***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 Susceptibility variants identified by genome-wide association studies ( GWAS ) have modest effect sizes . Whether such variants provide incremental information in assessing risk for common ' complex ' diseases is unclear . We investigated whether measured and imputed genotypes from a GWAS data set linked to the electronic medical record alter estimates of coronary heart disease ( CHD ) risk . Methods Study participants ( n = 1243 ) had no known cardiovascular disease and were considered to be at high , intermediate , or low 10-year risk of CHD based on the Framingham risk score ( FRS ) which includes age , sex , total and HDL cholesterol , blood pressure , diabetes , and smoking status . Of twelve SNPs identified in prior GWAS to be associated with CHD , four were genotyped in the participants as part of a GWAS . Genotypes for seven SNPs were imputed from HapMap CEU population using the program MACH . We calculated a multiplex genetic risk score for each patient based on the odds ratios of the susceptibility SNPs and incorporated this into the FRS . Results The mean ( SD ) number of risk alleles was 12.31 ( 1.95 ) , range 6 - 18 . The mean ( SD ) of the weighted genetic risk score was 12.64 ( 2.05 ) , range 5.75 - 18.20 . The CHD genetic risk score was not correlated with the FRS ( P = 0.78 ) . After incorporating the genetic risk score into the FRS , a total of 380 individuals ( 30.6 % ) were reclassified into higher-(188 ) or lower-risk groups ( 192 ) . Conclusion A genetic risk score based on measured/imputed genotypes at 11 susceptibility SNPs , led to significant reclassification in the 10-y CHD risk categories . Additional prospect i ve studies are needed to assess accuracy and clinical utility of such reclassification BACKGROUND Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease . The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown . METHODS Using a polygenic score of DNA sequence polymorphisms , we quantified genetic risk for coronary artery disease in three prospect i ve cohorts - 7814 participants in the Atherosclerosis Risk in Communities ( ARIC ) study , 21,222 in the Women 's Genome Health Study ( WGHS ) , and 22,389 in the Malmö Diet and Cancer Study ( MDCS ) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available . We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors : no current smoking , no obesity , regular physical activity , and a healthy diet . RESULTS The relative risk of incident coronary events was 91 % higher among participants at high genetic risk ( top quintile of polygenic scores ) than among those at low genetic risk ( bottom quintile of polygenic scores ) ( hazard ratio , 1.91 ; 95 % confidence interval [ CI ] , 1.75 to 2.09 ) . A favorable lifestyle ( defined as at least three of the four healthy lifestyle factors ) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle ( defined as no or only one healthy lifestyle factor ) , regardless of the genetic risk category . Among participants at high genetic risk , a favorable lifestyle was associated with a 46 % lower relative risk of coronary events than an unfavorable lifestyle ( hazard ratio , 0.54 ; 95 % CI , 0.47 to 0.63 ) . This finding corresponded to a reduction in the st and ardized 10-year incidence of coronary events from 10.7 % for an unfavorable lifestyle to 5.1 % for a favorable lifestyle in ARIC , from 4.6 % to 2.0 % in WGHS , and from 8.2 % to 5.3 % in MDCS . In the BioImage Study , a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category . CONCLUSIONS Across four studies involving 55,685 participants , genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease . Among participants at high genetic risk , a favorable lifestyle was associated with a nearly 50 % lower relative risk of coronary artery disease than was an unfavorable lifestyle . ( Funded by the National Institutes of Health and others . ) BACKGROUND Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas , which are characterized by elevated RAS-mitogen-activated protein kinase ( MAPK ) signaling . METHODS We conducted a phase 1 trial of selumetinib ( AZD6244 or ARRY-142886 ) , an oral selective inhibitor of MAPK kinase ( MEK ) 1 and 2 , in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics . Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule ( in 28-day cycles ) . We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma . Response to treatment ( i.e. , an increase or decrease from baseline in the volume of plexiform neurofibromas ) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma . RESULTS A total of 24 children ( median age , 10.9 years ; range , 3.0 to 18.5 ) with a median tumor volume of 1205 ml ( range , 29 to 8744 )  received selumetinib . Patients were able to receive selumetinib on a long-term basis ; the median number of cycles was 30 ( range , 6 to 56 ) . The maximum tolerated dose was 25 mg per square meter ( approximately 60 % of the recommended adult dose ) . The most common toxic effects  associated with selumetinib  included acneiform rash , gastrointestinal effects , and asymptomatic creatine kinase elevation . The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults . Treatment with selumetinib result ed in confirmed partial responses ( tumor volume decreases from baseline of ≥20 % ) in 17 of the 24 children ( 71 % ) and decreases from baseline in neurofibroma volume in 12 of 18 mice ( 67 % ) . Disease progression ( tumor volume increase from baseline of ≥20 % ) has not been observed to date . Anecdotal evidence of decreases in tumor-related pain , disfigurement , and functional impairment was observed . CONCLUSIONS Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects . ( Funded by the National Institutes of Health and others ; Clinical Trials.gov number , NCT01362803 . ) IMPORTANCE The use of mitogen-activated protein kinase ( MAPK ) kinase ( MEK ) inhibitors has become more common in the treatment of systemic cancer . These agents have been associated with a central serous-like retinopathy in some patients . Recognition of such retinal findings and the relatively benign nature of these events is important to avoid unnecessary intervention , including the cessation of a potentially life-prolonging medication . OBJECTIVES To evaluate the presence and characteristics of subretinal fluid ( SRF ) associated with the use of MEK inhibitors in the treatment of systemic cancer and to correlate the presence of SRF with visual acuity and symptoms over time . DESIGN , SETTING , AND PARTICIPANTS Post hoc analysis was conducted of prospect ively collected data from 51 patients with locally advanced or metastatic cancer undergoing treatment with the MEK inhibitor binimetinib in 1 of 4 clinical trials . All clinical trial participants underwent complete ophthalmic examination by retina specialists at a private practice in Boston , Massachusetts , and were monitored between February 29 , 2012 , and January 8 , 2014 . The examination included Snellen-measured visual acuity , dilated fundus examination , and spectral-domain optical coherence tomography at baseline , biweekly for 2 months , then monthly for the remainder of their trial participation . Post hoc design and data analysis were performed between December 1 , 2013 , and June 20 , 2014 . MAIN OUTCOMES AND MEASURES Visual symptoms , visual acuity , fundus appearance , and the presence and characteristics of SRF noted on optical coherence tomography . The characteristics of angiograms performed at the discretion of the treating physician were review ed . RESULTS Of the 51 participants , 18 ( 35 % ) were men ; the mean ( SD ) age was 60 ( 13 ) years ( range , 32 - 87 years ) . Forty-six ( 90 % ) study participants developed SRF during the study period , with 9 ( 20 % ) experiencing symptoms at any point . The mean ( SD ) central retinal thickness of 39 study participants who developed SRF at the first visit increased from 280 ( 26 ) µm at baseline to 316 ( 43 ) µm at the first visit after starting binimetinib treatment ( paired t test , P < .001 ) . On examination , SRF appeared as elevated , yellow-orange pockets in the fovea and /or along the arcades . Corresponding optical coherence tomographic imaging revealed SRF beneath the interdigitation zone . The fovea was affected in 37 of 46 ( 80 % ) individuals ; the location of SRF accumulation varied . Visual symptoms were mild and mainly transient , occurring in 9 participants with SRF ( 20 % ; 95 % CI , 10%-33 % ) . Only 2 participants ( 4 % ) were found to have SRF at the last study visit after discontinuation of treatment with binimetinib . Both had Snellen-measured visual acuity of 20/25 or better . CONCLUSIONS AND RELEVANCE The presence of SRF was common in study participants undergoing treatment with the MEK inhibitor binimetinib . Visual symptoms were mild and mainly transient . The presence of SRF did not lead to permanent ocular sequelae . Cessation of life-extending treatment with MEK inhibitors is not indicated when SRF is present Background — Whether knowledge of genetic risk for coronary heart disease ( CHD ) affects health-related outcomes is unknown . We investigated whether incorporating a genetic risk score ( GRS ) in CHD risk estimates lowers low-density lipoprotein cholesterol ( LDL-C ) levels . Methods and Results — Participants ( n=203 , 45–65 years of age , at intermediate risk for CHD , and not on statins ) were r and omly assigned to receive their 10-year probability of CHD based either on a conventional risk score ( CRS ) or CRS + GRS ( + GRS ) . Participants in the + GRS group were stratified as having high or average/low GRS . Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician . We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake , physical activity levels , or statin use . Participants ( mean age , 59.4±5 years ; 48 % men ; mean 10-year CHD risk , 8.5±4.1 % ) were allocated to receive either CRS ( n=100 ) or + GRS ( n=103 ) . At the end of the study period , the + GRS group had a lower LDL-C than the CRS group ( 96.5±32.7 versus 105.9±33.3 mg/dL ; P=0.04 ) . Participants with high GRS had lower LDL-C levels ( 92.3±32.9 mg/dL ) than CRS participants ( P=0.02 ) but not participants with low GRS ( 100.9±32.2 mg/dL ; P=0.18 ) . Statins  were initiated more often in the + GRS group than in the CRS group ( 39 % versus 22 % , P<0.01 ) . No significant differences in dietary fat intake and physical activity levels were noted . Conclusions — Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01936675 
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A recent systematic review of 21 r and omized , controlled trials suggested that fish-oil supplementation during pregnancy reduces the risk of both preterm delivery and low birth weight.2 It is therefore possible that the positive effect in relation to preterm birth might outweigh the potential for an increased risk of hemorrhage