***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: OBJECTIVE The aim was to determine long-term mortality rates and the underlying cause of death for subjects with different peripheral arterial disease ( PAD ) stages in a population based setting . METHODS A r and omly selected population sample of 5080 subjects was enrolled in the study in 2004 - 2005 . Participants completed health state question naires and underwent ankle brachial index ( ABI ) measurements for classification into PAD severity stages and reference subjects . A follow-up was conducted by the end of 2015 using data from Swedish governmental national registers for cause of death , which was then compared with PAD stage determined at baseline in 2005 . RESULTS The 10 year all cause mortality was 27 % for reference cases , 56 % for asymptomatic PAD ( APAD ) , 63 % for intermittent claudication ( IC ) , and 75 % for severe limb ischaemia ( SLI ) . Among all PAD subjects , cardiovascular ( CV ) causes were the most common main cause of death ( 45 % ) and a CV event was present as either the main or one of the three most common contributing causes of death in 64 % of the cases . The age adjusted hazard ratios for a main cause of death by a CV event were 1.9 ( 95 % CI 1.5 - 2.3 ) for APAD , 2.6 ( 95 % CI 2.1 - 3.4 ) for IC , and 3.5 ( 95 % CI 2.3 - 5.2 ) for SLI . CONCLUSION PAD subjects , including the APAD subjects , are still at high risk of CV death . The mortality risks are more than doubled in symptomatic PAD patients compared with reference subjects and increase by severity of PAD stage . Awareness and improved risk reduction management of PAD are still warranted BACKGROUND Patients with lower extremity peripheral artery disease ( PAD ) are at increased risk of major adverse cardiovascular events ( MACE ) and major adverse limb events ( MALE ) . There is limited information on the prognosis of patients who experience MALE . OBJECTIVES Among participants with lower extremity PAD , this study investigated : 1 ) if hospitalizations , MACE , amputations , and deaths are higher after the first episode of MALE compared with patients with PAD who do not experience MALE ; and 2 ) the impact of treatment with low-dose rivaroxaban and aspirin compared with aspirin alone on the incidence of MALE , peripheral vascular interventions , and all peripheral vascular outcomes over a median follow-up of 21 months . METHODS We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS ( Cardiovascular Outcomes for People Using Anticoagulation Strategies ) trial . COMPASS was a r and omized , double-blind placebo-controlled study of low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone . MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation . RESULTS A total of 128 patients experienced an incident of MALE . After MALE , the 1-year cumulative risk of a subsequent hospitalization was 61.5 % ; for vascular amputations , it was 20.5 % ; for death , it was 8.3 % ; and for MACE , it was 3.7 % . The MALE index event significantly increased the risk of experiencing subsequent hospitalizations ( hazard ratio [ HR ] : 7.21 ; p < 0.0001 ) , subsequent amputations ( HR : 197.5 ; p < 0.0001 ) , and death ( HR : 3.23 ; p < 0.001 ) . Compared with aspirin alone , the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43 % ( p = 0.01 ) , total vascular amputations by 58 % ( p = 0.01 ) , peripheral vascular interventions by 24 % ( p = 0.03 ) , and all peripheral vascular outcomes by 24 % ( p = 0.02 ) . CONCLUSIONS Among individuals with lower extremity PAD , the development of MALE is associated with a poor prognosis , making prevention of this condition of utmost importance . The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowered the incidence of MALE and the related complications , and this combination should be considered as an important therapy for patients with PAD . ( Cardiovascular Outcomes for People Using Anticoagulation Strategies [ COMPASS ] ; NCT01776424 ) Principled methods with which to appropriately analyze missing data have long existed ; however , broad implementation of these methods remains challenging . In this and 2 companion papers ( Am J Epidemiol . 2018;187(3):576 - 584 and Am J Epidemiol . 2018;187(3):585 - 591 ) , we discuss issues pertaining to missing data in the epidemiologic literature . We provide details regarding missing- data mechanisms and nomenclature and encourage the conduct of principled analyses through a detailed comparison of multiple imputation and inverse probability weighting .  Data from the Collaborative Perinatal Project , a multisite US study conducted from 1959 to 1974 , are used to create a masked data -analytical challenge with missing data induced by known mechanisms . We illustrate the deleterious effects of missing data with naive methods and show how principled methods can sometimes mitigate such effects . For example , when data were missing at r and om , naive methods showed a spurious protective effect of smoking on the risk of spontaneous abortion ( odds ratio ( OR ) = 0.43 , 95 % confidence interval ( CI ) : 0.19 , 0.93 ) , while implementation of principled methods multiple imputation ( OR = 1.30 , 95 % CI : 0.95 , 1.77 ) or augmented inverse probability weighting ( OR = 1.40 , 95 % CI : 1.00 , 1.97 ) provided estimates closer to the " true " full- data effect ( OR = 1.31 , 95 % CI : 1.05 , 1.64 ) . We call for greater acknowledgement of and attention to missing data and for the broad use of principled missing- data methods in epidemiologic research CONTEXT Among individuals with lower-extremity peripheral arterial disease ( PAD ) , specific leg symptoms and the ankle brachial index ( ABI ) are cross-sectionally related to the degree of functional impairment . However , relations between these clinical characteristics and objective ly measured functional decline are unknown . OBJECTIVE To define whether PAD , ABI , and specific leg symptoms predict functional decline at 2-year follow-up . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve cohort study among 676 consecutively identified individuals ( aged > or = 55 years ) with and without PAD ( n = 417 and n = 259 , respectively ) , with baseline functional assessment s occurring between October 1 , 1998 , and January 31 , 2000 , and follow-up assessment s scheduled 1 and 2 years thereafter . PAD was defined as ABI less than 0.90 , and participants with PAD were categorized at baseline into 1 of 5 mutually exclusive symptom groups . MAIN OUTCOME MEASURES Mean annual changes in 6-minute walk performance and in usual-paced and fast-paced 4-m walking velocity , adjusted for age , sex , race , prior-year functioning , comorbid diseases , body mass index , pack-years of cigarette smoking , and patterns of missing data . RESULTS Lower baseline ABI values were associated with greater mean ( 95 % confidence interval ) annual decline in 6-minute walk performance ( -73.0 [ -142 to -4.2 ] ft for ABI < 0.50 vs -58.8 [ -83.5 to -34.0 ] ft for ABI 0.50 to < 0.90 vs -12.6 [ -40.3 to 15.1 ] ft for ABI 0.90 - 1.50 , P = .02 ) . Compared with participants without PAD , PAD participants with leg pain on exertion and rest at baseline had greater mean annual decline in 6-minute walk performance ( -111 [ -173 to -50.0 ] ft vs -8.67 [ -36.9 to 19.5 ] ft , P = .004 ) , usual-pace 4-meter walking velocity ( -0.06 [ -0.09 to -0.02 ] m/sec vs -0.01 ( -0.03 to 0.003 ] m/sec , P = .02 ) , and fastest-pace 4-meter walking velocity ( -0.07 [ -0.11 to -0.03 ] m/sec vs -0.02 [ -0.04 to -0.006 ] m/sec , P = .046 ) . Compared with participants without PAD , asymptomatic PAD was associated with greater mean annual decline in 6-minute walk performance ( -76.8 ( -135 to -18.6 ] ft vs -8.67 ( -36.9 to 19.5 ] ft , P = .04 ) and an increased odds ratio for becoming unable to walk for 6 minutes continuously ( 3.63 ; 95 % confidence interval , 1.58 - 8.36 ; P = .002 ) . CONCLUSIONS Baseline ABI and the nature of leg symptoms predict the degree of functional decline at 2-year follow-up . Previously reported lack of worsening in claudication symptoms over time in patients with PAD may be more related to declining functional performance to than lack of disease progression OBJECTIVE To determine changes over time in the ankle brachial index ( ABI ) among subjects with and without intermittent claudication in the general population . DESIGN OF STUDY Population cohort study . SETTING General population in Edinburgh , Scotl and . SUBJECTS A total of 1592 men and women aged 55 to 74 years selected at r and om from age-sex registers of 11 general practice s and followed up over 12 years . Main outcome measures Changes in ABI  for each leg recorded at baseline in 1988 and at subsequent 5-year and 12-year clinical examinations . RESULTS Overall , 695 subjects ( 348 men and 347 women ) had valid  ABI measurements on both legs at all three examinations . At baseline , the ABI was on average.03 higher in the right leg than the left ( P < or = .001 ) . Men had a mean ABI that was.07 higher than women ( P < or = .001 ) . Mean ABI in the worse leg showed little change over 12 years in both men and women . However , in the whole population , the ABI in the better leg showed a significant drop , 1.15 to 1.08 ( P < or = .001 ) . A total of 179 cases of intermittent claudication were identified during the 12-year follow-up . At baseline , ABI in the worse leg of the claudicants was significantly lower than in healthy subjects ( .99 vs 1.08 ; P < or = .01 ) . In claudicants , mean ABI in the worse leg fell by.04 over 5 years ( P < or = .05 ) and in the better leg showed a highly significant drop of.09 ( P < or = .001 ) to levels similar to those of the worse leg . CONCLUSIONS The mean ABI in the worse leg of study subjects showed little progression over 12 years . Individuals with intermittent claudication experienced a greater decline in both legs compared with those without claudication . Deterioration occurred more rapidly in the limb with a higher ABI at baseline , which possibly indicates a systemic tendency to atherosclerosis Observational longitudinal research is particularly useful for assessing etiology and prognosis and for providing evidence for clinical decision making . However , there are no structured reporting requirements for studies of this design to assist authors , editors , and readers . The authors developed and tested a checklist of criteria related to threats to the internal and external validity of observational longitudinal studies . The checklist criteria concerned recruitment , data collection , biases , and data analysis and descriptive issues relevant to study rationale , study population , and generalizability . Two raters independently assessed 49 r and omly selected articles describing stroke research published from 1999 to 2003 in six journals : American Journal of Epidemiology , Journal of Epidemiology and Community Health , Stroke , Annals of Neurology , Archives of Physical Medicine and Rehabilitation , and American Journal of Physical Medicine and Rehabilitation . On average , 17 of the 33 checklist criteria were reported . Criteria describing the study design were better reported than those related to internal validity . No relation was found between study type ( etiologic or prognostic ) or word count and quality of reporting . A flow diagram for summarizing participant flow through a study was developed . Editors and authors should consider using a checklist and flow diagram when reporting on observational longitudinal research BACKGROUND The use of physical training in the treatment of intermittent claudication is well established . However , current data do not provide enough information about the prognosis for each case , and there are no data on how walking distances evolve over time with conservative treatment . The goal of this study was to evaluate improvement in walking capacity among patients with intermittent claudication who underwent unsupervised clinical treatment , observing whether sustained treatment would increase or decrease maximum walking distance , whether after 6 months there was a change in the maximum distance , and whether abstinence from smoking and well-conducted walking exercise 
    Output:
    
Conclusions Progression of PAD in IC patients is probably underestimated in the literature due to study design issues .
Predicting which patients with claudication are likely to deteriorate to critical limb ischaemia is difficult since there is a lack of evidence related to lower limb prognosis .