***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 Early-phase and pre clinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated , smear-positive pulmonary tuberculosis . METHODS We conducted a r and omized , double-blind , placebo-controlled , phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen . One group of patients received isoniazid , rifampin , pyrazinamide , and ethambutol for 8 weeks , followed by 18 weeks of isoniazid and rifampin ( control group ) . In the second group , we replaced ethambutol with moxifloxacin for 17 weeks , followed by 9 weeks of placebo ( isoniazid group ) , and in the third group , we replaced isoniazid with moxifloxacin for 17 weeks , followed by 9 weeks of placebo ( ethambutol group ) . The primary end point was treatment failure or relapse within 18 months after r and omization . RESULTS Of the 1931 patients who underwent r and omization , in the per- protocol analysis , a favorable outcome was reported in fewer patients in the isoniazid group ( 85 % ) and the ethambutol group ( 80 % ) than in the control group ( 92 % ) , for a difference favoring the control group of 6.1 percentage points ( 97.5 % confidence interval [ CI ] , 1.7 to 10.5 ) versus the isoniazid group and 11.4 percentage points ( 97.5 % CI , 6.7 to 16.1 ) versus the ethambutol group . Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses . The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups , as compared with the control group , ranged from 1.17 to 1.25 , indicating a shorter duration , with the lower bounds of the 95 % confidence intervals exceeding 1.00 in all cases . There was no significant difference in the incidence of grade 3 or 4 adverse events , with events reported in 127 patients ( 19 % ) in the isoniazid group , 111 ( 17 % ) in the ethambutol group , and 123 ( 19 % ) in the control group . CONCLUSIONS The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load , as compared with the control group . However , noninferiority for these regimens was not shown , which indicates that shortening treatment to 4 months was not effective in this setting . ( Funded by the Global Alliance for TB Drug Development and others ; REMoxTB Clinical Trials.gov number , NCT00864383 . ) Summary Background Tuberculosis is the world 's leading infectious disease killer . We aim ed to identify shorter , safer drug regimens for the treatment of tuberculosis . Methods We did a r and omised controlled , open-label trial with a multi-arm , multi-stage design . The trial was done in seven sites in South Africa and Tanzania , including hospitals , health centres , and clinical trial centres . Patients with newly diagnosed , rifampicin-sensitive , previously untreated pulmonary tuberculosis were r and omly assigned in a 1:1:1:1:2 ratio to receive ( all orally ) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol , 20 mg/kg rifampicin per day with 400 mg moxifloxacin , 20 mg/kg rifampicin per day with 300 mg SQ109 , 10 mg/kg rifampicin per day with 300 mg SQ109 , or a daily st and ard control regimen ( 10 mg/kg rifampicin , 5 mg/kg isoniazid , 25 mg/kg pyrazinamide , and 15–20 mg/kg ethambutol ) . Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks , followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day . Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation . The primary endpoint was time to culture conversion in liquid media within 12 weeks . Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis ( modified intention to treat ) . Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables . The proportional hazard assumption was tested using Schoelfeld residuals , with threshold p<0·05 for non-proportionality . The trial is registered with Clinical Trials.gov ( NCT01785186 ) . Findings Between May 7 , 2013 , and March 25 , 2014 , we enrolled and r and omly assigned 365 patients to different treatment arms ( 63 to rifampicin 35 mg/kg , isoniazid , pyrazinamide , and ethambutol ; 59 to rifampicin 10 mg/kg , isoniazid , pyrazinamide , SQ109 ; 57 to rifampicin 20 mg/kg , isoniazid , pyrazinamide , and SQ109 ; 63 to rifampicin 10 mg/kg , isoniazid , pyrazinamide , and moxifloxacin ; and 123 to the control arm ) . Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis . Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group ( median 48 days vs 62 days , adjusted hazard ratio 1·78 ; 95 % CI 1·22–2·58 , p=0·003 ) , but not in other experimental arms . There was no difference in any of the groups in time to culture conversion on solid media . 11 patients  had treatment failure or recurrent disease during post-treatment follow-up : one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm . 45 ( 12 % ) of 365 patients  reported grade 3–5 adverse events , with similar proportions in each arm . Interpretation A dose of 35 mg/kg rifampicin was safe , reduced the time to culture conversion in liquid media , and could be a promising component of future , shorter regimens . Our adaptive trial design was successfully implemented in a multi-centre , high tuberculosis burden setting , and could speed regimen development at reduced cost . Funding The study was funded by the European and Developing Countries Clinical Trials partnership ( EDCTP ) , the German Ministry for Education and Research ( BmBF ) , and the Medical Research Council UK ( MRC ) Cardiac safety was compared in patients receiving moxifloxacin and other antimicrobials in a large patient population from Phase II – IV r and omized active-controlled clinical trials .  Moxifloxacin 400 mg once-daily monotherapy was administered orally ( PO ) or sequentially ( intravenous/oral , IV/PO ) . Across 64 trials , 21,298 patients received PO therapy ( 10,613 moxifloxacin , 10,685 comparators ) while 6846 received sequential IV/PO therapy ( 3431 moxifloxacin  , 3415 comparators ) . Treatment-emergent cardiac adverse event ( AE ) rates were similar for moxifloxacin and comparators in PO ( 6.6 % vs 5.8 % ) and IV/PO ( 11.0 % vs 12.0 % ) trials . Treatment-emergent cardiac adverse drug reactions were rare in PO ( moxifloxacin 3.2 % vs comparators 2.4 % ) and IV/PO ( moxifloxacin 1.4 % vs comparators 1.5 % ) patients . There were five ( < 0.02 % ) treatment-emergent drug-related deaths due to cardiac events out of 28,144 patients ; one PO patient died treated with comparators , one patient died treated with IV/PO moxifloxacin , and three patients died after treatment with IV/PO comparators . Only one case of treatment-related non-fatal torsade de pointes occurred in the comparator arm . Incidence rates of cardiac AEs remained low in population s at elevated risk of cardiac events predisposed to QTc prolongation ( i.e. community-acquired pneumonia patients admitted to the intensive care unit and /or mechanical ventilation , patients with documented prolongation of baseline QTc interval , women , and patients ≥ 65 years old ) . There was no evidence of unexpected cardiac events . After moxifloxacin treatment , an expected small prolongation in QTcB and QTcF was found . This analysis of numerous clinical trials shows the favorable cardiac safety profile of moxifloxacin , when used appropriately and according to its label , versus other antibiotics Rifapentine is a highly active antituberculosis antibiotic with treatment‐shortening potential ; however , exposure – response relations and the dose needed for maximal bactericidal activity have not been established . We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine ( n = 405 ) with rifampin ( n = 252 ) as part of intensive‐phase therapy . Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed‐effects modeling . Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy . Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus , black , male , or fasting when taking drug .  Rifapentine exposure , large lung cavity size , and geographic region were independently associated with time to culture conversion in liquid media . Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily . Patients with large lung cavities appear less responsive to treatment , even at high rifapentine doses This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade , but no tuberculosis-specific drugs have been discovered in 40 years . We identified a diarylquinoline , R207910 , that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro ( minimum inhibitory concentration 0.06 μg/ml ) . In mice , R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit . Substitution of drugs included in the World Health Organization 's first-line tuberculosis treatment regimen ( rifampin , isoniazid , and pyrazinamide ) with R207910 accelerated bactericidal activity , leading to complete culture conversion after 2 months of treatment in some combinations . A single dose of R207910 inhibited mycobacterial growth for 1 week . Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers . Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate ( ATP ) synthase Tuberculosis kills more people than any other infectious disease . Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins ; however , approximately four-fifths of participants were cured . Through a pooled analysis of patient-level data with external validation , we identify population s eligible for 4-month treatment , define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes . In 3,405 participants included in analyses , baseline smear grade of 3 + relative to < 2 + , HIV seropositivity and adherence of ≤90 % were significant risk factors for unfavorable outcome . Four-month regimens were non-inferior in participants with minimal disease defined by < 2 + sputum smear grade or non-cavitary disease  . A hard-to-treat phenotype , defined by high smear grade s and cavitation , may require duration s > 6 months to cure all . Regimen duration can be selected in order to improve outcomes , providing a stratified medicine approach as 
    Output:
    
Authors ' conclusions Evidence to date does not support the use of shortened ATT regimens in adults with newly diagnosed drug‐sensitive pulmonary tuberculosis .
Four‐month ATT regimens that replace ethambutol with moxifloxacin or gatifloxacin , or isoniazid with moxifloxacin , increase relapse substantially compared to st and ard six‐month ATT regimens , although treatment success and serious adverse events are little or no different .