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: Objective : To analyse the effects of smoking reduction and smoking cessation on incidence of myocardial infa rct ion after adjustment for established cardiovascular risk factors . Design : Prospect i ve cohort study with record linkage to mortality and hospital registers . The association of individual change in smoking with myocardial infa rct ion was examined in Cox proportional hazard analyses with continuous heavy smokers ( ⩾5 cigarettes/day ) as reference . Setting : Pooled data from three population studies conducted in Copenhagen , Denmark . Participants : 10 956 men and 8467 women with complete information on smoking habits at two examinations five to ten years apart were followed up from the second examination for a first hospital admission or death from myocardial infa rct ion . Mean duration of follow up was 13.8 years . Main results : A total of 643 participants who were heavy smokers at baseline reduced their daily tobacco consumption by at least 50 % without quitting between first and second examination , and 1379 participants stopped smoking . During follow up 1658 men and 521 women experienced a fatal or non-fatal myocardial infa rct ion . After adjustment for cardiovascular risk factors , people who stopped smoking had a decreased risk of myocardial infa rct ion , hazard ratio 0.71 ( 95 % confidence intervals 0.59 to 0.85 ) . Smoking reduction was not associated with reduced risk of myocardial infa rct ion , hazard ratio 1.15 ( 95 % confidence intervals 0.94 to 1.40 ) . These associations remained unchanged after controlling for baseline illness in different ways . Conclusions : Smoking cessation in healthy people  reduces the risk of a subsequent myocardial infa rct ion , whereas this study provides no evidence of benefit from reduction in the amount smoked Extending a previous finding of an association between functional genetic variation in the mu-opioid receptor gene and response to nicotine replacement therapy , we explored the role of genetic variants in two genes encoding mu-opioid-receptor-interacting proteins , namely ARRB2 and HINT1 . Participants were 374 smokers treated for nicotine dependence with either transdermal nicotine or nicotine nasal spray for 8 weeks in an open-label r and omized trial . In a logistic regression model controlling for OPRM1 genotype , treatment type , and other covariates , we found no significant main effect of ARRB2 genotype on abstinence at either end of treatment or 6-month follow-up . Participants with the HINT1 TT genotype had significantly higher abstinence rates at 6-month follow-up , but this may not be a pharmacogenetic effect , given that the participants were drug free during this time . Haplotype analysis did not reveal any significant associations for either gene . We found an interaction of ARRB2 and OPRM1 genotype on abstinence at 6 months that approached significance ; however , interpretation of this finding is limited by the small number of participants with the minor alleles for both genes . Although these data do not provide support for the role of genetic variation in these mu-opioid-receptor-interacting proteins and smoking cessation , further exploration of opioid pathway genes in larger prospect i ve pharmacogenetic trials may be warranted We conducted gender-stratified analyses on a systems-based c and i date gene study of 53 regions involved in nicotinic response and the brain — reward pathway in two r and omized clinical trials of smoking  cessation treatments ( placebo , bupropion , transdermal and nasal spray nicotine replacement therapy ) . We adjusted P-values for multiple correlated tests , and used a Bonferroni-corrected α-level of 5 × 10−4 to determine system-wide significance . Four single-nucleotide polymorphisms ( rs12021667 , rs12027267 , rs6702335 , rs12039988 ; r2>0.98 ) in erythrocyte membrane protein b and 4.1 ( EPB41 ) had a significant male-specific marginal association with smoking abstinence ( odds ratio (OR)=0.5 ; 95 % confidence interval ( CI ) : 0.3–0.6 ) at end of treatment ( adjusted P<6 × 10−5 ) . rs806365 in cannabinoid receptor 1 ( CNR1 ) had a significant male-specific gene – treatment interaction at 6-month follow-up ( adjusted P=3.9 × 10−5 ) ; within males using nasal spray , rs806365 was associated with a decrease in odds of abstinence ( OR=0.04 ; 95 % CI : 0.01–0.2 ) . While the role of CNR1 in substance abuse has been well studied , we report EPB41 for the first time in the nicotine literature INTRODUCTION The α4β2 nicotinic receptor is of central importance in tobacco dependence , while the homomeric α7 receptor may also play a role . In this c and i date gene study , we examine the association between 8 single nucleotide polymorphisms ( SNPs ) in genes coding for nicotinic acetylcholine receptor subunits α4 ( rs1044396 , rs2273504 , rs2236196 , and rs2273502 ) , α7 ( rs2133965 and rs4779969 ) , and β2 ( rs2072660 and rs2072661 ) and smoking abstinence in a cohort of quitters enrolled in a clinical trial of behavioral support . METHODS Data were obtained from the " Patch in Practice " study , involving 925 smokers in the United Kingdom . All participants were given an 8-week course of 15 mg of transdermal nicotine replacement therapy and blood was taken for genotyping . RESULTS Logistic regression analyses assessed the association between each selected SNP and smoking abstinence at 4 , 12 , 26 , and 52 weeks . There were no statistically significant associations with smoking cessation success or nicotine intake assessed by plasma cotinine levels . However , rs2273502 was associated with a consistent ( though nonsignificant ) increase in the odds of abstinence . CONCLUSIONS There was no compelling evidence that these SNPs were associated with a reduced or higher chance of abstinence . However , rs2273502 may be worth investigating in future studies INTRODUCTION We previously reported evidence that the T allele of the dopamine type-2 receptor ( DRD2 ) rs1800497 polymorphism is associated with improved response to nicotine replacement therapy ( NRT ) relative to placebo and that this association may only be present in females . However , evidence of the poor replication validity of genetic association studies is growing , particularly among those that report subgroup analyses . We therefore attempted to replicate our previous finding of an association between the DRD2 rs1800497 genotype and response to NRT in a new , larger cohort , with greater statistical power . METHODS Participants were r and omly assigned to one of two levels of smoking cessation behavioral support ( usual care vs. weekly support ) . All participants received 8 weeks of 15-mg NRT transdermal patch . RESULTS The presence of one or more T alleles was associated with a slightly but not significantly lower likelihood of abstinence at 3 and 6 months . We found evidence of a genotype x sex interaction effect . However , stratified analyses indicated a main effect of genotype opposite to the effect reported previously , with females carrying one or more copies of the T allele less likely to be abstinent . DISCUSSION Our results do not support an association between the DRD2 rs1800497 ( Taq1A ) polymorphism and response to NRT , contrary to our previous study We investigated the association of the OPRM1 genotype with  long-term smoking cessation and  change in body mass index ( BMI ) following a smoking cessation attempt among smokers who attempted to quit using the nicotine replacement therapy ( NRT ) patch or placebo in a r and omized controlled trial , and were followed-up over an 8-year period following their initial cessation attempt . We also investigated possible sex differences in these relationships , given evidence for sex differences in smoking cessation and central opioid mechanisms , as well as some evidence for sex differences in response to NRT . Our results indicate that OPRM1 genotype may moderate the effect of  transdermal nicotine patch compared to placebo during active treatment , with a benefit of active NRT treatment evident in the OPRM1 AA genotype group only and those carrying one or more copies of the G allele demonstrating no benefit of active NRT versus placebo patch . Our results also indicate a sex difference in change in BMI at 8-year follow-up following a smoking cessation attempt , with ex-smokers demonstrating an increase in BMI , and this increase being greater in female subjects than in male subjects . We did not observe any association of OPRM1 genotype with change in BMI , although there was a trend for genotype to influence the observed sex difference in change in BMI over time . Future studies should attempt to replicate these findings , and investigate the relationship between both short- and long-term weight gain and smoking cessation and investigate possible mechanisms that may underlie these processes . Future studies should also investigate the role of OPRM1 genotype and smoking cessation on other appetitive and reward behaviours such as alcohol consumption This r and omized , double-blinded , placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation . Smokers of European ancestry ( N = 291 ) , who were r and omized to receive bupropion or placebo ( 12 weeks ) plus counseling , were genotyped for the dopamine D2 receptor ( DRD2-Taq1A ) , dopamine transporter ( SLC6A3 3 ' VNTR ) , and cytochrome P450 2B6 ( CYP2B6 1459 CT ) polymorphisms . Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2- , 6- , and 12-month follow-ups post quit date . Using generalized estimating equations , we found that bupropion , compared with placebo , was associated with significantly greater odds of abstinence at all time points ( all p values<.01 ) . We found a significant DRD2 x bupropion interaction ( B = 1.49 , SE = 0.59 , p = .012 ) [ corrected ] and a three-way DRD2 x bupropion x craving interaction on 6-month smoking cessation outcomes ( B = -0.45 , SE = 0.22 , p = .038 ) , such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion . Furthermore , there was a significant DRD2 x CYP2B6 interaction ( B = 1.43 , SE = 0.56 , p = .01 ) , such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype . Because the sample size of this study was modest for pharmacogenetic investigations , the results should be interpreted with caution . Although these results require replication , the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and , further , that exploration of gene x gene and gene x craving interactions in future , larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion The A1 allele of the dopamine D2 receptor gene ( DRD2 ) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior . In a study of smokers enrolled in an open-label , r and omized effectiveness trial , we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling .  Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months , respectively , following a target quit date . Compared to women who carry both A2 alleles , women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects ( odds ratio (OR)=1.91 , 95 % confidence interval (CI)=1.01–3.60 ; P<0.04 ) and at 12 months were somewhat more likely to report smoking ( OR=0.76 , 95 % CI=0.56–1.03 ; P<0.076 ) . Significant associations or trends were not observed in men . In women , individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function We investigated the association of catechol O-methyltransferase ( COMT ) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt . In addition , we examined the possible moderating influence of sex on any association . The genotype × treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group ( 33 % versus 12 % ) , in comparison to the Met/Val + Val/Val group ( 22 % versus 16 % ) . Our results indicate that 
    Output:
    
agent
Results : We confirmed the importance of the 4 main factors influencing SC : ( 1 ) environmental factors , ( 2 ) genomic factors , ( 3 ) gene-environment interactions , and ( 4 ) evidence -based interventions .
The model demonstrates the complex network of factors influencing SC .
***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 : To analyse the effects of smoking reduction and smoking cessation on incidence of myocardial infa rct ion after adjustment for established cardiovascular risk factors . Design : Prospect i ve cohort study with record linkage to mortality and hospital registers . The association of individual change in smoking with myocardial infa rct ion was examined in Cox proportional hazard analyses with continuous heavy smokers ( ⩾5 cigarettes/day ) as reference . Setting : Pooled data from three population studies conducted in Copenhagen , Denmark . Participants : 10 956 men and 8467 women with complete information on smoking habits at two examinations five to ten years apart were followed up from the second examination for a first hospital admission or death from myocardial infa rct ion . Mean duration of follow up was 13.8 years . Main results : A total of 643 participants who were heavy smokers at baseline reduced their daily tobacco consumption by at least 50 % without quitting between first and second examination , and 1379 participants stopped smoking . During follow up 1658 men and 521 women experienced a fatal or non-fatal myocardial infa rct ion . After adjustment for cardiovascular risk factors , people who stopped smoking had a decreased risk of myocardial infa rct ion , hazard ratio 0.71 ( 95 % confidence intervals 0.59 to 0.85 ) . Smoking reduction was not associated with reduced risk of myocardial infa rct ion , hazard ratio 1.15 ( 95 % confidence intervals 0.94 to 1.40 ) . These associations remained unchanged after controlling for baseline illness in different ways . Conclusions : Smoking cessation in healthy people  reduces the risk of a subsequent myocardial infa rct ion , whereas this study provides no evidence of benefit from reduction in the amount smoked Extending a previous finding of an association between functional genetic variation in the mu-opioid receptor gene and response to nicotine replacement therapy , we explored the role of genetic variants in two genes encoding mu-opioid-receptor-interacting proteins , namely ARRB2 and HINT1 . Participants were 374 smokers treated for nicotine dependence with either transdermal nicotine or nicotine nasal spray for 8 weeks in an open-label r and omized trial . In a logistic regression model controlling for OPRM1 genotype , treatment type , and other covariates , we found no significant main effect of ARRB2 genotype on abstinence at either end of treatment or 6-month follow-up . Participants with the HINT1 TT genotype had significantly higher abstinence rates at 6-month follow-up , but this may not be a pharmacogenetic effect , given that the participants were drug free during this time . Haplotype analysis did not reveal any significant associations for either gene . We found an interaction of ARRB2 and OPRM1 genotype on abstinence at 6 months that approached significance ; however , interpretation of this finding is limited by the small number of participants with the minor alleles for both genes . Although these data do not provide support for the role of genetic variation in these mu-opioid-receptor-interacting proteins and smoking cessation , further exploration of opioid pathway genes in larger prospect i ve pharmacogenetic trials may be warranted We conducted gender-stratified analyses on a systems-based c and i date gene study of 53 regions involved in nicotinic response and the brain — reward pathway in two r and omized clinical trials of smoking  cessation treatments ( placebo , bupropion , transdermal and nasal spray nicotine replacement therapy ) . We adjusted P-values for multiple correlated tests , and used a Bonferroni-corrected α-level of 5 × 10−4 to determine system-wide significance . Four single-nucleotide polymorphisms ( rs12021667 , rs12027267 , rs6702335 , rs12039988 ; r2>0.98 ) in erythrocyte membrane protein b and 4.1 ( EPB41 ) had a significant male-specific marginal association with smoking abstinence ( odds ratio (OR)=0.5 ; 95 % confidence interval ( CI ) : 0.3–0.6 ) at end of treatment ( adjusted P<6 × 10−5 ) . rs806365 in cannabinoid receptor 1 ( CNR1 ) had a significant male-specific gene – treatment interaction at 6-month follow-up ( adjusted P=3.9 × 10−5 ) ; within males using nasal spray , rs806365 was associated with a decrease in odds of abstinence ( OR=0.04 ; 95 % CI : 0.01–0.2 ) . While the role of CNR1 in substance abuse has been well studied , we report EPB41 for the first time in the nicotine literature INTRODUCTION The α4β2 nicotinic receptor is of central importance in tobacco dependence , while the homomeric α7 receptor may also play a role . In this c and i date gene study , we examine the association between 8 single nucleotide polymorphisms ( SNPs ) in genes coding for nicotinic acetylcholine receptor subunits α4 ( rs1044396 , rs2273504 , rs2236196 , and rs2273502 ) , α7 ( rs2133965 and rs4779969 ) , and β2 ( rs2072660 and rs2072661 ) and smoking abstinence in a cohort of quitters enrolled in a clinical trial of behavioral support . METHODS Data were obtained from the " Patch in Practice " study , involving 925 smokers in the United Kingdom . All participants were given an 8-week course of 15 mg of transdermal nicotine replacement therapy and blood was taken for genotyping . RESULTS Logistic regression analyses assessed the association between each selected SNP and smoking abstinence at 4 , 12 , 26 , and 52 weeks . There were no statistically significant associations with smoking cessation success or nicotine intake assessed by plasma cotinine levels . However , rs2273502 was associated with a consistent ( though nonsignificant ) increase in the odds of abstinence . CONCLUSIONS There was no compelling evidence that these SNPs were associated with a reduced or higher chance of abstinence . However , rs2273502 may be worth investigating in future studies INTRODUCTION We previously reported evidence that the T allele of the dopamine type-2 receptor ( DRD2 ) rs1800497 polymorphism is associated with improved response to nicotine replacement therapy ( NRT ) relative to placebo and that this association may only be present in females . However , evidence of the poor replication validity of genetic association studies is growing , particularly among those that report subgroup analyses . We therefore attempted to replicate our previous finding of an association between the DRD2 rs1800497 genotype and response to NRT in a new , larger cohort , with greater statistical power . METHODS Participants were r and omly assigned to one of two levels of smoking cessation behavioral support ( usual care vs. weekly support ) . All participants received 8 weeks of 15-mg NRT transdermal patch . RESULTS The presence of one or more T alleles was associated with a slightly but not significantly lower likelihood of abstinence at 3 and 6 months . We found evidence of a genotype x sex interaction effect . However , stratified analyses indicated a main effect of genotype opposite to the effect reported previously , with females carrying one or more copies of the T allele less likely to be abstinent . DISCUSSION Our results do not support an association between the DRD2 rs1800497 ( Taq1A ) polymorphism and response to NRT , contrary to our previous study We investigated the association of the OPRM1 genotype with  long-term smoking cessation and  change in body mass index ( BMI ) following a smoking cessation attempt among smokers who attempted to quit using the nicotine replacement therapy ( NRT ) patch or placebo in a r and omized controlled trial , and were followed-up over an 8-year period following their initial cessation attempt . We also investigated possible sex differences in these relationships , given evidence for sex differences in smoking cessation and central opioid mechanisms , as well as some evidence for sex differences in response to NRT . Our results indicate that OPRM1 genotype may moderate the effect of  transdermal nicotine patch compared to placebo during active treatment , with a benefit of active NRT treatment evident in the OPRM1 AA genotype group only and those carrying one or more copies of the G allele demonstrating no benefit of active NRT versus placebo patch . Our results also indicate a sex difference in change in BMI at 8-year follow-up following a smoking cessation attempt , with ex-smokers demonstrating an increase in BMI , and this increase being greater in female subjects than in male subjects . We did not observe any association of OPRM1 genotype with change in BMI , although there was a trend for genotype to influence the observed sex difference in change in BMI over time . Future studies should attempt to replicate these findings , and investigate the relationship between both short- and long-term weight gain and smoking cessation and investigate possible mechanisms that may underlie these processes . Future studies should also investigate the role of OPRM1 genotype and smoking cessation on other appetitive and reward behaviours such as alcohol consumption This r and omized , double-blinded , placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation . Smokers of European ancestry ( N = 291 ) , who were r and omized to receive bupropion or placebo ( 12 weeks ) plus counseling , were genotyped for the dopamine D2 receptor ( DRD2-Taq1A ) , dopamine transporter ( SLC6A3 3 ' VNTR ) , and cytochrome P450 2B6 ( CYP2B6 1459 CT ) polymorphisms . Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2- , 6- , and 12-month follow-ups post quit date . Using generalized estimating equations , we found that bupropion , compared with placebo , was associated with significantly greater odds of abstinence at all time points ( all p values<.01 ) . We found a significant DRD2 x bupropion interaction ( B = 1.49 , SE = 0.59 , p = .012 ) [ corrected ] and a three-way DRD2 x bupropion x craving interaction on 6-month smoking cessation outcomes ( B = -0.45 , SE = 0.22 , p = .038 ) , such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion . Furthermore , there was a significant DRD2 x CYP2B6 interaction ( B = 1.43 , SE = 0.56 , p = .01 ) , such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype . Because the sample size of this study was modest for pharmacogenetic investigations , the results should be interpreted with caution . Although these results require replication , the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and , further , that exploration of gene x gene and gene x craving interactions in future , larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion The A1 allele of the dopamine D2 receptor gene ( DRD2 ) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior . In a study of smokers enrolled in an open-label , r and omized effectiveness trial , we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling .  Adherence to treatment and point-prevalent smoking status were assessed at 3 and 12 months , respectively , following a target quit date . Compared to women who carry both A2 alleles , women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects ( odds ratio (OR)=1.91 , 95 % confidence interval (CI)=1.01–3.60 ; P<0.04 ) and at 12 months were somewhat more likely to report smoking ( OR=0.76 , 95 % CI=0.56–1.03 ; P<0.076 ) . Significant associations or trends were not observed in men . In women , individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function We investigated the association of catechol O-methyltransferase ( COMT ) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt . In addition , we examined the possible moderating influence of sex on any association . The genotype × treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met/Met genotype group ( 33 % versus 12 % ) , in comparison to the Met/Val + Val/Val group ( 22 % versus 16 % ) . Our results indicate that 
    Output:
    