Risk for non Hodgkin’s lymphoma in the vicinity of French municipal solid waste incinerators

<p>Abstract</p> <p>Background</p> <p>Dioxin emissions from municipal solid waste incinerators are one of the major sources of dioxins and therefore are an exposure source of public concern. There is growing epidemiologic evidence of an increased risk for non-Hodgkin's lymphoma (NHL) in the vicinity of some municipal solid waste incinerators with high dioxin emission levels. The purpose of this study was to examine this association on a larger population scale.</p> <p>Methods</p> <p>The study area consisted of four French administrative departments, comprising a total of 2270 block groups. NHL cases that had been diagnosed during the period 1990–1999, and were aged 15 years and over, were considered. Each case was assigned a block group by residential address geocoding. Atmospheric Dispersion Model System software was used to estimate immissions in the surroundings of 13 incinerators which operated in the study area. Then, cumulative ground-level dioxin concentrations were calculated for each block group. Poisson multiple regression models, incorporating penalized regression splines to control for covariates and dealing with Poisson overdispersion, were used. Five confounding factors were considered: population density, urbanisation, socio-economic level, airborne traffic pollution, and industrial pollution.</p> <p>Results</p> <p>A total of 3974 NHL incident cases was observed (2147 among males, and 1827 among females) during the 1990–1999 time period. A statistically significant relationship was found at the block group level between risk for NHL and dioxin exposure, with a relative risk (RR) of 1.120 (95% confidence interval [CI] 1.002 – 1.251) for persons living in highly exposed census blocks compared to those living in slightly exposed block groups. Population density appeared positively linked both to risk for NHL and dioxin exposure. Subgroup multivariate analyses per gender yielded a significant RR for females only (RR = 1.178, 95% CI 1.013 – 1.369).</p> <p>Conclusion</p> <p>This study, in line with previous results obtained in the vicinity of the incinerator located in Besançon (France), adds further evidence to the link between NHL incidence and exposure to dioxins emitted by municipal solid waste incinerators. However, the findings of this study cannot be extrapolated to current incinerators, which emit lower amounts of pollutants.</p

Development and validation of a multiplex UHPLC-MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV

The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to be taken lifelong raising issues regarding the maintenance of both therapeutic effectiveness and long-term tolerability. Recently approved or investigational antiretroviral drugs present considerable advantages, allowing once daily oral dosage along with activity against resistant variants (eg, bictegravir and doravirine) and also parenteral intramuscular administration that facilitates treatment adherence (eg, long-acting injectable formulations such as cabotegravir and rilpivirine). Still, there remains a risk of insufficient or exaggerated circulating exposure due to absorption issues, abnormal elimination, drug-drug interactions, and others. In this context, a multiplex ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) bioassay has been developed for the monitoring of plasma levels of bictegravir, cabotegravir, doravirine, and rilpivirine in PLWH. A simple and convenient protein precipitation was performed followed by direct injection of the supernatant into the UHPLC-MS/MS system. The four analytes were eluted in less than 3 minutes using a reversed-phase chromatography method coupled with triple quadrupole mass spectrometry detection. This bioassay was fully validated following international guidelines and achieved good performances in terms of trueness (94.7%-107.5%), repeatability (2.6%-11%), and intermediate precision (3.0%-11.2%) over the clinically relevant concentration ranges (from 30 to 9000 ng/mL for bictegravir, cabotegravir, and doravirine and from 10 to 1800 ng/mL for rilpivirine). This sensitive, accurate, and rapid UHPLC-MS/MS assay is currently applied in our laboratory for routine therapeutic drug monitoring of the oral drugs bictegravir and doravirine and is also intended to be applied for the monitoring of cabotegravir/rilpivirine levels in plasma from PLWH receiving once monthly or every 2-month intramuscular injection of these long-acting antiretroviral drugs

Population pharmacokinetic modelling to characterize the effect of chronic kidney disease on tenofovir exposure after tenofovir alafenamide administration

BACKGROUND: Tenofovir alafenamide is gradually replacing tenofovir disoproxil fumarate, both prodrugs of tenofovir, in HIV prevention and treatment. There is thus an interest in describing tenofovir pharmacokinetics (PK) and its variability in people living with HIV (PLWH) under tenofovir alafenamide in a real-life setting. OBJECTIVES: To characterize the usual range of tenofovir exposure in PLWH receiving tenofovir alafenamide, while assessing the impact of chronic kidney disease (CKD). METHODS: We conducted a population PK analysis (NONMEM®) on 877 tenofovir and 100 tenofovir alafenamide concentrations measured in 569 PLWH. Model-based simulations allowed prediction of tenofovir trough concentrations (Cmin) in patients having various levels of renal function. RESULTS: Tenofovir PK was best described using a one-compartment model with linear absorption and elimination. Creatinine clearance (CLCR, estimated according to Cockcroft and Gault), age, ethnicity and potent P-glycoprotein inhibitors were statistically significantly associated with tenofovir clearance. However, only CLCR appeared clinically relevant. Model-based simulations revealed 294% and 515% increases of median tenofovir Cmin in patients with CLCR of 15-29 mL/min (CKD stage 3), and less than 15 mL/min (stage 4), respectively, compared with normal renal function (CLCR = 90-149 mL/min). Conversely, patients with augmented renal function (CLCR > 149 mL/min) had a 36% decrease of median tenofovir Cmin. CONCLUSIONS: Kidney function markedly affects circulating tenofovir exposure after tenofovir alafenamide administration in PLWH. However, considering its rapid uptake into target cells, we suggest only a cautious increase of tenofovir alafenamide dosage intervals to 2 or 3 days only in case of moderate or severe CKD, respectively

CRH – Approches historiques des mondes contemporains (AhMoC)

Stéphane Audoin-Rouzeau, Marc Olivier Baruch, Christophe Prochasson, Paul-André Rosental, directeurs d’étudesLaura Lee Downs, directrice d’étudesJordi Canal, maître de conférencesVincent Duclert, professeur agrégéMarie-Laurence Netter, ingénieure d’étudesAlain Chatriot, chargé de recherche au CNRSPerrine Simon-Nahum, chargée de recherche au CNRS Histoire politique du contemporain Le programme du séminaire reposait cette année sur une série d’interrogations générales relatives à la recherche e..