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The authors examined associations between exposure to aluminum or silica from drinking water and risk of cognitive decline, dementia, and Alzheimer's disease among elderly subjects followed for 15 years (1988-2003). They actively searched for incident cases of dementia among persons aged 65 years or over living in 91 civil drinking-water areas in southern France. Two measures of exposure to aluminum were assessed: geographic exposure and individual exposure, taking into account daily consumption of tap water and bottled water. A total of 1,925 subjects who were free of dementia at baseline and had reliable water assessment data were analyzed. Using random-effects models, the authors found that cognitive decline with time was greater in subjects with a higher daily intake of aluminum from drinking water (>or=0.1 mg/day, P=0.005) or higher geographic exposure to aluminum. Using a Cox model, a high daily intake of aluminum was significantly associated with increased risk of dementia. Conversely, an increase of 10 mg/day in silica intake was associated with a reduced risk of dementia (adjusted relative risk =0.89, P=0.036). However, geographic exposure to aluminum or silica from tap water was not associated with dementia. High consumption of aluminum from drinking water may be a risk factor for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

2-Aminoethanethiol dioxygenase (ADO) is a thiol dioxygenase that sulfinylates cysteamine and amino-terminal cysteines in polypeptides. The pathophysiological roles of ADO remain largely unknown. Here, we demonstrate that ADO expression represents a vulnerability in cancer cells, as ADO depletion led to loss of proliferative capacity and survival in cancer cells and reduced xenograft growth. In contrast, generation of the ADO knockout mouse revealed high tolerance for ADO depletion in adult tissues. To understand the mechanism underlying ADO's essentiality in cancer cells, we characterized the cell proteome and metabolome following depletion of ADO. This revealed that ADO depletion leads to toxic levels of polyamines which can be driven by ADO's substrate cysteamine. Polyamine accumulation in turn stimulated expression of proline dehydrogenase (PRODH) which resulted in mitochondrial hyperactivity and ROS production, culminating in cell toxicity. This work identifies ADO as a unique vulnerability in cancer cells, due to its essential role in maintenance of redox homeostasis through restraining polyamine levels and proline catabolism.

Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease-initiating leukemia stem cells (LSC). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSC. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSC. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSC but is not essential for normal human hematopoietic stem and progenitor cell function. In order to elucidate the molecular mechanisms by which SIRT3 is essential in LSC we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support OXPHOS and ATP production in human LSC. Further, we discovered two approaches to further sensitize LSC to SIRT3 inhibition. First, we found that LSC tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSC to YC8-02 and potentiates LSC death. Second, SIRT3 inhibition sensitizes LSC to the BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.

WHIM Syndrome is a rare immunodeficiency caused by gain-of-function CXCR4 mutations. Here we report a decrease in bone mineral density in 25% of WHIM patients and bone defects leading to osteoporosis in a WHIM mouse model. Imbalanced bone tissue is observed in mutant mice combining reduced osteoprogenitor cells and increased osteoclast numbers. Mechanistically, impaired CXCR4 desensitization disrupts cell cycle progression and osteogenic commitment of skeletal stromal/stem cells, while increasing their pro-osteoclastogenic capacities. Impaired osteogenic differentiation is evidenced in primary bone marrow stromal cells from WHIM patients. In mice, chronic treatment with the CXCR4 antagonist AMD3100 normalizes in vitro osteogenic fate of mutant skeletal stromal/stem cells and reverses in vivo the loss of skeletal cells, demonstrating that proper CXCR4 desensitization is required for the osteogenic specification of skeletal stromal/stem cells. Our study provides mechanistic insights into how CXCR4 signaling regulates the osteogenic fate of skeletal cells and the balance between bone formation and resorption., (© 2023. The Author(s).)

In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or until death. A MCT contains several PDXs in which several mice are randomized to different treatment arms. Our aim was to compare longitudinal modeling of tumor growth using mixed and joint models. Mixed and joint models were compared in a real MCT ( N = 225 mice) to estimate the effect of a chemotherapy and a simulation study. Mixed models assume that death is predictable by observed tumor volumes (data missing at random, MAR) while the joint models assume that death depends on nonobserved tumor volumes (data missing not at random, MNAR). In the real dataset, of 103 deaths, 97 mice were sacrificed when reaching a predetermined tumor size (MAR data). Joint and mixed model estimates of tumor growth slopes differed significantly [0.24 (0.13;0.36)log(mm 3 )/week for mixed model vs. -0.02 [-0.16;0.11] for joint model]. By disrupting the MAR process of mice deaths (inducing MNAR process), the estimate of the joint model was 0.24 [0.04;0.45], close to mixed model estimation for the original dataset. The simulation results confirmed the bias in the slope estimate from the joint model. Using a MCT example, we show that joint model can provide biased estimates under MAR mechanisms of dropout. We thus recommend to carefully choose the statistical model according to nature of mice deaths., Significance: This work brings new arguments to a controversy on the correct choice of statistical modeling methods for the analysis of MCTs. We conclude that mixed models are more robust than joint models., Competing Interests: H. Savel reports other from Ipsen during the conduct of the study; other from Ipsen outside the submitted work. F. Meyer-Losic reports other from Ipsen during the conduct of the study. L. Richert reports grants from Ipsen during the conduct of the study. No disclosures were reported by the other authors., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Objective: To evaluate the effect of air pollution, from oocyte retrieval to embryo transfer, on the results of in vitro fertilisation (IVF) in terms of clinical pregnancy rates, at two fertility centres, from 2013 to 2019., Design: Exploratory retrospective cohort study., Setting: This retrospective cohort study was performed in the Reproductive Biology Department of Bordeaux University Hospital localised in Bordeaux, France and the Jean Villar Fertility Center localised in Bruges, France., Participants: This study included 10 763 IVF attempts occurring between January 2013 and December 2019, 2194 of which resulted in a clinical pregnancy., Primary and Secondary Outcome Measures: The outcome of the IVF attempt was recorded as the presence or absence of a clinical pregnancy; exposure to air pollution was assessed by calculating the cumulative exposure of suspended particulate matter, fine particulate matter, black carbon, nitrogen dioxide and ozone (O 3) , over the period from oocyte retrieval to embryo transfer, together with secondary exposure due to the presence of the biomass boiler room, which was installed in 2016, close to the Bordeaux University Hospital laboratory. The association between air pollution and IVF outcome was evaluated by a random-effects logistic regression analysis., Results: We found negative associations between cumulative O 3 exposure and clinical pregnancy rate (OR=0.92, 95% CI = (0.86 to 0.98)), and between biomass boiler room exposure and clinical pregnancy rate (OR=0.75, 95% CI = (0.61 to 0.91)), after adjustment for potential confounders., Conclusion: Air pollution could have a negative effect on assisted reproductive technology results and therefore precautions should be taken to minimise the impact of outdoor air on embryo culture., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Joint models for a longitudinal biomarker and a terminal event have gained interests for evaluating cancer clinical trials because the tumor evolution reflects directly the state of the disease. A biomarker characterizing the tumor size evolution over time can be highly informative for assessing treatment options and could be taken into account in addition to the survival time. The biomarker often has a semicontinuous distribution, i.e., it is zero inflated and right skewed. An appropriate model is needed for the longitudinal biomarker as well as an association structure with the survival outcome. In this article, we propose a joint model for a longitudinal semicontinuous biomarker and a survival time. The semicontinuous nature of the longitudinal biomarker is specified by a two-part model, which splits its distribution into a binary outcome (first part) represented by the positive versus zero values and a continuous outcome (second part) with the positive values only. Survival times are modeled with a proportional hazards model for which we propose three association structures with the biomarker. Our simulation studies show some bias can arise in the parameter estimates when the semicontinuous nature of the biomarker is ignored, assuming the true model is a two-part model. An application to advanced metastatic colorectal cancer data from the GERCOR study is performed where our two-part model is compared to one-part joint models. Our results show that treatment arm B (FOLFOX6/FOLFIRI) is associated to higher SLD values over time and its positive association with the terminal event leads to an increased risk of death compared to treatment arm A (FOLFIRI/FOLFOX6)., (© The Author 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

MEK1 and MEK2, the only known activators of ERK, are attractive therapeutic candidates for both cancer and autoimmune diseases. However, how MEK signaling finely regulates immune cell activation is only partially understood. To address this question, we specifically delete Mek1 in hematopoietic cells in the Mek2 null background. Characterization of an allelic series of Mek mutants reveals the presence of distinct degrees of spontaneous B cell activation, which are inversely proportional to the levels of MEK proteins and ERK activation. While Mek1 and Mek2 null mutants have a normal lifespan, 1Mek1 and 1Mek2 mutants retaining only one functional Mek1 or Mek2 allele in hematopoietic cell lineages die from glomerulonephritis and lymphoproliferative disorders, respectively. This establishes that the fine-tuning of the ERK/MAPK pathway is critical to regulate B and T cell activation and function and that each MEK isoform plays distinct roles during lymphocyte activation and disease development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Several studies have established the crucial role of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway in hematopoietic cell proliferation and differentiation. MEK1 and MEK2 phosphorylate and activate ERK1 and ERK2. However, whether MEK1 and MEK2 differentially regulate these processes is unknown. To define the function of Mek genes in the activation of the ERK pathway during hematopoiesis, we generated a mutant mouse line carrying a hematopoietic-specific deletion of the Mek1 gene function in a Mek2 null background. Inactivation of both Mek1 and Mek2 genes resulted in death shortly after birth with a severe anemia revealing the essential role of the ERK pathway in erythropoiesis. Mek1 and Mek2 functional ablation also affected lymphopoiesis and myelopoiesis. In contrast, mice that retained one functional Mek1 (1 Mek1 ) or Mek2 (1 Mek2 ) allele in hematopoietic cells were viable and fertile. 1 Mek1 and 1 Mek2 mutants showed mild signs of anemia and splenomegaly, but the half-life of their red blood cells and the response to erythropoietic stress were not altered, suggesting a certain level of Mek redundancy for sustaining functional erythropoiesis. However, subtle differences in multipotent progenitor distribution in the bone marrow were observed in 1 Mek1 mice, suggesting that the two Mek genes might differentially regulate early hematopoiesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Beuret, Fortier-Beaulieu, Rondeau, Roy, Houde, Balabanian, Espéli and Charron.)

The extrafollicular immune response is essential to generate a rapid but transient wave of protective antibodies during infection. Despite its importance, the molecular mechanisms controlling this first response are poorly understood. Here, we demonstrate that enhanced Cxcr4 signaling caused by defective receptor desensitization leads to exacerbated extrafollicular B-cell response. Using a mouse model bearing a gain-of-function mutation of Cxcr4 described in 2 human hematologic disorders, warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and Waldenström macroglobulinemia, we demonstrated that mutant B cells exhibited enhanced mechanistic target of rapamycin signaling, cycled more, and differentiated more potently into plasma cells than wild-type B cells after Toll-like receptor (TLR) stimulation. Moreover, Cxcr4 gain of function promoted enhanced homing and persistence of immature plasma cells in the bone marrow, a phenomenon recapitulated in WHIM syndrome patient samples. This translated in increased and more sustained production of antibodies after T-independent immunization in Cxcr4 mutant mice. Thus, our results establish that fine-tuning of Cxcr4 signaling is essential to limit the strength and length of the extrafollicular immune response.

Background: Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned., Methods: The association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model - allowing for the simultaneous analysis of multiple types of correlated events - to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data., Results: A statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that - with such an association - models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10-15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms., Conclusions: We have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.

Background and Objective: The use of valid surrogate endpoints can accelerate the development of phase III trials. Numerous validation methods have been proposed with the most popular used in a context of meta-analyses, based on a two-step analysis strategy. For two failure time endpoints, two association measures are usually considered, Kendall's τ at individual level and adjusted R2 ([Formula: see text]) at trial level. However, [Formula: see text] is not always available mainly due to model estimation constraints. More recently, we proposed a one-step validation method based on a joint frailty model, with the aim of reducing estimation issues and estimation bias on the surrogacy evaluation criteria. The model was quite robust with satisfactory results obtained in simulation studies. This study seeks to popularize this new surrogate endpoints validation approach by making the method available in a user-friendly R package., Methods: We provide numerous tools in the frailtypack R package, including more flexible functions, for the validation of candidate surrogate endpoints using data from multiple randomized clinical trials., Results: We implemented the surrogate threshold effect which is used in combination with [Formula: see text] to make decisions concerning the validity of the surrogate endpoints. It is also possible thanks to frailtypack to predict the treatment effect on the true endpoint in a new trial using the treatment effect observed on the surrogate endpoint. The leave-one-out cross-validation is available for assessing the accuracy of the prediction using the joint surrogate model. Other tools include data generation, simulation study and graphic representations. We illustrate the use of the new functions with both real data and simulated data., Conclusion: This article proposes new attractive and well developed tools for validating failure time surrogate endpoints., Competing Interests: The authors have declared that no competing interests exist.

Background: Pesticides exposures could be implicated in the excess of Central Nervous System (CNS) tumors observed in farmers, but evidence concerning individual pesticides remains limited. Carbamate derivative pesticides, including herbicides and fungicides (i.e. (thio/dithio)-carbamates), have shown evidence of carcinogenicity in experimental studies in animals. In the French AGRICAN cohort, we assessed the associations between potential exposures to carbamate herbicides and fungicides and the incidence of CNS tumors, overall and by histological subtype., Methods: AGRICAN enrolled 181,842 participants involved in agriculture. Incident CNS tumors were identified by linkage with cancer registries from enrollment (2005-2007) until 2013. Individual exposures were assessed by combining information on lifetime periods of pesticide use on crops and the French crop-exposure matrix PESTIMAT, for each of the 14 carbamate and thiocarbamate herbicides and the 16 carbamate and dithiocarbamate fungicides registered in France since 1950. Associations were estimated using proportional hazard models with age as the underlying timescale, adjusting for gender, educational level and smoking., Results: During an average follow-up of 6.9 years, 381 incident cases of CNS tumors occurred, including 164 gliomas and 134 meningiomas. Analyses showed increased risks of CNS tumors with overall exposure to carbamate fungicides (Hazard Ratio, HR = 1.88; 95% CI: 1.27-2.79) and, to a lesser extent, to carbamate herbicides (HR = 1.44; 95% CI: 0.94-2.22). Positive associations were observed with specific carbamates, including some fungicides (mancozeb, maneb, metiram) and herbicides (chlorpropham, propham, diallate) already suspected of being carcinogens in humans., Conclusions: Although some associations need to be corroborate in further studies and should be interpreted cautiously, these findings provide additional carcinogenicity evidence for several carbamate fungicides and herbicides., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Surrogate endpoints (SEs) for overall survival (OS) are specific to therapeutic class. The objective of this review was to document all alternative endpoints studied for their association with OS in Immune-Checkpoint Inhibitors (ICI)-treated patients., Methods: We searched PubMed and Embase for publications reporting the association between a clinical endpoint and OS in ICI-treated populations from 01/01/2003 to 03/31/2018., Results: Out of 6,335 references identified, 24 were selected. Only 3 studies assessed surrogacy at both the patient and trial levels. The main traditional alternative endpoints included progression-free survival (N = 10) and objective response rate (N = 8). New alternative endpoints, such as durable response rate (N = 1) and intermediate response endpoint (N = 1) statistically better correlate with OS in the cancer types analysed., Conclusion: Based on the published evidence, there is insufficient data to support validated SE for OS. Adequate surrogacy assessment of promising composite endpoints which consider a duration component is encouraged., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Pesticide exposures are suspected to be implicated in the excess of central nervous system (CNS) tumours observed in farmers, but evidence concerning individual pesticides remains limited. Carbamate insecticides, used on a wide range of crops, have shown evidence of carcinogenicity in some experimental studies. In the cohort AGRICAN (AGRIculture & CANcer), we assessed the associations between potential exposures to carbamate insecticides and the incidence of CNS tumours, overall and by histological subtype., Methods: AGRICAN enrolled 181 842 participants involved in agriculture. Incident CNS tumours were identified by linkage with cancer registries from enrolment (2005-07) until 2013. Carbamate exposure was assessed by combining information on lifetime periods of pesticide use on crop or livestock and the French crop-exposure matrix PESTIMAT, individually for each of the 19 carbamate insecticides registered in France since 1950. Associations were estimated using proportional hazards models with age as the underlying time scale, adjusting for gender, educational level and smoking., Results: During a 6.9-year average follow-up, 381 incident cases of CNS tumours occurred, including 164 gliomas and 134 meningiomas. Analyses showed increased risks of CNS tumours with overall exposure to carbamate insecticides and linear trends with duration of use of each carbamate. Considering tumour subtypes, hazard ratios for gliomas ranged from 1.18 for thiofanox to 4.60 for formetanate, and for meningiomas from 1.51 for carbaryl to 3.67 for thiofanox., Conclusions: Findings reinforce carcinogenicity evidence for already suspected active ingredients and draw attention to additional active ingredients, notably used on fruit trees, vineyards, potatoes and beets., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Alternative endpoints to overall survival (OS) are frequently used to assess treatment efficacy in randomized controlled trials (RCT). Their properties in terms of surrogate outcomes for OS need to be assessed. We evaluated the surrogate properties of progression-free survival (PFS), time-to-progression (TTP) and time-to-treatment failure (TTF) in advanced soft tissue sarcomas (STS)., Results: A total of 21 trials originally met the selection criteria and 14 RCTs ( N = 2846) were included in the analysis. Individual-level associations were moderate (highest for 12-month PFS: Spearman's rho = 0.66; 95% CI [0.63; 0.68]). Trial-level associations were ranked as low for the three endpoints as per the IQWiG criterion., Materials and Methods: We performed a meta-analysis using individual-patient data (IPD). Phase II/III RCTs evaluating therapies for adults with advanced STS were eligible. We estimated the individual- and the trial-level associations between then candidate surrogates and OS. Statistical methods included weighted linear regression and the two-stage model introduced by Buyse and Burzykowski. The strength of the trial-level association was ranked according to the German Institute for Quality and Efficiency in Health Care (IQWiG) guidelines., Conclusions: Our results do not support strong surrogate properties of PFS, TTP and TTF for OS in advanced STS., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Objectives: The aim of this study was to identify using implantable loop recorder (ILR) monitoring the mechanisms leading to sudden death (SD) in patients undergoing hemodialysis (HD)., Background: SD accounts for 11% to 25% of death in HD patients., Methods: Continuous rhythm monitoring was performed using the remote monitoring capability of the ILR device in patients undergoing HD at 8 centers. Clinical, biological, and technical HD parameters were recorded and analyzed., Results: Seventy-one patients (mean age 65 ± 9 years, 73% men) were included. Left ventricular ejection fraction was <50% in 16%. Twelve patients (17%) had histories of atrial fibrillation or flutter at inclusion. During a mean follow-up period of 21.3 ± 6.9 months, 16 patients died (14% patient-years), 7 (44%) of cardiovascular causes. Four SDs occurred, with progressive bradycardia followed by asystole. The incidence of patients presenting with significant conduction disorder and with ventricular arrhythmia was 14% and 9% patient-years, respectively. In multivariate survival frailty analyses, a higher risk for conduction disorder was associated with plasma potassium >5.0 mmol/l, bicarbonate <22 mmol/l, hemoglobin >11.5 g/dl, pre-HD systolic blood pressure >140 mm Hg, the longer interdialytic period, history of coronary artery disease, previous other arrhythmias, and diabetes mellitus. A higher risk for ventricular arrhythmia was associated with potassium <4.0 mmol/l, no antiarrhythmic drugs, and previous other arrhythmias. With ILR monitoring, de novo atrial fibrillation or flutter was diagnosed in 14 patients (20%)., Conclusions: ILR may be considered in HD patients prone to significant conduction disorders, ventricular arrhythmia, or atrial fibrillation or flutter to allow early identification and initiation of adequate treatment. Therapeutic strategies reducing serum potassium variability could decrease the rate of SD in these patients. (Implantable Loop Recorder in Hemodialysis Patients [RYTHMODIAL]; NCT01252823)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta-analysis (MA)., Materials and Methods: We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema., Results: Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer., Conclusion(s): The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In addition to tumor characteristics and lifestyle factors, cancer relapses are often related to the risk of death but have not been jointly studied. We investigate the prognostic factors of recurrent events and death after a diagnosis of breast cancer and predict individual deaths including a history of recurrences., Methods: The E3N (Etude Epidémiologique auprès de Femmes de la Mutuelle Générale de l'Education Nationale) study is a prospective cohort study that was initiated in 1990 to investigate factors associated with the most common types of cancer. Overall survival and three types of recurrent events were considered: locoregional recurrence, metastasis, and second primary breast cancer. Recurrent events and death were analyzed using a joint frailty model., Results: The analysis included 4926 women from the E3N cohort diagnosed with a first primary invasive breast cancer between June 1990 and June 2008; during the follow-up, 1334 cases had a recurrence (median time of follow-up is 7.2 years) and 469 women died. Cases with high grade, large tumor size, axillary nodal involvement, and negative estrogen and progesterone receptors had a higher risk of recurrence or death. Furthermore, smoking increased the risk of relapse. For cases with a medium risk profile in terms of tumor characteristics and lifestyle factors, the probability of dying between 5 and 10 years after diagnosis was 6, 20 and 36% for 0, 1 or 2 recurrences within the first 5 years after diagnosis, respectively., Conclusions: Our study showed the importance of considering baseline lifestyle characteristics and history of relapses to dynamically predict the risk of death in breast cancer cases. Medical experience coupled with an estimate of a patient's survival probability that considers all available information for this patient would enable physicians to make better informed decisions regarding their actions and thus improve clinical output.

The CXCL12/CXCR4 signaling exerts a dominant role in promoting hematopoietic stem and progenitor cell (HSPC) retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at the HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs, and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients., (© 2017 Freitas et al.)

Background: The identification of epidemiological pattern of infection with Plasmodium falciparum and Plasmodium vivax in malaria-endemic area, where multiple episodes are common, is important for intervention programmes., Methods: A longitudinal cohort study based on weekly house-to-house visits was conducted between July 2008 and June 2010 in 2040 children less than 10 years of age, living nearby the Gilgel-Gibe hydroelectric power dam reservoir in order to determine factors associated with increased P. vivax and P. falciparum incidence. Two types of multivariate frailty models were applied (using time-to-first malaria episode data and time-to-recurrent malaria episode data), allowing the estimation of adjusted hazard ratios (AHR) of potential risk factors (gender, age, proximity to the dam reservoir, and season) for species-specific malaria incidence., Results: Of 2040 children in 96 weeks of follow up, 864 children experienced at least one malaria episode: 685 due to P. falciparum in 548 children, and 385 due to P. vivax in 316 children. Plasmodium vivax and P. falciparum malaria incidence rates were 8.2 (95 % CI: 7.3-9.1) and 14.6 (95 % CI: 13.4-15.6) per 1000 children per month, respectively. According to the time-to-recurrent event models, children aged ≥7 years had a lower risk of presenting P. vivax episodes (AHR = 0.6; 95 % CI: 0.4-0.9), but a higher risk of P. falciparum episodes, when compared with children under ≤3 years (AHR = 1.2; 95 % CI: 1.1-1.6). In addition, P. vivax (AHR = 2.7; 95 % CI: 2.2-3.5) and P. falciparum (AHR = 16.9; 95 % CI: 14.3-20.2) episodes were respectively 2.7 and 16.9 times more frequent in the dry season than in the long rainy season., Conclusions: The analysis of all malaria episodes (first and recurrent episodes) in the malaria cohort suggests different species-specific patterns of malaria disease in children, with mild seasonality in the incidence of P. vivax episodes mostly observed in younger age groups, and with marked seasonality in the incidence of P. falciparum episodes mainly seen in older children.

Background: Cancer relapses may be useful to predict the risk of death. To take into account relapse information, the Landmark approach is popular. As an alternative, we propose the joint frailty model for a recurrent event and a terminal event to derive dynamic predictions of the risk of death., Methods: The proposed prediction settings can account for relapse history or not. In this work, predictions developed on a French hospital series of patients with breast cancer are externally validated on UK and Netherlands registry data. The performances in terms of prediction error and calibration are compared to those from a Landmark Cox model., Results: The error of prediction was reduced when relapse information was taken into account. The prediction was well-calibrated, although it was developed and validated on very different populations. Joint modelling and Landmark approaches had similar performances., Conclusions: When predicting the risk of death, accounting for relapses led to better prediction performance. Joint modelling appeared to be suitable for such prediction. Performance was similar to the landmark Cox model, while directly quantifying the correlation between relapses and death.

Background: High levels of asthma prevalence and severity of respiratory symptoms have been found in the Caribbean but little is known about the impact of air pollution in these regions. This study aimed to describe air pollution and measure the associations with child lung function in Guadeloupe (French West Indies)., Methods: Data from 30 randomly chosen elementary schools (8-13 years old) were obtained using a standardized protocol adapted from the ISAAC2 study. We considered two health outcomes: peak expiratory flow (PEF) before running and the variation in peak expiratory flow (ΔPEF) after running. The associations between pollutants and outcomes were investigated using several air pollution exposure models: i) medium-term exposure to close-proximity pollution both indoor and outdoor for ozone (O₃) and nitrogen dioxide (NO₂) and ii) short- and medium-term exposure to background pollution for O₃, NO₂, sulphur dioxide (SO₂) and small particulate matter (PM10)., Results: Of 1,463 children, 277 (16%) were found to have asthma. A 1-μg/m3 increase in medium-term exposure to outdoor close-proximity pollution by O₃ was associated with a PEF decrease (β = -0.32; 95% CI: -0.61;-0.03). No association was found with NO₂ regarding close-proximity pollution. The association between medium-term exposure to background pollution and PEF decrease was stronger in asthmatic children than in non-asthmatic children for O₃. No reduction in PEF or ΔPEF was shown with NO₂, SO₂ and PM₁₀ pollutants but a significant association was found between PM₁₀ and PEF increase., Conclusions: Our results suggest that O₃ could have an acute effect on child lung function in the Caribbean even at a low concentration (below the WHO guidelines). Further research in the Caribbean is needed to confirm these findings.

Background: We describe severe morbidity and health care resource utilization (HCRU) among HIV-infected children on antiretroviral therapy (ART) in Abidjan, Côte d'Ivoire., Methods: All HIV-infected children enrolled in an HIV-care program (2004-2009) were eligible for ART initiation until database closeout, death, ART interruption, or loss to follow-up. We calculated incidence rates (IRs) of density per 100 child-years (CYs) for severe morbidity, HCRU (outpatient care and inpatient care), and associated factors using frailty models with a Weibull distribution., Results: Of 332 children with a median age of 5.7 years and median follow-up of 2.5 years, 65.4% were severely immunodeficient by World Health Organization (WHO) criteria, and all received cotrimoxazole prophylaxis. We recorded 464 clinical events in 228 children; the overall IR was 57.6/100 CYs [95% confidence interval (CI): 52.1 to 62.5]. Severe morbidity was more frequent in children on protease inhibitor (PI)-based ART compared to those on other regimens [adjusted hazards ratio (aHR): 1.83; 95% CI: 1.35 to 2.47] and to those moderately/severely immunodeficient compared to those not (aHR: 1.57; 95% CI: 1.13 to 2.18 and aHR: 2.53; 95% CI: 1.81 to 3.55, respectively). Of the 464 events, 371 (80%) led to outpatient care (IR: 45.6/100 CYs) and 164 (35%) to inpatient care (IR: 20.2/100 CYs). In adjusted analyses, outpatient care was significantly less frequent in children older than 10 years compared with children younger than 2 years (aHR: 0.49; 95% CI: 0.31 to 0.78) and in those living furthest from clinics compared with those living closest (aHR: 0.65; 95% CI: 0.47 to 0.90). Both inpatient and outpatient HCRU were negatively associated with cotrimoxazole prophylaxis., Conclusions: Despite ART, HIV-infected children still require substantial utilization of health care services.

Exposure assessment is a critical point for epidemiological studies on pesticide health effects. PESTEXPO study provides data on levels of exposure and their determinants in real conditions of pesticide use. We described levels of exposure in vineyards during treatment tasks (mixing, spraying and cleaning) and we analysed their determinants. Sixty-seven operators using dithiocarbamates or folpet were observed. Detailed information on the tasks (general conditions, operator, farm and equipment characteristics) were collected and dermal contamination was measured, using patches placed onto the skin on eleven body parts, and washing the hands at the end of each phase. The spraying phase represented roughly half of the contamination, whereas mixing and equipment cleaning accounted for 30% and 20% of the contamination, respectively. The main determinants of exposure were the number of phases, the characteristics of the equipment, the educational level of the operator and his status (farm -worker or -owner) and the general characteristics of the vines. Algorithms were built to estimate daily external contamination, according to these characteristics during mixing, spraying or equipment cleaning. With additional information of frequency and duration of use, they will enable to develop exposure indices usable in epidemiological studies on farmers' health.