MD Amedeo Anselmi
email: amedeo.anselmi@chu-rennes.fr

PhD Jacques Tomasi

MD Marie Aymami

MD Julien Mancini²

MD PhD Nicolas Nesseler

PhD Thierry Langanay

MD Erwan Flecher

PhD Jean-Philippe Verhoye

Porcine Bioprostheses for SAVR: Very Long-Term Performance of a 3 rd Generation Device Running head: Epic© Bioprosthesis for SAVR

Keywords: SAVR, Bioprostheses, Durability, Outcomes

Aims. We aimed at investigating the long-term durability of the Epic© bioprosthesis for SAVR in a single-center series of 888 implantations (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018), expanding previous evaluations with shorter follow-up.

Methods. We retrieved prospectively collected in-hospital data and performed a systematic follow-up focusing on valve-related events (SVD, Structural Valve Deterioration; PPM, Patient-Prosthesis Mismatch; Reoperation) (Kaplan-Meier and Competing Risks methods). We distinguished between SVD (permanent changes in valve function due to evolutive structural deterioration, ≥10 mmHg average gradient vs. reference echocardiography) and PPM.

Results. Average age at SAVR was 75.4±7 years; 855 (96.3%) bioprostheses entered the follow-up and 396 (46.4%) were alive at last assessment. Follow-up was 99.9% complete, median duration was 7.7 years (entire cohort) and 9.9 years (survivors). At 10 years, overall survival was 50%±1.9, freedom from SVD was 99.3%±0.4 (Kaplan-Meier) and 99.4%±0.3 (competing risks) (7 SVD events after 8.1±4.3 years). Freedom from SVD at 15 years was 95.6%±2.7 (Kaplan-Meier) and 98.4%±0.8 (competing risks). Prevalence of severe PPM was higher in 19-mm (6.5%) and 21-mm (10.2%) size cohorts. PPM (severe or moderate/severe) had no significant impact on overall survival (log-rank p=0.27 and p=0.21, respectively). Freedom from any reintervention (reoperation or TAVI Valve-in-Valve) for SVD at 10 years was 99.3%±0.4 (Kaplan-Meier) and 99.4%±0.3 (competing risks); freedom from any valve-related reintervention was 96.9%±0.7 (Kaplan-Meier) and 97.4%±0.6 (competing risks).

Conclusions. The Epic© bioprosthesis for SAVR is limited by non-negligible rates of PPM, which has nonetheless no impact on late survival. This device shows excellent durability and low rates of adverse valve-related events.

Introduction

Bioprostheses for surgical aortic valve replacement (SAVR) are evaluated under both the profiles of durability over time and hemodynamic performances. These are major parameters, alongside ease of implantation, to be considered in decisionmaking. The Epic© valve for SAVR, a porcine 3 rd generation device, is diffuse in global practice; it has been the object of regulatory evaluations and of large series reporting very good durability in the mid-to long-term [START_REF] Jamieson | St Jude Medical Epic porcine bioprosthesis: results of the regulatory evaluation[END_REF][START_REF] Lehmann | Porcine xenograft for aortic, mitral and double valve replacement: long-term results of 2544 consecutive patients[END_REF][START_REF] Jawad | Midterm results after St Jude Medical Epic porcine xenograft for aortic, mitral, and double valve replacement[END_REF]. Nonetheless, with the current evolutions in the population of SAVR candidates, entailing reduction of average age and increased life expectancy due to the migration towards TAVI in older patients irrespective to the class of operative risk, the appreciation of long-to very long-term durability of bioprostheses acquires a growing importance. For these patients, the projected very late clinical outcomes need to be considered in decision-making, in addition to the immediate valve performance. Our purpose was to evaluate the longterm performance of the Epic bioprosthesis for SAVR in a large single-center series with uniform surgical and investigational protocols, adding to previous literature with an important duration of follow-up available for analysis, in order to support decisionmaking in an evolving patients' population.

Patients and Methods

Ethical Statement

This observational study was based on a prospective database approved, according to compliance regulations and to the French law, by the CNIL (Commission Nationale de l'Informatique et des Libertés -National Committee for Informatics and Freedom) under the number 1207754. Patients provided written informed consent to the management of personal data and to their use for research purposes.

Patients' selection and management of Data.

In early 2021, we performed a retrospective recall of all recipients of an Epic© and Epic Supra© xenograft for SAVR and who were operated on at our Institution during the April 2001 -December 2018 period. The completeness and consecutiveness of the series was ensured by a prospective collection of in-hospital data of each cardiac surgery recipient at our center. Such database comprises an array of variables per patient including the pre-, intra-and early postoperative domains.

Grounded on an 'all comers' inclusion strategy, all etiologies of aortic valve disease were included, and irrespective to the performance of SAVR as an isolated or combined, primary or reoperative intervention. The surgical technique was uniform across the dataset, and was based on a supra-annular implantation technique using noneverting, U-shaped interrupted stitches, after both intra-and supra-annular sizing.

The interrogation of the database yielded a total of 888 eligible SAVR operations with Epic© in 885 patients. We performed a systematic follow-up of all the included patients; the referring practitioners were sent a questionnaire inquiring about the patients' vital status, the occurrence of any adverse event since hospital discharge, their timing, and the last echocardiographic parameters of the aortic valve as well. In case of missing or incomplete information, the patients themselves or their families were contacted. Three included patients were reoperated and received a new Epic© bioprosthesis; in such circumstances, the day of reoperation was considered to be the last in the follow-up of the initial valve and the first in the follow-up of the second prosthesis.

Outcomes and Definitions.

All adverse events during follow-up, as well as causes of death, were adjudicated by the investigators, and in accordance with the referring practitioners, as either valverelated or non-valve-related with respect to their relationship with the index aortic bioprosthesis. As a general rule, non-lethal events (such as stroke) were considered to be valve-related unless proof of the contrary could be demonstrated. Similarly, causes of death were classified as either valve-related or non-valve-related. Unknown causes of death were frequently encountered in this series (entailing numerous elderly patients and operations performed >10 years before last follow-up); this needs to be considered in the interpretation of survival rates as a factor overestimating the rate of valve-related deaths. For the definition of non-lethal valve-related events, we were compliant with the Akins recommendations [START_REF] Akins | Guidelines for reporting mortality and morbidity after cardiac valve interventions[END_REF], as previously indicated [START_REF] Anselmi | Long-term follow-up of bioprosthetic aortic valve replacement in patients aged ≤60 years[END_REF], as well as with the more recent consensus document [START_REF] Varc-3 Writing Committee: | Valve Academic Research Consortium 3: Updated Endpoint Definitions for Aortic Valve Clinical Research[END_REF]. Structural Valve Deterioration (SVD) was any dysfunction or deterioration involving the prosthesis in any of its parts (exclusive of infection or thrombosis) as determined by reoperation, autopsy, or clinical investigation, and independently on need for reintervention. SVD could present as meaningful (≥2/4) intraprosthetic aortic regurgitation, or as significant stenosis, or as a combination of the two. Recently published documents [START_REF] Varc-3 Writing Committee: | Valve Academic Research Consortium 3: Updated Endpoint Definitions for Aortic Valve Clinical Research[END_REF][START_REF] Capodanno | Standardized definitions of structural deterioration and valve failure in assessing long-term durability of transcatheter and surgical aortic bioprosthetic valves: a consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) endorsed by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)[END_REF] have entailed the definition of SVD as a >10 mmHg increase in average transprosthetic gradient compared to baseline, or the demonstration of a >20 mmHg during the follow-up irrespective to the value of this parameter at the moment of hospital discharge. In compliance with previous literature and with the characterization of SVD as an event entailing a pejorative and permanent change over time in valve function (associated with alterations in the structure of the valve: leaflets, stent etc.), we considered that elevated transvalvular gradient without significant (<10 mmHg) change with respect to the reference postoperative period, and in absence of echocardiographically documented structural changes, did not constitute an SVD event. SVD could present as either significant stenosis or intraprosthetic regurgitation. Therefore, we herein distinguish between SVD and patient-prosthesis mismatch (PPM), referred to as an inadequacy between the prosthesis' Effective Orifice Area, EOA, and the patients' body surface area and metabolic needs, and observed at discharge echocardiography immediately after index surgery without evidence of morphological valve dysfunction.

PPM was categorized as severe when the indexed Effective Orifice Area (iEOA) was ≤0.65 cm²/m²), moderate (iEOA ≤0.85 cm²/m²), or absent (iEOA>0.85 cm²/m²) [START_REF] Blais | Impact of valve prosthesis-patient mismatch on short-term mortality after aortic valve replacement[END_REF].

Similarly, these events were exclusive of valve thrombosis. Other outcome measures were Nonstructural Valve Dysfunction (NSVD, which embraced valve thrombosis, periprosthetic leakage and hemolysis) and Prosthetic Infective Endocarditis (IE). We also distinguished between SVD and reintervention for SVD, and between reoperation and Valve-in-Valve TAVI within the domain of reinterventions for SVD. Early or magnetic resonance demonstration of new cerebral lesion, becoming evident immediately after awakening from the anesthesia, or occurring later after a normal awakening. Postoperatively, and similar to other aortic bioprostheses in our Institutional policy, patients were treated with antiaggregant (acetylsalicylic acid 160 mg / daily) only unless anticoagulant therapy was indicated due to other reasons than the aortic bioprosthesis itself.

Statistical analysis.

Continuous variables were described as mean ± standard deviation (SD) if normally distributed, or as median if non-normally distributed. The Kolmogoroff-Smirnoff test was used for assessment of normality. Categorical variables were described as percentages. Time-to-event analyses for non-lethal valve-related events were computed according both the Kaplan-Meier ("actuarial") and competing risks ("actual") methodologies, similarly to previous literature [START_REF] Anselmi | Long-term follow-up of bioprosthetic aortic valve replacement in patients aged ≤60 years[END_REF][START_REF] Bourguignon | Very long-term outcomes of the Carpentier-Edwards Perimount aortic valve in patients aged 50-65 years[END_REF]. As SVD is a non-lethal event, its description using the "actuarial" (Kaplan-Meier) method alone would provide excessively pessimistic estimations for individual patients' counseling, since death due to other causes censors the occurrence of SVD. Since the objectives of the present work focused on late valve-related events, the Kaplan-Meier curves were computed after exclusion of the operative mortality cases; confidence intervals were graphically represented as shaded areas. Opposed Kaplan-Meier curves were compared using the log-rank statistics; the alpha level was 0.05. The analyses were conducted using IBM SPSS Statistics 27.0 (IBM Inc., New York, USA) and survminer and cmprsk packages for R 4.0 (The R Foundation for Statistical Computing Platform, Vienna, Austria).

Results

Early clinical and echocardiographic results.

Table 1 describes the baseline characteristics in the population. Average age at index surgery was 75.4 ± 7 years (range: 37-90). The lesion leading to surgery was in most cases severe calcified aortic stenosis, with a 11.6% rate of bicuspid valve morphology. Table 2 reports the intraoperative details, as well as the early postoperative clinical results. The vast majority of procedures (96.1%) were elective, concordantly with the low rate of infectious endocarditis and other conditions associated with non-elective priority. Conversely, associated procedures were relatively frequent, coronary bypass being performed in 20.2% of cases and thoracic aortic surgery in 4.6% (including three cases where complete root replacement was performed with a composite valved graft constructed by assembling an Epic© bioprosthesis and a Dacron tube). Operative mortality was 3.7%. Of note, the rates of early valve-related complications were contained. More precisely, there were no instances of NSVD, of early infectious endocarditis or of early reoperations associated with the index bioprosthesis. We observed 4 cases (0.5%) of early valve thrombosis, which was managed medically in all instances until resolution, without need for reoperation. There was a total of 14 early neurological complications (1.6%); among these, 6 (0.7%) were permanent. All of these neurological events (embolic strokes and TIAs) were systematically attributed to the index bioprosthesis in absence of proof of cause-effect relationship. The rate of new permanent pacemaker implantation was 2.7%. Discharge echocardiography data were available for the 855 survivors. The size of the implanted Epic© bioprostheses was 19-mm in 46 patients (5.2%), 21-mm in 206 patients (23.2%), 23 mm in 376 patients (42.3%), 25-mm in 183 patients (20.6%) and 27/29-mm in 77 individuals (8.7%). Average LVEF in the entire population at that time was 59.7% ± 19.4; the average transvalvular gradient was 16.2 ± 5.9 mmHg. Data about EOA in discharge echocardiography was available for 658 cases only (77% of operative survivors); average EOA was 1.7 ± 0.8 cm². The hemodynamic performances by prosthesis size are summarized in Table 3. As expected, the rates of severe/moderate PPM decreased with increasing the prosthesis' size.

Follow-up results.

Eight-hundred fifty-five patients were discharged alive from the hospital and entered the follow-up (Figure 1). One patient was lost, and follow-up data were available for 854 patients (99.9% completeness); the median follow-up duration was 7.7 years (range: 0.1 to 19.2 years) in the overall cohort. A total of 396 patients (46.4%) were alive at the end of the follow-up; among them, the median follow-up duration was 9.9 years. The 'actuarial' overall survival (Figure 2A) was 50% ± 1.9 at 10 years and 19.5% ± 2.5 at 15 years. Table 4 summarizes the freedom rates from major time-dependent outcomes by follow-up timepoint, according to both the Kaplan Meier and competing risks methodologies. Concerning SVD, we accounted for a total of 7 events during the follow-up, occurring at 8.1 ± 4.3 years after index surgery. Freedom from SVD at 10 years was 99.3% ± 0.4 and 99.4% ± 0.3, and at 15 years was 95.6% ± 2.7 and 98.4% ± 0.8 (Kaplan-Meier and competing risks, respectively) (Figure 2B). Of these, 1 required conventional reoperation and one was waiting for the performance of Valvein-Valve TAVI at the time of closure of the follow-up; the remainders received medical treatment alone, due to either moderate and mildly symptomatic valve dysfunction, or to excessive risk for any reintervention. We observed 17 IE events occurring after 3.7 Anselmi et al.

± 4.1 years (Kaplan Meier curve for survival free from IE in Figure 2C), and 17 NSVD events occurring 2 ± 2.4 years after surgery (Table 4). We noted a total of 20 valverelated reinterventions during the follow-up (all causes including SVD, IE and NSVD); the freedom from any valve-related reintervention was 96.9% ± 0.7 (actuarial) and 97.4% ± 0.6 (competing risks) at 10 years, and 96.9% ± 0.7 (actuarial) and 97.4% ± 0.6 (competing risks) at 15 years (Figure 2D). The evaluation of freedom from valverelated mortality was hindered by a considerable number of deaths due to unknown reasons (N=271) in the current follow-up (late death was formally ascertained to be valve-related in 19 instances only -4.1% of all late deaths, N=458). Nonetheless, in order to comply with recommendations over event reporting, we present a 64% ± 2 freedom from valve-related death at 10 years and a 33.8% ± 3.6 freedom at 15 years; such rates need to be interpreted in the light of the important prevalence of deaths due to unknown reasons.

The existence of PPM at discharge was not associated with a decrease in overall survival at follow-up. In fact, stratified Kaplan-Meier survival curves according to either Absent-Moderate-Severe PPM (Figure 3A) or Absent-Any PPM (Figure 3B) did not disclose any statistically meaningful difference in global survival (log-rank p=0.27 and p=0.21, respectively).

Discussion

The expansion of indications to the use of TAVI for the management of severe aortic stenosis entails major evolutions in the populations of candidates to SAVR. Among these, the younger age of surgical candidates amplifies durability as a main requirement of bioprostheses. The Epic© bioprosthesis, an evolution of the Biocor© valve (itself characterized by very good durability properties [START_REF] Mykén | A 20-year experience of 1712 patients with the Biocor porcine bioprosthesis[END_REF]), features the ethanolbased Linx© anticalcification treatment, is constituted by a low-profile stent equipped with a pericardial shield for leaflet protection, and three independent porcine aortic leaflets. It is available in the standard and in the supra-annular version mounting a lowprofile suture ring (Figure 4). We started implanting this valve in 2001, which allows achieving a considerable follow-up (up to 19.2 years) and most appropriately address the study objectives. We include 888 patients in a single-center experience; few larger series have been previously published with, in example, 1,920 SAVR cases; nonetheless, this study was characterized by a mean 4.5 years follow-up, while we present herein a median 7.7 years (overall) and an about 10 years (survivors) median follow-up period. Similarly, an actualized series of 2,441 SAVRs with Epic© was limited by a 3.04 years median follow-up [START_REF] Jawad | Midterm results after St Jude Medical Epic porcine xenograft for aortic, mitral, and double valve replacement[END_REF]. Significant sample size and follow-up duration are required to appropriately evaluate aortic valve therapies, in order to support rational decision-making in younger candidates to aortic valve therapies. At 10 years, we report a 99.3% ± 0.4 actuarial freedom from SVD, despite it is defined irrespective to the need for reintervention [START_REF] Jawad | Midterm results after St Jude Medical Epic porcine xenograft for aortic, mitral, and double valve replacement[END_REF], which compares favorably to the 96.3 ± 0.6% freedom rate at the same timepoint in one major and larger series [START_REF] Lehmann | Porcine xenograft for aortic, mitral and double valve replacement: long-term results of 2544 consecutive patients[END_REF]. The latter one was nonetheless limited by a small number of patients at risk at 10 years (N=40 vs. N=302 in our investigation), with ensuing consequences on confidence intervals and reliability of this finding. Our 10-year freedom from SVD was comparable to that observed with another current porcine bioprosthesis [START_REF] Anselmi | Long-term results of the Medtronic Mosaic porcine bioprosthesis in the aortic position[END_REF]. Other valve-related adverse events, such as IE and NSVD, presented contained rates similar to those seen in competitor valves; the overall rate of valve-related reinterventions (all causes) is also small. We defined SVD not only independently on the need for reintervention, but also reflecting the concept of SVD as an evolutive decline in valve function over time due to intrinsic failure and demonstrable morphological alterations. The NOTION trial is illustrative of the importance of the definition of SVD in impacting the reported outcomes. This study randomized 280 all-comers patients to either TAVI or SAVR using an array of four different surgical bioprostheses (including porcine and pericardial devices); a significant higher rate of SVD was associated with the SAVR group when the definition of this outcome included the simple demonstration of mean transvalvular gradient >20 mmHg during the follow-up. In fact, TAVI valves are known for good hemodynamic performances [START_REF] Auffret | Temporal Trends in Transcatheter Aortic Valve Replacement in France: FRANCE 2 to FRANCE TAVI[END_REF]. When a modified definition of SVD was used (requiring also a stable >10 mmHg increase in mean transvalvular gradient with respect to discharge echocardiography to qualify SVD), there was no more significant difference in time-dependent occurrence of SVD among groups [START_REF] Jørgensen | Eight-year outcomes for patients with aortic valve stenosis at low surgical risk randomized to transcatheter vs. surgical aortic valve replacement[END_REF]. SVD should be distinguished from valve thrombosis, which is potentially reversible. More importantly, SVD is a definitely different condition than PPM, with unalike clinical implications.

Imaging (echocardiography) demonstration of valve deterioration (abnormalities of leaflets or other valve components) is also a component of the definition of SVD.

Porcine bioprostheses are associated with worse hemodynamic characteristics and greater incidence of PPM than pericardial bioprostheses for SAVR [START_REF] Ruzicka | The complete supraannular concept: in vivo hemodynamics of bovine and porcine aortic bioprostheses[END_REF][START_REF] Suri | A prospective, randomized comparison of 3 contemporary bioprosthetic aortic valves: should hemodynamic performance influence device selection?[END_REF], particularly with respect to smaller nominal sizes (19-mm to 23-mm). The rates of PPM reported herein for the Epic© valve confirm such conclusion in comparison to both valve models with externally-mounted and internally-mounted pericardium [START_REF] Anselmi | Mid-term durability of the Trifecta bioprosthesis for aortic valve replacement[END_REF][START_REF] Anselmi | Hemodynamic Results and Mid-term Follow-up of 850 19 to 23 mm Perimount Magna Ease Valves[END_REF]. Concordantly, Anselmi et al.

the current 'all-comers' study entailed a relatively low rate of 19-mm and 21-mm valves, which may reflect the tendency of surgeons to implant pericardial bioprostheses in smaller annuli and in patients with larger body surface area, where the likelihood of PPM is greater. PPM has been addressed in various dedicated studies mixing up various valve models. In a randomized investigation, no differences at one year were observed in left ventricular mass regression and survival among subgroups of bioprostheses (including 99 Epic© valves) presenting different hemodynamic performances [START_REF] Thalji | Do differences in early hemodynamic performance of current generation biologic aortic valves predict outcomes 1 year following surgery?[END_REF]. Left ventricular mass regression at 6 months has been found to be independent on iEOA in 3 rd -generation valves [START_REF] Sádaba | Left ventricular mass regression is independent of gradient drop and effective orifice area after aortic valve replacement with a porcine bioprosthesis[END_REF]. Such concept was strengthened by the NOTION trial itself, which reported an expected higher rate of PPM in the SAVR group than in the TAVR group; but the existence of severe PPM did not influence the rate of major adverse cardiovascular events, cardiac-related hospitalizations or NYHA class at 2 years after implantation [START_REF] Thyregod | No clinical effect of prosthesis-patient mismatch after transcatheter versus surgical aortic valve replacement in intermediate-and low-risk patients with severe aortic valve stenosis at mid-term follow-up: an analysis from the NOTION trial[END_REF]. Herein, we add to this body of knowledge by providing very long-term information about the impact of PPM as well in a large cohort of SAVR with a unique 3 rd generation valve. We found no significant impact on overall survival at 10 to 15 years after surgery neither with severe nor with any PPM (Figure 3). Relief of clinically significant aortic stenosis and stability of gradients over years, as it is indicated by the low rate of SVD, likely explain this observation. We also confirm limited rates of new permanent pacemaker implantation in the early postoperative period (2.7%).

The completeness of follow-up and the sample size are points of strength of the present series, associated with the tendency of our patients to reside in the same geographical region over time. Nonetheless, the series is limited by a considerable number of unknown causes of death at follow-up, which precludes in-depth evaluation of several valve-related parameters on cardiac-related death. Additionally, follow-up echocardiography explorations were not done in-house for all patients; we retrieved latest available information from referring cardiologists during systematic patients' follow-up.

In conclusion, the current data suggest excellent durability of a 3 rd generation porcine bioprosthesis for SAVR in the long-and very long-term follow-up. Rates of other valverelated adverse events are contained. These data need to be compared to cohorts of pericardial valves with comparable follow-up duration. This porcine valve is confirmed to present lesser hemodynamic properties than pericardial valves; nonetheless, PPM is less frequent in larger valve sizes and it has no demonstrated impact on survival, facilitating the use of this valve in annuli ≥23 mm after consideration of patients' body surface area.

(

  operative) complications and mortality were defined as occurring within the 30 th postoperative day, or later if during the index hospitalization. Early postoperative neurological events comprised stroke, coma, or transient ischemic attack (TIA). Stroke was a new focal neurological deficit (or coma) associated with computed tomography Anselmi et al.

Figure 1 .

 1 Figure 1. Study workflow.

Figure 2 .

 2 Figure 2. Kaplan-Meier survival curves. A. Global survival in the overall population. B. Freedom from SVD. C. Freedom from IE. D. Freedom from valve-related reintervention (any cause including SVD, NSVD and IE).

Figure 3 .

 3 Figure 3. Kaplan-Meier survival curves. A. Global survival stratified by Absent-Moderate-Severe PPM at the time of hospital discharge. B. Global survival stratified by Absent-Any PPM at the time of hospital discharge.

Figure 4 .

 4 Figure 4. The Epic© (left) and Epic Supra© (right) valves for SAVR. Courtesy of Abbott Cardiovascular France.

Table 1 .

 1 Baseline characteristics in the entire study population (N=888 operations).

	Characteristic	N (%) or Average (SD)
	Age (years)	75.4 ± 7
	Gender: Male	650 (73.2%)
	NYHA III or IV	328 (36.9%)
	Atrial fibrillation	110 (12.4%)
	Diabetes mellitus	131 (14.8%)
	Obesity	207 (23.3%)
	BSA (m²)	1.8 ± 0.2
	Serum creatinine (µmol/L)	89.2 ± 23.4
	Renal insufficiency	39 (4.4%)
	Hepatic insufficiency	9 (1%)
	Previous stroke	37 (4.2%)
	COPD	132 (14.9%)
	Previous chest radiation therapy	15 (1.7%)
	Previous cardiac surgery	29 (3.3%)
	LVEF (%)	59.8 ± 11.3
	AVA (cm²)	0.72 ± 0.2
	Average transvalvular gradient (mmHg)	50.5 ± 15.3
	Modality of native valve dysfunction
	-Prevalent regurgitation	60 (6.8%)
	-Prevalent stenosis	783 (88.2%)
	-Mixed	45 (5.1%)
	Bicuspid valve morphology	103 (11.6%)
	Infectious endocarditis (native)	26 (2.9%)
	Acute type A aortic dissection	4 (0.5%)
	SD: Standard Deviation. BSA: Body Surface Area. COPD: Chronic Obstructive
	Pulmonary Disease. LVEF: Left Ventricular Ejection Fraction. AVA: Aortic Valve Area.

Table 2 .

 2 Intraoperative characteristics and early postoperative results in the entire study population (N=888 operations).

	Characteristic			N (%) or Average
				(SD)
	Non-elective			35 (3.9%)
	Critical perioperative state		5 (0.6%)
	Associated procedures
	-Other valve surgery		42 (4.7%)
	-Coronary surgery		179 (20.2%)
	-Thoracic aortic surgery		41 (4.6%)
	-Septal myectomy		7 (0.8%)
	-Others			21 (2.4%)
	CPB time (min)			65.6 ± 34.3
	Aortic cross-clamp time (min)		51.8 ± 26.9
	Early (operative) mortality		33 (3.7%)
	Valve-related complications
	-NSVD			None
	-Thrombosis			4 (0.5%)
	-Neurological complications: permanent	6 (0.7%)
	-Neurological complications: transient	8 (0.9%)
	-Reoperation			None
	-Noncerebral embolism		2 (0.2%)
	-IE			None
	Non-Valve-related complications
	-New Permanent Pacemaker		24 (2.7%)
	-Reoperation			4 (0.5%)
	-Prolonged ventilation		25 (2.8%)
	-Renal failure (with dialysis)		7 (0.8%)
	-Renal failure (without dialysis)	70 (7.9%)
	-Atrial fibrillation			392 (44.1%)
	-Reoperation for bleeding		32 (3.6%)
	SD: Standard Deviation. CPB: Cardiopulmonary bypass. NSVD: Nonstructural Valve
	Dysfunction.	IE:	Infectious	Prosthetic	Endocarditis.

Table 3 .

 3 Hemodynamic characteristics of the aortic bioprosthesis at discharge by prosthesis size.

	Characteristic	19 (N=46)	21 (N=206)	23 (N=376)	25 (N=183) 27-29 (N=77)	p-value**	All (N=888*)
	Average	18.6 ± 5.3	17.6 ± 6.6	16 ± 5.8	15.8 ± 5.5	12.2 ± 4.1	<0.001	16.2 ± 5.9
	transvalvular
	gradient (mmHg)
	Peak transvalvular	33.7 ± 10.8	32.3 ± 11.5	30.3 ± 10.2	29.3 ± 10.3	22.7 7.6	<0.001	30.1 ± 10.7
	gradient (mmHg)
	EOA* (cm²)	1.3 ± 0.2	1.4 ± 0.2	1.7 ± 0.8	1.9 ± 1.1	2.3 ± 0.4	<0.001	1.7 ± 0.8
	iEOA* (cm²/m²)	0.79 ± 0.13	0.81 ± 0.16	0.92 ± 0.38	1.02 ± 0.58	1.18 ± 0.35	<0.001	0.94 ± 0.41
	PPM*						<0.001
	-Absent	8 (26.7%)	55 (39.9%)	150 (54.9%)	111 (71.6%)	56 (90.3%)		380 (57.8%)
	-Moderate	19 (63.3%)	63 (45.7%)	108 (39.6%)	43 (27.7%)	6 (9.7%)		239 (36.3%)
	-Severe	3 (10.0%)	20 (14.5%)	15 (5.5%)	1 (0.6%)	-		39 (5.9%)

EOA: Effective Orifice Area. iEOA: Indexed Effective Orifice Area. PPM: Patient Prosthesis Mismatch. *Data available for 658 cases (77% of operative survivors). ** Spearman's test for rank-order correlation.

Acknowledgements

The Authors are grateful to Mrs Sylvie Marié for her invaluable help in the performance of follow-up, data collection and management of the Institutional database.

Data Availability Statement

Data contained in the current database are not publicly available, but are available from the corresponding author (AA) upon reasonable request.


M El Rhaz

R Khalis

Giorgi

Keywords: Apprentissage statistique, Epid emiologie, Signatures, S eries temporelles, Syst emes dynamiques

CO10.6 -Imputation des données manquantes par un méta-algorithme (metaCART): étude de simulation

M ethodes : Dans cette etude, nous comparons les performances de plusieurs m ethodes d'imputation : "mice", "miceRF", "miceCART", "KNN", "CART", "missForest" et "missCforest", a une nouvelle m ethode m ethode d'imputation : "metaCART". Il s'agit d'un m etaalgorithme qui prend comme imputeur de base "KNN", "missCforest" et "missForest". Dans une etude de simulation, nous avons g en er e 600 jeux de donn ees complets de 1000 patients et ensuite introduit une proportion de 30 % de donn ees manquantes aux covariables sous le m ecanisme MCAR. Le mod ele de Cox a et e utilis e comme mod ele substantif pour la g en eration des donn ees et l' evaluation post-imputation. La performance d'imputation des m ethodes a et e evalu ee par trois param etres de simulation, le bias, bias relatif et MSE des HRs. R esultats : A l'aide de l' etude de simulation, nous d emontrons que notre approche peut donner lieu a des imputations plus plausibles et donc a des inf erences plus fiables que ceux issues suites aux imputations multiples et simples (Tableau 1). Ces r esultats sugg erent que l'imputation par metaCART peut être plus efficace si la minimisation du biais est un crit ere prioritaire pour le m ethodologiste. Introduction : Les donn ees cliniques et th erapeutiques « de vie r eelle » ont pris une place importante dans l' evaluation des produits de sant e et des strat egies th erapeutiques, imposant la cr eation de nouvelles plateformes dynamiques qui s'appuient sur les m ethodes de big data et de « machine learning ». Dans ce contexte et dans le cadre d'un partenariat public-priv e ouvert sous gouvernance scientifique acad emique, le « Onco Data Hub » (ODH) est un entrepôt de donn ees de Sant e (EDS) g er e par Unicancer et constitu e de donn ees extraites a partir des donn ees imm ediatement disponibles dans les etablissements de sant e (ETS) prenant en charge des patients atteints de cancer en France.

M ethodes : La plateforme centralise plus de 60 variables cl es (caract eristiques patients et maladie, traitements reçus, biomarqueurs, suivi du statut vital. . .) nativement structur ees et collect ees automatiquement via les logiciels de pr eparation des traitements anticanc ereux parent eraux (CHIMIO Ò . . .) mais egalement des donn ees issues du dossier m edical des patients n ecessitant l'usage d'outils de traitement automatique (NLP, RegEx) pour extraire la donn ee recherch ee. L'objectif est d'obtenir une base unique, structur ee et exhaustive adapt ee a de nombreux usages : description des populations cibles, etude d'efficacit e. . . La collecte des donn ees s'organise autour de deux campagnes annuelles avec l'int egration des donn ees de patients nouvellement pris en charge ainsi que la mise a jour des patients d ej a inclus lors des collectes pr ec edentes. Les patients ayant eu une administration d'une th erapie anticanc ereuse injectable au cours des six mois pr ec edant l'extraction sont s electionn es a partir du logiciel de pr eparation des traitements anticanc ereux. Pour la premi ere phase du projet, nous avons restreint la s election aux patients ayant un diagnostic de cancer broncho-pulmonaire ou du sein. Une g en eralisation aux autres cancers est pr evue ult erieurement. Les donn ees collect ees font syst ematiquement l'objet d'un contrôle visant a valider la qualit e et la coh erence des donn ees. R esultats : En 2022, 25 premiers ETS ont particip e a l'acquisition des donn ees. L'objectif est fix e a environ 60 ETS repr esentatifs (CHU, CH, CLCC, cliniques. . .) d'ici fin 2023. La base comptait, en novembre 2022, 30 953 patients trait es dans l'un des 25 ETS contributeurs entre le 01/01/2020 et le 30/06/2022, dont 18 782 patients atteints d'un cancer du sein et 12 171 patients atteints d'un cancer broncho-pulmonaire. Les caract eristiques des patients, de leur maladie et de leur prise en charge sont d ej a accessibles et seront pr esent ees. Dans certains cas, la non-structuration des donn ees a n ecessit e une collecte manuelle directement a partir du dossier patient source sur site. Un travail d'automatisation de la r ecup eration de ces donn ees est en cours avec les ETS permettant, en plus d'atteindre l'objectif d'automatisation compl ete du processus de recueil des donn ees pr evu pour ODH, de s'inscrire dans le processus d'optimisation des syst emes informatiques propre a chaque ETS. Conclusion : Le programme ODH va contribuer a une meilleure compr ehension des strat egies th erapeutiques « en vraie vie » en constituant a terme une nouvelle source de donn ees r ecentes, riche, dynamique et repr esentative de la prise en charge des patients qui permettra de mener des projets de recherche acad emiques et de produire des donn ees n ecessaires aux laboratoires pharmaceutiques, aux institutions de sant e impliqu ees dans l' evaluation des produits de sant e et a la d ecision en sant e publique. Mots cl es : Donn ees de vie r eelle; Cancer du sein; Cancer Bronchopulmonaire; Epid emiologie; Base de donn ees

  T a g g e d H 1 CO10.5 -Pr ediction du risque de d ec es au d ecours d'une circulation extra-corporelle avec oxyg enateur a membranes veino-art erielle (ECMO-VA), gr âce a des m ethodes d'intelligence artificielleT a g g e d E n d T a g g e d P K. Sallah 1,2, *, A. Balzano 1,2 , P. Eloy 1,2 , J. Do-Vale 3 , C. De Tymowski 3 , S. Provenchere 3 T a g g e d E n d Introduction : La circulation extra-corporelle par membranes d'oxyg enation de type veino-art erielle (ECMO-VA) est la technique d'assistance pour la prise en charge des chocs cardiog eniques. Cette technique est invasive et de disponibilit e limit ee. Une meilleure connaissance des facteurs pr edictifs de mortalit e post-ECMO-VA permettrait de mieux s electionner les patients pouvant utilement b en eficier de cette th erapeutique. Notre objectif etait de comparer les pr edictions de mortalit e a 90 jours obtenues a l'aide des m ethodes d'intelligence artificielle a celles obtenues en utilisant des scores classiques. M ethodes : Les donn ees de soins de 1356 patients adultes ayant b en efici e d'une ECMO-VA entre août 2017 et novembre 2021 ont et e extraites de l'Entrepôt de donn ees de sant e (EDS) de l'Assistance publique-Hôpitaux de Paris.

  Les analyses de sensibilit e introduisant de nouvelles m ethodes d'imputation (GAIN imputation, MICE imputation) ainsi que d'autres m ethodes de r eduction de dimension (ACP, s election sur Chi2) n'ont pas am elior e les r esultats. Conclusion : Dans notre etude, les mod eles propos es se sont r ev el es plus performants que les scores classiques utilis es pour la pr ediction du risque de mortalit e au sein d'une cohorte de 1356 patients. Ces r esultats encourageants m eritent d'être reproduits sur des jeux de donn ees plus vastes et encore plus complets car quelques variables ont et e exclues de notre etude en raison d'un grand nombre de donn ees manquantes. Mots cl es : Intelligence artificielle , ECMO-VA , R egression logistique , eXtreme Gradient Boosting , Deep Neural Network D eclaration de liens d'int erêts : Les auteurs n'ont pas pr ecis e leurs eventuels liens d'int erêts. https://doi.org/10.1016/j.respe.2023.101631 T a g g e d H 1 CO10.6 -Imputation des donn ees manquantes par un m eta-algorithme (metaCART): etude de simulationT a g g e d E n d T a g g e d P I. El Badisy 1,2, *, C. Nejjari 1,3 , A. Naim 1 , K. El Rhaz 3 , M. Khalis 1 , R. Giorgi 2,4 T a g g e d E n d Introduction : L'imputation multiple est rarement appliqu ee dans les analyses bas ees sur l'apprentissage automatique, o u la majorit e des algorithmes prennent comme input un jeu de donn ees unique. Alors que pour les analyses ax ees sur l'inf erence statistique (estimations des effets des facteurs, significativit e statistique), l'imputation multiple reste le gold standard. Par ailleurs, les m ethodes bas ees sur les arbres sont plus robustes aux valeurs aberrantes et peuvent capturer plus efficacement les interactions non lin eaires entre les variables. L'objectif de notre de travail consiste a evaluer les performances d'un nouvel algorithme d'imputation inspir e du m eta-apprentissage a d'autres algorithmes d'imputation simples et multiples.

Conclusion:

  La pr esente etude montre le potentiel d'une nouvelle approche d'imputation bas ee sur le principe du m eta-apprentissage. Des proc edures d'optimisation de performance (ex. Cross-Validation) peuvent être ajout ee a cette m ethode afin de booster sa performance d'imputation. D'autres combinaisons de m eta-algorithmes et imputeurs de base peuvent être explor ees egalement. Notre travail n'est qu'une initiation a un travail important d'investigation de cette nouvelle approche propos ee. Mots cl es : Imputation multiple , Imputation simple , M eta-apprentissage , Donn ees manquantes , CART D eclaration de liens d'int erêts : Les auteurs n'ont pas pr ecis e leurs eventuels liens d'int erêts. T a g g e d P T a g g e d E n d T a g g e d F i g u r e T a g g e d E n d https://doi.org/10.1016/j.respe.2023.101632 T a g g e d H 1 CO10.7 -Plateforme de donn ees de vie r eelle ODH: elaboration d'un observatoire du m edicament en oncologieT a g g e d E n d T a g g e d P N. Benhajkassen 1, *, L. Bosquet 1 , M. Deniau 1 , C. Bachot 2 , T. Guesmia 1 , V. Robert 1 , V. Machuron 2 , A. Martin 1 T a g g e d E n d

  Age, sexe, poids, taille, ant ec edents,

	ainsi que diagnostics, actes m edicaux, donn ees de biologie pendant
	le s ejour et statuts vitaux	a J90 ont	et e recueillis soit	a partir des
	tables structur ees, soit	a l'aide d'Expressions r eguli eres (Regex). Les
	scores classiques SAVE, ENCOURAGE et REMEMBER et autres scores
	de morbidit e utilis es en pratique courante par les cliniciens, ont	et e
	reconstruits sur la base des informations contenues dans les dossiers
	m edicaux. Les variables pr esentant plus de 25 % de donn ees man-
	quantes ont	et e exclues. Trois mod eles pr edictifs ont	et e	elabor es
	apr es split 80/20 sur un fichier initial contenant 33 variables explica-
	tives potentielles, retenues par les cliniciens: r egression logistique
	avec s election de variables (RL), « eXtreme Gradient Boosting »
	(XGBoost) et « Deep Neural Network » (DNN). Une imputation simple
	par la m ediane a	et e utilis ee pour les donn ees manquantes. L'appren-
	tissage a	et e renforc ee par cross-validation. Les performances des
	mod eles et celles des scores classiques ont	et e compar ees grâce	a
	l'aire sous la courbe ROC (AUC) et test de Delong. La validit e des
	Regex a	et e	evalu ee sur un jeu de donn ees restreint.
	R esultats : Les m ethodes Regex utilis ees dans l'extraction des
	donn ees renvoyaient un taux moyen de bon classement	a 82 %. RL,
	XGBoost et DNN montrent des performances statistiquement
	equivalentes pour la pr ediction du d ec es	a 90 jours, AUC respectifs
	avec IC	a 95% : 0,83[0,78-0,88] ; 0,81[0,76-0,86] et 0,82[0,77-0,87]

sur le jeu de donn ees test tandis que les scores classiques affichent des performances plus modestes, le meilleur etant 0,7[0,67-0,73] pour le SAVE score, p-value<0,001, test de Delong.


Solène Stoens

Paul Laffont

Rémi Daudin

Alexis Lenain

Guillaume Colas

Pierre-Henri Cornuault
email: pierre-henri.cornuault@ens2m.fr

Strong dependency of the tribological behavior of Cu-Zr based Bulk Metallic Glasses on relative humidity in ambient air

Keywords: Bulk Metallic Glasses, tribology, oxide transfer layer, relative humidity

Bulk Metallic Glasses (BMGs) are new competitors to traditional crystalline metals, thanks to their outstanding mechanical properties. However, the tribological response of BMGs is still poorly understood. In the present study, the control of relative humidity (RH) enabled to observe a high repeatability of the friction tests between Cu-Zr based BMG plates and 100Cr6 balls. Interestingly, the wear rate of BMGs is especially low thanks to a 3 rd -body tribolayer that forms on the BMG surface, composed of oxidized wear particles originating from the ball. The morphology of this tribolayer is highly correlated to RH.

Introduction

Bulk Metallic Glasses (BMGs) are known for their especially high mechanical properties among which high yield strength and high elastic strain [START_REF] Inoue | Bulk Glassy Alloys: Historical Development and Current Research[END_REF]. This explains why BMGs are currently finding more and more applications in different fields including magnetic applications (nanometer-accurate actuators), structural applications (sporting goods, medical implants), optical devices (mirrors), defense and space applications, and micromechanical systems (microgears for micromotors) [START_REF] Inoue | New Bulk Metallic Glasses for Applications as Magnetic-Sensing, Chemical, and Structural Materials[END_REF][START_REF] Telford | The case for bulk metallic glass[END_REF][START_REF] Greer | Metallic glasses…on the threshold[END_REF]. The last category involves ensuring good surface properties, namely good tribological behavior.

However, the tribological behavior of BMGs remains poorly understood, because of unpredictable wear resistance. Among the few studies that deal with the tribological behavior of BMGs, results and interpretations are in conflict with one another. Many factors do not have an explicit impact on friction and wear of BMGs: mechanical properties of BMGs (hardness specifically) [START_REF] Greer | Wear resistance of amorphous alloys and related materials[END_REF][START_REF] Fleury | Tribological properties of bulk metallic glasses[END_REF][START_REF] Prakash | Abrasive wear behaviour of Fe, Co and Ni based metallic glasses[END_REF][START_REF] Maddala | Sliding wear behavior of Fe50-xCr15Mo14C15B6Erx (x=0, 1, 2at%) bulk metallic glass[END_REF][START_REF] Jiang | Tribological Studies of a Zr-Based Glass-Forming Alloy with Different States[END_REF][START_REF] Liao | Correlations between the wear resistance and properties of bulk metallic glasses[END_REF], contact conditions (normal load, sliding velocity) [START_REF] Prakash | Abrasive wear behaviour of Fe, Co and Ni based metallic glasses[END_REF][START_REF] Parlar | Sliding tribological characteristics of Zr-based bulk metallic glass[END_REF][START_REF] Zhong | Tribological behaviors of Zr-based bulk metallic glass versus Zr-based bulk metallic glass under relative heavy loads[END_REF][START_REF] Wang | Effect of sliding velocity on the transition of wear mechanism in (Zr,Cu)95Al5 bulk metallic glass[END_REF], relaxation and partial crystallization [START_REF] Jiang | Tribological Studies of a Zr-Based Glass-Forming Alloy with Different States[END_REF][START_REF] Bhatt | Tribological behaviour of Cu60Zr30Ti10 bulk metallic glass[END_REF][START_REF] Zhao | Influence of annealing on the tribological properties of Zr-based bulk metallic glass[END_REF][START_REF] Jin | Reciprocating wear mechanisms in a Zr-based bulk metallic glass[END_REF][START_REF] Wu | Wear behaviour of Zr-based in situ bulk metallic glass matrix composites[END_REF][START_REF] Liu | Wear behavior of a Zr-based bulk metallic glass and its composites[END_REF][START_REF] Aditya | Amorphous Metallic Alloys: Pathways for Enhanced Wear and Corrosion Resistance[END_REF]. Contrary to most materials, BMGs do not seem to follow Archard's law, that predicts a linear relationship between hardness and wear volume of a material [START_REF] Archard | Contact and Rubbing of Flat Surfaces[END_REF]. However, many authors still try to make a connection between BMG wear resistance and their mechanical properties (hardness [START_REF] Greer | Wear resistance of amorphous alloys and related materials[END_REF], toughness [START_REF] Maddala | Sliding wear behavior of Fe50-xCr15Mo14C15B6Erx (x=0, 1, 2at%) bulk metallic glass[END_REF][START_REF] Hofmann | Optimizing Bulk Metallic Glasses for Robust, Highly Wear-Resistant Gears[END_REF], bulk modulus [START_REF] Liao | Correlations between the wear resistance and properties of bulk metallic glasses[END_REF]), but no common agreement emerges. This can be explained by the distinctive plastic strain of BMGs, described as homogenous flow at high temperature (near or above Tg) and shear bands mediated plastic deformation at lower temperature [START_REF] Telford | The case for bulk metallic glass[END_REF][START_REF] Greer | Metallic glasses…on the threshold[END_REF]. This leads to completely different wear mechanisms as compared to their crystalline counterparts. Instead of work-hardening for crystalline structures, several authors highlight a work-softening behavior of BMGs [START_REF] Wang | Effect of sliding velocity on the transition of wear mechanism in (Zr,Cu)95Al5 bulk metallic glass[END_REF][START_REF] Wu | Wear behaviour of Zr-based in situ bulk metallic glass matrix composites[END_REF][START_REF] Wu | Tribological studies of a Zr-based bulk metallic glass[END_REF][START_REF] Fu | Sliding behavior of metallic glass: Part I. Experimental investigations[END_REF], leading to surface softening after friction. Jiang et al. [START_REF] Jiang | Tribological Studies of a Zr-Based Glass-Forming Alloy with Different States[END_REF] tries to make a connection between hardness, free volumes and crack propagation, in order to explain this work-softening typical behavior of BMGs. The tribological consequences result in subsurface softening after friction, because of shear bands and free volumes creation [START_REF] Wu | Wear behaviour of Zr-based in situ bulk metallic glass matrix composites[END_REF].

Among BMGs, Cu-Zr based are known for the advantageous combination of the high glass forming ability (GFA) of Zr-based BMGs [START_REF] Telford | The case for bulk metallic glass[END_REF][START_REF] Wu | Research on high-Al Cu-Zr-Al-Y bulk metallic glass and its composites[END_REF], coupled with the good mechanical properties of Cu-based BMGs, especially their ductility and strength [START_REF] Wu | Research on high-Al Cu-Zr-Al-Y bulk metallic glass and its composites[END_REF]. Cu-Zr-based BMGs have a proven interest in microgears [START_REF] Hofmann | Optimizing Bulk Metallic Glasses for Robust, Highly Wear-Resistant Gears[END_REF], but there is little detailed understanding of their friction and wear mechanisms. Salehan et al. [START_REF] Salehan | Effects of annealing on the tribological behavior of Zr60Cu10Al15Ni15 bulk metallic glass[END_REF] suggested a classification of wear mechanisms of Zr-based BMGs into three categories. 1) microcracks followed by delamination and abrasive wear by detached particles, 2) Shear banding and subsequent work-softening, 3) oxide tribolayer formation and possible peeling-off. The third category introduces a possible contribution of oxide tribolayer in the friction and wear behavior of BMGs, in addition to the mechanical contribution discussed above. Indeed BMGs are known for their higher sensitivity to oxidation than their crystalline counterparts [START_REF] Jiang | Tribological Studies of a Zr-Based Glass-Forming Alloy with Different States[END_REF][START_REF] Jin | Reciprocating wear mechanisms in a Zr-based bulk metallic glass[END_REF][START_REF] Kai | Oxidation behavior of a Zr-Cu-Al-Ni amorphous alloy in air at 300-425[END_REF], and a few studies based on AFM measurements deal with the tribological impact of the native oxide present on the surface of BMGs [START_REF] Ma | Nanoscale friction and growth of surface oxides on a metallic glass under electrochemical polarization[END_REF][START_REF] Kang | Importance of surface oxide for the tribology of a Zr-based metallic glass[END_REF][START_REF] Caron | Effect of surface oxidation on the nm-scale wear behavior of a metallic glass[END_REF].

At the macroscale, some tribological studies highlight the formation of an oxide tribolayer that forms during friction [START_REF] Jiang | Tribological Studies of a Zr-Based Glass-Forming Alloy with Different States[END_REF][START_REF] Wang | Effect of sliding velocity on the transition of wear mechanism in (Zr,Cu)95Al5 bulk metallic glass[END_REF][START_REF] Jin | Reciprocating wear mechanisms in a Zr-based bulk metallic glass[END_REF][START_REF] Aditya | Amorphous Metallic Alloys: Pathways for Enhanced Wear and Corrosion Resistance[END_REF][START_REF] Wu | Research on high-Al Cu-Zr-Al-Y bulk metallic glass and its composites[END_REF], sometimes resulting from material transfer [START_REF] Parlar | Sliding tribological characteristics of Zr-based bulk metallic glass[END_REF][START_REF] Zhao | Influence of annealing on the tribological properties of Zr-based bulk metallic glass[END_REF][START_REF] Wu | Wear behaviour of Zr-based in situ bulk metallic glass matrix composites[END_REF][START_REF] Wu | Tribological studies of a Zr-based bulk metallic glass[END_REF][START_REF] Zhou | Mechanical and tribological properties of Zr-Cu-Ni-Al bulk metallic glasses with dual-phase structure[END_REF][START_REF] Cornuault | On the diversity of accommodation mechanisms in the tribology of Bulk Metallic Glasses[END_REF], leading to the establishment of a 3 rd body at the interface. However, oxidation highly depends on the oxidative environments considered, and the effective control of relative humidity (RH) is often lacking in tribological studies. RH is indeed of great importance, as it is known to have a strong impact on the tribology of metals and ceramics [START_REF] Lancaster | A review of the influence of environmental humidity and water on friction, lubrication and wear[END_REF][START_REF] Chen | Effect of Humidity on Friction and Wear-A Critical Review[END_REF]. In the field of BMGs, very few studies took into account the possible environmental impact on the friction and wear, and the few ones exclusively focus on vacuum, argon and oxygen [START_REF] Fu | Sliding behavior of metallic glass: Part I. Experimental investigations[END_REF][START_REF] Wu | Effects of environment on the sliding tribological behaviors of Zr-based bulk metallic glass[END_REF][START_REF] Jones | Environment-Dependent Tribological Properties of Bulk Metallic Glasses[END_REF]. To the best of our knowledge, there is, to the present day, no study dealing with the impact of RH on the tribological behavior of BMGs, this is why the current work aims at investigating their frictional and wear behavior with controlled RH.

Materials & Methods

Sample preparation

The four BMG compositions presented in this study are Cu-Zr based. Two compositions have an equivalent ratio of Cu and Zr (Cu47Zr46Al7 and Cu45Zr46Al7Nb2, at%) named CuZr and CuZr+Nb, respectively. The two other compositions are rich in Zr (Zr60Cu28Al12 and Zr61Cu25Al12Ti2, at%) named Zr and Zr+Ti, respectively.

The BMG samples were produced by arc-melting fragments of each elements of high purity (> 99.9 %) under argon atmosphere. The melting operation was repeated five times to ensure a high chemical homogeneity. The primary alloys obtained were then injected into dedicated moulds to produce plate-shaped samples of 15 × 10 × 1 mm 3 . X-rays diffraction measurements were performed to ensure the amorphous structure of each composition, using a X'Pert Pro MPD diffractometer from PANalytical with Cu-Kα radiations (cf. Supplementary Material fig. S1). Main mechanical properties of BMG plates are listed in Table 1. Young's modulus were determined using ultrasonic techniques, and Vickers hardness was measured under a load of 1 kg during 10 seconds (means and standard deviations are calculated from 20 measurements within two different samples).

Friction tests

Friction tests were performed using an in-house designed ball-on-plate tribometer in dry sliding condition against 5 mm diameter 100Cr6 steel balls of grade 10 quality. 100Cr6 is chosen for its usual use in industrial applications with tribological interest, such as ball bearings.

The tribometer achieved reciprocating linear motion with a ± 1 mm displacement stroke at 1 Hz, until a final number of cycles (N) ranging from 200 to 10,000 at a sliding velocity of 4 mm/s. A constant normal force (FN) of 1 N was applied using dead weight, that corresponds to an initial maximal hertzian contact pressure of 520 MPa and 540 MPa, for Zr-based plates and CuZr-based plates, respectively. A LVDT sensor (Linear Variable Differential Transformer) measured the relative displacement of the ball during the tests (Δh), simultaneously to a piezoelectric sensor that measured the frictional force (FT). For each friction cycle acquired, the average friction coefficient µi was calculated from an energetic point of view using Equation 1, where Δh0 refers to the distance between the two points of the track corresponding to FT = 0, namely the forward and backward motion (2 mm). After each friction test, a stabilized friction coefficient µstab is calculated (Equation 2), corresponding to the average of all µi from the beginning of µi stabilization (with Nstab the cycle that corresponds to the start of the steady-state regime) to the end of the test (with N the final number of cycles).

Δµi refers to the standard deviation of µi over the same cycle range (from Nstab to N).

µ 𝑖 = 1 2∆ℎ 0 ∫ |𝐹 𝑇 | 𝐹 𝑁 𝑑ℎ Equation 1 µ 𝑠𝑡𝑎𝑏 = 1 𝑁 -𝑁 𝑠𝑡𝑎𝑏 ∑ µ 𝑖 𝑁 𝑖=𝑁 𝑠𝑡𝑎𝑏 Equation 2
All friction tests were performed at room temperature (25 ± 2°C) in air, with a controlled RH ranging from 20 % to 80 % thanks to solutions of sodium hydroxide with variable concentrations, as described in several works [START_REF] Madge | The Control of Relative Humidity with Aqueous Solutions of Sodium Hydroxide[END_REF][START_REF] Stokes | Standard solution for humidity control at 25℃[END_REF]. The whole tribometer was located in a tightly sealed chamber, and the inner RH was controlled thanks to an external flask of NaOH solution. Air circulation from the flask to the chamber was ensured by a peristaltic pump. A fan located in the closed chamber allowed to homogenize the RH until reaching the desired value, and was turned off before starting friction tests. RH was continuously monitored throughout the test with an ALMEMO® Control Hygrometer.

Surface analyses

The surface topography of each friction tracks (plates and balls) was characterized by optical means, with a variable focus optical microscope (InfiniteFocus, Alicona Imaging GmbH). The raw 3D surface topography images were processed with the software Gwyddion in order to measure roughness and wear volume, according to the method described by Ayerdi et al [START_REF] Ayerdi | Ball-on-flat linear reciprocating tests: Critical assessment of wear volume determination methods and suggested improvements for ASTM D7755 standard[END_REF]. First, both plate and ball surfaces were flattened by subtracting analytical surfaces obtained from the least-squares method corresponding either to the analytic closest plane (for plates) or quadratic surface (for balls). Wear volumes were then calculated in reference to the resulting average plane. Through this definition, a positive volume means a loss of matter (e.g. ejected particles), and a negative volume means addition of matter (material transfer). The wear rates K (mm 3 .N -1 .m -1 ) of the plate (Kp) and the ball (Kb) were defined as the wear volume normalized by units of sliding distance and normal force, as described in Equation 3. Vplate and Vball represent the wear volumes of the plate and the ball respectively (mm 3 ), 2 × d the distance covered in one cycle (with d = 2 mm in the actual configuration), N the number of cycles, and FN the normal force applied (N).

𝐾 𝑝 = 𝑉 𝑝𝑙𝑎𝑡𝑒 2 × 𝑑 × 𝑁 𝑐𝑦𝑐𝑙𝑒𝑠 × 𝐹 𝑁 and 𝐾 𝑏 = 𝑉 𝑏𝑎𝑙𝑙 2 × 𝑑 × 𝑁 𝑐𝑦𝑐𝑙𝑒𝑠 × 𝐹 𝑁 Equation 3
All wear tracks were also observed by means of optical microscopy (Digital Microscope Keyence VHX-7000). Post-processing of images was performed with the software ImageJ, in order to estimate the 3 rd -body coverage of the wear tracks (cf. Supplementary Material fig. S2).

Scanning Electron Microscopy (SEM) observations were then performed on wear tracks, using a FEI Apreo SEM, equipped with SE detector (secondary electrons) and BSE detector (backscattered electrons), with a beam voltage and beam current of 5 keV and 0.1 nA. Energy

Dispersive Spectroscopy (EDS) analyses were conducted at 5 keV with a Bruker SD Detector.

A 3D-SEM image combined with EDS cartography was achieved thanks to the software Mountains® from Digital Surf. A FIB cross section was performed using a Zeiss ultra 55 MEG-FEG, through a regular cross section performed at 30 keV and 2.5 nA followed by two successive cleaning cross sections performed at 0.4 nA and 80 pA.

X-rays photoelectron spectroscopy (XPS) analyses were performed on BMG surfaces prior to friction tests (after polishing and cleaning) and after friction tests (localized on wear tracks) with an Al Kα monochromatic excitation source.

Results

XPS analyses on raw surfaces

The XPS analyses carried out on each BMG compositions give information about the chemical elements in presence on the extreme surface, until an approximate depth of 2 nm. The energy of each peak indicates that all the elements are in an oxidized form, namely ZrO2, Cu2O, Nb2O5, TiO2 and different aluminum oxides including Al2O3 and Al(OH)3 (cf. Supplementary Material fig. S3). A semi-quantitative analysis is made possible by the atomic sensitivity factor method [START_REF] Wagner | Empirical atomic sensitivity factors for quantitative analysis by electron spectroscopy for chemical analysis[END_REF], whose calculation is based on the area underneath each peak (Table 2). Among all BMG compositions, the major elements in presence are Zr and Al. Surprisingly, Cu is present in negligible proportion as compared to the bulk composition (Table 1 N. For instance, the stabilized friction coefficient µstab calculated for a test of 5,000 cycles is the mean of all friction coefficients µi calculated for each cycle between 2,000 to 5,000 cycles (Figure 1a).

The value of µstab is equal to 0.70 ± 0.02, 0.67 ± 0.03, 0.69 ± 0.04, 0.67 ± 0.03 for CuZr, CuZr+Nb, Zr and Zr+Ti respectively. As far as the RH is kept constant, both the running-in process and µstab are close enough between identical tests to consider a good repeatability of the tests. Only one test was therefore performed for each parameter combination in the following experiments. versus RH (c).

Tribological tests: RH impact

Friction and wear

The investigation of the impact of RH on the tribological behavior of BMGs was carried out on the four alloy compositions. The variation of the friction coefficient, the wear rate of the plate and the wear rate of the ball depending on RH are displayed on Figure 1b andc. A strong dependence of the friction coefficient to RH is highlighted: starting at 0.95 below 30 %RH, the friction coefficient quickly decreases with increasing RH down to 0.55 at 80 %RH. This variation is similar whatever the chemical composition of the alloy. Regarding the wear rates, BMG plates show a high wear resistance with wear rates ranging from -2.10 -5 to 5.10 - 5 mm 3 /Nm. Most of the values keep close to zero, and some are even negative, meaning that material transfer from the ball to the plate occurred. This is consistent with the wear rates of the ball, that is up to 10 times higher than the wear rates of the plate. The wear rate of balls strongly depends on RH: Kb gets lower and lower when increasing RH. patches that lay on the surface, with lots of small particles distributed around the patches (Figure 2c). At 20 %RH, the wear track is larger and covered with a homogeneous repartition of small and rough patches. Two profiles extracted from those tracks (Figure 2b) show that at 80 %RH the expanded and smooth patches are above the mean surface height, contrary to the islandshaped patches at 20 %RH that are above but also below the mean surface height. Conversely, the wear tracks of all the balls have the shape of a regular disc, without any 3 rd body on the surface (cf. Supplementary Material fig. S4). Wear particles are present outside of the track. and 80 %RH (red) (e). Solid lines refer to the theorical peaks of Fe metal, dash-dotted lines refer to FeO, dashed lines refer to Fe2O3 and dotted lines to Fe3O4 [START_REF] Hawn | Deconvolution as a correction for photoelectron inelastic energy losses in the core level XPS spectra of iron oxides[END_REF].

Morphology and composition of wear tracks

SEM observations with a BSE detector allowed the identification of two types of 3 rd body patches: most of the track is covered by dark patches, but a few white patches can be found in some localized areas (cf. Supplementary Material fig. S5). Indeed, the BSE detector enables to differentiate the light elements (i.e. low atomic number Z) and the heavy elements (i.e. high Z), leading to a grey scale correlated to the elemental composition: heavier elements appear bright compared to lighter elements. The elemental composition of 3 rd body patches was studied by EDS analyses. Dark patches are mostly composed of Fe and O, contrary to white patches that are composed of Cu, Zr, Al and O (cf. Supplementary Material fig. S5c). This suggests that most of the 3 rd body patches come from oxidized wear debris of the ball (Feoxides), and a few patches come from oxidized wear debris of the BMG (Zr-Cu-Al-oxides).

Two different structures of 3 rd -body patches are observed: either the superposition of Fe-oxides that spread over Zr-Cu-Al-oxides that can reach 3 µm-high (cf. Supplementary Material fig. S5), or a mixed dark-white patch in zebra stripes, perpendicularly to the sliding direction (Figure 3b), corresponding alternatively to Zr-Cu-Al-oxides and Fe oxides (cf. Supplementary Material fig. S6). A FIB cross section displayed on Figure 3c was performed on one of these zebra striped 3 rd -bodies. The stripes extend beneath the surface until a depth superior to 1 µm, and their morphology suggests a very high plastic deformation and surface ductility. There are porosities at the root of some stripes, and the greyscale contrast along the stripes exhibits a complex composite structure of Fe-oxides and Zr-Cu-Al-oxides (Figure 3d).

However, there are only few Zr-Cu-Al-oxide patches, and most of the 3 rd -body layer is composed of dark-appearing Fe-oxides patches. XPS analyses performed over the friction tracks of CuZr samples resulting from tests at 20 %RH and 80 %RH are displayed on Figure 2e. The Fe 2p3/2 peak positions at 20 %RH and 80 %RH are 710.8 eV and 710.9 eV respectively. This corresponds to Fe2O3 oxides, according to the theorical binding energy of Fe2O3 2p3/2 peak at 710.9 eV [START_REF] Hawn | Deconvolution as a correction for photoelectron inelastic energy losses in the core level XPS spectra of iron oxides[END_REF]. This shows that the nature of iron oxide formed remains the same from 20 %RH to 80 %RH.

The BSE detector enables to differentiate the 3 rd -body layer from the BMG raw surface, because of the strong proportion of Fe-oxides constituting the 3 rd -body as compared to the Zr-Cu-Al BMG raw surface, responsible for a sharp grey-level contrast (cf. Supplementary Material fig. S2). Thanks to image binarization of SEM observations, a 3 rd body coverage was estimated for each track at 20 %RH and 80 %RH (Figure 2d). The coverage ratio was calculated on the whole central part of the wear track deprived of its extremities. Figure 2d confirms that at 20 %RH, the 3 rd body coverage of wear tracks is smaller (49 % in average) than at 80 %RH (69 % in average).

The combination of XPS analyses and wear coverage shows that humidity only affects the track coverage and morphology of the 3 rd body, but not its chemical nature (cf. Figure 2c, d ande).

Tribological tests: increasing number of cycles

Friction and wear

In order to understand the wear mechanism of Cu-Zr-based BMG and more specifically the 3 rd -body-formation scenario, a tribological study with increasing number of cycles was performed, with one test performed with each following number of cycles (N): 200 -350 -500 -750 -1,000 -1,500 -2,000 -3,500 -5,000 -10,000. The µi superposition between each test is displayed on figure S7 of Supplementary Material. The RH chosen for this study was 50 %RH for three reasons: 1) The nature of the 3 rd -body does not change with varying RH, 2)

50% RH corresponds to a medium humidity in ambient conditions and 3) the stabilization of RH is easier and faster to obtain. Two BMG compositions were selected, namely Zr and CuZr, because of the close tribological behavior exhibited by CuZr and CuZr+Nb, and on the other hand by Zr and Zr+Ti (see Figure 1a). The variation of friction coefficient and wear rates of the ball and the plate against the number of friction cycles are displayed on Figure 4, for both Zr and CuZr. Tests were performed at 50 ± 1 %RH for both Zr (left) and CuZr plates (right).

Sliding can be described according to three successive stages:

1) From sliding initiation to 1,000 friction cycles, µstab fluctuates, and the BMG plate experiences severe wear, especially Zr. µ is highly reproductible from test to test (cf.

Supplementary Material fig. S7).

2) From 1,000 to 4,000 friction cycles, the ball wear rate suddenly increases contrary to the BMG wear that decreases, until a reversal. The standard deviation of µstab decreases progressively while µstab is reaching a stable value.

3) From 4,000 to 10,000 friction cycles, a stabilized value is reached for µstab and the wear rates of both the plate and the ball. The standard deviation of µstab reaches very low values.

Morphology of wear tracks

SEM observations carried out on the wear tracks are displayed on Figure 5. The track becomes larger as the number of cycles increases. First, a ploughing striation is created in the middle of the track, followed by other secondary striations when increasing the number of cycles. At the extremities and inside of each striation, white 3 rd -body patches composed of Zr-Cu-Al-oxides are formed (cf. Supplementary Material fig. S8a). Beside and between these striations, several 3 rd body patches are formed by agglomeration of small wear debris mainly composed of iron oxides, that appear darker on BSE pictures. After more than 4,000 cycles, most of the central part of the track is covered by these dark 3 rd body patches and no white patches are seen. At each extremities of the tracks, only one white patch is still present, positioned in the middle of the facing contact area of the ball (cf. Supplementary Material fig. S8c).

Discussion

In the literature, most oxide tribolayers formed on BMGs are composed of the elements constituting the BMG. Jiang et al. [START_REF] Jiang | Tribological Studies of a Zr-Based Glass-Forming Alloy with Different States[END_REF], Aditya et al. [START_REF] Aditya | Amorphous Metallic Alloys: Pathways for Enhanced Wear and Corrosion Resistance[END_REF], and Wu et al. [START_REF] Wu | Research on high-Al Cu-Zr-Al-Y bulk metallic glass and its composites[END_REF] studied the tribological behavior of Zr-Cu based BMGs under ball-on-plate reciprocating sliding against 100Cr6, WC and Si3N4 counterparts, respectively. Wang et al. [START_REF] Wang | Effect of sliding velocity on the transition of wear mechanism in (Zr,Cu)95Al5 bulk metallic glass[END_REF] studied a Zr-Cu based BMG under pin-on-disk configuration against a GCr6 steel counterpart. All these works describe a tribolayer adhering to the BMG surface composed of oxidized elements of the BMG. For instance, Jiang et al. [START_REF] Jiang | Tribological Studies of a Zr-Based Glass-Forming Alloy with Different States[END_REF] observed the formation of an oxide-based layer when testing Zr52.5Cu17.9Ni14.6Al10Ti5 against 100Cr6. Wear scars were described into two distinct regions: abrasion regions and adhesion regions covered by dark patches. Contrary to the present work, dark patches were exclusively composed of oxidized elements of the BMG, and no iron oxides were detected. A similar BMG sample was thermally and mechanically treated until a crystalline state, and no oxide layer was observed after friction tests. Oxidative wear is thus believed to be one of the predominant wear mechanisms of amorphous metallic alloys. On the other hand, Zhao et al. [START_REF] Zhao | Influence of annealing on the tribological properties of Zr-based bulk metallic glass[END_REF], Wu et al. [START_REF] Wu | Wear behaviour of Zr-based in situ bulk metallic glass matrix composites[END_REF] and Wu et al. [START_REF] Wu | Tribological studies of a Zr-based bulk metallic glass[END_REF] described a material transfer from the BMG to the counterface by adhesive wear, under pin-on-disk friction tests between Zr-Cu based BMGs and steel (unspecified), bearing steel and stainless steel, respectively. In all of these situations, BMGs experience a severe wear through particles generation and the formation of a tribolayer composed of the BMG elements. More rarely, material transfer from the counterface to the BMG surface occurs, but only in specific cases such as: 1) the counterface is softer than the BMG [START_REF] Fleury | Tribological properties of bulk metallic glasses[END_REF] , 2) material transfer concerns only the carbon present in the counterface, that mixes with BMG oxides [START_REF] Parlar | Sliding tribological characteristics of Zr-based bulk metallic glass[END_REF], 3) material transfer of Fe occurs when Fe is already present in the BMG composition [START_REF] Zhou | Mechanical and tribological properties of Zr-Cu-Ni-Al bulk metallic glasses with dual-phase structure[END_REF][START_REF] Prakash | Sliding wear behaviour of some Fe-, Co-and Ni-based metallic glasses during rubbing against bearing steel[END_REF]. To the best of our knowledge, only one study deals with the formation of a similar tribolayer as observed in the present study, composed of the particles of the harder steel counterpart, and which form a protective layer over the BMG surface. Indeed, Cornuault et al. [START_REF] Cornuault | On the diversity of accommodation mechanisms in the tribology of Bulk Metallic Glasses[END_REF] observed a comparable tribolayer when testing Zr52.5Cu17.9Ni14.6Al10Ti5 against 100Cr6 with similar contact conditions (reciprocating sliding at 4 mm/s, during 10,000 cycles of ± 1 mm, in ambient air, at 680 MPa of initial maximal hertzian pressure).

Figure 1b highlights the strong dependence to RH during friction of the couple Cu-Zrbased BMGs / 100Cr6. This impact of RH is made visible when looking at the contact interface:

the morphologies of patches and 3 rd body coverage of the BMG tracks change depending on RH. However, this morphological change is not supported by a chemical change of the oxides formed, which remain Fe2O3 whatever the RH. This means that RH does not affect the chemical nature of the oxide particles, but the agglomeration of steel ball debris responsible of the 3 rdbody patches aggregation. According to Leheup and Pendlebury [START_REF] Leheup | Unlubricated reciprocating wear of stainless steel with an interfacial air flow[END_REF], a higher RH would act as inhibitor for surfaces oxidation, despite the common thought that presupposes an increase of oxidation in wet environment. Indeed, the oxidative process (induced by O2 presence) is slowed down because of the presence of other molecules in the surrounding atmosphere (H2O). This phenomenon should lead to an increase of friction coefficient, in opposition to the present results. De Baets et al. [START_REF] De Baets | Experimental study by means of thin layer activation of the humidity influence on the fretting wear of steel surfaces[END_REF] observed the same dependency to RH between two steels (bearing steel ball and cold-down steel), with a decrease of the friction coefficient from 0.78 at 20 %RH to 0.60 at 90 %RH. They concluded that the influence of RH was not due to oxidation inhibition, but to boundary lubrication of contacting surfaces. They defined three possible mechanisms to explain this lubricating effect of RH. 1) A change of oxide nature can occur: at low RH, fretting mainly leads to the formation of Fe2O3, that can be inhibited at higher humidities, promoting other types of oxidation reactions. 2) Gas adsorption can occur between a molecule and the metal surface, forming a physisorbed layer that lubricates the contact. 3) Condensation of the moisture can happen at very high RH, forming a lubricant film. In the present study, both the second and the third mechanisms might be involved, i.e. physisorbed gas molecules and condensed water film between the two surfaces. Moreover, Fe2O3 is known to have high capability of water adsorption: Yamamoto et al. [START_REF] Yamamoto | Water Adsorption on r-Fe2O3(0001) at near Ambient Conditions[END_REF] demonstrates the increasing molecular adsorption of water on Fe2O3 with increasing RH up to a water coverage superior to 1,5 monolayers. In addition to the lubricant film at the interface, physisorbed water may be present around the wear particles coming from the ball (Fe2O3), therefore an enhanced agglomeration of particles to form layer patches is observed at high RH.

Tests performed with increasing number of friction cycles enables to describe the wear scenario into three successive stages, schematized on Figure 6.

During the first stage, the hard steel ball creates a first ploughing striation on the softer BMG surface. Wear debris produced during this abrasion process are originating from the native oxide present on the extreme surface, mainly composed of ZrO2, aluminum oxides (Al2O3 and Al(OH)3) and Cu2O, according to the XPS analyses (cf. Supplementary Material fig. S3). These oxidized particles are compacted and flattened into small patches adhering to the surface of the BMG. The newly exposed surface inside the ploughing striations is probably Cu-enriched according to the dissociation mechanism described by Kilo et al. [START_REF] Kilo | Reaction induced surface segregation in amorphous CuZr, NiZr and PdZr alloys-an XPS and SIMS depth profiling study[END_REF], with a Curich layer underneath the upper Zr-rich layer. This ploughing mechanism associated to the formation of Zr-Cu-Al-oxide patches can explain the high BMG wear volume and the fluctuating friction coefficient during this early stage of friction. These oxides are known to be hard and abrasive, especially ZrO2 and Al2O3 [START_REF] Bhowmik | Selection of Abrasive Materials for Manufacturing Grinding Wheels[END_REF]. Consequently, the abrasive mechanism gradually reverses: the Zr-Cu-Al-oxides become responsible of the progressive abrasion of the steel ball, leading to the production of iron oxides (Fe2O3) particles in the contact interface.

During the second stage, Fe2O3 particles are compacted into patches and get anchored inside the wear track through three distinct processes: 1) Fe-oxide patches adhere to the previously formed Zr-Cu-Al-oxide patches and cover them entirely or partially. 2) Fe2O3 get anchored into some cracks on the surface of Zr-Cu-Al-oxide patches. Indeed, adhesion between steel ball and BMG plate may induce some apertures in which iron oxides are trapped. Then, the successive forward and backward motions promote strain in elongation resulting into the observed stripe shape. 3) Fe-oxide patches adhere directly to the worn surface of the BMG. As a common prerequisite to these three adhesive mechanisms, the prior presence of Zr-Cu-Al- Finally, the third stage corresponds to a steady-state establishment. The tribolayer is on the one hand responsible of an increase of the wear of the steel ball because particles are detached from the ball, and on the other hand a decrease of the BMG wear, thanks to the protective tribolayer that is being formed from those iron oxide particles. However, this steady state is dependent to RH. At low RH, the wide track is covered by small and rough 3 rd -body patches, constituting a highly abrasive surface. The facing ball undergoes severe wear and much ironoxide particles are produced, that subsequently leave the contact area. At high RH, the high water adsorption on Fe2O3 leads to the agglomeration of particles into large and smooth 3 rdbody patches. Additionally, a lubricant film of water molecules may also contribute to the smaller friction coefficient and wear rates. The newly formed interface, after the steady state establishment, is composed of steel (ball) against iron oxides (plate). This is therefore comparable to steel against steel tribological studies with varying humidities. Klaffke et al. [START_REF] Klaffke | On the repeatability of friction and wear results and on the influence of humidity in oscillating sliding tests of steel-steel pairings[END_REF] studied the tribological contact between two 100Cr6 specimens through fretting tests, and the friction coefficient follows exactly the same tendency as in the present study (cf. Figure 7). Oh et al. [START_REF] Oh | The influence of atmospheric humidity on the friction and wear of carbon steels[END_REF] also obtained similar results with carbon steels (1020, 1040 and 1045). The behavior is described as severe wear at low RH (because of adhesive wear in metal-metal contact) to soft wear at high RH (because of oxides presence and water adsorption). This shows that the tribological behavior of the BMG is strongly correlated to the counterpart material. As mentioned above, the wear mechanism described in this study is firstly due to the formation of Zr-Cu-Al-oxide patches formed from the native oxide present on BMG surfaces, playing afterwards an anchoring site for Fe2O3 particles detached from the ball. These Fe-oxide patches protect the BMG from subsequent wear, although 100Cr6 steel is harder than the BMG.

Conclusion

Until the present day, the literature about BMGs shows an erratic behavior in their tribological response. This study is a first step towards a reproducibility of the tribological response, as long as the relative humidity (RH) is controlled in addition to the usual contact conditions (normal force, sliding distance and sliding velocity).

Contrary to crystalline metals for which hardness is a determinant parameter, the relationship between hardness and the tribological behavior of BMGs is debatable. Indeed, this work highlights a surprising wear resistance of Cu-Zr-based BMGs provided by a 3 rd -body tribolayer composed of Fe2O3 oxides coming from the facing 100Cr6 ball. Consequently, the BMG gets a protection despite the higher hardness of the facing counterpart: the 3 rd -body patches accommodate friction and protect the BMG substrate from wear. This anchoring process of Fe2O3 patches is made possible thanks to an intermediate formation of Zr-Cu-Aloxide patches composed of the native oxide of BMGs.

The results show a strong influence of RH on the friction and wear of BMGs and 100Cr6.

Indeed, the compaction morphology of iron oxides differs depending on RH. In dry environment, much debris are ejected from the contact and few are compacted into small patches that plays a role of hard asperities responsible of severe wear of the hard ball. In wet environment, because of the probable presence of physisorbed water molecules and condensed water film, much debris gather and compact into large and smooth 3 rd -body patches, that can reach 3 µm high.

While rarely questioned in the literature, this study highlights the importance of the chosen counterpart on the tribological behavior of BMGs. In this study, the 100Cr6 counterpart is driving the tribological response after a BMG-dependent running-in period. It might be questioned on whether another steel counterpart would lead to the same behavior. This would have to be addressed in future works.

Figure 1 -

 1 Figure 1 -Repeatability tests performed on the four BMG compositions: friction coefficient µi

Figure 2a displays optical

  Figure 2a displays optical images of Zr+Ti wear tracks after friction tests performed at 80 %RH and 20 %RH. Observations emphasize the presence of a 3 rd body at the contact

Figure 2 -

 2 Figure 2 -Optical images of Zr+Ti wear tracks after friction tests at 80 %RH and %RH (a).

Figure 3 -

 3 Figure 3 -Optical image of a CuZr+Nb wear track at 20 %RH (a) and MEB observation (BSE)

Figure 4 -

 4 Figure 4 -µstab (red stars), Kp (unfilled circles) and Kb (filled circles) against the number of

Figure 5 -

 5 Figure 5 -SEM observations of wear tracks on the CuZr plate after 200, 350, 1,000 and 5,000

  oxide patches is necessary to play an anchoring role of Fe2O3 patches. The spontaneous adhesion of Fe2O3 particles to the BMG surface could be explained by the chemical affinity between Fe and Zr / Al (heat of mixing Fe-Zr = -25 kJ/mol ; Fe-Al = -11 kJ/mol)[START_REF] Zhou | Mechanical and tribological properties of Zr-Cu-Ni-Al bulk metallic glasses with dual-phase structure[END_REF]. The wear mechanism described in this study depends on the chemical reactivity of elements Zr-Cu-Al and Fe.

Figure 6 -

 6 Figure 6 -Scheme of the three successive stages of wear mechanisms involved between Cu-Zr-

Figure 7 -

 7 Figure 7 -Friction coefficient depending on RH of the present study (dots), compared to the

Figure S3 -

 S3 Figure S3 -XPS analyses performed on CuZr, CuZr+Nb, Zr and Zr+Ti raw surfaces after

Figure S4 -

 S4 Figure S4 -Optical image of the wear track of a steel ball. Dark particles outside of the track

Figure S5 -

 S5 Figure S5 -SEM observation of a CuZr wear track at 60 %RH with BSE detector (a), combined

Figure S6 -

 S6 Figure S6 -SEM picture of a CuZr+Nb wear track at 20 %RH with BSE detector (left) and

Figure

  Figure S7µi against number of cycles with one test performed with each following number

Figure S8 -

 S8 Figure S8 -SEM observations with BSE detector of the wear tracks extremities on the CuZr

Table 1 -

 1 Denomination, composition and mechanical properties of the studied Bulk Metallic Glasses. Asterisk refers to data from the literature[START_REF] Liao | Correlations between the wear resistance and properties of bulk metallic glasses[END_REF][START_REF] Cornuault | On the diversity of accommodation mechanisms in the tribology of Bulk Metallic Glasses[END_REF].Prior to the friction tests, plates were mechanically polished with sandpapers (until P4000 grad) until a mean Sa roughness parameter close to 70 nm (see Table1), and then ultrasonically

		Sample	Composition	Young's	Poisson's	Hardness	Sa	roughness
		denomination	[at%]	modulus (GPa)	ratio	(HV)	parameter (nm)
	Cu-Zr	CuZr	Cu47Zr46Al7	90	0.36*	480 ± 5	68 ± 4
	based	CuZr+Nb	Cu45Zr46Al7Nb2 90	0.36*	485 ± 5	73 ± 2
	Zr	Zr	Zr60Cu28Al12	83	0.36*	452 ± 4	75 ± 5
	based	Zr+Ti	Zr61Cu25Al12Ti2 83	0.36*	453 ± 4	61 ± 2
		Ball	100Cr6	210*	0.29*	805*	97 ± 5

  About Al, between 22 at% to 30 at% are detected on all surfaces, much more than in the bulk (7 at% -12 at%). Microalloyings of Ti (in Zr+Ti) and Nb (in CuZr+Nb) are detected in the same proportion as in the bulk (2 at%). It is assumed that the presence of Si may come from the polishing process.The results are in good agreement with the literature revealing that a thin oxide film of a few nanometers grows on the surface of most BMGs exposed to ambient conditions[START_REF] Kang | Importance of surface oxide for the tribology of a Zr-based metallic glass[END_REF].Regarding Cu-Zr based BMGs, several authors show that after annealing, surfaces are enriched in Zr and Al, compared to the Cu rate which drops significantly[START_REF] Tam | Oxidation behaviour of a Cu-Zr-Al bulk metallic glass[END_REF][START_REF] Nie | The effect of oxidation on the corrosion resistance and mechanical properties of a Zr-based metallic glass[END_REF][START_REF] Kilo | Reaction induced surface segregation in amorphous CuZr, NiZr and PdZr alloys-an XPS and SIMS depth profiling study[END_REF] . Most identified oxides Primary tribological tests allowed us to identify whether the frictional behavior of BMGs is repeatable or not in similar conditions of RH, normal force and sliding velocity. Four tests were carried out at 50 ± 1 %RH, 1 N, during 5,000 cycles. The variations of the friction coefficient for each BMG are displayed on Figure1a. The variation of the friction coefficient is highly similar between the four tests for each BMG. The running-in-process occurring during the first 2,000 cycles is identical between both Zr-based (Zr and Zr+Ti) and between both Cu-

	Zr-based (CuZr and CuZr+Nb), but slightly different in between the two BMG categories. The
	steady-state regime of friction was quickly reached: from 2,000 cycles, µi was considered as
	stable for all tests. The stabilized coefficient of friction µstab defined in Equation 2, was therefore
	calculated with Nstab =	2 5
	Composition	Zr	Cu	Al		Nb		Ti		Si
	(at%)
	CuZr	55.7	(46) 9.5	(47) 24.9	(7)	-		-		9.9
	CuZr+Nb	46.7	(46) 12.3	(45) 27.8	(7)	2.4	(2)	-		10.8
	Zr	63.3	(60) 1.7	(28) 24.3	(12) -		-		10.6
	Zr+Ti	62.1	(61) 1.6	(25) 22.0	(12) -		2.1	(2)	12.3
	3.2 Tribological tests: repeatability survey

). In comparison, both Zr-based (Zr and Zr+Ti) contain more than 60 at% of Zr and less than 2 at% of Cu. Both Cu-Zr-based (CuZr and CuZr+Nb) contain less Zr (approx. 50 at%) and more Cu (approx. 10 at%). are ZrO2, Al2O3 and Cu2O

[START_REF] Tam | Oxidation behaviour of a Cu-Zr-Al bulk metallic glass[END_REF][START_REF] Kimura | The oxidation of amorphous Zr-base binary alloys in air[END_REF]

. Kilo et al.

[START_REF] Kilo | Reaction induced surface segregation in amorphous CuZr, NiZr and PdZr alloys-an XPS and SIMS depth profiling study[END_REF]

describes a Cu and Zr dissociation mechanism during oxidation, leading to a Zr-rich layer on the top surface and a Cu-rich layer underneath. This may explain the surprising amount of Zr and Al as compared to Cu.

Table

2

-Quantitative analyses by XPS of the extreme surface of the four alloys after polishing and cleaning in isopropanol (at%). Numbers in brackets refer to the theorical atomic composition of the bulk material.

Acknowledgements

This work was supported by the EUR EIPHI Graduate School (contact ANR-17-EURE-0002). The authors are thankful for the financial support provided by the French National Research Agency (ANR) through the contract ANR-19-CE08-0015. The authors would like to thank Paul Laffont (from SiMAP lab at Univ. Grenoble Alpes, France) for performing the XRD and mechanical properties measurements of the BMGs (Young's modulus and hardness), Olivier Heintz and Anna Krystianiak (from ICB lab at Univ. Bourgogne Franche-Comté, France) for providing the XPS spectrums, Marina Raschetti (from Femto-ST Institute, France) for her help in using Mountains® from Digital Surf, and the technology center MIMENTO (Femto-ST Institute, France).

Supplementary Material: Supplementary material displaying additional figures is available in the online version of this article.

Authors biographies

Solène

Graphical abstract