Ventrapati Pavan Kumar

Laura Paradis-Fortin

Pierric Lemoine

Gérard Le Caër

Bernard Malaman

Philippe Boullay

Bernard Raveau

Gabin Guélou

Emmanuel Guilmeau

Crossover from germanite to renierite-type structures in Cu 22-x Zn x Fe 8 Ge 4 S 32 thermoelectric sulfides

Keywords: germanite, renierite, disorder, sulfide, thermoelectric

Copper-rich sulfides with the composition Cu 22-x Zn x Fe 8 Ge 4 S 32 (0 ≤ x ≤ 2) have been investigated. The detailed structural study combining powder X-ray diffraction, electron microscopy and Mössbauer spectroscopy shows a crossover from a germanite-type domain for 0 ≤ x ≤ 0.4 to a renierite-type domain for 1.2 ≤ x ≤ 2.0, with a biphasic region for x = 0.8. Both sulfides are p-type thermoelectrics due to the presence of the conductive "Cu-S" network containing univalent copper as a major cationic element. All these sulfides exhibit a semiconducting behavior. However, the renierite-type sulfides show a higher resistivity and a lower thermal conductivity than the germanite ones. As a consequence, the ZT figures of merit are similar for germanite and renierite domains reaching values of around 0.23 at 700 K.

Introduction

Natural minerals involving copper-rich sulfides represent a huge source for designing new ptype thermoelectric materials. This originates from the fact that, in these systems, the major metallic element is univalent copper which is able to form, with sulfur, various tetrahedral conductive "Cu-S" frameworks. The association of CuS 4 tetrahedra with MS 4 tetrahedra of numerous metallic elements (namely M = Cr, V, Fe, Ge, Nb, Mo, Sn, Sb, Ta, W) allows not only the geometry of the conductive "Cu-S" network to be diversified but also offers the possibility of tuning the hole carrier density ("Cu 2+ concentration") by varying the charge balance. In this way, several classes of p-type thermoelectric sulfides, derivatives of natural minerals, have been synthesized. Bornite Cu 5 FeS 4 , [START_REF] Qiu | Sulfide Bornite Thermoelectric Material: A Natural Mineral with Ultralow Thermal Conductivity[END_REF][START_REF] Guélou | Ball Milling as an Effective Route for the Preparation of Doped Bornite: Synthesis, Stability and Thermoelectric Properties[END_REF][START_REF] Kumar | The Crucial Role of Selenium for Sulphur Substitution in the Structural Transitions and Thermoelectric Properties of Cu 5 FeS 4 Bornite[END_REF][START_REF] Long | High Thermoelectric Performance of Bornite through Control of the Cu(II) Content and Vacancy Concentration[END_REF] tetrahedrite Cu 12-x T x Sb 14 S 13 (with T = Mn, Ni, Zn, Fe), [START_REF] Suekuni | Thermoelectric Properties of Mineral Tetrahedrites Cu 10 Tr 2 Sb 4 S 13 with Low Thermal Conductivity[END_REF][START_REF] Suekuni | High-Performance Thermoelectric Mineral Cu 12-x Ni x Sb 4 S 13 Tetrahedrite[END_REF][START_REF] Lu | High Performance Thermoelectricity in Earth-Abundant Compounds Based on Natural Mineral Tetrahedrites[END_REF][START_REF] Barbier | Structural Stability of the Synthetic Thermoelectric Ternary and Nickel-Substituted Tetrahedrite Phases[END_REF][START_REF] Chetty | Tetrahedrites as Thermoelectric Materials : An Overview[END_REF][START_REF] Bouyrie | Crystal Structure, Electronic Band Structure and High-Temperature Thermoelectric Properties of Te-Substituted Tetrahedrites Cu 12 Sb 4-x Te x S 13 (0.5 ≤ x ≤ 2.0)[END_REF][START_REF] Barbier | Thermoelectric Materials: A New Rapid Synthesis Process for Nontoxic and High-Performance Tetrahedrite Compounds[END_REF][START_REF] Barbier | Up-Scaled Synthesis Process of Sulphur-Based Thermoelectric Materials[END_REF] kesterite Cu 2 ZnSnS 4 , [START_REF] Liu | A Wide-Band-Gap p-Type Thermoelectric Material Based on Quaternary Chalcogenides of Cu 2 ZnSnQ 4 (Q = S,Se)[END_REF][START_REF] Yang | Non-Toxic and Abundant Copper Zinc Tin Sulfide Nanocrystals for Potential High Temperature Thermoelectric Energy Harvesting[END_REF] stannoidite Cu 8 Fe 3 Sn 2 S 12 , [START_REF] Kumar | Copper Hyper-Stoichiometry: The Key for the Optimization of Thermoelectric Properties in Stannoidite Cu 8+x Fe 3-x Sn 2 S 12[END_REF] germanite Cu 22 Fe 8 Ge 4 S 32 , [START_REF] Kumar | Designing a Thermoelectric Copper-Rich Sulfide from a Natural Mineral: Synthetic Germanite Cu 22 Fe 8 Ge 4 S 32[END_REF] and colusite Cu 26 T 2 M 6 S 32 (with T = V, Cr, Nb, Mo, Ta, W and M = Ge, Sn), 17- 23 are among the best performing thermoelectric sulfides to date. Among all those copper-based minerals, the natural renierite (Cu,Zn) 22 Fe 8 (Ge,As) 4 S 32 [START_REF] Bernstein | Renierite Crystal Structure Refined from Rietveld Analysis of Powder Neutron-Diffraction Data[END_REF] has not been considered to date as a potential thermoelectric candidate in spite of its formula close to that of synthetic germanite Cu 22 Fe 8 Ge 4 S 32 and its structure closely related to germanite and colusite. [START_REF] Kumar | Designing a Thermoelectric Copper-Rich Sulfide from a Natural Mineral: Synthetic Germanite Cu 22 Fe 8 Ge 4 S 32[END_REF][START_REF] Kumar | High Power Factors of Thermoelectric Colusites Cu 26 T 2 Ge 6 S 32[END_REF] Based on the analysis of the close structural relationships between germanite and renierite, we have investigated the Cu 22-x Zn x Fe 8 Ge 4 S 32 series. Herein, we show a crossover from the germanite to the renierite-type structure as the zinc content increases from x = 0 to x = 2 with a biphasic state for x = 0.8. We observe that the transport properties are significantly influenced by an increase of the Zn content and that the ZT values are comparable for germanite and renierite-type structure compounds with different compositions, i.e. x = 0 and x = 1.2, respectively. This behavior stems from the fact that the renierite-type sulfides exhibit a higher resistivity and a lower thermal conductivity than the germanite ones.

Experimental Section

Polycrystalline samples of Cu 22-x Zn x Fe 8 Ge 4 S 32 (0 ≤ x ≤ 2) were synthesized by mechanical alloying followed by spark plasma sintering. All sample preparations and handling of powders were performed in an argon filled glovebox with oxygen content <1 ppm. Stoichiometric amounts of Cu (99.9%, Alfa Aesar), Fe (99.9%, Alfa Aesar), Zn (99.9%, Alfa Aesar), Ge (99.999%, Alfa Aesar), and S (99.99%, Alfa Aesar) were loaded in a 25 mL tungsten carbide jar under argon atmosphere. High-energy ball milling was performed in a Fritsch Pulverisette 7 Premium line planetary ball mill operating at room temperature (RT) at a disc rotation speed of 600 rpm. The jar contains 7 balls of 10 mm diameter. Jar and balls are made of tungsten carbide with a powder-to-ball weight ratio of 1:14. Powders were milled in an argon atmosphere for 6 h. The resulting powders were ground and sieved down to 150 μm. Powders were then placed in graphite dies of 10 mm diameter and densified by spark plasma sintering (SPS-FCT HPD 25) at 873 K for 30 min under a pressure of 64 MPa (heating and cooling rate of 50 and 20 K/min, respectively). This produced 10 mm diameter pellets, ca. 7 mm thick, with geometrical densities greater than 96% of the crystallographic value.

Powder X-ray diffraction (PXRD) measurements were performed using a D8 advance diffractometer with silicium band LynxEye detector (Cu Kα radiation with Ge (111) monochromator). Data were collected with the addition of 6 scans over the angular range 10  2θ/ °  140° with a step size of 0.0105°, and a step time of 1.3 s. PXRD patterns were refined by Le Bail analysis using the FullProf and WinPlotr software packages. [START_REF] Rodríguez-Carvajal | Recent Advances in Magnetic Structure Determination by Neutron Powder Diffraction[END_REF][START_REF] Roisnel | WinPLOTR: A Windows Tool for Powder Diffraction Patterns Analysis[END_REF] The shape of the diffraction peaks was modeled using a pseudo-Voigt profile function. Zero-point shift, lattice and asymmetry parameters were systematically refined, and the background contribution was manually estimated. Room temperature Hall effect measurements were carried out using the Physical Properties Measurement System (PPMS; Quantum Design) under an applied magnetic field up to 9 T. However, it is difficult to extract reliable carrier concentrations due to an A c c e p t e d M a n u s c r i p t anomalous contribution. Attempts to calculate the carrier concentration using the approximation of single parabolic band conduction model, using the formula p = 1/R H e, where e is the electronic charge, gives unrealistic values. 57 Fe Mössbauer spectra were measured at T = 300 K in transmission geometry with a spectrometer operated in the conventional constant acceleration mode. Polycrystalline absorbers, with natural abundance of 57 Fe and thickness of ∼15 mg cm -2 , were used. Sources were kept at room temperature (RT) to collect 57 Fe Mössbauer spectra. The source was 57 Co in Rh matrix with a nominal strength of 25 mCi.

Velocity calibration was performed against a 12-μm-thick α-Fe foil at RT. 57 Fe isomer shifts (δ) are referred to α-Fe at RT. The area fraction, that is associated to a given Mössbauer site, is the fraction of the total area comprised between the spectrum and its background measured far from resonance peaks. If the Lamb-Mössbauer factors are all equal at RT, an assumption done here, the area fraction of a site gives also the fraction of Fe atoms it represents. Mössbauer spectra were fitted with a least-squares method program assuming Lorentzian peaks.

Precession electron diffraction tomography (PEDT) [START_REF] Mugnaioli | ab Initio" Structure Solution from Electron Diffraction Data Obtained by a Combination of Automated Diffraction Tomography and Precession Technique[END_REF][START_REF] Boullay | Precession Electron Diffraction Tomography for Solving Complex Modulated Structures: The Case of Bi 5 Nb 3 O 15[END_REF] data were obtained using a JEOL 2010 (200 kV) transmission electron microscope (TEM) equipped with a side-mounted Gatan Orius CCD camera and a Nanomegas Digistar unit. Samples for TEM investigations were prepared by smoothly crushing powder under ethanol in an agate mortar and depositing drops of the mixture onto a holey carbon membrane supported by a Ni grid. 100 and 86 PED patterns were collected, respectively, on x = 0 and x = 2 Cu 22-x Zn x Fe 8 Ge 4 S 32 crystals with a precession angle of 1.2° and a tilt step about 1° between each pattern. PEDT data were processed using the programs PETS 2.0 [START_REF] Palatinus | Specifics of the data processing of precession electron diffraction tomography data and their implementation in the program PETS2.0[END_REF] and Jana2006. [START_REF] Petříček | Crystallographic Computing System Jana2006: General Features[END_REF] The electrical resistivity (ρ) and Seebeck coefficient (S) were measured simultaneously from ingots, from 300 K up to 700 K using an ULVAC-ZEM3 instrument under partial helium pressure. A NETZSCH LFA-457 apparatus was used for measuring the thermal diffusivity under argon flow. The thermal conductivity (κ) was determined as the product of the , where the Lorenz number, L, was approximated from the Seebeck 𝜅 𝑒 = 𝐿𝜎𝑇 coefficient using the single parabolic band (SPB) model. [31][START_REF] Anselm | Introduction to the Theory of Semiconductors (English Translation)[END_REF][START_REF] Ravich | Semiconducting Lead Chalcogenides (English Translation)[END_REF] This model was derived from the Boltzmann transport equation under the relaxation time approximation and we assumed a carrier relaxation time limited by acoustic phonon scattering, i.e. a scattering factor r = -1/2.

The estimated measurement uncertainties are 6% for the Seebeck coefficient, 8% for the electrical resistivity, 11% for the thermal conductivity, and 16% for the final figure of merit, ZT. [START_REF] Alleno | A Round Robin Test of the Uncertainty on the Measurement of the Thermoelectric Dimensionless Figure of Merit of Co 0.97 Ni 0.03 Sb 3[END_REF]

Analysis of the germanite and renierite structures.

In order to understand the relationship between the structure and the thermoelectric properties of these sulfides, a careful analysis of their structures is absolutely necessary, all the more so because they exhibit complex cationic ordering phenomena which have not been fully described in the literature. Both structures derive from the ZnS sphalerite structure (cubic space group 𝐹4

) but differ from each other by their crystal symmetry: germanite is cubic (a ~ 10.5 3𝑚 𝑃43𝑛

Å) whereas renierite is tetragonal (a ~ c ~ 10.5 Å), a feature which allows them to be 𝑃42𝑐 easily differentiated from powder X-ray diffraction study (See below).

The natural germanite, which cubic structure was determined by Tettenhorst and Corbato from powder X-ray analysis, [START_REF] Tettenhorst | Crystal Structure of Germanite, Cu 26 Ge 4 Fe 4 S 32 , Determined by Powder X-Ray Diffraction[END_REF] is characterized by the copper rich formula Cu 26 Fe 4 Ge 4 S 32 . It contains a large amount of Cu 2+ , a feature rarely observed in synthetic copper sulfides, which probably originates from the high pressure conditions generally associated with natural mineral A c c e p t e d M a n u s c r i p t formation. This structure derives from that of the well-known ZnS sphalerite (Fig. 1a). It consists of a semi-ordered sphalerite framework [Cu 24 Fe 4 Ge 4 S 32 ] built up of CuS 4 , FeS 4 and GeS 4 corner-shared tetrahedra (Fig. 1b). According to Tettenhorst, in this framework, the 6c, 6d and 12f sites are occupied by Cu, whereas Fe and Ge are statistically distributed over the same 8e site. The sphalerite network forms interstitial tetrahedral sites, among which, according to the authors, the 2a site is filled with remaining Cu atoms (Fig. 1b). The latter CuS 4 tetrahedra share their edges with the CuS 4 tetrahedra of the 12f sites. Note that these cations would form centered octahedral clusters Cu 2a (Cu 12f ) 6 similar to the CuL 6 clusters with L = V, Ta, Cr, Mo, W previously described for colusites. [START_REF] Kumar | High Power Factors of Thermoelectric Colusites Cu 26 T 2 Ge 6 S 32[END_REF][START_REF] Frank-Kamenetskaya | New Data on the Crystal Structures of Colusites and Arsenosulvanites[END_REF] The synthetic germanite with a cubic structure (space group ) was recently obtained but 𝑃43𝑛 with a different chemical formula Cu 22 Fe 8 Ge 4 S 32 , [START_REF] Kumar | Designing a Thermoelectric Copper-Rich Sulfide from a Natural Mineral: Synthetic Germanite Cu 22 Fe 8 Ge 4 S 32[END_REF] supporting the above statement that divalent copper rich sulfides are rarely stabilized. In this study, the two Cu cations of this formula were in a first approach formally attributed to the 2a site in compliance with Tettenhorst's study. [START_REF] Tettenhorst | Crystal Structure of Germanite, Cu 26 Ge 4 Fe 4 S 32 , Determined by Powder X-Ray Diffraction[END_REF] However, a coupled single crystal X-ray and Mössbauer investigation of this sulfide, currently in progress, shows that the 2a site is fully occupied by Fe 3+ cations. Thus, the synthetic germanite structure (Fig. 1c) exhibits a semi-ordered sphalerite framework, also built up of CuS 4 , FeS 4 and GeS 4 tetrahedra but with a different composition [Cu 22 Fe 6 Ge 4 S 32 ]. The distribution of the Cu, Fe and Ge cations over the 12f, 6c, 6d and 8e sites shows signature of preferential occupancy of several of them by the remaining iron but is currently not definitely established and will not be discussed further. In contrast to the natural germanite, it appears clearly that the interstitial tetrahedral 2a site occupied by iron forms FeS 4 tetrahedra sharing their edges with the LS 4 tetrahedra arising from L cations of the 12f site. Importantly, the values of the Fe 2a -L 12f distances close to 2.73 Å observed for this compound show that it exhibits octahedral metallic clusters FeL 6 similar to those encountered in colusites. [START_REF] Kumar | High Power Factors of Thermoelectric Colusites Cu 26 T 2 Ge 6 S 32[END_REF][START_REF] Frank-Kamenetskaya | New Data on the Crystal Structures of Colusites and Arsenosulvanites[END_REF] The natural renierite (Cu,Zn) 22 Fe 8 (Ge,As) 4 S 32 exhibits a structure (Fig. 1d) and a formula closely related to that of the synthetic germanite. [START_REF] Bernstein | Renierite Crystal Structure Refined from Rietveld Analysis of Powder Neutron-Diffraction Data[END_REF] This sulfide also derives from the sphalerite structure but exhibits a tetragonal distortion of the latter (a ~ c ~ 10.5 Å). Thus, it can be described as a semi-ordered but tetragonally distorted sphalerite framework [Cu 22-x Zn x Fe 8 (Ge,As) 4 S 32 ] built up of corner-shared CuS 4 , FeS 4 , ZnS 4 and GeS 4 tetrahedra. The cationic distribution in the different sites of this network appears to be more ordered compared to synthetic germanite: 4g, 4i, 4m and 8n sites are occupied by copper, and 4h and 2f sites are occupied by iron, whereas zinc and the remaining copper are randomly distributed over the 2e site, and germanium and arsenic are located on a 4j site. [START_REF] Bernstein | Renierite Crystal Structure Refined from Rietveld Analysis of Powder Neutron-Diffraction Data[END_REF] Remarkably, this sphalerite framework also hosts Fe 3+ as an interstitial cation in the 2b site (referring to space group). 𝑃42𝑐

As with synthetic germanite, the corresponding FeS 4 tetrahedron shares its edges with the surrounding polyhedra, i.e. with 4 CuS 4 tetrahedra arising from copper on the 4g and 4m sites and 2 FeS 4 tetrahedra arising from iron on the 4h site. Thus, alike germanite, renierite exhibits octahedral metallic FeL 6 clusters, but differently, metal L apices are occupied in an ordered way, with two apical iron cations and four equatorial copper cations. This results in an elongation of those Fe[Cu 4 Fe 2 ] octahedra with 4 equatorial Fe-Cu distances of 2.65-2.67 Å and 2 longer apical Fe-Fe distances of 2.81 Å, [START_REF] Bernstein | Renierite Crystal Structure Refined from Rietveld Analysis of Powder Neutron-Diffraction Data[END_REF] in agreement with the Fe 3+ -Cu 2+ and Fe 3+ -Fe 3+ Coulomb repulsions. Note that the average distance between central Fe 3+ and the surrounding L cations in octahedral metallic FeL 6 clusters is equivalent in both structures, synthetic germanite and renierite.

Results and Discussion

Structure analysis

In the following, we will show that under the same experimental conditions as those previously used for the preparation of the synthetic germanite Cu 22 Fe 8 Ge 4 S 32 , [START_REF] Kumar | Designing a Thermoelectric Copper-Rich Sulfide from a Natural Mineral: Synthetic Germanite Cu 22 Fe 8 Ge 4 S 32[END_REF] two series of compounds can be synthesized in the system Cu 22-x Zn x Fe 8 Ge 4 S 32 : a single phase germanite domain for 0 ≤ x ≤ 0.4 and a single phase renierite one for 1.2 ≤ x ≤ 2.0, with a biphasic domain for x = 0.8 corresponding to a mixture of the two sulfides. The PXRD patterns (Fig. 2) of the germanite samples (i.e. x = 0 and x = 0.4) show similarities with those of the renierite samples (i.e. x = 1.2, 1.6 and 2.0), due to the fact that the two structures have similar cell dimensions. However, the distortion of the structure from cubic in germanite to tetragonal in renierite induces a splitting of equivalent reflections either into two reflections (for (hhl) and (hkk) reflections allowed by the cubic space group) or into three reflections (for (hkl) reflections allowed by the cubic space group). This is illustrated by the splitting of the (622) peak of the cubic germanite into the non-equivalent intensity (622) and (226) peaks of the tetragonal renierite (Fig. 3a). In contrast, the (hhh) reflections are the only ones which are not splitted by the cubic to tetragonal distortion, as shown from the main intensity (222) diffraction peak (Fig. 3b) which is similar in renierite and germanite (Fig. 2).

Note also that the reflection conditions imposed by the two different space groups also allow the germanite and renierite to be clearly distinguished from their PXRD patterns, showing that (hhl), (hkk), and (hkh) reflections with l = 2n + 1, h = 2n + 1, and k = 2n + 1, respectively, are systematically absent in the space group of germanite, whereas the tetragonal space group 𝑃43𝑛 of renierite requires that only (hhl) reflections with l = 2n + 1 are absent.

M a n u s c r i p t

To confirm the germanite structure for samples with x  0.4, PEDT data were collected on a single crystal (size ~200 nm) for a sample x = 0. In Fig. 4a, the reciprocal space section 0kl reconstructed from PEDT data exhibit extra reflections compatible with the cubic primitive lattice of the germanite. The space group is further confirmed from the hkh and hhl 𝑃43𝑛 sections in Fig. 4c and4d, respectively, where the condition limiting the reflections hkh: k = 2n and hhl: l = 2n is clearly observed. Bearing in mind that the cationic distribution in both structures is complex due to disorder phenomena, Rietveld refinements from PXRD data are not expected to be of much help to elucidate ordering phenomena in such samples due to the equivalent scattering factors of the cations. It is especially the case in renierite where most of the crystallographic sites exhibit a simultaneous occupancy by two different cations involving either statistical or semi-ordered distributions. [START_REF] Bernstein | Renierite Crystal Structure Refined from Rietveld Analysis of Powder Neutron-Diffraction Data[END_REF] Considering this difficulty, only Le Bail refinements were used to fit the diffraction data in order to distinguish the two different structures. This is illustrated for the x = 0.8 biphasic sample which peak profiles suggest that the latter corresponds to a mixture of germanite and renierite phases (Fig. 3c). This is confirmed by refinements leading to a mixture of germanite with a = 10.598(1) Å and renierite with a = 10.620(1) Å and c = 10.554(2) Å. Due to the overlapping of the diffraction peaks of germanite and renierite, it is difficult to determine accurately the proportion of each phase in this sample. However, a peak profile fitting of the (622) peaks indicates that the area corresponding to the (622) peak of the germanite phase represents ≈ 36% of the total area, while it is of ≈ 42% and ≈ 22% for the (622) and (226) peaks of the renierite phase, respectively (Fig. 3c). Considering that the 2 for 1 intensity ratio expected for the (622) and ( 226) peaks of renierite is well reproduced, we can estimate the proportion of germanite and renierite phases in the x = 0.8 sample to be ≈ 1/3 and ≈ 2/3, respectively.

Note that the intensity of the superstructure diffraction peaks of renierite are strongly reduced for higher Zn content samples. This is confirmed by PEDT collected on a x = 2 sample (Fig. 4b) where the 0kl reciprocal space section shows mostly strong reflections related to the sphalerite subcell. In the insert of Fig. 4b, weak superstructure reflections confirm the existence Due to the weakness of the extra reflections and the presence of systematic twinning in the PEDT data, no conclusive result can be obtained regarding the possible space groups for this sample. This nonetheless suggests that an ordering compatible with both the briartite (Cu 2 FeGeS 4 , , a = 5.32 Å, c = 10.55 Å, see in Fig. 1e) and the renierite structure should 𝐼42𝑚 be considered for the refinements of samples for which x ≥ 1.2. However, in the briartite, both metal/sulfur ratio (equal to 1) and chemical composition differ significantly from our nominal chemical compositions, especially the Cu:Ge ratio. This should induce the existence of at least one secondary phase, which is not observed on the experimental PXRD patterns. Moreover, our nominal chemical compositions are coherent with the chemical compositions of natural renierite (Cu,Zn) 22 Fe 8 (Ge,As) 4 S 32 . [START_REF] Bernstein | Renierite Crystal Structure Refined from Rietveld Analysis of Powder Neutron-Diffraction Data[END_REF] Last but not least, 57 Fe hyperfine parameters of samples, for which x ≥ 1.2 determined from fits of RT Mössbauer spectra (see below), are much smaller than those expected for a briartite structure. Consequently, the multiple evidences are clearly in favor of a renierite structure. Consequently, it is reasonable to consider that higher Zn content samples exhibit a renierite-type structure in which the cationic site distribution is highly disordered, inducing the reduction of intensity of the superstructure diffraction peaks. This is supported by the complex crystal structure of renierite, where a partial occupancy of the cationic sites was reported by Bernstein et al., [START_REF] Bernstein | Renierite Crystal Structure Refined from Rietveld Analysis of Powder Neutron-Diffraction Data[END_REF] and by the synthesis and sintering conditions used to prepare our samples. Indeed, these conditions are well-known to be favorable to structural disorder. Such structural disorder associated with superstructure diffraction peaks extinction was also observed in closely related colusite structures. [START_REF] Suekuni | Atomic-Scale Phonon Scatterers in Thermoelectric Colusites with a Tetrahedral Framework Structure[END_REF] From these considerations, the refinements of the PXRD patterns of the x = 1.2, x = 1.6, and x = 2.0 samples were finally carried out by considering a renierite crystal structure.

The evolution of the refined unit cell parameters of germanite/renierite-type phases versus Zn content is shown in Fig. 5. From this figure, it could be noted that the a parameter of the cubic

Qualitative characteristics of room-temperature Mössbauer spectra

Mössbauer spectra of Cu 22-x Zn x Fe 8 Ge 4 S 32 with x (0 ≤ x ≤ 2.0), recorded at room-temperature (RT) between -2.5 mm/s and 2.5 mm/s, are shown in Fig. 6 for x = 0, 0.4, 0.8, 1.2, and 2.0. Solid lines, except for x = 0.8, are obtained from least-squares fits of the spectra that will be discussed later on. An asymmetrical shape of the main central component characterizes the at RT is <B> ~36 T for x = 0 and <B> ~35.4 T for x = 2.0. We recall that the hyperfine magnetic field of -Fe at RT is 33.1 T. The assumption of similar Lamb-Mössbauer factors for all phases leads to estimate that on the average ~25% of the total Fe might be contained in the magnetic phase, the maximum value of ~37% occurring for the "Cu 20 Zn 2 Fe 8 Ge 4 S 32 " sample. There is no possibility to obtain the observed <B>'s from a combination of Fe with one or more than one element chosen among Cu, Zn and Ge. Then, the magnetic phase includes Fe atoms, up to ~3 Fe for x = 2.0, and probably other metallic elements and sulfur atoms. It is worth mentioning that the studied samples are not attracted to a strong permanent magnet at RT. A Mössbauer spectrum of the x = 2.0 sample, recorded at 4.2 K, shows that the main phase becomes also magnetic (data not shown). The maximum hyperfine magnetic field of this mixture of two magnetic phases is ~36.4 T, a maximum close to the maximum field, 35.4 T, found at RT. The Mössbauer spectrum recorded at 4.2 K is however too complex to be fitted reliably. the center of gravity of these lines is 0.26 (3) mm/s. The area fractions of the central peaks of magnetic components, y, normalized to the total spectral areas measured between -2.5 mm/s and +2.5 mm/s, increase with x. The y values are 0.02(1), 0.04(2), 0.06(2), and 0.09(2) for x = 0, 0.4, 1.2, and 2.0 respectively. The area fractions associated with the magnetic phase are estimated by assuming that the intensity ratios of peaks of sextuplets are the theoretical ones for thin absorbers, i.e. 3 for external lines, 2 for intermediate lines and 1 for central lines. If the central area fraction of the magnetic phase is y, then its total area is (3+2+1)y = 6y when all peaks are included. The total area of the non-magnetic phase is by definition 1-y. The total area of the two phases is 1+5y. Finally, the area fractions of the magnetic phase are estimated to be given by 6y/(1+5y), that is 0.11, 0.20, 0.28, and 0.37 for x = 0, 0.4, 1.2, and 2.0, respectively, with an average of 0.24. The number of Fe atoms in the magnetic phase increases accordingly between ~1 and ~3 when x increases from 0 to 2.0 with the additional assumption of equal Lamb-Mössbauer factors for all Fe sites. For reasons explained below, no value is given for x = 0.8. These magnetic contributions may result from the presence of magnetic secondary phases, thus implying some significant changes of actual compositions with respect to nominal ones. However, the selectivity of 57 Fe Mössbauer spectroscopy makes these magnetic phases clearly visible despite the fact that their atomic fractions in the studied samples are possibly small. An alternative hypothesis to account for the presence at RT of a magnetic contribution in all samples is that the magnetic contribution is intrinsic to the germanite/renierite structure in which iron sublattices with different magnetic ordering temperatures would coexist. This might explain why powder X-ray diffraction fails to detect this "secondary phase". The close values of maximum hyperfine magnetic fields at 4.2 K and at RT mean that the magnetic phase has its magnetic transition temperature well above RT. However, the validation of those assumption Hereafter, we discuss no more the previous central lines due to the magnetic contribution at RT and we continue to use the nominal compositions. Only the two or three components of the central part of any spectrum that is relevant to the studied phases are numbered, starting with 1 and the sum of their area fractions is normalized to 1.

Fig. 6 shows that the main components of the spectra are packed with peaks (at least four) from the different sites in narrow velocity ranges. The determination of the exact number of Mössbauer sites is thus problematic all the more than lines may become broader as a consequence of aforementioned structural disorder. Nevertheless, asymmetrical spectra allow us to conclude unambiguously that their central components consist of at least two doublets.

Thinning of RT Mössbauer spectra

To highlight the various iron containing phases and the evolution of spectra with x, we "thin" them with a method described in section 7.2 (page 10759) of ref. [START_REF] Le Caër | General Models for the Distributions of Electric Field Gradients in Disordered Solids[END_REF] The latter performs a deconvolution of a Lorentz line, whose FWHM is chosen here as 0.22 mm/s (the natural linewidth of 57 Fe is 0.194 mm/s), from the experimental spectrum with the help of a constrained Hesse-Rübartsch method. This model independent method smoothes thinned spectra in a controlled way to bypass the ill-posed nature of the inverse problem which consists in deriving an underlying distribution from an experimental spectrum. [START_REF] Le Caër | Evaluation of Hyperfine Parameter Distributions from Overlapped Mossbauer Spectra of Amorphous Alloys[END_REF] The deconvolution procedure is indeed much the same as using the constrained Hesse-Rübatsch method for determining an isomer shift distribution. [START_REF] Le Caër | General Models for the Distributions of Electric Field Gradients in Disordered Solids[END_REF] The latter method involves a smoothing parameter that must be chosen small enough to avoid distorting excessively the thinned spectrum, and large enough to rub out at best oscillations above a flat zero background which are driven by counting statistics. Peaks in thinned spectra are thus considered as significant only if their amplitudes are clearly larger than low amplitude fluctuations above the zero background (~ 0.1 in Fig. 8). The thinning method yields in fine "spectra" whose resolutions are improved and, importantly, whose areas are normalized to 1 so that they are directly comparable (Fig. 8). The previous method was used by Hightower et al. [START_REF] Hightower | Sup 119]Sn Mössbauer Spectrometry Study of Li-SnO Anode Materials for Li-Ion Cells[END_REF] to study Li-SnO anode materials for Li-ion cells ( 119 Sn Mössbauer isotope). A final remark is that thinned spectra may be fitted in turn with Gaussian or Voigt lines to provide starting values for classical least-squares fitting methods of as-recorded spectra. The previous characteristics are fully consistent with the conclusions, based on X-ray diffraction patterns, according to which germanite and renierite structures are formed for x ≤ 0.4 and 1.2 ≤ x ≤ 2.0, respectively, while the x = 0.8 sample belongs to a two-phase domain.

Least-squares fits of RT Mössbauer spectra

As suggested by the thinned spectra of Fig. 8, as-recorded spectra may be least-squares fitted with either two doublets, two doublets and a singlet or three doublets accordingly to Zn content.

As far as possible, FWHM's are free to vary from doublet to doublet but peaks of a given doublet are constrained to have identical amplitudes and FWHM's. However, the narrowness of the central component leads sometimes to unreliable results with FWHM's less than the natural linewidth as peaks overlap strongly. In that case, all fitted peaks are constrained to have the same FWHM's.

Cases of x = 0 and x = 0.4 samples

Mössbauer sites, more particularly for x = 0 and x = 0.4, are crowded into a restricted velocity range. This makes it difficult to determine their number. Accordingly, we fitted these spectra with two doublets, two doublets and a singlet, and three doublets with FWHM's either free to vary or constrained to be all equal. The solid lines of Fig. 6 for x = 0 and x = 0.4 samples are obtained when fitting with two doublets and a singlet, all with the same FWHM. The fittings that we performed in the various conditions described above show that IS and QS of the two main doublets are robust parameters whose respective average values are similar for x = 0 and x = 0.4 samples (Table 1). The results shown in Table 1 are quite similar to those recently published. [START_REF] Kumar | Designing a Thermoelectric Copper-Rich Sulfide from a Natural Mineral: Synthetic Germanite Cu 22 Fe 8 Ge 4 S 32[END_REF] There are no differences between fits performed with the previous doublets adding either a singlet or a doublet because the latter has an almost zero QS (~ 0.03(3) mm/s). All FWHM's (i.e. ) are constrained to be the same in the final fits (Fig. 6). Singlets have FWHM's of 0.32(1) mm/s and 0.36(1) mm/s while IS's are equal to 0.30(3) mm/s and 0.27(7) mm/s for x = 0 and x = 0.4 samples, respectively.

A c c e p t e d M a n u s c r i p t

The most sensitive parameters to the fitting assumptions are the area fractions. a) Fits with two doublets:

If all FWHM's are the same, the area fractions p 1 and p 2 of doublets N°1 and N°2 are p 1 = 0.54(3), p 2 = 0.46(3) for x = 0, and p 1 = 0.52(4), p 2 = 0.48(4) for x = 0.4. If the latter constraint is removed, the area fractions become p 1 = 0.81, p 2 = 0.19 for x = 0, and p 1 = 0.73, p 2 = 0.27 for x = 0.4. However, in the second case the FWHM's are very different for sites 1 and 2, being 0.34 mm/s and 0.24 mm/s, respectively, for x = 0, and 0.38 mm/s and 0.29 mm/s for x = 0.4.

The value of 0.24 mm/s is approximately equal to the smallest possible FWHM that we measure generally. We are thus led to select the first set of results described above with doublets of identical FWHM's and of nearly equal fractions p 1 ≈ p 2 .

b) fits with two doublets and a singlet: When a singlet (N° 3) is included in fits, the area fractions become: p 1 = 0.64(3), p 2 = 0.28(3), p 3 = 0.08(3) for x = 0, and p 1 = 0.64(4), p 2 = 0.24(4), p 3 = 0.12(4) for x = 0.4.

To conclude, the existence of two Fe 3+ Mössbauer sites in germanite phases (i.e. x = 0 and x = 0.4 samples) is unambiguously proven and their hyperfine parameters are obtained. The presence of a third minor Fe 3+ Mössbauer site in a symmetrical environment (QS ≈ 0) is less firmly established from Mössbauer data only. However, this is in fair agreement with single crystal X-ray results obtained recently on synthetic germanite highlighting that the high symmetry 2a site is fully occupied by Fe (unpublished data).

Cases of the x = 1.2 and x = 2.0 samples

The central parts of the spectra of the second family, that are broader than those of the first family (Fig. 8), cannot be accounted for with only two doublets. Consequently, final leastsquares fits have been carried out with three doublets (Fig. 6). The fitting parameters do not differ significantly when FWHM's are constrained to be all equal or are let free to vary separately. The hyperfine parameters gathered in Table 2 are typical of Fe 3+ ions and are similar for both Zn contents. It should be noted that (i) the hyperfine parameters of sites 1 and 2 are comparable to those of sites 1 and 2 of the first family (x = 0 and 0.4, Table 1), suggesting some similarities in term of chemical environments, and (ii) the quadrupole splitting of site 3 is the largest one found in the present study, suggesting that the related Fe 3+ ions are in strongly distorted chemical environment. These pieces of information on the local environment of Fe atoms in this sulfide are in favor of the complex renierite crystal structure instead of the "simple" briartite one, as supposed from PXRD analyses for the x = 1.2 and x = 2.0 samples. This is confirmed by the huge difference of hyperfine parameters determined from 57 Fe Mössbauer spectroscopy between synthetic briartite Cu 2 FeGeS 4 40 and our samples. First, iron atoms are in a +II oxidation state in briartite [START_REF] Imbert | Etude Par Effet Mössbauer de La Briartite (Cu 2 FeGeS 4 )[END_REF] and in +III oxidation state in our samples (as expected in renierite).

Secondly, the quadrupole splitting associated to the doublet in briartite is ~2.56(2) mm/s at RT, [START_REF] Imbert | Etude Par Effet Mössbauer de La Briartite (Cu 2 FeGeS 4 )[END_REF] while those associated to the different iron sites in our samples are much smaller (i.e.

~0.4 mm/s and ~0.9 mm/s, Table 2). Hence, 57 Fe Mössbauer spectroscopy results indicate unambiguously that the crystal structure of our Zn-rich samples (x ≥ 1.2) is different from that of briartite. Consequently, these results in association with those obtained from powder X-ray diffraction are in favor of a disordered renierite crystal structure for x = 1.2 and x = 2.0 samples.

Case of the x = 0.8 sample

As discussed previously, the Mössbauer spectrum recorded for the x = 0.8 sample is intermediate between those of the two families discussed above. From PXRD patterns, the studied sample consists of a two-phase mixture. Thus, its spectrum (Fig. 6 and Fig. 8) is expected to consist of at least five doublets that overlap strongly. The a priori values of the hyperfine parameters of all these contributions, which change slightly with x, are not known with enough precision to attempt to fit reliably the observed spectrum so as to get trustworthy hyperfine parameters. This is the reason why this spectrum is not discussed further.

In summary:

 All the samples contain a phase magnetically ordered at room temperature.

 57 Fe Mössbauer spectra reflect the structural changes evidenced by PXRD patterns that occur in Cu 22-x Zn x Fe 8 Ge 4 S 32 series when x increases between 0 and 2.0 with a first pair of spectra (x = 0 and 0.4), an intermediate spectrum (x = 0.8), and a second pair of spectra (x = 1.2 and 2.0).

 The central parts of the spectra (other than those of the magnetic contribution) consist unambiguously of at least two sites. In agreement with structural arguments from single crystal X-ray diffraction, the spectra include a third site. The hyperfine parameters are obtained for samples of the two pairs. The narrow velocity ranges which contain the central parts prevent to fit reliably the spectrum with x = 0.8 as this sample is a mixture of two different phases.

 All the measured hyperfine parameters are consistent with iron being in the form of Fe 3+ .

 Hyperfine parameters determined for Zn-rich samples (x ≥ 1.2) indicate unambiguously that the crystal structure of the Zn-rich compounds is different from that of briartite.

Thermoelectric properties

The temperature dependences of the electrical resistivity, , and Seebeck coefficient, S, in the Cu compound could be filled by substituting Cu by a divalent transition element (Zn), as also reported in tetrahedrite and colusite, [START_REF] Suekuni | High-Performance Thermoelectric Mineral Cu 12-x Ni x Sb 4 S 13 Tetrahedrite[END_REF][START_REF] Suekuni | Tunable Electronic Properties and Low Thermal Conductivity in Synthetic Colusites Cu 26-x Zn x V 2 M 6 S 32 (x ≤ 4, M = Ge, Sn)[END_REF] leading to a semiconducting behavior. In other words, since Zn, Fe and Ge ions are strictly in the Zn 2+ , Fe 3+ and Ge 4+ states, the increase of S and ρ with x is consistent with a decrease in Cu 2+ content, i.e., of hole concentration. On the other hand, the introduction of additional Zn 2+ cations on the copper sites likely decreases the mobility of carriers due to the creation of point defects, which perturbates the percolation paths in the tridimensional "Cu-S" conductive network. Unfortunately, the variation of the carrier concentration with x was not verified as it was impossible to extract reliable carrier concentration values from Hall effect measurements due to an anomalous signal. Finally, the A c c e p t e d M a n u s c r i p t significant increase of the electrical resistivity with x induces a decrease of the power factor from 0.29 mW m -1 K -2 for x = 0 to 0.11 mW m -1 K -2 for x = 2.0, at 700 K (Fig. 9e).

The temperature dependence of the thermal conductivity in the Cu 22-x Zn x Fe 8 Ge 4 S 32 series (Fig. 9c) exhibits a systematic decrease of the thermal conductivity with increasing Zn content. This reflects the combined effects of a reduced electronic component of the thermal conductivity and a decreasing lattice contribution. By simply subtracting the electronic part from the total thermal conductivity, it can be observed that a higher Zn content (especially above x = 0.8) causes marked reductions in the lattice thermal conductivities of these compounds over the full temperature range (Fig. 9d). In fact, two distinct sets of values can be observed depending of the Zn content. For 0  x  0.4, the lattice thermal conductivity values are in the ranges of 1.60-1.65 W m -1 K -1 at 300 K and 0.90-0.95 W m -1 K -1 at 700 K, while for 1.2  x  2.0, the lattice thermal conductivity drops down to 1.13-1.25 W m -1 K -1 at 300 K and 0.70 W m -1 K -1 at 700 K. Interestingly, the x = 0.8 sample, composed of both renierite and germanite, exhibits intermediate values around 1.45 W m -1 K -1 at 300 K and 0.80 W m -1 K -1 at 700 K. This trend suggests that the additional number of crystallographic sites and the higher cationic disorder in the renierite-type compounds (1.2  x  2.0), induced by the tetragonal distortion, provides an effective way of scattering heat carrying phonons. Unfortunately, the crystal structure of our synthetic renierite-type compounds being quite complex (as discussed in the structure analysis section), it was not possible to perform phonon calculations and to address the role of specific crystal structure features on phonon scattering. Finally, it must be pointed out that the κ L values of the Zn-rich compounds (1.2  x  2.0) are in the same range as those of other copper-based sulfide minerals such as pristine Cu 8 Fe 3 Sn 2 S 12 stannoidite, [START_REF] Kumar | Copper Hyper-Stoichiometry: The Key for the Optimization of Thermoelectric Properties in Stannoidite Cu 8+x Fe 3-x Sn 2 S 12[END_REF] and ordered colusites. [START_REF] Bourgès | High-Performance Thermoelectric Bulk Colusite by Process Controlled Structural Disordering[END_REF][START_REF] Kumar | High Power Factors of Thermoelectric Colusites Cu 26 T 2 Ge 6 S 32[END_REF] From the above parameters, the figure of merit, ZT, was calculated for all the samples and displayed in Fig. 9f. Overall, the ZT increases with temperature for all compositions. Due to the

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A c c e

  p t e d M a n u s c r i p t geometrical density, the thermal diffusivity, and the theoretical heat capacity using the Dulong-Petit approximation. The lattice contribution to the thermal conductivity (κ L ) was determined by subtracting the estimated electronic component (κ e ) from the measured total thermal conductivity, κ. The electronic contribution, κ e , was derived from the Wiedemann-Franz law,

Figure 1 .

 1 Figure 1. Crystal structure representations highlighting the semi-ordered cation distribution of

Figure 2 .

 2 Figure 2. PXRD patterns in the Cu 22-x Zn x Fe 8 Ge 4 S 32 (0 ≤ x ≤ 2) series.

  𝑃42𝑐

Figure 3 .

 3 Figure 3. Evolution of a) (622) and b) (222) reflections with Zn content in the

Figure 4 .

 4 Figure 4. Reciprocal space sections reconstructed from PEDT data for samples Cu 22-

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 36 Paragon Plus Environment ACS Applied Energy Materials A c c e p t e d M a n u s c r i p t of an ordering with respect to the sphalerite with, at least, one cell parameter of about 10.6 Å.

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 36 Paragon Plus Environment ACS Applied Energy Materials A c c e p t e d M a n u s c r i p tgermanite is intermediate between the a and c parameters of the tetragonal renierite. Moreover, a linear variation of the a parameter of renierite with Zn content is observed, and the same trend is evidenced for germanite. Hence, by considering those linear tendencies and the refined unit cell parameters a for germanite and renierite phases in the x = 0.8 sample, it is possible to estimate the "real" Zn content which delimits the germanite and renierite domains to be 0 ≤ x ≤ 0.6 and 1.0 ≤ x ≤ 2.0, respectively.

Figure 5 .

 5 Figure 5. Evolution of the refined unit cell parameters of germanite/renierite phases versus Zn

  A c c e p t e d M a n u s c r i p t spectrum with x = 0 while the spectra (x = 1.2, 2.0) have central parts that are also asymmetrical but broader than the one with x = 0. Intermediate spectra (x = 0.4, 0.8) are less asymmetrical with somewhat flattened central parts.

Figure 6 .

 6 Figure 6. Room-temperature 57 Fe Mössbauer spectra of Cu 22-x Zn x Fe 8 Ge 4 S 32 for x = 0, 0.4, 0.8,

  A c c e p t e d M a n u s c r i p t

Figure 7 .

 7 Figure 7. Room-temperature 57 Fe Mössbauer spectrum of Cu 20 Zn 2 Fe 8 Ge 4 S 32 in a velocity

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 36 Paragon Plus Environment ACS Applied Energy Materials A c c e p t e d M a n u s c r i p t requires a perfect knowledge of both crystal and magnetic structure of germanite/renierite systems. Such determinations are in progress.

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 36 Paragon Plus Environment ACS Applied Energy Materials A c c e p t e d M a n u s c r i p t

Figure 8 .

 8 Figure 8. Thinned RT 57 Fe Mössbauer spectra of Cu 22-x Zn x Fe 8 Ge 4 S 32 obtained from as-

Fig. 8

 8 Fig.8highlights a first pair (x = 0, x = 0.4), whose peaks are narrower than those of other

  A c c e p t e d M a n u s c r i p t

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 36

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 36

A c c e

  p t e d M a n u s c r i p t counter-balanced effects of the decrease of both the power factor and the thermal conductivity, the ZT remains constant for Zn content below x  1.6 and decreases significantly for x = 2.0 due to the large increase of the electrical resistivity.

Figure 9 .

 9 Figure 9. Temperature dependences of a) electrical resistivity (), b) Seebeck coefficient (S),

Table 1 .

 1 Average isomer shifts (IS) and quadrupole splittings (QS) of the two main doublets for x = 0 and x = 0.4 samples found from all fits

	Doublet N°IS (mm/s)	QS (mm/s)	 (mm/s)
	1	x = 0 x = 0.4	0.28±0.02 0.29±0.02	0.37±0.03 0.37 5 ±0.03	0.32±0.02 0.37±0.02
	2	x = 0 x = 0.4	0.40±0.03 0.44±0.04	0.31±0.02 0.31±0.04	0.30±0.04 0.34±0.04

Table 2 .

 2 Isomer shifts (IS) and quadrupole splittings (QS) of the three doublets used to fit

		Mössbauer spectra for x = 1.2 and x = 2.0 samples
	Doublet N°IS (mm/s) QS (mm/s)  (mm/s) Area fraction p
	1	x = 1.2 x = 2.0	0.25±0.03 0.24±0.02	0.41±0.06 0.44±0.04	0.33±0.04 0.32±0.02	0.45±0.12 0.49±0.05
	2	x = 1.2 x = 2.0	0.39±0.03 0.41±0.02	0.33±0.03 0.37±0.02	0.33±0.03 0.31±0.02	0.39±0.08 0.43±0.05
	3	x = 1.2 x = 2.0	0.29±0.10 0.31±0.07	0.83±0.10 0.93±0.07	0.39±0.10 0.31±0.05	0.16±0.12 0.08±0.05

  22-x Zn x Fe 8 Ge 4 S 32 series are displayed in Fig.9a and 9brespectively. Regardless of the Zn content, a positive value for the Seebeck coefficient is measured, confirming holes as dominant charge carriers. For x = 0, the electrical resistivity, which decreases slightly as the temperature increases, shows that this material exhibits a semiconducting behavior, though approaching the transition towards a metallic state. The Seebeck coefficient varies slightly with temperature and in opposite trend relative to the electrical resistivity. This behavior is explained by the fact that the conduction regime is intermediate between metallic and semiconducting. When the Zn content increases, the magnitude of the electrical resistivity increases drastically at 300 K from 9.3 mΩ cm for x = 0 to 2.5710 3 mΩ cm for x = 2.0. The Seebeck coefficient also increases with the Zn content from +122 µV K -1 for x = 0 to +262 µV K -1 for x = 2.0 at 300 K. The temperature dependences of  and S for x = 2.0 tend toward a semiconducting behavior, as observed from the sharper decrease of  (plotted in log scale) with the increase of temperature. This behavior is consistent with a decrease of the carrier concentration. Indeed, from a formal charge point of view, stoichiometric Cu 22 Fe 8 Ge 4 S 32 is assumed to be (Cu + ) 20 (Cu 2+ ) 2 (Fe 3+ ) 8 (Ge 4+ ) 4 (S 2-)32 . By analogy to Cu 12 Sb 4 S 13 tetrahedrite, there are two unoccupied states in the valence band above E F . Therefore, the unoccupied states in such a

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Acknowledgements

The authors would like to thank Christelle Bilot and Jerôme Lecourt for technical support and the financial support of the French Agence Nationale de la Recherche (ANR), through the program Energy Challenge for Secure, Clean and Efficient Energy (Challenge 2, 2015, ANR-15-CE05-0027).

Funding Sources

French Agence Nationale de la Recherche (ANR), through the program Energy Challenge for Secure, Clean and Efficient Energy (Challenge 2, 2015, ANR-15-CE05-0027).

Author Information

Corresponding Authors E-mail: emmanuel.guilmeau@ensicaen.fr, phone: +33 231 451 367. Email : pierric.lemoine@univ-rennes1.fr, phone : +33 223 233 306.


Gabriel Eustache

Laurent Riffaud
email: laurent.riffaud@chu-rennes.fr

Pr L Riffaud

Reducing blood loss in pediatric craniosynostosis surgery by use of tranexamic acid

Keywords: Craniosynostosis, blood loss, blood transfusion, tranexamic acid

Introduction. Craniosysnostosis surgical corrections are routine procedures in the pediatric neurosurgical field. However, these procedures result in significant blood loss. Tranexamic acid (TXA) is an antifibrinolytic drug which has demonstrated a significant reduction in perioperative blood loss in many pediatric surgical procedures such as cardiac surgery and scoliosis surgery. We conducted a systematic review to evaluate protocols of TXA use in pediatric craniosynostosis procedures and its effect on intra-operative blood loss and transfusions.

Material and methods. A comprehensive literature review of the National Library of Medicine (PubMed) database was performed to identify relevant studies. We included any clinical study reporting on blood loss or blood transfusion for pediatric craniosynostosis surgery with intraoperative use of tranexamic acid, with the following limits: publication date from inception to May 2019; reports in English.

Results. Thirteen studies were eligible for our review. Of the 13 studies, 4 were prospective, randomized, double-blind controlled trials, 9 were retrospective studies, tailored as a "beforeafter" studies, comparing blood loss and transfusion without/with TXA. TXA significantly decreases the number and volume of packed red blood cell transfusions and the rate of transfusion in children undergoing craniosynostosis surgery. Significantly fewer fresh frozen plasma transfusions were required in the TXA groups in 2 randomized studies. Length of stay in hospital was significantly lower with the use of TXA in three studies. Advantages of TXA administration also include an excellent patient tolerance of side effects, ease of administration and low cost.

Conclusion. TXA significantly reduces blood loss and the need for transfusions in children undergoing craniosynostosis surgery. TXA administration should be a routine part of strategy to reduce blood loss and limit transfusions in these procedures.

J o u r n a l P r e -p r o o f

Introduction

Craniosysnostosis surgical corrections are routine procedures in the pediatric neurosurgical field.

However, these procedures result in significant blood loss, especially in patients younger than 18 months, weighing < 10 kg, in patients with craniofacial syndromes and those with multiple suture involvement [START_REF] Meyer | Anesthesiaresuscitation in the treatment of craniosynostosis[END_REF][START_REF] Van Uitert | Factors influencing blood loss and allogeneic blood transfusion practice in craniosynostosis surgery[END_REF]. Intraoperative total blood volume lost can be greater than 100% of the estimated preoperative volume [START_REF] White | Predictors of blood loss in fronto-orbital advancement and remodeling[END_REF] and should be considered as the major complication of these procedures, especially in syndromic craniosynostoses. Efforts to reduce perioperative blood loss have focused on endoscopic surgery, preparation with erythropoietin, autologous predonation, use of cell salvage, acute normovolemic hemodilution, and more recently intraoperative use of antifibrinolytics [START_REF] Velardi | Blood salvage in craniosynostosis surgery[END_REF]6]. Unlike other alternatives, antifibrinolytics are able to prevent further bleeding by stabilizing microclots formed at a surgical wound.

Tranexamic acid (TXA) is an antifibrinolytic drug which has demonstrated a significant reduction in perioperative blood loss in many pediatric surgical procedures such as cardiac surgery and scoliosis surgery [7 ,8]. Interest in using TXA in craniosynostosis surgery has appeared since publication of randomized-controlled studies in 2011 [START_REF] Dadure | Intraoperative tranexamic acid reduces blood transfusion in children undergoing craniosynostosis surgery: a randomized double-blind study[END_REF][START_REF] Goobie | Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial[END_REF][START_REF] Vergnaud | Reducing blood losses and transfusion requirements in craniosynostosis surgery: an endless quest?[END_REF]. Despite accumulation of evidence regarding its effectiveness, TXA was not unanimously employed in pediatric neurosurgery teams: Goobie et al [START_REF] Goobie | Safety of antifibrinolytics in cranial vault reconstructive surgery: a report from the pediatric craniofacial collaborative group[END_REF] reported a total of 1638 cases of cranial vault reconstruction from 2010 to 2015 in 31 institutions but antifibrinolytic administration occurred in only 59.5%. Similary, the Synostosis Research Group reported that TXA was routinely used in 3 sites but never in 2 others [START_REF] Kestle | Variation in the management of isolated craniosynostosis: a survey of the Synostosis Research Group[END_REF].

By conducting this systematic review, we aimed to evaluate protocols of TXA use in pediatric craniosynostosis procedures and its effect on intra-operative blood loss and transfusions.

Materials and Methods

A comprehensive literature review of the National Library of Medicine (PubMed) database was performed to identify relevant studies. We used the following keywords: "craniosynostosis" and "tranexamic acid". We included any clinical study reporting on blood loss or blood transfusion for pediatric craniosynostosis surgery with intraoperative use of J o u r n a l P r e -p r o o f tranexamic acid, with the following limits: publication date from inception to May 2019; reports in English. The references from the reports included were also manually searched to find further references and reported studies not identified using our initial search strategy. We did not included studies with other anti-fibrinolytics such as aprotinin, and aminocaproic acid.

Ethics committee approval was not required for our research protocol.

Results

Selection of reports and study design

Thirteen studies were eligible for our review. Of the 13 studies, 4 were prospective, randomized, double-blind controlled trials [START_REF] Dadure | Intraoperative tranexamic acid reduces blood transfusion in children undergoing craniosynostosis surgery: a randomized double-blind study[END_REF][START_REF] Goobie | Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial[END_REF][START_REF] Kim | Effects of tranexamic acid based on its population pharmacokinetics in pediatric patients undergoing distraction osteogenesis for craniosynostosis: rotational thromboelastometry (ROTEM TM ) analysis[END_REF][START_REF] Fenger-Eriksen | Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial[END_REF], 9 were retrospective studies, tailored as a "before-after" studies, comparing blood loss and transfusion without/with TXA [START_REF] Maugans | Comparative analysis of tranexamic acid use in minimally invasive versus open craniosynostosis procedures[END_REF][START_REF] Martin | Use of tranexamic acid in craniosynostosis surgery[END_REF][START_REF] Engel | The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis[END_REF][START_REF] Crantford | Evaluating the safety and efficacy of tranexamic acid administration in pediatric cranial vault reconstruction[END_REF][START_REF] Hansen | Reducing postoperative bleeding after craniosynostosis repair utilizing a low-dose tranexamic acid infusion protocol[END_REF][START_REF] Kurnik | Tranexamic acid reduces blood loss in craniosynostosis surgery[END_REF][START_REF] Kurnik | Craniosynostosis surgery and the impact of tranexamic acid dosing[END_REF][START_REF] Martin | Implementation of a tranexamic acid protocol to reduce blood loss during cranial vault remodeling for craniosynostosis[END_REF][START_REF] Escher | Minimizing transfusion in sagittal craniosynostosis surgery: the children's hospital of Minnesota protocol[END_REF]. Study characteristics are presented in Table 1 and2. A total of 729 patients were included: 160 in the randomized studies and 569 in the observational studies.

Analysis of protocols

Protocols of TXA administration varied from one study to another. A loading dose was commonly used, with doses ranging from 10 mg/kg [START_REF] Kim | Effects of tranexamic acid based on its population pharmacokinetics in pediatric patients undergoing distraction osteogenesis for craniosynostosis: rotational thromboelastometry (ROTEM TM ) analysis[END_REF][START_REF] Fenger-Eriksen | Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial[END_REF][START_REF] Engel | The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis[END_REF][START_REF] Hansen | Reducing postoperative bleeding after craniosynostosis repair utilizing a low-dose tranexamic acid infusion protocol[END_REF][START_REF] Kurnik | Tranexamic acid reduces blood loss in craniosynostosis surgery[END_REF][START_REF] Kurnik | Craniosynostosis surgery and the impact of tranexamic acid dosing[END_REF] to 100 mg/kg [START_REF] Maugans | Comparative analysis of tranexamic acid use in minimally invasive versus open craniosynostosis procedures[END_REF], usually infused over 15 minutes after induction of general anesthesia and before skin incision. A continuous infusion until skin closure was performed in all studies, with different protocols: 5 mg/kg/h [START_REF] Goobie | Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial[END_REF][START_REF] Kim | Effects of tranexamic acid based on its population pharmacokinetics in pediatric patients undergoing distraction osteogenesis for craniosynostosis: rotational thromboelastometry (ROTEM TM ) analysis[END_REF][START_REF] Engel | The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis[END_REF][START_REF] Hansen | Reducing postoperative bleeding after craniosynostosis repair utilizing a low-dose tranexamic acid infusion protocol[END_REF][START_REF] Kurnik | Tranexamic acid reduces blood loss in craniosynostosis surgery[END_REF][START_REF] Kurnik | Craniosynostosis surgery and the impact of tranexamic acid dosing[END_REF][START_REF] Martin | Implementation of a tranexamic acid protocol to reduce blood loss during cranial vault remodeling for craniosynostosis[END_REF] or 10 mg/kg/h [START_REF] Dadure | Intraoperative tranexamic acid reduces blood transfusion in children undergoing craniosynostosis surgery: a randomized double-blind study[END_REF][START_REF] Maugans | Comparative analysis of tranexamic acid use in minimally invasive versus open craniosynostosis procedures[END_REF][START_REF] Martin | Use of tranexamic acid in craniosynostosis surgery[END_REF][START_REF] Crantford | Evaluating the safety and efficacy of tranexamic acid administration in pediatric cranial vault reconstruction[END_REF][START_REF] Escher | Minimizing transfusion in sagittal craniosynostosis surgery: the children's hospital of Minnesota protocol[END_REF].

In their study, Goobie et al [START_REF] Goobie | Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial[END_REF] reported that a 50 mg/kg bolus dose followed by an infusion of 5 mg/kg/h could maintain TXA plasma concentrations above the in vitro thresholds reported for inhibition of fibrinolysis (10 µg/mL) and plasminogen-induced platelet activation (16 µg/mL). But in a further study, the same author reported that a loading dose of 10 mg/kg over 15 min followed by a 5 mg/kg/h maintenance infusion was sufficient to produce a steady-state TXA plasma concentrations above the 16 µg/mL threshold [START_REF] Goobie | Population pharmacokinetics of tranexamic acid in paediatric patients undergoing craniosynostosis surgery[END_REF].

No TXA was used postoperatively except in two recent studies [START_REF] Fenger-Eriksen | Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial[END_REF][START_REF] Kurnik | Craniosynostosis surgery and the impact of tranexamic acid dosing[END_REF]. Kurnik et al. [START_REF] Kurnik | Craniosynostosis surgery and the impact of tranexamic acid dosing[END_REF] compared a continous infusion during the 24 hours after the end of surgery to an infusion J o u r n a l P r e -p r o o f stopped 4 hours postoperatively. Blood loss volume showed no difference between the 2 groups, neither did length of stay in the pediatric intensive care unit. Fenger-Eriksen et al. [START_REF] Fenger-Eriksen | Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial[END_REF] used a protocol with a bolus dose of 10 ml/kg before incision followed by 8 hours' continuous infusion of 3 mL/kg/h.

Keys results of each study

Population and procedures

Studies compared efficacy of TXA for both syndromic and non syndromic craniosynostoses. Unfortunately, these 2 groups were grouped together in most of the studies [10, 14-16, 19, 20], and small numbers of complex craniosynostoses did not allow particular conclusions on syndromic craniosynostoses, supposed to be more hemorrhagic when compared to non syndromic. Furthermore, we observed the same confusion for monosutural and multisutural craniosynostoses.

Martin et al. [START_REF] Martin | Use of tranexamic acid in craniosynostosis surgery[END_REF] compared only sagittal craniosynostosis operated using a similar technique whatever the age of the child in order to maximize the uniformity of the patients included. In this study, as expected, the use of TXA was significantly associated with a lower total volume of packed red blood cell (PRBC) transfused. No significant correlation between duration of surgery or length of hospitalization was observed between the 2 groups with/without TXA.

Martin et al. [START_REF] Martin | Implementation of a tranexamic acid protocol to reduce blood loss during cranial vault remodeling for craniosynostosis[END_REF] collected a large cohort of patients less than 15 months of age operated on for single suture nonsyndromic craniosynostosis by the same interdisciplinary surgical team (a craniofacial surgeon and a pediatric neurosurgeon). They used the same TXA protocols as Goobie et al. [START_REF] Goobie | Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial[END_REF], and TXA-use was associated with a significant reduction in estimated intraoperative blood loss, cell saver volume transfused, red cell transfusion volume and length of stay in hospital.

Engel et al. [START_REF] Engel | The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis[END_REF] studied the value of TXA during fronto-orbital advancement in isolated metopic craniosynostosis only, with the same resulting benefit in reduction of blood loss and J o u r n a l P r e -p r o o f transfusion with TXA. Interestingly, the mean duration of the postoperative hospital stay was significantly lower in the TXA group.

Only one report studied the effect of TXA in craniosynostosis treated with minimally invasive techniques versus open procedures [START_REF] Maugans | Comparative analysis of tranexamic acid use in minimally invasive versus open craniosynostosis procedures[END_REF]. In this study, the sole parameter influenced by the use of TXA was the median weight-adjusted estimated blood loss in the mini-invasive procedure group. The other parameters such as weight-adjusted calculated blood loss, PRBC transfusion did not attain any statistical difference; moreover there was no difference whatever the parameters studied in the open procedure group. These results suggest an important bias in the estimation of data.

Blood loss and blood transfusion

Various parameters were studied in these reports including age, gender, weight, primary or redo surgery, ASA status, urine output, pre-and postoperative hematocrit/hemoglobin/platelet count/fibrinogen concentration, fluid therapy, but the most remarkable were PRBC transfusion volume and estimated/calculated blood loss. Because visual estimation of blood loss is known to be inaccurate in these procedures, blood loss volume was either estimated (EBVlost = Estimated red cell volume lost x hematocrit preop/100) and adjusted per kilogram of patient body weight, or calculated (CBL = RCM preop + RCM transfused -RCM postop) / average hematocrit; RCM indicates red cell mass = 0,7 x volume transfused) [START_REF] Goobie | Safety of antifibrinolytics in cranial vault reconstructive surgery: a report from the pediatric craniofacial collaborative group[END_REF][START_REF] Kurnik | Tranexamic acid reduces blood loss in craniosynostosis surgery[END_REF][START_REF] Martin | Implementation of a tranexamic acid protocol to reduce blood loss during cranial vault remodeling for craniosynostosis[END_REF][START_REF] Fergusson | A comparison of aprotinin and lysine analogues in high-risk cardiac surgery[END_REF].

In 10 of the 13 studies, results were obviously the same: the use of TXA significantly reduces the volume of PRBC transfusion when compared to the placebo group [START_REF] Dadure | Intraoperative tranexamic acid reduces blood transfusion in children undergoing craniosynostosis surgery: a randomized double-blind study[END_REF][START_REF] Goobie | Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial[END_REF][START_REF] Kim | Effects of tranexamic acid based on its population pharmacokinetics in pediatric patients undergoing distraction osteogenesis for craniosynostosis: rotational thromboelastometry (ROTEM TM ) analysis[END_REF][START_REF] Fenger-Eriksen | Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial[END_REF] or to a group without TXA [17-19, 21, 23, 24]. In 2 studies [START_REF] Maugans | Comparative analysis of tranexamic acid use in minimally invasive versus open craniosynostosis procedures[END_REF][START_REF] Hansen | Reducing postoperative bleeding after craniosynostosis repair utilizing a low-dose tranexamic acid infusion protocol[END_REF], the volume of PRBC transfused was similar between the TXA+ / TXA-groups of patients undergoing open procedures. However, in Hansen et al's report [START_REF] Hansen | Reducing postoperative bleeding after craniosynostosis repair utilizing a low-dose tranexamic acid infusion protocol[END_REF], the TXA protocol used low-dose TXA infusion: standard loading dose of 10 mg/kg over 15 minutes followed by a 5 mg/kg/h infusion until skin closure. This result underlines the need for an optimal dose regimen for TXA to find the most effective J o u r n a l P r e -p r o o f hemostatic effect. Although blood loss is considered to be more difficult to evaluate, results showed similar conclusions in favour of the benefit of TXA. When considered, the mean calculated blood loss [START_REF] Goobie | Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial[END_REF][START_REF] Kim | Effects of tranexamic acid based on its population pharmacokinetics in pediatric patients undergoing distraction osteogenesis for craniosynostosis: rotational thromboelastometry (ROTEM TM ) analysis[END_REF][START_REF] Fenger-Eriksen | Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial[END_REF][START_REF] Engel | The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis[END_REF] or the estimated blood loss [19-21, 23, 24] were significantly lower in the TXA+ group, except for Dadure et al. [START_REF] Dadure | Intraoperative tranexamic acid reduces blood transfusion in children undergoing craniosynostosis surgery: a randomized double-blind study[END_REF].

The same positive results were observed for fresh frozen plasma transfusions in the 2 recent randomized studies: significantly fewer fresh frozen plasma transfusions were required in the TXA groups [START_REF] Kim | Effects of tranexamic acid based on its population pharmacokinetics in pediatric patients undergoing distraction osteogenesis for craniosynostosis: rotational thromboelastometry (ROTEM TM ) analysis[END_REF][START_REF] Fenger-Eriksen | Reduced perioperative blood loss in children undergoing craniosynostosis surgery using prolonged tranexamic acid infusion: a randomised trial[END_REF].

Length of stay in hospital

Length of stay in hospital was significantly lower with the use of TXA in three studies [START_REF] Engel | The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis[END_REF][START_REF] Martin | Implementation of a tranexamic acid protocol to reduce blood loss during cranial vault remodeling for craniosynostosis[END_REF][START_REF] Escher | Minimizing transfusion in sagittal craniosynostosis surgery: the children's hospital of Minnesota protocol[END_REF].

It was not different between groups TXA+ / TXA-in 5 [START_REF] Goobie | Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial[END_REF][START_REF] Kim | Effects of tranexamic acid based on its population pharmacokinetics in pediatric patients undergoing distraction osteogenesis for craniosynostosis: rotational thromboelastometry (ROTEM TM ) analysis[END_REF][START_REF] Martin | Use of tranexamic acid in craniosynostosis surgery[END_REF][START_REF] Crantford | Evaluating the safety and efficacy of tranexamic acid administration in pediatric cranial vault reconstruction[END_REF][START_REF] Kurnik | Tranexamic acid reduces blood loss in craniosynostosis surgery[END_REF].

Adverse events

No adverse effects directly related to TXA were reported in the 13 studies of the review.

Discussion

Our review focused on TXA. This drug was substituted for aprotinin whose marketing in France was stopped because of serious adverse events [START_REF] Meyer | Anesthesiaresuscitation in the treatment of craniosynostosis[END_REF][START_REF] Fergusson | A comparison of aprotinin and lysine analogues in high-risk cardiac surgery[END_REF]. Aminocaproic acid is another antifibrinolytic, 6-10 less potent than TXA and not distributed in France. In clinical practice they may have comparable efficacy [START_REF] Goobie | Safety of antifibrinolytics in cranial vault reconstructive surgery: a report from the pediatric craniofacial collaborative group[END_REF][START_REF] Siotou | The role of antifibrinolytics in reducing blood loss during craniofacial or orthognathic Surgical procedures: A meta-analysis[END_REF].

Unfortunately, meta-analyses which studied efficacy of antifibrinolytics in pediatric craniofacial surgery did not compare drugs one with another [START_REF] White | Systematic Review of Interventions for Minimizing Perioperative Blood Transfusion for Surgery for Craniosynostosis[END_REF][START_REF] Siotou | The role of antifibrinolytics in reducing blood loss during craniofacial or orthognathic Surgical procedures: A meta-analysis[END_REF][START_REF] Song | Tranexamic acid reducing blood transfusion in children undergoing craniosynostosis surgery[END_REF]. Most of the literature analyzing strategies used to reduce perioperative blood transfusion (preoperative autologous donation, preoperative erythropoietin, intraoperative cell salvage, acute normovolemic hemodilution, fibrin sealants or fibrin glue; and postoperative drain reinfusion) was nonrandomized and noncomparative. Studies with TXA were comparatively well-conducted: TXA is clinically effective in reducing allogeneic blood transfusion. Already published meta-analyses neglected other drugs such as aprotinin and aminocaproic acid [START_REF] Siotou | The role of antifibrinolytics in reducing blood loss during craniofacial or orthognathic Surgical procedures: A meta-analysis[END_REF].

J o u r n a l P r e -p r o o f

TXA is a synthetic derivative of lysine which exerts an antifibrinolytic effect. It blocks lysine binding sites in a reversible manner on plasminogen molecules, which inhibits the interaction of plasminogen and plasmin with lysine residues on the surface of fibrin. This action leads to an inability of plasmin to degrade fibrin. The half-life of TXA is approximately 1.5 to 2 hours [START_REF] Goobie | Population pharmacokinetics of tranexamic acid in paediatric patients undergoing craniosynostosis surgery[END_REF]: it therefore continues to stabilize the clot and prevent bleeding in the immediate postoperative period after the infusion is stopped. TXA is considered as a well-tolerated medication with rare side effects: orthostatic reactions, diarrhea and nausea are the most commonly reported. Some authors have demonstrated no increased risk of thrombogenicity associated with TXA even in cases of complicated pregnancy [START_REF] Lindoff | Treatment with tranexamic acid during pregnancy, and the risk of thrombo-embolic complications[END_REF]. Goobie et al. [START_REF] Goobie | Safety of antifibrinolytics in cranial vault reconstructive surgery: a report from the pediatric craniofacial collaborative group[END_REF] published a report from the pediatric craniofacial collaborative group on the safety of antifibrinolytic use in cranial vault reconstructive surgery: among the 591 patients who received TXA, only 2 cases (0,34 %) of postoperative seizure were described and only one case of femoral deep vein thrombosis in a patient with an indwelling femoral venous catheter. No significant difference was detected in the incidence of postoperative seizures between patients who received TXA and those who did not. Recently, Chung E et al. [START_REF] Chung | Ulnar artery thrombosis following tranexamic acid administration for craniosynostosis repair[END_REF] described a case of ulnar artery thrombosis following ulnar arterial line placement in a patient who received TXA for cranial vault reconstructive surgery. Use of TXA may significantly reduce cost of these surgical procedures by reducing length of hospital stay [START_REF] Engel | The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis[END_REF][START_REF] Martin | Implementation of a tranexamic acid protocol to reduce blood loss during cranial vault remodeling for craniosynostosis[END_REF][START_REF] Escher | Minimizing transfusion in sagittal craniosynostosis surgery: the children's hospital of Minnesota protocol[END_REF]. Furthermore, Dadure et al [START_REF] Dadure | Intraoperative tranexamic acid reduces blood transfusion in children undergoing craniosynostosis surgery: a randomized double-blind study[END_REF] reported a reduction in the median cost of perioperative treatment for blood loss in the TXA group greater than 200 US$.

Taking into account the results of this review, we can consider that TXA should be systematically proposed in pediatric craniosynostosis surgery in order to reduce blood loss and transfusion. A protocol with a loading dose of 10 mg/kg over 15 minutes after induction of general anesthesia followed by a 5-10 mg/kg/h infusion until skin closure could be safely used when considering the Goobie et al. [START_REF] Goobie | Population pharmacokinetics of tranexamic acid in paediatric patients undergoing craniosynostosis surgery[END_REF][START_REF] Goobie | Safety of antifibrinolytics in cranial vault reconstructive surgery: a report from the pediatric craniofacial collaborative group[END_REF] study. We have used this protocol in our institution since 2011 with significant results on reducing transfusion [unpublished data].

Finally, we would like to emphasize that the use of antifibrinolytics is part of the arsenal which permits safer craniosynostosis surgical procedures but it's not the only element. We must also consider other methods: iron supplementation, erythropoietin as well as miniinvasive surgical techniques such as endoscopy when feasible, and surgical/anaesthesiological expert teams.

Conclusion

Tranexamic acid significantly reduces blood loss and the need for transfusions in children undergoing craniosynostosis surgery. Advantages of TXA administration also include an excellent patient tolerance of side effects, ease of administration and low cost. TXA administration should be a routine part of strategy to reduce blood loss and limit transfusions in these procedures.

Acknowledgment:

The authors thank Mrs. Deirdre McKeown for her help with the English language.

This work did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors. This work did not receive any specific grant from funding agencies in the public, commercial, or notfor-profit sectors.

Disclosure of interest

The authors declare that they have no competing interest.


Martin Leblanc

Gilles Leturcq

Eléonore Welcomme

Xavier Deschanels

Thibaud Delahaye

A new chemical route of nuclear fuel (U,Pu)O 2±δ by advanced thermal denitration in the presence of organic additive

INTRODUCTION

Within the U and Pu recycling process from nuclear spent fuels, the conversion of purified U and Pu solution on to oxide powder is a key step at the interface between the separation / purification processes and (re) fabrication stages of uranium-plutonium oxide fuels or MOx ("Mixed Oxides"). In order to simplify the industrial process, conversion must be able to integrate the fluxes with the minimum of possible adjustments while leading to oxides or mixtures of oxides adapted to a direct shaping of fuels. In the framework of generation IV reactor deployment that includes a multi-recycling of Pu, new conversion routes have to be developed to suit the new needs: increase of the quantity of oxides to synthetize, reduction of dust generation, no redox adjustment of feed actinide solutions, simplified effluent management, no proliferation risk. Currently, the production of MOx is based essentially on the mixture of single actinide oxides, UO 2 and PuO 2 powders (MIMAS and COCA) [START_REF] Haas | Mixed-oxide fuel fabrication technology and experience at the Belgonucleaire and CFCa plants and further developments for the MELOX plant[END_REF]. In the future, to obtain a better homogeneity of Pu repartition in the MOX associated to Pu multi-recycling, the use of a mixed oxide has to be favored explaining the large number of studies conducted to define a co-conversion route leading to the production of mixed oxides containing both uranium and plutonium. Different routes including mixed oxalate U(IV) / Pu(III) precipitation [START_REF] Arab-Chapelet | Multiscale structural characterizations of mixed U (IV)-An (III) oxalates (An (III) = Pu or Am) combining XAS and XRD measurements[END_REF]; (NH 4 (U,Pu) CO 3 ) carbonate route also named ADPuC [3], and; the denitration of actinide salt, MDD (modified direct denitration) process [START_REF] Kitts | Pilot-scale demonstration of the modified direct denitration process to prepare uranium oxide for fuel fabrication evaluation[END_REF], … However, all these methods do not match all the future needs of the nuclear fuel cycle, already exposed above: oxalate coprecipitation requires a redox adjustment and brings filterability difficulties, ADPuC route produces effluents hardly manageable, as for internal or external gelation routes (ammonium nitrate solutions) and finally all the so far denitration routes need a NOx treatment and produce dust oxides either directly or due to the requirement of a milling step prior to fuel fabrication. Therefore, the development of a new synthesis route tackling all these issues appears essential for generation IV deployment.

In the literature, another synthesis route of mono or poly cationic oxides, referenced as NPG (nitrate polyacrylamide gel) [START_REF] Goupil | Selection and study of basic layered cobaltites as mixed ionic-electronic conductors for proton conducting fuel cells[END_REF], permits to obtain good cation stoichiometry accuracy but has never been applied to actinide oxide synthesis. In this process, a cationic solution is embedded inside a polymeric gel that is then dried to form a xerogel to be calcined to make the oxide form. This present work explores the so called "advanced thermal denitration in the presence of organic additives" conversion route, based on this method, to make mixed actinide oxides which so far had not been attempted before. It will also describe all the development to suit the requirements linked to the production of nuclear fuel precursors (no Sulphur, no chloride, safe reagents).

Description of this new synthesis route

The various steps that take place during this synthesis process are shown Figure 1: the actinides (uranium and plutonium) are mixed into a nitric solution using the same stoichiometry that the targeted ratio expected in the final oxide.

RESULTS

Thermal decomposition of uranium / plutonium xerogel was studied under reconstituted air (See Figure 2 for TG-DSC curves). Complete degradation of the polymeric network was observed at a temperature of 440°C. The presence of several intense exothermic peaks at about 280°C, 340°C and 380°C in the DTA curve (Figure 2) indicates that polymer decomposition occurs between 280°C and 440°C, the biggest exothermic reaction being at 380°C corresponding to 30wt% loss mass. Thermal decomposition generated a total mass loss of 91%, in agreement with the expected, theoretical value. Fig. 2. Flowsheet of "advanced thermal denitration in the presence of organic dditives" synthesis route (photos illustrate the case of the (U,Pu)O 2±δ synthesis).

At the end of xerogel conversion, after calcination at 800°C in reconstituted air, an intimate mixture of PuO 2 and U 3 O 8 oxides was recovered as the XRD analysis attested (Figure 3-a). Similarly, after the calcination in reconstituted air at 800°C during 2h. After calcination in Ar/H 2 (95%/5%) at 800°C for 2h single-phase oxide was obtained as observed by XRD analyses showing the presence of a single fluoritelike structure (Fm-3m) for the sample (Figure 3-b).

Fig. 3. XRD diagram for a) U 3 O 8 / PuO 2 converted for 2h at 800°C in reconstituted air and b) (U,Pu)O 2 converted for 2h in Ar-95%/H 2 -5%. Peak matches with white squares match the plutonium oxide phase, black stars match the uranium phase, black squares uranium-plutonium phase, white circles match the golden phase and white triangles match the support phase.

The obtained oxide powder was also characterized using a nucleated Zeiss SUPRA 55 / 55VP FEG-SEM (field emission scanning electron microscope). The SEM images (Figure 4) show a typical morphology of samples obtained using a thermal denitration synthesis route. The powder is composed of large agglomerates of several tens of

Conclusion

The main objective of this work was to explore the possibility to synthetize a mixed U, Pu oxide using the "advanced thermal denitration in the presence of organic additives" synthesis route, a derivate synthesis route from one commonly used in other fields to obtain poly-cationic oxides. Feasibility is demonstrated here by the successful synthesis of U 0.55 Pu 0.45 O 2±δ batch. This route represents a significant breakthrough in the methods currently used for MOx synthesis. Indeed, it allows the synthesis of mixed oxides from solutions resulting from reprocessing without redox adjustment using U(VI)Pu(IV) nitrate solution and doesn't require any filtration step. However, the morphology of the produced mixed-oxide powder would probably require new way of MOx fuel fabrication.

Fig. 1 .

 1 Fig. 1. Flowsheet of "advanced thermal denitration in the presence of organic dditives" synthesis route (photos illustrate the case of the (U,Pu)O 2±δ synthesis). For U 0.55 Pu 0.45 O 2±δ syntheses, uranium nitrate (UO 2 (NO 3 ) 2 ) is dissolved in nitric acid then Pu in a nitric

  a hundred nanometers thick constituted of nanoparticles.

Fig. 4 .

 4 Fig. 4. Scanning electron images U 0.55 Pu 0.45 O 2±δ converted for 2h at 800 °C in reconstituted air and then under hydrogenated argon (Ar-95% / H 2 -5%) for 2h at 800 °C

Gel Xerogel Oxide Solution solution

  form is added. Total metal concentration was 0.105 mol.L -1 , total nitrate concentration was 0.5 mol.L -1 . To prevent premature precipitation during synthesis, urea was added to the actinide solution. A mixture of acrylic acid AA (C 2 H 3 COOH) and N, N'-methylene bis (acrylamide) MBAM ((C 2 H 3 CONH 2 ) 2 CH 2 ) in a molar ratio of 20: 1 (AA: MBAM) was then added to the previous solution.

	The
	resulting fully homogeneous solution was heated up to
	100°C and supplemented with 25 μl of hydrogen peroxide
	(30 wt%) to quickly allow complete polymerization into a
	gel. Hydrogen peroxide is here used in substitution of the
	common initiators of polymerisation (ammonium per
	sulphate or AIBN) to suit the specifications for further
	nuclear fuel fabrication (no Sulphur in the fuel and safe
	reagents). The xerogel is then formed by dehydration of the
	polymeric gel using a hot plate heated up at 150°C.
	Oxidative calcination of xerogel was then performed at
	800°C in reconstituted air for 2h leading to the total
	oxidation of all carbon compounds. A second calcination,
	performed under Ar-95% / H 2 -5% up to 800 °C for 2h,
	permitted obtaining the targeted mixed actinide oxide.