Délégation Régionale Grand Ouest

329 Objectives: Baseline positron emission tomography with fluorodeoxyglucose (FDG-PET) based radiomics are of increasing interest for lung cancer prognostic studies. However, many different strategies can be considered in particular to solve the issue of features selection for building a prognostic signature. In this study a radiomics-based Fully Connected Deep Neural Network (R-DNN) was developped to predict the prognosis without any prior need for a feature selection method. Methods: One hundred and thirty eight patients with stage I-III non-small cell lung cancer treated with radio-chemotherapy were retrospectively included in this analysis. Patients were classified according to median overall survival (OS) into high-risk or low-risk. Radiomics features following the IBSI standardization guidelines were extracted from automatically delineated metabolic tumor volumes (MTV) on baseline PET scans. A Fully Connected Deep Neural Network (DNN with 5 hidden layers, 400 hidden units per layer, 50% drop-out and the ELU activation function) was directly trained exploiting all radiomics features for prediction. The trained DNN was evaluated with 10-fold cross-validation using the area under the curve (AUC) of the receiver operating characteristic (ROC). Its performance was compared to each individual radiomics features. Results: The AUC for each individual radiomics features ranged from 0.60 (Sensitivity (Se)=45% and Specificity (Sp)=78%) to 0.70 (Se=86%, Sp=53%). By comparison, when using all radiomics features as input to the DNN, the mean AUC was 0.79 (Se=75% and Sp=68%) in training and 0.71 (Se=71% and Sp=64%) in cross-validation. Conclusions: PET-derived radiomics with Fully Connected Deep Neural Network (R-DNN) algorithm provided high accuracy in prognostication of lung cancer patients with multiple radiomics and could eliminate the need for any prior radiomics feature selection.

BACKGROUND: Autoimmune neutropenia (AIN) is the main cause of chronic neutropenia in children, but its infectious consequences remain poorly studied. The primary objective of this study was to evaluate infectious events leading to emergency department or hospital admissions during the first 2 years following the diagnosis of AIN in children. METHODS: We performed a retrospective, multicentre analysis of medical records from 21 French university hospitals of patients aged under 18 years diagnosed with AIN with positive antineutrophils autoantibodies. We collected data on emergency room visits and hospitalisations in the 2 years following diagnosis, causes of these events, microbiology results, management and outcome. RESULTS: One hundred and sixty-eight patients were enrolled. Median age at diagnosis of AIN was 13 months. AIN was predominantly diagnosed during an infectious episode (n=120, 71%). In the 2 years of follow-up after diagnosis, 248 events of emergency room visits and/or hospitalisations were reported (0.77 per patient-year). The most frequent diagnoses were common childhood viral or bacterial infections. The incidence rate of severe infections was 0.003 per patient-year. Despite the predominance of viral infections, 177 episodes (71%) led to hospitalisation and 166 (68%) to the initiation of antibiotic therapy, for a median duration of 7 days (IQR 3-10). CONCLUSION: The risk of severe infections in children with AIN is low. During follow-up, we suggest being attentive to signs of severity during fever, particularly in children over 3 years of age and/or with other immunological comorbidities but not proposing systematic hospitalisation or additional antibiotic therapy.

40 Purpose: Radiomic features are potential imaging biomarkers for prognosis and predictive modeling in oncology. Selection of features sufficiently robust or even completely insensitive to the variability of imaging characteristics in multicenter data (scanner mode, acquisition protocols and/or reconstruction settings), may help building robust models, however it also may lead to loss of potentially useful information (predictive features are being discarded beforehand). Our goal was to compare two approaches for radiomic predictive modelling relying on embedded feature selection methods of machine learning: using only robust features or all available features, in combination with the ComBat harmonization. Methods: ninety-two IBSI-compliant radiomic features were extracted from FDG-PET and MRI sequences (T1, T1c, T2 and ADC maps) of 189 cervical cancer patients treated with radiochemotherapy in 3 centers (Brest, n = 117 and Nantes, n = 44 in France, and Montreal, n = 28, in Canada). The distributions of the features were harmonized using different versions of ComBat including improved versions recently developed[1]. An interclass coefficient coefficient (ICC) g 0.90 was used to identify features robust across the 3 centers and the different scanners (two different PET scanners were used in Montreal). The predictive ability of these robust features was compared to the ones selected by three different machine learning pipelines: LASSO for multivariate regression (MR) and embedded feature selection associated with Random Forest (RF) and Support Vector Machine (SVM). After splitting the data 70/30 in training and testing sets, models to predict recurrence were built using the 3 pipelines that used either the untransformed or harmonized (with the 4 ComBat versions) features. They were compared using Matthews correlation coefficient (MCC), Area under the curve (AUC), and balanced accuracy (BAC) given the class imbalance. Results: Models built using features selected by either LASSO or RF/SVM embedded selection showed a consistent better predictive ability, with or without harmonization. In MR, models built using LASSO-based features outperformed those relying on ICC-selected features (BAcc 79% vs. 43%, AUC 80% vs. 45%, and MCC 0.48 vs. 0.05) using the untransformed data. Similar comparison was observed with RF and SVM, models built using embedded selected features outperforming those relying only on ICC-selected ones. Similarly to our previous results, performance of models was also consistently improved using harmonized features compared to untransformed ones, even in the case of models using only robust features. Conclusions: We have shown that feeding all available features to any machine learning pipeline relying on embedded features selection techniques leads to models with much better predictive performance than pre-selecting a smaller set of features based on their robustness to changes in multicentre data. This suggests that at least in our dataset, informative and predictive features were the ones sensitive to changes in imaging properties of the multicentre data and this information was lost during the pre-selection. We thus recommend on pooling datasets together then perform standardization to ensure that informative features are kept for model building. This study was partially funded by 766276 PREDICT H2020-MSCA-ITN-2017

<h3>Objective</h3> This study aimed to assess the fractions of cardiovascular diseases and depression attributable to five psychosocial work exposures in Europe (35 countries), for all countries together and each country separately. <h3>Methods</h3> We used the data of the sample of 35,571 employees from the 2015 European Working Conditions Survey to assess the prevalence of exposure to job strain, effort-reward imbalance, job insecurity, long working hours, and workplace bullying. The relative risks were extracted from published literature reviews and/or meta-analyses. The outcomes included: coronary/ischemic heart diseases (CHD), stroke, atrial fibrillation, peripheral artery disease, venous thromboembolism, and depression. We calculated individual attributable fractions (AF) for each exposure and overall AFs for all studied exposures together. <h3>Results</h3> The highest significant AF was found for job strain and depression (17%). The other AFs for depression were also significant: job insecurity (9%), bullying (7%), and effort-reward imbalance (6%). Almost all AFs for cardiovascular diseases were significant but lower than 5% (one exception was the fraction of peripheral artery disease attributable to job strain, 11%). There were differences in the AFs for depression between countries. Differences in the AFs were also observed between countries and between genders for long working hours. The overall AFs related to the five studied exposures together were found to be 17%-35% for depression and 5%-11% for CHD. <h3>Conclusion</h3> The fractions attributable to psychosocial work exposures were substantial, especially for depression. Preventive measures oriented towards the psychosocial work environment may contribute to reduce the burden of diseases attributable to these exposures.

<h3>Objectives</h3> Very little literature is available on the effects of psychosocial work exposures on mortality. The aim of the STRESSJEM project was to explore the prospective associations between these exposures and all-cause and cause-specific mortality. <h3>Methods</h3> The STRESSJEM project was based on a French national representative sample of 798,547 male and 697,785 female employees for which data on job history on the 1976–2002 period were linked to mortality and causes of death data from the national registry. Job strain model exposures were imputed using a job-exposure matrix and three time-varying exposure measures were constructed: current, cumulative, and recency-weighted cumulative exposure. The prospective associations between these exposure measures and mortality were explored using Cox proportional hazards models. <h3>Results</h3> 88,521 deaths occurred among men and 28,921 among women between 1976 and 2002. Low decision latitude, low social support, job strain, iso-strain, high strain, and passive job were found to be risk factors for all-cause mortality, cardiovascular mortality, suicide, and preventable mortality (including smoking- and alcohol-related mortality as well as external causes of death). The model with current exposure was the highest relative quality model. The fractions attributable to job strain were 5.64% and 4.13% for all-cause mortality, 5.64% and 6.44% for cardiovascular mortality, 5.29% and 9.13% for suicide, and 5.1% and 3.1% for preventable mortality, among men and women respectively (though non-significantly different from zero for cardiovascular and preventable mortality among women). <h3>Conclusion</h3> Our findings underlined the role of the job strain model exposures on all-cause and cause-specific mortality. The burden of mortality attributable to these exposures may be substantial, especially for suicide among women. Prevention oriented towards the psychosocial work environment may reduce mortality among working populations.

Introduction: The assessment of symptoms status is pivotal to optimize the timing of aortic valve intervention in aortic stenosis (AS). However, little is known about the effect of sex on health status decline (i.e. functional status and quality of life) in AS patients. We evaluated the change in health status according to sex in patients with mild to moderate AS. Methods: Two hundred eighty-five patients with AS (peak aortic jet velocity [V peak ]≥2.0 m/s) prospectively recruited in the PROGRESSA study (NCT01679431) were included in this analysis. Health status was evaluated using the New York Heart Association (NYHA) classification and the Duke Activity Score Index (DASI). Results: At baseline, men were older (67±12 vs 61±17 yr; p=0.001), had more comorbidities including hypertension, coronary artery disease, and atrial fibrillation (all, p≤0.01), and more severe AS compared to women (2.8±0.5 vs 2.6±0.4 m/s; p=0.01). However, women had more symptoms (class I, II, III: 44%, 53%, 3% versus 63%, 36%, 1%; p=0.02) and significantly lower DASI (38±14 vs 43±13; p=0.006). During a mean follow-up of 3.9±2.4 years, despite faster AS progression rate in men (V peak increase: 0.16±0.2 vs 0.12±0.2 m/s/year; p=0.02), the worsening of symptoms (NYHA ≥I class; n=70) and decline in DASI score were comparable according to sex (Figure). However, for the same hemodynamic AS progression rate, women had significantly faster decline in DASI score (Figure). In linear mixed analysis adjusted for several clinical and echocardiographic risk factors, female sex remained significantly associated with the worsening of NYHA class (odds ratio: 3.9; 95% CI: 2.1 to 7.2; p&lt;0.0001) and the decline in DASI score (coeff.: -9; 95% CI: -11 to -6; p&lt;0.0001). Conclusion: Despite a better clinical profile and less severe AS, women generally had worse symptomatic status compared to men, and this difference was accentuated throughout follow-up. These findings raise the question of symptoms minimisation in women.

<h3>Objective</h3> The objective of this study was to explore suicide ideation in association with multiple occupational exposures, especially those related to the psychosocial work environment, in the French working population. <h3>Methods</h3> The study relied on the data of the 2016 national working conditions survey, including a sample of the French working population of 20,430 employees, 8,579 men and 11,851 women. The outcome was suicide ideation within the 12 last months. All types of occupational exposures were explored including psychosocial work factors, working time/hours and physico-chemical exposures. The exposures-outcome associations were examined by weighted logistic regression models with adjustment for covariates. Sensitivity analyses were performed to check the robustness of the results. <h3>Results</h3> The prevalence of suicide ideation was of similar magnitude among men and women (5.2% and 5.7% respectively). A large number of psychosocial work factors were associated with suicide ideation: quantitative and cognitive demands, low influence and possibilities for development, low meaning at work, low sense of community, role conflict, job insecurity, temporary employment, changes at work, and internal violence. The risk of suicide ideation increased with the number of psychosocial work exposures linearly. There were some differences in the exposure-outcome associations between genders. No association was observed for working time/hours and physico-chemical exposures with suicide ideation. Sensitivity analyses provided similar results. <h3>Conclusion</h3> Psychosocial work exposures were associated with suicide ideation, and displayed cumulative effects on this outcome. Our study is one the first to study multiple occupational exposures in association with suicide ideation. More research and prevention are needed on psychosocial work exposures and their cumulative effects on suicide ideation.

<h3>Objective</h3> Knowledge on the cumulative effects of psychosocial work factors on mental health is sparse, and other occupational exposures such as those from the physical work environment remain understudied in this topic. Therefore, this study aimed to examine the associations between various types of occupational factors, including a large variety of psychosocial work factors (PWFs), and major depressive episode (MDE) and generalized anxiety disorder (GAD) in the French working population. <h3>Methods</h3> The study was based on data from the 2016 national survey on working conditions conducted on a representative sample of workers, including 20430 employees aged 15–65 years (8579 men, 11851 women). The MINI standardized diagnostic interview was used to assess MDE and GAD. The following occupational exposures were studied: 21 PWFs grouped in five dimensions (work demands, work organization and job content, interpersonal relations and leadership, work-individual interface, workplace violence), four working time/hours factors and four physico-chemical exposures. The associations between occupational exposures and MDE/GAD were assessed in each gender separately using weighted logistic regression models. <h3>Results</h3> We found a higher prevalence of MDE and GAD among women than among men (8.6% and 8.7% respectively versus 4.3% and 4.6%). There were significant associations between most psychosocial work factors, andMDE and/or GAD. The odds of MDE/GAD increased with the number of exposures for all psychosocial dimensions, except workplace violence. The odds of MDE also increased with multiple physico-chemical exposures. No association was found between working time/hours factors and MDE/GAD, except between unsocial work days, shift work and MDE in women. <h3>Conclusion</h3> Our results highlighted the negative impact of being exposed to multiple PWFs for depression and anxiety, and showed a cumulative association of the four studied physico-chemical exposures with depression. More research is needed on the effect of the accumulation of occupational exposures on these outcomes in working populations.

Introduction: Aortic stenosis (AS) is associated with progressive left ventricular (LV) remodeling and hypertrophy, ultimately leading to cardiac decompensation. Measurement of circulating biomarkers may be useful to identify AS patients with higher risk of maladaptive LV remodeling, a potent marker of the transition to heart failure. We hypothesized that multiple circulating biomarkers are associated with faster progression of LV hypertrophy in patients with AS. Methods: One hundred and forty-six asymptomatic AS patients (66±13years, 75% male) prospectively enrolled in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent Doppler-echocardiography to measure AS severity, LV mass indexed to body surface area (LVMi) and LV relative wall thickness (RWT). The annualized changes in LVMi and RWT were calculated between baseline and last follow-up visit (mean follow-up of 2.5±1.88 years). Results: At baseline, 16% of patients had mild (i.e. peak aortic jet velocity [Vpeak] 2.0-2.9 m/s),76% moderate (Vpeak 3.0-3.9 m/s), and 8% severe (Vpeak ≥4.0 m/s) AS, mean LVMi and RWT were 106±23 g/m 2 and 0.47±0.07 respectively. Among biomarkers, baseline level of triglycerides, D-dimer and tumor antigen 125(Ca-125) were significantly associated with LVMi progression rate (β:0.16,p≤0.05), (β:0.18,p≤0.05) and(β:-0.20,p≤0.05) respectively. Soluble (ST2) protein and alkaline phosphatase (ALP) were the only factors independently associated with the annualized change in RWT. In multivariate analysis adjusted for age, gender, comorbidities, AS severity, cardiac biomarkers; triglycerides and D-dimers remained significantly associated with faster progression rate of LVMi (all, p≤0.05), while lower level of CA125 remained significantly associated with LVMi annualized change (β=-0.21, p=0.01). After similar multivariate adjustment, higher levels of ST2 and ALP remained significantly associated with faster progression rate of RWT (all, p≤0.05). Conclusion: Several blood biomarkers were independently associated with faster progression of LV remodeling and hypertrophy in patients with AS. A multiple biomarker approach may be useful to assess LV health and predict the risk of early phases of heart failure in AS.

Background: Basal serum tryptase (bST) is the main marker of the mast cell compartment. In spite of the importance of mast cells regarding allergic manifestations, the relationship between bST and allergy-related outcomes has been seldomly described, particularly during early life. In addition, circulating tryptase concentrations depend of mast cell load, genetic determinants, and several physiological, pathological, and exposure factors. This study aimed to assess the potential association between bST and allergy-related outcomes in teenagers from a birth cohort. Methods: This cross-sectional study included 610 teenagers at 15/16 years participating to a French ongoing population-based prospective birth cohort. Participants answered to self-administered questionnaires, received a health check-up and blood sampling. Considered allergy-related outcomes consisted of sensitization by skin prick test and specific IgE measurements, fraction of exhaled NO measurements, and standardized diagnosis of allergy-related morbidities. Results: At 15 years , higher bST was associated with higher prevalence of sensitization to inhalants and foods. Furthermore, bST was positively associated with intermediate-to-high FeNO levels, even after adjustments for covariates including sensitization and eosinophils. After controlling for potential confounders, higher bST was also associated to higher risk of displaying any hypersensitivity reactions, reactions to drugs, and to asthma with associated sensitization. Furthermore, higher bST was associated with poorer control scores among sensitization-associated asthma. Conversely, higher bST was associated with lower risk of presenting dermatitis without associated sensitization. Conclusion: In teenagers from a birth cohort, higher bST was associated with more frequent sensitization, intermediate-to-high FeNO values, and allergy-related morbidities, including asthma.

Introduction: Bicuspid aortic valve (BAV) is frequently associated with aortic valve stenosis (AS) and concomitant aortopathy. However, few studies have evaluated the effect of aortic valve (AV) phenotype on the risk of progressive dilation of aorta dimensions. The aim of this study was to compare the progression rate of aorta dimensions according to AV phenotype (i.e. BAV vs tricuspid aortic valve [TAV]) and sex in patients with AS. Methods: Three-hundred twenty AS patients (231 TAV and 89 BAV; mean age: 64±14 years, 72% men) recruited in the PROGRESSA study (NCT01679431) were included in this analysis. Patients underwent Doppler-echocardiography annually to measure the AS hemodynamic severity and aorta dimensions including the aortic root (AR) at the sinus level and ascending aorta (AA) sections. The annualized change of echocardiographic parameters was assessed between baseline and last follow-up visit (median follow-up time: 4.01 [2.26 to 5.00] years). Results: Baseline AR diameters were similar between phenotypes and AA diameters were larger in BAV vs. TAV (34±5 vs. 34±4, p=0.43, 38±6 vs. 34±4, p&lt;0.001, respectively). Median change in AR root diameter was similar in BAV vs. TAV (0.15 [-0.07 to 0.44] cm/year vs. 0.13 [-0.07 to 0.41] cm/year, p=0.69), whereas AA annualized change was larger in BAV (0.26 [0.02 to 0.52] cm/year vs. 0.14 [-0.06 to 0.40] cm/year, p=0.02). After multivariable adjustment, BAV phenotype was not a significant predictor of faster progression rate of AR or AA dilation (β: -0.003, p=0.98 and -0.095, p=0.25). In a separate analysis according to sex, the median changes in AR and AA were similar between women and men (p=0.53 and p=0.18). Predictors of AA progression rate in men were baseline AA diameter and AS severity (i.e. baseline peak aortic jet velocity) (all p≤0.03). In women, only higher low-density lipoprotein levels were significantly associated with faster AA progression (p=0.02). Regarding the AR annualized dilation, there were no significant predictors in both women and men (all p≥0.07). Conclusion: This study suggests that AV phenotype is not independently associated with faster dilation of the AR or AA in patients with established AS. However, the determinants of aorta dilation may be different between women and men.

ABSTRACT The lymphatic system maintains interstitial fluid homeostasis and supports immune function through dynamic regulation of its architecture mediated by molecular signals—such as vascular endothelial growth factors (VEGFs)—and physical cues. While VEGFs are known to promote endothelial proliferation, their broader roles in tissue organization remain under investigation. Using a lymphatic vessel-on-a-chip platform, we examine how lymphatic endothelial cells (LECs) respond to VEGF-A, VEGF-C, or their combination. We find that co-stimulation synergistically enhances lymphangiogenic sprouting while preserving barrier integrity. Co-stimulation also induces axial polarization of the tissue along the vessel axis, even in the absence of external mechanical stimuli. This polarization requires activation of the VEGFR2/VEGFR3 heterodimer and is disrupted by inhibition of the Src-dependent mechanotransduction pathway. Further co-stimulation enhances LEC motility and triggers vessel contraction. Modeling suggests that the tubular geometry of the lymphatic monolayer imposes intrinsic mechanical anisotropy—softer in the circumferential than axial direction. This geometrically-encoded stiffness landscape directs cell migration along the stiffer axis, uncovering a form of durotaxis driven by curvature-induced anisotropy. These results highlight a previously unrecognized mechanism by which biochemical and biophysical cues direct lymphatic tissue polarization, offering new insight into how geometry and mechanosensing shape lymphatic function.

<h3>Objective</h3> Studies exploring occupational exposures comprehensively in association with depression measured using diagnostic instrument are lacking. The present study aimed to examine the associations of occupational exposures with depression in the national French working population. <h3>Methods</h3> We used the data from the 2016 SUMER survey including a national representative sample of 25,977 employees, 14,682 men and 11,295 women. The outcome was depression measured using the validated PHQ-9 instrument and algorithm. All types of occupational exposures were studied: psychosocial work factors, working time and hours, and physico-chemical exposures. The exposures-outcome associations were examined using weighted logistic regression analyses for each gender separately. The following covariates were taken into account: age, marital status, occupation, and economic activity of the company. <h3>Results</h3> The prevalence of depression was 5.70% for women and 3.78% for men, with a significant difference between genders. Low levels of decision latitude and reward, bullying, work-family conflict and ethical conflict for men and women, and high levels of psychological demands, low levels of social support, and long working hours for women were found to be associated with depression. There was no association between physico-chemical exposures and depression. <h3>Conclusion</h3> Our study showed that the main occupational risk factors for depression were psychosocial work exposures. The study had two major strengths: the assessment of the work environment comprehensively and the measurement of depression using a diagnostic instrument and algorithm. Prevention oriented towards the psychosocial work environment may be useful to prevent depression at the workplace.

Introduction: Oxidized phospholipids (OxPL) are carried by apolipoprotein B-100-containing lipoproteins (OxPL-apoB) including lipoprotein(a) [Lp(a)]. Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). Aims: We aimed to evaluate the independent associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. Methods: OxPL-apoB and Lp(a) were evaluated in the Multi-Ethnic Study of Atherosclerosis (MESA) and a participant-level meta-analysis of four randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity (V max )) was evaluated using multivariable linear regression models. Results: In MESA, both OxPL-apoB and Lp(a) were independently associated with prevalent AVC (OR (95% CI) per SD: 1.19 (1.07-1.32) and 1.13 (1.01-1.27), respectively) with a significant interaction between the two (p&lt;0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated independently (interaction p&lt;0.01). The OxPL-apoB*Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. Mediation analyses demonstrated that Lp(a) partially mediated the association between OxPL-apoB and AVC. In a 2x2 analysis, the greatest risk for both prevalent and incident AVC was observed when Lp(a) and OxPL-apoB were both above the 80 th percentile ( Figure ). In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were independently associated with faster increase in V max , but when evaluated together, only OxPL-apoB remained significant (ß 0.07, 95% CI 0.01-0.12, Figure ). Conclusions: OxPL-apoB is an independent predictor of the presence, incidence and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels and may represent a novel therapeutic target for CAVD.

<h3>Objective</h3> Many studies suggest that working conditions may have an impact on health, including sleep. One of the main limitations inthe literature, however, is that studies have explored a limited number of occupational exposures and have not addressed the issue of multiple exposures. Our objective was to study the associations of a large variety of occupational exposures with sleep problems, and to assess the impact of multiple occupational exposures on this outcome. <h3>Methods</h3> The study sample consisted of 20430 employees aged 15–65 years (8579 men, 11851 women) included in the representative sample of the working population from the 2016 French national survey on working conditions. Participants were classified as having sleep problems if they reported sleep disturbances and/or sleep medication, at least several times a week. Occupational exposures were: 21 psychosocial work factors (PWFs) further grouped in five dimensions (work demands, work organization and job content, interpersonal relations and leadership, work-individual interface, workplace violence), four working time/hours factors and four physico-chemical exposures. Weighted robust Poisson regressions were performed to study the associations between occupational exposures and sleep problems after adjustment for covariates, in men and women separately. <h3>Results</h3> Among the studied working time/hours factors, only night work among women was associated with sleep problems, while most of psychosocial work factors and physico-chemical exposures were significantly associated with sleep problems. Stronger exposure-outcome associations were found in men for some PWFs. The odds of sleep problems increased with increasing number of exposures for most dimensions of PWFs, and with increasing number of physico-chemical exposures (non-significant trend in women). <h3>Conclusion</h3> Psychosocial and physico-chemical exposures were found to be associated with sleep problems, and the higher the number of exposures, the higher the odds of sleep problems. More studies are needed on multiple occupational exposures in association with sleep problems among working populations.

<h3>Objective</h3> Literature reviews showed adverse effects of high job demands, low job control, and low social support at work on well-being in working populations. Other psychosocial work factors (PWFs) remain understudied in association with well-being. We aimed to examine the prospective associations of a large variety of PWFs and other occupational exposures with poor well-being, as evaluated by the WHO-5 well-being index. An additional objective was to explore the effects of multiple occupational exposures on this outcome. <h3>Methods</h3> The study sample consisted of 15776 employees aged 15–65 years (9181 women, 8579 men) included in the representative sample of the French national survey on working conditions and followed up from 2013 to 2016. Participants were classified as having poor well-being if they had a WHO-5 score below 13. Occupational exposures included 20 PWFs which were studied separately and then grouped into five dimensions (work demands, work organization and job content, interpersonal relations and leadership, work-individual interface, workplace violence), 4 factors related to working time/hours, and 4 physico-chemical exposures. Weighted robust Poisson regression models were used to investigate the associations between occupational exposures in 2013 and incident poor well-being in 2016 after adjustment for covariates, in men and women separately. <h3>Results</h3> The incidence rate of poor well-being in 2016 was 10.3% among men and 16.8% among women. Significant prospective associations were found between a wide range of PWFs and poor well-being, and the risk increased with the number of these factors globally and within almost all psychosocial dimensions (except work demands in men and workplace violence in both genders). Among the other studied occupational exposures, noise was prospectively associated with poor well-being in women. <h3>Conclusion</h3> Working conditions, especially PWFs, could have a negative impact on well-being and exposure to multiple PWFs could increase the risk of poor well-being still further.

Introduction: The assessment of changes in functional status during follow-up is critical to determine the timing of intervention in patients with aortic stenosis (AS). Fast progression of AS (annualized progression of peak jet velocity [V peak ] ≥30 cm/s) is among the risk markers recommended in the guidelines to trigger early intervention in asymptomatic severe AS. We investigated the association between the progression of AS hemodynamic severity and the change in functional status during follow-up of patients with asymptomatic mild to moderate AS. Methods: 285 patients with AS prospectively recruited in the PROGRESSA study (NCT01679431) were included in this analysis. Functional status was evaluated using the New York Heart Association (NYHA) classification. Results: Baseline NYHA class was similar (class I, II, III: 57%, 41%, 2% versus 58%, 41%, 1%; p=0.75) between patients with moderate (V peak progression ≥12 cm/s/year; median of cohort) versus those with slow AS progression rate. During a mean follow-up of 3.9±2.4 years, patients with moderate AS progression rate had larger increase in NYHA class compared to those with slow progression (+0.13±0.48 versus +0.01±0.21 class/year; p=0.008). From baseline to 2 years, a significant worsening of NYHA class occurred but only in the moderate AS progression group ( Figure ). In multivariable analysis, AS progression rate remained significantly associated with the change in NYHA class (p=0.04).A total of 156 clinical events (110 AVR and 46 deaths) occurred during a mean follow-up of 1.1±1.5 years after the last echocardiographic visit. Patients with ≥1 class increase in NYHA (n=70) had significantly higher risk of events (adjusted hazard ratio: 1.75 [95% CI: 1.12-2.75]; p=0.01). Conclusions: In this prospective cohort of patients with mild to moderate AS at baseline, the decline in functional status occurs early in the course of the disease and is in large part determined by the progression rate of AS hemodynamic severity.

Background: Aortic stenosis (AS) induces left ventricular (LV) remodeling and hypertrophy, which are key markers of the transition to heart failure. The present study aimed to evaluate the association between D-dimer plasma levels, LV hypertrophy and mortality with AS. Method: One-hundred and forty-six asymptomatic patients (mean age 65±13, men 76%) with mild or moderate AS prospectively recruited in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent Doppler-echocardiography annually to measure AS severity, LV mass indexed to body surface area (LVMi) and myocardial contraction fraction (MCF). The annualized changes in LVMi and MCF were calculated between baseline and last follow up. Results: Higher plasma levels of D-dimers at baseline were significantly associated with faster progression rate of LVMi and MCF (r 2 =0.18 and -0.22, respectively; all p&lt;0.01). On multivariable analysis adjusted for age, sex, comorbidities, creatinine level, peak aortic jet velocity at baseline, D-dimers remained significantly associated with faster change in LVMi and MCF (all, p&lt;0.01). Moreover, in multivariate analysis adjusted for age, sex, AS severity at baseline, higher levels of D-dimer were significantly associated with the progression to a higher grade of AS severity (HR [95% CI] 1.67 [1.14-2.46], p=0.009). During a median follow-up of 8.1 (5.6-9.9) years, 38 (26%) patients died. On multivariable Cox regression analysis, higher levels of D-dimer were associated with an increased risk of all-cause mortality (HR [95% CI]: 1.97 [0.98-1.97], p=0.05). Conclusion: Higher levels of D-dimer are associated with faster progression of AS severity, LV hypertrophy and dysfunction, and increased risk of mortality in patients with AS. This new blood biomarker may improve risk stratification and management of asymptomatic patients with AS. Further studies are needed to determine the mechanisms underlying this association between D-dimer and outcomes in AS.