Jean-Louis Pépin
email: jpepin@chu-grenoble.fr

Ognian Georgiev

Rumen Tiholov

Valérie Attali

Johan Verbraecken

Bertien Buyse

Markku Partinen

Ingo Fietze

Georgi Belev

Dejan

Dejan Dokic

Renaud Tamisier

Patrick Lévy

Isabelle Lecomte

Jeanne-Marie Lecomte

Jean-Charles Schwartz

Yves Dauvilliers

Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP

Keywords: clinicaltrials.gov NCT01072968; EudraCT N°: 2009-017251-94 Obstructive Sleep Apnea, residual Excessive Daytime Sleepiness, Continuous Positive Airway Pressure, pitolisant

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

Introduction

Obstructive sleep apnea (OSA) affects up to one billion people worldwide and constitutes a major health concern as it results in multi-organ consequences. [START_REF] Benjafield | Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis[END_REF][START_REF] Levy | Obstructive sleep apnoea syndrome[END_REF][START_REF] Mcnicholas | Challenges in obstructive sleep apnoea[END_REF] Excessive daytime sleepiness (EDS) is the dominant complaint for the majority of OSA patients and is often associated with fatigue, impaired attention and vigilance, irritability and depressive symptoms. This impairment in daily functioning results in considerable economic and societal burdens with loss of productivity at work, deterioration in quality-of-life, and an increased risk of accidents. [START_REF] Bucks | Reviewing the relationship between OSA and cognition: Where do we go from here?[END_REF][START_REF] Rosenzweig | Sleep apnoea and the brain: a complex relationship[END_REF] Continuous positive airway pressure (CPAP) is the primary treatment for symptomatic moderate to severe OSA, efficacious in suppressing pharyngeal collapse during sleep and thus normalizing oxygen saturation and sleep quality and architecture. CPAP reduces daytime sleepiness, and improves alertness, cognitive function, and quality-of-life in optimally adherent patients. [START_REF] Levy | Obstructive sleep apnoea syndrome[END_REF][START_REF] Bratton | Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis[END_REF][START_REF] Schwartz | Effects of CPAP and mandibular advancement device treatment in obstructive sleep apnea patients: a systematic review and meta-analysis[END_REF] However, despite well managed CPAP therapy, residual EDS is reported in 6 to 15% of CPAP-treated OSA. [START_REF] Gasa | Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure[END_REF][START_REF] Pepin | Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study[END_REF] Besides CPAP adherence, residual EDS requires appropriate management including good sleep hygiene. Other sleep disorders and depression should be assessed before considering pharmacological therapy with stimulants. [START_REF] Chapman | Residual Daytime Sleepiness in Obstructive Sleep Apnea After Continuous Positive Airway Pressure Optimization: Causes and Management[END_REF] Several wake-promoting agents such as modafinil/armodafinil and more recently solriamfetol as adjunct to CPAP therapy have shown significant improvement in residual sleepiness in randomized controlled trials. [START_REF] Schweitzer | Solriamfetol for Excessive Sleepiness in Obstructive Sleep Apnea (TONES 3): A Randomized Controlled Trial[END_REF][START_REF] Strollo | Solriamfetol for the Treatment of Excessive Sleepiness in OSA: A Placebo-Controlled Randomized Withdrawal Study[END_REF] Solriamfetol has been approved for treatment of residual sleepiness in individuals with OSA in the US and in Europe. The European Medical Agency (EMA) has removed the indication for modafinil due to potential cardiovascular safety concerns.

Pitolisant is a novel selective histamine H3 receptor antagonist/inverse agonist with strong wake-promoting effects that is well tolerated in patients with narcolepsy. [START_REF] Szakacs | Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial[END_REF][START_REF] Dauvilliers | Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial[END_REF][START_REF] Dauvilliers | Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study[END_REF] We recently reported that pitolisant significantly reduced self-reported daytime sleepiness and fatigue, and improved patient-reported outcomes and physician disease severity assessment in the specific phenotype of sleepy individuals with OSA refusing or non-adherent to CPAP. [START_REF] Dauvilliers | Pitolisant for Daytime Sleepiness in Obstructive Sleep Apnea Patients Refusing CPAP: A Randomized Trial[END_REF] The evaluation of pitolisant needs to be completed in the different subgroup of OSA individuals, those exhibiting residual sleepiness despite good adherence to CPAP treatment.

The objectives of the present study were to demonstrate the efficacy and safety of pitolisant given at 5, 10, or 20 mg once per day versus placebo, during 12 weeks for the treatment of residual EDS in individuals on well-managed CPAP therapy for moderate to severe OSA.

Methods

Study design

This phase 3, double-blind, placebo-controlled, parallel-group multicenter trial evaluated the Key non-inclusion criteria were: history of a medical disorder other than OSA associated with EDS (such as severe chronic insomnia, narcolepsy, restless legs syndrome, sleep deprivation, night-time or shift work); previous surgical intervention for OSA including uvulopalatopharyngoplasty (UPPP); use of a mandibular advancement device; current or recent history of drug, alcohol, or other substance abuse or dependence; history or presence of an unstable or clinically significant medical condition especially those related to the cardiovascular system (recent myocardial infarction, angina, arterial hypertension or dysrhythmia, ECG -Bazett's corrected QT interval higher than 450 ms, history of left ventricular hypertrophy or mitral valve prolapse), a psychiatric disorder, or a condition that could affect safety or interfere with study assessments; pregnancy or breast feeding; and/or the use of any treatment that could affect the evaluation of EDS.

Randomization and masking procedures

Procedures were similar to the companion study. [START_REF] Dauvilliers | Pitolisant for Daytime Sleepiness in Obstructive Sleep Apnea Patients Refusing CPAP: A Randomized Trial[END_REF] Randomization was centralized and performed via a website (Arone Projection; https://www.bioprojet-studies.org/). Randomization was on a 3:1 (three pitolisant for one placebo) basis (details in supplemental material). Pitolisant and placebo were contained within sealed capsules, similar in appearance and taste, and containing a one-fourth (5mg), one-half (10 mg), or one full tablet of pitolisant (20 mg) or lactose only (placebo). The participants, their sleep/respiratory physicians, study investigators and all research staff were masked to the treatment allocation.

Intervention

Treatment was taken once a day on an empty stomach within 1 hour of waking-up. The individual titration began with 5 mg/day during 1 week, then 10 mg/day was proposed during 1 week and then 20 mg during 1 week if necessary, based on efficacy and tolerability.

The best adapted and tolerated dose was administered for the 9 week stable dose period (Figure 1).

Outcomes

The primary efficacy endpoint was change in ESS score from baseline to the end of treatment at week 12.

The key secondary endpoint was change from baseline to week 12 in the Oxford Sleep Resistance Test (OSleR), which objectively measures ability to maintain vigilance. This consisted of three 40min sessions of sleep-resistance challenges at approximately 9:00 am, 11:00 am and 1:00 pm. The mean sleep latency and the number of errors (3 to 6 consecutive errors indicating micro-sleep and ≥7 errors indicating sleep onset) were collected. [START_REF] Dauvilliers | Pitolisant for Daytime Sleepiness in Obstructive Sleep Apnea Patients Refusing CPAP: A Randomized Trial[END_REF][START_REF] Crook | Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials[END_REF]

Statistical analysis

The statistical analysis plan was the same as for the companion study. [START_REF] Dauvilliers | Pitolisant for Daytime Sleepiness in Obstructive Sleep Apnea Patients Refusing CPAP: A Randomized Trial[END_REF]

Sample size calculation

Exploratory study results indicated residual ESS variability with a standard deviation (SD) of 6 points. Before the study the investigators agreed on a Minimum Important Difference (MID) in ESS = -3 corresponding to an effect size (ES) of 0.5. Recent independent studies, [START_REF] Crook | Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials[END_REF][START_REF] Patel | The Epworth Sleepiness Scale: Minimum Clinically Important Difference in Obstructive Sleep Apnea[END_REF] have established the MID ESS to lie between -2 and -3. The correlation between final and baseline ESS was conservatively estimated as r = -0•4. Assuming an ANCOVA 95% confidence interval (CI) for the main confirmatory test, a difference of >3 points should be detected with a power of 90% by including at least 60 participants in the placebo group and 180 in the pitolisant group.

Description of the study populations

The Intention-to-Treat (ITT) population included all randomized participants. The Safety population (SAF) was all participants who received at least one dose of study medication irrespective of the outcome, and for whom at least one valid post-baseline evaluation (including any AE) was available. The Per Protocol (PP) population included ITT participants without any major protocol violations and who did not prematurely discontinue the study drug or placebo during the 12-week treatment phase of the study.

The PP population was determined by a blinded review of the data prior to database lock. Demographic data and other baseline characteristics were analyzed using the ITT population.

Efficacy was analyzed for both the ITT and PP populations, with the ITT population analysis considered the primary analysis. Safety, concomitant medications, exposure, dosing, and compliance were analyzed using the Safety population.

The statistical analysis was done by an independent external statistician. Another third party statistician independently reviewed the results. Descriptive statistics were used for the quantitative variables, and frequency distribution for the ordinal and nominal variables.

Exact 95%CI are given for selected variables.

The final ESS score was compared using a linear mixed effects model, considering treatment as a fixed factor, center as a random factor, and ESS and BMI at baseline as adjustment covariates. The ESS score could be log transformed if necessary, depending upon normality of the residuals. The analysis of safety data was descriptive except for comparisons of the frequencies of participants with treatment-emergent adverse events (TEAEs) by logistic regression. Missing data for the primary efficacy variable and for response were allocated using the Last Observation Carried Forward (LOCF) method. A sensitivity analysis was performed using the baseline ESS value carried forward (BOCF) adjusting for ESS and Body Mass Index (BMI) at baseline. This trial was conducted considering a single primary endpoint (ESS) associated with the ITT dataset, with one test comparing pitolisant with placebo via one main statistical analysis (ANCOVA). All statistical tests were two-sided, at a 5% level of significance.

Results

Participants

We screened 298 individuals for inclusion, of which 244 (82%) were retained for the doubleblind phase of the study and randomized to either pitolisant (n=183) or placebo (n=61) (Figure 2 and e-table 1). All 244 participants received at least one dose of study medication and had a validated post-baseline assessment. In this safety population 36 had at least one major protocol deviation (e-table 2), and 12 participants discontinued the study prematurely (4 of them had also a major deviation). The PP population was 200 participants, 148 in the pitolisant and 52 in the placebo groups.

The ITT population was primarily male (82.8%), with a mean age of 53.1 (SD: 10.6) years.

Mean AHI under CPAP was 4.2 (SD: 3.5)/h, and mean CPAP pressure 10.7cm (SD: 2.8) H2O.

No significant differences in demographic or clinical characteristics were found between the treatment groups (Table 1).

Primary efficacy endpoint

The ESS geometric mean was 14.9 + 2.7 at baseline and decreased to 9.0 + 4.8 at the end of the 12-week intervention in the pitolisant group. In the placebo group, the ESS geometric mean decreased from 14.6 + 2.8 to 12.1 + 6.1. The change in ESS from baseline to end of treatment was -5.5 (95%CI [-6.2; -4.9]) in the pitolisant group and -2.8 (95%CI [-4.3; -1.2]) in the placebo group (p<0.001). There was a significant difference between the two arms in favor of pitolisant: -2.6 (95%CI: [-3.9; -1.4]) (p<0.001) (Figure 3, Table 2). Pre-specified sensitivity analyses adjusting for BMI and ESS at baseline did not change the results.

Secondary efficacy outcomes

Pitolisant resulted in normalization of the ESS score (ESS≤10) in 56.3% of participants versus 42.6% in the placebo group (p=0.028). ESS response defined as either ESS≤10 or improvement ≥3 points was observed in 71.0% and 54.1% in the pitolisant and placebo groups respectively (Table 2).

Baseline OSleR mean sleep latencies (mean (range)) were 15.5 (0.3;40.0) and 19.0 (0.7;40.0) minutes for pitolisant and placebo groups, respectively. The ratio of increase in mean latency during OSleR Tests was 1.4 in the pitolisant and 1.2 in the placebo group (p=0.050 using a mixed model for repeated measures) (Table 3). Similar results were found in the PP analysis.

There was a trend towards an improvement in sleep diary variables in the pitolisant group compared to placebo regarding the number of sleep/sleepiness episodes, p=0.06. No between-group differences were found regarding EQ-5D. In the Leeds questionnaire, 2 items were significantly improved in the pitolisant arm: "getting to sleep" (participants had less propensity to fall asleep p=0.020) and "quality of sleep" (p=0.05). There were no changes in mean time to perform parts A or B of the Trail Making Tests. At the end of the double-blind phase the CGI had improved for 78% of the pitolisant group compared to 53.4% of the placebo group (p<0.001). Improvement in the PGO endpoint was perceived by 76.4% of the participants in the pitolisant group compared to 56.9% on placebo (p=0.005).

The mean Pichot Fatigue Scale score decreased in both pitolisant and placebo groups (13.2±7.2 to 9.4±6.9, 11.4±7.2 to 8.6±6.0 respectively) without significant between-group difference (Table 3). During the double-blind phase, the maximum dose was 20 mg/day for 79.8% of participants in the pitolisant and 88.5% in the placebo group.

Safety

Safety evaluation was based on the incidence of TEAEs: 47.0% in the pitolisant and 32.8% in the placebo group (p=0.03). The most frequently reported TEAE was headache (14.8% and 11.5% for pitolisant and placebo respectively). Insomnia was reported in a higher proportion of participants treated with pitolisant (9.3%) than with placebo (3.3%) (Table 4). The frequency of treatment-related TEAEs was similar (headache, insomnia, diarrhea) and did not differ between groups (26.8 % with pitolisant and 19.7% with placebo; p=0.256). The frequency of severe treatment-related TEAEs was similar in both treatment groups (pitolisant: 27%; placebo: 32.8%).

TEAEs leading to study drug withdrawal were reported for 4 participants (2.2%) in the pitolisant group, and for 2 (3.3%) in the placebo group. Treatment-emergent SAEs were reported for 2 participants during pitolisant treatment (1.1%, irritable bowel syndrome and musculoskeletal pain; both were considered unlikely to be treatment-related), and in none on placebo.

None of the participants experienced dysphoria, or vivid and unpleasant dreams during the placebo wash-out one week after treatment termination. BDI scores, blood chemistry and hematological or cardiovascular parameters did not change significantly in either group.

During treatment, there were no changes from baseline in systolic and diastolic blood pressure (BP) or heart rate for either group (Figure 4, Table 4). Mean values of ECG variables were comparable in the two treatment groups. However, in the pitolisant group, 4 participants (2.2%) had at least one post-dose QTcF > 450 msec and 6 patients (3.3%) had one QTcF elongation ≥ 60 msec, while there were 2 participants (3.3%) with QTcF > 450 msec and 3 (4.9%) with QTcF elongation ≥60msec in the placebo group.

Discussion

In this large randomized controlled trial, residual excessive daytime sleepiness in individuals with OSA and adherent to CPAP was significantly improved with pitolisant. Such an improvement was reported both subjectively by a -2.6 (95%CI: [-3.9; -1.4]) reduction in ESS and objectively by the OSleR maintenance of wakefulness test. These results were in agreement with an overall improvement in both patient-reported outcomes and physician assessed severity of EDS.

ESS is a patient-reported outcome that assesses propensity to fall asleep in different everyday situations, while the OSleR test is an objective measure of the subject's ability to maintain wakefulness. Both types of assessment were consistent in demonstrating the superiority of pitolisant over placebo. Variations in ESS and OSleR sleep latencies were not explained by sleep duration, being 7.2 + 0.9 and 6.9 + 1.3 hours in the pitolisant and placebo groups respectively throughout the study, excluding chronic sleep deprivation. Some OSleR assessments (type and number of errors) reflecting micro-sleep episodes occurring during the tests did not differ significantly between groups. This might be related to a ceiling effect as a large proportion of included participants already exhibited normal values at baseline (23.6 % had mean sleep latency ≥30 minutes in the pitolisant group and 33.3 % in the placebo group).

One strength of our study was to have been conducted in a well-defined phenotype of residual sleepiness persisting in individuals with moderate to severe OSA adherent to CPAP. CPAP adherence at study inclusion was defined as a nightly usage above 4 hours/night. It is now admitted that an increase in adherence to nearer seven hours/night might better control residual EDS. [START_REF] Gasa | Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure[END_REF] However, the current results nicely complement those reported with pitolisant in another OSA phenotype, patients refusing or not adhering to CPAP. [START_REF] Dauvilliers | Pitolisant for Daytime Sleepiness in Obstructive Sleep Apnea Patients Refusing CPAP: A Randomized Trial[END_REF] Previous studies in the field evaluating modafinil, armodafinil or solriamfetol have often assessed mixed OSA populations in the same study whether adherent or not to CPAP. [START_REF] Schweitzer | Solriamfetol for Excessive Sleepiness in Obstructive Sleep Apnea (TONES 3): A Randomized Controlled Trial[END_REF][START_REF] Strollo | Solriamfetol for the Treatment of Excessive Sleepiness in OSA: A Placebo-Controlled Randomized Withdrawal Study[END_REF] In this study the magnitude of improvement in ESS with pitolisant was close to that previously reported in studies of modafinil, armodafinil and solriamfetol in OSA patients. In the present study, the maximum daily dose of pitolisant tested was 20 mg which was used by the majority of participants (79.8% in the pitolisant and 88.5% in the placebo group). This is half the maximum dose tested in narcolepsy studies [START_REF] Szakacs | Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial[END_REF][START_REF] Dauvilliers | Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial[END_REF] and approved by FDA and by EMA.

It is unclear whether higher doses might yield a more impressive benefit on sleepiness. [START_REF] Trotti | Treat the Symptom, Not the Cause? Pitolisant for Sleepiness in Obstructive Sleep Apnea[END_REF] An ongoing study, HAROSA III, is testing this hypothesis [NCT02739568]. However, the true answer in terms of comparison of efficacy merits to be evaluated by head to head comparisons between the different classes of wake-promoting agents. Also, further studies addressing combinations of drugs with different mechanisms of action would be of interest.

Concerning the other secondary outcomes, the superiority of pitolisant was clearly perceived at the end the 12 weeks of double-blind treatment both by physicians through the CGI-C and by participants through the PGO of effect. This optimal improvement of ESS is also observed after 12 weeks in narcolepsy patients. [START_REF] Dauvilliers | Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study[END_REF] "Residual sleepiness" is not only sleepiness but is associated with a constellation of multidimensional symptoms and neuropsychological dysfunctions [START_REF] Gasa | Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure[END_REF][START_REF] Vernet | Residual sleepiness in obstructive sleep apnoea: phenotype and related symptoms[END_REF] that can be reversed by appropriate management and certainly justify the implementation of pharmacological therapies.

Our results confirm the overall good safety profile of pitolisant already reported in patients with narcolepsy, [START_REF] Szakacs | Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial[END_REF][START_REF] Dauvilliers | Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial[END_REF] and observed in patients refusing CPAP. [START_REF] Dauvilliers | Pitolisant for Daytime Sleepiness in Obstructive Sleep Apnea Patients Refusing CPAP: A Randomized Trial[END_REF] No major changes were found in physical examination parameters or vital signs, depressive symptoms, ECG and laboratory test results during the study. Moreover, no withdrawal symptoms occurred following the abrupt discontinuation of pitolisant. This is consistent with the absence of an abusepotential signal for pitolisant in preclinical models, [START_REF] Uguen | Preclinical evaluation of the abuse potential of pitolisant, a histamine H3 receptor inverse agonist/antagonist compared with modafinil[END_REF] other clinical trials [START_REF] Szakacs | Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial[END_REF][START_REF] Dauvilliers | Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial[END_REF][START_REF] Dauvilliers | Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study[END_REF][START_REF] Dauvilliers | Pitolisant for Daytime Sleepiness in Obstructive Sleep Apnea Patients Refusing CPAP: A Randomized Trial[END_REF] and in a dedicated study of recreational stimulant abusers. [START_REF] Setnik | Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist for the treatment of adults patients with narcolepsy with or without cataplexy[END_REF] A small significant difference in TEAEs was observed in the pitolisant group. There were no major safety concerns raised during the study. The most frequently reported TEAEs were headache, followed by insomnia, diarrhea and back pain.

The study was conducted in a population of OSA patients in which half had a history of cardiovascular or metabolic diseases. The absence of any signal for elevation of systolic and diastolic blood pressure and heart rate with up to 20mg of pitolisant seems reassuring for its use in such at-risk populations with multimorbidities. In contrast, modafinil/armodafinil was associated with a slight increase in systolic BP of 3.0 mmHg (95%CI 0.8-5.2 mmHg) and diastolic BP of 1.9 mmHg (95%CI 0.5-3.3 mmHg) in some trials, while there was no change reported in other trials according to a recent meta-analysis. [START_REF] Chapman | Modafinil/armodafinil in obstructive sleep apnoea:a systematic review and meta-analysis[END_REF] In a recent study using solriamfetol the supratherapeutic dose of 300 mg caused a 2.5 mmHg increase in systolic BP and 1.5 mmHg increase in diastolic BP; and heart rate increased by 2-3 bpm at doses above 75mg. Again, head-to-head comparisons of the different available wakepromoting agents, with particular focus on cardiovascular outcomes are needed.

Our study had many strengths and adds to the literature in a number of important ways, but it also has limitations. The first one is related to the 12-week duration. This double-blind study was followed by a 9-month extension phase in open label to assess both the maintenance of efficacy and safety. CPAP adherence was not systematically collected during the trial, but this is part of the routine follow-up of these patients and study investigators did not report unexpected reductions in CPAP adherence. This outcome should be included in future studies.

In conclusion, in this 12-week, phase 3 randomized placebo controlled clinical trial, pitolisant reduced residual excessive daytime sleepiness in individuals with OSA adherent to CPAP treatment in both subjective (Epworth Sleepiness Scale) and objective (OSleR Test) assessments. This was confirmed by both patient reported outcomes and the physicians' clinical global impressions of efficacy, without any significant safety signal, in particular none regarding cardiovascular parameters. The significance of efficacy and safety is limited to the 12 week period and longer term studies will be needed to assess long term efficacy and safety.

  efficacy and safety of pitolisant over 12 weeks in adults with moderate to severe OSA treated by CPAP for at least 3 months, with at least 4-hour of nightly CPAP usage, residual EDS (Epworth Sleepiness Scale (ESS) score ≥12), and without unstable cardiovascular disease as judged by the investigator. The study was conducted in 35 sleep centers in 9 European countries between August 12, 2011 and June 21, 2013. The study protocol was approved by the institutional review board or ethics committees of each study site; the study was conducted in accordance with the principles of the Declaration of Helsinki and registered on clinicaltrials.gov (identifier NCT01071876] and EudraCT (n°: 2009-017248-14). All participants provided written informed consent prior to inclusion. Participants Included participants were adults with OSA diagnosed according to the International Classification of Sleep Disorders-2 criteria and treated with CPAP for at least 3 months with persistence of EDS despite mean nightly CPAP usage ≥4h. Only individuals assessed by polysomnography under CPAP before inclusion or during the previous year with an apnea + hypopnea index (AHI) ≤10/hour of sleep and EDS, defined as an ESS score ≥ 12, were eligible for inclusion. Additional inclusion criteria were a Periodic Limb Movement Disorder arousal index (PLMAI) ≤ 10 per hour, a 13-item Beck Depression Inventory (BDI-13) score < 16 and item G (suicidal ideation) =0, a Mini Mental State Examination (MMSE) score ≥ 28, and a Body Mass Index (BMI) ≤ 40 kg/m² (owing to the risk of obesity hypoventilation syndrome and because morbid obesity might be a significant cause for sleepiness).

  Other secondary endpoints were: responders by other ESS criteria (ESS≤10 or improvement ≥3 points (∆ESS≥3), episodes of sleepiness and daytime sleep recorded in sleep diaries (see online supplement protocol amendments for details of sleep diary data collection), parts A&B of the Trail Making Test (TMT), the clinicians' Clinical Global Impressions of Severity and Change (CGI-S and CGI-C), the Patient's Global Opinion (PGO), the Leeds Sleep Evaluation Questionnaire (LSEQ), EuroQoL (EQ-5D) quality-of-life questionnaire, and the Pichot Fatigue scale. Safety was assessed through clinical adverse events (AEs), clinical laboratory parameters (hematology, biochemistry, and electrolytes), vital signs, physical examination, electrocardiogram (ECG), BDI-13 scale, amphetamine-like withdrawal symptoms, and the patient's overall evaluation of tolerance. Blood pressure measurements were conducted following recommendations of European Society of Cardiology with at least 2 measurements taken at each assessment, both after 15 min in a supine position.

Figure 1 .Figure 2 .

 12 Figure 1. Study Design TC: telephone call; ESS: Epworth Sleepiness score Figure 2. Patient Flowchart See online supplement for reasons for non-eligibility (e-table 1) and dose titration details.

Figure 3 .Figure 4 .

 34 Figure 3. Mean change in Epworth Sleepiness Score (ESS) over 12 week double-blind phase, ITT population (N=244) Figure 4. Heart rate (HR), Systolic (SBP) and Diastolic (DBP) Blood Pressure in pitolisant and placebo groups over 12 week double blind phase

Table 1 : Baseline Characteristics

 1

	Parameter	Pitolisant (N=183)	Placebo (N=61)	All Participants (N=244)
	Age (years)
	Mean (SD)	53.8 (10.5)	51.0 (10.6)	53.1 (10.6)
	Range	[23; 81]	[25; 72]	[23; 81]
	Sex n (%)
	Male	149 (81.4%)	53 (86.9%)	202 (82.8%)
	Female	34 (18.6%)	8 (13.1%)	42 (17.2%)
	Weight (kg) at inclusion: mean (SD)	98.3 (18.8)	97.9 (14.6)	-
	BMI, kg/m 2 : mean (SD)	32.7 (5.2)	32.2 (4.3)	-
	Time since diagnosis (months):	44.8 (44.1)	49.0 (57.1)	45.9 (47.6)
	mean (SD)
	AHI under CPAP, number/hour of	4.1 (3.5)	4.5 (3.1)	4.2 (3.5)
	sleep: mean (SD)
	CPAP pressure (cm H2O): mean (SD)	10.7 (2.7)	10.7 (3.0)	10.7 (2.8)
	History of Cardiovascular Disease: n (%)	111 (60.7)	27 (44.3)	138 (56.6)

AHI: apnea-hypopnea index; BMI: Body mass index; CPAP: continuous positive airway pressure

Table 2 : Efficacy results for the primary endpoint: Change in ESS score

 2

	Parameter	Pitolisant (N=183)	Placebo (N=61)	P value
	ESS score at inclusion Mean (SD)	14.9 (2.7)	14.6 (2.8)	-
	ESS score at end of treatment Mean (SD)	9.0 (4.8)	12.1 (6.1)	-
	Final ESS score DB-LOCF
	Mean (SD)	9.4 (4.6)	11.9 (5.7)	<0.001
	95% CI	[8.8 ; 10.1]	[10.4 ; 13.3]
	Change in ESS score (DB-LOCF -
	inclusion Mean (SD)	-5.5 (4.4)	-2.7 (5.9)	<0.001
	95%CI	[-6.2 ; -4.9]	[-4.3 ; -12.4]
	ESS ≤10
	N (%)	103 (56.3%)	26 (42.6%)	0.028
	95% CI	[48.8% -63.6%] [30.0% -55.9%]
	EESS≤10 or reduction in
	EESS ≥3 N (%)	130 (71 %)	33 (54.1%)	0.013
	95% CI	[63.9% -77.5%] [40.8% -66.9%]
	CI: Confidence interval; DB-LOCF: Database with Last Observation Carried Forward; ESS:
	Epworth Sleepiness Scale; data is presented as means (SD) and confidence intervals.

Table 3 : Efficacy results for secondary outcomes

 3

	Parameter

Patient Global Opinion (PGO): improvement at end of double-blind treatment

  : Trail Making Test; VAS: Visual Analogue Scale; min: minutes; OSL: OSleR Sleep Latency for OSleR tests. Data is presented as means (SD), means and range for OSleR sleep latencies and number, percentages (%) and with 95% CI for CGI and PGO scales.

	N (%)	133 (76.4%)	33 (56.9%)
	95% CI	69.4% -82.5%	43.2% -69.8%

TMT

Table 4 : Safety parameters

 4 BDI: Beck Depression Inventory; DB: double blind; TEAE: treatment-emergent adverse event;V2 = visit 2; V6 = visit 6; TEAE are presented as numbers and percentages (%); Blood pressure and heart rate data are presented as means (SD) and ranges; and the 95% CI for BDI scores.

	Parameter	Pitolisant (N=183)	Placebo (N=61)	P value
	Any TEAE	86 (47.0%)	20 (32.8%)	0.030
	Any treatment-related TEAE	49 (26.8%)	12 (19.7%)	0.256
	Any Serious TEAE	2 (1.1%)	0 (0.0%)	0.998
	Any TEAEs leading to study drug withdrawal	4 (2.2%)	2 (3.3%)	0.625
	Systolic Blood Pressure, mean (SD)
	At baseline (V2)	129.3 (12.9)	130.2 (11.8)
	Range	100 to 180	110 to 163
	At the end of DB treatment (V6)	128.7 (12.0)	129.1 (12.0)
	Range	98 to 188	110 to 166
	Mean change (SD) Range	-0.6 (10.1) -50 to 25	-1.8 (10.1) -20 to 33	0.704
	Diastolic Blood Pressure, mean (SD)
	At baseline (V2)	80.3 (8.9)	80.6 (6.9)
	Range	56 to 109	59 to 96
	At the end of DB treatment (V6)	79.9 (8.3)	81.4 (9.0)
	Range	52 to 105	67 to 114
	Mean change (SD) Range	-0.4 (7.3) -25 to 20	0.6 (9.0) -18 to 30	0.228
	Heart rate (SD), mean (SD)
	At baseline (V2)	70.9 (11.9)	71.3 (9.6)
	Range	40 to 107	46 to 91
	At the end of DB treatment (V6)	70.0 (11.5)	70.3 (10.4)
	Range	43 to 115	39 to 96
	Mean change (SD) Range	-0.9 (9.6) -25 to 29	-1.4 (9.1) 0	0.845
	Total 13 item BDI score
	Mean score at baseline (V2) (SD)	4.5 (3.5)	4.0 (3.4)
	95% CI	[4.0 ; 5.0]	[3.1 ; 4.8]
	Mean score at the end of DB treatment (V6) (SD)	3.3 (3.2)	2.8 (3.1)
	95% CI	[2.9 ; 3.8]	[2.0 ; 3.7]
	Mean change between baseline and end of DB treatment	-1.2 (2.4)	-1.2 (2.0)	0.516
	95% CI	[-1.5 ; -0.8]	[-1.8 ; -0.7]

Acknowledgements

We are grateful to the members of HAROSA I study group: Valerie Attali, Sleep Disorder Unit, la Pitié-Salpêtrière Hospital, Paris, France; Patrice Bourgin, Hôpital Civil, Strasbourg, We thank Alison Foote (Grenoble Alpes University Hospital, France) for editing the manuscript.

Guarantor statement: Jean-Louis Pépin takes responsibility for the content of the manuscript, including the data and analysis.

UCB Pharma, Jazz, Theranexus, Flamel, Idorsia, Takeda, other from Idorsia, during the conduct of the study. Grants from Air Liquide Foundation , grants and personal fees from Agiradom, grants and personal fees from AstraZeneca, grants from Fisher and Paykel, grants from Mutualia, grants and personal fees from Philips, grants and personal fees from Resmed, grants from Vitalaire, grants from Boehringer Ingelheim, grants from Jazz Pharmaceuticals, grants from Night Balance, grants from Sefam, all outside the submitted work. Dr. Verbraecken reports grants from Antwerp University Hospital, during the conduct of the study; and grants from Bioprojet, grants from Jazz Pharmaceuticals, grants from UCB Pharma, outside the submitted work. Dr. Buyse reports no grants or fees during the conduct of the study, but received reimbursement fees for travel and conference expenses from VitalAire, outside the submitted work. Dr. Tamisier

Author's contributions:

IL and J-ML participated in the conception, design, and organization of the study. YD and J-LP participated in the conception and design of the study, and wrote the paper. J-CS participated in the conception and design, and minor revision to the paper. OG, RTi, VA, JV, BB, MP, IF, GB, DD, RTa and PL were investigators or coordinators of the study and assisted in revising the manuscript.

All authors shared the decision to submit the manuscript for publication.

Summary of conflict of interest statements:

Dr. IL helped organize the study.

Data sharing statement

Data collected for the study, including deidentified individual participant data and a data dictionary defining each field in the set, will be made available to others following the publication of this article, as well as additional related documents (study protocol, statistical analysis plan, informed consent form) for academic purposes (e.g. meta-analyzes) on request to the sponsor Bioprojet (jm.lecomte@bioprojet.com) and with a signed data access agreement.


Charlotte Henson
email: .charlotte.a.henson@gmail.com

Didier Truchot
email: didier.truchot@univ-fcomte.fr

WHAT PROMOTES POST TRAUMATIC GROWTH? A SYSTEMATIC REVIEW

Keywords: What Promotes Post Traumatic Growth? A Systematic Review PTG, post traumatic growth, contribution factors, trauma, systematic review

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

Background

The assumption that suffering can make individuals stronger [START_REF] Tedeschi | Trauma and transformation: Growing in the aftermath of suffering[END_REF] is not new in religious and philosophical literature. The idea that positive changes may result from adversity and trauma has been present across cultures for centuries. Indeed, from the rebirth of the phoenix in Egyptian mythology to the forgiveness of sin for all people who believed in the Christ's resurrection, ancient literature already long recognized the opportunities for growth that come from hardship. Philosophers also introduced this idea, in particular Friedrich Nietzsche with his famous quote "was mich nicht umbringt macht mich stärker" ("that which does not kill me makes me stronger", 1888), or "increscunt animi, virescit volnere virtus" ("spirits grow and courage increases through wounds", 1888). However, it is only recently that this notion was applied in the field of psychology. The available data suggests that at least a minority of individuals who have been confronted with trauma (e.g., sexual assault, military combat) report meaningful levels of personal growth (e.g., [START_REF] Calhoun | Facilitating posttraumatic growth: A clinician's guide[END_REF], 2006, 2013;[START_REF] Tedeschi | Trauma and transformation: Growing in the aftermath of suffering[END_REF][START_REF] Tedeschi | Posttraumatic growth: Conceptual foundations and empirical evidence[END_REF], i.e. the positive changes that may arise from the struggle to cope with a critical or traumatizing situation. Therefore, it is important to note that growth is not a result of the event itself, but rather a result of the struggle to deal with it. The types of changes that may occur as a result of the struggle to cope with major life crises are listed in the Post-Traumatic Growth Inventory (PTGI; [START_REF] Tedeschi | The Posttraumatic Growth Inventory: Measuring the positive legacy of trauma[END_REF], and include "improved relationships, new possibilities for one's life, a greater appreciation for life, a greater sense of personal strength, and spiritual development". Despite these positive changes, the link between post-traumatic growth (PTG) and "the sense of psychological comfort" remains uncertain. According to [START_REF] Tedeschi | Clinical applications of posttraumatic growth[END_REF], it would appear that PTG and psychological comfort may be distinct constructs.

Indeed, the literature mostly suggests that "growth will not necessarily decrease pain or increase happiness, but on the contrary, significant growth may only occur when it is preceded by, or when it occurs together with significant amounts of subjective distress" (Tedeschi, Park & Calhoun, 1998, p.217). The authors base this affirmation on several studies, including [START_REF] Edmonds | Perceived changes in life meaning following bereavement[END_REF] showing that positive psychological changes will occur after bereavement. Thus, growth experiences do not put an end to distress in trauma survivors [START_REF] Tedeschi | Posttraumatic growth: Positive change in the aftermath of crisis[END_REF][START_REF] Tedeschi | Trauma and transformation: Growing in the aftermath of suffering[END_REF]. [START_REF] Tedeschi | Clinical applications of posttraumatic growth[END_REF] add that "the maintenance of the growth experienced may require unpleasant periodic cognitive reminders of what has been lost, so that in an apparently paradoxical way, what has been gained remains in focus" (Tedeschi & Calhoun, 2014, p. 505). Thus, while PTG helps individuals live a fuller and more meaningful life, it does not allow a return to normality. The aim of this systematic review is to better understand in what circumstances posttraumatic growth may occur, and whether or not it has a protective effect on mental health outcomes.

Method

Search strategy:

Studies published between 1998 and 2019 were identified through four major database searches: Psychology and Behavioral Sciences Collection, PsycARTICLES, PsycINFO, and ScienceDirect. We used the following keywords: PTG, post-traumatic growth, posttraumatic growth, and vicarious PTG.

Inclusion criteria:

Studies were included if the title contained the words "posttraumatic growth" or "posttraumatic growth". 4

Exclusion criteria:

Studies were excluded if they didn't measure PTG or positive changes as a result of exposure to potentially traumatic events, and if they did not use the PTGI (Post-Traumatic Growth Inventory) to measure growth.

A total of 281 articles met inclusion criteria. Thirty-eight studies were longitudinal while 243 were cross-sectional. Samples were comprised of firefighters, HIV-positive individuals, cancer survivors, natural disaster survivors, sexual assault survivors, veterans, refugees, accident survivors, students, bereaved adults, medical staff, homeless women, police officers, and parents of children with severe illness. Studies were carried out in various countries: United States, Australia, Romania, Japan, Poland, France, Germany and Portugal.

[INSERT FIGURE 1 HERE]

Results

3.1

The role of "cognitive engagement" and "cognitive processing" in PTG Tedeschi and Calhoun (2014, p. 506) compare traumatic events (or life challenges) to "earthquakes" that can severely "shake, challenge, or sometimes shatter" the way individuals perceive the world and their place in it. Therefore, because they challenge the individual's assumptive world (Parkes, 1970), these "seismic events" have a great life-changing potential.

However, [START_REF] Tedeschi | Clinical applications of posttraumatic growth[END_REF] insist on the fact that, in order for growth to be possible, traumatic events must have a big enough impact to "force" individuals to reassess their representation of themselves and others, the world they live in, and what the future may bring. It had been demonstrated empirically that core beliefs must be challenged in order for growth to occur [START_REF] Ramos | The effectiveness of a group intervention to facilitate posttraumatic growth among women with breast cancer[END_REF][START_REF] Wilson | A structural equation model of posttraumatic growth after prostate cancer[END_REF][START_REF] Krosch | Grief, traumatic stress, and posttraumatic growth in women who have experienced pregnancy loss[END_REF]. Once they have been challenged or shattered, these representations (or "assumptive worlds") must be reconstructed. [START_REF] Tedeschi | Posttraumatic growth: Conceptual foundations and empirical evidence[END_REF] extend their seismic metaphor by comparing this reconstruction to the physical rebuilding that occurs after an earthquake.

According to them, the "reconstruction" that occurs after a trauma leads individuals to rethink repeatedly about the circumstances of the traumatic event they have experienced, in the hope of giving it some meaning: They refer to this process as "cognitive engagement". This first step towards growth may lead individuals to realize that some of their life goals are no longer feasible, and that some of their representations and beliefs do not reflect the world they live in anymore. These deep reconsiderations are what will enable individuals to establish new life goals. This process can sometimes take months or years and, in some cases, individuals who have been confronted with trauma may never experience positive psychological changes, as PTG also depends on personal and individual characteristics.

Furthermore, [START_REF] Tedeschi | Clinical applications of posttraumatic growth[END_REF] explain that individuals who face major life challenges generally tend to "cognitively engage" with two main purposes: 1) Finding an explanation to the immediate circumstances of the event ("why did this happen?"), and 2) understanding the fundamental issues raised by the event ("what impact does the event have in my life?"). [START_REF] Tedeschi | Clinical applications of posttraumatic growth[END_REF] refer to this process as "cognitive processing".

Empirical studies suggest that cognitive processing is associated with higher levels of PTG.

For example, [START_REF] Calhoun | A correlational test of the relationship between posttraumatic growth, religion, and cognitive processing[END_REF] investigated rumination and growth in a group of 54 young adults who had experienced a traumatic event. Their results indicated a positive relationship between event-related rumination and the level of reported PTG: The more rumination participants reported experiencing soon after the event, the greater the degree of posttraumatic growth. [START_REF] Palmer | Experience of post-traumatic growth in UK veterans with PTSD: A qualitative study[END_REF] add in one of their studies that veterans tend to report growth after reaching a certain "turning point" following the traumatic event. This turning point typically occurs after several years of living with PTSD symptoms and is generally prompted by the veterans themselves after reaching extreme levels of despair due to their symptoms. In other words, the authors suggest that, in 6 some cases, growth may be triggered by a posterior crisis situation caused by dealing with PTSD symptoms. This "crisis" may be what leads individuals to "cognitively engage" when rumination about the event hasn't occurred yet. Furthermore, they note that the individuals' acknowledgment of their PTSD symptoms is an important part of the growth process, as it enables them to separate these symptoms from their own identity and restore a sense of control. Thus, when dealing with individuals who are diagnosed with PTSD, focusing on helping them recognize and understand their symptoms may help promote PTG.

Going back to [START_REF] Tedeschi | Clinical applications of posttraumatic growth[END_REF] model, the authors also make a distinction between cognitive engagement characterized by "deliberate rumination" and cognitive engagement characterized by "intrusive rumination". While intrusive rumination is often associated with PTSD and depression, [START_REF] Taku | Intrusive versus deliberate rumination in posttraumatic growth across US and Japanese samples[END_REF] showed that both types of rumination were in fact associated with higher levels of PTG. More specifically, [START_REF] Taku | Intrusive versus deliberate rumination in posttraumatic growth across US and Japanese samples[END_REF] examined the effects of four types of rumination across US (n=224) and Japanese (n=431) samples: Intrusive and deliberate rumination soon after the event, and intrusive and deliberate rumination recently (still present well after the traumatic event).

The results indicate that both rumination types (intrusive and deliberate) were positively associated with posttraumatic growth; however, intrusive rumination recently did not significantly predict PTG, which is consistent with Cann et al.'s (2010) study.

Furthermore, the authors assume that intrusive rumination soon after the event was positively correlated to PTG because it may subsequently help trigger deliberate cognitive processing: Intrusive rumination soon after the event may therefore be considered as a "catalyst". Indeed, several studies confirm the positive link between intrusive rumination and PTG [START_REF] Ramos | The effectiveness of a group intervention to facilitate posttraumatic growth among women with breast cancer[END_REF][START_REF] Jeon | Post-traumatic growth in survivors of allogeneic hematopoietic stem cell transplantation[END_REF][START_REF] Hallam | Post-traumatic growth in stroke carers: A comparison of theories[END_REF][START_REF] Wilson | A structural equation model of posttraumatic growth after prostate cancer[END_REF].

In addition, for both samples, recent deliberate rumination predicted the strongest levels of PTG, possibly because, according to [START_REF] Taku | Intrusive versus deliberate rumination in posttraumatic growth across US and Japanese samples[END_REF], the presence of deliberate rumination long after the event occurred was proof of an ongoing process of sense-making and reconstructing of one's representations of the world over a large period of time (continuous cognitive processing = higher levels of growth). Several studies confirm the positive association between deliberate rumination and growth [START_REF] Hirooka | Quality of death, rumination, and posttraumatic growth among bereaved family members of cancer patients in home palliative care[END_REF][START_REF] Stockton | Cognitive processing, rumination, and posttraumatic growth[END_REF][START_REF] Hill | Women with ovarian cancer: Examining the role of social support and rumination in posttraumatic growth, psychological distress, and psychological well-being[END_REF][START_REF] Palacio-González | Cognitive processing in the aftermath of relationship dissolution: Associations with concurrent and prospective distress and posttraumatic growth[END_REF].

Experience sharing and social support

According to [START_REF] Tedeschi | Clinical applications of posttraumatic growth[END_REF], cognitive engagement and cognitive processing of traumatic events could be fostered by the sharing (or the "disclosure") of one's internal experience with others, as long as the individual's social environment is able to provide the necessary support. Indeed, the disclosure of internal cognitive processes with a supportive social environment reduces the risks of depression and/or promotes higher levels of growth [START_REF] Nolen-Hoeksema | Coping with loss[END_REF][START_REF] Saltzman | Post-combat adaptation: improving social support and reaching constructive growth[END_REF]. This is consistent with Ogińska-Bulik and Kobylarczyk (2015) and [START_REF] Dirik | Positive Sides of the Disease: Posttraumatic Growth in Adults with Type 2 Diabetes[END_REF] results

showing that venting negative emotions is positively associated with PTG.

[INSERT FIGURE 2 HERE]

Therefore, disclosure could be considered as a mediator of the relationship between cognitive engagement and PTG. This appears to be particularly true when sharing with people who have gone through similar traumatic experiences, as it has the positive effect of normalizing the individual's situation and feelings [START_REF] Palmer | Experience of post-traumatic growth in UK veterans with PTSD: A qualitative study[END_REF][START_REF] Richardson | The surviving sisters club: Examining social support and posttraumatic growth among FDNY 9/11 widows[END_REF].

Additionally, [START_REF] Palmer | Experience of post-traumatic growth in UK veterans with PTSD: A qualitative study[END_REF] showed it was not simply the presence of social support that contributed to PTG, but that the "support network" needed to have an in-depth knowledge of the individual's difficulties and trauma experiences (e.g. the spouse) in order to maximize growth. [START_REF] Canevello | Posttraumatic Growth: Spouses' Relationship Quality and Psychological Distress[END_REF] add that having a partner who experiences PTG will increase people's perception of partner's PTG, which predicts actor's increased relationship quality [START_REF] Lee | Posttraumatic growth in breast cancer survivors and their husbands based on the actor-partner interdependence model[END_REF] and, in turn, predicts people's decreased psychological distress. Thus, partners' PTG can benefit people' evaluations of their relationship and, ultimately, people' psychological well-being. This is supported by Weiss (2004), who shows that couples facing cancer together share not only the pain but also the potential for gain from the trauma.

Additionally, [START_REF] Albuquerque | Posttraumatic growth in bereaved parents: A multidimensional model of associated factors[END_REF] and [START_REF] Büchi | Shared or discordant grief in couples 2-6 years after the death of their premature baby: Effects on suffering and posttraumatic growth[END_REF] show that higher levels of stress communication by the partner and higher levels of emotional exchange between partners also promote actor's PTG. This is consistent with Canevello et al.'s (2016) longitudinal study, suggesting that the perception of the partner's responsiveness in married couples was greatly associated with PTG. Additionally, secure partner attachment seems to play an important role in the prediction of PTG [START_REF] Levi-Belz | Attachment Styles and Posttraumatic Growth Among Suicide-Loss Survivors: The Mediating Role of Interpersonal Factors[END_REF][START_REF] Salo | Adult attachment, posttraumatic growth and negative emotions among former political prisoners[END_REF]. Furthermore, the literature suggests that parents' PTG may also affect their children's experience with growth. For example, in families who had been directly exposed to the 2004 tsunami in Thailand, parents' self-reported PTG was a significant predictor of their children's PTG [START_REF] Hafstad | Parental adjustment, family functioning, and posttraumatic growth among Norwegian children and adolescents following a natural disaster[END_REF]. Thus, parents' functioning can affect children's positive adaptation after experiencing a disaster. This further suggests, along with the positive effect of partners' PTG, that interconnections and relatedness play a major role in the development of growth in individuals who experience trauma.

Coping strategies

As coping strategies foster a more positive perception of potentially threatening situations, influence behaviors, strengthen one's ability to adapt, and help individuals give meaning to the events they experience, they play a major role in the facilitation of growth. For instance, [START_REF] Prati | Optimisim, Social Support, and Coping Strategies as Factors Contributing to Posttraumatic Growth: A Meta-Analysis[END_REF] showed in a meta-analysis of 103 studies the influence of several coping strategies on PTG. Indeed, religious coping was strongly correlated to growth. As stated by [START_REF] Pargament | The many methods of religious coping: Development and initial validation of the RCOPE[END_REF], religious coping could have various positive consequences for individuals in their daily lives (e.g., giving meaning to negative events, providing a sense of control and comfort during difficult times, fostering social relations through the religious community, and helping individuals make major life changes).

Furthermore, spirituality predicted moderate positive changes [START_REF] Prati | Optimisim, Social Support, and Coping Strategies as Factors Contributing to Posttraumatic Growth: A Meta-Analysis[END_REF][START_REF] Tsai | Trajectories of posttraumatic growth among US military veterans: a 4-year nationally representative, prospective cohort study[END_REF][START_REF] Rzeszutek | Social support, stress coping strategies, resilience and posttraumatic growth in a Polish sample of HIV-infected individuals: results of a 1year longitudinal study[END_REF]Danhauer et al., 2013). Spirituality differs from religious coping in that it is defined as "an individual's sense of peace, purpose, and connection to others, and beliefs about the meaning of life"; whereas religion is defined as a set of beliefs and practices associated with a particular religious tradition or denomination [START_REF] Vallurupalli | The Role of Spirituality and Religious Coping in the Quality of Life of Patients with Advanced Cancer Receiving Palliative Radiation Therapy[END_REF]. According to [START_REF] Prati | Optimisim, Social Support, and Coping Strategies as Factors Contributing to Posttraumatic Growth: A Meta-Analysis[END_REF], spirituality may foster PTG because it increases feelings of belonging within the religious community, ensures the presence of social support through the community, and promotes beliefs that encourage individuals to search for meaning. Thus, spirituality may only be indirectly related to growth. Indeed, meaning-making has been positively associated with PTG in several studies [START_REF] Cadell | Posttraumatic growth in parents caring for a child with a life-limiting illness: A structural equation model[END_REF]Dursun et al., 2016). Additionally, the positive effect of the sense of belonging on PTG is supported by Armstrong, Shakespeare-Finch, and Shochet (2014), who found that belongingness was a mediator of the relationship between coping strategies and posttraumatic growth. Indeed, the sense of belonging may encourage individuals to seek social support which, consequently, will lead to higher levels of PTG. [START_REF] Prati | Optimisim, Social Support, and Coping Strategies as Factors Contributing to Posttraumatic Growth: A Meta-Analysis[END_REF] hypothesize that seeking social support could have a positive influence on the quantity and quality of social support and, therefore, also act as a mediator of PTG.

10 Positive reappraisal coping was also associated with PTG. This coping strategy implies the individual's attempt to construe negative events in a more positive way which, consequently, may generate positive changes. This is consistent with several studies suggesting that positive reframing/reinterpretation, positive affect/attitude, and positive sensemaking are positively correlated to PTG [START_REF] Hamama | Posttraumatic Growth and Subjective Well-Being among Caregivers of Chronic Patients: A Preliminary Study[END_REF][START_REF] Trzebiński | Basic trust and posttraumatic growth in oncology patients[END_REF]. Other coping strategies that promote growth include the appraisal of the event as a "challenge" ("challenge appraisal"; see [START_REF] Yeung | The roles of needs satisfaction, cognitive appraisals, and coping strategies in promoting posttraumatic growth: A stress and coping perspective[END_REF][START_REF] Goldberg | Predicting trajectories of posttraumatic growth following acquired physical disability[END_REF][START_REF] Wilson | A structural equation model of posttraumatic growth after prostate cancer[END_REF], which could be considered as a form of positive reinterpretation of the event, and "gratitude", also known as the tendency to show appreciation for something done or received which, consequently, may result in increased use of positive reappraisal [START_REF] Tsai | Trajectories of posttraumatic growth among US military veterans: a 4-year nationally representative, prospective cohort study[END_REF][START_REF] Tsai | Longitudinal course of posttraumatic growth among U.S. military veterans: Results from the National Health and Resilience in Veterans study[END_REF]. Additionally, [START_REF] Prati | Optimisim, Social Support, and Coping Strategies as Factors Contributing to Posttraumatic Growth: A Meta-Analysis[END_REF] show that acceptance coping, defined as "accepting that a difficult situation is real and must be addressed" [START_REF] Carver | Assessing coping strategies: a theoretically based approach[END_REF], had a small but significant effect on PTG. According to the authors, this supports the hypothesis that people's ability to accept whatever situation may come their way plays an important role in the growth process [START_REF] Zoellner | Posttraumatic growth in clinical psychology -A critical review and introduction of a two-component model[END_REF][START_REF] Rzeszutek | Social support, stress coping strategies, resilience and posttraumatic growth in a Polish sample of HIV-infected individuals: results of a 1year longitudinal study[END_REF].

In addition, three other coping strategies positively predict PTG: Self-care coping [START_REF] Armstrong | Predicting post-traumatic growth and post-traumatic stress in firefighters[END_REF], Problem-focused coping, and avoidance coping [START_REF] Akbar | Coping Mediates the Relationship Between Gender and Posttraumatic Growth[END_REF], the last two being quite contradictory. Indeed, several studies show that problem-focused coping is positively associated with growth [START_REF] Dirik | Positive Sides of the Disease: Posttraumatic Growth in Adults with Type 2 Diabetes[END_REF][START_REF] Rodríguez-Rey | Relation between parental psychopathology and posttraumatic growth after a child's admission to intensive care: Two faces of the same coin?[END_REF], which supports [START_REF] Lazarus | Stress, appraisal, and coping[END_REF] findings suggesting that individuals who use problem-based coping (vs. avoidance coping) feel they have more control over the situation and a greater ability to manage the problem. However, avoidance coping was also found to be positively related to growth [START_REF] Hallam | Post-traumatic growth in stroke carers: A comparison of theories[END_REF][START_REF] Akbar | Coping Mediates the Relationship Between Gender and Posttraumatic Growth[END_REF][START_REF] Carboon | Posttraumatic Growth Following a Cancer Diagnosis: Do World Assumptions Contribute?[END_REF], which is inconsistent with the literature on coping and health. Thus, how can avoidance and solution-focused coping both be correlated to PTG? [START_REF] Kunz | Coping and posttraumatic growth: A longitudinal comparison of two alternative views[END_REF] show in a longitudinal study that higher levels of growth are predicted by the use of both approach-and avoidance-oriented coping, as well as by coping flexibility, that is, the use both types of coping equally. The authors hypothesize that a flexible use of approach-and avoidance-oriented coping strategies may enable individuals to process trauma at times, but also avoid thoughts and activities when such a confrontation is too overwhelming, which together could promote PTG. Avoidance coping would therefore allow distress reduction preceding engagement in cognitive processing. Thus, this suggests that a flexible use of different coping strategies according to situational demands may be most predictive of posttraumatic growth. This is consistent with [START_REF] Su | Emerging posttraumatic growth: A prospective study with preand posttrauma psychological predictors[END_REF] longitudinal study, suggesting that distractive coping style, described as "a mode of purposefully turning one's attention away from one's distress to pleasant or neutral activities" (p. 104), is an important facilitator of growth.

Personality traits

The role of the personality traits of the Big Five [START_REF] Goldberg | The development of markers for the Big-Five factor structure[END_REF] on PTG has been examined in several studies. More specifically, Agreeableness, Extraversion, Openness [START_REF] Mattson | Personality Factors and Their Impact on PTSD and Post-traumatic Growth is Mediated by Coping Style Among OIF/OEF Veterans[END_REF][START_REF] Taku | Posttraumatic growth profiles and their relationships with HEXACO personality traits[END_REF] and Conscientiousness [START_REF] Owens | Predictors of Posttraumatic Growth and Posttraumatic Stress Symptom Severity in Undergraduates Reporting Potentially Traumatic Events[END_REF][START_REF] Karanci | Personality, posttraumatic stress and trauma type: Factors contributing to posttraumatic growth and its domains in a Turkish community sample[END_REF] were positively correlated to growth, which doesn't come as a surprise since these Big Five personality traits are generally associated with positive health outcomes [START_REF] Cheng | Personality traits and health behaviors as predictors of subjective wellbeing among a multiethnic sample of university-attending emerging young adults[END_REF]. We note that Mattson et al.'s (2018) findings suggest that Openness was the most predictive of PTG. The authors do not offer any explanation for this; however, given the personality traits associated with Openness, e.g. imagination and adventurousness, it is possible to hypothesize that individuals high in Openness may be more prone to adapt to unexpected life events [START_REF] Costa | NEO personality Inventory professional manual[END_REF].

Personality traits also have an indirect effect on growth through the use of either adaptive or maladaptive coping strategies [START_REF] Mattson | Personality Factors and Their Impact on PTSD and Post-traumatic Growth is Mediated by Coping Style Among OIF/OEF Veterans[END_REF]. On the one hand, Extraversion, Agreeableness, and Openness significantly predicted adaptive coping in a sample of 271 OIF and OEF veterans, and in turn promoted growth. We note that Optimism, which isn't one of the Big Five personality traits, also predicted PTG through the use of adaptive coping in Mattson et al.'s study (2018). On the other hand, Neuroticism significantly predicted maladaptive coping, which impeded the development of growth [START_REF] Mattson | Personality Factors and Their Impact on PTSD and Post-traumatic Growth is Mediated by Coping Style Among OIF/OEF Veterans[END_REF]. Nevertheless, while we expect neurotic individuals to be less likely to develop PTG because of their lower ability to manage stress, one study found a positive association between neuroticism and PTG in motor vehicle accident perpetrators [START_REF] Merecz | Psychological consequences of trauma in MVA perpetrators-Relationship between post-traumatic growth, PTSD symptoms and individual characteristics[END_REF]. However, [START_REF] Merecz | Psychological consequences of trauma in MVA perpetrators-Relationship between post-traumatic growth, PTSD symptoms and individual characteristics[END_REF] specify that the mean value of neuroticism in their sample was rather low and insufficient to assume that those individuals were emotionally unstable. Thus, the authors come to the conclusion that low levels of neuroticism may sensitize individuals to life events (which is essential for posttraumatic growth), but has no detrimental effect on the individual's ability to cope with them.

Additionally, altruistic behavior (e.g., the tendency for an individual to act out of concern for the well-being of others, regardless of his/her own self-interest) positively predicted PTG [START_REF] Tsai | Longitudinal course of posttraumatic growth among U.S. military veterans: Results from the National Health and Resilience in Veterans study[END_REF]. Indeed, while altruism is not a personality trait, it is a trait that could stem from high levels of Agreeableness.

Lastly, "narcissism" [START_REF] Levi | The moderating role of narcissism on the relationship between posttraumatic growth and PTSD symptoms[END_REF] was also reported as a predictor of PTG. Indeed, according to [START_REF] Levi | The moderating role of narcissism on the relationship between posttraumatic growth and PTSD symptoms[END_REF], narcissistic individuals are more inclined to use processes of self-deception associated with the adoption of positive attributions and the exclusion of negative attributions. Therefore, despite being a "negative" trait, narcissism may be relatively useful when confronted with stressful events as it may provide an illusory sense of control ("I have all the necessary qualities to face and overcome this situation").

Individuals who feel they have control over themselves or the situation they are facing usually feel they are more capable of managing the problem [START_REF] Lazarus | Stress, appraisal, and coping[END_REF]. Indeed, selfcontrol (or personal mastery) reduces the onset of PTSD symptoms [START_REF] Smith | Mindfulness Is Associated with Fewer PTSD Symptoms, Depressive Symptoms, Physical Symptoms, and Alcohol Problems in Urban Firefighters[END_REF]. In addition to being a protective factor against PTSD, the sense of control may also be a factor that promotes PTG. For example, for survivors of diverse traumatic events, control was a key determinant of psychological adjustment after adversity [START_REF] Dekel | Shared and unique predictors of post-traumatic growth and distress[END_REF][START_REF] Kaye-Tzadok | Posttraumatic growth among women survivors of childhood sexual abuse: Its relation to cognitive strategies, posttraumatic symptoms, and resilience[END_REF]. Kaye-Tzadok and Davidson-Arad ( 2016) specify that both realistic control and "unrealistic" control are associated with PTG. Thus, simply being under the impression that one is in control of their environment can facilitate growth. Consistent with these findings, [START_REF] Shuwiekh | What are the personality and trauma dynamics that contribute to posttraumatic growth[END_REF] show that striving for 'standards' (high performance expectations) and 'order' promotes PTG. Furthermore, [START_REF] Mamon | Obsessive Compulsive Symptoms Predict Posttraumatic Growth: A Longitudinal Study[END_REF] show in a group of Israeli Veterans that Obsessive Compulsive Behavior (OCB), a disorder characterized by the attempt to control one's environment, may facilitate psychological growth. Indeed, according to [START_REF] Mamon | Obsessive Compulsive Symptoms Predict Posttraumatic Growth: A Longitudinal Study[END_REF], OCB symptoms trigger an ongoing ruminative processing of the event, "initiating a more deliberate search for understanding and finding meaning in the trauma, which subsequently supports growth" (Mamon et al., 2016, p.488). However, an alternative explanation is that OCB promotes PTG due to a "cognitive bias towards exaggerated personal control" (Mamon et al., 2016, p.489). Indeed, "individuals with OC symptoms tend to use compulsive rituals as a way to compensate and instill an illusory sense of control" (p.489). However, in a paradoxical way, belief in social complexity (or the belief that the world is nearly impossible to control) also appears to be positively associated with PTG [START_REF] Nalipay | Social complexity beliefs predict posttraumatic growth in survivors of a natural disaster[END_REF]. Indeed, [START_REF] Nalipay | Social complexity beliefs predict posttraumatic growth in survivors of a natural disaster[END_REF] show that generalized beliefs about how the world functions, specifically social complexity, may be one of the factors that could provide a framework for individuals to understand and make sense of stressful events. More specifically, they argue that individuals who believe in social complexity may be more likely to engage in cognitive processes that will allow them to view a traumatic experience from various perspectives which, ultimately, will promote flexible coping strategies, positive cognitive restructuring, and acceptance of what happened [START_REF] Nalipay | Social complexity beliefs predict posttraumatic growth in survivors of a natural disaster[END_REF].

The sense of coherence (SOC), defined as "the extent to which one has a pervasive, enduring though dynamic, feeling of confidence that one's environment is predictable and that things will work out as well as can reasonably be expected" [START_REF] Antonovsky | Health, stress, and coping: New perspectives on mental and physical well-being[END_REF]), also appears to be a potential enhancer of PTG. Indeed, [START_REF] Xiu | Sense of Coherence and Posttraumatic Growth: The Moderating Role of Value Orientation in Chinese and Swiss Bereaved Parents[END_REF] and López et al. (2015) demonstrate that high levels of SOC are positively associated with growth. In other words, SOC could be described as a form of "optimism" and personal belief that one's environment is "controllable" (controllability), which are both known to enhance psychological growth. SOC, in contrast to the Big Five personality traits, is a trait that individuals develop through various life events. Thus, while biological personality characteristics (such as Extraversion) play a major role in the experience of PTG, socio-cognitive characteristics (such as the sense of control or the sense of coherence) can also be harnessed for positive psychological change.

Therefore, promoting SOC in individuals who are low on Extraversion or Openness may help them experience post-traumatic growth.

In addition to the sense of control and coherence, the sense of purpose also appears as a potential facilitator of PTG. According to [START_REF] Reker | Theoretical perspective, dimensions, and measurement of existential meaning[END_REF], the sense of purpose can be defined as having the ability to find meaning in non-materialistic aspects of life, having goals, a sense of direction, a sense of self-worth, a reason for existence (e.g. having children, enjoying the "little things", etc.). Reker states that the sense of purpose is "an important construct in the prevention of illness, the promotion of wellness and successful adaptation to life's changing circumstances" (Reker, 2000, p. 39). Indeed, it was found that having a sense of purpose promoted PTG in samples of U.S. Veterans, Traumatic brain injury survivors, adults living with chronic illness, and hurricane survivors [START_REF] Tsai | Trajectories of posttraumatic growth among US military veterans: a 4-year nationally representative, prospective cohort study[END_REF][START_REF] Powell | TBI 13 years on: factors associated with posttraumatic growth[END_REF][START_REF] Zeligman | Posttraumatic growth in individuals with chronic illness: The role of social support and meaning making[END_REF][START_REF] Lowe | Posttraumatic stress and posttraumatic growth among low-income mothers who survived Hurricane Katrina[END_REF]. Similar to purpose, "hope" also seems to play a significant role in reaching PTG [START_REF] Yuen | The mediating roles of cancer-related rumination in the relationship between dispositional hope and psychological outcomes among childhood cancer survivors[END_REF]. Like purpose, the hope construct represents a focus on significant future aims, and can be defined as "a belief that one knows how to reach one's goals and a belief that one has the motivation to use those pathways to reach one's goals" (Cotton Bronk et al., 2009, p.501).

Event centrality

According to [START_REF] Berntsen | The centrality of event scale: A measure of integration a trauma into one's identity and its relation to post-traumatic stress disorder symptoms[END_REF], "highly accessible and vivid personal memories help to give meaning and structure to our life narratives and help to anchor and stabilize our conceptions of ourselves" (p. 219). More specifically, the extent to which an individual feels a particular event has become central in the organization of his/her identity is called "Event Centrality" (EC). Indeed, [START_REF] Berntsen | Involuntary memories of emotional events. Do memories of traumas and extremely happy events differ[END_REF] hypothesized that a traumatic event accompanied by significant consequences and repercussions in one's life may be more likely to be centralized or viewed as an important part of one's life story [START_REF] Wright | Event Centrality After Trauma: Stability, Trauma Type, And Posttraumatic Stress Disorder[END_REF]. It has been reported that high EC is associated with high levels of PTSD [START_REF] Berntsen | The centrality of event scale: A measure of integration a trauma into one's identity and its relation to post-traumatic stress disorder symptoms[END_REF][START_REF] Bohn | Generational differences in cultural life scripts and life story memories of younger and older adults[END_REF][START_REF] Rubin | Narrative centrality and negative affectivity: Independent and interactive contributors to stress reactions[END_REF] and emotional distress (Zaragoza, Salgado, Shao, & Berntsen, 2014). Indeed, high EC may cause individuals to overestimate or emphasize the negative effects of the endured trauma which, in turn, will foster post-traumatic stress.

However, EC may also be associated with posttraumatic growth in survivors of different traumatic events [START_REF] Barton | Thinking About Trauma: The Unique Contributions of Event Centrality and Posttraumatic Cognitions in Predicting PTSD and Posttraumatic Growth[END_REF][START_REF] Roland | Event centrality and posttraumatic outcomes in the context of pervasive violence: a study of teachers in El Salvador[END_REF]Boals & Schuettler, 2011;[START_REF] Allbaugh | The role of repetitive thought in determining posttraumatic growth and distress following interpersonal trauma[END_REF][START_REF] Staugaard | Centrality of positive and negative deployment memories predicts posttraumatic growth in Danish veterans[END_REF]Schuettler & Boals, 2011). This positive link could be explained by the fact that construing a traumatic experience as central to one's identity may result in more posttraumatic cognitions (deliberate and intrusive rumination) which, as demonstrated previously, is highly associated with PTG. Thus, the centrality given to trauma 16 appears to serve as a "double-edged sword", in that this construct might foster both PTSD and PTG. However, [START_REF] Blix | Posttraumatic growth and centrality of event: A longitudinal study in the aftermath of the 2011 Oslo bombing[END_REF] showed in a longitudinal study that the positive association between EC and PTG attenuated over time. Thus, it is possible to hypothesize that high EC may only be beneficial soon after the traumatic event occurred, as it may help trigger cognitive processes related to growth outcomes (e.g. intrusive and deliberate rumination, see [START_REF] Taku | Intrusive versus deliberate rumination in posttraumatic growth across US and Japanese samples[END_REF].

Resilience

Resilience can be defined as a process characterized by the ability to successfully cope with a crisis and to return to pre-crisis status quickly (de Terte & Stephens, 2014). More specifically, resilience is the "ability to go on with life after hardship and adversity" and "to remain psychologically healthy despite very difficult circumstances" (Tedeschi & Calhoun, 2004, p.4). Therefore, Resilience differs from posttraumatic growth in that it is characterized by a return of the individual to its initial state (pre-crisis state), whereas PTG is characterized by the « gain » of positive psychological benefits. Indeed, according to [START_REF] Tedeschi | Posttraumatic growth: Conceptual foundations and empirical evidence[END_REF], "posttraumatic growth refers to a change in people that goes beyond an ability to resist and not be damaged by highly stressful circumstances […] posttraumatic growth, then, has a quality of transformation" (Tedeschi & Calhoun, 2004, p.4).

It has been demonstrated that high levels of resilience reduce the onset of PTSD symptoms in firefighters [START_REF] Lee | Resilience buffers the impact of traumatic events on the development of PTSD symptoms in firefighters[END_REF]. However, resilience may also promote growth in individuals who are confronted with various traumatic events [START_REF] Kong | Positive affect mediates the relationships between resilience, social support and posttraumatic growth of women with infertility[END_REF][START_REF] Rzeszutek | Social support, stress coping strategies, resilience and posttraumatic growth in a Polish sample of HIV-infected individuals: results of a 1year longitudinal study[END_REF]. Additionally, [START_REF] Liu | Relationships between family resilience and posttraumatic growth in breast cancer survivors and caregiver burden[END_REF] demonstrate that high levels of family resilience are positively correlated to PTG in patients with early-stage breast cancer. Thus, individuals facing adversity seem to benefit from their own level of resilience, but also from the levels of resilience displayed by their social environment. These findings suggest that individual resilience as well as collective resilience are key determinants of growth. However, some studies have found a negative correlation between resilience and PTG. Indeed, [START_REF] Garrido-Hernansaiz | Predictors of resilience and posttraumatic growth among people living with HIV: A longitudinal study[END_REF] and [START_REF] Levine | Examining the relationship between resilience and posttraumatic growth[END_REF] showed that high levels of resilience were associated with lower levels of posttraumatic growth. The authors hypothesize that resilience may decrease PTG because resilient individuals tend to struggle with adversity less than others, thus making them less likely to engage in the meaning-making behaviors that are associated with PTG. Therefore, it is argued that resilience may provide little opportunity for growth [START_REF] Westphal | Posttraumatic growth and resilience to trauma: Different sides of the same coin or different coins?[END_REF].

Resource loss

As stated by [START_REF] Hobfoll | Conservation of Resources, A New Attempt at Conceptualizing Stress[END_REF], individuals "strive to retain, protect, and build resources and […] what is threatening to them is the potential or actual loss of these valued resources" (Hobfoll, 1989, p. 516). Thus, according to Hobfoll's Conservation of Resource theory (COR; 1989), resource loss is known to increase traumatic stress. This assumption is verified by Cook et al.'s (2013) study, showing a negative association between resource loss and health in a sample of university students soon after Hurricane Katrina hit the Gulf coast in 2005.

However, Cook et al.'s results also show the presence of a positive association between resource loss and PTG. We note that resource loss was assessed by the 18-item measure developed by Sattler et al. (2002) specifically to assess resource loss in response to a hurricane. Respondents were asked to describe the amount of loss experienced as a result of the hurricane. Resource loss was a significant positive predictor of PTG. Since resource loss increases levels of distress, it is possible to assume that resource loss fosters growth through high levels of traumatic stress. This finding is consistent with [START_REF] Tedeschi | Posttraumatic growth: Conceptual foundations and empirical evidence[END_REF] model suggesting that growth can only occur through high levels of distress. al., 2017;[START_REF] Sharp | Posttraumatic growth in head and neck cancer survivors: Is it possible and what are the correlates?[END_REF][START_REF] Jeon | Post-traumatic growth in survivors of allogeneic hematopoietic stem cell transplantation[END_REF][START_REF] Val | Posttraumatic Growth, Positive Changes, and Negative Changes in Madrid Residents Following the March 11, 2004, Madrid Train Bombings[END_REF]. A possible explanation for this is that women may be more susceptible than men to sharing their experiences with others when confronted with adversity which, in turn, facilitates cognitive processes such as deliberate rumination. This hypothesis is consistent with [START_REF] Wu | Posttraumatic growth after motor vehicle crashes[END_REF] study, showing that women score significantly higher on the "Relating to Others" subscale of the PTGI than men.

Age

Additionally, it was largely found that individuals of a younger age tend to report higher levels of growth than older individuals [START_REF] Sharp | Posttraumatic growth in head and neck cancer survivors: Is it possible and what are the correlates?[END_REF][START_REF] Boyle | Posttraumatic growth in breast cancer survivors: does age matter?[END_REF]. [START_REF] Bellizzi | Predicting posttraumatic growth in breast cancer survivors[END_REF] explain this by hypothesizing that older individuals may be dealing with more comorbidities or other significant life events compared with younger survivors, such as dealing with the loss of loved ones, hearing and vision impairment, etc. However, Palgi (2016) suggests that time perspectives may also influence PTG. Indeed, Palgi found that older adults (age range 50-90) reporting younger subjective age and further distance to death reported higher levels of PTG than adults reporting older subjective age and closer distance to death. Thus, while being of a younger age promotes the chances of reaching growth, the perception of being young fosters PTG as well, regardless of the individual's actual age.

However, several studies found a positive association between older age and PTG in samples of sexual assault victims, individuals with Acquired Brain Injury, and breast cancer survivors [START_REF] Ullman | Correlates of posttraumatic growth in adult sexual assault victims[END_REF][START_REF] Grace | Post-traumatic growth following acquired brain injury: A systematic review and meta-analysis[END_REF]. A possible explanation may be that older adults have acquired more life experience, which may help them deal with stressful events more easily than younger individuals. As a matter of fact, [START_REF] Tallman | Well-being and posttraumatic growth in unrelated donor marrow transplant survivors: A nine-year longitudinal study[END_REF] report in their longitudinal study that older cancer survivors reported more enhanced spirituality on the PTGI. Furthermore, the level of education also stood out as a factor that influences PTG, even though the results remain equivocal. On the one hand, several studies demonstrate that higher levels of education are positively associated with growth (Danhauer et al., 2013;[START_REF] Grace | Post-traumatic growth following acquired brain injury: A systematic review and meta-analysis[END_REF]. Indeed, resources such as time, money, and education facilitate resistance to stress [START_REF] Hobfoll | Conservation of Resources, A New Attempt at Conceptualizing Stress[END_REF]: Individuals who come from an educated environment may perceive they have a wider range of possibilities and choices available to them in coping with stressful events. On the other hand, several studies also provide evidence that PTG may be associated with lower levels of education [START_REF] Ullman | Correlates of posttraumatic growth in adult sexual assault victims[END_REF][START_REF] Tang | Threatened with death but growing: Changes in and determinants of posttraumatic growth over the dying process for Taiwanese terminally ill cancer patients[END_REF]. [START_REF] Bellizzi | Predicting posttraumatic growth in breast cancer survivors[END_REF] hypothesize that individuals with lower educational levels may have "more room to grow in their relationships" (p. 54). In other words, individuals with lower levels of education may lean on other types of resources to overcome stressful situations. Thus, whether individuals rely more on their education or on their relationships to grow from adversity remains unclear.

Education/employment

Additionally, employment also seems to play an important role in the process of growth. Indeed, [START_REF] Salo | Adult attachment, posttraumatic growth and negative emotions among former political prisoners[END_REF], [START_REF] Bellizzi | Predicting posttraumatic growth in breast cancer survivors[END_REF], and [START_REF] Grace | Post-traumatic growth following acquired brain injury: A systematic review and meta-analysis[END_REF] show that individuals that hold high professional positions or a steady employment are more likely to experience PTG. [START_REF] Sattler | Trauma-exposed firefighters: Relationships among posttraumatic growth, posttraumatic stress, resource availability, coping and critical incident stress debriefing experience[END_REF] and [START_REF] Xu | Work satisfaction and posttraumatic growth 1 year after the 2008 Wenchuan earthquake: The perceived stress as a moderating factor[END_REF] add that occupation/work satisfaction predicts PTG as well. A possible explanation could be that general life satisfaction may help promote growth. 3.9.4 Ethnicity/stigmatized minorities Lastly, the literature suggests that belonging to an ethnic minority may promote PTG [START_REF] Hijazi | Predictors of posttraumatic growth in a multiwar sample of U.S. Combat veterans[END_REF][START_REF] Ullman | Correlates of posttraumatic growth in adult sexual assault victims[END_REF]. [START_REF] Hijazi | Predictors of posttraumatic growth in a multiwar sample of U.S. Combat veterans[END_REF] hypothesize that being part of an ethnic minority is associated with increased discrimination and life adversity, which may ultimately facilitate benefit finding. This is consistent with [START_REF] Zeligman | Posttraumatic growth and HIV: A study on associations of stigma and social support[END_REF] study, suggesting that stigma may foster PTG in HIV-positive individuals. Thus, while it is unusual to associate discrimination with positive mental outcomes [START_REF] Wei | Perceived social support, hopefulness, and emotional regulations as mediators of the relationship between enacted stigma and posttraumatic growth among children[END_REF][START_REF] Rzeszutek | Posttraumatic growth among people living with HIV: A systematic review[END_REF], studies suggest that individuals belonging to stigmatized groups may be more prone to developing positive changes due to their life experiences. Another hypothesis may be that stigmatized groups develop a strong sense of belonging which, ultimately, helps promote growth.

Conclusion

The aim of this literature review was to provide a critical analysis of different factors that may promote the development of growth among trauma-exposed individuals. Some of the factors that promote PTG include sharing negative emotions, cognitive processing or rumination, positive coping strategies (e.g. positive reappraisal), personality traits (e.g. agreeableness), experiencing multiple sources of trauma, event centrality, resilience, growth actions. Authors have also suggested that some factors may be mediators of PTG rather than direct influencers, such as seeking social support coping, social support, optimism, spirituality, and the sense of belonging. These mediators indirectly foster growth either by promoting the use of positive coping (e.g. optimism, social support), by influencing the quantity and quality of social support (e.g. seeking social support coping), by ensuring the presence of social support (e.g. spirituality), or by encouraging individuals to seek social support (e.g. sense of belonging).

Additionally, the studies suggest that PTG might be more nuanced than originally thought. Indeed, [START_REF] Hobfoll | Refining our understanding of traumatic growth in the face of terrorism: Moving from meaning cognitions to doing what is meaningful[END_REF] found that post-traumatic growth was positively associated with more right-wing political attitudes, support for aggressive behaviors, and ethnocentrism in a sample of individuals who experience ongoing violence and terrorism. As suggested previously, this could mean that there are multiple ways of developing growth, and that PTG may not express itself the same way in all contexts.

Growth actions

 [START_REF] Hobfoll | Refining our understanding of traumatic growth in the face of terrorism: Moving from meaning cognitions to doing what is meaningful[END_REF]show in a group of Jewish and Arab citizens of Israel highly exposed to terrorism that PTG may be beneficial when accompanied by action, not solely cognitive maneuvers. Indeed, while [START_REF] Tedeschi | Clinical applications of posttraumatic growth[END_REF] tend to describe the growth process as a search for meaning (e.g. cognitive engagement), [START_REF] Hobfoll | Refining our understanding of traumatic growth in the face of terrorism: Moving from meaning cognitions to doing what is meaningful[END_REF] make a distinction between growth actions and growth cognitions, stating that cognitive change alone is not sufficient for growth to occur. Indeed, they show in one of their studies that PTG may only be beneficial if it includes taking action.

The authors compared PTG levels between a group of settlers in Israel who took part in the resistance in the days prior to the disengagement from Gaza, and a group of settlers who did not take part in the resistance. The results show that individuals who took action by resisting the disengagement reported more PTG and were less likely to develop PTSD. Thus, this suggests that "growth actions" may play an important role in the development of posttraumatic growth and the reduction of post-traumatic stress. This hypothesis is consistent with Anderson et al.'s (2016) results, showing that volunteers in the March 2011 Disaster in Fukushima (Japan) reported significantly higher levels of PTG than non-volunteers. The authors found that volunteers were also less likely to feel guilty than non-volunteers. These findings, along with [START_REF] Hobfoll | Refining our understanding of traumatic growth in the face of terrorism: Moving from meaning cognitions to doing what is meaningful[END_REF], indicate that actions can have lasting positive effects and convey a protective benefit.

Sociodemographic characteristics

Gender

According to several studies, sociodemographic characteristics such as gender, age, education, and ethnicity play an important role in post-traumatic growth. Indeed, it was often found that women reported higher levels of growth than men [START_REF] Jin | The relationship between posttraumatic stress disorder and post traumatic growth: gender differences in PTG and PTSD subgroups[END_REF][START_REF] Nakayama | Factors associated with posttraumatic growth among parents of children with cancer[END_REF]