Radiation Environment and Medicine 2023 Vol.12, No.2 81–90

Review

Biophysical Simulations for Estimating Biological Effects after
Exposure to Ionizing Radiation: Current State and Future Prospects
Yusuke Matsuya1, 2* and Ryo Saga3
2

1
Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo 060-0812, Japan
Nuclear Science and Engineering Center, Japan Atomic Energy Agency, Shirakata 2-4, Tokai 319-1195, Japan3
Department of Radiation Science, Graduate School of Health Sciences, Hirosaki University,
66-1 Hon-cho, Hirosaki, Aomori, 036-8564, JAPANReceived 5 April, 2023; revised 6 June, 2023; accepted 14 June, 2023

Monte Carlo radiation transport simulations and biophysical models are powerful tools to evaluate
the biological effects after exposure to ionizing radiation in radiation protection and radiation
therapy. During human body exposure to radiation, DNA lesions as an early biological response
are induced by energy deposition, leading to cell death with a certain probability. Thus, conducting
translational studies focusing on radiation physics, cellular biology, and oncology is warranted.
Herein, two simulation tools for predicting biological effects are introduced, that is, Particle andHeavy-Ion Transport code System (PHITS) and integrated microdosimetric-kinetic model (IMKM).
To date, the PHITS code, which implements track-structure calculation at a DNA scale, allows
estimation of the DNA damage yields through electrons and protons in various forms, such as
single-strand break (SSB), double-strand break (DSB), and complex DSB (that is DSB coupled withadditional strand breaks within 10-bp separation). Meanwhile, the IMKM which was developed
to consider microdosimetry, the DSB damage responses and heterogeneous cell population can
successfully reproduce experimental cell surviving fraction for various irradiation conditions,which can realize the translational study between in vitro cell survival and clinical tumor control
probability in cancer treatment. These models would allow a precise understanding of cellularresponses after exposure to ionizing radiation. Throughout this review, we discuss the latest status
and future prospects of these simulation tools.
Key words: track-structure simulation, biophysical model, DNA damage, cell surviving fraction,
tumor control probability

1. Introduction
Energy deposition as a biological sequela of ionizing
radiation can induce mutations, cell deat h, andcarcinogenesis1). While cell-killing effects against cancer*Yusuke Matsuya: Faculty of Health Sciences, Hokkaido University, Kita-12,
Nishi-5, Kita-ku, Sapporo 060-0812, Japan
E-mail: matsuya.yusuke@hs.hokudai.ac.jp (Yusuke Matsuya)
https://doi.org/10.51083/radiatenvironmed.12.2_81
Copyright © 2023 by Hirosaki University. All rights reserved.

can be used as a positive phenomenon in radiation
therapy, radiation-induced biological effects should be
minimal as far as possible. Cell death is mainly induced
by DNA lesions, particularly double-strand breaks(DSBs) with a certain probability2-4). Energy deposited byatomic interactions of radiation (physical processes) andsubsequent reaction of free radicals to DNA (chemical
processes) are the major pathways of inducing DNA
damage, referred to as direct and indirect effects5).
Therefore, when evaluating the biological effects after

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radiation exposure, the mechanisms of early DNA
damage induction based on physics play a key role.
A simulation approach based on physical processes
for estimating radiation-induced biological effects is achallenging research topic but is effective for clarifying
cellular mechanisms, which has gained popularity
worldwide.
When evaluating early biological responses, the Monte
Carlo track-structure simulation codes which enable
simulating each atomic interaction (such as ionization andelectronic excitation) are useful. There are various kindsof track-structure simulation codes such as PARTRAC6),
Kyushu University Radiobiology Unit Code (KURBUC)7, 8),
Geant4-DNA 9-11), RITRACK 12, 13), NASIC14), TRACEL 15),
MCNP616), WLTrack 17), and Particle and Heavy Ion
Transport code System (PHITS)18). Some existing codessuch as Geant4-DNA and PHITS are available free ofcharge, whereas most of them are private code notavailable without the developerʼs permission. Using aspatial pattern of deposited energy or atomic interaction
density in a small target composed of liquid water, theyields of early DNA damage (i.e., single-strand break[SSB], DSB, and complex DSB) after ionizing radiation
exposure have been calculated19-22). The DNA damage
simulation plays an important role in elucidating theinduction mechanisms of initial DNA damage yields
after exposure23, 24). Particularly, the complex DSB (thatis DSB coupled with additional strand breaks within 10bp separation), which is recognized as a refractory lesion
but is difficult to be experimentally detected, can bequantitatively estimated through the simulation approach.
However, the computational time for calculating DNA
damage yields is generally prolonged because chemical
simulation for free radicals25, 26) is a time-consuming
method. Therefore, development of a DNA damage
estimation model with a short computational time iswarranted.
Meanwhile, for biological effects such as cell death, asimple mathematical model named the linear-quadratic(LQ) model is traditionally used27-29). The LQ model
enables interpolation of experimentally measured doseresponse curve of surviving fraction; however, the model
must be applied to experimental results measured foreach irradiation condition. Meanwhile, a few mechanistic
models have been proposed by researchers to predictsurviving fraction for various radiation qualities
representing linear energy transfer (LET), such as
microdosimetric-kinetic (MKM)30, 31) and local effect model(LEM)32). Once MKM is applied to the in vitro cell survival
curve after photon irradiation, MKM allows estimationof the curves for various LET irradiations 33) and isadvantageous in applying estimates of cell killing afterparticle therapy such as protons, carbon ions, and multiions34-36). In recent decades, detailed mechanistic models

based on physical, chemical, and biological processes havebeen proposed, that is, modified MKM37), BIophysicalANalysis of Cell death and chromosome Aberrations(BIANCA)38), NANodosimetry and OXydative (NanOX)39),
stochastic MKM (SMKM)40, 41), and integrated MKM(IMKM)42). As such, biophysical models have beenused for investigating cellular mechanisms related toradiosensitivity (i.e., cell killing).
Here, we introduce two simulation tools for predicting
biological effects, namely, PHITS, and IMKM. The
PHITS code is a general-purpose Monte Carlo code
which have been used for various applications such asradiation shielding, medical physics, and geosciences18).
To date, the track-structure modes in the PHITS code, socalled PHITS-ETS43) and PHITS-KURBUC44), have beendeveloped, and an analytical code for predicting DNA
damage yields based on the modes has been includedin the PHITS package43). Meanwhile, to estimate theradiosensitivities for various experimental conditions,
IMKM has a unique biophysical model considering thephysical, chemical, and biological factors33, 45-48). IMKM has
successfully reproduced in vitro cell surviving fraction
and clinical tumor control probability (TCP)48). In radiation
protection and radiation therapy, a precise understandingof cellular radiation responses after exposure to ionizing
radiation can be achieved through the combination ofthese estimation tools. In this review, we discuss the latest
status and future plans of these simulation tools.
2. Particle and Heavy Ion Transport Code System(PHITS)
The PHITS code18) is one of radiation transport simulation
codes which have been developed worldwide. The code
can handle most of the particle types with energies up
to 1 TeV/n using several nuclear reaction models anddata libraries. There are two types of radiation transportmodes: one is condensed-history method for macroscopic
calculation at the cm scale and track-structure simulationconsidering each atomic interaction at the DNA (nm)scale49). As for the former mode, the PHITS code uses the
ATIMA mode (http://web-docs.gsi.de/~weick/atima)
and electron gamma shower (EGS) mode50) available
for arbitrary materials. Meanwhile, the latter trackstructure mode can generate realistic tracks of electrons,
positrons, protons, and carbon ions in liquid water43, 44).
The track-structure mode has been used for investigating
biomolecular dissociation processes as a physicalstudy51). Using the spatial patterns of atomic interactions(ionizations and electronic excitations) calculating the
track-structure modes, the SSB, DSB, and complex
DSB yields can be estimated49). The DNA damage yieldstimulation is illustrated in Figure 1.

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83Fig. 1. Flow of DNA damage yield estimation using the Particle and Heavy-Ion Transport code System (PHITS) code.
When using the track-structure modes (PHITS-ETS, PHITS-KURBUC)43, 44), the coordinates of atomic interactions
are firstly calculated. Second, the number of events (ionizations and excitations), linkage (which is a pair within 10-bp
separation), and DNA damage (strand break and double-strand break [DSB]) yields for each radiation track is estimated.
The current DNA damage simulation model can be available for electrons, positrons, and protons43, 65).

2.1. Track-structure mode for physical processes
In 2018, to extend the transport of electrons andpositrons down to 10 -3 eV 18), a track-structure modefor electrons and positrons in PHITS was developed,
which is called PHITS-ETS or etsmode43). Other codessuch as Geant4-DNA can simulate kinetics of electrons
only for energies down to 7.4 eV52). Comparing PHITSETS with other codes, the electron transport using alower energy than 7.4 eV is an advantage. To simulate
each atomic interaction in liquid water, the PHITS-ETS
mode considers the cross-sections of elastic scattering,
five ionizations, six excitations, dissociative electron
attachment, vibrational excitations, photon excitations,and rotational excitations, which are used in the dynamic
Monte Carlo Code (DMCC)53-56). These cross-sections forelectrons are dedicated for liquid water. Meanwhile, thepath length of electron in material other than water canbe scaled based on electron densities of material, andthe scaling model has been benchmarked compared tothe track length using the EGS mode49). The PHITSETS mode has been available for PHITS version after
3.02. Additionally, in 2022, the track-structure mode forsilicon (so-called PHITS-ETS for Si) has been recently
developed, which is useful for investigating radiation
detectors such as semiconductor devices57).
In 2020, in collaboration with Nikjoo, and Liamsuwan,
developers of the track-structure code named as
KURBUC, the track-structure mode for protons andcarbon ions in liquid water has been developed44). The
mode uses the KURBUC algorithms for the ions and84

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Fig. 2. DSB yields calculated using the PHITS code. (A) DSBs induced after electron exposure and (B) DSBs induced
after proton exposure44, 65). To calculate the yields, activation of the PHITS-ETS mode occurs when electrons aretransported until they fully stop within liquid water. Meanwhile, in calculating the yields for protons, 1% of the protonenergy is being deposited in this region when PHITS-KURBUC is activated.

PHITS-ETS for electron transport, which is named as
PHITS-KURBUC. The PHITS-KURBUC mode considers
the cross-sections of ionizations, excitations, and charge
exchange, which was implemented in KURBUC code58-60).
The available energy ranges of protons and carbon
ions are from 1 keV to 300 MeV and from 1 keV/n to
10 MeV/n, respectively. The PHITS-KURBUC modeis implemented in PHITS version after 3.20. In 2021,
the Ion Track-Structure model for Arbitrary Radiation
and Targets referred to as ITSART has been further
developed61), which is implemented in PHITS version
after 3.25. The current ITSART mode considers theionization cross-sections and is now under development
to demonstrate elastic scattering, excitation, and charge
exchange.
Thus far, these modes have been benchmarked
by compa r ing t he ra nge, st opping pow er, a nd
microdosimetry calculated by the track-structure modes
to other simulation and recommended data (such as the
ICRU report)43, 44, 49). One of the advantages of the trackstructure modes in PHITS is not only considering thediscrete levels of ionizations, excitations, and molecular
excitations but also enabling simulating the spatial
distributions at a DNA scale. The discrete levels canbe used when evaluating generation of free radicals(physicochemical processes)62). Meanwhile, ionizationand excitation patterns can be useful for investigating
mechanisms of DNA damage induction6, 63). In addition, thechemical simulation also plays a key role in investigating
mechanisms on DNA damage induction5). The chemicalcode dedicated for PHITS is now under development andwill be included in the PHITS package in the near future.
2.2. DNA damage simulation based on atomic interactions
In the PHITS package in the PHITS version after 3.10,
an analytical code for estimating the yields of DNA
lesions is included43). The DNA damage estimation modelin PHITS is simple, which uses the spatial patterns ofionizations and excitations (so-called events). In themodel, the frequency of events per energy deposition andthat of linkages (composed of two events within the 10-bp
separation) per energy are assumed to be proportional to
the yields of strand break (SB) and DSB, respectively43).
Furthermore, the DSB coupled with an SB and that with
two SBs within 10-bp separation (which are defined as
DSB + and DSB ++) can be estimated by scoring thenumber of events within a 10-bp radius sphere64). The
DSB+ and DSB++ are called complex DSB in this review.
The criteria for predicting the complex DSBs are 2 –14
for a simple DSB, 14 – 26 for DSB+, and 26–38 for DSB++.
These DNA damage yields have been traditionallyestimated by energy deposited within a small target
or ion cluster size19, 21). The model of the PHITS code
can efficiently sample these frequencies of events andlinkages within a region where the track-structure modeis activated, leading to an efficient estimation of the SSB,
DSB, and complex DSB yields within a short calculation
time.
The accuracy of the DNA damage estimation model
has been benchmarked by comparing the estimationby the model with the corresponding experimental
data. Figure 2 shows the energy dependence of DSB
yields for (A) electrons and (B) protons, in which theyields for electrons and protons were estimated using
the P H ITS-ETS and the P H ITS-KU RBUC modes,
respectively43, 65). As shown in Figure 2, the yields by the
PHITS code were compared to the experimental results,
showing good agreements between the simulationand experimental data. The accuracy of the SSB yield(as well as the relative biological effectiveness [RBE])
estimated by PHITS was evaluated and compared to theother simulations (such as PARTRAC and Geant4-DNA)and experimental data66-71), as reported previously49, 65).
The DSB+ and DSB++ cannot be directly observed via

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Fig. 3. Overview of the integrated microdosimetric-kinetic model (IMKM). Setting the radiosensitive factor byresearchers, the IMKM allows estimation of cell killing (surviving fraction) and TCP42, 48). To date, the model considers
microdosimetry, oxygen effects, DNA repair during irradiation, cell-cycle phase, intercellular signaling, existence ofcancer stem-like cells, and cell proliferation. Using data from calculated or measured DNA damage yields, the IMKM canbe used as a mechanistic study for cellular responses after ionizing radiation exposure45, 83).

an experimental approach. To solve this problem, theexperimental yields of DSBs coupled with base lesions(so-called clustered DSB) induced after 70 kVp X-rays,
which was detected by atomic force microscopy72), wereused to validate the model in PHITS. As a result, it was
shown that scoring of the number of events within a 10bp radius sphere is simple but sufficient for reproducing
the experimental yields of clustered DSBs64). To date, themodel was further validated by comparing it with thephoton-induced γ -H2AX focus size representing DSB
complexity73). The γ -H2AX focus formation assay is wellknown as an experimental method that can detect the
DSB site within cultured cells after irradiation74-77).
The current DNA damage estimation model enables
the efficient estimation of DNA damage yields only for
low-LET radiations (i.e., < 30 keV/μm)65). This is because
in this model, the implicit consideration of chemical
reactions has some drawbacks. Therefore, the influenceof LET is not explicitly accounted for. Other simulations
using the KURBUC and PARTRAC codes consider theindirect effects induced after chemical processes (i.e., theG value of hydroxyl radical [radical])78, 79). To employ the
DNA damage model to high-LET irradiation, developing achemical simulation code is necessary to further develop
a mechanistic study and a simple chemical model for
expressing LET dependence on indirect DNA damage
yields for efficient estimation in the near future.
3. Integrated Microdosimetric-Kinetic Model(IMKM)
To investigate the dose-rate effects after protracted
exposure, the IMKM was developed to assess the DNA
repair during irradiation (DNA targeted effects) and nontargeted effects (NTEs) after low-dose acute irradiation42, 80-82).

In the IMKM, a cell nucleus is divided into hundreds ofmicron-order territories (so-called domains) which are in
general defined as 1–2-μm diameter spheres to evaluate
the heterogeneous energy deposition in the cell. To
demonstrate the DNA damage responses during and after
irradiation by using the rate equations, two lesions, thatis, potentially lethal lesion (PLL) and lethal lesion (LL),
are assumed46). The PLL and LL mean reparable lesion
and non-reparable one, respectively. To date, IMKM has
been developed to consider microdosimetry33), oxygen
effects45), DNA repair during irradiation46, 80-82), cell-cycle
phase46), NTEs (i.e., bystander effects and protective
effects induced by intercellular communication between
irradiated cells and non-irradiated cells)42, 83), existence ofcancer stem-like cells47), and cell proliferation48). As shownin Figure 3, using the physical, and biological information
previously, for example, radiation quality, oxygenpressure, and content of cancer stem-like cells, IMKM can
predict surviving fraction of mammalian cells and TCP ofcancer as a function of absorbed dose.
3.1. Prediction of cell survival considering various factors
Considering the development based on the MKM, the
IMKM allows for the estimation of LET dependence on
biological effects (i.e., RBE), and the dose-rate effects forvarious LET radiations33). To consider LET dependence,the dose-mean lineal energy (yD value)84) with saturationcorrection at a higher LET than approximately 100 keV/
μm is considered in the model. Using the tally (named ast-sed) in PHITS, the yD value can be easily calculated85).
For example, the IMKM was used to evaluate thesurviving fraction of melanoma after boron neutron
capture therapy (BNCT), in which 10B is administered tocancer cells and is rendered as one of the most effective
approaches for malignant tumor treatment using high-86

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LET α particles and Li ions generated by 10B(n, α )7 Li
reaction86, 87). From the model analysis, compared to 60Corays irradiation with low LET, the model estimation
exhibited a reduced impact on cell recovery during highLET irradiation33).
Through the repair dynamics of PLL, the IMKM canbe applied to study the biological effects after protracted
exposure. T he repair of PLLs during irradiationconsidered in the IMKM was found to correspond to DSB
repair from the γ -H2AX focus formation assay88). At ahigh-dose range, the DSB repair during irradiation canillustrate the characteristics of log of surviving fraction
in a rectilinear form80, 81). Traditionally, to express therectilinear form, several biophysical models, such as theuniversal survival curve (USC)89) and LQ-Linear (LQ-L)
model90), have been proposed; however, the IMKM canmechanistically illustrate the rectilinear form using thecorrelation factor, that is, the reduction of coefficient todose square β (Gy-1), which is called the Lea-Catchesides
time factor 91). Furthermore, cell-cycle distributions(where are intrinsically related to radiosensitivity) can be
modified depending on dose rate during the protracted
exposure46, 81). The cell-cycle change of Chinese Hamster
cell (CHO-K1) during irradiation was considered as
the changes of DNA amount per cell and the S-phasedependent repair efficiency46). Using the experimental cellcycle change, the model simulation suggested that thechange in cell-cycle phase during protracted irradiation
with 250-kVp X-rays modulates the dose-response curveand is possibly responsible for some inverse dose-rate
effects in mammalian cells46).
The impact of radiosensitivity can be enhanced byintercellular signaling from radiation-hit cells to nonhit cells. The time course of intercellular signals (suchas calcium92) and nitric oxide93)) has been modeled in
the IMKM42). In the model, a target of intercellularsignal release (which is defined as cell-killing signals in
the model) is micron-order site (domain)94, 95) linked tomitochondria96). Particularly, to release the signals, thenumber of hits follows a linear-quadratic function ofdose imparted in a domain42). Assuming that the yield of
LL in non-hit cells is proportional to the fractions of hit
cells and non-hit cells, the IMKM enables estimation ofcell killing of both normal fibroblasts and various cancer
cells induced by intercellular signaling (NTEs) after
acute exposure. To date, using the model, IMKM has
successfully reproduced the experimental low-dose hyperradiosensitivity and bystander effects42). Furthermore, themodel is useful when investigating the radiosensitizing
mechanisms of cancer cells through the hyaluronan
synthesis inhibitor 4-methylumbelliferone (4-MU)97).
Among the several outcomes of this model, a successful
theoretical analysis of the impacts of modulated radiation
fields on radiosensitivity and cell recovery during dosedelivery was conducted 83). In 2020, the DSB yields
depending on the oxygen pressure was considered in
the IMKM, which enables prediction of the oxygen
enhancement ratio (oxygen effects)45). By integratingintercellular signals and oxygen effects, the latest IMKM
facilitates a more precise understanding of intercellularsignaling and oxygen effects following exposure tointensity-modulated radiation fields for cancer therapy98, 99).
3.2. Application of the IMKM to clinical studies
During in vitro radiosensitivity analysis, the use of
IMKM, assuming that cultured cells are composed ofa homogeneous cell population, is sufficient. However,
the actual tumor tissue affected by radiotherapy iscomposed of heterogenous cell populations, that is, nonradioresistant cells (progeny cells) and radioresistantcells (cancer stem-like cells)100). Both radiosensitivity andcurative effects are largely dependent on the biologicalfactors based on the 4 ʻʻRʼs” concept, namely, repair,redistribution, repopulation, and reoxygenation101).
Additionally, the fifth biological factor, “radiosensitivity”(heterogeneity of radiosensitivity) has been highlighted
recently102, 103). Considering these, since 2019, we started
to develop IMKM to explicitly consider the existence ofcancer stem-like cells47).
The first model analysis for cancer stem-like cells was
performed by applying the IMKM to the experimental
dose-response of surviving fraction after X-ray irradiation
using three types of prostate cancer cells (DU145,
PC3, and LNCaP)47). In the fitting approach results, wefound that the model which considered the existenceof cancer stem-like cells illustrated the sigmoid nature
regarding the relationship between dose and log ofsurviving fraction and showed good agreement with theexperimental in vitro survival47). Next, the cancer stemlike cells within human oral squamous carcinoma celllines (SAS and HSC2) were investigated through cell
experimentation and model estimation104). Because of the
difficulty to perform cell experiments on heterogeneous
cell populations using the standard cell line, we used theradioresistant cell line named SAS-R and HSC2-R, which
has been established after daily exposure to 2 Gy of
X-rays for more than 1 year105). From the flow cytometricanalysis using a ALDH maker for detecting cancer stemlike cells, SAS-R and HSC2-R cell lines were found tocontain more cancer stem-like cells than SAS and HSC2.
From the hybrid study, it was found that enhanced cellrecovery of cancer stem-like cells is important when
predicting cell-killing effects in radiotherapy which
requires a long dose-delivery time104).
Based on the model development, focusing on thestereotactic body radiotherapy (SBRT) for non-small
cell lung cancer (NSCLC), we recently developed theall-in-one model (IMKM), which allows estimation of

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87

Fig. 4. Prediction of curative effects by the IMKM.
(A) In vitro surviving fraction and (B) TCP for various fractionation regimens. When estimating both in vitro surviving
fraction and clinical TCP, the cancer stem-like cells (7.983%) were considered. Using the same contents and model
parameters, the IMKM has successfully reproduced the in vitro cell survival and clinical TCP after the stereotactic bodyradiotherapy for non-small cell lung cancer48).

TCP of cancer patients as well as surviving fraction, andattempted to investigate the impact of cancer stem-likecells on curative effects (TCP)48). As a result, as shownin Figure 4, considering cancer stem-like cells, we havesuccessfully reproduced both in vitro survival of A549
(NSCLC cell line) after acute irradiation and the 3-year (aswell as 5-year and 8-year) TCP with various fractionationplans (6–10 Gy/fr)106, 107). The IMKM developed thus
far would contribute to high-precision estimation of thecurative effects of SBRT on NSCLC. Meanwhile, thetime course of radiosensitivity after high-dose exposureand the mechanisms on how to acquire radioresistanceafter high-dose irradiation remain unclear. Considering
these, accumulation of in vitro and in vivo scientific data
and further model development to reproduce curative
effects for any treatment cases (such as tumor types andirradiation conditions) are essential in the future.
4. Summary and future prospects
In this review, we introduce two simulation tools forpredicting biological effects, namely PHITS, and IMKM.
To date, the PHITS code has successfully reproduced theyields of various DNA damage, such as SSB, DSB, andcomplex DSB (DSB+ and DSB++) induced by electronsand protons. Meanwhile, the IMKM considers various
radiosensitive parameters, such as microdosimetry, DSB
repair kinetics, intercellular signaling, oxygen effects, andexistence of cancer stem-like cells. The IMKM has also
reproduced experimental surviving fraction for various
irradiation conditions (radiation qualities, dose rate,oxygen pressure, and cell type), enabling the translational
study between in vitro survival and clinical TCP forcancer therapy.
These simulation tools would contribute to a precise
understanding of biological effects (such as DNA damage

response and cell killing) to ionizing radiation. Meanwhile,the current DNA damage estimation model is available
only for electron and protons. To expand the applicabilityof the DNA damage simulation, the development of achemical code and the model is currently underway.
In addition, a comprehensive mechanistic model for
estimating various biological endpoints (micronuclei,
chromosome a ber ra t ion, inf la mma t ion, a nd
carcinogenesis) for normal tissue does not exist. Recently,
an estimation model for tissue reaction is required108). The
aim of the simulation tools (model) is to become a springboard for improving the theoretical/computational modelsof the biological effects for radiobiology. Accumulationof experimental data for further model development andfor predicting cellular responses after ionizing radiation
exposure in the future is warranted.
Conflict of interests
The authors declare that they have no conflict of interest.
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