A V Kartashev
email: akartashev@yandex.ru

V S Bondarev

I N Flerov

M V Gorev

E I Pogorel'tsev

A V Shabanov

M. S Molokeev

S Guillemet-Fritsch

I P Raevskii

The specific heat, thermal expansion, permittivity, and electrocaloric effect in bulk of BaTiO 3 (BT) samples in the form of nano-(nBT-500 nm) and micro-(mBT-1200 nm) ceramics fabricated using spark plasma sintering and solid-state plasma techniques have been investigated. The size effect has been reflected, to a great extent, in the suppression of the specific heat and thermal expansion anomalies and in the changes in the temperatures and entropies of phase transitions and permittivity, and a decrease in the maximum intensive electrocaloric effect: = 29 mK (E = 2.0 kV/cm) for nBT and = 70 mK (E = 2.5 kV/cm) for mBT. The conductivity growth at temperatures above 360 K leads to the significant irreversible heating of the samples due to the Joule heat release in the applied electric field, which dominates over the electrocaloric effect.

INTRODUCTION

An important problem of condensed matter physics is obtaining information about the effect of fields of different physical natures on the sequence, entropy, and temperature of the phase transitions in solids. This is related, in particular, to the search for new materials promising for application in coolers that operate on the basis of the caloric effects in solids. A promising direction in the solid-state cooling is based on the electrocaloric effect, which is the simplest to implement and thereby has stimulated a significant increase in the number of studies on it [1][2][3].

The electrocaloric effect (ECE) is the change in the temperature or entropy in an applied electric field under adiabatic or isothermal conditions, respectively. As was shown in [4], the change in the temperature of a solid-state cooling agent by 2-5 K due to the ECE is sufficient to create a more energy-efficient and commercially accessible cooling system as compared with the available vapor-liquid refrigerators. Since the ECE is proportional to the temperature derivative of polarization (dR/dT) E , its largest value can be implemented in ferroelectric materials near the phase transition in strong electric fields (E > 200 kV/cm). However, the electric breakdown in bulk ferroelectrics occurs, as a rule, already in fields up to 60 kV/cm, which leads to their destruction. On the other hand, thin ferroelectric films withstand stronger electric fields (1000-2000 kV/cm) [5][6][7]. For this reason, in the PbZr 0.95 Ti 0.05 O 3 films, a giant intensive ECE = 12 K was observed in an electric field of E = 480 kV/cm [8]. However, thin films have a small thermal mass and cannot effectively remove the electrocaloric heat.

The other type of ferroelectric materials promising for obtaining high ECE values is multilayer structures [9,10]. They are stable against strong electric fields due to the alternation of thin (~3 μm) layers in their volume; in addition, they have a large thermal mass and, therefore, high cooling power. Unfortunately, multilayer structures exhibit low ECE values (ΔT/ΔE = 1.7 mK cm/kV) as compared to bulk polycrystalline ferroelectrics (ΔT/ΔE = 30 mK cm/kV) due to the impact of size effects on the parameters of phase transitions and physical properties [11,12].

In view of the aforesaid, the question naturally arises how to enhance the electrocaloric coefficient and breakdown field in ferroelectric materials.

Δ max AD T Δ max AD T Δ max AD T

Study of the Physical Properties and Electrocaloric Effect in the BaTiO 3 Nano-and Microceramics

As was shown recently [13][14][15], the micro-and nanoceramics size strongly affects the stability of a material against the electrical breakdown. The studies of nanocrystalline oxide ceramic materials, in particular, barium titanate BaTiO 3 ceramics [16,17], demonstrated a significant dependence of the parameters of phase transitions and physical properties on the synthesis conditions and grain size [18]. For example, a decrease in the film thickness from 1100 to 20 nm leads to a decrease in the ferroelectric phase transformation temperature from 395 to 371 K. In this case, the specific heat anomaly is spread and the polarization decreases from 11 to 4 μC/cm 2 . Therefore, the problem of controlling the grain size during the formation of ceramic materials becomes crucially important. A study of the influence of the size effects, thermal history of materials, and methods for their fabrication on the electrical and thermodynamic characteristics is important for finding the conditions optimal for increasing the breakdown electric field and electrocaloric efficiency of solid cooling agents based on microand nanoceramic ferroelectrics and multilayers.

In this work, we present the results of investigations of the thermodynamic (specific heat and thermal expansion), structural, and dielectric properties and the ECE in BaTiO 3 micro-and nanoceramics in a wide temperature range. The integrated approach to studying the thermal and caloric properties makes it possible to obtain important information about the nature of physical phenomena in micro-and nanoceramic materials, temperatures of phase transitions, entropy and strain parameters, and caloric efficiency.

EXPERIMENTAL

BaTiO 3 nanopowders were synthesized by the oxalate precipitation. The procedure was described in detail in [19]. The precursors used were Prolabo BaCl 2 • 2H 2 O and TiOCl 2 . The precursors were weighed in a certain proportion to control the powder stoichiometry, dissolved in water, and added to the ethanol solution of oxalic acid. The BaTiO 3 powder was obtained after calcination in air at 850°C for 4 h. The powders were placed in a graphite crucible with an inner diameter of 8 mm and subjected to spark plasma sintering (SPS) in a Sumimoto 2080 SPS system under a pressure of 75 MPa at 1150°C for 3 min at a heating rate of 50 C/min) and then rapidly cooled. The obtained SPS grains were annealed in an oxidizing atmosphere at 850°C for 48 h to restore the oxygen stoichiometry. The main advantages of the SPS technique over conventional sintering are the lower temperature and significantly shorter time of the process, as well as the possibility of obtaining a very high (~97%) density of ceramics at small grain sizes.

The BaTiO 3 (mBT) microceramic was obtained using a conventional solid-state technology. The stoichiometric BaCO 3 and TiO 2 amounts with a main substance content of more than 98% were thoroughly mixed in distilled water. After drying the obtained mixture, the solid-phase synthesis was performed in two four-hour stages at 1100 and 1150°C, respectively. After each stage, the reaction product was crushed and stirred. Before the final sintering, the obtained powder was pressed into discs with a diameter of 30 mm and a height of 10 mm at 100 MPa. A three-percent aqueous solution of polyvinyl alcohol was used as a plasticizer. After burning out the plasticizer by slow heating to 600°C, sintering at 1330°C for 3 h in a closed alumina crucible on a corrugated ZrO 2 ceramic substrate was carried out. After sintering, the temperature was reduced at a rate of 100°C/h to 800°C; then, the samples were slowly cooled in a furnace to room temperature. The density of the obtained ceramics was 92.5% of the theoretical value.

The composition and quality of the samples were controlled using electron microscopy and X-ray diffraction analysis.

The structural morphology of the BaTiO 3 ceramic surface was studied on a Hitachi TM3000 scanning electron microscope (SEM) (Hitachi High-Technologies Co., Ltd., Tokyo, Japan). A typical SEM image of the BaTiO 3 nanoceramics (nBT) is shown in Fig. 1a. One can clearly see separate grains 100-400 nm in size and small channels between them on the sample surface. No grain damage in the form of cracks or inclusions was observed.

In the image of the mBT surface about 1.5 × 1.5 mm in size (Fig. 1b), it is difficult to distinguish individual particles, which speaks about the absence of a pronounced relief; however, at the stronger magnification (Fig. 1c), grains 30-50 μm in size become visible.

The X-ray diffraction investigations of the nBT and mBT samples were performed at room temperature on a D8-ADVANCE diffractometer (CuK α radiation, θ-2θ scanning) using a VANTEC linear detector. The 2θ angle scanning step was 0.016° and the exposure was 0.3 s per step. The obtained X-ray diffraction patterns (Fig. 2) were used to refine the structure by the Rietveld method using the TOPAS 4.2 program [START_REF] Bruker | TOPAS V4: General Profile and Structure Analysis Software for Powder Diffraction Data[END_REF].

All the reflections were reliably identified in the tetragonal lattice (P4mm) with the parameters similar to those of the BaTiO 3 single crystal [21]. This crystal structure was taken as an initial model for the Rietveld refinement. The X-ray diffraction patterns for both samples contained only few low peaks, which can be related to the impurity phases with a mass smaller than 1-2%. The narrow and broad main reflections observed for the micro-and nanoceramics, respectively, are consistent with the expected crystallite size. The estimated average crystallite sizes do have different values (Table 1).

The final refinements of all the parameters appeared stable with the low R factor values (Table 1 and Figs. 2a,2b). It should be noted that the ceU parameters of the BaTiO 3 micro-and nanoceramic samples are different, which caused an increase in the nBT unit ceU volume (Table !). The analysis of bond lengths showed that the d(Ba-O) distances for both compounds are very similar, in contrast to the d(Ti O) distances. We may assume that the compositions of the nano-and microcrystalline compounds are differ ent due to the formation of vacancies. The dielectric properties were measured using an E7-20 device at a frequency of I kHz for the nano cerarnics and 5 kHz for the microceramics. Gold elec trodes were used for nBT and a silver-based conduct ing paste, for mBT. The measurements were per formed in the heating mode at a rate of 0.5-2 K/min in the temperature range of 80-420 K.

The dilatometric investigations were carried out on the ceramic samples with a size of L "" 5 mm using a Netzsch DIL-402C inductive dilatometer in the dry helium gas flow. The sample heating rates in the tem perature range of 100-700 K were from 2 to 4 K/min. A fused silica reference was used to calibrate and take into account the expansion of the measuring system. The data obtained in several measurement series were consistent with each other with an error of 2-3%.

The specific heat investigations in the temperature range of90-430 K were carried out on an automated adiabatic calorimeter described in detail in (22]. The continuous heating rates ranged from 0.01 to I K/min and the discrete heating time was from 20 to 40 min. The samples were placed in a cell and fixed with Apie zonN and ApiezonH lubricants, which ensured a reli able thermal contact. To obtain the calorimetric data at high temperatures (T > 370 K), the measurements were performed using a Netzsch DSC 204 device.

J. Permittivity

Figure 3 shows temperature dependences of the permittivity and dissipation factor for the nBT and mBT samples.

ln the case of the nanoceramics (Fig. 3a), the per mittivity monotonically grows and its peak maximum at a temperature of T i = 399 K attains giant values (E = 39600). In the region of three BaTiO 3 phase transi tions, strongly blurred E(T) anomalies are observed. The dissipation factor in the low-temperature region has a maximum (0.63) at T= 105 K, then monotoni cally decreases to a minimum of -0. J in the tempera ture range of290-300 K, and starts gradually increas ing again to O. 12 at the maximum experimental tem perature. It is important that, in the temperature range 4 (a)

•

•• 0.6 • • 3 • • • • •-
corresponding to the three phase transitions, there are no features in the dielectric loss plot. This tan(T) behavior was observed earlier in the BaTiO 3 nanoce ramics [23,24] and corresponds to the temperature activation of the dielectric relaxation. Similar phe nomena were found in the weU-known CCTO mate rial with a colossal permittivity [25].

The dielectric properties of the microceramics behave completely differently (Fig. 3b). The E(T) dependence contains three anomalies corresponding to the phase transition in BaTiO 3 . At the temperature T i = 402 K of the transition between the cubic and tetragonal phases, the maximum perrnittivity attains E = 3700. The dielectric loss in the region of the phase transition at T 2 = 287 K and T i = 403 K has the pro nounced peculiarities. Near 100 K, similar to the case of nBT, there is a maximum in the tano(T) depen dence. The colossal difference between the E values and E(T) behaviors for the nano-and microceramics can be caused by the use of different sample fabrica tion technologies. The SPS process is effective for removal of the resistive component from the grain boundaries, which is usually observed in the conven tionally sintered BaTiO 3 cerarnics, which leads to a significant increase in the permittivity of the SPS nanoceramics [26]. In other words, the high-density ( over 98% of the theoretical value) nanoceramics con tains a fewer amount of the resistive components as compared with the microcerarnics and thereby have a lower free charge density at the grain boundaries. In such nanoceramics, a decrease in the grain size does not change the type of carriers, associated mainly with oxygen vacancies, but, during reoxidation, leads to a more significant decrease in the density of such carri ers, which affects the transport conductivity mecha nism controlled mainly by the grain boundaries [27].

1 1 0 • 0 2 "°2 • C: 0.10 B X • � X (,) • - -◊/ (,) o o • • • 0.2 1 i f '-.

Thermal Expansion

Figure 4 shows the measured data on the thermal expansion of the BaTiO 3 micro-and nanoceramic samples. The mBT α(T) anomalies related to the phase transitions Pm3m-P4mm-C2mm-R3m were found at temperatures of T 1 = 400 ± 2 K, T 2 = 290 ± 2 K, and T 3 = 206 ± 2 K and are fairly similar to the temperatures of the transition in the BaTiO 3 crystal; the thermal expansion coefficients agree with the data from [28,29].

It can be seen in Fig. 4 that all the α(T) anomalies in nBT are strongly spread, including especially the anomaly in the region of the low-temperature phase transition C2mm -R3m. In addition, a decrease in the particle (grain) size leads to the lowering of the Curie temperature T 1 = 384 ± 5 K for the phase transition Pm3m-P4mm. The changes in the temperatures of the phase transitions P4mm-C2mm and C2mm-R3m are not that obvious: T 2 = 303 ± 5 K and T 3 = 205 ± 15 K.

Specific Heat of the Nano-and Microceramics

Figures and 6a show temperature dependences of the nBT and mBT specific heat in the range of 80-430 K. For nBT, there are several small C p (T) anomalies with the spread peaks. On the contrary, the mBT data demonstrate three pronounced anomalies. To extract the anomalous specific heat component and calculate the entropy of the phase transitions, we determined the lattice specific heat by approximating the experimental data beyond the region of existence of the anomalies using a combination of the Debye and Einstein functions. The excess specific heats ΔC p (the difference between the total and lattice specific heats) calculated from these data for nBT and mBT are presented in Figs. 5b and6b, respectively. The temperature dependences of the anomalous entropy related to the sequential phase transitions were calculated by integrating the function (ΔC p /T)(T) (Figs. 5c and6c).

The comparison of the nBT and mBT data shows that a decrease in the grain size leads to the significant spread of the anomalies related to the phase transitions, narrowing of the temperature region of existence of the tetragonal phase, and a decrease in the phase transition entropy (Table 2). These results are consistent with the data on the size effects in thin films [30]. In study [31], however, the investigations of the specific heat of the nanostructured BaTiO 3 ceramics with grain sizes of 50-1200 nm obtained by the force impact combined with shear straining on a Netzsch DSC 204 facility showed a significant (manifold!) increase in the entropy of the phase transformations in the sample consisting of nanoparticles as compared with the sample consisting of microparticles. This entropy (and, consequently, polarization) growth was attributed by the authors to a great number of defects contained in crystallites.

In the repeated measurements, a decrease in the anomalous specific heat (and, consequently, entropy) caused by the temperature annealing of defects was observed. This obvious contradiction of the results forced us to carry out additional investigations on the similar differential scanning calorimeter. Figure 7 presents temperature dependences of the nBT and mBT specific heat.

Table 2 gives the thermodynamic parameters obtained on the adiabatic and differential scanning calorimeters. Generally, the results are in satisfactory agreement. Some differences between the PT temperatures and entropies are caused by the different accuracies and conditions of the measurements on the two facilities.

Electrocaloric Effect

The size effect was largely manifested in the suppression of the specific heat and thermal expansion anomalies and changes in the temperature and entropy of the phase transitions and permittivity.

The obtained experimental data on the thermal and dielectric properties of the nano-and microceramics are indicative of the pronounced size effect, which manifests itself in a decrease and spread of the phase transition temperature. According to the data from [32,33], the high permittivity of the nanoceramics as compared with the microceramics should facilitate the implementation of the significant ECE. However, the total excess entropy of the phase transitions in nBT is, first, lower than in mBT, and, second, spread in a wide temperature range, which can lead to a decrease in the ECE value.

The direct measurements of the intense ECE !).T A o( 1) were performed on an adiabatic calorimeter by the technique used by us earlier in studying the electro-and magnetocaloric effects [22,34,35). The electric field was induced by a stabilized high voltage source. The specific heat of the electrodes and lead wires was lower than 1 % of the total specific heat (sample + cell); therefore, the ECE Joss on their heat ing was ignored.

At a certain temperature, the adiabatic calorimeter was tuned so that the sample temperature drift was no worse than ± 10-3 K/min. Such a temperature behav ior points out that the conditions established in the cryostat are maxirnally sirnilar to the adiabatic ones: the system is stabilized in the stable dynamic equilib rium. Tuen, a voltage pulse with a length of 3-10 min was applied to the sample electrodes, which led to an increase in the sample temperature by means of the ECE. After switching off the field, the sample tem perature decreased. The ECE !).T value was deter mined as a difference between the temperatures obtained by the linear extrapolation of the T(t) depen dences by the instant of switching on/off the field. The error of determination of the !).T value was no larger than ±2 x 10-4 K.

Figure 8 shows time dependences of the tempera ture for the three series of experiments conducted in the tetragonal phase in the electric field on and off modes.

Near 320 K, the reversibility of the nBT tempera ture variation is reliably detected (Fig. 8a). However, in the region of 340 K, the sample temperature varia tion after switching on the field has the higher rate dT/ dt than before switching on, but after switching off the field, it retums to the initial rate (Fig. 8b). It can be seen that the sequence of processes E = 0 ➔ E :;t: 0 ➔ E = 0 results in the irreversible increase in the sample temperature, which increases with the number of the E on-off cycles. The results of the measurements at two temperatures show that the increase in the rate dT/dt in the applied field is related to the nBT conductivity, which increases with temperature. Thus, at 340 K, we observed the total temperature change caused by the ECE and Joule heat release on the sample resistance.

The temperature splashes during switching on/off the field are related to the peculiarities of temperature control system operation. The values of these effects are smaller than the ECE value, which makes it possi-

5.0

ble to reliably separate them via extrapolating the tem perature variations to the Eon-off instants.

The additional mBT heating in the applied field due to the Joule heat starts manifesting itself at a lower temperature (Fig. 8c) and, consequently, at a larger distance from the temperature of the phase transition to the cubic phase, as compared with nBT. This makes it even more complicated to distinguish this effect and ECE and reduces the reliability of the results. Table 3 gives the data on the rates of sample heating unrelated to the ECE at several temperatures.

To determine a real value of the intensive ECE !).TAo, it is necessary to correct the experimentally measured !).I'e x p value, since the heat released by means of the ECE is spent to the change not only in the sam ple temperature, but in the temperature of the entire sample-ceU system. The relation between the !).� x p and !).T A o values is established by the expression !).TAD = !).T e x p ( 1 + Ci/ C smp ), where C cell is the ceU spe cific heat determined in a separate experiment and C smp is the specific heat of the sample. The ratios between the !).TAo and !).Te x p values for nBT and mBT are given in Table 3. tively. For both samples, the ECE maxima !).Ttoa x = 29 mK at rm ax "" 410 K (nBT) and !).TAm Da x = 70 mK at 380-390 K (mBT) are reliably detected. In nBT, the maximum temperature is significantly higher than the phase transition temperature Ti = 383 K, while in mBT, rmax is lower than the corresponding phase transition temperature Ti = 396.7 K. Unfortunately, we could not study the temperature range above 400 K more fuUy and reliably because of the high conductiv ity and limited operation temperature (T < 430 K) of the adiabatic calorimeter.

Study of the nBT Conductivity

It is worth noting that the irreversible sample heat ing by means of the Joule heat was also observed in studying the ECE in single crystals and layered ceramic structures (35,36). The relatively high con ductivity makes it difficult not only to determine the real value of the effect, but also to use the ferroelectrics as solid-state cooling agents in practice.

Figure 10 shows 1-V characteristics for the nanoc eramic sample at two temperatures. The obviously nonlinear behavior suggests that the electrical resis tance is a function of the applied voltage. This behav- ior of the electrical resistance originates, as a rule, from the physical processes occurring on the electric contacts with the dielectric and the presence of oxygen vacancies and free charges localized in the intergrain boundaries and in grains as a result of SPS [23,24,26].

As was established in [37], the high-density nanoceramics has the p-type conductivity in grains and highresistance intergrain boundaries. Thus, in this material, the effect implemented on the contacts between surfaces is similar to the process occurring on parallel counter-connected p-n junctions in semiconductors.

CONCLUSIONS

Using the adiabatic calorimeter technique, we examined the intensive ECE ΔT AD in the vicinity of phase transitions in the BaTiO 3 nano-and microceramics. Some aspects of the influence of methods used for obtaining and thermal processing of the ceramic samples and crystallite size on the thermal, dielectric, and transport properties, as well as on the ECE value and degree of reversibility were studied.

The measurements of the thermal (thermal expansion and specific heat) and dielectric properties of the nano-and microceramics demonstrate a significant spread of the phase transitions in the nanoceramics as compared with the microceramics, which can be related to the smaller grain size in the nanoceramic sample. The total entropy change caused by all the phase transitions in nBT halved as compared with mBT.

The permittivities of the nano-and microceramics are essentially (30 times) different near the high-temperature phase transition. Such a huge difference between ε(T) is related to the technique used to obtain the ceramics and results from both the oxygen nonstoichiometry of the nanoceramic sample and the presence of free charges at the boundaries of nanograins formed at a fairly low temperature in a rarefied atmosphere during spark plasma sintering.

The results of the direct ECE measurements under adiabatic conditions with and without the electric field at low temperatures and weak electric fields are characterized by the high reproducibility and reversibility of the effect. The experimental conductivity of the nano-and microceramics results in the Joule heat release in the sample and irreversible contribution to the change in its temperature. In our opinion, the presence of the conductivity can be caused by a poor interface between the samples under study and electrodes or oxygen vacancies and free charges localized both in grains and in the grain boundaries. Unfortunately, we failed to implement the ECE in the nanoceramics in strong electric fields because of the high conductivity of the material. The determined nBT and mBT electrocaloric coefficients appeared to be significantly lower than in the single-crystal and polycrystalline BaTiO 3 samples [11,38].

Thus, the results obtained showed that, despite the different methods used to fabricate the BaTiO 3 ceramics, their conductivity does not allow one to implement a significant electrocaloric effect in such materials in strong electric fields. However, taking into account that all the data were obtained in weak fields, further investigations of the ceramics with the very low conductivity and high susceptibility to strong electric fields are undoubtedly interesting and promising. The development of new methods for synthesizing such materials will facilitate the creation of caloric elements for cooling systems based on the electrocaloric effect.

Fig. 1 .

 1 Fig. 1. SEM image of (a) the nBT and (b, c) mBT samples.

Fig. 2 .

 2 Fig. 2. Difference X-ray diffraction patterns for (a) the nBT and (b) mBT samples.

Fig. 3 .

 3 Fig. 3. Temperature dependences of the permittivity and dissipation factor for (a) the BaTi0 3 nano-and (b) microceramics.

Fig. 4 .

 4 Fig. 4. Temperature dependences of the thermal expansion coefficient for (1) the nBT and (2) mBT ceramic samples.

Fig. 5 .Fig. 6 .Fi g . 7 .

 567 Fig. 5. Temperature dependences of (a) the specific heat, (b) excess specific heat, and (c) entropy for nBT.

Figure 9 Fig. 9 .

 99 Figure9shows temperature dependences of !).TAo in fields of2 and 2.5 kY/cm for nBT and mBT, respec-

Fig. 10 .

 10 Fig. 10. 1-V characteristic for nBT at temperatures of 380 and 390 K.

Table 1 .

 1 Main results of the process ing of X-ray data on nano-and micro-BaTiO 3

	Compound	nBT	mBT
	Sp. gr.	P4mm	P4mm
	a,A	4.00209 (6)	3.99326 (2)
	c,A	4.01915 (8)	4.03517 (3)
	v, A3	64.374 (2)	64.3454 (8)
	z
	20-interval, deg	20-144	20-144
	Rwp, %	6.15	8.08
	Rp,%	4.73	5.90
	Rex p , %	2.87	2.98
	x2 RB ,%	2.15 1.39	2.71 2.93
	3. RESULTS AND DISCUSSION

Table 2 .

 2 Thermodynamic parameters of nBT and mBT obtained on an adiabatic calorimeter and DSC-204

			Cubic ↔ tetragonal	Tetragonal ↔ rhombic	Rhombic ↔ orthorhombic
			nBT	mBT	nBT	mBT	nBT	mBT
	Adiabat	T, K	383 ± 2	396.7 ± 0.5	310 ± 2	286.0 ± 0.5	227 ± 2	20 1.6 ± 0.1
		ΔS, J/mol K	0.6	1.3	0.25	0.65	0.1	0.23
	DSC	T, K	380 ± 5	400.1 ± 0.5	31 1.0 ± 2	285.6 ± 0.5	222 ± 2	203.3 ± 0.5
		ΔS, J/mol K	-	0.6	-	0.3	1.2	0.2
							(resulting)

Table 3 . Measured and real electrocaloric effects and spurious heating rate at the instants of switching on the field Temperature, K

 3

	�-

Fi g . 8. Temperature behavior variation in an applied electric field as a result of the intensive electrocaloric effect at temperatures of about (a) 320 and (b) 340 K for nBT (2 kV /cm) and (c) 340 K for mBT (2.5 kV/cm).


MD Laure Gossec

Vibeke Strand

PhD, Novartis Clare Proudfoot

MPH Chieh-I Chen

MSc, Sanofi Sophie Guillonneau

MSc Toshio Kimura

MD/PhD Hubert Van Hoogstraten

PhD Erin Mangan

MSc Matthew Reaney
email: matthew.reaney@sanofi.com

Regeneron Pharmaceuticals

Glaxosmithkline C Chen

Effects of Sarilumab on Patient-Reported Impact of Rheumatoid Arthritis Using the Rheumatoid Arthritis Impact of Disease Scale

Keywords: Rheumatoid arthritis, patient-perceived impact, RAID, disease-modifying antirheumatic drugs

important intellectual content, and approved the final version to be submitted for publication.

ABSTRACT

Objective. The impact of rheumatoid arthritis (RA) symptoms on patients' lives is significant. This study evaluated the effect of sarilumab on patient-perceived impact of RA using the 7-domain RA Impact of Disease (RAID) scale. Results. Sarilumab 150 mg and 200 mg+csDMARDs were nominally superior (p<0.05) versus placebo+csDMARDs and 200 mg versus adalimumab 40 mg in LSM differences for RAID total score at weeks 12 (-0.93 and -1.13; -0.49, respectively) and 24 (-0.75 and -1.01; -0.78), and all impacts of RA (except functional impairment in MONARCH week 12). Effects were greater in physical domains (e.g., pain) than mental domains (e.g., emotional well-being). More patients receiving sarilumab versus placebo or adalimumab reported improvements ≥MCID and PASS in total RAID scores at both assessments.

Methods

Conclusion.

Based on the RAID, sarilumab+csDMARDs or as monotherapy reduced the impact of RA on patients' lives to a greater extent than placebo+csDMARDs or adalimumab monotherapy.

Word count: 248 (max 250)

Patients with rheumatoid arthritis (RA) experience a variety of signs and symptoms, and report significant physical and psychological impacts of living with this condition 1- 3 . Quantifying key clinical symptoms and impacts of RA from the patient perspective, in addition to evaluating clinical markers, is therefore vital for comprehensively understanding the disease and evaluate its treatment, in line with current international consensuses and guidelines [START_REF]Guideline on clinical investigation of medicinal products other than NSAIDs for treatment of rheumatoid arthritis[END_REF][START_REF] Kirwan | Overview of the patient perspective at OMERACT 10--conceptualizing methods for developing patient-reported outcomes[END_REF][START_REF] Kirwan | Incorporating the patient perspective into outcome assessment in rheumatoid arthritis--progress at OMERACT 7[END_REF][START_REF] Felson | The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials[END_REF] .

The patient perspective can be feasibly and systematically collected through administration of patient-reported outcomes (PRO). Using well-defined and reliable PROs, in addition to physician-reported and laboratory data, is essential for drawing comprehensive conclusions regarding RA treatment outcomes. The RA Impact of Disease (RAID) scale is an internationally validated, composite PRO measure specifically designed for use in RA [START_REF] Gossec | Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative[END_REF][START_REF] Gullick | Rheumatoid arthritis: clinical utility of the RAID (RA impact of disease) score[END_REF][START_REF] Heiberg | Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to other patient-reported outcomes in a register of patients with rheumatoid arthritis[END_REF][START_REF] Dougados | Defining cut-off values for disease activity states and improvement scores for patient-reported outcomes: the example of the Rheumatoid Arthritis Impact of Disease (RAID)[END_REF][START_REF] Hewlett | The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: validation in six countries[END_REF] . RAID evaluates seven domains, each containing a single item, including 2 key symptoms (severity of pain and fatigue), and 5 primary impacts (coping, emotional and physical well-being, functional impairment and sleep). It also provides additional information for assessment of RA, such as coping and emotional well-being, compared with traditionally evaluated PROs of patient global assessment of disease activity, pain and physical functioning [START_REF] Gossec | Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative[END_REF][START_REF] Ferreira | Drivers of patient global assessment in patients with rheumatoid arthritis who are close to remission: an analysis of 1588 patients[END_REF][START_REF] Avila-Ribeiro | Psychometric properties of sleep and coping numeric rating scales in rheumatoid arthritis: a subanalysis of an etanercept trial[END_REF][START_REF] Dougados | Onset of action of etanercept in rheumatoid arthritis based on patient-reported outcomes[END_REF] .

Sarilumab is a recently approved human monoclonal antibody directed against both soluble and membrane-bound interleukin-6 receptor α (anti-IL-6Rα).

The RAID scale was administered to patients in 2 phase III randomized controlled trials (RCTs) of sarilumab: TARGET [NCT01709578] [START_REF] Fleischmann | Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors[END_REF] and MONARCH [NCT02332590] [START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] . Change from baseline in RAID score was a secondary end-point in both the TARGET and MONARCH RCTs.

TARGET compared the efficacy and safety of subcutaneous (SC) sarilumab 150 mg and 200 mg every 2 weeks (q2w) vs placebo plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with moderate-toseverely active RA intolerant of or with inadequate response to ≥1 tumor necrosis factor inhibitors (TNF-IR) [START_REF] Fleischmann | Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors[END_REF] . The co-primary end points in TARGET were the proportion of patients achieving American College of Rheumatology ≥ 20% (ACR20) responses [START_REF] Felson | The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials[END_REF] at week 24, and change from baseline in physical function assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI) [START_REF] Fries | Measurement of patient outcome in arthritis[END_REF] at week 12.

MONARCH compared the efficacy and safety of sarilumab SC 200 mg q2w monotherapy versus adalimumab SC 40 mg q2w monotherapy in patients with active RA who discontinued treatment with MTX [START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] . The primary efficacy end point in MONARCH was change from baseline in the 28-joint Disease Activity Score using erythrocyte sedimentation rate (ESR) (DAS28-ESR) at week 24. In both RCTs, sarilumab showed superiority over placebo or adalimumab reducing signs and symptoms of RA and improving physical function and its safety profile was consistent with IL-6R blockade [START_REF] Fleischmann | Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors[END_REF] .

The RAID is recognized by researchers, patients, and organizations such as EULAR [START_REF]EULAR Tools and products -the EULAR RAID and PsAID Questionnaires[END_REF] and OMERACT [START_REF] Hifinger | In rheumatoid arthritis, country of residence has an important influence on fatigue: results from the multinational COMORA study[END_REF] as a promising and interesting tool since it was developed with patient input and addresses all the key issues for patients with RA.

However, as a relatively new scale, RAID has so far only been applied in one clinical trial [START_REF] Dougados | Onset of action of etanercept in rheumatoid arthritis based on patient-reported outcomes[END_REF] other than TARGET [START_REF] Fleischmann | Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors[END_REF] and MONARCH [START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] , with the publications for these trials only describing high-level data on the RAID. It was therefore considered important to fully explore treatment outcomes measured from this novel measure as applied in the sarilumab trials.

The objective of the present analysis was, thus, to assess the effects of sarilumab treatment in combination with csDMARD or monotherapy on patient-reported impact of RA by the RAID scale.

PATIENTS AND METHODS

Data were collected from 2 phase III RCTs of sarilumab, TARGET and MONARCH; details of which have been published previously [START_REF] Fleischmann | Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors[END_REF][START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] . Both trials enrolled adult patients fulfilling the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA [START_REF] Aletaha | Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative[END_REF] . In TARGET, TNF-IR patients with moderate-toseverely active RA were included if disease duration was ≥6 months. Patients with uncontrolled concomitant diseases, significant extra-articular manifestations of RA, functional class IV RA, other inflammatory diseases, current/recurrent infections or receiving prednisone were excluded.

In MONARCH, moderate-to severely active RA patients with ACR class I-III functional status [START_REF] Hochberg | The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis[END_REF] were enrolled if they had disease duration ≥3 months, and no prior use of bDMARDs. Eligible patients were randomized to sarilumab SC 200 mg plus placebo q2w or adalimumab SC 40 mg plus placebo q2w for 24 weeks. After 16 weeks, patients without ≥20% improvement in tender and swollen joint counts in the sarilumab group were switched to once-weekly adalimumab or matching placebo [START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] .

RAID scale.

The RAID scale consists of 7 single-item domains, each rated by patients on an 11-point numeric rating scale from 0 (best) to 10 (worst) [START_REF] Gossec | Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative[END_REF] . There are 2 symptom domains, pain and fatigue, and 5 impact domains, consisting of functional impairment, emotional well-being, physical well-being, quality of sleep, and ability to cope. The domains can be reported separately [START_REF] Avila-Ribeiro | Psychometric properties of sleep and coping numeric rating scales in rheumatoid arthritis: a subanalysis of an etanercept trial[END_REF] and as a total score, which is a continuous variable ranging from 0 (best) to 10 (worst); lower scores are indicative of less impact of disease. In the total RAID score, each domain is given a specific weight reflecting its importance to patients (e.g., more given to pain, fatigue and functional impairment). Weights were obtained from international studies and are as follows: pain 0.21, functional disability 0.16, fatigue 0.15, and sleep problems, emotional well-being, physical well-being and coping all 0.12 8,10 . The RAID scale has been psychometrically validated at an international level [START_REF] Gossec | Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative[END_REF][START_REF] Heiberg | Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to other patient-reported outcomes in a register of patients with rheumatoid arthritis[END_REF][START_REF] Hewlett | The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: validation in six countries[END_REF][START_REF] Salaffi | Validity of the rheumatoid arthritis impact of disease (RAID) score and definition of cut-off points for disease activity states in a population-based European cohort of patients with rheumatoid arthritis[END_REF] .

Statistical analyses.

Least squares mean (LSM) differences from baseline in total RAID and domain scores were analyzed with a mixed model for repeated measures, including treatment, region, visit, and treatment-by-visit interaction (and number of prior TNFi in TARGET) as fixed effects and baseline as a covariate.

Post-hoc analyses were conducted to identify 'responders' in the total RAID score. Three 'responder' definitions were used. Two were based on an established Minimal Clinically Important Difference (MCID) from baseline. This was previously defined by different techniques using data from 108 patients receiving TNFi treatment for active RA, who were evaluated at screening and baseline, then after 4 and 12 weeks of treatment [START_REF] Dougados | Defining cut-off values for disease activity states and improvement scores for patient-reported outcomes: the example of the Rheumatoid Arthritis Impact of Disease (RAID)[END_REF] . The reliability of the overall RAID score, and various possible improvement thresholds proposed in the rheumatology scientific literature (e.g., improvements of at least 1, 2 or 3 points in total RAID score (total range 0-10 points), and relative changes ≥20%, 30% and 50% from baseline) [START_REF] Salaffi | Validity of the rheumatoid arthritis impact of disease (RAID) score and definition of cut-off points for disease activity states in a population-based European cohort of patients with rheumatoid arthritis[END_REF][START_REF] Wee | Content validity of the Dutch Rheumatoid Arthritis Impact of Disease (RAID) score: results of focus group discussions in established rheumatoid arthritis patients and comparison with the International Classification of Functioning, Disability and Health core set for rheumatoid arthritis[END_REF] were evaluated. The reliability of the RAID score between screening and baseline was found to be high: intra-class coefficients of correlation 0.85 (95% CI 0.79-0.90), with smallest detectable differences and smallest detectable changes of 1.8 and 1.3, respectively. The 2 optimal MCID thresholds were identified as a 3-point reduction in total RAID score from baseline, or a relative improvement of 50% in total RAID score. A patient was defined as a responder if they reported improvements from baseline ≥MCID. A third responder definition was based on a Patient Acceptable Symptom State (PASS), defined as a score ≤ 3 [START_REF] Dougados | Defining cut-off values for disease activity states and improvement scores for patient-reported outcomes: the example of the Rheumatoid Arthritis Impact of Disease (RAID)[END_REF] . Patients who discontinued therapy or required rescue medication prior to achieving responder end points were classified as nonresponders [START_REF] Wells | Minimal clinically important difference module: summary, recommendations, and research agenda[END_REF][START_REF] Tubach | Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement[END_REF][START_REF] Tubach | Evaluation of clinically relevant states in patient reported outcomes in knee and hip osteoarthritis: the patient acceptable symptom state[END_REF][START_REF] Tubach | Feeling good rather than feeling better matters more to patients[END_REF] .

In TARGET, RAID was positioned after the break in the hierarchy used to control for multiple testing and, therefore, statistical significance cannot be claimed; other analyses were conducted post hoc. In MONARCH, RAID was not included in the hierarchy. Therefore, to aid interpretation, statistical comparisons between treatment groups (to test for nominal significance) were supplemented by betweengroup effect size analyses (standardized mean differences) using Cohen's d Rule for Change Interpretation: important: d ≤ -0.8; moderate: -0.8 < d ≤ -0.5; and small: -0.5 < d ≤ -0.2 [START_REF] Cohen | Statistical Power Analysis for the Behavioral Sciences[END_REF] . RAID scores were separately evaluated in each trial at baseline, week 12 and week 24. For missing data at the item level, an imputation using the mean of the 6 other items was used.

Ethics approval.

The analyses carried out in this study were conducted on data from two previously published randomized controlled trials of sarilumab, TARGET (NCT01709578) and MONARCH (NCT02332590) [START_REF] Fleischmann | Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors[END_REF][START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] . The protocols for both of these studies were approved by the appropriate ethics committees/institutional review boards, and each patient provided written informed consent before participation in the studies. The studies were conducted in compliance with institutional review board regulations, the International Conference on Harmonisation Guidelines for Good Clinical Practice, and the Declaration of Helsinki [START_REF] Fleischmann | Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors[END_REF][START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] .

RESULTS

Analysis population. Overall, 546 patients from TARGET and 369 from MONARCH were included in the analysis (Table 1). Between-group baseline demographics were generally comparable within each study; however, in MONARCH, disease duration was longer in the sarilumab group versus the adalimumab group [mean years, standard deviation (SD) 8.1 (8.1) vs 6.6 (7.8), respectively]. Between studies, mean disease duration in MONARCH was shorter than in TARGET (mean 7.3 vs mean 12.1 yrs). Baseline RAID scores were generally comparable across all groups within the individual RCTs, ranging from a mean (SD) of 6.5 (2.0) to 6.8 (1.8) in TARGET [START_REF] Strand | Sarilumab improves patient-reported outcomes in rheumatoid arthritis patients with inadequate response/intolerance to tumour necrosis factor inhibitors[END_REF] and 6.4 (2.0) to 6.7 (1.7) in MONARCH [START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] (Table 1). All other demographics, including age, sex and race, were relatively comparable among the patients in the two studies.

Changes in RAID score from baseline. Total score: LSM differences in RAID total scores were greater with sarilumab versus placebo in TARGET at weeks 12 (-0.93 and -1.13, respectively, for sarilumab 150 mg and 200 mg versus placebo; nominal p < 0.0001) and 24 (-0.75 and -1.01, respectively, for sarilumab 150 mg and 200 mg vs placebo; nominal p < 0.01). LSM differences in RAID total score were also greater with sarilumab versus adalimumab in MONARCH at weeks 12 (-0.49 for sarilumab 200 mg vs adalimumab; nominal p < 0.05) and 24 (-0.78 for sarilumab 200 mg vs adalimumab; nominal p < 0.001) (Figure 1). Between-group effect sizes for RAID total scores (Figure 2) met thresholds for small to moderate levels of importance by Cohen's d Rule for Change Interpretation in both sarilumab dose groups versus placebo at weeks 12 and 24 (TARGET), and in the sarilumab 200 mg group versus adalimumab at week 24 (MONARCH) [START_REF] Cohen | Statistical Power Analysis for the Behavioral Sciences[END_REF] .

Domain scores:

Changes from baseline in individual domain scores were significantly greater with sarilumab versus placebo for differences between groups (all nominal p < 0.05 except sleep domain; see Figure 3). In MONARCH, sarilumab treatment demonstrated greater improvement compared with adalimumab at week 12 only in the functional impairment domain, and in all domains by week 24 .

Moderate benefits were reported in the pain domain at week 12 (effect sizes of 0.54 and 0.58 for sarilumab 150 mg and 200 mg, respectively, vs placebo) and week 24 in TARGET (effect sizes of 0.54 and 0.68 for sarilumab 150 mg and 200 mg, respectively, vs placebo) (all nominal p < 0.05). In addition, most other domains (other than sleep) met thresholds for small importance at week 24 in both studies [START_REF] Cohen | Statistical Power Analysis for the Behavioral Sciences[END_REF] .

Responder analyses, MCID ≥3:

In TARGET, greater proportions of patients in the sarilumab 150 mg and 200 mg groups versus placebo were responders defined by an MCID ≥3 (nominal p ≤ 0.0001 at week 12 for both doses; nominal p ≤ 0.01 and nominal p ≤ 0.0001 for sarilumab 150 mg and 200 mg, respectively, at week 24) (Figure 4A). In MONARCH, a greater proportion of the sarilumab 200 mg group versus adalimumab were responders (nominal p ≤ 0.01 at both weeks 12 and 24) (Figure 4A). MCID ≥50%: There were greater proportions of responders in both dose groups of sarilumab in TARGET than placebo (nominal p ≤ 0.001 at week 12); nominal p ≤ 0.01 and nominal p ≤ 0.001 for sarilumab 150 mg and 200 mg, respectively, at week 24). In MONARCH greater improvement with sarilumab 200 mg versus adalimumab was reported at week 24 (nominal p ≤ 0.05) (Figure 4B).

PASS:

Absolute total RAID scores ≤3 were reported by both sarilumab dose groups versus placebo in TARGET at weeks 12 (sarilumab 150 mg, nominal p ≤ 0.01; sarilumab 200 mg, nominal p ≤ 0.001) and 24 (sarilumab 200 mg, nominal p ≤ 0.05; sarilumab 200 mg, nominal p ≤ 0.001). In MONARCH at week 24, a greater proportion of patients receiving sarilumab 200 mg than adalimumab were defined as responders (nominal p ≤ 0.01), and in (Figure 4C).

DISCUSSION

The benefits of sarilumab treatment as combination therapy with csDMARDs or as monotherapy across a range of PROs have been previously reported in MTX-IR and TNF-IR populations, including patient global assessment of disease activity, pain, physical function, fatigue, and general health status. Based on the patientreported RAID scale collected in the TARGET and MONARCH RCTs, data indicate that sarilumab SC 150 mg or 200 mg q2w as combination therapy with a csDMARD or as 200 mg monotherapy reduced the impacts of RA on patients' lives to a greater extent than placebo+csDMARD or adalimumab SC 40 mg q2w or once weekly monotherapy. Mean baseline scores ranged from 6.4 to 6.8, indicating a high impact of disease in these trial populations. In both the TARGET and MONARCH RCTs, the benefits of sarilumab treatment on symptoms and impact of disease were clinically meaningful assessed by two definitions of MCID and by PASS, with differential effects compared with placebo or adalimumab across the majority of RAID domains (with exception of sleep for sarilumab vs placebo in the TARGET study), with marked improvements in RAID total scores and domains of pain and functional impairment across all sarilumab treatment groups.

The relatively new RAID scale has so far only been applied in 1 other clinical trial [START_REF] Dougados | Onset of action of etanercept in rheumatoid arthritis based on patient-reported outcomes[END_REF] , a smaller, open-label, single-arm study of etanercept 50 mg/wk. In this study 56% of 120 patients with active RA reported total RAID scores ≤3.0 at week 12, indicating reduced disease impact from baseline [START_REF] Dougados | Onset of action of etanercept in rheumatoid arthritis based on patient-reported outcomes[END_REF] . In comparison, patients in TARGET and MONARCH had longer disease duration and higher baseline RAID scores than in the etanercept study [START_REF] Dougados | Onset of action of etanercept in rheumatoid arthritis based on patient-reported outcomes[END_REF][START_REF] Fleischmann | Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors[END_REF][START_REF] Burmester | Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial[END_REF] .

In these 2 larger RCTs, 35% sarilumab-treated patients in TARGET at week 12 and 36% at week 24 reported RAID scores ≤3, in MONARCH it was 41% at week 24.

Newer PROs such as the RAID scale are demonstrating the additional importance of evaluating multidimensional patient outcomes, with content and construct validity, responsiveness, and precision. It is now widely recognized that PROs should reflect what is important for patients, and that they should be developed with patient input [START_REF] Tugwell | OMERACT: an international initiative to improve outcome measurement in rheumatology[END_REF][START_REF]Guidance for industry patient-reported outcome measures: use in medical product development to support labeling claims[END_REF] . As RAID was developed by a EULAR international task force of both clinicians and patients to provide a single instrument that integrates all relevant patient domains, with relevance in different disease states, countries and cultures, it is designed to better quantify the experience of living with RA. Several studies have shown that the domains assessed in RAID are applicable and important for patients [START_REF] Gossec | Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative[END_REF][START_REF] Heiberg | Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to other patient-reported outcomes in a register of patients with rheumatoid arthritis[END_REF][START_REF] Hewlett | The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: validation in six countries[END_REF][START_REF] Wee | Content validity of the Dutch Rheumatoid Arthritis Impact of Disease (RAID) score: results of focus group discussions in established rheumatoid arthritis patients and comparison with the International Classification of Functioning, Disability and Health core set for rheumatoid arthritis[END_REF][START_REF] Cheung | Patient-reported outcomes in Asia: evaluation of the properties of the Rheumatoid Arthritis Impact of Disease (RAID) score in multiethnic Asian patients with rheumatoid arthritis[END_REF] . The advantage of sarilumab treatment over adalimumab and placebo improving RAID domains in these trials offers important information for physicians to consider in the context of shared treatment decisionmaking [START_REF] Fraenkel | Preference phenotypes to facilitate shared decision-making in rheumatoid arthritis[END_REF] .

Pain, fatigue, sleep disturbance and ability to cope are all symptoms that are of importance to patients with RA, but not all (e.g., sleep and ability to cope) are routinely assessed in RA RCTs, or even in clinical practice [START_REF] Gossec | Patient-reported outcomes as end points in clinical trials in rheumatoid arthritis[END_REF] . RAID is unique in that it not only assesses patient-reported symptoms such as pain, but also fatigue, sleep disturbance and coping. Fatigue, frequently reported in RA can severely impact all aspects of health-related quality of life, with a multifactorial origin, not just inflammation but personal factors and psychological distress as well [START_REF] Hewlett | Fatigue in rheumatoid arthritis: time for a conceptual model[END_REF] .

In this analysis, some differences in responses to treatment were noted: sleep and coping were less responsive than other domains, suggesting these may be less amenable to short-term treatment effects of DMARDs and biologics than, for example, pain. It seems that sleep and coping in particular, are less accessible to biologic treatment than other patient-reported domains of impact. This may reflect that these aspects of HRQoL are less directly linked to the inflammatory process, than for example pain. [START_REF] Avila-Ribeiro | Psychometric properties of sleep and coping numeric rating scales in rheumatoid arthritis: a subanalysis of an etanercept trial[END_REF] This is consistent with findings from other RCTs of DMARD with other mechanisms of action where sleep responsiveness in particular has been reported as less than other PROs [START_REF] Avila-Ribeiro | Psychometric properties of sleep and coping numeric rating scales in rheumatoid arthritis: a subanalysis of an etanercept trial[END_REF][START_REF] Gossec | Improvement in patient-reported outcomes after rituximab in rheumatoid arthritis patients: An open-label assessment of 175 patients[END_REF] .

Our finding must be considered in light of some study limitations. While the RAID data were included in the statistical hierarchy in MONARCH and TARGET, results were after the break in the hierarchy; therefore, p-values were not controlled for multiplicity, and are nominal. Hence, we applied multiple approaches to assess the clinical relevance of the observed results, including Cohen's d, responder analysis using 2 different MCID definitions and PASS. All of the approaches consistently indicated clinically meaningful improvements across the RAID domains.

A further exploration of the relationships of the endpoints with RAID, and any added value of RAID within the context of a clinical trial, is warranted for a separate study.

Nonetheless, despite the relative novelty of the RAID scale, a range of tests support interpretation of the present results. In addition, as adalimumab is usually used as combination therapy, the added value of the current paper should not be seen as a comparison with adalimumab only, , but also as further validating a recent outcome measure, the RAID.

While the extreme burden on RA patients caused by their joint damage is widely recognized [START_REF] Uhlig | The burden of disease in rheumatoid arthritis[END_REF][START_REF] Peterson | Lifetime Economic Burden of Rape Among U.S. Adults[END_REF][START_REF] Shin | Cognitive impairment in persons with rheumatoid arthritis[END_REF] other manifestations of this systemic disease including multiple comorbidities and psychosocial outcomes continue to be revealed. [START_REF] Cutolo | Burden of disease in treated rheumatoid arthritis patients: going beyond the joint[END_REF][START_REF] Matcham | Are depression and anxiety associated with disease activity in rheumatoid arthritis? A prospective study[END_REF][START_REF] Matcham | Symptoms of depression and anxiety predict treatment response and long-term physical health outcomes in rheumatoid arthritis: secondary analysis of a randomized controlled trial[END_REF] Hence, in addition to the clinical markers of disease which are unequivocally necessary for informing RA treatment decisions, assessing improvement on PROs including HRQoL reveals the ultimate benefit of treatment in reducing patient burden. [START_REF] Uhlig | The burden of disease in rheumatoid arthritis[END_REF][START_REF] Peterson | Lifetime Economic Burden of Rape Among U.S. Adults[END_REF][START_REF] Smolen | EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs[END_REF] The objective of the RAID scale is to provide a comprehensive assessment of the effects of treatment on patient burden, and from his or her own perspective.

As a relatively new measure, RAID has yet to be widely applied in either RA RCTs or clinical practice settings. Although its use is increasing, its further inclusion in large prospective studies will provide more evidence of the scale's sensitivity, [START_REF] Gossec | Finalisation and validation of the rheumatoid arthritis impact of disease score, a patient-derived composite measure of impact of rheumatoid arthritis: a EULAR initiative[END_REF] assessment of acceptable levels of missing data and MCID/PASS definitions, and data from clinical practice settings in diverse patient populations will indicate its generalizability.

In conclusion, the present analyses indicate that RAID efficiently evaluated the benefits of sarilumab treatment on patient-reported impact of RA in both TARGET and MONARCH RCTs.

.

  Two phase III, randomized, controlled trials of sarilumab in patients with active, long-standing RA were analyzed: sarilumab 150 mg and 200 mg twice-weekly plus conventional synthetic disease-modifying antirheumatic drugs (+csDMARDs) versus placebo+csDMARDs [TARGET (NCT01709578)]; sarilumab 200 mg versus adalimumab 40 mg monotherapy (MONARCH [NCT02332590]). Least squares mean (LSM) differences in RAID total score (range 0-10), and 7 key RA symptoms, including pain and fatigue (baseline to weeks 12 and 24), were compared. 'Responders' by RAID total score were defined by improvements from baseline ≥Minimal Clinically Important Difference (MCID), and ≥Patient Acceptable Symptom State (PASS) at end point.

Figure 1 .

 1 Figure 1. Mean change in total Rheumatoid Arthritis Impact of Disease scores from

Figure 2 .

 2 Figure 2. Between-group effect sizes on Rheumatoid Arthritis Impact of Disease

Cohen's d

  Rule for Change Interpretation: important: d ≤ -0.8; moderate: -0.8 < d ≤ -0.5; and small: -0.5 < d ≤ -0.2 (25). *Nominal p ≤ 0.05; **Nominal p ≤ 0.01; ***Nominal p ≤ 0.001; ****Nominal p ≤ 0.0001 all versus placebo (TARGET) or adalimumab (MONARCH) for the difference between the groups in the least squares mean change from baseline.csDMARD: conventional synthetic disease-modifying antirheumatic drug; qw: once weekly; q2w: every 2 weeks; SC: subcutaneous.

Figure 3 .

 3 Figure 3. Between-group effect sizes on Rheumatoid Arthritis Impact of Disease

Figure 4 .

 4 Figure 4. Proportion of patients in TARGET (+ csDMARD) and MONARCH

ACKNOWLEDGEMENTS

The authors thank the patients, their families, and all investigators involved in the sarilumab studies. Medical writing assistance was provided by Gauri Saal, MA Economics and editorial support by Sinead Stewart, both of Prime (Knutsford, UK) according to Good Publication Practice guidelines 45 , funded by Sanofi and Regeneron Pharmaceuticals Inc., and under the direction of the authors. The Sponsor was involved in the study design, collection, analysis and interpretation of data, as well as data checking of information provided in the manuscript. The authors had unrestricted access to study data, were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.

Supported by Sanofi and Regeneron Pharmaceuticals Inc.

Author contributions: C. Proudfoot., C. Chen, S. Guillonneau, T. Kimura, H. van Hoogstraten, E. Mangan, and M. Reaney were responsible for acquisition of data. All authors contributed to study conception and design, data analysis and interpretation, and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors were involved in drafting the article or revising it critically for


Danielle Seilhean

Raymond Escourolle

Neuropathology in Pitié-Salpêtrière hospital: past, present and prospect

Pitié and La Salpêtrière, both founded in the17th century, were for long two distinct hospitals until they merged in 1964. The name La Salpêtrière is inherited from the initial purpose of the buildings designed to produce saltpeter for gun powder. But the place was soon transformed into an asylum to shelter the poor and the insane. From the care of this underprivileged population, alienists such as Pinel have paved the way for modern medicine for the mentally ill at the time of the French Revolution. In the second half of the 19th century, Jean-Martin Charcot and his students laid the foundations of modern neurology from the observation of the large population hosted in La Salpêtrière, mostly women with severe chronic diseases. Charcot led clinic-pathological studies in about all the fields of nervous system disorders. His successors (including Raymond, Dejerine, Pierre Marie) maintained the same close relationship between clinical neurology and neuropathology. In parallel with the development of neurosurgery at Pitié hospital, neuropathology first spread through small laboratories attached to clinical departments. The merger of the two hospitals in the early sixties coincided with the creation of a large university hospital in which the care and study of diseases of the nervous system were preponderant. An independent laboratory of neuropathology was created, led by Raymond Escourolle. This period was on the eve of important developments in neuroscience around the world. Today, the Pitié-Salpêtrière neuropathology laboratory still plays a central role between neurology and

neurosurgery clinics and major research institutes such as the Brain Institute (Institut du Cerveau et de la Moelle, ICM) and the Institute of Myology.

Introduction

The development of neuropathology has been closely related to the development of neurology and is now part of neurosciences. Pitié-Salpêtrière hospital has offered early in its history a favorable ground to the emergence of an interest in nervous system diseases and has hosted precursors in these fields. This tradition continues with permanent interactions between clinical neurology, applied neurosciences and leading research institutes, such as the Brain institute (Institut du Cerveau et de la Moelle, ICM) and the Institute of Myology.

Context of the rise of neurological sciences at Pitié-Salpêtrière

Interest in the pathology of the nervous system appeared in Paris in public hospitals designed to accommodate low-income populations. Since the Middle-Ages, Augustinian Christian nuns watched over the health of the poor at the Hôtel-Dieu Hospital, at the foot of Notre-Dame Cathedral, in the heart of the city. In the 15th and 16th centuries, during the Renaissance period, the Parisian population increased considerably, reaching 400,000 people, 70% of whom were poor or at risk of becoming so [START_REF] Roche | Paris capital of the poor: some thoughts on Parisian pauperism between the 17th and 18th centuries (in French)[END_REF].

At that time, religious institutions began to lose part of their hegemonic influence and king Francis I of France decreed the founding of the Great Office of the Poor "for the relief of the poor and the decline of begging in Paris". The first Pitié hospital was then built near the Royal Garden, known today as the Jardin des Plantes [START_REF] Langlois | The Pitié-Salpêtrière (bilingual edition in English and French)[END_REF].

Twenty-five years later, outside the city, a former gunpowder factory producing saltpeter (salpêtre in French), was turned into a hospice. It was the origin of "La Salpêtrière". However, all this was not enough because the number of poor was constantly increasing. Their image evolved in society, in which they were increasingly perceived as immoral and dangerous [START_REF] Foucault | History of Madness[END_REF]. The young king Louis XIV then promulgated the Great Confinement (Grand Renfermement) of the poor and ordered the building of large hospices to house them: La Salpêtrière for women and Bicêtre, south of Paris, for men [START_REF] Seilhean | Foundation of the General Hospital: from charity to social order (1656-1666)[END_REF]. Throughout the 18th century, La Salpêtrière looked like a prison, while the old Pitié included a maternity ward and an orphanage. At the beginning of the 20th century, the old Pitié was destroyed and rebuilt next to La Salpêtrière. In 1964, the two hospitals merged resulting in the creation of the university hospital Pitié-Salpêtrière [START_REF] Langlois | The Pitié-Salpêtrière (bilingual edition in English and French)[END_REF].

Parallel development of neurology and neuropathology

How did the neurological sciences develop in this context? Some women had been admitted at La Salpêtrière because of behavioral disorders. During the French Revolution, at the end of the 18th century, Philippe Pinel, both a physician and a politically engaged citizen, was appointed as an alienist in La Salpêtrière. He became famous by ordering the removal of the chains from women with mental illness. With the help of his student Esquirol, he wrote clinical medicine treatises for the stated purpose of delivering a "more precise and more accurate" description of mental diseases and was later credited for being one of the founders of medical psychiatry [START_REF] Langlois | The Pitié-Salpêtrière (bilingual edition in English and French)[END_REF].

But the real beginning of neurology dates back to 1862, when two young men, Alfred Vulpian and Jean-Martin Charcot were appointed at La Salpêtrière [START_REF] Bogousslavsky | Alfred Vulpian and Jean-Martin Charcot in each other's shadow? From Castor and Pollux at La Salpêtrière to neurology forever[END_REF]. Together, they accurately described the tremor of multiple sclerosis as opposed to the tremor seen in paralysis agitans, re-named Parkinson's disease by Charcot during his lessons [START_REF] Charcot | On shaking palsy[END_REF][7] [START_REF] Walusinski | Jean-Martin Charcot and Parkinson's disease: teaching and teaching materials[END_REF]. Vulpian left La Salpêtrière for La Charité Hospital, since then replaced by the Saints-Pères faculty of medicine. Charcot developed in La Salpêtrière what was then named neurology and published groundbreaking works in several areas of neurology and neuropathology, such as multiple sclerosis [START_REF] Rascol | Multiple sclerosis from Charcot and Vulpian to the present time (in French with English abstract)[END_REF], vascular diseases with Charcot and Bouchard aneurysms [START_REF] Charcot | New research on the pathogenesis of cerebral hemorrhage (in French)[END_REF], degeneration of peripheral nerves, and of course amyotrophic lateral sclerosis, also known as Charcot's disease [START_REF] Kumar | Jean-martin Charcot: the father of neurology[END_REF] [START_REF] Goetz | Amyotrophic lateral sclerosis: early contributions of Jean-Martin Charcot[END_REF].

His approach based on clinical observation supplemented by an anatomical analysis [Figures 123 was inseparable from his teaching [Figure 4]. His reputation attracted many students. One of his main interests was the mechanisms of hysteria, as illustrated by the famous painting "A clinical lesson at La Salpêtrière" [START_REF] Signoret | A clinical lesson in La Salpêtrière (1887) by André Brouillet (in French)[END_REF]. He is represented commenting on the condition of one of his patient, Blanche Wittman, supported by Joseph Babinski [START_REF] Gimenez-Roldan | Clinical history of Blanche Wittman and current knowledge of psychogenic non-epileptic seizure[END_REF]. Among the students, stand future big names like Gilles de La Tourette, Bourneville, Paul Richer (who became also a famous sculptor), Brissaud [Figure 5], Pierre Marie and the son of Charcot, Jean-Baptiste, better known as navigator and explorer. Foreign students were also attracted by Charcot's teaching. Among them, the young Sigmund Freud of Vienna, who developed an interest in hysteria from his stay at La Salpêtrière during the winter 1885, giving up his previous activity of neuropathology [START_REF] Bogousslavsky | Sigmund Freud and hysteria: the etiology of psychoanalysis?[END_REF] [START_REF] Freud | Observation of a severe case of hemianesthesia in a hysterical male (1886)[END_REF]. In 1892, Kinnosuke Miura, founder in 1902 of the Japanese Society of Neurology and considered the precursor of neurology in Japan, stayed at La Salpêtrière [START_REF] Kuzuhara | History of neurology and education of neurology in Japan[END_REF]. Among other students of Charcot 7], acromegalia, hypertrophic paraneoplastic osteoarthropathy, cerebellar heredo-ataxia, cleidocranial atrophy and rhizomelic spondylosis [START_REF] Broussolle | Figures and institutions of the neurological sciences in Paris from 1800 to 1950. Part III: neurology[END_REF]. Pierre Marie's cerebellar heredo-ataxia was to be distinguished from Friedreich ataxia (in which tendon reflexes were abolished): the former was to be considered a disease of the cerebellum when the latter was thought to be due to lesions involving the spinal cord. The type of hereditary cerebellar atrophy that Pierre Marie actually described has been discussed. T. Uchihara, examining an old post mortem case from La Salpêtrière concluded that it must have been a case of what is known today as SCA3 [START_REF] Uchihara | Was the ataxia of Pierre Marie Machado-Joseph disease? A reappraisal based on the last autopsy case from la Salpêtrière Hospital[END_REF].

Pierre Marie is also famous for challenging Broca's hypothesis about aphasia, published 40 years earlier from observations made in Bicêtre Hospital. Pierre Marie claimed that aphasia was due to a lesion of what he called a quadrangle, including basal ganglia and deep white matter [START_REF]The third left frontal convolution plays no special role in the function of language (in French)[END_REF]. Jules Dejerine, a former student of Vulpian, had adopted the notion established by Broca of the key role of the foot of the third frontal convolution. The rivalry between the two men only worsened between 1883 and 1906, with peaks of tension such as this challenge to a duel in 1892 which fortunately did not take place. Dejerine was working closely with his wife, Augusta Dejerine-Klumpke, who was an excellent anatomist and a neuroscientist [Figure 8]. Based on a horizontal section, taken higher than the one illustrated by Pierre Marie, Mrs Dejerine demonstrated that the section on which he based his reasoning actually passed below the plane of the third frontal convolution responsible for aphasia and that his quadrangle included actually degenerating association pathways in the underlying white matter [START_REF] Klippel | Discussion about aphasia. Paris neurology Society, session of June 11, 1908, and following[END_REF] [27] [START_REF] Lechevalier | Aphasia's quarrel. Colloque Jules Dejerine (1849-1917[END_REF]. In 1911 Dejerine obtained the Chair of neurology in La Salpêtrière, whereas Pierre Marie was appointed to the Chair of pathology. Pierre Marie succeeded to Dejerine after his death in 1917. All former collaborators of Dejerine including Augusta Dejerine-Klumpke, were asked to leave the department of neurology. She had to remove all Dejerine's archives, which are now hosted at the Dupuytren museum of anatomy at Sorbonne University [START_REF] Mikol | The Dejerine Foundation[END_REF]. A recent conference at La Salpêtrière organized in tribute to Jules Dejerine underlined the extent and depth of his work [START_REF] Lechevalier | Aphasia's quarrel. Colloque Jules Dejerine (1849-1917[END_REF] [START_REF] Iwata | Dejerines' findings about alexia and their meaning for the Japanese language[END_REF].

Charles Foix (1882-1927) worked with Pierre Marie heading the laboratory at La Salpêtrière [START_REF] Broussolle | Figures and institutions of the neurological sciences in Paris from 1800 to 1950. Part III: neurology[END_REF].

After he spent part of the First World War in Greece as a medical doctor in the French Army of the Orient, he was appointed to the ward of chronic patients in the hospice of Ivry-sur-Seine, near Paris (now Charles-Foix Hospital), where he led an impressive number of studies, especially on the basal ganglia and the cerebrovascular system. He was expected to succeed Guillain at the Chair of Neurology at La Salpêtrière but his promising career was soon interrupted by his early and unexpected death at the age of 44 [START_REF] Alajouanine | [END_REF].

Joseph Babinski (1857Babinski ( -1932)), one of Charcot's closest students, was a talented semiologist. He is world-renowned for the "Babinski sign" that he described in 1896 as an extension of the great toe after sole stimulation in patients with a lesion of the pyramidal tract [START_REF] Babinski | On the plantar skin reflex in certain diseases of the central nervous system (in French)[END_REF]. He was head of a medical department at Pitié hospital, where he developed the first neurosurgery unit in France, in collaboration with Thierry de Martel (1875-1940) and Clovis Vincent (1879-1947) [START_REF] Broussolle | Figures and institutions of the neurological sciences in Paris from 1800 to 1950. Part III: neurology[END_REF] [33] [START_REF] Mathon | Commentary: La Pitié-Salpêtrière hospital in Paris: the historic cradle of neurosurgery[END_REF].

Another department of neurosurgery was founded in La Salpêtrière after the Second World War [START_REF] Mathon | Commentary: La Pitié-Salpêtrière hospital in Paris: the historic cradle of neurosurgery[END_REF].

Starting in the 1930s, neuropathology, which until then had been an integral part of clinical practice, was gradually handed over to specialist practitioners. Each department had its own laboratory specialized in post mortem brain studies or more oriented towards muscular pathology, study initiated by Professor Raymond Garcin, followed by his students Jean Lapresle and Michel Fardeau [START_REF] Mikol | The renaissance of neuromuscular pathology at La Salpêtrière (in French)[END_REF]. The laboratories associated with the neurosurgery departments were dedicated to tumor pathology: one in Pitié run by Henri Berdet followed by Roger Messimy, Jean Racadot and Jacques Poirier; the other in La Salpêtrière run by Jean-Emmanuel Gruner followed by Jean-François Foncin. Ivan Bertrand (1893-1965), who led the laboratory of the nervous system clinics for nearly 40 years, had been first trained in histology. He had come to neuropathology under the influence of Gustave Roussy and Pierre Marie and worked in collaboration with G. Guillain, T. Alajouanine, P. Castaigne and many others [START_REF] Alajouanine | Board of directors of the journal). Ivan Bertrand (1893-1965[END_REF].

The merging of Pitié and Salpêtrière in 1964 into a large university hospital gave a new impulse to the care and study of nervous system diseases to which a new building was dedicated [START_REF] Vessier | The Pitié-Salpêtrière. Four centuries of history and stories[END_REF]. The neuropathology department was included in the building in close relationship but independent from the neurology clinics [Figure 9]. The head of the new laboratory was Raymond Escourolle, a neuropsychiatrist, former student of Théophile Alajouanine and Jean Delay. In Sainte-Anne psychiatric hospital, he had met another young neurologist and psychiatrist, Serge Brion, trained in neuropathology in Harry Zimmermann's laboratory at Montefiore Hospital in New York [START_REF] Brion | [END_REF].

Starting from this partnership, Raymond Escourolle initiated a renewal of neuropathology at Pitié-Salpêtrière hospital. The laboratories formerly attached to neurology and neurosurgery merged into the Department of neuropathology, which in 1985 was named after Raymond Escourolle [Figure 10]. His successors, Jean-Jacques Hauw, then Charles Duyckaerts, have developed research and national networks especially in the fields of prions and neurodegenerative diseases and created the conditions for a multi-purpose laboratory including all areas of neuropathology in adults.

Present and prospect: neuropathology and neurosciences

Neuropathology is as ever at the interface with neurology and neurosurgery, to which one should add today neuroscience that has won academic authority and for which Pitié-Salpêtrière hospital sclerosis, motor neuron disease, frontotemporal lobar degeneration and ataxia. This platform is an essential tool for carrying out research in neurodegenerative pathology. Correlation between genetics and histopathology is now one of the main topics in the neuropathology of degenerative diseases. Junko Takahashi [START_REF] Seilhean | Amyotrophic lateral sclerosis with neuronal intranuclear protein inclusions[END_REF], Takahiro Takeda [START_REF] Teyssou | Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology[END_REF] [44] [START_REF] Takeda | Amygdala TDP-43 pathology in frontotemporal lobar degeneration and motor neuron disease[END_REF] and Yuichi Riku [START_REF] Riku | Increased prevalence of granulovacuolar degeneration in C9orf72 mutation[END_REF] have explored this field in amyotrophic sclerosis and frontotemporal dementia, during their stay in La Salpêtrière.

Seeding and propagation of misfolded protein is a major topic of interest that Charles Duyckaerts explored at first with the collaboration of Toshiki Uchihara [START_REF] Duyckaerts | Dissociation of Alzheimer type pathology in a disconnected piece of cortex[END_REF]. They started with the observation of a small part of cortex, disconnected after neurosurgery, in an Alzheimer's disease patient. In this cortex A-β pathology was present but not tau pathology suggesting that the propagation of Aβ may occur independently of innervation. Since then, other evidence came from patients who developed CJD after treatment by cadaver-derived growth hormone [START_REF] Cali | Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study[END_REF] [START_REF] Duyckaerts | Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology[END_REF]. A recent observation made after post-traumatic dura mater grafting, without CJD, suggested a nearly 45 years long incubation of the amyloid seeds, leading finally to a devastating amyloid angiopathy without tau pathology [START_REF] Hervé | Fatal Aβ cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years[END_REF] .

The evolution of knowledge is particularly rapid in the field of neuro-oncology. Pathological analysis plays a major role in research on brain tumors to provide tumor models, select samples for innovative analyses, and validate, with in situ methods, hypotheses on cellular and molecular mechanisms. The central nervous system is characterized by wide cell diversity, involved in the patterns of regional differentiation during normal development. This diversity is also involved in a large number of tumor types as emphasized by methylation studies. An example of the close relationship between cell types and molecular profiles has been shown in chordoid gliomas of the third ventricle [START_REF] Bielle | Chordoid gliomas of the third ventricle share TTF-1 expression with organum vasculosum of the lamina terminalis[END_REF]. This rare tumor always expresses a missense mutation of the gene encoding a proteinase K (PRKCA). Substrate analysis of this enzyme opens up targeted therapeutic perspectives [START_REF] Rosenberg | A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas[END_REF]. Metabolic studies offer other perspectives: oxidative metabolism is increased in glioma cells with a FGFR3-TACC3 fusion and treatments directed against oxidative stress like metformin can induce tumor cell death [START_REF] Bielle | Diffuse gliomas with FGFR3-TACC3 fusion have characteristic histopathological and molecular features[END_REF] [START_REF] Frattini | A metabolic function of FGFR3-TACC3 gene fusions in cancer[END_REF].

Muscle biopsy is still mandatory for the diagnosis of vasculitis and amyloidosis. But it is also necessary for the diagnosis and research in heterogeneous groups of diseases such as necrotizing myopathies or dermatomyositis [START_REF] Benveniste | Advances in serological diagnostics of inflammatory myopathies[END_REF]. A collaborative work with Akinori Uruha showed that an interferon inducible molecule, myxovirus resistance protein A, was a reliable marker of dermatomyositis [START_REF] Uruha | Diagnostic potential of sarcoplasmic myxovirus resistance protein A expression in subsets of dermatomyositis[END_REF]. In addition, muscle biopsy allows the identification of new entities, such as severe inflammation of the muscle in which the reaction of T lymphocytes is predominant. This kind of myositis is observed in patients treated with immune checkpoint inhibitors, used against cancer to improve the T cell response [START_REF] Touat | Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer[END_REF]. Muscle biopsies also identified late onset sporadic nemaline myopathy, found in patients with monoclonal gammapathies (MGUS) [START_REF] Belhomme | Rare myopathy associated to MGUS, causing heart failure and responding to chemotherapy[END_REF].

Conclusion

Although neuropathology is not recognized in France as a primary specialty, unlike in other countries in Europe and America [START_REF] Bigio | Neuropathology training worldwideevolution and comparisons[END_REF], Pitié-Salpêtrière laboratory remains a pivot between neurology, neurosurgery, pathology and neuroscience. This privileged situation gives it national and international visibility. The resulting attractiveness and the welcoming of students and colleagues from all over the world are at the center of its missions. Due to its close relationship with the Institute of Myology and the ICM, it is fully in keeping with an unbroken tradition of 230 years of neuroscience studies.

Legends of the figures

  known for their important work in neuropathology, were those who worked on Parkinson's disease, after Charcot and Vulpian. Paul Richer modeled a famous statuette representing an old woman: "Attitude and facies in Parkinson's disease, after a patient of La Salpêtrière". Based on an observation made by Blocq and Marinesco, Brissaud emphasized the role of substantia nigra in Parkinsonism [18] [19] [20]. Later, in 1919, Tretiakoff, a Russian medical student who wrote his thesis at La Salpêtrière under the supervision of Pierre Marie, gave the name of "Lewy bodies" [Figure 6] to the inclusions initially described by Friedrich Lewy [19] [21 ][22]. Pierre Marie (1853-1940) was one of the most prolific among the disciples of Charcot. He left important contributions in the fields of neurology and rheumatology. He described Charcot-Marie amyotrophy [Figure

  offers a rich environment. The foundation of the Brain Institute (ICM) in 2005, preceded by that of the Institute of Myology in 1996, confirmed the dynamism of neuroscience on the site. Since 2012, the neuropathology laboratory has been organized into three units: neurosurgical pathology; muscle and nerve pathology; autopsy and pathology of neurodegenerative and prion diseases. The three units work together and in close relationship with the surrounding research teams. The department of neuropathology at Pitié-Salpêtrière has become the only adult medical autopsy center in Paris area. Its activity now accounts for nearly 30% of medical autopsy requests in France. This competence was maintained and developed first to ensure diagnosis of neurological diseases. Systematic analysis allows the Department of Neuropathology to be at the forefront of the detection and monitoring of new diseases or new forms of previously known disorders. It played a key role in distinguishing different types of AIDS encephalopathies and of prion diseases [39] [40]. The study of the latter was facilitated by the national network for neuropathological monitoring of Creutzfeldt-Jakob disease (CJD), created by Jean-Jacques Hauw with the support of the French health agency (Institut de Veille Sanitaire, InVS). This network aims to collect samples of all cases in which the diagnosis of Creutzfeldt-Jakob disease had been made and which have been autopsied on the French territory. The department of neuropathology is now involved, in collaboration with the Pasteur Institute, in the identification of emerging virus encephalitides, combining New Generation Sequencing (NGS), immunohistochemistry and in situ hybridization [41]. The NeuroCEB biobank, developed by Charles Duyckaerts ten years ago, runs a national brain donation network. Patient associations have financially supported the creation of the brain bank and now provide help to all phases upstream of brain donation: from initial information to the post mortem transport of the body. The current member associations give support in the following neurological disorders: Parkinson's and Alzheimer's diseases, multiple

Figure 1 .

 1 Figure 1. Tear (k) of the outer wall of an aneurysm (Charcot-Bouchard aneurysm). Drawing

Figure 2 .

 2 Figure 2. Border of a plaque of multiple sclerosis. Chromic acid impregnation technique.

Figure 3 .

 3 Figure 3. Bilateral degeneration of cortico-spinal bundles in medulla and spine at cervical,

Figure 4 .

 4 Figure 4. Charcot in the autopsy amphitheater at La Salpêtrière wearing clogs and a top hat.

Figure 5 .

 5 Figure 5. Edouard Brissaud in the histology laboratory of the neurological clinics of La

Figure 6 .

 6 Figure 6. Tretiakoff C. Thesis, University of Paris, 1919. Chart IV (Fig. 9): Intra-cellular

Figure 7 .

 7 Figure 7. Marinesco, MG. Contribution to the study of Charcot-Marie amyotrophy. Arch.

Figure 8 .

 8 Figure 8. Jules Dejerine and Augusta Dejerine-Klumpke around 1900.

Figure 9 .

 9 Figure 9. The new laboratory of neuropathology in the building of the neurological clinics of

Figure 10 .

 10 Figure 10. Marble plaque in memory of Raymond Escourolle, first department head of the

Acknowledgements

I would like to thank Charles Duyckaerts for his review of the manuscript and the relevance of his suggestions. Any imprecision or error remains however my own. Many thanks to Maya Higuchi and Umberto De Girolami for their translation of Raymond Escourolle's commemorative plaque into Japanese and English, respectively


A Artese

Sandrine Dourdain

Guilhem Arrachart

A Leydier

S Pellet-Rostaing

N Boubals

P Guilbaud

Use of bifunctional compounds N, P for uranium purification from aqueous solutions of nitric acid

published or not. The documents may come   L'archive ouverte pluridisciplinaire

USE OF BIFUNCTIONAL COMPOUNDS N, P FOR URANIUM PURIFICATION FROM AQUEOUS SOLUTIONS OF NITRIC ACID

ARTESE Alexandre 1 , 2 , DOURDAIN Sandrine 1 , ARRACHARD Guilhem 1 , LEYDIER Antoine 1 ,PELLET-ROSTAING Stéphane 1 , BOUBALS Nathalie 2 , GUILBAUD Philippe 2 1-ICSM/LTSM 2-CEA/DEN/DMRC/SPDS/LILA alexandre.artese@cea.fr The refining plants of natural uranium concentrates rely on a solvent extraction process to produce uranium at the so-called "nuclear" purity. Extraction of uranium (from yellow cake) is performed thanks to an organic phase containing a specific extractant, further washed to recover pure uranium in a new aqueous phase. The conventional extractant is tri-n-butyl phosphate (or TBP). However, even though the TBP works pretty well at industrial scale, it is still of research interest to find optimized and highly efficient systems. Research has therefore been undertaken to find alternatives to TBP ([1], [START_REF] Chaogong | [END_REF], [3], [4], [5]). It turns out that most of the tested extractants have a moderate affinity for uranium (VI) with little or no selectivity for this element toward the other metallic species. A new series of N, P bifunctional ligands showed excellent properties in a nitric medium in terms of affinity for uranium extraction [START_REF] Arrachart | Utilisation de composés bifonctionnels, à fonctions acide phosphonique/phosphonate et amine, pour extraire l'uranium(VI) de solutions aqueuses d'acide nitrique[END_REF]. Based on the know-how of the LTSM team in the field of bifunctional ligands synthesis and study and of the CEA / DMRC teams in the data acquisition on major actinides [START_REF] Leydier | Composés à fonctions oxyde de phosphine et amine, utiles comme ligands de l'uranium(VI), et leurs utilisations, notamment pour extraire l'uranium(VI) de solutions aqueuses d'acide sulfurique[END_REF], [START_REF] Leydier | Composés à fonctions oxyde de phosphine et amine, utiles comme ligands de l'uranium(VI), et leurs utilisations, notamment pour extraire l'uranium(VI) de solutions aqueuses d'acide sulfurique[END_REF], the objective of this study is to explore and study the capacity of new molecular architectures for uranium extraction, and to understand their extraction mechanisms. It is now established that the mechanisms underlying the liquid-liquid extraction processes are based not only on the complexing properties of the extracting molecules [9], but also on their capacity to form supramolecular aggregates because of their amphiphilic nature. This study concentrates therefore on both molecular and supramolecular mechanisms to understand and master both chelation and self-assembly properties of these molecules in order to optimize extraction processes. The molecular structures of the complexes are probed using different techniques such as infrared spectrometry. The extraction of cations, acid and water by the new bifunctional ligands are characterized by ICP, coulometry and potentiometry. The organization of the ligands in supramolecular aggregates is characterized by X-ray and neutrons scattering measurements. Critical aggregation concentrations are measured in detail by surface tensiometry to relate them to aggregation energies. All these molecular and supramolecular aspects of the system are related to its extraction properties.

[9] O. Pecheur et al., Solvent Extraction and Ion Exchange 2016, 34, 260 -273

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