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.     

New evidence supporting lung cancer screening with low dose CT & surgical implications

IntroductionLung cancer is the leading cause of cancer-death worldwide. The U.S. Preventative Services Task Force (USPTSF) approved screening for current or former smokers aged 55–80 based on the results of the National Lung Screening trial (NLST). Following the NLST, new evidence has emerged from clinical trials and updates to previous trials prior to the anticipated update to the USPSTF guideline. We review the new evidence on lung cancer screening with low dose computed tomography (LDCT) and the surgical implications.MethodsA review of new literature was performed pertaining to lung cancer screening since implementation of UPSTF guidelines. Articles for inclusion were identified by both authors’, then search of the Pubmed and Cochrane database was performed from January 1st, 2013 through February 4th, 2020 using the MeSH search terms: “lung cancer”; “screening”; “low dose CT”. The results of these studies are summarized.ResultsWe identified multiple prospective randomized control trials and meta-analysis since the NLST supporting lung cancer-specific mortality with screening. We identified new nodule classification systems and the development of risk-models which may reduce false positive rates and identify high risk patients not currently eligible for screening. Finally, we discussed the surgical implications of screening.ConclusionNew data supports NLST findings and show ongoing benefit to LDCT for lung cancer screening. Standardized LDCT screening classification has been shown to reduce harm and lower false positive rates. Further study is needed regarding use of risk-modeling. Screening will require an increase in the thoracic workforce to accommodate the amount of surgically operable cancers.     

Sleep trajectories and mediators of poor sleep: findings from the longitudinal analysis of 41,094 participants of the UK Biobank cohort

Study objectivesTo explore sleep trajectories and identify the risk factors and mediators of poor sleep in middle-aged adults.MethodsGroup-based multi-trajectory modelling was applied to the three waves of sleep data the from UK Biobank cohort to identify latent trajectories of sleep and group characteristics. Self-reported sleep duration, sleep problems (based on insomnia symptoms, snoring and trouble waking up) and daytime sleepiness (based on daytime tiredness and sleepiness) were included in the trajectory analyses. Multinomial logistic regression and mediation analysis were used to identify the main factors associated with poor sleep.ResultsAnalysis of sleep data from 41,094 participants (51.9% females) with a median age of 57 years (interquartile range 50–62 years) identified three distinct trajectories of sleep: healthy sleepers (40.8%); borderline poor sleepers (31.6%); and poor sleepers (27.6%). Socio-economic disadvantage, ethnic minority background, shift work, unhealthy lifestyle, poor health, depressive symptoms and obesity were the main risk factors associated with poor sleep. Around a third of the total effect of socio-economic deprivation on poor sleep was mediated through depressive symptoms.ConclusionsThe distinct groups with differential risk for developing sleep issues and stable sleep trajectories highlight the non-transient nature of sleep issues. Early management of depressive symptoms can help in reducing the future burden of poor sleep. Due to the increased risk of poor sleep, people from socio-economically deprived groups, particularly females from ethnic minorities, should be the highest priority for interventions aiming to improve population sleep health.     

Enhancement imaginaries: exploring public understandings of pharmaceutical cognitive enhancing drugs

Abstract

The growing use of psychoactive substances in everyday life, the increasing experimentation among users and the potential of poly drug use for non-medical, lifestyle or enhancement purposes presents an evolving policy challenge. The paper aims to build on previous research to gain a more in-depth qualitative understanding of the imaginaries around pharmaceutical cognitive enhancement (PCE). It focuses in particular on how the so-called pharmaceutical cognitive enhancing drugs (PCEDs) might be used and the social acceptability of these uses across multiple social contexts and groups. Data come from 23 focus groups (99 participants), representing a wide range of social groups, recruited in the UK. We discuss four distinct ‘enhancement practices’ where PCE use was conceptualised as a way to (1) become the best version of oneself; (2) gain a competitive edge over others; (3) for personal achievement or well-being; and (4) promote personal/public safety. The findings problematise the term ‘enhancement’ by showing the different ways in which the use of pharmaceutical ‘enhancement’ drugs can be imagined and understood. We argue for the value of policy responses that acknowledge and respond to a wider range of enhancement practices including those of prospective user groups.     

Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.