***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: Background New antimalarials are needed for P. vivax and P. falciparum malaria . This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria . Methods and Findings This phase III r and omized , double-blind , non-inferiority trial included five centers across Cambodia , Thail and , India , and Indonesia . In a double-dummy design , patients ( aged > 3–≤60 years ) with microscopically confirmed P. vivax mono-infection were r and omized ( 1∶1 ) to receive pyronaridine-artesunate ( target dose 7.2∶2.4 mg/kg to 13.8∶4.6 mg/kg ) or chloroquine ( st and ard dose ) once daily for three days . Each treatment group included 228 r and omized patients . Outcomes for the primary endpoint , Day-14 cure rate in the per- protocol population , were 99.5 % , ( 217/218 ; 95%CI 97.5 , 100 ) with pyronaridine-artesunate and 100 % ( 209/209 ; 95%CI 98.3 , 100 ) with chloroquine . Pyronaridine was non-inferior to chloroquine : treatment difference −0.5 % ( 95%CI −2.6 , 1.4 ) , i.e. , the lower limit of the 2-sided 95%CI for the treatment difference was greater than −10  % . Pyronaridine-artesunate cure rates were non-inferior to chloroquine for Days 21 , 28 , 35 and 42 . Parasite clearance time was shorter with pyronaridine-artesunate ( median 23.0 h ) versus chloroquine ( 32.0 h ; p<0.0001 ) , as was fever clearance time ( median 15.9 h and 23.8 h , respectively ; p = 0.0017 ) . Kaplan-Meier estimates of post-baseline P. falciparum infection incidence until Day 42 were 2.5 % with pyronaridine-artesunate , 6.1 % with chloroquine ( p = 0.048 , log-rank test ) . Post-baseline P. vivax or P. falciparum infection incidence until Day 42 was 6.8 % and 12.4 % , respectively ( p = 0.022 , log rank test ) . There were no deaths . Adverse events occurred in 92/228 ( 40.4 % ) patients with pyronaridine-artesunate and 72/228 ( 31.6 % ) with chloroquine . Mild and transient increases in hepatic enzymes were observed for pyronaridine-artesunate . Conclusion Pyronaridine-artesunate efficacy in acute uncomplicated P. vivax malaria was at least that of chloroquine . As pyronaridine-artesunate is also efficacious against P. falciparum malaria , this combination has potential utility as a global antimalarial drug . Trial registration Clinical trials.gov Objective : To compare the QT/RR relation in healthy subjects in order to investigate the differences in optimum heart rate correction of the QT interval . Methods : 50 healthy volunteers ( 25 women , mean age 33.6 ( 9.5 ) years , range 19–59 years ) took part . Each subject underwent serial 12 lead electrocardiographic monitoring over 24 hours with a 10 second ECG obtained every two minutes .  QT intervals and heart rates were measured automatically . In each subject , the QT/RR relation was modelled using six generic regressions , including a linear model ( QT = β + α × RR ) , a hyperbolic model ( QT = β + α/RR ) , and a parabolic model ( QT = β × RRα ) . For each model , the parallelism and identity of the regression lines in separate subjects were statistically tested . Results : The patterns of the QT/RR relation were very different among subjects . Regardless of the generic form of the regression model , highly significant differences were found not only between the regression lines but also between their slopes . For instance , with the linear model , the individual slope ( parameter α ) of any subject differed highly significantly ( p < 0.000001 ) from the linear slope of no fewer than 21 ( median 32 ) other subjects . The linear regression line of 20 subjects differed significantly ( p < 0.000001 ) from the linear regression lines of each other subject . Conversion of the QT/RR regressions to QTc heart rate correction also showed substantial intersubject differences . Optimisation of the formula QTc = QT/RRα led to individual values of α ranging from 0.234 to 0.486 . Conclusion : The QT/RR relation exhibits a very substantial intersubject variability in healthy volunteers . The hypothesis underlying each prospect i ve heart rate correction formula that a “ physiological ” QT/RR relation exists that can be mathematically described and applied to all people is incorrect . Any general heart rate correction formula can be used only for very approximate clinical assessment of the QTc interval over a narrow window of resting heart rates . For detailed precise studies of the QTc interval ( for example , drug induced QT interval prolongation ) , the individual QT/RR relation has to be taken into account 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 Summary Background Artemether – lumefantrine and artesunate – amodiaquine are used as first-line artemisinin-based combination therapies ( ACTs ) in west Africa .  Pyronaridine – artesunate and dihydroartemisinin – piperaquine are potentially useful for diversification of ACTs in this region , but further safety and efficacy data are required on malaria retreatment . Methods We did a r and omised , multicentre , open-label , longitudinal , controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso , Guinea , and Mali . Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria ( > 0 to < 200 000 parasites per μL of blood ) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria , an alanine aminotransferase concentration of more than twice the upper limit of normal , or a QTc greater than 450 ms were excluded . Using a r and omisation list for each site , masked using sealed envelopes , participants were assigned to either pyronaridine – artesunate or dihydroartemisinin – piperaquine versus either artesunate – amodiaquine or artemether – lumefantrine . Block sizes were two or four if two treatments were allocated , and three or six if three treatments were allocated . Microscopists doing the parasitological assessment s were masked to treatment allocation . All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre . Patients were followed up as out patients up to day 42 , receiving clinical assessment s on days 0 , 1 , 2 , 3 , 7 , 14 , 21 , 28 , 35 , and 42 . Two primary outcomes were compared for non-inferiority : the 2-year incidence rate of all microscopically confirmed , complicated and uncomplicated malaria episodes in patients in the intention-to-treat population ( ITT ; non-inferiority margin 20 % ) ; and adequate clinical and parasitological response ( ACPR ) in uncomplicated malaria across all episodes ( unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp ) in the per- protocol population on days 28 and 42 ( non-inferiority margin 5 % ) . Safety was assessed in all participants who received one dose of study drug . This study is registered at the Pan African Clinical Trials Registry ( PACTR201105000286876 ) . Findings Between Oct 24 , 2011 , and Feb 1 , 2016 , we assigned 4710 eligible participants to the different treatment strategies : 1342 to pyronaridine – artesunate , 967 to artemether – lumefantrine , 1061 to artesunate – amodiaquine , and 1340 to dihydroartemisinin – piperaquine . The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine – artesunate versus artemether – lumefantrine ( 1·77 , 95 % CI 1·63–1·93 vs 1·87 , 1·72–2·03 ; rate ratio [ RR ] 1·05 , 95 % CI 0·94–1·17 ) ; and versus artesunate – amodiaquine ( 1·39 , 95 % CI 1·22–1·59 vs 1·35 , 1·18–1·54 ; RR 0·97 , 0·87–1·07 ) . Similarly , this endpoint was non-inferior for dihydroartemisinin – piperaquine versus artemether – lumefantrine ( 1·16 , 95 % CI 1·01–1·34 vs 1·42 1·25–1·62 ; RR 1·22 , 95 % CI 1·06–1·41 ) and versus artesunate – amodiaquine ( 1·35 , 1·21–1·51 vs 1·68 , 1·51–1·88 ; RR 1·25 , 1·02–1·50 ) . For uncomplicated P falciparum malaria , PCR-adjusted ACPR was greater than 99·5 % at day 28 and greater than 98·6 % at day 42 for all ACTs ; unadjusted ACPR was higher for pyronaridine – artesunate versus comparators at day 28 ( 96·9 % vs 82·3 % for artemether – lumefantrine and 95·6 % vs 89·0 % for artesunate – amodiaquine ) and for dihydroartemisinin-piperaquine versus comparators ( 99·5 % vs 81·6 % for artemether – lumefantrine and 99·0 % vs 89·0 % for artesunate – amodiaquine ) . For non-falciparum species , unadjusted ACPR was greater than 98 % for all study drugs at day 28 and at day 42 was greater than 83 % except for artemether – lumefantrine against Plasmodium ovale ( in ten [ 62·5 % ] of 16 patients ) and against Plasmodium malariae ( in nine [ 75·0 % ] of 12 patients 
    Output:
    
Transiently high concentrations of quinine , quinidine , and chloroquine following parenteral administration have all been associated with hypotension , but there were no documented reports of death or syncope attributable to a cardiovascular cause , nor of electrocardiographic recordings of ventricular arrhythmia in these trials .
The large volume of missing outcome information and the heterogeneity of ECG interval reporting and measurement methodology did not allow pooled quantitative analysis of QT interval changes .