Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts.

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.

Relationships between Frailty and the Risk of Glaucoma in Middle-aged and Older Adults.

PURPOSE: Increased frailty in older individuals increases health risks, but its relationship with glaucoma, the leading cause of irreversible blindness in middle-aged and older adults, is unclear. We investigated the association between frailty and glaucoma in a large-scale representative sample and explored possible causal relationships. DESIGN: Combined cross-sectional and Mendelian randomization (MR) study. PARTICIPANTS: In the cross-sectional analysis, we included 5744 participants of the US National Health and Nutrition Examination Surveys 2005-2008 aged ≥40. For the MR analysis, frailty genome-wide association study (GWAS) data were sourced from a UK Biobank and TwinGen meta-analysis, and GWAS data on glaucoma subtypes were derived from FinnGen. METHODS: According to the 49-item frailty index, we classified participants into nonfrail (≤0.10), prefrail (0.10-0.21), and frail (>0.21) groups. Using survey-weighted logistic regression models adjusted for multiple covariates, we explored the association between frailty and glaucoma. We further assessed causation using MR. MAIN OUTCOME MEASURES: The associations between different levels of frailty (nonfrail, prefrail, and frail) and glaucoma, as well as causal relationships between genetically predicted frailty and various subtypes of glaucoma (primary open-angle glaucoma, primary angle-closure glaucoma, normotensive glaucoma, exfoliation glaucoma, and suspected glaucoma). RESULTS: After adjusting for covariates, higher frailty levels were significantly associated with glaucoma in frail individuals (odds ratio [OR]=1.83, 95% confidence interval [CI]=1.05-3.19, P=0.036) but not prefrail (OR=1.90, 95% CI=0.99-3.64, P=0.052). The association was significantly stronger among male participants (P interaction=0.042). The variation in the association between frailty and glaucoma did not reach statistical significance across age groups (P interaction=0.575) or race groups (P interaction=0.092). MR revealed that genetically predicted frailty was linked to greater risks for primary open-angle glaucoma (OR=1.67, 95% CI=1.24-2.25, P=0.001), primary angle-closure glaucoma (OR=2.78, 95% CI=1.48-5.20, P=0.001), exfoliation glaucoma (OR=1.70, 95% CI=1.18-2.43, P=0.004), and suspected glaucoma (OR=1.74, 95% CI=1.30-2.34, P<0.001), but not for normotensive glaucoma (OR=1.01, 95% CI=0.61-1.68, P=0.956). CONCLUSIONS: Our study revealed an association between frailty and increased glaucoma risk and emphasized the significance of glaucoma screening in frail individuals. Targeted healthcare strategies can help prevent or delay irreversible blindness among middle-aged and older adults.