ABSTRACT
The Randomized Endo‐vein Graft Prospective (REGROUP) trial (ClinicalTrials.gov NCT01850082) is a randomized, intent‐to‐treat, 2‐arm, parallel‐design, multicenter study funded by the ...Cooperative Studies Program (CSP No. 588) of the US Department of Veterans Affairs. Cardiac surgeons at 16 Veterans Affairs (VA) medical centers with technical expertise in performing both endoscopic vein harvesting (EVH) and open vein harvesting (OVH) were recruited as the REGROUP surgeon participants. Subjects requiring elective or urgent coronary artery bypass grafting using cardiopulmonary bypass with use of ≥1 saphenous vein graft will be screened for enrollment using pre‐established inclusion/exclusion criteria. Enrolled subjects (planned N = 1150) will be randomized to 1 of the 2 arms (EVH or OVH) after an experienced vein harvester has been assigned. The primary outcomes measure is the rate of major adverse cardiac events (MACE), including death, myocardial infarction, or revascularization. Subject assessments will be performed at multiple times, including at baseline, intraoperatively, postoperatively, and at discharge (or 30 days after surgery, if still hospitalized). Assessment of leg‐wound complications will be completed at 6 weeks after surgery. Telephone follow‐ups will occur at 3‐month intervals after surgery until the participating sites are decommissioned after the trial's completion (approximately 4.5 years after the full study startup). To assess long‐term outcomes, centralized follow‐up of MACE for 2 additional years will be centrally performed using VA and non‐VA clinical and administrative databases. The primary MACE outcome will be compared between the 2 arms, EVH and OVH, at the end of the trial duration.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background. Erythropoiesis-stimulating agents (ESAs) are frequently used to treat anaemia of chronic kidney disease (CKD) in the dialysis setting; however, few data are available regarding factors ...influencing initiation of ESAs and other therapies in non-dialysis patients. Methods. A retrospective cohort study of Veterans Health Administration data from 2003 to 2005 for 89 585 patients identified as having CKD and anaemia based on two outpatient estimated glomerular filtration rates <60 ml/min/1.73 m2 and at least one outpatient haemoglobin (Hb) <11 g/dL. Hb levels, patient demographics, clinical and provider characteristics and procedures predicted ESA treatment initiation over 1 year of follow-up. Multivariable logistic and pooled logistic survival models identified predictors of ESA initiation. Results. Overall, 6381 subjects (7.1%) initiated ESAs within 1 year of the index Hb; initiation was more common (8.6%) for patients with Hb <10 g/dL. Iron therapy use varied by initial Hb levels (27.6% to 52.4%) as did transfusions (12.5% to 42.8%); each was more common at lower Hb levels. Hbs rose to above 11 g/dL for 25–50% of patients in the absence of any treatment or by transfusion/iron therapy. Factors predicting time to ESA initiation included: nephrologist odds ratio (OR = 2.3) or haematologist care (OR = 2.2) and iron therapy (OR = 1.6). Transfusions increased for patients with increasing follow-up time. Conclusion. Iron therapy is more common than ESA treatment in patients with CKD and Hbs <11 g/dL in the VA. Correction of anaemia in the absence of any ESA treatment was common at higher Hbs levels, but much less so when Hb levels fell below 10 g/dL.
Background: Milk and dietary calcium may have antiproliferative effects against colorectal cancer, but milk intake also raises serum levels of insulin-like growth factor-I (IGF-I). A high ratio of ...IGF-I to IGF-binding protein-3 (IGFBP-3) has been linked to an increased risk of colorectal cancer. Methods: In a case–control study nested in the Physicians' Health Study, plasma samples were collected from the period 1982 through 1983 from 14 916 men, aged 40–84 years, who also answered dietary questionnaires. Circulating levels of IGF-I and IGFBP-3 were assayed among 193 men who developed colorectal cancer during 13 years of follow-up and 318 age- and smoking-matched cancer-free control men. Conditional logistic regression was used to assess relative risks (RRs) of colorectal cancer for tertiles of IGF-I/IGFBP-3 and dietary factors. Statistical tests were two-sided. Results: Overall, there was a moderate but statistically nonsignificant inverse association between intake of low-fat milk or calcium from dairy food and colorectal cancer risk. Intake of dairy food (especially low-fat milk) was also positively and moderately associated with plasma levels of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 among control men. We observed a statistically significant interaction between low-fat milk intake and IGF-I/IGFBP-3 in association with risk of colorectal cancer (Pinteraction = .03). Nondrinkers with IGF-I/IGFBP-3 in the highest tertile had a threefold higher risk than nondrinkers with IGF-I/IGFBP-3 in the lowest tertile (RR = 3.05; 95% confidence interval CI = 1.29 to 7.24), but no such increase was seen among frequent low-fat milk drinkers (RR = 1.05; 95% CI = 0.41 to 2.69). Conversely, among men with high IGF-I/IGFBP-3, frequent low-fat milk drinkers had a 60% lower risk (95% CI = 0.17 to 0.87; Ptrend = .02) than nondrinkers. Conclusion: Intake of dairy products was associated with a modest increase in circulating IGF-I levels, but intake of low-fat milk was associated with lower risk of colorectal cancer, particularly among individuals with high IGF-I/IGFBP-3. This subpopulation, which is at increased risk of colorectal cancer, might benefit the most from specific dietary intervention.
The authors conducted a nested case-control study from 1992 to 2003 among US women aged 45 years or older and free from cardiovascular disease and cancer to examine the prospective association among ...plasma lycopene, other carotenoids, and the risk of developing type 2 diabetes. During 10 years of follow-up, 470 cases of incident type 2 diabetes were selected and individually matched on age (±1 year) and follow-up time to 470 nondiabetic controls. Baseline plasma levels of lycopene, α-carotene, β-carotene, β-cryptoxanthin, and lutein/zeaxanthin were similar in cases and controls (all p > 0.05). A possible crude inverse association between plasma lycopene and risk of type 2 diabetes was attenuated upon multivariate adjustment. After control for plasma total cholesterol and known diabetes risk factors, the multivariate odds ratios of type 2 diabetes in the highest versus the lowest quartile of plasma carotenoids were 1.13 (95% confidence interval (CI): 0.60, 2.13) for lycopene, 1.27 (95% CI: 0.63, 2.57) for α-carotene, 1.10 (95% CI: 0.57, 2.13) for β-carotene, 0.91 (95% CI: 0.46, 1.81) for β-cryptoxanthin, and 1.35 (95% CI: 0.68, 2.69) for lutein/zeaxanthin. There was no prospective association between baseline plasma carotenoids and the risk of type 2 diabetes in middle-aged and older women.
IMPORTANCE: Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. OBJECTIVE: To identify novel, replicable genomic risk ...loci for SITB. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022. MAIN OUTCOME AND MEASURES: SITB. RESULTS: A total of 633 778 US military veterans were included in the analysis (57 152 9% female; 121 118 19.1% African ancestry, 8285 1.3% Asian ancestry, 452 767 71.4% European ancestry, and 51 608 8.1% Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10−8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry. CONCLUSIONS AND RELEVANCE: The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.
We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control ...studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 × 10−11, per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 × 10−8, per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 × 10−10, per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 × 10−7, per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear.
Methods
We pooled data from 26 ...prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided.
Results
Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers.
Conclusions
Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
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