Search

International audience; Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

Introduction The Eliminate Yellow fever Epidemics (EYE) strategy was launched in 2017 in response to the resurgence of yellow fever in Africa and the Americas. The strategy relies on several vaccination activities, including preventive mass vaccination campaigns (PMVCs). However, by how much PMVCs are associated with a decreased risk of outbreak to occur has not yet been quantified. Methods and Findings We used the self-controlled case series (SCCS) method to assess the association between the occurrence of yellow fever outbreaks and the implementation of PMVCs at the province level in the African endemic region. As all time-invariant confounders are implicitly controlled for, the SCCS method is an alternative to classical cohort or case-control study designs when the risk of residual confounding is high, in particular confounding by indication. The location and dates of outbreaks were identified from international epidemiological records, and information on PMVCs was provided by coordinators of vaccination activities and international funders. The study sample consisted of provinces that were both affected by an outbreak and targeted for a PMVC between 2005 and 2018. We compared the relative incidence of outbreaks before and after the implementation of a PMVC. The sensitivity of our estimates to a range of assumptions was explored, and the results of the SCCS method were compared to those obtained through a retrospective cohort study design. We further derived the number of yellow fever outbreaks that have been prevented by PMVCs. The study sample consisted of 33 provinces from 11 African countries. Among these, outbreaks occurred during the pre-PMVC period in 26 (79%) provinces versus 7 (21%) occurring in the post-PMVC period. At the province level, the post-PMVC period was associated with a 86% reduction (95% Confidence interval 66% to 94%, p-value A limitation of our study is the fact that it does not account for potential time-varying confounders, such as changing environmental drivers of yellow fever or possibly improved disease surveillance. Conclusion In this study, we provide new empirical evidence of the high preventive impact of PMVCs on yellow fever outbreaks. This study illustrates that the SCCS method can be advantageously applied at the population level in order to evaluate a public health intervention. AUTHOR SUMMARY Why Was This Study Done? Yellow fever is a mosquito-borne vaccine-preventable disease that may cause large urban outbreaks, especially in tropical African regions. Since 2006, Preventive Mass Vaccination Campaigns (PMVCs) have been implemented in many African provinces. These are large scale vaccination campaigns targeting all or most age group in a specific area. The preventive impact PMVCs may have on the risk of yellow fever outbreak has not been quantified yet. What Did the Researchers Do and Find? We used the self-controlled case series (SCCS) method to assess the association between PMVCs and outbreak risk at the province level over 34 African countries between 2005 and 2018. Using this method, we compared pre- and post-PMVC period are compared within each province individually, thus controlling for all possible confounders that do not vary in time, especially the fact that provinces indicated for PMVCs are generally those considered at highest baseline risk of yellow fever (ie confounding by indication). At the province level, we estimated that implementation of PMVCs was associated with an 86% reduction (66% to 94%) in the risk of yellow fever outbreak. Results from a complete cohort analysis provided less reliable results than the SCCS method, likely because of confounding by indication that was not entirely controlled for by adjusting on known drivers of yellow fever. We further estimated that all PMVCs conducted between 2006 and 2018 in Africa may have reduced the total number of yellow fever outbreaks by 34% (22% to 45%). What Do These Findings Mean? These results provide new empirical evidence of the high preventive impact of PMVCs on yellow fever outbreaks. These results may encourage rapid re-scheduling of yellow fever PMVCs that have been postponed due to the COVID-19 pandemic. The SCCS design may be advantageously applied at the population level to assess the impact of public health interventions.

BackgroundAlthough anti-inflammatory agents could theoretically have anticancer properties, results from cohort studies on nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer (BC) risk are inconsistent.MethodsWe investigated the association between NSAID use and BC incidence in the French E3N prospective cohort, which includes 98,995 women born between 1925 and 1950 and insured by a health insurance plan that covers mostly teachers. Self-reported information on lifestyle and medical history has been collected biennially by questionnaires and matched with data from a drug reimbursement database covering the period 2004–2014. Women who self-reported current NSAID use in the 2000 or 2002 questionnaires or with at least two reimbursements in any previous 3-month period were defined as exposed to NSAIDs. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for the association of NSAID use with BC risk.ResultsIn the current analysis, 62,512 postmenopausal women were followed between 2004 and 2014 (9 years on average, starting at a mean age of 63 years; 2864 incident BC). In multivariable models, there was no statistically significant association between NSAID use and BC risk [HR = 1.00 (0.92–1.08), compared with non-exposed women]. The NSAID-BC associations did not differ by NSAID types, BC subtypes, risk factors, and comorbidities, nor by duration and dose of use. However, a statistically significant interaction was observed by proton pump inhibitor (PPI) drug use (Pinteraction = 0.01) whereby a decreased risk of BC with NSAID use was only observed among women who also used PPI before.ConclusionOnly women who used NSAIDs after having used PPI had a lower risk of BC. This result is novel and requires replication in other studies.