The scattering of guided waves propagating through pipe bends is studied by means of normal mode expansion. First, the bi-orthogonality relationship for normal modes in pipe bends is derived, based on which the displacement and stress fields at the interfaces between the straight and curved parts are expanded with the normal modes in both parts. Then, based on the displacement and stress field continuity principle, the scattering problem is regarded as an eigenproblem of a transfer matrix, the solution of which gives the mode conversions at the interfaces. A case study is presented of the low-frequency longitudinal mode incident on a pipe bend, and it is found that the dominant mode conversions are L reflection and mode conversion from L to F. Finite element simulations and experiments are also conducted. L bend reflection and mode-converted F are clearly observed, which agrees well with the theoretical predictions. However, practical pipelines always have multiple bends that interfere with the propagation of the incident guided wave and thus complicate the testing signals significantly and even make them impossible to interpret. Therefore, the scattering mechanics of guided waves propagating through pipe bends are essential when inspecting complicated pipelines.Because it is highly efficient and can detect zones that would otherwise be inaccessible, guided-wave technology4 first derived the dispersion curves and mode structures of guided waves in pipe bends with the mode analysis method5 in commercial finite-element software, but the dispersion relationship can be calculated only at discrete frequencies. Hayashi et al.6 first calculated the dispersion curves of guided waves in pipe bends by using the semi-analytic finite-element method (SAFE)10, which requires only the pipe cross section to be discretized, thereby turning a three-dimensional (3D) problem into a two-dimensional (2D) one and hence saving computational time and memory. A curved cylindrical coordinate system is introduced for the curved pipe region, under which the governing equation of wave motion in pipe bends is derived and then solved with the SAFE method. That method is also applied to dispersion calculations of helical structures8 and structures with constant cross sections, such as rails9 and square tubes10.Because of the curved axis of a pipe bend, the wave motion therein is much more complex and must be investigated numerically rather than analytically. Demma et al.11, mode repulsion9, and natural focusing12. Demma et al.11 studied the mode-splitting feature and gave the explanation that the originally identical modes in straight pipes split into two different modes because of the loss of axisymmetry in pipe bends. Mode repulsion has also been observed in the dispersion curves for curved plates14, helical waveguides8, and rails9, among others. Loveday et al.9 studied the mode repulsion of guided waves in rails, following which Wu et al.15 studied the same in pipe bends. It is found that mode repulsion occurs when the second derivative of frequency with respect to wavenumber approaches infinity as the two curves approach each other. It is also found that mode repulsion occurs only between modes of the same type  and not between modes of different types .Compared with the dispersion curves of guided waves in straight pipes, those for pipe bends exhibit several distinct features, such as cut-off frequencies for the fundamental modes [L and T], mode splitting20 and experiments25. By means of 3D finite-element simulation, Aristegui et al.16 simulated the L mode traveling across pipe bends and observed mode conversions from L to F and F. Demma et al.11 studied scattering of the torsional T mode and found that it is more likely to be converted to F. Based on the definition of travel-time-preserving orthogonal parametric representations of curved tubes, Brath et al.12 models guided wave propagation and scattering in a bend with a 2-Dimensional approaches. Qi et al.17 and Heinlein et al.18 investigated reflection of the T mode from circumferential and axial defects in pipe bends, respectively. As well as the finite-element method, other numerical methods are also employed: Rudd et al.19 used elastodynamic finite integration to simulate guided waves in pipe bends, and Zhou et al.20 used the wave finite-element method to study the scattering mechanics of pipe bends.Although the propagation characteristics of guided waves in pipe bends are well known, the corresponding scattering mechanics remain less understood. Most studies of scattering mechanics are based on numerical simulations21 used a laser system to generate and sense guided waves in a stainless-steel pipe, and mode conversions in pipe bends were observed. Also using a laser system, Kim et al.22 assessed wall-thinning defects in pipe bends. Verma et al.23 generated the L mode with magnetostrictive transducers and investigated how the bend angle and radii affected the reflection and transmission coefficients. Similarly, Wu et al.25 used a magnetostrictive system to study scattering of the L and T modes passing through pipe bends. Brath et al.26 experimentally mapped the pipe elbows with a fast forward model-based guided wave tomography method.As for experimental studies, Nishino27 first derived the bi-orthogonal relationship in hollow cylinders based on the reciprocity theorem28, followed by a generalized mode excitation analysis of pipes with surface traction applied. More specifically, Ditri et al.29 analyzed the mode excitation of wedge- and comb-type transducers. Using the same NME method, Zhang et al.30 analyzed the force response of elastic hollow cylinders with respect to magnetostrictive loading. Ma et al.31 studied the excitation of torsional guided waves in pipes by reversed shear loading. Bakkali et al.32 studied the scattering at the junction between straight and curved pipes based on the bi-orthogonal relationship which is simply extended from the bi-orthogonal relationship in plates. Recently, Zhang et al.33 used the NME method to study forced guided-wave problems in loading zones and found that the classic NME solution does not satisfy Hooke’s law inside the loading zone. To address this shortcoming, Zhang et al.34 proposed a modified NME method.Based on a bi-orthogonal relationship, the normal-mode expansion (NME) method expresses the wave motion in a waveguide with orthogonal guided wave modes, thereby facilitating force response analysis. Ditri et al.Herein, the NME method is used to study the scattering mechanics of guided waves in pipe bends. In “6 is introduced to model the curved hollow cylinder, where the straight z axis in cylindrical coordinates is replaced by a curved z′ axis along the curvature of the bend. Thus, an arbitrary point  in Cartesian coordinates can be expressed in quasi-cylindrical coordinates  asR is the bending radius.As shown in Fig. 6In quasi-cylindrical coordinates, the stress–displacement relations are rewritten asλ is the Poisson ratio and µ is the shear modulus of elasticity.u in a pipe bend takes the formk is the wavenumber, z′ direction is assumed to be harmonic, finite-element discretization is required only over the cross section of the pipe bend, with the harmonic wave motion in the z′ direction included analytically. Because only the cross section is discretized and not a volume, thereby turning a 3D problem into a 2D one, this method decreases the number of nodes significantly and hence saves computational time and memory.Guided waves are assumed to propagate along the curved axis, hence the displacement 4U is the nodal displacement, K1, K2, and K3 are the stiffness matrices, and M is the mass matrix. The stiffness and mass matrices are all real and symmetric, except that K2 is antisymmetric. Let With the rewritten strain–displacement relation [Eq. ] and fol27, in which the bi-orthogonality relationship for a straight pipe is deduced.The NME method is based on a bi-orthogonal relationship and expresses the wave motion with orthogonal guided wave modes. The bi-orthogonality relationship for normal modes in pipe bends is derived in this section by following the work of Ref.27, which states thatV1, V2, The bi-orthogonality relationship for normal modes is derived from the complex reciprocity relationk is the modal wavenumber, and V and T are the particle velocity and stress fields, respectively, over the cross section of the pipe bend. Note that here and hereinafter, the harmonic time dependence Let Combining Eqs.  and 8)  8) givesV volume in Fig. Integrating Eq.  over a sV volume becomes the area integral over its surface, i.e.,V volume, z′ positions of z′ direction, and By using Gauss’s divergence theorem, the volume integral in the Δz′, its area integrals in For a free pipe bend, its inner and outer surfaces experience no traction, therefore the first term on the right-hand side of Eq.  vanishesore, Eq.  can be wLetting mentclasspt{minimaEquation  indicateEquation  is the bIn this subsection, the bi-orthogonality relationship of Eq.  is validC and LC modes, (ii) the mode-splitting phenomena marked with the frames, and (iii) the mode-repulsion phenomena marked with the circles. Note that Fig. The wave motion in the pipe bend is derived using the SAFE method introduced in “The excitation frequency of 30 kHz is chosen to investigate the bi-orthogonality relationship. Also, by solving Eq. , the mode denotes the element and The term ,k2 [Eq. ] in the The With the bi-orthogonality relationship for pipe bends derived in last section, the incident mode and all possible reflected modes can be expanded with the normal modes in pipe bends at the interfaces. Vise verse, the transmitted modes can be expanded with the normal modes in straight pipes. By taking the displacement and stress continuity principle into account, a transfer matrix between scattering coefficients can be established. Then, by solving the transfer matrix, the mode conversions at the interfaces are deduced.Assume that a guided wave excited in the straight part of a pipe propagates through a pipe bend, as shown in Fig. i denotes the ith section of the pipe shown in Fig. s and c denote the straight pipe and curved pipe, respectively, a and b are the expansion coefficients of the normal modes, and For each interface, the displacement and stress fields over the cross section should be consistent, i.e.,an) are different from those of the stress mode structures (bn). However, bn can be calculated according to the displacement–stress relationship.Because the displacement–stress relationship [Eq.  or (21)]27 and pipe bends, the expansion coefficients are calculated asBased on the bi-orthogonality relationships of both straight pipesNote that because the normal modes are essentially the solutions to the governing equation of wave motions in waveguides, the normal modes cannot satisfy two different governing equations for different waveguides simultaneously. Assume the displacement field of the interface is expressed by normal modes in straight pipes and pipe bends simultaneously. Then, the stress field of the interface can be expressed by normal modes either in straight pipes or pipe bends. Because the stress field is calculated according to different Hook Laws (different L operators in Eq. ), the stAt interface Then, by combining Eqs.  and 24)24) and cEquation  gives thi, r, and t are introduced to denote the incident, reflecting, and transmitting modes, respectively.All modes including the incident positive propagating modes, transmitting positive propagating modes, reflecting negative propagating modes, and non-propagating modes should be considered in the calculation. Therefore, the superscripts Conversely, by expanding each mode in pipe section 2 with normal modes in pipe section 1 and following the same derivation procedure, we haveCombining Eqs.  and 30)30) givesg to Eq. .In practical inspections, usually a single mode is excited in pipe section 1. Then, by setting Considered the acoustic field in either the straight or curved section as being linear, multimode incidence can be treated as multiple single-mode incidences, which can be done by calculating the scattering of each single-mode incidence separately and then linearly superposing these scattering acoustic fields.j, we havejth incident mode scattering at the Because multiple modes are scattered at the first interface, multimode incidence should be considered for the second interface. As mentioned before, multimode incidence is considered as multiple single-mode incidences. For each incident mode By superposing all the scattering acoustic fields, the scattering at the The modes reflected at the Combining the scattering fields of the In this section, we consider the example of the longitudinal low-frequency axisymmetric L mode in a small-bore pipe with a bend. The test pipe is the same as that used in “1, F2, F1, and F2 modes. The output transmitting modes are the LC, FC1, FC2, FC1, and FC2 modes. F1 and F2 are the same modes because they have the same wavenumber. The difference between them is their circumferential orientations of displacement fields, as shown in Fig. 1 and F2.The scattering at the ips [Eq. ], and thSolving the eigenproblem of i, which should be one in theory.Taking the absolute values of C mode, part is converted into the FC2 mode, and all other mode conversions are negligible.From the reflection and transmission coefficients of the C and FC2 modes are considered here. Expanding the LC and FC2 modes with the normalized modes in straight section 3 give the transfer matrices C are the incident LC and reflecting LC, FC1, FC2, FC1, and FC2 modes. The input modes for FC2 are the incident FC2 and reflecting LC, FC1, FC2, FC1, and FC2 modes. The output modes for both cases are the L, F1, F2, F1, and F2 modes.For the C and FC2 incidences:i and 0.0519 + 0.9121i.Solving the eigenproblems of Combining these scattering fields and the transmission coefficients of the Thus, 1, F2, F1, and F2 modes, and the transmission coefficients correspond to the transmitting L, F1, F2, F1, and F2 modes.where the reflection coefficients correspond to the reflecting L, FThe reflection and transmission coefficients show that for unit normalized L incidence, ~ 10% of the L mode is reflected and more than 100% of it is transmitted, which means that the law of energy conservation is broken here. This happens because the principle of displacement and stress consistency at the interfaces does not hold in the NME framework.C2 mode.However, although the scattering coefficients are not exact, inherent connections between normal modes in straight pipes and pipe bends are unveiled, and the main mode conversions at pipe bends are predicted correctly. In this case, it can be concluded that most of the incident L mode passes through the pipe bend, some of it is reflected, and some converted into the FThe evolution of scattering coefficients of L incidence with respect to frequency is shown in Fig. fmax is the maximum frequency within a half-power bandwidth.To validate the results of the case study in “A five-cycle sinusoidal tone burst modulated with the Hann window function at the excitation frequency of 30 kHz was applied on the cross section of one end of the pipe in the axial direction. The watchpoints were set on the other end of the pipe, as shown in Fig. Figure In summary, the numerical simulation results agree well with the theoretical predictions. Although the theoretically derived scattering coefficients are not exact, the dominant mode conversions are obtained correctly.In this section, the scattering of the L mode travelling through a bend is studied experimentally. The experimental rig is shown in Fig. The transmitting and receiving transducers were placed on the same end of the pipe. Magnetostrictive patch transducers were employed. Four pre-magnetized iron-cobalt alloy strips of 70 mm length, 5 mm width, and 0.15 mm thickness were spaced equally around the circumference and bonded longitudinally on the pipe with epoxy glue. A 40-finger solenoid coil was wound over the patches to transmit and receive the signals.Figure The amplitude ratio of the first L bend reflection in Fig. In summary, the experimental result that remarkable reflecting L and mode-converted F modes are scattered at the bend and ~ 10% of the incident L mode is reflected by the bend agrees well with the numerical simulations, thereby validating the theoretical predictions.Herein, the scattering of guided waves propagating across pipe bends was studied. First, the bi-orthogonality relationship of normal modes in pipe bends was derived. Then, based on that relationship and considering that the displacement and stress fields at the interfaces between the straight and curved parts of a pipe should be consistent, the scattering problem was regarded as an eigenproblem of a transfer matrix. By solving this eigenproblem, the mode conversions at the interfaces were deduced. Combining the mode conversions at two interfaces of one bend gave the reflection and transmission coefficients of guided waves traveling through the bend. A case study of a low-frequency longitudinal guided wave  mode) propagating across a pipe bend was given. Numerical simulations and experiments were further conducted to validate the theoretical predictions.Because the normal modes are essentially the solutions to the governing equation of wave motions in waveguides, the normal modes cannot satisfy two different governing equations for different waveguides simultaneously, indicating that the principle of consistent displacement and stress fields does not hold in the NME framework. For the case of L mode incidence, the theoretical prediction that ~ 10% of the incident mode is reflected, more than 100% is transmitted, and a remarkable part is converted into the F mode is obviously contrary to the law of energy conservation. However, the NME-based derivation still reveals the inherent connections between normal modes in straight pipes and pipe bends, and it gives valuable information about the mode conversions at pipe bends. It is proved by numerical simulations and experiments that L reflection and L–F conversion are the dominant mode conversions in this case.


Payment methods for human papillomavirus (HPV) vaccine could substantially influence vaccination behavior. In China, HPV vaccination uptake remains currently low. This study aims to determine willingness to pay (WTP) for HPV vaccines among Chinese female health care workers under different payment scenarios.This is a nationwide online survey recruiting female health care workers aged 18–45 years from 31 provinces throughout China. We collected the respondents’ vaccination status of HPV vaccines and their sociodemographics. Two WTPs were defined and estimated in the study. A general WTP for HPV vaccination was determined using the contingent valuation method with double dichotomous choice bidding. A WTP out-of-pocket was estimated for each HPV vaccine under two scenarios, including partial coverage by governmental subsidy or partial incorporation in basic medical insurance. Accordingly, a multivariable linear regression model was employed to determine the association between sociodemographis and general WTP. Then the maximum WTP out-of-pocket was compared among the respondents’ attitude shift towards HPV vaccination, payment scenarios, and levels of vaccine attributes, using non-parametric Kruskal-Wallis test.P < 0.05). Moreover, the median WTP out-of-pocket was 1250 CNY (540–2000 CNY). It was significantly higher for vaccines partly covered by governmental subsidy , imported vaccines , and 9-valent vaccines  (each P < 0.001). Additionally, majority of respondents did not change their attitude towards HPV vaccination between two payment scenarios; those remaining with more expensive HPV vaccines (51.1%) had higher WTP out-of-pocket  than those with cheaper vaccines (39.0%)  (P < 0.001).A total of 15,969 respondents were included in the study. The median general WTP was 2000 CNY , positively associated with younger age, unmarried status, higher monthly income, fewer children, more positive vaccination behavior, working in tertiary hospital, higher local GDP and HDI (each Chinese female health care workers have high WTP for HPV vaccines. A direct public funding for HPV vaccination is more preferable. Our findings may facilitate the adjustment of HPV vaccination strategy and payment mechanism in China.The online version contains supplementary material available at 10.1186/s12913-022-08716-6. Human papillomavirus (HPV) is the most common sexually transmitted infection , with thHPV vaccination has been proven effective in the prevention of cervical cancer in both high-income countries and low- and middle-income countries . HoweverSince 2020, multiple cities have included pilot HPV immunization programs in China’s mainland. Diverse strategies have been implemented, such as governmental subsidies and payment by basic medical insurance for certain or non-certain HPV vaccines . It has We performed a cross-sectional study to investigate the female health care workers on HPV vaccination behavior and their WTP for HPV vaccines. Using an online questionnaire with convenience sampling method, a total of 15,969 female health care workers aged 18 to 45 years were recruited from 31 provinces in China’s mainland between November 15 and December 22, 2021. In the questionnaire, sociodemographics and HPV vaccination behavior were collected. Moreover, WTP was determined for HPV vaccines, including four actual vaccines  and one assumed vaccine , under two payment scenarios .In addition, we included the Human Development Index (HDI), which is a long-standing summary measure developed by the United Nations Development Programme (UNDP) , to asseWe investigated the respondents’ vaccination status of HPV vaccines and prepared four responses, including “had been vaccinated”, “had not been vaccinated but had made an appointment”, “had not been vaccinated or made an appointment but intend to receive vaccination”, and “not intend to receive vaccination”.Subsequently, the first two responses were collapsed together, because they had a positive vaccination behavior. We classified these responses into three groups, “had been vaccinated or had made an appointment” (positive), “had not been vaccinated or made an appointment” , and “not intend to vaccinate” (negative). In a multivariable linear regression model, we scored three groups as follows: 3 points for “had been vaccinated or had made an appointment”, 2 points for “had not been vaccinated or made an appointment”, and 1 point for “not intend to vaccinate”.Using the contingent valuation method, a combination of closed and open-ended questions was used to precisely determine the respondents’ general WTP, which was defined as a WTP for general HPV vaccination rather than certain vaccines. In the double dichotomous choice bidding format, we prepared questions on two stages. In the initial stage, the questions contained a range of bid amounts , to which respondents stated their WTP as “yes” or “no” to hypothetical vaccine price. These initial bid amounts were randomly distributed among respondents during the questionnaire survey. In the follow-up stage, the questions were listed with bid amount of a 400 CNY plus or minus to the initial bid amounts depending on the response to the initial bid amounts. If the response to the initial bid amount was “yes”, follow-up bid amount increased by a 400 CNY; if the response to the initial bid amount was “no”, follow-up bid amount decreased by a 400 CNY. For example, in the initial stage, a question was asked to respondents, such as “Are you willing to pay for the HPV vaccine of 4000 CNY, regardless of your HPV vaccination status?”. If respondents answered “yes” to the initial bid amount, follow-up bid amount was redirected to be 4400 CNY in the follow-up stage; if response answered “no” to the initial bid amount, follow-up bid amount was redirected to be 3600 CNY.Consequently, responses to the double-bounded contingent valuation questions were classified as four dichotomous outcomes: (1) respondents were not willing to pay for HPV vaccines at both initial bid amount and a lower follow-up bid amount ; (2) respondents were not willing to pay for HPV vaccines at the initial bid amount but willing to pay at a lower follow-up bid amount ; (3) respondents were willing to pay for HPV vaccines at the initial bid amount but not at a higher follow-up bid amount ; and (4) respondents were willing to pay for HPV vaccines at both the initial bid amount and a higher follow-up bid amount . These four dichotomous outcomes were used as a categorical variable in the analysis. Furthermore, for all respondents, an open-ended question was prepared to ask for the maximum amount of general WTP, which was considered as a continuous variable in the analysis.In addition, we prepared two questions to investigate the minimum percentage of cost of an HPV vaccine under two payment scenarios, for which respondents are willing to pay the remaining cost of vaccine . We utilized a 9-item Likert scale, consecutively from 10% to 90% with an incremental percentage of 10%. Respondents’ maximum WTP out-of-pocket was calculated for each HPV vaccine, including four actual and one assumed vaccines, based on their actual and estimated prices and expected minimum percentage covered by governmental subsidy or basic medical insurance.P value greater than 0.05 in the White test and Kolmogorov-Smirnov test indicated no heteroscedasticity and normal distribution of residuals, respectively. Explanatory variables that were not significant at P < 0.05 in the initial model were excluded. The final model was achieved with stepwise regression method using EViews 9.0 .Descriptive statistics were presented. Four dichotomous responses of the general WTP  were compared across the sociodemographics using chi-square tests. Then a multivariable linear regression model was employed to determine the association between explanatory variables and general WTP , 25. TheP < 0.05.Respondents’ attitudes toward HPV vaccines between two payment scenarios were compared across sociodemographics using chi-square tests. Then the maximum WTP out-of-pocket was compared among the attitude shift, payment scenarios, and levels of vaccine attributes. As the maximum WTP out-of-pocket was non-normally distributed continuous variable, we utilized non-parametric Kruskal-Wallis test. All the analyses were conducted using SAS version 9.4 . Significance was assessed at A total of 15,969 female health care workers aged 18–45 years from 31 provinces in China’s mainland completed the questionnaire. The mean age of the respondents was 30.6 ± 6.2 years, with 4822 (30.2%) aged 18–26 years, 7714 (48.3%) aged 27–35 years, and 3433 (21.5%) aged 36–45 years. Majority of the respondents were married (61.1%), Han Chinese (93.3%), had a bachelor degree (68.3%), monthly income less than 8000 CNY (82.3%), primary professional title (57.7%), worked in tertiary hospitals (74.2%), lived in the city with GDP of ≥ 1.6 trillion CNY (42.4%) and HDI of 0.7–0.8 (63.0%).P < 0.05), whereas those aged 36–45, married, living in a city with a GDP ≤ 0.6 trillion CNY, with middle professional title or above, and who did not intend to vaccinate were more likely to choose “no, no” (each P < 0.05)  for HPV vaccination. A multivariable linear regression model indicated that respondents who were younger, unmarried, had a higher monthly income, fewer children, positive vaccination behavior, worked in tertiary hospitals, and lived in the cities with higher GDP and HDI, would intend to pay higher WTP . In the respondents, 51.1% and 39.0% intended to remain with more expensive HPV vaccines and remain with cheaper vaccines, respectively, regardless of payment scenario. Few respondents changed the attitudes, including choosing more expensive vaccines 7.2%) or cheaper vaccines (2.7%) if governmental subsidy is available instead of basic medical insurance. Respondents differed significantly by their attitude shift towards HPV vaccines across sociodemographics (Supplementary Table % or cheaP < 0.001). It was lowest  in those remaining with cheaper vaccine regardless of payment scenario, while highest  in those remaining with more expensive vaccine regardless of payment scenario  and significantly differed among the attitude shift (io Table .P < 0.05) (Table P < 0.001) , valency of vaccine , and payment scenario . Respondents preferred to pay higher WTP out-of-pocket if governmental subsidy is available for each HPV vaccine  and 1250 CNY (approximately 189 USD), respectively. As a female professional population, their WTP was moderately higher than the 49 USD which was documented in women in Vietnam in 2018 . HoweverWe found several demographic characteristics were strongly related to higher WTP for the HPV vaccines. HPV vaccination should preferably be performed in younger females to have the most impact, so respondents who were older, married, and had children in this study intended to pay a lower general WTP. Similar findings were also found in previous studies in Vietnam and Hong Kong , 30. NotWe found the payment mechanism significantly impacted WTP. Specifically, if HPV vaccines are partly covered by governmental subsidy, WTP out-of-pocket was significantly higher across all five HPV vaccines, compared to if vaccines are partly incorporated in basic medical insurance. It might be interpreted that respondents believe the payment for HPV vaccines by basic medical insurance would cost their own money in the medical insurance that would have paid for more medicine, while payment by governmental subsidy is kind of direct additional support. This finding may provide a clue to design more appropriate payment mechanism for HPV vaccination. In addition, WTP out-of-pocket was highest among respondents remaining with more expensive HPV vaccines, whereas lowest among those remaining with cheaper vaccines, regardless of payment scenario. It indicated the WTP varied along with choice of vaccines, though vaccine price had limited effect on the choice decision, which was also observed in parents of middle school students towards HPV vaccination in China . CurrentIn addition, our study explored the difference in the WTP associated with vaccine manufacturer and valency. We found that the WTP for 9-valent vaccine was higher than those for 4-valent and 2-valent (1400 CNY vs. 1250 CNY and 780 CNY). Similarly, a study in 2020 found that Chinese parents of primary school students were also willing to pay more for 9-valent HPV vaccines, rather than 4-valent or 2-valent . FurtherLimitations of this study need to be discussed. First, we recruited female health care workers in 31 provinces throughout China’s mainland, which may improve the representativeness and generalizability of our study. However, there could be biases due to the socioeconomic disparity across the nation. Second, in applying contingent valuation techniques, respondents could have been influenced by the range of values chosen for the payment scale question design rather than their true maximum WTP values. It is also possible that some respondents may have stated no WTP value or very low WTP value, especially if they feel that HPV vaccination should be paid by the government.Our study has several strengths. First, with our large sample size and robust findings, our study provides empirical evidence on the WTP for HPV vaccines among Chinese female health care workers. Second, we defined and calculated two WTPs in the study. A general WTP determined the cost for HPV vaccines that respondents could afford, and a WTP out-of-pocket determined the amount that respondents willing to pay for each vaccine under either a governmental subsidy or coverage in basic medical insurance. These WTPs may comprehensively reflect the respondents’ intent to pay for HPV vaccines and their payment preference.This study found that Chinese female health care workers had a high general WTP for HPV vaccines, which was associated with sociodemographics and local GDP and HDI. When comparing scenarios of payment that is covered by governmental subsidy vs. incorporation in basic medical insurance, 90.1% of respondents did not change their attitudes towards HPV vaccination. Moreover, they preferred to pay higher WTP out-of-pocket for vaccines partly covered by governmental subsidy, imported vaccines, and 9-valent vaccines. Our study suggests a direct public funding for HPV vaccination may be more preferable among Chinese female health care workers.Additional file 1:Supplementary Table 1. Response to diverse initial bid amounts across sociodemographics among Chinese female health care workers. Supplementary Table 2. Attitude shift towards HPVvaccines between two payment scenarios across sociodemographics.


Consequently, they can only travel to a certain distance in pipe, cannot access small-diameter pipes, and their deployment incurs high costs for highly skilled operators. In this paper, we introduce a miniaturised mobile robot for pipe inspection. We present an autonomous control strategy for this robot that is effective, stable, and requires only low-computational resources. The robots used here can access pipes as small as 75 mm in diameter. Due to their small size, low carrying capacity, and limited battery supply, our robots can only carry simple sensors, a small processor, and miniature wheel-legs for locomotion. Yet, our control method is able to compensate for these limitations. We demonstrate fully autonomous robot mobility in a sewer pipe network, without any visual aid or power-hungry image processing. The control algorithm allows the robot to correctly recognise each local network configuration, and to make appropriate decisions accordingly. The control strategy was tested using the physical micro robot in a laboratory pipe network. In both simulation and experiment, the robot autonomously and exhaustively explored an unknown pipe network without missing any pipe section while avoiding obstacles. This is a significant advance towards fully autonomous inspection robot systems for sewer pipe networks.Despite recent advances in robotic technology, sewer pipe inspection is still limited to conventional approaches that use cable-tethered robots. Such commercially available tethered robots lack autonomy, and their operation must be manually controlled  Sewer systems are a crucial element of urban infrastructure. They not only transport sewage to processing centers but also reduce flood risk for the cities. However, sewer systems are exposed to harsh conditions such as mixture chemical reaction, excessive traffic, geological change, earthquakes. Pipes may suffer from corrosion, damage, deformation, leakage, siltation, obstruction, and other defects due to long-term deterioration. These defects will reduce the efficiency of the sewer system and in extreme cases sewage may leak out, polluting soil and ground water. Leaked sewage may also wash away soil, eroding the foundations of buildings or street pavements, possibly causing surface collapse or weakening foundations. Thus, sewer inspection is required extensively and regularly to provide early detection of defects and hazards. From there, hazard prevention measures, maintenance and upgrades can be planned and provided.Today, sewer inspection still heavily relies on a manual field survey , in whicvia the manhole. After that, the robot is manually controlled via the cables to crawl into the pipe and the inspection camera is remotely operated to record a video inside the sewer system. Video footage will then be analyzed offline to detect defects. Although such a tethered crawler can provide stable remote control, continuous power for strong motors, long operational time and real-time video streaming to the central station, the robot has to pull the long cables behind it. These cables are heavy and often stiff causing poor mobility to pass any kind of pipe-bends such as curves and junctions. As a result, these robots are generally only capable of moving along straight pipe sections. Thus, after the inspection of a pipe section between two manholes, the robot and cables must be pulled back and re-deployed at the next manhole. This method for inspection of the sewer pipes makes the inspection process very slow and costly  for completely autonomous operations in buried pipes. To address this challenge, the Pipebots project  aims to As the most common size of sewer pipes is 100 mm in diameter , PipebotIn this paper, we introduce the Joey robot as well as an effective control method for autonomous pipe exploration. To evaluate the performance of the system, the Joey robot is deployed autonomously in a small diameter (150 mm) sewer pipe network. The 3D-printed robot runs the control algorithm on its on-board processor and relies on low-energy sensors namely: two low-resolution encoders (that are connected to the motors driving the left and right sets of wheel-legs); three laser-based range sensors installed at the robot front; and an IMU (inertia measurement unit) on the back of the robot. The processing unit is a low-power microcontroller (STMicroelectronics) with maximum clock speed of 64 MHz. The pipe network is a laboratory mockup of a typical underground plastic sewer pipe network built at ICAIR . In this paper, the goals include an autonomous exhaustive exploration of a given pipe network, and a safe return to the starting point without flipping, getting stuck, or depleting the battery. In our experiments, a Joey robot is able to complete the exhaustive exploration and return safely within 4 min in a 5-m-long pipe network with complex geometry.The remainder of this paper is organised as follows: The Joey is designed to operate in small sewer or drainage pipes . It features wheel-legs for locomotion, to enable the robot to traverse obstacles and slippery terrains. The wheel-legs allow the robot to “roll” like other wheel robots and “walk” over small rocks, pebbles, low steps in the pipes, manholes, and uneven junctions. via a set of spur gears. As a result, the robot uses a skid steering method . These range sensors measure distance to nearest points at straight front direction, and at 30° to the left and right of straight front direction. via 2.4 GHz Wi-Fi communication. To support camera vision, the robot is also equipped with three ultra-bright LED NeoPixels (WS2812 from WorldSemi) light sources.In addition to the encoders, Joey robots are equipped with three time-of-flight range sensors (VL53L1X from STMicroelectronics - Pololu 3415), an IMU (ICM-20948 from InvenSense) and a MEMS microphone (IMP34DT05 from STMicroelectronics). The range sensors are placed in front, front left, and front right of the robot . This is an ultra-low-power microcontroller supporting BluetoothIn summary, the miniature Joey robot is entirely autonomous, and operates without any tethered cables. When tested in a 100 mm pipe section/network, the Joey successfully walks while monitoring its accelerations and orientations with the integrated IMU, monitor the distances from the robot’s front to the closest straight front, front-left and front-right pipe wall/object with range sensors, monitor the left/right wheel-leg rotation with encoders, and record videos of the pipe conditions with on board camera and SD card. All recorded video and data can then be post-processed on a computer for pipe condition monitoring, asset mapping, maintenance, and upgrade.Task 1: To explore small pipe networks while performing a basic inspection.Task 2: To collect/record and process inspection data .Task 3: To collaborate and communicate with other robots.Joey robots are designed to work in hard-to-reach small sewer pipes. They have three main tasks:This paper focuses on the first task which is to autonomously explore an unknown pipe network. We assume the pipes are empty before inspection, we use clean, dry pipes. The robot must operate without any cable, remote control, or human intervention, and exhaustively traverse the entire pipe network without missing any section. The robot must autonomously decide  how to move in order to perform this navigation task without access to a map, GPS data, video or acoustic inputs. In addition to the above-described sensors, the Joey has a camera and light source. To reduce power-consumption and thus increase operation time, in an accompanying paper we propose only to switch on the camera and light source only when those are essential for inspection and mapping . When opAs explained in previous sections, the first challenge in autonomous control of the Joeys in sewer pipes is implementing a robust protocol for the execution of task 1 with only simple, low-power onboard sensors .The second challenge is to overcome physical flaws of Joey robots which are the design sacrifices to achieve miniaturized robot able to operate in small spaces. Six physical limitations and their consequences for robot mobility and stability are discussed here: First, as the pipe is not flat, the robot must constantly stabilize its motion using the encoders. But because the small and low-cost encoders cannot be mounted on the micro motor shafts, they are attached to the output side . Thus, a key constraint is the low sampling rate of the encoders: there are only a total of 12 pulses with quadrature reading mode for each revolution of the wheel-legs. Second, the initial angular position of the six wheel-legs is designed and assembled so that only three wheel-legs are in contact with the flat floor while the other three wheel-legs are in opposite phase . This tripod gait would maintain the balance for the robot base. However, in a physical robot, the left and right wheel-legs are often out of sync as a consequence of the 3D printed gear-set backlash. The limited tolerance can destabilize the robot body during locomotion, which in turn may result in deviations from the intended direction along the robot trajectory even when robot is walking on flat surface. The challenge to autonomously maintain the robot balance is exacerbated when the robot is carrying out a maneuver or moving in a pipe, or other inclined surfaces. Third, Joeys use differential drive for steering. As the wheel-legs on each side are geared together, some slipping is inevitable during turning maneuvers. Slipping interferes with odometry measurements and hence with closed-loop speed/position control. Fourth, as there are multiple spur gears connecting the micro-motor and wheel-legs and the current Joey version uses 3D printed plastic gears, there is significant backlash causing high overshoots for position control. Fifth, related to this gear backlash, when the wheel-legs are out of sync, robot locomotion makes its body wobble vertically, causing unstable readings on the range sensors and IMU. Finally, as the robot center of mass is quite high, the robot faces significant flipping risk. The prototype Joeys used in this paper are not able to recover once flipped. These challenges must be overcome even when the pipes are perfectly clean and horizontal. In this paper, we first test autonomous deployment of the robot in such ideal conditions and then confront the robot with additional challenges, including inclined pipes and liquid or granular substrates on the pipe interior .To overcome the challenges described in Straight center and straight sided: The robot is in a straight pipe section, but the former is when robot front-back centerline is “close” to the pipe centerline while the latter is when robot front-back centerline is far from the pipe centerline. The definition of “close” is:Sided: This state is similar to straight sided except its front range value is under a defined limit Fs . This state is often encountered during fine maneuvers and used in the control algorithm to keep the robot front-back centerline parallel to the pipe centerline or to steer the robot away from obstacles or from the pipe wall.Left corner and right corner: The robot is at a left or right corner from its front view direction.Crash left and crash right: The robot is about to crash to the pipe wall, dead-end wall, or obstacle. “Left” or “right” denotes the side from which the robot has rotated towards the crash object/wall. These two states provide limits for the robot as it steers and allow it to find stable states without crashing or flipping.Flip-risk: The robot has either detected a risk of flipping over if it moves forwards or backwards, or it has detected an over-inclined orientation risking flip sideways. This state requires fine steering out of this high-risk state.Dead-end: The robot is at a dead-end in the pipe network. The robot should turn around to exhaustively explore the whole pipe network.T junction, left branch, right branch: These three states refer to different perspectives of the same junction in the pipe network that depend on the robot’s direction of approach , the robot carries out the corresponding maneuver. The state of the robot in the sewer pipe network is estimated by a fusion of historical data of distance values from three range sensors, orientation values from the IMU, wheel-leg rotation, and previous robot states. An initial state is estimated based on range values to the nearest objects/pipe walls. If a new state  is detected, the robot stops to re-assess its sensor values and double check the state. This process is carried out at the next cycle of state estimation and high-level control. This cycle is called the high-level control cycle and the cycle frequency can be increased or decreased depending on the robot’s state to adapt to fine maneuvers at complex junctions or fast forwards in straight pipes. If a robot state is confirmed .- If the front range value is very small, the robot is about to crash into a wall/obstacle.- If all range values are high, the robot is in an open space or manhole.- If the front range value is just under the manhole range limit, the robot is in a straight pipe section (either at the pipe centerline or sided). It may also be approaching a right/left branch junction. The method of determining if there is a right branch is illustrated in. A similar method applies for left branch.- The robot states of T-junction and left/right corner are only determined when the robot is sufficiently close to the junction/corner at an assessing distance. This assessing distance is calculated so that robot range sensors are able to “detect” the pipe on the left/right . The method of calculating this distance is illustrated in - During a high-level maneuver, the current robot state is maintained until the robot yaw angle reaches the maneuver target (within tolerance), at which point the maneuver terminates.Some governing rules that determine the output state of the estimation algorithm are as followed:The pseudo-code of the state estimation is as follows:MH_FRONT and CRASH_FRONT are front limits to determine if the robot is facing a manhole and or it is going to crash to a wall or object; T_ASSESSING_DIS_MIN and T_ASSESSING_DIS_MAX are the minimum and maximum front range values that the robot starts checking if it is approaching a T-junction or a right/left corner. In addition, the sub-functions are:Here, check_flip_risk : reads robot pitch, roll angles and distances to nearest left, right, front objects/walls to estimate the risk of flipping over.check_manhole : determines the robot state when front range value is larger than the manhole front limit . Possible outputs states of this function include open space or manhole, straight center, straight sided, and left/right branch.check_crash_risk: calculates the robot speed and location relative to nearest wall/object when the front range value is below CRASH_FRONT or total value of three range sensors is below CRASH_SUM, and determines if it is facing a risk of crashing itself to the object/wall. Possible outputs of this function include crash left/right, dead end, and sided.check_dead_end_state: calculates the robot position relative to surrounding pipe walls, objects when the front range value is small but larger than front crash limit . Possible output states of this function include dead end, sided, T junction, and left/right corner.check_T_junction_corners: calculates the robot position relative to surrounding pipe walls when the robot is approaching a junction or corner at a certain front range value. Possible output states of this function include T junction, left/right corner, and left/right branch.check_left_right_branch : calculates the robot position relative to surrounding pipe walls when front range value is higher than the distance needed for assessing a T junction but smaller than the manhole front limit. Possible output states of this function include left/right branch and straight sided.Δ is the distance between the range sensor to the robot center , High-level control: After a robot state is confirmed, the robot chooses an appropriate action.Low-level control: In parallel with high-level control rules, there are low-level governing laws that maintain robot self-balance, maintain its center to pipe centerline, avoid flip and crash risks, and change robot speed according to environmental conditions.- During all high-level maneuvers, the robot is continuously (5 Hz) monitoring its roll, pitch angles, accelerations, and range values to assess and avoid potential risks  and to maintain low values of robot roll, pitch, and accelerations.- At low-level states , the robot uses closed-loop speed control and increases speed if it is close to the pipe centerline.- During all operations, the robot continuously monitors its range values, speed, and accelerations to avoid crashing, obstacles, and pipe walls.Battery control: In addition to high-level decision making and low-level motor control, it is essential to add a power management plan to the control algorithms when the robot operates autonomously in real underground pipe networks. The main control board of Joey robot integrates a battery monitoring and charging circuit. In real operations, when the battery voltage drops below a certain level, the robot will enter a charging mode in which it either navigates to the nearest pick-up point  or to the nearest charging station. Detailed power consumption calculations were carried out during the circuit design and robot design processes. Low power components were prioritized for the design to maximize the operation time. By design, the robot can theoretically operate in autonomous mode for about 53 min. We have also tested the physical robot total power consumption in the current autonomous control mode.To evaluate the capability and effectiveness of the proposed control method, we tested it in physical robots in the experimental pipe network described above . As specFrom the starting point at the entrance , the robAdditionally, extensive experiments were carried out to evaluate statistical results on high-level decision making and low-level maneuver performance by the robot when it encountered junctions, dead end, and obstacles. The Joey robot was deployed with the same sensors, components, load, and autonomous control program throughout all runs. For each junction or event, the robot was placed in front of the junction/object and a camera was used to record each autonomous run. We recorded videos of 12 successful exhaustive explorations performed with the same Joey in the pipe network in The above tests were performed in a horizontal and clean pipe network. Naturally, in realistic scenarios, we expect a slight inclination angle in sewer and water pipes. Worse, real pipes are rarely clean. They may contain fluids with different viscosities, and sediments such as sand. To address these challenges, we also tested the ability of the robot to autonomously locomote in the pipes under more complex and more realistic conditions, including: 1) dry sand, 2) dish-washing liquid, 3) mixture of sand and dish-washing liquid (mimicking a combination of muddy and slippery pipe conditions). In all three conditions, the miniature robot was controlled autonomously by the same pipe network exhaustive exploration program. In all repetitions of these experiments, the robot had no difficulty in locomoting and adjusting its motion to successfully traverse all three surfaces. 0). In reality, sewer pipes are designed to have much shallower gradients from one in 40 to one in 110 . The Joey robot was able autonomously navigate successfully without any issue.While this experimental result demonstrates the ability of the robot to effectively move through inclined pipes, if the slope in the pipe is too high, the robot may fail to estimate its state correctly . However, we have tested the autonomous pipe exploration with the same pipe network on an incline surface with a slope of one in 10 . Furthermore, as the number of states included in the control algorithm are limited, not every possible encounter has been accounted for in the control algorithm. For example, we can expect certain scenarios in which the robot may confuse between unusually-shaped obstacles and junctions. Many of these scenarios may be overcome with modifications or extensions to the control algorithm, while others may ultimately prove to require additional or improved sensors.As mentioned above, this paper does not directly address the challenge of localization and mapping. In an accompanying paper , we propJoeys were envisioned as small robots that can operate in groups or swarms in buried pipe networks. Due to their small size, Joeys are ideal for navigating small (100–150 mm diameter) water, sewage, and drainage pipes. However, their small size, limited speed and limited stability is also prohibitive. We therefore envision Joeys being delivered and picked up by larger robots from specific locations in a pipe network. In future work, collaborative control will be developed and implemented for multiple Joey robots collaboration and for their interaction with their carriers (larger robots developed by Pipebots). Our envisioned cooperative “multi-species” ecology of robots will increase the network covering speed and be better suited to carry out complex tasks. The ultimate aim of pipe robotics is not only to navigate but also to inspect the buried infrastructure. Therefore, additional future work involving individual autonomous Joey robots will include data collection task see . Immedia


This review discusses the timeline and development of the recommended screening tests, diagnosis system, and therapeutics implemented in clinics for precancer and cancer of the uterine cervix. The incorporation of the latest automation, machine learning modules, and state-of-the-art technologies into these aspects are also discussed.Cancer arising from the uterine cervix is the fourth most common cause of cancer death among women worldwide. Almost 90% of cervical cancer mortality has occurred in low- and middle-income countries. One of the major aetiologies contributing to cervical cancer is the persistent infection by the cancer-causing types of the human papillomavirus. The disease is preventable if the premalignant lesion is detected early and managed effectively. In this review, we outlined the standard guidelines that have been introduced and implemented worldwide for decades, including the cytology, the HPV detection and genotyping, and the immunostaining of surrogate markers. In addition, the staging system used to classify the premalignancy and malignancy of the uterine cervix, as well as the safety and efficacy of the various treatment modalities in clinical trials for cervical cancers, are also discussed. In this millennial world, the advancements in computer-aided technology, including robotic modules and artificial intelligence (AI), are also incorporated into the screening, diagnostic, and treatment platforms. These innovations reduce the dependence on specialists and technologists, as well as the work burden and time incurred for sample processing. However, concerns over the practicality of these advancements remain, due to the high cost, lack of flexibility, and the judgment of a trained professional that is currently not replaceable by a machine. Cervical cancer is a disease where cells in the uterine cervix, a region that connects the vaginal and upper uterus, grow uncontrollably. According to the latest Global Cancer Statistic 2020 (GLOBOCAN), cervical cancer continues to be the fourth most common cancer worldwide, with 604,127 estimated new cases and 341,831 deaths across the globe ,6. WhileIn general, the World Health Organization (WHO) has defined premalignant lesions of the uterine cervix as cervical intraepithelial neoplasia (CIN) , while tVirtually all of us are susceptible to HPV infection once in a lifetime, regardless of gender, genetic background, and geographical location. The virus is present ubiquitously in the environment. Upon gaining access to the basal cell of the squamous epithelium of the cervix uteri of a woman through microlesions, the virus enters the cells and establishes the viral life cycle. Once the virus gains entry, which is believed to occur via the clathrin or caveolin-independent endocytosis mechanism, the virus traffics through the subcellular compartments, uncoats, and translocates viral DNA into the nucleus. This then allows the virus to deploy the host cell replication machinery and start viral genomic replication . The expThe implementation of cytology tests, HPV screening, and HPV vaccination programs has successfully reduced the cervical cancer burden, particularly in developed countries . In the As early as the 1920s, techniques had been developed to scrutinize vaginal and cervical cytological samples for the detection of cancerous abnormalities. In the 1940s, a Greek physician, Georgios Nikolaou Papanikolaou, introduced the Papanicolaou stain to detect abnormal precancerous and cancerous morphological changes in cervical cytology samples, which is still widely used today. Other available detection methods include visual inspection, and detection of HPV nucleic acids and biomarkers predictive of cervical cancer. In the 2020s, with the advancement of technology, artificial intelligence (AI) has been a popular module incorporated for detecting and reading cervical cytology samples ,31,32,33A systematic screening program for the detection of neoplastic cervical cells is undoubtedly an effective measure to decrease the incidence and mortality of cervical cancer. Different countries may adopt slightly different screening strategies. This may depend on the availability of manpower, the health infrastructure, and the resources. The WHO published a standard screening method in the WHO HPV Laboratory Manual , which iVisual screening techniques can be classified into low- and high-technology approaches. The low-technology approach includes direct visual inspection (DVI), while the high-technology approach includes those that utilise electro-optical detectors to identify cervical cancer precursors and invasive cervical cancer. When performing DVI, 3–5% of acetic acid was applied to the uterine cervix of patients, and then, the inspection was performed using either the naked eye or a low-power magnifying device to identify the cervical lesion. Unfortunately, this method proved to be relatively nonspecific, and many women who lacked significant cervical lesions were classified as positive on the DVI . In the A Pap smear of the cervix is a simple, quick, and inexpensive screening procedure to detect cytological changes in the uterine cervix. This has also been the most widely adopted method worldwide since the 1940s . Over thAlternatively, DNA ploidy analysis and TrueScreen can be performed for the detection of cervical hyperplasia and dysplasia. These methods are preferred due to their low cost, non-dependence on cytopathologists, and they can be applied in a large-scale population screening . DNA ploAt the beginning of the 1980s, zur Hausen and his team identified the HPV genotype 16 as an important aetiological agent contributing to genital cancer and revealed the genetic organization of HPV DNA in cervical cancer cells . In 1986The polymerase chain reaction (PCR)-based assay is a promising method for the detection of HPV DNA . The PCRCurrently, there are FDA-approved and validated HPV tests, including the Hybrid Capture 2 (HC2) assay , based on the DNA-Probe-Hybrid immunoassay technique; CervistaHPV HR and Cervista™  HPV16/18, based on DNA-probe technology; the Cobas 4800 HPV test  and the PCR-based BD Onclarity™ HPV assay ; the APTIMA HPV assay , based on RNA capture and the amplification of HPV RNA ; and theINK4A, Ki-67, and p53, are often included as surrogate markers for HPV-associated cervical cancer. The dual staining of these biomarkers, for example, p16 and p53 immunohistochemistry test have been commonly performed in many laboratories worldwide. The overexpression of p16INK4A is indicative of a negative feedback loop following the degradation of retinoblastoma (pRB), a key cell cycle regulator, by HPV-encoded E7 [In addition to HPV nucleic acid and cellular morphological changes, the phenotypic cancer biomarker provides valuable evidence of protein expression alteration in the cervical biopsy. The immunostaining of tissue for p16coded E7 . Ki-67 icoded E7 . Other bcoded E7 ,65, and coded E7 , as wellcoded E7 ,69. ThesWith the rapid advancement of present-day clinical and computer technology, computer-aided (CAD) architectures are integrated into various screening and diagnostic strategies. As an auxiliary tool, artificial intelligence (AI) technology is also widely used in the field of medical diagnosis. The increasing interest in the development of CAD diagnosis systems for cervical cancer screening is closely related to the common practical difficulties experienced in under-resourced health facilities, with the shortage of trained cytotechnologists and equipment. Computer vision and machine learning approaches are often used in CAD systems to reduce the dependence on manual microscopic examination of cervical cytology smears. The CAD systems can be applied to the automated handling of smear variability, the detection of artifacts, the segmentation of individual cells and cell clusters ,71, the Through physical examination, visual inspection, and cytologic and histologic screening, the premalignant and malignant tissues are differentiated and classified primarily using two systems—the cervical intraepithelial neoplasia (CIN) and the FIGO system. The CIN system is used to classify the thickness of the precancerous lesion, while the FIGO system is used to stage malignant tissue based on the size of the tumour, the involvement of the lymph nodes, and the spread of the cancer cells. The latter system often liaises with the tumour, node, and metastasis (TNM) system.The cervical intraepithelial neoplasia (CIN) system is a classification system that evolved in 1968 to classify precancerous lesions of the cervix uteri based on the degrees of dysplasia. Cervical biopsies and histological examinations are used to classify CIN into 3 degrees—CIN1 (mild), CIN2 (moderate), and CIN3 (severe dysplasia) ,84, as iThe International Federation of Gynecology and Obstetrics (FIGO) system is a staging system for gynaecologic cancers. The system was established in 1958 to recognise the recurrence rate and patients’ outcomes with regard to the degree of tumour spread from initial sites. In response to the increased understanding of cancer, the system was then consistently revised and updated in 1988, 2009, 2014, and 2018 ,87. ThisIn the past, cervical cancer was mostly determined preoperatively, based on clinical examination. This was mainly due to the high prevalence of cervical cancer, particularly in developing countries, due to the lack of advanced imaging systems and uniform staging guidelines. The earlier FIGO system was based on pelvic examination, lesion biopsy, radiography, colposcopy, cystoscopy, sigmoidoscopy, barium enema (BE), and intravenous pyelogram (IVP). This staging was rather inaccurate as compared to surgical staging, in which 20% to 40% of stage IB—IIIB cancers were under-staged, and >60% of stage IIIB cancers were over-staged . MisestiThe American Joint Committee on Cancer (AJCC) provided a guideline for the tumour, node, and metastasis (TNM) staging system . The latThe T category is used to describe the size of the primary tumour and the depth of tumour invasion into adjacent tissues, which is staged numerically. TX represents that the primary tumour cannot be assessed, while T0 indicates there is no evidence of a primary tumour. T1–4 represent the tumour size and the tumour invasion, as shown in The N category is used to describe the involvement of regional lymph nodes in the tumour. N0 indicates no lymph node metastasis, while N1–2 indicate the degree of nodal spread. N1 indicates the pelvic lymph node involvement, and N2 indicates para-aortic lymph node involvement. The detailed N staging is described in The involvement of the lymph node is one of the most important prognostic factors for cervical cancer. Lymph node metastasis is often associated with poor prognosis and its involvement is critically considered in cancer treatment. However, it is challenging to diagnose lymph node metastasis using preoperative examination . Open raM category defines the presence of distant metastases of the primary tumour, and the latest description is shown in The premalignancy of the uterine cervix is preventable and treatable if neoplasia is detected early. “Screen-and-treat” is a commonly adopted clinical management for precancerous lesions. In general, the standard curative options for precancers include large loop excision of the transformation zone (LLETZ) or loop electrosurgical excision procedure (LEEP), cryotherapy, and cold knife conization, while for locally advanced cervical cancer, hysterectomy, radiotherapy, chemotherapy, and radiotherapy with concurrent chemotherapy and immunotherapy are offered to the patients .The screen-and-treat approach is mainly recommended for women of age ≥ 30, due to their higher cervical cancer risk than younger women. The screen-and-treat strategy is summarised in To perform an HPV nucleic acid detection test, the samples can either be self-sampled or collected by a health practitioner. In the case when HPV DNA is detected, depending on the eligibility, women should be assessed through visual inspection with acetic acid (VIA). VIA at the transformation zone is recommended for pre-menopausal women. This is because the transformation zone starts to recede during menopause. Ablative treatment can be performed via cryotherapy, in which the abnormal lesion is removed by heating it with thermal coagulation. Meanwhile, for high-grade lesions (CIN 2 or 3), cryotherapy is the first choice of treatment, provided that the entire lesion and the squamous-columnar junction are visible, and the lesion does not cover 75% of the ectocervix region. In the case when cryotherapy is not recommended, excisional treatment via loop electrosurgical excision procedure (LEEP) can be performed . For womFor patients diagnosed with precancer or malignant cervical cancer, surgery is the main therapeutic measure. For the treatment of cervical cancer, the National Comprehensive Cancer Network (NCCN)  and the In addition to surgery, for patients at the advanced stages, with either locally advanced carcinoma with or without lymph node involvement, or invasive or metastatic carcinoma, radiotherapy, cisplatin or cisplatin-based chemotherapy, radiotherapy concurrent chemotherapy and immunotherapy are offered. These therapies ultimately sensitize the cancer cells to undergo apoptosis, and the dead cells are subsequently eliminated by the immune system. These treatment modalities have been widely applied as standard treatments; however, they lack tissue selectivity and specificity. In addition, most of them are delivered systemically. This renders high toxicity and poses adverse consequences affecting multiple organs. Several onco-target compounds have been designed aiming at features of cancer. As cancer cells are often surrounded by blood vessels, anti-angiogenic drugs are designed to obstruct the infrastructure that provides nutrients to the tumour site. Another approach is to use a drug that has a tissue-targeting specificity and inhibits the oncogenic signalling pathways. In the following sections, we discuss the safety and efficacy of different treatment modalities in trials to treat cervical cancer patients, including the advancement of laparoscopy, radiotherapy, chemotherapy, immunotherapy, anti-angiogenic and target-specific drugs, drug-antibody conjugates, and HPV vaccines.Laparoscopic surgery is a type of minimally invasive surgery (MIS) that is less invasive than conventional open surgery. Laparoscopy is performed through a small incision (0.5–1.5 cm), where a small surgical instrument, light source, and a camera are inserted into the abdomen/pelvis, for diagnosis and/or surgery. In the 1970s, the concept of surgical robots was endorsed by the National Aeronautics and Space Administration (NASA) to replace the physical presence of surgeons in space or military zones. Since then, surgical robots have been developed and implemented for different types of surgery, such as, for example, orthopaedics , ophthaThe research and development of surgical robots have been increasingly active in recent decades. A robot is a device combining mechanics, electronics, and information that can be controlled manually or programmed to perform specific tasks. Surgical robots can be divided into master-slave robots or hand-held robotic forceps, which were developed to fit different surgical procedures. A master-slave surgical robot usually has a 6-degrees-of-freedom (DOF) motion. Surgeons can operate 4-DOF arms outside the abdominal cavity and a 2-DOF wrist joint at the tip. They can operate the remote slave arms directly in the master console or perform telesurgery through a network. One major disadvantage of the master-slave robot is that the master console requires large space and high installation and operating costs ,115. HenIn the early 2000s, the U.S. FDA gave clearance for the marketing of a robotic device, the da Vinci Robotic System (dVRS), for laparoscopic surgery. The advanced model, da Vinci Xi also gained FDA approval shortly after the success of the dVRS. Nonetheless, laparoscopy may face several limitations, such as limited range of motion and vision, surgeon fatigue, and ergonomic restrictions. With the continuous advancement of technology, these shortfalls can be overcome . In 2019The killing of cancer cells can be achieved via the introduction of the high energy of X-rays or chemicals to ultimately shrink the tumour. Radiotherapy is executed where high dose energy, a range of 40 to 85 Grays (Gys) ,123, depPatients who received cisplatin mono-chemotherapy did not have improved overall survival . The finDespite the better treatment outcome, adverse events are inevitable. There are more patients who receive combinatorial treatments who suffer grade 3 or 4 toxicities than those who undergo mono-treatment. Treatment-related hematological, gastrointestinal, urological, and neurological toxicities, including neutropenia, leukopenia, thrombocytopenia, myelosuppression, gastrointestinal effects, pulmonary effects, cardiovascular effects, nausea, vomiting, diarrhoea, fatigue, alopecia, and weight loss are among the commonly reported side effects ,141,142.Tumour cells exploit the immune checkpoint by expressing immunoreceptors on their cell surface, such as programme death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTL-4), allowing them to evade host immune surveillance. Immune checkpoint inhibitors work by blocking the binding of PD-1 to PD-1 ligand (PD-L1) or CTL-4 to cytotoxic T cells, thereby activating the T cells to recognise these tumour cells ,144. ImmPembrolizumab has become a standard, safe, and effective treatment option for advanced cervical cancer. A Phase II trial, KEYNOTE-158 (NCT02628067), revealed that this PD-L1 inhibitor is safe and has produced manageable after-treatment effects , while iUnlike pembrolizumab, ipilimumab monotherapy, an anti-CTL-4, showed modest efficacy in treating cervical squamous cell carcinoma (SCC) and adenocarcinoma . NonetheThe overexpression of oncoproteins and kinases is often observed in various cancers. This makes them a good target for anti-cancer drug designing. For instance, under normal conditions, the expression of receptor tyrosine kinases (RTKs) is controlled at a low or undetectable level. However, in cancer cells, RTKs are upregulated, leading to the dysregulation of cell proliferation, growth, and migration. Several drugs targeting RTKs marched to clinical trials. The tolerability of patients for these drugs is generally good. Anlotinib is a novel drug developed by Chia-tai Tianqing Pharmaceutical Co., Ltd.  that targets multiple RTKs, including vascular endothelial growth factors , c-Kit, platelet-derived growth factor receptor-alpha (PDGFR-α), and the fibroblast growth factor receptors  . In a PhAnother prominent target for cancer treatment is the epidermal growth factor (EGRF). Monotherapy with anti-EGRF, gefitinib, and erlotinib, is well tolerated by patients. These drugs showed no ORR in advanced, recurrent, and metastatic cervical cancer ,159. HowIn recent years, bevacizumab, a humanized monoclonal antibody that acts on neutralizing the vascular epidermal growth factor (VEGF), a key modulator involved in angiogenesis, has gained popularity. Phase II and III trials conducted by the Gynecologic Oncology Group (GOG) and the Spanish Research Group for Ovarian Cancer, revealed that bevacizumab combined with chemotherapy increased patients’ OS compared to chemotherapy alone ,162. MeaThe safety and efficacy of other anti-VEGF agents, including cediranib, pazopanib, and lapatinib were also explored. Compared to patients with metastatic or recurrent cervical cancer who were treated with carboplatin and paclitaxel, the addition of cediranib to these chemotherapeutics prolonged PFS, despite the increased toxicity . IntriguTissue factor (TF) is a protein expressed abundantly in solid tumours, including cervical cancer. The aberrant expression of TF contributes to tumour growth, angiogenesis, metastasis, and thrombosis. Tisotumab vedotin is an investigational antibody-drug conjugate, which acts directly against TF. So far, tisotumab vedotin is the only drug-antibody conjugate that recently gained accelerated approval from the FDA. A Phase II trial (NCT03438396) revealed that tisotumab vedotin poses an antitumour activity, with 24% ORR and tolerable treatment-related toxicity . This dr®9  and quadrivalent Gardasil®4  are produced by Merck , while bivalent Cervarix (protects against HPV16 and 18) is made by GlaxoSmithKline . Females aged 15 to 55 years old who received the AS04-HPV-16/18 vaccine (Cervarix) sustained 10-year immune protection, with anti-HPV16/18 titers higher than that of natural infection [®4 had a reduced risk of developing subsequent HPV-related disease, including HSIL (NCT00092521 and NCT00092534) [There are two types of vaccines designed for HPV-related diseases: HPV prophylactic and therapeutic vaccines. HPV prophylactic vaccines are essentially viral-like particles (VLPs) comprising the HPV L1 subunits. The HPV prophylactic vaccines gained FDA approval, and these vaccines have been included in HPV vaccination programmes worldwide. The 9-valent Gardasilnfection . Whilst 0092534) . Despite0092534) . This isOne important feature of HPV-associated malignancies is the abundant expression of the viral E6 and E7 oncoproteins, which are crucial elements for promoting and maintaining cancer phenotypes. In most cancers, the expression of other viral proteins might be disrupted. Hence, E6 and E7 are promising targets for the design of HPV therapeutic vaccines. The HPV therapeutic vaccines could treat persistent and recurrent HPV infections or HPV-associated malignancies. Ideally, these vaccines can elicit cell-mediated immunity to produce E6- and E7-specific CD4 and CD8 T cell responses, which may favour the regression of cervical lesions or cancer ,172. To ®, is safe and effective in reducing viral load and increasing T-helper type 1 cells among women with high-grade cervical lesions [Peptide-based HPV therapeutic vaccines are often combined with immunogenic adjuvant or added with agonist epitopes to elicit sufficient host immunological responses. A Phase II trial on a mix of nine HPV16E6 and four E7 synthetic long peptides (SLP) containing adjuvant Montanide ISA-51, showed that the treatment option can induce a broad interferon-gamma (INFγ)-associated T cell response in patients with advanced or recurrent gynaecological cancers, including cervical cancer, but did not induce cancer regression or prevent progression . Another lesions ,175. Ano lesions . Due to  lesions ,178, SLP lesions , and NP- lesions .Protein-based vaccines are designed based on E6 and/or E7 proteins and are produced as fusion proteins. They often contain bacterial toxins and additional adjuvants, such as imiquimod , CpG or Listeria monocytogenes, which was engineered to produce full-length E7 encoded by HPV16 conjugated with listeriolysin-o (LLO), was in Phase II trials for recurrent and metastatic (CTRI/2010/091/001232 and NCT01266460) cervical cancers [Unlike peptide- and protein-based therapeutic vaccines, viral (DNA or RNA) and bacterial vector vaccines are immunogenic and sufficient to elicit host rapid antibody and CD8 T cell responses. They can be easily engineered to carry immunogens of interest. One of the most used DNA virus vectors is of vaccinia origin, in which a large stretch of a gene of interest can be inserted into such a vector. For instance, the tipapkinogen sovacivec (TS) (NCT01022346) and TG4001 (NCT01022346) vaccines were produced from modified vaccinia virus Ankara (MVA), which is an attenuated and replication-deficient vector, carrying genes encoded for human cytokine IL-2, and modified forms of HPV16E6 and E7 proteins. Both of these vaccines were shown to be effective in reverting CIN2/3 histologic presentation, with viral clearance ,187. Ano cancers ,190. TreMycobacterium tuberculosis heat shock protein 70 (HSP70) were also developed. These vaccines are designated as pNGVL4a-CRT/E7 (NCT00988559) [In addition to these, the safety and efficacy of HPV DNA- and RNA-based vaccines were in trials for cervical precancerous lesions. One such vaccine is the VGX-3100, a DNA vaccine containing two plasmids of E6 and E7, encoded by HPV16 or 18. Intramuscular injection of VGX-3100 into patients with CIN2/3 was able to induce a robust cellular and humoral immune response, particularly in increasing interferon (IFN)γ and tumour necrosis factor (TNF)α production, as well as CD8+ T cell activation , leading to histological regression ,192. Mea0988559)  and pNGV0988559) , respect0988559) .On the other hand, the RNA-based vaccine is the emerging cutting-edge technology for the generation of safe and highly effective vaccines. The recent success is manifested by the vaccine for COVID-19, such as the BNT162b2 mRNA vaccine from Pfizer-BioNTech. For HPV malignancies, HPV16 RNA-LPX, where an E7 mRNA is encapsulated in RNA-lipoplex (LPX), is administered intravenously and selectively taken up by dendritic cells. In a mouse model, the vaccine possesses anti-tumour properties, induced robust E7-specific CD8 infiltration, and lasting memory response . This vaThe databases used for the search of primary literature were Pubmed, MEDLINE (EBSCOhost), Scorpus, and Google Scholar. To ensure all relevant influential factors were included in the search strategy, the MesH terms “cervical cancer”, “human papillomavirus and cervical cancer”, “pap smear”, “diagnosis of cervical cancer”, “human papillomavirus screening”, “computer-aided diagnosis for cervical cancer”, “robotic laparoscopy”, “cervical cancer treatment”, and “clinical trials for cervical cancer”, were used in the search engines.We reviewed all the relevant accepted publications, with particular focus on screening, diagnosis, and treatment regimens for cervical cancer within the recent decade (2012 to 2022). We read the title, abstract, and full text of the article and chose eligible and appropriate articles to be included in this review. The topics included (1) the prevalence, incidence, and mortality of cervical cancer worldwide; (2) how HPV promotes cervical dysplasia and cervical cancer; (3) diagnostic and screening platforms, staging for cervical neoplasia and carcinoma, as well as treatment modalities in clinical trials for cervical cancer; (4) articles written in English; and (5) the accessibility of the full text of the articles. From the initial selection process, we assessed a total of 44,692 relevant articles. Inappropriate articles  were excluded, and the remaining full text articles (n = 3297) were selected. After further stringent filtering with specific keywords, a total of 194 articles were included in this review article. Information from the selected articles was arranged, congregated, interpreted, and summarised.In conclusion, cervical cancer still poses a global health threat, particularly for women in underdeveloped and developing countries. An effective way to prevent and triage cervical cancer is the implementation of accurate screening strategies for the early detection of premalignant lesions of the cervix uteri. The primary screening strategy recommended for the triage of women with HPV-associated cervical lesions includes a combination of cytology, an HPV nucleic acid test, and the staining of biopsy tissues with p16 and/or Ki67 surrogate markers. Upon the detection of morphological anomalies, the presence of HPV nucleic acids and the expression of biomarkers in the tissue samples, these lesions and tumours are being classified based on standard guidelines. With the creation of state-of-the-art technology, artificial intelligence and robotic modules have been incorporated into diagnosis and treatment tools. These advancements provide a breakthrough in cancer treatment and aid in reducing the dependence on trained technologists and specialists, the workload, and the time from tissue processing to decision making. Despite the huge advantages, on top of the concern over cost-effectiveness, computer-assisted devices require further improvement as they are not without error. For instance, during diagnosis and surgical procedures, the flexibility and impromptu decision/judgement of surgeons and specialists are yet to be replaceable by the current technology. The downfall of relying on computer-aided tools is that the accountability of medical-legal issues should be taken into consideration, especially when diagnostic errors occur. Furthermore, practicality comes into question when implementing such a high-cost system in developing countries. Another concern faced by most low- and middle-income countries is the affordability of the HPV prophylactic vaccines. Even though HPV prophylactic vaccines successfully reduce cervical cancer incidence, the vaccine may have a higher protective value for females in their puberty or adolescent age who have not been exposed to HPV infection. Women who had been exposed to HPV infection, particularly the cancer-causing HPV genotypes, may have a chance to develop cervical cancer. To date, mono-treatment, either through surgical resection, radiotherapy, chemotherapy, immunotherapy, and anti-cancer drugs may not be effective in curing cervical cancer. Clinical trials revealed that a combination of these treatments could improve progression-free survival and the overall survival of patients with advanced, recurrent, and metastatic cervical cancer. In addition to cervical cancer, these treatment modalities are also applicable to HPV-related cancers. Although the clinical practice guidelines for the prevention and treatment of cervical cancer are published, the implementation of standardised and well-defined treatment regimens could be challenging. Moreover, the field is still in urgent need of precision medicine, where a safe, effective, and target-specific drug that acts on HPV-containing cervical cancer cells is needed.


Human papillomavirus (HPV) testing using self-collected vaginal specimens is the preferred choice to increase screening uptake. Although the HPV testing results of these samples depend on the cells that naturally exfoliate from the cervical lesion and drift into the vagina, the mechanism of when and how these exfoliated cells mix with the self-collected sample remains unclear. Hence, the study aimed to clarify the relationship between the vaginal drift of HPV-infected cells exfoliated from the cervix, and the menstrual cycle. A total of 180 scraped samples of the cervix and vagina were examined. The exfoliated cells were classified into two categories according to the HPV genotyping results of each sample: sufficient accumulation  and insufficient accumulation . A moderately strong statistically significant association was observed between exfoliated cell accumulation and the menstrual cycle, and insufficient accumulation was statistically significantly increased at the early proliferative phases. Self-collection of vaginal samples at the early proliferation phase indicates insufficient sample quantities or lower viral load, thereby affecting HPV genotyping. Due to its greater sensitivity than cytology for detecting precancerous lesions, human papillomavirus (HPV) testing has gradually become the primary method for cervical cancer prevention programs ,2. AlthoThe sources of HPV positive results in the vaginal sample are cells exfoliated from the female genitalia, including the cervix, and cells of unknown origin that were scraped where the self-sampling instrument contacted them . If vagiTherefore, using the HPV genotyping results of cervical and vaginal samples collected by physicians, this study aimed to clarify the relationship between HPV-infected cells that exfoliate from the cervix and drift into the vagina, and the menstrual cycle.This study used two types of SurePath™  liquid-based cytology (LBC) samples obtained from the cervix and vaginal canal of 324 patients. Prior to the study, these patients were referred for colposcopy because of abnormalities in cervical cytologic screening at the Tokyo Genki Plaza Health Medical Center from 2020 to 2021.Immediately before colposcopic assessment, a vaginal speculum was inserted into the patient to expose the cervix, and then the endocervix and the portio vaginalis were scraped using an IM sampler instrument , which includes a spatula and a brush, and eluted into a collection vial to collect the cervical sample. Next, with the vaginal speculum open, the bilateral parts from the vaginal fornix to the upper 1/2 of the vaginal canal was scraped and collected using a spatula for the vaginal sample. Written informed consent was obtained from the patients before sample collection. The Ethics Committee on Human Research of Kyorin University approved the study protocol. The protocol was implemented in accordance with the approved guidelines. Patients who had menopause, amenorrhea, or cervical and vaginal HPV negative by HPV genotyping (as described below) were excluded. We also excluded those with suspected vaginal preclinical HPV infection or vaginal intraepithelial neoplasia (VaIN) such as only low-risk (LR) HPV-type positive in cervical samples, HPV negative in cervical samples but HPV positive only in vaginal samples, or HPV positive in both samples but with more HPV types in vaginal samples. In particular, those who were only LR HPV-type positive in the cervical samples were excluded because LR types with suspected vaginal tropism  may haveDNA from the cell pellet of the LBC samples was isolated using the hot sodium hydroxide method . Cell peAccording to the HPV genotyping results of cervical and vaginal samples, we classified the HPV-infected cells that detached from the cervix and drifted into the vagina into two categories: sufficient and insufficient. HPV detected in the vagina is a possible result of contamination by exfoliated cells from the cervix . TherefoDöderlein bacilli, leukocytes, and predominant intermediate cells with markedly folded or degraded cytoplasm are present).Moreover, menstrual cycles were classified into five phases according to the date of the start of the last menstruation, days of menstrual cycle and bleeding period, and cyclic cytologic characteristics of the Pap smear: (1) menstrual phases ; (2) early proliferative phases ; (3) late proliferative phases ; (4) early secretory phases ; (5) late secretory phases  to determine whether the accumulation of exfoliated cells was significantly different among the five menstrual phases. We also calculated adjusted residuals for each phase to aid in interpretation.A total of 132 (73.3%) patients had the same HPV types detected in the cervical samples and vaginal samples, and were thereby classified as a sufficient accumulation of HPV-infected cells of cervical origin.However, 26 (14.4%) patients had fewer HPV types detected in the vaginal sample than in the cervical sample. Those HPV types detected in cervical samples only were HR and pHR types, which accounted for 76.9% and 23.1%, respectively. Furthermore, 22 (12.2%) patients were HPV positive in the cervix but HPV negative in the vagina. The HPV genotypes detected in the cervical samples were HR type, pHR type, and a mixture of both in 86.4%, 9.1%, and 4.5%, respectively. Both cases were classified as insufficient accumulation of HPV-infected cells of cervical origin.p < 0.05) (Cramer’s V = 0.243). p < 0.01).A chi-square test of independence was conducted between the accumulation of HPV-infected cells and the menstrual cycles. Results showed a moderately strong statistically significant association (χ2(4) = 10.642, Self-sampling HPV tests must be more consistent and reproducible with minimal false-negative results, considering that women who self-collect are distrustful of the results because they are uncertain whether they have collected the specimen correctly . The preThe reason why insufficient exfoliated cells accumulate at the early proliferative phase may be that this phase is the period after the vaginal exfoliated cells have been washed away by menstrual blood; in addition, estrogen is gradually affecting the cervical epithelium, and the squamous epithelial layer is in the process of forming , resultiFairly et al.  investigHowever, Sherman et al.  found thThe strength of this study is that all cervical and vaginal samples were carefully collected by a single gynecologist sequentially on the same day of examination; thus, cross-contamination caused by collection was unlikely. Vaginal sampling also included the distal vagina to maximize the evaluation of the accumulation of naturally exfoliated cells drifting from the cervical epithelium. In the present study, we used a highly sensitive PCR method to detect wide-ranging HPV genotypes in both samples and subsequently detected periods with insufficient accumulation of exfoliated cells according to the results of HPV negativity or genotype reduction in the vaginal samples. Of note, all patients associated with vaginal preclinical HPV infection or VaIN were excluded. We believe that the result of undetected HR or pHR types in the vaginal samples indicates that these oncogenic genotypes have tropism  for the The HPV genotyping results of the cervical and vaginal samples revealed that the accumulation of exfoliated cells in the vagina is insufficient at the early proliferative phase of the menstrual cycle. This finding provides new insights for standardization of the optimal timing for self-collection and contributes to the growing literature on the effect on HPV test results in self-collected samples.