Dalila Kamli

Douniazed Hannachi

Djamila Samsar

Henry Chermette

Bis-TTF-Ge derivates: Promising Linear and Nonlinear Optical Properties, a Theoretical Investigation

In this work, based on bis(tetrathiafulvalenyldithio)-germane (bis-TTF-Ge), 37 compounds (noted T0-T36) are designed by introduction of donor and acceptor groups at different substituent positions. The ground state electronic structures, reactivity indices, electronic transition, charge transfer properties (charge, distance and dipole moment), hyper-Rayleigh scattering and depolarization ratios (static and dynamic) of these compounds are fully investigated by DFT and TD-DFT theory. The quantum calculations were performed at the CAM-B3LYP/6-311g(d,p) level and the sum-over-states (SOS) approach in both static and dynamic cases. The chemical hardness (η) of the two substituted bis-TTF-Ge at the b position has a smaller value than those with the same substituent at positions d, e, a and c. In both static and dynamic regimes the investigations show that the bis-TTF-Ge substituted with donor or acceptor groups have larger first hyperpolarizability than T0. Our work predicts that the introduction of the substituent group at the b position can increase the hyperpolarizability values more than at the other positions, and the NO2, NO and COCN acceptor groups, lead to the largest values. For example, the dynamic value of T25 is about 145 times larger than that of T0 and about 11 times than that in the static regime. Interestingly, the of bis-TTF-Ge substituted with NO2 group increases with the number of NO2 in the TTF fragment. The large nonlinear optical (NLO) origin of bis-TTF-Ge substituted with NO2, NO and COCN is attributed to charge transfer from the TTF to the acceptor group at the second TTF fragment (overlap Sr index = 0). The studied bis-TTF-Ge substituted with NO2 compounds exhibit the possibility to be excellent second-order NLO materials.

Introduction

Nonlinear optics (NLO) is the study of the interaction of high intensity light with matter. In linear optics the relation between polarization (P) and electric field (E) is linear and the frequency is kept. For intense laser light, this linearity no longer holds and one gets different kind of frequencies, this frequency transformation has been observed experimentally by Franken 1 , the intense light induces change in the refraction index of the material (optical Kerr effect), which leads to a phenomenon called the self-phase modulation [START_REF] Shen | Supercontinuum Laser Source Ultim[END_REF] . The induced polarization at the macroscopic level is generally written as 3 : ∆ = ( ) + ( ) + ( ) + ⋯ ( ) , ( ) and ( ) are the first, second and third order susceptibility tensors, respectively. ( ) belongs to the domain of linear optics, whereas ( ) and ( ) quantifies second and third order NLO effects, respectively.

Since the discovery of laser by Maiman and Collins in 1960 4,5 a great interest is devoted to the discovery and design of new materials with large nonlinear optical properties. This is due to their important applications in different areas such as in photonic devices such as molecular switching, frequency doubling, telecommunications and optical information processing [6][7][8][9][10][11][12] .

Numerous techniques for developing new high-performance NLO materials have been proposed, including diradical character 13 , synthesizing molecular structures of electron-donor (D) -πelectron-acceptor (A) (D-π-A) 14 , reinforcing push-pull effects 15,16 , designing octupolar compounds 17,18 , multidecker sandwich complexes 19 , asymmetric coordination complexes [20][21][22][23] and excess electron [24][25][26][27][28][29] ,etc. Among the studied NLO materials the inorganic compounds exhibit exceptional interest because of their physicochemical stability and thermal stability 30,31 . For example, 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins tetrathiafulvalene (TTF) derivatives present excellent second-and third-order nonlinear optical responses, and it is a very active field in contemporary chemistry since shortly after its first synthesis in the early 1970s by Wudl and co-workers 32,33 . These properties derive from the large π conjugated system, the strong electrondonor character and the existence of polarizable sulfur atoms, leading to charge density redistribution within the molecule. [34][35][36] The combination of TTF group and an electron acceptor (A) units that are covalently linked by a π-conjugated bridging group is highly desirable and classified as excellent push-pull organic molecules (D-π-A). So far, TTF-π-A as promising NLO materials are widely studied by many scientific researchers, because these compounds exhibit intramolecular charge transfer (ICT) and have low energygap. [37][38][39] On the other hand, the binding of the TTF group with transition metals (TM) through covalent linkage or via electrostatic interactions allows the development of new metal complexes with π-conjugated ligands can present a respectable class of NLO material. 36,[40][41][42] For example, in 2015, Liu and coworkers studied static and dynamic HRS hyperpolarizability of a series of extended tetrathiafulvalene (exTTF) and TTF derivatives of metal cation (TM: Ni 2+ , Cu 2+ , Mg 2+ , Zn 2+ and Cd 2+ ) and they found that the TM complexes containing the redox-active TTF unit and pyridine group exhibit large hyperpolarizability values 43 . In addition, the nonlinear optical responses of several square-planar metal TTF complexes 44,45 have been studied theoretically and experimentally and have shown the important role of the ligand in perturbing the electron distribution in this complexes and its effect on both the ground and the excited states and, thus, on the linear and nonlinear optical properties [46][47][48][49][50][51] . In recent years growing attention has been expressed concerning the germanium, this interest is due to its high carrier mobility, good stability so that Ge is the most logical candidate to substitute carbon; moreover it has also potential applications in photodetectors and nonlinear optical fields. [52][53][54][55][56][57][58][59][60] Ueda et al. 61 reported the spiro molecules: bis(tetrathiafulvalenyldithio)-germane, (here named bis-TTF-Ge T36, see Figure 1). This asymmetric compound which contains large π systems should be a potential second-order NLO material. In this work, our aim is to study the effects of acceptor/donor substituents (NO, CN, COCN, CHO, NO2, NH2 and NMe2) and the substituent positions (a, b, c, d and e; see Figure 1) on the reactivity indices, linear and nonlinear optical properties of bis-TTF-Ge compounds. Also in this study, we focus to offer new prospects with respect to the origin of nonlinear optical for title compounds. Furthermore, to the best of our knowledge, there are no computational studies that address in detail the effect of the number and the nature of substituent groups in compounds made of two TTF groups linked by spiro germanium on the NLO properties.

Computational details

The geometries of the bis-TTF-Ge derivatives were fully optimized using Coulomb-attenuating exchange -correlation density functional method CAM-B3LYP 62 with 6-311g(d,p) 63,64 basis set. CAM-B3LYP is a long-range corrected functional developed to handle the inaccuracies of the non-Coulomb part of exchange functional at long distances. The quantum chemistry calculations were performed with Gaussian 09 program with the TIGHT SCF convergence and ultra-fine integration grid [START_REF] Frisch | Revision B.01[END_REF][START_REF] Kendall | [END_REF][67] . No symmetry constraints were applied and the local minima confirmed on potential energy surface by frequency calculations of the ground state for bis-TTF-Ge compounds at the same level.

Chemical reactivity analysis takes advantage of its ground in DFT through a functional Taylor expansion of energy that introduces several reactivity descriptors from energy derivatives of chemical significance 68 . According to a finite difference approximation and Koopmans' theorem [69][70][71] the electronic chemical potential (µ) and global hardness (η) can be evaluated from the frontier orbital energies HOMO and LUMO (ɛ and ɛ , respectively). Electronic chemical potential (µ) is the tendency of an atom or molecule to attract electrons; it is given by the following equation:

= (ɛ + ɛ ) = - (1)
is the electronegativity

The chemical hardness (η) expresses the resistance of a system to change its number of electrons; it is calculated with the relation:

= ɛ -ɛ (2)
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It is important to note that the global hardness (η) measures the stability of a system in terms of resistance to electron transfer and the chemical potential (μ) characterizes the escaping tendency of electrons from the equilibrium system.

Global electrophilicity index (ω), introduced by Parr et al. 72 , is calculated from the hardness and chemical potential:

= µ (3)
This index expresses the ability of a molecule to accept electrons from the environment.

Furthermore, to investigate and understand the electronic transition and optical properties, the electron excitation energies, oscillator strengths, for the studied compounds were calculated at the TD-CAM-B3LYP level.

The hyper-Rayleigh scattering (HRS) technique involves the detection of the incoherent scattering second harmonic generation at frequency 2ω from a laser with frequency ω incidence. In HRS, we can evaluate the first hyperpolarizability βHRS and its depolarization ratios DR, through the relation 6,73,74 〈β "# 〉 = %&〈β ''' 〉 + 〈β ('' 〉)

(4) DR = 〈, ---〉 〈, .--〉 (5)
Where, 〈β ''' 〉 and 〈β ('' 〉 are orientational averages of the β tensor without assuming Kleinman's conditions Previous works have pointed out that CAM-B3LYP, adopted in this work, can provide an absorption spectrum close to experimental results and has been proven to be efficient in calculating the static and dynamic NLO responses 7,[75][76][77] . The frequency-dependent hyperpolarizabilities were calculated using an incident wavelength of 1064 nm. The electron density difference maps (EDDM) corresponding to the crucial excited states can be exactly evaluated as follows:

〈 /// 〉 = 1 7 2 333 4,5,6 3 + 4 35 2 33: 4,5,6 3;
∆A(B) = A C4 (B) -A D (B)
A C4 (B) and A D (B) defining as the electronic densities associated to the excited and ground states, respectively. Following the procedure proposed by Bahers et al. 78 the excited states of interest were examined using charge-transfer indices (CT) including charge-transfer distance (E FG ). The product of these quantities E FG and H FG (transferred charge) gives the variation in dipole moment between the ground and the excited states (

I →K = H FG L E FG ).
On the other hand, the overlap distribution between the hole and electron can be expressed as:

S N (r) = Pρ RSTU (r)ρ UTU (r)
To characterize the overlapping extent of hole and electron, S r index is defined as:

S N (index) = [ S N (r)dr ≡ [ Pρ RSTU (r)ρ UTU (r) dr
In our work, the crucial excited state wavefunctions have been obtained by natural transition orbitals (NTOs) in terms of "excited particle" to "empty hole" of the electronic transition density matrix. The CT indices have been determined with MULTIWFN program 79

Results and Discussion

The optimized geometries of bis-TTF linked by a germane noted Ti (i=0 to 36) compounds obtained from DFT quantum chemical calculations is shown in Figure 2 along with the atom numbering schemes. As can be seen from this Figure, the optimized structure of the bis-TTF-Ge is tetrahedral, in which the Ge-S (S is: S1, S2, S3 and S4) average length is 2.259 Å and the ∠S3-Ge-S4 and ∠S1-Ge-S2 angles are ~97° whereas ∠S1-Ge-S3 and ∠S2-Ge-S4 are about 115°. On the other hand, The TTF groups deviate slightly from perfect planar geometry by 10°, showing a slightly distorted geometry. One of the reasons for this distortion is a steric repulsion between the sulphur atoms and the d orbitals from the germanium atom. This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins On the other hand we can observe that the TTF fragments in the title compounds are distorted into a boat form as shown in Figure 2 in their ground state and this shape agrees well with the available studies. For instance, Demiralp et al. in their study of organic donors (X) containing the TTF group found that X + always has a planar TTF region but that the neutral is distorted into a boat form. 80 They suggested that the off-planar geometry is caused by ring strain, which is developed when the H atoms of TTF are substituted by bulky ligands. 48 Furthermore, Linker et al. in their study of ethylenedioxy-TTF (EDO-TTF) indicated that a neutral derivative has a boat-shaped conformation, whereas the positively charged EDO-TTF is planar. 81

Reactivity

The values of the HOMO and LUMO frontier orbital energies ( ^_^ and `_^, respectively), the electronegativity (χ), the chemical hardness (η) and the electrophilicity index (ω), calculated for each bis-TTF-Ge compounds, are given in Table 1.

The electronegativity (χ= -µ) of the T1 to T25 bis-TTF-Ge which are substituted with acceptor group increases with the number of acceptor group in the title compounds. These results indicate that the trend of the electrons to leave the equilibrium systems increases from the four-acceptor substituted (e) to one-substituted (a) bis-TTF-Ge. The reverse trend is observed for the bis-TTF-Ge with electron donor R (NH2 and NMe2), so it can be concluded that the bis-TTF-Ge with four electron donors (e) have the largest tendency to donate electrons than d, b, c and a, respectively. On the other hand, we observe that the substituent position and the number of the substitution play in important role in the stability of studied bis-TTF-Ge. In each group with the same substituent, the substituent position b has a smaller hardness than the d, e, a and c substituent positions. The CHO and CN substituents in bis-TTF-Ge compounds show a decrease according to the following order: a, d, c and e. The ordering of the chemical hardness at the a position is: T1(NO) < T21 (NO2) < T11 (COCN) < T31 (NMe2) < T26 (NH2) < T6 (CN) < T16 (COH). The smallest η values are obtained for acceptor substituents and similar trends for the substituent positions b, c, d and e. Therefore, the hardness of bis-TTF-Ge can be effectively reduced when substituent positions are substituted with acceptor group. According to the theoretical scale of electrophilicity proposed by Domingo et al. [START_REF] Domingo | Please do not adjust margins Please do not adjust margins[END_REF] of global electrophilicity power (ω) the title compounds can be assigned to a strong electrophile class (2.51 to 6.70 eV).

Electronic transitions

The TD-DFT calculated results of absorption spectra parameters such as excitation energy (ΔE), absorption wavelength ( λ) and corresponding oscillator strength (f), charge transfer parameters (H FG ,E FG , and I →3 ) and g h index are calculated at the CAM-B3LYP/6-311g(d,p) level and summarized in Table S1 (Supplementary Information).

The simulated spectra and the electron density difference maps (EDDMs) are provided in Figure 3 The bis-TTF-Ge with NO electron acceptor substituents have five absorption bands, and their absorption wavelength range extends to 750 nm. The T1, T2 and T3 show electronic transition at 727, 680-637 and 654 nm, respectively, with small oscillator strength (i j 0.001), mainly arising from TTF rings 1, 2, 3 to NO, from TTF rings 1-3 to NO (at position R1 and R2) and from rings 5 and 6 to NO (at position R3) respectively. The HOMO→LUMO excitations of T1, T2 and T3 are located at 307, 456 and 418 nm, respectively, mainly ascribed to a π→π* charge transfer (CT) character. The electronic transition of T5 are assigned as a CT from rings 1, 2, 5, and 6 to four NO units (677, 637 and 455 nm) and from rings 1, 2, 5, and 6 to 4S-Ge unit (at 400 and 289 nm). For T4, the electronic transition appears in the 676, 455 and 316 nm from rings 1-2 to NO (at position R1 and R2) and from rings 5-6 to S-NO (position R1 and R2) π→π* CT character, besides the electronic transition at 290 nm ( f= 0.132) from rings 5-6 to NO ( at position R3) and to 4S-Ge unit.

For the T6 to T10 compounds, the HOMO→LUMO transition at ~399 nm is a charge transfer from rings 6 and 5 to 4S-Ge. The bis-TTF-Ge T6 is also ascribed to the same CT character at 292 nm (f= 0.141). For T8 the absorption bands located at 304 and 243 nm, with large oscillator strength, mainly arise from rings 1 and 2 to 4S-Ge and CN (at position R3). For bis-TTF-Ge T10, it involves three CT character at 363, 279 and 241 nm from rings 1-3 to C-S-COCN units attached to ring 1, from TTF rings to 4S-Ge (f= 0.198) and from ring 6-5 to C-S-COCN (at R1 and R2 positions) and C3-C4 atoms attached to ring 6 (f= 0.129), respectively. For T7 and T9, the absorption at 276 nm (f= 0.234 and 0.191, respectively) have a mixed character of charge transfer from rings 5 and 6 to S-CN units at the R1 and R2 positions of type n→π* and π→π* electronic transition. For T14 and T15, the electronic transition at 374, 351 nm, respectively, is mainly ascribed to the n→π* and π→π* CT mixed character from rings 4, 5 and 6 to S-COCN unit at position R3. The transition at 400 nm of T14 and T15 mainly comes from rings 1-3 to S-COCN (at R1 and R2 positions). The electronic transition of T13 at 398, 359 nm arises from rings 5 and 6 to 4S-Ge and from rings 1, 2, 5 and 6 to two COCN units CT, respectively. For T16, T17 and T19 the HOMO→LUMO transition at ~401 nm is CT from rings 6 and 5 to 4S-Ge unit. For T16 and T19 the HOMO-2→LUMO and HOMO-1→LUMO+4 excitations are CT from rings 1 and 2 to 4S-Ge unit and from rings 1-3 to 4-6, respectively (see Table S1 and Figure S2). Bis-TTF-Ge T18 exhibits absorption at 398 nm (HOMO→LUMO) with a charge transfer from rings 1, 2, 5 and 6 to 4S-Ge unit. The T20 compound has three absorption bands at 397, 304 and 278 nm with a charge transfer character from rings 6 and 5 to 4S-Ge, from rings 6 and 5 to the four units S-CHO and from rings 1, 2, 5 and 6 to 4S-Ge unit, respectively.

The bis-TTF-Ge with NH2 and NMe2 electron donors show three main absorption bands. The most intense absorption band of Ti (i=26 to 35) is at 269 nm, with the largest oscillator strength, mainly coming from intra-rings charge transfer (ICT). The band at ~ 404 nm is formed by a charge transfer from rings 1 and 2 to 4S-Ge unit between HOMO→LUMO. The absorption band at ~ 310 nm shows that the electronic transitions have a mixed character of charge transfer from rings 1-3 to rings 4-6 of type n→π* and π→π* electronic transition.

For T21, the electronic transition at 434 and 295 nm is assigned as a CT from rings 1 and 2 to S-NO2 and from rings 5 and 6 to S-NO2, respectively. For T23, there is a charge transfer from rings 1, 2, 5 and 6 to S-NO2 (at R4 position) and to 4S-Ge unit. For T25, it is interesting to find that there is a CT from rings 2 and 3 to two units C-S-NO2 (at R1 and R2 positions), from rings 1-2 and 5-6 to 4S-Ge unit and from rings 4-6 to C-S-NO2 unit (at R1 and R2 positions) at 524, 394 and 325 nm, respectively; besides n, π→π* mixed CT from 1-3 to 4-6 rings and from rings 2-3 and 5-6 to C-S-NO2 ( at ring 6). For T22, the electronic transition arises from rings 1-2 to S-NO2 and from rings 4-6 to S-NO2 (at R1 and R2 position), from rings 5-6 to 4S-Ge and from rings 1-2 to 4S-Ge. For bis-TTF-Ge T24, the electronic transition is mainly ascribed to a n, π→π* mixed character from rings 2-3 to S-NO2 (at R1 and R2 position), from rings 4-6 to S-NO2 (at R1 and R2 positions) and to S-NO2 at R3 position. The TD-DFT calculation on bis-TTF-Ge T0-T36 compounds show that the wavelength of the largest oscillator strength located at ~266 nm, are due to n→π* and π→π* mixed character type intra-TTF electron transition (see Table S1 and Figure S1). Furthermore, these excitations show a relatively small E FG and a large g h index, This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins indicating that the hole and electron are very close. For example, for T0, T36, T13, T18, T23 and T16 the electron density difference maps (EDDM) of this transition, shown in Figure 4, reveals a significant intramolecular CT (ICT) and, for all compounds, is reported in the supporting information in Figure S2.

On the other hand, the TD-DFT results show that the electronic transition HOMO→LUMO for T2, T4, T11, T12 T21 T22 and T24 ( R= NO, COCN and NO2; position is a, b and d) is a strong non-local excitation as indicated by the overlap index between the hole and the electron which is zero (Sr=0, Table S1).

Overall, T22, T24 and T25 show red-shift wavelength absorption compared to T23 and T12. On the other hand, the absorption wavelengths of T6 to T10 are close to T16 to T20. Furthermore, this study displays that the bis-TTF-Ge with electron-acceptor substituents (NO2 and NO) shows a red-shift wavelength absorption compared to the Ti with donor electron substituents. In general, from this calculation, we can conclude that the electronic transition characters and the absorption wavelength of Ti compounds can be tuned through the introduction of the electron donors or electron acceptor substituents at different positions.

Nonlinear optical properties

In current years, quantum chemical calculations have become a widely accepted method for predicting new NLO materials 20,21 . For the NLO calculation we made a test on T36 with the 6-311++G and 6-311G(d,p) basis set, but did not find significant differences (see Figure S3). This is not to surprise because of the quasi linear shape of the molecules and the 6-311G(d,p) basis is a good choice for the title compounds. On the other hand, we calculated the dynamic hyperpolarizabilities at the l value of 1064 nm ( =0.04282 au), which is sufficiently apart from the observed lowest-energy absorption of the title compounds (the mno values are in the range 250-270 nm). It is known that it is difficult to compare the calculated dynamic first hyperpolarizabilities to the experimental data measured in resonance conditions 83 . However the tendency is very similar between experimental and theoretical values 77 , and one has hyperpolarizabilities (experimental) > hyperpolarizabilities (dynamic) > hyperpolarizabilities (static) and our calculation shows the same tendency: hyperpolarizabilities (dynamic) > hyperpolarizabilities (static).

The second-order nonlinear responses calculated in static (λ= ∞) and dynamic regime (λ=1064 nm) for the 37 derivatives are summarized in Table 2. The reported quantities include the hyper-Rayleigh scattering (

) hyperpolarizabilities and the associated depolarization ration (DR). For bis-TTF-Ge T26, T28, T30 their z values are close to the value of T31, T33 and T35 (~ 111 |}) which indicates that when the NH2 (at a, c and e positions) is replaced by NMe2 group the effect on the value is not significant. On the other hand, the z value calculated for T26, T28, T30-T31, T33 and T35 are relatively close to the value of T0 (75 au). We can observe that the dynamic regime has the same behavior as static regime for NH2 and NMe2 donor groups. Furthermore, the hyperpolarizability ( = ∞, 1064 •€) of T27 and T29 are three times larger than that of the T26, T28 and T30. For T32 and T34 the values are about twice than that of T31, T33 and T35. We can observe that the introduction of donor substituents (NH2 and NMe2) at b and d positions can increase the hyperpolarizability of bis-TTF-Ge. For T1-T5 (acceptor NO unit) the (static and dynamic) of T2 is found about twice larger than that of T1, T3, T4, and T5.

For bis-TTF-Ge T11-T12, the values are larger than those of T13, T14 and T15, respectively. Comparing values of T11-T12 and T0, it can be seen that the T11-T12 values are about 11

Please do not adjust margins Please do not adjust margins times larger than that of T0. For bis-TTF-Ge substituted by CN and CHO unit, the (static and dynamic) values are also larger in the substitution at b and a positions than for d, c and e. For T6-T10, T11-T15 and T16-T20 compounds, we observe that the z and values of bis-TTF-Ge substituted with acceptor COCN group are larger than that of bis-TTF-Ge substituted by CN and COH group at the same substituent position, respectively. In static and dynamic regimes, the compounds T21-T25 exhibit larger hyperpolarizability values than the other bis-TTF-Ge compounds, which show that the introduction of acceptor NO2 group can effectively enhance values. This observation is in line with Gong et al.'s study of helicenes 84 and linear [3]spirobifluorenylene 85 . On the other hand, the z decreases slightly from T29 ≈ T27 to T25, T21 and T23, respectively, indicating that the substituent position (number) of NO2 substitutions in bis-TTF-Ge have little effect on the z values. On the other hand, the values decrease in the order T25 > T24 >T22 >T21 ≈ T23, indicating that the increases with the number of NO2 group in the bis-TTF-Ge compound (see Figure 5). The β "# value of T25 is about 7 times larger than that of T23. Furthermore, the β "# z value calculated for T0 (and T36) is about 11 times smaller than that of T21-T25 and β "# of T25, T24, T22 and T21 is 145, 92, 70 and 20 times larger than that of T0, respectively. T7, T17, T27 and T32 is about 10, 8, 6, 4, 4 and 3 times larger than that of T0 , respectively, and the value of these compounds is about 25, 10, 5, 4, 4 and 3 times larger than that of T0, respectively. We conclude that the highest hyperpolarizability value can be obtained by the introduction NO2, NO or COCN acceptor groups at b position for bis-TTF-Ge.

The experimental study of Bao et al. 86 , shows that the different numbers (mono-, di-, tri-, and tetra-) of ester substituents as well as their position (trans and cis) have a significant influence on the NLO properties of tetraphenylporphyrins. They indicate that the compounds with four ester groups present small value of hyperpolarizability. In static regime, the same results are observed for title compounds, the bis-TTF-Ge substituted with NO2 group excepted (see Figure 5 and Table 2).

Generally, in dynamic regime, the hyperpolarizability is 2-5 times larger than that in static regime, T22, T24 and T25 excepted, where is about 26, 15 and 12 times larger than the z , respectively. The static hyperpolarizability of T1 to T35 is about 2-11 times larger than that of T0. On the other hand, the TD-DFT results of T22, T24 and T25 show that the (between 524 and 554 nm) corresponds to twophoton resonance value (1048 ~ 1108 nm). This value is very close to near-resonant wavelength (1064 nm) causing resonance. The two-photon resonance value of T25 is 1048 nm and that of T22 and T24 is 1108 and 1096 nm, respectively. The resonance value of T25 is the closest to the near-resonant wavelength of 1064 nm and that of T22 and T24 is the most shifted from the near-resonant wavelength. This is the reason why the value of of T25 is larger than the value of of T24 and T22, respectively. Accordingly, the wavelength resonance is one of the reasons why the value of is much larger than the .

On the other hand, urea molecule is one of the prototypical compounds used in the study of the second-order NLO response of molecules. Therefore it is used frequently as a threshold value for comparative purposes 87,88 . The HRS hyperpolarizability of urea was calculated at the same level of theory. From our results we observe that the all bis-TTF-Ge derivate showed values for the static and dynamic HRS hyperpolarizability higher than the T0 (β "# z = 75 au and β "# = 137 au) and urea (β "# z = 38 au and β "# = 40 ua).

The depolarization ratio (DR) is an essential parameter for displaying the contribution of the hyper-Rayleigh scattering response. As revealed by the static and dynamic DR values collected in Table 2, the NLO responses of T1, T2, T4, T6, T7, T9, T11, T12, T17, T21, T22, T27, T29, T32, T33 and T34 compounds display a dominant dipolar character, with the exception of T9, T33 compounds (λ=1064 nm) dominated by their octupolar component. On the other hand, in our studied bis-TTF-Ge T3, T5, T8, T10, T13, T15, T18, T20, T23, T24, T25, T26, T28, T30, T31, T35 and T36 the octupolar component is dominant. From this study we observed that the (static and dynamic) DR values are more strongly sensitive to the substitution positions than to the nature of the substituent (donor and acceptor). Please do not adjust margins Please do not adjust margins (T10, T18, T20, T30 T36 and T0) characterizes typical octupolar systems. Furthermore, we observed that the DR value at λ= 1064 nm of T0, T10, T20, T22, T25 T30 and T36 is less than 1.5, indicating that those compounds are close to resonance.

On the other hand, we studied the correlation between the energy gaps (hardness) of the title compounds and their hyperpolarizability in the static regime. The results show that z values are increased with the decrease of the bis-TTF-Ge energy gaps (the correlation factor is 0.832, see Figure S4). Taking T24 as an example, the energy gap of T24 is the smallest (1.819 eV) but its hyperpolarizability value is the largest ( z = 829 au), which is in good agreement with the literature 89,90 .

In order to understand the nonlinear optical origins of studied compounds, the excitation energy (I →K ) and wavelength (I →K ), oscillator strengths (i →K ), transfer distance charges (E FG ), charge transfer (H FG ) and transition dipole moment (I →K ) calculated for the crucial singlet excited states are summarized in Table 3, with more details in Table S1, and the corresponding electron density difference maps (EDDMs) are shown in Figure S-2. Table 3. Vertical transition energy (I →K , eV) and wavelength (I →K , nm), oscillator strengths (i →K , dimensionless), charge transfer (H FG , |e|), charge transfer distance (E FG , Å), and dipole moment variation (I →K , D) associated to the S0 → Sn (g →K ) transition, as calculated at the CAM-B3LYP/6-311g(d,p) in Ti compounds The charge transfer involves both n → π* and π → π* transitions, the main factor being the conjugation of the p electrons through the delocalization domain.

Ti

From the EDDM of bis-TTF-Ge substituted with acceptor groups (T1-T5 (R: NO), T11-T15 (R: COCN) and T21-T25 (R:NO2)), it can be observed that there is obvious CT from TTF fragment to the substituted groups (R) at the other TTF fragment. These transitions are dominated by an electronic excitation from the HOMO to the LUMO and have a high charge transfer parameters (H FG , E FG and I →K ) character which is the necessary condition to obtain high NLO response. On the other hand, the CT characters of T6-T10, T16-T20 and T26-T36 are from TTF fragment (rings) to 4S-Ge unit and these transitions are also associated to a HOMO→LUMO excitation with less charge transfer parameters than the other compounds (see Figure S-2, Table 3 donor or acceptor at the position c. This can be attributed to the CT from the TTF to the substituted group on the same fragment, see for example T23 in Figure 6. In contrast, T0 undergoes a moderate CT excitation (H FG = 0.821 |e|) with weak CT distance and small dipole moment variation ( E FG = 0.035 Å and I → = 0.054 D)

(see Figure 6). Furthermore, the title compounds show a nice correlation between HRS hyperpolarizability and the largest dipole moment variation (Figure 7). Also, there is a good correlation between z and , except for T2, T4 and T5 (Figure 8).

Two-level model analyses for hyperpolarizability

The sum-over-states (SOS) method is one of the most commonly used methods for theoretical estimation of hyperpolarizability. [91][92][93][94][95][96] The full form of SOS formula of component ABC of hyperpolarizability is defined as 456 (-' ; , )

= " "•(-' ), -( ), -( )˜2 2 Where ∆E, f and ∆µ are excitation energy, oscillator strength and difference of dipole moment between ground state and excited state, respectively. According to this relation, it is observed that the static hyperpolarizability ( ) is inversely proportional to ∆ , demonstrating that lower excited energy (ΔE), greater dipole moment (∆µ) and oscillator strength (ƒ) will lead to the largest of compounds. Furthermore, it is well know that the molecular NLO properties calculated by the SOS method are closely related with the number of excited states 99 , therefore in our study we plotted the relation relationship between the first hyperpolarizability ( ^ ) and 100 excited states (Figure . S5). Generally, these graphs demonstrate that 100 excited states are sufficient for the convergence of the This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins ^ value. As shown in Table S2 and Figure S5 the introduction of the substituent group at the b position can increase the hyperpolarizability values more than at the other positions, and the NO2, NO and COCN acceptor groups, lead to the largest values. This prediction agrees well with hyperpolarizability calculated by CAM-B3LYP/6-311g(d,p). In addition, the two-level analysis discloses that the excited state S7 has the dominant contribution to the hyperpolarizability value of compounds T6, T7, T8, T16-T18, T20 and T26-T35; the crucial excited states S12, S13, S12, S13, S20 and S17 with largest hyperpolarizability in compounds T9, T10, T19, T11, T12, T13 respectively, these transitions can be assigned to the CT from TTF fragment (rings) to 4S-Ge unit (see Table S1-S2). For systems T1-T5 the dominant contribution to hyperpolarizability values can be assigned to S7, S18, S23, S22 and S5, respectively, are mainly made up of CT from TTF fragment to the NO groups at the other TTF fragment. For compounds T21 to T25 the excited states S1, S11, S1, S2 and S2, respectively, with CT from TTF fragment to NO2 groups have large contributions to the hyperpolarizability value. For compounds, T14 to T15 the crucial excited state is S9 and S8 respectively, with CT from TTF fragment to COCN groups have (see Table S1, S2 and Figure S2). On the other hand, The SOS calculations show that the local excitation transition at ~266 nm of title compounds (noted in italic in Table S2) exhibit a small hyperpolarizability value and a large dipole moment variation. These results agree well with the character of the electronic transition that we have noted before (in the section of nonlinear optical properties and Table 3).

As can be seen from Table S2 and Figure 9, as a whole, the hyperpolarizability ^ and ratio ¤¥ ^ values (calculated ¤¥ ^ ratio and ^ based on hyperpolarizability tensor derived by SOS formula) qualitatively reproduce the general trend of the HRS hyperpolarizabilities and DR character (Table 2) with few exceptions resulting from the limitation of the SOS method. On the other hand, it is worth stressing that the SOS method obviously overestimates the hyperpolarizability and DR value of Ti compounds (Figure 9 I and II). Furthermore, the frequency dispersion factor (FDF) between static and dynamic at a definite wavelength λ=1064nm depicted by the ratio /β , namely FDF and FDF , ^ , are calculated from the results in the Tables 2 andS2, respectively and are presented in Figure 10. From this Figure 10, as expected, both FDF and FDF , ^ follow the same trend and in addition, the FDF values are quite close to the FDF , ^ values, with the exception of T2, T4, T12, T22 and T25. On the other hand, we can observe that the dispersion of optical nonlinearity of T24, T25 and T22 have maximum frequency dispersion factor at λ = 1064.8 nm, confirming their great nonlinear optical properties, in contrast to the other compounds (dispersion factor from ~1 to 5.5). It is important to highlight that the SOS method consistently produces large hyperpolarizability and small FDF values of compound bis-TTF-Ge. Indeed, all the compounds containing NO2 substituent(s) (and, in a smaller extent, containing NO) are much more hyperpolarizable at 1064nm frequency than in static regime, whereas with other substituents, the difference is not significant. This may be related to Please do not adjust margins Please do not adjust margins the NO2 lone pairs, which may be more mobile through the molecular systems. To summarize, the large HRS hyperpolarizabilities origin of bis-TTF-Ge substituted with acceptor groups comes from the CT from the TTF fragment towards the acceptor group located on the second TTF unit. In the meantime, the values of the CT from the TTF to the acceptor group located on the same TTF fragment are weak, whereas the NLO origin of bis-TTF-Ge substituted with donor originates a CT from TTF fragment to the 4S-Ge unit.

Conclusions

The structural, reactivity parameters, linear and nonlinear optical properties of 37 bis-TTF-Ge derivatives differing by a donor and acceptor substitution on the TTF fragment have been investigated by using DFT and TD-DFT calculations. This calculations were performed at the CAM-B3LYP/6-311g(d,p) level and the sumover-states (SOS) approach in both static and dynamic regimes.

Our results indicate that the bis-TTF-Ge hardness can effectively be reduced when substituent positions are substituted with the acceptor group (NO, NO2, COCN). Furthermore, the b substituent position leads to a smaller hardness than the d, e, a and c substituent positions. The electronic excitation property of the title compounds can be described as a mixed transition of intra-TTF charge transfer (ICT) and charge transfer (CT) from TTF to 4S-Ge unit, TTF to acceptor group (NO2, NO and COCN) and TTF to TTF. For example, the electronic transition at ~266 nm is a local excitation with a relatively small d ct and large Sr indexes. The transition HOMO→LUMO of bis-TTF-Ge with the acceptor substituent (R= NO, COCN and NO2) at positions a, b and d is a non-local excitation with large dipole moment variation and small Sr index (Sr~0). In the case of bis-TTF-Ge with donor substituent (R: NH2 and NMe2 ) at positions a, b and d, the transition HOMO→LUMO from TTF fragment to 4S-Ge show moderate values of transition dipole moment and Sr indexes (Sr=~0.3) when we compare it with the results of acceptor substituent.

All bis-TTF-Ge derivate showed values for the static and dynamic HRS hyperpolarizability higher than the T0 and urea.

The quantum chemical calculations indicate that the position and the nature (donor/ acceptor) of the substituent have strong effects on the NLO responses. The introduction of a substituent group at b position induces a greater increase of the first hyperpolarizability and the acceptor NO2, NO and COCN groups show a large value of HRS hyperpolarizability which indicate that the acceptor group has a stronger effect on the second order NLO than the donor group. On the other hand, the compounds with c and e substitution positions are octupolar molecules and a, b and d substitution positions lead to a dominant dipolar nature of the NLO response.

The large first hyperpolarizability origin comes from the CT from the TTF fragment towards the acceptor group located on the second TTF unit. On the other hand, the z values of the compounds T21-T25 are high and relatively close, indicating that the introduction of acceptor NO2 group at any substituent position can effectively enhance the first hyperpolarizability. Interestingly, the of bis-TTF-Ge substituted with NO2 group increases with the number of NO2 in the TTF fragment.

Finally, it is important to emphasize that the intrinsic asymmetric geometry of the bis-TTF-Ge can tune the second order NLO response through the nature, position and number of the substituent group at the TTF fragment, as well as by the Sr index.

On the other hand, our study suggests that these compounds can be used as new materials for developing nonlinear second order photonics devices. Furthermore, the bis-TTF-Ge compounds substituted with NO2 group may become excellent candidates for second order NLO materials, which will also promote the evolution of high technological applications. This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins

Notes and references

Figure 1 .

 1 Figure 1. Chemical structures of the studied bis-TTF T0 to T36, where a, b, c, d and e are the substituent position (a: one substituent at R1; b: two substituents at R1 and R2; c: two substituents at R1 and R4; d: three substituents R1, R2 and R3; e: four substituents)

Figure 2 .

 2 Figure 2. Optimized molecular geometry of bis-TTF-Ge compoundsOn the other hand we can observe that the TTF fragments in the title compounds are distorted into a boat form as shown in Figure2in their ground state and this shape agrees well with the available studies. For instance, Demiralp et al. in their study of organic donors (X) containing the TTF group found that X + always has a planar TTF region but that the neutral is distorted into a boat form.80 They suggested that the off-planar geometry is caused by ring strain, which is developed when the H atoms of TTF are substituted by bulky ligands.48 Furthermore, Linker et al. in their study of ethylenedioxy-TTF (EDO-TTF) indicated that a neutral derivative has a boat-shaped conformation, whereas the positively charged EDO-TTF is planar.81

  and Figure S1-S2, respectively. In general, the absorption spectra of the title compounds are Please do not adjust margins Please do not adjust margins characterized by a strong band (B3) at 267 nm, two weak bands (B1 and B2) and two moderate absorption shoulders (S1 and S2).

Figure 3 .

 3 Figure 3. Calculated UV -vis absorp on spectra of bis-TTF-Ge T1-T5 compounds. (B: bands; S: shoulders)The bis-TTF-Ge with NO electron acceptor substituents have five absorption bands, and their absorption wavelength range extends to 750 nm. The T1, T2 and T3 show electronic transition at 727, 680-637 and 654 nm, respectively, with small oscillator strength (i j 0.001), mainly arising from TTF rings 1, 2, 3 to NO, from TTF rings 1-

Figure 4 .

 4 Figure 4. Electron density difference maps of T0, T36, T13, T8, T23 and T16 compounds from the ground state to the crucial excited state S0→Sn (S17, S17, S2, S19, S25 and S18 respectively), plotted using 0.008 au isovaluesThe TD-DFT calculation on bis-TTF-Ge T0-T36 compounds show that the wavelength of the largest oscillator strength located at ~266 nm, are due to n→π* and π→π* mixed character type intra-TTF electron transition (see TableS1and FigureS1). Furthermore, these excitations show a relatively small E FG and a large g h index,

Figure 5 .

 5 Figure 5. Static and dynamic hyperpolarizability values for T21-T25 calculated at the CAM-B3LYP/6-311g(d,p) level

  This reveals that the a, b and d substitution positions lead to a dominant dipolar nature of the NLO response; the b substitution positions show a larger DR value in static and dynamic regimes. On the other hand, the title compounds with c and e substitution positions are octupolar molecules. For the e substitution positions, the DR value (λ= ∞, 1064 nm), close to 1.5 This journal is © The Royal Society of Chemistry 20xx

Figure 6 .Figure 7 .

 67 Figure 6. Electron density difference maps of T0, T2, T21, T22, T31 and T36 compounds from the ground state to the crucial excited state S0→Sn (S1, S13, S1, S1, S1 and S14, respectively), plotted using of 0.008 au isovalues

Figure 8 .

 8 Figure 8. Correlation between static and dynamic hyperpolarizability, T2, T4 and T5 excepted

ω

  is the energy of external fields, and ω = 0 corresponds to the static electric field; ∆ 3 stands for excitation energy of state i with respect to ground state (0). " is the permutation operator that acts on the xyz indices of the β-components. 3<4 is x component of transition dipole moment between state i and j. Molecular NLO responses of material is intimately related to the electronic absorption properties and through the two-level model established by Oudar and Chemla can be expressed the static hyperpolarizabilities β as97,98 ∝ i L ∆ ∆

Figure 9 .

 9 Figure 9. I: Calculated static first-hyperpolarizabilities of Ti compounds by SOS method and at CAM-B3LYP/6-311g(d,p) level; II: depolarization ratios DR of Ti compounds calculated by SOS method and at CAM-B3LYP/6-311g(d,p) level .

Figure 10 .

 10 Figure 10. Variation of the frequency dispersion factor of bis-TTF-Ge derivatives calculated by SOS method and at CAM-B3LYP/6-311g(d,p) levelTo summarize, the large HRS hyperpolarizabilities origin of bis-TTF-Ge substituted with acceptor groups comes from the CT from the TTF fragment towards the acceptor group located on the second TTF unit. In the meantime, the values of the CT from the TTF to the acceptor group located on the same TTF fragment are weak, whereas the NLO origin of bis-TTF-Ge substituted with donor originates a CT from TTF fragment to the 4S-Ge unit.

Table 1 .

 1 Energy HOMO and LUMO (eV), electronegativity (χ, eV), chemical hardness (η, eV) and electrophilicity index (ω, eV) of the Ti (i=0 to 37) compounds

		Ti T0	a bcdc -5.311	a efdc -2.577	η 2.733	χ 3.944	ω 2.845
	a	T1	-5.329	-3.495	1.834	4.412	5.307
	b	T2	-5.341	-3.776	1.564	4.558	6.644

Table 2

 2

	Static ( = ) and dynamic ( = 1064 nm ) HRS first hyperpolarizability ( , au) and depolarization ratio (DR), as well
	as calculated dipole moment (D, Debye), calculated at the CAM-
	B3LYP/6-311g(d,p) level in Ti (i=0 to 37) compounds
	Ti T0	µ 2.048	rs 1.503	vwxy t bsu rs vwxy t bsu 75 1.407 137
	a T1	0,797	3.817	440	4.629	1266

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 5

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 9

J. Name., 2013, 00, 1-3 | 11

This journal is © The Royal Society of Chemistry 20xx

B. Li, P. Sathishkumar and F. L. Gu, Phys. Chem. Chem. Phys., 2021, 23, 8489-8499.

Acknowledgements

The authors gratefully acknowledge the GENCI/ CINES for HPC resources/computer time (Project cpt2130), and the PSMN of the ENS-Lyon for computing resources.

Author Contributions

All the authors discussed the results. Dalila Kamli: calculations achievements, data interpretation, draft writing. Douniazed Hannachi: project initiation, conceptualization, calculations supervision, data interpretation, draft writing. Djamila Samsar: calculations, data interpretation, draft writing. Henry Chermette: calculations, data interpretation, draft writing.

Conflicts of interest

There are no conflicts to declare.

ORCID

Henry CHERMETTE 0000-0002-5890-7479 Douniazed HANNACHI 0000-0001-6664-179X


A Gangi

F Proust

Cebula Hélène
email: helene.cebula@hotmail.fr

The Cryo-immunologic effect: A therapeutic advance in the treatment of glioblastomas?

Keywords:

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

Résumé

L'immunothérapie dans le traitement du glioblastome est un sujet d'actualité notamment avec l'essor des inhibiteurs de point de contrôle immunitaire marquant un changement de paradigme dans le traitement du cancer. Le traitement du glioblastome passera probablement par le développement de stratégies multimodales associant chirurgie, chimiothérapie, radiothérapie et immunothérapie. En parallèle, s'est développée la cryothérapie pour d'autres types de cancers ; peau, poumon, oesophage, foie, sein, rein, prostate et tumeurs osseuses ; basée sur la répétition de cycle rapide de gel et lent de dégel. L'immunomodulation pourrait être combinée à la cryothérapie dans les tumeurs cérébrales potentialisant ainsi la réponse immunitaire créée par la cryothérapie. L'objectif de cette étude était d'analyser la relation entre la cryothérapie pour les tumeurs cérébrales et le système immunitaire, basée sur une revue de la littérature selon la méthode PRISMA. Les études animales ont démontré l'activation et la maturation des cellules dendritiques avec une augmentation de la fonction présentatrice d'antigènes après la cryothérapie suggérant une association potentielle entre cryothérapie et immunothérapie dans le traitement des glioblastomes.

INTRODUCTION

Glioblastoma remains a therapeutic challenge. Surgery, radiotherapy and chemotherapy are currently the pillars of the cure intend treatment. However, since the publication of Stupp et al., therapeutic advances in glioblastoma seem to have stalled [START_REF] Stupp | Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[END_REF]. Consequently, every new treatment approach can be considered as a real opportunity to improve outcome of patients with glioblastoma.

The immunotherapy of cerebral glioblastoma has become a hot topic [START_REF] Sampson | Immunotherapy for Brain Tumors[END_REF][3] [START_REF] Adhikaree | Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma[END_REF]. Immune checkpoint blockade antibodies, particularly the program death 1 PD-1/PD-1 ligand pathway, have progressively acquired a role in the management of malignant tumors such as melanoma, lung cancer, breast cancer, prostate cancer and kidney cancer, since the first Food and Drug Agency (FDA) approval in 2014 of Pembrolizumab (a PD-1 inhibitor) to treat metastatic melanoma [START_REF] Larkin | Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma[END_REF][6] [START_REF] Reck | Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer[END_REF][8] [START_REF] Motzer | Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma[END_REF]. More recently, efficiency of immune system was shown in the central nervous system, despite the blood-brain barrier. Lead by microglia cells, glymphatic system and the cervical lymphatic node system that present antigens immune reaction can be observed [START_REF] Adhikaree | Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma[END_REF]. A constant interaction between the extra and intracranial immune responses was demonstrated and this relation can mount appropriate immune responses [START_REF] Adhikaree | Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma[END_REF]. Thus, different cerebral immunomodulatory pathways of glioblastoma are under development: vaccine-based strategies vaccine-based therapies; the use of convection-enhanced delivery to introduce tumoricidal viruses into the tumor microenvironment, leading to secondary immune responses; the emerging use of adoptive cell therapy; and future frontiers, such as the use of cerebral microdialysis for immune monitoring and the use of sequencing to develop patientspecific therapeutics or signaling blockages such as CTLA4 and PD-1 [START_REF] Adhikaree | Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma[END_REF].

In parallel, clinical applications of cryotherapy -freezing tumors based on repetition of rapid freeze-slow thaw cycle -for various cancers such as skin, lung, breast, esophagus, hepatic, kidney, prostate and bone tumors were developed [START_REF] Cazzato | Percutaneous image-guided cryoablation: current applications and results in the oncologic field[END_REF].

The applications of cryosurgery to endocranial lesions, study mainly in the 70s was phased out due to efficiency of microsurgery [START_REF] Gonski | Cryohypophysectomy for the relief of pain in malignant disease[END_REF][12] [START_REF] Copper | Cryogenic surgery: a new method of destruction or extirpation of benign or malignant tissues[END_REF][14] [START_REF] Stellar | Mortality and morbidity in cryothalamectomy for parkinsonism. A statistical study of 2868 consecutive operations[END_REF]. The current advances of imaging techniques, especially MRI-guided, and the development of technical competency of cryogenic devices stimulated again the interest of this procedure for neurosurgical lesions. As for the management of other solid tumors, one may wonder about the relevance of cryosurgery combined with immunotherapy to treat the glioblastoma [START_REF] Bisdas | Intraoperative MR Imaging in Neurosurgery[END_REF]. The combination of immunotherapy and cryotherapy could represent a new approach to treat glioblastomas.

The objective of this study was to analyze from the literature the relationship between brain cryosurgery and and its effect on immune system using PRISMA method [START_REF] Liberati | The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration[END_REF].

METHODS

Data sources and study selection

A comprehensive review of articles published from January 2000 to September 2019 was conducted. It was carried out on EMBASE, MEDLINE and the Cochrane Library. The search strategy contained the subject heading: "Brain AND Cryotherapy, Brain AND cryosurgery, animal study AND cryotherapy, Gliomas AND Cryotherapy, Cryoablation AND brain". We included article in English and/or French language. Study designs included case reports and series of case reports, human studies and animal studies. The exclusion criteria were historical review and analyze of cryotherapy without glioma model for animal study.

Quality assessment

The current analysis is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [START_REF] Liberati | The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration[END_REF]. Two investigators independently reviewed and selected abstracts from the database and full articles. The description of the data was summarized on tables.

The objectives, animal model, glioma cell lines, markers of inflammation, immune response were analyzed in each study.

RESULTS

On database searches through January 2000, 38 articles were identified. Twenty-eight were excluded secondary to: 8 articles were not available in English; Ten were a review of literature, nine were not an animal model of gliomas and one had only abstract available.

Ten articles were eligible: eight experimental studies included cryotherapy and model of gliomas and two feasibility studies of cryotherapy on brain tumors (Table 1).

a) Experimental studies

Models and the glioma cell line were detailed in table 2.

In 5 studies, the animal model was mice (C57BL/6 for five studies and among these five studies, two used also BALB/c mice model in more) [START_REF] Yin | Antitumor efficacy of argon-helium cryoablation-generated dendritic cell vaccine in glioma[END_REF][19] [START_REF] Liu | Extracts from glioma tissues following cryoablation have proapoptosis, antiproliferation, and anti-invasion effects on glioma cells[END_REF][21] [START_REF] Xu | Synergism between cryoablation and GM-CSF: enhanced immune function of splenic dendritic cells in mice with glioma[END_REF]. In all these studies, the tumor was developed from GL261 glioma cell line. In three studies, the animal model was Wistar rat and the implanted cells were C6 glioma cell line [START_REF] Li | Argon-helium cryosurgery for treatment of C6 gliomas in rats and its effect on cellular immunity[END_REF][24] [START_REF] Li | Functional Changes of Dendritic Cells in C6 Glioma-Bearing Rats That Underwent Combined Argon-Helium Cryotherapy and IL-12 Treatment[END_REF].

The cell injection were heterotopic in seven studies [START_REF] Yin | Antitumor efficacy of argon-helium cryoablation-generated dendritic cell vaccine in glioma[END_REF][23] [START_REF] Zhang | Cryo-ablation improves anti-tumor immunity through recovering tumor educated dendritic cells in tumordraining lymph nodes[END_REF][20] [START_REF] Li | Functional Changes of Dendritic Cells in C6 Glioma-Bearing Rats That Underwent Combined Argon-Helium Cryotherapy and IL-12 Treatment[END_REF][21] [START_REF] Xu | Synergism between cryoablation and GM-CSF: enhanced immune function of splenic dendritic cells in mice with glioma[END_REF]and orthotopic in one study [START_REF] Huang | Cryosurgery and rhTNF-α play synergistic effects on a rat cortex C6 glioma model[END_REF].

The procedures of Cryotherapy varied according to the different studies: variation of number of cycles (from 1 to 3 cycles) and temperature target (from -140°C to -196°C), detailed in Table 2. The size of cryoprobe varied between two or three millimeters. The argon-helium cryocare system were used in seven studies (Endocare, [START_REF] Yin | Antitumor efficacy of argon-helium cryoablation-generated dendritic cell vaccine in glioma[END_REF][19] [20][26][22] [START_REF] Li | Argon-helium cryosurgery for treatment of C6 gliomas in rats and its effect on cellular immunity[END_REF], no precision for argonhelium device in one study [START_REF] Lin | In-situ administration of dendritic cells following argon-helium cryosurgery enhances specific antiglioma immunity in mice[END_REF]) and one nitrogen system in one study (Frigitronics, Inc., Shelton, USA [START_REF] Huang | Cryosurgery and rhTNF-α play synergistic effects on a rat cortex C6 glioma model[END_REF]).

All authors analyzed the reaction of the immune system after cryotherapy.

-Dendritic cells Dendritic cells (DC) are the most potent antigen-presenting cells. The mature DCs migrate to tumor-draining lymph nodes. By production of large proinflammatory cytokines such as IL-2, the mature DCs induced T-cell immunity where they present tumor antigens to tumor-specific T cells, inducing their activation. [START_REF] Yin | Antitumor efficacy of argon-helium cryoablation-generated dendritic cell vaccine in glioma[END_REF].

By the release of large amounts tumor antigens induced by cryoablation, the cryosurgery could enhance the migration of DCs and increase the T cell immunity.

In vivo, Yin et al. reported the efficiency of cryoablation as immunostimulation procedure by induction of DCs maturation, increasing expression of immunostimulatory cytokines with higher level of cytotoxicity against glioma cells [START_REF] Yin | Antitumor efficacy of argon-helium cryoablation-generated dendritic cell vaccine in glioma[END_REF]. Li and al. analyzed the effect on cellular immunity after treatment of subcutaneous gliomas in rats (Wistar rat models) by argon-helium cryotherapy [START_REF] Li | Argon-helium cryosurgery for treatment of C6 gliomas in rats and its effect on cellular immunity[END_REF]. Cryosurgery, compared with surgical resection, resulted in increased percentages of CD3 + and CD4 + (p<0.005) with an increase of the CD4 + /CD8 + cell ratios 14 days after the cryotherapy. Highlighted on C6 glioma-bearing animals models, the association of cryotherapy and injection of Interleukine 12 (cytokine and immunomodulator factor which induced a direct antagonistic effect against tumors) activated the Th1-type immunity with an increase of CD11 + and CD86 + [START_REF] Li | Argon-helium cryosurgery for treatment of C6 gliomas in rats and its effect on cellular immunity[END_REF]. The necrotic tumor tissue, as a result of cryosurgery, promotes the release of soluble antigens stimulating the production of specific antitumor antibodies.

b) Series of patients

The characteristics of human studies were summarized in Table 3. The two articles demonstrated the feasibility of brain cryotherapy without demonstration of positive effect on overall survival. [START_REF] Li | MR imaging-guided cryoablation of metastatic brain tumours: initial experience in six patients[END_REF]. The localizations were: left temporal lobe, cerebellum, parietal and basal ganglia area. The procedure was realized under local anesthesia. Cryoablation was performed with argon-based system, MRI compatible. A drill hole was made at the entry point and when the dura was opened, the patient moved into the MRI device. Tumor cyst aspiration was performed before cryoablation. The cryoablation was performed using two freeze-thaw cycles (with lowest temperature measured at -185°C). The iceball was monitored using MR imaging. One patient died of a secondary complications 12 days after cryoablation. All patients tolerated the procedure without neurological deficits. The follow-up ranged from 12 days to 12 months. On follow-up at 3 and 7 days after the procedure, the lesions showed typical appearance of cryocoagulation necrosis (hypointense on T1W1, hyperintense on T2W). At 6 weeks, lesions had decreased in size.

Li et al. described their experience about MR imaging-guided cryoablation of cystic metastatic brain tumors in six patients

The second study was published by Martynov et al. [START_REF] Martynov | Stereotactic Cryodestruction of Gliomas[END_REF]. They analyzed 88 patients with supratentorial gliomas, not suitable for microsurgical resection, treated by stereotactic cryodestruction [START_REF] Martynov | Stereotactic Cryodestruction of Gliomas[END_REF]. The localizations were cerebral lobes, insula, thalamus, internal capsules and corpus callosum. The mean volume of lesions was 44.2 cm 3 . The histology of lesions was oligodendroglioma, diffuse astrocytomas, anaplastic astrocytomas and glioblastomas (according to the WHO classification of Tumors of the Central Nervous System, 2016 [START_REF] Louis | The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary[END_REF]).

The stereotactic cryotherapy was performed with a commercially non-available prototype device. Solid carbon dioxide (-78°C) was used for cooling the acetone within the cryoprobe. Stereotactic trajectories were planned, and surgery was done under awake condition for adults and general anesthesia was used for children. A burr hole was made, and biopsy realized. After this step, a cryoprobe was inserted into the target and cryodestruction was done (at least two cycles). After cryotherapy, 83% received fractioned radiotherapy and 38% chemotherapy. Surgical complications were identified in 11.4% of cases (hematoma, brain oedema, infection) with 1.1% postoperative mortality. Three patients underwent a craniotomy after cryodestruction to evacuate blood clot or necrotic tissue. Neurological deficit was observed in 42 % of cases including 8% permanent deterioration neurological function.

The median survival of patients with of astrocytomas and glioblastomas were 46.9 months and 12.4 months respectively.

DISCUSSION

The cryotherapy increases the cellular immunity through the activation of dendritic cell and the antigen-presenting function. One of the consequences of cryosurgery is the necrotic tissue promotes the release of soluble antigens stimulating the production of specific antitumor antibodies and increasing the activation of the immune system.

Cryoablation uses Argon/Helium gases to generate extreme cold temperatures, destroying tumors via direct cellular injury, induction of apoptosis, and micro-circulatory occlusion. A cryo-immunologic effect has also been proposed, where cryo-preserved tumoral antigens may provoke a host anti-tumoral response [START_REF] Cazzato | Percutaneous image-guided cryoablation: current applications and results in the oncologic field[END_REF]. In fact, cryotherapy release tumor antigens and enhances migration of DCs from the tumor to the draining lymph nodes. The animals' studies demonstrate the DC maturation and activation with the enhancement of antigen-presenting function after cryotherapy. The enhanced host immunity after cryotherapy is probably secondary to the release of the soluble tumor antigens. These examples, in animals' models, suggesting the potential usefulness of the association of cryotherapy and immunomodulator in the management of gliomas. In our knowledge, the series studies were limited to some clinical observations with the demonstration of feasibility of tumor brain cryotherapy. These two clinical series are not enough to issue indications of the cryotherapy. Patients will need to be well selected. The clinical attempts are scares secondary to the need for radiological expertise in the cryotherapy to realize MR-guided ablation. The potential complications of brain cryotherapy described for one study were hematoma, oedema and infections (11.4% of cases) with 1.1% of mortality and for the second study, no complication was described. Further study will be needed to quantify the exact rate of complications. MR-guidance enables precise lesion targeting and excellent ablation-zone (named "ice-ball") visualization/monitoring, facilitating optimal treatment margins while avoiding collateral eloquent parenchymal damage. In combination therapy, MR-guided Cryoablation potentially offers anti-tumor immunity for recurrent glioblastoma and represents a future immune strategy. However, MR-guided cryoablation, an established treatment for extra-cranial tumors with both ablative and immunomodulatory effects, has not yet been applied to recurrent glioblastoma.

Recurrent Glioblastoma invariably follows primary tumor therapy and portends a poor prognosis. In the absence of standard treatment guidelines, repeat surgery, re-irradiation, and second-line chemotherapy typically achieve 20-30% 6-month progression-free survival rates [30][31]. Recently, novel therapeutic approaches including minimally-invasive laser ablation and immunotherapy have been reported [START_REF] Kamath | MRI-Guided Interstitial Laser Ablation for Intracranial Lesions: A Large Single-Institution Experience of 133 Cases[END_REF][33] [START_REF] Bozinov | Laser interstitial thermal therapy in gliomas[END_REF]. The immunotherapy to treat glioblastoma represents a challenge secondary to the blood-brain barrier (BBB) associated with a suppressive tumor environment [START_REF] Adhikaree | Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma[END_REF] [START_REF] Cloughesy | Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma[END_REF][36] [START_REF] Wick | Lomustine and Bevacizumab in Progressive Glioblastoma[END_REF]. The BBB is a dynamic barrier and its integrity could be compromise by inflammation or brain pathologies [START_REF] Adhikaree | Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma[END_REF]. One other mechanism is developed by Carpentier et al. with the Ultrasound-induced BBB opening to increase the penetration of a large drugs [START_REF] Dréan | Temporary blood-brain barrier disruption by low intensity pulsed ultrasound increases carboplatin delivery and efficacy in preclinical models of glioblastoma[END_REF]. Cryotherapy on glioblastoma could increase the permeability of the BBB with infiltration of monocytes and lymphocytes from the periphery through the interaction between the extracranial and intracranial immune response.

Cells of the immune system assume a protective role for the cancer cells by masking cancer immunogenicity form circulating immune cells with the loss of microglia capacity to present antigens. To counter the inhibitory influences of cancer and intensify the immune potentiating effect of the cryoablation in glioblastomas, the immunomodulatory agents could be associate to the cryosurgery [START_REF] Sabel | Cryo-immunology: a review of the literature and proposed mechanisms for stimulatory versus suppressive immune responses[END_REF].

Glioblastomas are characterized by a T cell dysfunction with a potent suppression of systemic immunity [START_REF] Sampson | Brain immunology and immunotherapy in brain tumours[END_REF]. In this comprehensive review, the cryotherapy results in activation of DC with activation of T cell. The immunotherapy, such as the immune checkpoint inhibitors, on glioblastoma represents a therapeutic challenge secondary to the dysfunction of the T cell with the risk of treatment resistance. By activating DC and TC, cryotherapy could be associate to immune check point blockade and the immunotherapy could be effective.

CONCLUSION

The use of cryosurgery is dependent on image-guided control of freezing the tissue. Adjunctive MR-guided cryoablation may potentially improve therapeutic efficacy for recurrent glioblastoma. A multimodal approach using surgery, radiotherapy, chemotherapy and immunotherapy in combination with cryotherapy represent a potent weapon against glioblastomas. The future immunomodulatory approaches might be combined with brain tumors cryoablation to increase the cryoimmune response. Further research is required to elucidate its potential role in cutting-edge neurosurgical management of this devastating tumor.

  Huang et al. found a synergic anti-tumor action (on glioma C6 model orthotopically implanted) of cryotherapy and TNF-α (tumor necrosis factor-alpha, inducing apoptosis via Caspase 3) secondary to inhibition of proliferation and induction of apoptosis[START_REF] Huang | Cryosurgery and rhTNF-α play synergistic effects on a rat cortex C6 glioma model[END_REF]. Other authors demonstrated that the injection of dendritic cells (DC), in a murine subcutaneous GL261 glioma model, combined with cryosurgery reduces tumor size and significantly prolonged survival in comparison with injection of DC alone, or, with cryosurgery alone[START_REF] Lin | In-situ administration of dendritic cells following argon-helium cryosurgery enhances specific antiglioma immunity in mice[END_REF]. This association increase the percentages of CD3 + , CD3 + CD4 + cells and the ratio of CD3 + CD4 + /CD3 + CD8 + , the level of serum interleukine 12, which stimulated Th1 response and tumor-specific cytotoxic T lymphocytes cells[21]. Li et al. explored changes in tumor tissues of glioma rat that underwent argon-helium cryoablation combined with interleukin 12 treatment. This association boosted the immune function and increases antitumor ability[25]. Other authors analyze the synergism between cryoablation and GM-CSF (granulocyte macrophage colony-stimulating factor stimulating DCs). This association could recruit and activate DCs developing the tumoricidal T-cell responses. They demonstrated an activation of dendritic cells (DC) after cryoablation via the increase of rate of CD80, CD86, CD3, CD4, CD4/CD8, CD8+, CD11+, CD86+ [18][23][26][21][22]. These increases prove an activation of dendritic cells resulting of increase of cellular immunity. The increase of the immunostimulatory cytokines IL6, IL1β, IL 12 and TNFα activate the DC antigen-presenting function and the cytotoxic T lymphocytes to kill tumor cells [21][18]. Zhang et al. observed a decrease of IL10, playing a role on the anti-tumoral effect via DC [19]. IL10, immunomodulatory cytokine, promotes tumor growth. -Apoptosis Apoptosis is characterized by cell shrinkage, chromatin condensation, genomic fragmentation and caspase activation. Huang et al. observed a decrease of PCNA (proliferation cell nuclear antigen) with activation of DNA fragmentation. They demonstrated that the combined treatment, cryosurgery and rhTNFα have a synergic effect on glioma therapy by induction of apoptosis and inhibition of proliferation. Liu et al. found an activation of intrinsic apoptosis (rapid-onset apoptosis via activation of caspase-9) caused by freezing and activation of delayed apoptosis (extrinsic apoptosis via activation of caspase-8) induced by the released cellular contents. Glioma cells surviving under sublethal temperature undergo intrinsic or extrinsic apoptosis, increasing the induction of apoptosis. In vitro, cryoablation inhibits effects on cell proliferation and migration [24][20].


Guillaume Villatte
email: guivillatte@gmail.com

Pierre-Sylvain Marcheix

Maxime Antoni

Patrick Devos

Stéphane Descamps

Stéphane Boisgard

Roger Erivan

Do bibliometric findings differ between Medline, Google Scholar and Web of Science? Bibliometry of publications after oral presentation to the 2013 and 2014 French Society of Arthroscopy (SFA) Congresses

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

Introduction

Bibliometrics consists in quantitative and qualitative analysis of an individual's or group's communication (volume, visibility), and impacts research funding. There are a number of bibliometric data sources, functioning in different ways and liable to give rise to differing statistics. This point has not been investigated in relation to publication following presentation to a French congress. We therefore conducted a study comparing the main bibliometric instruments, aiming to assess: 1) publication rates following oral presentation to the 2013 and 2014 French Society of Arthroscopy (SFA) Congresses according to the database used, and 2) citation rates for these publications according to database. Hypothesis Publication and citation rates differ according to database.

Material and method

All 199 Abstracts of oral presentations to the 2013 and 2014 SFA Congresses were included.

Based on author names and key-words, manual search was conducted in the Medline, Web of Science and Google Scholar databases. Publication characteristics (citation rate) were studied using the 3 databases and the French SIGAPS (Système d'Interrogation, de Gestion et d'Analyse des Publications Scientifiques: Scientific Publication Search, Management and Analysis System) website.

Results

Publication rates according to Medline and Google Scholar were the same (48.2%: 96 articles for 199 presentations), but significantly lower on Web of Science (44.7%: 89/199; p= 0.002). mean 1.5-3.4-fold more citations per article than the other 2 databases. Citation rates between the 3 databases correlated strongly (r= 0.93).

Discussion

The example presented in this study illustrates the differences in bibliometrics found between different databases. There was a 4% difference (7/199 articles) in publication rates following oral presentation to an SFA Congress, and even greater differences in citation rates per article, with 1.5-3.4-fold more citations according to Google Scholar. Bibliometric studies need to acknowledge the database(s) being used, which should be as many as possible to enhance exhaustiveness.

Level of evidence: IV; descriptive epidemiologic study Keywords: publication rate; congress, bibliometry.

Introduction

Clinical and experimental medical research is fundamental to the initial training of young surgeons. It is also vital throughout a physician's career, continuous medical training being mandatory [START_REF] Saab | Publication output of French orthopedic and trauma surgeons: Quantitative and qualitative bibliometric analysis of their scientific production in orthopedics and other medical fields[END_REF][START_REF] Dartus | Bibliometric evaluation of orthopaedics and traumatology publications from France: 20-year trends (1998-2017) and international positioning[END_REF], so that practices can progress, providing ever-more well-adapted care.

Research results are communicated in the community by 2 principal vectors: oral presentation in a national or international congress, and publication of a written article in a journal [START_REF] Erivan | Full-text publication rate of studies reported as 2013 SoFCOT meeting abstracts[END_REF].

Both are often deployed together, as each has its pros and cons. [START_REF] Grant | Economic returns to medical research funding[END_REF][START_REF] Ploug | Should all medical research be published? The moral responsibility of medical journal editors[END_REF].

Bibliometric data can be found in a number of sources, including Web of Science, Google Scholar and Medline, which differ in origin, functioning and referencing system [START_REF] Randelli | Repair versus shaving of partial-thickness articular-sided tears of the upper subscapularis tendon. A prospective randomized controlled trial[END_REF][START_REF] Rouleau | Measurement of combined glenoid and Hill-Sachs lesions in anterior shoulder instability[END_REF][START_REF] Wein | Anteversion and length of the femoral tunnel in ACL reconstruction: in-vivo comparison between rigid and flexible instrumentation[END_REF][START_REF] Gusenbauer | Google Scholar to overshadow them all? Comparing the sizes of 12 academic search engines and bibliographic databases[END_REF]. This may lead to differences in bibliometric statistics that are relevant for researchers, journals and congress organizers. This point has not been investigated in relation to publication following presentation to a French congress. We therefore conducted a study comparing the main bibliometric instruments, aiming to assess: 1) publication rates following oral presentation to the 2013 and 2014 French Society of Arthroscopy (SFA) Congresses according to the database used, and 2) citation rates for these publications according to database. The study hypothesis was that publication and citation rates differ according to database.

Material and method 2.1 Material

A bibliometric study included all oral presentations to the December 2013 and 2014 SFA Congresses. This minimum 5 years' post-congress interval was chosen in the light of findings that 95% of publications following congress presentations are within 4 years [START_REF] Komagamine | Full-text publication rate of abstracts presented at the Japan Primary Care Association Annual Meetings (2010-2012): a retrospective observational study[END_REF]. Two consecutive years were included so as to have a sufficient number of presentations.

The following parameters were studied in the congress Abstracts: main topic (joint: shoulder, elbow, wrist and hand, hip, knee, foot and ankle) and subcategory (focus: ligament, tendon, meniscus, cartilage, anatomy, hardware), country of first author, number of centers involved, methodology (multicenter, prospective, randomized), level of evidence, and subsequent publication as article.

Systematic article search was manual on Medline and Google Scholar and digitized on Web of Science, based on author names and key-words in the Abstract, following a previously described methodology [START_REF] Komagamine | Full-text publication rate of abstracts presented at the Japan Primary Care Association Annual Meetings (2010-2012): a retrospective observational study[END_REF][START_REF] Scherer | Full publication of results initially presented in abstracts[END_REF][START_REF] Al-Hourani | Five-year publication rate of podium presentations at SICOT Annual Conference: an observational study and new objective proposal of conference power[END_REF][START_REF] Kleine-Konig | Publication rate of abstracts presented at European Paediatric Orthopaedic Society Annual Meetings, 2006 to 2008[END_REF][START_REF] Schulte | Publication rate of abstracts presented at the Annual Congress of the German Society of Orthopaedics and Trauma Surgery[END_REF], by two of the present authors. Abstracts were compared between the presentation and the article to check that the two concerned the same study; in case of disagreement, a consensus was reached.

One hundred and ninety-nine presentations were included: 159/199 individual presentations (80%), 28/199 instructional courses (14%), 8/199 fundamental research presentations (4%) and 4/199 symposia (2%). The first author was French in 168/199 cases (84%), other European in 24/199 (12%), North American in 4/199 (2%), and North African in 2/199 (1%). There were 43/199 multicenter studies (22%) and 48/199 reports from international teams (24%).

One hundred and twenty-seven abstracts (64%) concerned clinical studies, including 83/199 prospective (65%) and 14/199 randomized (17%). The retrospective studies (44/199: 35%) were comparative in 11/199 cases (25%). The other presentations concerned experimental studies (37/199: 19%), literature reviews (30/199: 15%), epidemiologic studies (3/199: 1.5%) and case reports (2/199: 1%).

Methods

Three bibliographic databases were searched for post-congress articles: Medline, Web of Science and Google Scholar. Citations per article were also retrieved from each database.

The SIGAPS category and impact factor (IF) of the journal were retrieved from the SIGAPS database. Pearson test. There were no missing data and all Abstracts were analyzed. First-order risk was set at 5% and confidence intervals at 95%.

Statistics

Statistical analyses used

Results

Post-congress publication rates were the same according to Medline and Google Scholar (48.2%: 96 articles for 199 presentations), and significantly lower on Web of Science (44.7%: (89/199; p= 0.002). Table 1 describes the 7 articles [START_REF] Randelli | Repair versus shaving of partial-thickness articular-sided tears of the upper subscapularis tendon. A prospective randomized controlled trial[END_REF][START_REF] Rouleau | Measurement of combined glenoid and Hill-Sachs lesions in anterior shoulder instability[END_REF][START_REF] Wein | Anteversion and length of the femoral tunnel in ACL reconstruction: in-vivo comparison between rigid and flexible instrumentation[END_REF][START_REF] Boughebri | Results of 45 arthroscopic Bankart procedures: Does the ISIS remain a reliable prognostic assessment after 5 years?[END_REF][START_REF] Guillo | Consensus in chronic ankle instability: Aetiology, assessment, surgical indications and place for arthroscopy[END_REF][START_REF] Maqdes | The intra-and inter-observer reliability of the CT-scan based X index to quantify glenoid bone loss in chronic anterior shoulder instability and its impact on decision making[END_REF][START_REF] Wajsfisz | Surgical management of combined anterior or posterior cruciate ligament and posterolateral corner tears: For what functional results?[END_REF] not indexed on Web of Science.

Citation rates differed significantly (p< 0.001) between the 3 databases, with Google Scholar listing 1.5-3.4-fold more citations on average than the other two: 21.7 ± 25.9 [0 -153], 14.1 ± 17.6 [0 -112] and 6.3 ± 9.4 [0 -71] respectively in Google Scholar, Web of Science and Medline. Citation rates in the 3 databases correlated strongly (r= 0.93) (Fig. 1).

Citation rates were significantly associated with the journal's SIGAPS category (p= 0.005) (Fig. 2 Mean IF was 2.6 ±1.8 [0.29-13.2] and figure 1 shows journals according to SIGAPS category.

Discussion

The example of publication following oral presentation at an SFA Congress confirmed the study hypothesis: there was a difference in indexed publication rates between databases, with a 4% lower rate on Web of Science (7/199) compared to Medline and Google Scholar (p= 0.002).

With the development of the Internet in the early 2000s, digitized bibliographic databases became the standard means of access to scientific data [START_REF] Gusenbauer | Google Scholar to overshadow them all? Comparing the sizes of 12 academic search engines and bibliographic databases[END_REF]. Numerous bibliographic sources are available, but it is difficult to determine which is best suited to a given question: several factors can be taken into account, such as how the database functions and its specialization, relevance and volume of contents [START_REF] Brophy | Is Google enough? Comparison of an internet search engine with academic library resources[END_REF][START_REF] Eastman | Coverage, relevance, and ranking: The impact of query operators on Web search engine results[END_REF][START_REF] Grigas | Just Google It"-The Scope of Freely Available Information Sources for Doctoral Thesis Writing[END_REF].

Web of Science is the oldest general scientific database, created in 1960. It is managed by Clarivate Analytics, and since 1997 on-line access has been by subscription. It indexes several specialist databases in medicine, biology, agriculture, mathematics, law, etc. It contains some 100 million articles, the oldest of which date back to the early 20 th century [START_REF] Gusenbauer | Google Scholar to overshadow them all? Comparing the sizes of 12 academic search engines and bibliographic databases[END_REF].

Google Scholar was created by Google in 2004 as an open-access general academic database, and is now the most widely used in the world [START_REF] Van Noorden | Online collaboration: Scientists and the social network[END_REF] thanks to its ease of access and of use. It is also the most widely criticized database, as it is said to be plagued by issues of validity [START_REF] Gusenbauer | Google Scholar to overshadow them all? Comparing the sizes of 12 academic search engines and bibliographic databases[END_REF]: indexing is not controlled by any committee or predefined official rules. Document quality is therefore very variable: articles in indexed peer-reviewed journals, articles in open-access journals, doctoral theses, books and also non-validated free or commercial "gray literature" documents [START_REF] Kesselman | Google Scholar TM and libraries: point/counterpoint[END_REF]. Some 389 million documents were indexed in 2019, the oldest of which date back to the 18 th century [START_REF] Gusenbauer | Google Scholar to overshadow them all? Comparing the sizes of 12 academic search engines and bibliographic databases[END_REF]. These features of the 3 databases can account for the present findings. Five [START_REF] Randelli | Repair versus shaving of partial-thickness articular-sided tears of the upper subscapularis tendon. A prospective randomized controlled trial[END_REF][START_REF] Rouleau | Measurement of combined glenoid and Hill-Sachs lesions in anterior shoulder instability[END_REF][START_REF] Wein | Anteversion and length of the femoral tunnel in ACL reconstruction: in-vivo comparison between rigid and flexible instrumentation[END_REF][START_REF] Boughebri | Results of 45 arthroscopic Bankart procedures: Does the ISIS remain a reliable prognostic assessment after 5 years?[END_REF][START_REF] Maqdes | The intra-and inter-observer reliability of the CT-scan based X index to quantify glenoid bone loss in chronic anterior shoulder instability and its impact on decision making[END_REF] of the 7 articles [START_REF] Randelli | Repair versus shaving of partial-thickness articular-sided tears of the upper subscapularis tendon. A prospective randomized controlled trial[END_REF][START_REF] Rouleau | Measurement of combined glenoid and Hill-Sachs lesions in anterior shoulder instability[END_REF][START_REF] Wein | Anteversion and length of the femoral tunnel in ACL reconstruction: in-vivo comparison between rigid and flexible instrumentation[END_REF][START_REF] Boughebri | Results of 45 arthroscopic Bankart procedures: Does the ISIS remain a reliable prognostic assessment after 5 years?[END_REF][START_REF] Guillo | Consensus in chronic ankle instability: Aetiology, assessment, surgical indications and place for arthroscopy[END_REF][START_REF] Maqdes | The intra-and inter-observer reliability of the CT-scan based X index to quantify glenoid bone loss in chronic anterior shoulder instability and its impact on decision making[END_REF] not found on Web of Science were published in journals not directly indexed there. The other 2 [START_REF] Guillo | Consensus in chronic ankle instability: Aetiology, assessment, surgical indications and place for arthroscopy[END_REF][START_REF] Wajsfisz | Surgical management of combined anterior or posterior cruciate ligament and posterolateral corner tears: For what functional results?[END_REF] were published in a journal indexed on Web of Science and there had probably been a problem of indexing the actual article's Digital Object Identifier (DOI). Citations rates increase with the number of indexed articles (i.e., size of the database). Thus, Google Scholar gives citations rates that are 1.5-3.4-fold higher on average than the others. However, several reports considered Google Scholar unreliable for bibliometric studies or assessing an author's visibility or that of a journal [START_REF] Burright | Google Scholar --Science &amp[END_REF][START_REF] Jacsó | Metadata mega mess in Google Scholar[END_REF], as its functioning is felt to be "obscure" [START_REF] Gusenbauer | Google Scholar to overshadow them all? Comparing the sizes of 12 academic search engines and bibliographic databases[END_REF] and results cannot be controlled.

The present study had 2 main limitations. Firstly, the initial search list comprised articles published following oral presentation to a general orthopedic congress dedicated to arthroscopy. There happen to have been many reports on bibliometric data for congresses, notably in orthopedics-traumatology, in recent years [START_REF] Scherer | Full publication of results initially presented in abstracts[END_REF], providing a benchmark for expected publication rates. Using a search methodology similar to that used in similar studies [START_REF] Erivan | Full-text publication rate of studies reported as 2013 SoFCOT meeting abstracts[END_REF] gave publications rates of 44.7-48.2%, which was around the average found for similar congresses [START_REF] Erivan | Full-text publication rate of studies reported as 2013 SoFCOT meeting abstracts[END_REF][START_REF] Scherer | Full publication of results initially presented in abstracts[END_REF]. Thus, using presentations to the SFA congresses as a basis for the study and as an example to illustrate the hypothesis was validated. Secondly, database search may not have been exhaustive, being manual for 2 of the 3. However, 2 investigators made the search separately for each oral presentation, using the names of the first and last authors and the key-words separately or together, so as to maximize retrieval.

Conclusion

Publication rates following oral presentation to the 2013 and 2014 SFA congresses ranged from 44.7% to 48.2%, depending on the database. This example illustrates the bibliometric differences found between databases. Google Scholar and Medline provided more indexed publications (both at the same rate). Even greater differences emerged for citation rates, with 1.5-3.4-fold more citations according to Google Scholar. Bibliometric

  Excel™ software (Microsoft, Redmond, WA) and the 2019 XLSTAT™ statistical and data analysis solution (Addinsoft, Long Island, NY). Quantitative results were reported as mean ± standard deviation (range), or median and quartiles in case of non-normal distribution on Shapiro-Wilk test. Differences in mean values were assessed on Student or non-parametric McNemar test, according to normality of distribution. Comparison of annual citation rates according to SIGAPS category used Kruskal-Wallis test. Frequencies were compared on Fisher exact or Chi 2 test as appropriate. Correlations were assessed on

  ). Mean congress-to-publication interval was 19.6 ±17 months [-15 to 63]. Mean number of authors was 6.1 ± 2.3 [2-15]. Publications appeared in 26 journals, 6 of which accounted for 75% (71/96): -Orthopedics &Traumatology: Surgery & Research (32 articles, 33%) (SIGAPS D), -Knee Surgery Sports Traumatology Arthroscopy (14 articles, 15%) (SIGAPS B), -Arthroscopy (11 articles, 12%) (SIGAPS B, then A since 2015), -American Journal of Sports Medicine (5 articles, 5%) (SIGAPS A), -Knee (5 articles, 5%) (SIGAPS C), -Journal of Shoulder and Elbow Surgery (4 articles, 5%) (SIGAPS B).

  Medline, since 1972, specializes in life sciences and biomedicine, with documents going back to the early 20 th century. It is publicly funded by the United States National Library of Medicine. Access is free of charge via PubMed. In 2019, it comprised over 31 million indexed documents in about 5,600 journals selected by its Literature Selection Technical Review Committee [24,25]. Selection is based on a set of criteria: quality and influence of published studies, credibility and independence of the editorial board, article selection methodology, etc. Only 20-25% of journals analyzed get selected, making Medline the database most widely used by researchers in biology and medicine.

Figure 1 :

 1 Figure 1: Scatter plot of citations per article according to database. Correlation between the 3 databases was excellent (coefficient r > 0.93).

Figure 2 :

 2 Figure 2: Citations rate according to journal SIGAPS category. The higher the SIGAPS category, the higher the citations rate (p= 0.005). (SIGAPS: Système d'Interrogation, de Gestion et d'Analyse des Publications Scientifiques (Scientific Publication Search, Management and Analysis System)).

Figure 3 :

 3 Figure 3: Distribution of articles according to journal SIGAPS category. 53% of articles (51/96) were in SIGAPS A, B or C. (SIGAPS: Système d'Interrogation, de Gestion et d'Analyse des Publications Scientifiques (Scientific Publication Search, Management and Analysis System)).

Acknowledgments:

The authors thank the SFA and MCO Congrès (Ms Audrey Martin Bayon) for transmission of data.

Disclosure of interest: RE, SD, MA, PSM and PD have no conflicts of interest to disclose.

Outside of the present study, SB is a consultant for Zimmer and GV a consultant for FH Ortho.

Funding: none

Author contributions: GV: study design, data analysis, article writing and re-editing. RE and PD: statistical analysis. PSM and MA: re-editing. SD and SB: supervision.