***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: We assessed the efficacy of trimethoprim/sulfamethoxazole ( TRM/SMX ) in vivo in relation to the frequency of dihydrofolate reductase ( dhfr ) and dihydropteroate synthase ( dhps ) alleles in 45 Sudanese malaria patients .  Plasma levels of TRM , SMX , and acetylsulfamethoxazole ( AcSMX ) were measured before treatment and at days 3 , 7 , and 14 or upon recrudescence to ascertain drug absorption . Forty patients ( 89 % ) had an adequate clinical response , one patient ( 2 % ) had an early treatment failure response , while four patients ( 8 % ) showed late treatment failure responses . Genotyping of merozoite surface protein 1 , MSP-1 , MSP-2 , and glutamate-rich protein before treatment and upon recrudescence showed that all recurring parasites were recrudescences . The plasma levels of TRM , AcSMX , and SMX indicated adequate drug absorption in all patients . This suggests parasite resistance as a cause of treatment failure . The presence of dhfr Ile 51 and Asn 108 alone or coupled with dhps Ala-436 among parasites that were cleared after treatment indicates that these alleles alone are insufficient to cause in vivo resistance . However , the presence of the triple mutant dhfr ( Ile-51/Arg-59/Asn-108 ) with the dhps Gly-437 genotype in all recurring infections , suggests the importance of codon 59 and 437 alleles in susceptibility to TRM/SMX . However , the number is too little to make firm conclusions 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 To determine the predictive value of  chloroquine ( CQ ) resistance markers in Senegal , Plasmodium falciparum DNA polymorphisms in pfmdr1 and pfcrt were examined in relation to clinical outcome . Despite CQ treatment , 17 % of patients had parasitemia after 28 days . Examination of molecular markers of CQ resistance revealed that 64 % of all isolates had the T76 resistant allele at the pfcrt locus , while 30 % carried the Y86 resistant allele at the pfmdr1 locus . The pfcrt T76 allele was present not only in all in vivo resistant isolates , 89 % of in vitro resistant isolates , but also in 35 % of in vitro sensitive isolates . The pfmdr1 N86Y polymorphism did not correlate with in vitro or in vivo  CQ resistance . Our data suggest that the pfcrt T76 allele alone is required but not a sufficient predictor for in vivo CQ resistance Both northern and southern Sudan are deploying artemisinin-based combinations against uncomplicated Plasmodium falciparum malaria ( artesunate+sulfadoxine-pyrimethamine [ AS+SP ] in the north , artesunate+amodiaquine [ AS+AQ ] in the south ) . In 2003 , we tested the efficacy of 3 day AS+SP and AS+AQ regimens in vivo in the isolated , seasonally endemic Nuba Mountains region ( the first study of AS combinations in southern Sudan ) . We also analysed pre-treatment blood sample s for mutations at the P. falciparum chloroquine transporter ( Pfcrt ) gene ( associated with CQ resistance ) , and at the dihydrofolate reductase ( Dhfr ) gene ( associated with pyrimethamine resistance ) . Among 161 r and omized children under 5 years , PCR-corrected cure rates after 28 days were 91.2 % ( 52/57 , 95 % CI 80.7 - 97.1 ) for AS+SP and 92.7 % ( 51/55 , 95 % CI 82.4 - 98.0 ) for AS+AQ , with equally rapid parasite and fever clearance . The Pfcrt K76 T mutation occurred in 90.0 % ( 144/160 ) of infections , suggesting CQ would work poorly in this region . Overall , 82.5 % ( 132/160 ) carried mutations at Dhfr ( N51I , C59R or S108N , but not I164L ) , but triple mutants ( more predictive of in vivo SP failure ) were rare ( 3.1 % ) . CQ use should be rapidly discontinued in this region . SP resistance may propagate rapidly , and AS+AQ is likely to be a better long-term option , provided AQ use is limited to the combination Plasmodium falciparum present in blood sample s collected before and 3 weeks after treatment with either pyrimethamine-sulfadoxine or chlorproguanil-dapsone  was analyzed for variants of the genes coding for the target enzymes of antifolate drugs , dihydrofolate reductase ( DHFR ) and dihydropteroate synthetase ( DHPS ) . Fragments of the genes were amplified by polymerase chain reactions , and variants were identified by specific restriction endonuclease digestion . Treatment with either drug combination selected for the variants Ile51 , Arg59 , and Asn108 of DHFR , which have been associated with in vitro resistance to pyrimethamine and cycloguanil . The genotype Ser436 , Gly437 , and Glu540 of DHPS was selected by pyrimethamine-sulfadoxine but not chlorproguanil-dapsone treatment , showing that a combination of these three variants is important for in vivo resistance to sulfadoxine in the area studied Sulfadoxine-pyrimethamine efficacy was determined with a 28-day follow-up in 97 children between 6 months and 15 years of age . The polymerase chain reaction (PCR)-corrected treatment failure was 8.2 % and the uncorrected was 21.6 % . The presence of the dihydrofolate reductase ( DHFR ) and dihydropteroate synthetase ( DHPS ) mutations linked to sulfadoxine-pyrimethamine resistance before and after treatment was determined by PCR-restriction fragment length polymorphism ( RFLP ) and by a fluorogenic PCR assay . Before treatment , the prevalence of the triple DHFR mutations was higher among the patients having had a recurrent parasitemia ( either recrudescence or new infection ; 28.6 % versus 9.3 % ) , although the difference was not significant ( P = 0.1 ) . The double mutation Ala-436/Gly-437 was observed in 67 % of sample s , whereas no Glu-540 mutation was found . After treatment , the triple DHFR mutation was found in 76.2 % of patients with recurrent parasitemia , recrudescence , and new infection alike . Such high prevalence of mutant parasites indicates that sulfadoxine-pyrimethamine should not be used as monotherapy 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 ) . Likewise ,  CQ failure rates were higher in the urban setting . Matching this pattern , pfcrt T76 was more frequently seen among parasite strains from urban areas ( 81 % ) when compared to rural ones ( 64 % , p=0.01 ) . In the presence of parasites exhibiting pfcrt T76 , the odds of overall clinical failure were increased to 2.6-fold ( [ 1.33 , 5.16 ] , p(LR)=0.005 ) .  CQ  was detected at baseline in 21 % and 2 % of children from the urban and the rural study area , respectively ( p(Chi)=0.002 ) . CONCLUSION Even within circumscribed geographical areas ,  CQ efficacy can vary dramatically . The differences in the prevalence of pfcrt T76 and in CQ failure rates are probably explained by a higher drug pressure in the urban area compared to the rural study area . This finding has important implication s for national malaria policies This study examines the relationship between malaria treatment failure after sulfadoxine-pyrimethamine ( S-P ) chemotherapy  and presence of mutations in the Plasmodium falciparum dihydropteroate synthase ( dhps ) and dihydrofolate reductase ( dhfr ) genes ( associated with resistance in vitro to S and P ) before treatment . In Kenya , 38 malaria patients in a holoendemic area , and 21 in an epidemic area , participated in the trial in 1997 - 98 . In the 2 areas , drug failure occurred in 76 % and 75 % of cases where any mutation in dhfr was seen ( positive predictive values 76 % and 75 % : P = 0.003 and 0.008 ) and an identical association was seen with dhfr Asn-108 . In the holoendemic area all occurrences of > or = 2 mutations in dhfr predicted drug failure . Only 3 instances were seen in the epidemic focus , but treatment failed in all . Only in the epidemic focus , 7 ( 88 % ) of 8 occurrences of > or = 1 mutations in dhps , and all occurrences of the Gly-437 allele of dhps , predicted failure . Association between mutations in dhps and mutations in dhfr was noted in the combined sites , irrespective of outcome . Although this makes the relationship of combined dhfr and dhps mutations to failure more difficult to interpret , it nevertheless supports S-P selection acting on both genes . In the holoendemic site , treatment success increased with age . In this location , acquired immunity may mask the impact of mutations in dhps , since sulfadoxine is a less effective treatment than pyrimethamine The 4-aminoquinolines chloroquine ( CQ ) and amodiaquine ( AM ) were used to treat Gambian children with uncomplicated falciparum malaria in a r and omized drug trial . Blood sample s were taken immediately before treatment ( day 0 ) , and at day 7 and day 28 after treatment . Sample s from those parasitologically positive at day 7 following treatment ( ' early positives ' ) and those positive at day 28 but negative at day 7 ( ' late positives ' ) have been studied by PCR followed by restriction enzyme digestion to determine the allelic status of the pfmdr 1 locus at the codon-86 position ( asparagine or tyrosine ) , previously associated with resistance to CQ . A significantly higher prevalence of the tyr-86 allele was observed in sample s taken immediately before treatment ( day 0 ) in the early posit 
    Output:
    
Genetic molecular markers were related to an increased risk of therapeutic failure .