***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 —Considerable evidence implicates the proinflammatory cytokine CD40 lig and ( CD40L ) in atherosclerosis and accumulating data link type 1 and 2 diabetes , conditions associated with accelerated atherosclerosis , to inflammation . This study therefore evaluated the hypothesis that diabetic patients have elevated plasma levels of soluble CD40L ( sCD40L ) and that treatment with the insulin-sensitizing thiazolidinediones lowers this index of inflammation . Methods and Results —Subjects with type 1 ( n=49 ) or type 2 diabetes ( n=48 ) had higher ( P < 0.001 ) sCD40L plasma levels  ( 6.56±3.27 and 6.67±2.90 ng/mL , respectively ) compared with age-matched control groups ( 1.40±2.21 and 1.32±2.68 ng/mL , respectively ) . Multiple regression analysis demonstrated a significant ( P < 0.001 ) association between plasma sCD40L and type 1 as well as type 2 diabetes , independent of total cholesterol , high-density lipoprotein cholesterol , low-density lipoprotein cholesterol , triglycerides , blood pressure , body mass index , gender , C-reactive protein , and soluble intracellular adhesion molecule-1 . Furthermore , in a pilot study , administration of troglitazone ( 12 weeks , 600 mg/day ) , but not placebo , to type 2 diabetics ( n=68 ) significantly ( P < 0.001 ) diminished sCD40L plasma levels by 29 % . The thiazolidinedione  lowered plasma sCD40L in type 2 diabetic patients with long-st and ing disease ( > 3 years ) with or without macrovascular complications ( −34 % and −29 % , respectively ) as well as in type 2 diabetic patients with more recent ( <3 years ) onset of the disease ( −27 % ; all P < 0.05 ) . Conclusions —This study provides new evidence that individuals with type 1 or 2 diabetes have a proinflammatory state as indicated by elevated levels of plasma sCD40L  . Troglitazone treatment of type 2 diabetic patients diminishes sCD40L levels , suggesting a novel antiinflammatory mechanism for limiting diabetes-associated arterial disease Reduced effectiveness of the most common antiplatelet drug , acetylsalicylic acid ( ASA , aspirin ) , in diabetes mellitus has been associated with a lowered platelet sensitivity to ASA and related to glycemic control in diabetic patients . Our objectives were ( a ) to monitor the chemical background of how chronic hyperglycemia affects platelet response to ASA in diabetes and ( b ) to study a chemical competition between the amount of bound acetyl residues and the extent of protein glycation in blood platelets . Using whole-blood impedance aggregometry and platelet function analyzer ( PFA-100 ) we observed a reduced platelet response to ASA in diabetic patients ( 14 % vs. 79 % for PFA-100 collagen-epinephrine occlusion time ) and an association between the index of glycemic control and platelet refractoriness to ASA ( rS=−0.378 ) . Impaired platelet response to ASA was related to enhanced platelet protein glycation ( 3.6±0.4 in diabetes vs. 2.3±0.4 µmol fructosamine/µg protein in control ) and reduced incorporation of acetyl residue into proteins of platelets from diabetic patients ( 47.4±2.0 in control vs. 33.1±0.7 µmol acetyl/µg protein in diabetic subjects ) . Incubation of blood platelets with increasing concentrations of glucose and ASA under in vitro conditions led to excessive modification in protein amino groups : glucose and ASA competed with each other in the course of nonenzymatic modifications , glycosylation , or acetylation , and their contributions to the occupancy of protein amino groups ( R2=0.22 for glucose , R2=0.43 for ASA ) were dependent upon the concentrations of glucose and ASA . Overall the effects of high glucose and high ASA on the overall occupancy of protein free amino groups are not additive . While at higher concentrations ASA overcomes the effects of hyperglycemia and retards glycation , high glucose makes acetylation less efficient , and therefore the result ant chemical modification becomes greatly reduced . In conclusion , diminished susceptibility of various platelet proteins and receptors on blood platelet membranes to acetylation and high ambient glucose might underlie the apparently differentiated sensitivity of blood platelets to ASA and determine platelet “ insensitivity to aspirin ” in diabetic Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Objective To determine whether aspirin and antioxidant therapy , combined or alone , are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease . Design Multicentre , r and omised , double blind , 2 × 2 factorial , placebo controlled trial . Setting 16 hospital centres in Scotl and , supported by 188 primary care groups . Participants 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease . Interventions Daily , 100 mg aspirin tablet plus antioxidant capsule ( n=320 ) , aspirin tablet plus placebo capsule ( n=318 ) , placebo tablet plus antioxidant capsule ( n=320 ) , or placebo tablet plus placebo capsule ( n=318 ) . Main outcome measures Two hierarchical composite primary end points of death from coronary heart disease or stroke , non-fatal myocardial infa rct ion or stroke , or amputation above the ankle for critical limb ischaemia ; and death from coronary heart disease or stroke . Results No evidence was found of any interaction between aspirin and antioxidant . Overall , 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups ( 18.2 % v 18.3 % ) : hazard ratio 0.98 ( 95 % confidence interval 0.76 to 1.26 ) . Forty three deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups ( 6.7 % v 5.5 % ) : 1.23 ( 0.79 to 1.93 ) . Among the antioxidant groups 117 of 640 ( 18.3 % ) primary events occurred compared with 116 of 636 ( 18.2 % ) in the no antioxidant groups ( 1.03 , 0.79 to 1.33 ) . Forty two ( 6.6 % ) deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 ( 5.7 % ) in the no antioxidant groups ( 1.21 , 0.78 to 1.89 ) . Conclusion This trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied . Trial registration Current Controlled Trials IS RCT N53295293 Observational epidemiological studies suffer from many potential biases , from confounding and from reverse causation , and this limits their ability to robustly identify causal associations . Several high-profile situations exist in which r and omized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings . In other observational sciences , the use of instrumental variable ( IV ) approaches has been one approach to strengthening causal inferences in non-experimental situations . The use of germline genetic variants that proxy for  environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies . The method has been referred to as ' Mendelian r and omization ' , and can be considered as analogous to r and omized controlled trials . This paper outlines Mendelian r and omization , draws parallels with IV methods , provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these OBJECTIVE We investigated in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with type 2 diabetes . RESEARCH DESIGN AND METHODS The Primary Prevention Project ( PPP ) is a r and omized , open trial with a two-by-two factorial design aim ed to investigate low-dose aspirin ( 100 mg/day ) and vitamin E ( 300 mg/day ) in the prevention of cardiovascular events in patients with one or more cardiovascular risk factors . The primary end point was a composite end point of cardiovascular death , stroke , or myocardial infa rct ion . A total of 1,031 people with diabetes in the PPP , aged > /=50 years , without a previous cardiovascular event were enrolled by 316 general practitioners and 14 diabetes outpatient clinics . RESULTS The PPP trial was prematurely stopped ( after a median of 3.7 years ) by the independent data safety and monitoring board because of a consistent benefit of aspirin compared with the control group in a population of 4,495 patients with one or more major cardiovascular risk factors . In diabetic patients , aspirin treatment was associated with a nonsignificant reduction in the main end point ( relative risk [ RR ] = 0.90 , 95 % CI 0.50 - 1.62 ) and in total cardiovascular events ( 0.89 , 0.62 - 1.26 ) and with a nonsignificant increase in cardiovascular deaths ( 1.23 , 0.69 - 2.19 ) . In nondiabetic subjects , RRs for the main end point , total cardiovascular events , and cardiovascular deaths were 0.59 ( 0.37 - 0.94 ) , 0.69 ( 0.53 - 0.90 ) , and 0.32 ( 0.14 - 0.72 ) , respectively . No significant reduction in any of the end points considered could be found with vitamin E in either diabetic or nondiabetic subjects . CONCLUSIONS Our data suggest a lower effect of primary prevention of cardiovascular disease ( CVD ) with low-dose aspirin in diabetic patients as opposed to subjects with other cardiovascular risk factors . If confirmed , these findings might indicate that the antiplatelet effects of aspirin in diabetic patients are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation , thus making the balance between benefits and harms of aspirin treatment unfavorable . Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure < or = 90 mm Hg , 6264 to < or = 85 mm Hg , and 6262 to < or = 80 mm Hg . Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned  placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the < or = 90 mm Hg , < or = 85 mm Hg , and < or = 80 mm Hg target groups , respectively . The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe .  In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group < or = 80 mm Hg compared with target group < or = 90 mm Hg ( p for trend=0.005 ) . Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and 
    Output:
    
Limited subgroup analyses suggested that the effect of aspirin  on major adverse cardiovascular events differed by baseline cardiovascular disease risk , medication compliance and sex ( P for interaction for all > 0.05).There was no significant reduction in the risk of myocardial infa rct ion , coronary heart disease , stroke , cardiovascular mortality or all-cause mortality .
Aspirin significantly reduced the risk of myocardial infa rct ion for a treatment duration of ≤ 5 years .
There was an increase in risk of major or gastrointestinal bleeding events , but estimates were imprecise and not significant .