domain: shs scco

text:
PhD Sophie Bayard
email: bayardsophie@yahoo.fr

PhD Jean-Pierre Jacus

PhD,* Ste´phane Raffard

PhD Marie-Christine Ge´ly-Nargeot

Conscious Knowledge and Decision Making Under Ambiguity in Mild Cognitive Impairment and Alzheimer Disease

Keywords: decision making, Iowa Gambling Task, mild cognitive impairment, Alzheimer disease

(Alzheimer Dis Assoc Disord 2014;00:000-000)

O lder adults face many situations that require them to make important decisions. Decision making is a broad and complex construct. One conceptualization of decision making is the somatic marker hypothesis developed by Bechara et al. [START_REF] Bechara | Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making[END_REF] These authors state that the experience of emotion that operates unconsciously is tied to the decisionmaking processes. Empirical support for the somatic marker hypothesis is largely based on performance on the Iowa Gambling Task (IGT), a paradigm designed to stimulate decisions in terms of uncertainty (ie, implicit rules), reward, and punishment.

According to Bechara et al, [START_REF] Guillaume | Somatic markers and explicit knowledge are both involved in decision-making[END_REF] normal participants started to make the right selections in that card game before they had conscious knowledge that those were the best selections. In this task, healthy controls demonstrate an anticipatory electrodermal response (ie, unconscious and automatic bodily signals) to card selection; before selecting a risky choice, they show a physiological reaction indicating that they are bodily experiencing the anticipated risk even before conscious knowledge is available. Since the seminal work of Bechara et al, 2 some authors have suggested that an explicit/analytical understanding can be sufficient to guide advantageous decision making measured by the IGT. [START_REF] Maia | A reexamination of the evidence for the somatic marker hypothesis: what participants really know in the Iowa gambling task[END_REF] In fact, healthy individuals with higher levels of conscious explicit knowledge of the advantageous strategy during the IGT also have better decision performance on the task 2,3 and there was no significant association between level of explicit knowledge and development of anticipatory skin conductance responses for these individuals. [START_REF] Guillaume | Somatic markers and explicit knowledge are both involved in decision-making[END_REF] Advantageous decision making therefore seems to be associated with 2 distinct, namely implicit and explicit, systems.

Patients with mild cognitive impairments (MCI) and Alzheimer disease (AD) typically perform less well on decision-making tasks than do healthy controls. [START_REF] Zamarian | The impact of mild cognitive impairment on decision making in two gambling tasks[END_REF][START_REF] Gleichgerrcht | Decision-making cognition in neurodegenerative diseases[END_REF] To the best of our knowledge, however, no study has directly compared decision-making performances of older adults with MCI and AD in ambiguous context. Furthermore, there are no data available on the relationship between conscious knowledge of contingencies and decision-making performances under conditions of uncertainty in AD and MCI. In the present study, we investigated these 2 questions and hypothesized that decision-making performances would be impaired in both MCI and AD patients. Explicit knowledge would be associated with advantageous decision-making performance under conditions of uncertainty in both AD and MCI.

PARTICIPANTS AND METHODS

Participants

Sixty participants took part in the study: 20 healthy controls, 20 patients suffering from AD, and 20 participants with MCI. AD and MCI patients were recruited from a memory clinic (Centre Hospitalier du val d'Arie`ge, France). MCI was diagnosed according to specific operational criteria. [START_REF] Petersen | Mild cognitive impairment: clinical characterization and outcome[END_REF] AD patients were diagnosed according to the NINCDS-ADRDA criteria. [START_REF] Mckhann | Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease[END_REF] The severity of their disease ranged from mild to moderate (range = 22 to 29). All patients underwent extensive medical, neurological, and neuroimaging examinations to ensure the absence of any other major neurological conditions. The control group included 20 healthy community-dwelling adults recruited from a volunteer registry or senior-citizen group advertisements. They had no history of neurological disease or psychiatric disorder. All controls had a Mini Mental State Examination (MMSE) score above the 10th percentile. None of the participants were prescribed medications known to affect memory or other cognitive functions.

Decision Making and Explicit Knowledge

Decision making was investigated using the computerized version of the IGT. [START_REF] Bechara | Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making[END_REF] The procedure has been described elsewhere. [START_REF] Bechara | Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making[END_REF] Briefly, participants have to resolve an uncertain situation by learning to sacrifice immediate rewards in favor of long-term rewards. The main dependent measure was the IGT net score. This score is the difference between the numbers of choices from advantageous decks for which little money is won but even less is lost (resulting in a net gain) and disadvantageous decks for which a lot of money is won but even more is lost (resulting in a net loss). The cutoff of 22/100 was applied to distinguish advantageous decision

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making from random and disadvantageous decision-making profiles. [START_REF] Denburg | Psychophysiological anticipation of positive outcomes promotes advantageous decision-making in normal older persons[END_REF] After the task, we assessed the explicit understanding of the participants of the contingencies in the IGT, by asking them which options yielded higher gain or loss. Answers were classified as "Full explicit knowledge" or "No explicit knowledge." Full explicit knowledge meant that the participant reported and correctly identified the 2 best decks (ie, producing small, immediate gains of money, but the unpredictable losses are small, with accumulated penalties being smaller than the accumulated gains).

RESULTS

Table 1 presents demographic data and differences between groups on IGT and explicit knowledge. Given the sample size, nonparametric methods were used (ie, Mann-Whitney and w 2 tests).

AD and aMCI participants were older, less educated, and had a lower premorbid intellectual level than controls (all P's < 0.05), without any difference between AD and aMCI participants (respectively, P = 0.10, P = 0.82, and P = 0.79). Groups were matched for sex. As expected, MMSE scores were significantly lower for AD participants as compared with aMCI participants (P = 0.006) or controls (P < 0.001). Significant differences in MMSE was also observed between aMCI participants and controls (P = 0.018). Despite significant group differences, age, premorbid intellectual level, and education were not associated with decision-making performances when comparing participants with advantageous decision-making profile (IGT net score Z22/100) to those with a disadvantageous profile (respectively, Z = À 0.67, P = 0.49; Z = À1.76, P = 0.08; Z = À1.67, P = 0.09). The same pattern of results was observed for the explicit knowledge variable (respectively, Z = À0.02, P = 0.98; Z = À 1.79, P = 0.07; Z = À0.72, P = 0.47).

The percentage of participants with advantageous decision-making profile (IGT net score Z22/100) was higher in controls (55%) than in AD and MCI (respectively, 15% and 10%, P = 0.006) (Table 1). No significant difference was observed between AD and MCI groups (w 2 = 0.23, P = 0.5). Within the entire sample, full explicit knowledge was significantly associated with an advantageous decision-making profile on the IGT (P < 0.001). Correct explicit understanding task was reported less often in both MCI and AD participants than in controls (10% and 10% vs. 55%, P = 0.002) without any difference between the 2 cognitively impaired groups (P = 1). As illustrated in Figure 1, the same pattern of association was observed in both MCI and AD (respectively, P = 0.046 and P = 0.005). In these groups, advantageous decision-making profile (IGT net score Z22/100) was associated with full explicit knowledge. This relationship was not observed in controls (P = 0.37). Neither age nor sex was associated with decision-making profile or explicit knowledge in the whole sample (all P's > 0.05).

DISCUSSION

Our study is the first to explore decision making under ambiguity in MCI and AD. Reduced decision-making performance was observed in both the groups. The profile of decision making for MCI patients also mimiced that of AD patients. In fact, both groups opted more frequently than controls for decks with high immediate reward regardless of higher future punishment. This study adds to previous investigations on decision making assessed by the IGT in MCI [START_REF] Zamarian | The impact of mild cognitive impairment on decision making in two gambling tasks[END_REF] and AD. [START_REF] Gleichgerrcht | Decision-making cognition in neurodegenerative diseases[END_REF] However, no study so far has jointly investigated decision making under ambiguity in patients with MCI and AD.

After the task, we assessed the explicit understanding of the participants of the contingencies in the IGT, by asking them which options yielded higher gain or loss. Correct explicit understanding was reported less often in MCI and AD participants than in controls with no difference between these 2 groups. Full explicit understanding was associated with better decision-making performance within the entire sample and in both MCI and AD, but not in healthy controls. This suggests that MCI and AD patients have impaired decision making because they are unable to acquire a sufficient explicit knowledge. These findings provided support for several reports that explicit knowledge may be of greater importance for successful performance in the IGT than previously suggested. [START_REF] Guillaume | Somatic markers and explicit knowledge are both involved in decision-making[END_REF][START_REF] Maia | A reexamination of the evidence for the somatic marker hypothesis: what participants really know in the Iowa gambling task[END_REF] Our results are also in line with several investigations of IGT performance in amnesic patients that emphasize the critical role of declarative memory on decision making under ambiguous conditions. [START_REF] Gupta | Declarative memory is critical for sustained advantageous complex decision-making[END_REF][START_REF] Gutbrod | Decision-making in amnesia: do advantageous decisions require conscious knowledge of previous behavioural choices?[END_REF] In fact, patients with amnesia due to bilateral hippocampal damage do not develop a preference for advantageous choices in the IGT. [START_REF] Gupta | Declarative memory is critical for sustained advantageous complex decision-making[END_REF] These results were corroborated by Gupta and colleagues who demonstrated impaired IGT performance in amnesic patients. This impairment occurred both when there was a 6-second delay between card selections and when no delay was interposed between card selections. These results suggest that the hippocampus (and perhaps other medial temporal lobe structures) is necessary for complex decision making of the type tapped by the IGT. Declarative memory seems to be necessary for forming and updating the relational representation between the decks and their associated rewards and punishments, resulting in the amnesic participants' impaired ability to make sustained advantageous decisions over time. We observed that nearly one half of the healthy controls showed impaired decision-making profile on the IGT. This heterogeneous result is consistent with a previous study carried out by Denburg et al [START_REF] Denburg | Psychophysiological anticipation of positive outcomes promotes advantageous decision-making in normal older persons[END_REF] who have reported a decision-making impairment in 48% of older healthy adults, despite otherwise intact cognitive functioning. It is possible that different nonexclusive processes (ie, emotional processes or implicit knowledge) are preferentially involved in this population. In fact, these authors documented that older healthy adults with disadvantageous decision making on the IGT did not demonstrate reliable anticipatory psychophysiological discrimination of good and bad choices, supporting the somatic marker hypothesis. [START_REF] Denburg | Psychophysiological anticipation of positive outcomes promotes advantageous decision-making in normal older persons[END_REF] Several limitations to our study need to be addressed. One is the difference in education, premorbid intellectual level, and age between groups. However, we found no association between age, premorbid intellectual level, education, and IGT performance. We are aware that our sample size is small. This statistical limitation might explain the similar IGT decision-making profiles of AD and aMCI.

In conclusion, our results provide evidence that explicit understanding is an essential condition to make advantageous decisions in uncertain situations (ie, where options are initially unknown and have to be learned through experience) in MCI and AD. In this clinical context, improving explicit/analytical understanding of real-life situations that require decision making in ambiguous context could be a critical point for such patients to make favorable choices. Future research might investigate whether our findings can be generalized to real-life decision situations.

FIGURE 1 .

 1 FIGURE 1. Percentage of participants with advantageous decision-making profile [Iowa Gambling Task (IGT) net score Z22/ 100] depending on explicit understanding of the contingencies in the task.

TABLE 1 .

 1 Demographic Data, Differences Between Groups on IOWA Gambling Task and on Explicit Knowledge French version of the National Adult Reading Test; MCI, mild cognitive impairment.

		Controls	MCI	AD	Statistics	P
	Demographical and clinical data [median (range)]
	Age	71 (64-86)	79.5 (67-85)	82 (71-90)	Z = 12.71	0.002*
	Education	11.5 (6-17)	7.5 (6-17)	7 (6-12)	Z = 13.23	0.001w
	f-NART	118 (100-125)	106 (96-121)	109 (93-120)	Z = 9.41	0.002w
	Mini Mental State Examination	28.5 (27-30)	27.5 (24-30)	25 (22-29)	Z = 21.33	< 0.001w
	Iowa Gambling Task
	Net score Z22/100 [n (%)]	10 (50)	3 (15)	2 (10)	w 2 = 10.13	0.006w
	Explicit knowledge
	Full explicit knowledge [n (%)]	11 (55)	3 (15)	2 (10)	w 2 = 12.44	0.002w
	*Controls < (MCI = AD).
	wControls > (MCI = AD).
	AD indicates Alzheimer disease; f-NART,

r 2014 Lippincott Williams & Wilkins

r 2014 Lippincott Williams & Wilkins www.alzheimerjournal.com | 3


1

Moi la Révolution -revolutionary poetics in the storm of counterrevolutionary times

Sophie wahnich, Pacte CNRS Grenoble, Moi la révolution is a strange text. It portrays a female figure, rather like a song by Moustaki entitled without naming her, in which the "living girl" is none other than the "Permanent Revolution". But here, the Revolution speaks of "I", "me, I" -and the subtitle speaks of "remembrances of an unworthy bicentenary", much as René Allio had told the story of The Unworthy Old Lady on the cinema screen back in 1965. In this movie, upon becoming a widow, an old lady discovered her love of life -raising the hackles of those who would have liked to see her plunge into sadness. In Moi la Révolution1 there is a dialectic of the dead and the living-dead, of spectres and bodies, of joy and pain. It is a whirlwind. Time is off its hinges and the reader moves between past and present, memories and afterthoughts, lived history and a history that is represented and recounted. It is about remembrances -an out-of-fashion word that Daniel Bensaïd prefers to "recollection" or "memory" or "commemoration". Literally, "remembrance" means giving back limbs, a body -so, to an old lady. It means to give back "human flesh", as Marc Bloch might have said. It means to give back body to the Revolution, to re-embody it, unlike a bicentenary in the masculine -and thus contemporary society and its rituals -that instead made her, the Revolution, disappear. It means to bring out living memories, as against the abusive embalming of the Revolution by the official, state-orchestrated commemoration. The word "remembrance" itself takes a stand against such embalming. By giving body to the Revolution, we give it voice. We also bring out the things that make a person and make a dialogue: emotions, anger, joy, sadness, disappointment, pride, and thusin the spectrum of all these colours of thought2 -the lived contradictions, where the simple story of a magnificent 1789 and a 1793 to make us blush leaves Daniel Bensaïd with doubts. But it is also a question of restoring the feminine, that is to say, perhaps the "limitless". So, we head back to the Permanent Revolution. The text portrays the political interpellation of the man who orchestrated the bicentenary event -and did so as Socialist president of the French Republic -by she (the Revolution) who cannot intervene, except in this fictional form. A reified revolution has become something mute. It is necessary to play Michelet's role and awaken the dead. The book thus sets two historical situations face-to-face and confronts them: the situation of the actors in the Revolution, and that of the heirs to the Revolution. The latter can do what they like with the heritage, but that does not mean that they can destroy every trace of what once was. Ideas leave behind something of a pratico-inertia, as my friend Sartre would have said, 3 and sometimes it is fundamentally active. Perhaps that was Saint-Just's intuition, as quoted in Daniel Bensaïd's book: "I despise the dust that makes me up, and that speaks to you, one could persecute this dust and kill it off; but I defy anyone to tear away this independent life that I have given myself in the centuries and in the heavens..." 4 . But what the reader is reading is also a woman's challenge to a man. In French, the word "revolution" is feminine and the word "president" or "king" masculine, and in the shadow-theatres staged at the time of the event, the Nation makes a scene -a domestic -with the King, because he has betrayed her. This is a theme taken up by Renoir in his La Marseillaise (1938). This is doubtless also what makes intelligible the graffiti from the Revolution in which a mocking woman calls out to a simpleton king -often misrepresented as a couple of sans-culottes. 5 In Moi la Révolution it is no longer the nation-woman and the king-man who are sizing each other up, but the Revolution-woman and the Socialist-president-man. One has the privilege of a speech that surpasses mere time, the other the privilege of acts and discourses in the present, a president who is no longer a simpleton-king. That is, another couple, to stage an analogous interpellation. How can you betray me to this degree? So, yes -there is hysteria in the air, anger, brawling, "a woman with a history to her" because she is "righting wrongs". 6 Bensaïd's text is, then, out of time and very much situated in the year 1989, the bicentenary year. What is offered for us to read is very much about the quarrels of the present. Now, more than thirty years later, can we still read this text -and why, and how, should we do so? What does the fictional uncertainty of the subject -of the narrator and of the speaking body -allow us to say, but also stop us from saying? What needs explaining here is a genuine poetics of knowledge. Under the stage of the commedia dell'arte, where a dog is donning a Phrygian cap and the revolution choking in front of the TV as it prepares its garlic salad, we must untangle the threads of a complex and polyphonic poetics of knowledge. And we must think about who hears -or else remains deaf to -the poetics engaged in here by the author Bensaïd, both in 1989 and still today. The present-day relevance of a poetics, or its lack of such relevance, lies in both its capacity to cross through time, to maintain its actuality, but also to keep alive the meaning of its address. To whom is this text addressed? Is the porosity of the fields today enough for such a poetics to be able to influence both flanks -activists, and also scholars -on the model of that which characterised Daniel Bensaïd's own life? How can science fiction still find its place in the contemporary institution of reading?

I. Embodying the revolution, a dream of carnivalesque omnipotence Daniel Bensaïd, fiction writer

Fiction as a theoretical position

In 1989, experiments in combining fiction and history were still few and far between. They had not been trivialised by their depoliticising generalisation like they have been today. Régine Robin published Le cheval blanc de Lénine ou l'histoire autre7 in 1979, and theorised these broad questions of fiction in a book titled le Roman mémoriel. 8 This latter reflected on the contemporary finality of history, in its so-called dangerous liaisons with memory and the Freudian novel. It sought to show that separating memory and history is no simple matter, and that history is a specific aspect of social memory. But it also sought to reject the fabrication of well-defined identities, the weight of the symbolic, legitimations and convenient identifications. Jacques Rancière had not yet published Les noms de l'histoire, 9 in which he made the case for a new poetics of historical knowledge, upholding a triple poetic, scientific and political contract. But without doubt something of this question was already circulating in the corridors of the Paris-VIII university's philosophy department. In writing history, we are playing with the very impossibility of history. Because, whatever we may do, reality resists all interpretation. The past is never what we thought it was; to write history is to artificially put things in order retrospectively, and thus always to betray the truth, which is unknowable by definition. The attempt to work with fiction is always to conceptualise anew the division that sets regimes of meaning in opposition to regimes of scientificity, in favour of a questioning of the order of narratives, whether they are capable of giving a glimpse of this inaccessible reality or otherwise. Régine Robin called for an "imaginative shift by the historian" that would allow them to leave behind History with a capital H, its material, its archives, and would allow them to openly embrace its incompleteness, saying this without refusing to maintain a clear position that distinguishes between the referent found in the archive and what the scholar, the historian, the writer does with it. Historians ought to acknowledge that they are capable of asking good questions, but not always of answering them. Régine Robin called for work against what she called a "brazen positivism" and in the direction of a certain deconstruction of the historian's complete (or completely absent) subject. In this respect, fiction can be more rigorous than history. Working in this way does not mean abandoning the rationality of knowledge, but rather changing the historian's approach to reading the archive, building up corpuses, the methodologies and analyses to be put to work, and the textual products that result from them.

Once the historian has paid this price, thanks to this reflection on writing, they become a critical and committed intellectual. Daniel Bensaïd seems to respond to this way of doing, with regard to the history of the Revolution, the commemoration-event, and the fiction of this dialogue. Indeed, Régine Robin had been hoping for an ironical, tormented historian. Such a historian would give the critical function a real social existence, without thereby confusing themselves for a spokesman for the social. By accepting discomfort, uncertainty and even intellectual torment, the historian would be confronted with their own ethics without being able to allow themselves any pre-determined compass. They would be "out-of-place" and would have to build up their bearings with what I today call "sensitive reason". This reflexivity -similar to that of the revolutionaries -is tied to a sensitive experience of the world, to a position in the world. So, the first work performed in Moi, la Révolution is a work on what makes it possible, through fiction, to know and hear this impossible knowledge. The first research, the singular one, is there in Daniel Bensaïd's writing where he gives his body and his voice to the Revolution and puts himself in the shoes of an old woman who still has something -her word -to say, with vivid emotions and persistent sadnesses. She is an old-aged, or ageless, woman. A figure who comes to haunt us like the dead haunt the living in Madagascar to demand that their silk lamba be changed. In Daniel Bensaïd's text, the Revolution turns over in her grave, and stands up from it.

The fictional operation: a permanent transmutation

There is constant transmutation in this text, which begins with a first untimely address from the Revolution to Mitterrand. But among people who know each other well, who see each other in the sans-culotte tradition, they are going to be on familiar terms. But the Revolution also becomes a narrator. Under the name Revolution -as a concept and as an event -is a woman who refuses the role people seem to want her to play in the commemoration -the "role of a good girl who is a bit clumsy". 10 The Revolution, if she is indeed a woman, is histrionic, quarrelsome, dissident. Casting this female figure allows us to play with this histrionics and to let an unlimited freedom develop according to the fantasy of the author's wit, for underneath the woman/Revolution is Daniel Bensaïd in drag. There is carnival in the literary choices that at work, here. There will be irony. And this is how it starts politically, for this histrionics brings back conflict where there had been consensus. In his poem Colchiques, Apollinaire describes ruminants being poisoned in toxic meadows. "The cows grazing there slowly are poisoned" 11 he said. Here, it is the guests of the President's garden party who "together chew the soft caramels" 12 of consensus. The tone is set; the text, and thought, will be unleashed by fiction. Daniel Bensaïd has slipped into the ghostly body of a mythical character. He could appear as a Leviathan who encompasses all the actors and actresses of the Revolution, manufacturing from this multiplicity a unified figure with -and this would be a dramatic choice, for the purists of formalism -a strong psychological thrust. But more than Leviathan, this figure reminds me of Claude Ponti's Pétronille et ses 120 petits, 13 the mouse who is proud to have so many children, but also of the mother's character, who appears as "the mother of all mothers" to save from distress a Pétronille drowning in history. And if I think about it, it is because this unifying move has nothing to do with an overbearing, statist fusion, but rather a tender, maternal one. Georg Buchner 14 had Danton speak as a ventriloquist, criticising the revolution for having devoured its children, Saturn-like. Here, the paternal function gives way to the maternal one, and it is no longer a matter of devouring them but of bringing them up, of telling them where they have failed, of leaving the project unfinished, for example on the equality of men and women, on the question of slavery or even on property. Everything remained unfinished. The Revolution would have liked its children to have gone further, to be stronger, more virtuous, more consistent. The Revolution as a character is so not an ambivalent figure where there is good and bad. No, this figure is a complete and maximalist one, and as such she has some similarities with a concept, but a concept that takes into account the inconceivable of feelings. Adorno made his plea for a philosophy that could no longer do without the inconceivable, and thus without pain -and, I would add, joy. Well, this Revolution is a concept endowed with joy and pain, a somehow Brechtian mother of courage.

The Revolution feels what is going on. It is her desire for truth, her grievances, her experiences, her way of thinking, of pushing back, and also her sadness, that give this character such powers of interpellation. So, the French Revolution is at the same time a living ghost, a concept, a mother, a feeling body, a character, which is to say, Daniel Bensaïd's mask. No doubt this means "learning to live at last" -the opening assertion of Jacques Derrida's Spectres of Marx. 15 In this, we can almost see Renée Allio's "unworthy old lady" enjoying a Chantilly-covered ice cream as if it were the first time she had ever tasted one. But no -it is not the first time, and it is a reunion with life that settles in with a disconcerting simplicity, in everyday life where the TV is on in the dining room and people in their underwear remark on what's going on in the world. The simplicity of this figure makes us forget the megalomaniacal character of this embodiment. For it means learning to live, of course, but above all "teaching a lesson in living at last" to one's children, whom one loves with one's favourites, but also to us, the men and women of the late twentieth century, who, as a recomposed sibling, must recognise that we are sons and daughters of the revolution.

11 Apollinaire, Alcools, Colchiques, 1920, Folio-Gallimard 2013. 12 MLR, p.10 13 Claude Ponti, Pétronille et ses 120 petits, L'école des Loisirs, 1990. 14 Georg Buchner, La mort de Danton, 1835. 15 Jacques Derrida, Spectres of Marx, In fact, our narrator knows that she is fallible, devoid of certainties, that her most crucial questions still lay unanswered. But she knows that they must be asked seriously and rigorously, and she says as much: "I have not only had virtues, I am neither a woman of marble nor a woman of iron. I am simply a woman. Humanly a woman, humanly flawed … I have my doubts and uncertainties". 16 But she has learned something at least, if only the value of her questions. She wants to pass them on, to share her thoughts with us. So that the reader is not put off, if there is a lesson to be learned, it is to be taught to the commemorator-state -even if Daniel Bensaïd baulks at doing so -and to all its figures, Mitterrand's figure being the one who orchestrates the whole. So, there are two mythical bodies: a masculine Leviathan, and a feminine mythical mother. If François Mitterrand was delighted to be president at the time of the bicentenary, Daniel Bensaïd was positively jubilant about his position as author. He, The And this jubilation was communicative. It meant getting by, as the working class do: life is too short to let it to be lost in sadness. We have to laugh about it, we have to cry about it, but we must remain alive, lively, vivifying. The transmutation is, then, that of the ventriloquist -but hidden under the table like the automaton described by Walter Benjamin in his theses on the concept of history. 17 The ventriloquist plays all the roles, that of the Revolution, that of Mitterrand, and he has followed this history so closely in real-life that it is almost natural to play the chameleon as a marrano. Yes, Daniel Bensaïd enjoyed playing all the roles, even though taking the side of the revolution so dear to him. A cannibal carnival? Some of the Revolution's children are clearly the object of a vote to purge them; the Revolution is a mother who judges and condemns, a highly demanding mother, who even risks appearing impossible to satisfy or console. A Revolution that remains intimidating.

II. A self-justifying anachronism, discontinuities against teleology; Daniel Bensaïd as historian

To render justice

This work of the historian "who judges and condemns" is that of Nietzsche's critical history. 18 And here it is the Revolution that seems to do justice to itself with the fictional operation, the stacking-together of the matryoshka. This justice is not one which seeks to judge the Revolution as such with today's arguments, but rather to judge the bicentenary commemorations. Thus, Bensaïd does battle against the hypothesis which casts the Revolution as the matrix of totalitarianisms -one that had already been disseminated among the right-wing public by François Furet. But Bensaïd also takes care to speak of this adversary-historian without citing him too much. Here, he was doing battle against a new common sense that allowed an "investment advisor" 19 to compare the Declaration of the Rights of Man and of the Citizen of 1789 and the autobahns of the 1930s, and -based on this absurd comparison -the Revolution and fascist and Nazi totalitarianism. It says it all that such a ridiculous comparison is made between, on the one hand, a tool of material and technical life and, on the other, the symbolic tool par excellence, an emancipatory, contentious text, which has sometimes stood for hope, sometimes as an alibi. This is why it is necessary to fight on two fronts: against the denigration of the Revolution, but also against its falsifying embalming. It is the Revolution's emotions, and her scruples, that alert her to what is happening in the present; and it is from this present that she looks back to the past to revisit all that could shed a different light on this present. So, we have a dialectic of times. The Revolution's vivid memories then have the value of arguments -even if it is necessary to consider the uncertainty of the revolutionary event itself, and of its actors, in order to judge this bicentenary. Several questions, indeed ones of great present relevance, draw our historian's attention: property and the question of natural right, the colonies, the question of women, the questions of slaves and foreigners. On all these fronts, the revolutionary actors needed to have had more constancy or more courage. This is why the Revolution speaks of "its unfinished rights" 20 . Was property a natural right or a social right? What right did the propertied have to starve the poor? There is, then, a connivance with Robespierre, who speaks of the right to existence as the first among all rights. 21 But this same Robespierre disappointed her when he seemed to reject her abolitionist impulses. There will be no idols, only fragile favourites. Daniel Bensaïd probably listened too much to Michelet, whom he often takes at face-value. So, under the lens here is all that was left unthought, and so, too, the revolutionary problems of contemporary France. Indeed, here the colonial wars from 1945 to 1989 are revisited, from the perspective of Saint-Domingue and the impossible giving-up of the colonies, from Sétif to the Ouvéa gendarmes in New Caledonia, which we hope will become Kanaky. We are still there. "The "generous", "exemplary", "glorious" Declaration of Rights fell short on the issue of slavery. "Will you admit it, when you set the light of 1789 against the shadows of 1793? 22 For the narrator, there is a long-lasting shadow that we would like to disguise by celebrating Toussaint Louverture. "I heralded a universal emancipation. Paradoxically, from my defeated victory springs the seed of a modern racism that still haunts you. 23 The "still" is unending. The reconquest of rights in the present is mediocre. Public liberties are sold to the big corporations and the right of asylum is weakened, foreigners are lured by promises that never come true. As for women, they are daughters of the Revolution, scorned by men who, with the exception of Gregoire and Saint-Just, did not want to listen to any talk of them becoming equals. Nicole Loraux, when she speaks of this kind of haunting, of a missed opportunity trapped in the clutches of repetition, refers to "slicks of motionless time". 24 This could be another name for an "indissoluble past in the present". 25 But for Loraux, this immobility is a denial of conflict. A time suspended from classical historical temporality, the time of forgetting and repetition, but also the time that brings into play a "blocked memory" of political conflictuality and the "muted work of a plea of desire". 26 25 That is, Sartre's pratico-inert in the present, as he describes it in Questions de méthodes dans la critique de la raison dialectique, Paris, Gallimard, 1960, republished in 1984. 26 Nicole Loraux, "Éloge de l'anachronisme en histoire", art. cit. p. 138.

subject or the collective remains immobile, not subjected to the labour of working through contradictions. These immobile layers of time would offer another explanation for a cold or stagnant history, without the subjects of history having to take responsibility for everything. In this respect, Loraux willingly speaks of the "Greek problems" of our democracy. By this she means not a continuous filiation of these problems, but rather the repetition of similar problems, encysted in a non-vectorised historical time. I believe that Daniel Bensaïd has reached exactly this point when he picks up the dossier on the Revolution and rereads the texts closely -very closely even, sometimes. But if he becomes a reader of printed archives and thinks like a committed researcher, he does not enter into the space of a real dialogue with the historians of the Revolution, even if they may share the same questions. He makes his selection without sharing it with us, except for those able to read in between the lines. He thus opts against emancipating us, the readers, from the towering position of he who knows -and knows better than anyone else -how to interpret the statements of the actors. In so doing, he skips past the contextuality and the work of production of categories, which revolutionary actors attempted to do with varying degrees of rigour, seriousness and effectiveness. Thus, the category of foreigner in Saint-Just is one that identifies foreigners with the European counter-revolutionary coalition and with French counter-revolutionaries, with traitors. It stands only partly opposed to the national question; and so, it seems to me more interesting to link it to the traitorous king who has become a stranger to the city, than to a simple national conception of political life. This stranger becomes a stranger to humanity and not to the nation, and this leads to the notion of the crime of lèse-humanité. 27 Contrary to what Bensaïd says, here we have not left behind the shores of the revolutionary universal. Saint-Just does not betray himself, at least not in this respect. I think that these shortcomings in his argumentation and his lucidity lead to flawed judgements. We could surely list them and see in what way ideology is a barrier to the possibility of a common knowledge on these crucial questions. At least the work has been begun in this text, which remains both a scientific and political book -and indeed, politics is never purged of all ideology. Then we must remember that in the revolutionary moment itself, the actors were confronted with a folding of time that was not only revolutionary but itself aimed at an immobile time, as Loraux again indicated.

Discontinuities: a philosophy of history

Daniel Bensaïd knows that there is no straight line of progress, but rather discontinuities. The Revolution is "irruption, interruption and parting-of-the-ways [bifurcation]", terms that allow us to rediscover the question of the event, but also that of the alarm that must be sounded when progress takes on the appearance of "a train hurtling at high speed into the wall" 28 . This is also the work he undertakes in discussion with Michael Löwy, commenting on Walter Benjamin. Michael Löwy, as a good Marxist, continues to see the French Revolution as an illusion, whereas Daniel Bensaïd takes seriously the question of the French revolutionary laboratory, which has already been appreciated anew by Walter Benjamin himself. The fourteenth of the theses on the concept of history is the one where Benjamin exchanges this supposed illusion for a flair for the present-day. "History is the subject of a structure whose site is not homogenous, empty time, but time filled by the presence of the now. … Thus, to Robespierre ancient Rome was a past charged with the time of the now which he blasted out of the continuum of history. The French Revolution viewed itself as Rome incarnate. It evoked ancient Rome the way fashion evokes costumes of the past. Fashion has a flair for the topical, no matter where it stirs in the thickets of long ago; it is a tiger's leap into the past. This jump, however, takes place in an arena where the ruling class give the commands. The same leap in the open air of history is the dialectical one, which is how Marx understood the revolution." Historians work in the arena, but real revolutionary history is nothing other than this dialectical leap. This is why the Revolution is neither a continuum of time, nor a tabula rasa, but rather a rearrangement of times. So, for a historian of the French Revolution, their work must then grasp how this rearrangement is carried out. In this respect, Benjamin becomes a historian of the French Revolution by showing that the revolutionary calendar is not a new institution of power but a sign of this capacity for rearrangement. Thesis fifteen: "The awareness that they are about to make the continuum of history explode is characteristic of the revolutionary classes at the moment of their action. The great revolution introduced a new calendar. The initial day of a calendar serves as a historical time-lapse camera. And, basically, it is the same day that keeps recurring in the guise of holidays, which are days of remembrance. Thus the calendars do no measure time as clocks do." So, here we are with a revolution that rejects the "living-room clock" and recognises "rhythm and beats", the "waves of expansion and contraction". 29 Against "triumphal progress" -a Thermidorian theme par excellence -it is necessary to push back against "the concealment of discontinuities" and "the dates that tick by" 30 . There was no straight line from the Revolution to the bicentenary -and especially not that straight line which sought to use the French Revolution to vindicate all manner of renunciations, starting with the renunciation of the Revolution itself. Indeed, historians who conceive of the line of social time as a continuous one, and the movement of this line as a largely regular and regulated movement, are opposed by those historians who emphasise the forms of discontinuity that either suspend or interrupt a given movement in a society's life, or displace, reverse or decompose it. And this question itself depends on one's attachment to the possibility of the Revolution, as a change of order, understood as the effect of deliberate action within a social fabric conceived as essentially divided. So, to salvage discontinuity means to emphasise political invention, or the possibility of it. But even without the revolutionary hypothesis, the hypothesis of deliberate action, thinking of time as discontinuous also means conceiving of the movement of time as the product of the interplay that develops in a society between the field of experience and the horizon of expectation. 31 That is so, whether these expectations are optimistic or pessimistic, whether the experience is dramatic, tragic or exciting, or even tragic and exciting. The emphasis is on conflicts and crises as the driving force behind the movement of historycrises that are of heterogeneous kinds and as such, in a rare and erratic way, "events" in the strong sense: i.e. that which cuts through the field of experience and pierces the horizon of expectation of the people living that experience. When applied to key historical moments such as the French Revolution, these conceptions have radically opposite effects on interpretation. On the one hand, there is the slippage; on the other, the event. On the one hand, there is a long periodisation in terms of the genesis of the contemporary world, from 1789 to 1889; 32 on the other, a sequentiality with sharp angles, one framed by events that effectively reconfigure the revolutionary movement.33 So, Daniel Bensaïd discusses this choice of key moments which are not those of the commemorative calendar but those of another of those histories of the vanquished which would otherwise disappear. Such is the case with the mention of the shootings at the Champs de Mars, a tricolore terror buried by the official genealogical history. In the first conception, the current French Republic appears as the heir of the Revolution, according to a movement of continuous transmission; in the second case, the Revolution does not produce an inheritance, but a space of possibilities which is to be revisited by restoring the specificity of each of the Revolution's sequences. In this critique of progress, levelled against François Mitterrand, Daniel Bensaïd rediscovers the critique that Edgar Quinet levelled against the Empire in his day. In 1857, Quinet could no longer tolerate a conception of history which, he said, was "teleological" because its only aim was to present the genealogy of the parliamentary system. "Historians, convinced that the regime of parliamentary omnipotence was the consummation of French history, explained the eras that went before as a preparation for this new era. Everything in the past seemed to them to gravitate towards this present, which they considered indissoluble. This was the thread with which they journeyed through the Middle Ages and modern times … As they held in their hands the denouement of the drama, they could easily explained the beginning and the twists and turns … what went before is the cause of what follows, so in France, it must be absolute power that begat freedom!" 34 Edgar Quinet wryly remarked on the pseudo-parliamentary regime of the time of the Empire, which did not produce republicans on the model of the French revolutionaries, but moderates who could accommodate to any historical situation, convinced as they are convinced that things are the best they could be. The history of France now becomes that of a generalised rehabilitation of everything that came before and after the French Revolution, since progress has led the men of France to the point where they are now at. For Quinet, what is being erased, through this, are all the efforts to bring about freedom. The revolutionary event itself could become a kind of incident along the way, its failures as well as its successes reduced to nought. The aspect of history most inimical to freedom could be rehabilitated. On the other hand, if we refuse this teleology, history becomes a universe of resources: laboratories for analysis, certainly, but also part of a relationship of involvement which extends beyond a simple ambition to describe, an incentive to action engaging both the present and the future. Faced with the imperative of objectification of knowledge, this would mean always grasping the measure of the subjective relationship that we also maintain with this present of potential actualisations, and finally with the past that dialogues with this feeling of dialectical leap. Then, it will not be historians who can dialogue with the Revolution, but rather Joan of Arc and Péguy. For this philosophy of history leads to the steep paths of the mysticism of commitment, the mysticism of politics, the mysticism of freedom which looks identical to the passion of love. 35 "Women with historians" are not the same thing as women with a love story, and according to the Revolution, love for her is exactly what historians lack. They have "courted" her, but "few are those who have really tried to understand me, who have loved me for what I am". We might compare the judgement that historians make of the Revolution to the judgement of Joan of Arc by the bishops, and contrast faith -Edgard Quinet's famous faith in the impossible -to raison d'état and the rationale of the Church. For Bensaïd, the historians are on this latter side. "Too many historians are not enamoured enough with love to love me, they only love marriage. 36 So, out with the historians. This demands that we propose a philosophy of the revolutionary fact as a political observer of the past as well as the present.

Daniel Bensaïd, a non-actual philosopher?

In this book, Daniel Bensaïd proposes a reflection on the tragedy of this revolution, indeed of any revolution. For the secret of its sadness lies therein, in this Terror where the fusion of law and power, of the state which begins from the people and in this people itself, the source of law. In this context, any contrary opinion becomes a crime. We must try to understand what was at stake then and what is at stake now, in this lightminded manner of putting the Terror on trial, of putting on shows in which today's people are led to judge the people of times past by judging the king again, and thus effectively bringing the Revolution into dispute in the contemporary eye. "More than grotesque, it was unworthy! 37 "Citizen president, a society that indulges in these judicial murders, in defiance of our fears and our own nerve, speaks volumes about itself and its decadence. And it claims to judge me!" 38 Can one judge the act of seizing, with uncertainty and the danger of doubt? This is the beginning of a reflection on responsibility, a reflection on opportunism and the decadence of political virtue with Thermidor. But what preoccupies Daniel Bensaïd, alias the Revolution, is the question of revolutionary time, of its non-coincidence, of its actors who come "too early in a world that is too old" or "too late in a world that is too modern", or "too early and too late at once". The Revolution is indeed that of a time out of its depth. But it "does not abdicate its principle of hope". 39 "In a history without a last judgment or a promised land, my responsibility is complete. This is the only practical morality worthy of the name". Ernst Bloch, and also Kant! But what is at stake here is the rejection of the scramble to separate morality from politics. "My politics is a concrete morality and my morality a politics. An aesthetic, even, if you'll allow me, with only one base of support. Without the refusal to capitulate to the force of things, we would always be on the winning side." 40 So, this philosophy of revolution is one of courage and responsibility, and this is why the book seeks above all to tell the story in order to educate the thymos, that skill of zeal, which prevents one from being cowardly and lazy, in thought as in action. And this effort of thought is itself portrayed; the Revolution thinks, and thinks itself. "Without renouncing universality, without resigning myself to a society that is the random sum of fragmented particularities, I now know that there is no authentic universality, except that which proceeds through the mediation of the particular, and no effective totality, except through the mediation of its moments. I have reached these conclusions at the enfd of a deconstruction of my received wisdom". 41 The wry reading of the present and the humour, here, conceal a great distress in the face of a society that has allowed itself to be domesticated, and a chronicle of the end of a world, the end of a revolutionary hope as the rights of man remain an open horizon far beyond "the bourgeois horizon". 42 Thirty years later, has this text aged? In fact, it has been transformed. It seems to me to have become a document on the bicentenary as much as a history of the Revolution told to those who do not love it. And today there are even more of these than in 1989, so much so that the universalism still lauded here has taken a hit with postcolonial theories. But, if this text does have some present relevance, this owes precisely to its ability to speak of incomplete rights and of the aesthetics of politics. For the particular struggles today are those of the descendants of slaves, those of the women of Me Too, those of undocumented migrants and those of asylum seekers. In this respect, this book has not aged; it is even ahead of its time, because it does not give up on what we do indeed need to rediscover, this universal which is not imperial universalism but "universally emancipated humanity" 43 -"The dissolution of all classes and all oppressions, when there is no longer any reason to oppose a truly good society". 44 So yes, we can still read this text, which anticipates the need to defend the French Revolution against its enemies and all its false friends who buried it in 1989. The fictional uncertainty of the subject makes it possible to play with anachronism -thus to make both history and philosophy, not historicist history in the manner of historians, but history that examines meaning and not just facts. Who today can be an audience for this work? Those who love the work of language, of wit in the double sense of thought and humour, those who want to know what happened in 1989. But there is no need for illusions; the ones which, at the time, drove Bensaïd to take up the fight against Mitterrand are now very far from these concerns and far from the revolutionary universal. This poetics, both political and erudite, the double aspect of a history useful for life, needs to be read in a manner as lively as its writing. Today today the academy seems to have eaten up, under a heavy system of self-fulfilling constraints, any wish of freedom of thought and action. For the moment, a brazen positivism has won out over any commitment. The poetics crosses through time, but its erudite dimension is now only addressed to the out-of-sync actors of a disastrous situation. But the text has been republished by some of these out-of-sync types; 45 they still believe that it is possible to read a work that works on the porosity of fields, knowledge and practices, a porosity that is all feminine, a porosity that has become revolutionary once again. Can science fiction, as Michel de Certeau 46 thought about it, still find its place in the contemporary institution of reading? We have to wager that much, if we want to remain alive and if we do not want to adopt the victors' camp too quickly, without a fight. Sophie Wahnich, April 2021. 43

  It is a time of the unconscious and of passions. What could not be made dialectical through the

	20 MLR, title of a large part, pp. 29-69.
	21	MLR, p. 44.
	22	MLR, p. 54.
	23	MLR, p. 68.

24

Nicole Loraux, Le genre humain, no. 27, Seuil, June 1993, republished in Les voies traversières de Nicole Loraux, Clio/Espace temps, 2005.

  MLR, p.223. 44 MLR, p.223. 45 Published by don quichotte in 2017, with a preface by Arlette Farge. 46 Michel de Certeau, L'histoire entre science et fiction, folio gallimard, 1986.

Daniel Bensaïd, Moi, la Révolution, Remembrances d'une bicentenaire indigne, Gallimard, 1989.

Raisons pratiques, no. 6/1995 -La couleur des pensées -Sentiments, émotions, intentions, Collectif, Paris, éditions de l'EHESS.

Jean Paul Sartre, Critique de la raison dialectique, Paris Gallimard, 1960 and Sophie Wahnich, La Révolution française n'est pas un mythe, Paris, Klinksieck, 2017.

Saint-Just, Fragments d'institutions républicaines, oeuvres complètes, edited and introduced by Miguel Abensour, Paris, Folio-Gallimard, 2004.

Sophie Wahnich, La Révolution française expliquée en images, Paris, Seuil, 2019.

MLR, p. 227.

Régine Robin, Le cheval blanc de Lénine ou l'histoire autre, Complexe 1979, republished in Le naufrage du siècle, Berg international, 1998.

Régine Robin, Le Roman mémoriel, Montreal, Le Préambule, 1989.

Jacques Rancière, Les noms de l'histoire, Le seuil, 1992.

MLR, p.10

MLR, p.26.

Walter Benjamin, Theses on the Concept of History.

Fredriech Nietzche, réédition de la deuxième considération intempestive de l'utilité et de l'inconvénient de l'histoire pour la vie, Les mille et une nuits, 2000.

This is the subject of my thesis, defended in 1994 and published in 1997, eight years after the publication of Moi la Révolution. Sophie Wahnich, L'impossible citoyen, l'étranger dans le discours de la Révolution française, Paris, Albin Michel, 1997.

Michael Lowy, Avertissement d'incendie, Paris,

MLR, p.16.

MLR, p.15.

Here we draw on categories from Reinhart Koselleck, Le futur passé, pour une sémantique du temps historique, Paris, EHESS, 1990.

This is the option taken by François Furet in the volume on the French Revolution published in Hachette's major collection on the history of France. Jean Chesnaux had already pointed this out in "L'axe passé/présent/avenir" in "Cet obscur objet de l'histoire", Espace-Temps 1985, p. 14.

On the meaning of historiographical divisions and in particular on the question of sequentiality, see Sylvain Lazarus "Que veulent donc ceux qui ne veulent ni vertu ni terreur? A propos de la politique et de la terreur" in Catherine Kintzler, Hadi Rizk ed, La République et la terreur, Paris, Kimé, 1995.


MD Geoffrey Chupp
email: geoffrey.chupp@yale.edu.

Isam Mda

MD, PhD Alobid

MD, MS f , Njira L Lugogo

MD, PhD Harsha H Kariyawasam

MD, PhD Arnaud Bourdin

MD Adam M Chaker

PhDk Steven G Smith

PhD Ana R Sousa

MSc Bhabita Mayer

MDl Robert H Chan

MDn Andrea Matucci

Mepolizumab Reduces Systemic Corticosteroid Use in Chronic Rhinosinusitis With Nasal Polyps

Keywords: Asthma, Mepolizumab, AERD, Aspirin-exacerbated respiratory disease, Refractory disease, Severe chronic rhinosinusitis with nasal polyps, Subgroup analysis, Systemic corticosteroid

What is already known about this topic? In the phase III SYNAPSE trial, mepolizumab versus placebo significantly reduced nasal polyp size and sinonasal symptoms, sinus surgery occurrence, and systemic corticosteroid (SCS) use in patients with severe chronic rhinosinusitis with nasal polyps.

What does this article add to our knowledge? This article demonstrates that mepolizumab versus placebo is associated with improved treatment responses irrespective of prior SCS use, and SCS-sparing capabilities, overall and in patients with differing clinical characteristics.

How does this study impact current management guidelines? Given the adverse effects associated with SCS use, mepolizumab could be used to reduce reliance on SCSs and the associated adverse effect burden of SCSs in patients with recurrent, refractory, severe chronic rhinosinusitis with nasal polyps.

INTRODUCTION

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of CRS characterized by inflammation of the nose and paranasal sinuses. 1,2 Type 2, predominantly eosinophilic inflammation is a common feature of CRSwNP, with other immunologic subtypes often present. 3,4 For patients, CRSwNP is often severe in nature and has a substantial negative impact on sleep 5,6 along with health-related quality-of-life impairments similar to those of other chronic diseases such as diabetes, chronic obstructive pulmonary disease, and asthma.

7-9.

For patients with uncontrolled severe disease despite treatment with nasal lavage and intranasal corticosteroids, the standard treatment approach is administration of single or recurrent courses of systemic corticosteroids (SCSs).10 However, SCS use has several limitations. For example, both short-and long-term SCS exposure is associated with adverse effects including osteoporosis, pneumonia, cardiovascular/cerebrovascular effects, cataract, and depression/anxiety, 11-15 the management of which can result in a substantial economic burden. 16 A cumulative exposure of 500 mg to less than 1000 mg SCSs is also associated with an increased risk for adverse effects compared with exposures of more than 0 mg to less than 500 mg.17 Furthermore, some patients with CRSwNP fail to achieve adequate disease control with SCSs.8,18 For these patients, sinus surgery may be indicated 10 ; however, the long-term recurrence rate following sinus surgery is high, particularly in patients with eosinophil-rich endotypes. [START_REF] Calus | Twelve-year follow-up study after endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyposis[END_REF][START_REF] Tosun | Relationship between postoperative recurrence rate and eosinophil density of nasal polyps[END_REF] In 2 studies of patients with CRSwNP who had undergone sinus surgery, disease recurrence was reported in 79% and 82% of patients within 12 years of follow-up. [START_REF] Calus | Twelve-year follow-up study after endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyposis[END_REF][START_REF] Arancibia | Twelve-year long-term postoperative outcomes in patients with chronic rhinosinusitis with nasal polyps[END_REF] Given the substantial burden associated with SCS use, biologic therapies directly or indirectly targeting eosinophils have the potential to reduce SCS use in dependent patients, as has been demonstrated in other eosinophilic diseases. [START_REF] Bel | Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma[END_REF][START_REF] Nair | Oral glucocorticoidsparing effect of benralizumab in severe asthma[END_REF][START_REF] Rabe | Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma[END_REF][START_REF] Solèr | The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics[END_REF][START_REF] Wechsler | Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis[END_REF] Mepolizumab is a humanized monoclonal antibodies that tar-gets IL-5, thereby blocking the proliferation, differentiation, activation, and survival of eosinophils. 27 Mepolizumab is associated with a range of clinical benefits in a number of eosinophilic diseases, including a reduced risk of exacerbations, improvement in symptom control and health-related quality of life, as well as having an SCS-sparing effect in severe eosinophilic asthma; increased time in remission and higher proportions of patients with remission in eosinophilic granulomatosis with polyangiitis; and a reduced occurrence of flares in hypereosinophilic syndrome. [START_REF] Bel | Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma[END_REF][START_REF] Wechsler | Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis[END_REF][START_REF] Chupp | Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial[END_REF][START_REF] Ortega | Mepolizumab treatment in patients with severe eosinophilic asthma[END_REF][START_REF] Pavord | Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, doubleblind, placebo-controlled trial[END_REF][START_REF] Roufosse | Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebocontrolled trial[END_REF] In the landmark randomized, placebo-controlled, phase III SYN-APSE trial, mepolizumab significantly improved nasal polyp (NP) size (total endoscopic NP score) and nasal obstruction (nasal obstruction visual analog scale [VAS] score 10) compared with placebo in patients with recurrent, refractory CRSwNP in need of repeat surgery, as well as significantly reducing the occurrence of sinus surgery and the use of SCSs, and improving health-related quality of life as assessed with the 22-item Sino-Nasal Outcome Test (SNOT-22). 32 As a result, mepolizumab is now approved for the treatment of severe eosinophilic asthma, CRSwNP, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome in multiple regions worldwide. [START_REF]Mepolizumab summary of product characteristics[END_REF][START_REF]Mepolizumab prescribing information[END_REF][START_REF]Mepolizumab prescribing information[END_REF] The objective of this analysis was to explore the relationship between prior SCS use and treatment response, and to characterize the SCSsparing effect of mepolizumab in patients with CRSwNP.

METHODS

Study design

Full details of the SYNAPSE study have been described previously. 32 In brief, SYNAPSE was a phase III randomized, double-blind, placebo-controlled, parallel-group, multicenter trial (GSK ID: 205687; NCT03085797). Patients were randomized (1:1) to receive mepolizumab 100 mg or placebo subcutaneously every 4 weeks, for 52 weeks, in addition to standard of care (daily mometasone furoate nasal spray and, if required, saline nasal lavage, and short courses of high-dose SCSs and/or antibiotics). The use of SCSs was based on the treating physician's assessment of clinical need and driven by clinical guidance. Patients maintained standard of care throughout the study period, and SCS rescue medication use was permitted at any time during the study.

The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines from the International Conference on Harmonisation, and any applicable country-specific regulatory requirements. All patients provided written informed consent before study initiation. The study was approved b local ethics review boards at the participating sites. The protocol is available at https://www.gskstudyregister.com/.

Patients

Full inclusion and exclusion criteria have been published previously. 32 Eligible patients were 18 years or older with recurrent, refractory, severe bilateral NPs (defined as nasal obstruction VAS symptom score of more than 5 [maximum 10]) who were eligible for repeat surgery, as evidenced by an overall VAS symptom score of more than 7 (maximum 10) and endoscopic bilateral NP score of 5 or more (maximum 8), with a score of 2 or more in each nasal cavity, despite standard of care treatment. Patients had to have 1 or more sinus surgery (defined as any incision of the paranasal sinuses and removal of polyp tissue from the nasal cavity [polypectomy] and the sinuses) in the previous 10 years. In addition, patients had received stable maintenance therapy with intranasal spray (mometasone furoate) for 8 weeks or more before screening and displayed 2 or more different sinonasal symptoms for 12 weeks or more before screening (nasal blockage, obstruction or congestion, and/or nasal discharge [anterior or posterior nasal drip], with 1 or more of the following: nasal discharge, facial pain or pressure, and/or a reduction in or loss of smell). CS use was not permitted in the 4 weeks before screening. Patients were not eligible for randomization if there were changes in their CRSwNP maintenance therapy during the run-in period, including changes in or addition of an intranasal corticosteroid, a short-burst course of an SCS, a leukotriene receptor antagonist, or allergen immunotherapy. Only short courses of SCSs were permitted during the study. Patients were excluded if they had received biologic or immunosuppressive treatment within 5 terminal phase half-lives of screening.

End points and assessments

To assess the impact of prior SCS use on treatment response and the need for surgery, changes from baseline in total endoscopic NP score at week 52, nasal obstruction VAS score at weeks 49 to 52, SNOT-22 total score at week 52, and time-to-first sinus surgery up to week 52 were analyzed post hoc by the number of SCS courses in the year before enrollment (0, 1, >1).

To assess the SCS-sparing effect of mepolizumab, prespecified end points relating to SCS use during the study included the proportion of patients requiring 1 or more course of SCSs for NPs, the total number of SCS courses for NPs, and time-to-first SCS course for NPs, all up to week 52 in the intent-to-treat population. Among patients with 1 or more SCS course during the study, end points included the total dose (mg/y) of prednisolone-equivalent oral corticosteroid (OCS) for NPs (post hoc analysis), the proportion of patients receiving distinct dose categories of prednisolone-equivalent OCSs for NPs (prespecified analysis; categories: >0-100 mg/y, >100-200 mg/y, >200-300 mg/y, >300-400 mg/y, >400-500 mg/y, >500-600 mg/y, and >600 mg/y) and the total number of days on SCSs for NPs (prespecified analysis), all up to week 52.

To assess the potential impact of patient clinical characteristics on the SCS-sparing effect of mepolizumab, prespecified analyses included the proportion of patients requiring SCSs for NPs up to week 52 by the number of prior sinus surgeries (1, 2, >2), blood eosinophil count (</=300, >/=300-</=500, >500-</=700, >700 cells/mL), comorbid asthma (yes, no), and comorbid AERD (yes, no). Post hoc analyses included total dose (mg/y) of prednisoneequivalent OCSs for NPs up to week 52 by the number of prior sinus surgeries (1, 2, >2), blood eosinophil count (<150 cells/mL, >/=150 cells/mL, <300 cells/mL, >/=300 cells/mL; different thresholds used vs prespecified analyses, owing to small patient numbers), comorbid asthma (yes, no), and comorbid AERD (yes, no). Safety data during SYNAPSE have been previously published. 32

Sample size and statistical analysis

All data reported up to week 52 were included in the analysis, regardless of treatment discontinuation. Sample size calculations and the hierarchical testing of secondary end points have been described previously. [START_REF] Han | Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF] For the purposes of this study, courses of SCSs less than 7 days apart were considered as 1 course. Within a subgroup, total endoscopic NP score, nasal obstruction VAS score, SNOT-22 total score, and estimates of the treatment effect accounting for covariates of treatment group, geographical region, baseline score, and loge baseline blood eosinophil count (if applicable) were presented as a difference in medians based on a quantile regression model.36,37 Within a subgroup, the proportion of patients requiring SCSs for NPs was analyzed using a logistic regression model with covariates of treatment group, baseline NP score (centrally read), baseline nasal obstruction VAS score, log e baseline blood eosinophil count (if applicable), number of SCS courses in the previous 12 months (0, 1, >1; ordinal), and geographic region. Time-to-first SCS course was determined using Kaplan-Meier estimates. All data were analyzed using SAS v 9.4 (SAS Institute, Inc, Cary, NC).

RESULTS

Patient population

A total of 407 patients were included in the SYNAPSE intent-to-treat population; 206 received mepolizumab and 201 received placebo. The demographic and clinical characteristics of these patients have been previously reported. [START_REF] Han | Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF] In the year before the study, 52% (n = 210) of patients had not received a course of SCSs for NPs, with 27% (n = 111) receiving 1 course and 21% (n = 86) more than 1 course.

Treatment response by prior SCS use

Improvements in total endoscopic NP score at week 52, nasal obstruction VAS score at weeks 49 to 52, and SNOT-22 total score at week 52 with mepolizumab versus placebo were largest in the subgroup of patients with 1 SCS course in the year before the study (Table I; see Figure E1 in this article's Online Repository at www.jaci-inpractice.org). The proportion of patients requiring sinus surgery up to week 52 was consistently lower with mepolizumab than with placebo across all baseline SCS use subgroups, with the largest benefit in patients with more than 1 SCS course in the year before the study (Table I).

SCS-sparing effect of mepolizumab

As previously reported, the proportion of patients requiring 1 or more course of SCSs for NPs during the study was lower with mepolizumab (n = 52 of 206 [25%]) versus placebo (n = 74 of 201 [37%]).32 Mepolizumab significantly reduced the odds of patients requiring 1 or more SCS course for NPs (odds ratio, 0.58; 95% CI, 0.36-0.92; P = .02), with mepolizumab-treated patients receiving a total of 82 courses compared with a total of 124 courses in the placebo group. 32 Figure 1 shows the time-to-first course of SCSs for NPs over the 52-week treatment period; the probability of requiring an initial course of SCSs for NPs by week 52 was lower in the mepolizumab group (25.4%; 95% CI, 20.0-32.1) than in the placebo group (37.5%; 95% CI, 31.1-44.6).

Among patients with 1 or more SCS course for NPs during the study, mepolizumab treatment reduced the mean+/-SD total prednisolone-equivalent OCS dose for NPs (438.9+/-350.4 mg/y) versus placebo (505.2 +/-455.1 mg/y). Furthermore, smaller proportions of patients treated with mepolizumab versus placebo received more than 200 mg/y (Figure 2), and more than 200 to 300 mg/y and more than 400 to 500 mg/y of prednisolone-equivalent OCSs for NPs (see Table E1 in this article's Online Repository at www.jaci-inpractice.org). Patients receiving mepolizumab spent a similar number of days on SCSs to those receiving placebo (mean +/-SD, 15.7 +/-11.9 vs 19.0 +/-18.5 days). One patient receiving mepolizumab with reported SCS use for 335 days was considered an outlier and was excluded from this analysis, because all other mepolizumab-treated patients had used SCSs for 51 days or less.

Impact of baseline characteristics on the SCS-sparing effect of mepolizumab

The proportion of patients receiving 1 or more SCS course during the 52-week study period was lower with mepolizumab than with placebo in patients with blood eosinophil counts less than or equal to 300 cells/mL, more than 300 to less than or equal to 500, and more than or equal to 700 cells/mL, in patients with 1 or more than 2 previous surgeries, and in patients with or without comorbid asthma and in patients with or without comorbid AERD (Figure 3). The total prednisolone-equivalent OCS dose during the study was reduced with mepolizumab versus placebo in patients with 1 or more than 2 previous surgeries and baseline blood eosinophil counts of less than 150 cells/mL, more than or equal to 150 cells/mL, and more than or equal to 300 cells/mL, and in patients with and without comorbid asthma and comorbid AERD (Table II).

DISCUSSION

The phase III SYNAPSE study demonstrated the efficacy and safety of mepolizumab versus placebo among patients with recurrent, refractory, severe, bilateral CRSwNP eligible for repeat surgery.32 SYNAPSE patients receiving mepolizumab experienced a range of clinical benefits including reduced polyp size, improved nasal obstruction, and a reduced need for sinus surgery and SCSs.32 This analysis demonstrated that clinical improvements were consistently observed with mepolizumab versus placebo in SYNAPSE patients, irrespective of baseline SCS use. In addition, the reduction in SCS use previously shown with mepolizumab during SYNAPSE was further characterized; mepolizumab versus placebo treatment was associated with a reduced probability of requiring SCSs for NPs during the study. In patients with 1 or more SCS course, the prednisolone-equivalent OCS dose was also reduced with mepolizumab versus placebo treatment. These data also show consistent reductions in SCS use across patients with varying clinical characteristics, including differing numbers of previous surgeries, a range of baseline blood eosinophil counts, and those with and without comorbid asthma or comorbid AERD. Together, these data demonstrate a range of clinical benefits with mepolizumab regardless of prior SCS use and pro-vide support for the SCS-sparing effects of mepolizumab in patients with recurrent, refractory CRSwNP. These findings are consistent with the clinical benefits and SCS-sparing effects of mepolizumab previously demonstrated in patients with severe eosinophilic asthma. [START_REF] Bel | Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma[END_REF][START_REF] Pavord | Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, doubleblind, placebo-controlled trial[END_REF] This analysis assessed the impact of SCS use in the year before SYNAPSE on several study outcomes. Mepolizumab improved total endoscopic NP score, nasal obstruction VAS score, and SNOT-22 total score versus placebo across sub-groups of patients with 0, 1, and more than 1 SCS courses in the year before the study. Between-group differences were consistently higher in patients with 1 SCS course during the previous year than in those who did not receive SCS in the year before the study, possibly reflecting greater disease severity in the patients requiring SCSs and therefore greater room for clinical improvement. However, this upward trend did not continue in those with more than 1 SCS course in the previous year, which may be due to the low number of patients in this subgroup. The reduction in occurrence of sinus surgery with mepolizumab versus placebo increased with increasing number of SCS courses in the year before the study, again likely reflecting disease severity in the subgroups with greater SCS dependence.

Approximately half the patients enrolled in SYNAPSE required at least 1 course of SCSs and more than 20% needed at least 2 courses of SCSs in the year before the study, highlighting that many were failing to achieve adequate disease control with standard of care therapy. During SYNAPSE, 75% of patients treated with mepolizumab received no courses of SCSs, compared with 63% of patients receiving placebo. For these patients, the reduced risk of SCSassociated adverse effects is an important benefit, given the high burden they bear. 11-15 Moreover, completing the 52-week study period with no SCS use is in line with treatment goals recommended in the most recent European Position Paper on Rhinosinusitis and Nasal Polyps, which include minimizing SCS courses to 2 or fewer per year in patients with partially controlled or uncontrolled NP.10

The baseline characteristics subgroup analysis presented here did not find any clinical characteristics that were predictive of the need for SCS use during the study. Notably, the response to mepolizumab was variable, with most but not all patients in the mepolizumab group completing the study without the need for SCSs. Given the multiple inflammatory subtypes known to be present among patients with CRSwNP, 4 it is tempting to speculate that patients who required SCSs during the study had a complex mix of inflammatory pathways contributing to their disease, including high levels of inflammation also driven by IgE, for example. All SYNAPSE patients had eosinophilic CRSwNP based on their baseline blood eosinophil counts; however, further research is needed to understand the relationship between blood and tissue levels of eosinophils and IL-5 in patients with CRSwNP. Investigation of other outcomes, such as olfaction, in the subset of patients who required SCSs despite mepolizumab treatment would be of interest, to determine whether improvements in other clinical outcomes were still observed. The present findings highlight the need for understanding of how symptoms relate to the underlying inflammatory processes in CRSwNP and for endotyping of those patients who are eligible for biologic treatment, to identify potential therapeutic targets and predict response to treatment. 10 For example, measurement of IL-5 to categorize patients on the basis of high or low IL-5 levels would be beneficial for predicting treatment response to mepolizumab and could potentially be carried out in a clinical laboratory setting. Interestingly, an analysis of the effect of blood eosinophil count on the response to mepolizumab in SYNAPSE suggested that higher counts were predictive of improvements in nasal obstruction VAS score but not total endoscopic NP score.32 However, patient numbers in the subgroups were low; thus, further investigation of blood eosinophil count as a potential biomarker of response to mepolizumab is warranted.

In addition to reducing the proportion of patients requiring SCSs during SYNAPSE, mepolizumab reduced the mean dose of prednisolone-equivalent OCSs over the year compared with placebo in those receiving SCSs. The mean total prednisolone-equivalent dose of 438.9 mg/y in the mepolizumab group (compared with 505.2 mg/y in the placebo group) was of particular clinical relevance given the results of a previous study in 2018. Price et al17 demonstrated a lower risk of several SCS-related adverse effects in patients with a cumulative SCS exposure of more than 0 mg to less than 500 mg, compared with those with exposures of 500 mg to less than 1000 mg.17 Furthermore, among those receiving at least 1 course of SCSs in the current SYNAPSE analysis, the proportion of patients receiving more than 200 mg prednisolone-equivalent OCSs per year was lower with mepolizumab than with placebo (75% vs 86%). This is important because a dose of 200 mg possibly reflects the typical treatment schedule of 40 mg OCSs for 5 days. Of note, analyses of total prednisolone-equivalent OCS dose per year and proportions of patients receiving different category levels of OCSs were restricted to patients receiving at least 1 SCS course during the study.

The SYNAPSE study has a number of strengths, including allowing patients to continue to receive SCS rescue medication in the study; this may be more representative of real-world clinical practice than other phase III CRSwNP studies, such as the dupilumab LIBERTY NP SINUS studies in which patients who received SCSs had their worst pre-SCS end-point values used for analysis. 39 Study limitations include the post hoc nature of the subgroup analyses presented here as well as the low number of patients in some of the subgroups. Despite these limitations, these data provide a comprehensive picture of the SCS-sparing capabilities of mepolizumab in a population of adults with severe CRSwNP and highlights the potential for mepolizumab as an SCS-sparing agent in CRSwNP.

This analysis of the SYNAPSE study found that mepolizumab was associated with clinical benefits regardless of prior SCS use in patients with severe CRSwNP in need of repeat surgery and that mepolizumab is associated with an SCS-sparing effect in this patient population. These data support the use of mepolizumab as a valuable add-on treatment to standard-of-care CRSwNP therapy with an SCS-sparing effect that can both improve efficacy outcomes and reduce the adverse effect burden associated with SCS use in patients with recurrent, refractory, severe CRSwNP.

Acknowledgment

Editorial support (in the form of writing assistance, including preparation of the draft manuscript under the direction and guidance of the authors, collating and incorporating authors 'comments for each draft, assembling tables and figures, and grammatical editing and referencing) was provided by Ciara Keogh, PhD, at Fishawack Indicia Ltd, UK, part of Fishawack Health, and was funded by GSK.

Data sharing statement:

GSK makes available anonymized individual participant data and associated documents from interventional clinical studies that evaluate medicines, on approval of proposals submitted to https://www.gsk-studyregister.com/en/.

Conflicts of interest:

G. Chupp has received advisory board fees, speaking fees, and research grants from GSK, AstraZeneca, Genentech, Sanofi Genzyme, Regeneron, Teva, and Novartis. I. Alobid has received advisory board fees and consultation fees from Maylan, Menarini, GSK, MSD, Novartis, Sanofi, and Roche. N. L. Lugogo reports receiving non-speaker fees from Amgen, AstraZeneca, Avillion, Genentech, GSK, Novartis, Regeneron, Sanofi, Teva; honoraria for nonspeaker bureau presentations from GSK and AstraZeneca; and travel support from Astra-Zeneca; her institution has received research support from Amgen, AstraZeneca, Avillion, Evidera, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, Novartis, and Teva; and she is an honorary faculty member of the Observational and Pragmatic Research Institute but does not receive compensation for this role. H. H. Kariyawasam has received speaker fees and conference attendance support from GSK. A. Bourdin has received research grants and consulting fees from Astra-Zeneca-MedImmune, Boehringer Ingelheim, Cephalon/Teva, GSK, Novartis, and Sanofi-Regeneron; consulting fees from Med-in-Cell, Actelion, Merck, Roche, and Chiesi; and is an investigator/coinvestigator for trials promoted by AstraZeneca MedImmune, Boehringer Ingelheim, GSK, Novartis, Sanofi/Regeneron, Chiesi, Actelion, Merck, Roche, Vertex, and Galapagos. A. M. Chaker has received research grants via Technical University Munich from Allegropharma, ALKAbelló, AstraZeneca, Bencard/Allergen Therapeutics, ASIT Biotech, GSK, Novartis, LETI, Roche, Zeller, Federal German Ministry of Education and Research, and the European Institute of Technology; advisory board/speaker fees via Technical University Munich from Allegropharma, ALK-Abelló, AstraZeneca, Bencard/Allergen Therapeutics, GSK, Immunotech, Lofarma, Novartis, LETI, Sanofi Genzyme/Regeneron, and Zeller; is a Board Member for the European Academy of Allergy and Clinical Immunology, European Forum of Research and Education in Allergy and Airway Disease, and German Society of Allergy and Clinical Immunology; and is also Scientific Advisor for the German Society of Applied Allergy, and former Chair of the German Society of Otorhinolaryngology and Head and Neck Surgery. S. G. Smith, A. R. Sousa, B. Mayer, and R. H. Chan are employees of GSK and own stocks/shares. A. Matucci has received speaker's honoraria from AstraZeneca, Novartis, and GSK, and honoraria for attending advisory panels with Sanofi, AstraZeneca, GSK, Novartis, and Chiesi.