Electrocardiographic safety evaluation of dihydroartemisinin piperaquine in the treatment of uncomplicated falciparum malaria.

Dihydroartemisinin-piperaquine (DP) could become a leading fixed combination malaria treatment worldwide. Although there is accumulating evidence of efficacy and safety from clinical trials, data on cardiotoxicity are limited. In two randomized controlled trials in Thailand, 56 patients had ECGs performed before treatment, 4 hours after the first dose, and 4 hours after the last dose. The mean (95% CI) changes in QTc interval (Bazett's correction) were 2 (-6 to 9) ms and 14 (7 to 21) ms, respectively. These small changes on the third day of treatment are similar to those observed elsewhere in the convalescent phase following antimalarial treatment with drugs known to have no cardiac effects and are therefore likely to result from recovery from acute malaria and not the treatment given. At therapeutic doses, DP does not have clinically significant effects on the electrocardiogram

The detection and treatment of Plasmodium falciparum malaria: Time for change

In most countries where malaria is endemic, P. falciparum malaria is on the rise. This is primarily due to the spread of drug-resistant strains. Drug resistance is mediated by spontaneous changes in the parasite genome that allow resistant parasites to escape the action of the drugs. The spread of drug resistance increases the transmission of malaria parasites. The consequences for the populations at risk are profound both in terms of consequences for health and economy. In order to halt the progression of drug resistance, we need to change the way antimalarials are used. As in tuberculosis and HIV/AIDS, we must use a combination of drugs for the treatment of malaria. Taking into account the pharmacokinetic and pharmacodynamic properties of the various anti-malarial agents, artemisinin-based combination therapy (ACT) seems to be the best option. This strategy should be used in conjunction with early diagnosis and appropriate vector control measures to achieve reduction in the emergence and spread of drug resistance

Efficacy and effectiveness of the combination of sulfadoxine/pyrimethamine and a 3-day course of artesunate for the treatment of uncomplicated falciparum malaria in a refugee settlement in Zambia.

In the Maheba Refugee Settlement, in the clinics supported by Medecins Sans Frontieres, all children aged up to 5 years with a confirmed diagnosis of uncomplicated falciparum malaria are treated with the combination of sulfadoxine/pyrimethamine (SP) and artesunate (AS). We compared the treatment's efficacy and effectiveness. Patients were randomized in order to receive the treatment supervised (efficacy) or unsupervised (effectiveness). Therapeutic response was determined after 28 days of follow up. The difference between recrudescence and re-infection was ascertained by polymerase chain reaction (PCR). We also assessed genetic markers associated to SP resistance (dhfr and dhps). Eighty-five patients received treatment under supervision and 84 received it unsupervised. On day 28, and after PCR adjustment, efficacy was found to be 83.5% (95% CI: 74.1-90.5), and effectiveness 63.4% (95% CI: 52.6-73.3) (P < 0.01). Point mutations on dhfr (108) and dhps (437) were found for 92.0% and 44.2% respectively of the PCR samples analysed. The significant difference in therapeutic response after supervised and unsupervised treatment intake can only be explained by insufficient patient adherence. When implementing new malaria treatment policies, serious investment in ensuring patient adherence is essential to ascertain the effectiveness of the new treatment schedules

International gestational age-specific centiles for umbilical artery Doppler indices: a longitudinal prospective cohort study of the INTERGROWTH-21st Project.

BACKGROUND: Reference values for umbilical artery Doppler indices are used clinically to assess fetal well-being. However, many studies that have produced reference charts have important methodologic limitations, and these result in significant heterogeneity of reported reference ranges. OBJECTIVES: To produce international gestational age-specific centiles for umbilical artery Doppler indices based on longitudinal data and the same rigorous methodology used in the original Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project. STUDY DESIGN: In Phase II of the INTERGROWTH-21st Project (the INTERBIO-21st Study), we prospectively continued enrolling pregnant women according to the same protocol from 3 of the original populations in Pelotas (Brazil), Nairobi (Kenya), and Oxford (United Kingdom) that had participated in the Fetal Growth Longitudinal Study. Women with a singleton pregnancy were recruited at <14 weeks' gestation, confirmed by ultrasound measurement of crown-rump length, and then underwent standardized ultrasound every 5±1 weeks until delivery. From 22 weeks of gestation umbilical artery indices (pulsatility index, resistance index, and systolic/diastolic ratio) were measured in a blinded fashion, using identical equipment and a rigorously standardized protocol. Newborn size at birth was assessed using the international INTERGROWTH-21st Standards, and infants had detailed assessment of growth, nutrition, morbidity, and motor development at 1 and 2 years of age. The appropriateness of pooling data from the 3 study sites was assessed using variance component analysis and standardized site differences. Umbilical artery indices were modeled as functions of the gestational age using an exponential, normal distribution with second-degree fractional polynomial smoothing; goodness of fit for the overall models was assessed. RESULTS: Of the women enrolled at the 3 sites, 1629 were eligible for this study; 431 (27%) met the entry criteria for the construction of normative centiles, similar to the proportion seen in the original fetal growth longitudinal study. They contributed a total of 1243 Doppler measures to the analysis; 74% had 3 measures or more. The healthy low-risk status of the population was confirmed by the low rates of preterm birth (4.9%) and preeclampsia (0.7%). There were no neonatal deaths and satisfactory growth, health, and motor development of the infants at 1 and 2 years of age were documented. Only a very small proportion (2.8%-6.5%) of the variance of Doppler indices was due to between-site differences; in addition, standardized site difference estimates were marginally outside this threshold in only 1 of 27 comparisons, and this supported the decision to pool data from the 3 study sites. All 3 Doppler indices decreased with advancing gestational age. The 3rd, 5th 10th, 50th, 90th, 95th, and 97th centiles according to gestational age for each of the 3 indices are provided, as well as equations to allow calculation of any value as a centile and z scores. The mean pulsatility index according to gestational age = 1.02944 + 77.7456*(gestational age)-2 - 0.000004455*gestational age3. CONCLUSION: We present here international gestational age-specific normative centiles for umbilical artery Doppler indices produced by studying healthy, low-risk pregnant women living in environments with minimal constraints on fetal growth. The centiles complement the existing INTERGROWTH-21st Standards for assessment of fetal well-being

Linking international clinical research with stateless populations to justice in global health

BACKGROUND: In response to calls to expand the scope of research ethics to address justice in global health, recent scholarship has sought to clarify how external research actors from high-income countries might discharge their obligation to reduce health disparities between and within countries. An ethical framework-'research for health justice'-was derived from a theory of justice (the health capability paradigm) and specifies how international clinical research might contribute to improved health and research capacity in host communities. This paper examines whether and how external funders, sponsors, and researchers can fulfill their obligations under the framework. METHODS: Case study research was undertaken on the Shoklo Malaria Research Unit's (SMRU) vivax malaria treatment trial, which was performed on the Thai-Myanmar border with Karen and Myanmar refugees and migrants. We conducted nineteen in-depth interviews with trial stakeholders, including investigators, trial participants, community advisory board members, and funder representatives; directly observed at trial sites over a five-week period; and collected trial-related documents for analysis. RESULTS: The vivax malaria treatment trial drew attention to contextual features that, when present, rendered the 'research for health justice' framework's guidance partially incomplete. These insights allowed us to extend the framework to consider external research actors' obligations to stateless populations. Data analysis then showed that framework requirements are largely fulfilled in relation to the vivax malaria treatment trial by Wellcome Trust (funder), Oxford University (sponsor), and investigators. At the same time, this study demonstrates that it may be difficult for long-term collaborations to shift the focus of their research agendas in accordance with the changing burden of illness in their host communities and to build the independent research capacity of host populations when working with refugees and migrants. Obstructive factors included the research funding environment and staff turnover due to resettlement or migration. CONCLUSIONS: Our findings show that obligations for selecting research targets, research capacity strengthening, and post-trial benefits that link clinical trials to justice in global health can be upheld by external research actors from high-income countries when working with stateless populations in LMICs. However, meeting certain framework requirements for long-term collaborations may not be entirely feasible

Geographical distribution of selected and putatively neutral SNPs in Southeast Asian malaria parasites.

Loci targeted by directional selection are expected to show elevated geographical population structure relative to neutral loci, and a flurry of recent papers have used this rationale to search for genome regions involved in adaptation. Studies of functional mutations that are known to be under selection are particularly useful for assessing the utility of this approach. Antimalarial drug treatment regimes vary considerably between countries in Southeast Asia selecting for local adaptation at parasite loci underlying resistance. We compared the population structure revealed by 10 nonsynonymous mutations (nonsynonymous single-nucleotide polymorphisms [nsSNPs]) in four loci that are known to be involved in antimalarial drug resistance, with patterns revealed by 10 synonymous mutations (synonymous single-nucleotide polymorphisms [sSNPs]) in housekeeping genes or genes of unknown function in 755 Plasmodium falciparum infections collected from 13 populations in six Southeast Asian countries. Allele frequencies at known nsSNPs underlying resistance varied markedly between locations (F(ST) = 0.18-0.66), with the highest frequencies on the Thailand-Burma border and the lowest frequencies in neighboring Lao PDR. In contrast, we found weak but significant geographic structure (F(ST) = 0-0.14) for 8 of 10 sSNPs. Importantly, all 10 nsSNPs showed significantly higher F(ST) (P < 8 x 10(-5)) than simulated neutral expectations based on observed F(ST) values in the putatively neutral sSNPs. This result was unaffected by the methods used to estimate allele frequencies or the number of populations used in the simulations. Given that dense single-nucleotide polymorphism (SNP) maps and rapid SNP assay methods are now available for P. falciparum, comparing genetic differentiation across the genome may provide a valuable aid to identifying parasite loci underlying local adaptation to drug treatment regimes or other selective forces. However, the high proportion of polymorphic sites that appear to be under balancing selection (or linked to selected sites) in the P. falciparum genome violates the central assumption that selected sites are rare, which complicates identification of outlier loci, and suggests that caution is needed when using this approach

Anti-Guest Statutes and Marital Immunity for Torts in Conflict of Laws: Techniques for Resolving Ostensible True Conflict Cases and Constitutional Limitations

In the now historic case of Babcock v. Jackson, decided in 1963, the New York Court of Appeals introduced an apparently novel mode of analyzing tort choice-of-law issues that has achieved remarkable popularity with the judges of other states. It has been adopted in tort cases where the facts and issues were quite different from those of Babcock v. Jackson and in contract cases as well. Why does the Babcock v. Jackson methodology appeal so strongly to the judges of the highest state tribunals? The short answer is that this methodology is extremely realistic; it brings the judges directly to grips with the basic elements of the choice problem: two divergent rules of law producing divergent practical results and effectuating divergent policies. Of these two rules the judges must choose one. The new methodology emancipates them from the simplistic place of injury formula with its distracting and misleading escape devices. It enables them to base their choice upon a rational consideration of the policies and effects of each of the proffered rules in relation to the domiciles of the parties and the location of other significant facts in the case

Relapses of Plasmodium vivax infection usually result from activation of heterologous hypnozoites.

BACKGROUND: Relapses originating from hypnozoites are characteristic of Plasmodium vivax infections. Thus, reappearance of parasitemia after treatment can result from relapse, recrudescence, or reinfection. It has been assumed that parasites causing relapse would be a subset of the parasites that caused the primary infection. METHODS: Paired samples were collected before initiation of antimalarial treatment and at recurrence of parasitemia from 149 patients with vivax malaria in Thailand (n=36), where reinfection could be excluded, and during field studies in Myanmar (n=75) and India (n=38). RESULTS: Combined genetic data from 2 genotyping approaches showed that novel P. vivax populations were present in the majority of patients with recurrent infection (107 [72%] of 149 patients overall [78% of patients in Thailand, 75% of patients in Myanmar {Burma}, and 63% of patients in India]). In 61% of the Thai and Burmese patients and in 55% of the Indian patients, the recurrent infections contained none of the parasite genotypes that caused the acute infection. CONCLUSIONS: The P. vivax populations emerging from hypnozoites commonly differ from the populations that caused the acute episode. Activation of heterologous hypnozoite populations is the most common cause of first relapse in patients with vivax malaria

Improved detection of intestinal helminth infections with a formalin ethyl-acetate-based concentration technique compared to a crude formalin concentration technique

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 samples 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 samples 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

pfmdr1 amplification is related to increased Plasmodium falciparum In Vitro sensitivity to the Bisquinoline Piperaquine

The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the Plasmodium falciparum multidrug resistance locus on chromosome 5, containing the pfmdr1 gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC(50)s) and IC(90)s for piperaquine and chloroquine in a set of 46 adapted P. falciparum cultures originating from the Thai-Burmese border, we have characterized the regions around the pfmdr1 gene and identified a significant association between the presence of pfmdr1 duplications and enhanced sensitivity to piperaquine (P = 0.005 for IC50 and P = 0.002 for IC90) and chloroquine, reaching statistical significance at IC(90)s (P = 0.026). These results substantiate the potential importance of pfmdr1 copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations.Swedish Development Cooperation Agency-Department for Research Cooperation [SWE 2005-0017, SWE 2005-4596, SWE-2007-174, SWE-2005-4027]; Fundacao para a Ciencia e Tecnologia (FCT)/Ministerio da Ciencia e Ensino Superior, Portugal-MCES [SFRH/BPD/76614/2011]; Wellcome Trust of Great Britaininfo:eu-repo/semantics/publishedVersio