Antoine Gbessemehlan

Julie Arsandaux

Massiliano Orri

Ilaria Montagni

Melissa Macalli

Marie Tournier

Christophe Tzourio

Cedric Galera
email: cedric.galera@u-bordeaux.fr

Cédric Galéra

Perceived stress partially accounts for the association between Attention Deficit Hyperactivity Disorder (ADHD) symptoms and suicidal ideation among students

Keywords: ADHD, perceived stress, suicidal ideation, students, path analysis, cohort study

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

Introduction

Suicide is the second leading cause of death among youths aged 15-29, after road accidents [START_REF] Who | Preventing suicide: A global imperative[END_REF]. According to the World Health Organization (WHO), suicide accounts for 8.5% of all deaths in this age group [START_REF] Who | Preventing suicide: A global imperative[END_REF]. Suicidal ideation is often the starting point of a process leading to suicide, thus representing a relevant target for suicidality screening and prevention [START_REF] Nicoli | Idéation et conduites suicidaires en France : prévalence sur la vie et facteurs de risque dans l'étude ESEMeD[END_REF]. Among young people, postsecondary students are particularly concerned by suicidal ideation (Mortier et al., 2017;[START_REF] Wilcox | Prevalence and predictors of persistent suicide ideation, plans, and attempts during college[END_REF]. A meta-analysis estimated that the lifetime prevalence of suicidal ideation among students was 22.3%, and several studies have shown that more than 10% of students reported suicidal ideation at least once a year [START_REF] Kirsch | Mental Health Issues Among College Students: Who Gets Referred for Psychopharmacology Evaluation[END_REF]Mortier et al., 2017;[START_REF] Wilcox | Prevalence and predictors of persistent suicide ideation, plans, and attempts during college[END_REF]. The university years can be challenging for students due to academic stress, but also because students are becoming autonomous in a process of separation from the family network [START_REF] Landry | Trouble déficitaire de l'attention à l'université[END_REF][START_REF] Wilcox | Prevalence and predictors of persistent suicide ideation, plans, and attempts during college[END_REF]. Thus, a significant proportion of students present psychological distress and adopt at-risk behaviors (e.g. psychoactive substance use) which in turn make suicidal behaviors more likely to occur [START_REF] Arria | Suicide ideation among college students: A multivariate analysis[END_REF][START_REF] Assari | Multiplicative Effects of Social and Psychological Risk Factors on College Students' Suicidal Behaviors[END_REF][START_REF] Wilcox | Prevalence and predictors of persistent suicide ideation, plans, and attempts during college[END_REF].

Beyond known risk factors of suicidal behaviors (e.g. mental health problems including excessive or chronic stress) [START_REF] Anastasiades | Perceived stress, depressive symptoms, and suicidal ideation in undergraduate women with varying levels of mindfulness[END_REF]; Attention Deficit Hyperactivity Disorder (ADHD) has recently been the focus of interest in scientific and clinical communities due to its high prevalence (5% of school-aged children and 2.5% of adults) and its association with suicidal behaviors [START_REF] Apa | Diagnostic and Statistical Manual of Mental Disorders[END_REF][START_REF] Galéra | Hyperactivityinattention symptoms in childhood and suicidal behaviors in adolescence: the Youth Gazel Cohort[END_REF][START_REF] Stickley | Attention-deficit/hyperactivity disorder symptoms and suicide ideation and attempts: Findings from the Adult Psychiatric Morbidity Survey 2007[END_REF].

The number of students with ADHD attending university has risen over the past years [START_REF] Aqicesh | Statistiques concernant les étudiants en situation d'handicap dans les universités québécoises[END_REF][START_REF] Nugent | Attention-deficit/hyperactivity disorder in postsecondary students[END_REF][START_REF] Sedgwick | University students with attention deficit hyperactivity disorder (ADHD): a literature review[END_REF]. The international situation regarding ADHD is variable. Whereas it is under-diagnosed in some countries (e.g. France), leaving ADHD students without specific support, ADHD is one of the major disabilities recorded at university in other countries (e.g. North America) [START_REF] Aqicesh | Statistiques concernant les étudiants en situation d'handicap dans les universités québécoises[END_REF][START_REF] Nugent | Attention-deficit/hyperactivity disorder in postsecondary students[END_REF][START_REF] Sedgwick | University students with attention deficit hyperactivity disorder (ADHD): a literature review[END_REF]. Various clinical dimensions associated with ADHD (i.e. inattention, hyperactivity/impulsivity, neuropsychological and emotional dysregulations) are likely to jeopardize individual functioning in the academic context [START_REF] Landry | Trouble déficitaire de l'attention à l'université[END_REF][START_REF] Mortier | The epidemiology of ADHD in first-year university students[END_REF]. Several recent studies have reported associations between ADHD and suicidal ideation in students [START_REF] Cheng | Factors Related to Self-Reported Attention Deficit Among Incoming University Students[END_REF]Mortier et al., 2017b[START_REF] Mortier | The epidemiology of ADHD in first-year university students[END_REF][START_REF] Stickley | Attention-deficit/hyperactivity disorder symptoms and suicide ideation and attempts: Findings from the Adult Psychiatric Morbidity Survey 2007[END_REF][START_REF] Van Eck | ADHD and suicidal ideation: The roles of emotion regulation and depressive symptoms among college students[END_REF]. Among mental health risk factors potentially involved in the association between ADHD and suicidal behaviors, perceived stress may play a significant role [START_REF] Yeguez | Stress Accounts for the Association Between ADHD Symptoms and Suicide Ideation When Stress-Reactive Rumination Is High[END_REF]. However, the interrelationships between ADHD, perceived stress and suicidal ideation are poorly understood. There are known associations in the student population between ADHD symptoms and levels of perceived stress [START_REF] Harrison | Higher Reported Levels of Depression, Stress, and Anxiety Are Associated With Increased Endorsement of ADHD Symptoms by Postsecondary Students[END_REF][START_REF] Salla | ADHD Symptomatology and Perceived Stress Among French College Students[END_REF][START_REF] Vogel | Attention-deficit/hyperactivity disorder symptoms and stress-related biomarkers[END_REF] and perceived stress is likely to increase suicidal ideation [START_REF] Anastasiades | Perceived stress, depressive symptoms, and suicidal ideation in undergraduate women with varying levels of mindfulness[END_REF]. These results suggest that perceived stress could partially accounts for the association, as shown by Yeguez et al. who reported that stress was a mediator of the association between ADHD and suicidal ideation among young adults [START_REF] Yeguez | Stress Accounts for the Association Between ADHD Symptoms and Suicide Ideation When Stress-Reactive Rumination Is High[END_REF]. This pathway remains underexplored in students. Therefore, exploring ADHD and perceived stress simultaneously will allow us to clarify the role of perceived stress on the association between ADHD and occurrence of suicidal ideation in students. It is important to understand the mechanism between ADHD, stress and suicidal ideation as this will help/promote the screening and identification of those at risk for suicidal ideation/attempts.

The main objective of this study was to investigate whether perceived stress accounts for the association between ADHD symptoms and suicidal ideation among university students in France.

Methods

Study population

This study was based on data from the internet-based Students HeAlth Research Enterprise (i-Share). This prospective cohort with annual online follow-up questionnaires was launched in 2013 throughout France. The objectives of i-Share are to evaluate the health status and well-being of university students over the years, including information on mental health, risk behaviors, addictions, accidents, infections and migraine. Students are informed about the objectives of the study through promotion campaigns (e.g. information stands at registration, lectures, flyers, social media and newsletters). Specifically, student ambassadors are trained to inform their peers about the study and collect contact information to initiate the online recruitment process.

To be eligible, students had to be aged 18 years or older, officially registered in a university or higher education institution in France, and able to read and understand French.

Inclusion in the study was performed in two steps. First, volunteer students who wished to participate in the study were registered on the website (www.i-share.fr). Second, students completed and validated the baseline questionnaire, collecting information on sociodemographic characteristics, personal and family medical history, student lifestyle and mental health issues. Each participant received an online follow-up questionnaire on each anniversary of the date of the completion of the baseline questionnaire. Our study used the data from the first two follow-ups available on July 9, 2018. For this study, we used the data from participants who had completed at least one of the two follow-up questionnaires. This study was approved by the National Commission for Information Technology and Liberties (CNIL) [DR-2013-019].

Measures

Assessment of suicidal ideation

The study outcome was self-reported suicidal ideation in the last 12 months. During follow-up 1 and/or follow-up 2 (corresponding to first-year and second-year follow-up respectively), participants answered the question: "In the past 12 months, have you ever thought about committing suicide (or have you ever had suicidal thoughts)?". Answer options were: "Never", "Yes, it has happened to me", "Yes, several times" or "Do not want to answer". The variable was dichotomized into Yes or No. The "Yes" category applied if participants had chosen option "Yes, it has happened to me" or "Yes, several times" at least once during the two during the two follow-up times. The "No" category applied if participants had chosen the option "Never" for the two follow-up times. The "Do not want to answer" option in both follow-up questionnaires was considered as missing data.

Assessment of ADHD symptoms and perceived stress at baseline

ADHD symptoms: ADHD symptoms were assessed using the 6-item version of the World Health Organization (WHO) standardized screening tool ASRS-v1.1 (Adult Self Report Scale) [START_REF] Kessler | The World Health Organization adult ADHD self-report scale (ASRS): a short screening scale for use in the general population[END_REF]. Students were asked to answer questions about their behavior during the past 6 months before completing the questionnaire. The first four items assessed inattention symptoms and the last two items assessed hyperactivity/impulsivity symptoms.

The questions were answered using a 5-point Likert scale ranging from never (0) to very often (4) and a total ADHD score was computed by summing the score obtained for each item (total score range 0-24). The higher the score, the greater the risk of presenting an ADHD diagnosis. Clinically relevant ADHD cutoff scores were based on ASRS screening strata:

[0-14[, [14-17], [18-24] [START_REF] Kessler | Validity of the World Health Organization Adult ADHD Self-Report Scale (ASRS) Screener in a representative sample of health plan members[END_REF]. The ASRS has demonstrated good reliability, good validity and is an easy-to-use tool for assessing ADHD symptoms in students and in the general population [START_REF] Gray | The Adult ADHD Self-Report Scale (ASRS): utility in college students with attention-deficit/hyperactivity disorder[END_REF][START_REF] Kessler | The World Health Organization adult ADHD self-report scale (ASRS): a short screening scale for use in the general population[END_REF]. ADHD information was collected at baseline.

Perceived stress: Perceived stress was assessed using the short version of the Perceived Stress Scale (PSS-4) [START_REF] Cohen | A global measure of perceived stress[END_REF]. This self-reported questionnaire measures the degree to which situations of daily life during the last month are perceived as stressful (i.e.

unpredictable, out of control and painful) through four questions. Responses range from never (0) to very often ( 4). An overall score (score range 0-16) is calculated by summing the four items (two are reverse-coded). The higher the score, the higher the levels of perceived stress. The PSS-4 has demonstrated good reliability and validity in student samples [START_REF] Cohen | A global measure of perceived stress[END_REF]. Perceived stress information was collected at baseline.

Co-variables at baseline

The co-variables included were the potential confounders of the relationship between ADHD, perceived stress and suicidal ideation.

Student characteristics included: age, gender, study level at baseline (first year, second year, third year, fourth year or more); current tobacco consumption (non-smoker, <10 cigarettes/day, ≥10 cigarettes/day); frequency of alcohol consumption (no, occasionally, frequently); cannabis consumption at least once in lifetime (yes, no), previous history of depression/anxiety disorders diagnosed by a physician (yes, no); economic resources (family/scholarships, job activity, other); student living conditions (living alone, not living alone); overall life satisfaction score (ranging from 5 to 25) [START_REF] Salla | ADHD Symptomatology and Perceived Stress Among French College Students[END_REF][START_REF] Stickley | Attention-deficit/hyperactivity disorder symptoms and suicide ideation and attempts: Findings from the Adult Psychiatric Morbidity Survey 2007[END_REF].

Family characteristics included: parents' educational level (≤ postgraduate, > postgraduate);

parents' marital status (not divorced, divorced); family economic conditions during childhood (not very/moderately comfortable, very comfortable); parents' previous history depression or anxiety problem (yes, no); family support during childhood and adolescence (not very/moderately satisfactory, very satisfactory) [START_REF] Salla | ADHD Symptomatology and Perceived Stress Among French College Students[END_REF][START_REF] Stickley | Attention-deficit/hyperactivity disorder symptoms and suicide ideation and attempts: Findings from the Adult Psychiatric Morbidity Survey 2007[END_REF].

All co-variables were collected at baseline.

Statistical analysis

We first described the study sample and compared baseline characteristics between participants and non-participants. Then, we compared the characteristics of students reporting suicidal ideation and those not reporting it during follow-up (t-tests/Wilcoxon test/chi-square tests). Our modeling strategy followed the following steps. First, we investigated the crude association between ADHD symptoms, perceived stress, and subsequent suicidal ideation by using a logistic regression model. Second, in order to rule out any moderation effect we tested the interaction term ADHD symptoms*perceived stress regarding suicidal ideation. When the interaction term was not significant, the interaction term was removed from the models and only adjusted effects were presented. Third, the existence of the potential effect of perceived stress was tested by simultaneously entering ADHD and perceived stress into the same model. Fourth, we estimated a fully adjusted model considering ADHD symptoms, perceived stress and all the co-variables identified as potential confounders. We then compared the strength of the association between ADHD and suicidal ideation from the models. When all conditions for mediation were met: association between ADHD and perceived stress; association between perceived stress and suicidal ideation (step 1) and difference between the strength of ADHD effect on suicidal ideation (step 1 and 3)), we then performed a Structural Equation Modelling (SEM) to test the mediation pathway (using Lavaan package in R). The total and direct effects of ADHD on suicidal ideation were estimated. Then, the indirect effect of ADHD on suicidal ideation through perceived stress was estimated by the product of the effect of ADHD on stress and the effect of stress on suicidal ideation. We estimated the proportion of the total effect explained by perceived stress (proportion mediated=indirect effect/total effect). Since gender is related to ADHD (males are overrepresented) [START_REF] Green | What do we really know about ADHD in college students?[END_REF][START_REF] Weyandt | ADHD in College Students[END_REF][START_REF] Weyandt | ADHD in college students: Developmental findings[END_REF] and suicidal ideation (females are overrepresented) (Mortier et al., 2017b), the contribution of ADHD to suicidal ideation via perceived stress could vary according to the gender. We then have conducted separate exploratory analyses for females and males.

The R statistical software (R version 3.6.2) was used to conduct the analyses.

Results

The flow chart is shown in Figure 1. A total of 4,374 students (among the 14,912 students recruited at baseline) had completed at least one of the two follow-up questionnaires, which made them eligible for the present study. Among them, 4,333 had no missing data on suicidal ideation at follow-up and were then included in the main analyses. Table S1 (supplemental material) shows the comparison between participants (N= 4,333) versus nonparticipants (N=10,579) at follow-up. Participants were more often females (p<0.001), smoked less tobacco (p<0.001), consumed less cannabis (p<0.001) and alcohol (p<0.001), lived more often alone (p<0.001), reported a higher overall life satisfaction (p<0.001), had slightly lower scores of ADHD symptoms (p<0.001) and perceived stress (p<0.001). They came less often from divorced families (p<0.001), had parents with a higher level of education (p<0.001), came from families with a better economic situation (p<0.001) and had more family support during childhood (p<0.001). Participants had a median age of 20.3 years [IQR: 18.7-21.9], and 79% were females. The median participation time was 24 months [IQR:

13.4-29.1]. The percentage of the sample with clinically significant symptoms of ADHD (score ≥ 18) was 4.6%. A total of 863 participants (19.9%) reported suicidal ideation at least once during the follow-up.

Table 1 shows the baseline characteristics of the sample according to subsequent suicidal ideation. Students reporting suicidal ideation were younger than those not reporting it.

Students consuming alcohol, tobacco and cannabis were significantly more likely to report suicidal ideation than their peers who did not use these substances. Students who were freshmen, living alone, presenting a low overall life satisfaction score, a history of diagnosed depression/anxiety disorders, and having parents with a history of depression/anxiety were significantly more likely to report suicidal ideation than their counterparts. The proportion of students reporting suicidal ideation was not significantly different according to economic resources. Participants who declared very good family support during childhood and adolescence reported suicidal ideation significantly less frequently than other participants.

Mean ADHD symptoms and perceived stress scores were significantly higher among students who reported suicidal ideation compared to those who did not report it.

Table 2 shows the associations between ADHD symptoms, perceived stress, and subsequent suicidal ideation. ADHD symptoms and perceived stress did not interact (p=0.099). When ADHD and perceived stress were entered simultaneously, the effect of ADHD symptoms on suicidal ideation decreased by 16% (relative difference between Odds Ratio=1.46 and OR=1.22) but it remained significant. (Table 2).

The perceived stress score increased significantly on average by ß= 0.268 [95% CI: 0.244 -0.292] (p<0.001) for an increase of one point of the ADHD score. ADHD (ß= 0.028; [95% CI: 0.015 -0.041]; p<0.001; effect for increase of one point of the score) and perceived stress (ß= 0.096; [95% CI: 0.082 -0.110]; p<0.001; effect for increase of one point of the score)

were associated with suicidal ideation. The path analysis showed that the direct (beta=0.028) and indirect (0.268 *0.096=0.026) effects of ADHD on suicidal ideation were statistically significant (p<0.001) (Fig 2). The proportion of ADHD total effect on suicidal ideation explained by perceived stress was 49% (Table 3). When separate analyses were performed among females and males, the proportion of ADHD total effect explained by perceived stress was 51% in females and 37.5% in males (Table 3).

Discussion

Previous investigations have shown a significant contribution of ADHD symptoms and perceived stress to suicidal ideation in post-secondary students [START_REF] Assari | Multiplicative Effects of Social and Psychological Risk Factors on College Students' Suicidal Behaviors[END_REF][START_REF] Cheng | Factors Related to Self-Reported Attention Deficit Among Incoming University Students[END_REF]Mortier et al., 2017b[START_REF] Mortier | The epidemiology of ADHD in first-year university students[END_REF][START_REF] Stickley | Attention-deficit/hyperactivity disorder symptoms and suicide ideation and attempts: Findings from the Adult Psychiatric Morbidity Survey 2007[END_REF][START_REF] Van Eck | ADHD and suicidal ideation: The roles of emotion regulation and depressive symptoms among college students[END_REF]. In addition to confirming the existence of these individual associations, the present study extends the literature by taking ADHD and perceived stress into account at the same time.

We found that ADHD symptoms are associated with high levels of perceived stress and that this increases the risk of suicidal ideation, which supports that association between ADHD symptoms and suicidal ideation could be explained by perceived stress. We found that perceived stress accounts around half of the total effect of ADHD on suicidal ideation. Our findings are consistent with those of Yeguez et al who reported that stress accounts for the association between ADHD and suicidal ideation in young adults aged 18 to 30 years [START_REF] Yeguez | Stress Accounts for the Association Between ADHD Symptoms and Suicide Ideation When Stress-Reactive Rumination Is High[END_REF]. Our study expands the knowledge on the association by providing insights into the results by gender subgroup. Separate analyses by gender did not suggest variations by gender. However, their exploratory nature calls for cautious interpretation and further analyses.

Although the effect of perceived stress on suicidal ideation was higher than the effect of ADHD, its presence did not remove the association between ADHD and suicidal ideation.

Several mechanisms may explain the association between ADHD symptoms and suicidal ideation. First, university may be a particularly challenging environment for individuals with ADHD. Many studies have shown that students with ADHD show several academic and social difficulties that may in turn influence the onset of mental health problems and suicidal behaviors [START_REF] Fleming | Developmental Context and Treatment Principles for ADHD Among College Students[END_REF][START_REF] Kleiman | Utilized social support and self-esteem mediate the relationship between perceived social support and suicide ideation: A test of a multiple mediator model[END_REF][START_REF] Landry | Trouble déficitaire de l'attention à l'université[END_REF][START_REF] Mortier | The epidemiology of ADHD in first-year university students[END_REF][START_REF] Orozco | Association between attempted suicide and academic performance indicators among middle and high school students in Mexico: results from a national survey[END_REF]. Indeed, students with ADHD, compared with peers without ADHD, have a greater risk of presenting difficulties at the academic and/or social level, poorer efficiency in preparing the exams, and greater adoption of inadequate behaviors during schoolwork (e.g. higher rates of scribbling, chatting on social networks, playing video games, watching movies) [START_REF] Fleming | Developmental Context and Treatment Principles for ADHD Among College Students[END_REF][START_REF] Landry | Trouble déficitaire de l'attention à l'université[END_REF][START_REF] Mortier | The epidemiology of ADHD in first-year university students[END_REF][START_REF] Weyandt | ADHD in College Students[END_REF]. Second, independently from the academic context, clinical variables related with ADHD could also be at play in the association with suicidal ideation. ADHD is frequently comorbid with depression [START_REF] Blase | Self-reported ADHD and adjustment in college: cross-sectional and longitudinal findings[END_REF], disruptive behavioral disorders and substance use disorders [START_REF] Blase | Self-reported ADHD and adjustment in college: cross-sectional and longitudinal findings[END_REF][START_REF] Breyer | A Longitudinal Study of Childhood ADHD and Substance Dependence Disorders in Early Adulthood[END_REF], which increase the risk of suicidal ideation and suicide attempts [START_REF] Assari | Multiplicative Effects of Social and Psychological Risk Factors on College Students' Suicidal Behaviors[END_REF][START_REF] Van Eck | ADHD and suicidal ideation: The roles of emotion regulation and depressive symptoms among college students[END_REF]. In addition, characteristics such as impaired working memory have been shown to mediate the link between increased negative affect and suicidal ideation [START_REF] Bauer | Working memory mediates increased negative affect and suicidal ideation in childhood attentiondeficit/hyperactivity disorder[END_REF]. Furthermore, impulsivity is an important factor that could influence the association between ADHD and suicidality (ideation, plan, attempt), but we think that its impact would be observed more in the transition from suicidal ideation to suicide attempts and therefore in the ADHD-suicide attempt relationship [START_REF] Wang | Associations between impulsivity, aggression, and suicide in Chinese college students[END_REF]. Third, there may be commonalities between ADHD and suicidal behaviors, including family and genetic factors [START_REF] Ljung | Common Etiological Factors of Attention-Deficit/Hyperactivity Disorder and Suicidal Behavior: A Population-Based Study in Sweden[END_REF]. Although ADHD symptoms and perceived stress provide independent contributions to suicidal ideation, we speculate that any underlying risk of the association ADHD-suicidal ideation may not manifest without some emotional component such as stress, depression or self-esteem, as shown Arsandaux et al, Yeguez et al [START_REF] Arsandaux | Pathways From ADHD Symptoms to Suicidal Ideation During College Years: A Longitudinal Study on the i-Share Cohort[END_REF][START_REF] Yeguez | Stress Accounts for the Association Between ADHD Symptoms and Suicide Ideation When Stress-Reactive Rumination Is High[END_REF] and the current study.

This study has several strengths, including its cohort design that provided temporal precedence of the exposure (ADHD) and the mediator (perceived stress) in relation to the event (suicidal ideation), the sample size that provided more precision in the estimates, and the adjustment on a wide range of potential confounding factors. Nevertheless, some limitations should be taken into consideration when interpreting the results. First, given the possibility of waning symptoms at age 18, the current study may have focused on persistent ADHD symptoms in participants aged 18 years or older, i.e. the most severely affected individuals. In addition, because participants were volunteers, and because there was a high proportion of females, the generalizability of our findings is somewhat limited. The i-Share cohort is not representative of the general student population of France, although it is the largest existing student cohort. Second, our sample was underrepresented in terms of key risk factors for ADHD (e.g. male gender, low socioeconomic status, and substance use problems) and not fully representative of the ADHD population, so the associations were possibly underestimated. Future research will have to replicate these findings in other general and clinical populations to consolidate our conclusions. Third, our study design may represent a weakness for path analysis. However, the results of the current study extend knowledge on the ADHD-suicidal ideation relationship in students and provide a large overview of the role of perceived stress in it. Further studies using an adequate design (i.e.

Time 1: ADHD, Time 2: perceived stress, Time 3: suicidal ideation) and including an equal female-male ratio are required to consolidate / further explain our observations. It would also be relevant to use stress biomarkers over time, which could provide more accurate stress measures. Fourth, suicidal ideation was assessed with only one question. Indeed, an evaluation with psychometric instruments would have provided a much better degree of suicidal ideation. Fifth, the associations may have been affected by a social desirability bias due to the self-reported nature of the measures. However, the impact of this bias is potentially minimal because previous literature has shown that the use of an online selfquestionnaire versus face-to-face interviews greatly reduces desirability in the responses [START_REF] Tourangeau | Sensitive questions in surveys[END_REF].

In a future research perspective, others emotional factors have been reported as mediators of the ADHD-suicidal ideation association [START_REF] Arsandaux | Pathways From ADHD Symptoms to Suicidal Ideation During College Years: A Longitudinal Study on the i-Share Cohort[END_REF]. Even if perceived stress and these other emotional factors (e.g. depression, self-esteem) are not direct or absolute consequences of ADHD in all instances, they may occur subsequently to the presence of ADHD and could influence the ADHD-suicidal ideation relationship [START_REF] Anastasiades | Perceived stress, depressive symptoms, and suicidal ideation in undergraduate women with varying levels of mindfulness[END_REF][START_REF] Arsandaux | Pathways From ADHD Symptoms to Suicidal Ideation During College Years: A Longitudinal Study on the i-Share Cohort[END_REF][START_REF] Salla | ADHD Symptomatology and Perceived Stress Among French College Students[END_REF][START_REF] Van Eck | ADHD and suicidal ideation: The roles of emotion regulation and depressive symptoms among college students[END_REF].

Therefore, a path analysis taking all these factors into account could provide additional knowledge about the relationship between ADHD and suicidal ideation in students.

In conclusion, the present study shows that perceived stress partially accounts for the association between ADHD symptoms and suicidal ideation among students. In addition, ADHD symptoms provide an independent contribution (beyond perceived stress) to suicidal ideation. It is relevant to consider both dimensions when addressing the prevention of suicidal ideation. Identification of ADHD, which is known to be under-diagnosed in countries like France, high levels of perceived stress, and suicidal ideation should be facilitated at university through screening measures and greater accessibility to mental health services.

When necessary, the implementation of both appropriate non-pharmacological and pharmacological interventions should be proposed. For instance, targeted psychological interventions implemented by public authorities in student health services (e.g. individual psychotherapies or cognitive behavioral and emotional therapy groups) could help students to cope better with the onset of ADHD and manage their stress. More generally, the promotion of mental health literacy and healthy lifestyles (e.g. physical activity, adequate nutrition and sleep) may also be of interest in this population. ADHD medication should also be considered in the most severe cases of ADHD, since it has been proven to reduce the risk of suicidal behaviors in treated versus non-treated people [START_REF] Liang | Suicide risk reduction in youths with attentiondeficit/hyperactivity disorder prescribed methylphenidate: A Taiwan nationwide population-based cohort study[END_REF]. Overall, it is important to screen for the risk of suicide among young people with ADHD. Future studies are needed to corroborate our results in students from other countries in order to inform the most appropriate interventions.

Fig 2 :

 2 Fig 2: Estimation of direct and indirect ADHD effect on suicidal ideation among college students (the i-Share cohort) using Structural Equation Modeling, n=3,669.a= Unadjusted effect of ADHD symptoms on perceived stress; b= effect of perceived stress adjusted on ADHD and co-variables; c'= effect of ADHD symptoms adjusted on perceived stress and co-variables; ab= indirect effect through perceived stress. **p-value <0.001. co-variables were: age; gender; study level at baseline; tobacco consumption; alcohol consumption; cannabis consumption at least once in lifetime; previous history of depression/anxiety disorders diagnosed by a physician; economic resources; student living conditions; overall life satisfaction; parents' educational level; parents' marital status; family economic condition during childhood; parents' previous history depression or anxiety problem; family support during childhood and adolescence; cohort participation time.

Table 1 :

 1 Sample baseline characteristics according to suicidal ideation France, N = 4,333).

	Fig 1: Participants flow chart

*For quantitative variables with non-normal distributions: median [IQR:interquartile range]; SD: standard deviation; N: number of participants included in the main analyses; ADHD: Attention Deficit Hyperactivity Disorder +Variables with missing data: Tobacco consumption (n=2); Cannabis consumption at least once in lifetime (n=7); Overall life satisfaction score (n=1); Parents' marital status (n=118); Parents' educational level (n=315); Parents' previous history depression or anxiety problem (n=281); Family support during childhood and adolescence (n=52).

Table 3 :

 3 Path analysis: estimation of total, direct and indirect ADHD effect on suicidal ideation via perceived stress France, N = 3,669)

		Estimate -Beta	CI 95%	p-value
	Direct effect	0.028	0.015 -0.041	<0.001
	Indirect effect	0.026	0.021 -0.030	<0.001
	Total effect	0.053	0.041 -0.066	<0.001
		Gender separate analyses
	Males (n=776)
	Direct effect	0.034	0.005 -0.064	0.022
	Indirect effect	0.021	0.012 -0.031	<0.001
	Total effect	0.056	0.028 -0.084	<0.001
	Females (n=2893)
	Direct effect	0.026	0.012 -0.040	<0.001
	Indirect effect	0.027	0.022 -0.032	<0.001
	Total effect	0.053	0.039 -0.067	<0.001

Acknowledgements

The authors are indebted to the participants of the i-Share project for their commitment and cooperation and to the entire i-Share staff for their expert contribution and assistance.

Funding

The i-Share research project has received funding from the French National Research Agency (Agence Nationale de la Recherche, ANR) via the program 'Investissements d'Avenir' reference ANR-10-COHO-05.

Data statement

Database for the i-Share cohort can be made available upon reasoned request to Cedric Galera.

Author contributions

Conceptualization, Methodology, Formal analysis: Antoine Gbessemehlan, Julie Arsandaux, and Cédric Galéra.

Writing -original draft: Antoine Gbessemehlan.

Writing -review & editing: Antoine Gbessemehlan, Julie Arsandaux, Massimiliano Orri, Ilaria Montagni, Melissa Macalli, Marie Tournier, Christophe Tzourio and Cédric Galéra.

Visualization: Antoine Gbessemehlan, Julie Arsandaux and Cédric Galéra.

Supervision: Cédric Galéra.

Project administration and funding acquisition: Christophe Tzourio.

Conflicts of interest

The authors declare that they have no conflict of interest.

Compliance with Ethical Standards

Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent: Informed consent was obtained from all participants included in the study. The full-adjusted model ran on 3,669 participants due to missing data on some co-variables.


Laure S Fournier
email: laure.fournier@aphp.frconflitd

Anne-Sophie Bats

Catherine Durdux

Diffusion MRI: technical principles and application to uterine cervical cancer IRM de diffusion : bases techniques et application au cancer du col utérin

Keywords: Cervix uteri, Cancer, Magnetic resonance, Imaging, Diffusion-weighted imaging, Chemoradiation, Treatment, Planning Cancer, col utérin, Imagerie, Résonance magnétique, Pondération diffusion, Chimioradiothérapie, Planification, Traitement

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

Introduction: Importance of imaging for radiation therapy in the management of cervical cancer

The majority of cervical cancers are squamous cell carcinomas (80-90 %) or adenocarcinomas (10-20 %). Positive diagnosis of cervical cancer will be made by histological examination on a cervical biopsy or conization and not by imaging. Imaging will be used in the management of the initial disease with several objectives: 1/ to assess the local and lymph node extension of the initial disease; 2/ to evaluate response to conservative therapy; 3/ to detect recurrence. Pelvic MRI is the first-line examination in all these indications, and the diffusion-weighted acquisition provides essential information that will be useful to both the radiologist and the radiation oncologist.

The initial spread of cervical cancer is determined by the International Federation of Gynaecology and Obstetrics (FIGO) classification which was revised in 2018 (Table) [START_REF] Bhatla | Revised FIGO staging for carcinoma of the cervix uteri[END_REF]. Until 2018, the FIGO staging did not take into account imaging or node status. These changes gave imaging a more prominent place in the initial assessment closer to the practices of expert centres. Briefly, stage I cancers are limited to the cervix; stage II cancers expand beyond the cervix without reaching the lower third of the vagina or the pelvic wall; stage III cancers present invasion of the lower third of the vagina or pelvic wall, present hydronephrosis or a non-functional kidney, have pelvic or retroperitoneal lymph nodes; stage IV cancers present invasion of pelvic organs or extrapelvic extension.

The challenge at the diagnostic stage is to make the right decision during the multidisciplinary tumour board between surgery or chemoradiation therapy [START_REF] Anon | Guide -affection longue durée. Tumeur maligne, affection maligne du tissu lymphatique ou hématopoïétique[END_REF]. For stages IA, IB1et IB2, patients will undergo surgical treatment. Starting at stage IA2, a complementary pelvic lymphadenectomy is indicated. For IB2 stages, initial uterine and vaginal brachytherapy can be proposed. If the patient has lymph node involvement, additional concomitant chemoradiation is administered. Stages IVB are rare and management will be discussed on a case-by-case basis depending on the extent of the disease and the patient's general condition. Treatment relies on chemotherapy and eventually complementary radiation.

Technical bases of diffusion MRI

Principle of diffusion-weighted imaging

The MRI signal is due to the dephasing of protons in water molecules. The contrast depends on the difference in proton dephasing rate between different tissues.

The principle behind diffusion weighted magnetic resonance imaging (DW-MRI) is the exploration of microscopic movements of water. It allows distinguishing between mobile water molecules in which diffusion is free (as in cerebrospinal fluid), and water molecules whose diffusion is restricted (by cell membranes fibres macromolecules, etc.). Diffusion is therefore dependent on the cellularity of the explored tissue (3), which makes this technique particularly interesting in cancers which are hypercellular and therefore present many obstacles restricting diffusion.

Image acquisition

The diffusion-weighted sequence is first and foremost a T2-weighted MRI sequence [START_REF] Bihan | Diffusion magnetic resonance imaging: what water tells us about biological tissues[END_REF]. Two intense, symmetrical, and opposite gradients are applied separated by a latency time during which the water molecules will diffuse more or less according to the intra-and extracellular obstacles they may encounter. These gradients will result in a dephasing and then rephasing of the protons in the voxel.

The mobile diffusing water molecules will move out of the voxel during the latency time and therefore be in completely rephased. They will thus see their contribution to this signal fall. On the contrary, static water molecules will be dephased and rephased completely and will have a signal that will not be affected by these gradients. They will therefore emit a high signal intensity. Water molecules inside cells have a much more limited degree of movement than water molecules in the extracellular space, due in particular to the existence of cell membranes and the cytoskeleton. A highly cellular tissue such as tumours will thus have a low diffusion coefficient, emitting a high signal on the MRI image, appearing brighter than normal tissues in which water molecules will diffuse much more [START_REF] Fournier | Imaging of response to treatment in oncology[END_REF].

The diffusion sequence was developed initially in brain imaging for the early diagnosis of stroke. Its use has been extended to whole body imaging thanks to technical developments allowing faster acquisition with fewer motion artefacts for use in oncology [START_REF] Hagmann | Understanding diffusion MR Imaging techniques: from scalar diffusion-weighted imaging to diffusion tensor imaging and beyond[END_REF].

Quantification of the diffusion of water molecules can be performed using the apparent diffusion coefficient (ADC), expressed in square millimetres per second (4). This quantitative parameter has been used in many studies to characterise tumours or assess their response to treatment [START_REF] Sala | The added role of mr imaging in treatment stratification of patients with gynecologic malignancies: what the radiologist needs to know[END_REF]. Its use in clinical practice has yet to be defined. Diffusion images suffer from low spatial resolution, but they can be merged with a morphological sequence providing anatomical information to compensate this drawback (figure 1).

Role of imaging in cervical cancer

Imaging for the initial staging of cervical cancer

Definition of the target volume

Two target volumes are important for patient management: the volume of tumour extent (gross tumour volume, GTV T et clinical target volume, CTV T) and the lymph node volume (GTV N et CTV N).

The imaging assessment will consist of a pelvic MRI exploring the lymph node regions up to the renal veins and including a diffusion-weighted sequence [START_REF] Balleyguier | Staging of uterine cervical cancer with MRI: guidelines of the European Society of Urogenital Radiology[END_REF].

Elements on imaging that may compromise surgical management:

• largest diameter greater than or equal to 4 cm (measured in all three planes); • extent to the parameters, the lower third of the vagina or the pelvic wall; • extent to adjacent organs.

MRI is considered the reference examination to define location, size and invasion of parameters, pelvic wall or adjacent organs [START_REF] Sala | The added role of mr imaging in treatment stratification of patients with gynecologic malignancies: what the radiologist needs to know[END_REF][START_REF]NNCN clinical practice guidelines in oncology -Cervical cancer[END_REF].

The accuracy of the definition of the lesion boundaries is improved by the contrast between normal and tumour tissues on the diffusion sequence (figure 2), thus contributing to the definition of the cervical volume. Diffusion-weighted imaging has an added value in particular for the detection of an extent to the parameters compared to the morphological T2-weighted sequence (diagnostic accuracy greater than 90% vs. 80 to 85% respectively), and more specifically by reducing false positives [START_REF] Park | Value of diffusion-weighted imaging in predicting parametrial invasion in stage IA2-IIA cervical cancer[END_REF][START_REF] Qu | Predicting parametrial invasion in cervical carcinoma (stages IB1, IB2, and IIA): diagnostic accuracy of T2-weighted imaging combined with DWI at 3 T[END_REF][START_REF] Mongula | Assessment of parametrial invasion of cervical carcinoma, the role of T2-weighted MRI and diffusion weighted imaging with or without fusion[END_REF]. MRI also has a high negative predictive value to eliminate bladder or rectal involvement [START_REF] Rockall | Can MRI rule out bladder and rectal invasion in cervical cancer to help select patients for limited EUA?[END_REF].

Beyond the definition of volume and local extent spread imaging has an important role in detecting lymph node involvement particularly retroperitoneal lymph nodes. This is important in order to discuss whether to perform a staging lymphadenectomy, and determine whether these areas should be treated surgically or with radiation [START_REF] Tanderup | Adaptive management of cervical cancer radiotherapy[END_REF]. MRI is highly specific when the size (small axis) of the lymph nodes is increased (greater than 10 mm). Its sensitivity ranges from 37 to 71% for the morphological sequences, to 86% when adding the diffusion-weighted sequence [START_REF] Haldorsen | What is the role of imaging at primary diagnostic work-up in uterine cervical cancer?[END_REF]. However it is not very sensitive nor specific for detecting lymph node metastasis in subcentimetric lymph nodes [START_REF] Choi | MRI for pretreatment lymph node staging in uterine cervical cancer[END_REF]. Of note, even normal lymph nodes show a high signal on the diffusion-weighted sequence which decreases its specificity (figure 3b). In these cases (normal-sized lymph nodes, 18 FDG PET-CT has a much better sensitivity (75%-100%) and specificity (87%-100%) particularly in patients with advanced stage disease [START_REF] Magne | New trends in the evaluation and treatment of cervix cancer: the role of FDG-PET[END_REF][START_REF] Selman | Diagnostic accuracy of tests for lymph node status in primary cervical cancer: a systematic review and meta-analysis[END_REF]. It could therefore be proposed during the multidisciplinary tumour board for the assessment of distant spread, particularly for tumours over 4 cm size (stage IB3 and higher) (2).

Identification of non-target organs

A lesser known application of diffusion MRI is the identification of normal organs, some of these appearing with a moderately high signal (figure 3). This is the case with ovaries, which are sometimes difficult to identify on morphological sequences especially if they are paucifollicular. The diffusion sequence thus makes it possible to improve the delineation for dosimetry after image fusion.

Evaluation of treatment response

MRI is the reference examination to assess the efficacy of chemoradiation, and to detect possible complications such as infection or fistulas [START_REF] Addley | Pelvic imaging following chemotherapy and radiation therapy for gynecologic malignancies[END_REF]. MRI is thus routinely used to evaluate response to chemoradiation and guide uterovaginal brachytherapy and should be performed 7 to 8 weeks after the end of treatment [START_REF] Schernberg | Diffusionweighted MRI in image-guided adaptive brachytherapy: Tumor delineation feasibility study and comparison with GEC-ESTRO guidelines[END_REF]. It allows evaluating whether complete remission has been achieved and detects possible residual disease, which may then be treated by surgery (Fig. 4) [START_REF] Balleyguier | Staging of uterine cervical cancer with MRI: guidelines of the European Society of Urogenital Radiology[END_REF]. If the response is considered complete on imaging with ad integrum restitution of the cervical signal (and in particular of the fibrous low signal), there is no need to perform further exploration [START_REF] Hricak | Irradiation of the cervix uteri: value of unenhanced and contrast-enhanced MR imaging[END_REF]. Indeed, this sign has a high negative predictive value (97%). If, on the contrary, an anomaly is detected, a PET-CT can be proposed to exclude distant spread before surgery is considered.

Diffusion MRI has been used in several studies to predict the final efficacy of therapy. The pretreatment value of apparent diffusion coefficient, as well its early changes from the pretreatment value were predictive of the observed MRI response at the end of therapy [START_REF] Yang | Multi-parametric MRI in cervical cancer: early prediction of response to concurrent chemoradiotherapy in combination with clinical prognostic factors[END_REF][START_REF] Harry | Diffusion-weighted magnetic resonance imaging in the early detection of response to chemoradiation in cervical cancer[END_REF].

Detection of recurrences

Recurrences of cervical cancer usually occur early i.e. within 2 years of starting treatment (60 to 70% of cases). Recurrence can be local (cervicovaginal), in lymph nodes or distant. They present similarly to the initial tumour with an intermediate signal on the T2-weighted sequence, but it may be difficult to distinguish between post therapeutic changes and tumour recurrence [START_REF] Lucas | Added value of diffusion-weighted MRI in detection of cervical cancer recurrence: comparison with morphologic and dynamic contrast-enhanced MRI sequences[END_REF]. Diffusion MRI is then useful because a high signal anomaly (other than infection or fistula) will be in favour of recurrence [START_REF] Padhani | Diffusionweighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations[END_REF]. For lymph node recurrence, the diffusion-weighted sequence is useful due to its ease of detection of pelvic or retroperitoneal lymph adenopathy due to their high signal (figure 5).

Conclusion

Pelvic MRI is the reference examination for initial assessment of cervical cancer. It is the key element for delineation of target volumes after image fusion when there is an indication for chemoradiation. It is also in central to guide the implementation of applicators and optimise the dosimetry of brachytherapy. In combination with the clinical examination, it allows evaluating the efficacy of treatment and detecting recurrences. Overall, the diffusion sequence, with the additional information it provides through a high contrast between tumour and surrounding tissues, facilitates the detection of cancer, evaluation of the volume and spread of the disease.

  For stages IB3-IVA, the reference treatment is concomitant chemoradiation. The irradiation fields are pelvic and retroperitoneal or not, followed by a uterovaginal brachytherapy. Irradiation volumes are based on imaging (MRI, [ 18 F]-fluorodeoxyglucose [FDG] positron emission tomography combined with computed tomography [PET-CT]) and/or the results of a laparoscopic retroperitoneal lymphadenectomy.

Figure 1 .

 1 Figure 1. Diffusion MRI: application to uterine cervical cancer. Fused T2-weighted images (greyscale) and diffusion-weighted images (colour) combining spatial resolution of the morphological sequence with the contrast of the functional sequence. The arrow indicates the cervical cancer extending in the posterior pelvic cavity. B: bladder.

Figure 2 .

 2 Figure 2. Diffusion MRI: application to uterine cervical cancer. a-d: images in two patients with cervical cancer; a,c: T2-weighted images; b,d: diffusion-weighted images. a, b: the cancer is limited to the cervix, with no extent to parameters; on the T2-weighted image (a), the cervical stromal ring is intact, seen as a circumferential low intensity line around the tumour (arrowheads); on the diffusionweighted image (b), the cancer is seen as a high intensity lesion; c,d: there is an extent to parameters left and right (arrows) seen as nodular or irregular hyperintense signal extending to the parametrium. Note the presence of large left iliac adenopathies.

Figure 3 .

 3 Figure 3. MRI of a 46 year-old patient with cervical cancer. a: T2-weighted image; b: diffusionweighted image. The ovaries (arrows), paucifollicular, are hard to detect on the T2-weighted sequence, but easily identifiable on the diffusion-weighted sequence. Note also the visible infracentimetric left external iliac lymph node on the diffusion-weighted sequence (arrowhead).

Figure 4 .

 4 Figure 4. T2-weighted pelvic MRI of two patients with cervical cancer. a: for patient 1, the initial tumour (FIGO stage IB3) presents as a mass with an intermediate T2 signal (arrow), i.e. less high than fluids such as the urine in the bladder, but higher than muscles; b: after therapy, the cervix returns to its normal appearance, with a circumferential low signal similar to muscles (arrow) corresponding to the fibrous ring, spiculated retractions (arrowhead) can be observed that are not related to residual disease. c: for patient 2, the initial tumour extended into the right parameter (arrow) (FIGO stage IIB); d: after therapy, though the tumour has decreased in size, residual tumour persists identified by its intermediate T2 signal. FIGO: International Federation of Gynaecology and Obstetrics.

Figure 5 .

 5 Figure 5. MRI for the detection of vaginal and lymph node recurrence of a cervical cancer treated by surgery and brachytherapy. a: the vaginal recurrence presents as an asymetrical thickening of the vaginal stump (arrows) with an intermediate signal on T2-weighted image ; b: clear high signal of the vaginal recurrence on the diffusion-weighted image; c: the lymph node recurrence (arrows) presents as a lymph node with high signal on the T2-weighted image, which can easily be missed amid the high signal of the surrounding fatty tissue or be taken for a lymphocele secondary to staging lymphadenectomy; d: the high signal on the diffusion-weighted sequences improves sensitivity for detection of lymph node metastasis.

Table 1 .

 1 Uterine cervical cancer stages classification according to the International Federation of Gynaecology and Obstetrics (FIGO), revised in 2018 (adapted from[START_REF] Bhatla | Revised FIGO staging for carcinoma of the cervix uteri[END_REF]).

	Stages	Criteria
	Stage I	Lesion limited to the cervix (whether there is an extent to the corpus or not)
	IA	Invasion of stroma < 5 mm depth
	IA1	Invasion of stroma < 3 mm depth
	IA2	Invasion of stroma ≥ 3 mm et < 5 mm depth
	IB	Lesion limited to the cervix, invasion ≥ 5 mm depth
	IB1	Size < 2 cm
	IB2	Size ≥ 2 cm and < 4 cm
	IB3	Size ≥ 4 cm
	Stage II	Lesion extending beyond the cervix without spread to lower third of vagina or pelvic
		wall
	IIA	Extent to higher two thirds of vagina, but no extent to parameters
	IIA1	Size < 4 cm
	IIA2	Size ≥ 4 cm
	IIB	Extent to parameters but not pelvic wall
	Stage III	Extent to lower third of vagina and/or pelvic wall and/or hydronephrose or non
		functional kidney and/or pelvic and/or retroperitoneal lymph node metastasis
	IIIA	Extent to lower third of vagina but no extent to pelvic wall
	IIIB	Extent to pelvic wall and/or hydronephrose or non functional kidney
	IIIC	Pelvic and/or retroperitoneal lymph node metastasis (r if on imaging, p if pathology)
	IIIC1	Pelvic lymph nodes only
	IIIC2	Retroperitoneal lymph nodes
	Stage IV	Extrapelvic extension or spread to adjacent organs
	IVA	Extent to adjacent organs (biopsy-proven extent to bladder or rectum mucosa)
	IVB	Distant metastasis


Anne-Marie Duguet Maitre
email: aduguet@club-internet.fr

Evaluation of research protocols by Committees for Protection of persons: balancing scientific criteria and protection of individuals

Keywords: Comités d'éthiques, Éthique de la recherche, Loi Huriet-Sérusclat, Loi Jardé, Protection des personnes Ethics committees, Research ethics, Loi Huriet-Sérusclat, Loi Jardé, Protection of persons

Récemment des voix se sont élevées pour reprocher aux Comités de Protection des Personnes (CPP) une évaluation des projets de recherche dominée par des critères scientifiques qui ne prend pas suffisamment en compte la relation de soins et le bien être des sujets. Cet article montre comment s'est construite en France l'éthique de la recherche dans un contexte historique et culturel spécifique qui la distingue de l'éthique de la recherche en Amérique du nord. Cette présentation n'est pas une comparaison entre les IRB et CER avec les CPP français. Elle vise à montrer que les CPP évaluent les protocoles en protégeant les sujets. La création des comités en France s'est opérée dans un système de santé dans lequel l'état organise la protection de la santé et encadre par la loi dans le code de la santé publique des pratiques qui relèvent dans d'autres pays de recommandations professionnelles. Ainsi les comités ont été nommés « Comités de Protection des Personnes » avec pour mission de veiller à ce que les protocoles soient respectueux des personnes tout en s'assurant de leur pertinence scientifique. Depuis la mise en place des CPP par la loi Huriet-Sérusclat, des lois successives ont adapté l'encadrement des recherches pour l'harmoniser avec les recommandations internationales. La loi Jardé a conservé aux CPP la même dénomination. Si les missions et la composition des comités ont évolué, ils continuent à évaluer à la fois la protection des personnes et les critères scientifiques.

La recherche médicale contribue au progrès du savoir pour l'individu mais aussi pour la société. Sa finalité est diverse, elle fait progresser les connaissances biologiques et médicales, les mécanismes de fonctionnement de l'organisme normal ou pathologique, l'efficacité et la sécurité de réalisation d'actes ou de l'utilisation de produits dans un but de diagnostic de traitement ou de prévention d'états pathologiques. L'éthique de la recherche s'est construite par étapes qu'il convient de replacer dans le contexte historique et culturel. Elle n'a pas suivi la même orientation en France et en Amérique du Nord.

L'éthique médicale a débuté en France dans un système de soins basé sur la déontologie avec une approche paternaliste de la protection de la santé. Il existait alors des comités d'éthique clinique centrés sur les nouvelles techniques [START_REF]Christian Byk L'irrésistible ascension des comités d'éthique (en France)[END_REF] (assistance à la procréation, greffes d'organes, diagnostic prénatal etc..), dans ce contexte, les comités d'éthique de la recherche sont apparus vers 1970. La recherche sur les médicaments est longtemps restée intimement liée aux soins, encadrée en 1972 par une règlementation basée sur le principe que l'état doit protéger la santé de ses citoyens. Depuis la loi Huriet-Sérusclat de 1988, les essais cliniques des médicaments sont intégrés l'organisation des recherches biomédicales est encadrée par la loi, rendant contraignants en France certains principes éthiques appliqués en Amérique du Nord sous forme de recommandations professionnelles (soft law). Aux USA, le rapport Belmont pose en 1979 les principes éthiques et les lignes de conduite pour la protection des sujets humains de recherche : consentement, balance bénéfice / risque de la recherche, sélection équitable des sujets. Peu après les Institutionnal Review Board (IRB) sont mis en place dans les établissements publics. Il s'agit plutôt de comités scientifiques, même s'ils comportent au moins un membre non scientifique.

Contexte

Au Canada, le Conseil des Recherches Médicales met sur pied un comité en vue de préparer des Lignes Directrices concernant la recherche sur les sujets humains, publiées en 1987 [START_REF] Doucet | l'éthique de la recherche[END_REF]. Ces directives ont été remplacées en 1998 par l'énoncé de politique des 3 conseils qui prévoit la mise en place de comités d'éthique de la recherche (CER) qui sont locaux, indépendants et multidisciplinaires pour évaluer la validité éthique des projets menés dans leur établissement.

Recherche médicale et essais cliniques, évolution historique en France

Au XIX ième siècle, la recherche médicale était liée aux soins, on cherchait des traitements pour soigner les maladies et des vaccins pour les prévenir avec pour but une amélioration de la vie pour tous (justice universelle). L'expérimentation des nouvelles techniques se faisait à l'intérieur de la relation médecin-malade. Claude Bernard [START_REF] Bernard | Introduction à l'étude de la médecine expérimentale[END_REF] admet que l'on a le droit de pratiquer des expérimentations sur l'homme quand cela peut sauver la vie, guérir ou procurer un avantage personnel au patient (principe de bienfaisance).

La recherche sur un nouveau médicament a pour objectif d'apporter la preuve de l'efficacité du produit et de sa sécurité afin qu'il soit puisse être mis sur le marché sans exposer les utilisateurs à des risques. En 1972 un décret1 organisait l'expérimentation des nouveaux médicaments, en France avec des sujets atteints de la maladie que le nouveau médicament était susceptible de traiter. Les premiers essais sur l'homme sain n'étaient pas possibles puisqu'il fallait que l'expérimentation présente un bénéfice direct pour le sujet.

En 1988, la Loi Huriet Serusclat 2 relative à la protection des personnes dépassant le cadre des essais de médicaments, autorisait dans des conditions très protectrices de conduire des recherches sans bénéfice pour le sujet, organisait la conduite des recherches biomédicales et créait les comités de protection des personnes. Contrairement aux comités d'Amérique du Nord, ces comités étaient indépendants des établissements et constitués de membres nommés sur proposition des institutions de recherche ou d'enseignement, des universités, des autorités de justice, des organisations professionnelles.

En 2012 la loi Jardé 3 vient compléter le dispositif existant: il s'agit principalement d'une loi sur la recherche mais qui a toutefois conservé aux comités le titre de CPP Comités de protection des personnes et a élargi leur compétence, reconnaissant ainsi leur rôle dans toutes les recherches impliquant la personne humaine.

Création et évolution des Comités de Protection des Personnes

Les Comités Consultatifs de Protection des Personnes qui se prêtent à la Recherche Biomédicale (CPPRB) ont été mis en place par la loi Huriet-Sérusclat. Initialement l'avis rendu par les comités était consultatif et les recherches biomédicales étaient placées sous un régime déclaratif, le médecin investigateur ayant la charge de déclarer la recherche aux autorités administratives (AFSSAPS : autorité de sécurité des produits de santé), avec l'avis du CCPPRB.

Les dispositions de la directive européenne 2001/20/CE sur les essais cliniques de médicaments [START_REF] Dubray | Conduite des essais cliniques de médicaments au niveau européen depuis la directive européennes essais cliniques. Revue des aspects réglementaires et pratiques dans différents pays[END_REF] et la loi du 9 Août 2004 relative à la politique de santé publique [START_REF] Manaouil | La recherche biomédicale en France, cadre législatif et réglementaire[END_REF]

Mission des CPP : protection des personnes et analyse du protocole

Le CPP procède à une analyse du protocole et des garanties pour les sujets dans la conduite de la recherche 4 . La protection des personnes et des participants à la recherche est l'axe majeur de la mission du comité qui doit vérifier également l'adéquation des informations et la procédure de recueil du consentement. La pertinence de la recherche et le caractère satisfaisant de la balance bénéfice risque sont évalués, ainsi que l'adéquation des objectifs et des moyens. Le comité s'assure enfin des modalités de la protection des données [START_REF] Lesaulnier | Recherches en santé et protection des données personnelles à l'heure du Règlement Général relatif à la Protection des Données[END_REF].

Tous les membres participent à l'analyse et à la discussion qui aboutit à l'avis motivé, le collège 1 composé de scientifiques et de professionnels de santé a une capacité d'analyse scientifique prépondérante et la présence indispensable d'un spécialiste de la méthodologie est garant de la qualité de l'analyse. La protection des personnes est l'affaire de tous les membres du comité mais la présence du représentant des associations de patients garantit la mise en oeuvre de la protection dans la conduite du protocole, le collège II est généralement beaucoup plus orienté vers l'analyse des formulaires d'information et la vérification des pièces justificatives des obligations légales (assurances, autorisation de lieux etc…).

1) Protection de la personne

Les sujets sont libres de se soumettre à la recherche et de se retirer à tout moment (volontariat). Dans le cadre des essais thérapeutiques, ils doivent être informés des alternative thérapeutiques existantes. Peu importe le type de recherche menée, ils doivent être informés de tous les éléments qui pourraient leur permettre de connaitre les risques et contraintes de la recherche.

La fiche d'information est le document essentiel puisqu'il présente le protocole mais aussi le cadre dans lequel la recherche sera conduite et la liste des garanties et documents respectant les droits des sujets.

Les modalités du recueil du consentement sont précisées avec toutes les particularités de la législation française, c'est pourquoi, dans les projets internationaux multicentriques, alors que le protocole est le même dans tous les pays, la fiche d'information est adaptée aux préconisations particulières à la France.

Une protection générale

Le cadre de la loi apporte une protection générale : le bénéfice de l'individu prime sur ceux de la science ou de la société 5 , pour les recherches présentant des risques l'investigateur qui conduit la recherche est obligatoirement un médecin. L'analyse des prérequis scientifiques dans la littérature évite que les patients ne soient pas être exposés à des recherches inutiles. La loi « Bertrand » sur la sécurité sanitaire du médicament et des produits de santé insiste sur la nécessaire transparence des liens d'intérêts, renforce la protection des patients dans la recherche [START_REF]Laigneau Sécurité des patients et développement des recherches : de la loi Bertrand à la loi Jardé[END_REF].

En cas de dommages du fait de la recherche, ils sont indemnisés, une assurance est obligatoire pour le promoteur. Les effets indésirables graves de la recherche sont déclarés aux comités qui évaluent s'il est nécessaire d'informer les sujets qui se prêtent à la recherche. Les bases de données regroupant les protocoles des essais sont consultables par les associations de patients.

Une protection individuelle

Le sujet est informé qu'un examen médical préalable à la recherche est prévu par le protocole afin de s'assurer que l'état de santé du sujet lui permet d'être inclus dans la recherche. Selon de type de personnes incluses dans les protocoles, il existe une protection spécifique pour les personnes vulnérables et incapables avec des modalités particulières d'information et de recueil du consentement, auxquelles les comités et les associations de malades sont particulièrement attentifs.

La vie privée est protégée au travers des données personnelles collectées pendant la recherche et la mention des origines ethniques sont des données sensibles protégées par le RGPD en Europe. Les CPP s'assurent que les sujets sont informés des risques d'atteinte à la vie privée si les données sont traitées dans un pays hors de l'Union Européenne qui ne dispose pas du même niveau de protection et que leur consentement au transfert est recueilli.

Pour les données génétiques, le comité veille à ce qu'un consentement express écrit soit recueilli.

2) L'analyse scientifique

L'objectif d'un protocole de recherche est de démontrer une hypothèse scientifique en se basant sur les données de la science (prérequis). Une méthodologie rigoureuse est nécessaire en fonction du type de recherches et des objectifs, avec une justification des critères de jugement, du nombre de sujets nécessaires et des critères d'inclusion et de non inclusion.

Le protocole prend en compte les principes scientifiques généralement acceptés, fondés sur une connaissance approfondie de la littérature scientifique.

Pour les essais sur les médicaments, l'évaluation doit être conforme à la réglementation européenne pour le médicament en vue de la mise sur le marché, en fonction des différentes phases des essais [START_REF] Deplanque | collaborateurs Loi Jardé et règlement Européen sur les essais de médicaments : harmonisation et mise en oeuvre des nouvelles réglementations[END_REF].

3) Évaluation des risques

La Loi Jardé prévoit que les CPP analysent les protocoles en fonction des risques décroissants dans les 3 catégories de recherches sur la personne humaine [START_REF] Chemtob-Concé | Anne Cailleux L'impact des nouvelles dispositions de la loi relative aux recherches impliquant la personne humaine[END_REF].

Si les recherches présentant un risque (catégorie 1 dont les essais de médicaments [START_REF]Claire Demiot La protection des personnes participant aux essais cliniques Actual[END_REF]), elle nécessite l'avis du CPP et l'autorisation de l'ANSM. Le consentement est recueilli par écrit et l'investigateur est obligatoirement un médecin.

Pour les recherches entrainant des risques et contraintes minimes (catégorie 2), le consentement est donné oralement, et la recherche peut être conduite par une personne qualifiée, la soumission au CPP est une procédure allégée, le CPP se réunit en comité restreint.

Enfin, les recherches non interventionnelles qui ne présentent aucun risque puisqu'elles ne modifient pas la prise en charge habituelle du sujet (catégorie 3) le consentement n'est pas recueilli une non opposition suffit après une information adéquate. Ces recherches peuvent être dirigées également par une personne qualifiée et bénéficient de la procédure allégée.

Le promoteur soumet le projet au CPP dans l'une des 3 catégories, si ce dernier estime que le niveau de risque du protocole n'est pas correctement pris en compte, il peut demander la requalification de la recherche dans une autre catégorie. La loi Jardé a mis un terme aux hésitations des promoteurs qui ne savaient pas si leur protocole devait être ou non soumis au CPP, avec les 3 catégories désormais tous les protocoles impliquant des êtres humains doivent recueillir l'avis d'un CPP.

Les liens des CPP avec l'ANSM

Les CPP assurent la protection des personnes et leur avis favorable motivé est indispensable avant de débuter la recherche qui doit par ailleurs avoir reçu une autorisation de l'ANSM. L'agence est garante de la qualité et de la sécurité des recherches et s'assure que les garanties réglementaires soient respectées. Les comités reçoivent des informations au sujet des événements indésirables graves qui peuvent survenir pendant la recherche et peuvent communiquer avec l'ANSM à leur sujet. Leur rôle est alors, si le comité l'estime nécessaire de demander à l'investigateur d'informer les personnes et éventuellement de recueillir un nouveau consentement.

Quelques remarques pour conclure

Les IRB et les CER en Amérique du Nord, tout en respectant les principes généralement acceptés en éthique de la recherche, s'appuient sur le principe d'autonomie et accordent une importance majeure au consentement, le sujet ayant la possibilité de refuser de participer à la recherche.

En France le consentement est déterminant, mais ne constitue pas une protection suffisante. Sous couvert d'autonomie et de liberté de consentir du sujet, le consentement éclairé recueilli après une information portant sur tous les risques oblige le patient à s'engager et à accepter des contraintes dont parfois il n'évalue pas la portée. En France le rôle des CPP est de s'assurer que le sujet consent avec des modalités loyales [START_REF]Chvetzoff Quels enjeux et quelle éthique pour les comités d'éthique ou de protection des personnes au XXiième siècle ?[END_REF].

Les garanties pour la protection des personnes imposées par la loi Huriet-Serusclat depuis 1988, évaluées par les CPP s'ajoutent aux précautions requises par l'éthique de la recherche. On doit reconnaitre que ces dispositions protectrices qui font la spécificité et l'originalité de l'organisation des recherches ont été maintenues et élargies dans les missions des CPP, dont l'indépendance s'est vue accrue par un tirage au sort de la répartition nationale des dossiers, prévu par la Loi Jardé.

  historique de l'éthique de la recherche : de la médecine expérimentale à la recherche sur la personne humaine L'éthique de la recherche Répondant à la prise de conscience des conditions inhumaines des expériences pratiquées dans les camps de concentration, le code de Nuremberg édicte les principes de base pour les expérimentations sur l'homme : elles se justifient pour le bien de la société, le consentement du sujet doit être volontaire, sans contrainte ou coercition et le sujet est libre d'interrompre l'expérimentation à tout moment. L'expérience doit être conduite par une personne qualifiée et éviter toute souffrance. L'Association Médicale Mondiale qui regroupe de représentants des associations de spécialités médicales dans le monde, a adopté en juin 1964 la déclaration d'Helsinki. Il s'agit d'un énoncé de principes applicables à toutes les recherches impliquant les êtres humains. Initialement destinée aux médecins, elle est devenue la référence internationale majeure pour les chercheurs partout dans le monde qui déclarent que leurs protocoles en respectent les dispositions. Elle énonce que l'objectif premier de la recherche médicale est de comprendre les causes, le développement et les effets des maladies et d'améliorer les interventions préventives, diagnostiques et thérapeutiques. A côté des principes humanistes du respect de la vie, de la dignité, de l'intégrité, du droit à l'autodétermination, la recherche doit se conformer aux principes scientifiques généralement acceptés. Enfin, elle dispose que le protocole de recherche soit soumis à un comité indépendant d'éthique de la recherche.

  ont profondément modifié la composition et le fonctionnement des comités, en introduisant des représentants des associations de malades et en passant à un régime d'autorisation par l'Agence Nationale de Sécurité du Médicament. Actuellement les Comités de Protection des Personnes sont composés de 14 membres titulaires, et 14 suppléants, répartis en 2 collèges. Le premier collège comprend des scientifiques, médecins et des professionnels de santé : 4 personnes ayant une connaissance approfondie en matière de recherche dont 2 médecins et un biostatisticien ou épidémiologiste, un médecin généraliste, un 2 Loi 88-1138 Relative à la protection des personnes qui se prêtent aux recherches biomédicales 20 décembre 1988 3 Loi 2012-300 relative aux recherches impliquant la personne humaine pharmacien hospitalier, un infirmier. Le deuxième collège est composé de membres de la société civile : une personne qualifiée pour les questions d'éthiques, un psychologue, un travailleur social, deux personnes qualifiées en matière juridique et deux représentants des associations de malades. Un quorum minimum de 7 membres est nécessaire pour siéger dont 3 du premier collège, comportant obligatoirement le biostatisticien, et 3 du deuxième collège dont obligatoirement un représentant des associations de malades. Ces 2 membres sont indispensables pour établir un équilibre entre les deux collèges le biostatisticien d'une part pour évaluer la méthodologie scientifique du protocole et le représentant des associations pour garantir la protection des personnes.

Décret 72-1062 du

Novembre 1972

Art L.1123-7 CSP

Art L 1121-2 CSP