Delphine Breuillard
email: delphine.breuillard@aphp.fr

Isabelle Jambaqué

Jacques Laschet

Rima Nabbout

& Nabbout

Delphine Mrs

Breuillard

the daily life executive function in myoclonic-atonic epilepsy

Keywords: BRIEF-P, MAE, Epilepsy, Executive functions, neuropsychology

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.

Introduction

Myoclonic Atonic Epilepsy (MAE) is a rare epilepsy syndrome characterized by a normal development before seizure onset, a peak of onset between 3 and 4 years with characteristic myoclonic atonic seizures and generalized spikes on EEG [START_REF] Koutroumanidis | The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 1)[END_REF]. Seizures outcome is variable [START_REF] Caraballo | Epilepsy with myoclonic atonic seizures: an electroclinical study of 69 patients[END_REF][START_REF] Inoue | Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy[END_REF][START_REF] Kaminska | Delineation of cryptogenic Lennox-Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis[END_REF]. Global intellectual impairment [START_REF] Kieffer-Renaux | Evolution neuropsychologique des enfants avec syndromes de Lennox-Gastaut et de Doose[END_REF][START_REF] Trivisano | Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution[END_REF], fine praxis disorders [START_REF] Kieffer-Renaux | Evolution neuropsychologique des enfants avec syndromes de Lennox-Gastaut et de Doose[END_REF][START_REF] Nabbout | Absence of mutations in major GEFS+ genes in myoclonic astatic epilepsy[END_REF], attention disorders, impulsivity and hyperkinesia [START_REF] Nabbout | Absence of mutations in major GEFS+ genes in myoclonic astatic epilepsy[END_REF][START_REF] Nolte | Behavioural and developmental aspects of primary generalized myoclonic-astatic epilepsy[END_REF][START_REF] Filippini | Neuropsychological findings: myoclonic astatic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS)[END_REF] have been described or tested using neuropsychological tools in MAE patients [START_REF] Kieffer-Renaux | Evolution neuropsychologique des enfants avec syndromes de Lennox-Gastaut et de Doose[END_REF][START_REF] Trivisano | Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution[END_REF][START_REF] Fukuda | Characterization of language and phonological working memory in patients with myoclonic astatic epileptic syndrome[END_REF].

Executive Functions (EF) are described as an umbrella term with 3 core domains: working memory (WM), inhibition and cognitive flexibility [11]. EF are a good predictor of quality of life and scholar achievement [11][START_REF] Clark | Longitudinal associations between executive control and developing mathematical competence in preschool boys and girls[END_REF][START_REF] Mcclelland | Links between behavioral regulation and preschoolers' literacy, vocabulary, and math skills[END_REF]. Deficit in EF will impact the understanding of complex social situations [START_REF] Carlson | How specific is the relation between executive function and theory of mind? Contributions of inhibitory control and working memory[END_REF],

and may lead to neuropsychiatric disorders such as Attention Deficit Hyperactivity Disorder [START_REF] Carlson | How specific is the relation between executive function and theory of mind? Contributions of inhibitory control and working memory[END_REF][START_REF] Krieger | Assessment of executive function in ADHD adolescents: Contribution of performance tests and rating scales[END_REF].

Neuropsychological tests targeting EF exist, particularly in school aged children and adults but these tests may not be representative of the everyday use of EF [START_REF] Sbordone | Neuropsychological tests are poor at assessing the frontal lobes, executive functions, and neurobehavioral symptoms of traumatically brain-injured patients[END_REF]. The Behavioral Rating Inventory of Executive Functions (BRIEF), for school aged patients and Behavioral Rating Inventory of Executive Functions -Preschool version (BRIEF-P) can better help in this assessment [START_REF] Gioia | Behavior rating inventory of executive function[END_REF][START_REF] Gioia | BRIEF-P : Behavior Rating Inventory of Executive of Executive Function -Preschool version[END_REF]. Both are translated and validated in French [START_REF] Roy | BRIEF-P : Inventaire d'évaluation comportementale des fonctions exécutives, version préscholaire[END_REF][START_REF] Roy | BRIEF: Inventaire d'évaluation comportementale des fonctions exécutives[END_REF]. These questionnaires allow an ecological evaluation of FE in the personal living spaces of the children and were already used in pediatric epilepsies studies [START_REF] Sherman | Executive Dysfunction Is a Significant Predictor of Poor Quality of Life in Children with Epilepsy[END_REF][START_REF] Slick | Frequency of Scale Elevations and Factor Structure of the Behavior Rating Inventory of Executive Function (BRIEF) in Children and Adolescents With Intractable Epilepsy[END_REF][START_REF] Parrish | Executive functioning in childhood epilepsy: parent-report and cognitive assessment[END_REF][START_REF] Pulsipher | Thalamofrontal Circuitry and Executive Dysfunction in Recent Onset Juvenile Myoclonic Epilepsy[END_REF][START_REF] Luton | Frontal Lobe Epilepsy in Children and Adolescents: A Preliminary Neuropsychological Assessment of Executive Function[END_REF][START_REF] Charbonnier | Étude d'un cas de syndrome dysexécutif à prédominance cognitive che un enfant présentant une épilepsie frontale symptomatique = A case study of executive dysfunction with predominant cognitive disorder in a child with symptomatic frontal lobe epilepsy[END_REF][START_REF] Sarco | Benign rolandic epileptiform discharges are associated with mood and behavior problems[END_REF][START_REF] Campiglia | Assessment of everyday executive functioning in children with frontal or temporal epilepsies[END_REF][START_REF] Krivitzky | Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors[END_REF][START_REF] Love | The role of executive functioning in quality of life in pediatric intractable epilepsy[END_REF][START_REF] Sepeta | The role of executive functioning in memory performance in pediatric focal epilepsy[END_REF][START_REF] Black | Everyday executive function in focal onset pediatric epilepsy on the parent-report BRIEF2[END_REF][START_REF] Maiman | Utility of the Behavior Rating Inventory of Executive Function -Preschool version (BRIEF-P) in young children with epilepsy[END_REF][START_REF] Van Den Berg | Executive and behavioral functioning in pediatric frontal lobe epilepsy[END_REF] but none focused on MAE population. As MAE is characterized by normal initial development and the absence of cerebral lesion, it constitutes an interesting model for the evaluation of the impact of epilepsy on the cognitive and behavioral areas in young childhood. The aim of this study is thus to investigate prospectively daily life executive functions in young children with MAE using BRIEF-P or BRIEF and to correlate BRIEF-P and BRIEF results with epilepsy characteristics.

Material and methods

Participants

We recruited patients with MAE diagnosed and followed in our institution. The inclusion criteria were (1) patients presenting MAE as for the criteria of the ILAE; (2) aged 3 years to 7.5 years [START_REF] Inoue | Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy[END_REF] parents able to read and understand French and (4) parents or legal guardians accepted to participate in this study.

We did not exclude patients with IQ lower than 70 in order to keep a representative MAE sample.

A group of typically developing children (TDC) aged 3-7.5 years were recruited from kindergarten and primary schools in Paris and suburbs. Inclusion criteria were the following: (1) no known learning or developmental disorder [START_REF] Caraballo | Epilepsy with myoclonic atonic seizures: an electroclinical study of 69 patients[END_REF] no previous maintain in the same preschool or primary school level, [START_REF] Inoue | Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy[END_REF] no other neurological conditions and (4) parents able to read and understand French in order to fill autonomously the questionnaire.

Scales and questionnaires

Patients with MAE had WPPSI-IV evaluation. Parents of patients with MAE and of TDC filled BRIEF and BRIEF-P questionnaires.

2.2.1-BRIEF and BRIEF-P

French versions of the BRIEF-P and BRIEF are questionnaires filled by the parents and including a series of statements targeting EF related behavior with a 3-points Likert scale (Never, Often, Always) and considering the last 6 months behavior. BRIEF-P is used for children from 3 to 5 years old and contains 63 items grouped in three composites (Inhibition self-control -ISCI ; flexibility index -FI ; and emergent metacognition index -EMI) and five scales (Inhibit, Shift, Emotional control, Working Memory and Plan/Organize). If the three composites are homogeneous, a Global Executive Composite (GEC) score can be calculated. BRIEF questionnaire is used for children aged 6 years and older and is composed of 86 items. The structure of the questionnaire is bifactorial with a Behavioral Regulation Index (BRI) and a Metacognition Index (MCI). Eight clinical scales are also described: Inhibit, Shift, Emotional Control (being part of the BRI), Initiate, Working Memory, Plan/Organize, Organization of Materials and Monitor (composing the MCI). If the MCI and BRI are homogeneous, the GEC can be calculated.

For both BRIEF-P and BRIEF, only questionnaires in the acceptable category for Inconsistency and Negativity scales were selected for the study and T-scores are reported (mean=50, standard deviation (SD)=10). Higher T-scores sign more problems reported by parents. T-scores over 65 were considered pathological.

2.2.2-Intellectual functioning

Wechsler intelligence scale for preschool children version IV (WPPSI-IV) was performed for all patients with MAE using the Full-scale IQ (FSIQ), Verbal Comprehension Index (VCI), Visual-Spatial Index (VSI) and Fluid Reasoning Index (FRI) according to age. All scores are reported in standardized scores according to the WPPSI-IV manual [START_REF] Wechsler | WPPSI-IV, échelle d'intelligence de Wechsler pour enfants[END_REF]. Composite scores are reported for indexes with mean =100, SD=15.

Patients' characteristics variables

In order to study medical variable link with BRIEF-P and BRIEF results, we report the age at seizure onset as well as number of AEDs, epilepsy duration (time between first seizure and neuropsychological evaluation) and response to treatment in months (time between treatment initiation and seizure cessation) at the time of assessment.

Study procedures

All participants' parents gave their consent. The study was approved by the Local Ethic Committee (CENEM) and registered for the treatment of medical and research data to the French authorities (CNIL, forms n°1931506 v 0 and n°1942878).

Statistical analysis

Statistical analyses were performed using JMP version 14 software from SAS Institute Inc. BRIEF and BRIEF-P T-scores were used. In addition, we transformed raw scores at BRIEF-P and BRIEF in standardized z scores for MAE group according to TDC scores. Twelve months age bands were used for the constitution of z-scores. Scores above 1.5 SD were considered in the pathological range.

Group comparisons were achieved by Student's t-test on z-scores (one tailed). Multiple regression analyses were performed with medical variables (age at onset, epilepsy duration, response to treatment, number of AED) used as predictors of BRIEF or BRIEF-P T-scores on scales and indexes.

For all analyses, the differences were considered as statistically significant if the p-value was below 0.05. The significances were further coded as following: * when p<0.05, ** when p<0.01, *** when p<0.001.

Results:

Sample characteristics

Demographic and clinical data concerning the patients and TDC are presented in Table 1. A total of 20 MAE patients and 67 TDC were recruited. Thirteen patients are in preschool and 7 patients are in primary school. Analysis of negativity and coherence showed a positive incoherent score for one BRIEF-P and one BRIEF respectively in one patient and one TDC. These data were excluded, and the remaining sample consisted of 19 patients with MAE and 66 TDC. Patients were aged between 41 and 87 months. TDCs were aged from 36 to 90 months. Analyses were performed for a total of 12 BRIEF-P and 7 BRIEF reports for patients as well as 44 BRIEF-P and 21 BRIEF reports for TDC. For the BRIEF-P questionnaires, 8 patients and 11 TDC had heterogeneous scores between ISCI, FI and EMI disabling the calculation of GEC. For the BRIEF questionnaires, 4 patients and 2 TDC had heterogeneous BRI and MI. We decided not to report the GEC score. Considering intelligence quotients, FSIQ, VIQ and FRI are in the average range for BRIEF and BRIEF-P groups except for VSI in BRIEF group (mean=82.4).

Only four patients from the BRIEF-P group had intellectual disability (FSIQ<70, #4, #8-9, #18). Patient Individual t-scaled results of BRIEF are reported in table 3. Six out of the 7 patients had pathological T-scores for at least one domain. BRI and MCI were pathological for respectively 1/7 and 6/7 patients. The one patient with IQ<70 (#18) had a pathological score for MCI. Comparing MAE and TDC z-scores, patients with MAE have higher scores for Initiate (p=0.0185), Working memory (p=0.005), Plan/organize (p=0.004), Monitor (p=0.03) and MCI (p=0.0095), suggesting worse EF scores in MAE patients. Score analysis for those subscales show pathological scores for 6/7 patients for WM, 3/7 for Initiate, 5/7 for Plan/organize and 3/7 for Monitor.

Executive functions and medical variables

Linear regression for the predictive value of age at onset, epilepsy duration and number of AEDs on BRIEF-P scores showed no link (all p>0.12), except for a tendency for number of AED on Emotional Control (t=2.00, p=0.07). Response to treatment predicts multiple BRIEF-P scores: Inhibit (t=2.60, p=0.027), Emotional Control (t=2.31, p=0.043), Plan/organize (t=2.58, p=0.027), ISCI and EMI (respectively, t=2.78, p=0.019 and t=2.42, p=0.036). A trend for significance for the prediction of response to treatment and WM is noticed (t=2.13, p=0.06).

Response to treatment and number of AEDs predictive value of BRIEF scores are not statistically significant (all p>0.10). Age at onset emerges as a predictive factor of WM scale (t=-3.35, p=0.020) and a trend for significance for Shift (t=-0.69, p=0.060) and Plan/Organize (t=-0.95, p=0.096). Those results direction suggests that the earlier onset of seizures, the higher EF scores. Epilepsy duration shows a significant predictive value of BRIEF Shift and WM domains (respectively t=3.11, p=0.027 and t=2.62, p=0.046). The direction of the coefficient estimate means that patients with longer epilepsy duration showed higher Shift scores.

Discussion

This is the first study using BRIEF and BRIEF-P questionnaires in a homogeneous group of MAE patients. Patients with MAE showed EF deficits compared to TDC group. A third of the preschool group (3-5 years old) had pathological scores on BRIEF-P. Patients had Emergent metacognition and especially WM disability compared to TDC. Response to treatment predicted some BRIEF-P subscales.

For the school aged patients (6-7 yo), BRIEF showed an alteration of metacognition scales. More precisely, planification, initiation, working memory and monitoring disabilities were reported in patients compared to TDC. Age at onset and epilepsy duration predicted BRIEF subscales.

Patients with MAE presented pathological scores for Working memory compared to TDC: 42% for the BRIEF-P and 86% for the BRIEF. Core working memory deficits at the BRIEF has been reported in the literature in samples of focal, newly diagnosed epilepsies or pharmacoresistant epilepsies ranging from 33 to 57% of patients [START_REF] Slick | Frequency of Scale Elevations and Factor Structure of the Behavior Rating Inventory of Executive Function (BRIEF) in Children and Adolescents With Intractable Epilepsy[END_REF][START_REF] Parrish | Executive functioning in childhood epilepsy: parent-report and cognitive assessment[END_REF][START_REF] Charbonnier | Étude d'un cas de syndrome dysexécutif à prédominance cognitive che un enfant présentant une épilepsie frontale symptomatique = A case study of executive dysfunction with predominant cognitive disorder in a child with symptomatic frontal lobe epilepsy[END_REF][START_REF] Campiglia | Assessment of everyday executive functioning in children with frontal or temporal epilepsies[END_REF][START_REF] Krivitzky | Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors[END_REF][START_REF] Love | The role of executive functioning in quality of life in pediatric intractable epilepsy[END_REF][START_REF] Black | Everyday executive function in focal onset pediatric epilepsy on the parent-report BRIEF2[END_REF][START_REF] Schraegle | Executive function and health-related quality of life in pediatric epilepsy[END_REF]. Interestingly, Krivitsky and collaborators found that this profile on BRIEF with higher deficits in WM domain is present in several pediatric disorders such as brain tumors, leukemia, fibromatosis type 1 [START_REF] Krivitzky | Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors[END_REF]. One study using the original American version of the BRIEF-P in young patients with various types of epilepsies found 65% of scores in the clinical rang for the WM domain, showing the highest frequency among all domains and a mean T score in the clinical range [START_REF] Maiman | Utility of the Behavior Rating Inventory of Executive Function -Preschool version (BRIEF-P) in young children with epilepsy[END_REF]. WM deficits are observed in patients with Attention Deficit Disorder without hyperactivity (ADD) [START_REF] Roy | BRIEF: Inventaire d'évaluation comportementale des fonctions exécutives[END_REF]. Attention disorders in children with epilepsy are widely reported [START_REF] Aldenkamp | A Clinical Comparative Study Evaluating the Effect of Epilepsy Versus Adhd on Timed Cognitive Tasks in Children[END_REF][START_REF] Sánchez-Carpintero | Attentional Ability in Children with Epilepsy[END_REF][START_REF] Bechtel | Attentiondeficit/hyperactivity disorder in childhood epilepsy: A neuropsychological and functional imaging study[END_REF][START_REF] Dunn | Childhood Epilepsy, Attention Problems, and ADHD: Review and Practical Considerations[END_REF] but standardized evaluation of EF and attention are scarcely reported in patients with MAE.

Using the Child Behavior CheckList (CBCL), authors reported that MAE patients had greater problems in Attention, Withdrawn/Depression and Aggressive Behavior domains [START_REF] Trivisano | Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution[END_REF]. However, the questionnaire failed to show individual impairment. In a retrospective study on 27 patients with MAE reported that approximatively half of them have attention disorders observed clinically during global efficiency tests in the first year of the disease [START_REF] Kieffer-Renaux | Evolution neuropsychologique des enfants avec syndromes de Lennox-Gastaut et de Doose[END_REF]. Only one prospective study used targeted evaluation of EF with neuropsychological standardized tools on a small series of 6 patients aged 8 to 18 years. This work initially evaluated the language skills of patients and group analysis showed a specific impairment of verbal working memory in all patients [START_REF] Fukuda | Characterization of language and phonological working memory in patients with myoclonic astatic epileptic syndrome[END_REF].

WM domain was the only domain significantly affected in BRIEF-P questionnaire in our series. A previous study using BRIEF-P in a group of 51 patients with either focal, generalized or mixed epilepsies reported disturbances as well for Inhibit, Emotional Control and Plan/Organize [START_REF] Maiman | Utility of the Behavior Rating Inventory of Executive Function -Preschool version (BRIEF-P) in young children with epilepsy[END_REF].Our results suggest specific WM impairment in MAE in daily life. For the BRIEF, Initiate, Plan/Organize and Monitor show deficits in addition to WM. All these domains are part of the MCI which is statistically impaired in our group. MCI appears to be more impaired in epilepsy groups [START_REF] Schraegle | Executive function and health-related quality of life in pediatric epilepsy[END_REF][START_REF] Macallister | Assessment of executive functioning in childhood epilepsy: The Tower of London and BRIEF[END_REF].

Previous studies failed to show a correlation between EF and epilepsy characteristics [START_REF] Campiglia | Assessment of everyday executive functioning in children with frontal or temporal epilepsies[END_REF][START_REF] Krivitzky | Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors[END_REF][START_REF] Love | The role of executive functioning in quality of life in pediatric intractable epilepsy[END_REF][START_REF] Maiman | Utility of the Behavior Rating Inventory of Executive Function -Preschool version (BRIEF-P) in young children with epilepsy[END_REF][START_REF] Van Den Berg | Executive and behavioral functioning in pediatric frontal lobe epilepsy[END_REF][START_REF] Macallister | Assessment of executive functioning in childhood epilepsy: The Tower of London and BRIEF[END_REF]. Only one study reported that patients with early onset frontal lobe epilepsy have greater EF disorders [START_REF] Luton | Frontal Lobe Epilepsy in Children and Adolescents: A Preliminary Neuropsychological Assessment of Executive Function[END_REF]. Our results show a significant linear regression with age at seizure onset and epilepsy duration as predictors of EF. Earlier age of seizures' onset predicts greater WM dysfunction and longer epilepsy duration predicts greater Shift and WM dysfunction. Hence, pharmacoresistance of seizure has implication in daily life EF according to parents of 3-5 yo children on BRIEF-P. This variable is not significant in older patients aged 6-7 yo assessed with BRIEF. The precocious seizures and the duration of the disease regardless of the pharmacoresistance seem to explain daily life difficulties of EF in 6-7 yo patients. These results support the hypothesis of the early vulnerability in preschool children with more difficulties reported in children with younger seizure start [START_REF] Anderson | Children's executive functions: Are they poorer after very early brain insult[END_REF]. Executive functions and attention are specifically dysfunctional in persons with early cerebral insult independently of the focus of the insult. MAE is an interesting model as no cerebral lesion and normal prior development is reported. Thus, the impact of seizure and the underlying supposed mutation seem to have an impact on executive function and attention following the same scheme as the lesional brain insult.

Our study has some limitations. First, we did not use the teacher report from BRIEF-P and BRIEF.

Although the correlation between parents and teacher reports are high teachers tend to report higher deficits [START_REF] Roy | BRIEF-P : Inventaire d'évaluation comportementale des fonctions exécutives, version préscholaire[END_REF][START_REF] Roy | BRIEF: Inventaire d'évaluation comportementale des fonctions exécutives[END_REF][START_REF] Van Den Berg | Executive and behavioral functioning in pediatric frontal lobe epilepsy[END_REF]. We could hypothesize that higher proportion of deficits could have been found using teacher reports. Yet, as these patients are mostly very young and preschool patients, the questionnaires were given before the possible apparition of learning disorders noticeable by teachers. Finally, we report a series with a small sample size. This is particularly due to the scarcity of this syndrome. Patients with genetic anomalies, had distinct intellectual and BRIEF profiles showing a heterogeneity. Thus, and due to the small number of the series and the lack of genetic data for all the series, we could not perform any statistical studies on genetic data. Future studies should address the question of MAE cognitive profile using cognitive standardized tests. Future studies should also assess attention using standardized measures and assess the proportion of ADD and Attention Deficit Hyperactivity Disorder in MAE population. Longitudinal study using BRIEF and BRIEF-P could enable the better understanding of the evolution of EF dysfunction with age. The better understanding of the phenotype could enable better rehabilitation programs for these patients.

Conclusions

This study reports EF dysfunction in MAE children from 3 to 7 using parental questionnaire. Thirteen out of 19 patients had at least one pathological score among the BRIEF or BRIEF-P domains. Core working memory deficit are reported in both versions of the questionnaires as previously reported in other pediatric epilepsy groups. Daily life EF scores are linked to age at onset, response to treatment and epilepsy duration.

# 4

 4 acquired walk at 13 months with balance issues reported by parents, first words are not dated by parents. First seizure appeared at 21 months. The patient had daily seizures at time of assessment and a FSIQ of 63 with VCI and FRI above 70. Patient #8 had normal development. First seizure appeared at 32 months. The patient was seizure free at time of assessment and had a FSIQ of 64 with VCI above 70. Patient #9 presented a normal development prior to seizures with first words and acquisition of walk at 13 months. First seizure was reported at 47 months. The patient was seizure free for 8 months at time of visit. FSIQ was of 67 with VSI and FRI above 70. Finally, patient #18 acquired walk at 13 months and the first words were slightly delayed as they appeared around 15 months. First seizure was observed at 43 months. Patient had monthly seizures at time of assessment and a global IQ of 62 with FRI above 70. Patient #9 has a loss of 886 kb in 2p22.3. Patient #14 has a heterozygous mutation in GRIN2B on exon 13. Patient #14 had an ID with impairment in the BRIEF while patient #9 had an IQ of 79 and no pathological scores on BRIEF. No mutation was found in 10 participants on a gene panel of 150 genes for epilepsies from whom 8 had a normal CGH array. Results are ongoing in 4 and 3 families did not accept genetic testing.3.2. EF impairment at BRIEF and BRIEF-PIndividual T-scaled results of BRIEF-P for patients are reported in table 2. ISCI and FI were pathological for 1/12 and EMI for 3/12 patients. A third of the sample (4/12) had pathological T-score for at least one domain.Considering patients with IQ lower than 70 (#4, #8, #9), one had a pathological score on two indexes (#9 -FI, EMI) while the other two had scores in the normal range for the three indexes.Group comparison are shown in table4. MAE group has more difficulties than TDC for WM domain and EMI (respectively p=0.04 and p=0,010). Considering the WM scale, 4/12 patients have a score in the pathological range.

FRI

  ; CLB= Clobazam ; CZP=Clonazapam ; ETX = Ethosuximide ; HYD = Hydrocortisone ; LTG = Lamotrigine ; LVT = Levetiracetam ; VPA = Sodium Valproate ; VCI = Verbal Comprehension Index ; VSI = Visual-Spatial Index ; FRI = Fluid Reasoning Index.

Table 1 . Demographic, clinical data and WPPSI-IV scores.

 1

		BRIEF-P (3 to 5 yo)		BRIEF (6 to 7 yo)
		MAE group (n=12) TDC group	EMAS group (n=7) TDC group
			(n=44)		(n=21)
	Sex ratio	2/10	22/22	4/3	12/9
	(girls/boys)
	Mean Age at	51.75 [41;63]	52.16 [36;72]	82.4 [77;87]	81,90 [74;90]
	evaluation (months)
	Mean age at first	37 [21;61]		40.9 [29;60]
	seizure (months)
	Mean Nb. AED	2.25 [1;4]		2 [0;4]
	[Min-Max]
	Type of AED
	CBZ	0		0
	CLB	1		1
	CZP	4		2
	ETX	1		0
	HYD	0		1
	LTG	7		4
	LVT	3		0
	VPA	11		6
	Presence of KD	5		0
	WPPSI-IV indexes
	VCI	94.2		94.9
	VSI	91.2		82.4

Table 4 . BRIEF-P z-scores for MAE groups and t-test for EMAS and TDC comparison

 4

		mean	SD	T-test
	Inhibit	0,75	1,26	t(14.57)=1.94 ;
				p=0.07
	Shift	0,70	1,83	t(14.07)=1.03 ;
				p=0.32
	Emotional	0,08	0,66	t(23.09)=0.66 ;
	Control			p=0.52
	Working	1,22	1,87	t(13.28)=2.23 ;
	Memory *			p=0.04
	Plan/organize	0,65	1,72	t(14.01)=1.32 ;
				p=0.21
	Inhibitory self	0,50	0,97	t(17.51)=1.56 ;
	control index			p=0.14
	Flexibility index 0,33	0,97	t(17.64)=1.04 ;
				p=0.31
	Emergent	1,06	1,91	t(54.0)=2.65 ;
	metacognition			p=0.01
	index*

*p<0.05 ; **p<0.01, statistically significant scores are reported in bold. T-test were made on z-scaled scores.

Table 5 . BRIEF z-scores for MAE groups and t-test for EMAS and TDC comparison

 5

		Mean	SD
	Inhibit	1,10	1,36	t(7.75)=1.97 ;
				p=0.08
	Shift	0,33	0,92	t(11.25)=0.75 ;
				p=0.47
	Emotional	1,08	1,54	t(7.29)=1.75 ;
	Control			p=0.12
	Initiate*	1,71	1,52	t(8.21)=2.93 ;
				p=0.02
	Working	2,47	1,61	t(7.53)=3.93 ;
	Memory **			p=0.0049
	Plan/organize	3,95	2,95	t(7.15)=4.15 ;
	**			p=0.0041
	Organization of	0,73	1,19	t(8.71)=1.39 ;
	materials			p=0.20
	Monitor *	1,83	1,67	t(7.22)=2.70 ;
				p=0.03
	Behavior	0,94	1,15	t(8.26)=1.91 ;
	regulation index			p=0.09
	Metacognition	2,47	1,86	t(7.25)=3.50 ;
	Index**			p=0.0095

*p<0.05; **p<0.01, statistically significant scores are reported in bold.

Acknowledgement:

We are grateful to Professor A. Roy for his collaboration. We would like to that patients and their parents for their participation as well as children from the TDC group, their parents and the teaching teams from kindergartens and elementary schools at Miollis (Paris, France) Anatole France (Aulnaysous-bois France) and Falguière (Paris) for their participation. We thank T. Baron, C. Bourne and A.

Delalande for their contribution in enrollments in school. We also thank Pr Desguerre, Dr M. Aubart, Dr N. Chemaly, Dr M. Hully, Dr H. Maurey, Dr M-A Rocchisani and Dr S. Wehbi for their participation to the recruitment of patients.


A Le Guen-Geffroy
email: antoine.le.guen.geffroy@ifremer.fr

P.-Y Le Gac

B Habert

P Davies

Physical ageing of epoxy in a wet environment: coupling between plasticization and physical ageing

Keywords: Epoxy, Physical Ageing, Water, Plasticization potential

This paper shows how physical ageing and plasticization processes are coupled in an amine-based epoxy. The study combines several ageing conditions including thermal ageing in the dry state (from 40 to 60°C), ageing in a humid environment (RH 50% and RH 75%) as well as immersion in seawater at several temperatures from 15 to 40°C. First results are presented to highlight that the two processes (physical ageing and plasticization) both occur when the epoxy is immersed in water. A step-by-step approach is then used to evaluate how the plasticization process induced by the presence of water is affected by physical ageing and vice versa. It appears that the plasticization process, which leads to a large decrease in maximum stress under tensile loading, is not affected by physical ageing of the epoxy. The physical ageing mechanism is not affected by the presence of water in the polymer, i.e. the same increase in maximum tensile stress (26 MPa) is observed in air and in water. However, the kinetic rate of physical ageing is much faster in water due to the plasticization of the polymer. These effects must be considered when accelerated aging methods are applied.

Highlights -

Plasticization process induced by water absorption is not greatly affected by physical ageing -Physical ageing process occurs in both dry and humid environments -Physical ageing is much faster in the presence of water (by a factor of 10)

Introduction

Epoxy materials are widely used in the marine domain as coatings [START_REF] Nakache | Degradation of rubber to metals bonds during its cathodic delamination, validation of an artificial ageing test[END_REF][START_REF] Bouvet | In situ monitoring of organic coating swelling by dynamic mechanical analysis and scanning electrochemical microscopy[END_REF], adhesives [START_REF] Ilioni | Prediction of Mechanical Behaviour of a Bulk Epoxy Adhesive in a Marine Environment[END_REF][START_REF] Bordes | Prediction of long term strength of adhesively bonded steel/epoxy joints in sea water[END_REF] and as a matrix for many composite materials [START_REF] Summerscales | Marine Applications of Advanced Fibre-reinforced Composites[END_REF][START_REF] Gagani | A novel method for testing and determining ILSS for marine and offshore composites[END_REF][START_REF] Baley | Application of Interlaminar Tests to Marine Composites[END_REF][START_REF] Colin | Humid Ageing of Organic Matrix Composites[END_REF]. Because long term durability is mandatory for structures used at sea for both ecological and economic reasons, the durability of epoxy polymers in a humid environment has been widely studied in the past [START_REF] Morgan | The Durability of Epoxies[END_REF][START_REF] Delozanne | Failure of epoxies bonded assemblies: comparison of thermal and humid ageing[END_REF][START_REF] De'nève | Water absorption by an epoxy resin and its effect on the mechanical properties and infra-red spectra[END_REF][START_REF] El Yagoubi | Thermomechanical and hygroelastic properties of an epoxy system under humid and cold-warm cycling conditions[END_REF].

When epoxy materials are immersed in seawater, water diffuses into the polymer. This water absorption usually follows a Fickian behaviour that allows a maximal water absorption and a diffusion rate to be defined. The water absorption depends largely on chemical formulation, especially the type of hardener [START_REF] Bonniau | A Comparative Study of Water Absorption Theories Applied to Glass Epoxy Composites[END_REF][START_REF] Morel | Structure-water absorption relationships for amine-cured epoxy resins[END_REF]. For amine-based epoxies, maximal water uptake is roughly 3% [START_REF] De'nève | Water absorption by an epoxy resin and its effect on the mechanical properties and infra-red spectra[END_REF][START_REF] Diamant | The effect of network structure on moisture absorption of epoxy resins[END_REF][START_REF] Maggana | Water sorption and diffusion studies in an epoxy resin system[END_REF][START_REF] Lin | Moisture sorption-desorption-resorption characteristics and its effect on the mechanical behavior of the epoxy system[END_REF] with a low water diffusion rate being between 1 and 3.10 -13 m²/s for amine based epoxies [START_REF] Diamant | The effect of network structure on moisture absorption of epoxy resins[END_REF][START_REF] Maggana | Water sorption and diffusion studies in an epoxy resin system[END_REF][START_REF] Nogueira | Effect of water sorption on the structure and mechanical properties of an epoxy resin system[END_REF][START_REF] Moy | Epoxy-water interactions[END_REF][START_REF] Vanlandingham | Moisture diffusion in epoxy systems[END_REF] compared to the anhydride-based epoxies for which the water uptake is low, about 0.5% [START_REF] Capiel | Water diffusion and hydrolysis effect on the structure and dynamics of epoxy-anhydride networks[END_REF]. The presence of water within the epoxy leads to a physical and reversible degradation known as plasticization, by which water leads to an increase in macromolecular chain mobility. This process is mainly observed in amine-based epoxy materials, due to the large amount of absorbed water. The increase in chain mobility leads to a large decrease in glass transition temperature (Tg), about 10°C per percent of water in the epoxy, and large changes in mechanical behaviour [START_REF] Morgan | The Durability of Epoxies[END_REF][START_REF] De'nève | Water absorption by an epoxy resin and its effect on the mechanical properties and infra-red spectra[END_REF][START_REF] Nogueira | Effect of water sorption on the structure and mechanical properties of an epoxy resin system[END_REF][START_REF] Moy | Epoxy-water interactions[END_REF][START_REF] Abanilla | Durability characterization of wet layup graphite/epoxy composites used in external strengthening[END_REF]. The most impressive consequence is the decrease in yield stress, that can be divided by a factor of 2 due to water absorption [START_REF] Sugiman | Effects of the media and ageing condition on the tensile properties and fracture toughness of epoxy resin[END_REF][START_REF] Loh | Modelling anomalous moisture uptake, swelling and thermal characteristics of a rubber toughened epoxy adhesive[END_REF]. The presence of water can also leads to an increase in strain at break [START_REF] Fredj | Some consequences of saline solution immersion on mechanical behavior of two marine epoxy-based coatings[END_REF]. In terms of modulus, both increases and decreases can be observed depending on the anti-plasticization effect [START_REF] Mijović | Local Dynamics and Molecular Origin of Polymer Network-Water Interactions as Studied by Broadband Dielectric Relaxation Spectroscopy, FTIR, and Molecular Simulations[END_REF][START_REF] Colombini | Dynamic mechanical investigations of the effects of water sorption and physical ageing on an epoxy resin system[END_REF].

It is also well known that polymers can undergo physical ageing when used below their Tg [START_REF] Struik | Physical aging in amorphous polymers and other materials[END_REF][START_REF] Sell | Influence of physical ageing on the yield response of model DGEBA/poly(propylene oxide) epoxy glasses[END_REF]. This kind of ageing is the result of a reduction in free volume and changes in the molecular configuration. Since this process has been widely studied, most of the results available are well reviewed in [START_REF] Hutchinson | Physical aging of polymers[END_REF]. One need only recall that physical ageing is a reversible process that occurs with time and can be erased by heating samples above Tg, a process known as thermal rejuvenation. Physical ageing leads to a small increase in Tg (about 5°C) and a large increase in yield stress. For example, Cook et al. found an increase from 50 MPa to 80MPa during physical ageing of an epoxy [START_REF] Cook Wayned | Ageing and yielding in model epoxy thermosets[END_REF]. Although this process has been widely studied in the past, most of the results available come from experiments performed in air. When considering coupling between water absorption and physical ageing, few results are available. Zheng et al. [START_REF] Zheng | Physical aging of an epoxy subsequent to relative humidity jumps through the glass concentration[END_REF] were the first to study the impact of water content on physical ageing through volume variation measurements. They found that water content has similar effects to temperature changes on physical ageing of epoxy but kinetics are different, which leads to difficulties in prediction; they did not consider mechanical changes induced by physical ageing. Here we focus on changes in yield stress of an epoxy during ageing in seawater where both plasticization and physical ageing occurs.

First, material and methods are presented. Then we will focus on primary results that clearly show that both physical ageing and plasticization occur when the epoxy is immersed in seawater. Based on these results, a step-by-step methodology will be used to highlight coupling between these two phenomena. Finally, a conclusion will be made.

Materials and methods a. Materials

The material studied is a commercial epoxy resin SR8100 from Sicomin® with an amine based slow hardener SD4772 which is suitable for Resin Transfer Moulding (RTM) and infusion processing of composites. The pre-polymers are diglycidyl ether of bisphenol F (DGEBF, ≥50%), diglycidyl ether of bisphenol A (DGEBA, ≥10%) and 1,6 hexa diglycidyl ether (≥10%).

b. Sample preparation and fabrication

Resin was cast vertically between two aluminium plates separated by an all-around 3 mm thick spacer. This thickness was chosen to allow an easier casting due to the resin's viscosity. This casting technique allows low surface contact with ambient air limiting unwanted reactions during curing of the resin. After 24 hours at ambient room temperature, the resin plates were removed from the mould, aluminium plates were covered by Teflon tape in order to assist removal of the epoxy plates. Then epoxy sheets were placed in vacuum bags and cured for 16 hours at 60°C as recommended by the supplier. Finally, the resin plates were post-cured for 2 hours at 120°C allowing full curing of the resin. The resulting glass transition temperature (Tg) was measured by DSC at 10°C/min with a TA instruments Q200 DSC at 75°C.

After curing, resin plates were machined down to 1 mm in thickness and tensile specimens were cut in accordance with 1BA dimensions from ISO 527-2 with a Charly DMC 300 CNC machine from Charly Robot®.

c. Tensile procedure and measurements

Tensile tests were performed according to ISO 527-2 under displacement control at 1 mm/min on a 10kN Instron™ machine, with a 500N Instron™ load cell and pneumatic grips. Tests were carried out in a 21°C 50% RH controlled room. Strain measurements were obtained by digital image correlation by applying a random graphite pattern on the specimens. Images were captured by a Basler™ camera at 1 frame per second and correlated with Aramis® software.

d. DMA

DMA were performed using a Metravib™ 150N machine in tensile mode with a dynamic strain of 5.10-4 and a ratio between static and dynamic displacement equal to 4. Samples were tested at 1Hz from -120°C to 200°C with a temperature increase of 2°C/min. For physical ageing in dry environment: Tensile specimens were first packed in vacuum bags in order to limit any oxidative reactions. Before any physical ageing, bags were placed in 90°C water for 5 minutes in order to expose specimens to above-Tg temperature and thus eliminate any physical ageing present in the material. Then specimens were immediately quenched by plunging the vacuum bags in 15°C water. Quenched samples were then placed in different temperature ovens. Before being tested in tension, samples were placed in the testing room for at least 15 minutes in order to cool to room temperature.

For physical ageing in wet environment: The tensile samples were first immersed in seawater at 40°C during one month, which corresponds to full saturation at 2.8% by weight of water. Samples were then placed in 90°C water for 5 minutes and quenched in 15°C water in order to erase any physical ageing present in the material. The samples were finally placed in different temperature-controlled seawater baths. This results in physical ageing without changing the water content inside the material.

f. Water ageing in air and in seawater

Water ageing was performed under three different humidity conditions and one temperature of 40°C. The 50% and 75% relative humidity conditions were applied in temperature and humidity controlled ovens, and natural seawater ageing was performed in a renewed, and temperature controlled natural seawater bath. For more details on the facility used see [START_REF] Tchalla | Polychloroprene behaviour in a marine environment: Role of silica fillers[END_REF].

Results and discussion

Preliminary tests and resulting coupling problematic

This first experimental results section aims to highlight the fact that both plasticization and physical ageing occur when amine based epoxy materials are immersed in seawater. Figure 2 shows tensile curves obtained on unaged and aged samples at 40°C in seawater, i.e. below Tg, for 1 month until saturation occurs. After ageing, samples were tested after several treatments.

First, the tensile behaviour of the unaged sample (#1 in Figure 2) shows a typical elastoplastic behaviour with a linear part for low strain with a modulus close to 2.6 GPa then a yield that is related to the maximal stress (here 57 MPa ± 1) and finally a failure that occurs at roughly 10% elongation. All these values are typical for epoxy materials [START_REF] Colin | Humid Ageing of Organic Matrix Composites[END_REF].

Then, samples were tested directly after removal from ageing tanks meaning that they are fully saturated by water (2.8% here), this is curve #2. It clearly appears that tensile behaviour is affected by ageing here. In fact, an increase in maximal stress from 57MPa to 64MPa is noted when water is in the epoxy material. A large decrease in maximal elongation is observed.

When water is removed, i.e. samples dried at 40°C with a relative humidity equal to 0%, a larger increase in maximal stress is observed, see curve #3 in Figure 2. In this case, maximal stress is equal to 76 MPa, which is 19 MPa more than for the unaged epoxy. Here again elongation is low.

At this stage, it appears that after 1 month at 40°C in seawater, epoxy samples are saturated by water up to 2.8% and tensile behaviour is strongly affected by ageing with a large increase in maximal stress and a decrease in elongation at break. Moreover, it appears that when samples are dried, we enhance the increase in maximal stress. This fact suggests that, as expected, matrix plasticisation by water plays a role in the tensile behaviour of the material.

In order to fully understand these results, samples after ageing in seawater at 40°C, have been subjected to a short (5 minutes) immersion at 90°C in seawater which will be referred as rejuvenation further in this article. This immersion above Tg aims to remove any physical ageing of the epoxy without changing the water content in the material. After this thermal treatment, tensile tests were performed with the presence of water in the polymer and results are presented on curve #4. We clearly see that the thermal treatment of saturated samples leads to a large decrease in maximal stress (from 62 MPa before thermal treatment to 40 MPa after). In the meantime, maximal elongation is largely improved due to plasticization of the matrix by water. Based on these results it is obvious that physical ageing is involved in the changes observed in mechanical behaviour of this epoxy when immersed below Tg.

Both plasticization and physical ageing are macroscopically reversible processes. They are removed respectively by drying samples and thermal treatment above Tg. In order to check if any irreversible degradation occurs during immersion at 40°C, samples were exposed to thermal treatment after being fully dried and then tested. Results obtained are also plotted in Figure 2 (curve #5). We can see that results are similar to those for unaged sample, both in terms of yield stress and maximal elongation. It can be thus concluded that no irreversible degradation occurs when this fully cured amine based epoxy is immersed at 40°C in seawater. As a conclusion to this first part of the study, it appears that maximal stress (the property of interest here) is strongly affected by two reversible processes when immersed in seawater: matrix plasticization and physical ageing. The next parts of this paper will focus on the study of the coupling between these two reversible processes. In the meantime, we have shown that there is no macroscopically irreversible degradation involved here.

i) Plasticization of the resin when physical ageing is removed

This section is devoted to the plasticization of the epoxy material induced by the presence of water between macromolecular chains. First, we will consider water absorption in the polymer at 40°C, then changes in Tg, and finally the impact of water content on tensile behaviour.

-Water uptake Water uptake (%) √time/thickness (h 0.5 .mm -1 )

Figure 3 Fickian diffusion of the resin at 40°C in seawater

In order to avoid any complexity with water profile through the thickness but to be able to assess the behaviour of the epoxy containing different amounts of water, samples have been aged in seawater as well as under 50 and 75% relative humidity. In all cases, a Fickian behaviour is observed with water diffusion coefficient D equal to about 4.10 -13 m²/s, which is in accordance with data from literature [START_REF] Nogueira | Effect of water sorption on the structure and mechanical properties of an epoxy resin system[END_REF][START_REF] Moy | Epoxy-water interactions[END_REF][START_REF] Abanilla | Durability characterization of wet layup graphite/epoxy composites used in external strengthening[END_REF]. As an example, the water uptake measured at 40°C in seawater is shown in Figure 3. In our case, for 1 mm thick samples, time to saturation is about 22 days. The maximal water uptake in the resin obviously depends on the water activity of the surrounding environment [START_REF] Moy | Epoxy-water interactions[END_REF]; data are available in Table 1. In seawater a maximal water uptake of 2.7% is observed, this is a typical value for amine based epoxy [START_REF] Morel | Structure-water absorption relationships for amine-cured epoxy resins[END_REF]. -Glass transition temperature

Maximal

Because water leads to an increase in mobility of macromolecular chains, we usually observe a decrease in the Tg of the polymer as shown in Figure 3. Here Tg drops from 75°C to 61°C when 2.7% of water is absorbed. Moreover, it has been shown that Tg reduction as a function of water content can be calculated using the Simha-Boyer equation [START_REF] Hancock | The Relationship Between the Glass Transition Temperature and the Water Content of Amorphous Pharmaceutical Solids[END_REF][START_REF] Kelley | Viscosity and glass temperature relations for polymer-diluent systems[END_REF][START_REF] Broudin | Water diffusivity in PA66: Experimental characterization and modeling based on free volume theory[END_REF] :

= 1 + × (1) With = - ( 2
)
Where Tg is the glass transition of the material with a known value of water, Tgp is the glass transition of the polymer without any water previously measured at 348 K, Tgs is the solvent glass transition that is water in our case taken at 136 K [START_REF] Velikov | The Glass Transition of Water, Based on Hyperquenching Experiments[END_REF][START_REF] Johari | The glass-liquid transition of hyperquenched water[END_REF] and being the volume ratio of water in the material.

Both experimental data and prediction are plotted in Figure 4. It appears that it is possible, based on the Simha-Boyer equation, to describe the decrease in Tg induced by the presence of water within this epoxy. Figure 5 shows the tensile behaviour of the epoxy when physical ageing is removed. Samples were aged under different water ageing conditions and, prior to tensile testing, exposed for 5 minutes at 90°C. One can observe the characteristic effect of plasticization as maximal stress decreases while water quantity increases. It may be noted that an increase in water content also leads to an increase in strain at break. When water is removed, tensile behaviour is the same as for the unaged sample showing that no irreversible degradation occurs. These results clearly confirm that plasticization leads to large changes in tensile properties of amine based epoxy. One of the remaining questions here is how this plasticization process is affected by physical ageing in the material. To answer this question it is necessary to decouple the two processes. To do so, in the next section we will study the plasticization process with samples that have been previously aged physically in a dry environment.

ii) Physical ageing in a dry environment

Physical ageing of epoxy material in dry environment has been described in detail in the literature [START_REF] Struik | Physical aging in amorphous polymers and other materials[END_REF][START_REF] Sell | Influence of physical ageing on the yield response of model DGEBA/poly(propylene oxide) epoxy glasses[END_REF]. Here sub-Tg ageing has been performed on tensile specimens in the dry state under inert atmosphere at three different temperatures (40, 50, and 60°C) for several durations. After ageing, samples were cooled to 21°C and characterized. Results obtained at 40°C are plotted in Figure 6.

During ageing, large mechanical changes occur; as expected an increase of maximal stress is observed (from 57MPa to 82MPa) as well as a decrease in elongation at break. At 50 and 60°C, the same behaviour is observed but the higher the temperature is, the faster the increase in maximal stress, as shown in Figure 7. Let us focus now on the mathematical description of the increase in maximal stress over time for the three different temperatures considered here, in order to be able to compare kinetic rates in air and in water (see later). It has been shown many times [START_REF] Struik | Physical aging in amorphous polymers and other materials[END_REF][START_REF] Hutchinson | Physical aging of polymers[END_REF][START_REF] Zheng | Physical aging of an epoxy subsequent to relative humidity jumps through the glass concentration[END_REF][START_REF] Lee | The physical ageing response of an epoxy glass subjected to large stresses[END_REF] that the increase in maximal stress during physical ageing of a polymer can be described by a modified Kohlrausch-Williams-Watts (KWW) equation, as:

( ) = + ∆ (1 -( ) ) (3)
Where σy is the maximal stress at a time t, is the maximal stress in the unaged state (57 MPa here), ∆ is the maximal stress increase (equal to 26 MPa here), t is ageing time, β the stretching parameter (fixed at 1/3 here based on published results with epoxy [START_REF] Lee | The physical ageing response of an epoxy glass subjected to large stresses[END_REF]) and τ is a relaxation time that depends on material and ageing conditions.

Using equation ( 3) and data plotted in Figure 6 it is possible to describe the increase in maximal stress with ageing time in air by adjusting the value ofτ. Results are shown in Table 2. An increase in ageing temperature leads to an acceleration of the ageing process meaning a decrease in the relaxation time. Temperature dependence of the relaxation time can be described by an Arrhenius plot, see Figure 8. The activation energy, in a dry environment, is equal to 106 kJ/mol. The physical ageing in dry environment (i.e. without any plasticisation of the resin) has been characterized considering maximal stress for ageing temperatures from 40°C to 60°C. The observed increase in maximal stress during ageing can be modelled using a KWW model and results can be extrapolated to lower temperatures using the Arrhenius expression.

iii) Plasticization of the resin with physically pre-aged samples

In this section, we will focus on the plasticization of the epoxy that has been physically aged previously. Samples were placed in a drying oven at 60°C under vacuum for a time equivalent to = 5 * " # °% , " # °% being the relaxation time at 60°C (see table 3); so that, according to the KWW equation, the influence of the physical ageing process on maximum stress has reached more than 80%. This means that the remaining effect during immersion will be relatively minor, less than 20%, and the contribution of plasticization to changes in maximum stress can thus be estimated. No changes in either water content or diffusivity were observed. Tensile results are plotted in Figure 9.

Here again we can observe that the presence of water within the polymer leads to a decrease in maximal stress. In the meantime, it appears that strain at break does not increase in the presence of water when samples are fully physically aged; this was not the case when physical ageing was removed before wet ageing (see Figure 5). If we focus on maximal stress, it is possible to link the decrease in maximal stress to the increase in mobility through the Tg value, this can be done using the modified Kambour equation [START_REF] Kambour | A review of crazing and fracture in thermoplastics[END_REF] (see below); results are plotted on Figure 10.

= ( & -) + ' (4)
Where σ is the maximal stress in MPa, Tg is the glass transition temperature in °C, T is the testing temperature in °C and A and B material properties.

Based on Figure 10, it clearly appears that the decrease in maximal stress due the presence of water (i.e. the slope) is present for both physically and non-physically aged conditions. The physical ageing seems to reduce this effect as a proportionality constant of 0.84 MPa/K is recorded whereas without physical ageing the value is 1.23 MPa/K. Values recorded in the literature by Cook et al. for different epoxy systems were in the same range [START_REF] Cook | Yielding behaviour in model epoxy thermosets -II. Temperature dependence[END_REF] but here, the variation is measured without changing the resin chemistry. The main remaining question is now to examine whether there is any effect of water on the physical ageing process, this is the aim of the next section. This section will investigate how the physical ageing process is affected by the presence of water within the epoxy. Samples were saturated in seawater and then rejuvenated by a 5 minutes thermal treatment at 90°C to erase any physical ageing that would have occurred during water absorption. Finally, samples were immersed at different temperatures from 15 to 40°C and tested after several durations. Tensile curves as a function of ageing time are plotted in Figure 11. As expected, an increase in maximal stress is observed as a function of ageing duration as well as a decrease in strain at break. This increase in maximal stress is due to physical ageing that occurs in the polymer. It should be noted that sample mass was recorded during ageing and no further weight changes were observed during physical ageing in wet environment. Figure 12 shows the increase of maximal stress induced by physical ageing with dry samples aged at 40°C and with wet samples aged in seawater at 40°C. The two main conclusions of this comparison are:

-The physical ageing process occurs to the same extent in the presence of water and with the same shape, in fact an increase of 26 MPa in maximal stress is observed in both cases. -Physical ageing is much faster in a wet environment. For example, an increase of 11 MPa is measured after 23 hours in air, whereas in water for the same duration, the increase is equal to 14 MPa. This behaviour can be explained by the fact that Tg is decreased by the presence of water from 75°C to 60°C. It means that the difference between the testing temperature and the Tg is much smaller in water than in air. Relaxation times have been determined using the KWW equation (Figure 13) in a wet environment with samples saturated previously, values are shown in Table 3. It appears that the acceleration factor induced by temperature can be, once again, described using an Arrhenius behaviour, see Figure 14. The activation energy is equal to 160 kJ/mol, a value that is much higher than in air. The origin of water effect on physical ageing is considered in the next section, dedicated to DMA results. Based on unaged results we clearly see that two transitions occurs in the material within the temperature range considered here. First, around -55°C the beta transition occurs, this transition is related to local movement in the polymer. Then, around +80°C the glass transition occurs. After physical ageing in dry environment, no large changes in the two transitions are observed. Only a slight increase of the beginning of the Tg can be detected. However, when considering samples fully saturated by water two changes occur:

-A decrease in Tg, as already shown in Figure 9; in the presence of water an increase of mobility between macromolecular chains occurs that leads to a 15°C drop in Tg compared to the dry state value.

A change in the Beta transition, in fact we can see that this temperature decreases from -55°C to -75°C, and the transition is much more visible after aging in seawater. This behavior has already been observed in the literature [START_REF] Colombini | Dynamic mechanical investigations of the effects of water sorption and physical ageing on an epoxy resin system[END_REF], where a decrease in beta transition temperature induced by water absorption is shown, so this change is not specific to the epoxy studied here but occurs in many amine based epoxies. Based on these results it can be concluded that the presence of water in epoxy leads to both a decrease in Tg and modification of Tβ. It is well known that physical ageing is faster when temperature is close to Tg, so when Tg decreases due to water content it accelerates the degradation process. However, we have seen that more than kinetic rate, the activation energy is affected by the presence of water within the polymer. We can imagine that this behaviour is due to changes in the beta transition. However, the exact role of the beta transition in physical ageing is still not fully understood. This point would need more attention in order to propose a model that is able to predict both plasticization and physical ageing.

Conclusions

The coupling between physical ageing and plasticization that occurs in amine-based epoxy when in contact with a humid environment has been considered here.

First, based on preliminary results, we have shown that two reversible processes occur when an epoxy is immersed in seawater below Tg: plasticization of the matrix by water and physical ageing. Then a step-by-step study has been performed to evaluate coupling between these two processes.

The plasticization process leads to a large decrease in terms of Tg (25°C for 2.8% of water) that induces a decrease in maximal stress (from 57 to 40 MPa). When physical ageing occurs, an increase in maximal stress occurs of 26 MPa. Physical ageing has no large effect on the plasticization process.

On the contrary, in the presence of water, which leads to an increase in chain mobility, physical ageing is strongly affected from a kinetic point of view with a large acceleration of the process by a factor of 10 (compared to air). Moreover, the effect of temperature on ageing rate is affected by the presence of water, with an increase of the activation energy from 108 to 160 kJ/mol. This change in activation might be related to the beta transition that becomes more important when water is present. This requires further study.

The results from this study highlight the interactions between water plasticization and physical ageing. These effects are present in the range of temperatures commonly used in accelerated aging tests on polymers and polymer composites. It is important that they be considered when defining ageing test strategies, in order to evaluate the proper ageing phenomenon.

Figure 1 :

 1 Figure 1: Molecular structures of pre-polymer

Figure 2 :

 2 Figure 2: Tensile behaviour of saturated and dried epoxy resin exposed to 40°C seawater

Figure 4 :

 4 Figure 4: Comparison of experimental measurements of Tg and theoretical Simha-Boyer values -Tensile properties

Figure 5 :

 5 Figure 5: Effect of water content on tensile behaviour when physical ageing is removed

Figure 6 :

 6 Figure 6: Tensile behaviour of epoxy resin subjected to physical ageing at 40°C in inert atmosphere

Figure 7 :

 7 Figure 7: Maximal stress as a function of sub-Tg ageing time at 60°C (red), 50°C (yellow) and 40°C (green)

Figure 8 :

 8 Figure 8: Arrhenius plot of relaxation time

Figure 9 :

 9 Figure 9: Tensile behaviour of a previously physical aged epoxy subjected to water ageing at saturation

Figure 10 :

 10 Figure 10: Maximal stress as a function of Tg-T induced by water absorption

Figure 11 :Figure 12 :

 1112 Figure 11: Tensile behaviour of a previously saturated epoxy resin subjected to 40°C physical ageing

Figure 13 :Table 3 :

 133 Figure 13: Maximal stress as a function of ageing time of a previously seawater saturated epoxy

Figure 14 :

 14 Figure 14: Arrhenius plot of relaxation time for physical ageing process in wet environment

Figure 15 :

 15 Figure 15: Maximal stress as a function of ageing time of a previously seawater saturated epoxy

Table 1 :

 1 maximal water content at saturation for different ageing condition.

		water content
		(%)
	SEAWATER	2.7
	75% RH	1.7
	50% RH	1

Table 2 :

 2

		τ (h)
	60°C	18
	50°C	43
	40°C	199

τ values obtained during physical ageing of the amine based epoxy in dry environment as a function of temperature.

Acknowledgment

The authors would like to thank the French DGA and Ifremer for the financial support.


Corentin Roger
email: roger.corentin@chu-amiens.fr

Emmanuel Debuyzer

Massinissa Dehl

Yassine Bulaïd

Lamrani Adnane

Eric Havet

Patrice Mertl

Lamrani

Facteurs influençant la durée de séjour, le mode de sortie et la réadmission à 30 jours après arthroplastie primaire de hanche et de genou

Keywords: Factors Associated with Hospital Stay Length, Discharge Destination prothèse totale de hanche, prothèse totale de genou, durée de séjour, comorbidités, réadmission, sortie d'hospitalisation

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Hypothèse :

Il existe des facteurs intrinsèques au patient non modifiables et extrinsèques organisationnels modifiables qui influencent la durée de séjour.

Matériel et méthode :

Tous PTG [START_REF] Brilhault | Projections d'activité hospitalière à l'horizon 2030[END_REF]. Il existe une tendance globale à la diminution de la Durée de Séjour (DS) en France [START_REF] Erivan | Ten-year epidemiological study in an orthopaedic and trauma surgery centre: Are there risks involved in increasing scheduled arthroplasty volume without increasing resources?[END_REF][START_REF] Putman | Épidémiologie des prothèses de hanche en France : analyse de la base nationale du PMSI de 2008 à 2014[END_REF] comme dans d'autres pays [START_REF] Napier | Modifiable factors delaying early discharge following primary joint arthroplasty[END_REF][START_REF] Dall | The influence of pre-operative factors on the length of in-patient stay following primary total hip replacement for osteoarthritis A multivariate analysis of 2302 patients[END_REF]. Les facteurs prédictifs connus de la DS sont le jour opératoire [START_REF] Napier | Modifiable factors delaying early discharge following primary joint arthroplasty[END_REF][START_REF] Monsef | Blood management may have an impact on length of stay after total hip arthroplasty[END_REF][START_REF] Newman | Day of surgery affects length of stay and charges in primary total hip and knee arthroplasty[END_REF], la sortie en centre de rééducation fonctionnelle (CRF) [START_REF] El Bitar | Hospital length of stay following primary total knee arthroplasty: Data from the nationwide inpatient sample database[END_REF][START_REF] Lernout | Cost analysis in total hip arthroplasty: Experience of a Teaching Medical Center located in Paris[END_REF] ou la présence de certaines comorbidités [START_REF] Napier | Modifiable factors delaying early discharge following primary joint arthroplasty[END_REF][START_REF] Dall | The influence of pre-operative factors on the length of in-patient stay following primary total hip replacement for osteoarthritis A multivariate analysis of 2302 patients[END_REF][START_REF] Monsef | Blood management may have an impact on length of stay after total hip arthroplasty[END_REF][START_REF] Newman | Day of surgery affects length of stay and charges in primary total hip and knee arthroplasty[END_REF][START_REF] El Bitar | Hospital length of stay following primary total knee arthroplasty: Data from the nationwide inpatient sample database[END_REF][START_REF] O'malley | Factors independently associated with complications and length of stay after hip arthroplasty: Analysis of the National Surgical Quality Improvement Program[END_REF][START_REF] Jans | Lundbeck Foundation Centre for Fasttrack Hip and Knee Replacement Collaborative Group. Role of preoperative anemia for risk of transfusion and postoperative morbidity in fast-track hip and knee arthroplasty[END_REF][START_REF] Inneh | Role of sociodemographic, co-morbid and intraoperative factors in length of stay following primary total hip arthroplasty[END_REF][START_REF] Abbas | Predictors of length of hospital stay after total hip replacement[END_REF]. Cependant, les résultats sont contradictoires et à notre connaissance aucune publication n'a été réalisée sur une population Française à la recherche des facteurs modifiant la durée de séjour, des facteurs influençant le mode de sortie et des facteurs influençant le taux de réadmission non planifiée après arthroplastie. Pourtant, une meilleure connaissance de ces facteurs est un moyen d'améliorer l'efficience des soins [START_REF] Lernout | Cost analysis in total hip arthroplasty: Experience of a Teaching Medical Center located in Paris[END_REF].

Aussi nous avons mené une étude de cohorte monocentrique rétrospective sur une large population afin de : 1) déterminer si ces facteurs influencent la DS après arthroplastie, 2) de déterminer quels facteurs étaient prédictifs d'une sortie en CRF et de la réadmission dans les 30 jours postopératoires. Notre hypothèse était qu'il existe des facteurs intrinsèques au patient non modifiables et extrinsèques organiationnels modifiables qui influencent la durée de séjour.

Matériel et méthode

Méthode de recueil

Les données recueillies incluaient les données démographiques (âge, genre, Indice de Masse

Modalités de prise en charge

L'admission des patients était systématiquement réalisée la veille de l'intervention. En postopératoire, un aide-soignant assurait chaque jour de la semaine ainsi que le samedi matin le lever précoce et la remise à la marche.

Méthode d'évaluation

Le Critère de jugement principal était la modification du « risque de sortie » au 5 ème jour de la DS. La durée de séjour était définie comme la durée en jours entre l'admission (le jour précédant la chirurgie) et la sortie du service d'orthopédie. Les critères de jugement secondaires étaient définis par l'association entre la sortie en CRF ou la réadmission à 30 jours et la présence des facteurs étudiés. Les réadmissions étaient définies par toutes les réhospitalisations survenant dans les 30 jours postopératoires (hors consultations aux urgences).

Analyse statistique

Analyse du critère de jugement principal :

La distribution de la durée de séjour hospitalier était discrète et fortement asymétrique. Même

Résultats

Après L'analyse multivariée du critère de jugement principal montrait un risque moindre de sortie au 5 ème jour avec l'avancée de l'âge (HR=0,986 95% IC : 0,98-0,99), de 13% pour les femmes (HR=0,871 95% IC : 0,77-0,986), de 39% lors d'un antécédent de diabète (HR=0,606 95% IC : 0,5-0,73), de 68% lors d'une sortie en CRF (HR=0,322 95% IC : 0,267-0,389) et de 27% lors d'une intervention le vendredi (HR=0,733 95% IC : 0,631-0,852) (Tableau 2).

Concernant les critères de jugement secondaires, les analyses multivariées montraient que les facteurs associés à une sortie en CRF étaient l'âge (OR=1,081 95% IC :

Discussion

L'analyse du critère de jugement principal a confirmé notre hypothèse ; les facteurs intrinsèques tels que l'âge, le genre féminin, la présence de diabète et extrinsèques tels que le jour opératoire vendredi et la sortie en CRF influençaient la DS après arthroplastie primaire de hanche et de genou. Les facteurs influençant la DS ont déjà été étudiés dans la littérature [START_REF] Napier | Modifiable factors delaying early discharge following primary joint arthroplasty[END_REF][START_REF] Dall | The influence of pre-operative factors on the length of in-patient stay following primary total hip replacement for osteoarthritis A multivariate analysis of 2302 patients[END_REF][START_REF] Monsef | Blood management may have an impact on length of stay after total hip arthroplasty[END_REF][START_REF] El Bitar | Hospital length of stay following primary total knee arthroplasty: Data from the nationwide inpatient sample database[END_REF][START_REF] O'malley | Factors independently associated with complications and length of stay after hip arthroplasty: Analysis of the National Surgical Quality Improvement Program[END_REF][START_REF] Jans | Lundbeck Foundation Centre for Fasttrack Hip and Knee Replacement Collaborative Group. Role of preoperative anemia for risk of transfusion and postoperative morbidity in fast-track hip and knee arthroplasty[END_REF][START_REF] Inneh | Role of sociodemographic, co-morbid and intraoperative factors in length of stay following primary total hip arthroplasty[END_REF][START_REF] Abbas | Predictors of length of hospital stay after total hip replacement[END_REF] cependant, seule une étude prenait en compte l'impact du mode de sortie dans l'analyse [START_REF] El Bitar | Hospital length of stay following primary total knee arthroplasty: Data from the nationwide inpatient sample database[END_REF]. À notre connaissance, cette étude est la seule qui analyse l'influence des facteurs sur la DS par un modèle de survie en prenant en compte l'âge en tant que variable continue, les comorbidités de façon distincte et en considérant l'impact du mode de sortie.

Cette méthode d'analyse a permis de maintenir la puissance statistique et d'éviter de potentiels biais d'information et d'interprétation [START_REF] Moser | Odds ratios for a continuous outcome variable without dichotomizing[END_REF][START_REF] Trinquart | Analyse de la durée de séjour hospitalier et du mode de sortie par des modèles de survie : application au lien durée de séjoursituations de précarité[END_REF][START_REF] Chazard | Comparer la durée de séjour de deux groupes de patients : quel test choisir ? Comparaison des risques alpha et bêta de douze tests statistiques[END_REF].

Conformément à certaines études, l'analyse multivariée retrouvait une influence du genre féminin sur la DS [START_REF] Monsef | Blood management may have an impact on length of stay after total hip arthroplasty[END_REF][START_REF] Jans | Lundbeck Foundation Centre for Fasttrack Hip and Knee Replacement Collaborative Group. Role of preoperative anemia for risk of transfusion and postoperative morbidity in fast-track hip and knee arthroplasty[END_REF][START_REF] Inneh | Role of sociodemographic, co-morbid and intraoperative factors in length of stay following primary total hip arthroplasty[END_REF][START_REF] Oldmeadow | Predicting risk of extended inpatient rehabilitation after hip or knee arthroplasty[END_REF] et également de l'âge [START_REF] Napier | Modifiable factors delaying early discharge following primary joint arthroplasty[END_REF][START_REF] Monsef | Blood management may have an impact on length of stay after total hip arthroplasty[END_REF][START_REF] Newman | Day of surgery affects length of stay and charges in primary total hip and knee arthroplasty[END_REF][START_REF] El Bitar | Hospital length of stay following primary total knee arthroplasty: Data from the nationwide inpatient sample database[END_REF][START_REF] O'malley | Factors independently associated with complications and length of stay after hip arthroplasty: Analysis of the National Surgical Quality Improvement Program[END_REF][START_REF] Jans | Lundbeck Foundation Centre for Fasttrack Hip and Knee Replacement Collaborative Group. Role of preoperative anemia for risk of transfusion and postoperative morbidity in fast-track hip and knee arthroplasty[END_REF][START_REF] Inneh | Role of sociodemographic, co-morbid and intraoperative factors in length of stay following primary total hip arthroplasty[END_REF][START_REF] Abbas | Predictors of length of hospital stay after total hip replacement[END_REF][START_REF] Oldmeadow | Predicting risk of extended inpatient rehabilitation after hip or knee arthroplasty[END_REF]. Cependant si l'effet du genre est important sur la DS, l'impact de l'âge est quasiment négligeable malgré sa forte L'analyse du critère de jugement secondaire retrouvait comme d'autres auteurs, que l'âge [START_REF] Oldmeadow | Predicting risk of extended inpatient rehabilitation after hip or knee arthroplasty[END_REF][START_REF] Pablo P De | Determinants of discharge destination following elective total hip replacement[END_REF][START_REF] Inneh | Disparities in discharge destination after lower extremity joint arthroplasty: Analysis of 7924 patients in an urban setting[END_REF] et le genre féminin [START_REF] Inneh | Disparities in discharge destination after lower extremity joint arthroplasty: Analysis of 7924 patients in an urban setting[END_REF]

Conclusion

Notre étude a confirmé l'influence de certains facteurs sur la DS, le mode de sortie et la (5) EH, PM : experimentation or surgery performance.

  dans le corps de l'email d'envoi à Elsevier Paris Manuscrits) Références éditoriales : [RCOT], article Roger Rubrique : Mise au point Titre article : Facteurs influençant la durée de séjour, le mode de sortie et la réadmission à 30 jours après arthroplastie primaire de hanche et de genou _________________________________________________________________ RESUME : Introduction : En France comme aux États-Unis, les prévisions à 2030 du nombre d'implantations de prothèses totales de hanche (PTH) ou de genou (PTG) sont croissantes avec une tendance globale à la diminution de la Durée de Séjour (DS). Les facteurs prédictifs connus de la DS sont le jour opératoire, la sortie en centre de rééducation fonctionnelle (CRF) ou la présence de certaines comorbidités. Cependant, les résultats sont contradictoires et à notre connaissance aucune étude n'a été réalisée sur une population Française concernant ces facteurs après arthroplastie. Pourtant, une meilleure connaissance de ces facteurs est un moyen d'améliorer l'efficience des soins. Aussi, nous avons mené une étude de cohorte monocentrique rétrospective sur une large population afin de : 1) déterminer si ces facteurs influencent la DS après arthroplastie, 2) de déterminer quels facteurs étaient prédictifs d'une sortie en CRF et de la réadmission dans les 30 jours postopératoires.

  Corporelle (IMC) et comorbidités); le jour opératoire, le type de chirurgie et les données postopératoires (mode de sortie et réadmissions survenant dans les 30 jours).Parmi les comorbidités enregistrées dans la base de données, étaient recueillis à l'aide des codes CCAM l'obésité (IMC ≥ 30 kg/m 2 ), l'hypertension artérielle (HTA), l'insuffisance cardiaque droite ou gauche (IC), la cardiopathie ischémique (IC), le diabète, le syndrome d'apnée obstructive du sommeil (SAOS), la broncho pneumopathie chronique obstructive (BPCO), l'insuffisance respiratoire chronique (IRC), l'asthme, le tabagisme, les antécédents d'accidents vasculaires cérébraux (AVC) et les troubles anxio-dépressifs (annexe 1). Les caractéristiques de la population étudiée sont détaillées selon l'intervention chirurgicale (tableau 1).

  après transformation de la durée de séjour, une modélisation par régression linéaire ne respectait pas les conditions de validité concernant la normalité des résidus. La durée de séjour était donc modélisée par un modèle de survie en considérant la sortie d'hospitalisation comme événement. Le lien entre les facteurs de risque étudiés et « le risque instantané de sortie » était analysé par un modèle à risques proportionnels de Cox en censurant tous les patients sortis après 5 jours. Ce seuil correspondait à la médiane de la DS. Des analyses de sensibilité étaient réalisées en modifiant le seuil de censure (4 jours 7 jours et 10 jours).Analyse des critères de jugement secondaires : L'analyse des facteurs de risque associés au mode de sortie de l'hôpital et à la réadmission à 30 jours a été faite à travers des modèles de régression logistique univariés.Pour chacun des critères de jugement (principal et secondaires), un modèle multivarié à partir des facteurs statistiquement significatifs au seuil de 10% a été construit.A chaque étape de l'analyse statistique un ajustement sur le type d'intervention (PTH et PTG) a été réalisé. Les hazard-ratios (HR) et les odds-ratio (OR) étaient calculés avec un intervalle de confiance à 95%. Le seuil de significativité était fixé à 5% pour le modèle multivarié.Pour la description des caractéristiques de la population, la durée de séjour hospitalier et les facteurs de risques étudiés, les variables quantitatives ont été décrites à l'aide de la moyenne, de son écart type et de la médiane (minimum -maximum). Les variables qualitatives ont été décrites par leur fréquence avec un pourcentage. L'ensemble de l'analyse statistique a été réalisée avec le logiciel SAS version 9.4 (SAS Institute, Cary, NC).

  significativité et ces deux variables ne sont pas modifiables. Une influence importante du diabète sur la DS était retrouvée. La fréquence du diabète dans notre population était une fois et demi supérieure à celle de la prévalence française[START_REF] Ricci | Diabète traité: quelles évolutions entre 2000 et 2009 en France[END_REF], mais elle se rapproche de celle du registre prothétique anglais [20] ou de celles observées par El bitar et al.[START_REF] El Bitar | Hospital length of stay following primary total knee arthroplasty: Data from the nationwide inpatient sample database[END_REF] et par O'Malley et al.[START_REF] O'malley | Factors independently associated with complications and length of stay after hip arthroplasty: Analysis of the National Surgical Quality Improvement Program[END_REF] dans une population d'arthroplasties. Ces différents résultats suggèrent un rôle favorisant du diabète dans la survenue de l'arthrose[START_REF] Eymard | Diabetes is a risk factor for knee osteoarthritis progression[END_REF] et la prise en charge optimale du diabète semble être un levier important sur la durée totale d'hospitalisation. Les analyses n'ont pas montré d'influence sur la DS des pathologies cardiaques, respiratoires, du tabagisme, des troubles anxio-dépressifs[START_REF] Inneh | Role of sociodemographic, co-morbid and intraoperative factors in length of stay following primary total hip arthroplasty[END_REF] ou d'un antécédent d'AVC. À notre connaissance, l'influence de l'antécédent d'AVC sur la DS n'avait pas encore été étudiée. Les pathologies cardiaques et respiratoires influencent la DS de façon variable selon les publications[START_REF] Dall | The influence of pre-operative factors on the length of in-patient stay following primary total hip replacement for osteoarthritis A multivariate analysis of 2302 patients[END_REF][START_REF] Jans | Lundbeck Foundation Centre for Fasttrack Hip and Knee Replacement Collaborative Group. Role of preoperative anemia for risk of transfusion and postoperative morbidity in fast-track hip and knee arthroplasty[END_REF][START_REF] Inneh | Role of sociodemographic, co-morbid and intraoperative factors in length of stay following primary total hip arthroplasty[END_REF]. Aussi, nous n'avions pas un effectif suffisant pour conclure sur les critères IC et IRC : une analyse de cohorte nationale pourrait éventuellement éclairer ce point.Concernant l'influence du jour opératoire, nos résultats sont concordants avec plusieurs études qui ont rapporté une DS augmentée pour les patients opérés le jeudi ou le vendredi[START_REF] Napier | Modifiable factors delaying early discharge following primary joint arthroplasty[END_REF][START_REF] Monsef | Blood management may have an impact on length of stay after total hip arthroplasty[END_REF][START_REF] Newman | Day of surgery affects length of stay and charges in primary total hip and knee arthroplasty[END_REF]. De façon inattendue, Dall et al.[START_REF] Dall | The influence of pre-operative factors on the length of in-patient stay following primary total hip replacement for osteoarthritis A multivariate analysis of 2302 patients[END_REF] retrouvaient une DS plus courte pour les patients opérés d'une PTH le vendredi dans une étude prospective à propos de 2302 patients, mais ce résultat n'était pas expliqué. La mobilisation précoce est un facteur connu diminuant la DS[START_REF] Smith | Rehabilitation implications during the development of the Norwich Enhanced Recovery Programme (NERP) for patients following total knee and total hip arthroplasty[END_REF] mais à la différence d'autres services, celle-ci était assurée par des aides-soignants dédiés à la remise à la marche et non par des kinésithérapeutes. Cependant, plus que le type de personnel dédié à la mobilisation, nous émettons l'hypothèse d'une plus grande DS pour les patients opérés le vendredi en raison d'une moindre présence de soignants pendant les 48 premières heures postopératoires, notamment dès le samedi après-midi[START_REF] Dall | The influence of pre-operative factors on the length of in-patient stay following primary total hip replacement for osteoarthritis A multivariate analysis of 2302 patients[END_REF].Concernant l'influence du mode de sortie sur la DS, nos résultats sont en accord avec ceux de El Bitar et al.[START_REF] El Bitar | Hospital length of stay following primary total knee arthroplasty: Data from the nationwide inpatient sample database[END_REF] qui ont montré une DS plus élevée chez les patients sortant en CRF dans une étude à partir d'une large base de données portant sur plus de 1,9 million de patients ayant bénéficié d'une PTH entre 2009 et 2011. Ce résultat a également été suggéré par Sharareh et al.[START_REF] Sharareh | Factors determining discharge destination for patients undergoing total joint arthroplasty[END_REF] dans une courte cohorte rétrospective de 100 patients. Comme l'ont supposé El Bitar et al.[START_REF] El Bitar | Hospital length of stay following primary total knee arthroplasty: Data from the nationwide inpatient sample database[END_REF], ce résultat serait principalement expliqué par l'impossibilité de sortir en CRF le week-end. Ces résultats complètent ceux de Lernout et al[START_REF] Lernout | Cost analysis in total hip arthroplasty: Experience of a Teaching Medical Center located in Paris[END_REF] portants sur le coût de l'arthroplastie.

réadmission à 30

 30 jours en population Française. Les futures études doivent tenir compte du mode de sortie comme facteur majeur de la DS. Aussi, mieux cibler la population nécessitant une prise en charge en CRF et optimiser la prise en charge des patients diabétiques ou obèses permettrait d'augmenter l'efficience des soins après arthroplastie primaire. Des études complémentaires sont nécessaires pour affiner les connaissances dans ces domaines. Financements : Cette étude n'a nécessité aucune source de financement. Conflits d'intérêts : P.Mertl présente un conflit d'intérêt en dehors de cette étude comme consultant occasionnel des sociétés Adler, De Puy, Stryker, Zimmer et X-nov. Les autres auteurs n'ont aucun conflit d'intérêt à déclarer en relation ou en dehors de ce travail. Contribution des auteurs : (1) AL, CR, EH, PM : conception and design of the study, or acquisition of data, or analysis and interpretation of data. (2) CR, ED, EH, MD, PM, YB : drafting the article or revising it critically for important intellectual content. (3) AL, CR, ED, EH, MD, PM, YB : final approval of the version to be submitted. (4) AL, CR, YB : statistics.

  extraction des données de la base locale du PMSI, 1739 patients étaient éligibles. Après

application des critères d'exclusion, 1663 patients étaient inclus ; (938 dans le groupe PTH et 725 dans le groupe PTG) (figure

1

). Quarante patients du groupe PTH (4,3%) et 11 du groupe PTG (1,5%) ont été réadmis dans les 30 jours après arthroplastie (tableau 1). Concernant le critère de jugement principal, l'analyse univariée ne montrait pas d'influence sur la DS de l'obésité, du SAOS, de la BPCO, de l'asthme et des troubles anxio-dépressifs (Tableau 2).

  étaient associés à la sortie en CRF. Cependant, ces facteurs ne sont pas modifiables. Contrairement à Sharareh et al.[START_REF] Sharareh | Factors determining discharge destination for patients undergoing total joint arthroplasty[END_REF] nous avons retrouvé plus de sorties en CRF pour les patients ayant un antécédent de trouble anxio-dépressif, mais leur étude rétrospective portait sur un faible effectif et pouvait donc présenter un manque de puissance statistique. L'influence de l'antécédent d'AVC sur le mode de sortie est retrouvée dans notre cohorte et cet antécédent comportait une prévalence similaire (3,6%) à celles de deux études Française et Européenne[START_REF] Crimmins | Gender differences in health: results from SHARE, ELSA and HRS[END_REF][START_REF]Comparaison des taux d'accidents vasculaires cérébraux entre les femmes et les hommes : apports des Registres de Dijon, Brest et Lille, 2008-2012[END_REF]. Keswani et al.[START_REF] Keswani | Discharge destination after total joint arthroplasty: an analysis of postdischarge outcomes, placement risk factors, and recent trends[END_REF] retrouvait un résultat proche de la significativité (p=0,06) malgré une très faible prévalence d'AVC dans leur série (0,6%).Concernant les facteurs prédictifs de réadmission dans les 30 jours postopératoires, nos résultats sont similaires à ceux d'Otero et al.[START_REF] Otero | Length of hospitalization after joint arthroplasty: Does early discharge affect complications and readmission rates?[END_REF] qui ont analysé plus de 108000 patients et qui retrouvaient que l'obésité et le genre masculin étaient source de réadmission à 30 jours.Leur étude montrait une influence du tabagisme, de la BPCO et des cardiopathies Les limites de cette étude sont le caractère rétrospectif et l'utilisation des facteurs de risque connus de la littérature. En effet, il existe possiblement d'autres facteurs qui n'ont pas été analysés et qui pourraient influencer les critères de jugements. Le seuil de censure choisi pour le modèle statistique correspondait à la médiane de la durée de séjour, ce choix était arbitraire, toutefois, les analyses de sensibilité réalisées en modifiant le seuil de censure retrouvaient des résultats similaires en prenant les seuils de 4 jours, 7 jours et 10 jours. Étant donné le caractère monocentrique, les résultats de notre étude peuvent ne pas être complètement généralisables à d'autres populations mais le grand effectif de notre étude a permis d'obtenir des estimations robustes par rapport aux critères de jugements étudiés. La base locale du PMSI pouvait contenir des biais de renseignement. Cependant, les prévalences observées étaient comparables aux prévalences des études épidémiologiques françaises[START_REF] Godet-Mardirossian | Patterns of hypertension management in France (ENNS 2006-2007)[END_REF][START_REF] De Peretti | Prévalences et statut fonctionnel des cardiopathies ischémiques et de l'insuffisance cardiaque dans la population adulte en France : apports des enquêtes déclaratives « Handicap-Santé[END_REF][START_REF] Fuhrman | Epidemiology of chronic obstructive pulmonary disease in France[END_REF][START_REF] Memtsoudis | The impact of sleep apnea on postoperative utilization of resources and adverse outcomes[END_REF][START_REF] Cohidon | Prevalence of common mental disorders and their work consequences in France, according to occupational category[END_REF] ou à celles des études portant sur les arthroplasties[20,[START_REF] Pugely | de l'étude. Tableau 1 : Caractéristiques démographiques de la cohorte pour chaque type d'arthroplastie : prothèse totale de hanche et prothèse totale de genou. Prothèse totale de hanche n=938 Prothèse totale de genou n=725 Age, moyenne (années)  SD (min-max) 66  12 (19[END_REF] et la plupart des résultats sont concordants avec la littérature internationale comme cités ci-dessus, renforçant la validité externe de l'étude. De plus, aucun patient n'a été perdu de vue grâce à l'utilisation de la base de données locale du PMSI.

ischémiques, ce que nous n'avons pas retrouvé. Notre étude a également montré l'influence du diabète et de la sortie en CRF sur la réadmission à 30 jours. De plus, l'analyse des motifs de réadmission montrait dans le groupe PTH plus de complications médicales et de réinterventions notamment pour infection lors d'une sortie en CRF mais une tendance à moins de luxations. Nous émettons l'hypothèse qu'un meilleur encadrement médical des patients en CRF et qu'une population différente en termes d'âge, de comorbidités et d'autonomie expliqueraient en partie ces observations. Toutefois, des études complémentaires seraient nécessaires pour conclure sur ces événements de faibles prévalences.

Tableau 2 : Critère de jugement principal : facteurs associés au risque de sortie à 5 jours.