S Tadier

N Le Bolay

S Girod Fullana

C Rey

C Combes

Control of the injectability of calcium carbonate-calcium phosphate mixed cements for bone reconstruction

Keywords: injectability, bone cement, co-grinding

The purpose of this study was to improve injectability and cohesiveness of original calcium carbonate-calcium phosphate mixed (CaCO 3 -CaP) self-setting paste for bone filling and repair. With this aim in view dry co-grinding was implemented on the solid phase (vaterite and dicalcium phosphate dihydrate) of this cement. A protocol designed to quantify paste injectability has been established and pointed out the synergistic positive effects of solid phase co-grinding treatment on injectability, cohesiveness and setting time of the paste. The improvement of these properties are related to close and homogeneous association of reactive powders and to the decrease of specific surface area favoring the powders hydration process enhancing setting reaction rate. In addition, the particle size decrease and morphology modification improved flowability of the paste which results in a low and constant (320 g) force level to extrude the paste.

Introduction

With the development of minimally invasive surgery techniques, injectable biomaterials have attracted much attention in recent years. Fast-setting calcium phosphate cements for bone reconstruction are good candidates due to their excellent biocompatibility and bioactivity properties and their ease of use as mouldable and injectable self-setting pastes [1]. However two phenomena, "filter-pressing" (solid particles separate from liquid within the syringe and plug the tip of the canula while the liquid passes through) and "cement washout" (disintegration of the paste on contact with tissue or fluids) affect paste cohesion and greatly limit their implantation using an injection process [2][3]. Several groups have explored the possibility to improve cement paste cohesiveness during injection using the rheological properties of natural and synthetic polymer additives [4][5]. Another approach consists in controlling reactive powders particle size and particle size distribution which are determining factors affecting paste cohesiveness, hydration process and mechanical properties of cements [2,[6][7]. However little attention has been paid to the use of cogrinding treatment of solid phase mixtures for biomedical cements.

Recently, calcium carbonate-calcium phosphate mixed (CaCO 3 -CaP) cements have been presented as promising resorbable bone cements [8] and the rheological properties of these original cement compositions are just beginning to be explored. The objective of this study is to set up a protocol for injectability characterization of CaCO 3 -CaP cement paste and to improve its cohesiveness and injectability by controlling the powder particle size and morphology using grinding or co-grinding processes.

Materials and Methods

The reactive powders (CaCO 3 vaterite and dicalcium phosphate dihydrate (DCPD, CaHPO 4 , 2 H 2 O) constituting the solid phase (S) of the cement were synthesized by precipitation at ambient temperature, following protocols described previously [8]. The precipitates were filtered, washed with deionized water, lyophilized and stored in a freezer to avoid any evolution of these metastable powders before their use.

In order to reach the smallest particle size and intimate powders mixture, dry batch grinding and co-grinding experiments were performed using a laboratory tumbling ball mill. It consists in a ceramic cylindrical chamber, 1 L in capacity, rotating around its horizontal axis, and containing ceramic balls of different diameters: 19, 9.2 and 5.6 mm. The rotating speed of the chamber was fixed at 100 rpm, i.e. at 75 % of the critical speed, while the ball loading volume represented 20 % of the whole volume of the chamber. The powder filling rate represents 10 % of the void space between the balls. The DCPD powder was ground separately during a period ranging from 1 to 30 minutes, but also together with vaterite powder (co-grinding period from 1 to 20 minutes). Powder samples were taken from different regions of the chamber at various times to be analyzed. The removed sample mass was small enough, so as not to modify significantly the powder proportion in the mill.

SEM observations after silver plating (LEO 435 VP), FTIR spectroscopy (Nicolet 5700), X-ray diffraction (INEL CPS 120), laser diffraction granulometry (Malvern, Mastersizer 2000), and specific surface area analyses (Monosorb MS22, Quantachrom) were carried out to characterize the powders before and after (co)grinding treatment.

Cement paste was prepared by mixing equal quantities of vaterite and DCPD (unground, ground or co-ground) with the liquid phase (L) composed of deionized water (L/S = 0.5). Injectability was measured using a TAXT2 texture analyzer (Stable Micro Systems) equipped with a specific syringe system and following a protocol designed to measure the force needed to extrude a volume of paste corresponding to a displacement of 15 mm of the syringe piston (surface = 64 mm 2 ). Measurements were performed 5 min after paste preparation.

The setting rate of the cement was followed using the same texture analyzer fitted with a cylindrical needle (surface = 0.785 mm 2 ). The setting time was considered to be reached when the paste developed a resistance to needle penetration over 600 g/mm 2 .

Results and Discussion

Table 1 gives the specific surface area and the particle mean size (d 50 is the mean particle diameter corresponding to cumulated volume fractions of 50 %) of vaterite and DCPD powders obtained by precipitation. Because of its small particle size (d 50 = 1.7 µm), vaterite do not require grinding treatment, whereas crystals of DCPD can be ground until particle size reaches 2.8 µm; the corresponding optimal grinding time (offering the smallest mean size while avoiding agglomeration phenomena) has been determined equal to 27 minutes. The reference solid phase was prepared by mixing unground vaterite with unground DCPD and was compared with two other solid phases: one is composed of a mixture of vaterite with ground DCPD and the other one of co-ground reactive powders (13 minutes was determined as the optimal co-grinding time for the solid phase). Figure 1.b shows that after co-grinding, most of lentil-like vaterite particles are stuck on DCPD crystals, which have been broken during grinding. In addition, when compared with unground solid phase (fig 1.a), powders are more intimately and homogeneously mixed; furthermore, the contact surface between the two reactive components has increased using co-grinding process. XRD patterns of hardened cements prepared with the 3 different solid phases are presented on figure 2. It showed that grinding and co-grinding have no effect on the cement setting reaction: in all cases, the hardened cement is composed of poorly crystalline apatite (A) and excess vaterite (V). This result was confirmed by FTIR spectroscopy analyses (data not presented). In addition, co-grinding the reactive powders has a strong influence on the paste setting time which is nearly divided by two when using co-ground powders (t setting = 75 min) compared to reference cement (t setting = 140 min). The increased specific surface and contact area between reactive powders speed up the hydration process necessary for the setting reaction.

We can see on figure 3 that the force needed to extrude the reference paste (unground powders) from a syringe increases almost linearly all along the extrusion, up to 33 kg whereas its increase is strongly attenuated (7 kg) when using ground DCPD and is no more occurring for co-ground powders. The co-grinding process greatly improves the injectability of the paste nearly by a factor 100 and prevents the "filter pressing" phenomenon: with co-ground reactive powders the force level to extrude the paste remains low and constant (320 g) during the paste extrusion underlining the determinant effect of particles size and morphology on the paste flowability. We can assume that, because of their morphology, platelet particles of DCPD hinder the paste flow more or less depending on their orientation towards flow direction. Ground DCPD particles are greatly smaller and closer to spherical morphology and should therefore obstruct the path less than unground particles.

Moreover, the cohesion of the paste can be checked by observing how it is extruded: disjointed spaghettis can be seen using unground powders whereas a long homogeneous spaghetti is obtained

co-ground unground V V V V V A A A V A DCPD ground
using co-ground powders; these observations indicate how solid phase co-grinding treatment could possibly lead to a decrease of paste "washout" phenomenon in vivo. In the case of CaCO 3 -CaP mixed cement, co-grinding favors fragmentation of DCPD large platelet-crystals and close association of the two reactive powders allowing a satisfactory flowability of the paste and faster rate of setting chemical reaction. The improvement of the latter is probably related to better powder hydration enhancing the formation of an apatite analogous to bone mineral through dissolution-reprecipitation process and reaction between carbonate ions from vaterite and hydrogenphosphate ions from DCPD to give phosphate of apatite.

Co-grinding treatment of the solid phase leads therefore to synergistic positive effects resulting in better paste injectability, cohesiveness and cement setting time.

Conclusions

We demonstrated that the protocol we have designed for the injectability measurements of CaCO 3 -CaP mixed cement paste is quantitative, reliable and discriminating; interestingly a low and constant (320 g) force level to extrude the paste can be obtained using co-ground reactive powders. This study pointed out the usefulness of the co-grinding process to improve and control powders reactivity and paste rheological properties which constitute a decisive advantage for ease of use of CaCO 3 -CaP self-setting pastes.

  (a) unground solid phase (b) co-ground solid phase Fig. 1: SEM micrographs of cement solid phase before and after co-grinding process.

Fig. 2 :

 2 Fig.2: XRD patterns of hardened cements prepared with unground, DCPD ground and co-ground solid phases.

Fig. 3 :

 3 Fig.3: Evolution of the force needed to extrude a determined volume of paste prepared with unground, DCPD ground only or co-ground reactive powders.

Table 1 :

 1 Mean size (d 50 ) and specific surface area (S BET ) of the reactive powders used to prepare cements.

		vaterite	DCPD	ground DCPD
	d 50 [µm] S BET [m 2 /g]	1.7 36.8	9.2 1.8	2.8 2.3


Samantha Huo

Yung Kai

Jean Ferrières

Mélisande Rossignol

Frédéric Bouisset

Julie Herry

Yolande Esquirol
email: yolande.esquirol@univ-tlse3.fr

Prevalence and determinants of return to work after various coronary events: meta-analysis of prospective studies

Keywords: myocardial infarction, ACS, angina pectoris, angioplasties, coronary artery bypass,, return to work, sick leave, myocardial infarction, heart attack, angina, coronary syndrome,, return to work, return to occupational activity, work resumption, sickness absence

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Study eligibility criteria.

All observational prospective studies assessing RTW in adults after a cardiovascular event (MI, ACS, and angina pectoris) were included. Retained studies were written in English or in French. Retrospective, cross-sectional studies, controlled trials, case reports, oral presentations, posters, opinion articles, books, and articles with only an abstract were excluded.

Study selection.

Article selection was carried out independently by three medical physicians (MR, SHYK, YE). Article list was managed with Endnote software (version X.8) and duplicates were removed using this reference manager. Screening of titles and then of abstracts was conducted by the three reviewers who also pursue a further selection after reading the full articles and checked the appropriateness of the studies. In case of disagreement, a discussion with a fourth reviewer (JF) resolved it. The references listed in the included articles were checked and compared to those obtained after the selection to ensure that important articles were not omitted.

Data extraction and coding. Three review authors extracted and organized in a Microsoft Office Excel database the following information: first author, publication year, country, study design, recruitment period and site, study size, age, gender, type of cardiovascular events, treatment type (PCTA, CABG), occupational characteristics, number of workers returning to work (frequency and/or percentage), duration of follow-up and time to RTW (mean, median, standard deviation).

Events were classified into three categories: acute events, stable angina or elective interventions, and acute events or stable angina or elective interventions (when events were not distinguished by the authors). Patients' follow-up duration was categorized into: ≤ 3, ]3-6], ]6-12], and > 12 months. To consider patient's care progress, notably with the introduction of the aspirin-clopidogrel association and drug-eluting stents around 2000, recruitment time was dichotomized into two periods: before and after 2000. Study countries was organized according to the WHO (World Health Organization) regions. The method of assessment of the cardiovascular events was recoded into three classes: clinical examination from experts, patient's interview, and ICD-10 codes obtained from registries. RTW could be self-declared or determined using administrative or employer databases or data from occupational medicine visits.

Regarding work conditions, several models have been constituted: firstly, white-collar (aggregating non-manual, executive, mostly mental workload, very light/light work) versus blue-collars workers (aggregating manual, workers, mostly physical workload, moderate/heavy work), secondly workstation with low or high occupational physical activity (OPA). Study population mean age was used to classify studies in three age categories: mean age < 51 years old, mean age between 51 and 53 years old and mean age ≥ 54 years old. Two levels of education were compared: < high school versus ≥ high school, as well as two levels of LVEF: < 40% versus ≥ 40%. study quality. This scale assesses three dimensions: selection, comparability, and outcome. Stars are assigned according to the study quality and bias risk with a maximal number of 9 stars. The higher the number of stars, the lower the bias risk is. The threshold of 7 stars at the NOS scale was used to highlight the high-quality studies.

Data synthesis and analysis. The package "meta" (v.4.13-0) of R (v.4.0.2) and RStudio (v. 1.3.1073) were used to undertake the meta-analysis. Assuming estimates may vary across studies due to differences in population or study settings (country, size, date) for instance, random-effects meta-analyses were carried out to pool the data. We used the Freeman-Tukey double arcsine transformation to include studies with extreme prevalence [START_REF] Barendregt | Meta-analysis of prevalence[END_REF][START_REF] Nyaga | Metaprop: A Stata command to perform meta-analysis of binomial data[END_REF] . Pooled prevalence estimates of RTW along with 95% confidence interval were calculated. Studies weights were calculated using the inverse variance method. The DerSimonian and Laird method was used to estimate the between-study variance. Heterogeneity was reported as I 2 statistics [START_REF] Higgins | Quantifying heterogeneity in a meta-analysis[END_REF] . Prediction intervals (PI) were used to describe the range of expected estimates (narrow PI indicate consistence across studies whereas wide PI indicate variation across studies) [START_REF] Borenstein | Common Mistakes in Meta-Analysis and How to Avoid Them[END_REF] . Significance threshold was set at 0.05. Subgroup analyses were conducted. To further explore heterogeneity, sensitivity analyses were undertaken to measure the effect of the size of the studies by removing some studies. Small study effects bias were assessed with funnel plot [START_REF] Egger | Bias in meta-analysis detected by a simple, graphical test[END_REF] and Begg and Egger tests, and were considered significant if p-value < 0.05.

Results

Study characteristics. A total of 480 records were identified and 43 prospective studies described in Supplementary Table S1 online were finally included (Fig. 1). Publication years and recruitment periods range respectively from 1988 to 2018 and from 1981 to 2017. Most of the studies took place in Europe (72%) and the patients were recruited during hospital stays (91%) (Supplementary Table S2 online).

Quality and risk of bias assessment of the 43 included studies by using the NOS scale (Supplementary Fig. 1 online) reported a low risk of bias for 27 studies (7-9 stars) and a higher risk of bias for 16 studies (4-6 stars). For these last ones, the limited number of adjustment factors lead to a low score for the comparability criteria and most of them were implemented before 2010.

RTW after a coronary event.

Considering the longest follow-up time for all the studies , RTW overall random effects pooled prevalence was calculated at 81.1% [75.8; 85.8], with substantial heterogeneity (I 2 = 99.1% and an expected prevalence ranging between 41.2% and 100%) (Supplementary Fig. S2 online) and no evidence for small study effects (p-value respectively for Begg's and Egger's test: 0.267 and 0.284) (Supplementary Fig. S3 online).

Figure 2 shows the pooled prevalence estimates of RTW according to the type of coronary events: 80.3% [73.6; 86.2] for acute events, 83.6% [73.7; 91.5] for stable angina or elective interventions, and 77.4% [62.3; 89.5] when the event was not clearly defined in the published studies (acute events or stable angina or elective interventions) (P = 0.731, I 2 = 98.8%, no evidence for small study effects).

RTW according to the characteristics of the studies. RTW pooled prevalence estimates after a coronary event were significantly different (P < 0.001, I 2 = 99.7%, PI [23.2%; 100%]) according to the follow-up periods expressed in months: ≤ 3 [START_REF] Fioretti | Social fate and long-term survival of patients with a recent myocardial infarction, after cardiac rehabilitation[END_REF][START_REF] Bryant | Prediction of outcome after coronary artery surgery[END_REF][START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Abbott | Return to work during the year following first myocardial infarction[END_REF][START_REF] Abbas | Frequency of returning to work one and six months following percutaneous coronary intervention for acute myocardial infarction[END_REF][START_REF] De Jonge | The presence of a depressive episode predicts lower return to work rate after myocardial infarction[END_REF][START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Mirmohammadi | Evaluation of the return to work and its duration after myocardial infarction[END_REF][START_REF] Osler | Impact of gender, co-morbidity and social factors on labour market affiliation after first admission for acute coronary syndrome. A cohort study of Danish patients 2001-2009[END_REF][START_REF] Latil | Returning to work after an acute coronary syndrome: When waiting is wasting[END_REF][START_REF] Stendardo | Predicting return to work after acute myocardial infarction: Socio-occupational factors overcome clinical conditions[END_REF][START_REF] Fiabane | Does job satisfaction predict early return to work after coronary angioplasty or cardiac surgery?[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF] , ]3-6] [START_REF] Giordano | The proposal of the Italian Committee on Occupational Cardiology[END_REF][START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Abbott | Return to work during the year following first myocardial infarction[END_REF][START_REF] Petrie | Role of patients' view of their illness in predicting return to work and functioning after myocardial infarction: Longitudinal study[END_REF][START_REF] Abbas | Frequency of returning to work one and six months following percutaneous coronary intervention for acute myocardial infarction[END_REF][START_REF] Brink | Illness consequences after myocardial infarction: Problems with physical functioning and return to work[END_REF][START_REF] Fukuoka | Effect of job strain and depressive symptoms upon returning to work after acute coronary syndrome[END_REF][START_REF] Yonezawa | Effects of phase II cardiac rehabilitation on job stress and health-related quality of life after return to work in middle-aged patients with acute myocardial infarction[END_REF][START_REF] Lamberti | Work-related outcome after acute coronary syndrome: Implications of complex cardiac rehabilitation in occupational medicine[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF][START_REF] Miglioretti | Quality of work experience after angioplasty or heart surgery: A monocentric cohort study[END_REF] , ]6-12] [START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Bryant | Prediction of outcome after coronary artery surgery[END_REF][START_REF] Abbott | Return to work during the year following first myocardial infarction[END_REF][START_REF] Soejima | Psychosocial and clinical factors predicting resumption of work following acute myocardial infarction in Japanese men[END_REF][START_REF] Mittag | Return to work after myocardial infarction/coronary artery bypass grafting: Patients' and physicians' initial viewpoints and outcome 12 months later[END_REF][START_REF] Sellier | Factors influencing return to work at one year after coronary bypass graft surgery: Results of the PERISCOP study[END_REF][START_REF] Söderman | Depression as a predictor of return to work in patients with coronary artery disease[END_REF][START_REF] Mcburney | Work-related outcomes after a myocardial infarction[END_REF][START_REF] Bhattacharyya | Psychological and clinical predictors of return to work after acute coronary syndrome[END_REF][START_REF] Mcgee | Impact of briefly-assessed depression on secondary prevention outcomes after acute coronary syndrome: A one-year longitudinal survey[END_REF][START_REF] Hemingway | Outcome of stable angina in a working population: The burden of sickness absence[END_REF][START_REF] De Jonge | The presence of a depressive episode predicts lower return to work rate after myocardial infarction[END_REF][START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Mirmohammadi | Evaluation of the return to work and its duration after myocardial infarction[END_REF][START_REF] Osler | Impact of gender, co-morbidity and social factors on labour market affiliation after first admission for acute coronary syndrome. A cohort study of Danish patients 2001-2009[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Dreyer | Return to work after acute myocardial infarction: Comparison between young women and men[END_REF][START_REF] Latil | Returning to work after an acute coronary syndrome: When waiting is wasting[END_REF][START_REF] Jiang | Factors associated with return to work after acute myocardial infarction in China[END_REF][START_REF] Stendardo | Predicting return to work after acute myocardial infarction: Socio-occupational factors overcome clinical conditions[END_REF][START_REF] Butt | Return to the workforce following coronary artery bypass grafting: A Danish nationwide cohort study[END_REF] and > 12 [START_REF] Danchin | Exercise training, cardiac rehabilitation and return to work in patients with coronary artery disease[END_REF][START_REF] Mcgee | Return to work following coronary artery bypass surgery or percutaneous transluminal coronary angioplasty[END_REF][START_REF] Christensen | The effect of streptokinase on return to work 18 months after a first myocardial infarction[END_REF][START_REF] Speziale | Return to work and quality of life measurement in coronary artery bypass grafting[END_REF][START_REF] Isaaz | Return to work after acute ST-segment elevation myocardial infarction in the modern era of reperfusion by direct percutaneous coronary intervention[END_REF][START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Osler | Impact of gender, co-morbidity and social factors on labour market affiliation after first admission for acute coronary syndrome. A cohort study of Danish patients 2001-2009[END_REF][START_REF] Babić | Re-initiating professional working activity after myocardial infarction in primary percutaneous coronary intervention networks era[END_REF][START_REF] Duijts | Cancer and heart attack survivors' expectations of employment status: Results from the English Longitudinal Study of Ageing[END_REF][START_REF] Butt | Return to the workforce following coronary artery bypass grafting: A Danish nationwide cohort study[END_REF] . Patients were more likely to return to work after 3 months following the coronary event: 47.3% [41.7; 52.8] (PI [26.6; 68.4]) of the patients had returned to work before 3 months, 88% [79.9; 94.3] (PI [50.1; 100]) between 3 and 6 months. The overall random effects pooled prevalence decreased to reach 77.4% [66.6; 86.7] (PI [20.2; 100]) between 6 and 12 months and 80.2% [68.0; 90.1%] (PI [29.3; 100]) after 12 months (Fig. 3 and Supplementary Fig. S4 online). Heterogeneity significantly decreases in the 0-3 months follow-up group when the two larger studies were removed from the model [START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Osler | Impact of gender, co-morbidity and social factors on labour market affiliation after first admission for acute coronary syndrome. A cohort study of Danish patients 2001-2009[END_REF] (I 2 = 68.1%). There was no evidence for small study effects except for the 6-12 months follow-up subgroup (Egger test P = 0.03).

RTW pooled prevalence estimates were not significantly different between studies according to the date of recruitment (Table 1) (P = 0.458, I 2 = 99.1%, PI [41.2%; 100%]): 79.6% [74.4; 84.4] before 2001 [START_REF] Danchin | Exercise training, cardiac rehabilitation and return to work in patients with coronary artery disease[END_REF][START_REF] Fioretti | Social fate and long-term survival of patients with a recent myocardial infarction, after cardiac rehabilitation[END_REF][START_REF] Giordano | The proposal of the Italian Committee on Occupational Cardiology[END_REF][START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Bryant | Prediction of outcome after coronary artery surgery[END_REF][START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Abbott | Return to work during the year following first myocardial infarction[END_REF][START_REF] Mcgee | Return to work following coronary artery bypass surgery or percutaneous transluminal coronary angioplasty[END_REF][START_REF] Christensen | The effect of streptokinase on return to work 18 months after a first myocardial infarction[END_REF][START_REF] Petrie | Role of patients' view of their illness in predicting return to work and functioning after myocardial infarction: Longitudinal study[END_REF][START_REF] Speziale | Return to work and quality of life measurement in coronary artery bypass grafting[END_REF][START_REF] Soejima | Psychosocial and clinical factors predicting resumption of work following acute myocardial infarction in Japanese men[END_REF][START_REF] Mittag | Return to work after myocardial infarction/coronary artery bypass grafting: Patients' and physicians' initial viewpoints and outcome 12 months later[END_REF][START_REF] Sellier | Factors influencing return to work at one year after coronary bypass graft surgery: Results of the PERISCOP study[END_REF][START_REF] Söderman | Depression as a predictor of return to work in patients with coronary artery disease[END_REF][START_REF] Abbas | Frequency of returning to work one and six months following percutaneous coronary intervention for acute myocardial infarction[END_REF][START_REF] Mcburney | Work-related outcomes after a myocardial infarction[END_REF][START_REF] Hemingway | Outcome of stable angina in a working population: The burden of sickness absence[END_REF][START_REF] Isaaz | Return to work after acute ST-segment elevation myocardial infarction in the modern era of reperfusion by direct percutaneous coronary intervention[END_REF][START_REF] De Jonge | The presence of a depressive episode predicts lower return to work rate after myocardial infarction[END_REF][START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Butt | Return to the workforce following coronary artery bypass grafting: A Danish nationwide cohort study[END_REF] (respectively P-values for Begg and Egger tests, 0.592 and 0.004) and 82.7% [75.7; 88.8] after 2001 [START_REF] Bhattacharyya | Psychological and clinical predictors of return to work after acute coronary syndrome[END_REF][START_REF] Mcgee | Impact of briefly-assessed depression on secondary prevention outcomes after acute coronary syndrome: A one-year longitudinal survey[END_REF][START_REF] Brink | Illness consequences after myocardial infarction: Problems with physical functioning and return to work[END_REF][START_REF] Fukuoka | Effect of job strain and depressive symptoms upon returning to work after acute coronary syndrome[END_REF][START_REF] Waszkowska | Return to work after myocardial infarction: A retrospective study[END_REF][START_REF] Yonezawa | Effects of phase II cardiac rehabilitation on job stress and health-related quality of life after return to work in middle-aged patients with acute myocardial infarction[END_REF][START_REF] Mirmohammadi | Evaluation of the return to work and its duration after myocardial infarction[END_REF][START_REF] Osler | Impact of gender, co-morbidity and social factors on labour market affiliation after first admission for acute coronary syndrome. A cohort study of Danish patients 2001-2009[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Babić | Re-initiating professional working activity after myocardial infarction in primary percutaneous coronary intervention networks era[END_REF][START_REF] Dreyer | Return to work after acute myocardial infarction: Comparison between young women and men[END_REF][START_REF] Lamberti | Work-related outcome after acute coronary syndrome: Implications of complex cardiac rehabilitation in occupational medicine[END_REF][START_REF] Duijts | Cancer and heart attack survivors' expectations of employment status: Results from the English Longitudinal Study of Ageing[END_REF][START_REF] Latil | Returning to work after an acute coronary syndrome: When waiting is wasting[END_REF][START_REF] Jiang | Factors associated with return to work after acute myocardial infarction in China[END_REF][START_REF] Korzeniowska-Kubacka | Impact of exercise-based cardiac rehabilitation on attitude to the therapy, aims in life and professional work in patients after myocardial infarction[END_REF][START_REF] Stendardo | Predicting return to work after acute myocardial infarction: Socio-occupational factors overcome clinical conditions[END_REF][START_REF] Fiabane | Does job satisfaction predict early return to work after coronary angioplasty or cardiac surgery?[END_REF][START_REF] Fiabane | Psychological and work stress assessment of patients following angioplasty or heart surgery: Results of 1-year follow-up study[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF][START_REF] Miglioretti | Quality of work experience after angioplasty or heart surgery: A monocentric cohort study[END_REF] (respectively P-values for Begg and Egger tests, 0.809 and 0.018) (Supplementary Fig. S5 online).

To assess the impact of the method used to characterize the coronary event on RTW, three subgroups were identified: studies using clinical diagnosis established by experts [START_REF] Danchin | Exercise training, cardiac rehabilitation and return to work in patients with coronary artery disease[END_REF][START_REF] Fioretti | Social fate and long-term survival of patients with a recent myocardial infarction, after cardiac rehabilitation[END_REF][START_REF] Giordano | The proposal of the Italian Committee on Occupational Cardiology[END_REF][START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Bryant | Prediction of outcome after coronary artery surgery[END_REF][START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Abbott | Return to work during the year following first myocardial infarction[END_REF][START_REF] Mcgee | Return to work following coronary artery bypass surgery or percutaneous transluminal coronary angioplasty[END_REF][START_REF] Christensen | The effect of streptokinase on return to work 18 months after a first myocardial infarction[END_REF][START_REF] Petrie | Role of patients' view of their illness in predicting return to work and functioning after myocardial infarction: Longitudinal study[END_REF][START_REF] Speziale | Return to work and quality of life measurement in coronary artery bypass grafting[END_REF][START_REF] Soejima | Psychosocial and clinical factors predicting resumption of work following acute myocardial infarction in Japanese men[END_REF][START_REF] Mittag | Return to work after myocardial infarction/coronary artery bypass grafting: Patients' and physicians' initial viewpoints and outcome 12 months later[END_REF][START_REF] Sellier | Factors influencing return to work at one year after coronary bypass graft surgery: Results of the PERISCOP study[END_REF][START_REF] Abbas | Frequency of returning to work one and six months following percutaneous coronary intervention for acute myocardial infarction[END_REF][START_REF] Bhattacharyya | Psychological and clinical predictors of return to work after acute coronary syndrome[END_REF][START_REF] Mcgee | Impact of briefly-assessed depression on secondary prevention outcomes after acute coronary syndrome: A one-year longitudinal survey[END_REF][START_REF] Brink | Illness consequences after myocardial infarction: Problems with physical functioning and return to work[END_REF][START_REF] Fukuoka | Effect of job strain and depressive symptoms upon returning to work after acute coronary syndrome[END_REF][START_REF] Waszkowska | Return to work after myocardial infarction: A retrospective study[END_REF][START_REF] Yonezawa | Effects of phase II cardiac rehabilitation on job stress and health-related quality of life after return to work in middle-aged patients with acute myocardial infarction[END_REF][START_REF] Isaaz | Return to work after acute ST-segment elevation myocardial infarction in the modern era of reperfusion by direct percutaneous coronary intervention[END_REF][START_REF] De Jonge | The presence of a depressive episode predicts lower return to work rate after myocardial infarction[END_REF][START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Mirmohammadi | Evaluation of the return to work and its duration after myocardial infarction[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Babić | Re-initiating professional working activity after myocardial infarction in primary percutaneous coronary intervention networks era[END_REF][START_REF] Dreyer | Return to work after acute myocardial infarction: Comparison between young women and men[END_REF][START_REF] Lamberti | Work-related outcome after acute coronary syndrome: Implications of complex cardiac rehabilitation in occupational medicine[END_REF][START_REF] Latil | Returning to work after an acute coronary syndrome: When waiting is wasting[END_REF][START_REF] Jiang | Factors associated with return to work after acute myocardial infarction in China[END_REF][START_REF] Korzeniowska-Kubacka | Impact of exercise-based cardiac rehabilitation on attitude to the therapy, aims in life and professional work in patients after myocardial infarction[END_REF][START_REF] Stendardo | Predicting return to work after acute myocardial infarction: Socio-occupational factors overcome clinical conditions[END_REF][START_REF] Fiabane | Does job satisfaction predict early return to work after coronary angioplasty or cardiac surgery?[END_REF][START_REF] Fiabane | Psychological and work stress assessment of patients following angioplasty or heart surgery: Results of 1-year follow-up study[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF][START_REF] Miglioretti | Quality of work experience after angioplasty or heart surgery: A monocentric cohort study[END_REF] , studies collecting the information (ICD) in population register databases [START_REF] Söderman | Depression as a predictor of return to work in patients with coronary artery disease[END_REF][START_REF] Mcburney | Work-related outcomes after a myocardial infarction[END_REF][START_REF] Osler | Impact of gender, co-morbidity and social factors on labour market affiliation after first admission for acute coronary syndrome. A cohort study of Danish patients 2001-2009[END_REF][START_REF] Butt | Return to the workforce following coronary artery bypass grafting: A Danish nationwide cohort study[END_REF] , and studies based on patient interviews [START_REF] Hemingway | Outcome of stable angina in a working population: The burden of sickness absence[END_REF][START_REF] Duijts | Cancer and heart attack survivors' expectations of employment status: Results from the English Longitudinal Study of Ageing[END_REF] . Whatever the subgroups, no significant difference (P = 0.971, I 2 = 99.1%, PI [41.2%; 100%], no evidence for small study effects) was observed although pooled prevalence estimate calculated for studies using register databases was lower (78.8%) compared to the others (81.3% with clinical diagnosis and 81.1% with interviews) (Table 1 and Supplementary Fig. S6 online).

To analyze the effect of the method to measure RTW, studies were dichotomized (Table 1 and Supplementary Fig. S7 online): studies based on self-report [START_REF] Danchin | Exercise training, cardiac rehabilitation and return to work in patients with coronary artery disease[END_REF][START_REF] Fioretti | Social fate and long-term survival of patients with a recent myocardial infarction, after cardiac rehabilitation[END_REF][START_REF] Giordano | The proposal of the Italian Committee on Occupational Cardiology[END_REF][START_REF] Bryant | Prediction of outcome after coronary artery surgery[END_REF][START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Abbott | Return to work during the year following first myocardial infarction[END_REF][START_REF] Mcgee | Return to work following coronary artery bypass surgery or percutaneous transluminal coronary angioplasty[END_REF][START_REF] Christensen | The effect of streptokinase on return to work 18 months after a first myocardial infarction[END_REF][START_REF] Petrie | Role of patients' view of their illness in predicting return to work and functioning after myocardial infarction: Longitudinal study[END_REF][START_REF] Speziale | Return to work and quality of life measurement in coronary artery bypass grafting[END_REF][START_REF] Soejima | Psychosocial and clinical factors predicting resumption of work following acute myocardial infarction in Japanese men[END_REF][START_REF] Mittag | Return to work after myocardial infarction/coronary artery bypass grafting: Patients' and physicians' initial viewpoints and outcome 12 months later[END_REF][START_REF] Sellier | Factors influencing return to work at one year after coronary bypass graft surgery: Results of the PERISCOP study[END_REF][START_REF] Söderman | Depression as a predictor of return to work in patients with coronary artery disease[END_REF][START_REF] Abbas | Frequency of returning to work one and six months following percutaneous coronary intervention for acute myocardial infarction[END_REF][START_REF] Mcburney | Work-related outcomes after a myocardial infarction[END_REF][START_REF] Bhattacharyya | Psychological and clinical predictors of return to work after acute coronary syndrome[END_REF][START_REF] Mcgee | Impact of briefly-assessed depression on secondary prevention outcomes after acute coronary syndrome: A one-year longitudinal survey[END_REF][START_REF] Brink | Illness consequences after myocardial infarction: Problems with physical functioning and return to work[END_REF][START_REF] Fukuoka | Effect of job strain and depressive symptoms upon returning to work after acute coronary syndrome[END_REF][START_REF] Waszkowska | Return to work after myocardial infarction: A retrospective study[END_REF][START_REF] Yonezawa | Effects of phase II cardiac rehabilitation on job stress and health-related quality of life after return to work in middle-aged patients with acute myocardial infarction[END_REF][START_REF] Isaaz | Return to work after acute ST-segment elevation myocardial infarction in the modern era of reperfusion by direct percutaneous coronary intervention[END_REF][START_REF] De Jonge | The presence of a depressive episode predicts lower return to work rate after myocardial infarction[END_REF][START_REF] Mirmohammadi | Evaluation of the return to work and its duration after myocardial infarction[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Babić | Re-initiating professional working activity after myocardial infarction in primary percutaneous coronary intervention networks era[END_REF][START_REF] Dreyer | Return to work after acute myocardial infarction: Comparison between young women and men[END_REF][START_REF] Lamberti | Work-related outcome after acute coronary syndrome: Implications of complex cardiac rehabilitation in occupational medicine[END_REF][START_REF] Duijts | Cancer and heart attack survivors' expectations of employment status: Results from the English Longitudinal Study of Ageing[END_REF][START_REF] Korzeniowska-Kubacka | Impact of exercise-based cardiac rehabilitation on attitude to the therapy, aims in life and professional work in patients after myocardial infarction[END_REF][START_REF] Stendardo | Predicting return to work after acute myocardial infarction: Socio-occupational factors overcome clinical conditions[END_REF][START_REF] Fiabane | Does job satisfaction predict early return to work after coronary angioplasty or cardiac surgery?[END_REF][START_REF] Fiabane | Psychological and work stress assessment of patients following angioplasty or heart surgery: Results of 1-year follow-up study[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF][START_REF] Miglioretti | Quality of work experience after angioplasty or heart surgery: A monocentric cohort study[END_REF] and studies using administrative or employer databases or occupational medicine consultation [START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Hemingway | Outcome of stable angina in a working population: The burden of sickness absence[END_REF][START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Osler | Impact of gender, co-morbidity and social factors on labour market affiliation after first admission for acute coronary syndrome. A cohort study of Danish patients 2001-2009[END_REF][START_REF] Latil | Returning to work after an acute coronary syndrome: When waiting is wasting[END_REF][START_REF] Jiang | Factors associated with return to work after acute myocardial infarction in China[END_REF][START_REF] Butt | Return to the workforce following coronary artery bypass grafting: A Danish nationwide cohort study[END_REF] , and no significant difference was noticed (respectively, 80.5% and 83.9%, P = 0.610, I 2 = 99.1%, PI [41.2%; 100%], no evidence for small study effects).

The pooled prevalence estimates did not differ according to study quality defined with the NOS scale : 81.6% for score ≥ 7 and 80.2% for score < 7 (P = 0.821, I 2 = 99.1%, PI [41.2%; 100%], no evidence for small study effects) (Table 1 and Supplementary Fig. S8 online).

The region where the studies took place did not impact RTW pooled prevalence estimates (P = 0.654, I 2 = 99.1%, PI [41.2%; 100%], no evidence for small study effects) (Table 1 and Supplementary Fig. S9 online 1 and Supplementary Fig. S10 online). Small study effects were observed for the men subgroup (respectively P-values for Begg and Egger tests, 0.938 and 0.001). People aged less than 51 years old tended to present lower RTW prevalence estimates (74.9%), compared to the 51-53 years old (82%), and people aged 54 years old or older (86.2%) (P = 0.387, I 2 = 98.8%, PI [37.6%; 100%], no evidence for small study effects) (Table 1 and Supplementary Fig. S11 online).

RTW prevalence estimates did not significantly differ according to LVEF [START_REF] Danchin | Exercise training, cardiac rehabilitation and return to work in patients with coronary artery disease[END_REF][START_REF] De Jonge | The presence of a depressive episode predicts lower return to work rate after myocardial infarction[END_REF][START_REF] Mirmohammadi | Evaluation of the return to work and its duration after myocardial infarction[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Jiang | Factors associated with return to work after acute myocardial infarction in China[END_REF] (respectively 65.3% and 77.8% for < 40% and ≥ 40%, P = 0.346, I 2 = 96.5%, PI [19.3%; 100%]) (Table 1 and Supplementary Fig. S12 online).

Education level was not significantly associated to RTW [START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Söderman | Depression as a predictor of return to work in patients with coronary artery disease[END_REF][START_REF] Fukuoka | Effect of job strain and depressive symptoms upon returning to work after acute coronary syndrome[END_REF][START_REF] De Jonge | The presence of a depressive episode predicts lower return to work rate after myocardial infarction[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Dreyer | Return to work after acute myocardial infarction: Comparison between young women and men[END_REF][START_REF] Miglioretti | Quality of work experience after angioplasty or heart surgery: A monocentric cohort study[END_REF] (respectively 76.1% and 85.6% for < high school and ≥ high school, P = 0.085, I 2 = 82.9%, PI [62.8%; 95.5%], no evidence for small study effects) (Table 1 and Supplementary Fig. S13 online).

RTW overall random effects pooled prevalence was higher among white-collar workers compared to bluecollar workers, and among patients with low OPA compared to those with high OPA (Figs. 4 and5), even if the differences were not statistically significant [START_REF] Fioretti | Social fate and long-term survival of patients with a recent myocardial infarction, after cardiac rehabilitation[END_REF][START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Waszkowska | Return to work after myocardial infarction: A retrospective study[END_REF][START_REF] Isaaz | Return to work after acute ST-segment elevation myocardial infarction in the modern era of reperfusion by direct percutaneous coronary intervention[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Lamberti | Work-related outcome after acute coronary syndrome: Implications of complex cardiac rehabilitation in occupational medicine[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF] (respectively 81.2% vs. 65.0%, P = 0.251, I 2 = 96.7%, PI [11.1%; 100%], and 78.3% vs. 64.1%, P = 0.344, I 2 = 96.7%, PI [10.2%; 100%]; no evidence for small study effects).

Table 1 and Supplementary Fig. S14 online shows RTW prevalence estimates of PCTA patients [START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Söderman | Depression as a predictor of return to work in patients with coronary artery disease[END_REF][START_REF] Abbas | Frequency of returning to work one and six months following percutaneous coronary intervention for acute myocardial infarction[END_REF][START_REF] Fukuoka | Effect of job strain and depressive symptoms upon returning to work after acute coronary syndrome[END_REF][START_REF] Isaaz | Return to work after acute ST-segment elevation myocardial infarction in the modern era of reperfusion by direct percutaneous coronary intervention[END_REF][START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Babić | Re-initiating professional working activity after myocardial infarction in primary percutaneous coronary intervention networks era[END_REF][START_REF] Jiang | Factors associated with return to work after acute myocardial infarction in China[END_REF][START_REF] Stendardo | Predicting return to work after acute myocardial infarction: Socio-occupational factors overcome clinical conditions[END_REF][START_REF] Fiabane | Does job satisfaction predict early return to work after coronary angioplasty or cardiac surgery?[END_REF][START_REF] Fiabane | Psychological and work stress assessment of patients following angioplasty or heart surgery: Results of 1-year follow-up study[END_REF] and CABG patients [START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Bryant | Prediction of outcome after coronary artery surgery[END_REF][START_REF] Speziale | Return to work and quality of life measurement in coronary artery bypass grafting[END_REF][START_REF] Sellier | Factors influencing return to work at one year after coronary bypass graft surgery: Results of the PERISCOP study[END_REF][START_REF] Söderman | Depression as a predictor of return to work in patients with coronary artery disease[END_REF][START_REF] Fukuoka | Effect of job strain and depressive symptoms upon returning to work after acute coronary syndrome[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Jiang | Factors associated with return to work after acute myocardial infarction in China[END_REF][START_REF] Butt | Return to the workforce following coronary artery bypass grafting: A Danish nationwide cohort study[END_REF][START_REF] Fiabane | Does job satisfaction predict early return to work after coronary angioplasty or cardiac surgery?[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF] , with respectively 80.8% and 75.9% (P = 0.524, I 2 = 98.6%, PI [39.7%; 99.7%]). Small study effects were observed in the CABG subgroup (respectively Results of RTW prevalence estimates, by type of event, according to the characteristics of the studies and the clinical and socio-professional characteristics of the patients are summarized in Supplementary Table S3 online. RTW prevalence estimates by time of follow-up were similar for all types of events. Regarding acute www.nature.com/scientificreports/ events, RTW prevalence estimates were higher in patients recruited after 2001 (85.1% versus 73.1%, P = 0.042), in patients with a higher LVEF (73.6% versus 54.7%, P = 0.086) and a higher education level (85.2% versus 74.5%, P = 0.054). RTW prevalence estimates after stable angina or an elective coronary intervention were lower among blue-collars compared to white-collars (35.9% versus 63.0%, P < 0.001) and people with a high occupational physical activity (33.4% versus 57.2%).

Discussion

This study is to our knowledge the first systematic review of prospective studies about RTW after a coronary event. The objectives were to assess the prevalence of RTW after a coronary event and to identify the determinants which could impact job resumption with particular interest in work conditions. The main finding obtained from the 43 included articles was a RTW overall random effects pooled prevalence of 81.1% with a progressive increase of RTW prevalence estimates from 47.3% before three months to reach 88.0% at six months, followed by a substantial decrease to obtain a final RTW prevalence estimate at 80%. Prevalence estimates did not vary significantly according to gender, age, study quality, regions, date of recruitment of the participants, methods of evaluation of the disease and outcome, and type of treatment. Few studies focused on the occupational conditions which could impact RTW were published. RTW prevalence estimates among white collars or among people with high educational level tends to be higher compared to blue collars and low education level. In line with these results, the pooled prevalence of RTW among patients with low OPA was estimated at 78.3% versus 64.1% among those with high OPA.

Subgroup meta-analyses according to psychological factors was not done since these factors were seldom considered. Similarly, few studies provided data on RTW according to LVEF, and because of the different time of measurement (baseline, during the acute event or at discharge) and the different thresholds used, results should be carefully interpretated.

Strengths and weaknesses of the study.

A comprehensive systematic research using a broad search strategy was conducted by multidisciplinary specialists in cardiology, epidemiology, and occupational health allowing a better understanding of the types of coronary events as well as the return-to-work conditions. Recall and selection bias which are frequently encountered in cross-sectional and retrospective studies were minimized by including only prospective studies in the present meta-analysis. The large number of analyzed studies covering a wide period and the large number of cases (34,964) allowed to provide robust estimates of prevalence of RTW and to perform subgroup and sensitivity analyses. www.nature.com/scientificreports/ However substantial heterogeneity was observed in our study. Indeed, the meta-analyses yielded extreme I 2 values (about 99%) and wide PI (ranging between 20 and 100%, depending on the model). Although extreme heterogeneity is commonly observed in meta-analyses of prevalence as shown by Migliavaca et al. [START_REF] Migliavaca | Meta-analysis of prevalence: I2 statistic and how to deal with heterogeneity[END_REF] (median I 2 of 134 prevalence meta-analyses assessed at 96.9% [IQR 90.5-98.7]), we sought to examine the potential sources of heterogeneity in our study. Heterogeneity remains in the subgroup and sensitivity analyses. Combining studies differing in several aspects such as the country, date and size of the study, or length of follow-up may partially explain these results. Moreover, some individual characteristics (e.g., cardiovascular risk factors) could not be used in the analyses because they were scarcely reported with the added hurdle due to the varying definitions. The type of coronary event can also be discussed. Most of the included studies considered patients with MI or ACS but few of them involved patients with angina. Moreover, some studies including patients who had undergone PCTA or CABG did not detailed the exact diagnosis. Also, the variability of the definition used for RTW could be involved. Indeed, little information was available regarding the conditions of RTW: part-time or full-time, possibility of workstation changes at the workplace, partial or full recovery of capacity allowing to maintain the employees at their previous workstation. Thus, results should be interpreted with caution.

Unpublished studies and the selection of English and French-written studies can constitute a potential publication bias.

RTW varied in time after a coronary event. We highlighted that RTW pooled prevalence estimates varied with the time of the follow-up. RTW prevalence estimates varied from 47.3% before three months, 88.0% at 3-6 months, 77% at 6-12 month, to 80% after 12 months. In their systematic review without meta-analysis, Sun et al. reported that RTW occurred in 21.5% to 62.5% of the participants within three months which agrees with the expected prevalences observed in our meta-analyses (PI [26.6; 68.4]) [START_REF] Sun | Factors associated with return to work following myocardial infarction: A systematic review of observational studies[END_REF] . They also suggested that 55.9% to 90% of the participants RTW within 6 to 12 months while our estimations were wider (expected prevalences between 20.2 and 100%). Failure to maintain working can be explained by early retirement, depression but also by the recurrence of a new coronary event. Indeed, in a study based on Swedish registries [START_REF] Jernberg | Cardiovascular risk in post-myocardial infarction patients: Nationwide real world data demonstrate the importance of a long-term perspective[END_REF] , the authors have shown that the risk of non-fatal MI, non-fatal stroke, or cardiovascular death after a MI reached 18.3% in the up-coming year. Moreover, depression following a coronary event is frequently described [START_REF] Mcgee | Impact of briefly-assessed depression on secondary prevention outcomes after acute coronary syndrome: A one-year longitudinal survey[END_REF] .

Date of implementation and country of the study.

The WHO proposed very early, in 1964, a definition of cardiac rehabilitation followed in the nineties by the first European recommendations focused on patients with heart failure and aimed to improve physical capacity. However, it must be noted that despite of the unquestionable benefit of cardiac rehabilitation, the access to rehabilitation programs is still heterogeneous [START_REF] De Araújo Pio | Interventions to promote patient utilisation of cardiac rehabilitation[END_REF] . Urbinati et al. [START_REF] Urbinati | Cardiac rehabilitation after STEMI[END_REF] have reported that, probably due to the different type of health systems, the difficult access to these programs, and the economic cost, only 35% of the patients with ST-segment elevated MI have undergone this type of care in occidental countries.

Regarding the therapeutic and diagnostic progresses, we hypothesized that the year of the implementation of the studies could influence RTW, but a subgroup analysis revealed no significant difference when comparing prevalence before or after 2000.

Most of the studies took place in Europe (> 70%) and RTW did not differ between the WHO regions.

Type of treatment during hospitalization. PCTA and CABG have considerably improved patient care and their quality of life. Based on the available studies [START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Bryant | Prediction of outcome after coronary artery surgery[END_REF][START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Speziale | Return to work and quality of life measurement in coronary artery bypass grafting[END_REF][START_REF] Sellier | Factors influencing return to work at one year after coronary bypass graft surgery: Results of the PERISCOP study[END_REF][START_REF] Söderman | Depression as a predictor of return to work in patients with coronary artery disease[END_REF][START_REF] Abbas | Frequency of returning to work one and six months following percutaneous coronary intervention for acute myocardial infarction[END_REF][START_REF] Fukuoka | Effect of job strain and depressive symptoms upon returning to work after acute coronary syndrome[END_REF][START_REF] Isaaz | Return to work after acute ST-segment elevation myocardial infarction in the modern era of reperfusion by direct percutaneous coronary intervention[END_REF][START_REF] Laut | Impact of health care system delay in patients with ST-elevation myocardial infarction on return to labor market and work retirement[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Babić | Re-initiating professional working activity after myocardial infarction in primary percutaneous coronary intervention networks era[END_REF][START_REF] Jiang | Factors associated with return to work after acute myocardial infarction in China[END_REF][START_REF] Butt | Return to the workforce following coronary artery bypass grafting: A Danish nationwide cohort study[END_REF][START_REF] Fiabane | Does job satisfaction predict early return to work after coronary angioplasty or cardiac surgery?[END_REF][START_REF] Fiabane | Psychological and work stress assessment of patients following angioplasty or heart surgery: Results of 1-year follow-up study[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF] , our results did not highlight any significant difference in the pooled prevalence estimates of work resumption between these two interventions. However, we can assume that time taken to RTW is longer for patients with CABG than those with PCTA 68 . To explain these contrasted results, we can suppose that other essential determinants of RTW were omitted as factors related to workstation, and notably psychological factors.

Method and quality of the studies.

The methods used to determine the coronary event (use of the ICD from registries, clinician's expertise, or patient self-report) as well as the way to assess RTW (self-reported or not) did not influence RTW pooled prevalence estimates.

It appears that earlier studies [START_REF] Danchin | Exercise training, cardiac rehabilitation and return to work in patients with coronary artery disease[END_REF][START_REF] Fioretti | Social fate and long-term survival of patients with a recent myocardial infarction, after cardiac rehabilitation[END_REF][START_REF] Giordano | The proposal of the Italian Committee on Occupational Cardiology[END_REF][START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Abbott | Return to work during the year following first myocardial infarction[END_REF][START_REF] Mcgee | Impact of briefly-assessed depression on secondary prevention outcomes after acute coronary syndrome: A one-year longitudinal survey[END_REF][START_REF] Yonezawa | Effects of phase II cardiac rehabilitation on job stress and health-related quality of life after return to work in middle-aged patients with acute myocardial infarction[END_REF] and some more recent [START_REF] Lamberti | Work-related outcome after acute coronary syndrome: Implications of complex cardiac rehabilitation in occupational medicine[END_REF][START_REF] Latil | Returning to work after an acute coronary syndrome: When waiting is wasting[END_REF][START_REF] Korzeniowska-Kubacka | Impact of exercise-based cardiac rehabilitation on attitude to the therapy, aims in life and professional work in patients after myocardial infarction[END_REF] omitted clinical, demographic or occupational parameters as confounders when assessing RTW.

While the study methodology could be sometimes improved, the global quality of the studies (NOS scale) did not lead to difference in return-to-work prevalence.

Patients' expectations.

Although data collected for this study were not sufficient to perform analyses on this aspect of RTW, patients' expectations after a cardiac event appears to be a key element for work resumption. Salzwedel et al. [START_REF] Salzwedel | Determinants of return to work after multicomponent cardiac rehabilitation[END_REF] have shown that after a cardiac event, including MI, patients with initial lower self-assessed occupational prognosis were less likely to be fit to work at the end of cardiac rehabilitation.

Patients' sociodemographic characteristics. Despite the results not being significant, RTW pooled prevalence estimates in men seemed higher than in women which was also observed by Sun et al. [START_REF] Sun | Factors associated with return to work following myocardial infarction: A systematic review of observational studies[END_REF] As reported by Gauthier et al. [START_REF] Gauthier | Sex differences in time trends in acute coronary syndrome management and in 12-month lethality: Data from the French MONICA registries[END_REF] in a study based on the French ischemic heart diseases registries, although medical care improved over time in both men and women, men receive more frequently revascularization treatment, platelet aggregation inhibitors and statins prescription, and functional rehabilitation which could participate in a delayed or unsuccessful RTW in women.

Whereas Sun et al. [START_REF] Sun | Factors associated with return to work following myocardial infarction: A systematic review of observational studies[END_REF] systematic review suggested that older participants were less likely to RTW based on seven studies, our meta-analysis did not highlight any significant difference of RTW prevalence estimates between age classes.

Work conditions.

RTW after an ACS depends on medical management, clinical, psychological, and occupational factors. The meta-analysis of the few studies detailing RTW according to socio-professional categories and workload has shown a lower prevalence of work resumption among blue-collar workers and those who perform a job with high physical activity even if no significant difference was observed [START_REF] Fioretti | Social fate and long-term survival of patients with a recent myocardial infarction, after cardiac rehabilitation[END_REF][START_REF] Monpere | Return to work after rehabilitation in coronary bypass patients. Role of the occupational medicine specialist during rehabilitation[END_REF][START_REF] Fitzgerald | Return to work after percutaneous transluminal coronary angioplasty[END_REF][START_REF] Waszkowska | Return to work after myocardial infarction: A retrospective study[END_REF][START_REF] Isaaz | Return to work after acute ST-segment elevation myocardial infarction in the modern era of reperfusion by direct percutaneous coronary intervention[END_REF][START_REF] Worcester | Resumption of work after acute coronary syndrome or coronary artery bypass graft surgery[END_REF][START_REF] Lamberti | Work-related outcome after acute coronary syndrome: Implications of complex cardiac rehabilitation in occupational medicine[END_REF][START_REF] Mehrdad | Predictors of early return to work after a coronary artery bypass graft surgery (CABG)[END_REF] .

No studies aiming to implement modifications of work conditions at the workplace has been carried out. We noted some trials consisting in interventions to assist RTW in patient with coronary heart diseases during the rehabilitation program period. According to Hegewald et al. review and meta-analysis [START_REF] Hegewald | Interventions to support return to work for people with coronary heart disease[END_REF] , there is no definitive conclusion on the efficacy of psychological counselling aiming to erase some of the misconceptions and reassure patients about the fears they may have regarding the disease and the perspective to RTW. Also, programs based only on physical exercises did not significantly improve the number of patients returning to work.

Implications for clinicians and policymakers. Occupational physical constraints seem to have a negative role on RTW while psychological factors at work are insufficiently investigated. A better understanding of the real-life work conditions influencing RTW is crucial since physical and psychological constraints at the workstation, before and after the event, can constitute hurdles to maintain coronary patients in the labor market. A failed RTW could indeed lead to occupational disintegration, negative repercussion in one social life, business disorganization, and more widely to an increased cost for the society.

Thus, the detailed knowledge of work conditions, the collaboration between the occupational health and the health care teams, and an extended and regular support could help to anticipate and ensure an adapted, successful, and permanent RTW.

Conclusions

This systematic review and meta-analysis of prospective studies have shown an overall random-effects pooled RTW prevalence of 81.1% after a coronary event, in other words a pooled prevalence of no work resumption of nearly 20%. After a gradual increase during the first 6 months following the event (88.0%), this pooled prevalence lessens later (80%). Occupational physical constraints have a negative impact on RTW while psychological factors at work are insufficiently investigated.

Figure 1 .

 1 Figure 1. Study selection.

Figure 2 .

 2 Figure 2. Random-effects meta-analysis of return-to-work prevalence according to the type of events. The squares and horizontal lines correspond to the study-specific prevalence and 95% CIs. Proportionally sized boxes represent the weight of each study. The diamond represents the pooled prevalence and 95% CI of the overall population. The horizontal thick line corresponds to the 95% prediction interval.

Figure 3 .

 3 Figure 3. Return-to-work prevalence according to follow-up time.

Figure 4 .

 4 Figure 4. Random-effects meta-analysis of return-to-work prevalence according to socio-professional category. The squares and horizontal lines correspond to the study-specific prevalence and 95% CIs. Proportionally sized boxes represent the weight of each study. The diamond represents the pooled prevalence and 95% CI of the overall population. The horizontal thick line corresponds to the 95% prediction interval.

Figure 5 .

 5 Figure 5. Random-effects meta-analysis of return-to-work prevalence according to occupational physical activity. The squares and horizontal lines correspond to the study-specific prevalence and 95% CIs. Proportionally sized boxes represent the weight of each study. The diamond represents the pooled prevalence and 95% CI of the overall population. The horizontal thick line corresponds to the 95% prediction interval.

Table 1 .

 1 Return to work overall random effects pooled prevalence, according to the characteristics of the studies and the clinical and socio-professional characteristics of the patients. CABG, coronary artery bypass graft surgery; CI, confidence interval; ICD, International Classification of Diseases; LVEF, Left Ventricular Ejection Fraction;N°, number of studies; NOS, Newcastle-Ottawa scale; P, p-value; PCTA, percutaneous coronary transluminal angioplasty; RTW %, return to work overall random effects pooled prevalence.

a Between group difference.

No.

RTW % [95%-CI] I 2 p a

	Recruitment date	< 2001 ≥ 2001	22 21	79.6 [74.4; 84.4] 82.7 [75.7; 88.8]	97.2 0.458 98.8
		Clinical	37	81.3 [75.8; 86.2]	97.9 0.971
	Disease definition	ICD	4	78.8 [57.5; 94.0]	99.8
		Interview	2	80.5 [74.9; 85.5]	99.7
	Outcome definition	Self-reported Not self-reported	36 7	83.9 [70.0; 94.0] 81.6 [75.2; 87.2]	96.7 0.610 99.8
	NOS-scale score	7 stars or more < 7 stars	27 16	80.2 [67.3; 90.6] 85.2 [81.1; 88.9]	99.3 0.821 97.9
		International	3	79.8 [73.0; 85.8]	78.6 0.654
		Europe	31	85.0 [62.3; 98.4]	99.2
	WHO region	Western Pacific	5	81.9 [70.5; 91.0]	98.9
		America	2	82.2 [71.8; 90.7]	67.0
		Eastern Mediterranean	2	75.9 [59.6; 89.1]	84.2
	Gender	Male Female	11 11	64.4 [44.3; 82.3] 74.9 [62.8; 85.4]	99.6 0.336 99.0
		< 51 years	6	82.0 [63.5; 95.0]	96.6 0.387
	Age	51-53 years	9	86.2 [73.4; 95.4]	99.1
		54 years and more	7	65.3 [45.2; 83.0]	98.2
	Education level	< High school ≥ High school	7 7	85.6 [81.2; 89.6] 80.8 [67.1; 91.5]	87.6 0.085 74.2
	LVEF	< 40% ≥ 40%	5 5	77.8 [57.1; 93.2] 76.1 [64.1; 86.5]	86.4 0.346 98.2
	Treatment	PCTA CABG	11 11	75.8 [65.9; 84.5] 80.5 [74.9; 85.5]	99.0 0.524 96.9

Vol.:(0123456789) Scientific Reports | (2022) 12:15348 | https://doi.org/10.1038/s41598-022-19467-z

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author. Received: 1 December 2021; Accepted: 30 August 2022

www.nature.com/scientificreports/ Essential cardiovascular determinants of RTW were often omitted. For example, LVEF evolution could be reported more precisely (during the acute event, at discharge, and after cardiac rehabilitation). Given the few studies investigating the stress conditions at the workstation, this occupational factor should be considered in future research to identify patients in need of psychosocial assistance to support them with appropriate interventions. Physical constraints should also be systematically examined in future studies.

Thus, we note the need to implement further studies to determine the occupational conditions which could play a role in earlier work resumption. A better understanding of the whole spectrum of occupational constraints is necessary to coordinate, anticipate and ensure a successful return to work.

Author contributions

Competing interests

The authors declare no competing interests.


D Poquillon

N Vialas

D Monceau

Numerical modelling of diffusion coupled with cyclic oxidation. Application to alumina-forming coatings used for industrial gas turbine blades

Keywords: Modelling, interdiffusion, long term oxidation, coating, nickel aluminide, NiPtAl

A model using a finite elements code is developed to simulate degradation due to combined cyclic oxidation and interdiffusion in materials used in high temperature components of gas turbines. Coating recession due to cyclic oxidation (oxide growth and spalling) is also modelled using a statistical approach. Interdiffusion between coating and superallloy is modelled to predict total Al depletion in the coating. The phase transformations in the alumina-forming coating and the effects of the precipitates at the coating / superalloy interface are investigated. The results of simulations are compared with experimental data. Effects of diffusion parameters and of cyclic oxidation kinetics are discussed.

Introduction

Materials used in high temperature components of land-based gas turbines are subjected to mechanical stresses, high temperature oxidation and corrosion when low-grade fuels are burnt. Gas turbine efficiency requires the highest possible temperature but blade degradation due to creep and oxidation shortens its life. Ni based superalloys are widely used as turbine blades materials because of their good mechanical properties (creep and creep-fatigue). A protective coating is added at their surface to improve high temperature oxidation resistance. So far, coatings used for turbine blades are chosen for their oxidation-corrosion resistance: they form a protective oxide scale at the air/coating interface which decreases oxidation kinetics. During cooling, the large mismatch between oxide and coating thermal expansion coefficients induces stresses. The amount of stresses depends on many factors (temperature drop, temperature rate, oxide scale thickness…). The adherence of the oxide onto the coating is also difficult to assess depending on surface roughness, sulphur content… During thermo-mechanical cycling of the blade, spalling of the oxide is observed, accelerating oxidation kinetics. Different coatings are used on blades: overlay MCrAlY, diffusion aluminides or more recently thermal barrier coatings. For these systems, aluminium content in the coatings is large enough to ensure alumina formation and then to slow down oxidation kinetics. When spallation occurs, overlay MCrAlY and diffusion aluminides coating act as an aluminium reservoir and a new alumina scale is formed. Cyclic oxidation models have been developed [1][START_REF] Smialek | [END_REF][START_REF] Lowell | High Temperature Corrosion, Proceedings of the International Conference[END_REF][START_REF] Lowell | [END_REF][5][START_REF] Poquillon | TMS Annual Meeting symposium : Materials Lifetime Science and Engineering[END_REF][START_REF] Poquillon | [END_REF][8][9][10] with simple assumptions to calculate the Al consumption due to cyclic oxidation (spalling and reoxidation). The use of gas turbines for energy production or aeronautical applications, requires to identify, to understand and to model the mechanisms of degradation which take place in service conditions in these coating/Ni based superalloy systems. Many studies have been devoted to this subject [11][START_REF] Evans | Proc. R. Soc. Lond. A[END_REF][13][14][15][16][17][18]. The objectives of the European program ALLBATROS (Advanced Long Life BlAde TuRbine cOating Systems) [19] were to increase the efficiency, reliability and maintainability of industrial gas turbine blades. The hot parts (900-1100°C) of these turbines are subjected to strong thermal and mechanical requests. Innovative coatings proposed during this program were characterized and compared to existing coating/superalloy systems. Long term cyclic oxidations (35*300h at 1050°C) have given valuable information on the chemical and microstructural evolution of the studied systems. Degradation due to long term cyclic oxidation tests have been investigated [20][21][22][23]. For the studied systems, it was shown that Al depletion in the coating was due to oxidation and spalling of the protective oxide but also that that the contribution of Al diffusion from the coating toward the substrate was a key element in life assessment. That is the reason why the present study focuses on numerical modelling of combined diffusion and cyclic oxidation of alumina forming systems. Coupled oxidation-diffusion calculations using the finite difference methods have already been performed by Whittle in 1972 [START_REF] Whittle | 34th Proc. AGARD Meeting High Temperature Corrosion Alloys[END_REF], then by Nesbitt [START_REF] Nesbitt | [END_REF][27]. Finite element calculations of oxidizing zirconium alloy have already been carried out taking into account diffusion [28]. However, the originality of the simulations presented here is to model in the same calculations cyclic oxidation (oxide growth and spalling), interdiffusion between the coating and the substrate, coating recession (mobile boundary) and precipitates effects. Furthermore, calculations are compared to experimental data.

Materials and experimental results

The materials of the present study are composed of two different Ni-base superalloys coated with two Pt modified aluminides (RT22 developed by pack cementation and CN91 developed by chemical vapour deposition). These systems are RT22/IN792, RT22/CMSX-4, CN91/CMSX-4. and CN91/IN792. IN792 is a polycrystal alloy whereas CMSX-4 is a single crystal. The experimental database for these systems comes from long term cyclic oxidation tests performed in laboratory air at 1050°C. Cycle duration was 300 h. The Net Mass Change (NMC) curves of these oxidation tests have been reported elsewhere [20][21][22][23]. The shape of these curves is characteristic of the competition between oxidation (mass gain) and spallation (mass loss). The microstructure of the oxides formed as well as the evolution of the microstructure of the coating have been studied at different stages during the cyclic oxidation, including SEM, XRD and cross-section observations followed by chemical analysis (EDS: Energy Dispersive X-ray Spectroscopy). These concentration profiles came from different samples of each studied system removed from the furnace after 6 cycles, 17 cycles or 35 cycles of 300 h. Concentration profiles are available for each system and their evolution during cyclic oxidation were used to test the accuracy of the model.

Methods applied for the numerical simulations

The nickel base superalloys of this study have a smaller Al content (8-12at%) than the coating (>45at%). Turbine blades operate in temperature range where interdiffusion cannot be neglected.

During coating processing, Ti, Ta, Cr and Mo diffusion from the substrate towards the coating leads to the formation of precipitates at the coating/superalloy interface (Fig. 1). We will not take into account the influence of platinum content on interdiffusion. In the numerical simulations detailed in this paper, the problem of the diffusion of Ti, Ta, Cr has to be considered. In fact, as long as the coating is not transformed into γ-Ni, these species are primarily present in precipitates (Fig. 1) at the coating/superalloy interface. As long as these precipitates remain stable, there is no need to calculate the diffusion of these various elements. So, diffusion simulation will take into account only Al and Ni. However, we will show how simulations confirm the active role of these precipitates during interdiffusion. Then, simulations will be modified as detailed later to take this phenomenon into account. Initial conditions. Heat treatments are carried out during coating processing and these treatments give the initial microstructure of the system. This microstructure and chemical composition associated have been characterised using SEM and EDS. These initial profiles (reduced to Al/ Ni ratio) are introduced in the model as initial condition.

Boundary conditions. As the effect of the precipitates will be investigated, a 2-D Finite Element (FE) simulation is chosen with the boundary condition illustrated in Fig. 2: Fluxes equal zero at the centre of the superalloy and on each side. At the coating / oxide interface, Al flux is given by the cyclic oxidation model so oxide is not meshed.

The numerical simulations carried out in the present study also need to take into account coating recession due to oxide formation and partial oxide scale spallation during cycles.

The cyclic oxidations of the systems observe during this study induced significant Al consumption at the oxide/coating interface. To illustrate that point, 7µm of the 75 µm thick coating is consumed in the RT22/IN792 system after 6 cycles of 300h at 1050°C. During the simulations, the calculation of the Al consumption is carried out once at the beginning of the program and the results used during the former steps (See Fig. 4).

Coating recession. Re-meshing is time consuming and error generating, so the re-meshing step has to be optimised.

Cyclic oxidation modelling

The experimental NMC curves are given in Fig.

3 [21][22]. For the four systems reported in this study, during the first 30 cycles, oxide scale is mainly (but not only) α-alumina. The p-k p cyclic oxidation model [START_REF] Poquillon | [END_REF] is used. Only two parameters are be identified (Table 1), a spalling probability p corresponding to the mass proportion of the oxide scale spalled at each cooling and the parabolic constant k p , which characterizes the oxidation kinetics during high temperature dwells. This model is relevant when the nature of the oxide formed remains constant. It allows us to calculate not only the Net Mass Change but also the metal consumption as a function of the number of cycle (Met(n)). These values are the fourth boundary condition of the FE calculation.

Fig. 4. Scheme of the algorithm used to model coating recession

To limit the numerical errors during remeshing due to the interpolation of Al content at each node of the new mesh, coating recession (and then remeshing) occurs for a chosen step ∆e. Different values from 0.2 µm to 2 µm have been tested for ∆e.The simulation is carried out with the same mesh until coating recession is more than the chosen step. The value ∆e=0.5 µm chosen for the simulations, offering a good compromise between precision and computation time. Fig. 4 summarizes the algorithm used for these combined simulation of interdiffusion and cyclic oxidation.

The coating recession (t) e BC rec is calculated as follows using the input of the cyclic oxidation model:

{ } ∑ = = + ∆ ∆ + = n j j A 1 ox Al ox Al BC rec ) 1 n ( J t t n - t ) i ( J (t) e ( 1
)
with A=2.84 10 -7 m 3 s -1 . This value is calculated using the theoretical density for stoechiometric β-NiAl as an approximation for the coating density.

Results

Without taking into account precipitates at the coating/superallloy interface. Simulations were carried out on CN91/CMSX-4 system. Comparisons between calculated Al profile and experimental data shows (Fig. 5, curve "simu1") that simulation did not manage to account for the profile (strong decrease) at the coating/superalloy interface. In fact, the precipitates evidenced (Fig. 1) act as a diffusion barrier. For the 4 systems studied, EDS analyses carried out for 6 and 15 cycles show that Al distribution does not follow a classical fickian diffusion profile. It was then necessary to take into account this diffusion barrier. Taking into account precipitates first method consists in introducing holes in the mesh with a surface fraction (30%) and a localisation corresponding to the SEM cross section observations (Fig. 6). In fact the size and distribution of precipitates evolve during the oxidation but the surface fraction measured with the SEM on cross section remains roughly constant as long as Al in the coating is not lower than 7at% [21]. When the simulations are performed with this diffusion barier, results (Fig. 5 curve "simu2") are in better agreement with experimental data. However, meshing the precipitates did not seem to be sufficiently simple to be used by industrial partners. We thus propose an intermediate solution easier to implement. The precipitates zone acts as a diffusion barrier for Al. As the precipitates increase the tortuousness of diffusion path, we simply applied a penalization coefficient on the diffusion coefficient in the zone where precipitates are located. So a particular zone has been defined in the mesh between 55 and 75 µm from the initial coating surface where a reduction of the interdiffusion coefficient (shadow mask effect) was imposed (ratio x so Al D ~ becomes x Al D ~).

Distance from initial air/coating interface [µ µ µ µm]

Different values of x have been tested in order to get the same results than previously. The value x=0.3 has given good results on systems CN91/CMSX-4 (Fig. 5 curve "simu3") and RT22/IN792 after cycles of 300h. This value and this method have been chosen for all the other simulations. A more detailed study might be undertaken to correlate x with the volume fraction of precipitates in each system. 2). In reality, the coating remains β phase with slow Al diffusion during a longer time than in the simulation. Furthermore, experimental results reveal an increasing amount of spinels in the oxide scale. These changes in oxidations kinetics are not yet taken into account in the simulations. As the nature of oxide formed depends on the Al contents just beneath the oxide scale, such simulations could be performed with the present simulation code. Diffusion calculations have also been extremely simplified: the materials composition was reduced to a Al-Ni binary system. Phase transformations have been taken into account only through sharp variation of Al interdiffusion coefficient ( Al D ~ ). For the four studied system, experimental data on Al profiles in the coating are always flater than the calculated ones. This is partly due to the fact that phase transformation and equilibrium between phases is not simulated. Both CN91 and RT22 coatings contain a large amount of Pt. Several studies [START_REF] Nakamura | [END_REF][34][35][36][37] have been devoted to the effect of Pt contents on diffusion and/or oxidation in PtNiAl alloys.

Taking into account Pt content effects requires to take into account the diffusion under an activity gradient in the ternary system PtNiAl. The use of Al content does not take into account that Pt decreases the chemical activity of Al [36] because the chemical bond between Al and Pt is stronger than that between Al and Ni.

Conclusion

Numerical simulations have been carried out to predict Al content in the coating and especially, beneath the oxide scale in four different superalloys coated platinum modified aluminide systems.

Theses coupled simulations of cyclic oxidation kinetics and interdiffusion include many simplifying assumptions. They can now be refined by removing the more penalizing ones. Improvements are to be tested like refining the modelling of the outgoing aluminium flow i.e. cyclic oxidation kinetics and improving diffusion calculations. However, to our knowledge, this type of calculations taking into account cyclic oxidation kinetics, coating recession, interdiffusion and the effects of precipitates at the coating/superalloy interface represent an improvement on existing oxidation/interdiffusion modelling. Later on, only a flexible approach as that permitted by CAST3M will enable us to introduce the mechanical stresses that intervene on the diffusion and the transformations of phases and on oxide scale spalling. These points would be perhaps to take into account. A good knowledge of the thermomechanical loadings and properties of the materials (superalloy, coating in its various phases and alumina) are then necessary

Fig. 1 .

 1 Fig. 1. SEM observation of RT22/CMSX-4 cross section before cyclic oxidation showingprecipitates at the coating/superalloy interface[21]

RT22 CMSX- 4

 4

Fig. 2 .

 2 Fig. 2.: Scheme of the boundary conditions used for FE diffusion calculations

4 Fig. 3 .

 43 Fig. 3. Net mass change at 1050°C of each coating systems during cyclic oxidation in laboratory air (35 cycles of 300h corresponding to 10,500h)

Fig. 5 .

 5 Fig. 5. CN91/CMSX-4, Al profiles from simulations compared with experimental data.

Fig. 6 .

 6 Fig. 6. Mesh used for 2D FE simulation taking into account precipitates at the coating/superalloy interface and coating recession.

Fig. 7 .

 7 Fig. 7. RT22/IN792, calculated Al profiles compared with experimental data

Table . 1

 . Cyclic oxidation modelling for several systems

	System	CN91/IN792	CN91/CMSX-4	RT22/IN792	RT22/CMSX-4
	p	0.05	0.11	0.065	0.185
	k p [mg 2 cm -4 s -1 ]	1.1 10 -7	8. 10 -6	1.8 10 -7	8.3 10 -6

  Diffusion calculations. The approach was very simplified as it takes into account only Al and Ni contents. Nevertheless, Fick's equation is solved for Al with a diffusion coefficient depending on content. Indeed, diffusion of Al in β-NiAl and γ'-NiAl is strongly dependent of Al content. Data are available in the literature[29][30][31]. A simplified piecewise linear function for Al interdiffusion coefficient was chosen. Data are given in Table2. This way was chosen in order to take into

	account phase transformations through severe	D ~ variations.
	Table.2 Piecewise linear function for Al interdiffusion coefficient
	Al at%	0	7	19	29	36	40	48
	Al ~ [10 -14 m 2 /s] D	2.	2.	0.3.	0.3	0.3	0.1	0.03