Abstract
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Femoral version (FV) is more widely adopted with the definition as the angle between the long axis of the femoral neck and the tangent line of the posterior femoral condyles on the axial plane, and the normal range between 5 and 20°.
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FV can be measured by imaging and functional tests. Cross-sectional CT including both the hip and the knee is the typically used imaging technique, yet variation exists according to the different landmarks used. As MRI investigations are routinely performed preoperatively, and protocols can be easily adopted to include version measurement, they are frequently used as an alternative to CT and offers several advantages.
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Abnormal FV has adverse effects on the biomechanics and musculoskeletal health of the whole lower limb. It affects the lever arm of muscles and the forces that the hip and patellofemoral joints suffer, and can lead to disorders such as osteoarthritis and impingement.
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In adult hip preservation surgery for developmental dysplasia of the hip (DDH), abnormal FV is sometimes accompanied by other morphological abnormities of the hip, a more severe DDH, and can help predict postoperative range of motion (ROM), and postoperative impingement.
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Currently, the most frequently used surgical technique for abnormal FV is femoral derotational osteotomy.
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Many controversies are left to be solved, including the specific origin of FV, the indication for femoral derotational osteotomy, especially in patients with combined DDH and abnormal FV, and the explicit compensation mechanism of abnormal FV by tibial torsion.
Introduction
Femoral version (FV) is a crucial hip alignment metric referring to the rotation of the femur. Because of its anatomical properties, it has an enormous effect on all aspects of the whole limb. Developmental dysplasia of the hip (DDH) is a common disorder characterized by various morphological abnormalities, including acetabular undercoverage. Currently, hip preservation surgery is one of the most commonly used surgical techniques for treating adult DDH. Abnormal FV is a common comorbidity that may aggravate hip instability and lead to articular cartilage degeneration as well as early development of osteoarthritis. Nevertheless, the significance of FV in adult hip preservation surgery for DDH is a hot topic that has rarely been reviewed. In addition, although an additional femoral derotational osteotomy can be performed as a part of hip-preserving procedures for DDH, its indications remain unclear, and to date, no agreement has been reached on the threshold value and the amount of correction in femoral derotational osteotomy for dysplastic hips with increased FV. The purpose of this study is to investigate current knowledge involving FV, as well as the role that abnormal FV plays in hip preservation surgery for adult DDH patients.
Femoral version: definition, abnormality, and origin
FV is a broadly studied alignment metric with wide variation in its definition. For instance, some authors define it as the angle between the long axis of the femoral neck and the tangent line of the posterior femoral condyles on the axial plane (1), which is relatively more accepted, while others define it as the angle between the axis of the femoral neck and the transcondylar axis of the knee on the top view (2).
Similar to the variation in its definition, the normal range of FV also varies and is highly dependent on the landmarks and imaging techniques used (3). While some consider it to be between 10° and 14° with a standard deviation of 12° (4) and others consider it to be between 10° and 25° (5), the widely accepted normal range is between 5° and 20°, and many studies related to FV are grouped according to this range (6, 7, 8). In addition, FV varies greatly among patients with diseases and healthy individuals. For example, in patients with DDH, FV not only increases but also varies greatly according to the coverage of the acetabulum (9). Even among apparently healthy adults, FV varies by up to 30° (10).
As the widely accepted normal range of FV is between 5 and 20°, abnormal FV is commonly defined as less than 5° or more than 20° (7, 11, 12, 13), with the former called retroversion and the latter called anteversion. However, there have been other studies that describe decreased/low FV or retroversion as less than 4° (14) or 10° (5, 15) and increased/high FV or anteversion as more than 15° (16), 25° (5, 15), or 28° (14).
Although an increasing number of studies have focused on FV, many studies have confused FV with femoral torsion (FT) (17), which are actually two different parameters. In the past, researchers have considered that these two parameters could not be differentiated roentgenologically and had no practical significance (18). However, because of the development of computed tomography (CT) techniques and the differences between treatments, it is feasible as well as necessary to distinguish between them. FV mainly refers to the anterior tilt of the femoral neck or regions proximal to the lesser trochanter, while FT mainly refers to the rotation of the femoral shaft or regions distal to the lesser trochanter (19). In fact, when used and discussed by clinicians, the term FV mainly refers to the proximal part and is largely considered to be the angle formed by the projection of the proximal femoral neck axis and the distal tangent line of the posterior femoral condyles on the axial plane.
Although FV is a well-studied anatomical entity, its origin has not been investigated until recently (19, 20, 21, 22). As FV is formed by the proximal femoral neck and distal femoral condyle, any part of the femur, including the femoral neck and shaft, has the potential to contribute to the overall FV. To date, taking the lesser trochanter as the boundary, FV is conventionally separated into neck version or neck torsion, and shaft version or shaft torsion. Seitlinger et al. (20), Archibald et al. (21), and Kim et al. (22) all found that both the proximal and distal femur contributed to FV. Additionally, Seitlinger et al. (20) found a strong correlation between neck torsion and shaft torsion and a positive correlation between the average neck-to-shaft torsion ratio and the total torsion, which indicates that neck torsion may contribute more to the total FV. In addition, Archibald et al. (21) found that neck version had a slightly stronger correlation with the total FV than with shaft version, while neither of them could predict the total FV alone. However, Waisbrod et al. (23) held the opposite view. They found that approximately two-thirds of torsional changes occurred distal to the lesser trochanter, suggesting that shaft version has a greater contribution. To conclude, different levels of the femur collectively contribute to the total FV, but which part contributes more remains controversial and merits further research. Because neither neck version nor shaft version alone can be used to predict the total FV, it is of great necessity to measure both of them as significant factors in choosing the optimal level for osteotomy correction.
Measurement: imaging and functional tests
Imaging
Many imaging techniques have been used to measure FV; among them, cross-sectional CT, including both the hip and the knee is typically used (4). Nevertheless, many other imaging techniques, such as magnetic resonance imaging (MRI) (24) and low-dose biplanar radiography (EOS imaging) (25) are also frequently used, and the best option remains controversial. In addition, the measurement varies greatly according to the technique and landmarks used (3). Here, we reviewed the measurement of FV using CT and MRI.
CT: advantages, disadvantages, and different landmarks
There are five main methods for measuring FV on CT, all of which calculate the included angle between the proximal and distal reference lines using a line tangent to the posterior condyles as the distal reference and the center of the femoral head as the proximal landmark (26). Differences between methods may originate from the slice orientation, the use of one or imposed images, and the other proximal landmark used to confirm the proximal reference line. The specific protocols for these five methods are detailed in Fig. 1. Murphy et al. (27) took an axial slice and used two superimposed images, with the center of the base of the femoral neck midway between the distal end of the greater trochanter and the proximal end of the lesser trochanter as another landmark. Tomczak et al. (24) used a method similar to that described by Murphy et al. (27) but chose the center of the greater trochanter as the other landmark. Lee et al. (28) and Reikerås et al. (29) both took a single slice; while Lee et al. (28) used a single image, drawing a line to connect the femoral head center and the most cephalic junction of the greater trochanter and the femoral neck, Reikerås et al. (29) used two superimposed images, connecting the femoral head center and femoral neck center where the anterior and posterior cortices were parallel. In contrast, Jarrett et al. (30) took an axial–oblique slice, with a line connecting the femoral head center and femoral neck center on a single image. Schmaranzer et al. (26) compared these five methods and found that the FV measured by choosing the most proximal landmarks, such as in Lee et al.’s (28) method, was lower than that measured by choosing the most distal landmarks, such as in Murphy et al.’s (27) method. According to their study, FVs are measured as 28 ± 13, 25 ± 12, 11 ± 11, 15 ± 11, and 19 ± 11 by Murphy et al.’s (27), Tomczak et al.’s (24), Lee et al.’s (28), Reikerås et al.’s (29), and Jarrett et al.’s (30) methods, respectively, and the differences are enlarged as FV increases. In addition, they also created a linear regression model with high correlation, enabling the conversion of one measurement to another, which has contributed greatly to the union of FV values.
Illustration of the five proximal reference lines and the shared distal reference line to calculate FV.
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0145
Magnetic resonance imaging
As MRI investigations are routinely performed preoperatively, and protocols can be easily adopted to include version measurement, they are frequently used as an alternative to CT and offer several advantages. One typical measurement of FV using MRI is the Tomczak technique (24), which is interestingly different from his CT-based measurement. Briefly, he obtains a scout view by coronal section to place oblique axial-to-sagittal sections parallel to the femoral neck axis, in order to help visualize the true neck axis. Then, he defines FV as the angle between the true neck axis and the posterior femoral condyles tangent line. Compared with CT as a relative gold standard, MRI is especially suitable for depicting proximal as well as distal contours of the femur in children, with immature bones, because of its high soft tissue resolution (24). Another advantage of MRI is that it allows direct alignment with anatomical structures such as the femoral neck (31), which is of great benefit when FV is excessively increased, causing the greatest bias (30). In addition, MRI does not involve radiation. However, there are also many disadvantages. For example, MRI scans typically take more time, cost more (32), and are not accessible in all research and clinical facilities, which to some extent limits the wide use in screening FV. Additionally, MRI has been reported to have lower interobserver reliability than CT (33). In spite of its disadvantages, MRI measurements are strongly correlated with CT outcomes (24, 33, 34, 35, 36) and are almost always lower than CT results, with an average difference of approximately 8.9° (33).
Functional assessment
Apart from imaging techniques, there are many other ways to indirectly measure FV, such as by functional assessments. The trochanteric prominence angle test, also known as Craig’s test, was first invented by Ruwe et al. (37). It is performed with the patient in the prone position with the knees flexed 90°; the hip joint is rotated until the greater trochanter is palpated most prominently. The angle formed by the tibia and the sagittal plane can be measured as the FV (4). However, Maier et al. (38) found that the trochanteric prominence angle test alone is not sufficient to measure FV or even screen for gross anomalies. Therefore, although it is inexpensive and convenient, this test is more suitable for reference and auxiliary use. In addition, there are other clinical examinations that can indicate abnormal FV. For instance, ‘W sitting’ during childhood may suggest persistently increased FV (39).
Clinical relevance of FV in adult hip preservation surgery for DDH
Hip preservation surgery is a relatively novel surgical procedure, with the aim of increasing the longevity of the native hip joint to prevent hip arthroplasty (40). The techniques applied in hip preservation surgery, including periacetabular osteotomy (PAO) (41), hip arthroscopy (42), femoral osteotomy (2) and so on, can be used to treat a great number of hip disorders such as DDH (41), femoroacetabular impingement (FAI) (43) and slipped capital femoral epiphysis (SCFE) (44). Among these conditions, hip preservation surgery for adult DDH patients is performed earlier and has been more deeply studied, and many studies have focused and will continue to focus on this issue.
FV has influence on various facets of the hip joint, as well as the whole lower extremity. Reviewing findings regarding the altered biomechanics and musculoskeletal health caused by abnormal FV, as well as its correlation in adult hip preservation surgery for DDH, can help us understand the significance of FV in adult hip preservation surgery for DDH and perform better operations. Current findings are summarized as seen in Fig. 2.
Summarization involving the adverse effect on the biomechanics and musculoskeletal health of the whole lower limb caused by abnormal FV, as well as the significance of FV in many aspects of adult hip preservation surgery for DDH.
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0145
Biomechanical effects of abnormal FV
Altered FV, because of the resultant change in contact with muscles, ligaments, and other structures, has an impact on the biomechanics of the hip as well as the whole lower extremity. Moment arm length and altered contact force are among the most frequently influenced biomechanical factors.
As a morphological parameter of the femur, FV affects the biomechanics of the hip joint to a large extent.
First, increased FV has been demonstrated to affect the lever arm of hip muscles. For example, Li et al. (45) found that increased FV is significantly and negatively correlated with the lever arm length of hip abductor muscles, which may lead to osteoarthritis in DDH patients. Scheys et al. (46) completed one comprehensive research study revolving the effect on the lever arm of hip muscles. In the coronal plane, both the abductor and adductor lever arms are decreased in the setting of increased FV. Additionally, they found increased flexion and internal rotation lever arms, as well as decreased extension and external rotation lever arms caused by increased FV.
Second, both increased and decreased FV could affect the forces in the hip because of the lever arm alterations. Heller et al. (47) performed a simulation study and found that when FV was increased to 30°, hip contact forces were increased, while little or no decrease in hip contact forces was found when FV was decreased to −5°. Moreover, Fishkin et al. (48) further found that compared to patients with normal FV, patients with hips that retroverted to neutral or 12.5° of retroversion showed a 42% and 85% increase in the strain on the physis, respectively.
Because of the integrity of the lower extremity as a whole, abnormal FV is bound to have an effect on other parts of the lower extremity. To improve the impaired coverage of the acetabulum caused by increased FV, many patients will present compensatory internal rotation of the hip, as well as an in-toeing gait, which is partly because of the increased lever arm length of internal rotation (49). This changes the transverse plane of the whole femoral segment, including the knee, as well as the patellofemoral joint function. Lee et al. (50) found that both femoral and tibial rotating activity resulted in an increase in patellofemoral contact pressures, with femoral rotation mainly affecting the contralateral facets and tibial rotation mainly influencing the ipsilateral facets. Additionally, they elucidated that internal rotation of the femur leads to impingement of the lateral articular surface of the trochlea on the lateral articular facets of the retropatellar surface, which pushes the patella medially. This may explain the reason why increased FV increases the risk of instability of the patellofemoral joint, including subluxation and lateral dislocation (39). In addition, an in-toeing gait, which is often caused by increased FV, would increase the tension on the medial patellofemoral ligament, which may result in an increased risk of developing recurrent dislocation or displacement of the patella (51), and the force on the lateral part of the patella while decreasing the force on the medial part of the patella (52). However, patients with high FV can also be seen walking with normal foot positioning, which may be the result of compensatory tibial torsion to maintain normal foot positioning on the coronal plane during gait (53, 54). Similarly, research by Lerch et al. (55) showed that although in-toeing is of high specificity for detecting increased FV, most patients with increased FV walk with a normal foot progression angle, which further suggests the existence of compensation by tibial torsion. Furthermore, decreased FV has a negative impact on the strain on the sciatic nerve during flexion (56).
Overall, both increased and decreased FV can have a harmful effect on the biomechanics of the whole lower limb. Currently, evaluating patients’ biomechanical properties in clinical practice is not very workable. However, with the rapid development of medical techniques, it may be greatly necessary to assess the biomechanical properties of the lower extremity in the setting of DDH combined with abnormal FV in the future, which could help us decide whether and how to address the altered biomechanics so that patients can recover thoroughly and achieve healthy biomechanics after adult hip preservation surgery for DDH.
Impairment of musculoskeletal health by abnormal FV
Abnormal FV, whether increased or decreased, will impair musculoskeletal health to a large extent by changing the normal biomechanics of the entire lower extremity.
First, abnormal FV is bound to predispose patients to a few hip diseases. For example, increased FV can bring about instability of the hip because of impaired coverage of the femoral head, especially in those with anterolateral dysplasia or insufficient coverage (4). In addition, the resultant enhanced load on the acetabulum and its altered relation with the femur will result in degenerative changes and ultimately osteoarthritis (57, 58, 59).
Similarly, increased FV has been demonstrated to be associated with intraarticular as well as extraarticular impingement. For example, increased FV will lead to impingement between the lesser trochanter and the ischium, which is termed ischiofemoral impingement and can further lead to anterior dislocation (60, 61). This may be because increased FV places the greater trochanter in a posterior position, therefore decreasing the abductor effect of the gluteus muscles, which may cause prolonged adduction and a narrowed ischiofemoral gap (62). Moreover, in the setting of borderline DDH (BDDH) with coxa profunda, FV is significantly and negatively correlated with ischiofemoral space and quadratus femoris space, making increased FV a risk factor for ischiofemoral impingement (63). Furthermore, increased FV is considered to be related to anterior labral tears (64), which is probably because of the increased force exerted anteriorly by the femoral head on the iliopsoas and labrum (2). Interestingly, decreased FV also has an enormous effect on impingement of the hip. For instance, decreased FV can lead to cam-type impingement because of the diminished head–neck offset (65). Additionally, decreased FV can lead to abutment of the femoral neck against the acetabular rim, resulting in pincer-like impingement (14). Furthermore, patients with decreased FV have an increased risk of developing extraarticular subspine impingement (66). For patients with severely decreased FV, impingement of the anterior part of the greater trochanter against the anterior acetabular rim or subspine region can be seen during flexion or internal rotation (67). Furthermore, decreased FV increases the risk of developing slipped capital femoral epiphysis to a large extent because of the increased shearing force on the physis, as mentioned above (68).
Second, increased FV is associated with many other disorders as well. For instance, patients with increased FV have an increased risk of anterior cruciate ligament injuries (69). Additionally, an increase in FV asymmetry also affects musculoskeletal health. Piazzolla et al. (70) found that patients with unilateral increased FV present low back pain, while those with bilateral increased FV do not.
To conclude, abnormal FV can adversely impair musculoskeletal health to a severe degree in many ways. Therefore, DDH patients with abnormal FV are likely to exhibit these disorders as comorbidities. When treating such patients with hip preservation surgery, it is of great importance to screen for possible concomitant disorders preoperatively to create a detailed surgical plan. The plan should include whether to treat the comorbidity as well as the specific time of correction. With this plan, all the possible existing disorders can be cured, and revision surgery or reoperation can be avoided.
Significance of FV in many aspects of adult hip preservation surgery for DDH
As a routine preoperative measurement, many studies have investigated the relationship between FV and various facets of adult hip preservation surgery for DDH. Previous studies have found that DDH patients tend to exhibit increased FV (71). However, FV also plays an important role in those with femoral retroversion during adult hip preservation surgery for DDH. Here, we suggest emphasizing the evaluation of FV when performing any type of hip preservation surgery in DDH, for its guiding significance.
First, many studies have found that FV may be accompanied by other morphological abnormalities of the hip in DDH patients. For example, there is a significant positive correlation between FV and acetabular version in DDH patients with anterior or global deficiency (9). In addition, FV in DDH patients is significantly negatively correlated with the preoperative or postoperative lateral center-edge angle (72, 73). Additionally, the anterior center-edge angle, as well as the Tönnis angle, also varies significantly according to differences in FV (74). Moreover, the neck-shaft angle is weakly but positively and significantly correlated with FV in patients with hip pain (75). As a consequence, by measuring FV, we can infer other characteristics of the hip and gain a primary impression of the condition of the entire joint as well as possible deformities.
Second, FV is sometimes accompanied by a more severe DDH. Jia et al. (76) found that for unilateral DDH patients at an early walking age, FV was not significantly different in the Tönnis grade II and III groups but was significantly increased in the Tönnis grade IV group. As a consequence, in such patients, significantly increased FV on one side compared to the contralateral side may indicate a Tönnis grade of IV, and it should be taken into account whether to perform PAO or total hip arthroplasty (THA).
Third, FV has been demonstrated to have an effect on postoperative range of motion (ROM). For example, Hayashi et al. (73) found that after PAO, FV was negatively and significantly correlated with the postoperative abduction as well as external rotation ROM. Additionally, they discovered that the preoperative FV could predict the internal rotation ROM at 90° of flexion after PAO, with positive and significant relevance.
Fourth, FV can help predict postoperative impingement. Decreased FV or combined version positively correlates with anterior impingement after curved or rotational PAO for DDH (77, 78). Furthermore, Hayashi et al. (78) created a receiver operating characteristic (ROC) curve using 48° of combined version as the cutoff point for postoperative anterior impingement and found significantly different postoperative modified Harris hip scores. In addition, according to Ida et al. (79), approximately 40% of acetabular dysplasia patients have radiographic evidence of cam-type deformity as well, presenting with relatively decreased FV compared to those with dysplasia alone. Hence, for acetabular dysplasia patients with relatively decreased FV, it is very important to determine whether a cam-type deformity is also present to prepare for the related surgery, such as osteochondroplasty.
Furthermore, in borderline dysplasia, the clinical results in patients with femoral anteversion treated with arthroscopy have been demonstrated to be inferior to those in patients with normal FV (6). Therefore, for borderline dysplasia patients with increased FV, arthroscopic therapy should be carefully considered, and open PAO or femoral osteotomy should be considered as alternatives (80, 81, 82).
Treatment for abnormal FV: femoral derotational osteotomy
Because of the significant anatomical importance of FV and the disastrous effects of abnormal FV on biomechanics as well as musculoskeletal health, there is a tremendous necessity to treat and correct abnormal FV, which is most frequently achieved by femoral derotational osteotomy (80).
Femoral derotational osteotomy can be performed at three levels: the proximal intertrochanteric or subtrochanteric level, diaphyseal level, and distal supracondylar level (2). These different levels contribute differently to the total FV (20, 22); thus, it is essential to account for segmental variation during osteotomy to ensure healthy biomechanics postoperatively (81). Articles by Nelitz et al. (2) and Noonan et al. (39) elaborate on detailed surgical procedures.
Because femoral derotational osteotomy has many potential complications, which can be miserable and painful, strict indications for femoral derotational osteotomy should be considered. In fact, there are not yet clear guidelines on the surgical indications of abnormal FV, and suggested indications vary according to different researchers. For instance, Nelitz et al. (2) held the idea that surgery should be based on symptomatology and considered patients with symptomatic patellofemoral malalignment and femoral anteversion greater than 25–30° to be proper candidates. However, Noonan et al. (39) held a similar but slightly different opinion. They considered patients with 20–30° of FV combined with further evidence of patellofemoral pathology, patients with 30–40° of FV combined with other patellofemoral anatomical risk factors, and patients with over 40° of FV to be suitable candidates for derotational osteotomy. Importantly, age is an essential factor that should be taken into consideration when deciding whether or not to perform femoral derotational osteotomy, for FV physiologically decreases approximately 1.5° per year during childhood until fully grown (82). According to our clinical practice, for pediatric patients, abnormal FV will sometimes correct itself without intervention, which should be attached importance to.
Additionally, apart from the effects of FV on the biomechanics of the lower limb and gait, tibial torsion can also affect the lower limb in terms of the muscle lever arm (83, 84) and patellofemoral articulation (85) to a large extent. Combined abnormality of FV and tibial torsion, previously termed torsional malalignment syndrome (86) or miserable malalignment syndrome (53), is not rare in patients with hip diseases (5). In such conditions, altered tibial torsion can exacerbate the deleterious effects of abnormal FV and is also capable of compensating to ameliorate the negative consequences. This is in accordance with the phenomenon that not all patients with increased FV require femoral derotational osteotomy. However, patients with increased FV can be observed to have increased, normal, and decreased tibial torsion, and vice versa (5). Hence, the specific compensating or aggravating mechanism of tibial torsion remains a puzzle that merits further research. Therefore, when considering femoral derotational osteotomy, tibial torsion should be taken into account simultaneously, especially for patients with combined deformities, to prevent complications such as postoperative out-toeing gait.
Similarly, studies on whether to adjust abnormal FV simultaneously during adult hip preservation surgery for DDH, as well as on the proper cutoff point for this in DDH patients, are needed. Spiker et al. (71) found that only 5% of patients with increased FV and DDH required femoral derotational osteotomy. This may also be the consequence of compensation by tibial torsion. Hence, more studies should focus on this issue to achieve a consensus on the treatment of abnormal FV in DDH patients.
To conclude, indications vary among studies and various combinations of disorders. Further studies are required to focus on this issue and develop a unified and widely agreed-upon standard.
Conclusion
FV mainly refers to the rotation of the femur and is among the most significant anatomical structural parameters of the hip. However, the specific origin of FV remains controversial, and further research is required to gain a full understanding. FV can be measured by many approaches, consisting of imaging techniques such as CT and MRI or functional tests. FV is of great significance in adult hip preservation surgery for DDH, as there is great possibility of adversely altered biomechanics and comorbidities caused by abnormal FV. Moreover, FV measurement can provide clinicians with much extra information, such as other morphological parameters of the hip and possible surgical complications. The most frequently applied technique for correcting abnormal FV is femoral derotational osteotomy. However, because of the poorly understood compensating or exacerbating effect of tibial torsion, further research is needed to fully elucidate the underlying mechanisms and determine detailed indications for addressing FV in patients with femoral anteversion alone or in combination with DDH. Hence, it is of great necessity for FV to be measured pre- and postoperatively, and clinicians as well as researchers should attach more importance to it.
This study has some limitations. One limitation is that this review is based on the author’s summarization. Although efforts have been made to remain objective during analysis, subjectivity is still an inevitable issue. Another limitation is that although we point out here that FV and FT are two distinct parameters, current opinion leaders use the terms interchangeably and do not differentiate accordingly. Therefore, little emphasis is put on FT and the consequence of interchangeable use. Future research should be undertaken to explore the necessity of distinguishing FV and FT, both in researches as well as in clinical routine.
ICMJE Conflict of Interest Statement
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding Statement
This study was supported by the National Natural Science Foundation of China (grant no. 82172473).
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