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Prevention of ABO-incompatible red cell transfusions (ABO-it) requires accurate donor and patient identification and correct application of processes for transfusion safety. In France and Germany, a bedside identity check and ABO compatibility test are performed. In the UK, an identity check, often structured as a bedside checklist, is performed with or without electronic patient identification (ePID). To compare the efficacy of ABO-it bedside preventive measures, frequencies and causes of ABO-it between 2013 and 2022 were investigated in all three countries. Despite differing bedside safety measures, similar average ABO-it frequencies were observed in France (0.19 [SD:0.09]/100 000 issued red cell units) and in the UK (0.28 [SD:0.17]/100 000), whereas a higher frequency (0.71 [SD:0.23]/100 000) was observed in Germany which has similar bedside safety measures to France. ABO-it resulted mostly from erroneous patient identification and transfusion of a red cell unit intended for another patient. In France and Germany, all ABO-it were associated with incorrectly performed identity check and ABO compatibility test. In the UK, most ABO-it were associated with incorrectly performed identity checks. Current measures to prevent ABO-it are not fully effective. Further development and implementation of effective patient identification systems, including electronic information systems, across the entire transfusion process, should be considered., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

BackgroundSyphilis in blood donors (BD) has increased in many countries.AimWe aimed to describe trends in syphilis seroposivity in BD in France, to identify risk factors and assess if a non-treponemic test (NTT) could define BD having recovered from syphilis for more than 1 year.MethodsThe analysis covered the period 2007 to 2022 and 45,875,939 donations. Of the 474 BD syphilis-positive in 2022, 429 underwent additional investigations with an NTT. History of syphilis was obtained at the post-donation interview or based on serology results for repeat donors.ResultsUntil 2021, positivity rates remained stable (mean: 1.18/10,000 donations, range: 1.01-1.38). An increased rate was observed in 2022 (1.74/10,000; p = 0.02). Over the whole study period, prevalence was 2.2 times higher in male than in female BD (4.1 times higher in 2022). The proportion of males with an identified risk factor who have sex with men increased from 16.7% in 2007 to 64.9% in 2022. Based on NTT, 79 (18%) of the donors who were seropositive in 2022 were classified as having been infected in the previous year. History of syphilis was available for 30 of them. All had an infection within the previous 3 years. Among seven donors with a syphilis < 12 months before testing, one had an NTT titre ≥ 8, three a titre between 1 and 4, three were negative.ConclusionSyphilis seropositivity increased considerably in BDs in 2022, mostly in males, notably MSM. Available data did not allow appropriate evaluation of the NTT to distinguish recent from past infection.

In France, blood donations are tested in pools of 96 samples for parvovirus B19 (B19V) DNA to discard plasma for fractionation when it contains high viral loads. Between January 2015 and March 2024, B19V-positive donations decreased during the COVID-19 pandemic, followed by a strong rebound in 2023 and unusually high circulation during winter 2023/24 (ca 10 times higher December 2023-March 2024 vs the pre-pandemic period). Variations over time are probably related to measures implemented to limit SARS-CoV-2 spread.

We recently proposed an equation to estimate the glomerular filtration rate (GFR) in children with cancer based on plasma cystatin C and serum creatinine levels together with body weight (the "CysPed equation"). The current clinical study reports a prospective evaluation of this equation in 18 children treated by nephrotoxic chemotherapy. The CysPed equation resulted in less bias and greater precision compared to two equations previously proposed equations by Schwartz, with or without plasma cystatin C. Moreover, the decrease in GFR due to chemotherapy was clearly identified by the CysPed equation. This equation may be used to monitor the renal function in childhood cancer units., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Pathogen reduction (PR) technology may reduce the risk of transfusion-transmitted infections (TTIs), notably transfusion-transmitted bacterial infection (TTBI) associated with platelet concentrates (PCs). PR (amotosalen/UVA treatment) was implemented for all PCs transfused in France in November 2017. No bacterial detection was in place beforehand. The study aimed to assess the impact of PR PC on TTI and TTBI near-miss occurrences., Materials and Methods: TTI and TTBI near-miss occurrences were compared before and after 100% PR implementation. The study period ran from 2013 to 2022. Over 300,000 PCs were transfused yearly., Results: No PC-related transmission of human immunodeficiency virus, hepatitis C virus, hepatitis B virus and human T-cell lymphotropic virus was reported throughout the study period. PC-mediated hepatitis E virus and hepatitis A virus infections occurred irrespective of PR implementation. Mean PC-mediated TTBI occurrence before PR-PC implementation was 3/year (SD: 1; n = 15; 1/92,687 PC between 2013 and 2016) with a fatal outcome in two patients. Since PR implementation, one TTBI has been reported (day 4 PC, Bacillus cereus) (1/1,645,295 PC between 2018 and 2022; p < 0.001). Two PR PC quarantined because of a negative swirling test harboured bacteria: a day 6 PC in 2021 (B. cereus and Staphylococcus epidermidis) and a day 7 PC in 2022 (Staphylococcus aureus). Five similar occurrences with untreated PC were reported between 2013 and 2020., Conclusion: Transfusion of 100% PR PC resulted in a steep reduction in TTBI occurrence. TTBI may, however, still occur. Pathogen-reduced PC-related TTI involving non-enveloped viruses occurs as well., (© 2023 International Society of Blood Transfusion.)

Abstract: Red blood cell (RBC) transfusion is a major therapy for sickle cell disease (SCD). Patients are at risk of forming antibodies to RBC antigens, which can result in the impossibility to find compatible units and can cause hemolytic transfusion reactions. This retrospective study investigates the evolution of RBC consumption and the frequencies, specificities, and chronology of the appearance of antibodies in a population of patients consistently receiving RH (C, D, E, c, e) and K-matched RBC units (RBCus) from a predominantly European donor population. Over the 11-year period in the Paris area, 6496 patients received transfusion at least once for a total of 239 944 units. Antibodies were made by 1742 patients. The first antibodies of a patient were predictive of subsequent immunization. By the 17th RBCu transfused (by the 20th, excluding warm autoantibodies), 75% of the patients who would make antibodies had made their first. By the 16th, 90% who would make antibodies to a high frequency antigen had made their first antibody to these antigens. Females made their first antibodies slightly earlier than males. Patients who received multiple transfusions (>50 units) had a higher immunization prevalence than those who rarely received transfusion (<12 units) but fewer clinically significant antibodies. Patients with SCD and prophylactic RH-K matching not immunized by the 20th RBCu are likely to have a low alloimmunization risk (to antigens other than RH-K), that is, be low responders, especially relative to the most clinically significant antibodies. This number of 20 units is a point before which close monitoring of patients is most important but remains open to future adjustment., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background and Objectives: Since the advent of AIDS, men who have sex with men (MSM) have often been deferred from blood donation. In France, quarantine plasma donation by MSM donors with the same deferral rules as for other donors was introduced in July 2016 and continued up to March 2022. At this time, MSM-specific deferral criteria were lifted for all blood or plasma donation. The donor deferral, as well as rate of infectious markers in plasma donors who would have been otherwise deferred for MSM activity, was evaluated and compared with those of the other donors during the same time period from June 2016 to March 2022., Results: A total of 8843 MSM donors made 12,250 plasma donation applications. The overall deferral rate was very high (75.2%), mainly due to the absence of apheresis capacity at the donation site. The deferral criteria for sexual risk were present in 12.1% of MSM donors compared with 1.0% in other plasma and blood donors (p < 0.001). Overall, 994 MSM donors made 2880 plasma donations. Of these, one donation was HIV positive (34.7 vs. 0.6/10 5 donations by other donors, relative risk [RR]: 61.0 [95% confidence interval [CI]: 8.5-437.7]), one was HBV positive (34.7 vs. 4.5/10 5 , RR: 7.7 [95% CI: 1.1-54.6]) and none were HCV positive (0 vs. 2.4/10 5 ). Additionally, 21 donations were syphilis positive (729.2 vs. 10.7/10 5 , RR: 67.9 [95% CI: 44.2-104.4]). A post hoc analysis of eligible MSM donors who were unable to donate plasma due to logistic constraints yielded similar findings., Conclusion: Plasma donation by donors who would have been otherwise deferred for MSM activity was associated with both an increased deferral rate for sexual risk and an increased rate of infectious markers, notably syphilis., (© 2023 International Society of Blood Transfusion.)

Background and Objectives: Implementing a ferritin testing policy for whole blood (WB) donors may prevent iron deficiency (ID, ferritin <26 ng/mL) and anaemia, but may induce donation losses. As part of a national prevention plan in France, we aimed to estimate its impact on ID, anaemias and WB donations among donors at high risk of ID., Materials and Methods: A micro-simulation model was developed to evaluate different scenarios compared to the current situation without ferritin testing as a reference scenario. The following scenarios were simulated: a minimum scenario with a 6-month deferral for donors with absent iron store (AIS, ferritinemia <15 ng/ml), a main scenario with additional delayed invitations for donors with ferritinemia 15-25 ng/ml and a supplementation scenario with additional iron supplementation for 50% of the donors with AIS., Results: In the main scenario, 52,699 WB donations per year were estimated to be lost after 1 year (-8%), falling to 27,687 (-4.7%) after 5 years. IDs and anaemias were reduced by 13.6% and 29.3%, respectively, after 1 year. The supplementation scenario increased the number of prevented IDs and anaemias to 24.1% and 35.4%, respectively, after 1 year, and halved the number of anaemias at 5 years. The latter scenario also had the least impact on the number of donations (-3.2% after 5 years)., Conclusion: A ferritin testing policy resulting in delayed donations for ID donors is effective in reducing IDs and anaemias, but significantly impacts the number of donations, thereby posing a self-sufficiency challenge., (© 2022 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Background and Objective: The SARS-CoV-2 Omicron variant displays increased infectiveness as well as mutations resulting in reduced neutralizing activity of antibodies acquired after vaccination or infection involving earlier strains. To assess the ability of vaccinated COVID-19 convalescent plasma (CCP-V) collected before November 2021 to seroneutralize Omicron, we compared neutralizing antibody (nAb) titres of 63 samples against Omicron and earlier B.1 (D614G) strains., Methods and Findings: Relationship between anti-Omicron titres and IgG anti-S1 levels (binding arbitrary unit: BAU/ml) was studied. Although correlated, anti-Omicron titres were significantly lower than anti-B.1 titres (median = 80 [10-1280] vs. 1280 [160-10,240], p < 0.0001). Omicron nAb titres and IgG anti-S1 levels were correlated (Spearman's rank correlation coefficient = 0.67). Anti-S1 IgG threshold at 7000 BAU/ml may allow to discard CCP-V without anti-Omicron activity (nAb titre <40). Conversely, only those with highest titres (≥160) had systematically anti-S1 IgG levels >7000 BAU/ml., Conclusion: A fraction of CCP-V collected before November 2021 retains anti-Omicron seroneutralizing activity that may be selected by quantitative anti-IgG assays, but such assays do not easily allow the identification of 'high-titre' CCP-V. However, collecting plasma from vaccinated donors recently infected with Omicron may be the best option to provide optimal CCP-V for immunocompromised patients infected with this variant., (© 2022 International Society of Blood Transfusion.)

Quantitation of anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) neutralizing antibodies (Nabs) is a key parameter in determining the effective dose for treatment with COVID-19 convalescent plasma (CCP). Interpretation of results from clinical trials conducted worldwide requires comparison of Nabs titres obtained from different methods. As virus neutralization tests (VNTs) are not standardized scalable or commercially available, strategies based on intensity of ELISA (Enzyme Linked Immunosorbent Assay) or chemiluminescent binding serological tests were implemented to allow comparisons and establish criteria for determining 'high-titres' of anti-SARS-CoV-2 antibodies (Abs). To this end, the FDA (Food and Drug Administration) has proposed criteria to define high-titre plasmas using different serological assays, including the one used in France for the CCP SARS-CoV-2 Abs screening (Euroimmun anti-S1 IgG). A retrospective study revealed that when using the FDA criteria (ELISA signal-to-cut-off [S/C ratio] ≥3.5), 91% of CCP had Nabs titres ≥40 as assessed with an in-house VNT. French strategy to ensure sufficient stocks of CCP of increasing titre has evolved over time. Recently, we improved our strategy by collecting only plasma from vaccinated convalescent donors as we confirmed that the mean IgG antibody level (ELISA S/C ratio) was significantly higher in plasma from vaccinated convalescent donors compared to donations from unvaccinated convalescent donors: 9.31 (CI 95%: 8.46-10.16) versus 3.22 (CI 95%: 3.05-3.39) (p < 0.001)., (© 2021 International Society of Blood Transfusion.)

Protists are abundant and play key trophic functions in soil. Documenting how their trophic contributions vary across large environmental gradients is essential to understand and predict how biogeochemical cycles will be impacted by global changes. Here, using amplicon sequencing of environmental DNA in open habitat soil from 161 locations spanning 2600 m of elevation in the Swiss Alps (from 400 to 3000 m), we found that, over the whole study area, soils are dominated by consumers, followed by parasites and phototrophs. In contrast, the proportion of these groups in local communities shows large variations in relation to elevation. While there is, on average, three times more consumers than parasites at low elevation (400-1000 m), this ratio increases to 12 at high elevation (2000-3000 m). This suggests that the decrease in protist host biomass and diversity toward mountains tops impact protist functional composition. Furthermore, the taxonomic composition of protists that infect animals was related to elevation while that of protists that infect plants or of protist consumers was related to soil pH. This study provides a first step to document and understand how soil protist functions vary along the elevational gradient., (© 2021 The Authors. Environmental Microbiology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Soil bacteria are largely missing from future biodiversity assessments hindering comprehensive forecasts of ecosystem changes. Soil bacterial communities are expected to be more strongly driven by pH and less by other edaphic and climatic factors. Thus, alkalinisation or acidification along with climate change may influence soil bacteria, with subsequent influences for example on nutrient cycling and vegetation. Future forecasts of soil bacteria are therefore needed. We applied species distribution modelling (SDM) to quantify the roles of environmental factors in governing spatial abundance distribution of soil bacterial OTUs and to predict how future changes in these factors may change bacterial communities in a temperate mountain area. Models indicated that factors related to soil (especially pH), climate and/or topography explain and predict part of the abundance distribution of most OTUs. This supports the expectations that microorganisms have specific environmental requirements (i.e., niches/envelopes) and that they should accordingly respond to environmental changes. Our predictions indicate a stronger role of pH over other predictors (e.g. climate) in governing distributions of bacteria, yet the predicted future changes in bacteria communities are smaller than their current variation across space. The extent of bacterial community change predictions varies as a function of elevation, but in general, deviations from neutral soil pH are expected to decrease abundances and diversity of bacteria. Our findings highlight the need to account for edaphic changes, along with climate changes, in future forecasts of soil bacteria., (© 2021. The Author(s).)

Extreme environmental conditions, such as temperature, can lead to meristic trait variation and skeletal deformities, which may have major impacts on individual fitness. As intertidal ecosystems experience rapid temperature and physicochemical fluctuations, intertidal fish living and reproducing in these environmental conditions may have phenotypes influenced by such variable environments. The impact of intertidal variability on fish development, however, has not been previously investigated. Skeletal deformities and meristic traits were assessed for Bathygobius cocosensis, a common intertidal fish living across the Indo-Pacific region, using a clearing and staining method on 72 individuals. Over 87% of individuals presented meristic variation and over 70% exhibited at least one type of skeletal deformity, mostly recorded in the caudal fin area. The unexpected prevalence of skeletal deformities among this intertidal fish population suggests that such deformities may be suitable markers to evaluate an individual's stress exposure during development and the subsequent fitness effects., (© 2021 John Wiley & Sons Ltd.)

Background: Plasma cystatin C is a potential marker of the glomerular filtration rate (GFR), and urinary cystatin C has been proposed as a marker of tubular dysfunction., Procedure: A prospective study (NCT02822404) was conducted to assess the benefit of considering cystatin C plasma and urinary levels to better evaluate cisplatin and/or ifosfamide renal toxicity in children with cancer. Plasma 51 Cr-EDTA clearance as a marker of GFR and urinary markers of tubular toxicity were monitored in 40 children treated by cisplatin and/or ifosfamide. Several equations previously proposed to estimate GFR, with or without inclusion of plasma cystatin C level, were compared. A population pharmacokinetic approach was also used to analyze plasma 51 Cr-EDTA data, and evaluate the relationship between patient covariates (including plasma cystatin C level) and GFR during the course of chemotherapy treatment., Results: Equations including plasma cystatin C described GFR changes during chemotherapy better than those without this variable. An equation based on plasma cystatin C, serum creatinine, and body weight enabled us to accurately describe the evolution of GFR during chemotherapy. The urinary cystatin C/creatinine ratio was compared between children with or without tubular toxicity, according to a standard assessment of tubular dysfunction. However, although the urinary cystatin C/creatinine ratio was increased in children with tubular toxicity, this marker does not provide additional information to the well-known markers of tubulopathy., Conclusions: Monitoring of plasma cystatin C may be substituted to radionucleide glomerular exploration in children treated by cisplatin and/or ifosfamide., (© 2020 Wiley Periodicals LLC.)

Background: The objectives of this study are to estimate the prevalence of iron deficiency (ID) among French whole-blood (WB) donors to identify factors associated with ID and to generate decision trees., Study Design and Methods: A prospective National multicentre study was performed on WB donors from March 11, to April 5th, 2019. Samples were selected randomly to perform serum ferritin. ID was defined as ferritin value under 26 ng/ml. All results were stratified by sex. Factors associated with ID were analysed using multivariate logistic regression model. CART algorithm was used for decision trees., Results: Eleven thousand two hundred fifty eight WB donors were included. ID was more frequent in women (39·5%) than in men (18·0%). Among 7200 repeated donors, women below 50 yo had a higher risk (OR = 2·37; [1·97-2·85] IC95) than those above 50 yo. Factors associated with ID were: haemoglobin level under the threshold at donation n-1 except for women and n-2 donation; a low mean corpuscular haemoglobin at n-1 and n-2 donations; a shorter interval since n-1 donation and between n-1 and n-2 donations except for women; and women who had given three or four times in the last year. CART algorithm defined high risk of ID subgroups within three populations of donors, new female donors, repeated male donors and repeated female donors. In these identified subgroups, prevalence of ID was up to 72·1%., Conclusions: Our study showed the high prevalence of ID among French WB donors, identified well-known and new factors associated with ID and defined algorithms predicting ID in three populations., (© 2020 International Society of Blood Transfusion.)

Background: Among labile blood products, platelet concentrates (PCs) are the leading cause of hypersensitivity transfusion reactions (HTRs). These reactions often lead to interruption of PC transfusion and can result in a prolonged transfusion process leading to significant morbidity and use of premedication and close monitoring for patients with a history of allergic transfusion reactions. The French hemovigilance database is one of the largest standardized databases providing information on HTRs following administration of labile blood products. In this study, we analyzed this database to assess the relative risk of HTR for each type of PC., Study Design and Methods: HTRs following PC transfusion were retrospectively extracted from the e-Fit Hemovigilance database of the French National Agency for Medicines and Health Products Safety (ANSM). Frequencies were calculated using the number of specific PCs transfused., Results: Between 2008 and 2014, the overall estimated incidence of HTRs following PC administration was calculated at 232 HTRs per 100,000 PCs transfused. The rate of HTRs was significantly higher with apheresis PC (337/100,000) than with buffy-coat PC (94/100,000). Platelets in additive solutions (PAS) were associated with a significantly lower frequency of HTRs when compared with PCs in native plasma. Amotosalen/UVA- PCs (APCs and BCPCs) which are always in PAS in France, exhibited the lowest frequency of HTRs when compared with their corresponding PCs in native plasma or in PAS (p < 10 -7 in all comparisons)., Conclusion: Our results showed that the type of PC and its processing may have an impact on the risk of HTR., (© 2019 AABB.)

Background: Recent reports have indicated that the risk of anti-D alloimmunization following D-incompatible platelet (PLT) transfusion is low in hematology and oncology patients. We investigated the rate of anti-D alloimmunization in RhD-negative (D - ) patients with chronic liver disease transfused with D + platelet concentrates (PCs) and the factors involved, at a liver transplant (LT) center., Study Design and Methods: We reviewed the blood bank database from January 2003 to October 2016. D - patients who had received D + PLT transfusions were eligible if they had undergone antibody screening at least 28 days after the first D + PC transfusion, had no previous or concomitant exposure to D + blood products, and had not received anti-D immunoglobulins., Results: Six of the 56 eligible patients (10.7%) had anti-D antibodies. All had received whole blood-derived PCs. Four of 20 patients (20%) untransplanted or transfused before LT and only two of 36 patients (5.6%) transfused during or after LT produced anti-D antibodies. These two patients were on maintenance immunosuppression based on low-dose steroids and tacrolimus. The factors identified as significantly associated with anti-D immune response were the presence of red blood cell immune alloantibodies before D + PLT transfusion (p = 0.003), and D + PLT transfusion outside the operative and postoperative (5 days) periods for LT (p = 0.023)., Conclusion: D - patients with chronic liver disease transfused with D + PLTs before LT are at high risk of developing anti-D antibodies. Preventive measures should be considered for these patients., (© 2019 AABB.)

Purpose: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling interpatient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative. Experimental Design: Eighty-nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/mL over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients, and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction. Results: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentiles, respectively). The new covariate equation [CL (mL/min) = 130.7 × (Scr/83) -0.826 × (BW/76) +0.907 × (Age/36) -0.223 with Scr in μmol/L, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared with other equations. Conclusions: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young male patients, could be used if TDM cannot be implemented. Clin Cancer Res; 23(23); 7171-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: The 2008 economic crisis may have had an impact on mental health but the studies on this topic are sparse, in particular among the working population. However, mental health at work is a crucial issue involving substantial costs and consequences. The aim of the study was to assess changes in behaviors and indicators of mental health in the French working population between 2006 and 2010, and to explore the differential changes according to age, origin, occupation, activity sector, public/private sector, self-employed/employee status and work contract., Methods: The data came from the prospective national representative Santé et itinéraire professionnel (SIP) survey, including a sample of 5600 French workers interviewed in 2006 and 2010. The behaviors and indicators of mental health studied were excessive alcohol consumption, smoking, sleep problems (sleep disorders and/or insufficient sleep duration), psychotropic drug use (antidepressants, anxiolytics and/or hypnotics), and poor self-reported health. Generalized estimating equations were used to analyze changes in behaviors and indicators of mental health, and the analyses were adjusted for age. Covariates (age, origin, occupation, activity sector, public/private sector, self-employed/employee status and type of contract) were added separately to assess differential changes., Results: Increases in excessive alcohol consumption among women, sleep problems among men, and smoking, insufficient sleep duration and poor self-reported health for both genders were observed in the French working population between 2006 and 2010. Some differential changes were observed, negative changes being more likely to affect young workers and workers with a permanent contract., Conclusion: Prevention policies should consider that behavior and indicators of mental health may deteriorate in times of economic crisis, especially among some sub-groups of the working population, such as young workers and workers with a permanent contract. These changes might foreshadow a forthcoming increase in mental disorders., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: This study aimed at assessing the changes in mental disorders in the French working population between 2006 and 2010, using nationally representative prospective data and a structured diagnostic interview for major depressive episode (MDE) and generalized anxiety disorder (GAD), and also at exploring the differential changes in mental disorders according to age, origin, occupation, public/private sector, self-employed/employee status and work contract., Methods: The data came from the prospective national representative Santé et Itinéraire Professionnel (SIP) survey, including a sample of 5600 French workers interviewed in 2006 and 2010. The Mini International Neuropsychiatric Interview (MINI) was used to measure MDE and GAD. Analyses were performed using weighted generalized estimation equations, and were stratified by gender., Results: No changes in MDE and GAD were observed for both genders among the working population. No differential changes were observed, except one: the prevalence of GAD increased among women working in the public sector while there was no change among women in the private sector., Limitations: Two data collections over a 4-year period may not capture the effects of the crisis on mental disorders properly., Conclusion: No changes in mental disorders between 2006 and 2010 were found but the increase in the prevalence of anxiety among women in the public sector may be of particular interest for prevention policies. High levels of social protection in France might contribute to explain these non-significant results., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: The literature has been extensive on the associations between psychosocial work factors and mental health. Nevertheless, the studies using prospective design, various concepts and more than one measurement point in time for these factors and diagnostic interview to assess mental disorders remain seldom in the literature. This study is an attempt to fill the gap in this topic., Methods: The study was based on a national representative sample of 4717 workers of the French working population (SIP survey), interviewed in 2006 and reinterviewed again in 2010 and free of mental disorders at baseline. Psychosocial work factors, measured in both 2006 and 2010, included: psychological demands, decision latitude, social support, reward, emotional demands, role conflict, ethical conflict, tensions with the public, job insecurity and work-life imbalance. Other occupational factors related to working time/hours and physical work environment were also studied. Major depressive (MDD) and generalized anxiety disorders (GAD) were measured using a standardised diagnostic interview (MINI). Covariates were age, occupation, marital status, having a child under 3 y, social support outside work and stressful life events. Multivariate analyses were performed using weighted logistic regression models., Results: Using models taking all occupational factors into account simultaneously, low reward and job insecurity predicted MDD. Psychological demands, low reward, emotional demands and job insecurity were predictive of GAD. The more frequent the exposure to job insecurity, the higher the risk of MDD and GAD, and the more frequent the exposure to psychological demands and low reward, the higher the risk of GAD. No effect was observed for repeated exposure to occupational factors., Conclusions: Classical and emergent psychosocial work factors were predictive factors of depression and anxiety with dose-response associations in terms of frequency of exposure. More attention may be needed on emergent psychosocial work factors and frequent exposure to these factors.

Purpose: The aim of the study was to assess the changes in psychosocial work factors in the French working population between 2006 and 2010 and to examine potential differential changes according to age, occupation, public/private sector, work contract and self-employed/employee status., Methods: The study sample included 5,600 workers followed up from 2006 to 2010 from the national representative Santé et Itinéraire Professionnel (SIP) survey. Psychosocial work factors included decision latitude, psychological demands, social support, reward, overcommitment, long working hours, predictability, night- and shift work, emotional demands, role conflict, ethical conflict, tensions with the public, job insecurity and work-life imbalance, and were measured using scores. Linear regressions were used to analyse the change in the scores of these factors adjusted for age and initial score. All analyses were stratified by gender., Results: Psychosocial work factors worsened between 2006 and 2010: decision latitude, social support, reward, role conflict and work-life imbalance for both genders, and psychological demands, emotional demands, ethical conflict and tensions with the public for women. Differential changes according to age, occupation, public/private sector, work contract and self-employed/employee status were observed suggesting that some groups may be more likely to be exposed to negative changes especially the younger, low- and high-skilled and public sector workers., Conclusion: Monitoring exposure to psychosocial work factors over time may be crucial, and prevention policies should take into account that deterioration of psychosocial work factors may be sharper among subgroups such as younger, low- and high-skilled and public sector workers.

Purpose: The aim of this study was to explore the associations between psychosocial working conditions and psychological well-being among employees in 34 European countries. Another objective was to examine whether these associations varied according to occupation and country., Methods: The study was based on data from the European Working Conditions Survey 2010 including 33,443 employees, 16,512 men and 16,931 women, from 34 European countries. Well-being was measured by the WHO-5 well-being index. Twenty-five psychosocial work factors were constructed including job demands, role stressors, work hours, job influence and freedom, job promotion, job insecurity, social support, quality of leadership, discrimination and violence at work, and work-life imbalance. The associations between these factors and well-being were examined using multilevel logistic regression analyses. Different models were performed including interaction tests., Results: When all 25 psychosocial work factors were studied simultaneously in the same model with adjustment variables, 13 showed a significant association with poor well-being among both genders: quantitative demands, demands for hiding emotions, low possibilities for development, low meaning of work, low role conflict, low quality of leadership, low social support, low sense of community, job insecurity, low job promotion, work-life imbalance, discrimination, and bullying. The association with low sense of community on poor well-being was particularly strong., Conclusions: A large number of psychosocial work factors were associated with poor well-being. Almost no country and occupational differences were found in these associations. This study gave a first European overview and could be useful to inform cross-national policy debate.

AMP-activated protein kinase (AMPK) is an evolutionarily conserved master regulator of metabolism and a therapeutic target in type 2 diabetes. As an energy sensor, AMPK activity is responsive to both metabolic inputs, for instance the ratio of AMP to ATP, and numerous hormonal cues. As in mammals, each of two genes, aak-1 and aak-2, encode for the catalytic subunit of AMPK in C. elegans. Here we show that in C. elegans loss of aak-2 mimics the effects of elevated serotonin signaling on fat reduction, slowed movement, and promoting exit from dauer arrest. Reconstitution of aak-2 in only the nervous system restored wild type fat levels and movement rate to aak-2 mutants and reconstitution in only the ASI neurons was sufficient to significantly restore dauer maintenance to the mutant animals. As in elevated serotonin signaling, inactivation of AAK-2 in the ASI neurons caused enhanced secretion of dense core vesicles from these neurons. The ASI neurons are the site of production of the DAF-7 TGF-β ligand and the DAF-28 insulin, both of which are secreted by dense core vesicles and play critical roles in whether animals stay in dauer or undergo reproductive development. These findings show that elevated levels of serotonin promote enhanced secretions of systemic regulators of pro-growth and differentiation pathways through inactivation of AAK-2. As such, AMPK is not only a recipient of hormonal signals but can also be an upstream regulator. Our data suggest that some of the physiological phenotypes previously attributed to peripheral AAK-2 activity on metabolic targets may instead be due to the role of this kinase in neural serotonin signaling.

The regulation of energy balance involves an intricate interplay between neural mechanisms that respond to internal and external cues of energy demand and food availability. Compelling data have implicated the neurotransmitter dopamine as an important part of body weight regulation. However, the precise mechanisms through which dopamine regulates energy homeostasis remain poorly understood. Here, we investigate mechanisms through which dopamine modulates energy storage. We showed that dopamine signaling regulates fat reservoirs in Caenorhabditis elegans. We found that the fat reducing effects of dopamine were dependent on dopaminergic receptors and a set of fat oxidation enzymes. Our findings reveal an ancient role for dopaminergic regulation of fat and suggest that dopamine signaling elicits this outcome through cascades that ultimately mobilize peripheral fat depots.

Background: The Angiotensin-Converting Enzyme-2 (ACE2) gene, located on chromosome X, is believed to be implicated in blood pressure regulation. However the few studies that have examined this association have yielded mixed results. The objective of this study was to assess the association between tag single nucleotide polymorphisms (SNPs) in the angiotensin-converting enzyme-2 gene with blood pressure and blood pressure change in adolescents., Methods: Participants in the Nicotine Dependence in Teens (NDIT) cohort study with blood or saliva samples and at least 3 blood pressure measurements over 5 years were included in the analytic sample (n = 555). Linear growth curve models stratified on sex and ethnicity were used to assess the association between four tag SNPs in the ACE2 gene and systolic (SBP) and diastolic blood pressure (DBP), and blood pressure change., Results: In males of European descent, rs2074192 and rs233575 were significantly associated with SBP and DBP, and rs2158083 was associated with SBP. In French Canadian males, rs233575 and rs2158083 were significantly associated with DBP. Among females of European descent, rs2074192, rs233575, and rs2158083 were significantly associated with change in SBP over 5 years., Conclusions: This is the first study to assess the association between the ACE2 gene with blood pressure and blood pressure change in a cohort of adolescents. Results indicate that several ACE2 gene SNPs are associated with blood pressure or blood pressure change in persons of European descent. However the therapeutic potential of these SNPs should be explored.

We report real-time observation of the interlayer shearing mode, corresponding to the lateral oscillation of graphene planes, for bi- and few-layer graphene. Using a femtosecond pump-probe technique, we have followed coherent oscillations of this vibrational mode directly in the time domain. The shearing-mode frequency, as expected for an interlayer mode, exhibits a strong and systematic dependence on the number of layers, varying from 1.32 THz for the bulk limit to 0.85 THz for bilayer graphene. We explored the role of interactions with the external environment on this vibrational mode by comparing the response observed for graphene layers supported by different substrates and suspended in free space. No significant frequency shifts were observed.

Objective: The aim was to assess the changes in psychosocial work factors among European employees between 2005 and 2010., Methods: The study samples came from the European Working Conditions Survey, involving 23,580 and 32,516 employees in 2005 and 2010, respectively, from 30 European countries. The psychosocial work factors studied were based on job strain and effort-reward imbalance models, and more recent factors. Multilevel linear and logistic regression models were used. Differences according to occupations and countries were tested., Results: Results were mixed with improvement for some factors and decline for other factors. Some countries and occupations were more likely to be affected by negative changes, especially low-skilled employees., Conclusion: Prevention policies at the workplace should take into account that the degradation of some psychosocial work factors may be sharper for some countries and occupations.

Purpose: The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both imatinib and its main active metabolite (N-desmethyl-imatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations., Patients and Methods: The quantification of unbound fraction of imatinib and N-desmethyl-imatinib was performed using plasma ultrafiltration coupled with LC-MS/MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients., Results: The mean unbound fractions of imatinib and N-desmethyl-imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for imatinib and 34 % for N-desmethyl-imatinib. No correlation was observed between these measured individual imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-imatinib/imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with inter-individual variabilities of 71 and 86 %, respectively., Conclusion: The large inter-individual variability for the unbound fraction of both imatinib and N-desmethyl-imatinib warrants further evaluation of the pharmacokinetic-pharmacodynamic relationship as a potential relevant marker of imatinib therapeutic outcomes.

Unlabelled: A clinical study was conducted to determine the safety and efficacy of neoadjuvant erlotinib treatment in patients with head and neck squamous cell carcinoma [Thomas F, Rochaix P, Benlyazid A, et al. Pilot study of neoadjuvant treatment with erlotinib in non-metastatic head and neck squamous cell carcinoma. Clin Cancer Res 2007;13:7086-92]. The aim of the present analysis was to explore the impact of several covariates on the pharmacokinetics of erlotinib and its main metabolite (OSI-420) and to determine PK/PD relationships., Patients and Methods: Plasma concentrations of erlotinib and OSI-420 of 42 patients were analysed using the NONMEM program to evaluate the impact of patients' covariates on erlotinib pharmacokinetics. The presence of single nucleotide polymorphisms (SNP) in ABCB1 (2677G>T/A and 3435C>T), ABCG2 (421C>A) and CYP3A5 (6986G>A) was investigated. Pharmacokinetic/pharmacodynamic relationships between plasma drug exposure (AUC) and early drug response or toxicity were also studied., Results: The covariates retained to predict erlotinib clearance were ALAT (alanine amino transferase), age and ABCG2 polymorphism. A significant link between drug exposure and the grade of skin rash was observed but early response to treatment was not correlated to the erlotinib AUC., Conclusions: Erlotinib treatment may present criteria justifying dose individualisation but further studies, including more patients, are necessary to define the modalities of this adaptation.

A receiver operating curve analysis was performed to assess the predictive value of the urinary cystatin C to urinary creatinine ratio for the renal monitoring of tenofovir. Urinary cystatin C to urinary creatinine ratio was measured in 37 samples from patients referred for suspected tenofovir-induced Fanconi syndrome. The best threshold (14 microg/mmol) was associated with sensitivity, 90.9%; specificity, 88.5%; positive predictive value, 76.9%; and negative predictive value, 95.8%. Urinary cystatin C to urinary creatinine ratio allows to rule out a Fanconi syndrome in most cases; thus, it should be used for the safety follow-up of nucleotide reverse transcriptase inhibitor-treated patients.

Cystatin C is a protein freely filtered in the renal glomerulus, then reabsorbed and completely metabolised within the tubular cells. The possibility to predict the clearance of compounds eliminated by the kidneys (and then to control their interindividual variability) was evaluated for two cytotoxic drugs (carboplatin and topotecan) in adults and EDTA (ethylene diamine tetraacetic acid), a compound used to determine the glomerular filtration rate in children. The population pharmacokinetic approach based on NONMEM program was used. For each of the three compounds, the cystatin C serum level was better predictive of clearance than that of creatinine. Moreover, for carboplatin and EDTA, the best equation between clearance and patients' characteristics included both cystatin C and creatinine level. A generalisation of cystatin C assay would contribute to standardise the clinical practices in Oncology.

Background: Serum creatinine (SCr) and Cockcroft-Gault creatinine clearance (CG CrCL) are used to estimate glomerular filtration rate (GFR). Other markers have been proposed including serum cystatin C (cysC) and the Modification of Diet in Renal Disease (MDRD) study equation., Patients and Methods: We have compared the diagnostic performances of SCr, cysC, CG CrCL, and the MDRD equation in 144 cancer patients. For reference we used either the measured or the predicted carboplatin clearance, which is around the GFR + 25 mL/min., Results: CysC was more sensitive than SCr (70.1% vs 13.4%) but was not very specific (61% for a cut-off = 0.95 mL). CysC values were higher in 40 cancer patients vs 40 healthy controls with a similar and normal mean CG CrCL (1.08 vs 0.71 mg/L; p < 0.001). CG and the MDRD equations gave similar values for Pearson's coefficient, ROC-plot AUC, and precision, except for patients with poor general status, where the MDRD equation was better (MAPE: 12.4% vs 19.6%, p < 0.001; R: 0.908 vs 0.813)., Conclusions: In cancer patients, cysC is a more sensitive indicator of the glomerular filtration rate than SCr, but its diagnostic performance is lower than for CG CrCL. There may be no advantage in replacing the CG equation by the MDRD equation except for patients with severe malnutrition and/or inflammation.

Purpose: To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics. Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance., Experimental Design: Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients)., Results: Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06](-0.60) [IBW (kg) / 57](0.95). Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area., Conclusion: Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.