Marcela Ovando-Tellez

Benjamin Rohaut

Nathalie George

Theophile Bieth

Laurent Hugueville

Yoan Ibrahim

Ophelie Courbet

Lionel Naccache

Richard Levy

Béatrice Garcin

Emmanuelle Volle
email: emmavolle@gmail.com

Does adding beer to coffee enhance the activation of drinks ? An ERP study of semantic category priming

Keywords: Abstract thinking, Categorization, Semantic Priming, EEG, N400, Semantic Memory

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Introduction

Categorization is a complex cognitive process that allows brains to classify objects and events based on common characteristics (Cohen, 2005). Based on our knowledge, we categorize everything we perceive, and this allows us to make sense of our environment and experiences. This process of categorization is essential for human thinking, learning or forming general concepts, and problem-solving [START_REF] Gelman | Child categorization[END_REF][START_REF] Kotovsky | Comparison and categorization in the development of relational similarity[END_REF].

However, the cognitive mechanisms by which we categorize or fail to categorize are poorly understood.

Categorization abilities are typically measured by the Wechsler Adult Intelligence Scale (WAIS) similarity subtest (Wechsler, 2008). In this test, subjects are asked to categorize two items (e.g., "How are an orange and a banana alike?") and name their taxonomic category ("fruits"). Previous studies report impairment in categorization tasks, such as the similarity task, in patients with frontal neurodegenerative diseases [START_REF] Garcin | A mosquito bites and a butterfly flies: A specific response type of frontal patients in a similarity task[END_REF][START_REF] Lagarde | Why do patients with neurodegenerative frontal syndrome fail to answer: "In what way are an orange and a banana alike?[END_REF], suggesting a critical role of executive control functions in this task. However, categorization has also been shown to occur automatically and to rely on semantic associations [START_REF] Praß | Ultra rapid object categorization: effects of level, animacy and context[END_REF], suggesting that categorization depends on the organization of semantic memory. In particular, a given category seems to be implicitly pre-activated by an exemplar of this category (e.g., seeing "dog" pre-activates "animal") [START_REF] Mirman | Taxonomic and thematic semantic systems[END_REF]. The critical role of executive control function in the similarity task may seem paradoxical with the notion that categorization occurs implicitly, based on semantic associations. Hence, how the category is activated during the similarity task remains an open question. More specifically, the question we raised is: do two exemplars of a given category pre-activate this category more than each exemplar would do alone, in a semantic priming paradigm? Addressing this question is essential to clarify the cognitive processes underlying categorization. It is also essential to better appreciate the cognitive difficulties of neurological patients.

The semantic priming paradigm is commonly used to explore implicit categorization and the organization of semantic memory, including the organization into categories [START_REF] Chen | Automatic processing of taxonomic and thematic relations in semantic priming -Differentiation by early N400 and late frontal negativity[END_REF][START_REF] Jones | Different influences on lexical priming for integrative, thematic, and taxonomic relations[END_REF][START_REF] Maguire | EEG theta and alpha responses reveal qualitative differences in processing taxonomic versus thematic semantic relationships[END_REF] (for reviews [START_REF] Hutchison | Is semantic priming due to association strength or feature overlap? A microanalytic review[END_REF][START_REF] Jones | Lexical priming: Associative, semantic, and thematic influences on word recognition[END_REF][START_REF] Lucas | Semantic priming without association: A meta-analytic review[END_REF]). The principle of a semantic priming paradigm is to measure how much people are faster and/or more accurate in processing a target word when it is preceded by a semantically related prime word, as compared to an unrelated prime word. This measure reflects the semantic priming effect. The semantic priming effect is also explored with electrophysiological measures using event-related potentials (ERPs). ERPs provide temporal measures of the neural activity following stimulus presentation. Specifically, the N400 component, a negative deflection occurring approximately 400 ms after the stimulus onset and typically maximal at centro-parietal electrodes sites, is an electrophysiological landmark of semantic priming effects (for review see [START_REF] Kutas | Thirty Years and Counting: Finding Meaning in the N400 Component of the Event-Related Brain Potential (ERP)[END_REF]. The N400 appears very sensitive to semantic relatedness. Its amplitude is smaller when a word is preceded by a related rather than an unrelated word [START_REF] Kutas | Psycholinguistics electrified: Event-related brain potential investigations[END_REF][START_REF] Lau | A cortical network for semantics: (de)constructing the N400[END_REF]. The difference in the N400 amplitude in different semantic priming conditions is referred to as the N400 priming effect, and it can occur even in the absence of response time (RT) priming effect [START_REF] Chwilla | Mediated Priming in the Lexical Decision Task: Evidence from Event-Related Potentials and Reaction Time[END_REF][START_REF] Chwilla | Event-related potential and reaction time evidence for inhibition between alternative meanings of ambiguous words[END_REF], suggesting a higher sensitivity. Many studies using a semantic priming paradigm have shown a relationship between the N400 amplitude and the strength of prime-target associative relatedness [START_REF] Bentin | Event-related potentials, lexical decision and semantic priming[END_REF][START_REF] Holcomb | Automatic and attentional processing: An event-related brain potential analysis of semantic priming[END_REF][START_REF] Rugg | The Effects of Semantic Priming and Word Repetition on Event-Related Potentials[END_REF].

Using these behavioural and ERP measures, the semantic priming paradigm has allowed showing that different types of semantic relationships can yield priming effects. In particular, a series of studies show that both thematic (items that share a common context without necessarily sharing similar features, e.g., "rabbit" -"carrot" [START_REF] Lin | Thematic relations in adults' concepts[END_REF] and taxonomic (items sharing specific features such as attributes and functional properties, e.g., "dog" -"cat"; [START_REF] Gelman | Child categorization[END_REF][START_REF] Mirman | Taxonomic and thematic semantic systems[END_REF][START_REF] Murphy | The big book of concepts, The big book of concepts[END_REF] relationships between prime and target yield a significant priming effect [START_REF] Chen | Automatic processing of taxonomic and thematic relations in semantic priming -Differentiation by early N400 and late frontal negativity[END_REF][START_REF] Hagoort | Lexical-semantic event-related potential effects in patients with left hemisphere lesions and aphasia, and patients with right hemisphere lesions without aphasia[END_REF][START_REF] Khateb | Processing of semantic categorical and associative relations: an ERP mapping study[END_REF][START_REF] Maguire | EEG theta and alpha responses reveal qualitative differences in processing taxonomic versus thematic semantic relationships[END_REF][START_REF] Mirman | Taxonomic and thematic semantic systems[END_REF]. However, whether thematic and taxonomic relationships have distinct semantic priming characteristics, is an open question.

In addition, the behavioural and electrophysiological semantic priming effects have been shown to occur for consciously perceived primes and target, but also unconsciously perceived primes in masked-priming paradigms [START_REF] Brown | The processing nature of the n400: evidence from masked priming[END_REF][START_REF] Naccache | Unconscious semantic priming extends to novel unseen stimuli[END_REF][START_REF] Rohaut | Unconscious semantic processing of polysemous words is not automatic[END_REF][START_REF] Van Gaal | Can the meaning of multiple words be integrated unconsciously?[END_REF]. This evidence suggests that a semantic priming effect can occur unconsciously. However, a conscious context and task setting effects related to control functions can influence even unconscious priming [START_REF] Naccache | Unconscious semantic priming extends to novel unseen stimuli[END_REF][START_REF] Rohaut | Unconscious semantic processing of polysemous words is not automatic[END_REF][START_REF] Van Gaal | Can the meaning of multiple words be integrated unconsciously?[END_REF], indicating that the interplay between unconscious, implicit and controlled processes during semantic priming is complex and not entirely elucidated.

Nevertheless, the priming effect on semantic categories, whether taxonomic or thematic, suggests that categorization could occur in the context of tasks, such as the similarity task, where two presented words converge to a given category.

A few studies on semantic memory have used a "double semantic priming" paradigm to explore whether two primes impacted the processing of the target more than each prime would do alone [START_REF] Balota | Summation of Activation: Evidence From Multiple Primes That Converge and Diverge Within Semantic Memory 19[END_REF]Chwilla andKolk, 2005, 2003;Python et al., 2018a). In the double semantic priming paradigm, the influence of the convergence of two primes on the target processing is assessed by comparing the conditions in which the two primes are related to the target, to conditions in which only one of the two primes relates to the target. These studies demonstrated a larger double as compared to single priming effect with various primes-target relationships: exemplars-taxonomic category, e.g., copper + bronze -metal [START_REF] Balota | Summation of Activation: Evidence From Multiple Primes That Converge and Diverge Within Semantic Memory 19[END_REF]; associated contexts or characteristics-object, e.g., alley + window -house [START_REF] Lavigne | Time course of activatory and inhibitory semantic priming effects in visual word recognition[END_REF] or naked + shy -towel [START_REF] Chwilla | Accessing world knowledge: Evidence from N400 and reaction time priming[END_REF]; mediated associations, e.g., lion + stripes -tiger [START_REF] Chwilla | Event-related potential and reaction time evidence for inhibition between alternative meanings of ambiguous words[END_REF]; exemplars-exemplar, e.g., helicopter + bus -airplane (Python et al., 2018a). Only one of these studies used exemplars of a category as primes and the category as a target [START_REF] Balota | Summation of Activation: Evidence From Multiple Primes That Converge and Diverge Within Semantic Memory 19[END_REF] and showed a shorter RT in the double priming condition as compared to single priming, suggesting that categorization can occur implicitly.

The measurement of the N400 priming effect using multiple primes has been less explored [START_REF] Chwilla | Event-related potential and reaction time evidence for inhibition between alternative meanings of ambiguous words[END_REF]Python et al., 2018a). To our knowledge, only two studies have explored the double semantic priming effect by combining behavioural and electrophysiological approaches. [START_REF] Chwilla | Event-related potential and reaction time evidence for inhibition between alternative meanings of ambiguous words[END_REF] showed that the existence and the strength of the double priming effect depend on the behavioural task, are altered when primes are polysemous and are easier to observe in ERPs than in behaviour.

Although this study did not focus on category relationships, it demonstrates the importance of exploring the neural correlates of semantic priming as a complement to behavioural data.

Python and colleagues (Python et al., 2018a) examined category relationships, including thematic relationships and taxonomic relationships. In the taxonomic relationships, targets and primes were exemplars of a specific category (e.g., food or animals). The author described an increased semantic facilitation effect using multiple primes as compared to single primes.

Although single semantic priming studies did not show differences in priming effect between taxonomic and thematic relationships [START_REF] Chen | Automatic processing of taxonomic and thematic relations in semantic priming -Differentiation by early N400 and late frontal negativity[END_REF][START_REF] Hagoort | Lexical-semantic event-related potential effects in patients with left hemisphere lesions and aphasia, and patients with right hemisphere lesions without aphasia[END_REF][START_REF] Khateb | Processing of semantic categorical and associative relations: an ERP mapping study[END_REF][START_REF] Maguire | EEG theta and alpha responses reveal qualitative differences in processing taxonomic versus thematic semantic relationships[END_REF], in this double priming study, the behavioural priming effect was larger for thematic than taxonomic relationships. In contrast, the ERP priming effect was similar for both relationships. Hence, these findings suggest that categorization can be studied in semantic priming paradigms and may depend on the type of relationships between primes and target. However, this study does not allow to directly test whether exemplars of a category activate the name of that category because the targets used were exemplars of categories, not category names. Whether the double priming effect can be observed in the context of the similarity task, i.e., whether several exemplars prime the category name, is an unresolved question.

The current study aims to explore whether categorization -as it occurs in the similarity task -can also occur in a semantic priming paradigm, i.e., without explicit instructions. We explore more specifically whether two exemplars of a given category activate this category name more than each exemplar would do alone in a semantic priming paradigm. For this purpose, we designed a double semantic priming task. This task allowed us to test whether two words belonging to the same taxonomic category (e.g., "banana" -"orange") elicited a stronger priming effect on the target category word (e.g., "fruits") than each exemplar separately did.

Given the observed differences in priming paradigms between distinct types of relationships, we also examined this effect for thematic relationships where the target was contextually associated with the primes (e.g., primes "banana" and "cage" with the target "monkey"). We measured both the behavioural (RTs) and ERPs (N400) priming effects. We expected a larger priming effect in double-prime trials as compared to single-prime ones.

Materials and Methods

Participants:

Forty subjects (20 women) with a mean age of 23 years old (± standard deviation (S.D.) = 1.31) participated in this study and performed the priming task and other cognitive tasks. One participant was excluded because she did not carry out the task until the end. Thirty-nine subjects were included in the behavioural analyses (n = 39, 19 women, mean age = 22.5 ± 1.3 years old). Electrophysiological data were recorded in a subgroup of 24 participants (13 women, mean age = 23 ± 1.19 years old).

Subjects were French native speakers, right-handed, and all had a normal or corrected-tonormal vision. Participants had no medical history of neurological or psychiatric disorders, no cognitive impairment (Mini mental State test score > 28) and were free of any drug or psychotropic medication. The local ethical committee (Comité de Protection des Personnes "CPP Ile de France V", approval n o C14-17) approved the study. All sections of the experiment were performed in accordance with relevant guidelines and regulations. All participants provided written informed consent and received financial compensation for their participation.

Experimental paradigm

General principle

We developed a priming paradigm based on a Lexical Decision Task (LDT), in which participants decided whether a displayed chain of letters (the target) was a word or not. This target was preceded by two prime words, each of which could be either semantically related or unrelated to the target, so that there were three semantic relatedness to the target fell into three possibilities: 1) they were both semantically related to the target, 2) one was related and one unrelated, or 3) none was related to the target. Two types of relationships were explored: taxonomic (e.g., "coffee" -"drink") and thematic (e.g., "banana" -"monkey") relationships, using a distinct verbal material. The participants performed two blocks of thematic trials and two blocks of taxonomic trials. We followed the general principles proposed by [START_REF] Balota | Summation of Activation: Evidence From Multiple Primes That Converge and Diverge Within Semantic Memory 19[END_REF] to design the double semantic priming paradigm: considering the relatedness between the prime and the target (related -unrelated) and the position of the prime (first -second), four different conditions were compared: Related-Related (RR), Related-Unrelated (RU), Unrelated-Related (UR), Unrelated-Unrelated (UU). The influence of the convergence of multiple primes on target processing was assessed by comparing the effect (either behavioural or electrophysiological) in the multiple prime condition (RR) with the effect of both single prime conditions (RU and UR). Three different effects can be observed: additive, over-additive, or under-additive effects. A simple additive effect occurs when the facilitation of the target processing in RR condition (double priming effect) corresponds to the sum of the facilitation in RU and UR conditions (sum of single priming effects). Over-additivity indicates that the double priming effect is larger than the sum of the single priming effects. Conversely, under-additivity means that the double priming effect is smaller than the sum of the single priming effects.

Experimental conditions:

We created a set of words for taxonomic relationships and another one for thematic relationships (see word lists in Supplementary Table S1). Each set consisted of 26 triplets of one category target word and two prime words. The prime words had a taxonomic relationship with the target (taxonomic set) or a thematic relationship with the target (thematic set). Four different conditions were obtained for both sets by recombining all the elements in each set and considering the relation between the primes and the target (related or unrelated). First, a double priming condition or RR condition consisted of each of the original lists of 26 triplets of words in which the two primes were related to the target. Second, RU and UR conditions were single priming conditions, in which only the first or the second prime, respectively, was related to the target word (the other prime being unrelated to this target). Finally, we created a fourth condition, UU, in which neither the first nor the second prime word were related to the target. This last condition was the baseline condition.

Overall, each condition (RR, RU, UR, and UU for taxonomic and thematic relationships) included 26 trials. To operationalize the LDT, we also created trials with pseudowords as targets. These pseudoword targets were pseudo-randomly combined with the same prime pairs as in the RR (13 trials), RU (13 trials), UR (13 trials), and UU (13 trials). When the target was not a word, the relatedness to the target did not make sense anymore (UU, UR, and RU are equivalent), and only the relatedness between primes made sense (RR as opposed to UU, RU, UR). Hence, the combination of primes with pseudowords defined two conditions for pseudowords targets: RR (13 trials) and UU (39 trials) conditions (see Table 1 andSupplementary Table S2 andS3). Therefore, the probability of a pseudoword target occurring after two related (RR) or after two unrelated primes (UU) was identical (1/3). In total, this first set of trials included 156 taxonomic and 156 thematic trials (including word and pseudoword trials).

Another set of trials was obtained by reversing the order of the first and second prime words (which were displayed sequentially) for all the trials described above, while keeping the other parameters identical. This second set was built to counterbalance the order of the primes over conditions and allowed us to double the total number of trials. Overall, the participants performed four blocks of trials corresponding to the four sets of 156 trials that were formed: two taxonomic blocks (that differed in the order of the primes in each trial) and two thematic blocks (that also differed in prime order). Each prime was repeated six times: three times in the first position and three times in the second position (see Supplementary Table S3), and each target was repeated four times (Table 1). The order of the trials was pseudo-randomized in each session of 156 trials, with the constraint so that at least nine trials separated two repetitions of the same target. We used the software Mix [START_REF] Van Casteren | Mix, a program for pseudorandomization[END_REF] to pseudorandomize the trials. Each session lasted about 15 minutes. The order of the sessions was counterbalanced between subjects using the following latin square pattern: 1-2-3-4 / 2-3-4-1 / 3-4-1-2 / 4-1-2-3. Before the task, each participant completed a training session of 6 trials with different triplets of words than those used in the main task. The task was coded and administered with MATLAB 2016b (The MathWorks, Inc., Natick, MA) using the Psychophysics Toolbox extensions [START_REF] Brainard | The Psychophysics Toolbox[END_REF][START_REF] Kleiner | What's new in psychtoolbox-3[END_REF].

Condition

Prime this table provides the number of trials presented in one session. In RR-pseudoword trials, the two primes belong to the same category while in the UU-pseudoword trials the two primes are not related. The proportion of primes that belong to the same category is thus similar for words and pseudo-words trials (0.25). Trials were created from the original list of 26 triplets of words and a total 156 trials were used for each session (Four sessions in total: taxonomic and thematic;

prime order 1-2 or 2-1). French words are presented in brackets.

Selection of the verbal material:

We used nouns or adjectives that were concrete, composed of 3 syllables or less, and with a reasonably high lexical frequency (lemma frequency > 1 per million occurrences in the Lexicon book database; www.lexique.org; [START_REF] New | Lexique 2: A new French lexical database[END_REF].

Three databases of free association norms in French were used to select the words presented as primes and as targets: the norms of verbal associations for concrete words and abstract words [START_REF] Ferrand | Normes d'associations verbales pour 260 mots « abstraits[END_REF][START_REF] Ferrand | Normes d'associations verbales pour 366 noms d'objets concrets[END_REF] and a dictionary of French verbal associations accessible online [START_REF] Debrenne | La création du dictionnaire des associations verbales du français[END_REF]. These tools allowed us to assess the association strength between different pairs of words for the creation of word triplets (two primes and one target).

The association strength is the probability that a cue word elicits a specific target word in a verbal free association task. It is measured as the percentage of participants who produced the target in response to the cue word. We ensured that each prime word alone was not strongly associated with the target word (less than 15% of association strength), to avoid a ceiling effect and prevent the priming effect from being significantly boosted by direct verbal associations beyond the semantic relationship itself [START_REF] Tyler | Towards a distributed account of conceptual knowledge[END_REF].

Pseudowords were created by modifying target words using the Wuggy® software [START_REF] Keuleers | Wuggy: a multilingual pseudoword generator[END_REF]. This software allowed us to create pseudowords that matched the target words in terms of the number of syllables and letters, and the frequency of letters.

Pseudowords were words that do not belong to the French language, but pronounceable under French phonological rules. Pseudowords were then pseudo-randomly combined with pairs of primes to form trials so that a given target and the pseudoword generated from this target did not occur in the same trial.

Experimental task (Figure 1):

Participants were seated in front of the screen and asked to perform the LDT using two mouse buttons. Subjects who participated in the electrophysiological recording were seated inside an electrically shielded room (Faraday cage). Stimuli were presented in white letters on a black background. Each trial started with the presentation of a fixation cross displayed at the centre of the monitor. After 500 ms, the first prime was presented during 300 ms and was followed by a fixation cross for 100 ms. Then, the second prime was displayed during 300 ms and was followed by a new fixation cross during 800 ms, and then by the target that was displayed in bold font for 2 seconds. Hence, the total Stimulus-Onset Asynchrony (SOA) in all the trials was 1500 ms. During this period, participants were instructed to decide whether the target was a word or a pseudoword, by doing a left-or right-click on the mouse to select their response with the right hand. An inter-trial-interval whose duration was jittered from 1.8 to 2.2 seconds (with steps of 2.6 ms) followed. Subjects were instructed to focus only on bold words and to answer, "as accurately and as fast as possible". The mouse buttons corresponding to the answer "word" and "pseudoword" were counterbalanced between participants.

Figure 1. Experimental model. Each trial starts with the presentation of a fixation cross. Each prime is presented during 300 ms, separated by 100 ms of cross fixation. The target is presented during 2000 ms, and it can be a word (e.g., "colour") or a pseudoword (e.g., "rainon").

EEG data acquisition and preprocessing

For a subset of 24 subjects, EEG data were recorded on 66 electrodes using BRAINAMP DC system (Brain Products GmbH, Münich, Germany) with actiCAP64-active electrodes mounted in an elastic cap according to the extended International 10-20 system and including a row of low fronto-temporo-occipital electrodes (PO9/10, TP9/10, FT9/10). The FCz electrode was the reference during the recording, and the AFz electrode was the ground. Additional electrodes placed above and below the right or left eye and lateral to the outer canthus of both eyes recorded vertical and horizontal EOG, respectively. Electrode impedances were at or below ten kOhm. The EEG data were recorded at 1 kHz with an online 0.016-250 Hz bandpass filter.

The EEG signal was downsampled offline to 250 Hz, and filtered with a zero-phase, third order high pass and low pass Butterworth filter (0.5 to 30 Hz). Epochs of 200 ms before and 1000 ms after target onset were considered for the analysis. Independent Component Analysis (ICA) was used to detect and remove artefacts caused by eye-blinks. On average, two independent components were removed after a visual inspection of the time series and topographies. Noisy channels were interpolated using the averaged signal of neighbouring channels. A mean of 5.6 electrodes (± S.D. = 1.1) was interpolated among the participants.

Trials containing more than 10% of noisy channels were removed. A mean of 13.7 trials per subject was rejected (± S.D. = 19.6; Range = 0-77) among the total number of trials. After the rejection of the noisy trials, 96.4% (± S.D. = 3.3) of all trials remained for the analysis. For the remaining trials, we performed baseline correction between -200 ms to 0 ms relative to the target onset and the signal was re-referenced to the average of all electrodes (retrieving the FCz electrode signal that was initially used as the reference). EEG signals were averaged for each experimental condition (RR, UR, RU, UU) separately. Only correct response trials with a word as a target were considered for the analysis. Note that our experimental design was optimized to analyze the target-evoked responses, minimizing contamination by the primes-evoked responses. Thus, the ERPs analysis did not consider the exploration of the priming effects triggered by the primes, which would be difficult to disambiguate from one another. We provide a figure of the ERP time course across the whole trial period in Supplementary Figure S1. All EEG preprocessing and analyses were performed using the FieldTrip toolbox running under MATLAB 2016b [START_REF] Oostenveld | FieldTrip: Open Source Software for Advanced Analysis of MEG, EEG, and Invasive Electrophysiological Data[END_REF].

Behavioural and electrophysiological analyses

Behavioural measures

Reaction time was measured as the duration from the target onset to the participants' button press. Median RTs on correct trials with a word as a target were computed for each condition and each participant. We chose median RTs for the analyses to limit the influence of extreme values in the results. The priming effect was measured by subtracting RT in the baseline condition (UU) to RT in the related conditions (UR, RU, or RR). The difference in RTs between RR and UU measured the double priming effect. We also calculated the overall single priming effect by averaging RTs from both single priming conditions (RU and UR) -labelled as RUR

RT -and subtracting it to UU.

ERP measures

Our a priori hypothesis focuses on the N400 component that typically occurs between 300-500 ms after the target onset [START_REF] Kutas | Brain potentials during reading reflect word expectancy and semantic association[END_REF]. A predetermined time-window of interest between 300-500 ms after the target onset was thus selected and analyzed. However, to provide a more comprehensive analysis of the evoked response, we analyzed other time windows of 200 ms duration each, going from 100 ms to 900 ms after the target onset.

Therefore, in total we analyzed the following time windows: 100-300 ms, 300-500 ms, 500-700 ms and 700-900 ms.

For each condition, we measured the mean amplitude of ERPs in the different time windows, averaging ERP data across nine electrodes around the central Cz position (FC1, FCz, FC2, C1, Cz, C2, CP1, CPz, CP2). We selected a priori the frontocentral and centroparietal sites because the N400 component is maximal at this location [START_REF] Martin | Brain potentials reveal semantic priming in both the 'active' and the 'non-attended' language of early bilinguals[END_REF]. To assess the N400 priming effect, we subtracted the N400 component of each of the conditions containing a related prime (RR, RU and UR) to the baseline condition (UU). We also computed the overall N400 single priming effect by averaging priming effects across both single priming conditions (UR and RU).

Statistical analyses

The following procedure was used for the behavioural data (RTs) and ERPs (N400s). We first tested for the semantic priming effect and for the differences according to the semantic category type (taxonomic or thematic). We performed a two-way repeated-measures ANOVA with semantic category type (2 levels, taxonomic and thematic) and condition (4 levels, RR, UR, RU, UU) as within-subject factors. For the ERPs analyses, independent ANOVAs were performed for each time window, and a Bonferroni correction was used for multiple comparisons. Then, as our interest was the existence of a double priming effect and the additivity properties of double as compared to single priming, we performed two additional two-way repeated-measures ANOVAs, in order to compare single and double priming effect (priming factor) across semantic category types (thematic vs taxonomic). In the first set of ANOVAs, we tested for a double priming effect in each time window (with a Bonferroni correction for this multiple comparison). For this, the two levels of the priming factor corresponded to the priming effects computed separately for the single (RUR -UU) and the double (RR -UU) priming conditions. When a double priming effect was significant, we tested for additivity or over-additivity of the priming effect. For this, the two levels of the priming factor corresponded to i) the sum of the priming effect for the two single priming conditions (that is, (RU -UU) + (UR -UU)) and ii) the double (UU -RR) priming conditions. For comparisons with more than one degree of freedom, we used the Mauchly's test to verify the assumption of sphericity and the Greenhouse-Geisser coefficient e to correct for deviations to this assumption. We report the Greenhouse-Geisser corrected p-values but the original, uncorrected degrees of freedom. The Greenhouse-Geisser epsilon (e) value is reported in cases where the assumption of sphericity was violated. When the main effect of priming condition was significant, we performed post-hoc pairwise comparisons between conditions with Bonferroni correction for multiple comparisons.

Finally, to explore whether the ERPs priming effects were significant in electrodes that we did not consider a priori in our analysis, we employed a cluster-based permutation approach in the Fieldtrip toolbox [START_REF] Oostenveld | FieldTrip: Open Source Software for Advanced Analysis of MEG, EEG, and Invasive Electrophysiological Data[END_REF]. We examined whether the priming effect in the double priming condition RR was significantly different from the baseline condition UU. This statistical procedure can optimally correct for the problem of multiple comparisons in EEG data.

All statistical analyses were performed using SPSS software (v22.0; LEAD Technologies, Inc.).

Results

Behavioural analysis:

Mean accuracy reached 98.4% (± S.D. = 1.2; Range = 95-100) of all trials. Only the correct trials were kept and analyzed. The mean and standard deviations of the median RTs are provided for all conditions in Supplementary Table S4. We first performed a two-way repeatedmeasures ANOVA with semantic category type (2 levels, taxonomic and thematic) and condition (4 levels, RR, UR, RU, UU) to explore priming effects across conditions. There was no significant main effect of semantic category type (taxonomic vs thematic) on median RTs (F < 1). However, there was a main effect of the priming condition (F(3,114) = 15.53; e = 0.75; p < 0.001). Post-hoc pairwise comparisons with Bonferroni correction for multiple comparisons revealed that RT was longer in the baseline condition UU when compared to double priming condition RR (p < 0.001) and to each single priming condition UR (p = 0.007) and RU (p < 0.001). RT was shorter in the double priming condition RR compared to the single priming condition UR (p = 0.005) but not compared to the single priming condition RU (p = 0.068) (Figure 2a). The interaction between semantic category type and conditions was not significant (F(3,114) = 1.61; p = 0.2).

To examine whether there was a double priming effect and whether it was over-additive, we ran two additional ANOVAs on the single and double priming effects. In the first ANOVA, the double priming effect (RR -UU) was compared to the average of the single priming effects (RUR -UU) to explore the existence of a double priming effect. There was no main effect of semantic category type (F < 1) but a significant effect of priming type (double versus single) (F(1,38) = 7.66; p = 0.009). The interaction between semantic category type and priming type was significant (F(1,38) = 4.58; p = 0.04). Post-hoc comparisons revealed that RT was significantly shorter in the double priming than the single priming condition for taxonomic t(38) = -4.26; p < 0.001) but not thematic (t(38) = -0.82; p = 0.26) categories (Figure 2b). In the second ANOVA, we tested over-additivity by examining if the priming effect in the double priming condition (RR -UU) was larger than the sum of the priming effect in the single priming conditions (RU -UU + UR -UU). This final ANOVA did not reveal any significant main effect or interaction (all F < 1). Thus, the double priming effect was not significantly larger than the sum of the single priming effects, indicating that the double priming effect was only additive. UU: unrelated-unrelated; RU: related-unrelated; UR: unrelated-related; RR: related-related.

ERP analysis

We measured the mean amplitude of the N400 component in all conditions in both types of semantic relationships. The N400 mean amplitudes and standard deviations for all conditions are provided in the Supplementary Table S5. Figure 3 shows the individual time course of the N400 component for the nine electrodes averaged for the analyses, and the scalp distribution.

The statistical analysis followed the same strategy as for the behavioural data. First, for each time window, we performed an ANOVA with semantic category type (2 levels, taxonomic and thematic) and condition (4 levels, RR, UR, RU, UU) as within-subject factor allowed us to explore priming effects across conditions. This analysis did not show any effect of the semantic category type (taxonomic versus thematic) (F < 1) in any of the four time windows. A significant effect of the priming conditions (F(3,69) = 11.60; e = 0.65; p < 0.001) was found in the 300-500 ms time window, but not in the other time windows (F < 1). The post-hoc pairwise comparisons with Bonferroni correction for multiple comparisons performed in the 300-500 ms time window showed that the N400 component was larger in the baseline condition UU compared to the double priming condition RR (p = 0.001) and to both single priming conditions UR (p = 0.029) and RU (p = 0.002) (Figure 4a). Moreover, double priming condition RR showed a significantly lower amplitude of the N400 component compared to single priming condition UR (p = 0.014), but not compared to RU (p = 0.2). There was no significant interaction between semantic category type and priming condition factors in any of the time windows (F < 1). RR: related-related; RU: related-unrelated; UR: unrelated-related; UU: unrelated-unrelated.

To examine whether there was a double priming effect, we ran additional ANOVAs on single and double priming effects computed as the differences in amplitude for RUR and RR relative to the UU conditions for each time window. These analyses revealed a significant difference between the single and double priming effects (F(1,23) = 8.780; p = 0.007) in the 300-500 ms time window. Participants presented a larger N400 priming effect in the double semantic priming condition compared to the averaged single semantic priming condition (Figure 4). This effect was not significant in any other time window (F < 1). No significant effect of semantic category type (F < 1) and no significant interaction between semantic category and priming effect types (F < 1) was observed in any of the time windows. RR: related-related; RU: related-unrelated; UR: unrelated-related; UU: unrelated-unrelated.

To explore whether the ERPs priming effects were restricted to the a priori selected electrodes for the analysis, we employed a cluster-based permutation approach. We examined whether the priming effect in the double priming condition RR was significantly different from the baseline condition UU in other electrodes in any of the time windows from 0.1 to 0.9 seconds after target onset. The analysis revealed that the double priming effect RR was significantly different from the baseline condition UU (p < 0.01) between the times 0.34 to 0.48 seconds over the frontocentral and centroparietal electrodes (Figure 5). This result is consistent with the a priori hypothesized N400 effect. Then, to explore over-additivity, we examined if the N400 double priming effect (RR-UU)

was larger than the sum of the N400 single priming effects ((RU -UU) + (UR -UU)). This analysis was performed in the 300-500 ms time window in which the double priming effect was significantly larger that the single priming effect. This final ANOVA did not reveal any significant effect or interaction (all F < 1). Thus, the N400 priming effect for the double priming condition was not significantly different from the sum of the priming effect for the single priming conditions, indicating a mere additivity of the priming effects.

Discussion

In the present study, we used a double semantic priming task to explore categorization of taxonomically and thematically related multiple primes in humans. We explored the priming effects through behaviour (as a time decrease to process the primed compared to the unprimed targets) and electrophysiology (as a decreased amplitude of the N400 in the primed conditions).

Our study yielded three essential results. First, both behavioural and ERP measures showed robust single (RU and UR) and double (RR) priming effects. Second, both behavioural and ERP measures demonstrated a larger priming effect for double priming than for single priming conditions. However, there was no evidence for an over-additivity of double priming compared to single priming. Finally, the more substantial priming effect of double compared to single primes was observed for both taxonomic and thematic relationships in the N400 analysis, whereas it was observed only for the taxonomic relationships in the behavioural analysis.

Categorization in a double vs single priming condition

Our results showed a greater priming effect with two primes than with single primes on both behavioural and ERP measures. We observed additivity but no over-additivity of multiple primes: the facilitation induced by multiple primes was not significantly larger than the sum of the facilitation yielded by each prime separately, for both behavioural and electrophysiological analyses.

Underlying processes of multiple priming effect

Our study confirms the additivity of two primes at the behavioural level in an LDT task.

This finding is consistent with previous studies showing an additive effect in multiple priming conditions at the behavioural level, in both semantic category types [START_REF] Balota | Summation of Activation: Evidence From Multiple Primes That Converge and Diverge Within Semantic Memory 19[END_REF][START_REF] Chwilla | Event-related potential and reaction time evidence for inhibition between alternative meanings of ambiguous words[END_REF][START_REF] Lavigne | Time course of activatory and inhibitory semantic priming effects in visual word recognition[END_REF].

Consistent with behavioural results, the ERP findings also revealed an additive pattern of double priming. We are aware of only one study that explored ERPs in a multiple priming task using a LDT paradigm. Chwilla and Kolk [START_REF] Chwilla | Event-related potential and reaction time evidence for inhibition between alternative meanings of ambiguous words[END_REF] showed different N400 additivity patterns varying according to the task (LDT or relatedness judgment task) and the type of words used as primes (ambiguous or unambiguous). In the LDT, the results showed an additive effect using both ambiguous and unambiguous words, which is consistent with our findings. In the relatedness judgment task, there was an over-additive effect with unambiguous words but an under-additive effect with ambiguous words. Another study that explored ERPs in a multiple priming task used a picture naming task (Python et al., 2018a). Although the authors did not explore additivity, they described an increased semantic facilitation effect with multiple primes compared to a single prime in both taxonomic and thematic categories. Overall, these findings suggest that a double priming effect can occur in priming paradigms that use different tasks, i.e., naming, LDT, relatedness judgement tasks, suggesting that distinct mechanisms can be involved and combined both at the semantic, lexical, and strategic levels.

The task and material used to explore a double priming effect are both critical and an overadditivity effect might be difficult to observe using an LDT, possibly due to its reliance on processes not optimally captured by this task.

The putative mechanisms of additivity remain debated. First, the multiple priming effect might depend on an enhanced influence of one of the primes. It refers to an associative "boost" [START_REF] Moss | Accessing different types of lexical semantic information: Evidence from priming[END_REF] in which the presence of a semantic association between each prime and the target generates a larger priming effect by "accumulation". We controlled the association strength between primes and target, to ensure that verbal associations beyond the semantic relationship itself did not boost the priming effect [START_REF] Tyler | Towards a distributed account of conceptual knowledge[END_REF]. For this reason, we consider that it is unlikely that the double priming effect was due to two separate priming effects or to an enhanced influence of the second prime on the target. We suggest that the multiple priming effect instead reflects the pre-activation of the target induced by primes that have convergent semantic relationships with this target. Previous studies using masked semantic primes and attentional blink paradigms have shown the sensitivity of the N400 priming effect to automatic semantic processes [START_REF] Deacon | Event-related potential indices of semantic priming using masked and unmasked words: evidence that the N400 does not reflect a post-lexical process[END_REF][START_REF] Kiefer | The N400 is modulated by unconsciously perceived masked words: further evidence for an automatic spreading activation account of N400 priming effects[END_REF][START_REF] Kiefer | Time course of conscious and unconscious semantic brain activation[END_REF][START_REF] Rolke | Missed prime words within the attentional blink evoke an N400 semantic priming effect[END_REF]. Hence, the higher facilitation in multiple primes conditions may reflect the organization of concepts into categories.

Second, top-down processes such as controlled strategies might be involved in the multiple priming effect. Several authors have argued against the involvement of purely automatic processes in priming experiments using long SOA (> 300 ms), because such duration allows controlled processing and strategies during task performance [START_REF] Lucas | Semantic priming without association: A meta-analytic review[END_REF][START_REF] Neely | Semantic priming and retrieval from lexical memory: Roles of inhibitionless spreading activation and limited-capacity attention[END_REF]. In the present study, we used a long SOA (1500 ms) to avoid the ERPs in response to target words to be affected by the ERPs in response to the second prime. Therefore, it is possible that both automatic and controlled processes contributed to the semantic priming effect.

More specifically, two controlled processes may be involved, the expectancy generation and semantic matching. Expectancy generation [START_REF] Becker | Semantic context effects in visual word recognition: An analysis of semantic strategies[END_REF][START_REF] Becker | Semantic context and word frequency effects in visual word recognition[END_REF][START_REF] Neely | Semantic priming effects in visual word recognition: A selective review of current findings and theories[END_REF][START_REF] Neely | Semantic priming in the lexical decision task: Roles of prospective prime-generated expectancies and retrospective semantic matching[END_REF]) is defined as the use of the semantic information of the prime to activate a set of potential words that could correspond or strongly relate to the following target. To limit the impact of the expectation component, we instructed participants not to pay attention to primes. However, as the target was a category, participants may make correct expectations about the following target. This expectation is more likely to be correct in the RR condition were the two primes belong to the same category, and especially in the taxonomic condition where there are fewer options than in the thematic condition. The expectation is less likely to be correct in the RU or UR conditions as the R and U primes do not belong to the same category. However, in our experiment, the relatedness proportion of RR trials (i.e., the proportion of related trials among the total of trials (including related and unrelated conditions) was low (25%), which does not typically favour the occurrence of strategic expectation processes during priming paradigms [START_REF] De Groot | Primed lexical decision: Combined effects of the proportion of related prime-target pairs and the stimulus-onset asynchrony of prime and target[END_REF][START_REF] Neely | Semantic priming in the lexical decision task: Roles of prospective prime-generated expectancies and retrospective semantic matching[END_REF]. Another controlled process that can be involved in semantic priming is semantic matching [START_REF] Colombo | Effects of word-and sentence-level contexts upon word recognition[END_REF][START_REF] Heyer | Strategic factors in a lexical-decision task: evidence for automatic and attention-driven processes[END_REF][START_REF] Neely | Semantic priming effects in visual word recognition: A selective review of current findings and theories[END_REF][START_REF] Neely | Semantic priming and retrieval from lexical memory: Roles of inhibitionless spreading activation and limited-capacity attention[END_REF][START_REF] Neely | Semantic priming in the lexical decision task: Roles of prospective prime-generated expectancies and retrospective semantic matching[END_REF], in which the participants verify the relation between the prime and the target. It is induced by the type of target-prime relatedness, and primarily occurs when most unrelated prime-target trials use pseudoword targets. With such proportion, unrelated pairs could bias the lexical decision to a "pseudoword" response, and related words, to a "word" response [START_REF] Neely | Semantic priming in the lexical decision task: Roles of prospective prime-generated expectancies and retrospective semantic matching[END_REF]. In our paradigm, there were as many related as unrelated primes in both words and pseudowords trials, and it is thus less likely that semantic matching processes explain our results. It is noteworthy that the facilitation effect of the first word prime appeared greater than the effect of the second word prime, with a larger difference between RR and UR than between RR and RU conditions. Although this result is difficult to interpret due to a lack of statistical difference between RU and UR, it may suggest that the first prime played a larger role in the semantic facilitation effect than the second one. This tendency might however be better explained by expectancy generation triggered by the first prime than by semantic matching.

Furthermore, some masked priming paradigms showed that unconscious semantic processes are affected by the conscious context and engagement of executive attention [START_REF] Greenwald | Long-term semantic memory versus contextual memory in unconscious number processing[END_REF][START_REF] Naccache | Unconscious Masked Priming Depends on Temporal Attention[END_REF][START_REF] Rohaut | Unconscious semantic processing of polysemous words is not automatic[END_REF], highlighting the complexity of the role of controlled processes in implicit priming. Additionally, the increased activation of semantic associations in schizophrenic patients ("hyperpriming") with impaired frontal functions also suggests the role of control functions on semantic priming [START_REF] Dehaene | Conscious and subliminal conflicts in normal subjects and patients with schizophrenia: The role of the anterior cingulate[END_REF][START_REF] Kreher | Neural Evidence for Faster and Further Automatic Spreading Activation in Schizophrenic Thought Disorder[END_REF][START_REF] Spitzer | Indirect semantic priming in schizophrenic patients[END_REF]. "Hyperpriming" has also been described in neurological patients, including semantic dementia [START_REF] Laisney | When the zebra loses its stripes: Semantic priming in early Alzheimer's disease and semantic dementia[END_REF] and Alzheimer disease [START_REF] Borge-Holthoefer | Modeling Abnormal Priming in Alzheimer's Patients with a Free Association Network[END_REF][START_REF] Giffard | The dynamic time course of semantic memory impairment in Alzheimer's disease: clues from hyperpriming and hypopriming effects[END_REF][START_REF] Giffard | The nature of semantic memory deficits in Alzheimer's disease: New insights from hyperpriming effects[END_REF][START_REF] Ober | Semantic priming in Alzheimer's disease: Meta-analysis and theoretical evaluation[END_REF], but also patients with post-stroke aphasia and left frontal lesions [START_REF] Dyson | Semantic processing in aphasia: evidence from semantic priming and semantic interference[END_REF]; see also Python et al., 2018b). Among other interpretations, this effect had been explained by a decreased competition or interference among fewer pre-activated or available knowledge. It may also be related to attentional or controlled deficits. The left inferior frontal region may be critical to shaping semantic facilitation by thresholding lexical selection. These studies highlight the complex intricacy of controlled and automatic processes during implicit priming. Hence, we cannot exclude that the categorization we observe also involves controlled processes exerted on implicit priming, and thus may engage at least in part the frontal lobe functions.

Overall, we show a double priming effect on both taxonomic (both behaviourally and on ERPs) and thematic (on ERPs only) relationships in a similarity priming task. These results indicate that some of the processes involved in the similarity task -allowing to activate the shared category between two items -can occur during a semantic priming task. Such processes may include automatic semantic processes and (mostly pre-lexical) controlled processes. The results also suggest that the N400 can be considered as an electrophysiological marker of such primed categorization.

Additive but not over-additive effect

The double priming effect was additive but not over-additive. One putative explanation relates to the design of our paradigm. According to the spreading activation theory, the activation of concepts decays with time. The long SOA used in our task may have allowed a decay in the pre-activation of the target over time, thus decreasing the double priming effect.

Another potential factor is the repetition of the primes (six times) and targets (four times)

within the same session that can impact the semantic priming effect. The repetition of each word can yield to a higher baseline level of activation of the concepts, generating a lower semantic priming effect (see [START_REF] Kutas | Thirty Years and Counting: Finding Meaning in the N400 Component of the Event-Related Brain Potential (ERP)[END_REF]. However, to limit this effect, we ensured that each word was presented only once for each condition, and we ensured that at least nine trials separated any target repetition. We also created two lists for each type of semantic association to counterbalance the order of the primes, and the order of the sessions alternated between the participants, which allowed us to balance the number of times each of the primes was presented in the first and in the second position.

Hypothetically, an additive rather than the over-additive effect in our double priming task might have a behavioural significance, because it could reflect an adaptive balance between over-constraining the activation of one given concept in response to given stimuli (overadditivity) and failing to activate the appropriate converging concept between them (underadditivity).

4.2

The amount of behavioural double priming effect varies with the type of semantic association.

In the behavioural analysis, the double priming effect was larger when primes were taxonomically related to the target, than when they were thematically related. Based on the results of Python and colleagues (Python et al., 2018a), we were instead expecting a larger behavioural priming effect for thematic than for taxonomic relationships. The reason for a lower double priming effect of thematic relationships remains unclear. Both automatic and controlled mechanisms can explain this result.

In the framework of the spreading activation model, when the first prime is presented, its activation propagates to neighbouring nodes. We propose that as taxonomically related concepts share various features, they are highly interlinked and close to each other in semantic memory. Therefore, a given target category could be primed by the cumulative effect of preactivation provoked by many neighbouring nodes, resulting in an increased target facilitation.

In contrast, thematically related words do not necessarily share similar features. Therefore, the presentation of thematically related primes may activate a much broader set of concepts that are not necessarily interlinked to each other. Thus, there may be no (or less) cumulative effect yielded by multiple primes.

In addition, and as mentioned above, although most factors were controlled in the paradigm to counteract the effect of controlled processes, some factors such as the long SOA and the conscious perception of the stimuli may have allowed controlled processes to occur. We believe that the expectancy generation process could have contributed to the difference in double priming RT between taxonomic and thematic categories. It is possible that due to the presentation of the same type of trials in the taxonomic sessions, namely, exemplars (primes)category (target) relation, the set of words activated according to the expectancy generation hypothesis was more limited than in thematic trials. In addition, thematic items included different types of functional relations and participants could have generated a broader set of expected targets. Then, the probability that the real target of the task corresponds to the expected one may have been lower for the thematic condition, which may have decreased the influence of expectancy generation in the semantic priming effect.

Regarding more typical effects such as the single priming effect, our findings are in agreement with several studies that have shown no difference in the RT priming effect between taxonomic and thematic [START_REF] Chen | Automatic processing of taxonomic and thematic relations in semantic priming -Differentiation by early N400 and late frontal negativity[END_REF][START_REF] Hagoort | Lexical-semantic event-related potential effects in patients with left hemisphere lesions and aphasia, and patients with right hemisphere lesions without aphasia[END_REF][START_REF] Khateb | Processing of semantic categorical and associative relations: an ERP mapping study[END_REF][START_REF] Maguire | EEG theta and alpha responses reveal qualitative differences in processing taxonomic versus thematic semantic relationships[END_REF]. This result suggests that the semantic facilitation yielded by a single prime involves similar processes in both types of semantic categories. However, multiple primes may favour the access to taxonomic relationships behaviourally, which should be interpreted with caution since we did not observe differences between semantic category types in N400 amplitudes.

Conclusion

The present study provides evidence for an additive effect of double priming of taxonomic and thematic categories and suggests that categorization can occur without explicit instructions in a semantic priming task. At the behavioural level, the effect of double priming suggested that taxonomic relations may be stronger or more easily accessed than thematic relations. In contrast, the N400 double priming effect was equivalent for both types of semantic relations, highlighting the importance of the N400 as an electrophysiological marker of categorization.

Our findings have implications in understanding the cognitive processes at play during the similarity task in particular, and in categorization in general. The results also place our "similarity priming task" in a promising position as a tool to better characterize the patients' difficulties in abstract thinking, especially in the context of a frontal or temporal degenerative disease or in patients with schizophrenia. Finally, our research has broad significance in Supplementary Table S1. List of words for both taxonomic and thematic associations translated in English (French in brackets). Twentysix triplets of words were created for taxonomic and thematic relationships, containing one target and two related primes. The triplets in the present list were used as stimuli for the RR-word condition. The combination of all words in the list allowed us the creation of UR, RU and UU conditions. S3. Trials organization to counterbalance the order of the primes over conditions. The table contains real trials that were used in the taxonomic sessions. In the first session, each prime (e.g., beer) was repeated six times: three times in the first position and three times in the second position. The additional set of trials (second session) was constructed by reversing the order of the primes of each trial of the first session.

Figure 2 .

 2 Figure 2. Behavioural data. a) Mean of the median RTs across subjects in the four priming conditions (taxonomic and thematic conditions pooled together). b) Priming effects in double and single priming conditions for the taxonomic and thematic conditions are represented as the difference in RTs between RR and UU, and between RUR and UU, respectively. There is a significant interaction between category and priming effect. *** p < .001; ** p <.01; * p <.05; ns: not significant. Error bars correspond to 95% confidence intervals.

Figure 3 .

 3 Figure 3. ERP grand average over the nine electrodes separately and N400 scalp distribution. a) The ERP grand average elicited by the four conditions is provided for the nine electrodes separately. Time 0 corresponds to the target presentation, and the grey area represents the studied time window. b) Topographic maps show the mean N400 amplitude (μV) for the studied time window for all the conditions. Black dots indicate the nine electrodes considered in the ERP analysis.

Figure 4 .

 4 Figure 4. N400 time course over the nine averaged electrodes and N400 analysis per condition. a) The ERP grand average is displayed for the four conditions. Amplitude (μV) corresponds to the average of the nine electrodes considered in the analysis. Time 0 corresponds to the target presentation, and the grey area represents the studied time window. b) N400measurements (average signal in the 300-500 ms time window) for the four different conditions (taxonomic and thematic trials averaged). c) N400 priming effects in double and single priming conditions for the taxonomic and thematic trials. Here, priming effects are the difference in the N400 amplitude between RR and UU (double priming), and between RUR and UU (single priming) in the 300-500 ms time window.

Figure 5 .

 5 Figure5. Cluster-based permutation analysis. Testing for the N400 effect and the ERPs effect in the whole epoch of analysis (0.1 to 0.9 seconds after the target onset), the cluster-based permutation tests revealed a significant difference between the double priming condition RR and the baseline condition UU (p < 0.01). The forty topographic plots equally spaced between 0.1 to 0.9 seconds are displayed, the black dots represent the 65 electrodes, and the significant clusters are indicated with stars. A single cluster was observed, indicating a significant difference between 0.34 and 0.48 seconds over the frontocentral and centroparietal electrodes.

Table 1 . Examples of the six different conditions used as stimuli

 1

		1	Prime 2	Target	Number of Trials
	RR-word	coffee (café)	beer (bière)	drink (boisson) 26 Trials
	RU-word	beer (bière)	pigeon (pigeon) drink (boisson) 26 Trials
	UR-word	boot (botte)	coffee (café)	drink (boisson) 26 Trials
	UU-word	copper (cuivre) sight (vue)	drink (boisson) 26 Trials
	RR-pseudo-word* coffee (café)	beer (bière)	asimum	13 Trials
	UU-pseudo-word sorbet (sorbet) sight (vue)	disseya	39 Trials

. The table contains real trials used in the taxonomic session. Each condition included two primes and one target, and

Table S2 . List of pseudowords for both taxonomic and thematic associations.

 S2 Two pseudowords for target word were created for each session. In total, fifty-two pseudowords were used for each session in the UU-pseudoword and RR-pseudoword trials conditions.

	Taxonomic	Thematic
	word métal boisson céréale chaussure jeu membre meuble outil plante couvert couleur dessert sentiment vêtement animal arme bijou élément fruit insecte légume mois oiseau saison sens sport Condition RR-word RU-word UR-word UU-word RR-pseudoword mélax meusson baussin pseudoword méril bélal biossin cémuole cémurle cévurle blousture bleussore draisture drainsure sétol muisson cémuane jee jui keu seu murbre beuvre meltre bimbre moiple muivre meivre beuple oulol ourim ouryl outaf drende pronte dranle flonte pouvexe coumart pouset pouvort counour coutier poulier cousuir dassecs disseon disseng disseya sennisant senlisant sesrident pontident nytament tâtegent tômement tytament asimum asimom asimié asigol esme erte erne anle bizoï bizoa bifau bifui écèvent érénent écésant évècent frout friat fruiz fruif incuote incoste incuate incirte néduge nésude hénude téduge moil moinf mias mias oisiag oiniau oiviau eusiou saivin rainon moiron maisan hens bens dens nens spoya gnort spoll spolt Prime 1 Prime 2 Target beer coffee drink copper beer metal pigeon beer drink beer football sense beer coffee asimom UU-pseudoword frog beer baussin Supplementary Taxonomic (first session) Supplementary Table	word tristesse corps couture écriture femme ferme hiver maison bateau nuit prison savane pompier vacances vie chasse avion armée sorcière mariée soleil cheveu singe bouche chant école Taxonomic (second session) printasse primmesse chattesse pseudoword coyal coxon dorps saicure saipure soivure éscodère escodore éscogyre fulme faîme fampe farpe fenre forve niper jimer zimer bainon maunon vauson batoub batué batioc niot nuif juit plinon brinon brivon parale pacene sarele pombeur pempoir pemmier nacondes galences lamences nacorces prantesse concs soinure éscosore famde terde zider saivon bariau nuet clisan patale purpier vio hie bie vei cresse bresse trosse blâsse anain anéon anoen anien ercée erbée ancée anbée serboire serlière servaure serloire marong maroyé marorn maropé soreul sotial rolial roteil chumeu chemoa chuvio truveu cirge rinde minde simbe tougne cougne cauche coubre chint brant chacs chont évuse épune ésune éruse Prime 1 Prime 2 Target coffee beer drink beer pigeon drink beer copper metal football beer sense coffee beer asimum beer frog meusson

Acknowledgement:

The research leading to these results has received infrastructure funding from the French programs "Investissements d'avenir" ANR-11-INBS-0006 and ANR-10-IAIHU-06. This work was supported by the "Fondation pour la Recherche Médicale" (FRM), [grant numbers FDM20150632801 and DEQ20150331725], and by the ENP-Chilean internships of the "École des Neurosciences de Paris Île-de-France" and Becas-Chile of ANID (CONICYT).

understanding how semantic memory is organized and accessed to, and how it shapes the way humans think and generate abstract concepts.

Supplementary material

Does adding beer to coffee enhance the activation of drinks? An ERP study of semantic category priming Marcela Ovando-Tellez 1 , Benjamin Rohaut 1,2,5 , Nathalie George 1,3 , Theophile Bieth 1 , Laurent Hugueville 3 , Yoan Ibrahim 1 , Ophelie Courbet 1 , Lionel Naccache 1 , Richard Levy 1,2 , Béatrice Garcin 1,4, + and Emmanuelle Volle 1, +, * Supplementary Figure S1. Time course of the ERPs during the full trial period. The time course of the averaged ERP data of the four priming conditions across the nine frontocentral and centroparietal electrodes (FC1, FCz, FC2, C1, Cz, C2, CP1, CPz, CP2) is displayed. The time course starts with the fixation cross onset (time = 0) and considers the 2.5 seconds of the entire trial period. We considered 0.2 seconds before the cross onset as the baseline period. The onset of the first prime was at 0.05 seconds and the second prime onset was at 0.45 second. The target onset was at 1.55 second. Our a priori period of interest was between 1.85 and 2.05 seconds (0.3 to 0.5 seconds after the target onset).


Camille Rolland-Debord

Anthony Canellas

Pascaline Choinier

Audrey Milon

Isabelle Debrix

Emmanuelle Blin

Nicolas Belaube

Sarah Mattioni

Floriane Millet

Martine Nadal

Camille Petit-Hoang

Pierre Rigaud

Jean Simon Rech

Martin Siguier

Deborah Sroussi

Michel Denis

Corinne Amiel

Muriel Fartoukh

Sophie Georgin-Lavialle

Ludovic Lassel

Antoine Parrot

Jacques Cadranel
email: jacques.cadranel@aphp.fr

Daily multidisciplinary COVID-19 meeting: experiences from a French university hospital

Keywords: COVID-19, Multidisciplinary meetings, standard of care, prospective cohorts, therapeutic trials

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

Methods: All consecutive patients who were hospitalized in our institution due to COVID 19, from March 31 to April 15, 2020, were included. Criteria to be presented at MDT meetings were defined as a proven COVID-19 by PCR or strongly suspected on CT scan, requiring hospitalization and treatment not included in the standard of care. Three investigators identified the patients who met the predefined criteria and compared the treatment and outcomes of patients with predefined criteria that were presented during MDT meeting with those not presented during MDT meeting. COVID-19 MDT meeting implementation and adhesion were also assessed by a hospital medical staff survey.

Results: 318 patients with confirmed or suspected COVID-19 were examined in our hospital. Of these, 230 (87%) were hospitalized in a COVID-19 unit, 91 (40%) of whom met predefined MDT meeting criteria. Fifty (55%) patients were presented at a MDT meeting versus 41 (45%) were not. Complementary exploration and inclusion in the CorImmuno cohort were higher in MDT meeting group (respectively 35 vs 15%, p=0.03 and 80 versus 49%, p = 0.0007). Prescription of hydrocortisone hemisuccinate was higher in group of patients not presented during MDT meeting (24 vs 51%, p= 0.007). Almost half of the patients fulfilling the inclusion criteria were not presented at MDT meeting, which can be partly explained by technical software issues.

Conclusions: Multidisciplinary COVID-19 meetings helped implementing a single standard of care, avoided using treatments that were untested or currently being tested, and facilitated the inclusion of patients in prospective cohorts and therapeutic trials.

Introduction

On March 11, 2020, the World Health Organization (WHO) declared the outbreak of severe acute respiratory coronavirus 2 (SARS-CoV-2) a global pandemic. SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID- [START_REF] Arabi | Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome[END_REF], leading to death in 2.5% of confirmed cases and 10.8% of hospitalized patients in France [START_REF]COVID-19[END_REF].

In the midst of the pandemic, scientists attempted to better understand COVID-19 pathophysiology in order to develop an effective treatment. However, despite multiple emerging therapies and numerous daily publications, there were not yet any strong international treatment recommendations. Recently, studies revealed that dexamethasone resulted in lower 28-day mortality among patients receiving either invasive mechanical ventilation or oxygen alone [START_REF] Recovery Collaborative Group | Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report[END_REF], that remdesivir was superior to placebo in shortening the recovery time in COVID-19 hospitalized adults [START_REF] Beigel | Remdesivir for the Treatment of Covid-19 -Final Report[END_REF], and that tocilizumab likely reduced the risk of mechanical ventilation or death by day 14 [START_REF] Hermine | Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial[END_REF]. In our university hospital, located in Paris, France, several departments were involved in COVID-19 management, including the departments of infectious diseases, virology, pulmonology, internal medicine, nephrology, pharmacy and intensive care.

Due to the lack of official recommendations, an urgent need for implementing daily multidisciplinary COVID-19 meetings was unanimously felt during the first wave. These meetings were aimed to investigate the various disease phenotypes, propose a standard of care (SOC) for COVID-19, and collectively decide on the best possible treatment for each patient based on the available evidence.

Our aim was to describe our initial institutional SOC for the first-wave COVID-19 management, as well as the implementation of a multidisciplinary team (MDT) COVID-19 meeting and its preliminary impact on our daily practice.

Methods

MDT meeting criteria

The setting-up of a MDT meeting in France relies on the recommendations from both the Plan Cancer 2003-2007 and Haute Autorité de Santé française, as defined by the Article D. 6124-131 of the French Public Health Code. These recommendations are similar to many others, as recently described in a systematic review [START_REF]Réunion de concertation pluridisciplinaire[END_REF].

We have reviewed specifications of MDT meeting: 1) relevance for the institution; 2) affiliation to our institution; 3) name of the meeting; 4) professionals concerned by the meeting; 5) meeting coordinator and 6) medical conclusions (or consensual decision).

The meeting operating procedures were also checked as for the following: 1) use of a secure software; 2) name of the referring physician; 3) date and time of the meetings established at specific time intervals; 4) selection criteria of the patients presented; 5) mandatory items for the file's content; 6) traceability of the questions asked with the answers provided; 7) justified inclusion in therapeutic trials, and justified use of a treatment different to the one recommended by the MDT meeting.

We evaluated the compliance of the MDT meetings with predefined quality criteria and their impact on therapeutic management, to amend the operating procedures as necessary and further improve the quality of subsequent MDT meetings. Data analysis was restricted to the first 15 days because they correspond to the epidemic peak and allowed analysing the data and quickly validating the method.

Overall population and MDT meeting study population

Overall population was identified by two databases: patients with a positive SARS CoV2 polymerase chain reaction (PCR), and patients with a CT-scan defined as suspected of COVID 19 by radiologists. We included all consecutive patients who were hospitalized in our institution due to COVID-19, during the two first weeks of implementation of the MDT meetings, i.e. between March 31 and April 15, , 2020.

MDT study population was patients among the overall population who required a hospitalization but not in ICU and a treatment not included in the standard of care. Three of us (AC, PC and CRD) identified and adjudicated the patients who met the predefined criteria to be presented at MDT meetings. Finally, MDT study population was divided in two groups, patients who were and those who were not presented at a MDT meeting.

Data collection

Data collections were: demographic data, medical history, clinical and biological data at presentation. Need for oxygen, complementary exploration and treatment during hospitalization were collected. Days 14 and 28 status were also reported.

Statistical analysis

Statistical analysis was performed using GraphPad ® (San Diego, CA, USA).

Quantitative data were reported as median (interquartile range [IQR]) and categorical data as number of events (percentages). Differences between groups were assessed with the Mann-Whitney test for quantitative variables. Differences between groups were assessed using the chi-squared test for categorical variables or Fisher's exact test if the expected value was lower than 5. This work was approved by the "Comité d'évaluation des protocoles de recherche (CEPRO)" from the "Société de Pneumologie de Langue Française (SPLF)" on August 26, 2020.

Results

Institutional SOC for COVID-19 management before MDT meeting implementation

At the beginning of the COVID-19 epidemic, the initial SOC in our conventional unit was based on evidence for treating hypoxemic bilateral pneumonia: i) dual intravenous antibiotherapy [START_REF] Wiersinga | Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT)[END_REF]; ii) oxygenotherapy; iii) venous thromboembolism prevention [START_REF] Smith | Practical considerations in prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19[END_REF]. The antibiotherapy combined a third-generation cephalosporin with a macrolide or, in case of potential drug-drug interactions, with a quinolone as proposed in the ATS/IDSA guidelines [START_REF] Metlay | Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America[END_REF]. The macrolide used was azithromycin, for his anti-infective property (intracellular germ target) and potential antiviral/antiinflammatory effects ("cytokine storm" in COVID-19 pneumonia) [START_REF] Metlay | Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America[END_REF].

In case of respiratory worsening evolution, an alternative diagnosis to COVID-19 aggravation was searched for, such as pulmonary embolism, pulmonary oedema, or bacterial superinfection. Due to the lack of randomized controlled trials, it was decided to assess disease evolution and discuss additional treatments on a case-bycase scenario, including alternative treatments alone rather than in association, such as oral hydroxychloroquine, oral lopinavir/ritonavir, intravenous hydrocortisone hemisuccinate, or methylprednisolone. Each department decided on their own which drug was likely to be the most appropriate.

Urgent need for a COVID-19 MDT meeting

In the COVID-19 setting and pending on the results of ongoing and future therapeutic trials, some clinicians wished to prescribe certain medications on a "compassionate" basis. However, such prescriptions can only be deemed acceptable when, according to the practitioner, there are sufficient scientific data to support these treatments' ability to improve or stabilise the patient's clinical state. For this purpose, our Pharmacy department edited a drug prescription form including reminders of dosage, duration and contra indication for the treatments prescribed off label. The patient was orally informed and gave his/her consent for this prescription, both of which were documented in the patient file.

In addition, our institution requested that such prescriptions be made only following a collective assessment that was to be validated by a "compassionate treatment committee." Given the lack of official recommendations, the medical hospital community decided on March 31, 2020 to create and implement institutional COVID-19 MDT meetings (figure 1).

Daily COVID-19 MDT meeting's operating procedures

MDT meeting characteristics are listed in table 1. Due to the number of daily hospitalized patients and the rapid change in their clinical condition, we decided to set up daily afternoon meetings using videoconferencing with the institutional secured software Lync ® for social distancing. The institutional software single patient file was employed, enabling us to create a standardized file as shown in table 2, following discussions among the experts of each COVID-19-involved specialty.

Report of the first 15 days of COVID-19 MDT meetings

From March 31 to April 15, 2020, 318 patients with COVID-19 symptoms and either a positive PCR for the SARS-CoV-2 or a COVID-19-compatible CT-scan were examined in our institution. Among these 318 patients, 263 (83%) needed hospitalization, and the 55 others were discharged. Among these 263 patients, 230 (87%) required conventional hospitalization in one of the four COVID-19 units (pulmonology, infectious disease, internal medicine, and nephrology), 28 (10.6%) were admitted to the intensive care unit (ICU), three were hospitalized in the emergency department, and one in the psychiatry and thoracic surgery departments, respectively (figure 2). Among the 230 patients hospitalized in conventional unit, 91 (40%) were retrospectively analysed as fulfilling the MDT meeting criteria, 50 (55%) of whom were presented, whereas the remaining 41 (45%) were not (figure 2).

Figure 2 illustrates the number of patients fulfilling the MDT meeting criteria and the number of patients discussed during COVID-19 MDT meetings for each of the four COVID-19 units. Among the patients fulfilling the criteria, the proportion of patients actually discussed during COVID-19 MDT meetings was 75% for the pulmonology unit, 64% for the infectious disease unit, 38% for the nephrology unit, and 31% for the internal medicine unit (table 3, figure 2). Among the patients hospitalized in internal medicine, 16 (57%) were in a specific geriatric unit and 13/16 (81%) were not presented at the MDT meeting. Three ICU patients were presented during a MDT meeting (data not shown).

Baseline patient characteristics

The baseline characteristics of the 91 patients fulfilling the MDT meeting criteria are listed in table 3. The patients who were presented during MDT meeting were likely to be older than those not presented, the between-group difference being not statistically significant. Furthermore, among the patients hospitalized in geriatric internal medicine unit, there were significantly more patients who were not presented during a MDT meeting.

Treatment and issues

Table 4 describes the treatment and issues pertaining to the 91 patients fulfilling the MDT meeting. There were significantly more additional investigations, mostly thoracic CT-scans for pulmonary embolism, in patients presented during MDT meeting than in those not presented (p=0.003). The number of patients included in the CORIMUNO cohort [START_REF] Hermine | Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial[END_REF] was significantly higher among patients presented during MDT meeting as compared with those not presented (p=0.0007). Patients not presented in MDT meetings received more frequently corticosteroids (51 versus 24%; p=0.007) and referring physicians less frequently defined their resuscitation status (37 versus 14%; p=0.01). However, they were similarly included in described clinical trials (p=0.54).

On Days 14 and 28, no significant differences were observed in terms of hospital discharge, hospitalisation or alive status between patients presented during MDT meetings and those not presented.

Adhesion to and limitations of MDT meetings for caregivers

Adhesion to and limitations of MDT meetings for caregivers were evaluated in COVID-units (table 5). Overall, 43 (84.3%) out of 51 non-ICU physicians involved in the COVID-19 units answered our survey, including 20 residents (46.5%), six fellows (13.9%), and 18 attending physicians (41.8%). Pulmonology and internal medicine were the most represented departments with 18 (41.8%) and 15 physicians (34.8%), respectively. All participants declared being aware of the MDT meetings, which helped them in their patient care (93.0%). MDT meetings were permitted more often by the titular physicians than by the residents (51.1% versus 13.9%). Creation of a MDT meeting file and access to the standardized COVID-19 MDT record were deemed easy for half of the residents and for over 75% of the titular physicians. The cases were presented by residents (n=12, 27.9%), fellows, (n=6, 13.9%), and attending physicians (n=11, 25.5%), and particularly by pneumologists (n=17), internal medicine specialists (n=8), and infectious disease specialists (n=3). MDT meetings also aimed to promote the clinical trials and help physician (>90%) to include their patients and to remain informed of the progress of the different trials (table 5).

Discussion

This study demonstrates the feasibility of rapidly implementing MDT meeting in the context of a pandemic. However, while caregivers recognize the value of MDT meetings, their attendance to such meetings was not optimal. Significant differences in the therapeutic management of patients with similar WHO Group clinical severities were observed, depending on whether their medical file was presented or not at a MDT meeting. Patients not presented at a MDT meeting more often received drugs that were not yet validated as part of a trial.

MDT meetings help define a SOC in the absence of recommendations

At the beginning of pandemic, physicians treated COVID-19 pneumonia as they would do it in case of severe community-acquired pneumonia [START_REF] Wiersinga | Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT)[END_REF], provided that the patients were likely immunocompetent and did not require ICU admission. Such treatment strategy was implemented in 92% of patients who were eligible for discussion at a MDT meeting. Arterial oxygen saturation was targeted to ≥94% and patients received venous thromboembolic prophylaxis, unless contraindicated. The favourite anti-infective treatment was combination of a beta-lactam with a macrolide, quinolones being reserved for patients with long QT syndrome or potential drug-drug interactions (26%). Physicians preferred macrolides over quinolones because COVID-19 pneumonia resembles atypical pneumonia [START_REF] Revel | COVID-19 patients and the radiology department -advice from the European Society of Radiology (ESR) and the European Society of Thoracic Imaging (ESTI)[END_REF]; most patients are nonsmokers [START_REF] Lechien | COVID-19 Task Force of YO-IFOS. Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019[END_REF] and macrolides reduce inflammation [START_REF] Zimmermann | The Immunomodulatory Effects of Macrolides-A Systematic Review of the Underlying Mechanisms[END_REF]. Nevertheless, no therapeutic trials or cohort studies has yet demonstrated the macrolide benefits in this indication, so far [START_REF] Molina | No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection[END_REF]. In addition, many studies have reported a risk of cardiac toxicity [START_REF] Choi | Risk Evaluation of Azithromycin-Induced QT Prolongation in Real-World Practice[END_REF],

particularly when macrolides are combined with chloroquine or hydroxychloroquine [START_REF] Chorin | QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin[END_REF][START_REF] Fiolet | Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and metaanalysis[END_REF] and, especially, when they are used in hospitalized COVID-19 patients, many of whom display cardiovascular comorbidities [START_REF] Aggarwal | Cardiovascular Safety of Potential Drugs for the Treatment of Coronavirus Disease 2019[END_REF].

Most teams currently favour discontinuing antibiotic treatment early if PCR testing is positive for COVID-19 pneumonia, and in the absence of evidence of bacterial coinfection, this last being less common in COVID-19 pneumonia (6%, [START_REF] Lansbury | Co-infections in people with COVID-19: a systematic review and meta-analysis[END_REF]) than in influenza-associated pneumonia (20%, [START_REF] Macintyre | The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09[END_REF]). MDT meeting was not used to discuss treatment or ICU admission limitation, which have to be defined before as stipulated on the form for patient presentation at COVID-19 MDT meeting.

MDT meetings help reduce the use of non-evaluated therapeutic strategies

Daily COVID-19 MDT meetings were meant for diagnosis, therapeutic discussion, and as an exchange vector of great educational value among professionals, as it enables analysing the treatment's risk, benefit, and impact on the patient's quality of life. MDT meetings can be used in other specialties like non-oncologic services, especially for complex management issues [START_REF]Réunion de concertation pluridisciplinaire[END_REF]. In such cases, all disciplines that are essential for diagnosis and treatment must be represented.

Corticosteroids were the treatment most frequently administered in combination with antibiotics, with 62% of patients discussed at MDT meetings receiving them (data not shown). The rational for the use of corticosteroids was its anti-inflammatory effect in a context of cytokine storm that appeared secondary to the viral step in rapidly worsening patients. However, there were no data yet on using corticosteroids in COVID-19 patients. Concerning their use in severe acute respiratory syndrome coronavirus-1 and Middle East respiratory syndrome-related coronavirus, most publications did not recommend them [START_REF] Arabi | Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome[END_REF], while their use in influenza cases still appeared conflicting [START_REF] Torres | Severe flu management: a point of view[END_REF][START_REF] Lansbury | Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis[END_REF]. They were administered to patients who scored 5 on the WHO 10-point Clinical Progression Scale, who were receiving at least 6L/min of oxygen, or who deteriorated on 3L/min but who did require neither respiratory support (non-invasive ventilation or high flow oxygen) nor ICU admission.

Corticosteroids were also deemed warranted if alveolar consolidation mimicking organizing pneumonia was found on chest CT-scan and if no evidence of bacterial superinfection was documented. The corticosteroid regimen was adapted from the one developed by the French GERMOP study group on rare lung diseases for organizing pneumonia [START_REF] Crestani | Pneumopathie organisée[END_REF]. The results of the the British Recovery trial mean that dexamethasone is now widely considered as the standard of care for hypoxemic Covid-19 pneumonia [START_REF] Recovery Collaborative Group | Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report[END_REF].

We used hydroxychloroquine (4%) and lopinavir/ritonavir (10%) very little, owing to the scandal in France surrounding the first, while the results with the second have been fairly poor, and we were awaiting the Discovery trial to begin in our institution.

The trial results with these two treatments have been broadly negative so far [START_REF] Ader | Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults[END_REF].

With no clear guidelines to follow, most patients were included in the prospective CORIMUNO cohort (80%), 42% of whom were randomized into the cohortembedded CORIMUNO-TOCI 1 trial [START_REF] Hermine | Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial[END_REF].

Patients presented to MDT meeting were not representative of the overall population treated in the institution

Although physicians strongly agreed that MDT meetings were useful (table 5), nearly half of cases eligible for MDT discussion were not presented at meetings for discussing the use of additional treatments besides antibiotics, which particularly applied to internists (31%) that were also those who had the poorer attendance. This can be partly accounted for by that several participants experienced technical issues while trying to follow meetings on Webex. In contrast, pulmonologists showed good attendance (75%) maybe since the meetings were held in the pulmonology department building.

While being able to rely on the MDT meetings provided physicians with reassurance, the meetings were not appropriate to every situation encountered across the departments. Particularly for acute geriatric patients that were older, had more comorbidities, have higher need for oxygen therapy and with limitation for ICU admission. As in all diseases, this demonstrates once more why specific guidelines on diagnosing and treating the geriatric population are urgently needed [START_REF] Turnheim | Drug therapy in the elderly[END_REF].

The MDT meetings seem less appropriate for intensive care patients and very few were indeed presented. There are several reasons for this: 1) patients were presented during ICU daily meeting; 2) some ICU patients were referred from other hospitals, with their therapeutic strategy discussed before their venue in our institution; 3) during the COVID-19 epidemic peak, some patients from our region were transferred from the ICU to another institution, including those receiving mechanical ventilation in attempt to offer bed admission for outside patients.

To conclude, the sudden arrival of the global COVID-19 pandemic coupled with the discovery of a novel disease made imperative to set up MDT meetings that respected social distancing. Nevertheless, the urgency of the situation did not prevent us from implementing strict MDT best practices. However, this study highlighted that the patients presented at MDT meetings were not representative of the entire population treated in our institution, particularly the elderly and critically ill patients who probably should have specific MTD meetings. These meetings helped us to: i) implement a single standard of care within our institution; ii) avoid using treatments that are untested or only just being tested outside a therapeutic trial; iii) facilitate the inclusion of patients in prospective cohorts and therapeutic trials; iv) share our feelings and experiences among colleagues. Furthermore, these meetings have contributed to collectively disseminate evolving knowledge in the pathophysiology and treatments of the COVID-19 in the face of this unprecedented health crisis. Finally, coming together to face decisions and the difficulty of certain end-of-life situations was also a qualitative benefit on a human level, although not quantifiable by this study.

Author contributions: All authors have approved the manuscript and have significantly contributed to it.

FiguresFIGURE 1

 1 Figures

FIGURE 2

 2 FIGURE 2 Flow chart of COVID-19 patients between March 31 and April 15, 2020.

TABLE 1

 1 Characteristics of the MDT meetings' operating procedures

	Name	COVID-19 MDT meeting
	Coordinator	Five COVID-19 expert members, from different specialties, for each
		of the five working days: two pneumology, one internal medicine,
		one infectious disease, and one ICU
	Quorum	Five experts of the main specialty departments (pneumology, ICU,
		infectious disease, internal medicine) were required to ensure the
		quorum of the MDT meeting. As thoracic CT-scan suggestive
		features were essential for COVID-19 diagnosis, the presence of a
		thoracic radiologist was deemed essential. Because of potential
		drug-drug interactions, as well as the strain on medications, a
		pharmacist was also required. In addition, a virologist should also be
		present to discuss the virologic results
	Name of referring	For follow-up on the decision taken, including explanation to the
	physician	patient and subsequent organization of care
	Patients to be

presented With the exception of ICU patients, all COVID-19 patients (confirmed by a positive PCR or a thoracic CT-scan suggestive of COVID-19)

who required a therapeutic escalation or inclusion in a clinical trial (defined in figure

1

) were recommended to be presented.

All available therapeutic options were similarly discussed. COVID-19, coronavirus disease 19; MDT, multi-disciplinary team; ICU: intensive care unit; CT, computed tomography; PCR, polymerase chain reaction.

TABLE 2

 2 Standardized form for patient presentation at COVID-19 MDT meeting

	Item

TABLE 4

 4 Treatment and issues

	MDT meeting	No MDT	p
	n=50	meeting
		n=41

TABLE 5

 5 Survey to evaluate MDT meeting adherence and limitations for caregivers Did this meeting help you include patients in clinical trials, yes, n (%) 29 (65.9%) Does this meeting allow you to learn about clinical trials, yes, n (%) 38 (86.3%)

	n=43
	(86.2%)

Conflict of interest: None declared.