Justine Walter
email: justine.walter@univ-montp3.fr

Benjamin Glaviaux

Marine Buon

Excluded but not alone. Does social exclusion prevent the occurrence of a Joint Simon Effect (JSE)?

INTRODUCTION

Imagine that you and a friend have to move a couch up a tight staircase. In order to climb the stairs, and achieve the goal, you both have to constantly coordinate your actions with each other. This example is a perfect illustration of the concept of joint action. Joint actions might seem to be a simple, everyday activity but, in fact, they reflect a complex socio-cognitive dynamic between two actors. The two individuals have different, or complementary tasks (e.g., one person is pulling the couch up the stairs, while the other is pushing it up), and success relies on their combined abilities. Achieving the goal goes beyond a simple addition of strengths, because each individual must constantly adapt their behaviors to the other. In other words, the success of joint actions depends, on the one hand, on individual performance but, on the other hand, on individuals' ability to predict, plan, and coordinate their actions.

Since [START_REF] Sebanz | Representing others' actions: just like one's own?[END_REF] made the seminal claim that "one's own actions and other's actions are represented in a functionally equivalent way" (p. [START_REF] Mathôt | OpenSesame: An open-source, graphical experiment builder for the social sciences[END_REF], it is been widely acknowledged that our own actions are influenced by others' actions. The Sebanz experiment led to consider that performing a joint task activates one's own action system, into which the other person's actions are integrated (Sebanz, Rebbechi, Knoblich, Prinz & Fritth, 2007). This integration is called shared representations of actions or corepresentation, and is considered to be crucial for social cognition [START_REF] Costantini | Action co-representation and social exclusion[END_REF]).

1.1The Joint Simon Effect

The natural tendency to co-represent others' actions was first measured experimentally by [START_REF] Sebanz | Representing others' actions: just like one's own?[END_REF], and is known as the Joint Simon Effect (JSE). Typically, during a non-spatial feature discrimination task (e.g., a shape discrimination task), a spatial compatibility effect (or Simon Effect, following [START_REF] Craft | Processing symbolic information from a visual display: Interference from an irrelevant directional cue[END_REF]) is observed. Specifically, participants perform the task faster when the stimulus that must be categorized, and the corresponding response are spatially compatible, rather than incompatible. For example, when the stimulus is presented on the right-hand side of the screen, and the corresponding response is located on the right-hand side of the keyboard, the response is faster than when the stimulus is presented on the left-hand side of the screen and the corresponding response is located on the right-hand side of the keyboard.

Initially, this spatial compatibility effect was assumed to only be observed when one individual performed a two-choice, but not a single-choice task, such as an individual gonogo task [START_REF] Sebanz | Representing others' actions: just like one's own?[END_REF]. However, and surprisingly, when the task is distributed over two participants (Joint go-nogo Simon Task, JST), a spatial compatibility effect is observed [START_REF] Sebanz | Representing others' actions: just like one's own?[END_REF]; see Dolk, Hommel, Colzato, Schütz-Bosbach, Prinz, & Liepelt, 2014 for a review) even though the actions of each participant separately are exactly the same as in the individual go-nogo task: the participant must detect one type of stimulus (go trials) and inhibit the other (nogo trials).

As the JSE seems to emerge from the active presence of another individual, [START_REF] Sebanz | Representing others' actions: just like one's own?[END_REF] proposed that the effect is automatic, and relies on social processes: observed and planned actions are represented in a functionally similar way. This functional similarity causes a conflict when an action must be selected, and the JSE emerges from this conflict (for a review, see [START_REF] Dolk | The joint Simon effect: A review and theoretical integration[END_REF]. Nevertheless, Dolk, Hommel, Prinz and Lieplet's experimental work (2013) challenged the social nature of the JSE. The authors of the latter study placed participants in a joint go-nogo setting, but replaced the active human co-actor with a dynamic agent (a mechanical Japanese cat). As the presence of this non-human co-actor also led to a JSE, it seemed that individuals could also integrate the action of a dynamic agent into their own action system.

In subsequent work, Dolk et al. (2014, p. 5) stated that, "the JSE may be socially induced by the presence of a responding co-actor without necessarily being social in nature", and proposed a referential coding account that argued that the response conflict (or overlap) was linked to the number of active, concurrent actions, independent of their nature. The JSE would, therefore, seem to reflect the individual's ability to inhibit concurrent representations, and the magnitude of the effect could reflect the ease with which an individual co-represent a concurrent action. Early work [START_REF] Sebanz | Representing others' actions: just like one's own?[END_REF] suggested that co-representing others' actions should be automatic, meaning that co-representation occurs when acting together with someone even though this phenomenon might involve a mixture of automatic and controlled mechanisms. Later studies argued that it also depends on the perceived self-other overlap, or a real interpersonal similarity (Sellaro, Dolk, Colzato, Liepelt, & Hommel, 2015).

Social influence on the JSE

The perceived self-other overlap has been associated with the (socio-)cognitive process of Perspective Taking (PT) (for a review, see [START_REF] Galinsky | Perspective-taking and self-other overlap: Fostering social bonds and facilitating social coordination[END_REF]. The latter authors considered that PT increases the perceived self-other overlap in cognitive representations. Perspective Taking can be defined as the ability to put oneself in someone else's shoes, and consider the world from another point of view. It can refer to a simple, visuo-spatial perspective, or it can be more social and include others' intentions and mental states. In any case, PT is thought to increase the attention that is directed to others [START_REF] Galinsky | Perspective-taking and self-other overlap: Fostering social bonds and facilitating social coordination[END_REF] as well as to be increased by the presence of others [START_REF] Bukowski | From gaze cueing to perspective taking: Revisiting the claim that we automatically compute where or what other people are looking at[END_REF]. Typically, there are two dimensions: PT-state reflects the effective perspective taken by an individual at a given moment, and can be assessed experimentally, for example as the number of pictures turned to oneself or to the audience [START_REF] Knowles | Social rejection increases perspective taking[END_REF]; PT-trait reflects the individual's usual tendency to adopt another's perspective in daily life, and is traditionally assessed by a self-administered questionnaire such as the Interpersonal Reactivity Index1 (IRI) [START_REF] Davis | A multidimensional approach to individual differences in empathy[END_REF].

If we return to our two friends who are moving a couch up a staircase, at some point, they will both have to pivot: one to the left, the other to the right. Failure is certain if the person giving directions does not take the other person's visuo-spatial perspective into account: the instruction is given to pivot, but the spatial limitations of the staircase do not allow it. Furthermore, consideration of limitations specific to the environment and the individual (which requires adopting the co-actor's perspective) is necessary to maintain constant adaptation and, thus, to carry out the joint action. In this context, several authors have investigated the potential link between joint action and PT. [START_REF] Ford | Exploring social influences on the joint Simon task: empathy and friendship[END_REF] focused on a potential link between trait empathy (i.e., the spontaneous tendency to share and understand another's state of mind and feelings), friendship, and the co-representation of actions. Using the Interpersonal Reactivity Index to assess trait empathy, they found evidence of a positive correlation between PT-trait and the magnitude of the JSE: the JSE was more pronounced for individuals with higher PT-trait scores. In other words, the more the participant spontaneously tend to adopt other's perspective, the more they co-represent the other person's actions during a JST. Interestingly, the latter study also found that the relation between PT-trait and the JSE was moderated by the degree of acquaintance of co-actors: it was stronger for pairs who were friends than pairs of strangers.

The Ford and Aberdein study (op. cit.) showed that individuals' natural tendency to take another person's perspective is positively correlated with their ability to co-represent another person's actions. This finding supports the hypothesis that PT-trait might increase the perceived self-other overlap, corroborating with Galinsky et al.'s (2015) viewpoint, and might thus influence the magnitude of the JSE (however, to date, no empirical data has yet directly tested this hypothesis). The experimental manipulation of PT lends greater support to the idea of a link between PT and joint action. In two experiments, [START_REF] Müller | Perspective taking eliminates differences in co-representation of out-group members' actions[END_REF] showed that group membership (specifically, people with either black or white skin tone) impacted the appearance of the JSE: individuals co-represented actions of an in-group member, but not an out-group member. However, the impact of group membership was erased by explicitly requesting participants to take the other person's perspective (i.e., a PTstate manipulation). Taken together, these findings suggest that first, PT is an important way for individuals to spontaneously co-represent another person's actions and, secondly, the social context (in particular, group membership) may remove the effect.

The above findings indicate that PT-trait can influence JSE magnitude, and PT-state can influence its occurrence. Therefore, it seems likely that PT influences the execution of joint actions in general. In the same vein, studies have shown that manipulating the real selfother overlap through situational or social factors (the relationship between co-actors, their social attitudes, etc.) can influence the magnitude or occurrence of the JSE.

The social relationship between co-actors has been found to have a powerful influence on the magnitude of the JSE. Several studies have demonstrated a close link between the socio-emotional relationship between co-actors, and the size of the JSE. [START_REF] Ford | Exploring social influences on the joint Simon task: empathy and friendship[END_REF] reported that the magnitude of the JSE was higher for friends than strangers. In the same vein, a positive correlation has been found between the degree of socio-emotional closeness 2 and JSE magnitude [START_REF] Shafaei | Effect of Perceived Interpersonal Closeness on the Joint Simon Effect in Adolescents and Adults[END_REF]. Furthermore, Quintard, Jouffre, Croizet, and Bouquet (2020) found higher JSE magnitude between romantic lovers than opposite sex friends, and that the degree of passionate feelings was positively correlated with the size of the JSE. Taken together, these findings provide strong support for the hypothesis that a positive social relationship between co-actors increases JSE magnitude.

Similarly, a negative social relationship between co-actors has been found to reduce the size of the JSE, and may even eliminate its occurrence. For instance, a competitive relationship has been demonstrated to negatively impact the co-representation of others' actions. Ruissen and De Bruijn (2016) found that when competition was introduced prior to the joint action, the JSE weakened. Finally, Iani, Anelli, Nicoletti, Arcuri, and Rubichi (2011) found that when competition occurred during the joint task, it erased the shared representation and no JSE was observed.

Socio-emotional attitudes have also been observed to affect the appearance of a JSE.

For instance, Kuhbandner, Pekrun, and Maier (2010) showed that positive mood (i.e., a positive socio-emotional attitude) increased the magnitude of the JSE, while negative mood erased its occurrence. The impact of a negative socio-emotional attitude is corroborated by Hommel, Colzato, and Van Den Wildenberg (2009), who found that an intimidating co-actor resulted in the absence of the JSE.

Drawing upon the same idea, Costantini and Ferri (2013) manipulated another form of negative social attitude: exclusion or ostracization. The authors experimentally manipulated social exclusion (participants were included or excluded from an online game), and found that a JSE was observed for included, but not excluded participants. Costantini and Ferri interpreted their results in terms of attention allocation: after being socially excluded, individuals tend to allocate their attention to the self rather than others; consequently, the coactor's actions are not co-represented and no JSE is observed. However, their interpretation does not fit with social exclusion literature. First, [START_REF] Galinsky | Perspective-taking and self-other overlap: Fostering social bonds and facilitating social coordination[END_REF] argue that PT can be increased by an episode of social exclusion.

Empirical evidence [START_REF] Knowles | Social rejection increases perspective taking[END_REF]) corroborates this hypothesis. The latter study assessed Visual Perspective Taking (i.e., the number of pictures turned towards the individual or the audience) and demonstrated that excluded participants tended to shift perspective from egocentric (i.e., centered to the self) to allocentric (i.e., centered to the other). The experiment adopted a similar approach to the [START_REF] Costantini | Action co-representation and social exclusion[END_REF] that when asked whether they preferred to perform a task alone or with someone else, only previously excluded participants significantly chose to perform it with someone else. Furthermore, [START_REF] Bernstein | Research in social psychology: Consequences of short-and longterm social exclusion[END_REF] argued that resources for affiliation can be withheld if the new partner is not clearly available for affiliation. Taken together, these studies indicate that socially excluded individuals tend to seek for social reconnection instead of disregarding others. It highly suggests that the setting of the Joint Simon Task might be a key aspect for a JSE to emerge following social exclusion and might also explain the discrepancy between Costantini and Ferri's results and the social exclusion literature. Indeed, it should be noted that unlike other studies (Sebanz et particular Simon Task setting: the participant was asked to perform the task alone with the belief that a human co-actor was located in the adjacent room. Although this setting has been reported as sufficient for a JSE to emerge (Tsai, Kuo, Hung, & Tzeng, 2008), some studies have failed to observe a JSE under these conditions (e.g., Welsh, Higgins, Ray, & Weeks, 2007; [START_REF] Sellaro | Referential coding does not rely on location features: Evidence for a nonspatial joint simon effect[END_REF]. Therefore, the absence of a JSE for socially excluded individuals in Costantini and Ferri's study might be challenged when the Joint Simon Task is performed with a perceivable co-actor who is arguably more available for affiliation than an unperceivable co-actor.

The current study

At the intersection of the JSE, social exclusion and PT fields of research, the current study investigates the complex socio-cognitive dynamics that occur during joint action in a social exclusion context. While there is evidence that social exclusion negatively impacts the JSE occurrence [START_REF] Costantini | Action co-representation and social exclusion[END_REF], there is also evidence that social exclusion facilitates PT [START_REF] Knowles | Social rejection increases perspective taking[END_REF] and that PT positively correlates with the size of the JSE [START_REF] Ford | Exploring social influences on the joint Simon task: empathy and friendship[END_REF]. Although PT might not be at the origin of the JSE, the literature has shown its importance in the context of joint actions and social exclusion. In our opinion, the feelings and attitudes engendered by social exclusion merit particular attention. To the best of our knowledge, only one study [START_REF] Costantini | Action co-representation and social exclusion[END_REF] has investigated the effects of social exclusion on co-representation.

The assumption that social exclusion erases all forms of shared representation appears counterintuitive, given the above literature review. Therefore, the main objective of the current study was to challenge the absence of the JSE with excluded individuals, based on a classical, in-person, joint go-nogo task (i.e., with a perceivable co-actor), while controlling for PT-trait levels. In addressing this issue, our aim is to articulate the joint action and social exclusion literature, while also considering the role of PT-trait. Hence, we firstly expect to replicate findings on a positive relation between PT-trait and the JSE and explore the potential relation in a context of ostracism.

Hypotheses on the specific effect of social exclusion on co-representation are more speculative given the contradictions between the JSE and social exclusion literature. At least two empirically-driven hypotheses can be considered. First, based on the JSE literature, if social exclusion triggers a mechanism that eliminates all signs of co-representation, then using a classical in-person task setting should not change the appearance of a JSE and we might not observe a JSE for excluded participants. An alternative hypothesis emerges from the social exclusion literature: if social exclusion triggers a desire to associate with others and increases PT, then the JSE might be observed among socially-excluded participants in an inperson task setting where they are given the opportunity to interact with another person, as is the case in the classical joint go-nogo setting (i.e., in the active presence of another individual).

Finally, the present study explores how PT-trait levels and ostracism might interact and influence co-representation during a joint action. The literature shows that social exclusion increases PT [START_REF] Knowles | Social rejection increases perspective taking[END_REF] and that PT can overcome the negative influence on co-representation [START_REF] Müller | Perspective taking eliminates differences in co-representation of out-group members' actions[END_REF]. In this context, we explore how PT-trait levels are linked to the magnitude of the JSE in social exclusion vs. inclusion contexts.

METHOD

Participants

Sixty students (52 females; mean age (SD) = 19.44 (1.97)) took part in the study.

They were recruited on a voluntary basis at the University Paul Valéry-Montpellier III and were compensated with a course credit. All participants had normal, or corrected-to-normal visual acuity, and gave informed consent.

Materials and stimuli

The Interpersonal Reactivity Index questionnaire

In order to measure trait empathy, participants completed the French version of the Interpersonal Reactivity Index (Gilet, Mella, Studer, Grühn, & Labouvie-Vief, 2013), which assesses four dimensions of empathy: Empathic Concern (EC), Personal Distress (PD), Fantasy (F), and Perspective Taking (PT). Like Ford and Aberdein (2015), we were specifically interested in PT scores.

Social attitude manipulation: the Cyberball game

To manipulate participants' social attitude, we replicated the tool used by [START_REF] Costantini | Action co-representation and social exclusion[END_REF]. Cyberball is a well-known ball-tossing game that can experimentally induce a feeling of exclusion [START_REF] Williams | Cyberball :A program for use in research on interpersonal ostracism and acceptance[END_REF].

Our game was designed in QUALTRICS software. As in the original game, the participant played with two other virtual players, who were pre-programmed to exclude or include the participant (see Figure 1). The participant sends the ball to another player using the left or right keyboard arrows. In the Inclusion condition, each player (including the participant) receives 10 out of a total of 30 throws. In the Exclusion condition, the participant only receives three throws, then watches the two other players tossing the ball to each other.

In order to control for gender effects, we manipulated the gender of the other players: male participants played with virtual male players, and female participants played with virtual female players.

The game ended with a check of our manipulation. This took the form of the following question that appeared on the screen: "Did all players receive the same amount of throws?". If the participant answered "No", a new multiple-choice question appeared: "Which player received the ball the least?", with three possible answers: "Player 1", "Player 2" or "Me".

In order to verify whether the emotional response was linked to the induction of ostracism, we measured the participant's mood pre-and post-manipulation with a questionnaire. The questionnaire was composed of eight items, half of them positive (happy, good, friendly, relaxed) and the other half negative (sad, angry, unfriendly, tense).

Participants were asked to rate each item on a 5-point scale, ranging from 1 (not at all) to 5 (very much). Pre-and post-manipulation mood was calculated by subtracting the average score for negative emotions from the average score for positive emotions. The Cyberball game, and related measurements took about five minutes.

The joint go-nogo Simon Task

To measure participants' ability to co-represent actions, we used a shape categorization JST designed using OpenSesame software [START_REF] Mathôt | OpenSesame: An open-source, graphical experiment builder for the social sciences[END_REF]. Stimuli took the form of solid black shapes (a disc or square, 4x4 cm) presented on an LCD monitor (1440x900 pixels), which were displayed on a white background, 12 cm to the left or right of a central fixation cross (1x1 cm). Each participant was assigned a shape (either the disc or the square), and both were provided with a pedalboard (Scythe USB Switch) that they could press with their hand whenever they detected the shape that had been assigned to them.

The task consisted of seven blocks of 20 trials. Each trial began with the presentation of the fixation cross for 1 second, then a stimulus (the square or the disc) appeared on either the left-or right-hand side of the screen for 200 ms (participants then still had time to answer during a maximum delay of 1 second). This was followed by a blank screen (1 second) to prepare the participant for the next trial. In order to observe the spatial compatibility effect, Compatible and Incompatible trials were run. In Incompatible trials, the side of stimulus presentation and the pedalboard were opposed: the shape was presented on the right-hand side of the screen, while the participant assigned to this shape was seated on the left-hand side. In Compatible trials, both the stimulus and the pedalboard were on the same side.

Shapes appeared in random order within each block of trials. At the end of each block, participants were able to take a short break, and the message "Call the experimenter to continue" appeared on the screen.

Procedure

Participants were accompanied to the experimentation room in pairs. Each person was invited to sit in front of a computer, and the two computers were placed far enough apart to avoid visual contact (see Figure 1 for an illustration of the setting). Participants were asked not to interact during the experiment. First, they were asked to sign an informed consent form and completed the IRI questionnaire. Then, they were told that each of them was going to play an online ball-tossing game, on their own computer. Social attitude (Inclusion vs.

Exclusion) was randomly manipulated between pairs: interacting partners were assigned to the same condition. To avoid suspicion, they were told that the other Cyberball players were students from other universities in France.

The first step was to create a login. Then, the instructions appeared on the screen, and the experimenter explained them again, to check that both participants understood the rules.

Participants then completed the pre-manipulation Mood Questionnaire. During the game, participants were free to send the ball to another player using the left or right keyboard arrows. When the Cyberball game ended, the post-manipulation Mood Questionnaire appeared on the screen followed by the manipulation check questions. Both participants were then asked to sat together in front of a third computer, and proceeded with the JST.

Here, the experimenter began by assigning a shape to each participant, and explained the task (fixation cross, stimulus, response delay, white screen, fixation cross, etc.). The final instruction was to respond as fast as possible when the relevant stimulus appeared. The response assignment was counterbalanced between participants, and the total duration of the experiment was approximately 30 minutes. overall mood being lower post-manipulation (M=1.59, SD=1.33) than pre-manipulation (M=2.00, SD=1.01). The main effect of social attitude did not reach significance (F(1,47)=1.08, p=.31, ² = .098).

The analysis also revealed a marginal interaction of phase × social attitude (F(1,47)=2.82, p=.099, ² = .057). We analyzed this interaction in more detail, as we had prior hypothesis that mood would vary as a function of the manipulation. First, an independent samples t-test compared for group differences in moods in pre-manipulation phase. This revealed no pre-manipulation difference between groups (t(47)=-0.27, p=.77).

Then, a paired samples t-test compared overall mood, pre-and post-manipulation separately for included and excluded participants. This revealed a significant difference in mean overall mood, pre-and post-manipulation for excluded participants (M=0.63, SD=1.20) (t(25)=2.70, p=.012), but not for included participants (M=0.16, SD=0.65) (t( 22)=1. 21, p=.24). This indicates that the mood of excluded participants significantly decreased from pre-to postmanipulation while it did not for included participants.

As we observed an effect of social attitude on mood, we decided to add mood as a control variable in the subsequent analysis (see section 3.2).

IRI dimensions

We then ensured that participants were comparable on IRI dimensions, specifically on the PT scale. Independent samples t-tests were applied to the average of each IRI score for social attitude (inclusion vs. exclusion). Table 1 shows all comparisons and p values. We did not find any significant effect of the experimental group (included vs. excluded) for Empathic Concern, Personal Distress, or Perspective Taking (all p>.1). However, we did find a significant difference for Fantasy (t(46)=-2.66, p=.01); specifically, excluded participants (M=22.46) scored lower than included participants (M=27.39). As Fantasy was not linked to the JSE in the earlier study by [START_REF] Ford | Exploring social influences on the joint Simon task: empathy and friendship[END_REF], we did not expect this difference to impact our results. The next step in the analysis was to process reaction times (RTs) in the Simon Task.

Only correct responses were included in analyses. The error rate 1.17%. Data were then analyzed for outliers with a criterion of responses longer than 2 standard-deviations from the individual mean and form each experimental group (representing 4.06% of the dataset).

Analyses were conducted both with and without outlier's data. Since the pattern of results

was not modified, the analyses reported below included all participants data for correct trials.

Moods treatment

In order to control for the effect of mood on the JSE, we computed an Emotional Index. This was calculated by subtracting the ovjerall pre-manipulation mood score from the post-manipulation score for Social Inclusion Condition (M=-0.16, SD=0.65) and Social Exclusion Condition (M=-0.63, SD=1.20). The total was then transformed into Z scores within each condition (inclusion vs. exclusion) so that the mean of the Emotional Index does not differ in social attitude groups and can thus be added as a covariable in subsequent analyses.

ANCOVA and verification of ANCOVA assumptions

To test the hypothesis of an effect of social attitude manipulation on the size of the JSE and explore how PT-trait relate to the size of the JSE, we performed an ANCOVA with RTs in the Simon Task as a repeated dependent measure, compatibility as a within-subjects factor (Compatible vs. Incompatible trials), social attitude (exclusion vs. inclusion) as a between-subjects factor, PT scores and the Emotional Index as continuous covariates, and participant as a random factor. Thus, all significant main effects and interactions controlled for differences in emotional state and PT levels.

We then verified if ANCOVA assumptions were met. Analyses revealed that the equality of slopes-interaction was not significant (all interaction term between experimental groups and PT or Emotional Index were not significant (all >.1)) and that both covariates (PT and Emotional Index) were independent of groups (all p>.1). Analyses also revealed the homogeneity of variance for both covariates (both Levene's Test for homogeneity of variance were not significant, all p>.1) and the normality of residuals (Shaprio-Wilk test (W=.99, p>.1). A visual inspection revealed a linear relationship between the dependent variable and both covariates.

More importantly, we found a significant, three-way compatibility × social attitude × PT interaction (F(1,41)=5.76, p=.021, ² = .123; see Figure 2) independent of variation in the Emotional Index. In order to decompose this interaction, we computed a JSE for each participant (by subtracting Compatible-RT from Incompatible-RT, see Table 2) and performed separate individual regression analyses, with JSE magnitude as the dependent measure and PT as a continuous predictor for both social attitude conditions. In the Inclusion condition, we found a significant effect of PT (ß=+.54, t=2.927, p<.001) indicating that the size of the JSE was positively predicted by PT. Whereas in the Exclusion condition the main effect of PT was not significant (ß=-.13, t=-0,667, p=.51). These regression analyses must be taken with caution because of our small sample size.

DISCUSSION

The JSE is classically observed during the JST. Its magnitude can be seen as the ease with which an individual can co-represent a concurrent action. While some authors [START_REF] Sebanz | Representing others' actions: just like one's own?[END_REF] have suggested that the co-representation of another person's actions is, to some extent, automatic, others have argued that it also depends on the perceived self-other overlap, or real interpersonal similarities [START_REF] Sellaro | Referential coding does not rely on location features: Evidence for a nonspatial joint simon effect[END_REF]. In this context, there is evidence of a direct link between PT-trait scores and JSE magnitude (Ford & Aberdein, 2005). Therefore, one may hypothesize that a manipulation known to increase PT magnitude might also increase JSE magnitude.

Social exclusion is claimed to lead to negative self-evaluation (Williams et al., 2000).

In order to compensate for this negative state, people tend to actively seek new bonds [START_REF] Maner | Does social exclusion motivate interpersonal reconnection? Resolving the "porcupine problem[END_REF][START_REF] Bernstein | Research in social psychology: Consequences of short-and longterm social exclusion[END_REF], probably to reduce the interpersonal distance between themselves and others. We might, therefore, expect the magnitude of the JSE to be higher for excluded participants than for included participants, as they seek to reduce interpersonal distance. However, the only result reported in the literature [START_REF] Costantini | Action co-representation and social exclusion[END_REF] found the reverse pattern, concluding that the experience of social exclusion increased attention directed toward the self, and increased interpersonal distance, thus preventing the corepresentation of others' actions.

Therefore, the aim of the current study was to challenge the lack of co-representation (i.e., JSE) for excluded individuals, by controlling for PT levels in a classical JST. To this end, we measured participants trait empathy (including PT-trait) with the IRI, manipulated social attitude (included vs. excluded) using the Cyberball game, and observed whether the manipulation impacted participants' ability to co-represent others' actions, measured as reaction time.

Our experiment confirmed the classical JSE result, namely a main effect of compatibility, indicating that participants co-represented the co-actor's actions. We did not find a significant main effect of PT or social attitude on JSE magnitude, despite the significant main effect of our manipulation on both the manipulation check and participants' mood. Independent of our social attitude manipulation, there was an interaction between JSE magnitude and participants' mood: the lower the reported mood, the larger the JSE.

Furthermore, we found a significant interaction between compatibility, PT and social attitude: JSE magnitude increased as PT-trait increased, but only in the Inclusion condition.

At the same time, our results showed that excluded individuals could co-represent others' actions since a JSE was observed, but its magnitude did not vary with PT-trait levels. We discuss these results, first with respect to the link between PT-trait and the JSE, and then in the light of the social exclusion literature.

An alternative explanation for the absence of a link between JSE magnitude and PTtrait level in the Exclusion condition might be related to the construct. PT-trait, as assessed by the IRI, reflects a person's tendency to adopt another's perspective in daily life, which can be assumed to be either mostly positive or neutral. The construct measured by this scale might not reflect PT-trait following a negative experience, such as social exclusion. To validate this hypothesis, future research should examine the link between PT-trait and co-representation in different negative social contexts. This would not only clarify the link between PT-trait and joint action, but also specify the effect of social exclusion on PT measures. Future research that investigates the link between PT in general, and action co-representation in particular, should consider the limitations of the PT-IRI.

There is growing evidence that PT is a (socio)-cognitive process that plays a part in the phenomenon of co-representation. Our results suggest that the dispositional aspect of PT is positively linked to co-representation, but is not mandatory to activate a shared task representation. Further research is needed to clarify the impact of PT, in general, on joint actions and, more importantly, in negative contexts.

The JSE and mood

Our study found that variation in participants' mood was related to the size of the JSE.

The lower the mood, the more participants co-represented the other person's action (independent of the manipulation of social attitudes and PT-trait). This result contradicts previous findings that show that negative mood can erase action co-representation [START_REF] Kuhbandner | The role of positive and negative affect in the "mirroring" of other persons' actions[END_REF]. It is possible that, during joint action, individuals seek to reduce interpersonal distance with the co-actor and, thus, better co-represent their action in order to reduce the discomfort associated with negative mood (irrespective of the source). In order to test this hypothesis, future research should focus on how the manipulation of mood affects the subsequent shared task representation, and how variation in negative mood impacts the magnitude of the JSE.

The JSE and Social Exclusion

Finally, our study sheds new light on the co-representation of action in the context of social exclusion. While [START_REF] Costantini | Action co-representation and social exclusion[END_REF] found experimental evidence that actors suppressed their co-representation of action after social exclusion, our study revealed the reverse pattern. We identified a capacity to co-represent others' actions (unrelated to PT-trait levels) using the same social attitude manipulation (the Cyberball Game) while controlling for mood and PT-trait variation. However, how the JSE emerges when people feel ostracized

is not yet understood. Social exclusion has been shown to elicit a desire to renew affiliative bonds [START_REF] Maner | Does social exclusion motivate interpersonal reconnection? Resolving the "porcupine problem[END_REF] and also impair self-regulation [START_REF] Baumeister | Social exclusion impairs self-regulation[END_REF], which would both result in a greater JSE.

From a theoretical viewpoint, both explanations are plausible. On the one hand, social exclusion triggers a need to affiliate, thus increasing the attention directed toward others [START_REF] Knowles | Social rejection increases perspective taking[END_REF]. As a consequence, there might be a greater perceived self-other overlap, the co-actor's actions are more likely to be incorporated into the action system of the actor, the response conflict is accentuated, and the magnitude of the JSE increases. On the other hand, social exclusion is known to impair self-regulation. Therefore, even though individuals do not pay more attention to others, they find it more difficult to inhibit their answer, it takes longer to resolve the response conflict, and RTs increase. Although both explanations are possible, and not mutually exclusive, they must be discussed with regard to the absence of the JSE in other joint task settings [START_REF] Costantini | Action co-representation and social exclusion[END_REF].

DeWall, Baumeister, and Vohs (2008) provide evidence that supports the hypothesis of a desire to create new bonds. The authors showed that self-regulation can be effective, despite social exclusion, if the self-regulation task is presented as an indicator of social skills (e.g., the ability to get along with others). Arguably, the joint Simon Task is an example of this, as it is presented as a social activity that is performed in pairs. If the social interaction opportunity offered by the joint task is sufficient to restore the self-regulation of excluded participants, then the emergence of the JSE might be explained by the increased allocation of attention to others and perhaps, by increasing the perceived self-other overlap.

Moreover, this hypothesis would explain the discrepancy between the results reported by [START_REF] Costantini | Action co-representation and social exclusion[END_REF] and ours since, in their experimental setting, the co-actor was not physically present. Performing the task with a perceivable co-actor might offer participants a clear opportunity to renew affiliative bonds [START_REF] Bernstein | Research in social psychology: Consequences of short-and longterm social exclusion[END_REF]., which is not possible in a setting in which the co-actor is not perceived. This hypothesis explains the JSE we observed for excluded individuals, as the latter participants might have used the social interaction offered by the joint task to increase their efforts to fit in. It also explains its absence when the co-actor is not perceivable; here, participants make no effort or don't have enough resources to affiliate since the social interaction is implicit. If it is the case that social exclusion does not increase the attention paid to others, but only affects cognitive control then, theoretically, a JES should have been observed among participants in Costantini and

Ferri's study (2013).

Another explanation for the discrepancy in results between the two studies could be that social exclusion does not impact the ability to co-represent the other's action per se but, instead, influences the ability to simulate (or enact) a virtual co-actor, as performing a task with a credible individual requires simulating his/ her presence and/ or behavior [START_REF] Tsai | Action Co-representation is Tuned to Other Humans[END_REF]. Two possible explanations arise from this hypothesis. First, the simulation of another In our version of the task, the co-actor was present, therefore, participants did not need to simulate him/ her and, thus, to imagine him/ her as friendly or not.

Whether the results reported here are consistent with the difference in the setting for the joint Simon Task (a perceivable or unperceivable co-actor), the reason for the discrepancy in findings from the two studies remains unclear, and no definitive conclusions can be drawn from the present study. However, future research should seek to understand the mechanisms by which excluded individuals form an active representation of actions during a joint task.

To conclude our study sheds a new light on the phenomenon of the co-representation of actions in a social exclusion context, and its potential link with PT. We highlight several avenues for future research that would investigate how excluded individuals co-represent others' actions.

  study to induce social exclusion, and clearly contradicts Costantini and Ferri's explanation in terms of an attention allocation shift from others to the self. Being excluded is known to have specific and severe consequences on individuals' functioning (for a review, see Bernstein, 2016). For instance, it impairs self-regulation (Baumeister, DeWall, Ciarocco, & Twenge, 2005), and it also quickly threatens the four fundamental needs of Belonging, Self-esteem, Control, and Meaningful Existence (Williams et al., 2000, and the more recent meta-analysis by Hartgerink, van Beest, Wicherts, & Williams, 2015) unlike other forms of interpersonal aversive behaviors. In response to a perceived threat, and to reduce psychological discomfort, people tend to look for new affective bonds (Maner, DeWall, Baumeister, & Schaller, 2007). Maner et al. (2007) showed

Figure 1 .

 1 Figure 1. Schematic overview of the experimental procedure. (1a) A schematic of

Figure 2 .

 2 Figure 2. Magnitude of the JSE (ms) as a function of social attitude (exclusion vs.

  were not significant: social attitude × compatibility (F(1,41)=1.31, p=.26, ² = .031), PT × compatibility (F(1,41)=0.69, p=.41, ² = .017), Emotional Index × PT (F(1,41)=0.00, p=.98, ² = .000), Emotional Index × social attitude (F(1,41)=1.70, p=.20, ² = .525), PT × social attitude (F(1,41)=0.07, p=.80, ² = .042), Emotional Index × PT × social attitude (F(1,41)=1.07 p=.31, ² = .409), Emotional Index × PT × compatibility (F(1,41)=0.01, p=.94, ² = .000), Emotional Index × compatibility × social attitude (F(1,41)=0.28, p=.60, ² = .007), Emotional Index × compatibility × social attitude × PT (F(1,41)=0.03, p=.87, ² = .001).

  person's actions might simply be impossible after an episode of social exclusion. Secondly, the simulation might be altered by the experience of social exclusion: excluded individuals might have simulated an unfriendly co-actor. This idea is supported by several studies that show that performing the joint Simon Task in a hostile context (e.g., competition,[START_REF] Iani | The role of group membership on the modulation of joint action[END_REF]; an intimidating co-actor,[START_REF] Hommel | How social are task representations?[END_REF] erased the co-representation of action.

  al., 2003; Ford et al., 2015; Müller et al., 2011; Quintard et al., 2020; Ruissen et al., 2016; Iani et al., 2011; etc.), Costantini and Ferri chose a

Table 1 . Mean (SD) and t-test comparisons for each IRI dimension as function of social attitude (exclusion and inclusion).

 1

		Social	Social	t-test comparison
		Exclusion	Inclusion	t(46)	p value
	Perspective Taking	26.31 (5.79)	25.13 (4.44)	0.8	p=.43
	Personal Distress	22.00 (7.37)	20.13 (9.05)	0.79	p=.44
	Fantasy	22.46 (5.76)	27.39 (7.06)	-2.66	p=.01*
	Empathic Concern	32.00 (6.73)	30.70 (6.37)	0.7	p=.49
	* = p<.05
	3.2. Joint Simon Task
	3.2.1. Reactions Times (RTs) treatment

This index reflects four dimensions of empathy: Perspective Taking, Empathic Concern, Personal Distress and Fantasy.

Assessed by The Inclusion of Other in the Self scale[START_REF] Aron | Inclusion of other in the self scale and the structure of interpersonal closeness[END_REF]).

RESULTS

Manipulation checks

Amount of throws

In order to determine whether our manipulation of ostracism was effective, we analyzed data for the manipulation check and the mood questionnaire.

We first analyzed data from the manipulation check that followed the Cyberball game (Did all the players receive the same number of throws? Which player received the ball the least?). There were 30 participants per condition, of these, six noticed an exclusion in the Inclusion condition (i.e., they stated that they received the least throws), compared to 26 in the Exclusion condition (χ2 (1)=26.79, p<.05). Our manipulation was, thus, perceived.

Participants who did not notice the exclusion in the Exclusion condition or the inclusion in the Inclusion Condition were removed from subsequent analyses. One other participant was removed due to technical issues that prevented them from completing the whole task. In the end, 23 for Inclusion, 26 for Exclusion, a total of 49 participants.

Moods

We then checked whether there was a change in mood among participants who notice the exclusion ("I played less than the other players") or inclusion ("All participants received the same amount of throws") during the Cyberball game. A two-way, repeated measures analysis of variance (ANOVA) was applied, with overall mood as the dependent variable, phase (pre-or post-manipulation) as a within-subjects factor, social attitude (inclusion vs. exclusion) as a between-subjects factor, and participant as a random factor. This found a significant main effect of phase (F(1,47)=8.72, p=.005, ² = .157), with participants'

Joint Simon Task, Social Exclusion and Perspective Taking

As expected, the ANCOVA revealed a significant main effect of compatibility (F(1,41)=34.59, p<.001, ² = .458), indicating that participants answered faster in Compatible trials (M=240 ms, SD=64 ms) than in Incompatible trials (M=261 ms, SD=67ms).

This indicates a classical spatial compatibility affect (see Table 2). We found a significant interaction between compatibility and the Emotional Index covariate (F(1,41)=6.63, p=.014, ² = .139). This interaction indicates that, independent of the manipulation, mood was related to compatibility, with lower mood linked to greater JSE magnitude. We examine this interaction in more detail in the discussion.

The JSE and PT-trait

The first important point is that our study supports the hypothesis of a link between co-representation and dispositional PT. Individuals with a high level of PT-trait corepresented others' actions more than individuals with a low level of PT-trait. However, the relationship was only seen in the positive, Inclusion condition. Although excluded participants showed a classical JSE, indicating that they co-represented the other's actions, in this case, we did not find a link with PT-trait. These observations are consistent with Ford and Aberdein's (2015) findings, which identified a stronger PT/ JSE link in a positive context (friends) compared to a neutral context (strangers). However, the small sample size of our study limits its findings on socially excluded individuals and future study should try replicate for larger sample.

An initial explanation could be that the negative context eliminates the link between PT-trait and JSE magnitude. This hypothesis relies on evidence that social exclusion increases PT-state [START_REF] Knowles | Social rejection increases perspective taking[END_REF], and that PT-trait does not necessarily correlate with PTstate (see, for example, Will, Crone, van den Bos, & Güroǧlu, 2013). If social exclusion does increase PT-state, it is possible that this erased variability in PT-trait among our participants, to the point that all of our excluded participants were comparable with respect to PT. This hypothesis is relatively supported by the larger (but not significant) JSE observed in the Exclusion condition (24 ms) compared to the Inclusion condition (16 ms). In other words, the PT-trait measure was no longer representative of participants' PT-state during the Simon Task and, as a consequence, the link between PT-trait and JSE magnitude could no longer be observed. The study by [START_REF] Müller | Perspective taking eliminates differences in co-representation of out-group members' actions[END_REF] supports this idea, as the authors showed that the negative impact of interpersonal distance (social status) on JSE disappeared when participants were actively engaged in taking the co-actor's perspective.


Clémence Basse

Catherine Daniel

Allain Livartowski

Sophie Beaucaire-Danel

Nicolas Girard
email: nicolas.girard2@curie.fr

Alain Livartowski

Impact of COVID-19 on the management of patients with thoracic cancers in a tertiary referral center

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

INTRODUCTION

Coronavirus Disease 2019 (COVID-19) is caused by a novel beta-coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [START_REF] Lu | Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding[END_REF]. The first cases of pneumonia were reported in Wuhan City, China, in December 2019 [START_REF] Huang | Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[END_REF] and were rapidly followed by a worldwide dissemination. The World Health Organization (WHO) declared COVID-19 a public health emergency of international concern [START_REF]WHO Coronavirus Disease outbreak news[END_REF]. COVID-19 has affected more than 30 million people all over the world and has been responsible for more than 900,000 deaths [START_REF]Point épidémiologique su[END_REF]. France has the 9th highest number of cases of COVID-19 cases in the world, with more than 354,000 confirmed cases and almost 30,000 deaths as of September 2020 [START_REF]Point épidémiologique su[END_REF]. The French hospital emergency response ("Plan Blanc") and a nation-wide lockdown were implemented from March 16 th to May 11 th , 2020. The Paris area (Ile-de-France) remained the epicenter of the epidemic in France at this period [START_REF]Point épidémiologique au[END_REF].

Cancer patients could represent a high-risk population. Wu et al. reported a 2.3% death rate in the general population versus 5.6% among cancer patients, based on 44,672 confirmed cases in China [START_REF] Wu | Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention[END_REF].

Patients with thoracic cancers are at even higher risk to develop severe disease and die from COVID-19; mortality rate was 36% in the largest series reported. Besides landmark prognostic factors such as performance status, age, disease progression, prior administration of chemotherapy, as unique modality or in combination with immune checkpoint inhibitors, was associated with increased risk of death; admission of patients in intensive care units was lower compared to other tumor types [START_REF] Garassino | COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study[END_REF].

In this setting, clinical practice recommendations for the management of patients with thoracic malignancies based on expert consensus were published by several groups, including the European Society for Medical Oncology [START_REF] Curigliano | Managing cancer patients during the COVID-19 pandemic: an ESMO multidisciplinary expert consensus[END_REF]; the Oncology group of the French Society for Respiratory Medicine released national guidelines on March 23 th 2020 [START_REF] Girard | Proposals for managing patients with thoracic malignancies during COVID-19 pandemic[END_REF]. Here we report how these guidelines were implemented at the beginning of the pandemia, at the level of an expert center for thoracic cancers, analyzing the clinical situation, the modification of the management, and the outcome of patients over the month following the publication of the national guidelines. Ultimately, we provide a unique insight in the actual decision making for patients with thoracic malignancies in the setting of COVID-19 outbreak.

MATERIAL AND METHODS

Patient care at Institute Curie

Located in Paris, Institute Curie is a comprehensive cancer center founded by Marie Curie in 1921 and one of the leading hospitals dedicated to the treatment of patient with cancer. Overall, more than 1000 patients with thoracic cancer have been treated at Institute Curie every year since 2017, making Institute Curie one of the most dynamic cancer center for the management of thoracic tumors in France. Five fulltime thoracic oncologists are dedicated to the management of those patients. Since 2019, Institute Curie implemented virtual consultation via webcam and phone calls, to enable physicians to contact patients for follow-ups and planning of cancer treatment administration in the outpatient clinic.

Clinical practice guidelines during COVID-19 pandemic

National clinical practice guidelines for the management of patients with thoracic malignancies under the auspices of the Oncology group of the French Society for Respiratory Medicine are presented in Table 1. The key points are the following: 1) avoid the appointment of patients at cancer treatment facilities where patients could be infected by COVID-19 and encourage virtual consultation whenever possible; 2) to postpone surgery for early-stage tumors whenever applicable; 3) adapt cancer treatment regimens for patients with advanced, metastatic tumors, through modifying dose scheduling and discontinuing immune checkpoint inhibitors, especially in patients with durable disease control.

Data collection

Inclusion criteria for this analysis were the following: 1) histologically-confirmed thoracic malignancy, including lung cancer, mesothelioma, and thymic tumors, 2) with scheduled appointment for a consultation and/or administration of cancer treatment and/or hospitalized in the inpatient clinic, 3) from March 23 rd to April 17 th 2020 in the month following the publication of the clinical practice recommendations for the management of patients with thoracic malignancies in the context of the pandemia . This retrospective study was approved by the Institutional Data Review Committee of Institute Curie; all patients gave consent at the initiation of their care for the retrieving of healthcare information from their electronic medical record. Clinical data were then retrospectively collected, including patients baseline characteristics, histology, stage, treatment regimen, dates of treatment, and treatment modification, as well as COVID-19 status and death.

RESULTS

Patients' characteristics

During the study period, a total of 343 patients with thoracic malignancies had been scheduled for an appointment at Institute Curie (Figure 1). Three patients were not able to actually attend because of quarantine, and one patient without cancer was excluded from the analysis. Overall, 288 patients (85%) had Non-Small Cell Lung Cancer (NSCLC), 26 had Small-Cell Lung Cancer (8%), 11 had mesothelioma (3%), and 14 had a thymic tumor (4%). Among NSCLC patients, 23 patients had early-stage/localized disease (8%), 48 had a locally advanced disease (17%), and 217 metastatic disease (75%) (Table 2).

A total of 25 patients were new patients and had their first appointment during the period; 127 (37%) patients were seen through virtual consultation, and 228 (67%) were physically seen by a physician at Institute Curie, and 16 (5%) had both types of appointment (virtual and physical appointments) during the period.

Treatment adaptations

During the study period, 110 (32%) patients had the treatment strategy adapted because of COVID-19.

A total of 34 (31%) of those patients were receiving immune checkpoint inhibitors (ICI), including durvalumab for locally advanced NSCLC, and pembrolizumab for metastatic NSCLC, with a switch to flat dosing every 4 to 6 weeks (Table 3). Additional 55 (50%) patients received primary G-CSF prophylactic treatment after chemotherapy, among whom 30 were receiving a combination of chemotherapy plus immune checkpoint inhibitors. We did not notice any uncommon nor relevant adverse event related to the administration of G-CSF concomitantly to immunotherapy. Oral, instead of intravenous, vinorelbine was administered to 8 (7%) patients at home after blood test control.

Treatment was suspended for 12 patients (3.5% of the cohort) because of the COVID-19 context, including early discontinuation of chemotherapy or immunotherapy in 7 patients with controlled disease; 1 additional patient with SCLC had altered general status discontinuated chemotherapy, and finally died from cancer; 1 patient had a delayed initiation of radiotherapy for locally-advanced disease, because of COVID-19 disease suspicion (he finally was tested negative).

Through the important use of virtual consultation, no impact was observed for the 18 patients under surveillance after surgical resection of early-stage NSCLC, and for the 46 patients with oncogeneaddicted NSCLC, especially those receiving targeted agents.

Concordance with guidelines

Of the 110 modifications of treatment strategies, 101 (92%) were in accordance with the recently published guidelines; for 9 patients, treatment modification had not been stated in the guidelines: cancellation of the fourth cycle of adjuvant chemotherapy (n=2), cancellation of the fourth cycle of chemotherapy during concomitant chemo-radiotherapy (n=2), no initiation or early discontinuation of durvalumab before one year in patient with controlled disease (n=2), 3 patients did not received the planned treatment: one patient did not receive post-operative radiotherapy -an option highly debated and ultimately known as potentially deleterious -, and 2 elderly patients were directed to palliative care because of their age and poor performance status.

Death related to COVID-19

A total of 5 (1.5%) patients were diagnosed with COVID-19 disease, 1 of whom (with mesothelioma) died from disease complications; 11 (3.2%) additional patients died from cancer during the study period.

DISCUSSION

Our report is the first study, to our knowledge, to analyze how treatment strategies for thoracic malignancies were adapted during the COVID-19 outbreak in early 2020 at an expert institution level, after guidelines were implemented. Our data show only 32% of patients had the treatment strategy adapted during the study period; the vast majority of those adaptations were done in accordance with guidelines. Only 5 patients were infected with COVID-19.

Our data indicate that 68% of patients experienced no change in the treatment strategy during the COVID-19 outbreak; this may be explained by 1/ the French health authorities recommendation to continue cancer care at cancer centers such Institute Curie, and sparing these centers from the referral by emergency units of non-cancer patients with COVID-19, 2/ the early organization of our center to avoid COVID-19 positive patients to come to the hospital, through systematic call the day before their appointment, and to orientate such patients presenting with symptoms potentially related to COVID-19 in a dedicated pathway within the hospital, thus securing non-COVID-19 patients regarding the safety of outpatient visits at Institute Curie, and 3/ the high proportion of patients in the setting of surveillance, or treated with targeted agents not requiring such adaptations. Through such organization, as well as systematic delivery of neutropenia prophylaxis, only few patients in our cohort presented with COVID-19 infection. The combination of G-CSF and immunotherapy was never described before in thoracic oncology, but no relevant adverse event was described for patients receiving G-CSF after a combination of chemotherapy and immunotherapy. Still 1 (20%) patient with mesothelioma died from the disease, showing the high fragility of these patients among patients with thoracic tumors. The death rate was in line with previous studies focusing on the mortality of COVID-19 in patients with thoracic malignancies.

Meanwhile, the high proportion of patients receiving ICI allowed us to reduce the number of patients visit at the hospital through adaptation of dosing regimens, in line of the guidelines based on pharmacokinetics studies and dosing modification released after the approval of those agents. Whether such adaptations will be continued beyond the COVID-19 outbreak remains to be evaluated.

In the future, redefining patient pathways in the setting of ICI treatment may also include virtual consultation the day before treatment delivery, the use of web-based application for follow-up and capture of patient-related outcomes or side effects, or the at-home administration of treatment Ultimately, our data validate the guidelines released in an emergency setting at the beginning of the COVID-19 outbreak in early 2020, as 92% of treatment adaptations actually done were in accordance with those guidelines [START_REF] Girard | Proposals for managing patients with thoracic malignancies during COVID-19 pandemic[END_REF]; only 8% of treatment modifications were not anticipated by the guidelines, but were actually based on standard clinical practice.

To conclude, our study provides a unique insight in the decision making for patients with thoracic malignancies in the setting of COVID-19 outbreak, showing how guidelines were implemented in the clinic. This work also describes what may be optimize in clinical practice of thoracic oncology in the future to reduce the number of physical appointments to the hospital. The COVID-19 pandemia may have been a triggering event for the development of virtual medicine.

Absence of targetable alteration

1st line -continuation of chemotherapy plus immunotherapy until 4 cycles if already started -systematic discussion before the initiation of maintenance -single-agent immunotherapy with PEMBROLIZUMAB : if treatment started for less than 1 year, possibility to double the dose and the delay the time between injections (PEMBROLIZUMAB 400mg every 6 weeks). If stable disease and treatment for more than 1 year, discussion of discontinuation ≥2 lines -systematic discussion before the initiation of a chemotherapy -single-agent immunotherapy : if treatment started for less than 1 year, possibility to double the dose and the delay the time between injections (NIVOLUMAB 480mg every 4 weeks, PEMBROLIZUMAB 400mg every 6 weeks, ATEZOLIZUMAB 1200mg every 3 weeks). If stable disease and treatment for more than 1 year, discussion of discontinuation -chemotherapy : discussion of cancelation of day 8 and day 15 (PACLITAXEL, VINORELBINE)

Figure 1 .

 1 Figure 1. Flow-chart

Table 1 .

 1 Table 1. French national guidelines concerning thoracic tumors and COVID-19, according to the SPLF (Société de Pneumologie de Langue Française), published on March 18th 2020

Table 2 .

 2 Patients'characteristics

Table 3 .

 3 Impact of COVID-19 pandemia on patient management

	Patients scheduled for a consultation
	n=343	-1 new patient who did not come
		-1 patient without cancer
		-2 patients from the international services
	Patients who had a consultation
	n=339

Table 1 . French national guidelines concerning thoracic tumors and COVID-19, according to the SPLF (Société de Pneumologie de Langue Française), published on March 18th 2020

 1

	NSCLC	Surgery	Radiotherapy

Small-cell lung cancer

-continuation of treatment if already started -continuation of treatment -CARBOPLATIN preferred to CISPLATIN -systematic G-CSF prophylaxis to avoid neutropenia

MESOTHELIOMA

-systematic discussion before the initiation of treatment in advanced disease -single-agent immunotherapy : if treatment started for less than 1 year, possibility to double the dose and the delay the time between injections (NIVOLUMAB 480mg every 4 weeks). If stable disease and treatment for more than 1 year, discussion of discontinuation -systematic discussion to discontinue BEVACIZUMAB maintenance THYMIC TUMOR -postponing of surgery whenever possible Legend : G-SCF = Granulocyte-Colony Stimulating Factor; NSCLC = Non Small cell Lung Cancer; SCLC = Small Cell Lung Cancer.


Frédéric Costes
email: fcostes@chu-clermontferrand.fr

F Pr

Costes

Effets physiologiques de l'activité physique Physiological adaptations with physical activity

Keywords: cardiovascular function, skeletal muscle, exercise training, metabolism

Numerous adaptations have been observed with physical activity (PA), interesting every organs. Among them, skeletal muscle and cardiovascular functions, metabolism, bone mass, mental state,sleep, pain and immunity are the more evident. These beneficial health-related adaptations are associated with an increase in maximal aerobic capacity (VO2max) or muscle strength which are strong predictors of survival (12 % decrease of death per 3,5 ml/kg/min increase of VO2max). These effects and their magnitude are linked to the type of PA performed (leisure time, domestic , occupational tasks) and their duration/frequency. These adaptations are observed all along the life span but are particularly important during elderly when they can slow down the aging process by improving cardiovascular risk factors and sarcopenia.

2

Résumé

Les adaptations de l'organisme avec l'activité physique (AP) sont multiples et touchent tous les organes. Parmi celles-ci citons les fonctions musculaire, cardiovasculaire, le métabolisme, la masse osseuse, l'état psychique, le sommeil, la douleur et l'immunité. Ces adaptations bénéfiques pour la santé permettent d'augmenter la capacité maximale aérobie (VO2max) ou la force musculaire qui sont de puissants prédicteurs de mortalité (diminution de 12 % de mortalité par augmentation de 3,5 ml/kg/min de VO2max). La nature et l'amplitude de ces effets sont dépendantes du type d'AP réalisées (exercices en endurance ou en résistance) du cadre dans lequel elles sont réalisées (loisir, domestique, professionnelle) et de la dose. Ces adaptations sont observées à tous les âges de la vie et elles sont d'autant plus importantes chez le sujet âgé où elles peuvent ralentir l'effet du vieillissement en améliorant les facteurs de risque cardiovasculaire et en luttant contre la sarcopénie.

Mots-clés :

fonction cardiovasculaire / muscle squelettique/ entraînement physique / métabolisme L'exercice est une médecine professait déjà Hippocrate. Plus récemment, des rapports de l'ANSES et de l'INSERM [START_REF]Actualisation des repères du PNNS -Révisions des repères relatifs à l'activité physique et à la sédentarité[END_REF][START_REF]Inserm. Activité physique. Prévention et traitement des maladies chroniques. Collection Expertise collective[END_REF] ont synthétisé les données concernant les adaptations physiologiques avec l'activité physique (AP) ainsi que les effets bénéfiques sur la prévention des maladies. Des adaptations intéressent de multiples organes et fonctions schématisée dans la figure 1; dans ce texte, nous allons décrire les plus importantes et les mécanismes biologiques qui les expliquent. Bien qu'il s'agisse d'un apport majeur pour la santé, nous ne traiterons pas de l'effet reconnu de l'AP sur la prévention de 35 maladies.

Capacité physique

La capacité maximale aérobie est habituellement déterminée par la mesure de la consommation maximale d'oxygène (VO2max) lors d'un test d'effort incrémental mené jusqu'à l'épuisement. VO2max correspond à la capacité maximale des systèmes respiratoire et cardiovasculaire à apporter l'oxygène aux muscles actifs, traduisant l'aptitude du sujet à réaliser un effort intense et par analogie peut être comparée à la cylindrée d'un moteur. Elle peut également être estimée à partir de tests sous-maximaux, ou de la puissance maximale d'exercice. VO2max est un puissant facteur de mortalité, indépendamment du genre, de l'âge, des facteurs de risque cardiovasculaires ou de l'existence de pathologies [START_REF] Ross | Importance of Assessing Cardiorespiratory Fitness in Clinical Practice: A Case for Fitness as a Clinical Vital Sign: A Scientific Statement From the American Heart Association[END_REF] . Il s'agit d'un paramètre qui diminue régulièrement avec l'âge, environ 10 % par décade après 30 ans.

Néanmoins, VO2max est modifiable par la pratique régulière d'une activité physique ou d'un entraînement en endurance [START_REF] Jackson | Role of lifestyle and aging on the longitudinal change in cardiorespiratory fitness[END_REF]. Une augmentation de VO2max de 10 à 15 % (soit 3 à 5 ml/kg/min) est mesurée habituellement après un entraînement endurant de 6 à 8 semaines chez un sujet d'aptitude moyenne ou, à plus long terme, après une reprise régulière des activités physiques quotidiennes. Ce gain un impact sur la survie puisque, il a été montré sur un suivi de 20 ans, qu'une augmentation de 1 MET de la capacité maximale aérobie (3,5 ml O2/kg/min) est associée à une réduction de 12 % de la mortalité. De plus les sujets initialement non entrainés qui amélioraient leur capacité maximale pendant le suivi voyaient leur risque de décès diminuer de 35 % [START_REF] Kokkinos | Exercise capacity and mortality in older men: a 20-year follow-up study[END_REF]. Un niveau de 15 à 18 ml/kg/min est considéré comme le seuil minimal pour préserver l'indépendance fonctionnelle des sujets.

Ceci correspond à marcher entre 4 et 5 km/h, à plat ou avec une faible pente, monter lentement des étages, activités de jardinage alors que le coût métabolique des activités de la vie quotidienne (prendre soin de soi, tâches ménagères…) se situant entre 8 à 12 ml/kg/min. Lors de l'épreuve d'effort cardiorespiratoire, la mesure du seuil ventilatoire permet également d'apprécier le niveau d'indépendance fonctionnelle. Il s'agit de l'intensité des efforts pouvant être maintenus sans inconfort (dyspnée ou fatigue) et elle se situe approximativement à 60-70 % de VO2max. Sa diminution (<40%VO2max théorique) traduit un déconditionnement musculaire et altère la qualité de vie des sujets quand il se situe au niveau ou en dessous du coût des activités de la vie quotidienne (soit 2 à 4 METs).

Adaptations musculaires

La réalisation d'un exercice physique, d'intensité suffisante, aboutit à un déséquilibre de l'homéostasie musculaire, induisant une réponse biologique (facteurs de transcription) et la répétition de ces réponses avec l'entrainement permet les modifications du phénotype [START_REF] Egan | Exercise metabolism and the molecular regulation of skeletal muscle adaptation[END_REF].

Les exercices dits endurants améliorent la capillarisation des fibres, la sensibilité à l'insuline, le volume des mitochondries et leur fonction (augmentation de l'expression de PGC1a et de SIRT3, augmentation des enzymes oxydatives, diminution de l'index de fission). Les exercices dits résistants augmentent la masse et la force des groupes musculaires stimulés, impliquant des processus intracellulaires de protéosynthèse sous le contrôle de la voie IGF1/AKT/mTOR, avec une inhibition concomitante des voies de protéolyse ubiquitine-dépendantes ou autophagie [START_REF] Favier | Cellular and molecular events controlling skeletal muscle mass in response to altered use[END_REF]. Les recommandations d'AP préconisent de combiner les exercices endurants avec un renforcement musculaire afin d'optimiser les effets musculaires. Ceci est d'autant plus important qu'il s'agit de sujets âgés ou présentant une pathologie chronique afin de contre-carrer le développement d'une sarcopénie. En effet chez des sujets en bonne santé, une méta-analyse récente a retrouvé un impact positif de la force de préhension de la main sur la mortalité (HR 0,69), avec un effet plus marqué chez les femmes [START_REF] García-Hermoso | Muscular Strength as a Predictor of All-Cause Mortality in an Apparently Healthy Population: A Systematic Review and Meta-Analysis of Data From Approximately 2 Million Men and Women[END_REF] ; un effet comparable mais de moindre amplitude est noté avec la force du quadriceps (HR 0,86). Une influence de la perte de force du handgrip sur la mortalité a également été mise en évidence dans plusieurs groupes de patients souffrant de pathologie aiguë (soins intensifs) ou chronique (cancer, insuffisances respiratoire, rénale) [START_REF] Jochem | Association Between Muscular Strength and Mortality in Clinical Populations: A Systematic Review and Meta-Analysis[END_REF]. Chez le sujet âgé, des adaptations musculaires sont constatées après des programmes d'entraînement tant en endurance qu'en résistance de façon comparable à celles constatées chez des sujets plus jeunes [START_REF] Bangsbo | Copenhagen Consensus statement 2019: physical activity and ageing[END_REF].

Les exercices de renforcement musculaire permettent d'améliorer la masse musculaire et le rapport force/masse traduisant une amélioration de l'activation motrice. Il a été montré chez la personne âgée, que l'activité physique, incluant un renforcement musculaire, diminue la fatigabilité (gain d'endurance musculaire), permet de réduire le risque de chute, d'améliorer l'indépendance fonctionnelle (augmentation de la souplesse) et ralentit le déclin cognitif d'autant plus que l'AP est importante.

Le muscle squelettique est actuellement reconnu comme un organe sécrétoire, « dialoguant » avec les autres tissus dont le tissu adipeux, et les myokines produites modulent des réponses métaboliques en réponse à l'exercice. L'interleukine 6 est la myokine la plus étudiée, exerçant une action régulatrice de la glycémie en stimulant la captation musculaire du glucose et en augmentant la sécrétion d'insuline [START_REF] Pedersen | Muscles, exercise and obesity: skeletal muscle as a secretory organ[END_REF]. Elle a par ailleurs des effets sur l'hypertrophie musculaire et l'angiogénèse. Parmi, les nombreuses cytokines musculaires citons l'irisin qui permet la transformation de la graisse blanche en brune et augmente la dépense énergétique, l'IL15 qui stimule le fonctionnement mitochondrial, diminue l'insulinorésistance et inhibe l'inflammation. Enfin, la myostatine et la myonectine sont des régulateurs négatifs de la masse musculaire [START_REF] Das | Myokines in Skeletal Muscle Physiology and Metabolism: Recent Advances and Future Perspectives[END_REF].

Le dernier niveau de régulation des adaptations musculaires avec l'exercice aigu ou l'entraînement est représenté par des modifications épigénétiques, comme la méthylation des promoteurs dePGC1α, PPARγ ou l'acétylation des histones de GLUT4, impliqués dans le métabolisme énergétique, glucidique et l'adipogénèse. Enfin la stabilité des ARN messagers peut être modulée par l'AP, avec la sur-ou sous-expression de microARN (miR 1, 181, 308, 499…) dont certains sont spécifiques du muscle squelettique [START_REF] Egan | Exercise metabolism and the molecular regulation of skeletal muscle adaptation[END_REF][START_REF] Francaux | Exercise and the control of muscle mass in human[END_REF]

Effets cardiovasculaires

La mortalité et l'incidence de la maladie coronarienne sont diminuées avec l'activité physique, avec une réduction du risque de 20 à 50 % selon la quantité d'AP réalisée [START_REF] Mora | Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms[END_REF].

Une augmentation de 1 MET de la capacité maximale aérobie diminue de 15 % la mortalité cardiovasculaire et de 12 % la mortalité générale [START_REF] Kodama | Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis[END_REF]. Ceci est observé dès des faibles niveaux d'AP (15 minutes quotidienne d'AP d'intensité modérée). Cet effet est plus marqué pour les activités de loisir que celles liées au travail ou aux activités domestiques. Il parait indépendant de l 'effet direct de l'AP sur le poids corporel des sujets. Ce bénéfice est retrouvé, mais à un moindre degré, chez les sujets ayant des facteurs de risque cardiovasculaires tels que l'obésité, l'hypertension artérielle, le syndrome métabolique ou le diabète de type 2.

Cet effet protecteur de l'AP sur le coeur est expliqué par le remodelage cardiaque constaté chez les sujets entrainés par rapport aux inactifs (hypertrophie myocardique, augmentation du volume télédiastolique, et de la vitesse de relaxation) conduisant à augmenter le débit cardiaque maximal et par là VO2max. L'AP régulière et fréquente tout au long de la vie (4 à 5 séances hebdomadaires) permet de contre-carrer le vieillissement physiologique cardiovasculaire, en améliorant la compliance et la distensibilité ventriculaire [START_REF] Bhella | Impact of lifelong exercise "dose" on left ventricular compliance and distensibility[END_REF] . Par ailleurs, l'entraînement physique permet de diminuer la fréquence cardiaque de repos et la vitesse de récupération après un exercice. La FC de repos plus basse offre une capacité d'augmentation plus large, la fréquence cardiaque maximale étant fixe pour un sujet donné et à un âge donné. Cette adaptation bénéfique est liée à l'augmentation du tonus parasympathique cardiaque.

De plus la fonction endothéliale vasodilatatrice est améliorée, ce qui permet d'augmenter la libération de monoxyde d'azote, y compris au niveau de la microcirculation coronarienne [START_REF] Lavie | Exercise and the cardiovascular system: clinical science and cardiovascular outcomes[END_REF]. On a également mis en évidence une production de cytokines protectrices et de précurseurs endothéliaux circulants. D'autre part, l'AP améliore le profil lipidique (diminution du LDL cholestérol et des triglycérides, augmentation du HDL) ce qui réduit l'effet du LDL Cholestérol pour la formation de la plaque d'athérome, et donc la survenue de pathologie cardiovasculaire. Au niveau des cardiomyocytes, des adaptations biologiques ont été retrouvées au niveau de la traduction des protéines SERCA2 et phospholambane impliquées dans les mouvements calciques, permettant une augmentation de la contractilité et de la relaxation [START_REF] Lavie | Sedentary Behavior, Exercise, and Cardiovascular Health[END_REF]. La pression artérielle augmente avec l'inactivité physique et l'impact est plus marqué chez l'hypertendu. L'AP régulière permet de diminuer la pression artérielle, avec en moyenne une réduction de 3,4 et 2, 4 mmHg des pressions systolique et diastolique avec 3 à 5 séances d'AP par semaine [START_REF] Nystoriak | Cardiovascular Effects and Benefits of Exercise[END_REF]. Or un effet sur l'incidence des pathologies cardiovasculaires est observé dès une réduction de 1 mmHg. Cet effet s'explique par la diminution des résistances périphériques liée à une meilleure capacité de vasodilatation NO dépendante.

Enfin, les AP d'intensité modérée à élevée (mais pas faible) permettent de réduire le risque d'accidents vasculaires cérébraux (AVC) de 10 à 30 %. Ceci a pu être montré chez les sujets courant plus de 8 km par jour par rapport à ceux courant moins de 2 km, avec une réduction du risque de 60 %. Cet effet bénéfique est lié à une réduction de l'épaisseur intima media de la carotide, ainsi qu'une diminution du fibrinogène et de l'activation plaquettaire qui participent à la survenue de l'AVC.

Effets métaboliques

L'AP a un effet bénéfique sur le poids quel que soit l'âge du sujet. Elle est associée à une diminution de l'adiposité, de l'obésité ou du surpoids tant chez l'enfant (< 5 ans) que chez l'adolescent. En outre l'incidence de l'obésité est augmentée avec le temps passé devant les écrans chez le jeune enfant.

Les rapports récents ont confirmé l'expertise INSERM de 2008 statuant avec le plus haut niveau de preuve (grade A) que l'AP chez l'adulte permet de prévenir la prise de poids, et de maintenir la perte de poids. Globalement, l'AP permet de prévenir les comorbidités de l'obésité, en particulier le risque cardiométabolique lié à la graisse viscérale. Les AP d'intensité élevée sont celles qui induisent l'effet le plus important avec un effet anoréxigène transitoire.

Il existe un fort niveau de preuve que l'AP permet de prévenir la survenue d'un diabète de type 2 (DT2) chez les sujets à risque. Une pratique régulière associée à une alimentation équilibrée a monté son efficacité lors d'études interventionnelles, et pendant un suivi allant jusqu'à 3 ans après l'intervention [START_REF]Actualisation des repères du PNNS -Révisions des repères relatifs à l'activité physique et à la sédentarité[END_REF]. L'effet bénéfique est plus relié à la quantité d'AP réalisée qu'à son intensité et est observé quel que soit l'index de masse corporelle ou l'alimentation. Son mécanisme passe par la diminution en aigu de la glycémie et la diminution de l'insulinorésistance avec l'entraînement. De plus l'AP permet de diminuer le stockage des graisses viscérales, et au niveau musculaire augmente l'oxydation mitochondriale des lipides.

La réduction du temps de sédentarité a des effets similaires à l'AP avec une réduction de l'incidence du DT2 de 12 % par tranche de 2h de diminution du temps assis.

Effets squelettiques

L'AP permet d'activer la formation osseuse et de freiner la résorption aux sites où les contraintes mécaniques s'exercent. Elle a un effet bénéfique sur le pic de masse osseuse chez l'enfant et l'adolescent, et un gain modeste de contenu minéral osseux et de densité minérale osseuse est retrouvé après des programmes d'entrainement incluant des exercices en charge chez l'enfant et l'adolescent [START_REF] Behringer | Effects of weight-bearing activities on bone mineral content and density in children and adolescents: a meta-analysis[END_REF].

La pratique d'une activité physique pendant l'adolescence et jusqu'à l'âge adulte permettrait de conserver la masse osseuse constituant un facteur de protection contre les fractures ostéoporotiques. Les données actuelles ne permettent pas d'établir un effet dose-réponse de la durée, intensité, la fréquence des AP ayant un bénéfice sur l'os. Chez le sujet âgé, en particulier chez la femme ménopausée, l'AP avec impact augmente la densité minérale osseuse au niveau du rachis, du col fémoral et du trochanter et réduit le nombre de fractures. Les programmes d'entrainement permettent de prévenir une perte de 1 % par an de la masse osseuse au niveau de la colonne lombaire et du col fémoral.

Effets sur le sommeil et le psychisme

L'AP permet d'améliorer la qualité et la quantité de sommeil. Elle agirait comme un synchronisateur du rythme circadien. Le sommeil est plus long et plus profond et l'éveil diurne de meilleure qualité. Une méta-analyse récente a regroupé 66 études et 2863 sujets, dont 25 études avec des pratiques régulières d'exercice [START_REF] Kredlow | The effects of physical activity on sleep: a meta-analytic review[END_REF]. La durée et l'efficacité du sommeil sont augmentées de façon modérée. La latence d'endormissement est raccourcie et la qualité de sommeil est améliorée de façon importante (coefficient de Cohen 0,74). L'âge diminue l'effet de l'AP sur la latence d'endormissement mais n'a pas d'impact sur les autres paramètres du sommeil. Concernant le type des AP réalisées, aucune influence significative n'a été retrouvée de la durée des séances, leur fréquence hebdomadaire ou la durée des programmes (de 2 à 52 semaines) sur la qualité de sommeil.

Une pratique régulière d'AP permet de diminuer l'anxiété, l'état de stress et le risque de dépression [START_REF] Asmundson | Let's get physical: a contemporary review of the anxiolytic effects of exercise for anxiety and its disorders[END_REF]. Cet effet protecteur serait plus important avec les AP de loisirs. Certaines études ont rapporté une amélioration de l'anxiété après des programmes d'exercice de posture de type Yoga ou Tai Chi. L'effet bénéfique de l'AP sur l'anxiété nécessite des séances d'au moins 20 minutes répétées 3 à 4 fois par semaine. Le mécanisme d'action de l'effet de l'AP sur la réduction du stress n'est pas complètement élucidé mais pourrait être lié la diminution de la production du cortisol et de catécholamines avec l'AP régulière.

Effet sur la douleur

L'effet de l'exercice aigu peut être double avec un effet analgésiant constaté chez le sujet sain, (augmentation du seuil douloureux, modification de l'intégration centrale du stimulus par une augmentation de la sécrétion d'opioïdes) ou à l'inverse déclencher une douleur notamment chez les sujets arthrosiques ou fibromyalgiques [START_REF] Lima | Does exercise increase or decrease pain? Central mechanisms underlying these two phenomena[END_REF]. Néanmoins, les programmes d'AP ont montré leur bénéfice dans différents groupes de sujets souffrant de douleur chronique, même si l'effet est jugé modeste et inconstant [START_REF] Geneen | Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews[END_REF].

8 .Figure 1 .

 81 Figure 1. Effets reconnus de l'activité physique sur différentes fonctions physiologiques (adapté d'après Sharma et coll. [26]) CV: cardiovasculaire, PA: pression artérielle, AVC: accident vasculaire cérébral