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Antimicrob Agents Chemother. 2011 June; 55(6): 2629–2635.
PMCID: PMC3101389

Effect of Nutritional Status on Response to Treatment with Artemisinin-Based Combination Therapy in Young Ugandan Children with Malaria[down-pointing small open triangle]

Abstract

The relationship between malnutrition and malaria in young children is under debate, and no studies evaluating the association between malnutrition and response to artemisinin-based combination therapies (ACTs) have been published. We evaluated the association between malnutrition and response to antimalarial therapy in Ugandan children treated with ACTs for repeated episodes of malaria. Children aged 4 to 12 months diagnosed with uncomplicated malaria were randomized to dihydroartemisinin-piperaquine (DP) or artemether-lumefantrine (AL) and followed for up to 2 years. All HIV-exposed and HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis (TS). The primary exposure variables included height-for-age and weight-for-age z scores. Outcomes included parasite clearance at days 2 and 3 and risk of recurrent parasitemia after 42 days of follow-up. Two hundred ninety-two children were randomized to DP or AL, resulting in 2,013 malaria treatments. Fewer than 1% of patients had a positive blood smear by day 3 (DP, 0.2%; AL, 0.6% [P = 0.18]). There was no significant association between height-for-age or weight-for-age z scores and a positive blood smear 2 days following treatment. For children treated with DP but not on TS, decreasing height-for-age z scores of <−1 were associated with a higher risk of recurrent parasitemia than a height-for-age z score of >0 (hazard ratio [HR] for height-for-age z score of <−1 and ≥−2 = 2.89 [P = 0.039]; HR for height-for-age z score of <−2 = 3.18 [P = 0.022]). DP and AL are effective antimalarial therapies in chronically malnourished children in a high-transmission setting. However, children with mild to moderate chronic malnutrition not taking TS are at higher risk for recurrent parasitemia and may be considered a target for chemoprevention.

INTRODUCTION

Malaria and malnutrition are major causes of morbidity and mortality in children in sub-Saharan Africa. Malaria, predominantly caused by Plasmodium falciparum, is estimated to cause 880,000 deaths each year, with the majority of deaths occurring in children under 5 years of age sub-Saharan Africa (31). At the same time, malnutrition is a major public health problem in developing countries. Approximately one-half of the 10.6 million children under 5 who die in low- and middle-income countries are malnourished (30). Common anthropometric indices used to assess the extent of malnutrition include height-for-age (a measurement for linear growth and an indicator of long-term growth deficits), weight-for-height (a measurement of body proportion and an indicator of acute growth disturbances), and weight-for-age (which represents a synthesis of linear growth and body proportion) (6). In Africa, malnutrition is highly prevalent; 39%, 8%, and 28% of children under 5 are stunted (height-for-age z [HAZ] score of <−2), wasted (weight-for-height z score of <−2), or underweight (weight-for-age z [WAZ] score of <−2), respectively (20).

Although malaria and malnutrition frequently coexist (28), there have been few studies evaluating the effect of malnutrition on malaria, and results of such studies have been conflicting. Some studies have reported that children with evidence of malnutrition as characterized by either stunting, underweight, or wasting have a higher risk of malaria, some have reported a lower risk, and others have reported no association (5, 9, 11, 12). However, in these studies, the anthropometric growth references, age ranges, transmission intensities, and definitions of malaria differed. To our knowledge, no studies have evaluated the effects of malnutrition on the risk of recurrent parasitemia.

Data are also lacking on the effect of malnutrition on response to antimalarial therapy (28). Vulnerable populations, such as very young children, the HIV infected, and the malnourished, are typically excluded from or underrepresented in studies of antimalarial drug efficacy (2). The World Health Organization (WHO) currently recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated P. falciparum malaria (28). Although the WHO recognizes that malnutrition may affect the response to antimalarial therapy (28), there are no published studies examining the association between malnutrition and the response to antimalarial therapy with ACTs.

Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are two of the most important ACTs for the treatment of uncomplicated P. falciparum malaria. AL is highly efficacious and well tolerated and has been recommended by the WHO for use as a first-line treatment for malaria since 2004. DP is a newer ACT that has proven to be equivalent to or more effective than other ACT regimens in clinical trials (1, 3, 24, 32) and is now also recommended by the WHO for use as a first line-treatment for P. falciparum malaria (28). The potential advantages of DP over AL are convenient once-a-day dosing and a longer half-life (3 to 4 weeks) of the partner drug, piperaquine, than of lumefantrine (~4 days), leading to a prolonged posttreatment prophylactic effect and thus reducing the risk of new infection. In this study, we evaluated the associations between measures of malnutrition and response to antimalarial therapy in a cohort of young Ugandan children treated with DP or AL for repeated episodes of uncomplicated P. falciparum malaria.

MATERIALS AND METHODS

Study area and population.

This study was conducted in rural eastern Uganda in the district of Tororo. Malaria transmission in this area is holoendemic, occurring perennially, with the entomological inoculation rate (EIR) estimated to be 562 infective bites per person-year (21). The study participants were part of a clinical trial designed to compare the efficacies of two ACT regimens, involving AL and DP, for the treatment of uncomplicated malaria in very young children. The clinical trial was part of a larger cohort study. The study protocol was approved by the Uganda National Council of Science and Technology and the institutional review boards of Makerere University, the University of California San Francisco, the U.S. Centers for Disease Control and Prevention, and the University of Washington.

A full description of the study design has been presented elsewhere (1). Briefly, convenience sampling was used to enroll 100 HIV-unexposed children (born to HIV-uninfected mothers), 48 HIV-infected children, and 203 HIV-exposed children (HIV-uninfected children born to HIV-infected mothers) between August 2007 and April 2008. The eligibility criteria included the following: (i) age 6 weeks to 12 months, (ii) documented HIV status of mother and child, (iii) agreement to return to the study clinic for any febrile episode or other illness, (iv) agreement to avoid medications administered outside the study protocol, (v) residence within a 30-km radius of the study clinic, (vi) current breastfeeding if HIV exposed, and (vii) parent/guardian provision of informed consent. All mother-child pairs received two long-lasting insecticide-treated bed nets (ITNs), a safe water vessel, multivitamins, and condoms at the beginning of the study. All HIV-infected children received antiretroviral therapy (ART) consisting of nevirapine plus lamivudine plus zidovudine or stavudine, if eligible according to WHO criteria. All HIV-exposed children and HIV-infected children received daily trimethoprim-sulfamethoxazole (TS) prophylaxis. Following cessation of breastfeeding, HIV-exposed children who remained HIV uninfected were randomized to continue or discontinue TS through 24 months of age. Children who were HIV exposed and subsequently seroconverted continued TS prophylaxis.

Malaria diagnosis and treatment.

Subjects were followed for all medical problems at a dedicated study clinic open 7 days a week. After-hours care was available at the Tororo District Hospital, which provides service for the entire Tororo district area. Subjects who presented to the clinic with a fever (tympanic temperature of ≥38.0°C) or reported history of fever in the past 24 h provided blood obtained by a finger prick for a thick blood smear. If the thick blood smear was positive, the patient was diagnosed with malaria regardless of parasite density. All episodes of malaria were classified as uncomplicated if the following criteria were met: fever (≥38.0°C tympanic) or history of fever in the previous 24 h, positive thick blood smear, and absence of complicated malaria (presence of severe malaria and parasitemia, danger signs and parasitemia, and/or parasite density of ≥500,000/μl).

At the first diagnosis of uncomplicated malaria, study participants 4 months of age or older and at least 5 kg in weight were randomized to open-label treatment with AL or DP and received the same antimalarial treatment regimen for all subsequent episodes of uncomplicated malaria. A nurse administered study drugs according to weight-based guidelines as follows: AL (tablets of 20 mg of artemether and 120 mg of lumefantrine; Coartem; Novartis), administered as 1 (5 to 14 kg) or 2 (15 to 24 kg) tablets given twice daily for 3 days, and DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine; Duocotecxin; Holley Pharm) targeting total doses of 6.4 and 51.2 mg/kg of dihydroartemisinin and piperaquine, respectively, given as 3 equally divided doses to the nearest one-quarter tablet. Each dose was given once (for DP) or twice (for AL) a day over 3 days (days 0, 1, and 2). Patients were given a glass of milk or asked to breast-feed after each dose of study medication to optimize drug absorption. The first daily dose of study medication was administered in the clinic and directly observed by a study nurse. Any patient who vomited the medication within 30 min of administration was retreated with a second dose.

Malaria follow-up and outcome classification.

Study participants diagnosed with malaria were asked to return to the clinic on days 1, 2, 3, 7, 14, 21, and 28 or on any other day when the parents thought the child was ill. Study participants who did not return for a scheduled visit were visited at home and, if necessary, transported to the study clinic. At these visits and on any unscheduled day when a fever was documented or had been reported in the previous 24 h, blood was obtained by a finger prick for thick blood smears and filter paper collection. Study participants were actively followed through day 28, and treatment outcomes were classified according to the 2006 WHO treatment guidelines (29). Study participants who took antimalarials outside the protocol, who were lost to follow-up, or whose parent/guardian withdrew consent were not assigned a treatment outcome. Recurrent episodes of malaria recurring within 14 days of previous treatment were treated with quinine, and recurrent episodes occurring more than 14 days after therapy were treated as a new episode. After 28 days of active follow-up, study participants were followed passively until their next episode of malaria or to the end of the observation period. This study includes all episodes of malaria diagnosed from the time of enrollment through August 2009.

Anthropometric measurements.

Anthropomorphic measurements were collected in accordance with internationally accepted practices on the day malaria was diagnosed. Weight was taken using a spring scale for younger children (up to approximately 1 year of age) or with a standing scale for older children (Seca, Hamburg, Germany), both precise to the nearest 100 g. Recumbent length measurements were taken using a steidiometer for children up to approximately 1 year of age. After that age, standing height measurements were taken. All length and height measurements were precise to the nearest 1 cm. Age was calculated using the date of birth of the child.

Laboratory methods. (i) Malaria diagnosis.

Thick and thin blood smears were stained with 2% Giemsa for 30 min and read by experienced laboratory technologists who were not involved in direct patient care. Parasite densities were calculated by counting the number of asexual parasites per 200 leukocytes (or per 500 leukocytes, if the count was <10 asexual parasites/200 leukocytes), assuming a leukocyte count of 8,000/μl. A blood smear was considered negative when the examination of 100 high-power fields did not reveal asexual parasites. Thin smears were used for parasite species identification. For quality control, all slides were read by a second microscopist and a third reviewer settled any discrepant readings. Microscopists were blinded to the study participants' treatment assignments.

(ii) Molecular genotyping.

Parasite species on the day malaria was diagnosed were determined using nested PCR as described elsewhere (26). For recurrent episodes of parasitemia, molecular genotyping was used to distinguish new infections from recrudescent infections. DNA was recovered from blood spots, and samples were genotyped in a stepwise fashion with the use of six polymorphic markers as described elsewhere (13). For any of the six loci, if an allele was not shared between consecutive episodes of parasitemia, the episode was classified as a new infection. If at least one allele was shared at all six loci, the episode was classified as a recrudescence.

Statistical analysis.

All analyses included patients with uncomplicated falciparum malaria and were stratified according to the treatment arm (AL or DP). The primary exposure variables of interest were measures of malnutrition classified according to height-for-age and weight-for-age z scores, using the 2006 WHO child growth standards. Because the thresholds for classifying nutritional status have not been universally defined, for the purpose of this analysis, height-for-age (HAZ) and weight-for-age (WAZ) z scores were divided into four categories, with the following cutoffs: ≥0, <0 and ≥ −1, <−1 and ≥−2, and <−2.

Associations were evaluated between measures of malnutrition and two treatment outcomes: (i) parasite clearance at day 2 and day 3 and (ii) the risk of recurrent parasitemia. Parasite clearance was defined as the proportion of patients with a positive blood slide 2 or 3 days following initiation of therapy, and comparisons were made using generalized estimating equations, with adjustment for repeated measures in the same patient, by using exchangeable correlation, binomial distribution, and robust standard errors. Recurrent parasitemia was defined as any early treatment failure, a positive blood smear between 4 and 28 days of active follow-up, or malaria diagnosed between days 29 and 42 of passive follow-up. The risk of recurrent parasitemia was estimated using the Kaplan-Meier product limit formula with censoring for patients with incomplete follow-up. The risk of recrudescence after adjustment by genotyping was not evaluated, because previously published data showed that this risk was less than 3% for both treatment arms (1). Measures of association between categories of malnutrition and the risk of recurrent parasitemia were made using Cox proportional hazard models, with inference adjusted for repeated measures (14) in the same patient and adjustment for potential confounders, including age, cumulative piperaquine or lumefantrine dose (provided over 3 days of dosing and based on mg/kg of body weight), place of residence, breastfeeding status, and ART use. In addition, Cox proportional hazard models were stratified by TS use because of the presence of significant interaction.

Data were double entered in ACCESS (Microsoft Corporation, Redmond, WA). Statistical analysis was performed using STATA, version 9.0 (Stata Corporation, College Station, TX). For all analyses, a P value (two-sided) of less than 0.05 was considered statistically significant.

RESULTS

Of the 351 participants enrolled in the study, 292 (83%) were diagnosed with at least one episode of uncomplicated malaria and randomized to therapy. Of these, 145 were randomized to DP and 147 were randomized to AL, resulting in 981 and 1,032 treatments for uncomplicated P. falciparum malaria, respectively, which were included in this study (Fig. 1).

Fig. 1.
Trial profile.

Demographic and anthropomorphic baseline characteristics of all episodes of uncomplicated falciparum malaria stratified by treatment are presented in Table 1. At the time of treatment, 90% of the study participants resided in a rural area, approximately one-third of all participants were breastfeeding, 30% were taking TS prophylaxis, 8.5% were HIV infected, and 92% of these were taking ARTs. Forty-three percent of the study participants had an HAZ score of <−2, and 13% had a WAZ score of <−2, consistent with rates reported to occur across Uganda (16).

Table 1.
Demographic and anthropomorphic characteristics of all episodes of uncomplicated P. falciparum malaria treated with DP and AL

Effect of nutritional status on parasite clearance for AL and DP.

The proportion of patients with a positive blood smear 2 days following initiation of therapy was lower in patients treated with DP than in those treated with AL (5.0% versus 10.0%; P < 0.001). There were very few patients with a positive blood smear 3 days following the initiation of therapy in either the DP or the AL treatment arms (0.2% versus 0.6%; P = 0.18). There was no significant association between HAZ and WAZ scores and a positive blood smear 2 days following treatment with DP or AL (Table 2).

Table 2.
Associations between measures of malnutrition and parasite clearance at day 2 following therapy with DP or AL

Effect of nutritional status on risk of recurrent parasitemia.

The overall risk of recurrent parasitemia after 42 days of follow-up was higher in study participants treated with AL than in those treated with DP (54% [95% confidence interval {CI}, 51 to 57%] versus 29% [95% CI, 27 to 32%]). During model fitting, concomitant use of TS prophylaxis was associated with a significantly lower risk of recurrent parasitemia (hazard ratio [HR] = 0.57 [P = 0.001] and HR = 0.66 [P = 0.002] for patients receiving DP and AL, respectively), and there was significant interaction between TS use and associations between measures of malnutrition and the risk of recurrent parasitemia. Therefore, each model was stratified by TS use.

In study participants not on TS prophylaxis treated with DP, the risk of recurrent parasitemia after 42 days of follow-up increased as HAZ score decreased (log rank test P = 0.03) (Fig. 2). After place of residence, breastfeeding status, cumulative dose of piperaquine received, and ART use were controlled for, a decreasing HAZ score was independently associated with a higher risk of recurrent parasitemia (Table 3). However, statistical significance was reached only when HAZ scores of <−1 were compared with those of ≥0. There were no significant associations between HAZ scores and the risk of recurrent parasitemia among patients treated with DP and taking TS prophylaxis (Table 3). Similarly, there were no significant associations between WAZ scores and the risk of recurrent parasitemia among patients treated with DP, regardless of whether or not the patient was taking TS prophylaxis (Table 3).

Fig. 2.
Cumulative risks of recurrent parasitemia stratified by HAZ following treatment with AL or DP using the Kaplan-Meier product limit formula. HAZ score of 0 = HAZ score of ≥0; HAZ score of 1 = HAZ score of <0 and ≥−1; HAZ ...
Table 3.
Associations between measures of malnutrition and recurrent parasitemia following therapy with DP after 42 days of follow-up

In study participants not on TS prophylaxis treated with AL, the unadjusted risk of recurrent parasitemia after 42 days of follow-up increased as HAZ scores decreased (log rank test P = 0.05) (Fig. 2). After age, place of residence, breastfeeding status, cumulative dose of lumefantrine received, and ART use were controlled for, a decreasing HAZ score was independently associated with a higher risk of recurrent parasitemia, although statistical significance was not achieved. There were no significant associations between HAZ scores and the risk of recurrent parasitemia among patients taking TS prophylaxis and treated with AL (Table 4). As with DP, the WAZ score was not associated with recurrent parasitemia in those not taking TS prophylaxis. For study participants taking TS prophylaxis, there was an association of WAZ scores and recurrent parasitemia. However, this was significant only when those with the lowest (<−2) and highest (<0 and ≥−1) WAZ scores were compared to those with a WAZ score of ≥0 (Table 4).

Table 4.
Associations between measures of malnutrition and recurrent parasitemia following therapy with AL after 42 days of follow-up

DISCUSSION

This is the first longitudinal study assessing the effect of malnutrition on the posttreatment prophylactic effect of ACTs; thus, no direct comparisons to previous studies can be made. We evaluated patients prospectively, taking advantage of a comprehensive clinic infrastructure which provided assurance that all episodes of malaria were captured and followed and that compliance with the treatment regimen was high. Compared to other studies which have evaluated this vulnerable patient population, our sample size of over 2,000 malarial episodes is one of the largest published. In addition, this study utilized the new 2006 WHO growth standards, which provide a more accurate tool for monitoring growth differences, as they evaluate growth patterns from healthy breastfed children from around the world (7). Our results indicate that in a high-transmission setting, both AL and DP are efficacious antimalarial regimens for treatment of P. falciparum malaria in children under 3 years of age, regardless of nutritional status. Parasite clearance overall was excellent, with more than 99% of study participants clearing all primary parasites by day 3. Recrudescence could not be directly evaluated as an outcome of this study, due to low numbers (less than 3%), though the lack of recrudescence is further support of the efficacy of these two drug regimens. Compared to children treated with DP, children treated with AL were at higher risk for recurrent parasitemia after 42 days of follow-up. Children with signs of mild to moderate chronic malnutrition not taking TS prophylaxis were at higher risk for recurrent parasitemia. However, this was significant only in the DP group.

Although there are no published studies evaluating the relationship of malnutrition and recurrent parasitemia, a few studies have assessed the association between malnutrition and malaria risk. In a cross-sectional study in Kenya of 1,862 children under 36 months of age, stunted children were more likely to have more parasitemia (odds ratio [OR] = 1.98) and clinical malaria (OR = 2.65) than nonstunted children (11). Likewise, a prospective cohort study of 487 children under 5 years of age in the Gambia found that stunted children were at higher risk for malaria (RR = 1.35) than nonstunted children (5). Contrary to our findings, a prospective cohort study of 136 children 4 months to 10 years of age in Papua New Guinea found that the incidence rate of malaria (of any type, as well as P. falciparum alone) increased with increasing HAZ (12), indicating that lower HAZ was protective against an attack of clinical malaria. Two longitudinal studies, one in Senegal with children 12 months to 5 years of age and the other in Burkina Faso with children 10 months to 10 years of age, found that stunting and being underweight were not associated with an increased risk of P. falciparum malaria (9, 19). There may be several explanations for the conflicting findings. The study conducted in Kenya was conducted with children representing an age range similar to that of the children in the Tororo study, while the studies conducted in Papua New Guinea and Burkina Faso were conducted with older children. Moreover, the study in Kenya was conducted in an area of high transmission (60 to 300 infective bites per person per year), whereas the studies which found compromised nutritional status to be protective or to have no effect on malaria risk were conducted in areas where malaria transmission occurred seasonally with lower transmission rates than in Kenya as well as in the Tororo district in Uganda. Both the differences in age and the transmission intensity may lead to differences in acquired immunity and thus differences in malaria risk.

The mechanism behind the increased risk of recurrent parasitemia in children with signs of mild to moderate chronic malnutrition is unclear, but is likely due in part to the impact of chronic malnutrition on the immune system. Chronic malnutrition and accompanying micronutrient deficiencies (e.g., zinc, magnesium, iron, selenium, and vitamin A) can lead to immune dysfunction and increased infection in children by impairing both the innate and the adaptive immune systems, affecting thymic activity and cytokine production, by impairing T cell response and macrophage activation, and by disrupting IgA and IgG antibody response (4, 25). Results from the few studies evaluating the relationship between malnutrition and immune response in children with malaria have been conflicting. A cross-sectional study with preschool-aged children conducted in Senegal found that IgG antibody levels were significantly lower in stunted children than in controls, regardless of differences in parasite density (10). In contrast, a study of children up to 10 years of age conducted in Papua New Guinea found an increase in cytokine production in response to stimulation by specific antimalarial antigens in undernourished (stunted and wasted) children and a decrease in antibody response in wasted children (12). Future studies evaluating the effect of malnutrition on immune response are warranted. In addition to altering immune function, malnutrition may have an impact on the pharmacokinetics of antimalarial treatment. Total body water has been shown to be increased in malnourished children, leading to a greater volume of distribution of drugs, which in turn would result in lower blood concentrations of drug. In addition, malnutrition is associated with intestinal malabsorption and villous atrophy of the jejunal mucosa, which can impair drug absorption (22). The few pharmacokinetic studies conducted with children have indicated that because of differences in drug metabolism and elimination, children may be receiving suboptimal doses of antimalarial drugs (23, 27). Additional analysis of data from a subset of this patient population, including complete pharmacokinetic profiles, is under way.

Interestingly, the association of increased risk of recurrent parasitemia with decreasing HAZ was evident only for children not taking TS prophylaxis. TS is an antifolate which has been associated with reduced morbidity and mortality in HIV-infected children and adults. TS also has antimalarial properties. Though TS has been used to treat P. falciparum malaria in the past, its effectiveness as an antimalarial treatment is limited (8), and it is no longer considered acceptable as a first-line therapy. However, TS has been shown to reduce the incidence of malaria even in areas of high parasite resistance to antifolates (15, 17, 18). Perhaps the chronic use of TS, a moderately effective antimalarial when used alone, acts synergistically with the administration of a relatively more potent artemisinin-based treatment to override the deleterious effect of chronic malnutrition on the immune system. TS is easy to administer, with treatment once a day or thrice weekly for prophylaxis, is widely available, and is relatively inexpensive. The results from this study indicate that children with mild to moderate signs of chronic malnutrition at risk for malaria may benefit from TS prophylaxis.

The limitations of this study should be considered. First, we may have not controlled for all potential confounders that may be involved in the complex relationship between malnutrition and malaria. Second, we made multiple comparisons evaluating the relationship between malnutrition and the risk of recurrent parasitemia, which could potentially lead to spurious findings. Only by comparing the lowest levels of malnutrition to those for the baseline group was statistical significance achieved. Finally, the mechanisms underlying the differences in risk of recurrent parasitemia in children with mild to moderate chronic malnutrition could not be elucidated.

Conclusion.

AL and DP are effective antimalarial therapies for clearing primary infection in chronically malnourished young children in a high-transmission setting. However, young children with signs of mild to moderate chronic malnutrition not taking TS prophylaxis are at increased risk for recurrent parasitemia. Further studies are warranted to evaluate if this risk is mediated by altered drug metabolism in chronically malnourished children or through differences in immune response. Children with chronic malnutrition should be targeted for malaria prevention strategies such as provision of bed nets or chemoprevention integrated with nutrition-based interventions.

ACKNOWLEDGMENTS

We are grateful to all the parents/guardians for kindly giving their consent and the study participants for their cooperation. We thank the members of the Tororo study team. The research was carried out by the Makerere University-University of California, San Francisco Malaria Research Collaboration, supported by the Doris Duke Charitable Foundation and the Centers for Disease Control and Prevention. G.D. is a recipient of the Doris Duke Clinical Scientist Development Award. T.S. was funded through the Puget Sound Partners in Global Health and NIH/NIAID K23-AI082553.

The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Footnotes

[down-pointing small open triangle]Published ahead of print on 7 March 2011.

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