***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: BACKGROUND Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease . There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border , historically a site of emerging antimalarial-drug resistance . METHODS In two open-label , r and omized trials , we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin , western Cambodia , and Wang Pha , northwestern Thail and : oral artesunate given at a dose of 2 mg per kilogram of body weight per day , for 7 days , and artesunate given at a dose of 4 mg per kilogram per day , for 3 days , followed by mefloquine at two doses totaling 25 mg per kilogram . We assessed in vitro and in vivo Plasmodium falciparum susceptibility , artesunate pharmacokinetics , and molecular markers of resistance . RESULTS We studied 40 patients in each of the two locations . The overall median parasite clearance times were 84 hours ( interquartile range , 60 to 96 ) in Pailin and 48 hours ( interquartile range , 36 to 66 ) in Wang Pha ( P<0.001 ) . Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients ( 30 % ) receiving artesunate monotherapy and 1 of 20 ( 5 % ) receiving artesunate-mefloquine therapy in Pailin , as compared with 2 of 20 ( 10 % ) and 1 of 20 ( 5 % ) , respectively , in Wang Pha ( P=0.31 ) . These markedly different parasitologic responses were not explained by differences in age , artesunate or dihydroartemisinin pharmacokinetics , results of isotopic in vitro sensitivity tests , or putative molecular correlates of P. falciparum drug resistance ( mutations or amplifications of the gene encoding a multidrug resistance protein [ PfMDR1 ] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [ PfSERCA ] ) . Adverse events were mild and did not differ significantly between the two treatment groups . CONCLUSIONS P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thail and . Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing . Containment measures are urgently needed . ( Clinical Trials.gov number , NCT00493363 , and Current Controlled Trials number , IS RCT N64835265 . Background In Malawi , there has been a return of Plasmodium falciparum sensitivity to chloroquine ( CQ ) since sulfadoxine-pyrimethamine ( SP ) replaced CQ as first line treatment for uncomplicated malaria . When used for prophylaxis , Amodiaquine ( AQ ) was associated with agranulocytosis but is considered safe for treatment and is increasingly being used in Africa . Here we compare the efficacy , safety and selection of resistance using SP or CQ+SP or artesunate (ART)+SP or AQ+SP for the treatment of uncomplicated falciparum malaria . Methodology and Findings 455 children aged 1–5 years were recruited into a double-blinded r and omised trial comparing SP to the three combination therapies . Using intention to treat analysis with missing outcomes treated as successes , and without adjustment to distinguish recrudescence from new infections , the day 28 adequate clinical and parasitological response ( ACPR ) rate for SP was 25 % , inferior to each of the three combination therapies ( p<0.001 ) . AQ+SP had an ACPR rate of 97 % , higher than CQ+SP ( 81 % ) and ART+SP ( 70 % ) , p<0.001 . Nineteen children developed a neutropenia of ≤0.5 × 103 cells/µl by day 14 , more commonly after AQ+SP ( p = 0.03 ) . The mutation pfcrt 76 T , associated with CQ resistance , was detected in none of the pre-treatment or post-treatment parasites . The prevalence of the pfmdr1 86Y mutation was higher after treatment with AQ+SP than after SP , p = 0.002 . Conclusions The combination AQ+SP was highly efficacious , despite the low efficacy of SP alone ; however , we found evidence that AQ may exert selective pressure for resistance associated mutations many weeks after treatment . This study confirms the return of CQ sensitivity in Malawi and importantly , shows no evidence of the re-emergence of pfcrt 76 T after treatment with CQ or AQ . Given the safety record of AQ when used as a prophylaxis , our observations of marked falls in neutrophil counts in the AQ+SP group requires further scrutiny . Trial Registration Controlled-Trials.com IS RCT Objectives : In the Gambia , the combination of chloroquine ( CQ ) and sulphadoxine-pyrimethamine ( SP ) has replaced CQ monotherapy for treatment of malaria caused by Plasmodium falciparum . We measured the efficacy of the combination CQ/SP , and the prevalence of parasites carrying alleles associated with resistance to CQ or SP . Design : We conducted a single-blind , r and omised , controlled trial to compare the efficacy of CQ/SP to that of SP or CQ alone . Setting : The study took place in the town of Farafenni and surrounding villages in the Gambia . Participants : Participants were children aged 12 mo to 10 y presenting as out patients with uncomplicated P. falciparum malaria . Interventions : 500 children were r and omised to receive CQ , SP , or CQ/SP as supervised treatment and actively followed over 28 d. Outcome Measures : Primary outcome was parasitaemia at any time during follow-up . Secondary outcomes were PCR-confirmed recrudescent infections among treatment failures , and clinical failure requiring rescue medication by day 28 . Pretreatment parasite isolates from 161 patients were tested for the presence of resistance-associated genetic markers . Results : The prevalence of parasitological failure by day 28 for the CQ group was 60.3 % , compared to 17.6 % for SP ( odds ratio [ OR ] , 0.106 ; 95 % confidence interval [ CI ] , 0.057–0.194 ; p < 0.001 ) and 13.9 % for CQ/SP ( OR versus CQ , 0.140 ; 95 % CI , 0.078–0.250 ; p < 0.001 ) . There was no difference between the SP and CQ/SP groups ( OR , 1.324 ; 95 % CI , 0.705–2.50 ) . The projected prevalence of PCR-corrected treatment failure was 30.2 , 6.06 , and 3.94 % in the CQ , SP , and CQ/SP groups , respectively . The pfdhfr-triple mutant and pfdhps-437 G mutation were common , with prevalences of 67.4 and 51.2 % , respectively . Pretreatment carriage of pfdhps-437 G and of multidrug-resistant parasite genotypes was associated with treatment failure in the SP group , but not in the CQ or CQ/SP groups . Conclusions : The combination of CQ/SP was an efficacious treatment for uncomplicated malaria in Gambian children in this study , but the frequent occurrence of multidrug-resistant parasites suggests that this observed efficacy is not sustainable Background To up date the National Malaria Control Programme of Mali on the efficacy of chloroquine , amodiaquine and sulphadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria . Methods During the malaria transmission seasons of 2002 and 2003 , 455 children – between six and 59 months of age , with uncomplicated malaria in Kolle , Mali , were r and omly assigned to one of three treatment arms . In vivo outcomes were assessed using WHO st and ard protocol s.  Genotyping of msp1 , msp2 and CA1 polymorphisms were used to distinguish reinfection from recrudescent parasites ( molecular correction ) . Results Day 28 adequate clinical and parasitological responses ( ACPR ) were 14.1 % , 62.3 % and 88.9 % in 2002 and 18.2 % , 60 % and 85.2 % in 2003 for chloroquine , amodiaquine and sulphadoxine-pyrimethamine , respectively . After molecular correction , ACPRs ( cACPR ) were 63.2 % , 88.5 % and 98.0 % in 2002 and 75.5 % , 85.2 % and 96.6 % in 2003 for CQ , AQ and SP , respectively . Amodiaquine was the most effective on fever . Amodiaquine therapy selected molecular markers for chloroquine resistance , while in the sulphadoxine-pyrimethamine arm the level of dhfr triple mutant and dhfr/dhps quadruple mutant increased from 31.5 % and 3.8 % in 2002 to 42.9 % and 8.9 % in 2003 , respectively . No infection with dhps 540E was found . Conclusion In this study , treatment with sulphadoxine-pyrimethamine emerged as the most efficacious on uncomplicated falciparum malaria followed by amodiaquine . The study demonstrated that sulphadoxine-pyrimethamine and amodiaquine were appropriate partner drugs that could be associated with artemisinin derivatives in an artemisinin-based combination therapy Emphasis on retaining chloroquine as the first-line therapy for Plasmodium falciparum infections in most of sub-Saharan Africa for as long as it remains effective has result ed in widespread reliance on chloroquine in areas where it can have little effect on P. falciparum parasitemia . To address this issue , clinical , parasitologic , and hematologic responses to chloroquine or pyrimethamine/sulfadoxine treatment were assessed among very young children in Malawi ( n = 153 ) and Kenya ( n = 73 ) . The median time to resumption of clinical symptoms in chloroquine-treated children was 13.5 days in Malawi and 9.5 days in Kenya . Children treated with pyrimethamine/sulfadoxine maintained clinical improvement and had greater increases in their hemoglobin concentration during the follow-up period than did children treated with chloroquine . Treatment with chloroquine failed to produce either a durable clinical improvement or optimal hematologic recovery . Consequently , chloroquine can no longer be considered adequately effective therapy of clinical P. falciparum malaria in very young children in these areas of Africa Chloroquine-resistant falciparum malaria is a serious problem in much of sub-Saharan Africa . However , it is desirable to continue to use chloroquine as first-line therapy for uncomplicated malaria where it remains clinical ly effective . To identify predictors of chloroquine treatment failure , a 14-day clinical study of chloroquine resistance in patients with uncomplicated falciparum malaria was performed in Kampala , Ug and a. Among the 258 patients ( 88 % follow-up ) , 47 % were clinical failures ( early or late treatment failure ) and 70 % had  parasitological resistance  ( RI-RIII ) . Using multivariate analysis , an age less than five ( odds ratio [ OR ] = 3.4 , 95 % CI = 1.8 - 6.3 ) and a presenting temperature over 38.0 degreesC ( OR = 2.0 , 95 % CI = 1.1 - 3.7 ) were independent predictors of treatment failure . In addition , patients who last took chloroquine 3 to 14 days prior to study entry were significantly more likely to be treatment failures compared to patients with very recent ( less than 3 days ) or no recent chloroquine use . In areas with significant chloroquine resistance , easily identifiable predictors of chloroquine  treatment failure might be used to stratify patients into those for whom chloroquine use is acceptable and those for whom alternative treatment should be used BACKGROUND Chloroquine ( CQ ) resistance has reached high levels in Africa in recent years . Little is known about variations of resistance between urban and rural areas . OBJECTIVES To compare the rates of in vivo resistance to CQ and the prevalences of the main molecular marker for CQ resistance among young children from urban and rural areas in Burkina Faso . METHODS The current analysis used the frame of a r and omized controlled trial ( IS RCT N27290841 ) on the combination CQ-methylene blue ( MB )  ( n=177 ) compared to CQ alone  ( n=45 ) in young children with uncomplicated malaria . We examined clinical and parasitological failure rates as well as the prevalence of the Plasmodium falciparum chloroquine resistance transporter gene ( pfcrt ) T76 mutation . RESULTS Clinical and parasitological failure rates of CQ-MB differed significantly between urban ( 70 % ) and rural areas ( 29 % , p<0.0001 ) . 
    Output:
    
Among eight countries with longitudinal molecular resistance data , the four countries where the highest proportion of children treated for fever received chloroquine ( Ug and a , Burkina Faso , Guinea Bissau , and Mali ) also showed no significant declines in the prevalence of chloroquine-resistant infections .
Conclusions This study demonstrates that in 2006 - 2007 , chloroquine and SP continued to be used at high rates in many African countries .
In countries reporting sustained chloroquine use , chloroquine-resistant malaria persists .
In contrast , a low level of estimated chloroquine use is associated with a declining prevalence of chloroquine resistance