***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 Radical cure of Plasmodium vivax malaria with 8-aminoquinolines ( primaquine or tafenoquine ) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase ( G6PD ) deficiency . G6PD heterozygous females , because of individual variation in the pattern of X-chromosome inactivation ( Lyonisation ) in erythroid cells , may have low G6PD activity in the majority of their erythrocytes , yet are usually reported as G6PD “ normal ” by current phenotypic screening tests . Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized . Methods and Findings In a cohort study nested within a r and omised clinical trial that compared different treatment regimens for P. vivax malaria , patients with a normal st and ard NADPH fluorescent spot test result ( ≳30%–40 % of normal G6PD activity ) were r and omised to receive 3 d of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine , either the st and ard high dose of 0.5 mg base/kg/day for 14 d or a higher dose of 1 mg base/kg/d for 7 d. Patterns of haemolysis were compared between G6PD wild-type and G6PD heterozygous female participants . Between 21 February 2012 and 04 July 2014 , 241 female participants were enrolled , of whom 34 were heterozygous for the G6PD Mahidol variant . Haemolysis was substantially greater and a larger proportion of participants reached the threshold of clinical ly significant haemolysis ( fractional haematocrit reduction > 25 % ) in G6PD heterozygotes taking the higher ( 7 d ) primaquine dose ( 9/17 [ 53 % ] ) compared with G6PD heterozygotes taking the st and ard high ( 14 d ) dose ( 2/16 [ 13 % ] ; p = 0.022 ) . In heterozygotes , the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose ( 7-d regimen ) : −20.4 % ( 95 % CI −26.0 % to −14.8 % ) ( nadir on day 5 ) compared with the st and ard high ( 14 d ) dose : −13.1 % ( 95 % CI −17.6 % to −8.6 % ) ( nadir day 6 ) . Two heterozygotes taking the higher ( 7 d ) primaquine dose required blood transfusion . In wild-type participants , mean haematocrit reductions were clinical ly insignificant and similar with both doses : −5.8 ( 95 % CI −7.2 % to −4.4 % ) ( nadir day 3 ) compared with −5.5 % ( 95 % CI −7.4 % to −3.7 % ) ( nadir day 4 ) , respectively . Limitations to this nested cohort study are that the primary objective of the trial was design ed to measure efficacy and not haemolysis in relation to G6PD genotype and that the heterozygote groups were small . Conclusion Higher daily doses of primaquine have the potential to cause clinical ly significant haemolysis in G6PD heterozygous females who are reported as phenotypically normal with current point of care tests . Trial Registration Clinical Trials.gov NCT01640574 Background The World Health Organization recommends artemisinin-based combination ( ACT ) for the treatment of uncomplicated malaria . Post-licensure safety data on newly registered ACT is critical for evaluating their risk/benefit profile in malaria endemic countries . The clinical safety of the newly registered combination , Eurartesim ® , following its introduction into the public health system in four African countries was assessed . Methods This was a prospect i ve , observational , open-label , non-comparative , longitudinal , multi-centre study using cohort event monitoring . Patients with confirmed malaria had their first dose observed and instructed on how to take the second and the third doses at home . Patients were contacted on day 5 ± 2 to assess adherence and adverse events ( AEs ) . Spontaneous reporting of AEs was continued till day 28 . A nested cohort who completed full treatment course had repeated electrocardiogram ( ECG ) measurements to assess effect on QTc interval . Results A total of 10,925 uncomplicated malaria patients were treated with Eurartesim ® . Most patients , 95 % ( 10,359/10,925 ) , did not report any adverse event following at least one dose of Eurartesim ® . A total of 797 adverse events were reported . The most frequently reported , by system organ classification , were infections and infestations ( 3 . 24 % ) and gastrointestinal disorders ( 1 . 37 % ) . In the nested cohort , no patient had QTcF > 500 ms prior to day 3 pre-dose 3 . Three patients had QTcF > 500 ms ( 509 ms , 501 ms , 538 ms ) three to four hours after intake of the last dose . All the QTcF values in the three patients had returned to < 500 ms at the next scheduled ECG on day 7 ( 470 ms , 442 ms , 411 ms ) . On day 3 pre- and post-dose 3 , 70 and 89 patients , respectively , had a QTcF increase of ≥ 60 ms compared to their baseline , but returned to nearly baseline values on day 7 . Conclusion Eurartesim ® single course treatment for uncomplicated falciparum malaria is well-tolerated . QT interval prolongation above 500 ms may occur at a rate of three per 1,002 patients after the third dose with no association of any clinical symptoms . QT interval prolongation above 60 ms was detected in less than 10 % of the patients without any clinical abnormalities BACKGROUND Single low doses of primaquine , when added to artemisinin-based combination therapy , might prevent transmission of Plasmodium falciparum malaria to mosquitoes . We aim ed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali . METHODS In this phase 2 , single-blind , dose-ranging , adaptive r and omised trial , we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre ( MRTC ) field site in Ouelessebougou , Mali . All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase ( G6PD ) on colorimetric quantification . In the first phase , participants were r and omly assigned ( 1:1:1 ) to one of three primaquine doses : 0 mg/kg ( control ) , 0·125 mg/kg , and 0·5 mg/kg . R and omisation was done with a computer-generated r and omisation list ( in block sizes of six ) and concealed with sealed , opaque envelopes . In the second phase , different participants were sequentially assigned ( 1:1 ) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine . Primaquine tablets were dissolved into a solution and administered orally in a single dose . Participants were also given a 3 day course of dihydroartemisinin-piperaquine , administered by weight ( 320 mg dihydroartemisinin and 40 mg piperaquine per tablet ) . Outcome assessors were masked to treatment allocation , but participants were permitted to find out group assignment . Infectivity was assessed through membrane-feeding assays , which were optimised through the beginning part of phase one . The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay , had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement , and who were given the correct primaquine dose . The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit . This study is registered with Clinical Trials.gov , number NCT01743820 . FINDINGS Between Jan 2 , 2013 , and Nov 27 , 2014 , we enrolled 81 participants . In the primary analysis sample ( n=71 ) , participants in the 0·25 mg/kg primaquine dose group ( n=15 ) and 0·5 mg/kg primaquine dose group ( n=14 ) had significantly lower mean within-person reductions in infectivity at day 2 - 92·6 % ( 95 % CI 78·3 - 100 ; p=0·0014 ) for the 0·25 mg/kg group ; and 75·0 % ( 45·7 - 100 ; p=0·014 ) for the 0·5 mg/kg primaquine group-compared with those in the control group ( n=14 ; 11·3 % [ -27·4 to 50·0 ] ) . Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group ( n=16 ; 41·9 % [ 1·4 - 82·5 ] ; p=0·16 ) and the 0·125 mg/kg dose group ( n=12 ; 54·9 % [ 13·4 - 96·3 ] ; p=0·096 ) . No clinical ly meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis ( n=70 ) during follow-up . No serious adverse events were reported and adverse events did not differ between treatment groups . INTERPRETATION A single dose of 0·25 mg/kg primaquine , given alongside dihydroartemisinin-piperaquine , was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD . Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine . FUNDING Bill & Melinda Gates Foundation BACKGROUND Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited , particularly among women who live in sub-Saharan Africa . METHODS We conducted a multicenter , r and omized , open-label trial of treatments for malaria in pregnant women in four African countries . A total of 3428 pregnant women in the second or third trimester who had falciparum malaria ( at any parasite density and regardless of symptoms ) were treated with artemether-lumefantrine , amodiaquine-artesunate , mefloquine-artesunate , or dihydroartemisinin-piperaquine . The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates ( i.e. , cure of the original infection ; new infections during follow-up were not considered to be treatment failures ) at day 63 and safety outcomes . RESULTS The PCR-adjusted cure rates in the per- protocol analysis were 94.8 % in the artemether-lumefantrine group , 98.5 % in the amodiaquine-artesunate group , 99.2 % in the dihydroartemisinin-piperaquine group , and 96.8 % in the mefloquine-artesunate group ; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2 % , 96.9 % , 98.0 % , and 95.5 % , respectively . There was no significant difference among the amodiaquine-artesunate group , dihydroartemisinin-piperaquine group , and the mefloquine-artesunate group . The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups , although the absolute difference was within the 5-percentage-point margin for equivalence . The unadjusted cure rates , used as a measure of the post-treatment prophylactic effect , were significantly lower in the artemether-lumefantrine group ( 52.5 % ) than in groups that received amodiaquine-artesunate ( 82.3 % ) , dihydroartemisinin-piperaquine ( 86.9 % ) , or mefloquine-artesunate ( 73.8 % ) . No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups . Drug-related adverse events such as asthenia , poor appetite , dizziness , nausea , and vomiting occurred significantly more frequently in the mefloquine-artesunate group ( 50.6 % ) and the amodiaquine-artesunate group ( 48.5 % ) than in the dihydroartemisinin-piperaquine group ( 20.6 % ) and the artemether-lumefantrine group ( 11.5 % ) ( P<0.001 for comparison among the four groups ) . CONCLUSIONS Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis , whereas dihydroartemisinin-pi 
    Output:
    
INTERPRETATION Dihydroartemisinin-piperaquine was associated with a low risk of sudden unexplained death that was not higher than the baseline rate of sudden cardiac death .