Posttraumatic Stress Symptoms Increase the Efficiency of Memory Functioning for Trauma-Related Information.

OBJECTIVE: The present study explored the resources reallocation explanation for memory biases in posttraumatic stress disorder (PTSD), whereby a preferential allocation of cognitive resources to the processing of threatening stimuli could result in both improvements in their memorization and deficits for other types of information. METHOD: To this end, 25 participants presenting significant symptoms of PTSD (i.e., total PCL-5 score ≥33) and 32 participants presenting low levels of symptoms (i.e., total PCL-5 score <20) took part in a Remember/Know recognition procedure associated with a dual-task encoding of positive, neutral, negative, and trauma-related words. In order to manipulate the availability of cognitive resources, the encoding of each word was associated with a simultaneous encoding of series of letters and numbers. RESULTS: Results replicated the increased production of Remember recognitions for trauma-related words in participants with significant PTSD symptoms. However, the dual-task load only impaired remember recognitions for non-trauma-related words. CONCLUSIONS: Contrary to expectations, these findings suggest that the encoding of trauma-related information in PTSD is relatively independent from the availability of cognitive resources. Thus, rather than reflecting an increased allocation of cognitive resources to the processing of threatening information, memory biases in PTSD appeared to be supported by an enhanced efficiency of their processing.

Combining Trauma Script Exposure With rTMS to Reduce Symptoms of Post-Traumatic Stress Disorder: Randomized Controlled Trial.

BACKGROUND: Innovative therapeutic interventions for post-traumatic stress disorder (PTSD) are required. We opted to facilitate fear extinction by combining trauma script exposure with repetitive transcranial magnetic stimulation (rTMS) to reduce symptoms of PTSD. OBJECTIVE: The efficacy and safety of 10 Hz rTMS of the right dorsolateral prefrontal cortex simultaneously with exposure to personal traumatic narrative were studied in patients with PTSD. MATERIALS AND METHODS: This trial was a single-center randomized controlled trial (NCT02584894). Patients were randomly assigned 1:1 to receive eight daily sessions of 110% of motor threshold high frequency (HF) 10 Hz rTMS (110% HF rTMS) or 70% low frequency (LF) 1 Hz rTMS (70% LF rTMS) with trauma script exposure in both groups. Severity of PTSD, depression, and anxiety were assessed before and after study treatment (one month, three months) by an assessor masked to the trial group assignment. The primary outcome was the severity of PTSD assessed by the Clinician Administered PTSD Scale (CAPS). We used mixed linear regression models for statistical comparisons. RESULTS: Thirty-eight patients (65.8% females) were randomly assigned to 110% HF rTMS (n = 18, 31.3 ± 10.0 years, 13 females) or 70% LF rTMS (n = 20, 33.5 ± 11.1 years, 12 females). From baseline to three months, mean CAPS scores decreased by 51% in the 110% HF rTMS group (from 83.7 ± 14.4 to 41.8 ± 31.9) and by 36.9% in the 70% LF rTMS group (from 81.8 ± 15.6 to 51.6 ± 23.7), but with no significant difference in improvement (time by treatment interaction -3.61 [95% confidence interval (CI), -9.70 to 2.47]; p = 0.24; effect size 0.53). One serious adverse event occurred during the study (psychogenic nonepileptic seizure). CONCLUSION: We found no evidence of difference in clinical improvement or remission rates between the 110% HF and 70% LF stimulation. These findings may reflect the importance of exposure procedure and that larger number of participants is needed.

Beyond Clinical Outcomes: Posttraumatic Stress Symptoms Favor Attentional and Memory Control Abilities for Trauma-Related Words.

Memory alterations and biases are core features of posttraumatic stress symptoms (PTSS). Although a large number of studies have investigated memory biases associated with PTSS, some inconsistencies remain regarding the nature of the mechanisms behind the threat-related biases observed in prior findings. The present study explored the extent to which inhibitory deficits, both for automatic and controlled processes, can account for these biases. Participants (N = 64) took part in a remember/know recognition procedure for positive, neutral, negative, and trauma-related words associated with negative priming and directed forgetting encoding. Half of the participants had high levels of PTSS (i.e., PCL-5 score > 40) and half had low levels (i.e., total PCL-5 score < 20). As both negative priming and directed forgetting effects are posited to depend on inhibitory abilities, we expected these effects to be absent for trauma-related words in participants with more severe PTSS. Replicating classic memory biases, participants with high levels of PTSS produced more "remember" recognition responses for trauma-related words, ηp 2 = .10. However, contrary to our expectations, directed forgetting, ηp 2 = .26; and negative priming effects were observed for trauma-related words but not for words of other valences, ηp 2 = .07 and .06, respectively. Hence, rather than the expected inhibitory deficits, our results suggest that PTSS preserve the ability to inhibit trauma-related information in both attentional and memory processes. As it appears to occur at the expense of other information, this preserved cognitive functioning for trauma-related stimuli is discussed with regard to resource reallocation theories.

The memory deficit hypothesis of compulsive checking in OCD: what are we really talking about? A narrative review.

We reviewed studies that have specifically explored the memory deficit hypothesis of Obsessive Compulsive Disorder (OCD) checking, highlighting the methodological differences between these studies that may explain inconsistencies regarding memory deficits in OCD checkers. Based on Conway's proposition that one function of episodic memories is to keep an adaptive record of recent goal processing in order to check that actions have actually been accomplished, we suggest that impaired autonoetic consciousness -one of the main features of episodic memory- may be at the heart of the issue of checking compulsion. Autonoetic consciousness, that can be experimentally assessed by the Remember/Know/Guess paradigm,could be impaired in OCD checkers leading them to be unable to mentally relive their actions in order to be assured that they have been accomplished (e.g., having locked the door). We make methodological suggestions to improve the assessment of autonoetic consciousness deficit in OCD checkers and understand its role in the etiology and maintenance of compulsive checking.

Inhibitory control of threat remembering in PTSD.

Intrusive traumatic recollections suggest an inability in Posttraumatic Stress Disorder (PTSD) to control and notably to inhibit memories for trauma-related information. Supported by inhibitory deficits found on experimental settings in PTSD, memory functioning and memory biases in the disorder were usually explained through inhibitory and control deficits in the processing of trauma-related information. The present study aimed to directly assess this hypothesis by investigating memory control abilities for emotional information in PTSD. For this purpose, 34 patients diagnosed with PTSD were compared to 37 non-PTSD controls on an item-cued directed forgetting paradigm for emotional words combined with a Remember/Know recognition procedure. Results revealed enhanced amounts of Remember recognitions for trauma-related words in PTSD. Moreover, we replicated findings of memory control impairments in the disorder. However, such impairments only occurred for non-trauma-related words. Accordingly, it appeared that PTSD patients presented preserved memory control abilities for trauma-related words, at the expenses of other emotional valences. Surprisingly, PTSD patients presented a preserved ability to control and notably to inhibit their memory functioning for trauma-related material. In addition to potential theoretical and clinical relevance, these results are discussed in the light of resource reallocation hypotheses and vigilant-avoidant theories of information processing in PTSD.

Aging Stereotypes Must be Taken Into Account for the Diagnosis of Prodromal and Early Alzheimer Disease.

Because of a dramatic increase of older people worldwide, screening for prodromal state of Alzheimer disease (AD) is a major societal challenge. Many individuals diagnosed with prodromal AD, do not convert to AD, some remaining stable and others reversing back to normal. We argue that an important source of this overdiagnosis comes from negative aging stereotypes (eg, the culturally shared beliefs that aging inescapably causes severe cognitive decline and diseases). Many laboratory studies show that such stereotypes impair memory performance in healthy older adults, producing inflated age differences. Research is needed to examine how aging stereotypes implicitly permeate neuropsychological testing and contribute to false positives.

The effect of ageing on recollection: the role of the binding updating process.

The aim of this study was to highlight the underlying process responsible for the age-related deficit in recollection. Through two experiments using the Remember-Know-Guess procedure (Gardiner, J. M., & Richardson-Klavehn, A. [2000]. Remembering and knowing. In The Oxford handbook of memory (pp. 229-244). New York, NY: Oxford University Press) in recognition, we manipulated the opportunity to update bindings between target items and their encoding context, in young and older adults. In the first experiment we impaired the binding updating process during the encoding of items, while in the second we supported this process. The results indicated that the "Remember" responses in the younger group were specifically reduced by the impairment of the binding updating process (Exp. 1), suggesting that this ability is useful for them to encode a specific episode. Conversely, only the "Remember" responses in the older group were improved in accuracy by supporting the binding updating process (Exp. 2), suggesting that their weakness in this ability is the source of their failure to improve the accuracy of their memories. The overall results support the hypothesis that the age-related decline in episodic memory is partly due to a greater vulnerability to interference on bindings, impairing the ability to update content-context bindings as and when events occur.

The emotional memory effect in Alzheimer's disease: emotional words enhance recollective experience similarly in patients and control participants.

The purpose of the present study was to investigate emotional memory enhancement (EME) in Alzheimer's disease (AD). In particular, we were interested in exploring which memory process (i.e., recollection or familiarity) could be improved by emotional information in the course of the disease. Eighteen AD patients were compared with 15 normal controls on the Remember/Know/Guess paradigm following encoding of emotional and neutral words. AD patients' recollective experience was improved for emotional compared to neutral words to the same extent as that of normal controls, whereas emotion had no effect on participants' memory performance involving familiarity processes. Our results showed that AD patients' memory can be enhanced qualitatively but not quantitatively by an emotional material. Furthermore, we found that AD patients were as able as normal controls to benefit from the emotional content of information to improve the recollection of details.

[Les effets de la méditation de pleine conscience sur les symptômes cognitivo- émotionnels dans le trouble cognitif léger et la maladie d'Alzheimer : une revue de littérature narrative].

La maladie d'Alzheimer se manifeste par des troubles de la mémoire et un déclin cognitif plus général, le plus souvent associés à des troubles de l'humeur et du comportement. Les traitements médicamenteux ayant une efficacité assez modeste, il apparaît nécessaire de leur associer une prise en charge non pharmacologique. La méditation de pleine conscience, qui a des effets bénéfiques sur le fonctionnement cognitif et sur l'état émotionnel, semble être une piste intéressante. Cette revue de littérature narrative se propose de recenser les études ayant testé l'efficacité d'une intervention basée sur la pleine conscience auprès de personnes souffrant de la maladie d'Alzheimer ou à risque de développer cette maladie. Il apparaît que ces interventions présentent un intérêt pour réduire les symptômes cognitifs (troubles attentionnels et mnésiques notamment) et émotionnels (affects dépressifs et anxiété en particulier). Cependant, elles nécessitent un certain nombre de modifications pour être adaptées à ce public.

Self-reference effect and autonoetic consciousness in Alzheimer disease: evidence for a persistent affective self in dementia patients.

Episodic memory deficits are predominately the first cognitive impairment in Alzheimer disease (AD). Previous studies have demonstrated that these deficits are specifically linked to autonoetic consciousness impairment, whereas noetic consciousness remains preserved in AD. This study focused on the self-reference effect and examined emotional valence, as it has been shown that emotional content can enhance memory in AD. A task involving recognition of emotional versus neutral adjective traits after self-reference versus semantic encoding, and using the Remember/Know/Guess paradigm was administered to 22 AD patients and 18 normal controls. Results for AD patients show that self-reference increased autonoetic consciousness only for emotional and particularly negative trait adjectives. This interesting result indicates that neutral valence does not allow properties of the self to emerge in AD patients because of the progressive loss of the sense of self-linked to the disease, whereas emotional valence does.

Positive impact of social relationships fostered by physical and/or cognitive group activity on older people's quality of life: PRISMA systematic review.

Introduction: This review identified and examined the research literature on the effect of participating in physical and/or cognitive activities on older people's quality of life, to establish whether the social relationships fostered by these activities can be a vector of better physical, mental and social quality of life. Method: A systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched four databases (MEDLINE, APA PsycArticles/PsycInfo, PubMed, and Web of Science) for articles published between 1975 and 2022 using search terms related to psychosocial, population, and intervention topics. Studies were eligible if they involved older adults, participation in at least one activity (physical or cognitive), and at least one quality of life related outcome measure. Results: We selected 20 articles published between 1990 and 2021, the majority concerning studies conducted in English-speaking countries. Ten studies were interventional (introduction of program of activities), and 10 studies were observational (60% quantitative, 40% qualitative). Overall, results revealed a positive impact of the activities on every aspect of quality of life (i.e., cognitive, physical, social, psychological, and quality of life in general). Conclusion: The present review confirmed the beneficial impact of practicing physical and/or cognitive group activities on older people's quality of life, but the contribution of social factors and social relationships remains underestimated and not well defined in researches.

Effects of combined physical and cognitive program performed in socially enriched environment on older people's cognitive abilities and quality of life (StimCoAPS): study protocol for a randomized controlled trial.

The number of older people worldwide is constantly increasing. However, ageing is accompanied by a decline in cognitive ability that can affect quality of life. Cognitive, physical and social activities can all slow this decline but social factors and their contribution to the well-being remain under-researched. The aim of this study is to analyse how the practice environment can foster these social relations and thus enhance well-being and to identify the psychological dimensions that are activated by social relations. This study is a 3-year randomised controlled trial designed to assess the effects on participants' cognitive abilities and quality of life of a combined (ie, physical and cognitive) training programme in different social practice environments. A total of 159 older people (≥65 years old) will be recruited and randomly assigned to one of three practice environments: individual practice at home (n=53), group practice in a gymnasium (n=53) and group practice in an enriched environment (n=53). All participants will complete 12-week combined training sessions and will be assessed four times: before the start, in the middle, at the end and 6 months after the end of the programme. They will undergo cognitive function (episodic memory and executive functions), physical capacity (aerobic fitness, muscle strength and dynamic balance) and psychosocial assessments (indicators of psychological well-being, social support, self-esteem, anxiety, depression and achievement goal strategies), as well as semistructured interviews. Statistical analyses will be conducted to assess the effect of the practice environment on the perceived benefits of this programme in terms of cognitive abilities and quality of life, and to determine the role of psychosocial factors in this relationship. This protocol has been approved by an institutional review board (CERSTAPS: IRB00012476-2022-20-01-146). Trials registration number: NCT05721508.

Working memory processing of traumatic material in women with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with medial frontal and amygdala functional alterations during the processing of traumatic material and frontoparietal dysfunctions during working memory tasks. This functional magnetic resonance imaging (fMRI) study investigated the effects of trauma-related words processing on working memory in patients with PTSD. METHODS: We obtained fMRI scans during a 3-back task and an identity task on both neutral and trauma-related words in women with PTSD who had been sexually abused and in healthy, nonexposed pair-matched controls. RESULTS: Seventeen women with PTSD and 17 controls participated in the study. We found no behavioural working memory deficit for the PTSD group. In both tasks, deactivation of posterior parietal midline regions was more pronounced in patients than controls. Additionally, patients with PTSD recruited the left dorsolateral frontal sites to a greater extent during the processing of trauma-related material than neutral material. LIMITATIONS: This study included only women and did not include a trauma-exposed non-PTSD control group; the results may, therefore, have been influenced by sex or by effects specific to trauma exposure. CONCLUSION: Our results broadly confirm frontal and parietal functional variations in women with PTSD and suggest a compensatory nature of these variations with regard to the retreival of traumatic memories and global attentional deficits, respectively, during cognitively challenging tasks.

Recollection of negative information in posttraumatic stress disorder.

The purpose of the present study was to investigate the effects of posttraumatic stress disorder (PTSD) associated with the effects of emotional valence on recall processes in recognition memory. Patients suffering from PTSD (n = 15) were compared with 15 nontraumatized patients with anxious and depressive symptoms and with 15 nontraumatized controls on the remember/know paradigm using negative, positive, and neutral words. The PTSD group remembered more negative words than the nontraumatized controls, F(1, 42) = 7.20, p = .01, but there was no difference between those with PTSD and those with anxiety or depression, F(1, 42) = 2.93, p = .09, or between the latter and controls, F(1, 42) < 1. This study did not allow us to determine whether this recollection bias for negative information was specific to the PTSD status or was triggered by the greater level of anxiety displayed in this group.

Impact of physical activity on executive functions in aging: a selective effect on inhibition among old adults.

The purposes of this study were to determine the impact of physical activity on three different executive functions (shifting, inhibition, and updating) and to examine whether cardiovascular fitness was a good mediator of the positive link(s) between these variables. Sixty-three young adults (18-28 years), 30 young-old adults (60-70 years) and 30 old adults (71-81 years) were divided into physically active and sedentary groups according to physical activity level (assessed from an accelerometer and the Historical Leisure Activity Questionnaire). Cardiovascular fitness was assessed by VO2max from the Rockport 1 mile. Each executive function was assessed through three different experimental tasks. ANCOVAs revealed that the effect of physical activity level was specific to the old adults and significant for inhibition, but not for updating and shifting. Mediation analysis showed that this positive effect in the old adults group was mediated by cardiovascular fitness level. The present findings highlight the positive linkages among physical activity, cardiovascular fitness, and inhibition in aging.

Trauma reactivation under propranolol among traumatized Syrian refugee children: preliminary evidence regarding efficacy.

Background: There is a dearth of therapeutic solutions for traumatized young patients. Trauma reactivation conducted under the influence of the reconsolidation blocker propranolol (Reconsolidation Therapy) is a simple, cost-effective treatment option that has some promising initial results in adults suffering from posttraumatic stress disorder (PTSD). Objective: To explore the usefulness of this novel treatment in children. The primary outcome was the reduction of PTSD symptoms at the end of treatment, while secondary outcomes included reduction in anxiety and in depressive symptoms. Method: An open-label clinical trial was conducted in a refugee camp in Syria, investigating the safety and efficacy of this therapeutic strategy in 117 children suffering from enduring PTSD symptoms. Participants received propranolol 90 minutes before briefly recalling (i.e. reactivating) a single personal traumatic memory, for 5 consecutive days. Self-reported anxiety, depressive, and PTSD symptoms were assessed at baseline, as well as 4 and 13 weeks after treatment. Results: A significant, clinically meaningful symptom reduction was observed at all post-treatment measurement times vs. baseline. More specifically, between baseline and the 13-week follow-up we observed a 64% PTSD symptoms reduction (d = 2.71). In a similar vein, we obtained a 39% symptoms reduction for depressive symptoms (d = 1.01). The general anxiety symptoms improved, but eventually returned to prior level, probably because of the deteriorating living conditions in the camp. Conclusions: This therapy appeared as a potentially safe and useful treatment strategy for children suffering from PTSD symptoms, warranting replication studies using stronger study designs. The social acceptability and ease of implementation of the treatment should also be noted.

Introducción: Existe una escasez de soluciones terapéuticas para pacientes jóvenes traumatizados. La reactivación del trauma conducida bajo los efectos del propanolol bloqueador de reconsolidación (Terapia de Reconsolidación) es una opción de tratamiento simple, costo-efectiva, que tiene algunos resultados iniciales prometedores en adultos que sufren del trastorno de estrés postraumático (TEPT).Objetivos: Explorar la utilidad de este novedoso tratamiento en niños. El resultado primario fue la reducción de los síntomas de TEPT al final del tratamiento, mientras que los resultados secundarios incluyeron la reducción de los síntomas ansiosos y depresivos.Métodos: Se condujo un estudio clínico abierto en un campo de refugiados en Siria, investigando la seguridad y eficacia de esta estrategia terapéutica en 117 niños que permanecían con síntomas de TEPT. Los participantes recibieron propranolol 90 minutos antes de recordar brevemente (es decir, reactivación) un único recuerdo personal traumático, por 5 días consecutivos. Se evaluó los síntomas de ansiedad, depresión y TEPT auto-reportados, tanto al inicio, como a las 4 y 13 semanas después del tratamiento.Resultados: Se observó una reducción sintomática significativa, clínicamente importante en todas las mediciones post tratamiento versus el nivel basal. Más específicamente, observamos un 64% de reducción de síntomas de TEPT entre el nivel basal y el seguimiento en la semana 13 (d = 2.71). De forma similar, obtuvimos un 39% de reducción de los síntomas depresivos (d =1.01). Los síntomas generales de ansiedad mejoraron, pero retornaron a sus niveles previos al final, probablemtente por las condiciones de vida deteriorantes en el campo de refugiados.Conclusiones: Esta terapia pareciera ser una estrategia de tratamiento potencialmente segura y útil en niños que sufren síntomas de TEPT, justificando estudios de replicación que usen diseños más estrictos. Se debería hacer notar también la aceptabilidad social y la fácil implementación del tratamiento.

Executive functioning and processing speed in age-related differences in memory: contribution of a coding task.

The aim of the present study was to examine executive dysfunctioning and decreased processing speed as potential mediators of age-related differences in episodic memory. We compared the performances of young and elderly adults in a free-recall task. Participants were also given tests to measure executive functions and perceptual processing speed and a coding task (the Digit Symbol Substitution Test, DSST). More precisely, we tested the hypothesis that executive functions would mediate the age-related differences observed in the free-recall task better than perceptual speed. We also tested the assumption that a coding task, assumed to involve both executive processes and perceptual speed, would be the best mediator of age-related differences in memory. Findings first confirmed that the DSST combines executive processes and perceptual speed. Secondly, they showed that executive functions are a significant mediator of age-related differences in memory, and that DSST performance is the best predictor.

Ageing, remembering, and executive function.

This study was designed to investigate the relationship between executive functions and the age-related decline in episodic memory through the states-of-awareness approach. Following the presentation of a word list, a group of younger adults and a group of older adults undertook a recognition test in which they classified their responses according to the Remember-Know-Guess procedure (Gardiner & Richardson-Klavehn, 2000). In order to operationalise the executive function hypothesis, we investigated three specific executive functions (updating, shifting, and inhibition of a prepotent response) described in Miyake et al.'s (2000) theoretical model, and a complex executive task. The results revealed that fewer "R" responses were made during the recognition test by the older than the younger group, whereas there was no difference between the groups in the number of "K" responses. In addition, correlations indicated that remembering depended on executive function measures, whereas knowing did not. The hierarchical regression analyses showed that controlling for executive function, and particularly for the 2-back test, largely removed the age-related variance in remembering. These findings support the notion that executive dysfunction, and specifically updating decline, plays a central role in age-related memory loss.

Effortful memory processes under stereotype threat and self-concept in aging.

The present study aimed at exploring the effect of stereotype threat on the controlled part of memory in older adults using a deep level of processing, namely, self-reference encoding. To meet this objective, 25 younger adults and 25 older adults performed a Remember/Know recognition task following self-reference versus other-reference encoding of adjective traits, under stereotype threat or not. The results indicated that under stereotype threat, older adults' production of Remember responses was specifically impaired following self-reference encoding. Moreover, whereas executive functioning and group identification did not moderate stereotype threat effect, measure of self-worth did. These findings suggest that stereotype threat in older adults may be a self-concept threat and that moderators of stereotype threat found in other groups (i.e., group identification and executive functioning) may not be generalised to this group. Rather, as stereotype threat in aging may represent a threat to the self, self-worth might have a central role, whereby individuals with high self-worth remain self-confident even under stereotype threat and are thus able to down-regulate their negative affects to face such a threat.

Ageing stereotypes and prodromal Alzheimer's disease (AGING): study protocol for an ongoing randomised clinical study.

INTRODUCTION: The number of older people diagnosed with amnestic mild cognitive impairment (aMCI), the prodromal state of Alzheimer's disease (AD), is increasing worldwide. However, some patients with aMCI never convert to the AD type of dementia, with some remaining stable and others reverting to normal. This overdiagnosis bias has been largely overlooked and gone unexplained. There is ample evidence in the laboratory that negative ageing stereotypes (eg, the culturally shared belief that ageing inescapably causes severe cognitive decline) contribute to the deteriorating cognitive performances of healthy older adults, leading them to perform below their true abilities. The study described here is intended to test for the first time whether such stereotypes also impair patients' cognitive performances during neuropsychological examinations in memory clinics, resulting in overdiagnosis of aMCI. METHODS AND ANALYSIS: The ongoing study is a 4-year randomised clinical trial comparing patients' physiological stress and cognitive performances during neuropsychological testing in memory clinics. A total of 260 patients attending their first cognitive evaluation will be randomised to either a standard condition of test administration, assumed here to implicitly activate negative ageing stereotypes or a reduced-threat instruction condition designed to alleviate the anxiety arising from these stereotypes. Both groups will be tested with the same test battery and stress biomarkers. For 30 patients diagnosed with aMCI in each group (n=60), biomarkers of neurodegeneration and amyloidopathy will be used to distinguish between aMCI with normal versus abnormal AD biomarkers. A 9-month follow-up will be performed on all patients to identify those whose cognitive performances remain stable, deteriorate or improve. ETHICS AND DISSEMINATION: This protocol has been approved by the French National Agency for Medicines and Health Products Safety and the Sud-Est I French Ethics Committee (2017-A00946-47). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03138018.