***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: Pathological formation of reactive oxygen species within the coronary circulation has been hypothesized to mediate some clinical manifestations of ischemic heart disease ( IHD ) by interfering with physiological regulation of coronary tone . To determine the degree to which coronary tone responds to acute changes in ambient levels of oxidants and antioxidants in vivo in a clinical setting , we measured the effect of an acute oxidative stress ( breathing 100 % oxygen ) on coronary capacitance artery diameter ( quantitative angiography ) and blood flow velocity through the coronary microcirculation ( intracoronary Doppler ultrasonography ) before and after treatment with the antioxidant vitamin C ( 3-g intravenous infusion ) in 12 IHD patients undergoing a clinical coronary interventional procedure . Relative to room air breathing , 100 % oxygen breathing promptly reduced coronary blood flow velocity by 20 % and increased coronary resistance by 23 % , without significantly changing the diameter of capacitance arteries .  Vitamin C administration promptly restored coronary flow velocity and resistance to a slightly suprabasal level , and it prevented the reinduction of coronary constriction with rechallenge with 100 % oxygen . This suggests that acute oxidative stress produces prompt and substantial changes in coronary resistance and blood flow in a clinical setting in patients with IHD , and it suggests that these changes are mediated by vitamin C-quenchable substances acting on the coronary microcirculation . This observation may have relevance for clinical practice OBJECTIVES We sought to determine whether abnormal myocardial blood flow ( MBF ) responses to the cold pressor test ( CPT ) in patients with various risk factors may involve different mechanisms that could lead to varying responses of short- and long-term administration of antioxidants . BACKGROUND There is a growing body of evidence that increased vascular production of reactive oxygen species markedly reduces the bioavailability of endothelium-derived nitric oxide , leading to impaired vasodilator function . It is unknown whether increased oxidative stress is the prevalent mechanism underlying endothelial dysfunction in patients with different coronary risk factors . METHODS Fifty patients with normal coronary angiograms were studied . The MBF responses to CPT was determined by means of positron emission tomography before and after intravenous infusion of 3 g vitamin C or saline ( placebo ) , as well as after 3 months and 2 years of 2 g vitamin C or placebo supplementation daily . RESULTS In hypertensive patients , the change in MBF ( DeltaMBF ) was not modified significantly by short-term vitamin C administration challenges ( 0.20 + /- 0.20 ml/g/min ; p = NS ) but was significantly increased after three months and two years of treatment with vitamin C versus baseline ( 0.58 + /- 0.27 and 0.63 + /- 0.17 vs. 0.14 + /- 0.18 ml/g/min ; both p < or = 0.001 ) . In smokers , DeltaMBF in response to CPT was significantly increased after short-term vitamin C infusion and long-term vitamin C treatment ( 0.52 + /- 0.10 , 0.54 + /- 0.13 , 0.50 + /- 0.07 vs. -0.08 + /- 0.10 ml/g/min ; all p < or = 0.001 ) . In hypercholesterolemic patients , no improvement in DeltaMBF during CPT was observed after short- and long-term vitamin C treatment ( 0.05 + /- 0.14 , 0.08 + /- 0.18 , 0.02 + /- 0.19 vs. 0.08 + /- 0.16 ml/g/min ; p = NS ) . The CPT-induced DeltaMBF in hypertensive patients and smokers after follow-up was significant as compared with placebo and control subjects ( p < or = 0.001 ) . CONCLUSIONS The present study revealed marked heterogeneous responses in MBF changes to short- and long-term vitamin C treatment in patients with various risk factors , which highlights the quite complex nature underlying abnormal coronary vasomotion CONTEXT Basic research and observational studies suggest vitamin E or vitamin C may reduce the risk of cardiovascular disease . However , few long-term trials have evaluated men at initially low risk of cardiovascular disease , and no previous trial in men has examined vitamin C alone in the prevention of cardiovascular disease . OBJECTIVE To evaluate whether long-term vitamin E or vitamin C supplementation decreases the risk of  major cardiovascular events among men . DESIGN , SETTING , AND PARTICIPANTS The Physicians ' Health Study II was a r and omized , double-blind , placebo-controlled factorial trial of vitamin E and vitamin C that began in 1997 and continued until its scheduled completion on August 31 , 2007 . There were 14,641 US male physicians enrolled , who were initially aged 50 years or older , including 754 men ( 5.1 % ) with prevalent cardiovascular disease at r and omization . INTERVENTION Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily . MAIN OUTCOME MEASURES A composite end point of major cardiovascular events ( nonfatal myocardial infa rct ion , nonfatal stroke , and cardiovascular disease death ) . RESULTS During a mean follow-up of 8 years , there were 1245 confirmed major cardiovascular events . Compared with placebo , vitamin E had no effect on the incidence of major cardiovascular events ( both active and placebo vitamin E groups , 10.9 events per 1000 person-years ; hazard ratio [ HR ] , 1.01 [ 95 % confidence interval { CI } , 0.90 - 1.13 ] ; P = .86 ) , as well as total myocardial infa rct ion ( HR , 0.90 [ 95 % CI , 0.75 - 1.07 ] ; P = .22 ) , total stroke ( HR , 1.07 [ 95 % CI , 0.89 - 1.29 ] ; P = .45 ) , and cardiovascular mortality ( HR , 1.07 [ 95 % CI , 0.90 - 1.28 ] ; P = .43 ) . There also was no significant effect of vitamin C on major cardiovascular events  ( active and placebo vitamin E groups , 10.8 and 10.9 events per 1000 person-years , respectively ; HR , 0.99 [ 95 % CI , 0.89 - 1.11 ] ; P = .91 ) , as well as total myocardial infa rct ion ( HR , 1.04 [ 95 % CI , 0.87 - 1.24 ] ; P = .65 ) , total stroke ( HR , 0.89 [ 95 % CI , 0.74 - 1.07 ] ; P = .21 ) , and cardiovascular mortality ( HR , 1.02 [ 95 % CI , 0.85 - 1.21 ] ; P = .86 ) . Neither vitamin E ( HR , 1.07 [ 95 % CI , 0.97 - 1.18 ] ; P = .15 ) nor vitamin C ( HR , 1.07 [ 95 % CI , 0.97 - 1.18 ] ; P = .16 ) had a significant effect on total mortality but vitamin E was associated with an increased risk of hemorrhagic stroke ( HR , 1.74 [ 95 % CI , 1.04 - 2.91 ] ; P = .04 ) . CONCLUSIONS In this large , long-term trial of male physicians , neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events . These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00270647 One gram of ascorbic acid ( Vitamin C ) administered r and omly to a group of healthy young people ( aged 29 ± 5 years ) produced a significant mean fall in serum cholesterol of 16 per cent within two months . A similar supplement to a group of healthy older people ( aged 58 ± 3 years ) produced a significant mean fall in serum cholesterol of 14 per cent but required six to 12 months ' administration . Serial observations on a mixed age group of healthy people ( aged 38 ± 12 years ) over one calendar year revealed a seasonal fluctuation in serum cholesterol , the lowest levels being in summer ( June 5.5 ± 0.7 mmols/l ) and the highest levels in winter ( January 6.4 ± 0.8 mmols/l ) , a significant rise of 16 per cent . These changes showed an inverse relationship with the leucocyte and serum ascorbic acid levels which also revealed a seasonal fluctuation , the months April/September being higher than the months October/March . The administration of 1 g of ascorbic acid per day throughout the year abolished the winter rise in serum cholesterol levels . These results are discussed in the light of the relationship between cholesterol and vascular disease and the observations by Sir Richard Doll that lowering the cholesterol level , whether achieved by drugs or diet , results in a reduction in morbidity from myocardial infa rct ion Background —Self-selected supplementation of vitamin E has been associated with reduced coronary events and atherosclerotic progression , but the evidence from clinical trials is controversial . In the first 3 years of the ASAP trial , the supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C twice daily slowed down the progression of carotid atherosclerosis in men but not women . This article examines the 6-year effect of supplementation on common carotid artery ( CCA ) intima-media thickness ( IMT ) . Methods and Results —The subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to 69 years with serum cholesterol ≥5.0 mmol/L ( 193 mg/dL ) , 440 ( 84.6 % ) of whom completed the study . Atherosclerotic progression was assessed ultrasonographically . In covariance analysis in both sexes , supplementation reduced the main study outcome , the slope of mean CCA-IMT , by 26 % ( 95 % CI , 5 to 46 , P = 0.014 ) , in men by 33 % ( 95 % CI , 4 to 62 , P = 0.024 ) and in women by 14 % ( not significant ) . In both sexes combined , the average annual increase of the mean CCA-IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group ( 25 % treatment effect , 95 % CI , 2 to 49 , P = 0.034 ) . In men , this treatment effect was 37 % ( 95 CI , 4 to 69 , P = 0.028 ) . The effect was larger in subjects with either low baseline plasma vitamin C levels or CCA plaques . Vitamin E had no effect on HDL cholesterol . Conclusions —These data replicate our 3-year findings confirming that the supplementation with combination of vitamin E and slow-release vitamin C  slows down atherosclerotic progression in hypercholesterolemic persons Background The grading of recommendation , assessment , development and evaluation ( GRADE ) approach is widely implemented in health technology assessment and guideline development organisations throughout the world . GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention , but is complex and therefore challenging to apply in a consistent manner . Methods We developed a checklist to guide the research er to extract the data required to make a GRADE assessment . We applied the checklist to 29 meta-analyses of r and omised controlled trials on the effectiveness of health care interventions . Two review ers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome . Results For most ( 70 % ) checklist items , there was good agreement between review ers . The main problems were for items relating to indirectness where considerable judgement is required . Conclusions There was consistent agreement between review ers on most items in the checklist . The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessment s , particularly for inexperienced users or in rapid review s without the re sources to conduct assessment s by two research ers independently OBJECTIVES To study the efficacy of vitamin E and C supplementation on the progression of carotid atherosclerosis  , hypothesizing an enhanced preventive effect in men and in smokers and synergism between vitamins . DESIGN AND SUBJECTS Double-masked two-by-two factorial trial , r and omization in four strata ( by gender and smoking status ) to receive twice daily either 91 mg ( 136 IU ) of d-alpha-tocopherol , 250 mg of slow-release vitamin C , a combination of these or placebo for three years . A r and omized sample of 520 smoking and nonsmoking men and postmenopausal women aged 45 - 69 years with serum cholesterol > /= 5.0 mmol L-1 were studied . SETTING The population of the city 
    Output:
    
There is limited low- and very low- quality evidence currently on the effect of vitamin C supplementation and risk of CVD risk factors