***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: A  Bayesian hierarchical modelling approach  to the analysis of cluster r and omized trials has advantages in terms of allowing for full parameter uncertainty , flexible modelling of covariates and variance structure , and use of prior information . Previously , such modelling of binary outcome data required use of a log-odds ratio scale for the treatment effect estimate and an approximation linking the intracluster correlation ( ICC ) to the between-cluster variance on a log-odds scale . In this paper we develop this method to allow estimation on the absolute risk scale , which facilitates clinical interpretation of both the treatment effect and the between-cluster variance . We describe a range of models and apply them to data from a trial of different interventions to promote secondary prevention of coronary heart disease in primary care . We demonstrate how these models can be used to incorporate prior data about typical ICCs , to derive a posterior distribution for the number needed to treat , and to consider both cluster and individual level covariates . Using these methods , we can benefit from the advantages of Bayesian modelling of binary outcome data at the same time as providing results on a clinical ly interpretable scale Background Sulphadoxine-pyrimethamine ( SP ) a widely used treatment for uncomplicated malaria and recommended for intermittent preventive treatment of malaria in pregnancy , is being investigated for intermittent preventive treatment of malaria in infants ( IPTi ) . High levels of drug resistance to SP have been reported from north-eastern Tanzania associated with mutations in parasite genes . This study compared the in vivo efficacy of SP in symptomatic 6–59 month children with uncomplicated malaria and in asymptomatic 2–10 month old infants . Methodology and Principal Findings An open label single arm ( SP ) st and ard 28 day in vivo WHO antimalarial efficacy protocol was used in 6 to 59 months old symptomatic children and a modified protocol used in 2 to 10 months old asymptomatic infants . Enrolment was stopped early ( 87 in the symptomatic and 25 in the asymptomatic studies ) due to the high failure rate . Molecular markers were examined for recrudescence , re-infection and markers of drug resistance and a review of literature of studies looking for the 581 G dhps mutation was carried out . In symptomatic children PCR-corrected early treatment failure was 38.8 % ( 95 % CI 26.8–50.8 ) and total failures by day 28 were 82.2 % ( 95 % CI 72.5–92.0 ) . There was no significant difference in treatment failures between asymptomatic and symptomatic children . 96 % of sample s carried parasites with mutations at codons 51 , 59 and 108 in the dhfr gene and 63 % carried a double mutation at codons 437 and 540 . 55 % carried a third mutation with the addition of a mutation at codon 581 in the dhps gene . This triple : triple haplotype maybe associated with earlier treatment failure . Conclusion In northern Tanzania SP is a failed drug for treatment and its utility for prophylaxis is doubtful . The study found a new combination of parasite mutations that maybe associated with increased and earlier failure . Trial Registration Clinical Trials.gov Intermittent preventive treatment in pregnancy ( IPTp ) is used to prevent Plasmodium falciparum malaria . However , parasites resistant to the IPTp drug sulfadoxine-pyrimethamine ( SP ) have emerged worldwide , and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice . In a prospect i ve delivery cohort in Muheza , Tanzania , we examined the effects of SP IPTp on parasite resistance alleles , parasite diversity , level of parasitemia , and inflammation in the placenta .  IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581 , an increase in the level of parasitemia , and more intense placental inflammation . The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use . These findings support a model of parasite release and facilitation , whereby the most highly resistant parasites out-compete less fit parasite population s and overgrow under drug pressure . Use of partially effective anti-malarial agents for IPTp may exacerbate  malaria infections in the setting of widespread drug resistance OBJECTIVE --To compare treatment and protection against falciparum malaria in pregnant and non-pregnant women with three drug regimens . DESIGN -- Prospect i ve intervention study with six weeks ' follow up . Patients received one of three drug regimens in order of entry . SETTING -- Primary care hospital and secondary girls ' school in rural western Kenya . PATIENTS --158 of 988 pregnant women ( 89 primigravid and 69 multigravid ) in the third trimester and 105 of 1488 non-pregnant schoolgirls of reproductive age were parasitaemic ( more than 500 asexual forms/microliter . These women were divided into three treatment groups by gravid state . INTERVENTIONS --Women were treated with chloroquine base 25 mg/kg over three days or pyrimethamine 75 mg and sulfadoxine 1500 mg as a single dose or chlorproguanil 1.2 mg/kg and dapsone 2.4 mg/kg as a single dose . MAIN OUTCOME MEASURES --Parasitaemia and haemoglobin concentrations measured at seven day intervals for six weeks . RESULTS --Primigravid women were more likely to be parasitaemic on follow up than multigravidas or nulligravidas , whose response was about the same . Parasites did not clear by day 7 in primigravidas in six ( 20 % ) of 30 who received chloroquine , three ( 8 % ) of 35 treated with pyrimethamine and sulfadoxine , and none of 23 treated with chlorproguanil and dapsone . At day 28 , 83 % , 19 % , and 67 % of primigravidas in these treatment groups were parasitaemic . Haemoglobin concentrations rose in all women , but improvement was sustained only in women who remained free of parasites . CONCLUSIONS --Clearance of parasites was better with either pyrimethamine and sulfadoxine or chlorproguanil and dapsone than with chloroquine . Longest protection was obtained with pyrimethamine and sulfadoxine 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 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 BACKGROUND Malaria control is difficult where there is intense year-round transmission of multiple plasmodium species , such as in Papua New Guinea . METHODS Between April 2005 and July 2007 , we conducted an open-label , r and omized , parallel-group study of conventional chloroquine-sulfadoxine-pyrimethamine and artesunate-sulfadoxine-pyrimethamine , dihydroartemisinin-piperaquine , and artemether-lumefantrine in children in Papua New Guinea 0.5 to 5 years of age who had falciparum or vivax malaria . The primary end point was the rate of adequate clinical and parasitologic response at day 42 after the start of treatment with regard to Plasmodium falciparum , after correction for reinfections identified through polymerase-chain-reaction ( PCR ) genotyping of polymorphic loci in parasite DNA . Secondary end points included the rate of adequate clinical and parasitologic response at day 42 with regard to P. vivax without correction through PCR genotyping . RESULTS Of 2802 febrile children screened , 482 with falciparum malaria and 195 with vivax malaria were included . The highest rate of adequate clinical and parasitologic response for P. falciparum was in the artemether-lumefantrine group ( 95.2 % ) , as compared with 81.5 % in the chloroquine-sulfadoxine-pyrimethamine group ( P=0.003 ) , 85.4 % in the artesunate-sulfadoxine-pyrimethamine group ( P=0.02 ) , and 88.0 % in the dihydroartemisinin-piperaquine group ( P=0.06 ) . The rate of adequate clinical and parasitologic response for P. vivax in the dihydroartemisinin-piperaquine group ( 69.4 % ) was more than twice that in each of the other three treatment groups . The in vitro chloroquine and piperaquine levels that inhibited growth of local P. falciparum isolates by 50 % correlated significantly ( P<0.001 ) . Rash occurred more often with artesunate-sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine than with chloroquine-sulfadoxine-pyrimethamine ( P=0.004 for both comparisons ) . CONCLUSIONS The most effective regimens were artemether-lumefantrine against P. falciparum and dihydroartemisinin-piperaquine against P. vivax . The relatively high rate of treatment failure with dihydroartemisinin-piperaquine against P. falciparum may reflect cross-resistance between chloroquine and piperaquine . ( Australian New Zeal and Clinical Trials Registry number , ACTRN12605000550606 . Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes . This study analyzed pretreatment  dihydrofolate reductase ( DHFR ) and dihydropteroate synthase ( DHPS ) genotypes  and treatment outcomes in a double-blind , placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment for uncomplicated P. falciparum malaria . Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors . Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations ( the " quintuple mutant " ) were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure . The presence of a single DHFR mutation ( Arg-59 ) with a single DHPS mutation ( Glu-540 ) accurately predicted the presence of the quintuple mutant . If this model is vali date d in other population s , it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa BACKGROUND There is a high incidence of opportunistic infection among HIV-1-infected patients with tuberculosis in Africa and , consequently , high mortality . We ass 
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The map illustrates particularly high prevalence of both the dhfr triple and dhps double mutant genotypes along the Kenya-Tanzania border and Malawi .
The regression model shows a statistically significant increase in the prevalence of both the dhfr triple and dhps double mutant genotypes in Africa .
Conclusion Increasing prevalence of the dhfr triple mutant and dhps double mutant genotypes in Africa are consistent with the loss of efficacy of SP for treatment of clinical malaria in most parts of this continent .