The designs of BaVO(IO3)5 and BaTaO(IO3)5 from BaNbO(IO3)5 are based on the following motivation: BaVO(IO3)5 should have a larger second-harmonic generation (SHG) coefficient than BaNbO(IO3)5, as V will result in a stronger second-order Jahn-Teller effect than Nb due to its smaller ion radius; at the same time, BaTaO(IO3)5 should have a larger laser-damage threshold, due to the fact that Ta has a smaller electronegativity leading to a greater band-gap. Established on reliable first-principle calculations, it is demonstrated that BaVO(IO3)5 has a much larger SHG coefficient than BaNbO(IO3)5 (23.42 × 10−9 vs. 18.66 × 10−9 esu); and BaTaO(IO3)5 has a significantly greater band-gap than BaNbO(IO3)5 (4.20 vs. 3.55 eV). Meanwhile, the absorption spectra and birefringences of both BaVO(IO3)5 and BaTaO(IO3)5 are acceptable for practice, suggesting that these two crystals can both be expected to be excellent infrared NLO materials.Two nonlinear optical crystals, BaVO(IO Great effort has been made in searching for new second-order nonlinear optical (NLO) materials for their increasingly important role in many advanced scientific and technological areas, especially in laser technology ,4,5,6,7.3)5, was synthesized by Sun, et al. [2PO4(KDP); meanwhile, its band-gap (gE) is greater than 3.5 eV. It is well known that SHG and LDT  are the two main indices for a NLO material, and the general criteria for the scientific research and industrial application of a NLO crystal are that the SHG coefficient should be 10 times larger than that of KDP (1.1 × 10−9 esu) [gE should be greater than 3.0 eV. The SHG coefficient and gE determine that BaNbO(IO3)5 is a very promising NLO crystal that can be used in the infrared region. As the NLO crystals used in the infrared region are inadequate for applications at present [3)5 has been widely studied [Recently, one metal iodate, BaNbO5, the anionic group NbO(IO3)52− is a typical non-centrosymmetric octahedron structure: Nb atom locates at the center of NbO6 octahedron and it links with five IO3− and one terminal oxygen atom. The SOJT effect of NbO(IO3)52− comes from both the IO3− group and the cation Nb5+ [3)5 by enlarging the SOJT effect of its anionic group MO(IO3)52−. The simplest way is to substitute the d0 transition metal Nb with other ones in the same family which can result in lager SOJT effect. It has been determined that the SOJT effect resulting from V, Nb and Ta follows the order V5+ > Nb5+ > Ta5+ [3)5 has a lager SHG efficient than BaNbO(IO3)5. In fact, a similar material Ba2VO2(IO3)4(IO3) [3)5, 0.63 [2(IO3)2(H2O) [3)5 can be expected to have a greater gE than BaNbO(IO3)5 because the electronegativity decreases from V to Nb then to Ta. Therefore, BaVO(IO3)5 and BaTaO(IO3)5 should both be promising crystals for practical applications.According to the anionic group theory proposed by Chen , the SHGion Nb5+ ,21,22,23+ > Ta5+ ; therefo3)4(IO3)  reported)5, 0.63 ; the SHG3)2(H2O)  synthesi3)5  have been proposed, and their NLO properties were predicted based on first-principles calculations. As there are still no reports on their syntheses, vibration analyses were firstly carried out to demonstrate their kinetic stability. To validate the thermodynamic stability of BaMO(IO3)5 , the ab initio molecular dynamics simulations were also performed. Then, to verify the precision and reliability of our prediction, comparisons between our calculated and the experimentally measured properties of BaNbO(IO3)5 were carried out. Finally, the SHG coefficient, gE, the birefringence Δn, and the absorption spectrum of BaMO(IO3)5 (M = V and Ta) were obtained. The first-principle calculations were executed by CASTEP [Based on the above idea, in this work, two nonlinear optical crystals BaMO5 crystallizes in the non-centrosymmetric space group Cc (No. 9). In constructing the models of BaMO(IO3)5 , we firstly replaced the Nb atom in BaNbO(IO3)5 with V and Ta, respectively, and then carried out geometry optimizations for them. The atom structure of a BaMO(IO3)5 unit (molecular) is illustrated in 3)52− shows a typical “zero-dimensional” structure: the M atom is in the center of a MO6 octahedron, and it links to five oxygen atoms in iodate groups and one terminal oxygen atom. This anionic group plays the main role in the SOJT effect thus the SHG response [gE of the crystal, while the Ba2+ cation just acts as a spacer between the anions.BaNbO, is estimated to represent the out-of-center distortion of the MO6 octahedron.x denote the transition metal and oxygen atom indexed in x respectively as shown in x| is the bond length, and ∠Ox-M-Ox is the bond angle.As the SHG response comes from the SOJT effect, and the SOJT effect can be reflected by the non-centrosymmetry of a crystal, a parameter, ∆6 and IO3− polyhedra in a MO(IO3)52− are calculated based on analyzing the Mulliken charges of each atom.More fundamentally, the SOJT effect comes from the asymmetric of the electronic distribution. Therefore, the local dipole moments of the MOijd can be expressed by ε(ω),Quantitative SHG coefficients are estimated by the AHO model; the SHG tensor component  χ(1)(ω) ,(2)χ(2)m is the electron mass; e is electron charge; ε0 is the permittivity of vacuum; N is the density number of molecules in a crystal [a, which characterizes the nonlinear response, can be further written as ω0, determined by gE, is the electronic transition frequency in the molecule; and d is the lattice constant, which can be estimated by In Equation (2),  crystal . a, whicε(ω) can be written as ε(ω) = ε1(ω) + iε2(ω). In CASTEP, the imaginary part of the dielectric constant is estimated byu is the vector defining the polarization of the incident electric field. This expression is similar to Fermi’s Golden rule for time-dependent perturbations; therefore, ε2(ω) can be thought of as detailing the real transitions between occupied and unoccupied electronic states.From Equations (2) and (3), it can be easily identified that the foremost important parameter in the AHO model is the complex dielectric function tensor,ε1(ω), can be obtained asP denotes the principal value of the integral.The real and imaginary parts of the dielectric constant can be linked by a Kramers-Kronig transform, by which the real part of the dielectric function, λ = 1064 nm, which correspond to a photon energy of ω = 1.165 eV, are obtained. With the restriction of Kleinman’s symmetry, only ten independent SHG tensor components remain.We have used the optados code to process the CASTEP results to obtain the SHG tensor components. In addition, to keep in touch with the experiment measurements , the SHGon and en are the refractivities for the ordinary-ray and the extraordinary-ray, respectively, and they can be obtained by Given the complex dielectric function, all other linear optical properties can be also calculated. Here, the absorption function, 3)5 and BaTaO(IO3)5 are both hypothetical, their lattice vibration spectra and dynamics simulations were also calculated to verify their stability.Band-gap is another important parameter of an infrared crystal, as it determines the LDT. Therefore, the band structures of each crystal were also investigated. To make clear which groups contribute to the SHG effect, the partial density of states (DOS) around Fermi level combined with wavefunction isosurfaces are also analyzed. Above all, as the BaVO(IO3)5, with an error ratio less than 0.8%. The spin-polarized effect was considered and the convergence thresholds for energy change, maximum force, maximum stress, and maximum displacement were set as 5 × 10−6 eV/atom, 0.01 eV/Å, 0.02 GPa and 5 × 10−4 Å, respectively.Calculations on the geometry structures, electronic and optical properties were all carried out using the total-energy code of CASTEP. In geometry optimization, the Perdew-Burke-Ernzerhof functional of solid (PBEsol) was used according to Ref. , as it h25p66s2, Ta-5d36s2, V-3d34s2, Nb-4d45s1, I-5s25p5 and O-2s22p4. The number of plane waves included in the basis was determined by a cutoff energy of 830 eV. The numerical integration of the Brillouin zone was performed using a 4 × 4 × 2 Monkhorst-Pack k-point sampling for BaMO(IO3)5, which has been carefully tested to obtain enough accuracy. In addition, 373 empty bands (energy range of 20 eV) were used in our calculations, which are enough for optical properties. The single-point energy was calculated within the framework of nonlocal gradient-corrected approximations, i.e., the PBE functional . The intgE. An exact calculation for the band structure, as well as gE, is critical, as the imaginary part of the dielectric constant reveals the electronic transitions among bands and gE determines the LDT of a crystal.The band-gaps predicted by PBE functional are usually much smaller than the experimental data due to the discontinuity of XC energy. Fortunately, it can usually give the accurate shape of the band structures. Therefore, the scissor-corrected PBE method can be applied widely to research NLO materials even without any experimental data ,38,39. TThe vibration spectra were calculated using the DMol3 code with the same functional, GGA-PBE; and k-point sampling was set to 3 × 3 × 1. The DFT semi-core pseudopotential was adopted for core treatment and the basis set was DNP.3)5, dynamic simulation of 1.5 ps was carried out at 600 K; and for BaTaO(IO3)5, dynamic simulations of 2.0 ps were carried out at 600 K, 500 K and 450 K.The ab initio molecular dynamics simulations were performed by CASTEP based on the above optimized crystal. The same functional and pseudopotential as above were used, while only the Gamma point was selected in k-point sampling. The time step was set as 1.0 fs. For BaVO(IO3)5  are hypothetical, before investigating their optical properties, we need to validate their kinetic stability in order to judge whether they are possible to be synthesized. For this purpose, we firstly plotted the energy curves versus the lattice volume for BaMO(IO3)5 , as given in 3)5 and BaTaO(IO3)5, there is only one minimum point corresponding to their optimized structure in the wide range of volume modifications. This result indicates that they both have kinetically stable structures [3)5  to further confirm their kinetic stability. Their obtained lattice vibration spectra are given in 3)5 and BaTaO(IO3)5, constituting more reliable evidence for their kinetic stability. Therefore, both BaVO(IO3)5 and BaTaO(IO3)5 are possible to be synthesized [As BaMO5 and BaTaO(IO3)5 are shown in 3)5, the energy changes to fluctuate around a constant value after 0.7 ps, which means the system reaches an equilibrium state. In addition, from the inset in 3)5 keeps its intrinsic structure after a dynamics process at 600 K, which indicates that BaVO(IO3)5 is the most thermodynamically stable. In addition, we can find that all the atoms vibrate around their balance positions during the dynamics simulations, as shown in the 3)5, except for that it is the most thermodynamically stable only under 450 K. The simulation results at 600 K and 500 K are given in the Therefore, we carried out ab initio molecular dynamics simulations to check the thermodynamic stability of these two compounds. The energy evolution curves of BaVO(IO3)5 . To this end, we calculated many properties of BaNbO(IO3)5 and compared them with reported calculated and experimental results, as given in To ensure the reliability and precision of our calculated results is the premise for the significance of our predictions on the NLO properties of BaMO(IO3)5 , which is the basis for studying the electronic properties. Meanwhile, the accurate lattice parameters also ensure the accuracy for the calculation of Δd (Equation (1)) and the SHG coefficients which need an input parameter N (Equation (2)). Then, we calculated the band-gap of BaNbO(IO3)5 using the hybrid functional HSE06, 3.55 eV, which is very similar to  the experimental value, 3.64 eV. This result is more accurate than the reported calculated value, which is obtained using the PBE functional with lattice parameters from experimental measurements. This result confirms the reliability of using HSE06 functional in calculating gE of BaMO(IO3)5. Combined with the accuracy of the PBE in predicting the shape of band structures, such a result can ensure the reliability of our predictions on both the SHG response and gE of BaMO(IO3)5 . Dielectric function is the foremost essential parameter in calculating the SHG coefficients. The veracity of our calculations on dielectric function can be verified by the fact that the static dielectric constant ε(0) we calculated is very comparable to the reported calculated results. This ensures the accuracy of our predictions on the SHG response of BaMO(IO3)5  and on the birefringence Δn, which is a determining parameter for phase-matching conditions.At first, it can be seen that the lattice parameters we calculated are nearly the same as the experimental measurements, with a maximum error of 0.7%. This ensures the reliability of our predictions on the geometrical structures of BaMO5 .As a verification, the value of our calculated SHG coefficient, directly , but carm point group has six independent SHG tensor components , which are used to characterize the SHG coefficient. In addition, as LDT is generally in proportion to gE of a crystal, here, we use gE to represent LDT.The SHG coefficient and LDT are the two main indices in estimating whether a crystal is practical for NLO conversion. SHG coefficient determines the nonlinear frequency conversion efficiency of a crystal, and LDT determines the maximum optical power density that the crystal can withstand. Considering the spatial symmetry and the Kleinman’s full permutation symmetry condition for a lossless nonlinear medium, crystal class with 3)5 at a wavelength of 1064 nm (1.165 eV) are listed in 3)5 has pretty large SHG coefficients: the maximum component d12 reaches 23.42 × 10−9 esu, which is about 25.5% larger compared with that of BaNbO(IO3)5, 18.66 × 10−9 esu. Such a great SHG coefficient means that BaVO(IO3)5 is likely to provide a high nonlinear frequency conversion efficiency. For BaTaO(IO3)5, its biggest component of SHG coefficient is slightly smaller than that of BaNbO(IO3)5, but it is also quite large, d11 = 17.02 × 10−9 esu, which means that BaTaO(IO3)5 can also provide high NLO conversion efficiency.The frequency-dependent SHG tensor components of BaMO(IO2 which corresponds to gE > 3.0 eV. From the electronic band structures in gE of BaVO(IO3)5 is 2.927 eV, which is very close to 3.0 eV. Considering that gE is always underestimated by PBE, even if using the HSE06 functional [gE of BaNbO(IO3)5 is 0.09 eV smaller than the experimental value, 3.55 vs. 3.64 eV), the real gE of BaVO(IO3)5 is very likely to be greater than 3.0 eV, which satisfies the practical requirement. For BaTaO(IO3)5, it can be observed from gE reaches 4.203 eV. If we take the underestimation of PBE method into account, its real gE may be somewhat larger. Such a great gE can effectively suppress the two-photon and multi-photon absorptions; therefore, BaTaO(IO3)5 is possible to have a much larger LDT than BaVO(IO3)5.LDT has become the major limitation for the practical application of many new materials ,13,15. Anctional  5 at 1064 nm are given in 3)5 is 0.04, which completely meets the requirement. Meanwhile, the birefringence of BaTaO(IO3)5 is only 0.02, which seems to fail to satisfy the phase-matching condition. Nevertheless, it should be noted here that Δn of BaMO(IO3)5 may be underestimated in our calculations. This assumption is based on the fact that the calculated Δn of BaNbO(IO3)5 is also only 0.02 (n of BaTaO(IO3)5 may also satisfy the phase-matching condition, but this requires further confirmation. At the very least, even if a bare BaTaO(IO3)5 crystal cannot realize phase-matching, its Δn can also be manipulated by pressure engineering [Besides SHG and LDT, an infrared NLO crystal should also have an appropriate birefringence Δnly 0.02 , while sineering .n, an excellent infrared NLO crystal should also have a wide transparent wavelength region with low optical absorption. The absorption spectra of BaMO(IO3)5 are given in 3)5 shows large absorption coefficients, which is in agreement with experimental results [3)5 widens gradually with M varies from V to Nb then to Ta, and this is consistent with the gradually increased gE.In addition to the large SHG coefficient, large LDT, and appropriate Δ results , while i3)5 has larger SHG coefficients than BaNbO(IO3)5, its gE satisfies the basic requirement gE > 3.0 eV, its Δn is appropriate for an infrared NLO crystal, and its light absorption coefficient is pretty low in the wide visible-infrared region. The SHG coefficient and band-gap of BaVO(IO3)5 are close to the calculated results of NaVO2(IO3)2(H2O). BaTaO(IO3)5 also has quite a large SHG coefficient (only slightly decreased compared with BaNbO(IO3)5); moreover, its gE is significantly greater than that of BaNbO(IO3)5, which indicates a much higher LDT. Additionally, BaTaO(IO3)5 has a wider transparent wavelength region than BaNbO(IO3)5; and its birefringence Δn can basically meet the requirement. BaVO(IO3)5 and BaTaO(IO3)5 both are expected to be excellent infrared NLO materials.In summary, BaVO(IO3)5  originally comes from the SOJT effect. From the aspect of geometry configuration, the SOJT effects can be represented by ∆d as given in Equation (1), which describes the out-of-center distortion in MO(IO3)52− octahedron. The calculated ∆d of the VO6, NbO6, and TaO6 octahedrons are 1.004, 0.605 and 0.663, respectively. The bond lengths and bond angles used in the calculation of ∆d are given in V5+ =R 5.3 Å, Nb5+ =R 6.4 Å, and Ta5+ =R 6.4 Å [5+ has the smallest ionic radius which results in the strongest SOJT effect. Meanwhile, Nb5+ and Ta5+, have nearly the same, but much greater radii than V5+; therefore, they lead to slightly weaker SOJT effects than V5+. This explanation is generally consistent with the reduced SHG coefficients of BaMO(IO3)5 , 23.42, 18.66 and 17.02 × 10−9 esu.The different SHG performance of BaMO(IO = 6.4 Å . V5+ has3)5. Therefore, the local dipole moment should be a better indicator of the SOJT effect. Nonetheless, before calculating the local dipole moments in BaMO(IO3)5, we firstly demonstrated that only the IO3− and V5+ play the important role in the large SHG response of BaMO(IO3)5. We mapped the wavefunction isosurfaces for the VBM and CBM of BaVO(IO3)5 in 3− units but no electron distributes around V5+; in the CBM, some electrons transfer from the IO3− units to V5+, as denoted by the black dash circle in 3− units and V5+ play an important role in producing the SHG response. These results are in accordance with the anionic group theory and the research by Lei [More fundamentally, the SHG response comes from the asymmetric electronic distribution in BaMO5, BaNbO(IO3)5 and BaTaO(IO3)5 are 89.93, 83.12 and 80.84, respectively. This consists with the general rule of the SOJT effect for d0 metal: V5+ > Nb5+ > Ta5+ [d) with it, and thus can accurately explain the sequence of the SHG coefficients of the three crystals.According to the above analyses, only local dipole moments of the MOrted one ,48,49,503)5 crystal is significantly determined by the electronegativity of the M atom. As the electronegativity decreases from V to Nb and then to Ta, the band-gaps of BaVO(IO3)5, BaNbO(IO3)5, and BaTaO(IO3)5 are expected to increase in sequence. This roughly explains the results of gE in 3)5, BaNbO(IO3)5 and BaTaO(IO3)5. More detailed effects of congener substitution on gE should be analyzed by combining the electronic band structures and DOS. The band structures are given in The band-gap of a BaMO5 is given here in 3)5 crystal. The only difference is that the position of their peaks increases with a sequence V-3d, Nb-4d, and Ta-5d, which reflects the decreased electronegativity. During the time, in the conduction band regions, the PDOS of V-3d, Nb-4d and Ta-5d in the conduction band regions shows some discrepancies; the shapes for V-3d and Nb-4d are similar, albeit that of Ta-5d is not the same. This different situation of the Ta-5d orbital can be analyzed by analyzing its hybrid situation with other orbitals.From (1)There is an obvious sharp peak at the bottom of the conduction band, and from (2)3−; at the same time, their energy range (I and O) is intertwined with that of the transition metal V and Nb.In the conduction band region, the DOS of I and O are very comparable, which exhibits the full hybrid interaction in IOFrom 3)5 and BaNbO(IO3)5 are localized around the M atom under excited states, and therefore, the M-d orbital in the conduction band shows weak hybridization with the O-2p, I-5s, and I-5p orbitals. In 3)5), the sharp peak vanishes, and it can be seen that the DOS of I and O is distinctly different from that in 3)5 crystal, its excited d-orbital is delocalized and has stronger hybrid interaction with IO3− than Nb-4d, which lifts the energy of the conductive band, thus resulting in a larger gE.These results suggest that some electrons in the M-O bond in BaVO(IO3)5 crystals can also be explained by the band structures. In 3)5, BaNbO(IO3)5 and BaTaO(IO3)5 are all direct-gap semiconductors based on the fact that both VBM and CBM locate at the middle point of the LM line. Direct-gap means a fast-decaying optical absorption coefficient near the absorption edge, as shown in ε2(ω) of the dielectric function ε(ω), as given in ε2(ω) for BaVO(IO3)5 are given due to space limitations. At first, it can be seen that ε2(ω) of BaVO(IO3)5 shows a slight anisotropy along different dielectric axes. This is the original reason of the birefringence Δn, which can be attributed to the fact that the lone pairs in IO3− units are arranged in parallel in BaVO(IO3)5. Then, the averaged ε2(ω) of BaVO(IO3)5 are plotted in ε2(ω) of all three crystals are pretty low when the photon energy is less than 3.5 eV. This indicates that all three BaMO(IO3)5 have very low light absorption in the visible and infrared wavebands. The light absorption properties of the BaMO(IO3)5, whose value is about 5.8 eV, corresponds to the absorption of direct transition at absorption edge. Combined with 3)5, BaVO(IO3)5, and BaVO(IO3)5 show a few disparities, which are 5.79 eV, 5.82 eV and 5.91 eV, respectively. This variation tendency of theirs is in keeping with that of gE of the three crystals. In addition, it can also be seen that peak-1 of BaTaO(IO3)5 is broadened, which can be explained by the stronger hybrid interactions between the Ta-5d and the I-5p, O-2p orbitals.From 3)5 to V, Nb and Ta, the SHG coefficient of BaMO(IO3)5 decreases, while the band-gap (gE) of BaMO(IO3)5 increases. This is coherent with the rule that a strong SHG effect and a large band-gap are a pair of trade-off indices [gE of the system containing the SOJT anions is too large, the interaction between VBM and CBM would be very small, which would decrease the SOJT effect. Therefore, it is necessary to strike a balance between a large band-gap and a large SHG response in the design of new infrared NLO crystals.In summary, with variation of the M in BaMO5 and BaTaO(IO3)5, are designed, and the main optical indices for their practical application are predicted based on first principle calculations. At first, we demonstrated that they have no imaginary frequency vibrations, which verifies that they are kinetically stable, and thus are possible to be synthesized. The ab initio molecular dynamics simulations were performed at high temperatures to testify their thermodynamic stabilities. Then, the reliability of our calculations is validated by comparing our predicted gE and SHG coefficients with the measured values for BaNbO(IO3)5. Next, the NLO properties of BaMO(IO3)5  are investigated, where the SHG coefficients are calculated by classical AHO model. Finally, the effects of substituting Nb with V and Ta on the NLO performance of BaMO(IO3)5 are analyzed in detail. In this work, two promising NLO crystals, BaVO(IO3)5 has a 25.5% enlarged SHG coefficient compared with BaNbO(IO3)5, a big gE that satisfies the general criterion of practical application (gE > 3.0 eV), an appropriate birefringence meeting the requirement of phase matching, and a pretty low light absorption coefficient within a wide visible-infrared region. With regard to BaTaO(IO3)5, it also has quite a large SHG coefficient 5). Furthermore, its gE is significantly greater than that of BaNbO(IO3)5 (4.203 vs. 3.550 eV), which indicates an improved LDT; meanwhile, it shows wider transparent wavelength region than BaNbO(IO3)5. Last but not least, its birefringence also meets the practical applications. In summary, BaVO(IO3)5 and BaTaO(IO3)5 both are expected to be excellent infrared NLO materials.It is demonstrated that BaVO(IO3)5  come from the distinct SOJT effects brought along by the V, Nb, and Ta atoms. In terms of geometry configuration, the SOJT effect can be inferred by ∆d of the VO6, NbO6, and TaO6 octahedrons, which are 1.004, 0.605 and 0.663, respectively; from a more fundamental point of view, the SOJT effect can be characterized by the local dipole moment of the BaVO(IO3)5, BaNbO(IO3)5, and BaTaO(IO3)5 units, which are 89.93, 83.12 and 80.84, respectively. Both the sequences of ∆d and the local dipole moment agree well with that of the SHG coefficients, and this explains the effect of congener element substitution on the SHG response on BaMO(IO3)5.The different SHG responses of BaMO(IOgE of BaVO(IO3)5, BaNbO(IO3)5 and BaTaO(IO3)5 can be reasonably explained by the fact that the electronegativity of V, Nb, and Ta decreases in sequence. Such decreasing electronegativity results in the degree of hybridization between the M-d orbital and the I- and O-orbitals in the IO3− group increasing, thus in gradually raising the energy of the conductive band. In particular, the Ta-d orbital hybridizes strongly with the O-2p, I-5s, and I-5p orbitals. Therefore, BaTaO(IO3)5 shows a significantly increased gE. The gradually increasing 3)5 are all direct-gap crystals, which will result in fast-decaying optical absorption near the absorption edge. It is also found that the imaginary part of the dielectric function for BaMO(IO3)5  has very small values when the photon energy is less than 3.5 eV, which justifies their very low light absorption coefficient over a wide visible and infrared waveband. The birefringence Δn of BaMO(IO3)5 can be derived and thus interpreted by the anisotropy of their dielectric function along different dielectric axes. In addition, the effect of Ba on the NLO performance of BaMO(IO3)5 can be clearly excluded by the fact that its PDOS distributes far away from the Fermi level, which confirms the anionic group theory. We hope the discoveries and insights in this work are helpful for exploring new infrared NLO materials.The good light absorption performance can be attributed to the fact that BaMO(IO


US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV). The US28 protein (pUS28) is a potent signaling molecule that alters a variety of cellular pathways that ultimately alter the host cell environment. This viral GPCR is expressed not only in the context of lytic replication but also during viral latency, highlighting its multifunctional properties. pUS28 is a functional GPCR, and its manipulation of multiple signaling pathways likely impacts HCMV pathogenesis. Herein, we will discuss the impact of pUS28 on both lytic and latent infection, pUS28-mediated signaling and its downstream consequences, and the influence this viral GPCR may have on disease states, including cardiovascular disease and cancer. We will also discuss the potential for and progress towards exploiting pUS28 as a novel therapeutic to combat HCMV. HCMV is a ubiquitous member of the herpesviridae family, which characteristically establishes lifelong, latent infections that are largely asymptomatic in healthy individuals, as the virus is controlled by a robust immune response. Despite this, HCMV is linked with cardiovascular diseases (CVD) and cancers, where it is potentially an oncomodulatory virus ,2. In imUL33, UL78, US27, and US28. Three of these viral genes were initially identified by sequence homology analyses of the HCMV genome to the cellular GPCR, rhodopsin [UL78 was discovered upon comparing the HCMV genome to that of human herpesvirus-6 (HHV-6) [US28, the subject of this review, is a well-studied GPCR homologue. Herein, we will review its role as a signaling molecule, its involvement in HCMV models of CVD and cancers, and its requirement for HCMV latent infection.The herpesviruses have large DNA genomes, and the beta- and gamma-herpesvirus families encode G protein-coupled receptor (GPCR) homologues . HCMV is (HHV-6) . US28, tGPCRs are seven-transmembrane signaling proteins that represent a large and diverse group of eukaryotic signaling proteins with a transmembrane structure, which respond to an array of different stimuli acting via a common signaling mechanism . GPCRs i3C, and C [Chemokine receptors are a subfamily of Class A GPCRs, which bind chemokine proteins to activate cellular signaling, most often causing cellular migration . ChemokiC, and C . These cC, and C ,17.Chemokine receptors have a number of common characteristics in their structures . They rei/o, Gαq/11, Gα12/13, Gαs, Gαt, and Gαolf [i and Gαq have wide tissue distribution, while Gα15 and Gα16 display myeloid and lymphoid lineage specificity [Ligand activation of GPCRs promotes interactions with Gα proteins. These Gα proteins are further divided into subfamilies based on sequence similarity: Gαnd Gαolf . Memberscificity ,38. ThisUS27, UL33, and UL78 encode orphan receptors with no known ligand(s) [US27 is not expressed during latency [UL33 and UL78 were detected in a recent RNA sequencing (RNA-seq) analyses of viral transcripts from both experimentally and naturally latently infected CD34+ hematopoietic progenitor cells (HPCs) [All four HCMV chemokine receptor homologues are expressed during lytic infection ,40, but igand(s) ,42. Whiligand(s) ,44,45,46igand(s) . pUL78 iigand(s) . While pigand(s) , in colligand(s) . To dateigand(s) ,51. Disc latency , howevers (HPCs) . A summaMany cellular GPCRs form dimeric or oligomeric complexes, which modulate their trafficking and signaling properties ,58. SimiUS28 signaling during lytic infection has been studied extensively, providing us with a broad understanding of how pUS28 signaling affects diverse cell types in assorted ways . The strpUS28 signals constitutively via multiple Gα proteins ,71,78, rAlthough pUS28 is associated with many signaling pathways, some activities have yet to be confirmed during the context of infection , while opUS28’s constitutive signaling activity also interferes with the potentiating activity of cellular GPCRs. For example, pUS28 signaling ablates CXCR4 chemokine-induced signaling, as well as membrane trafficking and arrestin binding in HEK293T cells. This signal attenuation is not due to the dimerization of pUS28 with CXCR4, but is rather a result of signaling cross-talk, as attenuation of CXCR4 signaling is lost when pUS28’s DRY motif is disrupted (R129Q) . These fpUS28 is additionally implicated in the HCMV-mediated restructuring of lipid rafts in fibroblasts, by enhancing cholesterol efflux from HCMV infected cells . This re3CR1 [3CL1 [3C chemokines, but there are no reports to date detailing pUS28’s interaction with any known member of the CXC-chemokine family. pUS28 binding of CC and CX3C chemokines is mediated by both the N-terminal domain of pUS28, which contains the chemokine binding site, TTEFDY, as well as pUS28’s transmembrane helices, which form a deep pocket into which the chemokine binds to activate G-protein signaling [Upon ligand binding at a GPCR’s N-terminus, the chemokine subsequently embeds within the transmembrane domains to stabilize the active conformation of the receptor. pUS28 is a unique GPCR, in that it not only signals constitutively, but also signals in response to ligand binding . pUS28 d3CR1 . In turnR1 [3CL1 ,69,90,91ignaling .3CL1 and pUS28 by X-ray crystallography by inducing random mutations into the CX3CL1 amino terminus [3CL1 mutants show that pUS28 remains activated by CX3CL1, despite these significant structural differences [3CL1 reveals that the mutant binds this viral receptor, but is rotated 16.8° and contacts the receptor via different amino acids when compared to the wild type ligand. This is the first investigation to provide a structural understanding for pUS28’s promiscuous ligand binding, suggesting that pUS28 is forced open by ligand binding, rather than activated by specific amino acid contacts [3CL1 interaction that of an additional ligand, such as CCL5. How these ligands differentially contact pUS28 could explain this viral GPCR’s diverse signaling properties in varied cell types.Recent work from the Garcia Lab has resulted in the visualization of the interaction between CXterminus . Calciumferences . Crystalcontacts . In the US28 has shown that mutation of its N-terminal chemokine binding site greatly reduces the affinity of pUS28 for all chemokines, and while the aforementioned recent studies have given us greater insight into pUS28-CX3CL1 binding, it is clear that pUS28 binds the CC and CX3C chemokines differently. In fact, CCL5 and CX3CL1 binding are disrupted by mutation of distinct residues [3CL1 differentially suggests that it may adopt diverse open conformations for distinct ligands, which is consistent with previous findings with regards to other GPCRs [In agreement with structural investigations of pUS28, genetic manipulation of residues , suggester GPCRs ,23,24. Ter GPCRs ,64.q-PLC-β signaling, is dependent on CCL5 or CX3CL1 ligand binding in fibroblasts  [q. There are possible ways to explain why pUS28 alters its behavior upon ligand binding. For example, upon binding either CCL5 or CX3CL1, pUS28 adopts an open conformation, perhaps distinct from that which it constitutively adopts, to also activate calcium release via Gαq in HFFs and human coronary artery smooth muscle cells (HASMCs). Alternatively, it is possible that a higher percentage of the pUS28 receptors adopt this open conformation in these cells, enabling the detection of a rapid, short-lived calcium spike. In U373MG (a glioblastoma cell line), however, pUS28 potently activates PLC-β in a constitutive manner, but fails to activate calcium in response to a ligand [q, which mediates this signaling. Alternatively, perhaps pUS28 fails to adopt the same open conformation in U373MG cells, thus Gαq cannot couple upon ligand binding, a concept that warrants further investigation. In Cos-7 cells, pUS28 constitutively activates PLC-β via Gαq, which is unaffected by the addition of CCL5, but is attenuated by CX3CL1 binding [q, but it displays a mutually exclusive conformation that is dependent upon CX3CL1 binding. Alternatively, transient expression may not wholly recapitulate pUS28’s functional capabilities when it is expressed during infection, and indeed, this effect is Cos-7 cell-specific [Ligand-induced pUS28-mediated signaling results in the release of intracellular calcium, activation of the small G-protein, Rho, and activation of the Focal Adhesion Kinase (FAK) when US28 is expressed in isolation in SMCs and macrophages ,64. Thiss; HFFs) ,55,60. Hs; HFFs) ,84. This binding . This daspecific . Nonethei/o, Gα16, and Gα12/13, but CX3CL1 binding to pUS28 blocks this migration by promoting pUS28 coupling to Gαq. In contrast, CX3CL1 binds pUS28 to induce macrophage migration, while the CC-chemokine, RANTES (or CCL5), acts as a competitive inhibitor of this process [3CL1 differentially interact with the N-terminus of pUS28, as detailed above [Another demonstration of pUS28’s varied signaling activity is in its “functional selectivity” in mediating chemotaxis ,94. CC-c process ,61,64. Ged above . HypothepUS28 is expressed during lytic infection with early kinetics ,95 and wO-glycosylation of threonine-12 [N-glycosylation has been detected to date in the amino acid 30-32 region of pUS28, though there is a putative N-glycosylation site 14 amino acids downstream of the TTEFDY chemokine binding site [Apart from chemokine binding, the N-terminal region of pUS28 is also involved in protein trafficking, as mutation of tyrosine-16 to alanine (Y16A) abrogates pUS28 trafficking to the plasma membrane . Some ofonine-12 ,97. Desping site .Like other GPCRs, ligand binding to pUS28 at the plasma membrane causes internalization of the receptor via phosphorylation of its C-terminus and arrestin binding, which likely increases receptor recycling. This causes temporary signal deactivation and is followed by recycling pUS28 back to the plasma membrane ,98. ThisUS28 is one. US28 mRNA was first detected in latently infected THP-1 cells [+ HPCs [+ HPCs [US28 mRNA was not detected by one RNA-seq screen of latently infected CD14+ monocytes [US28, as well as UL33 and UL78 mRNA, during experimental and natural infection of CD34+ HPCs [UL33, and UL78, and these findings confirm previous work from our lab that revealed US27 is not detectable during experimental latency [Herpesvirus latent infection is defined as the maintenance of the viral genome, coupled with the absence of infectious virus production, with the potential to reactivate in response to the proper cues . Viral l-1 cells , and lat [+ HPCs ,104,105, [+ HPCs  and CD34 [+ HPCs . Althougonocytes , a more 34+ HPCs . This wa latency . The bio latency , as well latency , while d latency .US28 expression in early myeloid lineage cells is required to maintain latent infection -negative Hodgkin lymphoma, and gliomas ,120,121.Investigators have focused on pUS28 as a prime candidate that could regulate, at least in part, HCMV’s proposed oncomodulatory effects in the tumor environment. pUS28 activates a variety of signaling cascades that can function to promote cancer, including PLC , cyclooxIn addition to its association with GBM, pUS28 is also linked to the progression of other cancers. pUS28 expression also promotes intestinal neoplasia in transgenic mice  and may HCMV infection is associated with a significantly increased relative risk of CVD, including atherosclerosis, restenosis following angioplasty, and transplant-associated vasculopathy in solid organ transplant patients ,152, whi−/−apoE murine model of the disease. HCMV DNA is detected in diseased vessels and in SMCs in early stage atherosclerotic lesions  [HCMV seropositivity is linked to a higher rate of mortality from atherosclerosis ,156, anded SMCs) ,158. Vired SMCs) . Thus, i3CL1 [3CR1 binding to pUS28 to block chemotaxis, or a full inverse agonist, which could also reduce pUS28-mediated inflammatory activation, could have significant clinical benefits for this patient population.It is attractive to speculate that pUS28 perhaps plays a role in this HCMV-mediated progression of atherosclerosis . For ins3CL1 . pUS28 c3CL1 ,70,75 an3CL1 , which c3CL1 , cell su3CL1 ,149,160 3CL1 . These d3CL1 ,162,163,US28 is dispensable for HCMV lytic infection in fibroblasts [As mentioned above, roblasts , but doeroblasts . Targetiroblasts ,164. The basal activity of a GPCR is altered by the addition of different types of agonists. A GPCR agonist  is defined as a ligand or compound that increases the signaling from the receptor above basal levels after binding. An inverse agonist, therefore, is a protein, molecule, or compound that opposes the agonist or active state of the receptor, thus inverse agonist binding to a GPCR reduces its basal signaling. Finally, an antagonist is a ligand or molecule that binds a GPCR, but does not alter the receptor’s balance between its active and inactive states. Several groups have taken aim at pUS28 signaling to develop compounds that function as antagonists or inverse agonists. However, inhibiting pUS28 has proven complicated due to its multifaceted signaling properties. 3CR1 [pUS28 antagonists, starting with methiothepin and later octoclothepin , were de3CR1 , flavono3CR1 , or biph3CR1 . Continu3CR1 ,173. Suc3CR1 . One cou3) accumulation. Furthermore, this nanobody impairs US28-enhanced growth of U251 cells, a GBM cell line, as well as HCMV-infected primary GBM cells [In addition to small molecule inhibitors, others have targeted pUS28 with macromolecules. Heukers et al. have isolated a bivalent nanobody based on its ability to displace CCL5 binding to pUS28. Promisingly, this nanobody appears to act as an inverse agonist, preventing constitutive pUS28 activation of NFκB and inositol triphosphate (IPBM cells . The proBM cells . 3CL1 was fused to pseudomonas exotoxin A (PE). This FTP exploits the high affinity binding of pUS28 to CX3CL1 to target PE to infected cells [3CL1 portion of the FTP greatly reduces its ability to bind CX3CR1, thereby generating high selectivity towards pUS28 and HCMV infected cells. This therapy, F49A-FTP, showed great potential to target and kill HCMV lytically infected MRC-5 (embryonic lung fibroblast) cells, as well as HCMV infected engraftments in a SCID-hu mouse model of systemic HCMV infection [+ HPCs, as well as naturally latently infected monocytes, via pUS28 expressed on the cell surface of these latently infected cells [3CR1 is therefore a key priority, given that the binding of CX3CR1, which is also expressed in many uninfected cells including monocytes [Another effort to target pUS28 with a macromolecule details the use of a fusion toxin protein (FTP), wherein the soluble extracellular domain of CXed cells . An F49Anfection . In addied cells . Exploited cells . Indeed onocytes , proved onocytes .As a GPCR, clearly pUS28 is an attractive target for novel therapeutics. Further dissecting the specific pUS28-manipulated pathways during both lytic and latent infections, as well as continued understanding of pUS28’s structural elements, will prove paramount to rational drug design. Whether these findings result in the development of new compounds or the repurposing of currently approved compounds, new means by which to prevent CMV disease will benefit immunosuppressed individuals, including transplant patients, and perhaps those suffering from CVD or cancer.US28 has garnered much attention from GPCR biologists and HCMV virologists, alike. Much of the large body of literature focused on pUS28 has detailed the multifaceted nature of this viral protein, a chemokine receptor homologue that binds multiple chemokines from both CC and CX3C classes that signals both in constitutive and ligand-dependent fashions, resulting in diverse downstream consequences that have proved variable between different cell types. Continued work aimed at understanding this signaling protein in disease, first in atherosclerosis and then in cancer, has provided more details into how pUS28 impacts the host cell environment and viral pathogenesis. Our recent findings detailing the requirement for pUS28 during latency has also opened a new avenue for interrogating the biological functions of pUS28, which we and others continue to pursue. Together, research on pUS28 continues to increase in intensity. It is critical as research on this viral GPCR moves forward that we cross-validate and confirm each other’s findings using parallel, yet slightly different systems, which may allow us to dissect the fine details underlying the relevant biological functions of pUS28. This would undoubtedly propel the entire pUS28 field forward. Uncovering such detail will afford us, as a field, the ability to focus future research that may include using pUS28 as a therapeutic target in some disease settings, while perhaps exploiting it as a biomarker for another. Nonetheless, we will undoubtedly continue to learn more about this multifaceted protein.Despite being only one of over 200 ORFs encoded by HCMV,


Chemokine receptors are the target of small peptide chemokines. They play various important roles in physiological and pathological processes. CXCR7, later renamed ACKR3, is a non-classical seven transmembrane-spanning receptor whose function as a signaling or non-signaling scavenger/decoy receptor is currently under debate. Even for cell signaling mechanisms, there has been inconsistency on whether CXCR7 couples to G-proteins or β-arrestins. Several reasons may contribute to this uncertainty or controversy. In one hand, it has been neglected that CXCR7 has more than five natural ligands and unfortunately, most of the prior research only studied SDF-1 (CXCL12) and/or I-TAC (CXCL11); on the other hand, there are mounting evidence supporting ligand and tissue bias for receptor signaling, but limited such information is available for CXCR7. In this review we focus on summarizing the endogenous and exogenous ligands of CXCR7, the main diseases related to CXCR7 and the biased signaling events happening on CXCR7. These three aspects of CXCR7 pharmacologic properties may explain why the contradicting opinions of whether CXCR7 is a signaling or non-signaling receptor exist. Further, potential new direction and perspective for the study of CXCR7 biology and pharmacology are highlighted. Chemokines, with molecular weights in the range of 8 to 12 kDa, consist of about 50 small peptides in this superfamily . These wi protein coupling and signaling  and this structural difference was considered the reason on why CXCR7 is unable to induce cell signaling transduction through Gi proteins  family. Most ACKRs lack functional domains for Gignaling . The genignaling . Originaignaling . In 2005ignaling . The genignaling . Althougignaling . Originaignaling . Unlike proteins . At thisproteins . Other eproteins . In addiproteins . Interesproteins . None ofThis review focuses on discoveries related to endogenous and exogenous ligands for CXCR7. Some of them exclusively bind to CXCR7 while others have additional target receptors apart from CXCR7. Although all these ligands can bind to CXCR7, they can trigger totally different functional outcomes, with additional complexity of tissue-biased signaling as well. These aspects of consideration may explain why the contradicting opinions of CXCR7 exist. We will also emphasize the main disease relevance of CXCR7 and the therapeutic prospects CXCR7 may offer.Stromal-cell derived factor (SDF-1), also known as CXCL12, is a pleiotropic chemokine  widely ei subunits inhibit cAMP formation; and the βγ subunits can activate PLC-β, which in turn hydrolyzes PIP2  facilitating the production of DAG (diacylglycerol) and IP3 (inositol) 1, 4, 5 triphosphate. These secondary messengers lead to release of Ca2+ from ER and activate protein kinase C. CXCL12 can activate PI3K (phosphoinositide 3-kinase)/Akt, IP3, and MAPK (mitogen activated protein kinase) through CXCR4 to regulate cell survival, chemotaxis, and proliferation. In addition, CXCL12 also activates JNK and p38 to control cell survival , also termed CXCL11, is mainly expressed in the pancreas, peripheral blood leukocytes, thymus, liver, spleen, and lung. To a lesser degree, it is expressed in the prostate, placenta, and intestine . Just lill lines . The conMacrophage inhibitory factor acts as a pro-inflammatory cytokine with chemokine-like functions which regulate innate immunity. Originally, it was regarded as a T-cell derived factor which plays a role in inhibiting macrophage migration . It is wSeveral receptors have been shown to mediate MIF functions. The first is CD (cluster of differentiation) 74. CD74 is a single-pass type II transmembrane protein which is also known as the plasma membrane form of the major histocompatibility class II invariant chain (Ii) . BindingKd of 1.9 × 10-7 M -Hu Thy/Liv mouse model  .50 of 350 nM for TC14012 vs. 140 μM for AMD3100) and only one log unit weaker than the natural ligand CXCL12 (35 nM)  . Signifi (35 nM) , which p50 of 4.1 nM. It was patented by ChemoCentryx and has not been commercially available  and measurable passive permeability (Papp > 5 × 10-6 cm/s). The bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration , which is controlled by trans-endothelial migration. Since CXCR7 is highly expressed on EPCs, it determines the survival effect of CXCL12 on EPCs. In addition, CXCR7 also influences these CXCL12-regulated processes including trans-endothelial migration, proliferation, adhesion, and tube formation of EPCs . The incDespite the accumulating evidence, whether the binding of CXCL12 to CXCR7 can directly induce cell migration is still in debate, so in non-small lung cancer cells, CXCR7 has not been conclusively implicated in CXCL12-regulated behavior . HoweverThe discovery of CXCR7 has provided human beings a viable target for anti-tumor and anti-metastatic drugs. Using the model of mice engrafted with breast and lung cancer cell lines, inhibiting CXCR7 with believed antagonists showed that CXCR7 is able to promote tumor growth . The maiin vitro study indicating that although CXCR7 is not an intrinsic signaling receptor for CXCL12 on CD34+ HSCs, its blocking can be useful for therapeutic interference with CXCR4-mediated activation of integrins and cell adhesion  to the niches which sustain their migration capacity, CXCR7 is a potential regulatory target for HSCs mobilization-inducing agent development. This is supported by an adhesion . In addiCID mice ; howeverCID mice .The structural model for CXCR7 is very helpful for elucidating the pharmacology and potential therapeutic utility of CXCR7 antagonists. Unfortunately, there are no detailed structures available at present and only a limited number of ligands for CXCR7 have been reported . Therefoin vivo model of GBM, NOX-A12 was effective in inhibiting or delaying recurrences following irradiation (The molecules which can block CXCR4 and CXCR7 simultaneously, represent an ideal pharmacological approach because both receptors are involved in cancer malignancy and GBM angiogenesis . Howeveradiation .CXCR7 gene can lead to a phenotype of hypertrophy including thickened pulmonary, aortic valves, and partially overridden aortas (CXCR7 is expressed in the developing heart and associated with defects in the cardiovascular system. Knocking out n aortas . These an aortas . CXCR7 wn aortas . Howevern aortas . It is an aortas , strengtn aortas . Again, n aortas .The pivotal role of CXCL12 in the cardiovascular system makes itself and its receptors a hotspot of cardiovascular disease research. During the past few years, scientists focused on the CXCL12-CXCR4 axis in myocardial infarction and heart ischemia whereas very few studies mentioned the function of CXCR7. Of the few studies available, one study discovered that CXCL12-β protects cardiac cells via CXCR7  and evidThe axis of CXCL12-CXCR4 plays a very important role in physiology and pathology, and the discovery of CXCR7 as a new high affinity receptor for CXCL12 made this interaction system much more sophisticated. Previous studies mainly focused on the triangle relationship of CXCL12, CXCR4, and CXCR7, while other ligands for CXCR7 have been ignored. CXCR7 itself can play multiple roles with its endogenous and exogenous ligands. It may just act as a rheostat for certain ligands through scavenging them and not transducing any cell signaling pathways. It may also act as a co-factor to dimerize with other receptors in cell signaling transduction. In addition, CXCR7 may independently induce cell signaling transduction, either through G protein or β-arrestin, or other unknown transducer, depending on the cell types or different stages of cell differentiation. We are just discovering the tip of the iceberg of the biased signaling network system for CXCR7 and its ligands in various cell types. More interesting and vital connections are emerging from study of the massive iceberg that is CXCR7.CW collected the original materials and wrote the first draft. WC and JS made significant changes on the scope and format of this review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This qualitative study uses interviews with 22 Canadian clinicians to examine the perceived barriers to discussing fertility and fertility preservation with young women with cancer. What do clinicians perceive as barriers to engaging in fertility preservation discussions with young women with cancer?In this qualitative study, interviews with 22 Canadian clinicians found that they perceived knowledge, attitudes, practice environments, and patient factors influenced the likelihood of discussions regarding fertility preservation. While clinicians acknowledged the importance of fertility preservation discussions, most reported feeling unprepared to discuss it with patients with cancer.Active strategies, such as regular and sustained interprofessional collaboration and communications that can facilitate fertility preservation education, are needed to overcome the perceived challenges to fertility conversations with young patients with cancer and to improve care. Infertility can be a devastating adverse effect of cancer treatment for young women. Fertility preservation may be an important and influential factor in treatment decisions. Despite American Society of Clinical Oncology guidelines recommending discussion around potential infertility with patients, nearly 50% of young women with cancer remain uninformed.To understand and describe from clinicians’ perspectives the barriers to discussing infertility and fertility preservation with young women with cancer.This qualitative study used purposeful, maximum variation, and snowball sampling strategies to recruit 22 clinicians from cancer centers and community hospitals in 5 Canadian provinces, 5 practice areas, and 12 practice sites. Eligibility criteria included clinicians who regularly treat young women with cancer who might need fertility preservation. Telephone interviews that lasted between 30 to 75 minutes were conducted between May and November 2014 using a semistructured interview guide. Thematic analysis was used to discern the nature of barriers, and the Cabana framework was used to organize and interpret these findings. Analysis was conducted from May 2014 until May 2015.Clinician perspectives on what influences their nonadherence to American Society of Clinical Oncology guidelines, which recommend discussing fertility preservation with patients.A total of 22 clinicians were interviewed, including 8 medical oncologists, 4 surgical oncologists, 4 fertility specialists, 3 hematology and oncology specialists, and 3 nurse practitioners or clinician nurse specialists. Seventeen clinicians were women and 5 clinicians were men; the median (range) time in practice was 10 (0.67-37) years. Analysis suggested that clinicians’ unfamiliarity with infertility risks, fertility preservation technologies, referral processes, and procedures, as well as environmental factors and their perceptions of fertility preservation, influenced their practices regarding fertility discussions.The findings of this qualitative study suggest that the individual and environmental challenges that clinicians experience might negatively affect their willingness and ability to raise fertility-related issues with young women with cancer. Multiple strategies are needed to address these challenges to improve overall care of young women with cancer. These guidelines state that clinicians should “address the possibility of infertility with patients…[and] discuss possible fertility preservation options or refer appropriate and interested patients to reproductive specialists.”7 Despite these guidelines, an estimated 50% of women with cancer remain uninformed about the potential for cancer-related infertility,10 and even fewer are referred to fertility specialists.13 Given the gap between guideline recommendations and practice, we wished to explore current clinical practice to determine barriers that limit these discussions.When facing a cancer diagnosis, women should be informed about potential fertility effects of cancer treatment and have the opportunity to discuss preservation options.14In this article, we report findings on the experiences and perspectives of clinicians who treat young women with cancer who might need fertility preservation. The findings were drawn from the first phase of a 3-phase study aimed at understanding fertility preservation in the context of cancer treatment by exploring the experiences of clinicians and female and male patients with cancer. Study goals included development of fertility preservation decision-making tools for patients with cancer and improving oncology care. We used data from a study of the experiences and perspectives of clinicians who regularly treat young patients with cancer to understand and describe the nature of the challenges to discussing infertility and fertility preservation. We used the Cabana framework deductively to deepen understanding of the findings and to highlight possible areas of intervention that might contribute to uptake of the ASCO guidelines. The framework identifies core factors that influence clinician nonadherence to practice guidelines.COREQ) reporting guideline.This study was approved by the ethics review board at St. Michael’s Hospital. All participants provided verbal informed consent to be interviewed, for their interview to be audio-recorded, and for the data to be used in publications. The study results are reported in compliance with the Consolidated Criteria for Reporting Qualitative Research  who have firsthand experience treating young  women with cancer whose treatment might negatively affect their fertility. Participants were asked to suggest others who had the experience we were investigating and who may have been willing to participate.We used purposeful maximum variation and snowball sampling techniques19 We pilot tested the guide .23 Qualitative data were analyzed from May 2014 to May 2015.A literature review that explored clinical knowledge and practices regarding infertility and fertility preservation was completed to aid in the design of the interview guide.24 NVivo data management software version 10  was used to manage the data and facilitate analysis. Analysis included both inductive and deductive strategies. Inductive thematic analytic techniques27 followed the conventional first stage methods of qualitative analysis: sorting, organizing, and coding the data and searching for similarities and differences in and dimensions of codes and themes. A codebook was used to track ongoing changes to definitions and to ensure consistency in coding. Data were double coded in instances of discrepancies between coders. Codes and themes were inductively discerned and refined through multiple reads and comparative analyses of transcripts by 2 of us (M.F. and A.C.) and through ongoing team discussions of detailed data summaries. These data summaries included descriptive and analytic observations of the data with illustrative quotes. Themes were discerned from discussions of these summaries. Final thematic decisions were based on whether and how they addressed our research questions, whether they offered new or interesting knowledge about cancer care and fertility preservation, and whether there were enough data to thickly describe themes and attend to contradictory data.The interviews were transcribed and audited to ensure accuracy of transcription and to help ensure research rigour.14  time in practice was 10 (0.67-37) years .Most participants said that they were aware of ASCO guidelines, but many admitted to a general lack of familiarity with fertility preservation among clinicians . CliniciBox 1. “Most people [oncologists] in my workplace know about oncofertility in a sort of theoretical way.” (Clinician 7)“Some oncologists do not understand the fertility preservation process, have little or no understanding of available technologies, have inadequate knowledge and understanding of how and where to refer patients, do not have education materials at their fingertips to give to patients.” (Clinician 1)“So I think the fertility community is aware and on board, and it’s the oncology community that still needs more work. [A major obstacle] for oncologists is just knowing what’s available and where to send patients.” (Clinician 14)“This information gap is one that goes from oncology to patients and another from fertility specialists to oncologists. This lack of [in-depth] knowledge is one factor that prevents some practitioners from referring patients and/or raising fertility issues with them.” (Clinician 17)“The risks of cancer treatments with patients…these risks cannot be quantified. With breast cancer-related chemotherapy for example the risk of infertility is about 50% to 60%; in colon or GI cancers they are unknown. There’s uncertainty, ‘This is the treatment I’m going to give you. I don’t know what’s going to happen to your fertility.’” (Clinician 9)“The referring docs, I don’t think they think of it [fertility preservation] at all, …I don’t think it goes into the algorithms and the thought process at all. And then within the oncology community, I really think there’s a lot of variation among practitioners, with some people having a special interest and others who really pay no attention or pay only cursory attention. Some of them will only bring it [fertility] up if someone brings it up with them.” (Clinician 13)“I actually did a survey in approximately 2008, and a lot of oncologists don’t know about some of the stuff we can do out there. And in fact, one of my patients went back to tell her oncologist what we were planning and he was like, ‘Well, I’ve never even heard of that. I didn’t even know you could do that, so tell Dr [name redacted] she’d better call me because I don’t understand.’ … We were going to do, she has ovarian cancer and they’re going to take out both her ovaries, so we’re going to take the eggs out of the ovaries at the time of surgery and we’re going to mature them.” (Clinician 11)GI indicates gastrointestinal.Even when clinicians were aware of fertility preservation, the dearth of knowledge was still evidenced in their uncertainty about links between cancer treatments and infertility, options, or risks. Clinician 17, a surgical oncologist, said, “…I don’t know in colon cancer whether the chemo is as bad for fertility or not, I don’t know.” Clinician 9, a medical oncologist, said, “…I can’t truly answer the question, ‘What is the advantage of freezing eggs vs embryos vs an ovarian transplant vs…?’ I can’t give the exact specifics.” Clinician 9 said she admits to patients that she is uncertain how cancer treatments may put them at risk of infertility, “I don’t know what’s going to happen to your fertility.” In part, clinicians’ uncertainty appeared to stem from contrary research evidence and from existing uncertainties about treatment effects. For example, clinician 16 admitted, “We can’t predict whose fertility will be impacted.” These uncertainties likely contributed to clinicians’ experiences of lack of self-efficacy.Clinicians’ lack of self-efficacy or the absence of confidence in their ability to appropriately and correctly engage in fertility preservation discussions with patients was partly a function of their (1) lack of preparation; and (2) perceptions of fertility preservation discussions as difficult and complex, as “really sensitive,” “awkward,” “tricky,” “a can of worms,” as clinician 7 described them, and as a “Pandora’s Box,” as clinician 21 put it . These pBox 2. “I can’t truly answer the question, is, ‘what is the advantage of freezing eggs vs embryos vs an ovarian transplant vs…?’ I can’t, like, I can’t give the exact specifics. I know to a certain extent embryos are a bit hardier than eggs when they’re frozen, but I can’t, I don’t have that full expertise…” (Clinician 9)“I think people realize that many of these patients are going to have long-term problems with, you know, premature menopause, difficulty having kids, et cetera. I don’t know that there is great knowledge about what the options are, just because there’ve been so few options that, just, there hasn’t been much to have knowledge about.” (Clinician 1)“So if you know the risk [of infertility] is 100% because you took the ovaries out, that’s a no-brainer. If you know the risk is close to zero because they only got 2 drugs and neither of them damages the ovary, that’s a no-brainer too. But unfortunately, most of the time it’s in between, and then you have to make some sort of assessment of what’s the risk of infertility vs—an even more difficult assessment—what’s the risk of delaying treatment? I mean, there’s even less data on that score.” (Clinician 6)“Discussions are difficult when patients want guarantees.” (Clinician 12)“Fertility preservation is a Pandora’s Box, it may force patients to confront issues they may not want to discuss, ‘Do I want to trust that this relationship is permanent enough?’ ‘What if my cancer comes back?’ ‘What if I don’t survive?’” (Clinician 21)“I think it’s a black box. they’re (clinicians) afraid to open it because they don’t have the time, generally, to stay and talk about all of the ramifications…I don’t think they maliciously avoid the topic because, you know, I think it’s simply they don’t know enough about what they could be offering or how simple it could be.” (Clinician 10)“If they ask me, you know, you know I’ve slightly more information than a layperson on fertility issues, so I can’t be answering those questions because I might answer them wrong.” (Clinician 18)“The last thing we like as physicians is, number 1, to have something interfere with a treatment that we want to give, and number 2, to have something delay the treatment that we want to give…. I can’t even think of a situation where fertility was the primary concern, the primary concern is always...survival.” (Clinician 13)“The last thing you want, I think, as a surgeon, is some hormone fertility therapy to delay your treatment.” (Clinician 17)“Infertility is not the end of the world, it is not like having irreversible heart disease or another tumor, and there are other avenues to parenthood. The perception of infertility as an unnatural phenomenon is rooted in the understanding that it is a known toxicity of cancer therapies. Outside its causal relationship to cancer it is perceived as a natural occurrence.” (Clinician 5)“Although it [fertility] is an important issue it is not life-threatening, it’s not like the life and death threat of cancer.” (Clinician 6)“When you’re faced with a patient that has cancer that needs treatment…worrying about preservation is secondary. For males, it’s probably a lot easier to go to sperm bank, for females it seems hard to go and egg-harvest.” (Clinician 12)“Overwhelming them [patients] with additional information about fertility preservation, particularly when patients are in shock on learning they have cancer and when multiple treatments are required.” (Clinician 9)“We’re asking young women to make decisions about something that may or may not be a problem. And not only that, we’re asking them to pay for it, and at an emotionally charged time in their lives, and it may incur a delay in treatment because they go see the fertility expert, they want to wait a cycle to harvest or so forth …it’s another thing they have to deal with at a really high-pressure time.” (Clinician 16)“I know surgeons who see patients who don’t even know if they’re going to need chemo, and you won’t know because you don’t have the pathology until you take the whole tumor out, and then it’s almost like, ‘Well, we’ll get to that problem if we need to,’ because they may not need chemo, and they may not need this and they may not need that, and so their fertility may not be affected, so why start this whole talk for nothing, right?” (Clinician 17)“Doctors don’t understand just how urgent this is, first of all how fast some of these lymphomas can progress so we need to get them going [receiving treatment] very quickly.” (Clinician 13)“For aggressive cancers…well, a woman cannot have a baby if she is dead.” (Clinician 5)“Not knowing in advance of surgery that chemotherapy will be needed or only finding out after surgery means women are not referred for fertility consultations early enough.” (Clinician 14)“Physical recovery might be difficult because of risks related to fertility preservation; eg, endocrine-related side effects and hyper ovarian stimulation syndrome, which causes pain and discomfort.” (Clinician 21)“From a psychological standpoint, it [fertility preservation] does add another stress because you are adding a whole other element of treatment because you have to take the medications to stimulate your ovaries, you have to go to the procedure to harvest them, and then after that then we then hit you with your chemotherapy. Like, it’s a lot physically and mentally for someone to endure, like even each on their own is actually not easy, and now you’ve got both of them together.” (Clinician 9)triple-negative breast cancer, which seems to be a more rapidly progressive kind of breast cancer, so could those few weeks make a difference? And the literature is contradictory, some suggest yes, some suggest no.” (Clinician 7)“There are women for whom, you know, waiting a few weeks to do fertility preservation could compromise their cure rate. So there are these women who have something called “We can’t guarantee that that’s not going to happen if they (A) delay their treatment or (B) if they have a hormone-sensitive tumor. We can’t say definitively that an IVF cycle doesn’t increase their risk. It doesn’t appear to, research doesn’t show that it does, but we can’t say 100%.” (Clinician 10)“I guess what’s hard to find is the true success rate of making babies from frozen eggs, number 1; number 2, you know, which fertility bank is the best bank to send patients to for egg freezing. Like, embryo freezing is pretty standard, fine, but the concern is for women who don’t have partners and they want to just freeze their eggs, you know, should they go, where should they go, because it’s a big cost and it’s a big deal to refer people without knowing.” (Clinician 2)“You’re paying for an unknown return on investment… with most fertility centers, they’re going to underwrite everything and not make any promises that anything’s going to work out, right, and then you’ve expensed x thousands of dollars, you’ve delayed your care and treatment for a hope… It’s not like, ‘Oh, yeah, here you have a 40% chance if you subscribe to this menu, this recipe, and sign here, and pay,’ right? If you have a 40% chance, at least they sort of know. But because of the nature of fertility, it’s a lot of unknown, a lot of hope.” (Clinician 3)“Although egg cryopreservation is good, the thawing process is still unreliable.” (Clinician 21)IVF indicates in vitro fertilization.Some surgeons expressed fears about being asked fertility-related questions because they “might answer them wrong,” as clinician 18 put it, or “give them inaccurate information,” as clinician 17 put it. Clinician 6 expressed concerns about engaging in “informed guesswork.” The clinicians’ experience of lack of self-efficacy would likely be heightened in situations in which patients were fairly well informed but were seeking additional information or advice. Clinicians who did not regularly treat young patients with cancer were particularly likely to feel unprepared and not raise fertility issues. According to clinician 12, a hematologist, “Unless you’re doing a young patient…or that’s your typical practice, it might fall off the radar, and then the less you do it, the more uncomfortable you become, the more you might forget it.”Participants all agreed in principle with the ASCO guidelines, but they also voiced skepticism about fertility preservation and its relevance to their practices. Some clinicians’ comments suggested adherence to guidelines was impractical and reduced their autonomy. Discussing fertility preservation might be inappropriate in cases of very young or older patients, when patients have aggressive forms of cancer, or when mortality is imminent. In such cases, clinician 19 suggested fertility was a “luxury.” Also, clinicians’ perspectives and characterizations of fertility preservation and infertility suggested they did not fully support or believe in its applicability to their practice. Clinicians conceived of infertility as nonfatal and therefore fertility preservation was secondary to cancer treatments. As clinician 5 explained, “A woman cannot have a baby if she’s dead.” Clinician 6, a hematologist, contended that infertility was not the worst possible scenario, that it was not “like having irreversible heart disease or another tumor.”Clinicians’ lack of agreement was also suggested in the characterization of fertility preservation as a burden on both clinicians and patients. Clinician 6, a surgeon, said it was “one more thing to deal with,” and clinician 9, a medical oncologist, said a cancer diagnosis was traumatic for patients and discussing fertility preservation added another layer of distress. Clinician 9 went on to explain, “Even at the best times, when you don’t have cancer and you’re trying to figure out fertility and family planning, it’s not easy.” These discussions also added to clinicians’ workload, particularly when they were unfamiliar with it; for example, clinician 13, a hematologist, admitted, “We hate being asked questions that we know nothing about because it means that we have to figure it out and spend time outside of the clinic to go and find out, and figure out, and call up, and stuff.” Other clinicians perceived fertility preservation as a complication that might negatively affect treatment outcomes or interfere with treatment, ie, the time required for fertility preservation may lead to delays or potentially worse oncologic outcomes. Such concerns were suggested in the comments of clinician 17, a surgical oncologist, who said, “The last thing you want, I think as a surgeon, is some hormone therapy to delay your treatment” and in the comments of clinician 12, a hematologist, who asked, “How long is it going to take to get this person seen and get done whatever needs to be done so I can get on with treatment?”Clinicians also suggested fertility preservation was a financial burden with ethical undertones because it is costly and, as clinician 16, a surgical oncologist, observed, “We’re asking them to pay for it at an emotionally charged time in their lives.” Indeed, clinician 19, a fertility specialist, asserted that fertility preservation was both a “new and untested science [and] a private, for-profit venture.” Clinicians’ concerns about the physical risks involved  and potential psychosocial burdens of undergoing fertility preservation all suggested lack of agreement with it.Clinicians’ lack of outcome expectancy or the expectation or belief that engaging patients in fertility preservation discussions and referring them for preservation would not result in successful outcomes was suggested in their negative assessments of and reservations about fertility preservation evidence, technologies, benefits, and successes in the oncologic context. Clinician 13, an oncologist, noted that, outside of embryo cryopreservation, the evidence regarding the success of preservation had “not been great,” was “contradictory,” and that outcomes were largely unknown and difficult to quantify. Others pointed to the experimental nature of technologies, such as ovarian tissue preservation, which had success rates that clinician 11, a fertility specialist, described as “okay,” and in vitro maturation, which had success rates that clinician 14 characterized as “not great.” Perhaps just as important, clinicians’ lack of outcome expectancy was based on their awareness of successful birth rates among healthy women and their perceptions that fertility preservation in the context of cancer was likely to be less successful. They maintained that fertility preservation outcomes in healthy women could not be readily extrapolated to the cancer context because, as clinician 10 put it, healthy women have “tons of eggs; [donors] are young and do not have cancer.”Clinicians’ descriptions of current practices about fertility preservation were characterized by contrary perspectives about fertility preservation and attributions of responsibility for it to others . AlthougBox 3. “The failure of oncologists to engage with fertility is truly a failure because it is not a lack of available information or knowledge, it’s more the physicians’ lack of interest, lack of accessing available information, lack of acting on it, and a lack of patience to actually take the initiative.” (Clinician 6)“Oh, yeah, I heard about this. That’s a problem, isn’t it? But I don’t know where to send them, yet there are multiple fertility preservation clinics in [urban Canadian city].” (Clinician 6)“It’s [fertility] an important thing that’s overlooked, especially in oncology care.” (Clinician 12)“Although infertility is a big-time side effect of cancer treatments or a huge component of treating patients, fertility preservation does not tend to be high on the priority list of some cancer-treating specialists.” (Clinician 20)‘Well I’m not giving them chemo, why should I do the referral?’ or ‘It’s not my problem,… I don’t destroy the ovary.’” (Clinician 11)“Some [clinicians] do not see the relevance of [in]fertility to their practice, others tend to focus on their own scope of practice, on their part of the body, and still others do not see fertility preservation as being their concern, “Patients that report ‘nobody told me’ are just too many to list. For every 1 patient who is sent [to a fertility specialist], I’m sure there are 10 or 20 who were diagnosed but weren’t offered the option to see a fertility specialist. The word just doesn’t feel like it’s getting out to all of oncology. How [can] a treatment that can compromise fertility so severely not be discussed?” (Clinician 10)“Sometimes doctors just don’t have the luxury of time or resources to be able to assure them that they are going to remain fertile.” (12)“My center does not even have pamphlets/reading materials to give to patients, I think that’s how bad we are at it, just not even hitting the radar, really.” (Clinician 12)“When they come from afar sometimes they aren’t [offered fertility preservation]. Sometimes the physician may not have access to that in their community so they don’t offer it as an option, but once they’re in [urban Canadian city], we really kind of mobilize and say, you know, ‘You need a second opinion because we can offer you that service in this city.’” (Clinician 10)“Preservation options are sometimes not available, there is no place to send patients for preservation procedures, or that options are limited to medications such as birth control pills.” (Clinician 16)“You cannot make an assumption about finances. You have to offer the service, and then it’s up to the patient to decide if they can afford it. But I think… some of these people feel that there’s no way, because she works at Tim Hortons, that she can afford this. Sometimes we’ll even see in the referral… it’ll say something like, ‘Not a financially feasible option, but she wanted to see you anyway,’ type of thing, You’re kind of like, ‘Okay, so the people who weren’t pushing and maybe didn’t seem like they had the money, they probably weren’t referred at all.’” (Clinician 10)“Although costs for male fertility preservation is largely nominal, it is not the case for women, whose processes are more complex. The costs are a game changer for many women.” (Clinician 15)“The costs are not completely covered, and many patients, such as students and new immigrants, are still unable to afford it.” (Clinician 8)“Patients might not have easy access to fertility clinics because of their geographic location. In these instances, they may have to travel long distances to gain access, which often means travel costs are added to the fertility preservation-related ones.” (Clinician 15)“They might want children 10 years down the line…they can’t think that far into the future and see the cancer in front of them, they don’t really want to have to think about the other aspects.” (Clinician 9)Clinician 9, a medical oncologist, admitted that they are the entry point into fertility preservation discussions but maintained that it was really the purview of “true fertility people”. One such specialist, clinician 10, stated that the number of times “patients report that ‘nobody told me about fertility preservation,’ are just too many to list. For every 1 patient who is referred, there are many more who are not.” Although some clinicians said they had agreed within their multidisciplinary teams that whoever meets with the patient first should introduce the topic of fertility issues and although fertility specialists and oncologists have formed partnerships to develop educational programs for oncologists, overall, participants admitted that there was very little interprofessional collaboration or communication between fertility specialists and oncologists.Environmental factors, such as the organization of care , lack of time and resources , structural supports , and patient education were also challenges to fertility preservation and discussions. Clinicians noted that it was difficult to provide patients with risk information or advise them when there was uncertainty about diagnoses and treatment plans. Clinicians said they might learn late in the diagnosis-treatment continuum that a patient needs chemotherapy, and if the cancer is aggressive, there might not be time for fertility preservation. In such instances, clinicians said they might not introduce the topic. Likewise, clinicians said that when a treatment plan was already in place, it was very difficult to pause the process by introducing the issue of fertility.Clinicians stated that there was already insufficient time for oncology consultations, which can be complex and lengthy, and thus there was not enough time to discuss fertility preservation. They also pointed to insufficient resources, such as nurses or social workers, who could act as backup for fertility discussions and referrals. Fertility discussions and referrals may not happen when clinicians must navigate the system themselves or when they work in geographic locations where access to fertility preservation options are limited or referral systems were not well established. Referrals were also less likely to happen when clinicians had no relationships with fertility clinics.Along with the nature of diagnoses, mortality concerns , psychosocial considerations , and clinicians’ perceptions of patients’ status  were also factors that informed fertility discussions. Clinician 4 expressed concerns that patients were “already very stressed [and] were getting a lot of information at a time when they’re already overwhelmed with this diagnosis.” Many clinicians voiced concerns about affordability of fertility options for patients. Clinician 15, a nurse practitioner, observed that “the costs are a game changer for many women,” and clinician 8 noted that “many patients, such as students and new immigrants, are still unable to afford it.” Perceptions about patients’ socioeconomic status also appeared to influence clinicians’ willingness to initiate fertility preservation discussions. About their colleagues, clinician 10 said, “Some of these people feel that there’s no way, because she works at Tim Hortons, that she can afford this. Sometimes we’ll even see [that] in the referral.”In this qualitative study, we used data from a study of the experiences and perspectives of oncology practitioners to describe factors that influence their nonadherence to ASCO guidelines. We found that unfamiliarity with fertility preservation processes and risks, lack of agreement with guidelines and fertility preservation, perceptions of infertility and fertility preservation, lack of confidence in their abilities, uncertainty about successful outcomes, environmental considerations, deficient referral systems, and patient-related factors all contributed to nonadherence.30 Another finding of the study is the reluctance among clinicians to engage in conversations that may negatively affect patient survival. This hesitancy is likely a function of their perceptions of infertility as nonfatal, beliefs about the urgency and importance of timely oncologic treatment, the potential fatality of cancer, and the desire to protect patients from potential harms. It is also likely a consequence of their perceptions of fertility preservation as a burden, a complication, and a secondary and often opposing objective. Not initiating fertility discussions challenges the principles of patient-centered care and, in the context of cancer, suggests that clinicians in this study may be overestimating the importance of survival outcomes while underappreciating the psychosocial concerns of patients with cancer beyond that of survival, namely potential future infertility33 and quality of life.Our finding of a connection between outcome uncertainty and discussions of fertility is reaffirmed in existing studies that found that the likelihood of success of preservation techniques and perceived poor oncologic prognosis were deterrents to fertility discussions.36Our findings also suggest a siloing in practice whereby clinicians do not see the relevance of fertility preservation to their practices and feel that these discussions are not their responsibility because their treatments do not cause infertility. This finding suggests insufficient interprofessional education and collaborations . Such lack of communication likely contributes to clinicians’ lack of awareness of fertility preservation and referral processes, a finding that has been reported in several studies.14 in this study helped to highlight how knowledge around treatment options and outcomes, beliefs about oncology care, and limited access to fertility specialists and referral resources may have interacted to negatively affect oncology specialists’ engagement in fertility preservation discussions. The findings suggest that knowledge and attitudes are closely aligned with behavior and reaffirm research that found that modifying knowledge and attitudes is fundamental to successful adoption and implementation of clinical practice changes.38 These findings also suggest that knowledge translation strategies, such as galvanizing local opinion leaders and society endorsements, conducting educational meetings, and continuing medical education opportunities,39 are potential solutions to improving clinicians’ competencies, reorienting attitudes, and improving patient care. Such approaches could operate in tandem with patient education and development of support resources and patient navigation tools to help young adults initiate fertility discussions.Using the Cabana framework35 demonstrating that the barriers we described have relevance for other treatment sites, health care systems, and oncologic diagnoses. A potential limitation of this study is self-selection bias because clinicians who chose to participate may have had more interest in fertility preservation than clinicians who chose not to participate.Our study had some strengths and limitations. Although we used maximum variation sampling in our study, qualitative research sampling is purposeful rather than random, thus findings are not generalizable in the statistical sense. The study design facilitated in-depth insights into the barriers to fertility preservation discussions, and the use of a conceptual framework increased the transferability of the findings to other contexts. The findings reflect and expand on what has previously been described for individual treatment centers, single disease sites, and other health care infrastructure,The findings in this qualitative study suggest that although fertility preservation discussions have been a long-standing standard of care, in many instances they are not standard care in oncology. Our findings also suggest that medical education has not kept pace with fertility preservation technologies, which has left many clinicians uninformed about them. Moreover, awareness of the ASCO guidelines has not translated into increased discussions about fertility preservation. Active knowledge translation strategies, such as interprofessional collaborations and communications, identification of local opinion leaders or champions, society endorsements, continuing medical education opportunities, dedicated fertility preservation programs, referral networks, and decision-support systems, are needed. Creating resource tools  for clinicians and patients also has potential to improve levels of fertility-related discussions.