As we all know, vacuum system is the essential part for the accelerators and colliders, which provide the vacuum environment to minimize beam-gas interactions and maintain normal operation of the beams. With the proposals of future accelerators and colliders, such as Future Circular Collider (FCC), Super Proton-Proton Collider (SPPC), and International Linear Collider (ILC), it is time to review and focus on the key technologies involved in the optimization designs of the vacuum system of various kinds of accelerators and colliders. High vacuum gradient and electron cloud are the key issues for the vacuum system design of high-energy accelerators and colliders. This chapter gives a brief overview of these two key issues of vacuum system design and operations in high-energy, high-intensity, and high-luminosity accelerators and collider.
- vacuum system
- beam-gas interaction
- electron cloud
- secondary electron yield
- non-evaporable getters
The high-energy accelerators and colliders, such as the Intersecting Storage Rings (ISR) [1, 2] at European Organization for Nuclear Research (CERN), the Super Proton Synchrotron (SPS) (CERN) [3, 4], the Tevatron proton-antiproton collider (United States) [5, 6], the abandoned Superconducting Super Collider (SSC) (United States) [7, 8], the Very Large Hadron Collider (VLHC) (United States) [9, 10, 11], the Large Hadron Collider (LHC) [12, 13, 14], the High-Luminosity Large Hadron Collider (HL-LHC) , and the High-Energy Large Hadron Collider (HE-LHC) [16, 17], have been proposed one after another for the discoveries and the establishing of standard model of particle physics.
Circular Electron Positron Collider (CEPC) (120 GeV) [18, 19] and the upgraded stage of Super Proton-Proton Collider (SPPC) (100 TeV) [20, 21, 22] based on lepton-proton colliders were proposed in China to explore the Higgs physics and the new physics beyond standard model, respectively. Moreover, in order to precisely study the flavour physics, such as the top particles, Higgs, Z and W, a luminosity-frontier, low-emittance and highest-energy electron-positron collider (FCC-ee) was proposed by the scientists from European Organization for Nuclear Research (CERN) [23, 24]. As the secondary stage, an energy-frontier hadron collider (FCC-hh) will be used to explore the possibility of existence of the dark matter candidates and get the detailed information of Higgs self-coupling and the mechanism of electroweak symmetry breaking. FCC-ee [25, 26] and FCC-hh  are the two stages of Future Circular Collider (FCC) . FCC has a center-of-mass energy of 100 TeV with proton-proton collisions finally. The key parameters of CEPC, FCC-hh, FCC-ee, HE-LHC, HL-LHC, and LHC are shown in Table 1.
|Luminosity per IP [1034cm−2s−1]||1.8||5–30||1.55–230||28||5||1|
|Circumference C [km]||54||97.8||97.75||26.7||26.7||26.7|
|Beam current [mA]||16.6||500||5.4–1390||1120||1120||584|
|SR power per beam [kW]||50||2400||50||100||3.6||0.0036|
Beam-related instabilities and electron cloud are the critical aspects for vacuum system of the high-energy, high-intensity, and high-luminosity accelerators, which could affect the machine performance and operation .
2. Electron cloud
Electron cloud (EC) issue is one of the important aspects for high-energy accelerators and colliders. The primary electrons produced by the ionization of residual gases or by photoemission are accelerated by the beam and impact on the vacuum chambers and generate secondary electrons. Then, the secondary electrons can be reflected, accelerated, or absorbed in the vacuum chambers, even induce electron avalanche.
Secondary electron yield (SEY) is an important parameter to understand the formation and dissipation of the EC in accelerators . The average of SEY over all electron-wall collisions for a certain time is the effective SEY (), which depends on the chamber and beam parameters. When is less than 1, the net number of secondary electrons balances that of electrons absorbed by inner surfaces of vacuum chambers. When is larger than 1, the secondary electrons grow exponentially and then the EC reaches a dynamical equilibrium with value equating to 1.
The electron accumulation can induce beam losses, beam instabilities, the emittance growth, the heating of the vacuum chambers, vacuum instabilities, and the decrease of detection precision , as shown in Figure 1. The detrimental effects of EC on beam quality have been observed and studied in many accelerators. The estimation and simulation of EC formation process and the exploration of EC inhibition methods are critical for the understanding of EC build-up and related effects.
2.1 Numerical simulations of electron cloud
High-energy beam-induced synchrotron radiation can result in the increase of vacuum pressure and the primary photoelectrons. These can finally contribute to the EC formation. Many parameters can affect the EC formation, such as beam energy , bunch spacing , bunch size, bunch intensity, vacuum pressure, the geometry of the vacuum pipes , the properties of inner surface of vacuum chamber , the secondary electron energy spectrum , etc.
There are three kinds of EC simulation codes: build-up simulation codes, instability simulation codes, and self-consistent simulation codes. The EC density distribution as the function of time and energy and the details of the interaction between electrons and walls can be obtained based on the EC build-up simulation codes with 2D and 3D versions. For the study of EC in isolated regions like field-free regions, 2D codes are preferable. For the study of EC in magnetic regions like fringe fields regions, 3D codes are usually adopted. EC build-up simulation codes cannot get the information on the interaction between the EC and the beam , while instability simulation codes can get the details on the interaction between dynamical beam particles and the prescribed EC. For instability simulation codes, the interaction between electrons and the walls is simplified or negligible. Self-consistent simulation codes are more computational than the above two simulation codes, to better understand the dynamic effects between the electrons and the beams, such as WARP-POSINST codes .
Guillermo et al. studied the details of the build-up of electron cloud and the effect of synchrotron radiation on EC formation based on the code of Synrad3D and the 2D macro-particle code of PyECLOUD . The results demonstrated that the different surface conditions could influence the heat load and average electron line density. The smoother the surfaces, the higher the average linear density for all SEY values selected. For smooth surface, the heat load is the highest. Moreover, the heat load on the inverted sawtooth vacuum surface was slightly smaller than that on the oriented sawtooth surfaces.
The EC build-up and the effect of EC on the proton beam in the SPS accelerator were simulated by Vay et al. , based on the WARP-POSINST codes. The analysis results indicated that the interaction between EC and the proton bunches can induce the increase of emittance, vertical bunch size, leading to the increase of electron density.
The Fortran code ECLOUD was developed to understand the EC effect depending on the specified secondary emission model [41, 42]. The true secondary electrons and reflected electrons and their energy distribution are included in this code, which contribute to the secondary emission. Various shapes such as round pipes, elliptical pipes, and rectangular pipes can be simulated in this code. The detector effect and the scrubbing effect can be simulated to better compare with the experimental results. The general layout of the ECLOUD code (first version in 1997 at CERN by Zimmermann) , the PEI code (in 1995 at KEK by Ohmi) , and the POSINST code (in 1996 at LBNL by Furman and Lambertson)  is basically similar.
The POSINST code was employed by Crittenden et al., to study the EC build-up in the arc dipole region of positron damping ring of International Linear Collider (ILC) . The secondary electron emission (SEE) parameters of a TiN surface tested at Cornell Electron Storage Ring Test Accelerator (CESRTA) were used in the SEY model during the POSINST simulations. The distribution of photons and photon transport in the arc region were calculated by SYNRAD3D code. For the estimations of EC densities in quadrupoles, sextupoles, and field-free regions, the ECLOUD code [41, 47] was used. The simulation results demonstrated that the beam emittance growth during 300 turns and 18,550 turns were 0.16 and 10% because of ECs. When the averaged electron cloud density was 3.5 × 1010 m−3, the beam emittance increased about 0.2% as the chromaticity values increased from 0 to 6 .
The 3D code CLOUDLAND was adopted by Wang et al., to study the EC evolution in the quadrupole and sextupole regions of the ILC/CESRTA with and without ante-chamber . The simulation results indicated that the average EC density in the quadrupole magnet of the ILC can be reduced by 98% under the presence of ante-chamber when the SEY was less than 1.1. When the SEY was larger than 1.1, the effect of ante-chambers on EC densities was not notable. Larger SEY can induce higher EC average densities. The strong space charge can reduce the EC density and change the EC distribution dramatically. Therefore, the reduction of SEYs in quadrupole and sextupole regions is important for the decrease of the photon flux.
2.2 Single and coupled bunch instabilities
When the head of the bunch is diverged from the beam axis and interacts with the EC, it will induce the single bunch head-tail instability . The following bunches will be affected by the new EC distributions and the tails can be deflected finally. The property of EC here is similar to the short-range wake field. The electron distribution, the energy spectrum of electrons, and the evolution of the EC can be simulated and compared with the experimental results. Then, the EC densities were obtained and used for the input parameters to analyze the impact of EC on the bunches.
The bunch instability caused by EC in a linac can induce the beam break-up in the case without synchrotron radiation. And in the case of synchrotron radiation, the instability caused by EC is analogous to the transverse mode coupling instability (TMCI) . The impacts of space charge, magnetic field, the chromaticity, the amplitude detuning, and the broad-band resonator are also considered in the study of the bunch instability caused by EC [50, 51, 52, 53].
The single and coupled bunch instabilities are mainly related to the frequency of the EC, the synchrotron tune, the machine circumference, the beam sizes, the bunch length, the chromaticity, and the relativistic factor , as shown in Figure 2.
Various single bunch instability codes such as MICROMAP (developed at GSI) [55, 56], PEHTS (developed at KEK) [35, 57, 58, 59, 60], CMAD [61, 62], and HEADTAIL (developed at CERN) [52, 63] were developed to study the related effects.
The CMAD code, the HEADTAIL code, and the WARP code were used by Li et al.  to study the effects of various wideband feedbacks on the EC instabilities in CERN SPS, which provided valuable information for HL-LHC. The results showed that a bandwidth of 500 MHz was needed to mitigate the EC when the EC densities were above 1 × 1012 m−3. When the EC densities were above 1.4 × 1012 m−3, a bandwidth of 1 GHz may be required.
The single bunch instability caused by EC with different densities in LHC and SPS was investigated by E. Benedetto et al.  based on the HEADTAIL simulation code [53, 63]. The EC effect on transverse single bunch instabilities in the bending region was simulated and compared with observations in the SPS. And for the LHC, the simulation results indicated that the chromaticity is a key factor for the head-tail instability, but may not for a short- and long-term emittance growth .
Based on the HEADTAIL code and ECLOUD program, the simulation results demonstrated that the instability growth process and the chromaticity beneficial effect were consistent with the observed results, which were reported by G. Rumolo et al. .
Ohmi studied the interaction between the EC and the single bunch via PIC method (PEHTS) in High Energy Accelerator Research Organization B-factory Low Energy Ring (KEKB LER) . The simulation results showed that the strong head-tail instability in KEKB-LER was related to the coherent instability caused by the EC.
In Beijing Electron Positron Collider (BEPC), the single and coupled bunch instabilities caused by EC were studied systematically by Wang et al. . The effects of ante-chamber, TiN films, and clearing electrodes on electron cloud instability (ECI) were explored by simulations and experiments. The simulation and experimental results manifested that the single bunch instability can be reduced below the threshold and the coupled bunch instability can be restricted by the feedback systems.
2.3 Electron cloud mitigation methods
Various methods, such as the electrode cleaning, the solenoid, the beam scrubbing, the film coatings, and geometrical modification (like laser processed surfaces), have been developed for EC mitigation in accelerators and colliders, as shown in Figure 3 [64, 65, 66, 67]. The test results in Relativistic Heavy Ion Collider (RHIC) showed that the solenoids with the magnetic field of 0.5 mT were effective for the EC suppression .
With the advantage of no additional parts introduced, film coatings (like TiN coatings, diamond-like carbon film, highly oriented pyrolytic graphite, and the amorphous carbon film)  and geometrical modification methods were studied widely.
Compared to other films, TiN coatings were applied in accelerators and colliders extensively. Therefore, the related properties and the application of TiN film will be introduced emphatically.
Recently, laser ablation method was proposed as a novel and potential way for reducing the SEY [65, 68] with several advantages, such as low cost, no requirement of vacuum, etc. The impedance issue, desorption properties, and the compatibility with cryogenic vacuum should be evaluated and studied carefully in the future accelerators and colliders.
2.3.1 TiN film
In order to mitigate EC in accelerators, TiN film coatings were employed in the inner surface of vacuum chambers [69, 70, 71, 72, 73, 74, 75]. The experimental results indicate that TiN film coating is an effective way for EC mitigation. The effects of substrate materials, the stoichiometry, film thicknesses, ion/electron bombardments, and deposition parameters on the SEY and related properties of TiN have been investigated systematically [70, 72, 74, 76, 77, 78, 79, 80, 81, 82, 83].
TiN film coatings were deposited on the inner surfaces of copper beam ducts in KEK by Shibata et al. [74, 75]. As an example, a pipe length of 3.6 m was coated and installed in the KEK B-factory positron ring using a titanium rod of 4.2 m long. The maximum SEY () of the TiN film coatings varied between 0.70 and 1.58 with the electron doses ranging between 10−1 and 10−5 C mm−2. The coated chambers were tested in LER. The test results manifested that the EC density in the coated chambers decreased about ~33% comparing to that of the uncoated ones at the beam current of 800 mA.
In Laboratory of the Linear Accelerator-Orsay (LAL-Orsay), TiN film coating was used as the EC inhibition method in the RF ceramic windows . The planar and cylindrical alumina ceramics were the substrates with the properties of high mechanical strength, high stability, and low outgassing rate. The SEY of the alumina ceramic was decreased by depositing the TiN film on its surfaces, which will benefit for the avoiding of electron multipactor.
The effects of H2 gas, ion, and electron conditioning on the SEY of TiN coating for EC suppression in storage rings were investigated by F. Le Pimpec et al. in Stanford Linear Accelerator Center (SLAC)  and Lawrence Berkeley National Laboratory (LBNL) [70, 72, 84]. The of TiN coating was reduced from 1.50 to 1.10 after N2+ ion bombardment. During N2+ ion bombardment, the contaminants, such as hydrocarbons, water, and oxide with high SEY, were removed, which contributed to the SEY decrease of TiN coating. Ion bombardment could induce the interstitial N, while the vacancies may be filled by the nitrogen from the beam pipe . The of TiN coating with Al substrates ranged from 1.52 to 1.99. The thickest TiN coatings with Al or stainless steel substrates had the lowest SEY here. As the electron conditioning doses increased, the maximum energy (Emax) corresponding to the shifted to lower energy and the SEY curves bend disappeared. This SEY evolution may be related to the removal or dissociation (from TiO2 into defective suboxide) of the surface contaminants. When the TiN coatings were baked out in vacuum at 150°C for 2 h, the decreased from 1.70 to 1.60 . For the TiN coating deposited on the grooved Al surface, the of TiN coatings decreased to 1.30 from 2.30.
The vacuum pipes of different sizes in Spallation Neutron Source (SNS) were coated with TiN films by reactive DC magnetron sputtering in Brookhaven National Laboratory (BNL) [64, 71]. The arc regions, straight sections, injection kicker ceramic chambers, and extraction kicker modules were deposited with TiN, with the lengths of 0.5–5 m and the diameters of 20–36 cm.
The TiN films were coated on the racetrack-type ceramic pipe for the EC suppression in National Synchrotron Radiation Laboratory by Wang et al. [86, 87]. CST PARTICLE STUDIO software was used to optimize the TiN film thickness in magnetron sputtering system. Moreover, two kinds of Ti cathodes (Ti rods and Ti plates) were adopted and compared to improve the TiN film deposition rate.
In order to reduce the electron multipactor effects and improve power transmission in the TESLA couplers at DESY, TiN films were applied on the inner surface of the wave guides and the RF windows . The performance of low SEY remained steady even after 24 h air exposure. In addition, the RF conditioning time reduced from ~3 days to 4–6 h due to the TiN films.
Above all, the thicknesses, SEYs, and substrates of the TiN films were summarized in Table 2. The film thicknesses of TiN films were usually ranging from 7 to 200 nm. Aluminum alloy, stainless steel, copper, and ceramic are generally chosen as the substrates.
|KEK [74, 75]||Copper (beam ducts)||100–200||1.05–1.60|
|LAL ||Ceramic (RF windows)||7–15||1.50|
|SLAC & LBNL [72, 78, 84]||6063 aluminum alloy/stainless steel||100–204||1.01–1.99 (ion and electron conditioning)|
|BNL [64, 71]||Ceramic/stainless steel (chambers)||~100||Less than 1.80|
(coupler windows, couplers)
|NSRL [86, 87]||Ceramic||45–3200||/|
2.3.2 Other films
Besides TiN coatings, other low SEY film coatings, like the carbon film , highly oriented pyrolytic graphite (HOPG) , the diamond-like carbon film (DLC) , and the amorphous carbon coatings (a-C)  will be introduced in this section.
Ceramic pipes were used in the rapid-cycling synchrotron (RCS) of the Japan Proton Accelerator Research Complex (J-PARC) to avoid the eddy current effect . In order to reduce the electron emission from the internal surfaces of the ceramic pipes, the DLC coating was applied as a possible alternative method. The experimental results indicated that the SEYs of DLC coating exposing to the water/oxygen/electron beam were 1.15–1.20 and less than that of TiN coatings (1.50–1.70).
Amorphous carbon films with the of 0.92–1.33 have been used on the vacuum pipes for the EC elimination in SPS with LHC-type beam [90, 91, 92]. The test results demonstrated that the EC can be suppressed in the liners even after air exposure for 3 months. Moreover, the properties of a-C films were stable after 3 years beam operations.
Carbon films  were prepared with the of ~0.97, which was lower than that of HOPG (~1.23) . The SEY difference between carbon films and HOPG can be ascribed to that the density of carbon films was smaller and the larger penetration range and the SEs scattering to defects/pores than that of HOPG. The XPS results showed that the SEY values were related to the C 1 s high binding energy. When the concentration of oxygen was below 16 at%, it would not affect the SEY of carbon films.
3. High vacuum gradient
The rough pumps, the turbo molecular pumps, and the ion pumps are usually adopted between the ends of vacuum pipes in accelerators and colliders. These pumps can reduce the pressure efficiently near it, while the pressure in the middle of the vacuum pipes is higher than the ones near the pumps. In other words, the application of traditional pumps can induce the high vacuum gradient. In order to reduce the vacuum gradient in the long vacuum pipes, non-evaporable getter (NEG) coatings were proposed to solve this issue [94, 95, 96, 97, 98, 99].
Generally, NEGs are the alloys Fe, Al, Zr, etc., with the property of absorbing residual gases, like H2, CO, and CH4, after high-temperature activation in vacuum systems. NEGs are widely used in accelerators and colliders for the achievement of ultra-high vacuum (UHV) and provide distributed pumping [97, 100, 101]. The H2 outgassing rate for aluminum alloys or stainless steel is about 10−13 Torr l s−1 cm−2, which is the main obstacle for UHV achieving. In order to reduce the outgassing rate and achieve the required ultimate pressure, NEG alloys were applied in vacuum systems.
3.1.1 NEG binary NEG alloy
Binary NEG alloy Zr-Al (St101)  was prepared on both sides of strips of getter pumps with the activation temperature of ~700°C and applied in the vacuum pipes of Large Electron Positron (LEP) Collider at CERN.
Zr-Fe (St198) NEG alloy has been applied in various scenarios, such as the N2-filled devices, the integrated electronic circuit for N2 purifier, the conversion of tritiated water, hydrogen storage devices, and the hydrogen isotopes absorption and desorption . The XPS results indicated the surface chemical state changes during thermal activation. At higher activation temperatures, the concentration of metallic Zr improved in the surfaces. The concentration of carbon increased gradually under the case of activation temperature of less than 400°C and then decreased.
The ESD, pumping speed, and ultimate pressure of Ti-Hf, Hf-Zr, and Ti-Zr binary  NEG were studied and compared by C. Benvenuti et al. Thereinto, the Ti-Zr NEG alloy has the lowest activation temperature of ~200°C. The ultimate pressure of ~10−11 Pa can be obtained using the binary coatings, which can provide the pumping speed for H2 of ~0.5 l s−1 cm−2.
3.1.2 Ternary NEG alloy
Ternary NEG alloys, like Ti-Zr-V and Zr-V-Fe (St707, St737) NEG films [96, 104, 105, 106, 107], have been applied in the vacuum system of accelerators and colliders. Ti-Zr-V NEG coatings have the activation temperature of less than 200°C . The absorption and desorption mechanisms during thermal activation and pumping properties of ternary NEG alloy coatings have been investigated extensively.
The research results showed that the concentrations of Ti and Zr were enriched on the surface of activated Ti-Zr-V NEG films [108, 109]. The oxygen detected on the activated surface was mainly in the form of Zirconium suboxides and titanium suboxides.
For the sake of reducing the activation temperature of ternary NEG alloys, different compositions of Ti, Zr, and V elements were produced on stainless steel surfaces. The surface chemical state and crystal structure variations of Ti, Zr, and V elements were analyzed by Auger electron spectroscopy (AES) and X-ray diffraction (XRD) during thermal activation . The getters with a nanocrystalline structures could be activated more easily as the activation behavior is related to the solubility and the diffusion of oxygen.
3.1.3 Quaternary NEG alloy
Quaternary Ti-Zr-Hf-V NEG films were proposed by Malyshev with the advantage of lowest activation temperature of ~150°C [110, 111, 112]. Comparing to the ESD yields for all desorbed species (H2, CO, and CO2) of Ti-Zr-V NEG films, those of Ti-Zr-Hf-V NEG films were lower. Two kinds of Ti-Zr-Hf-V NEG films, the dense one and the columnar one, were prepared. The experimental results demonstrated that the columnar one has lower initial ESD yields, the higher pumping speeds, and capacities for all desorbed species than that of the dense one. In addition, a dual-layer NEG coating was prepared with the bottom dense layer and the top columnar layer. Here, hydrogen diffusion can be barred by the bottom layer. The ESD of hydrogen can be improved and the pumping properties can be enhanced by the top layer.
To understand the effect of the coatings on the wakefield impedance, the surface resistance of Ti-Zr-Hf-V NEG films was tested and analyzed at 7.8 GHz . Based on the analytical model, the conductivities of dense and columnar NEG coatings were 8 × 105 S/m and 1.4 × 104 S/m. The surface resistance of copper increased slightly after NEG coating depositions.
3.2 Photons-/electrons-/ions-stimulated desorption
The photons-/electrons-/ions-induced gas desorption may result in pressure instability and then lead to the beam loss. The ionization of residual gases is proportional to the beam current. Therefore, the materials, the geometry, and the pumping speed of the vacuum systems should be considered carefully [113, 114, 115, 116, 117, 118, 119, 120]. In order to reach the base pressures of ~10−9 Pa and reduce the pressure instability, low photon-stimulated gas desorption (PSD) yield, electron-stimulated gas desorption (ESD) yield, and ion-stimulated gas desorption (ISD) yield materials are preferable in vacuum systems.
The ESD and ISD yield of the commonly used materials like the OFHC, the stainless steel in accelerators and colliders, were measured and analyzed during the bake out at 150–600°C . The test results indicated that the surfaces of metallic oxide may have the porous structures, which can trap the residual gases such as H2 and CH4.
The ion-induced pressure instability, firstly observed at CERN, can limit the beam current in accelerators and colliders and has been studied intensively [121, 122, 123]. The effects of the ion dose, the mass, and the energy on the ISD yields of copper and aluminum were investigated . The desorption yields of the copper and the aluminum decreased by two times after the bake out. NEG coatings are the mostly used solution for reducing the ion-induced vacuum stability .
It was found that the application of beam screen can effectively reduce the vacuum instability caused by ISD, ESD, and PSD at room temperature and cryogenic regions in LHC . For example, the average H2 density caused by PSD could be reduced by over 50 times by incorporating the beam screen in the vacuum pipes . Moreover, glow discharge and baking are also useful methods for the reduction of ion-induced pressure instability [125, 126].
4. Final remarks
This chapter introduces the two key issues: electron clouds and high vacuum gradient. Electron cloud issue may influence the beam quality and stability in accelerators and colliders. Various methods, such as the DLC film, the a-C film and laser processed surfaces, have been proposed for the EC mitigation in the warm and cryogenic regions. As for the high vacuum gradient issue, the preparation and properties of binary/ternary/quaternary NEG alloy films have been studied to decrease the activation temperature and beam-gas interactions and also to improve the pumping properties, PSD, ESD, and ISD yields at room temperature and cryogenic temperature. For the design of UHV vacuum system of accelerators and colliders, the quality, the conformity, and the engineering aspects should be investigated and analyzed carefully. In regard to vacuum operations, the safety, reliability, and the machine performance limitations should be considered and tested carefully.
We would like to thank our colleagues from Xi’an Jiaotong University: Prof. Shaoqiang Guo, Prof. Zhanglian Xu, and Ms. Jing Zhang for useful suggestions. This research was funded by the National Natural Science Foundation for the Youth of China No. 11905170, the Fundamental Research Funds for the Central Universities No. XJH012019018, and the National Natural Science Foundation of China under Grant No. 11775166.
Conflict of interest
The authors declare no conflict of interest.