MD Marine Freist
email: mfreist@chu-clermontferrand.fr

MD Dominique Bertrand
email: dominique.bertrand@chu-rouen.fr

MD, MSc Elodie Bailly
email: elodiebailly20@gmail.com

PhD Céline Lambert
email: clambert@chu-clermontferrand.fr

MD Paul Olivier Rouzaire
email: porouzaire@chu-clermontferrand.fr

MD Richard Lemal
email: rlemal@chu-clermontferrand.fr

MD Julien Aniort
email: janiort@chu-clermontferrand.fr

MD Matthias Buchler
email: buchler@med.univ-tours.fr

MD Anne Elisabeth Heng

MD, MSc Cyril Garrouste
email: cgarrouste@chu-clermontferrand.fr

Anne Elisabeth

Management of Immunosuppression After Kidney Transplant Failure: Effect on Patient Sensitization

Keywords: kidney transplant failure, immunosuppression regimen, immunization, HLA antibodies, kidney transplantation

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

Introduction

The number of patients on kidney transplant (KT) waiting lists is continuously increasing. About 15% of these patients have already had a KT [START_REF] Hiesse | Épidémiologie de la transplantation rénale en France[END_REF][START_REF] Unos | annual report[END_REF] . In many cases they develop human leucocyte antigen (HLA) sensitization during their first graft or during renal replacement therapy after reduction of immunosuppressive treatment [START_REF] Scornik | Human leukocyte antigen sensitization after transplant loss: timing of antibody detection and implications for prevention[END_REF] , which makes access to a repeat KT more difficult. Longer waiting time is associated with lower patient survival [START_REF] Ojo | Prognosis after primary renal transplant failure and the beneficial effects of repeat transplantation: Multivariate Analyses from the United States Renal Data System1,2[END_REF][START_REF] Redfield | Graft and patient survival outcomes of a third kidney transplant[END_REF][START_REF] Meier-Kriesche | Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: a paired donor kidney analysis[END_REF] and with less likelihood of a repeat transplant [START_REF] Wong | Waiting Time Between Failure of First Graft and Second Kidney Transplant and Graft and Patient Survival[END_REF] . It is necessary therefore to avoid the appearance of new HLA antibodies. Documented information on the effect of maintaining immunosuppression (IS) after kidney transplant failure (KTF) is scarce. Retrospective studies suggest that maintenance decreases both the rate of allograft nephrectomy [START_REF] Bello | Donor-specific antibodies after ceasing immunosuppressive therapy, with or without an allograft nephrectomy[END_REF][START_REF] Woodside | Fever, infection, and rejection after kidney transplant failure[END_REF] and the development of HLA antibodies [START_REF] Augustine | Independent of nephrectomy, weaning immunosuppression leads to late sensitization after kidney transplant failure[END_REF][START_REF] Nimmo | The Impact of Withdrawal of Maintenance Immunosuppression and Graft Nephrectomy on HLA Sensitization and Calculated Chance of Future Transplant[END_REF][START_REF] Casey | Prolonged immunosuppression preserves nonsensitization status after kidney transplant failure[END_REF][START_REF] Del | Immunosuppression with Calcineurin Inhibitor after Renal Transplant Failure Inhibits Allosensitization[END_REF] thereby improving access to a second graft. However, maintenance immunosuppression is associated with higher rates of infection [START_REF] Woodside | Fever, infection, and rejection after kidney transplant failure[END_REF][START_REF] Gregoor | Infections after renal allograft failure in patients with or without low-dose maintenance immunosuppression[END_REF] , cardiovascular events [START_REF] Meier-Kriesche | Kidney transplantation halts cardiovascular disease progression in patients with end-stage renal disease[END_REF] and neoplasia [START_REF] Van Leeuwen | Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study[END_REF] . Firstyear mortality in patients going back to dialysis after KT failure is greater than in those not having received a graft [START_REF] Kaplan | Death after graft loss: an important late study endpoint in kidney transplantation[END_REF][START_REF] Aniort | CKD complications in kidney-transplanted patients going back to dialysis: impact on patients outcomes[END_REF] mainly for cardiac or infectious reasons [START_REF] Gill | Mortality after kidney transplant failure: the impact of non-immunologic factors[END_REF] . Hence, there are no current official guidelines for the management of immunosuppressive treatment after KTF [START_REF] Andrews | Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant[END_REF] .

In most instances, previous studies have suggested (i) stopping anti-metabolite treatments in the event of KTF, (ii) progressive reduction of CNI treatment followed by cessation within 1 month [START_REF] Pham | Immunosuppressive management of dialysis patients with recently failed transplants[END_REF][START_REF] Marinaki | Patients After Kidney Allograft Failure: Immunologic and Nonimmunologic Considerations[END_REF] or 3 months [START_REF] Morales | Management of patients after renal graft loss: an open question for nephrologists[END_REF] and (iii) reduction of corticosteroids with delayed cessation followed by resumption of treatment on the occurrence of symptoms related to graft intolerance 24 . The British Transplantation Society suggests maintenance of immunosuppression when the living donor transplant is planned in the year following KTF [START_REF] Andrews | Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant[END_REF] .

The authors of a recent literature review suggested continuing CNI treatment at least as long as the allograft was viable but to stop it in the event of nephrectomy [START_REF] Bunthof | Review: Management of patients with kidney allograft failure[END_REF] .

The aim of this study was to assess the effect of cessation or maintenance of immunosuppressive treatment on patient sensitization after a return to dialysis, and treatment tolerance so as to devise the best strategy for managing immunosuppressive drugs after KTF.

Patients and methods

Patients and data

This retrospective study was performed in three French KT centers (Gabriel Montpied Hospital, CHU Clermont-Ferrand; Bois-Guillaume Hospital, CHU Rouen; Bretonneau Hospital, CHRU Tours). Inclusion criteria were: (i) kidney transplant patients aged more than The following data were collected: (i) general patient characteristics: sex, date of birth, weight, height, blood group, type of dialysis before transplantation, initial kidney disease, (ii) information relating to the transplantation: date of the graft, number of previous transplants, type and age of the donor, number of HLA mismatches, induction therapy, kidney rejection classification and treatment undertaken, transfusion, (iii) evolution after return to dialysis: date of loss of KTF, type of dialysis, immunosuppressive drugs being taken at time of KTF and date at when they were discontinued, infections requiring hospitalization, cardiovascular events such as cerebrovascular accidents, acute coronary syndrome, cardiac rhythm disorders, hospitalization for heart failure, symptomatic occlusive disease of the lower extremities (type and date of first episode), neoplasia (type and date of diagnosis), graft intolerance syndrome (date), allograft nephrectomy (date, indication and occurrence of complication), (iv) date of waiting list registration for retransplantation, patient status at last follow-up (v) date of any new graft.

Immunological data

Anti-HLA antibodies were detected by LUMINEX LabScreen Single Antigen assays, either One Lambda, Canoga Park, CA (Clermont-Ferrand and Tours) or Immucor Lifecodes, (Rouen). The two techniques are comparable [START_REF] Bertrand | Comparison of Two Luminex Single-antigen Bead Flow Cytometry Assays for Detection of Donor-specific Antibodies After Renal Transplantation[END_REF] .

The data collected were: (i) presence of antibodies before transplantation, DSA or not, (ii) presence of HLA class I and/or class II antibodies on KTF (mean fluorescence intensity

[MFI] of the dominant DSA), (iii) development of de novo DSA, defined by MFI greater than or equal to 1000, (iv) panel reactive antibodies (PRA) provided by the French biomedical agency. Hypersensitized candidates to kidney transplantation were defined by an PRA ≥85%.

Definition of groups

Prolonged treatment (PT) with immunosuppressive drugs after KTF was defined as maintenance of therapy for at least 3 months after function loss. Patients who stopped treatment during this period were assigned to the early cessation (EC) group. For the main analysis, only calcineurin inhibitors (CNI) were taken into consideration.

A complementary analysis to assess the rate of development of HLA antibodies with and without CNI treatment was performed after establishment of two study periods.

Treatment period (T+) was the period from KTF to the date of cessation of immunosuppressive treatment, during which patients received IS. Those who stopped treatment during the first 3 months were excluded from analysis. Patients studied during the period from cessation of immunosuppressive treatment to performance of a new graft, death or last follow-up were assigned to the non-treatment (T-) period. Those in whom DSAs developed during the T+ period were excluded from the T-group.

Statistical analyses

Statistical analysis was performed using Stata software (version 13; StataCorp, College Station, Texas, USA). All tests were two-sided, with a Type I error set at 0.05. Categorical parameters were expressed as number of patients (associated percentages), and continuous data as mean ± standard deviation or as median [interquartile range], according to statistical distribution. The patients were divided into two groups according to the duration of anti-calcineurin treatment received after KTF (less than 3 months or greater than or equal to 3 months). Because there was no effect of the center (tested by mixed models), comparisons of these two independent groups were realized by statistical inference usual tests: categorical variables were compared using the chi-square test or the Fisher exact test; and quantitative data were compared between groups with the Student's t-test or the Mann-Whitney test, as appropriate. The Gaussian distribution was verified by the Shapiro-Wilk test and homoscedasticity by the Fisher-Snedecor test. The same analyses were performed to compare patients according to the duration of their corticosteroid treatment. When there were more than two groups to be compared (type of treatment: EC vs MMF vs ICN vs MMF+ICN), quantitative data were compared between groups by ANOVA or Kruskal-Wallis test (normality verified by the Shapiro-Wilk test and homoscedasticity by the Bartlett's test).

Categorical variables were compared as described previously, followed by the Marascuilo procedure if appropriate (omnibus p-value less than 0.05). For multivariate analysis, multiple logistic regression was used to study the development of DSA, considering the covariables according to the results of univariate analysis and their clinical relevance, notably for prolonged treatment with anti-calcineurin. The results were expressed as odds ratio (OR) and 95% confidence interval (95% CI). For secondary outcomes, other multivariate analyses, linear or logistic depending on the nature of the dependent variable, were performed according to the same principles. The development of DSA was also estimated using the Kaplan-Meier method, and the two groups (prolonged corticosteroid treatment and early cessation) were compared using the log-rank statistic. In addition, the patient sample was divided into two periods (T+ and T-), and events such as the development of de novo DSA, cardiovascular disorders and allograft nephrectomy were studied by mixed logistic regressions to take into account non-independence of the data (because a patient could be classified in both periods).

Institutional review board

This study was approved on 03 September 2019 by the ethical research committee ("Comité de Protection des Personnes Sud-Est 6") (IRB 00008526)

Results

General characteristics (Table 1)

A total of 119 patients with KTF were included in the study. Their general characteristics are given in Table 1. The patients were predominantly male (72.3%), aged 49.2 ± 14.5 years and had received a first KT (85.7%) whose median duration was 54 [9; 122] months. At the last KT follow-up, 68.9% had a DSA. The main cause of graft loss was rejection (60.5%). In the event of KTF, patients received triple IS comprising calcineurin inhibitors (95.0%), mycophenolate mofetil (MMF) (91.6%) and corticosteroids (91.6%). One hundred patients (84.0%) were on a waiting list for KT. Median follow-up time was 2.9 [1.6;

4.6] years.

Influence of prolonged treatment with calcineurin inhibitors (Tables 1 and2) There were no significant differences in general characteristics between the TP group (n=52, 43.7%) and the EC group (n=67, 56.3%) (Table 1).

During follow-up, de novo DSAs were observed in 30/52 (57.7%) patients in the TP group as against 52/67 (77.6%) in the EC group (p=0.02) (Figure 1). In multivariate analysis, adjusted for prolonged corticosteroid treatment, prolonged MMF treatment, graft loss by rejection, allograft nephrectomy and duration of graft function, prolonged treatment with CNI was always associated with a lower development of DSA (OR=0.39, 95% CI [0.16; 0.98] p=0.04) (Figure 2). The median levels of panel reactive antibody (PRA) class I and II (assessed in 99 patients) at first follow-up were similar in the two groups (Table 2), at last follow-up was higher in the EC group (97 [67; 99]) than in the PT group (41 [24; 96], p=0.002), as was the number of sensitized patients, who accounted for 38% in the EC group and 17% in the PT group (p=0.03). In multivariate analysis adjusted for prolonged corticosteroid treatment, prolonged MMF treatment, graft loss by rejection, allograft nephrectomy, transfusion, the presence of DSA at the time of KTF and duration of graft function, the number of patients with an PRA ≥85% was significantly lower in the PT group, OR=0.28, 95% CI [0.10; 0.78] p=0.02.

The rate of graft intolerance syndrome was 15.4% in the PT group as against 17.9% in the EC group (p=0.72). Allograft nephrectomy was observed in 19 (36.5%) PT patients and in 33 (49.3%) EC patients, p=0.17. PT and EC patients had similar rates of infections, cardiovascular events, neoplasia and deaths (Table 2). At 3 years, the rate of retransplantation was similar in the two groups : 36.1% [24.4; 51.2] in EC group, 39.9% [25.5; 58.5] in PT group p=0.73.

Analysis of periods with (T+) or without (T-) treatment with CNI (Table 3)

We excluded from the final analysis i) 34/86 patients in the T+ period because their treatment had been stopped in the first 3 months, ii) 18/108 patients in the T-period because a DSA had developed during the T+ period. Overall, patients were significantly less sensitized during the T+ period than during the T-period (34.6% and 70.0%, respectively, p=0.01). Of the 18 patients sensitized during the T+ period, 11 (61.1%) were still receiving corticosteroid treatment at 3 months and 13 (72.2%) had stopped MMF.

Cardiovascular and neoplastic events and deaths occurred with the same frequency during the two periods studied. The allograft nephrectomy rate was also comparable, 15 (28.8%) during the T+ period, and 24 (26.7%) during the T-period, p=0.78. 4 and5)

Effect of corticosteroid and/or MMF treatment after KTF (Tables

Corticosteroid treatment was maintained for more than 3 months (prolonged treatment) in 69/119 patients (58.0%). However, the rate of development of DSA in this group was similar to that in the EC group, respectively 47/69 (68.1%) and 35/50 (70.0%), p=0.83. The PRA at last follow-up and the rate of allograft nephrectomy were the same in the two groups of patients (Table 4). However, the rate of infections was significantly higher in patients with prolonged corticosteroid treatment (39.1%) than in those in the EC group (20.0%), p=0.03. Multivariate analysis adjusted for age, prolonged CNI treatment, prolonged MMF treatment, graft loss by rejection and graft duration confirmed that prolonged corticosteroid treatment is associated with a greater risk of infection, OR=2.66, 95% CI [1.09; 6.46], p=0.03.

Combined MMF and CNI treatment was observed in 23/52 patients receiving PT and in 9 patients without CNI treatment at 3 months. Development of DSA was similar in patients on combined therapy than in those receiving CNI treatment alone (52.2% vs 62.1% respectively, p=0.92) and there was also no difference of PRA between these two groups (69 [23; 97] vs 77 [32; 95] respectively, p=1.00). A lower rate of hypersensitized patients was observed in combined therapy (n=6, 35.3%) than in CNI monotherapy (n=11, 45.8%) and without immunosuppressive treatment (n=30, 60%), p=0.04. The rate of infections was also higher with MMF + CNI treatment (52.2%) than with CNI alone (24.1%), p=0.21 (Table 5).

Discussion

We report the first multicenter retrospective study to compare the effects of prolonged CNI immunosuppression following KTF on patient sensitization. Our results show that prolonged CNI treatment is associated with lower levels of de novo DSA and patient hypersensitization at the last follow-up. Several studies have also shown lower sensitization in patients continuing immunosuppressive treatment after LGF. In a retrospective American series involving 49 KT patients with graft failure, anti-HLA sensitization was lower when immunosuppressive treatment (either CNI or MMF) was maintained for more than 3 months than in the event of early cessation: OR=5.78, 95% CI [1.37; 24.44] [START_REF] Casey | Prolonged immunosuppression preserves nonsensitization status after kidney transplant failure[END_REF] . A single-center retrospective study performed in the USA compared the rate of hypersensitized patients at last follow-up, defined as such by a PRA >80%, in 119 recipients of a kidney or kidney-pancreas transplant following KTF. The rate of hypersensitized patients was 8% (n=2/24) when immunosuppression was maintained and 68% (n=65/95) if it was stopped (p<0.001) [START_REF] Augustine | Independent of nephrectomy, weaning immunosuppression leads to late sensitization after kidney transplant failure[END_REF] . A recent English study of 41 patients confirmed that a reduction of IS after KTF followed by cessation resulted in the development of DSAs and in all the patients becoming sensitized whether they had undergone nephrectomy or not [START_REF] Nimmo | The Impact of Withdrawal of Maintenance Immunosuppression and Graft Nephrectomy on HLA Sensitization and Calculated Chance of Future Transplant[END_REF] .

Our results showed that the development of de novo DSA after KTF was greater when anti-calcineurin treatment was stopped during the first 3 months than when it was maintained.

They also showed that DSAs recurred mainly (in 70% of cases) after cessation of treatment, including for patients continuing treatment at least 3 months after KTF. The results are similar to those reported in a retrospective Spanish series involving 76 patients in which the authors observed that DSAs developed in 78.4% of patients after cessation of IS [START_REF] Montemayor | Development of Donor-Specific Anti-HLA Antibodies After Restarting Hemodialysis Due to Graft Failure[END_REF] .

In our study, maintenance or cessation of prolonged CNI treatment was not associated with an increased rate of infections, cancers, cardiovascular complications or deaths. These results are consistent with those in previously reported case series. For example, in a study performed in the USA of 102 KT patients with KTF receiving or not immunosuppressive therapy of more than 3 months' duration the authors recorded similar rates of cancer (n=0 and n=4, respectively), death from infection (4% and 23%, respectively) and death from all causes (22% and 44%, respectively) [START_REF] Casey | Prolonged immunosuppression preserves nonsensitization status after kidney transplant failure[END_REF] . In contrast, another study recently performed in the USA involving 186 patients with KTF, the infection rate was significantly higher in the group continuing to receive IS (88%) than in the group where IS was discontinued (38%), p<0.001 10 14 . However, the authors did not specify which type of immunosuppressive treatment was used.

Prolonged corticosteroid therapy is the most commonly implemented regimen [START_REF] Andrews | Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant[END_REF][START_REF] Pham | Immunosuppressive management of dialysis patients with recently failed transplants[END_REF][START_REF] Kendrick | Managing the failing allograft[END_REF][START_REF] Gregoor | Immunosuppression should be stopped in patients with renal allograft failure[END_REF] but we did not observe its effect on i) the development of DSAs, (ii) PRA, (iii) the incidence of graft intolerance syndrome and (iv) allograft nephrectomy rate. In contrast, multivariate analysis showed an increased likelihood of infection with prolonged corticosteroid treatment.

Another retrospective multicenter series showed simular results [START_REF] Lucisano | Allosensitization after transplant failure: the role of graft nephrectomy and immunosuppression -a retrospective study[END_REF] . The authors reported an increase in infectious complications (OR=3.4, 95% CI [2.5; 4.5] p<0.001), cardiovascular complications (OR=3.0, 95% CI [1.1; 8.0] p=0.02) and deaths (OR=3.4, 95% CI [1.8; 6.3] p<0.001) in patients receiving IS treatment after KTF mainly corticosteroids (98%) [START_REF] Lucisano | Allosensitization after transplant failure: the role of graft nephrectomy and immunosuppression -a retrospective study[END_REF] .

Our study has certain limitations. First, because it was retrospective and performed in three different centers, the management of IS was not uniform. In the absence of guidelines for the management of immunosuppressive treatment after KTF [START_REF] Andrews | Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant[END_REF] , current treatment protocols differ between KT centers (appendix Table ) and the decision to reduce immunosuppressive therapy is often left to the discretion of the nephrologist in the dialysis center [START_REF] Andrews | Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant[END_REF] . Our study suggests maintenance of CNI immunosuppression until a new transplant is performed, irrespective of any intervening transplantectomy, so as to reduce the sensitization level, time on the waiting list [START_REF] Unos | annual report[END_REF][START_REF]Réseau épidemiologie et information en néphrologie[END_REF] . We didn't observe any difference of length of time on the waiting list between patients with early cessation or prolonged CNI treatment. Indeed French biomedical agency give a priority access to renal transplantation for patients with PRA >85%. That allowed to reduce their waiting time. Second, in these studies, as in ours, the dose or target level of CNI during maintenance treatment was not specified [START_REF] Del | Immunosuppression with Calcineurin Inhibitor after Renal Transplant Failure Inhibits Allosensitization[END_REF] . Only in a recent study was the development of HLA antibodies assessed according to levels of tacrolimus. This study showed a cut-off residual level of tacrolimus of 3ng/ml, below which patients had a higher cPRA at M24 (89 [70; 99] vs 0 [0; 43], p<0.001). [START_REF] Lucisano | Allosensitization after transplant failure: the role of graft nephrectomy and immunosuppression -a retrospective study[END_REF] In conclusion, our findings show that maintenance of long term CNI therapy limits patient sensitization after KTF without increasing the rates of infections or cardiovascular events. The dose and target rates of CNI treatment remain to be determined and our results should be validated by a prospective randomized study. In this analysis, duration of allograft survival is log-transformed.

  18 years (ii) loss of graft function between June 2007 and June 2017 requiring renal replacement therapy (iii) investigation for HLA antibodies over at least 12 months after return to dialysis or development of a donor specific antibody (DSA) in the follow-up period, (iv) recorded dates of cessation of immunosuppressive treatments and (v) minimum follow-up of 12 months. The medical and demographic characteristics of the patients were recovered from the CRISTAL prospective database and from patient medical files in the dialysis and transplantation centers taking part.

Figure 1 -

 1 Figure 1-Development of de novo DSAs according to prolonged CNI treatment (after month 3) or early cessation.

Figure 2 -

 2 Figure 2 -Multivariate analysis of predictive factors of development of de novo DSAs after loss of graft function

Figure 1 -

 1 Figure 1-Development of de novo DSAs according to prolonged CNI treatment (after month 3) or early cessation.

Figure 2 -

 2 Figure 2 -Multivariate analysis of predictive factors of development of de novo DSAs after loss of graft function

Table 1 -

 1 Characteristics of prolonged immunosuppressive treatment or early cessation (before month 3) after kidney transplant failure .

Table 2 -

 2 Outcomes of prolonged immunosuppressive treatment or early cessation (before month 3) after kidney transplant failure.

Table 3 -

 3 Outcomes under calcineurin inhibitors treatment (period T+) and weaned off calcineurin inhibitors treatment (period T-).

Table 4 -

 4 Outcomes of prolonged corticosteroid treatment or early cessation (before month 3) after kidney transplant failure.

Table 5 -

 5 Outcomes of prolonged CNI and MMF traitement or early cessation after kidney transplant failure.

Table 6 -

 6 Management of immunosuppression in 11 adult transplant centers of the Spiesser group

Table 1 -

 1 Characteristics of prolonged immunosuppressive treatment or early cessation (before month 3) after kidney transplant failure .

	Total n=119	Prolonged n=52 treatment	Early n=67 cessation	p-value

Table 2 -

 2 Outcomes of prolonged immunosuppressive treatment or early cessation (before month 3) after kidney transplant failure.

		Total n=119	Prolonged n=52 treatment	Early n=67 cessation	p-value
	Development of DSA	82 (68.9)	30 (57.7)	52 (77.6)	0.02
	Class 1	39/82 (47.6)	11/30 (36.7)	28/52 (53.9)
	Class 2	21/82 (25.6)	10/30 (33.3)	11/52 (21.2)	0.29
	Classes 1 and 2	22/82 (26.8)	9/30 (30.0)	13/52 (25.0)
	PRA last FU (n=100)	88.5 [53.5; 99]	71 [24; 96]	97 [67; 99]	0.002
	PRA ≥ 85%	55/100 (55.0)	17/41 (41.5)	38/59 (64.4)	0.03
	Transplantectomy	52 (43.7)	19 (36.5)	33 (49.3)	0.17
	Graft intolerance syndrome	20 (16.8)	8 (15.4)	12 (17.9)	0.72
	Booked on waiting list	100 (84.0)	41 (78.8)	59 (88.1)	0.17
	New graft	53/100 (53.0)	21/41 (51.2)	32/59 (54.2)	0.77
	Retransplant waiting time (years) (n=53)	2.4 [1.5; 4.0]	2.5 [1.5; 3.2]	2.4 [1.4; 4.3]	0.45
	Transfusion after LGF	63 (52.9)	27 (51.9)	36 (53.7)	0.85
	Patients on corticosteroids at M3	69 (58.0)	35 (67.3)	34 (50.7)	0.07
	Infection	37 (31.1)	19 (36.5)	18 (26.9)	0.26
	Cancer	11 (9.2)	7 (13.5)	4 (6.0)	0.21
	Cardiovascular event	24/118 (20.3)	9/51 (17.6)	15 (22.4)	0.53
	Deaths	6/105 (5.7)	4/49 (8.2)	2/56 (3.6)	0.41

Abbreviations: CNI, calcineurin inhibitors; DSA, donor specific antibody; FU, follow up; LGF, loss of graft function, PRA, panel reactive antigen.

The data are expressed as number of patients (associated percentage), or median [interquartile range].

Table 3 -

 3 Outcomes under calcineurin inhibitors treatment (period T+) and weaned off calcineurin inhibitors treatment (period T-).

		Period T+ n=52	Period T-n=90	p-value
	Development of DSA	18 (34.6)	63 (70.0)	0.01
	Transplantectomy	15 (28.8)	24 (26.7)	0.78
	Cancer	4 (7.7)	5 (5.6)	0.62
	Cardiovascular event	5 (9.6)	15 (16.7)	0.25
	Deaths	0 (0.0)	5 (5.6)	NE
	Abbreviations: CNI, calcineurin inhibitors; DSA, donor specific antibody; NE, not estimated.

Treatment period (T+) was the period from KTF to the date of cessation of immunosuppressive treatment, during which patients received IS. Those who stopped treatment during the first 3 months were excluded from analysis. Patients studied during the period from cessation of immunosuppressive treatment to performance of a new graft, death or last follow-up were assigned to the non-treatment (T-) period. Those in whom DSAs developed during the T+ period were excluded from the T-group.

The data are expressed as number of patients (associated percentage).

Table 4 -

 4 Outcomes of prolonged corticosteroid treatment or early cessation (before month 3) after kidney transplant failure.

		Prolonged	Early
		corticosteroid treatment	corticosteroid cessation	p-value
		n=69	n=50
	Development of DSA	47 (68.1)	35 (70.0)	0.83
	PRA last FU (n=100)	86 [51; 98]	90 [59; 99]	0.56
	PRA ≥85%	34/61 (55.7)	21/39 (53.8)	0.85
	Transplantectomy	29 (42.0)	23 (46.0)	0.67
	Infection	27 (39.1)	10 (20.0)	0.03
	Cancer	6 (8.7)	5 (10.0)	1.00
	Cardiovascular event	14 (20.3)	10 (20.4)	0.99
	Deaths	3/63 (4.8)	3/42 (7.1)	0.68

Abbreviations: DSA, donor specific antibody; PRA, panel reactive antigen.

The data are expressed as number of patients (associated percentage) or median [interquartile range].

Table 5 -

 5 Outcomes of prolonged CNI and MMF traitement or early cessation after kidney transplant failure.

		Early cessation n=58	MMF n=9	CNI n=29	MMF + CNI n=23	p-value
	Development of DSA	45 (77.6)	7 (77.8)	18 (62.1)	12 (52.2)	0.11
	Transplantectomy	27 (46.6)	6 (66.7)	9 (31.0)	10 (43.5)	0.27
	PRA on LGF (n=100)	0 [0;65]	87 [0; 99]	0 [0; 55]	0 [0; 48]	0.24
	PRA last FU (n=100)	96 [61; 99]	97 [90; 99]	77 [32; 95]	69 [23; 97]	0.02
	PRA ≥85%	30 (60.0)	8 (88.9)	11 (45.8)	6 (35.3)	0.04
	Delta PRA	46 [0;99]	5.6[-1-86]	23 [0; 82]	24 [10; 65]	0.39
	Corticosteroids at M3	28 (48.3)	6 (66.7)	22 (75.9)	13 (56.5)	0.09
	Infections	16 (27.6)	2 (22.2)	7 (24.1)	12 (52.2)	0.13
	Cancer	3 (5.2)	1 (11.1)	6 (20.7)	1 (4.3)	0.10
	Cardiovascular event	13 (22.4)	2 (22.2)	4 (14.3)	5 (21.7)	0.83
	Deaths	2/47 (4.3)	0 (0.0)	2/28 (7.1)	2/21(9.5)	0.80

Abbreviations: CNI, calcineurin inhibitors; DSA, donor specific antibody; LGF, loss of graft function; MMF, mycophnolate mofetil ; PRA, panel reactive antigen. Delta PRA= PRA last FU -PRA on LGF The data are expressed as number of patients (associated percentage), or median [interquartile range].

Proc. 2008;40(9):2909-2911. doi:10.1016/j.transproceed.2008.09.047


Mathilde Lochmann
email: mathilde.lochmann@univ-tlse2.fr

Myriam Guedj

Guedj Myriam

Lacassagne Léa

Duchel Stéphanie

a patient with signs of terrorist radicalization ?

Keywords: breaching doctor-patient confidentiality, terrorist radicalization, ethic

Sous quelles conditions le grand public et les professionnels de santé acceptent-ils de rompre le secret médical face à un patient présentant des signes de radicalisation terroriste ?

Introduction : Le secret médical est crucial pour établir une solide relation patientmédecin. Toutefois, certaines situations peuvent créer un dilemme pour le médecin qui doit alors choisir entre le respect du secret médical ou la protection de tiers face à un risque sérieux de violence.

Objectif : Cette étude visait à observer comment des personnes issues du grand public et des professionnels de santé évaluaient l'acceptabilité de la rupture du secret médical lorsqu'un médecin est confronté à un patient présentant des signes de radicalisation terroriste.

Méthode : 228 participants (174 issus du grand public et 54 professionnels de santé) devaient évaluer l'acceptabilité de 54 scénarios construits grâce à la combinaison orthogonale de 4 facteurs fréquemment mentionnés dans la littérature : présence d'un « Trouble psychiatrique » ; « Signes de radicalisation » ; « Projets de violence » ; « Collégialité ». Des analyses de variance et de cluster ont été effectuées sur l'ensemble des données.

Résultats : Les résultats ont montré que tous les facteurs ont influencé le jugement des participants mais que les "Troubles psychiatriques" avaient un impact plus faible. Cinq clusters ont été identifiés : « Favorable si collégialité » (n=23) ; « Favorable à la rupture du secret médical » (n=77) ; « Défavorable à la rupture du secret médical (n=26) ; « Sensible à tous les facteurs » (n=71) ; « Favorable si violence » (n=31), avec des moyennes respectives de 5. 87, 8.42, 3.64, 6.30, et 7.16 sur une échelle d'acceptabilité allant de 0 à 10.

Conclusion:

L'importance que la grande majorité des participants attribue aux facteurs indique que ces derniers influencent leurs jugements dans ce contexte spécifique.

Mots-clés: rupture du secret médical; radicalisation terroriste; éthique.

Ethical conflict and legal framework

From the original Hippocratic Oath until today, medical confidentiality has been one of the fundamental rules of all health professions [START_REF] Barthélémi | Confidentialité et secret professionnel : enjeux pour une société démocratique [Confidentiality and professional secrecy: stakes for a democratic society[END_REF][START_REF] Mouneyrat | Ethique du secret et secret médical [Ethics of secrecy and medical secret[END_REF]. Its legitimacy is based on a simple principle: to offer the best care and the maximum therapeutic effectiveness while assuring the quality of care which depends on confidentiality and trust [START_REF] Hoerni | Medical confidentiality: confidentiality and discretion in medicine[END_REF]. Besides being a fundamental value of the ethics code, medical confidentiality is protected by law.

At present, French law is quite strict: breaching confidentiality is only allowed if the practitioner reports abuse on a minor -or a major if he/she has given his/her consent -or if the practitioner knows that a dangerous individual possesses a weapon or manifests the intention to obtain one (Conseil National de l'Ordre des Médecins [CNOM], 2017). This legal framework varies from one country to another: legislators of certain countries have introduced more dispensations.

Despite this legal framework, doctors are faced with ethically problematic professional situations, leading to a debate on the limits of this confidentiality. The debate generally revolves around two opposing theses: a "relativist" one which tolerates a flexibility proportional to the severity of the threat, and an "absolutist" one that categorically refuses any impediment to confidentiality [START_REF] Crook | The Risks of Absolute Medical Confidentiality[END_REF]. Ambivalence arises when the two imperatives of individual interest and collective interest conflict [START_REF] Mouneyrat | Ethique du secret et secret médical [Ethics of secrecy and medical secret[END_REF].

Health professionals thus find themselves at the heart of many societal issues with which they must deal. The Tarasoff case, or the issue of protecting a close friend or relative from a patient infected by HIV, are major examples [START_REF] Crook | The Risks of Absolute Medical Confidentiality[END_REF][START_REF] Guedj | Under what conditions is the breaking of confidentiality acceptable to lay people and health professionals[END_REF]. For several years now, to counterbalance the rise in terrorist radicalization, some governments have tried to introduce new measures that could involve the health sector. Mental health researchers are being increasingly called upon to notify the authorities of individuals undergoing violent terrorist radicalization [START_REF] Aggarwal | Questioning the current public health approach to countering violent extremism[END_REF].

Individuals with psychiatric disorders are sometimes pointed out as being more receptive to terrorist ideology [START_REF] Speckhard | Alarms raised over safeguarding professional ethics in FBI proposed « Shared Responsibility Committees » addressing potentially radicalized individuals[END_REF]. Some data in the literature suggests that isolated terrorists may suffer more from psychopathological disorders than terrorists belonging to a group [START_REF] Schulten | Radicalization, terrorism and psychopathology: state of affairs, gaps and priorities for futures research[END_REF].

The following example presents a realistic situation highlighting the ethical conflict faced by the physician: "Dr. Burdin has known Ludovic, who is now 25 years old, since he was a child. His mother had always described him as a young man with violent behavior. She had already reported many aggressive episodes since adolescence as well as the presence of a criminal record (mainly for robbery, fights, and possession of knives). Three weeks ago, during a consultation, his mother explained to the doctor that Ludovic had previously broken with his family several months ago: He isolated himself, no longer talks to his friends, and lives reclusively in a caravan. She said: "One day he will do something stupid, I feel it but I have no way to approach him. I'm ashamed to say it but I'm afraid he's become a terrorist!"

The physician found out from her that he had converted to Islam, and that now, he wears only traditional Muslim clothing. When the doctor asked him about it during a consultation, he replied that he didn't want to talk about it. He responded: "I can no longer trust anyone." What should the doctor do? Should he warn the authorities or maintain confidentiality?

Governments' anti-terrorism projects

For some governments, the current climate concerning the fight against terrorism justifies a partial breach of laws relating to confidentiality.

In the United States, as part of the "Countering Violent Extremism" [CVE] strategy, various projects have been endorsed. For instance, the "Shared Responsibility Committees" in 2015 have allowed the FBI to call on many professionals from civil society to intervene in multidisciplinary groups directed at individuals who are vulnerable to radicalization in order to contain the process. According to [START_REF] Speckhard | Alarms raised over safeguarding professional ethics in FBI proposed « Shared Responsibility Committees » addressing potentially radicalized individuals[END_REF], this necessarily involves the exchange of confidential data, although this is prohibited by law.

In the United Kingdom, new government recommendations "Prevent" were drafted in 2015. They exhort all health professionals to identify individuals undergoing terrorist radicalization and report them to the authorities (Secretary of state for home department by command of her Majesty, 2011). Prevent considers that the medical profession, by virtue of its direct contact with a large part of the population, encounters many opportunities to identify individuals in the process of being radicalized. Over 700 nurses have been trained in this vein, and training will also be given to medical students [START_REF] Dean | Healthcare Staff Told to Report Patients at Risk of Radicalization[END_REF].

In Belgium, the Flemish government also attaches importance to the prevention of radicalization. The Belgian Senator De Gucht (2016) argued that if professional confidentiality must be broken, it is necessary to consider a legal framework that would protect professionals, such as a specific derogation when radicalization is suspected.

This is what some French deputies (MPs) tried to do in 2016. A bill proposal to adapt professional confidentiality to tackle the evolution of radicalization was proposed, but it was not sent to a special commission [START_REF] Dubby-Muller | Proposition de loi portant adaptation du secret professionnel aux évolutions de la radicalisation pour les professions médicales, sociales et éducatives [Proposed law adapting professional secrecy to radicalization trends for the medical, social and educational professions[END_REF]. However, following a recent decree (Ministère des Solidarités et de la Santé, 2019), the French authorities will now be warned -with the help of file-linking -as soon as a patient filed for "terrorist radicalization" is hospitalized to receive psychiatric care without his or her consent. Furthermore, the CNOM (2017) has published an interministerial guidance document of indicators of radicalization, which doctors can refer to in the event of worrying signs (Ministère de l'Intérieur [MI], 2015).

Health professionals' and the general public's attitudes

In October 2016, a study called "Eroding Trust" inventoried the numerous criticisms made against these new recommendations. It revealed that the Royal College of Psychiatrists

[RCPSY] (2016) had serious doubts about the predictive value of the vulnerability factors on which Prevent is based [START_REF] Middleton | Preventing violent extremism: the role of doctors[END_REF]. [START_REF] Mohammed | The prevent strategy: A cradle to grave police-state[END_REF] contended that there is no medical solution to all these factors, which require instead to be dealt with on a socio-economic or political level. Conversely, Bhui and colleagues suggested that a public health message should be delivered to specify that violence may be the cause or the consequence of a poor general or mental state of health (Bhui, Warfa & Jones, 2014a;[START_REF] Bhui | Might depression, psychosocial adversity, and limited social assets explain vulnerability to and resistance against violent radicalisation[END_REF][START_REF] Kmietowicz | Radicalization is a public health problem that needs to be discussed to be prevented, says psychiatrist[END_REF]. Thus, bringing forth the argument that public health can play a prominent role in preventing violence in order to fight against extremism [START_REF] Aggarwal | Questioning the current public health approach to countering violent extremism[END_REF]. In one of their studies, [START_REF] Bhui | Might depression, psychosocial adversity, and limited social assets explain vulnerability to and resistance against violent radicalisation[END_REF] observed that depression may be independently associated with greater tolerance for terrorist violence. Many French psychiatric federations are worried that psychiatric disorders and the process of radicalization are sometimes confused. According to them, this could stigmatize individuals suffering from mental illness even further [START_REF] Beloucif | Communiqué : Appel à l'abrogation du décret Hopsyweb[END_REF]. Witharana, Olumoroti and Larkin (2012) advocated a discussion to define whether terrorism can be considered as a mental disorder; and if so, what appropriate assessment tools should be employed in its diagnosis -tools that need to be scientifically validated and evidence-based (RCPSY, 2017). Currently, no clinical procedure or psychiatric tool can predict or detect the risk factors for terrorist radicalization [START_REF] Davies | Global Health in International Relations: Editors' Introduction[END_REF]RCPSY, 2017).

For many health professionals, these recommendations mainly constitute a form of espionage that mostly targets Muslim patients [START_REF] Summerfield | Mandating doctors to attend counter-terrorism workshops is medically unethical[END_REF], with the underlying risk of stigma that this could induce (RCPSY, 2017). The Council of American-Islamic relations

[CAIR] (2015) criticized the fact that in some northern cities in the United States, programs related to the CVE's counter-terrorism initiative are used to "profile" Muslims [START_REF] Aggarwal | Questioning the current public health approach to countering violent extremism[END_REF].

Many nurses have mentioned how uncomfortable they feel with making personal judgments about individuals [START_REF] Dean | Healthcare Staff Told to Report Patients at Risk of Radicalization[END_REF]. Other fears imply the consequences of reporting errors, and of being accused of racism [START_REF] English | Doctors should not agree to identify potential terrorists[END_REF].

Prevent insidiously targets only a religious group and could be called into question by anti-discrimination legislation [START_REF] Mohammed | The prevent strategy: A cradle to grave police-state[END_REF]. At the European level, this report tends to violate the right to privacy of the European Convention on Human Rights. It exposes physicians to the risk of litigation [START_REF] Middleton | Preventing violent extremism: the role of doctors[END_REF]. According to [START_REF] Speckhard | Alarms raised over safeguarding professional ethics in FBI proposed « Shared Responsibility Committees » addressing potentially radicalized individuals[END_REF], to waive confidentiality, we should refer only to the law. But health providers seem to be confronted with a major dilemma: on the one hand, no specific legal protection for professionals who report a radicalized patient has been clearly established (Weine, Eisenman, Kinsler & Polutnik, 2016), and on the other hand they are worried about the threat of being prosecuted for not reporting a radicalized individual [START_REF] Aggarwal | Questioning the current public health approach to countering violent extremism[END_REF]. According to the RCPSY (2017), in the face of the pressure exerted by some governments, health professionals should respond by respecting their own guidelines and code of ethics. If a member of the medical community encounters a problematic situation related to terrorism, Jenkins, Mair, Lester and Khan (2016) advise having recourse to a collegiate decision. Breaching medical confidentiality on a permanent basis without strong justification could have a devastating effect on the therapeutic relationship, and could even hinder access to care [START_REF] Aggarwal | Questioning the current public health approach to countering violent extremism[END_REF][START_REF] Barthélémi | Confidentialité et secret professionnel : enjeux pour une société démocratique [Confidentiality and professional secrecy: stakes for a democratic society[END_REF][START_REF] Jenkins | Radicalization and the law[END_REF][START_REF] Middleton | Preventing violent extremism: the role of doctors[END_REF][START_REF] Rizq | Pre-crime', Prevent, and practices of exceptionalism: Psychotherapy and the new norm in the NHS[END_REF][START_REF] Samari | Islamophobia and Public Health in the United States[END_REF]. Indeed, since the implementation of these various anti-terrorism programs, some patients report that, for fear, they resort to self-censorship during their psychotherapy sessions [START_REF] Rizq | Pre-crime', Prevent, and practices of exceptionalism: Psychotherapy and the new norm in the NHS[END_REF].

Generally, what patients fear if confidentiality is no longer respected is that it will hamper care and treatment [START_REF] Jones | The utilitarian argument for medical confidentiality: a pilot study of patients' views[END_REF][START_REF] Lee | Deathly silence: doctors' duty to disclose dangers of death[END_REF]. [START_REF] Jones | The utilitarian argument for medical confidentiality: a pilot study of patients' views[END_REF] asked 30 patients to assess the need to breach confidentiality in five different situations: when it came to protecting a third party, patients assumed more responsibility for breaching confidentiality. [START_REF] Guedj | Under what conditions is the breaking of confidentiality acceptable to lay people and health professionals[END_REF] compared the extent to which breaching confidentiality was acceptable for both physicians and the general public, in France. They observed that the general public was much more supportive than physicians. The French general public seems to be more in agreement with the Anglo-American laws than with the French laws when it is a question of breaching confidentiality to protect the wife of a potentially violent patient for example [START_REF] Guedj | Is it acceptable for a psychiatrist to break confidentiality to prevent spousal violence[END_REF]. From one country to another, from one situation to another, opinions can diverge [START_REF] Olivari | Breaking Patient Confidentiality: Comparing Chilean and French Viewpoints Regarding the Conditions of its Acceptability[END_REF][START_REF] Olivari | Is it Acceptable for a Psychologist to Break a Young Client's Confidentiality? Comparing Latin American (Chilean) and Western European (French) Viewpoints[END_REF]. When laws and ethical guidelines differ, beyond the professionals involved, the viewpoint of the public can also influence this kind of societal issue because as a patient, future patient, or potential victim, everyone is concerned [START_REF] Bartholomew | The relationship between alliance ruptures and hope for change through counseling: A mixed methods study[END_REF][START_REF] Ormrod | Public perceptions about confidentiality in mental health services[END_REF][START_REF] Rubanowitz | Public attitudes toward psychotherapist-client confidentiality[END_REF].

The present study

This study aimed to observe how a sample of the French population -health professionals and participants from the general public -evaluates the acceptability of breaching confidentiality by reporting to the authorities a patient with signs of terrorist radicalization.

As in previous research [START_REF] Cantisano | Lay people's conceptualizations regarding what determines fear of death[END_REF][START_REF] Mazoyer | Mapping French people and health professionals' positions regarding the circumstances of morphine use to relieve cancer pain[END_REF][START_REF] Olivari | Breaking Patient Confidentiality: Comparing Chilean and French Viewpoints Regarding the Conditions of its Acceptability[END_REF], a methodology, derived from the functional theory of cognition [START_REF] Anderson | Foundations of information theory[END_REF][START_REF] Anderson | A functional theory of cognition[END_REF] and based on the construction of fictitious scenarios, was used. In our study, the various vignettes illustrate situations of ethical cases (or moral dilemmas) concerning medical confidentiality that can be experienced by doctors confronted with patients presenting various signs of radicalization. The scenarios were developed from factors frequently encountered in the literature: Signs of radicalization [START_REF] Bénézech | A la recherche d'une âme : psychopathologie de la radicalisation et du terrorisme [In search of a soul: psychopathology of radicalization and terrorism[END_REF][START_REF] Karagiannis | European Converts to Islam: Mechanisms of Radicalization[END_REF], Projects of violence [START_REF] Feddes | Increasing self-esteem and empathy to prevent violent radicalization: a longitudinal quantitative evaluation of a resilience training focused on adolescents with a dual identity[END_REF]MI, 2015), Psychiatric disorders [START_REF] Bénézech | A la recherche d'une âme : psychopathologie de la radicalisation et du terrorisme [In search of a soul: psychopathology of radicalization and terrorism[END_REF]Bhui et al., 2014a;[START_REF] Bhui | Might depression, psychosocial adversity, and limited social assets explain vulnerability to and resistance against violent radicalisation[END_REF][START_REF] Schulten | Radicalization, terrorism and psychopathology: state of affairs, gaps and priorities for futures research[END_REF]Speckard, 2016), and Collegiality [START_REF] Jenkins | Radicalization and the law[END_REF]RCPSY, 2017).

These factors can be considered as indicators affecting the threshold of acceptability during decision-making. Acceptability depends in part on the perception of the risk of "the judging individual". According to [START_REF] Anderson | A functional theory of cognition[END_REF], when an individual makes a judgment, he/she resorts to diverse mental operations. In particular, he/she attributes a subjective value to each item of information encountered, and gives it a specific weight depending on the meaning and the importance that it has for him/her. The objective of this study was therefore to investigate on what grounds it is considered acceptable, or not, to report a patient who appears as radicalized to the authorities -implying a breach of confidentiality. In other words, we wanted to examine the thought path leading the participants in this research to make a decision. On the one hand by tracing how they combine the information given and, one the other hand, by observing if the weight attributed to each piece of information varies.

Hypotheses

Our first hypothesis was that participants would rely on all the factors -Psychiatric disorders, Signs of radicalization, Projects of violence, Collegiality -to assess the acceptability of breaching confidentiality. Secondly, we expected some factors to have more weight than others in participants' decision-making. More specifically, since the link between psychiatric disorders and terrorism radicalization mentioned several times in the literature [START_REF] Bénézech | A la recherche d'une âme : psychopathologie de la radicalisation et du terrorisme [In search of a soul: psychopathology of radicalization and terrorism[END_REF]Bhui et al., 2014a;[START_REF] Bhui | Might depression, psychosocial adversity, and limited social assets explain vulnerability to and resistance against violent radicalisation[END_REF][START_REF] Schulten | Radicalization, terrorism and psychopathology: state of affairs, gaps and priorities for futures research[END_REF]Speckard, 2016), we presumed that the Psychiatric disorders factor would have considerable weight in decision-making. Thirdly, it was also hypothesized that sociodemographic variables -sex, age, professional status and level of education -would influence how participants position themselves on the acceptability scale. More especially, we expected that health professionals -in comparison to the general public -would give more weight to the Collegiality factor. This latter, is linked to the recommendations mentioned by health actors in the literature [START_REF] Jenkins | Radicalization and the law[END_REF]RCPSY, 2017).

Fourthly, the fear of stigmatizing the Muslim community mentioned by several authors [START_REF] Aggarwal | Questioning the current public health approach to countering violent extremism[END_REF]CAIR, 2015;[START_REF] Dean | Healthcare Staff Told to Report Patients at Risk of Radicalization[END_REF][START_REF] English | Doctors should not agree to identify potential terrorists[END_REF][START_REF] Mohammed | The prevent strategy: A cradle to grave police-state[END_REF]RCPSY, 2017;[START_REF] Summerfield | Mandating doctors to attend counter-terrorism workshops is medically unethical[END_REF] allowed us to suppose that patients' names' sound in the scenarios -French vs Arabic-sounding names -would modify the way in which the scenarios were evaluated.

Finally, in our last and fifth hypothesis, we envisioned that different groups of respondents would be observed based on their response profiles. In view of the data found in the literature [START_REF] Jenkins | Radicalization and the law[END_REF]RCPSY, 2017), we assumed that a group containing more health professionals would rely primarily on the factor of Collegiality, while other groups would give more importance to Projects of violence or Signs of radicalization.

Method

Participants

Two hundred and fifty-six participants were recruited through word of mouth in France, mainly, in the Occitania region. Two hundred and twenty-eight (155 women, 73 men) agreed to freely participate and signed a consent form (estimated response rate was 85%, the estimated refusal rate was 12% and the estimated incomplete response rate was 3%).

Participants were 18-95 years old (M = 39.56). One hundred and seventy-four were part of the general population (7 craftsmen/storekeepers, 33 executives and intellectual professions, 19 intermediate occupations, 38 employees, 3 workers, 44 students, 11 unemployed, 14 retirees and 5 unspecified professions) and 54 were health professionals (11 physicians, 7 psychologists, 5 paramedical professionals, 26 nurses, 5 nursing assistants). Seventy-nine percent of our sample had an educational level beyond high school.

Material

Fifty-four scenarios illustrating different situations that a health professional might encounter were constructed through the orthogonal combination of 4 factors frequently mentioned in the literature (following a factorial plan 3 x 3 x 3 x 2): "Presence of a psychiatric disorder" (No pathology; Major depression; Psychotic disorder) x "Signs of radicalization" (Change in physical appearance but non-violent language; Recent social isolation and use of conspiracy theories; High social isolation and terrorist ideology) x "Projects of violence" (No established plan; Plan to leave France for Syria; Plan to acquire a weapon) x "Collegiality" (Individual decision to breach confidentiality; Collegiate decision to breach confidentiality).

Systematically, at the end of each scenario, the doctor decided to breach confidentiality by warning the authorities. The following question was then asked: "How acceptable do you think the doctor's decision is?" Participants answered using an 11-point (0-10) scale ranging from "not at all acceptable" at the left of the scale, to "fully acceptable" at the right of the scale.

Here is an example of a scenario: "Mr. Mimoune came to see Dr. Pujol for sleep disorders.

During the consultation, Dr Pujol discovered that Mr. Mimoune suffers from a psychotic disorder that alters his thinking and reasoning. Mr. Mimoune explained that he broke-up with his friends and family a long time ago. His speech was punctuated by expressions of hate linked to a terrorist ideology. He also revealed his intention to acquire a weapon in the near future. Worried by this change in his behavior and concerned that the potential safety of others may be at risk, Dr Pujol decided to warn the authorities. Dr Pujol took this decision alone. How acceptable do you think Dr Pujol's decision is?"

In each scenario, a fictitious name was attributed to the patient and to the doctor. The consonance of the patients' names was introduced as an inter-variable with two modalities: for 128 participants, the names of patients were Arab-sounding and for 100 participants the names of patients were French-sounding.

Procedure

Following Anderson's recommendations (1982), the procedure comprised two steps. The "familiarization" phase enabled participants to discover the tool by training on seven scenarios, with the possibility of comparing, modifying and revising their answers. This step allowed participants to acclimatize to and understand the material in order to be able to carry out the experimental phase. During this second phase called "experimentation", participants had to judge all scenarios previously mixed in a random order, but this time without being allowed to go back or modify their answers. These two steps lasted 35 to 45 min altogether.

Experiments took places in quiet public places, mainly in libraries.

Results

An analysis of variance was performed on all the raw data. It was found that the factors with the greatest influence on acceptability judgments were, in decreasing order, "Projects of violence" (F (2, 414) = 215.97, p < .001, Eta²p =.51), "Signs of radicalization" (F (2, 414) = 178.28, p < .001, Eta²p =.46), and "Collegiality" (F (1, 207) = 99.88, p < .001, Eta²p =.32).

Even if it had a lower weight, the factor "Psychiatric disorders" was also significant (F (2, 414) = 11.49, p < .001, Eta²p =.05). The results are presented on Table 1.

The results also showed a significant interaction between "Radicalization" x "Violence" (F (4, 828) = 25.04, p < .001, Eta²p =.11): the more extreme the "Projects of violence" and "Signs of radicalization" were, the higher the acceptability of breaching medical confidentiality. There was also a significant interaction between "Psychiatric disorders" x "Radicalization" (F (4, 828) = 18.96, p < .001, Eta²p =.08). Participants in this study appeared to take "Psychiatric disorders" into consideration more when "Signs of radicalization" were minimal.

Regarding the impact of some individual variables on how participants positioned themselves on the acceptability scale, results showed a significant effect of the level of education (F (1, 206) = 11.93, p < .001, Eta²p =.05). Participants who had a high school level or higher considered it less acceptable to breach confidentiality than subjects who had not completed high school. Age, sex and professional status variables had no significant effect, yet, a significant group interaction between "Professional status" x "Collegiality" (F (5, 196) = 3.91, p < .002, Eta²p =.09) was found. Doctors and nurses, compared to the general public and other health professionals, judged the breach of medical confidentiality as more acceptable when the decision was made collegially. Lastly, the analyses also revealed a significant effect of the inter-name factor (F (1, 206) = 8.27, p < .004, Eta²p =.04): on average, acceptability was higher when patients' names sounded French.

A K-means analysis identified five clusters. ANOVA analyses were then performed for each of the five clusters. The results are shown on Table 1 and Figure 1.

The first and smallest cluster (n=23) was named "Favorable if collegiality" since the factor of "Collegiality" had the most significant effect (F (1, 20) = 234.34, p < .001, Eta²p =.92). The mean response (M=5.87) is positioned in the middle of the acceptability scale. This can be explained by a polarization of the answers: in the presence of a collegiate decision the level of acceptability is strong, otherwise acceptability is weak. Participants in this group also considered the factors "Signs of radicalization" (F (2, 40) = 7.90, p < .001, Eta²p =.28) and "Projects of violence" (F (2, 40) = 6.50 p < .003, Eta²p =.24) even if they had a lower impact.

"Psychiatric disorders" is the only factor that had no significant effect on their judgments. This cluster contains individuals from the general population (n=15) and health professionals (n=8), but proportionately to these two samples of participants, there are more individuals from health professions (14%) than those from the general population (8%). It is composed mainly of participants who have a level of education beyond the high school level (n=19).

The second cluster (n=77) was named "Favorable to breach" since the mean response is 8.42 -the highest of the five clusters. The factor "Projects of violence" has a predominant effect (F (2, 132) = 86.82, p < .001, Eta²p =.57), followed by "Signs of radicalization" (F (2, 132) = 55.04, p < .001, Eta²p =.45), "Collegiality" (F (1, 66) = 39.03, p < .001, Eta²p =.37), and "Psychiatric disorders" (F (2, 132) = 9.22, p < .001, Eta²p =.12). This cluster is mainly made up of participants from the general population (n=60) and includes the highest number of respondents who had not completed high school (n=27) -i.e. 56% of the sample of participants has the lowest academic level. Results also show that for more than half of this group (n=43) the modality of inter-name variable is "French-sounding" whereas, according to the expected value, it was predicted that this modality would be the smallest with 29 participants (X² = 20.03, p < .001).

The third cluster (n=26) was named "Unfavorable to breach". Individuals in this group are the most reluctant to breach medical confidentiality, their mean ratings were the lowest on the response scale (M=3.64). They took into account the factors "Collegiality" (F (1, 24) = 32.36, p < .001, Eta²p =.57), "Projects of violence" (F (2, 48) = 26.83, p < .001, Eta²p =.53) and "Signs of radicalization" (F (2, 48) = 19.22, p < .001, Eta²p =.44). To assess each situation, this cluster's participants considered all factors except "Psychiatric disorders".

Although they were generally unfavorable to breach confidentiality, they tended to find a breach of confidentiality more acceptable when a "Collegiate" decision (M=4.20) is requested and when "Projects of violence" (M=4.92) and "Signs of radicalization" (M=4.36) are the most extreme. This group is made up of participants from the general public (n=19) and health professionals (n=7) (with respect to the entire sample, 11% of the general population and 12% of health professionals). Almost all participants had a level of education beyond high school (n=24). Here, there were more scenarios with the modality of the inter-name factor "Arab-sounding" (n=17) than scenarios with the modality "French-sounding" (n=9).

The fourth cluster (n=71) was named "Sensitive to all factors" since it is similar to cluster 2, this group relies on all of them. However, contrary to cluster 2, acceptability is notably lower with an average score of 6.30. "Projects of violence" is the factor having the most important effect (F (2, 130) = 88.93, p < .001, Eta²p =.58), followed by "Signs of radicalization" (F (2, 130) = 77.73, p < .001, Eta²p =.54) and "Collegiality" (F (1, 65) = 48.91, p < .001, Eta²p =.43). "Psychiatric disorders" had the lowest effect (F (2, 130) = 3.94, p < .021, Eta²p =.06). This cluster mainly includes participants from the general public (n=49), yet health professionals (n=22) are also present -i.e. 40% of the sample of health professionals. It was predicted that the two modalities of the inter-name factor would be evenly distributed in this group, however the "Arab-sounding name" modality predominates with 52 participants out of 71 (X² = 20.03, p < .001).

Finally, the fifth cluster (n=31) named "Favorable if violence" has a high response average of 7.16. In this group, the "Projects of violence" factor is the most important (F (2, 56) = 198.77, p < .001, Eta²p =.88), followed by "Signs of radicalization" (F (2, 56) = 40.23, p < .001, Eta²p =.59) and "Psychiatric disorders" (F (2, 56) = 5.36, p < .007, Eta²p =.16). This cluster is the only one where participants did not rely on the "Collegiality" factor, even though it contains 14% of the total sample's health professionals. Results show an interaction between "Projects of violence" and "Signs of radicalization" (F (4, 112) = 15.46, p < .001, Eta²p =.35). When there is no project of violence, acceptability gradually increases in response to signs of radicalization. As soon as a project of violence occurs, participants only take this factor into account and acceptability increases immediately and very strongly.

Discussion

This study on the acceptability of breaching medical confidentiality when faced with patients showing signs of terrorist radicalization has highlighted various elements.

Firstly, the analyses confirm our first hypothesis. All four factors have a significant effect in participants' decision-making. Participants tried to assess each situation by looking at all the elements. Their contextual sensitivity is therefore considerable. The importance that they attribute to the factors indicates that these factors are intelligible and meaningful for them in this specific context.

Nevertheless, the factors "Signs of radicalization", "Collegiality" and "Projects of violence" have more weight in participants' decision-making. Despite data in the literature about "Psychiatric disorders" [START_REF] Bénézech | A la recherche d'une âme : psychopathologie de la radicalisation et du terrorisme [In search of a soul: psychopathology of radicalization and terrorism[END_REF]Bhui et al., 2014a;[START_REF] Bhui | Might depression, psychosocial adversity, and limited social assets explain vulnerability to and resistance against violent radicalisation[END_REF][START_REF] Schulten | Radicalization, terrorism and psychopathology: state of affairs, gaps and priorities for futures research[END_REF]Speckard, 2016), our results highlight that the impact of this factor is much weaker -which refutes the second hypothesis. It appears to influence participants' judgment additionally when the "Signs of radicalization" are not strong. In light of these results, the presence of psychiatric disorders does not seem to be a sufficient argument for the general public and health professionals -or at least an argument sufficiently explained -to justify government recommendations regarding detection of radicalized patients by health professionals. [START_REF] Schulten | Radicalization, terrorism and psychopathology: state of affairs, gaps and priorities for futures research[END_REF] argue that it is tricky to use this factor as a statistical predictor since many individuals with a psychiatric disorder will not inevitably radicalize into violent terrorist extremism.

Therefore, the "Projects of violence" factor carries more weight than the "Signs of radicalization" factor, as if participants were mostly influenced by acts and facts, rather than by speech content or physical appearance. This is particularly noticeable if we look more closely at cluster 5: in scenarios where no "Project of violence" is established, respondents primarily focus on "Signs of radicalization" to evaluate the acceptability of breaching confidentiality, but as soon as a "Project of violence" appears they rely almost exclusively on the latter factor and to a marked degree. It is conceivable that these participants apprehend the process of terrorist radicalization on a bottom-up model ranging from the evolution of "Signs of radicalization" (from the least to the most consequential) to concrete "Projects of violence" (here, a project of departure for Syria or acquiring a weapon). In this study, the project of acquiring a weapon -corresponding to one of the legal derogations about medical confidentiality enforced in France -is the modality having the most influence. However, scores of the "departure for Syria" modality are also high, indicating a risk assessment that is almost equivalent to that of acquiring a weapon. It is likely that the level of dangerousness associated with the departure to Syria result, partially, from collective beliefs built in recent years.

In support of our third hypothesis, we observed that less educated individuals appear to be more inclined to breach medical confidentiality. It would be relevant to study this point in more depth in future studies. Moreover, regarding other sociodemographic variables explored in the present study, professional status by itself did not significantly influence how participants position themselves on the acceptability scale as well as age and gender -which refutes part of the third hypothesis. Nevertheless, we observed that the "Collegiality" factor is very important for health providers, especially for nurses and physicians. This finding is certainly linked to the fact that these participants were more aware of the concept of collegiality given their educational and professional background. In their daily practices, they are used to employing collegial advice. In addition, since they are responsible for reports (or more broadly for decisions taken) they may prefer not to be alone when deciding. Similar results were observed in studies about of end-of-life decisions (eg. [START_REF] Guedj | The acceptability of ending a patient's life[END_REF].

However, in the present research, not all health professionals are concentrated in the "Favorable if collegiality" cluster; they are scattered among the five groups. The "Collegiality" factor by itself does not seem to define how they respond. It is conceivable, therefore, that the question of terrorism affects most individuals in a specific way, leading them to evaluate risk factors personally and independently from their professions -which counteracts part of the fifth and last hypothesis.

Lastly, in answer to our fourth hypothesis, results show that the inter-variable "Names" also influences participants' judgments: those who responded to scenarios where patients' names sounded French often evaluated the breaching of confidentiality as more acceptable than those responding to scenarios where names were Arab-sounding. It is possible that the fear of stigmatizing a community, as mentioned in the literature [START_REF] English | Doctors should not agree to identify potential terrorists[END_REF][START_REF] Mohammed | The prevent strategy: A cradle to grave police-state[END_REF]RCPSY, 2017;[START_REF] Summerfield | Mandating doctors to attend counter-terrorism workshops is medically unethical[END_REF], may change the way in which each situation is evaluated. Participants responding to scenarios in which patients' names sound French do not seem concerned by stigmatization, and thus allow themselves to judge a breach of confidentiality as more acceptable. It is also possible that the "black sheep effect" explains their response behavior: according to Abrams, Palmer, Rutland, Cameron and Van de Vyver ( 2014), an individual may judge more harshly a deviant member in the ingroup than in the out-group, in order to preserve and reaffirm a positive social identity in the in-group that is endangered by the deviant member. In the same way, [START_REF] Shaw | Effects of prohibitive and informative judicial instructions on jury decision making[END_REF] observed in their study focusing on fictitious jurors, that white jurors judged white defendants more harshly than black defendants. They call this "the bias of reverse racism".

Finally, this study has certain limitations. Our sample is heterogeneous, with fewer health professionals, and individuals with a low level of education. In addition, the scenarios are not real-life situations [START_REF] Froberg | Methodology for measuring health-state preferences-IV: Progress and a research agenda[END_REF][START_REF] Guedj | French lay people's views regarding the acceptability of involuntary hospitalization of patients suffering from psychiatric illness[END_REF][START_REF] Ulrich | Hypothetical vignettes in empirical bioethics research[END_REF]. Although none of the participants complained about scenarios' unrealistic nature, it would be relevant in future research to carry out a pre-test beforehand, in order to verify the realistic characteristics of fictitious scenario.

Conclusion

Many participants find it acceptable to breach medical confidentiality, even in the presence of indicators that are not derogated by the law. It is plausible that health professionals' concerns relate to the injunctive nature of government recommendations associated to a legal uncertainty [START_REF] Aggarwal | Questioning the current public health approach to countering violent extremism[END_REF]Weine et al., 2016) and to the lack of consideration regarding the possible negative consequences generated [START_REF] Aggarwal | Questioning the current public health approach to countering violent extremism[END_REF][START_REF] Barthélémi | Confidentialité et secret professionnel : enjeux pour une société démocratique [Confidentiality and professional secrecy: stakes for a democratic society[END_REF]RCPSY, 2017;[START_REF] Jenkins | Radicalization and the law[END_REF][START_REF] Middleton | Preventing violent extremism: the role of doctors[END_REF][START_REF] Rizq | Pre-crime', Prevent, and practices of exceptionalism: Psychotherapy and the new norm in the NHS[END_REF][START_REF] Samari | Islamophobia and Public Health in the United States[END_REF], rather than the breaching of medical confidentiality in cases of proven danger. Moreover, governmental recommendations could be more specific regarding what each indicator of radicalization involves [START_REF] Coppock | Dangerous Minds'? Deconstructing Counter-Terrorism Discourse, Radicalisation and the 'Psychological Vulnerability' of Muslim Children and Young People in Britain[END_REF][START_REF] Gill | Toward a scientific approach to identifying and understanding indicators of radicalization and terrorist intent: Eight key problems[END_REF], particularly the psychiatric disorders factor. Many health professionals wonder what initiatives can be taken and are welcome to opportunities for discussion in order to respond independently to these important ethical questions (Lacour-Gonay, 2017). Discussions should be collegial and multidisciplinary. The general public's viewpoint, also concerned by this topic, could help health professionals to enlarge their reflections.

Weine, S., Eisenman, D. P., Kinsler, J., Glik, D. C., & Polutnik, C. (2016). Addressing violent extremism as public health policy and practice. Behavioral Sciences of Terrorism and Political Aggression, 9(3), 208-221. doi:10.1080/19434472.2016.1198413 Witharana, D., Olumoroti, O. J., & Larkin, F. (2012) He, nevertheless, revealed his intention to acquire a weapon in the near future.

Worried by this change in his behavior and concerned that the potential safety of others may be at risk, Dr Pujol decided to warn the authorities.

Before taking this step, Dr. Guitton took the precaution of seeking the advice of Professor Umbert, a specialist in the field.

How acceptable do you think Dr Guitton's decision is?

Not acceptable at all -0-0-0-0-0-0-0-0-0-0-Fully Acceptable Mr. Mimoune came to see Dr. Pujol for sleep disorders.

During the consultation, Dr Pujol discovered that Mr. Mimoune suffers from a psychotic disorder that alters his thinking and reasoning.

Mr. Mimoune explained that he broke up with his friends and family a long time ago.

His speech was punctuated by expressions of hate linked with a terrorist ideology.

He also revealed his intention to acquire a weapon in the near future.

Worried by this change in his behavior and concerned that the potential safety of others may be at risk, Dr Pujol decided to warn the authorities.

Dr Pujol took this decision alone.

How acceptable do you think Dr Pujol's decision is?

Not acceptable at all -0-0-0-0-0-0-0-0-0-0-Fully Acceptable Note. On each panel, the y-axis corresponds to the degree of acceptability for breaching confidentiality; the x-axis bears the "Projects of violence" factor; the two curves correspond to the "Collegiality" factor, and the five panels correspond to the clusters.

1: Favorable if collegiality

  . Identifying terror suspects: the role of psychiatrists. The psychiatrist, 36(4),155. doi:10.1192/pb.36.4.155 During the consultation, Dr Guitton discovered that Mr. Asmaa doesn'

	Table 1
	Main results of ANOVA and composition of clusters
		df	MS	F	p	Eta²p
	Factors
	Violence	2	5166.6	215.97	.001	.51
	Signs of radicalization	2	2356.4	178.28	.001	.46
	Collegiality	1	4428.8	99.88	.001	.32
	Psychiatric disorders	2	66.1	11.49	.001	.05
	Radic x Violence	4	103.8	25.04	.001	.11
	Radic x Psy Dis	4	58.2	18.96	.001	.08
	Radic x Collegiality	4	10.9	3.42	.034	.02
	Inter-variables
	Names	1	1220.9	8.27	.004	.04
	Level of education	1	1730.2	11.93	.001	.05
	Profession x Coll	5	161.3	3.91	.002	.09
	Cluster Signs of radicalization	2	29.02	7.90	.001	.28
	Violence	2	43.36	6.50	.003	.24
	Collegiality	1	8689	243.34	.001	.92
	Cluster 2: Favorable to breach
	Signs of radicalization	2	452.5	55.04	.001	.45
	Violence	2	793.4	86.82	.001	.57
	Collegiality	1	369.4	39.03	.001	.37
	Psychiatric Disorders	2	29.2	9.22	.001	.12
	Radic x Psy Dis	4	23.8	13.41	.001	.17
	Radic x Violence	4	72.5	25.93	.001	.28
	Radic x Collegiality	2	11.8	4.16	.017	.06
	Radic x Psy Dis x Violence	8	4.2	2.75	.005	.04
	Radic x Violence x Collegiality	4	7.2	3.50	.008	.05

t suffer from any psychiatric disorder.

  However, Mr. Asmaa's appearance

recently changed. He grew a beard and dressed in religious clothes. His speech, however, is open and peaceful to others.

Note. The higher order interactions that were not significant are not reported here.

The following abbreviations "Radic", "Violence", and "Psy Dis" corresponding respectively to the factors "Signs of radicalization", "Projects of violence", and "Psychiatric disorders".

Figure 1

Patterns of results for the five clusters

["Insert the figure here"]

Note. On each panel, the y-axis corresponds to the degree of acceptability for breaching confidentiality; the x-axis bears the "Projects of violence" factor; the two curves correspond to the "Collegiality" factor, and the five panels correspond to the clusters.

Appendix

Two examples of scenario

Mr. Asmaa came to see Dr. Guitton for sleep disorders.