeneous influences and is a major contributor to neonatal mortality and morbidity that continues to have adverse effects on infants beyond the neonatal period. This protocol describes the procedures to determine molecular signatures predictive of PTB through high-frequency s ling during pregnancy, at delivery and the postpartum period. Four hundred first trimester pregnant women from either Myanmar or Thailand of either Karen or Burman ethnicity, with a viable, singleton pregnancy will be enrolled in this non-interventional, prospective pregnancy birth cohort study and will be followed through to the postpartum period. Fortnightly finger prick capillary blood s ling will allow the monitoring of genome-wide transcript abundance in whole blood. Collection of stool s les and vaginal swabs each trimester, at delivery and postpartum will allow monitoring of intestinal and vaginal microbial composition. In a nested case–control analysis, perturbations of transcript abundance in capillary blood as well as longitudinal changes of the gut, vaginal and oral microbiome will be compared between mothers giving birth to preterm and matched cases giving birth to term neonates. Placenta tissue of preterm and term neonates will be used to determine bacterial colonisation as well as for the establishment of coding and non-coding RNA profiles. In addition, RNA profiles of circulating, non-coding RNA in cord blood serum will be compared with those of maternal peripheral blood serum at time of delivery. This research protocol that aims to detect perturbations in molecular trajectories preceding adverse pregnancy outcomes was approved by the ethics committee of the Faculty of Tropical Medicine, Mahidol University in Bangkok, Thailand (Ethics Reference: TMEC 15–062), the Oxford Tropical Research Ethics Committee (Ethics Reference: OxTREC: 33–15) and the local Tak Province Community Ethics Advisory Board. The results of this cooperative project will be disseminated in multiple publications staggered over time in international peer-reviewed scientific journals. NCT02797327 Pre-results.
Publisher: F1000 Research Ltd
Date: 18-01-2023
DOI: 10.12688/WELLCOMEOPENRES.17743.2
Abstract: Background: Gestational diabetes mellitus (GDM) contributes to maternal and neonatal morbidity. As data from marginalized populations remains scarce, this study compares risk-factor-based to universal GDM screening in a low resource setting. Methods: This is a secondary analysis of data from a prospective preterm birth cohort. Pregnant women were enrolled in the first trimester and completed a 75g oral glucose tolerance test (OGTT) at 24-32 weeks' gestation. To define GDM cases, Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO trial) criteria were used. All GDM positive cases were treated. Sensitivity and specificity of risk-factor-based selection for screening (criteria: age ≥30y, obesity (Body mass index (BMI) ≥27.5kg/m 2 ), previous GDM, 1 st degree relative with diabetes, previous macrosomia (≥4kg), previous stillbirth, or symphysis-fundal height ≥90th percentile) was compared to universal screening using the OGTT as the gold standard. Adverse maternal and neonatal outcomes were compared by GDM status. Results: GDM prevalence was 13.4% (50/374) (95% CI: 10.3-17.2). Three quarters of women had at least one risk factor (n=271 women), with 37/50 OGTT positive cases correctly identified: sensitivity 74.0% (59.7-85.4) and specificity 27.8% (3.0-33.0). Burman women (self-identified) accounted for 29.1% of the cohort population, but 38.0% of GDM cases. Percentiles for birthweight (p=0.004), head circumference (p=0.002), and weight-length ratio (p=0.030) were higher in newborns of GDM positive compared with non-GDM mothers. 21.7% (75/346) of newborns in the cohort were small-for-gestational age (≤10 th percentile). In Burman women, overweight/obese BMI was associated with a significantly increased adjusted odds ratio 5.03 (95% CI: 1.43-17.64) for GDM compared with normal weight, whereas in Karen women, the trend in association was similar but not significant (OR 2.36 95% CI 0.95-5.89). Conclusions: Risk-factor-based screening missed one in four GDM positive women. Considering the benefits of early detection of GDM and the limited additional cost of universal screening, a two-step screening program was implemented.
Publisher: F1000 Research Ltd
Date: 02-11-2017
DOI: 10.12688/WELLCOMEOPENRES.12338.2
Abstract: Background : Inherited red blood cell disorders are prevalent in populations living in malaria endemic areas G6PD deficiency is associated with oxidant-induced haemolysis and abnormal haemoglobin variants may cause chronic anaemia. In pregnant women, microcytic anaemia caused by haemoglobinopathies mimics iron deficiency, complicating diagnosis and treatment. Anaemia during pregnancy is associated with morbidity and mortality. The aim of this study was to characterise the prevalence of G6PD deficiency and haemoglobinopathies among the pregnant population living along the Thailand-Myanmar border. Pregnant women attending antenatal clinics in this area belong to several distinct ethnic groups. Methods : Data were available for 13,520 women attending antenatal care between July 2012 and September 2016. Screening for G6PD deficiency was done by fluorescent spot test routinely. G6PD genotyping and quantitative phenotyping by spectrophotometry were analysed in a subs le of women. Haemoglobin variants were diagnosed by HPLC or capillary electrophoresis and molecular methods. The prevalence and distribution of inherited red blood cell disorders was analysed with respect to ethnicity. Results : G6PD deficiency was common, especially in the Sgaw Karen ethnic group, in whom the G6PD Mahidol variant allele frequency was 20.7%. Quantitative G6PD phenotyping showed that 60.5% of heterozygous women had an intermediate enzymatic activity between 30% and 70% of the population median. HbE, beta-thalassaemia trait and Hb Constant Spring were found overall in 15.6% of women. Only 45.2% of women with low percentage of HbA 2 were carriers of mutations on the alpha globin genes. Conclusions : Distribution of G6PD and haemoglobin variants varied among the different ethnic groups, but the prevalence was generally high throughout the cohort. These findings encourage the implementation of an extended program of information and genetic counselling to women of reproductive age and will help inform future studies and current clinical management of anaemia in the pregnant population in this region.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2019
Publisher: Elsevier BV
Date: 03-2020
Publisher: Oxford University Press (OUP)
Date: 03-2013
DOI: 10.1093/CID/CIS979
Publisher: Cold Spring Harbor Laboratory
Date: 24-09-2019
DOI: 10.1101/776781
Abstract: Imported cases present a considerable challenge to the elimination of malaria. Traditionally, patient travel history has been used to identify imported cases, but the long-latency liver stages confound this approach in Plasmodium vivax . Molecular tools to identify and map imported cases offer a more robust approach, that can be combined with drug resistance and other surveillance markers in high-throughput, population-based genotyping frameworks. Using a machine learning approach incorporating hierarchical FST (HFST) and decision tree (DT) analysis applied to 831 P. vivax genomes from 20 countries, we identified a 28-Single Nucleotide Polymorphism (SNP) barcode with high capacity to predict the country of origin. The Matthews correlation coefficient (MCC), which provides a measure of the quality of the classifications, ranging from −1 (total disagreement) to 1 (perfect prediction), exceeded 0.9 in 15 countries in cross-validation evaluations. When combined with an existing 37-SNP P. vivax barcode, the 65-SNP panel exhibits MCC scores exceeding 0.9 in 17 countries with up to 30% missing data. As a secondary objective, several genes were identified with moderate MCC scores (median MCC range from 0.54-0.68), amenable as markers for rapid testing using low-throughput genotyping approaches. A likelihood-based classifier framework was established, that supports analysis of missing data and polyclonal infections. To facilitate investigator-lead analyses, the likelihood framework is provided as a web-based, open-access platform (vivaxGEN-geo) to support the analysis and interpretation of data produced either at the 28-SNP core or full 65-SNP barcode. These tools can be used by malaria control programs to identify the main reservoirs of infection so that resources can be focused to where they are needed most.
Publisher: Oxford University Press (OUP)
Date: 2007
DOI: 10.1086/509809
Publisher: Public Library of Science (PLoS)
Date: 21-05-2018
Publisher: BMJ
Date: 02-2021
DOI: 10.1136/BMJGH-2020-004325
Abstract: To examine the interactions between short maternal stature, body mass index (BMI) and gestational weight gain (GWG) among appropriate for gestational age (AGA) term newborns in a population of refugees and migrants in Southeast Asia. This is a retrospective cohort study from 2004 to 2016, including women delivering term, singleton newborns, with first trimester height, weight and gestation dated by ultrasound and a last body weight measured within 4 weeks of birth. AGA newborns were those not classified as small for gestational age or large for gestational age by either INTERGROWTH-21st or Gestation Related Optimal Weight standards. The influence of maternal stature on GWG in delivering an AGA newborn was analysed, with GWG compared with existing National Academy of Medicine (NAM) recommendations. 4340 women delivered AGA newborns. Mean maternal height (SD) was 151.5 cm (5.13), with 58.5% of women considered too short by INTERGROWTH-21st standards. Only one in four women (26.5%, 1150/4340) had GWG within NAM recommendations. Women of shorter stature had a significantly lower mean GWG compared with taller women in underweight and normal BMI categories (p .001 for both BMI categories). Mean GWG of overweight and obese women did not differ by height (p=1.0 and p=0.85, respectively) and fell within the lower range of NAM recommendations. These results suggest that short maternal stature can be an important predictor of GWG and should be considered with prepregnancy BMI. Limited-resource settings and special populations need robust GWG recommendations that reflect height and BMI.
Publisher: Oxford University Press (OUP)
Date: 09-2000
DOI: 10.1016/S0035-9203(00)90082-8
Abstract: The efficacy and safety of the 6-dose regimen of artemether-lumefantrine were assessed in an open randomized trial in children and adults presenting with acute, uncomplicated Plasmodium falciparum malaria in Thailand between November 1997 and March 1998. 200 patients were enrolled in 2 centres: 150 received artemether-lumefantrine (i.e., a median total dose of 9.6 mg/kg [interquartile range 8.7-10.7] and 57.9 mg/kg of lumefantrine [52.4-64.0]) and 50 the standard combination of artesunate (12 mg/kg over 3 d) and mefloquine (25 mg/kg). All patients had rapid initial clinical and parasitological responses. The 28 d cure rates were high: 97.7% (95% confidence interval [95% CI] 93.5-99.5%) for artemether-lumefantrine and 100% (95% CI 92.5-100%) for artesunate-mefloquine. The 6-dose regimen of artemether-lumefantrine was better tolerated than, and as effective as, artesunate-mefloquine, the current standard treatment in this area of multidrug-resistant P. falciparum malaria.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2021
DOI: 10.1186/S12884-021-03612-Z
Abstract: Hepatitis B Virus (HBV) is transmitted from mother to child which can be prevented via birth dose vaccine combined with three follow up hepatitis B vaccines, hepatitis B immunoglobulins (HBIG), and maternal antiviral treatment with Tenofovir Disoproxil Fumarate (TDF). This study evaluates the cost effectiveness of six strategies to prevent perinatal HBV transmission in a resource limited setting (RLS) on the Thailand-Myanmar border. The cost effectiveness of six strategies was tested by a decision tree model in R. All strategies included birth and follow up vaccinations and compared cost per infection averted against two willingness to pay thresholds: one-half and one gross domestic product (GDP) per capita. Strategies were: 1) Vaccine only, 2) HBIG after rapid diagnostic test (RDT): infants born to HBsAg+ are given HBIG, 3) TDF after RDT: HBsAg+ women are given TDF, 4) TDF after HBeAg test: HBeAg+ women are given TDF, 5) TDF after high HBV DNA: women with HBV DNA 200,000 are given TDF, 6) HBIG & TDF after high HBV DNA: women with HBV DNA 200,000 are given TDF and their infants are given HBIG. One-way and probabilistic sensitivity analyses were conducted on the cost-effective strategies. Vaccine only was the least costly option with TDF after HBeAg test strategy as the only cost-effective alternative. TDF after HBeAg test had an incremental cost-effectiveness ratio of US$1062 which would not be considered cost-effective with the lower threshold of one-half GDP per capita. The one-way sensitivity analysis demonstrated that the results were reasonably robust to changes in single parameter values. The PSA showed that TDF after HBeAg test had an 84% likelihood of being cost effective at a willingness to pay threshold of one GDP per capita per infection averted. We found that TDF after HBeAg test has the potential to be cost-effective if TDF proves effective locally to prevent perinatal HBV transmission. The cost of TDF treatment and reliability of the RDT could be barriers to implementing this strategy. While TDF after RDT may be a more feasible strategy to implement in RLS, TDF after HBeAg test is a less costly option.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2018
DOI: 10.1038/S41467-018-04965-4
Abstract: The incidence of Plasmodium vivax infection has declined markedly in Malaysia over the past decade despite evidence of high-grade chloroquine resistance. Here we investigate the genetic changes in a P. vivax population approaching elimination in 51 isolates from Sabah, Malaysia and compare these with data from 104 isolates from Thailand and 104 isolates from Indonesia. Sabah displays extensive population structure, mirroring that previously seen with the emergence of artemisinin-resistant P. falciparum founder populations in Cambodia. Fifty-four percent of the Sabah isolates have identical genomes, consistent with a rapid clonal expansion. Across Sabah, there is a high prevalence of loci known to be associated with antimalarial drug resistance. Measures of differentiation between the three countries reveal several gene regions under putative selection in Sabah. Our findings highlight important factors pertinent to parasite resurgence and molecular cues that can be used to monitor low-endemic populations at the end stages of P. vivax elimination.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2014
Publisher: Springer Science and Business Media LLC
Date: 11-11-2015
Publisher: Oxford University Press (OUP)
Date: 03-2002
DOI: 10.1016/S0035-9203(02)90297-X
Abstract: Quinine (n = 246) was used to treat uncomplicated Plasmodium falciparum and chloroquine (n = 130) was used to treat P. vivax, in a total of 376 episodes of malaria in the first trimester of pregnancy, in 300 Karen women (Thailand, 1995-2000). Parasites were still present on day 6 or 7 in 4.7% (11/234) of episodes treated with quinine. The overall 28 day parasite reappearance rate following quinine was 28.7% (60/209) for primary treatments and 44% (11/25) for re-treatments. Quinine treatment resulted in a high rate of gametocyte carriage: person-gametocyte-weeks = 42.5 (95% CI 27.8-62.1) per 1000 woman-weeks. For P. vivax, the reappearance rate for all episodes by day 28 was 4.5% (5/111). Significantly more women complained of tinnitus following quinine treatment compared to on admission: 64.5% (78/121) vs 31.6% (59/187), P < 0.001. Using survival analysis, the community rate of spontaneous abortion in women who never had malaria in pregnancy, 17.8% (16.5-19.0), did not differ significantly from rates in women treated with quinine: 22.9% (95% CI 15.5-30.3), or chloroquine: 18.3% (95% CI 9.3-27.3), P = 0.42. Pregnancies exposed to quinine or chloroquine and carried to term did not have increased rates of congenital abnormality, stillbirth or low birthweight. These results suggest that therapeutic doses of quinine and chloroquine are safe to use in the first trimester of pregnancy.
Publisher: Public Library of Science (PLoS)
Date: 22-08-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 05-02-2019
Abstract: The positioning of chromosomes in the nucleus of a eukaryotic cell is highly organized and has a complex and dynamic relationship with gene expression. In the human malaria parasite Plasmodium falciparum , the clustering of a family of virulence genes correlates with their coordinated silencing and has a strong influence on the overall organization of the genome. To identify conserved and species-specific principles of genome organization, we performed Hi-C experiments and generated 3D genome models for five Plasmodium species and two related apicomplexan parasites. Plasmodium species mainly showed clustering of centromeres, telomeres, and virulence genes. In P. falciparum , the heterochromatic virulence gene cluster had a strong repressive effect on the surrounding nuclear space, while this was less pronounced in Plasmodium vivax and Plasmodium berghei , and absent in Plasmodium yoelii . In Plasmodium knowlesi , telomeres and virulence genes were more dispersed throughout the nucleus, but its 3D genome showed a strong correlation with gene expression. The Babesia microti genome showed a classical Rabl organization with colocalization of subtelomeric virulence genes, while the Toxoplasma gondii genome was dominated by clustering of the centromeres and lacked virulence gene clustering. Collectively, our results demonstrate that spatial genome organization in most Plasmodium species is constrained by the colocalization of virulence genes. P. falciparum and P. knowlesi , the only two Plasmodium species with gene families involved in antigenic variation, are unique in the effect of these genes on chromosome folding, indicating a potential link between genome organization and gene expression in more virulent pathogens.
Publisher: Oxford University Press (OUP)
Date: 14-10-2011
DOI: 10.1093/CID/CIR631
Publisher: Springer Science and Business Media LLC
Date: 10-2016
DOI: 10.1007/S10903-015-0294-X
Abstract: The objective of this project was to document and increase vaccine coverage in migrant school children on the Thailand-Myanmar border. Migrant school children (n = 12,277) were enrolled in a school-based immunization program in four Thai border districts. The children were evaluated for vaccination completion and timing, for six different vaccines: Bacille Calmette-Guerin (BCG) Oral Polio vaccine (OPV) Hepatitis B vaccine (HepB) Diphtheria, Pertussis and Tetanus vaccine (DTP) Measles Containing Vaccine or Measles, Mumps and Rubella vaccine (MMR) Tetanus and Diphtheria containing vaccine (Td). Vaccine coverage proportions for BCG, OPV3, DTP3, HepB3 and measles containing vaccine were 92.3, 85.3, 63.8, 72.2, and 90.9 % respectively. Most children were able to receive vaccines in a time appropriate manner. School-based immunization programs offer a suitable vaccine delivery mechanism for hard-to-reach populations. However, these data suggest overall low vaccine coverage in migrant populations. Further efforts toward improving appropriate vaccine coverage and methods of retaining documentation of vaccination in mobile migrant populations are necessary for improved health.
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 28-10-2011
Abstract: Nucleic acid lification provides the most sensitive and accurate method to detect and identify pathogens. This is primarily useful for epidemiological investigations of malaria because the infections, often with two or more Plasmodium species present simultaneously, are frequently associated with microscopically sub-patent parasite levels and cryptic mixed infections. Numerous distinct equally adequate lification-based protocols have been described, but it is unclear which to select for epidemiological surveys. Few comparative studies are available, and none that addresses the issue of inter-laboratory variability. Blood s les were collected from patients attending malaria clinics on the Thai-Myanmar border. Frozen aliquots from 413 s les were tested independently in two laboratories by nested PCR assay. Dried blood spots on filter papers from the same patients were also tested by the nested PCR assay in one laboratory and by a multiplex PCR assay in another. The aim was to determine which protocol best detected parasites below the sensitivity level of microscopic examination. As expected PCR-based assays detected a substantial number of infected s les, or mixed infections, missed by microscopy (27 and 42 for the most sensitive assay, respectively). The protocol that was most effective at detecting these, in particular mixed infections, was a nested PCR assay with in idual secondary reactions for each of the species initiated with a template directly purified from the blood s le. However, a lesser sensitivity in detection was observed when the same protocol was conducted in another laboratory, and this significantly altered the data obtained on the parasite species distribution. The sensitivity of a given PCR assay varies between laboratories. Although, the variations are relatively minor, they primarily diminish the ability to detect low-level and mixed infections and are sufficient to obviate the main rationale to use PCR assays rather than microscopy or rapid diagnostic tests. The optimal approach to standardise methodologies is to provide PCR template standards. These will help researchers in different settings to ensure that the nucleic acid lification protocols they wish to use provide the requisite level of sensitivity, and will permit comparison between sites.
Publisher: Public Library of Science (PLoS)
Date: 13-06-2006
Publisher: Elsevier BV
Date: 04-1993
DOI: 10.1016/0140-6736(93)92412-M
Abstract: In a prospective electrocardiographic study of Karen patients with acute uncomplicated falciparum malaria, mefloquine (25 mg/kg) had no cardiac effects (n = 53), but halofantrine (72 mg/kg) induced consistent dose-related lengthening of the PR and QT intervals in all 61 patients treated. The likelihood of significant QTc prolongation (by more than 25% or a QTc of 0.55 s1/2 or more) was greater after halofantrine as retreatment following mefloquine failure than as primary treatment (7/10 vs 18/51 relative risk 2.0 [95% Cl 1.1-3.4], p = 0.04). More than 60% of the effect occurred with three doses of halofantrine (24 mg/kg). The arrhythmogenic potential of halofantrine should now be investigated.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2008
Abstract: Plasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine. Chloroquine inhibits the polymerization of haem to inert haemozoin. Free haem monomers are thought to catalyze oxidative damage to the Plasmodium spp. trophozoite, the stage when haemoglobin catabolism is maximal. However preliminary in vitro observations on P. vivax clinical isolates suggest that only ring stages (early trophozoites) are sensitive to chloroquine. In this study, the stage specific action of chloroquine was investigated in synchronous cryopreserved isolates of P. vivax . The in vitro chloroquine sensitivity of paired ring and trophozoite stages from 11 cryopreserved P. vivax clinical isolates from Thailand and two Plasmodium falciparum clones (chloroquine resistant K1 and chloroquine sensitive FC27) was measured using a modified WHO microtest method and fluorometric SYBR Green I Assay. The time each stage was exposed to chloroquine treatment was controlled by washing the chloroquine off at 20 hours after the beginning of treatment. Plasmodium vivax isolates added to the assay at ring stage had significantly lower median IC 50s to chloroquine than the same isolates added at trophozoite stage (median IC 50 12 nM vs 415 nM p 0.01). Although only 36% (4/11) of the SYBR Green I assays for P. vivax were successful, both microscopy and SYBR Green I assays indicated that only P. vivax trophozoites were able to develop to schizonts at chloroquine concentrations above 100 nM. Data from this study confirms the diminished sensitivity of P. vivax trophozoites to chloroquine, the stage thought to be the target of this drug. These results raise important questions about the pharmacodynamic action of chloroquine, and highlight a fundamental difference in the activity of chloroquine between P. vivax and P. falciparum .
Publisher: Wiley
Date: 29-09-2009
DOI: 10.1002/UOG.7350
Publisher: American Society of Tropical Medicine and Hygiene
Date: 07-08-2013
Publisher: Oxford University Press (OUP)
Date: 11-2000
DOI: 10.1016/S0035-9203(00)90235-9
Abstract: Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995-97 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for MAS3 and 67.0% (95% CI 43x3-90x8) (n = 41) for Q7, P = 0x001. The MAS3 regimen was also associated with less gametocyte carriage the average person-gametocyte-weeks for MAS3 was 2.3 (95% CI 0-11) and for Q7 was 46x9 (95% CI 26-78) per 1000 person-weeks, respectively (P < 0.001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently.
Publisher: American Society of Hematology
Date: 05-2014
DOI: 10.1182/BLOOD-2013-12-541698
Abstract: P vivax infected cells rosette exclusively to normocytes. Thus, rosetting does not directly facilitate P vivax merozoite invasion. Glycophorin C (CD236R) mediates vivax malaria parasite rosetting. This finding will help in the search for the P vivax rosette ligand.
Publisher: eLife Sciences Publications, Ltd
Date: 06-12-2022
DOI: 10.7554/ELIFE.83433
Abstract: Tafenoquine is a newly licensed antimalarial drug for the radical cure of Plasmodium vivax malaria. The mechanism of action and optimal dosing are uncertain. We pooled in idual data from 1102 patients and 72 healthy volunteers studied in the pre-registration trials. We show that tafenoquine dose is the primary determinant of efficacy. Under an Emax model, we estimate the currently recommended 300 mg dose in a 60 kg adult (5 mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5 mg/kg (i.e. 450 mg) would result in 90% reduction in the risk of P. vivax recurrence. After adjustment for dose, the tafenoquine terminal elimination half-life, and day 7 methaemoglobin concentration, but not the parent compound exposure, were also associated with recurrence. These results suggest that the production of oxidative metabolites is central to tafenoquine’s hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.
Publisher: Springer Science and Business Media LLC
Date: 10-2003
DOI: 10.1007/S00228-003-0652-9
Abstract: To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil. Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily. The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (+/- SEM) oral clearance (Cl/F) estimates were 313+/-33 ml/h/kg and 1109+/-43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0+/-1.3 l/kg and 22.9+/-1.4 l/kg, and terminal elimination half-life 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria. Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.
Publisher: Public Library of Science (PLoS)
Date: 14-02-2013
Publisher: Oxford University Press (OUP)
Date: 03-2010
DOI: 10.1086/649928
Publisher: Wiley
Date: 24-09-2009
Publisher: Geological Society of London
Date: 15-06-2023
DOI: 10.1144/JGS2022-171
Abstract: The Turkana Basin in NW Kenya and SW Ethiopia hosts remarkable fossil-rich sediments that are central to our understanding of early hominin evolution, with interbedded volcanic tuffs providing critical time markers. However, the resolution of existing Early Pleistocene–Pliocene ages is limited to c. 20–60 kyr, inhibiting the evaluation of climatic and environmental drivers of evolution. We present high-precision, single-feldspar 40 Ar/ 39 Ar age and elemental data for four stratigraphically significant tuffs. These s les exhibit variably dispersed age distributions correlated with feldspar compositional trends, interpreted to indicate the partial retention of inherited 40 Ar related to crustal ‘cold storage’ and rapid melt infiltration preceding eruption. We evaluated various statistical methods and calculated astronomically calibrated Bayesian age estimates of 1879.1 ± 0.6 ka (±2.4 ka including external errors) for the Kay Behrensmeyer Site (KBS)/H2 Tuff, 1837.4 ± 0.9 ka (±2.4 ka) for the Malbe/H4 Tuff, 1357.5 ± 1.8 ka (±2.5 ka) for the Chari/L Tuff and 1315.4 ± 1.9 ka (±2.5 ka) for the Gele Tuff. Our results permit refined age constraints for important early Homo fossils, including the cranium KNM-ER1813 ( Homo habilis ) and various Homo erectus fossils. The KBS Tuff age also provides an important calibration locus for orbital tuning of palaeoclimate proxy records, revealing the complex interplays between palaeoclimate and geological drivers of sedimentation. Supplementary material : The supplementary tables and figures include previously published ages (Table S1), s le and irradiation information (Table S2), electron probe microanalytical results for tuff glasses (Table S3, Figs S2 and S3) and feldspars (Table S4), 40 Ar/ 39 Ar analytical data (Tables S5 and S6, Fig. S4), orbital tuning model parameters (Table S7), a summary of previous and revised hominin ages (Table S8) and a worked Bayesian estimation ex le (Fig. S1) and are available at 0.6084/m9.figshare.c.6602994
Publisher: Elsevier BV
Date: 05-2012
Publisher: Springer Science and Business Media LLC
Date: 14-06-2013
Publisher: Springer Science and Business Media LLC
Date: 22-09-2021
DOI: 10.1186/S12889-021-11749-X
Abstract: Providing at-risk communities with uninterrupted access to early diagnosis and treatment is a key component in reducing malaria transmission and achieving elimination. As programmes approach malaria elimination targets it is critical that each case is tested and treated early, which may present a challenge when the burden of malaria is reduced. In this paper we investigate whether malaria testing rates decline over time and assess the impacts of integrating malaria and non-malaria services on testing rates in the malaria elimination task force (METF) programme in the Kayin state of Myanmar. A retrospective analysis was conducted using weekly collected data on testing rates from a network of more than 1200 malaria posts during the period from 2014 to 2020. To determine whether monthly testing rates changed over the years of programme operations, and whether integrating malaria and non-malaria services impacted these testing rates, we fitted negative binomial mixed-effects regression models to aggregate monthly data, accounting for malaria seasonal variation. In the first year of malaria post operation, testing rates declined, correlating with a decline in attendance by people from outside the malaria post catchment area, but then remained fairly constant (the Rate Ratio (RR) for 2nd versus 1st year open ranged from 0.68 to 0.84 across the four townships included in the analysis, the RR for 3rd to 6th year versus 1st year open were similar, ranging from 0.59–0.78). The implementation of a training programme, which was intended to expand the role of the malaria post workers, had minimal impact on testing rates up to 24 months after training was delivered (RR for integrated versus malaria-only services ranged from 1.00 to 1.07 across METF townships). Despite the decline in malaria incidence from 2014 to 2020, there has been no decline in the malaria testing rate in the METF programme after the establishment of the complete malaria post network in 2016. While the integration of malaria posts with other health services provides benefits to the population, our evaluation questions the necessity of integrated services in maintaining malaria testing rates in areas approaching elimination of malaria.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 06-12-2010
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Society of Tropical Medicine and Hygiene
Date: 1999
Abstract: Parasite genotyping by the polymerase chain reaction was used to distinguish recrudescent from newly acquired Plasmodium falciparum infections in a Karen population resident on the northwestern border of Thailand where malaria transmission is low (one infection erson/year). Plasmodium falciparum infections were genotyped for allelic variation in three polymorphic antigen loci, merozoite surface proteins-1 and -2 (MSP-1 and -2) and glutamaterich protein (GLURP), before and after antimalarial drug treatment. Population genotype frequencies were measured to provide the baseline information to calculate the probability of a new infection with a different or the same genotype to the initial pretreatment isolate. Overall, 38% of the infections detected following treatment had an identical genotype before and up to 121 days after treatment. These post-treatment genotypes were considered recrudescent because of the low (< 5%) probability of repeated occurrence by chance in the same patient. This approach allows studies of antimalarial drug treatment to be conducted in areas of low transmission since recrudescences can be distinguished confidently from newly acquired infections.
Publisher: Wiley
Date: 05-10-2006
DOI: 10.1111/J.1365-3156.2006.01724.X
Abstract: Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.
Publisher: Oxford University Press (OUP)
Date: 02-02-2011
DOI: 10.1093/CID/CIQ249
Publisher: Massachusetts Medical Society
Date: 19-03-2009
DOI: 10.1056/NEJMC090023
Publisher: American Society of Hematology
Date: 14-09-2017
DOI: 10.1182/BLOOD-2017-02-764787
Abstract: Zoonotic P cynomolgi switches red cell tropism for reticulocytes expressing Trf1 (CD71+) and DARC (CD234+). In the human host, P cynomolgi displays an almost identical rheopathobiology to P vivax.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2011
Publisher: eLife Sciences Publications, Ltd
Date: 18-02-2020
DOI: 10.7554/ELIFE.51546
Abstract: In malaria, rosetting is described as a phenomenon where an infected erythrocyte (IRBC) is attached to uninfected erythrocytes (URBC). In some studies, rosetting has been associated with malaria pathogenesis. Here, we have identified a new type of rosetting. Using a step-by-step approach, we identified IGFBP7, a protein secreted by monocytes in response to parasite stimulation, as a rosette-stimulator for Plasmodium falciparum- and P. vivax-IRBC. IGFBP7-mediated rosette-stimulation was rapid yet reversible. Unlike type I rosetting that involves direct interaction of rosetting ligands on IRBC and receptors on URBC, the IGFBP7-mediated, type II rosetting requires two additional serum factors, namely von Willebrand factor and thrombospondin-1. These two factors interact with IGFBP7 to mediate rosette formation by the IRBC. Importantly, the IGFBP7-induced type II rosetting h ers phagocytosis of IRBC by host phagocytes.
Publisher: Informa UK Limited
Date: 2008
Publisher: Elsevier BV
Date: 02-2007
Publisher: Oxford University Press (OUP)
Date: 03-08-2017
Publisher: eLife Sciences Publications, Ltd
Date: 10-08-2021
DOI: 10.7554/ELIFE.62997
Abstract: National Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple s le collection procedures in routine public health procedures. S les from symptomatic patients are processed by SpotMalaria, a high-throughput system that produces a comprehensive set of genotypes comprising several drug resistance markers, species markers and a genomic barcode. GenRe-Mekong delivers Genetic Report Cards, a compendium of genotypes and phenotype predictions used to map prevalence of resistance to multiple drugs. GenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9623 s les from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces, informing decision-making by NMCPs. GenRe-Mekong provides detailed knowledge about drug resistance at a local level, and facilitates data sharing at a regional level, enabling cross-border resistance monitoring and providing the public health community with valuable insights. The project provides a rich open data resource to benefit the entire malaria community. The GenRe-Mekong project is funded by the Bill and Melinda Gates Foundation (OPP11188166, OPP1204268). Genotyping and sequencing were funded by the Wellcome Trust (098051, 206194, 203141, 090770, 204911, 106698/B/14/Z) and Medical Research Council (G0600718). A proportion of s les were collected with the support of the UK Department for International Development (201900, M006212), and Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
Publisher: American Society for Microbiology
Date: 07-2006
DOI: 10.1128/AAC.00040-06
Abstract: A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood s ling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life ( t 1/2 ) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t 1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.
Publisher: Elsevier BV
Date: 05-2016
Publisher: F1000 Research Ltd
Date: 04-10-2018
DOI: 10.12688/GATESOPENRES.12869.1
Abstract: Background: INTERBIO-21 st is Phase II of the INTERGROWTH-21 st Project, the population-based, research initiative involving nearly 70,000 mothers and babies worldwide coordinated by Oxford University and performed by a multidisciplinary network of more than 400 healthcare professionals and scientists from 35 institutions in 21 countries worldwide. Phase I, conducted 2008-2015, consisted of nine complementary studies designed to describe optimal human growth and neurodevelopment, based conceptually on the WHO prescriptive approach. The studies generated a set of international standards for monitoring growth and neurodevelopment, which complement the existing WHO Child Growth Standards. Phase II aims to improve the functional classification of the highly heterogenous preterm birth and fetal growth restriction syndromes through a better understanding of how environmental exposures, clinical conditions and nutrition influence patterns of human growth from conception to childhood, as well as specific neurodevelopmental domains and associated behaviors at 2 years of age. Methods: In the INTERBIO-21 st Newborn Case-Control Study, a major component of Phase II, our objective is to investigate the mechanisms potentially responsible for preterm birth and small for gestational age and their interactions, using deep phenotyping of clinical, growth and epidemiological data and associated nutritional, biochemical, omic and histological profiles. Here we describe the study sites, population characteristics, study design, methodology and standardization procedures for the collection of longitudinal clinical data and biological s les (maternal blood, umbilical cord blood, placental tissue, maternal feces and infant buccal swabs) for the study that was conducted between 2012 and 2018 in Brazil, Kenya, Pakistan, South Africa, Thailand and the UK. Discussion: Our study provides a unique resource for the planned analyses given the range of potentially disadvantageous exposures (including poor nutrition, pregnancy complications and infections) in geographically erse populations worldwide. The study should enhance current medical knowledge and provide new insights into environmental influences on human growth and neurodevelopment.
Publisher: Elsevier BV
Date: 03-2017
Publisher: F1000 Research Ltd
Date: 05-02-2019
DOI: 10.12688/GATESOPENRES.12869.2
Abstract: Background: INTERBIO-21 st is Phase II of the INTERGROWTH-21 st Project, the population-based, research initiative involving nearly 70,000 mothers and babies worldwide coordinated by Oxford University and performed by a multidisciplinary network of more than 400 healthcare professionals and scientists from 35 institutions in 21 countries worldwide. Phase I, conducted 2008-2015, consisted of nine complementary studies designed to describe optimal human growth and neurodevelopment, based conceptually on the WHO prescriptive approach. The studies generated a set of international standards for monitoring growth and neurodevelopment, which complement the existing WHO Child Growth Standards. Phase II aims to improve the functional classification of the highly heterogenous preterm birth and fetal growth restriction syndromes through a better understanding of how environmental exposures, clinical conditions and nutrition influence patterns of human growth from conception to childhood, as well as specific neurodevelopmental domains and associated behaviors at 2 years of age. Methods: In the INTERBIO-21 st Newborn Case-Control Study, a major component of Phase II, our objective is to investigate the mechanisms potentially responsible for preterm birth and small for gestational age and their interactions, using deep phenotyping of clinical, growth and epidemiological data and associated nutritional, biochemical, omic and histological profiles. Here we describe the study sites, population characteristics, study design, methodology and standardization procedures for the collection of longitudinal clinical data and biological s les (maternal blood, umbilical cord blood, placental tissue, maternal feces and infant buccal swabs) for the study that was conducted between 2012 and 2018 in Brazil, Kenya, Pakistan, South Africa, Thailand and the UK. Discussion: Our study provides a unique resource for the planned analyses given the range of potentially disadvantageous exposures (including poor nutrition, pregnancy complications and infections) in geographically erse populations worldwide. The study should enhance current medical knowledge and provide new insights into environmental influences on human growth and neurodevelopment.
Publisher: eLife Sciences Publications, Ltd
Date: 28-06-2021
Publisher: Oxford University Press (OUP)
Date: 09-2000
DOI: 10.1016/S0035-9203(00)90080-4
Abstract: Following a marked decline in the efficacy in vivo of mefloquine between 1990 and 1994, a combination of artesunate (4 mg/kg/d for 3 d) and mefloquine (25 mg/kg) has been used as first line treatment of uncomplicated falciparum malaria in c s for displaced persons located along the north-western border of Thailand. Antimalarial drug susceptibility of fresh isolates of Plasmodium falciparum from this population was evaluated using a radioisotope microdilution assay between 1995 and 1999. In total, 268 isolates were collected, of which 189 were from primary infections and 79 from recrudescent infections. The geometric mean 50% inhibitory concentration (IC50) values from primary infections were: dihydroartemisinin 1.2 ng/mL, artesunate 1.6 ng/mL, artemether 4.8 ng/mL, atovaquone 0.4 ng/mL, lumefantrine 32 ng/mL, chloroquine 149 ng/mL, quinine 354 ng/mL, mefloquine 27 ng/mL and halofantrine 4.1 ng/mL. A significant positive correlation was found between the susceptibility in vitro to artesunate and quinine (r = 0.43, P < 0.001), mefloquine (r = 0.46, P < 0.001), and halofantrine (r = 0.51, P < 0.001). These levels of resistance in vitro are among the highest reported and confirm continuing high level multidrug resistance in this area. Despite intensive use of the combination between 1995 and 1999 there has been a significant improvement in mefloquine sensitivity (P < 0.001) and artesunate sensitivity (P < 0.001). This supports observations in vivo that the combination of artesunate and mefloquine has reversed the previous decline in mefloquine sensitivity.
Publisher: Cold Spring Harbor Laboratory
Date: 31-01-2023
DOI: 10.1101/2023.01.31.526483
Abstract: Radical cure of Plasmodium vivax malaria must include elimination of quiescent ‘hypnozoite’ forms in the liver however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials. A drug repurposing screen reveals antihypertension drugs are active against P. vivax hypnozoites and epigenetic mechanisms play a role in hypnozoite quiescence.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2019
DOI: 10.1186/S12889-019-7825-7
Abstract: This study aims to provide a comprehensive understanding of maternal risk factors, infant risk factors and maternal infant feeding practices among refugees and migrants along the Thailand-Myanmar border. This study employed a mixed-methods approach with two components: (1) cross-sectional survey ( n = 390) and (2) focus group discussions ( n = 63). Participants were chosen from one of three clinics providing antenatal and delivery services for Karen and Burman refugees and migrants along the border. Participants were pregnant women and mother-infant dyads. Refugee and migrant mothers demonstrated high rates of suboptimal breastfeeding and low rates of minimum dietary ersity and acceptable diet. Multivariable regression models showed infant stunting (AOR: 2.08, 95% CI: 1.12, 3.84, p = 0.020) and underweight (AOR: 2.26, 95% CI: 1.17, 4.36, p = 0.015) to have increased odds among migrants, while each 5 cm increase in maternal height had decreased odds of stunting (AOR: 0.50, 95% CI: 0.38, 0.66, p 0.001) and underweight (AOR: 0.64, 95% CI: 0.48, 0.85, p = 0.002). In addition, small-for-gestational-age adjusted for length of gestation, infant age and gender increased odds of infant’s stunting (AOR: 3.42, 95% CI: 1.88, 6.22, p 0.001) and underweight (AOR: 4.44, 95% CI: 2.36, 8.34, p 0.001). Using the Integrated Behavioural Model, focus group discussions explained the cross-sectional findings in characterising attitudes, perceived norms, and personal agency as they relate to maternal nutrition, infant malnutrition, and infant feeding practices. Inadequate infant feeding practices are widespread in refugee and migrant communities along the Thailand-Myanmar border. Risk factors particular to maternal nutrition and infant birth should be considered for future programming to reduce the burden of chronic malnutrition in infants.
Publisher: BMJ
Date: 10-2020
DOI: 10.1136/BMJOPEN-2020-041631
Abstract: A successful pregnancy relies on the interplay of various biological systems. Deviations from the norm within a system or intersystemic interactions may result in pregnancy-associated complications and adverse pregnancy outcomes. Systems biology approaches provide an avenue of unbiased, in-depth phenotyping in health and disease. The molecular signature in pregnancy (MSP) cohort was established to characterise longitudinal, cross-omic trajectories in pregnant women from a resource constrained setting. Downstream analysis will focus on characterising physiological perturbations in uneventful pregnancies, pregnancy-associated complications and adverse outcomes. First trimester pregnant women of Karen or Burman ethnicity were followed prospectively throughout pregnancy, at delivery and until 3 months post partum. Serial high-frequency s ling to assess whole blood transcriptomics and microbiome composition of the gut, vagina and oral cavity, in conjunction with assessment of gene expression and microbial colonisation of gestational tissue, was done for all cohort participants. 381 women with live born singletons averaged 16 (IQR 15–18) antenatal visits (13 094 biological s les were collected). At 5% (19/381) the preterm birth rate was low. Other adverse events such as maternal febrile illness 7.1% (27/381), gestational diabetes 13.1% (50/381), maternal anaemia 16.3% (62/381), maternal underweight 19.2% (73/381) and a neonate born small for gestational age 20.2% (77/381) were more often observed than preterm birth. Results from the MSP cohort will enable in-depth characterisation of cross-omic molecular trajectories in pregnancies from a population in a resource-constrained setting. Moreover, pregnancy-associated complications and unfavourable pregnancy outcomes will be investigated at the same granular level, with a particular focus on population relevant needs such as effect of tropical infections on pregnancy. More detailed knowledge on multiomic perturbations will ideally result in the development of diagnostic tools and ultimately lead to targeted interventions that may disproportionally benefit pregnant women from this resource-limited population. NCT02797327 .
Publisher: Public Library of Science (PLoS)
Date: 15-02-2019
Publisher: Elsevier BV
Date: 03-2014
Publisher: Springer Science and Business Media LLC
Date: 03-05-2012
Publisher: Proceedings of the National Academy of Sciences
Date: 13-03-2017
Abstract: Slow-clearing artemisinin-resistant malaria parasites are now well established in the Greater Mekong Subregion. This large multinational therapy efficacy study incorporating clinical data, molecular drug-resistance markers, and immune profiling aimed to understand how variations in population levels of naturally acquired malarial immunity affect the slow-clearing phenotype, emergence of artemisinin resistance-associated mutations, and assessment of the geographical spread of artemisinin resistance. We found that slow-clearing mutant parasites occur at higher frequencies in areas where immunity is lowest, patients with higher immunity have faster clearance times, and immunity has the greatest effect on clearance in patients with slow-clearing mutant parasites. Immunity plays an important role in the emergence of resistant parasites and can confound the World Health Organization’s phenotype and genotype definitions of artemisinin resistance.
Publisher: Springer Science and Business Media LLC
Date: 14-10-2011
DOI: 10.1038/SREP00118
Publisher: American Society of Tropical Medicine and Hygiene
Date: 09-12-2015
Publisher: Oxford University Press (OUP)
Date: 07-06-2017
Publisher: Public Library of Science (PLoS)
Date: 13-10-2017
Publisher: Springer Science and Business Media LLC
Date: 12-2012
Publisher: Oxford University Press (OUP)
Date: 13-06-2013
DOI: 10.1093/PHE/PHT015
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.2165/00003495-200363060-00006
Abstract: Atovaquone roguanil is a fixed-dose combination tablet of two antimalarial agents and is highly effective for the prevention of Plasmodium falciparum malaria. In combination with proguanil, the ability of atovaquone to inhibit parasitic mitochondrial electron transport is markedly enhanced. Both atovaquone and proguanil are active against hepatic (pre-erythrocytic) stages of P. falciparum, thereby providing causal prophylaxis and eliminating the need to continue post-travel treatment beyond 7 days. Both agents are also active against erythrocytic stages of P. falciparum, thereby providing suppressive prophylaxis. Atovaquone roguanil is highly effective against drug-resistant strains of P. falciparum, and cross-resistance has not been observed between atovaquone and other antimalarial agents. In comparative, randomised clinical trials, there were no cases of P. falciparum malaria in nonimmune adults, adolescents and children (>/=11 kg) visiting malaria-endemic regions for </=28 days and receiving atovaquone roguanil (250/100 mg in adults and dosage based on bodyweight in children /=11 kg) from endemic regions who may carry some immunity to malaria (semi-immune), the prophylactic efficacy rating for atovaquone roguanil based on placebo-controlled trials was 95-100%. Atovaquone roguanil is generally well tolerated by both adults and children. The most common treatment-related adverse events in placebo-controlled trials were headache and abdominal pain, which occurred at a rate similar to that observed with placebo. Atovaquone roguanil therapy was associated with significantly fewer gastrointestinal adverse events than chloroquine plus proguanil, and significantly fewer neuropsychiatric adverse events than mefloquine in nonimmune in iduals. Significantly fewer recipients of atovaquone roguanil discontinued treatment because of adverse events than in iduals receiving chloroquine plus proguanil or mefloquine (p < 0.05). Atovaquone roguanil is a fixed-dose combination antimalarial tablet that provides effective prophylaxis of P. falciparum malaria, including drug-resistant strains. Both atovaquone and proguanil are effective against hepatic stages of P. falciparum, which means that treatment need only continue for 7 days after leaving a malaria-endemic region. Atovaquone roguanil was generally well tolerated and was associated with fewer gastrointestinal adverse events than chloroquine plus proguanil, and fewer neuropsychiatric adverse events than mefloquine. Thus, atovaquone roguanil provides effective prophylaxis of P. falciparum malaria and compared with other commonly used antimalarial agents has an improved tolerability profile, and, overall, a more convenient dosage regimen, particularly in the post-travel period.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2009
Abstract: Analytical approaches for the interpretation of anti-malarial clinical trials vary considerably. The aim of this study was to quantify the magnitude of the differences between efficacy estimates derived from these approaches and identify the factors underlying these differences. Data from studies conducted in Africa and Thailand were compiled and the risk estimates of treatment failure, adjusted and unadjusted by genotyping, were derived by three methods (intention to treat (ITT), modified intention to treat (mITT) and per protocol (PP)) and then compared. 29 clinical trials (15 from Africa and 14 from Thailand) with a total of 65 treatment arms (38 from Africa and 27 from Thailand) were included in the analysis. Of the 15,409 patients enrolled, 2,637 (17.1%) had incomplete follow up for the unadjusted analysis and 4,489 (33.4%) for the adjusted analysis. Estimates of treatment failure were consistently higher when derived from the ITT or PP analyses compared to the mITT approach. In the unadjusted analyses the median difference between the ITT and mITT estimates was greater in Thai studies (11.4% [range 2.1–31.8]) compared to African Studies (1.8% [range 0–11.7]). In the adjusted analyses the median difference between PP and mITT estimates was 1.7%, but ranged from 0 to 30.9%. The discrepancy between estimates was correlated significantly with the proportion of patients with incomplete follow-up p 0.0001. The proportion of studies with a major difference ( 5%) between adjusted PP and mITT was 28% (16/57), with the risk difference greater in African (37% 14/38) compared to Thai studies (11% 2/19). In the African studies, a major difference in the adjusted estimates was significantly more likely in studies in high transmission sites (62% 8/13) compared to studies in moderate transmission sites (24% 6/25) p = 0.035. Estimates of anti-malarial clinical efficacy vary significantly depending on the analytical methodology from which they are derived. In order to monitor temporal and spatial trends in anti-malarial efficacy, standardized analytical tools need to be applied in a transparent and systematic manner.
Publisher: American Society for Microbiology
Date: 11-2004
DOI: 10.1128/AAC.48.11.4271-4280.2004
Abstract: To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in in idual trials) but could be used to predict the true failure rate if either parasite genotyping was performed ( r 2 = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.
Publisher: Public Library of Science (PLoS)
Date: 03-2021
DOI: 10.1371/JOURNAL.PNTD.0009219
Abstract: Soil-transmitted helminth (STH) infections are widespread in tropical and subtropical regions. While many STH infections are asymptomatic, vulnerable populations such as pregnant women face repercussions such as aggravation of maternal anaemia. However, data on prevalence and the effect of STH infections in pregnancy are limited. The aim of this analysis was to describe the burden of STH infections within and between populations of pregnant women from a local refugee c to a mobile migrant population, and to explore possible associations between STH infection and pregnancy outcomes. This is a retrospective review of records from pregnant refugee and migrant women who attended Shoklo Malaria Research Unit antenatal care (ANC) clinics along the Thailand-Myanmar border between July 2013 and December 2017. Inclusion was based on provision of a stool s le during routine antenatal screening. A semi-quantitative formalin concentration method was employed for examination of faecal s les. The associations between STH mono-infections and maternal anaemia and pregnancy outcomes (i.e., miscarriage, stillbirth, preterm birth, and small for gestational age) were estimated using regression analysis. Overall, 12,742 pregnant women were included, of whom 2,702 (21.2%) had a confirmed infection with either Ascaris lumbricoides , hookworm, Trichuris trichiura , or a combination of these. The occurrence of STH infections in the refugee population (30.8% 1,246/4,041) was higher than in the migrant population (16.7% 1,456/8,701). A . lumbricoides was the predominant STH species in refugees and hookworm in migrants. A . lumbricoides and hookworm infection were associated with maternal anaemia at the first ANC consultation with adjusted odds ratios of 1.37 (95% confidence interval (CI) 1.08–1.72) and 1.65 (95% CI 1.19–2.24), respectively. Pregnant women with A . lumbricoides infection were less likely to miscarry when compared to women with negative stool s les (adjusted hazard ratio 0.63, 95% CI 0.48–0.84). STH infections were not significantly associated with stillbirth, preterm birth or being born too small for gestational age. One in five pregnant women in this cohort had STH infection. Association of STH infection with maternal anaemia, in particular in the event of late ANC enrolment, underlines the importance of early detection and treatment of STH infection. A potential protective effect of A . lumbricoides infection on miscarriage needs confirmation in prospective studies.
Publisher: MDPI AG
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 15-04-2015
Publisher: Wiley
Date: 08-2000
Publisher: Public Library of Science (PLoS)
Date: 16-11-2010
Publisher: Public Library of Science (PLoS)
Date: 16-11-2010
Publisher: American Society of Hematology
Date: 29-09-2011
DOI: 10.1182/BLOOD-2011-04-348748
Abstract: Currently, there are no reliable RBC invasion assays to guide the discovery of vaccines against Plasmodium vivax, the most prevalent malaria parasite in Asia and South America. Here we describe a protocol for an ex vivo P vivax invasion assay that can be easily deployed in laboratories located in endemic countries. The assay is based on mixing enriched cord blood reticulocytes with matured, trypsin-treated P vivax schizonts concentrated from clinical isolates. The reliability of this assay was demonstrated using a large panel of P vivax isolates freshly collected from patients in Thailand.
Publisher: Bentham Science Publishers Ltd.
Date: 2006
DOI: 10.2174/157488606775252584
Abstract: In this review we examine the available information on the safety of antimalarials in pregnancy, from both animal and human studies. The antimalarials that can be used in pregnancy include (1) chloroquine, (2) amodiaquine, (3) quinine, (4) azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine, (7) dapsone-chlorproguanil, (8) artemisinin derivatives, (9) atovaquone-proguanil and (10) lumefantrine. Antimalarial drugs that should not be used in pregnancy including (1) halofantrine, (2) tetracycline/doxycycline, and (3) primaquine. There are few studies in humans on the pharmacokinetics, safety and efficacy of antimalarials in pregnancy. This is because pregnant women are systematically excluded from clinical trials. The absence of adequate safety data, especially in the first trimester, is an important obstacle to developing treatment strategies. The pharmacokinetics of most antimalarial drugs are also modified in pregnancy and dosages will need to be adapted. Other factors, including HIV status, drug interactions with antiretrovirals, the influence of haematinics and host genetic polymorphisms may influence safety and efficacy. For these reasons there is an urgent need to assess the safety and efficacy of antimalarial treatments in pregnancy, including artemisinin based combination therapies.
Publisher: Wiley
Date: 13-02-2012
Publisher: Public Library of Science (PLoS)
Date: 02-04-2013
Publisher: F1000 Research Ltd
Date: 16-01-2023
DOI: 10.12688/WELLCOMEOPENRES.18681.1
Abstract: We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 s les from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot s les that were sequenced after selective whole genome lification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show ex les of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2012
Abstract: Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax . Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low ( .5 mg/kg- 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4–6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13) p 0.0001). Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.
Publisher: F1000 Research Ltd
Date: 23-11-2018
DOI: 10.12688/WELLCOMEOPENRES.14767.2
Abstract: Background: Screening and monitoring serum bilirubin (SBR) in neonates is crucial to prevent neonatal hyperbilirubinemia (NH)-associated morbidity and mortality worldwide. A lack of resources is often a barrier for measuring SBR in developing countries. Reliable, cost-effective, easy to use point-of-care (POC) SBR tests are needed. This study aimed to evaluate the technical accuracy and usability of the Bilistick System (BS), a new bilirubin POC test, in a tropical setting. Methods: This was a mixed-methods study, including laboratory validation of the BS, direct observation of technical procedures as performed by the midwives and midwives’ assessment of the device’s easiness of use through focus group discussions (FGD) and a self-administered questionnaire. The study was conducted in a field clinic of the Shoklo Malaria Research Unit along the Thailand-Myanmar border between January and December 2017. Results: A total of 173 s les were tested at a median age of 4 days. BS generated an error message—providing no SBR readout—in 48.6% of the tests performed. For the tests that yielded a result, the correlation coefficient (95% CI) between BS and routine laboratory bilirubinometer SBR was 0.87 (0.77-0.93). The accuracy decreased with increasing haematocrit and at higher humidity (≥75%). Direct observation of the operators using the device and analysis of the focus group discussions and questionnaires indicated that the BS was considered easy to use and required limited training. Conclusions: This evaluation showed that the BS, in its current formulation, does not provide reliable results for measuring SBR in a tropical, low-resource setting but has acceptable usability features.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2019
Publisher: Oxford University Press (OUP)
Date: 05-2003
DOI: 10.1016/S0035-9203(03)90140-4
Abstract: Nutritional deficiency and malaria are 2 major causes of anaemia during pregnancy in tropical areas. The relationship between anaemia, its treatment with iron and folate, and malaria was studied in a prospective cohort of 2112 pregnant Karen women on the north-western border of Thailand between 1993 and 1997. The development of Plasmodium vivax malaria was associated with a past mean haematocrit > 30% (hazard ratio = 1.5, 95% CI 1.2-2, P = 0.001) and recent (< or = 30 d) iron and folate supplementation (hazard ratio = 1.7, 95% CI 1.1-2.6, P = 0.01). There were no associations with P. falciparum infections. Plasmodium vivax has a predilection for young erythrocytes, and these results suggest that pregnant women with larger numbers of circulating young red cells are at greater risk of developing P. vivax malaria. In P. vivax-endemic areas, systematic iron and folate supplementation confers both benefit and risk in pregnancy.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 02-07-2012
Publisher: F1000 Research Ltd
Date: 04-09-2018
DOI: 10.12688/WELLCOMEOPENRES.14767.1
Abstract: Background: Screening and monitoring serum bilirubin (SBR) in neonates is crucial to prevent neonatal hyperbilirubinemia (NH)-associated morbidity and mortality worldwide. A lack of resources is often a barrier for measuring SBR in developing countries. Reliable, cost-effective, easy to use point-of-care (POC) SBR tests are needed. This study aimed to evaluate the technical accuracy and usability of the Bilistick System (BS), a new bilirubin POC test, in a tropical setting. Methods: This was a mixed-methods study, including laboratory validation of the BS, direct observation of technical procedures as performed by the midwives and midwives’ assessment of the device’s easiness of use through focus group discussions (FGD) and a self-administered questionnaire. The study was conducted in a field clinic of the Shoklo Malaria Research Unit along the Thailand-Myanmar border between January and December 2017. Results: A total of 173 s les were tested at a median age of 4 days. BS generated an error message—providing no SBR readout—in 48.6% of the tests performed. For the tests that yielded a result, the correlation coefficient (95% CI) between BS and routine laboratory bilirubinometer SBR was 0.87 (0.77-0.93). The accuracy decreased with increasing haematocrit and at higher humidity (≥75%). Direct observation of the operators using the device and analysis of the focus group discussions and questionnaires indicated that the BS was considered easy to use and required limited training. Conclusions: This evaluation showed that the BS, in its current formulation, does not provide reliable results for measuring SBR in a tropical, low-resource setting but has acceptable usability features.
Publisher: Oxford University Press (OUP)
Date: 15-10-2003
DOI: 10.1086/378678
Publisher: Springer Science and Business Media LLC
Date: 15-04-2020
DOI: 10.1186/S12888-020-02572-6
Abstract: Perinatal depression is a significant contributor to maternal morbidity and mortality globally. Migrant women, particularly those living in low- and middle-income settings, represent a particularly vulnerable group due to stressors experienced before, during and after migration. The vast majority of global migration flows occurring within and between low- and middle-income regions, yet existing evidence focuses predominantly on migrants in high-income destinations. This study aimed to redress this significant gap in the evidence by determining the prevalence and determinants of perinatal depression among migrant women on the Thai-Myanmar border. A cohort of labour migrant and refugee women was followed-up from the first trimester of pregnancy to one month post-partum. Depression status was assessed in the first, second and third trimesters of pregnancy and at one month post-partum using the Structured Clinical Interview for the Diagnosis of DSM-IV Disorders. Women diagnosed with depression had immediate access to care. Data on potential demographic, social and clinical associated factors was collected using a questionnaire. Prevalence and incidence of any depressive disorder and moderate-severe depressive disorder was calculated. Univariable and multivariable logistic regression using complete case analysis was used to estimate odds ratios (OR) of association between exposure variables and depression status. Five hundred sixty-eight women participated. Period prevalence (from first trimester of pregnancy to one month post-partum) of moderate-severe perinatal depression was 18.5% (95% CI 15.4–21.9%). Overall, 15.4% (95% CI 11.8–19.6%) of women developed new-onset moderate-severe depression during the study period. Forty-two participants received treatment for depression. Risk factors were interpersonal violence (OR 4.5 95% CI 1.9–11.1) history of trauma (OR 2.4 95% CI 1.4–4.3) self-reported history of depression (OR 2.3 95% CI 1.2–4.2) labour migrant status (OR 2.1 95% CI 1.1–4.0) low social support (OR 2.1 95% CI 1.1–3.7) and maternal age (OR 1.1 per year 95% CI 1.0–1.1). Limitations of the study include that culturally specific manifestations of depression may have been missed. Perinatal depression represents a significant burden among migrant women on the Thai-Myanmar border. Programmes to address the determinants along with early case identification and effective treatment and referral systems are key to addressing perinatal depression in this low-resource setting.
Publisher: Cold Spring Harbor Laboratory
Date: 30-01-2021
DOI: 10.1101/2021.01.27.428390
Abstract: The emergence of artemisinin (ART) resistance in Plasmodium falciparum parasites, driven by K13 mutations, has led to widespread antimalarial treatment failure in Southeast Asia. In Africa, our genotyping of 3,299 isolates confirms the emergence of the K13 R561H variant in Rwanda and reveals the continuing dominance of wild-type K13 across 11 countries. We show that this mutation, along with M579I and C580Y, confers varying degrees of in vitro ART resistance in African parasites. C580Y and M579I cause substantial fitness costs, which may counter-select against their dissemination in high-transmission settings. We also define the impact of multiple K13 mutations on ART resistance and fitness in multiple Southeast Asian strains. ART susceptibility is unaltered upon editing point mutations in ferrodoxin or mdr2, earlier resistance markers. These data point to the lack of an evident biological barrier to mutant K13 mediating ART resistance in Africa, while identifying their detrimental impact on parasite growth.
Publisher: Springer Science and Business Media LLC
Date: 20-10-2006
DOI: 10.1007/S00228-006-0199-7
Abstract: To determine the pharmacokinetic properties of artemether and lumefantrine (AL) in pregnant women with recrudescent uncomplicated multi-drug resistant falciparum malaria. Pregnant women who had recurrence of parasitaemia following 7 days supervised quinine treatment were treated with AL. Serial blood s les were taken over a 7-day period, and pharmacokinetic parameters were estimated. For lumefantrine, these data were compared in a population pharmacokinetic model with data from non-pregnant, mainly male adults with acute malaria. The pregnant women (five in the second trimester and eight in the third trimester) had lower concentrations of artemether, dihydroartemisinin and lumefantrine, and the elimination of lumefantrine in pregnant women was more rapid than reported previously in non-pregnant adults. Pregnancy is associated with reduced plasma concentrations of both artemether and lumefantrine. This is likely to be of therapeutic significance as plasma concentrations of lumefantrine, after elimination of artemether, are an important determinant of cure. Further studies are needed to determine the optimum dose regimen of artemether-lumefantrine in pregnancy.
Publisher: Public Library of Science (PLoS)
Date: 24-07-2013
Publisher: Springer Science and Business Media LLC
Date: 10-02-2016
DOI: 10.1038/SREP20859
Abstract: During pregnancy immunolglobulin G (IgG) antibodies are transferred from mother to neonate across the placenta. Studies in high transmission areas have shown transfer of P. falciparum -specific IgG, but the extent and factors influencing maternal-foetal transfer in low transmission areas co-endemic for both P. falciparum and P. vivax are unknown. Pregnant women were screened weekly for Plasmodium infection. Mother-neonate paired serum s les at delivery were tested for IgG to antigens from P. falciparum , P. vivax and other infectious diseases. Antibodies to malarial and non-malarial antigens were highly correlated between maternal and neonatal s les (median [range] spearman ρ = 0.78 [0.57–0.93]), although Plasmodium spp. antibodies tended to be lower in neonates than mothers. Estimated gestational age at last P. falciparum infection, but not P. vivax infection, was positively associated with antibody levels in the neonate ( P. falciparum merozoite, spearman ρ median [range] 0.42 [0.33–0.66], Pf VAR2CSA 0.69 P. vivax ρ = 0.19 [0.09–0.3]). Maternal-foetal transfer of anti-malarial IgG to Plasmodium spp. antigens occurs in low transmission settings. P. vivax IgG acquisition is not associated with recent exposure unlike P. falciparum IgG, suggesting a difference in acquisition of antibodies. IgG transfer is greatest in the final weeks of pregnancy which has implications for the timing of future malaria vaccination strategies in pregnant women.
Publisher: Elsevier BV
Date: 11-2010
Publisher: Public Library of Science (PLoS)
Date: 17-06-2022
DOI: 10.1371/JOURNAL.PGPH.0000475
Abstract: Very high unconjugated bilirubin plasma concentrations in neonates (neonatal hyperbilirubinaemia NH) may cause neurologic damage (kernicterus). Both increased red blood cell turn-over and immaturity of hepatic glucuronidation contribute to neonatal hyperbilirubinaemia. The incidence of NH requiring phototherapy during the first week of life on the Thailand-Myanmar border is high (approximately 25%). On the Thailand-Myanmar border we investigated the contribution of genetic risk factors to high bilirubin levels in the first month of life in 1596 neonates enrolled in a prospective observational birth cohort study. Lower gestational age ( weeks), mutations in the genes encoding glucose-6-phosphate dehydrogenase (G6PD) and uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1 were identified as the main independent risk factors for NH in the first week, and for prolonged jaundice in the first month of life. Population attributable risks (PAR%) were 61.7% for lower gestational age, 22.9% for hemi or homozygous and 9.9% for heterozygous G6PD deficiency respectively, and 6.3% for UGT1A1*6 homozygosity. In neonates with an estimated gestational age ≥ 38 weeks, G6PD mutations contributed PARs of 38.1% and 23.6% for “early” (≤ 48 hours) and “late” (49–168 hours) NH respectively. For late NH, the PAR for UGT1A1*6 homozygosity was 7.7%. Maternal excess weight was also a significant risk factor for “early” NH while maternal mutations on the beta-globin gene, prolonged rupture of membranes, large haematomas and neonatal sepsis were risk factors for “late” NH. For prolonged jaundice during the first month of life, G6PD mutations and UGT1A1*6 mutation, together with lower gestational age at birth and presence of haematoma were significant risk factors. In this population, genetic factors contribute considerably to the high risk of NH. Diagnostic tools to identify G6PD deficiency at birth would facilitate early recognition of high risk cases.
Publisher: MDPI AG
Date: 15-04-2021
DOI: 10.3390/TROPICALMED6020051
Abstract: Intestinal helminth infections are the most prevalent neglected tropical diseases, predominantly affecting rural and marginalised populations. The mainstay of diagnosis is the microscopic examination of faecal s les to detect parasites in the form of eggs, larvae and cysts. In an effort to improve the standard of care, the comparative accuracy in detecting helminth infections of the hitherto used formalin-based concentration method (FC) was compared to a previously developed formalin ethyl-acetate-based concentration technique (FECT), prior to the systematic deployment of the latter at a research and humanitarian unit operating on the Thailand–Myanmar border. A total of 693 faecal s les were available for the comparison of the two diagnostic methods. The FECT was superior in detecting hookworm, Trichuris trichiura and small liver flukes. Interestingly, there was no significant difference for Ascaris lumbricoides, possibly due to the high observed egg density. Despite the minor increase in material cost and the fact that the FECT is somewhat more time consuming, this method was implemented as the new routine technique.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Elsevier BV
Date: 09-2004
Publisher: Springer Science and Business Media LLC
Date: 02-06-2020
DOI: 10.1186/S12916-020-01592-Z
Abstract: Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. In idual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection. A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and 37.0 weeks), small for gestational age (SGA, birthweight of 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013. Of the 22 eligible studies ( n = 5015), IPD from16 studies were shared, representing 95.0% ( n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine ( n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine ( n = 1087), artesunate-amodiaquine ( n = 775), artesunate-mefloquine ( n = 965), and dihydroartemisinin-piperaquine ( n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p 0.001). The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2018
DOI: 10.1038/S41467-018-04295-5
Abstract: The development of malaria parasites throughout their various life cycle stages is coordinated by changes in gene expression. We previously showed that the three-dimensional organization of the Plasmodium falciparum genome is strongly associated with gene expression during its replication cycle inside red blood cells. Here, we analyze genome organization in the P. falciparum and P. vivax transmission stages. Major changes occur in the localization and interactions of genes involved in pathogenesis and immune evasion, host cell invasion, sexual differentiation, and master regulation of gene expression. Furthermore, we observe reorganization of subtelomeric heterochromatin around genes involved in host cell remodeling. Depletion of heterochromatin protein 1 (PfHP1) resulted in loss of interactions between virulence genes, confirming that PfHP1 is essential for maintenance of the repressive center. Our results suggest that the three-dimensional genome structure of human malaria parasites is strongly connected with transcriptional activity of specific gene families throughout the life cycle.
Publisher: Blue Eyes Intelligence Engineering and Sciences Engineering and Sciences Publication - BEIESP
Date: 30-11-2019
DOI: 10.35940/IJRTE.B2530.118419
Abstract: recently, a rapidly increasing type of education that is mostly adopted by higher education in developed countries is known as E-learning. The aim of the research was to evaluating students’ satisfaction of e-Learning. In the current research, both the theory of technology acceptance model (TAM) and the method of employed structural equation modelling (SEM) with Smart PLS were used to examine the process of students' adoption. It has been found that the learning satisfaction was positively influenced by the perceived ease of use (PEOU), perceived usefulness (PU) and intention to use (IU) as witnessed among university students. Significant and positive perceptions towards e-learning and intend to practice it by university students in Malaysia have been observed by this research.
Publisher: Public Library of Science (PLoS)
Date: 04-01-2013
Publisher: Elsevier BV
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 08-10-2012
Abstract: Blood s les collected in epidemiological and clinical investigations and then stored, often at room temperature, as blood spots dried on a filter paper have become one of the most popular source of material for further molecular analyses of malaria parasites. The dried blood spots are often archived so that they can be used for further retrospective investigations of parasite prevalence, or as new genetic markers come to the fore. However, the suitability of the template obtained from dried blood spots that have been stored for long periods for DNA lification is not known. DNA from 267 archived blood spots collected over a period of 12 years from persons with microscopically confirmed Plasmodium falciparum infection was purified by one of two methods, Chelex and Qiagen columns. These templates were subjected to highly sensitive nested PCR lification targeting three parasite loci that differ in length and/or copy number. When a 1.6 kb fragment of the parasites’ small subunit ribosomal RNA was targeted (primary lification), the efficiency of P. falciparum detection decreased in s les archived for more than six years, reaching very low levels for those stored for more than 10 years. Positive lification was generally obtained more often with Qiagen-extracted templates. P. falciparum could be detected in 32 of the 40 negative Qiagen-extracted templates when a microsatellite of about 180 bp was targeted. The remaining eight s les gave a positive lification when a small region of 238 bp of the higher copy number (20 to 200) mitochondrial genome was targeted. The average length of DNA fragments that can be recovered from dried blood spots decreases with storage time. Recovery of the DNA is somewhat improved, especially in older s les, by the use of a commercial DNA purification column, but targets larger than 1.5 kb are unlikely to be present 10 years after the initial blood collection, when the average length of the DNA fragments present is likely to be around a few hundred bp. In conclusion, the utility of archived dried blood spots for molecular analyses decreases with storage time.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2017
Publisher: SAGE Publications
Date: 2007
DOI: 10.1177/026010600701800402
Abstract: Background: Lower proportions of docosahexaenoic acid (DHA) and total n-3 metabolites have been reported in breast milk of European, Australian and North American women compared with milk of mothers from non-Western countries. This difference is not always explained by intakes of marine products. Objective: We investigated the possibility that the relative composition of DHA and total n-3 metabolites in breast milk of non-Western mothers with low fat intakes is higher than the levels commonly reported in their Western counterparts. Subjects: Mature milk of refugee Karen women from two different c s in Thailand (n = 26 and n = 53), and transition milk from urban Korean mothers (n = 12) in Seoul was collected. In common with their respective community, the mothers have low fat intake, which is predominately of plant origin. Results: The percentage levels of DHA and n-3 metabolites in the milk of the Karen mothers were 0.52 ± 0.14 and 0.85 ± 0.24 (c 1) and 0.54 ± 0.22 and 0.92 ± 0.42 (c 2). In the Korean milk, DHA was 0.96 ± 0.21 and total n-3 metabolites 1.51 ± 0.3. Conclusion: We postulate that the levels of DHA and total n-3 metabolites may be compromised in breast milk of mothers on the Western high fat diet. This calls into question the use of DHA composition of such milk as a reference for the formulation of milk designed, for infant feed or, to test the function of DHA in neuro-visual development.
Publisher: Wiley
Date: 06-2003
Publisher: Elsevier BV
Date: 02-2007
Publisher: Public Library of Science (PLoS)
Date: 07-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9LC00921C
Abstract: An intrahepatic Plasmodium vivax liver stage schizont and hypnozoite develop in a microfeature-based, 384-well culture system for primary human hepatocytes.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2012
Publisher: Research Square Platform LLC
Date: 25-08-2020
DOI: 10.21203/RS.3.RS-60017/V1
Abstract: Background Mass drug administration (MDA) has received growing interest to accelerate the elimination of multi-drug resistant malaria in the Greater Mekong Subregion. The potential effectiveness of delivering targeted MDA was demonstrated in a recent intervention in Kayin State, Myanmar. Policymakers and funders need to know what resources are required if MDA is to be included in elimination packages beyond existing malaria interventions. Methods We used financial data from a malaria elimination initiative, conducted in Kayin State, to estimate the programmatic costs of the MDA component using a micro-costing approach. Three activities (community engagement, identification of villages for MDA, and conducting mass treatment in target villages) were evaluated. We then estimate the programmatic costs of implementing targeted MDA to support P . falciparum malaria elimination in Kayin State. A costing tool was developed to aid future analyses. Results The cost of delivering MDA within an integrated malaria elimination initiative in Eastern Kayin State was approximately US$ 910 000. The cost per person reached for MDA was US$ 2·5. Conclusion This cost analysis can assist policy makers in determining the resources required to clear malaria parasite reservoirs. The analysis demonstrated the value of using financial data from research activities to predict programmatic implementation costs of MDA in different numbers of target villages.
Publisher: Elsevier BV
Date: 08-2004
DOI: 10.1016/J.TMAID.2004.03.008
Abstract: Malaria in pregnancy contributes to significant maternal and foetal mortality and morbidity in women in the tropics. Adverse effects for non-immune travellers are potentially devastating for mother and foetus. Women travellers should always be strongly advised against visiting malarious areas if they are pregnant or intend to get pregnant. Chemoprophylactic and treatment options for pregnant women (or those planning to conceive) are extremely limited and lag behind what can currently be offered to non-pregnant travellers. This is because of spread of multi-resistant strains of P. falciparum. Personal protection from malaria vectors remains essential. Mosquito-net and skin repellents (DEET (20%)) are effective. Diagnosis of malaria in travellers is difficult and is more likely to be missed in pregnant travellers due to lower parasitaemia. Pregnant women can succumb rapidly to severe malaria. Should the returned traveller survive an episode of malaria in pregnancy and go on to deliver, the adverse effects on the infant are potentially irreversible. These risks need to be clearly communicated.
Publisher: Informa UK Limited
Date: 09-2002
DOI: 10.1179/027249302125002029
Abstract: Research assessing the neurological development of infants in developing countries is scanty as no suitable standardised tests are available for field-use in constrained circumstances. We describe the development and application of two simple assessments. Firstly, we aimed to develop a test suitable for assessing acute neurological disturbances caused by such erse effects as infections, drugs or toxins. This test (Shoklo Neurological Test) is aimed at infants between 9 and 36 months. The second test (Shoklo Developmental Test) is aimed not only to follow the evolution of the signs tested initially in the acute phase but also to evaluate later neurodevelopmental sequelae which might be caused by the same events. The latter test is suitable for infants aged from 3 to 12 months. Both tests can be performed easily in non-optimal conditions. The examinations were tested in a cohort of infants from a Karen refugee c and administered in a rural setting by health workers, after appropriate training. In order to validate the tests we also applied them to a cohort of London infants. The Griffiths Developmental Scales were applied in the same infants and both the Shoklo Neurological and the Shoklo Developmental Tests showed good correlation with this standardised neurodevelopmental assessment.
Publisher: Public Library of Science (PLoS)
Date: 06-06-2011
Publisher: Oxford University Press (OUP)
Date: 06-2006
DOI: 10.1086/503423
Publisher: Oxford University Press (OUP)
Date: 2011
Publisher: Oxford University Press (OUP)
Date: 16-06-2016
DOI: 10.1093/CID/CIW388
Publisher: Public Library of Science (PLoS)
Date: 14-05-2020
Publisher: Springer Science and Business Media LLC
Date: 04-11-2013
Publisher: Informa UK Limited
Date: 16-03-2016
DOI: 10.1080/08870446.2016.1146719
Abstract: The current article details a position statement and recommendations for future research and practice on planning and implementation intentions in health contexts endorsed by the Synergy Expert Group. The group comprised world-leading researchers in health and social psychology and behavioural medicine who convened to discuss priority issues in planning interventions in health contexts and develop a set of recommendations for future research and practice. The expert group adopted a nominal groups approach and voting system to elicit and structure priority issues in planning interventions and implementation intentions research. Forty-two priority issues identified in initial discussions were further condensed to 18 key issues, including definitions of planning and implementation intentions and 17 priority research areas. Each issue was subjected to voting for consensus among group members and formed the basis of the position statement and recommendations. Specifically, the expert group endorsed statements and recommendations in the following areas: generic definition of planning and specific definition of implementation intentions, recommendations for better testing of mechanisms, guidance on testing the effects of moderators of planning interventions, recommendations on the social aspects of planning interventions, identification of the preconditions that moderate effectiveness of planning interventions and recommendations for research on how people use plans.
Publisher: F1000 Research Ltd
Date: 21-05-2018
DOI: 10.12688/WELLCOMEOPENRES.14613.1
Abstract: Background: Currently there are more adolescents (10-19 years old) and young adults (20-24 years old) than ever. Reproductive health among this age group is often overlooked, although it can have a profound impact on the future. This is especially the case in conflict zones and refugee settings, where there is a heightened need for reproductive health care, and where both the resources and possibility for data collation are usually limited. Methods: Here we report on pregnancies, birth outcomes and risk factors for repeat pregnancies among adolescent and young adult refugees and migrants from antenatal clinics on the Thailand-Myanmar border across a 30 year time span. Results: Pregnancy and fertility rates were persistently high. Compared with 20-24-year-olds, 15-19-year-olds who reported being unable to read had 2.35 (CI: 1.97 – 2.81) times the odds for repeat pregnancy (gravidity ). In primigravidae, the proportion of small for gestational age (SGA) and preterm births (PTB), and neonatal deaths (NND) decreased with increasing maternal age (all p .001). After adjustment, this association retained significance for PTB (cut-off point, ≤18 years) but not for SGA and NND. Conclusions: There is considerable room for improvement in adolescent pregnancy rates in these border populations, and educational opportunities may play a key role in effective interventions.
Publisher: Oxford University Press (OUP)
Date: 03-2001
Publisher: Wiley
Date: 31-05-2013
DOI: 10.1111/DEWB.12031
Abstract: It has been suggested that community advisory boards (CABs) can play a role in minimising exploitation in international research. To get a better idea of what this requires and whether it might be achievable, the paper first describes core elements that we suggest must be in place for a CAB to reduce the potential for exploitation. The paper then examines a CAB established by the Shoklo Malaria Research Unit under conditions common in resource-poor settings - namely, where in iduals join with a very limited understanding of disease and medical research and where an existing organisational structure is not relied upon to serve as the CAB. Using the Tak Province Border Community Ethics Advisory Board (T-CAB) as a case study, we assess the extent to which it might be able to take on a role minimising exploitation were it to decide to do so. We investigate whether, after two years in operation, T-CAB is capable of assessing clinical trials for exploitative features and addressing those found to have them. The findings show that, although T-CAB members have gained knowledge and developed capacities that are foundational for one-day taking on a role to reduce exploitation, their ability to critically evaluate studies for the presence of exploitative elements has not yet been strongly demonstrated. In light of this ex le, we argue that CABs may not be able to perform such a role for a number of years after initial formation, making it an unsuitable responsibility for many short-term CABs.
Publisher: Oxford University Press (OUP)
Date: 15-08-2005
DOI: 10.1086/432011
Abstract: Dihydroartemisinin-piperaquine (DP) is a fixed-combination antimalarial drug increasingly deployed in Southeast Asia. The current regimen involves 4 doses given over 3 days. Simplification of the dose regimen should facilitate treatment adherence and thereby increase effectiveness. In a randomized, controlled, 3-arm trial conducted along the northwestern border of Thailand, the standard 4-dose course of DP (DP4) was compared to an equivalent dose given as a once-daily regimen (DP3) and to the standard treatment of mefloquine-artesunate (MAS3). A total of 499 patients were included in the study. Times to fever and parasite clearance were similar in all groups. The PCR genotyping-adjusted cure rates at day 63 after treatment initiation were 95.7% (95% confidence interval [95% CI], 92.2%-98.9%) for MAS3, 100% for DP4, and 99.4% (95% CI, 98.1%-100%) for DP3. The DP4 and DP3 cure rates were significantly higher than that for MAS3 (P=.008 and P=.03, respectively). All regimens were well tolerated. There were 3 deaths (1 in the MAS3 group and 2 in the DP3 group), all of which were considered to be unrelated to treatment. Rates of other adverse events were comparable between the groups, except for diarrhea, which was more common in the DP4 group (P=.05 vs. the MAS3 group). A once-daily, 3-dose regimen of DP is a highly efficacious treatment for multidrug-resistant falciparum malaria. This simple, safe, and relatively inexpensive fixed combination could become the treatment of choice for falciparum malaria.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2013
DOI: 10.1038/NG.2624
Publisher: Public Library of Science (PLoS)
Date: 09-07-2020
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.IJPARA.2015.08.003
Abstract: The invasion of CD71+ reticulocytes by Plasmodium vivax is a crucial yet poorly characterised event. The application of flow cytometry to ex vivo invasion assays promises to facilitate the quantitative analysis of P. vivax reticulocyte invasion. However, current protocols suffer from a low level of sensitivity due to the absence of a particular design for P. vivax cell tropism. Importantly, merozoite invasion into contaminating red blood cells from the schizont inoculum (auto-invasion) may confound the analysis. Here we present a stable two-color flow cytometry assay for the accurate quantification of P. vivax merozoite invasion into intracellularly labelled CD71+ reticulocytes. Various enzymatic treatments, antibodies and invasion inhibitory molecules were used to successfully demonstrate the utility of this method. Fluorescent labelling of red blood cells did not affect the invasion and early intra-erythrocytic development of P. vivax. Importantly, this portable field assay allows for the economic usage of limited biological material (parasites and reticulocytes) and the intracellular labeling of the target cells reduces the need for highly purified schizont inoculums. This assay will facilitate the study of P. vivax merozoite biology and the testing of vaccine candidates against vivax malaria.
Publisher: Oxford University Press (OUP)
Date: 05-2004
Publisher: Proceedings of the National Academy of Sciences
Date: 17-12-2012
Abstract: The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum -specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.
Publisher: Oxford University Press (OUP)
Date: 09-2001
Abstract: Malaria during pregnancy reduces birth weight, and low birth weight is a major determinant of infant mortality. The authors estimated the impact of malaria during pregnancy on infant mortality in a Karen population living in Thailand. Between 1993 and 1996, a cohort of 1,495 mothers and their infants was followed weekly from admission of the mother to antenatal clinics until the first birthday of the infant. Both falciparum malaria and vivax malaria during pregnancy were associated with low birth weight but did not shorten gestation. Febrile illness in the week before delivery was associated with premature birth. Preterm and full-term low birth weight and fever in the week before delivery were associated with neonatal mortality. Maternal fevers close to term were also associated with the deaths of infants aged between 1 and 3 months, whereas no risk factors could be identified for deaths that occurred later in infancy. Thus, malaria during pregnancy increased neonatal mortality by lowering birth weight, whereas fever in the week before birth had a further independent effect in addition to inducing premature birth. The prevention of malaria in pregnancy and, thus, of malaria-attributable low birth weight should increase the survival of young babies.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2012
Publisher: Public Library of Science (PLoS)
Date: 05-03-2012
Publisher: Oxford University Press (OUP)
Date: 22-12-2011
Publisher: Oxford University Press (OUP)
Date: 04-2008
Publisher: Wiley
Date: 15-12-2010
DOI: 10.1111/J.1471-0528.2010.02810.X
Abstract: Pregnant women are at increased risk from malaria. Resistance to all classes of antimalarials has affected the treatment and prevention of malaria in pregnancy. To review the therapeutic efficacy of antimalarials used for treatment and intermittent preventive treatment (IPT) in pregnancy. We searched MEDLINE and the Cochrane Library between January 1998 and December 2009 for publications using the medical subject headings: efficacy, antimalarials, malaria, pregnancy, pharmacokinetics, treatment, IPT and placenta positive. In May 2010 we searched the register of clinical trials (clinicaltrials.gov/) and of WHO (apps.who.int/trialsearch/) using 'malaria', and 'pregnancy' and 'treatment'. We identified 233 abstracts, reviewed 83 full text articles and included 60 studies. Two authors entered extracted data to an excel spreadsheet. Parasitological failure rates, placenta positivity rates (assessed by microscopy) or both were reported in 44% (21/48), 46% (22/48) and 10% (5/48) of articles, respectively. Most pharmacokinetic studies (9/12) suggested dose optimisation. In 23 treatment studies 17 different antimalarial drugs were delivered in 53 study arms 43.4% (23/53) reported a failure rate of 10% in 68% (23/34) of SP trial arms and > 15% in all seven chloroquine arms. The ACT provided lower parasitological failure and gametocyte carriage rates. Drugs used in pregnancy should aim for 95% efficacy but many currently deployed regimens are associated with much lower cure rates.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2018
Publisher: Wiley
Date: 05-03-2017
DOI: 10.1002/UOG.17347
Publisher: Springer Science and Business Media LLC
Date: 06-08-2013
Abstract: Plasmodium vivax infections in pregnancy are associated with low birth weight and anaemia. This parasites species is also characterised by relapses, erythrocytic infections initiated by the activation of the dormant liver stages, the hypnozoites, to mature. Genotyping of P. vivax using microsatellite markers has opened the way to comparative investigations of parasite populations. The aim of the study was to assess whether there were any differences between the parasites found in pregnant and non-pregnant patients, and/or between the admission infections and recurrent episodes during follow-up. Blood s les were collected from 18 pregnant and 18 non-pregnant patients, who had at least two recurrent episodes during follow-up, that were recruited in two previous trials on the efficacy of chloroquine treatment of P. vivax infections on the Thai-Myanmar border. DNA was purified and the P. vivax populations genotyped with respect to eight polymorphic microsatellite markers. Analyses of the genetic ersity, multiplicity of infection (MOI), and a comparison of the genotypes in the s les from each patient were conducted. The P. vivax parasites present in the s les exhibited high genetic ersity (6 to 15 distinct allelic variants found for the 8 loci). Similar expected heterozygosity ( H e ) values were obtained for isolates from pregnant (0.837) and non-pregnant patients (0.852). There were modest differences between the MOI values calculated for both admission and recurrence s les from the pregnant patients (2.00 and 2.05, respectively) and the equivalent s les from the non-pregnant patients (1.67 and 1.64, respectively). Furthermore, the mean number of distinct alleles enumerated in the admission s les from the pregnant (6.88) and non-pregnant (7.63) patients were significantly lower than that found in the corresponding recurrent episodes s les (9.25 and 9.63, respectively). The P. vivax populations circulating in inhabitants along the Thai-Myanmar border, an area of low malaria transmission, displayed high genetic ersity. A subtle increase in the multiplicity of P. vivax infections in pregnant patients suggests a higher susceptibility to infection. The higher allelic ersity in the relapse as compared to the admission s les in both patient groups is consistent with the hypothesis that a febrile episode promotes the activation of hypnozoites.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-09-2010
Abstract: Spiroindolones were discovered as promising antimalarial drug candidates through a high-throughput screening approach that should be applicable to a range of neglected infectious diseases. Rottmann et al. (p. 1175 see the Perspective by Wells ) present the preclinical profile for an optimized spiroindolone drug candidate, NITD609. They obtained evidence for a decrease in drug sensitivity in strains of the malaria parasite Plasmodium falciparum bearing amino acid mutations in the P-type ATPase, indicating possible mechanisms of action and/or resistance.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2021
DOI: 10.1186/S12916-021-01960-3
Abstract: Malaria and hypertensive disorders of pregnancy (HDoP) affect millions of pregnancies worldwide, particularly those of young, first-time mothers. Small case-control studies suggest a positive association between falciparum malaria and risk of pre-ecl sia but large prospective analyses are lacking. We characterized the relationship between malaria in pregnancy and the development of HDoP in a large, prospectively followed cohort. Pregnant women living along the Thailand-Myanmar border, an area of low seasonal malaria transmission, were followed at antenatal clinics between 1986 and 2016. The relationships between falciparum and vivax malaria during pregnancy and the odds of gestational hypertension, pre-ecl sia, or ecl sia were examined using logistic regression amongst all women and then stratified by gravidity. There were 23,262 singleton pregnancies in women who presented during the first trimester and were followed fortnightly. Falciparum malaria was associated with gestational hypertension amongst multigravidae (adjusted odds ratio (AOR) 2.59, 95%CI 1.59–4.23), whereas amongst primigravidae, it was associated with the combined outcome of pre-ecl sia/ecl sia (AOR 2.61, 95%CI 1.01–6.79). In contrast, there was no association between vivax malaria and HDoP. Falciparum but not vivax malaria during pregnancy is associated with hypertensive disorders of pregnancy.
Publisher: Wiley
Date: 11-1995
DOI: 10.1111/J.1479-828X.1995.TB02172.X
Abstract: We utilized a one-step hydrothermal process for the synthesis of precious metal-doped titanium dioxide (TiO
Publisher: Public Library of Science (PLoS)
Date: 12-08-2021
DOI: 10.1371/JOURNAL.PONE.0255902
Abstract: Four in five neonatal deaths of preterm births occur in low and middle income countries and placental histopathology examination can help clarify the pathogenesis. Infection is known to play a significant role in preterm birth. The aim of this systematic review is to explore the association between placental histopathological abnormality and preterm birth in the presence of confirmed infection. PubMed/Medline, Scopus, Web of Science and Embase were searched using the keywords related to preterm birth, placental histopathology and infection. Titles and abstracts were screened and the full texts of eligible articles were reviewed to extract and summarise data. Of 1529 articles, only 23 studies (13 bacterial, 6 viral and 4 parasitic) were included, and they used 7 different gestational age windows, and 20 different histopathological classification systems, precluding data pooling. Despite this, histopathological chorioamnionitis, and funisitis (when examined) were commonly observed in preterm birth complicated by confirmed bacterial or viral, but not parasitic, infection. The presence of malaria parasites but not pigment in placenta was reported to increase the risk of PTB, but this finding was inconclusive. One in three studies were conducted in low and middle income countries. An array of: definitions of preterm birth subgroups, histological classification systems, histopathologic abnormalities and diagnostic methods to identify infections were reported in this systematic review. Commitment to using standardised terminology and classification of histopathological abnormalities associated with infections is needed to identify causality and potential treatment of preterm birth. Studies on preterm birth needs to occur in high burden countries and control for clinical characteristics (maternal, fetal, labor, and placental) that may have an impact on placental histopathological abnormalities.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2014
Publisher: F1000 Research Ltd
Date: 04-11-2022
DOI: 10.12688/WELLCOMEOPENRES.18417.1
Abstract: Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency represents a barrier to the full deployment of anti-malarial drugs for vivax malaria elimination and of first-line antibiotics. Lack of established reference ranges for G6PD activity in breast-fed infants puts them at risk of drug-induced haemolysis and restricts access to safe treatment of their mothers. Methods: The present work was undertaken to establish age-specific G6PD normal values using the gold standard spectrophotometric assay to support the future clinical use of tafenoquine in lactating women and safer antibiotic treatment in infants. Results: Spectrophotometric results from 78 healthy infants between the ages of 2 and 6 months showed a trend of decreased enzymatic activity with increasing age and provided a reference normal value of 100% activity for infants 2-6 months old of 10.18IU/gHb. Conclusions: Normal reference G6PD activity in 2–6-month-old infants was approximately 140% of that observed in G6PD normal adults from the same population. Age specific G6PD activity thresholds should be used in paediatric populations to avoid drug-induced haemolysis.
Publisher: American Society for Microbiology
Date: 09-2011
DOI: 10.1128/IAI.05048-11
Abstract: Apical membrane antigen 1 (AMA-1) is an invasion-related Plasmodium antigen that is expressed during both intracellular and extracellular asexual stages of the parasite's life cycle, making it an ideal target for induction of humoral and cellular immune responses that can protect against malaria. We show here that when it is administered as a recombinant protein (P) in Montanide ISA720 adjuvant, followed by a recombinant human type 5 adenovirus (Ad), intense and long-lasting Plasmodium vivax AMA-1-specific antibody responses (including both IgG1 and IgG2a), as well as proliferative memory T cell responses, can be detected in immunized mice. Memory T cells displayed both central (CD44 hi CD62L hi ) and effector (CD44 hi CD62L lo ) phenotypes, with the central memory phenotype prevailing (56% of AMA-1-specific proliferating cells). Considering the main traits of the memory immune responses induced against AMA-1, this particular sequence of immunogens (P followed by Ad), but no others (Ad/Ad, Ad/P, or P/P), displayed an optimal synergistic effect. These results give further support to the need for preclinical studies of P. vivax vaccine candidate AMA-1 administered in prime/boost protocols that include recombinant proteins and adenoviral vectors.
Publisher: eLife Sciences Publications, Ltd
Date: 16-11-2022
Publisher: F1000 Research Ltd
Date: 02-11-2018
DOI: 10.12688/F1000RESEARCH.16622.1
Abstract: Monitoring of blood transcriptional changes during disease or treatment could improve the understanding of cellular mechanisms associated with that particular condition. This can be achieved through serial s ling of small blood volumes. However, molecular analysis of gene expression from low volume s les remains a challenging task. To address this issue, we have developed a set of standard operating procedures (SOP), starting from collection of small volume blood to measurement of gene expression. Previously we published an SOP for the collection of a small volume of blood via finger stick and stabilization of RNA. The aim of this manuscript is to share a modified Tempus TM solution based RNA extraction method, developed in our lab, for the extraction of total RNA from low volume whole blood s les collected via finger stick.
Publisher: F1000 Research Ltd
Date: 19-07-2018
DOI: 10.12688/WELLCOMEOPENRES.10352.2
Abstract: Background : Countries vary on the demarcation gestational age that distinguishes miscarriage and extreme preterm birth (PTB). This study provides a synopsis of the outcome of pregnancy between 22 to weeks’ gestation from a low resource setting. Methods : A retrospective record review of a refugee and migrant population on the Thailand-Myanmar border with outcome between 22 to weeks’ gestation, was conducted. Outcomes were classified as miscarriage: non-viability prior to 22 week’s gestation with expulsion of products between 22 to 28 weeks’ gestation or extreme PTB when the fetus was viable at ≥22 weeks and delivered between 22 to 28 weeks’ gestation. Termination of pregnancy and gestational trophoblastic disease were excluded. Results : From 1995-2015, outcomes occurred between 22 to weeks’ gestation in 0.9% (472/49,931) of pregnancies and 3.8% (18/472) met the exclusion criteria. Most included pregnancies (n=454) had ultrasound done 72.5% (n=329). Overall 43.6% (n=197) were miscarriage and 56.4% (n=257) extreme PTB. Miscarriage (late expulsion) between 22 to weeks was observed with non-viability occurring at an estimated median gestation of 16 weeks. For cases with available data (n=252, 5 missing) the proportion of stillborn was 47.6% (n=120), liveborn 52.4% (n=132) and congenital abnormality 10.5% (24/228, 29 missing). Neonatal death was high 98.5% (128/131, 1 missing). Introduction of ultrasound was associated with a 2-times higher odds of classification of outcome as birth rather than miscarriage. Conclusion : In this low resource setting % of pregnancy outcomes occur in the 22 to weeks’ gestation window nearly half were miscarriage and neonatal mortality approached 100%. In the scale-up to preventable newborns deaths, at least initially, greater benefits will be obtained by focusing on the greater number of viable newborns with a gestation of 28 weeks or more.
Publisher: F1000 Research Ltd
Date: 06-12-2018
DOI: 10.12688/WELLCOMEOPENRES.10352.3
Abstract: Background : No universal demarcation of gestational age distinguishes miscarriage and stillbirth or extreme preterm birth (exPTB). This study provides a synopsis of outcome between 22 to weeks gestation from a low resource setting. Methods : A retrospective record review of a population on the Thailand-Myanmar border was conducted. Outcomes were classified as miscarriage, late expulsion of products between 22 to 28 weeks gestation with evidence of non-viability (mostly ultrasound absent fetal heart beat) prior to 22 weeks or exPTB (stillbirth/live born) between 22 to 28 weeks gestation when the fetus was viable at ≥22 weeks. Termination of pregnancy and gestational trophoblastic disease were excluded. Results : From 1995-2015, 80.9% (50,046/ 61,829) of registered women had a known pregnancy outcome, of whom 99.8% (49,931) had a known gestational age. Delivery between 22 to weeks gestation included 0.9% (472/49,931) of pregnancies after removing 18 cases (3.8%) who met an exclusion criteria. Most pregnancies had an ultrasound: 72.5% (n=329/454) 43.6% (n=197) were classified as miscarriage and 56.4% (n=257) exPTB. In idual record review of miscarriages estimated that fetal death had occurred at a median of 16 weeks, despite late expulsion between 22 to weeks. With available data (n=252, 5 missing) the proportion of stillbirth was 47.6% (n=120), congenital abnormality 10.5% (24/228, 29 missing) and neonatal death was 98.5% (128/131, 1 missing). Introduction of ultrasound was associated with a 2-times higher odds of classification of outcome as exPTB rather than miscarriage. Conclusion : In this low resource setting few ( %) pregnancy outcomes occurred in the 22 to weeks gestational window four in ten were miscarriage (late expulsion) and neonatal mortality approached 100%. In the scale-up to preventable newborns deaths (at least initially) greater benefits will be obtained by focusing on the viable newborns of ≥ 28 weeks gestation.
Publisher: F1000 Research Ltd
Date: 23-12-2016
DOI: 10.12688/WELLCOMEOPENRES.10352.1
Abstract: Background: The WHO definition of stillbirth uses 28 weeks’ gestation as the cut-point, but also defines extreme preterm birth as 24 to weeks’ gestation. This presents a problem with the gestational limit of miscarriage, and hence reporting of stillbirth, preterm birth and neonatal death. The objective of this study is to provide a synopsis of the outcome of a population cohort of pregnancies on the Thailand-Myanmar border between 24 to weeks’ gestation. Methods: Records from the Shoklo Malaria Research Unit Antenatal Clinics were reviewed for pregnancy outcomes in the gestational window of 24 to weeks, and each record, including ultrasounds reports, were reviewed to clarify the pregnancy outcome. Pregnancies where there was evidence of fetal demise prior to 24 weeks were classified as miscarriage those viable at 24 weeks’ gestation and born before 28 weeks were coded as births, and further sub ided into live- and stillbirth. Results: Between 1995 and 2015, in a cohort of 49,931 women, 0.6% (318) of outcomes occurred from 24 to weeks’ gestation, and 35.8% (114) were miscarriages, with confirmatory ultrasound of fetal demise in 45.4% (49/108). Of pregnancies not ending in miscarriage, 37.7% (77/204) were stillborn and of those born alive, neonatal mortality was 98.3% (115/117). One infant survived past the first year of life. Congenital abnormality rate was 12.0% (23/191). Ultrasound was associated with a greater proportion of pregnancy outcome being coded as birth. Conclusion: In this limited-resource setting, pregnancy outcome from 24 to weeks’ gestation included: 0.6% of all outcomes, of which one-third were miscarriages, one-third of births were stillborn and mortality of livebirths approached 100%. In the scale-up to preventable newborns deaths, at least initially, greater benefits will be obtained by focusing on the greater number of viable newborns with a gestation of 28 weeks or more.
Publisher: Informa UK Limited
Date: 09-2003
DOI: 10.1179/027249303322296510
Abstract: Thirty-eight babies born to Karen mothers living in c s for displaced persons in north-western Thailand have delayed visual maturation (DVM type 1) that recovers within 6 months. Vitamin A concentrations were deficient in 16% of breast-milk s les from lactating mothers and vitamin B(1) concentrations were deficient in 60% of plasma s les. Infantile beriberi was common in this population. The levels of fatty acids in plasma and milk in Karen women were excellent at birth and in the postpartum period. The degree of deficiencies in these vitamins and the concentration of essential fatty acids in cord blood and maternal breast-milk did not correlate significantly with visual impairment in the infants. DVM might be caused by nutritional deficiency or toxic effects during critical periods of gestation that lead to delayed cortical myelination or structural defects which impinge on parietal cortex function.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2015
Publisher: Springer Science and Business Media LLC
Date: 29-04-2021
DOI: 10.1186/S12889-021-10842-5
Abstract: Mass drug administration (MDA) has received growing interest to accelerate the elimination of multi-drug resistant malaria in the Greater Mekong Subregion. Targeted MDA, sometimes referred to as focal MDA, is the practice of delivering MDA to high incidence subpopulations only, rather than the entire population. The potential effectiveness of delivering targeted MDA was demonstrated in a recent intervention in Kayin State, Myanmar. Policymakers and funders need to know what resources are required if MDA, targeted or otherwise, is to be included in elimination packages beyond existing malaria interventions. This study aims to estimate the programmatic cost and the unit cost of targeted MDA in Kayin State, Myanmar. We used financial data from a malaria elimination initiative, conducted in Kayin State, to estimate the programmatic costs of the targeted MDA component using a micro-costing approach. Three activities (community engagement, identification of villages for targeted MDA, and conducting mass treatment in target villages) were evaluated. We then estimated the programmatic costs of implementing targeted MDA to support P. falciparum malaria elimination in Kayin State. A costing tool was developed to aid future analyses. The cost of delivering targeted MDA within an integrated malaria elimination initiative in eastern Kayin State was approximately US$ 910,000. The cost per person reached, distributed among those in targeted and non-targeted villages, for the MDA component was US$ 2.5. This cost analysis can assist policymakers in determining the resources required to clear malaria parasite reservoirs. The analysis demonstrated the value of using financial data from research activities to predict programmatic implementation costs of targeting MDA to different numbers of target villages.
Publisher: Oxford University Press (OUP)
Date: 11-2020
DOI: 10.1093/INTHEALTH/IHAA052
Abstract: Research ethics guidelines set a high bar for conducting research with vulnerable populations, often resulting in their exclusion from beneficial research. Our study aims to better characterise participants’ vulnerabilities, agency, resourcefulness and sources of support. We undertook qualitative research around two clinical studies involving migrant women living along the Thai–Myanmar border. We conducted 32 in-depth interviews and 10 focus group discussions with research participants, families, researchers and key informants. We found that being ‘undocumented’ is at the core of many structural vulnerabilities, reflecting political, economic, social and health needs. Although migrant women lead challenging lives, they have a support network that includes family, employers, community leaders, non-governmental organisations and research networks. Migrant women choose to participate in research to access quality healthcare, gain knowledge and obtain extra money. However, research has the potential to exacerbate existing vulnerabilities, such as the burdens of cross-border travel, foregoing work and being more visible as migrants. Our study confirms that research is important to provide evidence-based care and was viewed by participants as offering many benefits, but it also has hidden burdens. Migrant women exercised agency and resourcefulness when navigating challenges in their lives and research participation.
Publisher: Elsevier BV
Date: 02-2007
Publisher: Springer Science and Business Media LLC
Date: 02-08-2008
Abstract: Malaria is a very important cause of anaemia in tropical countries. Anaemia is assessed either by measurement of the haematocrit or the haemoglobin concentration. For comparisons across studies, it is often necessary to derive one measure from the other. Data on patients with slide-confirmed uncomplicated falciparum malaria were pooled from 85 antimalarial drug trials conducted in 25 different countries, to assess the haemoglobin/haematocrit relationship at different time points in malaria. Using a linear random effects model, a conversion equation for haematocrit was derived based on 3,254 measurements from various time points (ranging from day 0 to day 63) from 1,810 patients with simultaneous measurements of both parameters. Haemoglobin was also estimated from haematocrit with the commonly used threefold conversion. A good fit was obtained using Haematocrit = 5.62 + 2.60 * Haemoglobin. On average, haematocrit/3 levels were slightly higher than haemoglobin measurements with a mean difference (± SD) of -0.69 (± 1.3) for children under the age of 5 (n = 1,440 measurements from 449 patients). Based on this large data set, an accurate and robust conversion factor both in acute malaria and in convalescence was obtained. The commonly used threefold conversion is also valid.
Publisher: Elsevier BV
Date: 05-2012
Publisher: Springer Science and Business Media LLC
Date: 23-12-2022
DOI: 10.1038/S42003-022-04352-2
Abstract: Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection’s country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.
Publisher: Public Library of Science (PLoS)
Date: 04-10-2019
Publisher: Springer Science and Business Media LLC
Date: 28-05-2015
Publisher: F1000 Research Ltd
Date: 10-06-2014
DOI: 10.12688/F1000RESEARCH.4190.1
Abstract: Objective: The antenatal prevalence of syphilis and HIV/AIDS in migrants and refugees is poorly documented. The aim of this study was to audit the first year of routine syphilis screening in migrant and refugee women on the Thai Myanmar border. Methods: From August 2012 to July 2013, 3600 pregnant women were screened for HIV (ELISA) and syphilis (VDRL with TPHA confirmation) at clinics along the Thai-Myanmar border. Results: Seroprevalence for HIV 0.47% (95% CI 0.30-0.76) (17/3,599), and syphilis 0.39% (95% CI 0.23-0.65) (14/3,592), were low. Syphilis was significantly lower in refugees (0.07% 95% CI 0.01-0.38) (1/1,469), than in migrants (0.61% 95% CI 0.36-1.04) (13/2,123). The three active (VDRL≥1:8 and TPHA reactive) syphilis cases with VDRL titres of 1:32 were easy to counsel and treat. Women with low VDRL titres ( % were 1:8) and TPHA reactive results, in the absence of symptoms and both the woman and her husband having only one sexual partner in their lifetime, and the inability to determine the true cause of the positive results presented ethical difficulties for counsellors. Conclusion: As HIV and syphilis testing becomes available in more and more settings, the potential impact of false positive results should be considered, especially in populations with low prevalence for these diseases. This uncertainty must be considered in order to counsel patients and partners accurately and safely about the results of these tests, without exposing women to increased risk for abuse or abandonment. Our findings highlight the complexities of counselling patients about these tests and the global need for more conclusive syphilis testing strategies.
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: F1000 Research Ltd
Date: 15-05-2015
DOI: 10.12688/F1000RESEARCH.4190.2
Abstract: Objective: The antenatal prevalence of syphilis and HIV/AIDS in migrants and refugees is poorly documented. The aim of this study was to audit the first year of routine syphilis screening in the same population and reassess the trends in HIV rates. Methods: From August 2012 to July 2013, 3600 pregnant women were screened for HIV (ELISA) and syphilis (VDRL with TPHA confirmation) at clinics along the Thai-Myanmar border. Results: Seroprevalence for HIV 0.47% (95% CI 0.30-0.76) (17/3,599), and syphilis 0.39% (95% CI 0.23-0.65) (14/3,592), were low. Syphilis was significantly lower in refugees (0.07% 95% CI 0.01-0.38) (1/1,469), than in migrants (0.61% 95% CI 0.36-1.04) (13/2,123). The three active (VDRL≥1:8 and TPHA reactive) syphilis cases with VDRL titres of 1:32 were easy to counsel and treat. Women with low VDRL titres ( % were 1:8) and TPHA reactive results, in the absence of symptoms and both the woman and her husband having only one sexual partner in their lifetime, and the inability to determine the true cause of the positive results presented ethical difficulties for counsellors. Conclusion: As HIV and syphilis testing becomes available in more and more settings, the potential impact of false positive results should be considered, especially in populations with low prevalence for these diseases. This uncertainty must be considered in order to counsel patients and partners accurately and safely about the results of these tests, without exposing women to increased risk for abuse or abandonment. Our findings highlight the complexities of counselling patients about these tests and the global need for more conclusive syphilis testing strategies.
Publisher: American Society for Microbiology
Date: 21-02-2020
DOI: 10.1128/AAC.01140-19
Abstract: Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased.
Publisher: Oxford University Press (OUP)
Date: 24-07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
Publisher: American Society for Microbiology
Date: 02-2015
DOI: 10.1128/AAC.04419-14
Abstract: Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC 50 s) of nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2007
Publisher: Public Library of Science (PLoS)
Date: 08-10-2013
Publisher: Oxford University Press (OUP)
Date: 07-2015
Publisher: American Society for Microbiology
Date: 12-2011
DOI: 10.1128/AAC.05067-11
Abstract: Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood s les were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure ( P = 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) ( P = 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women ( P = 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days P = 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml, P = 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.
Publisher: Elsevier BV
Date: 12-2001
Abstract: Before its recognition, infantile beriberi was the leading cause of infant death in c s for displaced persons of the Karen ethnic minority on Thailand's western border. This study aimed to document thiamine status in the peripartum period to examine the current supplementation program and the correlation between the clinical manifestations of thiamine deficiency and a biochemical measure of thiamine status. Women were enrolled prospectively at 30 wk of gestation and were followed up weekly until delivery and at 3 mo postpartum. Thiamine supplementation during pregnancy was based on patient symptoms. At 3 mo postpartum, thiamine deficiency reflected by an erythrocyte transketolase activity (ETKA) > or = 1.20% was found in 57.7% (15/26) of mothers, 26.9% (7/26) of whom had severe deficiency (ETKA > 1.25%). No significant associations between ETKA and putative maternal symptoms or use of thiamine supplements were found. Biochemical postpartum thiamine deficiency is still common in Karen refugee women. This situation may be improved by educating lactating women to reduce their consumption of thiaminase-containing foods and by implementing an effective thiamine supplementation program.
Publisher: Cold Spring Harbor Laboratory
Date: 25-07-2020
DOI: 10.1101/2020.07.23.20159624
Abstract: National Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple s le collection procedures in routine public health procedures. S les are processed by high-throughput technologies to genotype several drug resistance markers, species markers and a genomic barcode, delivering reports of genotypes and phenotype predictions, used to map prevalence of resistance to multiple drugs. GenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9,623 s les from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces. GenRe-Mekong facilitates data sharing by aggregating results from different countries, enabling cross-border resistance monitoring. Large-scale genetic surveillance of malaria implemented by National Malaria Control Programmes informs public health decision makers about the spread of strains resistant to antimalarials. Bill & Melinda Gates Foundation, Wellcome Trust, UK Medical Research Council, UK Department for International Development, NIAID
Publisher: F1000 Research Ltd
Date: 02-01-2018
DOI: 10.12688/WELLCOMEOPENRES.13373.1
Abstract: Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited enzymatic disorder associated with severe neonatal hyperbilirubinemia and acute haemolysis after exposure to certain drugs or infections. The disorder can be diagnosed phenotypically with a fluorescent spot test (FST), which is a simple test that requires training and basic laboratory equipment. This study aimed to assess the diagnostic performances of the FST used on umbilical cord blood by locally-trained staff and to compare test results of the neonates at birth with the results after one month of age. Methods : We conducted a cohort study on newborns at the Shoklo Malaria Research Unit, along the Thai-Myanmar border between January 2015 and May 2016. The FST was performed at birth on the umbilical cord blood by locally-trained staff and quality controlled by specialised technicians at the central laboratory. The FST was repeated after one month of age. Genotyping for common local G6PD mutations was carried out for all discrepant results. Results: FST was performed on 1521 umbilical cord blood s les. Quality control and genotyping revealed 10 misdiagnoses. After quality control, 10.7% of the males (84/786) and 1.2% of the females (9/735) were phenotypically G6PD deficient at birth. The FST repeated at one month of age or later diagnosed 8 additional G6PD deficient infants who were phenotypically normal at birth. Conclusions : This study shows the short-comings of the G6PD FST in neonatal routine screening and highlights the importance of training and quality control. A more conservative interpretation of the FST in male newborns could increase the diagnostic performances. Quantitative point-of-care tests might show higher sensitivity and specificity for diagnosis of G6PD deficiency on umbilical cord blood and should be investigated.
Publisher: Elsevier BV
Date: 04-2019
Publisher: American Society for Microbiology
Date: 05-2016
DOI: 10.1128/AAC.02476-15
Abstract: Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.
Publisher: Oxford University Press (OUP)
Date: 31-05-2019
DOI: 10.1093/OFID/OFZ264
Abstract: Follow-up for 28–42 days is recommended by the World Health Organization to assess antimalarial drug efficacy for nonpregnant populations. This study aimed to determine the optimal duration for pregnant women, as no specific guidance currently exists. The distributions of time to recrudescence (treatment failure), confirmed by polymerase chain reaction genotyping for different antimalarial drugs in pregnancy, were analyzed by accelerated failure time models using secondary data on microscopically confirmed recurrent falciparum malaria collected in prospective studies on the Thailand–Myanmar border between 1994 and 2010. Of 946 paired isolates from 703 women, the median duration of follow-up for each genotyped recurrence (interquartile range) was 129 (83–174) days, with 429 polymerase chain reaction–confirmed recrudescent. Five different treatments were evaluated, and 382 Plasmodium falciparum recrudescences were identified as eligible. With log-logistic models adjusted for baseline parasitemia, the predicted cumulative proportions of all the recrudescences that were detected by 28 days were 70% (95% confidence interval [CI], 65%–74%) for quinine monotherapy (n = 295), 66% (95% CI, 53%–76%) for artesunate monotherapy (n = 43), 62% (95% CI, 42%–79%) for artemether–lumefantrine (AL n = 19), 46% (95% CI, 26%–67%) for artesunate with clindamycin (n = 19), and 34% (95% CI, 11%–67%) for dihydroartemisinin–piperaquine (DP n = 6). Corresponding figures by day 42 were 89% (95% CI, 77%–95%) for AL and 71% (95% CI, 38%–91%) for DP. Follow-up for 63 days was predicted to detect ≥95% of all recrudescence, except for DP. In low-transmission settings, antimalarial drug efficacy assessments in pregnancy require longer follow-up than for nonpregnant populations.
Publisher: Public Library of Science (PLoS)
Date: 2030
Publisher: BMJ
Date: 12-2022
DOI: 10.1136/BMJOPEN-2022-066529
Abstract: New point-of-care (POC) quantitative G6PD testing devices developed to provide safe radical cure for Plasmodium vivax malaria may be used to diagnose G6PD deficiency in newborns at risk of severe neonatal hyperbilirubinaemia, improving clinical care, and preventing related morbidity and mortality. We conducted a mixed-methods study analysing technical performance and usability of the ‘STANDARD G6PD’ Biosensor when used by trained midwives on cord blood s les at two rural clinics on the Thailand–Myanmar border. In 307 cord blood s les, the Biosensor had a sensitivity of 1.000 (95% CI: 0.859 to 1.000) and a specificity of 0.993 (95% CI: 0.971 to 0.999) as compared with gold-standard spectrophotometry to diagnose G6PD-deficient newborns using a receiver operating characteristic (ROC) analysis-derived threshold of ≤4.8 IU/gHb. The Biosensor had a sensitivity of 0.727 (95% CI: 0.498 to 0.893) and specificity of 0.933 (95% CI: 0.876 to 0.969) for 30%–70% activity range in girls using ROC analysis-derived range of 4.9–9.9 IU/gHb. These thresholds allowed identification of all G6PD-deficient neonates and 80% of female neonates with intermediate phenotypes. Need of phototherapy treatment for neonatal hyperbilirubinaemia was higher in neonates with deficient and intermediate phenotypes as diagnosed by either reference spectrophotometry or Biosensor. Focus group discussions found high levels of learnability, willingness, satisfaction and suitability for the Biosensor in this setting. The staff valued the capacity of the Biosensor to identify newborns with G6PD deficiency early (‘We can know that early, we can counsel the parents about the chances of their children getting jaundice’) and at the POC, including in more rural settings (‘Because we can know the right result of the G6PD deficiency in a short time, especially for the clinic which does not have a lab’). The Biosensor is a suitable tool in this resource-constrained setting to identify newborns with abnormal G6PD phenotypes at increased risk of neonatal hyperbilirubinaemia.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2015
Publisher: Springer Science and Business Media LLC
Date: 22-07-2021
DOI: 10.1038/S41564-021-00939-3
Abstract: More than one-third of the world's population is exposed to Plasmodium vivax malaria, mainly in Asia
Publisher: Frontiers Media SA
Date: 08-07-2015
Publisher: Oxford University Press (OUP)
Date: 26-05-2014
Publisher: Elsevier BV
Date: 11-1998
Publisher: Oxford University Press (OUP)
Date: 15-11-2010
DOI: 10.1086/656723
Publisher: Public Library of Science (PLoS)
Date: 13-03-2013
Publisher: Informa UK Limited
Date: 12-05-2014
DOI: 10.3402/GHA.V7.23887
Publisher: eLife Sciences Publications, Ltd
Date: 03-12-2021
DOI: 10.7554/ELIFE.66277
Abstract: The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13- propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2 , earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.BIOMATERIALS.2019.05.032
Abstract: Hypnozoites are the liver stage non- iding form of the malaria parasite that are responsible for relapse and acts as a natural reservoir for human malaria Plasmodium vivax and P. ovale as well as a phylogenetically related simian malaria P. cynomolgi. Our understanding of hypnozoite biology remains limited due to the technical challenge of requiring the use of primary hepatocytes and the lack of robust and predictive in vitro models. In this study, we developed a malaria liver stage model using 3D spheroid-cultured primary hepatocytes. The infection of primary hepatocytes in suspension led to increased infectivity of both P. cynomolgi and P. vivax infections. We demonstrated that this hepatic spheroid model was capable of maintaining long term viability, hepatocyte specific functions and cell polarity which enhanced permissiveness and thus, permitting for the complete development of both P. cynomolgi and P. vivax liver stage parasites in the infected spheroids. The model described here was able to capture the full liver stage cycle starting with sporozoites and ending in the release of hepatic merozoites capable of invading simian erythrocytes in vitro. Finally, we showed that this system can be used for compound screening to discriminate between causal prophylactic and cidal antimalarials activity in vitro for relapsing malaria.
Publisher: Public Library of Science (PLoS)
Date: 07-10-2021
DOI: 10.1371/JOURNAL.PONE.0258127
Abstract: Population risks for neonatal hyperbilirubinaemia (NH) vary. Knowledge of local risks permits interventions that may reduce the proportion becoming severe. Between January 2015 and May 2016, in a resource-limited setting on the Thailand-Myanmar border, neonates from 28 weeks’ gestation were enrolled into a prospective birth cohort. Each neonate had total serum bilirubin measurements: scheduled (24, 48, 72 and 144 hours of life) and clinically indicated and weekly follow up until 1 month of age. Risk factors for developing NH were evaluated using Cox proportional hazard mixed model. Of 1710 neonates, 22% (376) developed NH (83% preterm, 19% term). All neonates born weeks, four in five born 35–37 weeks, and three in twenty born ≥38 weeks had NH, giving an overall incidence of 249 per 1000 livebirths [95%CI 225, 403]. Mortality from acute bilirubin encephalopathy was 10% (2/20) amongst the 5.3% (20/376) who reached the severe NH threshold. One-quarter (26.3%) of NH occurred within 24 hours. NH onset varied with gestational age: at a median [IQR] 24 hours [24, 30] for neonates born 37 weeks or prematurely vs 59 hours [48, 84] for neonates born ≥38 weeks. Risk factors for NH in the first week of life independent of gestational age were: neonatal G6PD deficiency, birth bruising, Sgaw Karen ethnicity, primigravidae, pre-ecl sia, and prolonged rupture of membranes. The genetic impact of G6PD deficiency on NH was partially interpreted by using the florescent spot test and further genotyping work is in progress. The risk of NH in Sgaw Karen refugees may be overlooked internationally as they are most likely regarded as Burmese in countries of resettlement. Given high levels of pathological jaundice in the first 24 hours and overall high NH burden, guidelines changes were implemented including preventive PT for all neonates weeks and for those 35–37 weeks with risk factors.
Publisher: Wiley
Date: 02-11-2017
DOI: 10.1111/BJH.14976
Abstract: Erythropoiesis is marked by progressive changes in morphological, biochemical and mechanical properties of erythroid precursors to generate red blood cells (RBC). The earliest enucleated forms derived in this process, known as reticulocytes, are multi-lobular and spherical. As reticulocytes mature, they undergo a series of dynamic cytoskeletal re-arrangements and the expulsion of residual organelles, resulting in highly deformable biconcave RBCs (normocytes). To understand the significant, yet neglected proteome-wide changes associated with reticulocyte maturation, we undertook a quantitative proteomics approach. Immature reticulocytes (marked by the presence of surface transferrin receptor, CD71) and mature RBCs (devoid of CD71) were isolated from human cord blood using a magnetic separation procedure. After sub-fractionation into triton-extracted membrane proteins and luminal s les (isobaric tags for relative and absolute quantitation), quantitative mass spectrometry was conducted to identify more than 1800 proteins with good confidence and coverage. While most structural proteins (such as Spectrins, Ankyrin and Band 3) as well as surface glycoproteins were conserved, proteins associated with microtubule structures, such as Talin-1/2 and ß-Tubulin, were detected only in immature reticulocytes. Atomic force microscopy (AFM)-based imaging revealed an extended network of spectrin filaments in reticulocytes (with an average length of 48 nm), which shortened during reticulocyte maturation (average spectrin length of 41 nm in normocytes). The extended nature of cytoskeletal network may partly account for increased deformability and shape changes, as reticulocytes transform to normocytes.
Publisher: American Society for Microbiology
Date: 07-2008
DOI: 10.1128/AAC.00169-08
Abstract: Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax ( n = 30) and P. falciparum ( n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum , compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter- Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum . PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found.
Publisher: Public Library of Science (PLoS)
Date: 26-06-2015
Publisher: American Society of Tropical Medicine and Hygiene
Date: 05-05-2021
Abstract: Non-intubated patients with acute respiratory failure due to COVID-19 could benefit from awake proning. Awake proning is an attractive intervention in settings with limited resources, as it comes with no additional costs. However, awake proning remains poorly used probably because of unfamiliarity and uncertainties regarding potential benefits and practical application. To summarize evidence for benefit and to develop a set of pragmatic recommendations for awake proning in patients with COVID-19 pneumonia, focusing on settings where resources are limited, international healthcare professionals from high and low- and middle-income countries (LMICs) with known expertise in awake proning were invited to contribute expert advice. A growing number of observational studies describe the effects of awake proning in patients with COVID-19 pneumonia in whom hypoxemia is refractory to simple measures of supplementary oxygen. Awake proning improves oxygenation in most patients, usually within minutes, and reduces dyspnea and work of breathing. The effects are maintained for up to 1 hour after turning back to supine, and mostly disappear after 6–12 hours. In available studies, awake proning was not associated with a reduction in the rate of intubation for invasive ventilation. Awake proning comes with little complications if properly implemented and monitored. Pragmatic recommendations including indications and contraindications were formulated and adjusted for resource-limited settings. Awake proning, an adjunctive treatment for hypoxemia refractory to supplemental oxygen, seems safe in non-intubated patients with COVID-19 acute respiratory failure. We provide pragmatic recommendations including indications and contraindications for the use of awake proning in LMICs.
Publisher: eLife Sciences Publications, Ltd
Date: 23-06-2021
Publisher: American Society for Microbiology
Date: 04-2012
DOI: 10.1128/AAC.05756-11
Abstract: Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.
Publisher: F1000 Research Ltd
Date: 24-02-2021
DOI: 10.12688/WELLCOMEOPENRES.16168.1
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2019
Publisher: F1000 Research Ltd
Date: 13-07-2021
DOI: 10.12688/WELLCOMEOPENRES.16168.2
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Informa UK Limited
Date: 03-2004
DOI: 10.1179/000349804225003145
Abstract: To study the influence of season on Plasmodium vivax gametocyte carriage, the relationship between monthly rainfall and the proportion of P. vivax patients with detectable gametocytaemia was analysed. Most of the data used came from 6807 aggregated observations collected, in a refugee c on the Thai-Burmese border, between January 2000 and December 2002. There was a positive correlation between rainfall and the incidence of P. vivax infection (Spearman's rho=+0.42 P =0.01) but the prevalence of gametocyte carriage among those with P. vivax infection was negatively correlated with rainfall (Spearman's rho=-0.58 P <0.001). The latter, negative correlation remained significant after controlling for the proportion of visitors relative to c residents (P =0.003). Migrations, changes in transmission patterns, seasonal haematological changes, and ultraviolet immunosuppression are discussed as potential explanations for these observations.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.IJPARA.2012.08.010
Abstract: The lack of a continuous culture method for Plasmodium vivax has given the impression that investigations on this important species are severely curtailed. However, the use of new or improved ex vivo methods and tools to study fresh and thawed isolates from vivax malaria patients is currently providing useful data on P. vivax, such as sensitivity to antimalarial drugs, invasion mechanisms and pathobiology. This review discusses a practical framework for conducting ex vivo studies on the asexual erythrocytic stages of P. vivax and considers the synergies between ex vivo defined phenotypes, ex vivo derived 'omic' studies and in vivo clinical studies.
Publisher: Public Library of Science (PLoS)
Date: 02-05-2017
Publisher: Public Library of Science (PLoS)
Date: 13-02-2017
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Publisher: Wiley
Date: 30-07-2010
Publisher: SAGE Publications
Date: 10-2018
DOI: 10.3851/IMP3341
Abstract: Tenofovir disoproxil fumarate (TDF), the oral prodrug of tenofovir (TFV), is advocated in pregnancy for prevention of mother-to-child transmission (PMCT) with failure of hepatitis B immunoglobulin and vaccination. The pharmacokinetics of TDF monotherapy for PMCT-HBV is important if deployment is to emulate the success of multiple antiretrovirals (ARVs) for PMCT-HIV in resource-constrained settings. This systematic review followed a protocol and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) guidelines. We included studies that enrolled pregnant women who received oral TDF therapy as mono-therapy or in combination with other ARVs: irrespective of the reason for receiving the drug (for ex le, HIV, HBV or pre-exposure prophylaxis) and reported pharmacokinetics. The area under the concentration–time curve (AUC), maximum plasma concentrations (C max ) and last measurable plasma concentration (C last ) of TFV were decreased in the second and third trimester compared with first trimester or post-partum. In none of the manuscripts was the non-pregnant HBV threshold of C max of 300 ng/ml reached, but the 50% effective concentration (EC 50 ) of TFV is lower for treatment of HBV compared with HIV. The TFV concentration in breastfed infants was 0.03% of the recommended infant dose. Most knowledge of pharmacokinetics of TFV in pregnancy results from studies on HIV involving multiple ARVs. Increased TFV clearance occurred in the second and third trimester when optimal TFV concentrations are required to maximize suppression of HBV in the window before birth. Dose or duration adjustments will be better conceptualized with concurrent analysis of the pharmacokinetics of TFV monotherapy and hepatitis B pharmacodynamics in pregnancy.
Publisher: Elsevier BV
Date: 07-2000
DOI: 10.1016/S0140-6736(00)02505-8
Abstract: Worsening drug resistance in Plasmodium falciparum malaria is a major threat to health in tropical countries. We did a prospective study of malaria incidence and treatment in an area of highly multidrug-resistant P. falciparum malaria. We assessed incidence of P. falciparum malaria and the in-vivo responses to mefloquine treatment over 13 years in two large c s for displaced Karen people on the northwest border of Thailand. During this time, the standard mefloquine dose was first increased, and then combined artesunate and mefloquine was introduced as first-line treatment for uncomplicated P. falciparum malaria. Early detection and treatment controlled P. falciparum malaria initially while mefloquine was effective (cure rate with mefloquine [15 mg/kg] and sulphadoxine-pyrimethamine in 1985, 98% [95% CI 97-100]), but as mefloquine resistance developed, the cure rate fell (71% [67-77] in 1990). A similar pattern was seen for high-dose (25 mg/kg) mefloquine monotherapy from 1990-94. Since the general deployment of the artesunate-mefloquine combination in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of P. falciparum malaria in the study area. In-vitro susceptibility of P. falciparum to mefloquine has improved significantly (p=0.003). In this area of low malaria transmission, early diagnosis and treatment with combined artesunate and mefloquine has reduced the incidence of P. falciparum malaria and halted the progression of mefloquine resistance. We recommend that antimalarial drugs should be combined with artemisinin or a derivative to protect them against resistance.
Publisher: Public Library of Science (PLoS)
Date: 18-07-2012
Publisher: Oxford University Press (OUP)
Date: 1998
DOI: 10.1016/S0035-9203(98)90950-6
Abstract: The differentiation of malaria from other causes of fever in the absence of microscopy is notoriously difficult. Clinical predictors of malaria have been studied in an area of low and unstable transmission on the western border of Thailand. In 1527 children aged 2-15 years who were followed prospectively for 7 months, 82% (1254) had at least one febrile episode. Malaria caused 24% (301) of the first febrile episodes (Plasmodium falciparum 128, P. vivax 151, P. malariae 1, mixed infections with P. falciparum and P. vivax 21). Each malaria case was matched with the next child of similar age presenting to the dispensary with another cause of fever. Clinical symptoms or signs associated with a final diagnosis of malaria were: confirmed fever (> or = 38 degrees C) (odds ratio [OR] 1.6, 95% confidence interval [95% CI] 1.4-1.9), headache (OR 1.5, 95% CI 1.3-1.9), muscle and/or joint pain (OR 2.0, 95% CI 1.6-2.8), nausea (OR 1.7, 95% CI 1.4-2.3), clinical anaemia (OR 1.4, 95% CI 1.3-3.3), palpable spleen (OR 1.3, 95% CI 1.1-1.7), palpable liver (OR 1.4, 95% CI 1.1-2.1), absence of cough (OR 1.6, 95% CI 1.4-2.0), and absence of diarrhoea (OR 1.5, 95% CI 1.2-2.4). None of these signs alone or in combination proved a good predictor of malaria. The best diagnostic algorithms (history of fever and headache without cough, and history of fever with an oral temperature > or = 38 degrees C [sensitivity 51% for both, specificity 72 and 71%, respectively]) would result in prescription of antimalarial drugs in 28-29% of the non-malaria febrile episodes, and only 49% of the true malaria cases. Thus half of the potentially life-threatening P. falciparum infections would not be treated. Although multivariate analysis identified vomiting, confirmed fever, splenomegaly and hepatomegaly as independent risk factors for a diagnosis of falciparum malaria, use of these signs to differentiate falciparum from vivax malaria, and thus to determine antimalarial treatment, was insufficiently sensitive or specific. Malaria diagnosis should be confirmed by microscopical examination of a blood slide or the use of specific dipstick tests in areas of low transmission where highly drug-resistant P. falciparum coexists with P. vivax.
Publisher: Oxford University Press (OUP)
Date: 09-2005
DOI: 10.1086/432551
Abstract: There is no safe, practical, and effective treatment for pregnant women infected with multidrug-resistant Plasmodium falciparum. We recruited pregnant Karen women in the second or third trimesters of pregnancy who had uncomplicated falciparum malaria for a randomized, open-label trial with a restricted sequential trial design of 7 days of supervised quinine (SQ7) versus 3 days of artesunate-atovaquone-proguanil (AAP). Eight-one pregnant women entered the study between December 2001 and July 2003 42 were treated with SQ7 and 39 were treated with AAP. Fever, parasite clearance, and duration of anemia were significantly better with AAP the treatment failure rate was 7 times lower (5% [2/39] vs. 37% [15/41] relative risk, 7.1 [95% confidence interval, 1.7-29.2] P = .001). There were no significant differences in birth weight, duration of gestation, or congenital abnormality rates in newborns or in growth and developmental parameters of infants monitored for 1 year. AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.
Publisher: Oxford University Press (OUP)
Date: 12-06-2013
Publisher: Springer Science and Business Media LLC
Date: 19-03-2010
Publisher: eLife Sciences Publications, Ltd
Date: 16-04-2019
DOI: 10.7554/ELIFE.41023
Abstract: The global malaria burden has decreased over the last decade and many nations are attempting elimination. Asymptomatic malaria infections are not normally diagnosed or treated, posing a major hurdle for elimination efforts. One solution to this problem is mass drug administration (MDA), with success depending on adequate population participation. Here, we present a detailed spatial and temporal analysis of malaria episodes and asymptomatic infections in four villages undergoing MDA in Myanmar. In this study, in iduals from neighborhoods with low MDA adherence had 2.85 times the odds of having a malaria episode post-MDA in comparison to those from high adherence neighborhoods, regardless of in idual participation, suggesting a herd effect. High mosquito biting rates, living in a house with someone else with malaria, or having an asymptomatic malaria infection were also predictors of clinical episodes. Spatial clustering of non-adherence to MDA, even in villages with high overall participation, may frustrate elimination efforts.
Publisher: Oxford University Press (OUP)
Date: 19-06-2014
Publisher: Public Library of Science (PLoS)
Date: 19-11-2020
DOI: 10.1371/JOURNAL.PMED.1003393
Abstract: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an in idual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P . vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P . vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P . falciparum monoinfection and 1,195 (7.8%) mixed infection with P . falciparum and P . vivax . The median age was 17.0 years (interquartile range [IQR] = 9.0–29.0 years range = 0–80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P . falciparum was 31.1% (95% CI 28.9–33.4) after AL, 14.1% (95% CI 10.8–18.3) after AA, 7.4% (95% CI 6.7–8.1) after AM, and 4.5% (95% CI 3.9–5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6–43.3), 42.4% (95% CI 34.7–51.2), 22.8% (95% CI 21.2–24.4), and 12.8% (95% CI 11.4–14.5), respectively. In multivariable analyses, the highest rate of P . vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0–19.5 p = 0.002) patients treated with AL (AHR = 6.2, 95% CI 4.6–8.5 p 0.001), AA (AHR = 2.3, 95% CI 1.4–3.7 p = 0.001), or AM (AHR = 1.4, 95% CI 1.0–1.9 p = 0.028) compared with DP and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4–2.3 p 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. In this meta-analysis, we found a high risk of P . vivax parasitaemia after treatment of P . falciparum malaria that varied significantly between studies. These P . vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent however, the benefits of such a novel strategy will vary considerably between geographical areas.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 02-04-2014
Publisher: BMJ
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 06-08-2012
Abstract: Published literature on surgical care in refugees tends to focus on the acute (‘emergent’) phase of crisis situations. Here we posit that there is a substantial burden of non-acute morbidity amenable to surgical intervention among refugees in the ‘chronic’ phase of crisis situations. We describe surgery for non-acute conditions undertaken at Mae La Refugee C , Thailand over a two year period. Surgery was performed by a general surgeon in a dedicated room of Mae La Refugee C over May 2005 to April 2007 with minimal instruments and staff. We obtained the equivalent costs for these procedures if they were done at the local Thai District General Hospital. We also acquired the list (and costs) of acute surgical referrals to the District General Hospital over September 2006 to December 2007. 855 operations were performed on 847 patients in Mae La Refugee C (60.1% sterilizations, 13.3% ‘general surgery’, 5.6% ‘gynaecological surgery’, 17.4% ‘mass excisions’, 3.5% ‘other’). These procedures were worth 2,207,500 THB (75,683.33 USD) at costs quoted by the District General Hospital. Total cost encountered for these operations (including staff costs, consumables, anaesthesia and capital costs such as construction) equaled 1,280,000 THB (42,666 USD). Pertaining to acute surgical referrals to District General hospital: we estimate that 356,411.96 THB (11,880.40 USD) worth of operations over 14 months were potentially preventable if these cases had been operated at an earlier, non-acute state in Mae La Refugee C . A considerable burden of non-acute surgical morbidity exists in ‘chronic’ refugee situations. An in-house general surgical service is found to be cost-effective in relieving some of this burden and should be considered by policy makers as a viable intervention.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2012
Abstract: Globally, alcohol use contributes to close to 4% of all deaths and is a leading cause of ill health and premature death among men of reproductive age. Problem alcohol use is an unaddressed public health issue among populations displaced by conflict. Assessing the magnitude of the problem and identifying affected groups and risk behaviours is difficult in mobile and unstable populations. From 15–28 December 2009 we conducted a simple rapid screening test of risky alcohol use using the single item modified Short Assessment Screening Questionnaire (mSASQ) by all women currently enrolled in the antenatal care clinic in Mae La refugee c , a long standing displaced setting on the Thai Burma border. Women self- reported and gave a secondary report of their male partners. Gender differences in alcohol use were further explored in semi-structured interviews with c residents on attitudes, behaviours, and beliefs regarding alcohol and analysed thematically. Of 636 women screened in the antenatal clinic, almost none (0.2%, 95CI 0.0-0.9%) reported risky alcohol use prior to pregnancy, whereas around a quarter (24.4%, 95CI 21.2-27.9%) reported risky alcohol use by their male partners. Interviews with 97 c residents described strong social controls against women’s alcohol use and men’s drinking to intoxication, despite a dominant perception that the social context of life in displacement promoted alcohol use and that controls are loosening. As a stigmatised behaviour, alcohol use is difficult to assess, particularly in the context of highly mobile adult male populations: the simple assessment methods here show that it is feasible to obtain adequate data for the purposes of intervention design. The data suggest that risky drinking is common and normalised among men, but that the population may have been partially protected from rapid rises in problem alcohol use observed in nation-wide data from Thailand. The changing social context contains vulnerabilities that might promote problem alcohol use: further investigation, ongoing monitoring, and development of targeted interventions are warranted.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-12-2018
Abstract: Malaria parasites are evolutionarily prepared to resist drug attack. Resistance is emerging to even the latest frontline combination therapies, which target the blood stages of the Plasmodium parasite. As an alternative strategy, Antonova-Koch et al. investigated the possibilities of drugs against liver-stage parasites (see the Perspective by Phillips and Goldberg). To do so, they devised a luciferase-reporter drug screen for the rodent parasite Plasmodium berghei. Three rounds of increasingly stringent screening were used. From this regime, several chemotypes that inhibit Plasmodium mitochondrial electron transport were identified. Excitingly, several new scaffolds, with as-yet-unknown modes of action but solely targeting the parasites' liver stages, emerged as promising drug leads for further development. Science , this issue p. eaat9446 see also p. 1112
Publisher: The Royal Society
Date: 12-2015
Publisher: Springer Science and Business Media LLC
Date: 05-02-2015
Publisher: Oxford University Press (OUP)
Date: 15-11-2008
DOI: 10.1086/592451
Publisher: F1000 Research Ltd
Date: 23-03-2023
DOI: 10.12688/WELLCOMEOPENRES.19049.1
Abstract: Background: Measurement of antibody titers directed against mosquito salivary antigens in blood s les has been proposed as an outcome measure to assess human exposure to vector bites. However, only a handful of antigens have been identified and the specificity and longitudinal dynamics of antibody responses are not well known. We report the protocol of a clinical trial of controlled exposure to mosquito bites that aims to identify and validate biomarkers of exposure to bites of mosquito vector species that transmit malaria and dengue in Southeast Asia and some other parts of the world. Methods: This study is an exploratory factorial randomized control trial of controlled exposure to mosquito bites with 10 arms corresponding to different species ( Aedes aegypt , Ae. albopictus , Anopheles dirus , An. maculatus and An. minimus ) and numbers of bites (35 or 305 bites in total over 6 weeks). Blood s les will be collected from study participants before, during and after mosquito biting challenges. Candidate peptides will be identified from published literature with antigen prediction algorithms using mosquito DNA sequence data and with immunoblotting assays carried out using protein extracts of dissected mosquito salivary glands and participants s les. Antibody titers against candidate peptides will be determined in participants s les with high-throughput cutting-edge immuno-assays. Quantification of the antibody response profile over time (including an estimate of the decay rate) and the effect of the number of bites on the antibody response will be determined using linear and logistic mixed-effects models for the continuous and the binary response, respectively. Conclusion: This research is expected to generate important knowledge for vector sero-surveillance and evaluation of vector-control interventions against malaria and dengue in the Greater Mekong Subregion. Registration: This study is registered with clinicaltrials.gov (NCT04478370) on July 20 th , 2020.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2009
Publisher: Oxford University Press (OUP)
Date: 15-07-2008
DOI: 10.1086/589287
Abstract: The reported case-fatality rate associated with severe malaria varies widely. Whether age is an independent risk factor is uncertain. In a large, multicenter treatment trial conducted in Asia, the presenting manifestations and outcome of severe malaria were analyzed in relation to age. Among 1050 patients with severe malaria, the mortality increased stepwise, from 6.1% in children (age, 50 years (P<0.001). Compared with adults aged 21-50 years, the decreased risk of death among children (adjusted odds ratio, 0.06 95% confidence interval, 0.01-0.23 P 50 years (adjusted odds ratio, 1.88 95% confidence interval, 1.01-3.52 P<0.001) was independent of the variation in presenting manifestations. The incidence of anemia and convulsions decreased with age, whereas the incidence of hyperparasitemia, jaundice, and renal insufficiency increased with age. Coma and metabolic acidosis did not vary with age and were the strongest predictors of a fatal outcome. The number of severity signs at hospital admission also had a strong prognostic value. Presenting syndromes in severe malaria depend on age, although the incidence and the strong prognostic significance of coma and acidosis are similar at all ages. Age is an independent risk factor for a fatal outcome of the disease.
Publisher: Elsevier BV
Date: 10-2014
Publisher: Elsevier BV
Date: 15-06-2006
DOI: 10.1016/J.SCITOTENV.2005.06.032
Abstract: Populations living in endemic malaria areas maybe exposed simultaneously to DDT and malaria infection. DDT may impair status of vitamins, which are implicated in the immunity and pathophysiology of malaria. To explore possible interactions, DDT residues, retinol, alpha-tocopherol, beta-carotene and cholesterol were measured in plasma s les of malaria-infected pregnant women (cases, n=50) and age matched malaria-free controls (n=58). DDT residues were found in all s les: mean (sd) total DDT levels of 29.7 and 32.7 ng/ml in cases and controls, respectively. Mean (sd) p,p'-DDT was higher in the controls than the cases (13.5 vs. 9.5 ng/ml, p=0.006). Malaria infection was associated with lower mean (sd) plasma retinol (0.69 vs. 1.23 micromol/L) and cholesterol (2.62 vs. 3.48 mmol/L) compared to controls (p<0.001). Mean (sd) plasma alpha-tocopherol (7.65 vs. 15.58 micromol/L) and alpha-tocopherol/cholesterol ratio (2.3 vs. 6.7 micromol/L/mmol/L) were significantly lower among the controls (p<0.001). Mean (sd) plasma beta-carotene was low (<0.3 micromol/L) in both groups, but higher among malaria cases (0.19 vs. 0.15 micromol/L). Plasma retinol among the controls showed highly significant positive correlations with in idual DDT compounds, particularly with p,p'-DDT (r=0.51, p<0.001). Plasma alpha-tocopherol and beta-carotene seemed not to be affected by DDT residues.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2018
DOI: 10.1038/S41467-018-04817-1
Abstract: The original version of this Article contained an error in the spelling of Richard Thomson-Luque, which was incorrectly given as Richard Thomson Luque. This error has now been corrected in both the PDF and HTML versions of the Article.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2021
DOI: 10.1186/S12884-021-03914-2
Abstract: Globally 90 % of transmission of Hepatitis B virus (HBV) is from mother-to child and occurs predominantly in resource limited countries where the prevalence of HBV is high. Transmission could be interrupted by timely vaccinations but coverage remains problematic in these areas. Low knowledge or awareness of HBV may play a part in low vaccination coverage. This study examines the provision of antenatal care counselling with a focus on HBV in two different regions of northern Thailand, Sarapee Hospital (SH), Chiang Mai, and Shoklo Malaria Research Unit (SMRU), Tak Province. A mixed-methods sequential explanatory study design was used to evaluate antenatal services for migrants. Cross-sectional knowledge, attitude and practice (KAP) surveys were conducted immediately after counselling at first ANC contact, at 3–6 months after first ANC contact and at delivery. Surveys provided quantitative data, and qualitative methods included observations, focus group discussions (FGD) and in-depth interviews (IDI) analysed thematically to explore concepts of knowledge and understanding, attitude and practice of pregnant women and providers. Between September-2019 and May-2020, 757 women participated to KAP surveys, and 31 observations of counselling, 16 FGD and 9 IDI were conducted. KAP surveys showed in spite of low knowledge about HBV transmission, infection, or vaccination (correct response: SH 5.7 %, 9/157 SMRU 34.0 %, 204/600), most women (≥ 93 %, either site) understood they were screened for HBV and were willing to vaccinate infants for HBV. In explaining KAP survey results, qualitative analysis suggests counselling should: use the appropriate language be tailored to the local health literacy level, provide only pertinent information, be repeated over the antenatal period and attempt to ensure patient privacy (where possible). Programme effectiveness benefits from positive attitudes to screening and vaccinations and a high level of trust in the providers nevertheless participants provided good suggestions for improvements of the service. Limited knowledge of HBV among migrant women can be improved by counselling that emphasizes actionable knowledge such as vaccination schedule. Key improvements to the counselling process include training counsellors to conduct interactive counselling sessions in the woman’s language, using appropriate visual aids and timely repetition over the course of the antenatal period.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2017
Publisher: Oxford University Press (OUP)
Date: 16-04-2013
Publisher: Public Library of Science (PLoS)
Date: 08-2006
Publisher: Proceedings of the National Academy of Sciences
Date: 20-12-2010
Abstract: Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic–pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03–0.67 in log 10 scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration–effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.
Publisher: Public Library of Science (PLoS)
Date: 28-11-2006
Publisher: Springer Science and Business Media LLC
Date: 12-2008
Publisher: Springer Science and Business Media LLC
Date: 27-11-2013
DOI: 10.1038/NATURE12782
Publisher: Elsevier BV
Date: 06-2001
Abstract: The rising prevalence of multidrug resistant falciparum malaria is occurring at an alarming rate and has serious implications for the health of many of the world's poorest countries. The dangers of not changing treatment practices immediately are huge and irreversible, threatening to both exacerbate the scale and scope of the malaria pandemic, and deprive policymakers of future options against the disease. If a health care disaster is to be avoided then massive and long term funding is urgently required. Funds need to be applied in a cohesive manner, accountable to funding bodies and tailored to the specifics of each endemic region. The key elements of such an approach should be improving early diagnosis and treatment of infection and the deployment of combination regimens containing an artemisinin derivative. These short term measures will need to be accompanied by a longer term strategy to encourage antimalarial drug research and development.
Publisher: Public Library of Science (PLoS)
Date: 09-02-2012
Publisher: Journal of Infection in Developing Countries
Date: 28-04-2016
DOI: 10.3855/JIDC.7422
Abstract: Introduction: Infection from Hepatitis B primarily results from peri-partum vertical transmission and the risk increases in the presence of hepatitis B e antigen. We aimed to evaluate a new screening program for hepatitis B in pregnant women as a component of antenatal services in a marginalized population. Methodology: Counseling and screening for hepatitis B screening was offered to all women at the first visit, at Shoklo Malaria Research Unit (SMRU) antenatal clinics on the Thai-Myanmar border. Point-of-care rapid diagnostic tests (RDT) were used throughout the period of evaluation. A certified Thai Public Health laboratory at Mae Sot Hospital verified RDT positive cases using enzyme-linked immunosorbent assay (ELISA) for HBsAb and HBeAg. Risk factors for hepatitis B were identified by data linkage to antenatal care records. Results: There were 523 (8.5%) RDT positive for HBsAg among 6158 women tested (Aug-2012 to April-2014). Of these 373 (96.9%) of 385 sent for confirmation were positive by ELISA i.e. RDT false positive rate of 3.1% (95% CI 1.7- 5.4). The overall confirmed HbsAg prevalence was 8.3% (511/6158) (95%CI 7.6-9.0). HBeAg prevalence was 32.7% (114/350) (95%CI 27.9-37.7) of cases tested. Risk factors for HBsAg positivity included age years (OR 1.24, CI 1.03-1.49, p 0.021) and Karen heritage (OR 1.73, CI 1.39-2.15, p 0.01). Conclusions: High hepatitis B seroprevalence amongst migrants and refugees accessing SMRU antenatal services likely reflects that of Kayin State, Myanmar, and perinatal prevention programs are required. False positive cases with HBsAg RDT complicate what is theoretically a straightforward screening.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2017
Publisher: Elsevier BV
Date: 02-2012
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1016/S0140-6736(98)09247-2
Abstract: Plasmodium vivax is more common than P. falciparum as a cause of malaria in many parts of the tropics outside Africa. P. falciparum infection has harmful effects in pregnancy, but the effects of P. vivax have not been characterised. We investigated the effects of P. vivax infection during pregnancy. Since 1986, pregnant Karen women living in c s for displaced people on the western border of Thailand have been encouraged to attend antenatal clinics. Karen women were screened for malaria and anaemia at each week of pregnancy until delivery, and pregnancy outcome recorded. We compared the effects of P. vivax infection on anaemia and pregnancy outcome with those of P. falciparum and no malaria infection in the first pregnancy recorded at the antenatal clinics. There were 634 first episodes of pure P. vivax malaria in 9956 women. P. vivax malaria was more common in primigravidae than in multigravidae and was associated with mild anaemia and an increased risk of low birthweight (odds ratio 1.64 [95% CI 1.29-2.08], p<0.001). The birthweight was a mean of 107 g (95% CI 61-154) lower in women with P. vivax infection than in uninfected women. By contrast with P. falciparum malaria, the decrease in birthweight was greater in multigravidae. P. vivax malaria was not associated with miscarriage, stillbirth, or with a shortened duration of pregnancy. P. vivax malaria during pregnancy is associated with maternal anaemia and low birthweight. The effects of P. vivax infection are less striking than those of P. falciparum infection, but antimalarial prophylaxis against P. vivax in pregnancy may be justified.
Publisher: American Society for Microbiology
Date: 03-2011
DOI: 10.1128/AAC.01103-10
Abstract: Plasmodium species ex vivo sensitivity assay protocols differ in the requirement for leukocyte removal before culturing. This study shows that the presence of leukocytes significantly increases the 50% inhibitory concentration (IC 50 ) of P. vivax and P. falciparum to artesunate and chloroquine relative to results with the paired leukocyte-free treatment. Although leukocyte removal is not an essential requirement for the conduct of ex vivo assays, its use has important implications for the interpretation of temporal and spatial antimalarial sensitivity data.
Publisher: Oxford University Press (OUP)
Date: 21-08-2014
DOI: 10.1093/JAC/DKU326
Publisher: Informa UK Limited
Date: 15-12-1999
Abstract: Plasmodium falciparum malaria is increasing world-wide, as is resistance to the available antimalarials. On the Thai-Burmese border this problem is most acute in pregnant women, as options for their treatment are even more restricted because of the unknown effects of antimalarials on the foetus. Presented here are the results of descriptive, clinical, drug studies on quinine, mefloquine and artemisinin derivatives for P. falciparum in pregnant women. Mefloquine and quinine have high failure rates for primary and recrudescent infections. Artemisinin-based treatments in pregnant women have proved safe, tolerable and efficacious. However, randomized drug studies with these drugs and other new antimalarials are required to define the true safety and efficacy of these drugs in pregnant women.
Publisher: Informa UK Limited
Date: 09-1998
Abstract: Between 1991 and 1996, 372 pregnant women with uncomplicated, multidrug-resistant Plasmodium falciparum malaria, living on the western border of Thailand, were treated with either mefloquine (N = 194), quinine (N = 93) or both drugs (N = 85). Antimalarial treatment was generally well tolerated the most common side-effects were dizziness (42%) and tinnitus (35%) following quinine, and anorexia (23%) and dizziness (36%) following mefloquine. In the patients treated for primary infections with melfloquine, 6% failed to clear their parasitaemia by day 7 and 28% failed by day 42. The corresponding figures for quinine were 4% and 23%, respectively. The failure rates in the 117 women treated for recrudescent infections were higher, the increase being significant for quinine (38% P = 0.03) but not for mefloquine (37%). The percentage of pregnant women who had patent gametocytaemia on presentation ranged from 4%-19%. Over 50% of the patients were anaemic (haematocrit < 30%) on presentation and 52% of those not anaemic on enrolment developed anaemia during follow-up. Mefloquine and quinine, the only antimalarials generally available for the treatment of highly drug-resistant P. falciparum in pregnancy, give unsatisfactory treatment responses when used as single agents. New, safe and effective regimens are needed for the treatment of pregnant women with multidrug-resistant falciparum malaria.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2022
DOI: 10.1186/S12936-022-04175-W
Abstract: The collection and utilization of surveillance data is essential in monitoring progress towards achieving malaria elimination, in the timely response to increases in malaria case numbers and in the assessment of programme functioning. This paper describes the surveillance activities used by the malaria elimination task force (METF) programme which operates in eastern Myanmar, and provides an analysis of data collected from weekly surveillance, case investigations, and monitoring and evaluation of programme performance. This retrospective analysis was conducted using data collected from a network of 1250 malaria posts operational between 2014 and 2021. To investigate changes in data completeness, malaria post performance, malaria case numbers, and the demographic details of malaria cases, summary statistics were used to compare data collected over space and time. In the first 3 years of the METF programme, improvements in data transmission routes resulted in a 18.9% reduction in late reporting, allowing for near real-time analysis of data collected at the malaria posts. In 2020, travel restrictions were in place across Karen State in response to COVID-19, and from February 2021 the military coup in Myanmar resulted in widescale population displacement. However, over that period there has been no decline in malaria post attendance, and the majority of consultations continue to occur within 48 h of fever onset. Case investigations found that 43.8% of cases travelled away from their resident village in the 3 weeks prior to diagnosis and 36.3% reported never using a bed net whilst sleeping in their resident village, which increased to 72.2% when sleeping away from their resident village. Malaria post assessments performed in 82.3% of the METF malaria posts found malaria posts generally performed to a high standard. Surveillance data collected by the METF programme demonstrate that despite significant changes in the context in which the programme operates, malaria posts have remained accessible and continue to provide early diagnosis and treatment contributing to an 89.3% decrease in Plasmodium falciparum incidence between 2014 and 2021.
Publisher: Oxford University Press (OUP)
Date: 11-2001
DOI: 10.1016/S0035-9203(01)90106-3
Abstract: In areas where multidrug-resistant Plasmodium falciparum (MDR-Pf) is prevalent, only quinine is known to be safe and effective in pregnant women. On the western border of Thailand, 7 days of supervised quinine (30 mg/kg daily) cures two-thirds of P. falciparum-infected women in the 2nd and 3rd trimesters of pregnancy. Artesunate is effective against MDR-Pf and the limited data on its use in pregnancy suggest it is safe. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) in combination with clindamycin (5 mg/kg every 8 h) for 7 days (QC7) versus artesunate 2 mg/kg per day for 7 days (A7) was conducted in 1997-2000 in 129 Karen women with acute uncomplicated falciparum malaria in the 2nd or 3rd trimesters of pregnancy. There was no difference in the day-42 cure rates between the QC7 (n = 65) and A7 (n = 64) regimens with an efficacy of 100% in both, confirmed by parasite genotyping. The A7 regimen was also associated with less gametocyte carriage the average person-gametocyte-weeks for A7 was 3 (95% CI 0-19) and for QC7 was 39 (95% CI 21-66) per 1000 person-weeks, respectively (P < 0.01). There was no difference in gastrointestinal symptoms between the groups but there was significantly more tinnitus in the QC7 group compared to the A7 group (44.9% vs 8.9% RR 5.1 95% CI 1.9-13.5 P < 0.001). The favourable results with quinine-clindamycin mean that there is a useful back-up treatment for women with falciparum malaria who experience quinine and artesunate failures in pregnancy. Adherence to the 7-day regimen and cost (US$18.50 per treatment) are likely to be the main obstacles to this regimen.
Publisher: BMJ
Date: 29-06-2006
Publisher: Wiley
Date: 30-07-2012
DOI: 10.1002/UOG.11091
Publisher: Oxford University Press (OUP)
Date: 15-02-2010
DOI: 10.1086/650301
Publisher: Springer Science and Business Media LLC
Date: 26-05-2021
DOI: 10.1038/S41467-021-23422-3
Abstract: Despite the high burden of Plasmodium vivax malaria in South Asian countries, the genetic ersity of circulating parasite populations is not well described. Determinants of antimalarial drug susceptibility for P. vivax in the region have not been characterised. Our genomic analysis of global P. vivax ( n = 558) establishes South Asian isolates ( n = 92) as a distinct subpopulation, which shares ancestry with some East African and South East Asian parasites. Signals of positive selection are linked to drug resistance-associated loci including pvkelch10, pvmrp1, pvdhfr and pvdhps , and two loci linked to P. vivax invasion of reticulocytes, pvrbp1a and pvrbp1b . Significant identity-by-descent was found in extended chromosome regions common to P. vivax from India and Ethiopia, including the pvdbp gene associated with Duffy blood group binding. Our investigation provides new understanding of global P. vivax population structure and genomic ersity, and genetic evidence of recent directional selection in this important human pathogen.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2011
Abstract: Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. To identify key features associated with the delayed parasite clearance phenotype, we employed DNA microarrays to profile the physiological gene expression pattern of the resistant isolates. In the ring and trophozoite stages, we observed reduced expression of many basic metabolic and cellular pathways which suggests a slower growth and maturation of these parasites during the first half of the asexual intraerythrocytic developmental cycle (IDC). In the schizont stage, there is an increased expression of essentially all functionalities associated with protein metabolism which indicates the prolonged and thus increased capacity of protein synthesis during the second half of the resistant parasite IDC. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of regulatory proteins such as transcription factors or chromatin remodeling associated proteins. In addition, there is a unique and uniform copy number variation pattern in the Cambodian parasites which may represent an underlying genetic background that contributes to the resistance phenotype. The decreased metabolic activities in the ring stages are consistent with previous suggestions of higher resilience of the early developmental stages to artemisinin. Moreover, the increased capacity of protein synthesis and protein turnover in the schizont stage may contribute to artemisinin resistance by counteracting the protein damage caused by the oxidative stress and/or protein alkylation effect of this drug. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides insight to the complexities of the molecular basis of pathogens with drug resistance phenotypes in vivo .
Publisher: American Society of Tropical Medicine and Hygiene
Date: 03-05-2017
Publisher: American Society of Tropical Medicine and Hygiene
Date: 08-01-2020
Publisher: Public Library of Science (PLoS)
Date: 06-06-2019
Publisher: Springer Science and Business Media LLC
Date: 16-07-2012
Publisher: Springer Science and Business Media LLC
Date: 20-02-2014
Abstract: 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.
Publisher: Springer Science and Business Media LLC
Date: 02-06-2009
Abstract: Investigations of Plasmodium vivax are restricted to s les collected from infected persons or primates, because this parasite cannot be maintained in in vitro cultures. Contamination of P. vivax isolates with host leukocytes and platelets is detrimental to a range of ex vivo and molecular investigations. Easy-to-produce CF11 cellulose filters have recently provided us with an inexpensive method for the removal of leukocytes and platelets. This contrasted with previous reports of unacceptably high levels of infected red blood cell (IRBC) retention by CF11. The aims of this study were to compare the ability of CF11 cellulose filters and the commercial filter Plasmodipur at removing leukocyte and platelet, and to investigate the retention of P. vivax IRBCs by CF11 cellulose filtration. Side-by-side comparison of six leukocyte removal methods using blood s les from five healthy donor showed that CF11 filtration reduced the mean initial leukocyte counts from 9.4 × 10 3 per μl [95%CI 5.2–13.5] to 0.01 × 10 3 [95%CI 0.01–0.03]. The CF11 was particularly effective at removing neutrophils. CF11 treatment also reduced initial platelet counts from 211.6 × 10 3 per μl [95%CI 107.5–315.7] to 0.8 × 10 3 per μl [95%CI -0.7–2.2]. Analysis of 30 P. vivax blood s les before and after CF11 filtration showed only a minor loss in parasitaemia (≤ 7.1% of initial counts). Stage specific retention of P. vivax IRBCs was not observed. CF11 filtration is the most cost and time efficient method for the production of leukocyte- and platelet-free P. vivax -infected erythrocytes from field isolates.
Publisher: American Society for Microbiology
Date: 09-2018
DOI: 10.1128/IAI.00239-18
Abstract: Plasmodium vivax parasites preferentially invade reticulocytes in human beings. P. vivax merozoite surface protein 1 (PvMSP1) and PvMSP1 paralog (PvMSP1P) may have important functions in reticulocyte adherence during invasion.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2009
Publisher: Informa UK Limited
Date: 12-2000
DOI: 10.1080/02724936.2000.11748154
Abstract: The aim of the study was to design and test a neurological examination for newborns that could be performed reliably by paramedical staff in resource-poor settings. The examination was adapted from a method established by Dubowitz et al., the latest version of which includes an optimality score. The final items in the test were chosen because they were culturally acceptable, could be elicited according to strict but easily comprehensible instructions and because the expected responses could be scored by the descriptions given or by diagrams in the proforma. The shortened examination was easily taught to paramedical staff who achieved a high degree of inter-observer reliability. This shortened version of the examination was piloted by comparing newborns from a Karen refugee c on the western border of Thailand and from a large maternity hospital in Bangkok with a standardized cohort of newborns in London. The modified shortened version of the test was sufficiently sensitive to identify a number of differences between the cohorts, notably the poor vision performance and markedly reduced tone of the Karen newborns. In conclusion, the test can be used very reliably by paramedical staff and is a useful, simple and portable tool for the neurological assessment of newborn babies where resources are limited.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 12-07-2017
Publisher: Mary Ann Liebert Inc
Date: 05-2015
Publisher: Informa UK Limited
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 18-03-2021
Publisher: Oxford University Press (OUP)
Date: 07-1999
DOI: 10.1016/S0035-9203(99)90149-9
Abstract: The efficacy of chloroquine (25 mg base/kg over 3 days) in Plasmodium vivax malaria was evaluated in 1995/96 in 342 patients living in an endemic area on the western border of Thailand. Clearance of fever and parasites was obtained within 2 days in > 95% of the patients, and all were aparasitaemic by day 4. Reappearance of P. vivax occurred in 1 patient on day 21 and in 8 by day 28, giving a 28-day cure rate of 97% [95% confidence interval (CI) 95-99%]. By day 63, the relapse/re-infection rate was 63% (95% CI 57-69%). Most reappearances of parasitaemia (85% 121/143) were symptomatic. These patients were retreated either with chloroquine alone (n = 70) or with chloroquine and primaquine (0.25 mg/kg daily for 14 days) (n = 43). Only 1 patient (in the chloroquine-only group) had prolonged parasite clearance (D8) and he developed recurrent P. vivax by day 21 suggesting possible recrudescence. The addition of primaquine to chloroquine reduced the risk of having a third vivax episode within 2 months by 96% (95% CI 83-99%). This resulted in a significantly higher haematocrit at day 42 despite a greater decrease in haematocrit during the first week of treatment with chloroquine-primaquine (P = 0.04). Chloroquine remains highly effective on the western border of Thailand and the use of strictly supervised primaquine effectively prevents relapse. The introduction of primaquine on a large scale in an endemic area still requires a long-term risk-benefit assessment which must take into account potential toxicity, low compliance and reductions in the incidence and severity of P. falciparum infections by co-existent P. vivax.
Publisher: Elsevier BV
Date: 12-2012
Publisher: Public Library of Science (PLoS)
Date: 04-05-2023
DOI: 10.1371/JOURNAL.PGPH.0001875
Abstract: Despite advances, international research ethics guidelines still tend to consist of high-level ethical principles reflecting residual influence from North American and European traditions of ethics. Local ethics committees and community advisory boards can offer more culturally-sensitive approaches to training but most institutions lack substantive practical ethics guidance to engage rich moral understandings in day-to-day research practice in erse cultural contexts. To address this gap, we conducted an international series of qualitative research ethics case studies, linked prospectively to active research programs in erse settings. Here, we share findings from two case studies with a research team working on malaria and hepatitis B prevention with pregnant women in clinics serving migrants along the Thai-Myanmar border. In this sociocultural ethical analysis, we consider how core ethical requirements of voluntary participation, provision of fair benefits, and understandings of research risks and burdens are shaped, enriched, and in some instances challenged, by deep-seated and widespread Burmese, Karen and Thai cultural norms known as Arr-nar (in Burmese and Karen) or Kreng-jai (in Thai), encompassing multiple meanings including consideration for others and graciousness. We offer a model illustrating how one might map ethically significant sociocultural influences across the research practice pathway and close with lessons for developing a more culturally responsive research ethics practice in other international settings.
Publisher: Wiley
Date: 18-01-2007
DOI: 10.1111/J.1365-3156.2006.01785.X
Abstract: Adherence to antimalarial drug regimens is improved by simple dosing. If the fixed antimalarial drug combination artemether-lumefantrine (AL) could be given once daily, this should improve adherence and thus effectiveness and lower the risk of selecting for resistance. In an open randomized study, 43 patients with uncomplicated falciparum malaria were given equivalent doses of AL with 200 ml flavoured milk either as the conventional twice-daily regimen or as a single daily dose for 3 days. The primary end point was a comparison of the areas under the plasma lumefantrine concentration-time curves (AUC). Secondary end points were the day 42 polymerase chain reaction (PCR)-adjusted cure rates and the tolerability profiles. Lumefantrine pharmacokinetic profiles were obtained for 36 patients. The AUC((0-->infinity)) of the once-daily regimen was 30% lower than that in the conventional regimen (P = 0.011) with a median (range) value of 306 (114-5781) microg/ml h, compared with 432 (308-992) microg/ml h. There was no significant difference in the peak plasma concentrations reached. PCR-adjusted cure rate estimates at day 42 of follow-up were 94% (95% CI: 84-100) in the six-dose arm and 85% (70-100) in the three-dose arm (P = 0.3). Artemether-lumefantrine efficacy is reduced by once-daily dosing, because absorption of lumefantrine is dose limited. At currently recommended doses, this antimalarial should be given twice daily in a 3-day regimen, with food containing fat.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.TMAID.2005.06.009
Abstract: Malaria is increasing worldwide due to the emergence and spread of drug resistant strains. This poses major health and economic problems for the population living in endemic areas and increases the risk of infections in travelers. The diagnosis of malaria relies on a biological proof of infection by microscopy or with a rapid test. The treatment must be initiated without delay preferably with an artemisinin containing regimen. Uncomplicated malaria can be treated with oral drugs while severe infections will be hospitalized and treated with injectables. Special attention will be given to the most susceptible groups: children and pregnant women.
Publisher: Public Library of Science (PLoS)
Date: 13-02-2020
Publisher: Oxford University Press (OUP)
Date: 05-05-2011
Publisher: American Society for Microbiology
Date: 10-2018
DOI: 10.1128/AAC.02193-17
Abstract: Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses.
Publisher: American Society for Microbiology
Date: 18-03-2021
DOI: 10.1128/AAC.02473-20
Abstract: Quinoline antimalarials cause drug-induced electrocardiograph QT prolongation, a potential risk factor for torsade de pointes. The effects of currently used antimalarials on the electrocardiogram (ECG) were assessed in pregnant women with malaria.
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 09-2012
Publisher: Wiley
Date: 13-01-2006
Publisher: The Royal Society
Date: 14-04-2010
Abstract: Malaria parasites vary in phenotypic traits of biomedical or biological interest such as growth rate, virulence, sex ratio and drug resistance, and there is considerable interest in identifying the genes that underlie this variation. An important first step is to determine trait heritability ( H 2 ). We evaluate two approaches to measuring H 2 in natural parasite populations using relatedness inferred from genetic marker data. We collected single-clone Plasmodium falciparum infections from 185 patients from the Thailand–Burma border, monitored parasite clearance following treatment with artemisinin combination therapy (ACT), measured resistance to six antimalarial drugs and genotyped parasites using 335 microsatellites. We found strong relatedness structure. There were 27 groups of two to eight clonally identical (CI) parasites, and 74 per cent of parasites showed significant relatedness to one or more other parasites. Initially, we used matrices of allele sharing and variance components (VC) methods to estimate H 2 . Inhibitory concentrations (IC 50 ) for six drugs showed significant H 2 (0.24 to 0.79, p = 0.06 to 2.85 × 10 −9 ), demonstrating that this study design has adequate power. However, a phenotype of current interest—parasite clearance following ACT—showed no detectable heritability ( H 2 = 0–0.09, ns) in this population. The existence of CI parasites allows the use of a simple ANOVA approach for quantifying H 2 , analogous to that used in human twin studies. This gave similar results to the VC method and requires considerably less genotyping information. We conclude (i) that H 2 can be effectively measured in malaria parasite populations using minimal genotype data, allowing rational design of genome-wide association studies and (ii) while drug response (IC 50 ) shows significant H 2 , parasite clearance following ACT was not heritable in the population studied.
Publisher: BMJ
Date: 05-2019
DOI: 10.1136/BMJOPEN-2018-027503
Abstract: Pregnant women are more vulnerable to malaria leading to adverse impact on both mothers and fetuses. However, knowledge on the efficacy and safety of antimalarials in pregnancy is limited by the paucity of randomised control trials and the lack of standardised protocols in this special subpopulation. Pooling in idual patient data (IPD) for meta-analysis could address in part these limitations to summarise accurately the currently available evidence on treatment efficacy and risk factors for treatment failure. To assess the treatment efficacy of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy, seven databases (Medline, Embase, Global Health, Cochrane Library, Scopus, Web of Science and Literatura Latino Americana em Ciências da Saúde) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrial.gov) were searched. Both interventional and observational cohort studies following up for at least 28 days will be included. IPD of the identified eligible published or unpublished studies will be sought by inviting principal investigators. Raw IPD will be shared through the web-based secure platform developed by the WorldWide Antimalarial Resistance Network using the established methodology. The primary objective is to compare the risk of PCR-corrected treatment failure among different treatments and to find the risk factors. One-stage IPD meta-analysis by Cox model with shared frailty will be conducted. A risk of bias assessment will be conducted to address the impact of unshared potential data and of the quality of in idual studies. Potential limitations include difficulty in acquiring the IPD and heterogeneity of the study designs due to the lack of standard. This IPD meta-analysis consists of secondary analyses of existing anonymous data and meets the criteria for waiver of ethics review by the Oxford Tropical Research Ethics Committee. The results of this IPD meta-analysis will be disseminated through open-access publications at peer-reviewed journals. The study results will lead to a better understanding of malaria treatment in pregnancy, which can be used for clinical decision-making and conducting further studies. CRD42018104013.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.JCHROMB.2008.10.021
Abstract: A bioanalytical method for the analysis of artesunate (ARS) and its metabolite dihydroartemisinin (DHA) in human plasma using protein precipitation and liquid chromatography coupled to positive tandem mass spectroscopy was developed. The method was validated according to published US FDA-guidelines and showed excellent performance. However, when it was applied to clinical pharmacokinetic studies in malaria, variable degradation of the artemisinins introduced an unacceptable large source of error, rendering the assay useless. Haemolytic products related to s le collection and malaria infection degraded the compounds. Addition of organic solvents during s le processing and even low volume addition of the internal standard in an organic solvent caused degradation. A solid phase extraction method avoiding organic solvents eliminated problems arising from haemolysis induced degradation. Plasma esterases mediated only approximately 20% of ex vivo hydrolysis of ARS into DHA. There are multiple sources of major preventable error in measuring ARS and DHA in plasma s les from clinical trials. These various pitfalls have undoubtedly contributed to the large inter-subject variation in plasma concentration profiles and derived pharmacokinetic parameters for these important antimalarial drugs.
Publisher: American Society for Microbiology
Date: 09-2009
DOI: 10.1128/AAC.00195-09
Abstract: Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women ( n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma s les for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interin idual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of ng/ml (which corresponds to approximately ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.
Publisher: American Society for Microbiology
Date: 03-2014
DOI: 10.1128/IAI.01169-13
Abstract: In a recent vaccine trial performed with African children, immunization with a recombinant protein based on Plasmodium falciparum apical membrane antigen 1 (AMA-1) conferred a significant degree of strain-specific resistance against malaria. To contribute to the efforts of generating a vaccine against Plasmodium vivax malaria, we expressed the ectodomain of P. vivax AMA-1 (PvAMA-1) as a secreted soluble protein in the methylotrophic yeast Pichia pastoris . Recognized by a high percentage of sera from in iduals infected by P. vivax , this recombinant protein was found to have maintained its antigenicity. The immunogenicity of this protein was evaluated in mice using immunization protocols that included homologous and heterologous prime-boost strategies with plasmid DNA and recombinant protein. We used the following formulations containing different adjuvants: aluminum salts (Alum), Bordetella pertussis monophosphoryl lipid A (MPLA), flagellin FliC from Salmonella enterica serovar Typhimurium, saponin Quil A, or incomplete Freund's adjuvant (IFA). The formulations containing the adjuvants Quil A or IFA elicited the highest IgG antibody titers. Significant antibody titers were also obtained using a formulation developed for human use containing MPLA or Alum plus MPLA. Recombinant PvAMA-1 produced under “conditions of good laboratory practice” provided a good yield, high purity, low endotoxin levels, and no microbial contaminants and reproduced the experimental immunizations. Most relevant for vaccine development was the fact that immunization with PvAMA-1 elicited invasion-inhibitory antibodies against different Asian isolates of P. vivax . Our results show that AMA-1 expressed in P. pastoris is a promising antigen for use in future preclinical and clinical studies.
Publisher: Oxford University Press (OUP)
Date: 05-1996
DOI: 10.1016/S0035-9203(96)90241-2
Abstract: Electrocardiographic monitoring over 24 h was performed with 53 patients with severe Plasmodium falciparum malaria (11 adults and 42 children) to assess the frequency of unrecognized cardiac arrhythmias. Nine patients (17%) died, 5 during the monitoring period and 4 afterwards. Pauses lasting 2-3 s were observed in 3 children, a single couplet in one, and a further child experienced frequent supraventricular ectopic beats which had not been detected clinically. In none of the patients who died could death be attributed to cardiac arrhythmia. Furthermore, no abnormality was detected which could have resulted from the often large doses of quinine, chloroquine or the artemisinin derivatives used for treatment. These results suggest that the heart is remarkably resilient even in the face of heavy parasite sequestration and other vital organ dysfunction, and that deaths from cardiac arrhythmias in severe malaria are rare. The need for routine cardiac monitoring of patients with severe and complicated P. falciparum malaria is questionable.
Publisher: Wiley
Date: 02-11-2012
DOI: 10.1111/MEC.12099
Publisher: Proceedings of the National Academy of Sciences
Date: 21-10-2008
Abstract: Plasmodium vivax causes over 100 million clinical infections each year. Primarily because of the lack of a suitable culture system, our understanding of the biology of this parasite lags significantly behind that of the more deadly species P. falciparum . Here, we present the complete transcriptional profile throughout the 48-h intraerythrocytic cycle of three distinct P. vivax isolates. This approach identifies strain specific patterns of expression for subsets of genes predicted to encode proteins associated with virulence and host pathogen interactions. Comparison to P. falciparum revealed significant differences in the expression of genes involved in crucial cellular functions that underpin the biological differences between the two parasite species. These data provide insights into the biology of P. vivax and constitute an important resource for the development of therapeutic approaches.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2005
Abstract: The use of antimalarial drug combinations with artemisinin derivatives is recommended to overcome drug resistance in Plasmodium falciparum . The fixed combination of oral artemether-lumefantrine, an artemisinin combination therapy (ACT) is highly effective and well tolerated. It is the only registered fixed combination containing an artemisinin. The trial presented here was conducted to monitor the efficacy of the six-dose regimen of artemether-lumefantrine (ALN) in an area of multi-drug resistance, along the Thai-Myanmar border. The trial was an open-label, two-arm, randomized study comparing artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated falciparum malaria with 42 days of follow up. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish recrudescent from newly acquired P. falciparum infections. The PCR adjusted cure rates were evaluated by survival analysis. In 2001–2002 a total of 490 patients with slide confirmed uncomplicated P. falciparum malaria were randomly assigned to receive artemether-lumefantrine (n = 245) or artesunate and mefloquine (n = 245) and were followed for 42 days. All patients had rapid initial clinical and parasitological responses. In both groups, the PCR adjusted cure rates by day 42 were high: 98.8% (95% CI 96.4, 99.6%) for artemether-lumefantrine and 96.3% (95% CI 93.1, 98.0%) for artesunate-mefloquine. Both regimens were very well tolerated with no serious adverse events observed attributable to either combination. Overall, this study confirms that these two artemisinin-based combinations remain highly effective and result in equivalent therapeutic responses in the treatment of highly drug-resistant falciparum malaria.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2020
Publisher: Springer Science and Business Media LLC
Date: 26-06-2014
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Publisher: Elsevier BV
Date: 05-2004
Publisher: Oxford University Press (OUP)
Date: 29-08-2016
Publisher: Oxford University Press (OUP)
Date: 15-12-2001
DOI: 10.1086/324349
Abstract: The emergence and spread of multidrug-resistant Plasmodium falciparum compromises the treatment of malaria, especially during pregnancy, where the choice of antimalarials is already limited. Artesunate (n=528) or artemether (n=11) was used to treat 539 episodes of acute P. falciparum malaria in 461 pregnant women, including 44 first-trimester episodes. Most patients (310 [57.5%]) received re-treatments after earlier treatment with quinine or mefloquine. By use of survival analysis, the cumulative artemisinin failure rate for primary infections was 6.6% (95% confidence interval, 1.0-12.3), compared with the re-treatment failure rate of 21.7% (95% confidence interval, 15.4-28.0 P=.004). The artemisinins were well tolerated with no evidence of adverse effects. Birth outcomes did not differ significantly to community rates for abortion, stillbirth, congenital abnormality, and mean gestation at delivery. These results are reassuring, but further information about the safety of these valuable antimalarials in pregnancy is needed.
Publisher: Mary Ann Liebert Inc
Date: 03-2010
Publisher: Springer Science and Business Media LLC
Date: 15-10-2008
Abstract: Haematological changes associated with malaria in pregnancy are not well documented, and have focused predominantly on anaemia. Examined here is thrombocytopaenia in pregnant women infected with Plasmodium falciparum or Plasmodium vivax in a low transmission area on the north-western border of Thailand. In this observational study we reviewed the platelet counts from routine complete blood count (CBC) in a cohort of healthy and malaria infected Karen pregnant women attending weekly antenatal clinics. A platelet count of 75,000/μL was the threshold at 2 standard deviations below the mean for healthy pregnant women used to indicate thrombocytopenia. Differences in platelet counts in non-pregnant and pregnant women were compared after matching for age, symptoms, malaria species and parasitaemia. In total 974 pregnant women had 1,558 CBC measurements between February 2004 and September 2006. The median platelet counts (/μL) were significantly lower in patients with an episode of falciparum 134,000 [11,000–690,000] (N = 694) or vivax malaria 184,000 [23,000–891,000] (N = 523) compared to healthy pregnant women 256,000 [64,000–781,000] (N = 255), P 0.05 for both comparisons. Plasmodium falciparum and P. vivax caused a 34% (95% CI 24–47) and 22% (95% CI 8–36) reduction in platelet count, respectively. Pregnant compared to non pregnant women were at higher risk OR = 2.27 (95%CI 1.16–4.4) P = 0.017, for thrombocytopaenia. Platelets counts were higher in first compared with subsequent malaria infections within the same pregnancy. Malaria associated thrombocytopaenia had a median [range] time for recovery of 7 [2–14] days which did not differ by antimalarial treatment (P = 0.86), or species (P = 0.63) and was not associated with active bleeding. Pregnant women become more thrombocytopenic than non-pregnant women with acute uncomplicated malaria. Uncomplicated malaria associated thrombocytopaenia is seldom severe. Prompt antimalarial treatment resulted in normalization of platelet counts within a week.
Publisher: Elsevier BV
Date: 08-2005
Publisher: Wiley
Date: 11-06-2015
DOI: 10.1111/TMI.12541
Publisher: BMJ
Date: 16-03-2012
DOI: 10.1136/MEDETHICS-2011-100301
Abstract: Bioethicists have long debated the content of sponsors and researchers' obligations of justice in international clinical research. However, there has been little empirical investigation as to whether and how obligations of responsiveness, ancillary care, post-trial benefits and research capacity strengthening are upheld in low- and middle-income country settings. In this paper, the authors argue that research ethics guidelines need to be more informed by international research practice. Practical guidance on how to fulfil these obligations is needed if research groups and other actors are to successfully translate them into practice because doing so is often a complicated, context-specific process. Case study research methods offer one avenue for collecting data to develop this guidance. The authors describe how such methods have been used in relation to the Shoklo Malaria Research Unit's vivax malaria treatment (VHX) trial (NCT01074905). Relying on the VHX trial ex le, the paper shows how information can be gathered from not only international clinical researchers but also trial participants, community advisory board members and research funder representatives in order to: (1) measure evidence of responsiveness, provision of ancillary care, access to post-trial benefits and research capacity strengthening in international clinical research and (2) identify the contextual factors and roles and responsibilities that were instrumental in the fulfilment of these ethical obligations. Such empirical work is necessary to inform the articulation of obligations of justice in international research and to develop guidance on how to fulfil them in order to facilitate better adherence to guidelines' requirements.
Publisher: Springer Science and Business Media LLC
Date: 10-06-2021
DOI: 10.1186/S12916-021-02002-8
Abstract: Artemisinin and artemisinin-based combination therapy (ACT) partner drug resistance in Plasmodium falciparum have spread across the Greater Mekong Subregion compromising antimalarial treatment. The current 3-day artemether-lumefantrine regimen has been associated with high treatment failure rates in pregnant women. Although ACTs are recommended for treating Plasmodium vivax malaria, no clinical trials in pregnancy have been reported. Pregnant women with uncomplicated malaria on the Thailand-Myanmar border participated in an open-label randomized controlled trial comparing dihydroartemisinin-piperaquine (DP), artesunate-mefloquine (ASMQ) and a 4-day artemether-lumefantrine regimen (AL + ). The primary endpoint for P. falciparum infections was the PCR-corrected cure rate and for P. vivax infections was recurrent parasitaemia, before delivery or day 63, whichever was longer, assessed by Kaplan-Meier estimate. Between February 2010 and August 2016, 511 pregnant women with malaria (353 P. vivax , 142 P. falciparum , 15 co-infections, 1 Plasmodium malariae ) were randomized to either DP ( n =170), ASMQ ( n =169) or AL + ( n =172) treatments. Successful malaria elimination efforts in the region resulted in premature termination of the trial. The majority of women had recurrent malaria (mainly P. vivax relapses, which are not prevented by these treatments). Recurrence-free proportions (95% confidence interval [95% CI]) for vivax malaria were 20.6% (5.1–43.4) for DP ( n =125), 46.0% (30.9–60.0) for ASMQ ( n =117) and 28.7% (10.0–50.8) for AL + ( n =126). DP and ASMQ provided longer recurrence-free intervals. PCR-corrected cure rates (95% CI) for falciparum malaria were 93.7% (81.6–97.9) for DP ( n =49), 79.6% (66.1–88.1) for AMSQ ( n =55) and 87.5% (74.3–94.2) for AL + ( n =50). Overall 65% (85/130) of P. falciparum infections had Pfkelch13 propeller mutations which increased over time and recrudescence occurred almost exclusively in them risk ratio 9.42 (95% CI 1.30–68.29). Among the women with falciparum malaria, 24.0% (95% CI 16.8–33.6) had P. vivax parasitaemia within 4 months. Nausea, vomiting, dizziness and sleep disturbance were more frequent with ASMQ. Miscarriage, small-for-gestational-age and preterm birth did not differ significantly among the treatment groups, including first trimester exposures ( n =46). DP was well tolerated and safe, and was the only drug providing satisfactory efficacy for P. falciparum -infected pregnant woman in this area of widespread artemisinin resistance. Vivax malaria recurrences are very common and warrant chloroquine prophylaxis after antimalarial treatment in this area. ClinicalTrials.gov identifier NCT01054248 , registered on 22 January 2010.
Publisher: Public Library of Science (PLoS)
Date: 17-06-2008
Publisher: Public Library of Science (PLoS)
Date: 23-12-2008
Publisher: Public Library of Science (PLoS)
Date: 17-03-2015
Publisher: Elsevier BV
Date: 06-2017
Publisher: Wiley
Date: 18-02-2011
Publisher: Elsevier BV
Date: 04-1996
Publisher: Springer Science and Business Media LLC
Date: 20-06-2015
Publisher: Springer Science and Business Media LLC
Date: 22-03-2006
DOI: 10.1007/S00228-006-0118-Y
Abstract: To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy. Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] l hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h. The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.
Publisher: Wiley
Date: 24-11-2006
Publisher: Springer Science and Business Media LLC
Date: 19-08-2016
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Francois Nosten.