human
***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: Certain epidemiological and experimental studies suggest that n-3 fatty acids and folate can reduce blood pressure ( BP ) . We investigated the effect of a daily supplementation with dietary doses of B-vitamins or n-3 fatty acids for 5 years on BP in patients with a history of CVD who participated in the Supplémentation en Folates et Omega-3 trial . The patients ( n 2501 ; 1987 men and 514 women ) were r and omly assigned in a 2 × 2 factorial design to one of four groups : B-vitamins ( 5-methyl-THF ( 560 μg ) ; vitamin B₆ ( 3 mg ) and vitamin B₁₂ ( 20 μg ) ) and a placebo capsule for n-3 fatty acids ; n-3 fatty acids ( 600 mg of EPA and DHA at a ratio of 2:1 ) and a placebo capsule for B-vitamins ; both B-vitamins and n-3 fatty acids ; or placebo capsules for both treatments . The patients took two capsules daily in a double-blind manner for a median duration of 4·7 years . At baseline and annual examination for 5 years , the patients underwent a clinical examination where BP and clinical and biological parameters were assessed . No effect of supplementation with either n-3 PUFA or B-vitamins  on BP was observed in crude and adjusted multivariate models . Change in BP was not associated with change in homocysteine . In conclusion , the present results do not support the routine use of dietary supplements containing B-vitamins , or of n-3 fatty acids , to reduce BP in people with prior CVD During the past 25 years , 24 r and omized trials of intravenous ( IV ) fibrinolytic treatment have been reported , involving a total of some 6000 patients in the acute phase of myocardial infa rct ion . Most tested IV streptokinase ( SK ) , but a few tested IV urokinase ( UK ) . In the past 2 or 3 years numerous small r and omized trials of intracoronary ( IC ) SK have been started , 9 of which , involving a total of about 1000 such patients , have been reported . Because all of these IV and IC trials were small ( the largest including only 747 patients ) , their separate results appear contradictory and unreliable . But , an overview of the data from these trials indicates that IV treatment produces a highly significant ( 22 % + /- 5 % , P less than 0.001 ) reduction in the odds of death , an even larger reduction in the odds of reinfa rct ion , and an absolute frequency of serious adverse effects to set against this that is much smaller than the absolute mortality reduction . The apparent size of the mortality reduction in the IV trials was similar whether anticoagulants were compulsory or optional , whether treatment was in a coronary care unit or an ordinary ward and , surprisingly , whether treatment began early ( less than 6 h from onset of symptoms ) or late ( generally 12 - 24 h ) . In addition , there was no evidence that UK was more effective than the less expensive SK , or that , despite their technical complexity , the new IC regimes were more effective than the old IV regimes . Even the IV schedules that have been studied in r and omized trials were , however , quite complex , and the IC schedules were far more so . Perhaps partly because of this , none of them is widely used . If so , then some much simpler , and hence more widely practicable , IV SK regimes should be developed and tested . For example , a simple one hour high-dose IV SK infusion , without anticoagulation , will successfully convert virtually all of the available plasminogen into plasmin . But , it may be several years before the net effects on mortality of any more widely practicable IV SK regimes can be agreed unless many of the hospitals that do not wish routinely to use IC regimes or the complex previous IV regimes will collaborate in multicentre r and omized trials that can , if necessary , continue rapid intake until some tens of thous and s of patients have been r and omized , and some thous and s of deaths have been observed among the control and treated patients . The same , of course , may be true for any other fibrinolytic regimes ( e.g. infusion of tissue plasminogen activator ) if their net effects on mortality are comparable to those of IV SK Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading , despite our best efforts to improve the design and analysis of studies . Mendelian r and omization-the r and om assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures . The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies . Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian r and omization and are described . The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study , that polymorphisms may have several phenotypic effects associated with disease , the lack of suitable polymorphisms for study ing modifiable exposures of interest , and canalization-the buffering of the effects of genetic variation during development . Nevertheless , Mendelian r and omization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to underst and ing and preventing the adverse effects on human health of modifiable exposures Total plasma homocysteine ( tHcy ) is an independent risk factor for coronary artery disease , and tHcy is lowered by B vitamins . To assess the effect of homocysteine-lowering B-vitamin treatment on angiographic progression of coronary artery disease , this sub study of the Western Norway B Vitamin Intervention Trial ( WENBIT ) included patients who had undergone percutaneous coronary intervention . The patients were r and omized to daily oral treatment with folic acid , vitamin B(12 ) , and vitamin B(6 ) or placebo in a 2 x 2 factorial design . The coronary angiograms obtained at baseline and follow-up were evaluated . The primary angiographic end points were the changes in minimum lumen diameter and diameter stenosis .  A total of 348 subjects ( 288 men ) with a mean + /- SD age of 60 + /- 10.2 years were followed up for a median of 10.5 months ( twenty-fifth , seventy-fifth percentile 9.2 , 11.8 ) . The baseline median plasma tHcy level was 10.0 mumol/L ( twenty-fifth , seventy-fifth percentile 8.1 , 11.0 ) , and treatment with folic acid/vitamin B(12 ) lowered the tHcy levels by 22 % . At follow-up , we found 309 lesions with a significant decrease from baseline in the minimum lumen diameter of a mean of -0.16 + /- 0.4 mm and an increase in the diameter stenosis of 4.4 + /- 0.7 % . Treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) was not associated with a change in diameter stenosis or minimum lumen diameter . In a post hoc analysis , folic acid/vitamin B(12 ) treatment was significantly associated with rapid progression ( odds ratio 1.84 , 95 % confidence interval 1.07 to 3.18 ) . In conclusion , vitamin B treatment showed no beneficial effect on the angiographic progression of coronary artery disease , and the post hoc analyses suggested that folic acid/vitamin B(12 ) treatment might promote more rapid progression Background and Purpose — Elevated concentrations of homocysteine are associated with cerebral small vessel disease ( CSVD ) . b-vitamin supplementation with folate and vitamins b12 and b6 reduces homocysteine concentrations . In a sub study of the VITAmins TO Prevent Stroke ( VITATOPS ) trial , we assessed the hypothesis that the addition of once-daily supplements of b vitamins would reduce the progression of CSVD-related brain lesions . Methods — A total of 359 patients with recent stroke or transient ischemic attack , who were r and omly allocated to double-blind treatment with placebo or b vitamins , underwent brain MRI at r and omization and after 2 years of b-vitamin supplementation . MR images were analyzed blinded to treatment allocation . Outcomes related to the prespecified hypothesis were progression of white matter hyperintensities and incident lacunes . We also explored the effect of b-vitamin supplementation on the incidence of other ischemic abnormalities . Results — After 2 years of treatment with b vitamins or placebo , there was no significant difference in white matter hyperintensities volume change ( 0.08 vs 0.13cm3 ; P=0.419 ) and incidence of lacunes ( 8.0 % vs 5.9 % , P=0.434 ; odds ratio=1.38 ) . In a sub analysis of patients with MRI evidence of severe CSVD at baseline , b-vitamin supplementation was associated with a significant reduction in white matter hyperintensities volume change ( 0.3 vs 1.7cm3 ; P=0.039 ) . Conclusions — Daily b-vitamin supplementation for 2 years did not significantly reduce the progression of brain lesions result ing from presumed CSVD in all patients with recent stroke or transient ischemic attack but may do so in the subgroup of patients with recent stroke or transient ischemic attack and severe CSVD . Clinical Trial Registration — http://vitatops.highway1.com.au/. Unique identifier : NCT00097669 and IS RCT N74743444 CONTEXT Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease . Oral administration of folic acid and vitamin B(12 ) can lower plasma total homocysteine levels . OBJECTIVE To assess the effect of treatment with folic acid and vitamin B(12 ) and the effect of treatment with vitamin B(6 ) as secondary prevention in patients with coronary artery disease or aortic valve stenosis . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999 - 2006 . A total of 3096 adult participants undergoing coronary angiography ( 20.5 % female ; mean age , 61.7 years ) were r and omized . At baseline , 59.3 % had double- or triple-vessel disease , 83.7 % had stable angina pectoris , and 14.9 % had acute coronary syndromes . INTERVENTIONS Using a 2 x 2 factorial design , participants were r and omly assigned to 1 of 4 groups receiving daily oral treatment with folic acid , 0.8 mg , plus vitamin B(12 ) , 0.4 mg , plus vitamin B(6 ) , 40 mg ( n = 772 ) ; folic acid plus vitamin B(12 ) ( n = 772 ) ; vitamin B(6 ) alone ( n = 772 ) ; or placebo ( n = 780 ) . MAIN OUTCOME MEASURES The primary end point was a composite of all-cause death , nonfatal acute myocardial infa rct ion , acute hospitalization for unstable angina pectoris , and nonfatal thromboembolic stroke . RESULTS Mean plasma total homocysteine concentration was reduced by 30 % after 1 year of treatment in the groups receiving folic acid and vitamin B(12 ) . The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention . During a median 38 months of follow-up , the primary end point was experienced by a total of 422 participants ( 13.7 % ) : 219 participants ( 14.2 % ) receiving folic acid/vitamin B(12 ) vs 203 ( 13.1 % ) not receiving such treatment ( hazard ratio , 1.09 ; 95 % confidence interval , 0.90 - 1.32 ; P = .36 ) and 200 participants ( 13.0 % ) receiving vitamin B(6 ) vs 222 ( 14.3 % ) not receiving vitamin B(6 ) ( hazard ratio , 0.90 ; 95 % confidence interval , 0.74 - 1.09 ; P = .28 ) . CONCLUSIONS This trial did not find an effect of treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) on total mortality or cardiovascular events . Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00354081 IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data . OBJECTIVE To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension . DESIGN , SETTING , AND PARTICIPANTS The China Stroke Primary Prevention Trial , a r and omized , double-blind clinical trial conducted from May 19 , 2008 , to August 24 , 2013 , in 32 communities in Jiangsu and Anhui provinces in China . A total of 20,702 adults with hypertension without history of stroke or myocardial infa rct ion ( MI ) participated in the study . INTERVENTIONS Eligible participants 
    Output:
    
agent
In this third up date of the Cochrane review , there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6 , B9 or B12 given alone or in combination comparing with placebo on myocardial infa rct ion , death from any cause or adverse events .
***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: Certain epidemiological and experimental studies suggest that n-3 fatty acids and folate can reduce blood pressure ( BP ) . We investigated the effect of a daily supplementation with dietary doses of B-vitamins or n-3 fatty acids for 5 years on BP in patients with a history of CVD who participated in the Supplémentation en Folates et Omega-3 trial . The patients ( n 2501 ; 1987 men and 514 women ) were r and omly assigned in a 2 × 2 factorial design to one of four groups : B-vitamins ( 5-methyl-THF ( 560 μg ) ; vitamin B₆ ( 3 mg ) and vitamin B₁₂ ( 20 μg ) ) and a placebo capsule for n-3 fatty acids ; n-3 fatty acids ( 600 mg of EPA and DHA at a ratio of 2:1 ) and a placebo capsule for B-vitamins ; both B-vitamins and n-3 fatty acids ; or placebo capsules for both treatments . The patients took two capsules daily in a double-blind manner for a median duration of 4·7 years . At baseline and annual examination for 5 years , the patients underwent a clinical examination where BP and clinical and biological parameters were assessed . No effect of supplementation with either n-3 PUFA or B-vitamins  on BP was observed in crude and adjusted multivariate models . Change in BP was not associated with change in homocysteine . In conclusion , the present results do not support the routine use of dietary supplements containing B-vitamins , or of n-3 fatty acids , to reduce BP in people with prior CVD During the past 25 years , 24 r and omized trials of intravenous ( IV ) fibrinolytic treatment have been reported , involving a total of some 6000 patients in the acute phase of myocardial infa rct ion . Most tested IV streptokinase ( SK ) , but a few tested IV urokinase ( UK ) . In the past 2 or 3 years numerous small r and omized trials of intracoronary ( IC ) SK have been started , 9 of which , involving a total of about 1000 such patients , have been reported . Because all of these IV and IC trials were small ( the largest including only 747 patients ) , their separate results appear contradictory and unreliable . But , an overview of the data from these trials indicates that IV treatment produces a highly significant ( 22 % + /- 5 % , P less than 0.001 ) reduction in the odds of death , an even larger reduction in the odds of reinfa rct ion , and an absolute frequency of serious adverse effects to set against this that is much smaller than the absolute mortality reduction . The apparent size of the mortality reduction in the IV trials was similar whether anticoagulants were compulsory or optional , whether treatment was in a coronary care unit or an ordinary ward and , surprisingly , whether treatment began early ( less than 6 h from onset of symptoms ) or late ( generally 12 - 24 h ) . In addition , there was no evidence that UK was more effective than the less expensive SK , or that , despite their technical complexity , the new IC regimes were more effective than the old IV regimes . Even the IV schedules that have been studied in r and omized trials were , however , quite complex , and the IC schedules were far more so . Perhaps partly because of this , none of them is widely used . If so , then some much simpler , and hence more widely practicable , IV SK regimes should be developed and tested . For example , a simple one hour high-dose IV SK infusion , without anticoagulation , will successfully convert virtually all of the available plasminogen into plasmin . But , it may be several years before the net effects on mortality of any more widely practicable IV SK regimes can be agreed unless many of the hospitals that do not wish routinely to use IC regimes or the complex previous IV regimes will collaborate in multicentre r and omized trials that can , if necessary , continue rapid intake until some tens of thous and s of patients have been r and omized , and some thous and s of deaths have been observed among the control and treated patients . The same , of course , may be true for any other fibrinolytic regimes ( e.g. infusion of tissue plasminogen activator ) if their net effects on mortality are comparable to those of IV SK Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading , despite our best efforts to improve the design and analysis of studies . Mendelian r and omization-the r and om assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures . The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies . Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian r and omization and are described . The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study , that polymorphisms may have several phenotypic effects associated with disease , the lack of suitable polymorphisms for study ing modifiable exposures of interest , and canalization-the buffering of the effects of genetic variation during development . Nevertheless , Mendelian r and omization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to underst and ing and preventing the adverse effects on human health of modifiable exposures Total plasma homocysteine ( tHcy ) is an independent risk factor for coronary artery disease , and tHcy is lowered by B vitamins . To assess the effect of homocysteine-lowering B-vitamin treatment on angiographic progression of coronary artery disease , this sub study of the Western Norway B Vitamin Intervention Trial ( WENBIT ) included patients who had undergone percutaneous coronary intervention . The patients were r and omized to daily oral treatment with folic acid , vitamin B(12 ) , and vitamin B(6 ) or placebo in a 2 x 2 factorial design . The coronary angiograms obtained at baseline and follow-up were evaluated . The primary angiographic end points were the changes in minimum lumen diameter and diameter stenosis .  A total of 348 subjects ( 288 men ) with a mean + /- SD age of 60 + /- 10.2 years were followed up for a median of 10.5 months ( twenty-fifth , seventy-fifth percentile 9.2 , 11.8 ) . The baseline median plasma tHcy level was 10.0 mumol/L ( twenty-fifth , seventy-fifth percentile 8.1 , 11.0 ) , and treatment with folic acid/vitamin B(12 ) lowered the tHcy levels by 22 % . At follow-up , we found 309 lesions with a significant decrease from baseline in the minimum lumen diameter of a mean of -0.16 + /- 0.4 mm and an increase in the diameter stenosis of 4.4 + /- 0.7 % . Treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) was not associated with a change in diameter stenosis or minimum lumen diameter . In a post hoc analysis , folic acid/vitamin B(12 ) treatment was significantly associated with rapid progression ( odds ratio 1.84 , 95 % confidence interval 1.07 to 3.18 ) . In conclusion , vitamin B treatment showed no beneficial effect on the angiographic progression of coronary artery disease , and the post hoc analyses suggested that folic acid/vitamin B(12 ) treatment might promote more rapid progression Background and Purpose — Elevated concentrations of homocysteine are associated with cerebral small vessel disease ( CSVD ) . b-vitamin supplementation with folate and vitamins b12 and b6 reduces homocysteine concentrations . In a sub study of the VITAmins TO Prevent Stroke ( VITATOPS ) trial , we assessed the hypothesis that the addition of once-daily supplements of b vitamins would reduce the progression of CSVD-related brain lesions . Methods — A total of 359 patients with recent stroke or transient ischemic attack , who were r and omly allocated to double-blind treatment with placebo or b vitamins , underwent brain MRI at r and omization and after 2 years of b-vitamin supplementation . MR images were analyzed blinded to treatment allocation . Outcomes related to the prespecified hypothesis were progression of white matter hyperintensities and incident lacunes . We also explored the effect of b-vitamin supplementation on the incidence of other ischemic abnormalities . Results — After 2 years of treatment with b vitamins or placebo , there was no significant difference in white matter hyperintensities volume change ( 0.08 vs 0.13cm3 ; P=0.419 ) and incidence of lacunes ( 8.0 % vs 5.9 % , P=0.434 ; odds ratio=1.38 ) . In a sub analysis of patients with MRI evidence of severe CSVD at baseline , b-vitamin supplementation was associated with a significant reduction in white matter hyperintensities volume change ( 0.3 vs 1.7cm3 ; P=0.039 ) . Conclusions — Daily b-vitamin supplementation for 2 years did not significantly reduce the progression of brain lesions result ing from presumed CSVD in all patients with recent stroke or transient ischemic attack but may do so in the subgroup of patients with recent stroke or transient ischemic attack and severe CSVD . Clinical Trial Registration — http://vitatops.highway1.com.au/. Unique identifier : NCT00097669 and IS RCT N74743444 CONTEXT Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease . Oral administration of folic acid and vitamin B(12 ) can lower plasma total homocysteine levels . OBJECTIVE To assess the effect of treatment with folic acid and vitamin B(12 ) and the effect of treatment with vitamin B(6 ) as secondary prevention in patients with coronary artery disease or aortic valve stenosis . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999 - 2006 . A total of 3096 adult participants undergoing coronary angiography ( 20.5 % female ; mean age , 61.7 years ) were r and omized . At baseline , 59.3 % had double- or triple-vessel disease , 83.7 % had stable angina pectoris , and 14.9 % had acute coronary syndromes . INTERVENTIONS Using a 2 x 2 factorial design , participants were r and omly assigned to 1 of 4 groups receiving daily oral treatment with folic acid , 0.8 mg , plus vitamin B(12 ) , 0.4 mg , plus vitamin B(6 ) , 40 mg ( n = 772 ) ; folic acid plus vitamin B(12 ) ( n = 772 ) ; vitamin B(6 ) alone ( n = 772 ) ; or placebo ( n = 780 ) . MAIN OUTCOME MEASURES The primary end point was a composite of all-cause death , nonfatal acute myocardial infa rct ion , acute hospitalization for unstable angina pectoris , and nonfatal thromboembolic stroke . RESULTS Mean plasma total homocysteine concentration was reduced by 30 % after 1 year of treatment in the groups receiving folic acid and vitamin B(12 ) . The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention . During a median 38 months of follow-up , the primary end point was experienced by a total of 422 participants ( 13.7 % ) : 219 participants ( 14.2 % ) receiving folic acid/vitamin B(12 ) vs 203 ( 13.1 % ) not receiving such treatment ( hazard ratio , 1.09 ; 95 % confidence interval , 0.90 - 1.32 ; P = .36 ) and 200 participants ( 13.0 % ) receiving vitamin B(6 ) vs 222 ( 14.3 % ) not receiving vitamin B(6 ) ( hazard ratio , 0.90 ; 95 % confidence interval , 0.74 - 1.09 ; P = .28 ) . CONCLUSIONS This trial did not find an effect of treatment with folic acid/vitamin B(12 ) or vitamin B(6 ) on total mortality or cardiovascular events . Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00354081 IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data . OBJECTIVE To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension . DESIGN , SETTING , AND PARTICIPANTS The China Stroke Primary Prevention Trial , a r and omized , double-blind clinical trial conducted from May 19 , 2008 , to August 24 , 2013 , in 32 communities in Jiangsu and Anhui provinces in China . A total of 20,702 adults with hypertension without history of stroke or myocardial infa rct ion ( MI ) participated in the study . INTERVENTIONS Eligible participants 
    Output:
    