Olivier Guillaud

Emmanuel Jacquemin

Eduardo Couchonnal

Claire Vanlemmens

Claire Francoz

Yasmina Chouik

Filomena Conti

Christophe Duvoux

Marie-Noëlle Hilleret

Nassim Kamar

Pauline Houssel-Debry

Martine Neau-Cransac

Georges-Philippe Pageaux

Emmanuel Gonzales

Oanez Ackermann

Jean Gugenheim

Alain Lachaux

Mathias Ruiz

Sylvie Radenne

Dominique Debray

Florence Lacaille

Valérie Mclin

Jean-Charles Duclos-Vallée

Audrey Coilly

MD Jérôme Dumortier
email: jerome.dumortier@chu-lyon.fr

Long term results of liver transplantation for alpha-1 antitrypsin deficiency

Keywords: liver transplantation, alpha1 antitrypsin, outcome, survival

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

Introduction

Alpha1 antitrypsin (A1AT) deficiency is an autosomal recessive disorder with codominant expression, involving lungs and/or liver. Its prevalence in Northern Europe nears 1/2,500 and 1/6,000 in France and Western Europe [START_REF] Sesboue | Alpha-1-antitrypsin (PI) polymorphism in France, with special regard to the PI*Z allele[END_REF][START_REF] De Serres | Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys[END_REF][START_REF] Stoller | Alpha1-antitrypsin deficiency[END_REF][START_REF] Blanco | Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries[END_REF]. A1AT is a protein predominantly synthesized by the liver, and then released into the circulation. Its function is to protect lung tissue by inhibiting neutrophil elastase and several other destructive neutrophil proteinases. The classical form of severe A1AT deficiency is due to a homozygous point mutation (Glu342Lys, Z allele, PI*ZZ genotype) in the SERPINA gene that leads to misfolding of the mutant protein, intracellular polymerization, and consequent accumulation of protein aggregates in the endoplasmic reticulum (ER) of hepatocytes. This toxic gain of function induces chronic ER stress, development of fibrosis, and in some cases progression to cirrhosis and/or hepatocellular carcinoma. On the other hand, decreased secretion leads to a lack of circulating antiprotease activity in the lung, which can in turncause emphysema [START_REF] Strnad | Alpha1-Antitrypsin Deficiency[END_REF].

The clinical presentation of PI*ZZ disease is extremely variable (3). In children with the PI*ZZ genotype/phenotype, transient elevation of aminotransferases has been reported in as many as 73% of infants while it may only affects 15% of patients by 12 years of age [START_REF] Sveger | Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants[END_REF][START_REF] Sveger | The natural history of liver disease in alpha 1-antitrypsin deficient children[END_REF]. Prolonged cholestastic jaundice was reported in 11% of children with the PI*ZZ ,while clinical features of chronic liver disease developed in 6%. While clinical symptoms usually resolved by the second year of life, 15% of children with cholestatic jaundice developed cirrhosis, mostly with severe portal hypertension. In adults, akin to what is known in children, the risk of cirrhosis related to PI*ZZ A1AT deficiency has been recognized for many decades [START_REF] Berg | Liver disease in adults with alpha-1 -antitrypsin deficiency[END_REF]. Nevertheless, the natural history is still incompletely understood. The prevalence of advanced liver disease in adults with A1AT deficiency varies widely from 2 to 63% in available reported cohorts and increases with age (age>50), gender (male) and metabolic syndrome [START_REF] Larsson | Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z[END_REF][START_REF] Cox | Risk for liver disease in adults with alpha 1-antitrypsin deficiency[END_REF][START_REF] Eriksson | Alpha 1-antitrypsin deficiency and liver cirrhosis in adults. An analysis of 35 Swedish autopsied cases[END_REF][START_REF] Elzouki | Risk of hepatobiliary disease in adults with severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma?[END_REF][START_REF] Bowlus | Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency[END_REF][START_REF] Clark | Liver test results do not identify liver disease in adults with alpha(1)-antitrypsin deficiency[END_REF]. A recent cross-sectional biopsy study in an adult PI*ZZ population (not previously known to have cirrhosis) showed a prevalence of clinically significant liver fibrosis (≥F2) in 35% and severe fibrosis (≥F3) in 6% of patients [START_REF] Clark | Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort[END_REF]. This variability suggests that other genetic and environmental modifiers influence the development of significant liver disease both in children and adults.

slower rate than the Z allele, and leads to higher circulating levels of A1AT. However, PI*SZ compound heterozygote patients have been reported to present with less severe liver disease both in childhood [START_REF] Teckman | Baseline Analysis of a Young alpha-1-Antitrypsin Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension[END_REF][START_REF] Ruiz | Liver disease related to alpha1antitrypsin deficiency in French children: The DEFI-ALPHA cohort[END_REF] and adulthood [START_REF] Carey | Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency-related cirrhosis[END_REF]. Case reports and family studies have also described an association between liver disease and rarer A1AT variants also causing protein misfolding such as Siiyama, Mmalton, MDuarte.

Like for other forms of end-stage-liver disease, LT is the ultimate treatment of severe liver complications of A1AT deficiency, both in children and adults. Based on the UNOS (United Network for Organ Sharing, US) database, it has been reported that this rare indication could represent 1% of all indications [START_REF] Kemmer | Alpha-1-antitrypsin deficiency: outcomes after liver transplantation[END_REF]. Nevertheless, there is little data on outcomes. Therefore, the aim of the present study was to evaluate the long-term outcome after LT for A1AT deficiency, in a large multicenter adult and pediatric cohort.

Patients and Methods

Study design

Pediatric and adult patients having undergone LT for A1AT deficiency in France (all centers) and in Geneva (Switzerland) were identified from medical records spanning October 1982 and December 2017. Data collection was performed by comprehensive medical chart review. All PI*ZZ, PI*SZ patients were included. Dual-organ (lung-liver) transplant recipients were includedA1AT serum levels and phenotyping and/or genotyping data were collected. Other comorbid causes of liver disease such as alcohol-related liver disease, non-alcoholic fatty liver disease, autoimmune liver disease, chronic viral hepatitis, and other conditions (iron overload, Wilson disease) were recorded. According to French law (Loi Jardé), anonymous retrospective studies do not require Institutional Review Board (IRB) approval. In Switzerland, the study was approved by the local IRB (CER 11-010R).

Liver transplantation

All patients received grafts from cadaveric or living donors. Initial immunosuppressive regimen was based on a calcineurin-inhibitor: cyclosporine or tacrolimus. Some patients could also receive 500 mg IV methylprednisolone after reperfusion and/or basiliximab. As from 1985, patients initially received cyclosporine (Sandimmun ® or Neoral ® , Novartis Pharma). Since 1996, patients may also have received tacrolimus (Prograf ® , Astellas). Starting on postoperative day 1, methylprednisolone was tapered to reach a maintenance dose of 0 to 5 mg/day at 6 months post-transplantation.

Azathioprin,mycophenolate mofetil (MMF) (since 1996) or sirolimus/everolimus (since 2002) was either administered as part of an initial triple immunosuppressive regimen, or introduced during follow-up as a maintenance immunosuppressive agent. Outpatient follow-up visits were tailored to individual patient needs, usually monthly during the first year, and every 3 to 12 months thereafter, regardless of the time elapsed since transplantation. Extensive laboratory investigations were carried out at each visit: hematology, liver parameters, coagulation, electrolytes, total protein, renal parameters, fast blood glucose, lipid profile and blood CNI trough levels.

Statistics

Statistical analysis was performed with SPSS 23.0 (IBM, Armonk, NY, US). Survival rates were clinical visit or the data cut-off point (May 1 st , 2018). Graft survival was calculated from the date of LT to that of retransplantation, death, last visit or data cut-off point if no retransplantation. Survival curves were constructed with the Kaplan-Meier method and compared with the log-rank test. The Cox proportional hazards regression model was used in univariate analysis for continuous variables. Values in this paper are shown as median with ranges and mean. Continuous variables were compared using Mann-Whitney's test. P values lower than or equal to 0.05 were considered to be statistically significant.

Results

Study population

This report included 32 adults (age >18 years) and 58 children having undergone LT for A1AT deficiency between October 1982 and December 2017 in 18 different transplant centers throughout France and Geneva (Switzerland). Figure 1 displays the number of LT according to age bracket and genotype/phenotype. In this study, we observed a main peak of LT during childhood and a second peak in adulthood after 45 years of age. Figure 2 shows the number of LT according to era in children and adults. The overall number of LT for A1AT deficiency remained stable over decades. However, the distribution between pediatric and adults recipients has varied somewhat.

During the eighties and nineties there were more children than adults who underwent LT, but this proportion reversed since 2000. Patient characteristics are summarized in Table 1. The median age of all patients was 13.0 years (range: 0.2-65.1), and 65/90 were male (72.2%). The vast majority of patients (91.1%) had the PI*ZZ genotype/phenotype. When considering only children, 55/58 (94.8%) had the PI*ZZ genotype/phenotype and three children were PI*SZ. In adults, 26/32 (81.2%) were PI*ZZ, 6/32 (18.8%) were PI*SZ. Before transplantation, the median serum A1AT level was lower for the PI*ZZ patients (0.31 g/L, range: 0.13-0.52), compared to the PI*SZ patients (0.56 g/L, range: 0.23-0.70) (p<0.05). One child had a coexisting liver disease (biliary atresia). In adults, coexisting liver disease was identified in 10/26 (38.5%) PI*ZZ patients: alcohol-related (n=6), non-alcoholic fatty liver disease (NAFLD) (n=3), HCV (n=1). Likewise, 4/6 (66.7%) PI*SZ patients also had evidence of a comorbid condition affecting the liver: alcohol-related (n=3), NAFLD (n=1). All patients (n=6) presenting with an HCC were adults (median age 51.8, range 37.0-61.9); HCC was diagnosed before LT in all cases. Eight patients, all adults with PI*ZZ genotype/phenotype, had emphysema at the time of LT, and three of them underwent a combined lung-liver transplantation.

Complications after liver transplantation

Surgical complications included hepatic artery stenosis (n=5, 5.6%), hepatic artery thrombosis (n=2, 2.2%) and biliary stenosis (n=20, 22.2%).

Thirty-two (32/90) patients (35.6%) experienced at least one episode of biopsy-proven acute rejection, 11 of whom developed histological features of chronic rejection. Sixty seven (67/90) (74%) patients had normal liver function tests at their last follow-up visit.

Medical complications included arterial hypertension (n=20, 22.2%), hyperlipidemia (n=8, 8.9%) and diabetes (n=7, 7.8%). At the time of the last visit, median glomerular filtration rate (estimated using the Cockroft formula) was 90 µmol/L (10->120); 13 patients (10 adults) (14.4%) suffered from stage II renal insufficiency (i.e.30 mL/min <clearance <60 mL/min), and 3 (1 adult) (3.3%) had ≥ stage III renal insufficiency (i.e. clearance <30 mL/min). One patient developed respiratory failure due to emphysema. One adult patient developed a solid organ (non-skin) de novo malignancy (head and neck carcinoma).

Survival

Median follow-up after LT was 13.6 years (0.1-31.7). Seven patients died after LT and eight were re-transplanted. The overall cumulative patient survival rates post-transplant were 97.8% at 1 year, and 95.5%, 95.5%, 92.0%, 89.1% at 5, 10, 15, 20 years post-transplant respectively (Figure 3A).

The cause of death was sepsis (n=2), cardiovascular disease (n=1), respiratory failure (n=1), de novo malignancy (n=1) or unknown (n=2). All 3 patients who received combined lung/liver transplantation survived. The overall cumulative liver graft survival rates post-transplant were 92.2% at 1 year, and 89.9%, 89.9%, 84.4%, 81.5% at 5, 10, 15 and 20 years, respectively (Figure 3B). The indications for re-transplantation included primary non-function (n=3), chronic rejection (n=4) and hepatic artery thrombosis (n=1).

Gender, recipient age (as a continuous variable or considering adult vs. pediatric), genotype/phenotype (Pi*ZZ vs Pi*SZ), emphysema, HCC, type of graft (whole vs partial), type of donor (living vs. cadaveric) were not associated with patient and graft survival in the univariate analysis. Patient (but not graft) survival was slightly higher for pediatric LT recipients, but the difference did not reach statistical significance (Figure 4).

Discussion

Using a large, multi-center cohort comprising 90 pediatric and adult patients, we report that longterm outcomes after LT or combined lung-liver transplantation for A1AT deficiency are favorable and similar to those for other indications The burden of liver disease associated with A1AT deficiency has been evaluated from registry studies. A large survey focusing on clinical characteristics included 1,953 questionnaires returned in North America (1,810 with severe A1AT deficiency) [START_REF] Strange | Results of a survey of patients with alpha-1 antitrypsin deficiency[END_REF]. Lung or liver transplantation was reported by 9% of all respondents (n = 175), including 66 single lung transplants, 68 double lung transplants, and 47 LT; additional 6.6% (n = 128) reported that they were currently on a transplant list. In the National Heart, Lung, and Blood Institute registry, cirrhosis accounted for 10% of deaths and has been reported as the primary cause of death in 28% of PI*ZZ nonsmoker individuals [START_REF] Stoller | Mortality in individuals with severe deficiency of alpha1-antitrypsin: findings from the National Heart, Lung, and Blood Institute Registry[END_REF][START_REF] Tanash | Clinical course and prognosis of never-smokers with severe alpha-1-antitrypsin deficiency (PiZZ)[END_REF]. It can therefore be summarized that A1AT deficiency is a severe illness for many of those affected as reflected in a high incidence of transplantation for liver and/or lung disease.

In A1AT deficiency, LT is able to cure both the liver disease and the underlying metabolic defect. This has been demonstrated from early experience in children, in whom normal levels of A1AT and phenotype change were detected soon after transplant [START_REF] Putnam | Liver replacement for alpha1-antitrypsin deficiency[END_REF]. The first large case series of LT for A1AT deficiency came from Pittsburgh, reporting 39 patients (29 children and 10 adults), transplanted between 1980 and 1986 [START_REF] Esquivel | Orthotopic liver transplantation for alpha-1-antitrypsin deficiency: an experience in 29 children and ten adults[END_REF]. Interestingly, 30 of 36 patients with available data (83%) were homozygous PI*ZZ, but 6 were heterozygotes, either PI*MZ or PI*SZ, and 5-year actuarial survival was 83% and 60% in pediatric and adult recipients respectively, suggesting that LT in this indication could be associated with a particularly favorable outcome.

The largest published cohort available was built using the UNOS database, including 567 children and adults, who underwent LT from 1995 to 2004 [START_REF] Kemmer | Alpha-1-antitrypsin deficiency: outcomes after liver transplantation[END_REF]. A1AT deficiency accounted for 1.06% of all adult LT and 3.51% for pediatric LT during that time interval. The 1-, 3-, and 5-year patient survival was better for pediatric patients compared to adults: 92%, 90%, and 90% respectively, vs. 89%, 85%, and 83%, even if graft survival was similar: 84%, 81%, and 78% for pediatric patients vs. 83%, 79%, and 77% for adults. Age was the only predictor of patient survival.

Regarding the indication for LT in this specific liver disease, the vast majority of patients, including in the present study, were transplanted for end-stage liver disease or severe portal hypertension rather than hepatocellular carcinoma (HCC). The reported risk and prevalence of HCC in A1AT deficiency are highly variable and dependent on the population studied. In the case-control autopsy study from Sweden, the reported prevalence of HCC was 28% [START_REF] Elzouki | Risk of hepatobiliary disease in adults with severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma?[END_REF], while no cases of HCC were reported in the large UNOS study [START_REF] Kemmer | Alpha-1-antitrypsin deficiency: outcomes after liver transplantation[END_REF]. It can be surmised that this information was lacking in the UNOS database (or not collected), since subsequent analyses of other LT cohorts reported HCC prevalence from 10.2% to 17.9% [START_REF] Carey | Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency-related cirrhosis[END_REF][START_REF] Chu | Is severe progressive liver disease caused by alpha-1antitrypsin deficiency more common in children or adults?[END_REF], and6.3% in our cohort.

The present report confirms that the clinical spectrum of A1AT patients undergoing LT is wide, spanning young children to adults in their fifties. In summary, among pediatric LT recipients, most were PI*ZZ patients without other cause of liver disease, whereas, adult LT recipients (and probably more and more as their age increases) presented more often with heterozygous phenotypes and frequent liver co-morbidities. Our pediatric study population strongly resembles that of the UNOS study with a median age at LT of 3 years (range 0.5-17), and a male predominance 60.9% [START_REF] Kemmer | Alpha-1-antitrypsin deficiency: outcomes after liver transplantation[END_REF]. Similarly, 72% of adults were men, and the median age at transplant was 52 years (range 18-70). Nevertheless, limitations of the UNOS study must be pointed out: no A1AT phenotype was available, so the adult population may have included both homozygous and heterozygous individuals and no information on contributing factors such as hepatitis C virus infection, obesity and metabolic syndrome, or alcohol, was available. Before the present report, the best characterized adult A1AT LT population included 50 PI*ZZ patients and 23 PI*SZ patients, a group of 50 PI*MZ patients used for comparison, transplanted from 1987 to 2012 [START_REF] Carey | Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency-related cirrhosis[END_REF]. More than 40% of the PI*SZ patients had an additional cause for liver disease, 8% in the PI*ZZ group, and 90% of the PI*MZ group. This strongly supports the theory that heterozygosity usually requires an additional injury to cause liver cirrhosis and highlights the importance of testing individuals with liver disease for A1AT deficiency.

Given that A1AT deficiency is associated with both liver disease and chronic obstructive pulmonary disease, this warrants special discussion. First, lung disease rarely occurs before the age of 30 [START_REF] Bernspang | Respiratory symptoms and lung function in 30-year-old individuals with alpha-1-antitrypsin deficiency[END_REF], therefore only affecting the evaluation of adult patients. Pulmonary function can range from normal to severe airway obstruction. Therefore, LT candidates must undergo an exhaustive pulmonary evaluation including a full set of pulmonary function tests as part of the pre-LT evaluation, taking into account that concurrent ascites, hepatic hydrothorax, and/or malnutrition can interfere with both the patient's ability to perform the test and test results.

In case of combined lung and liver compromise, combined lung/liver transplantation should be discussed. This is a rare occurrence, as illustrated in the present cohort (3/95, 3.2%). Only three other cases have been reported so far [START_REF] Grannas | Indications for and outcomes after combined lung and liver transplantation: a single-center experience on 13 consecutive cases[END_REF][START_REF] Yi | Combined lung and liver transplantation: analysis of a single-center experience[END_REF]. Similarly to our 3 patients, outcomes were satisfactory with all patients alive at 4, 7, and 13 years of follow-up. Not only have combined liverlung transplantations been reported, but sequential transplantations have also been performed: in the large UNOS study, there were 3 liver-after-lung transplants (out of 567 patients, i.e. 0.5%) [START_REF] Kemmer | Alpha-1-antitrypsin deficiency: outcomes after liver transplantation[END_REF].

Another concern is the evolution of the chronic obstructive pulmonary disease after LT, because lung and liver diseases do progress independently (29). This has not been extensively studied. The largest and most comprehensive series reported paired pre-LT and post-LT pulmonary function tests of 17 patients, all with PI*ZZ phenotype [START_REF] Carey | Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency-related cirrhosis[END_REF]. Despite the normalization of A1AT levels after LT, the forced expiratory volume in 1 second (FEV1) continued to decline for the majority of patients (PI*ZZ or PI*SZ) patients; individual data suggest a continued decline in 65% with an improvement in 35% with wide variations. More importantly, 53% of the PI*ZZ patients had an annual reduction in FEV1 greater than the expected 30 mL/y from aging. In addition, Jain and coll. reported data of 7 adult patients who had pulmonary function tests available before and after LT [START_REF] Jain | Effect of liver transplant on pulmonary functions in adult patients with alpha 1 antitrypsin deficiency: 7 cases[END_REF]. The FEV1 was nearly unchanged after LT (mean total interval of nearly 3 years), suggesting, for the authors, that LT could have prevented the progression of pulmonary disease. Further studies on pulmonary function after LT are needed, including children, because long-term pulmonary outcomes after pediatric LT are unknown. However, we do recommend these recipients not to smoke.

Finally, while augmentation therapy can address the loss of A1AT in the lung, no treatment exists for the associated liver disease other than LT for patients with advanced liver disease. Several strategies are currently under evaluation in early-phase clinical trials to address this lack of available treatment: reduction of the production of the mutant protein by gene silencing (siRNA), blockage of intracellular polymerization (small molecules or antibodies), clearance of intracellular polymers by enhancing autophagy (carbamazepine, sirolimus), increasing of secretion of less polymerogenic variants [START_REF] Strnad | Alpha1-Antitrypsin Deficiency[END_REF][START_REF] Lomas | Update on alpha-1 antitrypsin deficiency: New therapies[END_REF]. In the future, the need for LT could decrease if efficacy of these

Legends for figures

2 ( 12 )

 212 CHU de Rennes, Hôpital de Pontchaillou, Service d'Hépatologie, Rennes, France (13) CHU de Bordeaux, Hôpital Haut Lévêque, Service de Chirurgie Hépatobiliaire et de Transplantation Hépatique, Bordeaux, France (14) CHU de Montpellier, Hôpital Saint-Eloi, Fédération Médico-Chirurgicale des Maladies de l'Appareil Digestif, Montpellier, France (15) CHU de Nice, Hôpital L'Archet 2, Service de Chirurgie Digestive, Nice, France (16) Université de Lyon, Lyon, France (17) Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Service d'Hépatologie, Lyon, France (18) Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Unité d'Hépatologie pédiatrique, Centre de référence de l'Atrèsie des voies biliaires et cholestases génétiques, filière de santé Filfoie, Paris, France (19) Centre Suisse du Foie de l'Enfant, Hôpitaux Universitaires de Genève, Département de Pédiatrie, Gynécologie et Obstétrique, Genève, Suisse (20) Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France

Figure 1 .Figure 2 .Figure 3 .

 123 Figure 1. Number of LT according to the age bracket and the genotype/phenotype

Figure 4 .

 4 Figure 4. Graft and patient actuarial survival according to Kaplan-Meier estimates Fig 3A: Overall patient survival (adults vs. children) Fig 3B. Overall graft survival (adults vs. children)

Table 1 .

 1 Characteristics of the study population (n= 90) Characteristic Age at LT (years, median and range, mean) 13.0 (0.2-65.1), 22.3

	Male/female [n (%)]

treatments is confirmed.

In conclusion, A1AT deficiency is a rare indication for LT but enables a very good long-term outcome for both children and adults. Pulmonary outcomes need further analysis.


Fabrice Lorignon

Alban Gossard
email: alban.gossard@cea.fr

Michaël Carboni
email: michael.carboni@cea.fr

Daniel Meyer

Fabrice Lorignon Ab

From wastes to interconnected porous monolith: Upcycling of Al-based metal organic framework via pickering emulsion template

Keywords: Metal-organic frameworks, Shaping, Pickering emulsion, Upcycling, Li-ion battery waste, Interconnected porosity

Introduction

Porous materials (carbon, silica or even coordination polymers) have attracted lot of attention these past years due to their formidable properties for many applications [1]. In particular, MOFs, constructed from the assembly of organic and inorganic compounds in a crystalline structure, are probably the most promising of these porous materials due to the different possibilities of structure [2].

However, for a broad applicability, producing MOFs (generally obtained as powder) as handleable materials is crucial and the literature is lacking in efficient, simple and economic shaping procedures that do not alter the material properties (mainly porosity and crystallinity) [3]. Consequently, numerous routes to fix MOFs onto monolithic supports have been studied [4]. The simplest involves mechanical treatments of pre-synthesized MOFs. Unfortunately, the compacting process drastically reduces the powder porosity and is not suited to the shaping of macroporous materials. MOFs can also be shaped into solid materials by pressing, granulation, extrusion, spray drying and even 3D printing [4].

Recently, Pickering emulsions have shown their interest to shape MOFs as monolith [5]. By growing a solid skeleton in the continuous phase of the emulsion and eliminating the internal phase, a monolithic material can be obtained containing macropores as a replica of the emulsion droplets and MOFs covering the macroporous surface area. For that purpose, we have recently shown that MIL-96(Al) particles, obtained as an upcycled materials from Li-ion batteries [6], can stabilize paraffin-in-water Pickering emulsions due to their amphiphilic properties [7]. In this work we now aim to use this emulsion as a template for hierarchically porous materials synthesis.

Experimental

MIL-96(Al) was obtained as an upcycled material from Li-Ion battery wastes as previously reported [6]. Different monoliths have been synthesized to evaluate the concentrations of MOFs, the polymeric precursors (acrylamide, noted AM, and methylene bisacrylamide) and the presence of adhesive binder (polyvinyl alcohol, PVA) on the porosity. Each monolith are designed as M[MOFs]/[AM]/[PVA]. For example, M100/10/0.5 corresponds to a material obtained with a [MOFs]=100 mg.mL -1 in H2O, [AM]= 10 wt. % relative to H2O and [PVA]= 0.5 wt. % relative to H2O. To prepare M100/10/0.5, 375 mg of MIL-96(Al), 375 mg of acrylamide, 18.75 mg of methylene bisacrylamide and 18.75 mg of KPS (Potassium Persulfate) are introduced into a beaker. After addition of 3.02 mL of water, homogenization is performed using an IKA Ultra Turrax T25 homogenizer with a single rotor (S25N-10 G) at 15.000 rpm. 0.73 mL of PVA is added while still under agitation as well as oil (paraffin) with a fixed ratio of 0.75 v/v, i.e. 11.25 mL. Agitation is maintained at 15.000 rpm for 2 min to obtain the emulsion, which is then placed at 80 °C to polymerize for 24 hours. The polyHIPE (for emulsion-templated polymers obtained within high internal phase emulsion) is finally washed using a Soxhlet extractor with ethanol for 48 hours to remove the oil, the polymer precursors in excess and PVA, and the material is dried under vacuum at 100 °C.

Results and discussion

The MOFs particles are oval like grains of rice and the material revealed a high crystallinity with a specific surface area of 655 m 2 .g -1 (Figure S1). In HIPEs, droplets are organised in a compact network and the continuous phase separating the oil droplets is a thin film of liquid, which favours the formation of an interconnected porous network. Polymer precursors are added to the emulsion to create a solid skeleton. As they are water-soluble, polymerization occurs in the continuous phase. PVA is known to be a particle adhesive. PVA is used to hold MOFs particles together at the oil-water interface and therefore contributes to the stabilisation of the emulsion [8]. After polymerisation and elimination of the oil, a modification of the skeleton as well as the porosity is observed. TGA analyses have been performed to prove that no residual oil, polymer precursor or PVA remain in the final monolith (Figure S3). The synthesis of polyHIPEs leads to the formation of macropores as a replica of the oil droplets and small porosity due to the space between the particles. As observed on Figure 2, as an illustrating example, the M100/10/0.5 monolith is white with visible macropores on the surface. The SEM analyses reveals the presence of a network of interconnected pores with various sizes. MIL-96(Al) particles can be identified over the entire internal surface of the pores where the droplets were located, confirming the Pickering-stabilization mechanism. Note that some MOFs particles are also irregularly present outside the pores (Figure 2e), probably because these particles aggregate in the continuous phase during formulation and are trapped in the walls during polymerisation [7]. PXRD (Figure S4) and FTIR (Figure S5) analyses are performed on pristine MOFs as well as on monoliths and show that the MOFs structure is retained in the final composites.

(c)

increases from 0 wt. % to 0.5 wt. %. Indeed, PVA is a surface active component and can thus participate to the stabilization mechanism of the emulsion. The PVA also interposes itself among the droplets and creates open windows (pore throats) between the pores after polymerization. In this way, the presence of PVA in the emulsion formulation promotes the formation of pore throats and thus improves interconnectivity of the porous network. Note that, the variation of MIL-96(Al) amount has only a small impact on pore size at PVA= 0.5 wt. % . abundance of MOFs in the pores. One part of these particles will be trapped in the polymer structure while the other part will be accessible. Furthermore, the presence of PVA induces the formation of pore throats and thus opens the porous network. This leads to a higher availability of MOFs in the composite, which is reflected by the increase of the specific surface between M100/10/0 (51 m2 .g -1 ) and M100/10/0.5 (91 m 2 .g -1 ). By combining these results with those of the thermogravimetric analysis, the accessible surface of the particles in the monolith model M100/10/0.5 can be evaluated. TGA presents a mass loss due to MIL-96(Al) about 60 wt. % (Figure S3) meaning that a maximum of surface area of 393 m 2 .g -1 (instead of 655 m 2 .g -1 ) can be obtained if the all MOFs porosity is accessible at the surface of the monolith. However, the specific surface area of the material is 91 m 2 .g -1 . The polymer support does not contribute to the specific surface area [9], this means that some particles are embedded in the polymer and a part of the surface area is lost. The ratio between the real and theoretical surfaces is thus 91/393 = 0.23, so the shaping of the monoliths reduces the accessible surface of the powder by 77%. We have demonstrated in this work the possibility to form monoliths of polymer-MOFs composites via a Pickering emulsion templating approach with addition of polymer and adhesive binder in the continuous phase of the emulsion. By optimizing the formulation of the emulsion, we are able to propose a best formulation keeping some porous properties of the pristine MOF in the range or higher than those observed in the literature with similar strategy [9][10][11][12][13][14]. As a perspective, we assume that this strategy can be transposed to other MOF materials and generalized as a way to shape powdery MOFs, which will increase their application fields.

Figure 1 :

 1 Figure 1: (a) Photograph of Pickering emulsions precursor of M100/10/0.5; (b) Optical micrographs of the emulsion droplets and (c) Droplet size distribution in the emulsion.

Figure 1a exhibits

  Figure1aexhibits the HIPE template before polymerization and shows that emulsion behaves a gel. The droplet size distribution is relatively homogeneous with droplets diameters centred around 20 µm. The presence of polymers has only a slight impact on the rheological properties, but PVA induces in the thickening of the continuous phase (FigureS2).

Figure 2 :

 2 Figure 2: (a) Photograph of the M100/10/0.5 monolith, seen from the front and from below; (b-e) SEM images of the M100/10/0.5 monolith at different magnifications

Figure 3 :

 3 Figure 3: Average pore diameters (black) and pore throats (blue) of different monoliths.

Figure 4 :

 4 Figure 4: Nitrogen isotherm adsorption/desorption of the corresponding MIL-96(Al) powder, M100/10/0.5, M100/10/0 and M25/10/0.5.Finally, M100/10/0.5 shows to have a good mechanical resistance until 1 kg (FigureS6).

/g

Acknowledgements

This work was supported by the Occitanie Region and by the CEA through the VADEN project.


Christian Guerin

Wissam Réveillère

El-Hage

Disentangling the link between mindfulness and dissociation: The mediating role of attention and emotional acceptance

Keywords: Dissociation, mindfulness, attention, emotional acceptance

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

Introduction

Dissociation is described as a disruption in the usually integrated functions of consciousness, memory, identity, and perception of the environment (American Psychiatric Association, 2013). Dissociation is a transdiagnostic symptom [START_REF] Mckinnon | A review of the relation between dissociation, memory, executive functioning and social cognition in military members and civilians with neuropsychiatric conditions[END_REF] that is frequently observed in Post-Traumatic Stress Disorder (PTSD). The dissociative subtype of PTSD has consequently been included in the DSM-5 (American Psychiatric Association, 2013), due to the strong correlation between dissociation and PTSD [START_REF] Murphy | A Cross-Lagged Panel Study of Dissociation and Posttraumatic Stress in a Treatment-Seeking Sample of Survivors of Childhood Sexual Abuse[END_REF]. In addition to common PTSD symptoms, the dissociative subtype of PTSD is marked by depersonalization (i.e., feeling detached from oneself, a sense of not being real) and/or derealization (i.e., feeling as if the world is not real).

To date, Trauma Focused-Cognitive Behavioral Therapy (TF-CBT) and Prolonged Exposure Therapy [START_REF] Foa | Prolonged Exposure Therapy for PTSD: Emotional Processing of Traumatic Experiences, Therapist Guide[END_REF] are the most widely recommended and scientifically validated treatments for PTSD [START_REF] Foa | Effective Treatments for PTSD: Practice Guidelines from the International Society for Traumatic Stress Studies[END_REF]; National Collaborating Centre for Mental Health (UK), 2005; World Health Organization, 2013). However, dissociation, while much more prominent than PTSD symptoms, is one of the contraindications of Prolonged Exposure Therapy [START_REF] Foa | Prolonged Exposure Therapy for PTSD: Emotional Processing of Traumatic Experiences, Therapist Guide[END_REF]. Although some studies found no moderating effect of dissociation on treatment outcomes [START_REF] Hagan | Predictors of nurses considering leaving the profession due to work-related stress in a large pediatric and women's hospital in the United States[END_REF][START_REF] Halvorsen | Does dissociation moderate treatment outcomes of narrative exposure therapy for PTSD? A secondary analysis from a randomized controlled clinical trial[END_REF][START_REF] Zoet | Presence of the dissociative subtype of PTSD does not moderate the outcome of intensive traumafocused treatment for PTSD[END_REF], others indicated that dissociation could moderate the outcome of psychotherapy through positive associations with poor treatment results and/or residual symptoms [START_REF] Feeny | PTSD, dissociation and treatment[END_REF][START_REF] Kleindienst | State dissociation moderates response to dialectical behavior therapy for posttraumatic stress disorder in women with and without borderline personality disorder[END_REF][START_REF] Lanius | Fear conditioning and early life vulnerabilities: two distinct pathways of emotional dysregulation and brain dysfunction in PTSD[END_REF][START_REF] Lanius | The dissociative subtype of posttraumatic stress disorder: rationale, clinical and neurobiological evidence, and implications[END_REF][START_REF] Price | Emergency Department Predictors of Posttraumatic Stress Reduction for Trauma-Exposed Individuals With and Without an Early Intervention[END_REF]Steuwe et al., 2012;[START_REF] Wolf | The dissociative subtype of PTSD: a replication and extension[END_REF]. Furthermore, dissociation appears to interfere with treatment, particularly when patients are faced with intense emotions [START_REF] Lanius | Fear conditioning and early life vulnerabilities: two distinct pathways of emotional dysregulation and brain dysfunction in PTSD[END_REF]Lanius, Vermetten, et al., 2010). It therefore seems important to understand which mechanisms are implicated in traumatic dissociation in order to adapt treatment to the presence and severity of dissociative symptoms. Some authors suggest that mindfulness-based interventions could be appropriate for treating dissociative symptoms [START_REF] Cloitre | An examination of the influence of a sequential treatment on the course and impact of dissociation among women with PTSD related to childhood abuse[END_REF][START_REF] Forner | What Mindfulness can learn about Dissociation and what Dissociation can learn from Mindfulness[END_REF][START_REF] Frewen | Healing the Traumatized Self: Consciousness[END_REF][START_REF] Zerubavel | Staying Present: Incorporating Mindfulness into Therapy for Dissociation[END_REF]. To date, only a few studies have been conducted on the links between dissociation and mindfulness; a negative correlation has been found between mindfulness and dissociation in the general population [START_REF] Baer | Assessment of mindfulness by self-report: the Kentucky inventory of mindfulness skills[END_REF][START_REF] Perona-Garcelán | Relationship between childhood trauma, mindfulness, and dissociation in subjects with and without hallucination proneness[END_REF][START_REF] Walach | Measuring mindfulness-the Freiburg Mindfulness Inventory (FMI)[END_REF], among patients suffering from auditory and verbal hallucinations [START_REF] Escudero-Pérez | Dissociation and mindfulness in patients with auditory verbal hallucinations[END_REF], among patients suffering from Post-Traumatic Stress Disorder [START_REF] Kratzer | Mindfulness and pathological dissociation fully mediate the association of childhood abuse and PTSD symptomatology[END_REF], and among patients suffering chronic pain [START_REF] Michal | Depersonalization, mindfulness, and childhood trauma[END_REF]. Those results suggest that the more patients have mindfulness abilities, the less they have dissociative symptoms. A positive effect was found in only one study, which investigated the effect of mindfulness-based group therapy on dissociative symptoms. However, it only included 7 patients suffering from dissociative symptoms and there was no control group [START_REF] Sharma | Role of mindfulness in dissociative disorders among adolescents[END_REF].

In 2004, Bishop et al. proposed a two-component model of mindfulness that includes selfregulation of attention and orientation to experience. Self-regulation of attention consists of maintaining awareness of current experience [START_REF] Bishop | Mindfulness: A Proposed Operational Definition[END_REF] and the ability to disengage from thoughts that come to mind and to which attention naturally turns. This component is strongly related to the executive functions of inhibition, sustained attention, and attention switching, which are predicted to improve with mindfulness. The second component, orientation to experience, consists of accepting internal experiences (emotions, feelings, thoughts) without judgment, and maintaining an attitude of openness and curiosity. These two components, leading to a decentered perspective of emotion, contribute to adaptive emotion regulation, by enabling the individual to gain insight and greater emotional awareness and acceptance [START_REF] Bishop | Mindfulness: A Proposed Operational Definition[END_REF][START_REF] Bondolfi | Les approches psychothérapeutiques basées sur la pleine conscience (mindfulness)[END_REF]. It would be interesting to identify which of the mechanisms described in this model (self-regulation of attention or orientation to experience) mediates the link between mindfulness and dissociation.

Previous studies have reported that dissociation is associated with emotion dysregulation within the general population [START_REF] Moulton | Childhood trauma and eating psychopathology: a mediating role for dissociation and emotion dysregulation?[END_REF] and within patients suffering from PTSD [START_REF] Powers | PTSD, emotion dysregulation, and dissociative symptoms in a highly traumatized sample[END_REF]. Moreover, dissociative pathologies are strongly correlated with alexithymia, which is the inability to identify and describe emotions [START_REF] Mark | Symptom overreporting and dissociative experiences: A qualitative review[END_REF]. Daytime EEGs in highly dissociative patients have shown that dissociative experiences are positively associated with reduced attentional control [START_REF] Kirino | P300 is attenuated during dissociative episodes[END_REF][START_REF] Krüger | Dissociative mental states are canonically associated with decreased temporal theta activity on spectral analysis of EEG[END_REF].

It has also been found that highly dissociative patients, especially those experiencing intense negative emotions, have difficulty sustaining and controlling attention when faced with distracting stimuli [START_REF] Soffer-Dudek | Dissociation and dissociative mechanisms in panic disorder, obsessive-compulsive disorder, and depression: A review and heuristic framework[END_REF]. Overall, these findings suggest that both emotional regulation and attentional abilities may mediate the link between dissociation and mindfulness.

Identification of the mechanisms that link dissociation and mindfulness would make it possible to set up appropriate therapeutic programs to reduce dissociative symptoms. The main aim of this study was thus to disentangle the different cognitive and affective mechanisms that connect mindfulness and dissociation in a non-clinical population. We postulate that this connection is partially mediated by, first, attention control, and secondly, emotional acceptance.

Method

Procedure

Participants were recruited through social networks and had to be at least 18 years old. After reading an information note online, they gave their consent to participate in the study by ticking a box. Data were collected anonymously using Sphinx software. The experiment and consent procedures were approved by the ethics committee of the University (Comité d'Ethique de la Recherche Tours-Poitiers, n°2020-01-08).

Participants were asked to answer a few short questions about their age, sex, and years of study after high school. They then completed questionnaires and scales assessing history of childhood trauma, dissociative experiences, emotion regulation abilities, cognitive difficulties, attention control, and mindfulness abilities.

Measures

Dissociative Experience Scale (DES)

The DES is a 28-item self-report questionnaire evaluating trait dissociation [START_REF] Bernstein | Development, reliability, and validity of a dissociation scale[END_REF]. A typical item is "Some people have the experience of driving a car and suddenly realizing that they don't remember what has happened during all or part of the trip".

Participants are asked to rate how often each experience happens to them on a scale ranging from 0% (never) to 100% (always). The overall score is the mean of the scores of all the items ranging from 0 to 100. French validation studies show good internal consistency (α=0.94) [START_REF] Darves-Bornoz | Validation of a French Version of the Dissociative Experiences Scale in a Rape-Victim Population[END_REF]. This questionnaire is composed of 3 subscales: amnesia, depersonalization/derealization and absorption.

Difficulties in Emotion Regulation Scale (DERS)

The Difficulties in Emotion Regulation Scale [START_REF] Gratz | Multidimensional Assessment of Emotion Regulation and Dysregulation: Development, Factor Structure, and Initial Validation of the Difficulties in Emotion Regulation Scale[END_REF] The FFMQ is a 39-item self-report questionnaire assessing five facets of mindfulness [START_REF] Baer | Construct validity of the five facet mindfulness questionnaire in meditating and nonmeditating samples[END_REF]. A typical item is: "While walking, I am aware of the sensations in my body".

Participants respond on a 5-point Likert scale ranging from 1 (never) to 5 (always true). The

French version has been shown to have good psychometric properties [START_REF] Heeren | Crosscultural validity of the Five Facets Mindfulness Questionnaire: Adaptation and validation in a French-speaking sample[END_REF].This questionnaire is composed of 5 subscales: observing, describing, acting with awareness, non-judging and non-reactivity.

Childhood Trauma Questionnaire (CTQ)

The Childhood Trauma Questionnaire is a 28-item self-report questionnaire assessing the history of sexual, emotional, and/or physical abuse during childhood (D. P. [START_REF] Bernstein | Development and validation of a brief screening version of the Childhood Trauma Questionnaire[END_REF]. A typical item: "When I was growing up, people in my family hit me so hard that it left me with bruises or marks". Participants answer on a 5-point Likert scale ranging from 1 (never true) to 5 (very often true). Studies have shown that the French version has good psychometric properties [START_REF] Paquette | Validation of the French version of the CTQ and prevalence of the history of maltreatment[END_REF]. This questionnaire is composed of 5 subscales: emotional abuse, physical abuse, sexual abuse, emotional neglect, physical neglect.

Statistical Analyses

We conducted correlation analysis (Bravais-Pearson) and multiple linear regressions. We used the bootstrapping technique for mediation analysis. Statistical analyses were performed using SPSS software, 23rd version. The mediation analyses were performed using the 4 th model of Preacher and Hayes' macro (Introduction to Mediation, Moderation, and Conditional Process Analysis, 2018).

Results

Descriptive data

We recruited 312 participants (269 women, 43 men), who completed the study protocol online. Their mean age was 29.5 years (SD=12.78) and mean years of higher education was 3.75 (SD=2.48). Descriptive statistics were used to summarize total and subscale scores (see Table 1).

-Insert Table 1-

Correlational analyses

We used Pearson's correlation analysis to explore the association between the different variables. All the results are presented in Table 2. Dissociation was positively related to all the sub-dimensions of the DERS, all the sub-dimensions of the CDS, and the Childhood Trauma Questionnaire. We also found a negative relationship between mindfulness and dissociation (-0.423, p<0.01). There was a positive relationship between dissociation and emotional acceptance (r=0.370, p<0.001) and attention-concentration (r=0.585, p<0.001). We also found a negative relationship between mindfulness and emotional acceptance (r=-0.523, p<0.001) and attention-concentration (r=-0.626, p<0.001). These results enabled us to run a mediation analysis.

-Insert Table 2-

Causal analysis

We used multiple linear regressions to analyze causal relations, with dissociation as the dependent variable. All the steps are presented in Table 3.

When entered alone (Model 1), mindfulness was a significant predictor of dissociation (β=0.761, p<0.001). When entered simultaneously (Model 2), mindfulness and emotional acceptance were significant predictors (respectively β=0.215, p<0.001 and β=0.649, p<0.001).

However, the β value of mindfulness was lower than in Model 1, which suggests that the effect of mindfulness on dissociation is partly mediated by emotional acceptance. In Model 3, mindfulness and attention-concentration were the independent variables; attentionconcentration was a significant predictor of dissociation (β=0.825, p<0.001) but mindfulness was not. This suggests that the effect of mindfulness on dissociation is mediated by attentionconcentration. Finally, we entered mindfulness, attention-concentration and emotional acceptance as the independent variables. We found that emotional acceptance and attentionconcentration were significant predictors of dissociation (respectively β=0.699, p<0.001 and β=0.0201, p<0.001), but mindfulness was not significant and its Beta value reached almost zero. This suggests that the effect of mindfulness on dissociation is mediated by attentionconcentration and emotional acceptance.

-Insert Table 3-

Bootstrapping analyses

Following the recommendations of [START_REF] Preacher | Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models[END_REF], we used a bootstrapping technique to assess the mediation effect. Overall, we found a significant model predicting dissociation, with emotional acceptance and attention-concentration as mediators and mindfulness as the independent variable (F=58, 04, R²=0.3612; p<0.001). More specifically we found a mediating effect of attention-concentration (bias-corrected 95% confidence interval CI=-0.0027 to -0.0017) and a mediating effect of emotional acceptance (biascorrected 95% confidence interval, CI=-0.008 to -0.0002). Details of the mediation analysis are presented in Figure 1.

-Insert Figure 1-

Discussion

The aim of the present study was to disentangle the cognitive and affective mechanisms that connect dissociation and mindfulness. In line with previous studies, we found that dissociation was positively correlated with childhood trauma (e.g. [START_REF] Sanders | Dissociation and childhood trauma in psychologically disturbed adolescents[END_REF].

Similarly, we also found that dissociation was negatively related to mindfulness [START_REF] Baer | Assessment of mindfulness by self-report: the Kentucky inventory of mindfulness skills[END_REF][START_REF] Perona-Garcelán | Relationship between childhood trauma, mindfulness, and dissociation in subjects with and without hallucination proneness[END_REF][START_REF] Walach | Measuring mindfulness-the Freiburg Mindfulness Inventory (FMI)[END_REF] and positively correlated with attention-concentration difficulties, in line with previous studies reporting impaired attention control and sustained attention among patients with dissociative disorders [START_REF] Kirino | P300 is attenuated during dissociative episodes[END_REF][START_REF] Krüger | Dissociative mental states are canonically associated with decreased temporal theta activity on spectral analysis of EEG[END_REF][START_REF] Soffer-Dudek | Dissociation and dissociative mechanisms in panic disorder, obsessive-compulsive disorder, and depression: A review and heuristic framework[END_REF]. Furthermore, in our nonclinical sample, dissociation was positively correlated with: a) non-acceptance of emotional responses; b) difficulty engaging in goal-directed behavior and impulse control; c) lack of emotional awareness; d) lack of emotional clarity; and e) limited access to emotion regulation strategies. These results are consistent with previous studies that found emotion dysregulation and alexithymia among patients with dissociative disorders [START_REF] Mark | Symptom overreporting and dissociative experiences: A qualitative review[END_REF][START_REF] Powers | PTSD, emotion dysregulation, and dissociative symptoms in a highly traumatized sample[END_REF].

Conversely, and as expected, mindfulness was negatively correlated with dissociation, cognitive difficulties, and difficulties in emotion regulation. These results are consistent with the two-component model of mindfulness proposed by [START_REF] Bishop | Mindfulness: A Proposed Operational Definition[END_REF], in which selfregulation of attention and emotion were predicted to increase with mindfulness. Furthermore, we found that the effect of mindfulness on dissociation was mediated by attentionconcentration and emotional acceptance. Our results thus indicate the mediating effects of emotional acceptance and attention-concentration on dissociation.

These results support previous studies indicating that mindfulness could be combined with other psychotherapies to reduce and treat dissociative symptoms [START_REF] Cloitre | An examination of the influence of a sequential treatment on the course and impact of dissociation among women with PTSD related to childhood abuse[END_REF][START_REF] Forner | What Mindfulness can learn about Dissociation and what Dissociation can learn from Mindfulness[END_REF][START_REF] Frewen | Healing the Traumatized Self: Consciousness[END_REF][START_REF] Heeren | Les interventions basées sur la pleine conscience: une revue conceptuelle et empirique[END_REF][START_REF] Zerubavel | Staying Present: Incorporating Mindfulness into Therapy for Dissociation[END_REF], by improving self-regulation of attention, orientation to experience, and emotion regulation. For example, mindfulness is used in Dialectic Behavioral Therapy to help patients with Borderline Personality Disorder develop distress-tolerance skills [START_REF] Linehan | Cognitivebehavioral treatment of chronically parasuicidal borderline patients[END_REF], and it could thus be proposed as an experimental protocol for patients with dissociative disorders. However, some researchers have noted that mindfulness may be detrimental for patients suffering from dissociative symptoms (Alexandre [START_REF] Heeren | Les interventions basées sur la pleine conscience: une revue conceptuelle et empirique[END_REF]. They explain that dissociation is a way to avoid aversive emotions. In that way, exposing patients to aversive emotions during mindfulness exercises may create a dissociative reaction. Therefore, a preliminary work on emotion regulation may be necessary before practicing mindfulness with patients suffering from dissociative symptoms. This would help patients face their emotions. Psychotherapy programs focusing on emotion regulation and attention processes for dissociative symptoms could also be developed.

This study has a number of limitations. As an exploratory study, we measured attentionconcentration through a questionnaire, and cognitive tests such as the D2-R [START_REF] Brickenkamp | D2 Test of Attention[END_REF] would be a more accurate way of evaluating attention. However, previous results

did not indicate a consistent relationship between cognitive difficulties evaluated using cognitive tasks [START_REF] Mckinnon | A review of the relation between dissociation, memory, executive functioning and social cognition in military members and civilians with neuropsychiatric conditions[END_REF]. Further studies are therefore required to explore the links between cognitive performance and dissociation before using such tasks to evaluate the mediating effect of attention between mindfulness and dissociation. Moreover, our sample is not a clinical sample. We can wonder if dissociation in the general population corresponds to dissociation in a psychiatric population and more precisely within patients suffering from PTSD. This study should be performed with patients suffering from dissociative disorder or dissociative subtype of post-traumatic stress disorder. Furthermore, the fact that mindfulnesstrait is negatively associated with dissociative symptoms does not mean that mindfulnessbased interventions are necessary efficient for treating dissociative symptoms. Finally, we conducted correlational analyses, which do not show causal relationships. To provide evidence of a causal relationship and strengthen the existence of mediator effects between a)

emotional acceptance and dissociation, and b) attention-concentration and dissociation, it would be interesting to assess the effect of a mindfulness-based experimental protocol on patients suffering from dissociative symptoms. This would be the only way to assure that mindfulness is a relevant way to treat dissociative symptoms.

Finally, most participants in our study were women, and our findings should be replicated with a more gender-balanced sample.

Conclusion

In addition to a negative correlation between mindfulness-trait and dissociation (meaning that the more subjects have mindfulness abilities, the less they have dissociative symptoms), this study demonstrates that attention-concentration and emotion regulation have mediating effects

  on dissociation. More research within a clinical population are required to argue that mindfulness-based interventions are efficient to reduce dissociative symptoms. Other approaches based on attention processes and emotion regulation could also be developed to treat or reduce the dissociative symptoms of Post-Traumatic Stress Disorder. Our findings thus have clinical implications for the treatment of traumatic dissociation and suggest directions for future research.

  * .251 ** .085 .220 ** .143 * .148 ** .195 ** .179 ** .123 * .163 ** .200 ** .109 Experiences Scale; DERS-NA: Non-acceptance of emotional responses; DERS-DE: Difficulty engaging in Goal-directed behavior; DERS-I: Impulse control difficulties; DESR-C: Lack of emotional awareness; DERS-S: Limited access to emotion regulation strategies; DERS-CL: Lack of emotional clarity; McNair-AC: Attention-concentration; McNair-P: Praxis; McNair-RD: Delayed recall; McNair-OP: Orientation to people; McNair-OT: Temporal orientation; McNairMP: Prospective memory; FFMQ: Five Facet Mindfulness Questionnaire; CTQ= Childhood Trauma Questionnaire; *<0.05; **<0.001

Figure 1 .

 1 Figure 1. Mediation analysis (n.s.: non-significant).

Table 1 .

 1 Descriptive Data.

		Minimum	Maximum	Mean	SD
	DES	.0	.799	.235	.164
	DERS-NA	6	30	13.91	6.79
	DERS-DE	5	25	15.67	5.29
	DERS-I	6	30	12.57	5.62
	DESR-C	6	30	15.76	5.39
	DERS-S	9	45	23.57	8.54
	DERS-CE	5	25	11.72	4.44
	McNair-AC	0	38	16.90	8.09
	McNair-P	0	14	3.08	2.97
	McNair-RD	0	12	3.71	2.80
	McNair-OP	0	16	5.37	3.11
	McNair-OT	0	8	2.75	2.27
	McNairMP	0	8	4.01	1.96
	FFMQ	49	183	122.92	23.51
	CTQ	29	118	47.68	14.38

DES: Dissociative Experiences Scale; DERS-NA: Non-acceptance of emotional responses; DERS-DE: Difficulty engaging in Goal-directed behavior; DERS-I: Impulse control difficulties; DESR-C: Lack of emotional awareness; DERS-S: Limited access to emotion regulation strategies; DERS-CL: Lack of emotional clarity; McNair-AC: Attention-concentration; McNair-P: Praxis; McNair-RD: Delayed recall; McNair-OP: Orientation to people; McNair-OT: Temporal orientation; McNairMP: Prospective memory; FFMQ: Five Facet Mindfulness Questionnaire; CTQ= Childhood Trauma Questionnaire.

Table 2 . Correlational Analyses

 2 * .223 ** .281 ** .194 ** .156 ** .250 ** .330 ** .512 ** .320 ** .430 ** .492 ** 1 McNairMP .322 ** .257 ** .234 ** .193 ** .116 * .252 ** .234 ** .436 ** .247 ** .412 ** .350 ** .343 ** 1

				DER	DER	DER	DES	DER	DER	McNa	McNa	McNa	McNa	McNa	McNa	FFM
		DES	S-NA	S-DE	S-I	R-C	S-S	S-CE	ir-AC	ir-P	ir-RD	ir-OP	ir-OT	irMP	Q	CTQ
	DES		1
	DERS-NA .370 **	1
	DERS-DE .316 ** .496 **	1
	DERS-I	.397 ** .562 ** .648 **	1
	DESR-C	.184 ** .213 ** .105 .147 **	1
	DERS-S	.361 ** .641 ** .729 ** .701 ** .143 *	1
	DERS-CE .494 ** .501 ** .454 ** .566 ** .525 ** .553 **	1
	McNair-AC	.585 ** .423 ** .522 ** .443 ** .210 ** .512 ** .547 **	1
	McNair-P .426 ** .266 ** .193 ** .159 ** .079 .254 ** .253 ** .465 **	1
	McNair-RD	.398 ** .253 ** .270 ** .241 ** .195 ** .227 ** .334 ** .497 ** .368 **	1
	McNair-OP	.501 ** .239 ** .196 ** .139 * .095 .207 ** .250 ** .576 ** .429 ** .451 **	1
	McNair-OT .436 FFMQ	-
		.423 **

*

Table 3 .

 3 Multiple linear regression models predicting dissociation.

	Predictor of dissociation	Standardized β	T	R	R²	F	p
	Model 1			0.761 0.579 427.4 <0.001
	FFMQ	0.761	20.67				<0.001
	Model 2			0.838 0.703 366.8 <0.001
	FFMQ	0.215	3,78				<0.001
	Emotional acceptance	0.649	11,39				<0.001
	Model 3			0.886 0.784 562.0 <0.001
	FFMQ	0.071	1.49				0.138
	Attention-concentration	0.825	17,17				<0.001
	Model 4			0.889 0.791 390.3 <0.001
	FFMQ	0.008	0.16				0.876
	Attention-concentration	0.699	11.43				<0.001
	Emotional acceptance	0.201	3.24				<0.001

FFMQ: Five Facet Mindfulness Questionnaire.

Ethical approval:

The experiment and consent procedures were approved by the ethics committee of the University (Comité d'Ethique de la Recherche Tours-Poitiers, n°2020-01-08). We would like to thank all the participants and the University of Tours for the software support. This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The datasets gathered and/or analyzed during the current study are available from the corresponding author on reasonable request.