Potamotherium), focusing in particular on how it used its whiskers (vibrissae). For this purpose, we analyse the coronal gyrus of the brain of 7 fossil and 31 extant carnivorans. This region receives somatosensory input from the head. Our results show that the reliance on whiskers in modern pinnipeds is an ancestral feature that favoured survival of stem pinnipeds in marine habitats. This study provides insights into an impressive ecological transition in carnivoran evolution: from terrestrial to amphibious marine species. Adaptations for underwater foraging were crucial for this transition.Pinnipeds  use their whiskers to explore their environment and locate their prey. Today they live mostly in marine habitats and are adapted for a highly specialised amphibious lifestyle with their flippers for locomotion and a hydrodynamically streamlined body. The earliest pinnipeds, however, lived on land and in freshwater habitats, much like mustelids today. Here we reconstruct the underwater foraging behaviour of one of these earliest pinnipeds ( Potamotherium, may have relied on its whiskers when foraging.Analysis of the coronal gyrus from 7 fossil and 31 extant carnivorans suggests that one of the earliest pinnipeds,  Adaptations for underwater feeding and foraging were crucial for this transition2. While the feeding strategy of fossil pinnipeds can be inferred from their teeth and skeleton3, their foraging behaviour is more challenging to reconstruct. Modern pinnipeds use their whiskers (vibrissae) to explore their environment by detecting vibrations in the water, e.g., refs. 5. This includes hydrodynamic prey sensing, as observed in harbour seals (Phoca vitulina), elephant seals (Mirounga angustirostris) and ringed seals (Pusa hispida)7. We do not know, however, when this behaviour first appeared during pinniped evolution. The most basal stem pinnipeds differed considerably from their modern counterparts. They were otter-like animals occupying freshwater environments8. These stem pinnipeds occupied the ecological gap between semiaquatic freshwater and semiaquatic marine species. Among stem pinnipeds Puijila, arguably the most basal form, was the least specialised for swimming8. Potamotherium had webbed feet and was adapted to freshwater habitats9. Both Puijila and Potamotherium were otter-like in appearance. Enaliarctos, a more derived stem pinniped, occupied marine habitats, and had a streamlined body, a reduced tail, and limbs that were highly modified to form flippers10. During this transition, the underwater foraging strategy may have changed from otter-like behaviour to that which we see in pinnipeds today.The shift from a terrestrial to an aquatic lifestyle in the evolution of the mammalian order Pinnipedia  is an impressive ecological transition in carnivoran evolutionLutra lutra), use a piscivorous mouth-oriented foraging behaviour, whereas others, e.g., the African clawless otter (Aonyx capensis) favour an invertebrate hand-oriented mode of predation13. Similarly, the marsh mongoose  forages by feeling for prey with its forepaws14, whereas the otter civet , uses its whiskers to locate food on the stony bottom of rivers15. Thus, modern analogues indicate that early pinnipeds could have used either a whisker- or a hand-foraging behaviour.Living freshwater species, not directly related to pinnipeds, can be used as analogues of what that otter-like foraging behaviour of stem pinnipeds could have looked like. Modern otters follow two principal foraging ecologies. Some otters, e.g., the Eurasian otter  and fissures (sulci) of their brain. Electrophysiological brain mapping data on northern fur seals 20, sea lions 21 as well as on canids, felids and procyonids26, demonstrate that one particular gyrus, known as the coronal gyrus, receives somatosensory projections from the head, and particularly from the vibrissae. Therefore, the relative size of the coronal gyrus can inform us about the somatic sensory specialisations of fossil pinnipeds.Preserved remains of whiskers or associated soft tissues are unknown for stem pinnipeds. There are, however, other indicators of the importance of whiskers. Whisker-foraging mammals have thicker infraorbital nerves and thus a wider infraorbital foramen, through which these nerves passPotamotherium, the only freshwater stem pinniped for which endocasts are known31 and compared it with that of fossil and living carnivorans . This is crucial for constructing an accurate picture of an important transition in carnivoran evolution.We, therefore, used external brain anatomy as preserved in endocranial casts to reconstruct the foraging ecology of pinnipeds at the time of the transition from terrestrial to marine habitats. To do so, we investigated the coronal gyrus of Potamotherium shows an increased size of the coronal gyrus, which provides further evidence that it was a whisker specialist. We postulate that the increased tactile performance of mystacial vibrissae of modern pinnipeds was already present around the beginning of the transition from a terrestrial to an aquatic lifestyle and facilitated their transition to an amphibious lifestyle.We found that the coronal gyrus remained narrow in most terrestrial carnivorans. In contrast, the coronal gyrus expanded disproportionately in semi-aquatic carnivorans that use their whiskers for exploring their environment, while it did not expand in carnivorans that use their hands in foraging. Potamotherium is pear-shaped . Pachycynodon lacks a cruciate sulcus and the sigmoid gyri are less expanded. Phoberogale and Promartes both have a clear cruciate sulcus. In all three taxa, the size and shape of the coronal gyrus is comparable to that of most modern terrestrial carnivorans (see below).Cynogale bennettii; Fig. Lutra lutra; Fig. Aonyx cinerea) is narrower with a dimple or short sulcus near its rostral end  indicates enlarged cortical representations of peripheral sensory receptor fields from the head, and particularly from the vibrissae. These carnivorans use their mystacial vibrissae to explore their environment. The expanded coronal gyrus in the otter civet  and those otters that have a piscivorous mouth-oriented foraging behaviour, is also suggestive of increased facial tactile sensitivity41. Living pinnipeds have distinctive mystacial vibrissae, which they use to explore their environment. Hydrodynamic trail following has only been shown in the harbour seal (Phoca vitulina) and sea lion 44. Sea lions, seals and walruses have been shown to be able to use their whiskers to differentiate objects by their size and shape, and to perform complex sensorimotor tasks45.Apart from its phylogenetic value, the brain of ids Fig.  and sealids Fig.  shows thPotamotherium, which provides further evidence that it was a whisker specialist. This confirms the hypothesis of increased tactile performance of mystacial vibrissae in stem pinnipeds as inferred from their enlarged infraorbital foramen8.Our results show an increased size of the coronal gyrus in Potamotherium exclusively relied on its whiskers. Potamotherium could have used its forelimbs for manipulating its prey. Modern carnivorans such as otters and seals, do so and the same has been suggested for Enaliarctos3. However, the ability to grasp and manipulate objects is more likely to involve specialisations of motor rather than somatic sensory cortex.An important note should be made here. The ability to sense with whiskers, instead of with hands, does not mean that Based on the above, we postulate that the increased tactile performance of mystacial vibrissae of modern pinnipeds was already present around the beginning of the transition from a terrestrial to an aquatic lifestyle and facilitated their transition to an amphibious lifestyle Fig. .Potamotherium, Enaliarctos and Pinnarctidion), an early lutrine mustelid (Mionictis), an oligobunine mustelid (Promartes), an amphicynodontid (Pachycynodon), an archaic ursid  and 31 species of extant carnivorans. For a list of fossil specimens, see Supplementary Table Our analysis includes endocranial casts from three stem pinnipeds  as figured by Michell and Tedford56.Pinnarctidion is also known from the early Miocene of California and Oregon55. It is considered sister taxon to the crown group of Pinnipedia that includes the three living pinniped families Otariidae , Phocidae  and Otobenidae 57. The endocranial cast used here has been described under the name Enaliarctos mealsi47 and as Enaliarctos sp31. Here, we follow Barnes58 in attributing this specimen to Pinnarctidion bishopi.Mionictis is an early Lutrinae from North America59. Here we use a partial endocranial cast reproduced from a partial skull from the Miocene (Clarendonian) of Texas, described by Radinsky11.Promartes is an oligobunine terrestrial mustelid from the late Oligocene - early Miocene of North America33. It is contemporary with the stem pinnipeds that are examined here. The endocast used here has been described by Radinsky29 and Mödden and Wolsan30.Pachycynodon is an arctoid carnivoran belonging to a basal ursoid group, generally referred to as Amphicynodontinae, which gave rise to Pinnipedimorpha60. Most of the known specimens of Pachycynodon are from the Oligocene of Europe47. Phoberogale is an early stem ursid. The endocast of Phoberogale minor used here has been described by Radinsky29.26. Because our aim is to reconstruct the importance of the whiskers in foraging behaviour in basal pinnipeds relative to that observed in crown pinnipeds on the one hand, and mustelids on the other, our region of interest here is the coronal gyrus. The description of endocasts will thus primarily focus on the representation of this gyrus.Electrophysiological mapping of the coronal gyrus in canids, felids, procyonids and seals Fig.  shows th62. Endocasts were latex and plaster endocasts from made from skulls or fossil natural endocasts. All specimens are curated at natural history museum collections, as specified in Supplementary Table Endocasts were scanned with a Next Engine 3D laser scanner , we isolated the coronal gyri using sulcal maps from published works on Otariidae64, Phocidae20 and Odobenidae65, Enaliarctidae56, terrestrial Mustelidae67, Lutrinae11, Procyonidae25, Canidae68, Felidae69, Ursidae70, Viverridae and Herpestidae40.For surface area calculation of the entire neocortex, we separately mark and measure the area bordered ventrally by the rhinal fissure and rostrally by the entry of the olfactory tractphytools71 of the statistical software R72 and the R code as developed by refs. 74. To differentiate between groups  and rcompanion (version 2.3.25), respectively, to perform our permutation tests and the function ‘ggboxplot’ from the package ggplot2 (version 3.3.0)75 to graphically represent our results following R code as developed by refs. 74. Surface area of the coronal gyrus was measured on 3D virtual models of the brain of 7 fossil and 31 extant carnivoran species .For the ancestral state reconstruction and the statistical analysis, we used the package Further information on research design is available in the Peer Review FileSupplementary InformationDescription of Additional Supplementary FilesSupplementary Data 1Reporting Summary


This survey study analyzed data from a nationally representative sample of US veterans to examine ratings and correlates of well-being. The report evaluated and made recommendations for the US Department of Veterans Affairs’ national implementation of a Whole Health initiative, which emphasizes a person-centered, values-based approach to health and well-being.2 To help inform this initiative, this cross-sectional survey study analyzed data from a nationally representative sample of US veterans to examine ratings and correlates of well-being.The National Academies of Science, Engineering, and Medicine recently published a reportAAPOR reporting guidelines, and participants provided electronic informed consent. The ethics committee of VA Connecticut Healthcare System approved the NHRVS.A total of 2435 veterans participated in the 2022 National Health and Resilience in Veterans Study . Ratings range from 0 to 10 (higher scores indicate higher well-being) and are averaged to yield an overall measure of well-being  were then conducted to identify significant correlates of well-being. Interaction terms were incorporated into this analysis to evaluate the potential role of protective psychosocial characteristics  in moderating associations between negative correlates of well-being . Analyses were conducted using SPSS, version 29 (IBM Corp).Analyses of variance were conducted between June 10 and 12, 2023, to compare well-being ratings by age, sex, and race and ethnicity. Pearson correlations (Bonferroni-corrected α = .05/33 = .002) and multivariable linear regression (2-sided d = 0.77) (The sample of 2435 veterans had a mean (SD) age of 63.3 (13.9) years and was predominantly male  and White, non-Hispanic  . Younger = 0.77) .P < .001). Among veterans with a greater number of physical health conditions, those with a higher purpose in life scored substantially higher  than those with lower purpose in life.The strongest correlates of well-being were protective psychosocial characteristics (β = 0.41), physical health conditions (β = −0.14), and greater age (β = 0.19). Purpose in life moderated the negative association of the number of physical health conditions with well-being 4 and prevalence of trauma and psychiatric disorders among younger veterans.5 Furthermore, lower well-being ratings among female and Hispanic veterans may be partly explained by these subpopulations being overrepresented among younger veterans.5To our knowledge, this study is the first to examine ratings and correlates of well-being in a nationally representative sample of US veterans. The positive age gradient in well-being ratings aligns with a recent study using the same scale in the general US adult population.A composite measure of protective psychosocial factors  was the strongest correlate of well-being, and purpose in life moderated the negative association of physical health conditions with well-being. Furthermore, having fewer physical health difficulties and greater emotional stability and social connectedness were strongly correlated with overall well-being, which suggests that interventions targeting these clinical and psychosocial factors may have potential utility in enhancing well-being in veterans.6 may help bolster well-being among veterans.Limitations of this study include the cross-sectional design and the use of self-reported measures. Further research is needed to examine whether correlates of well-being may differ between veterans and nonveterans and whether Whole Health interventions designed to increase meaning and purpose in life


Additionally, the pipe jacking behavior, pipe–slurry–soil contact frictional force, and variation law of the jacking force are also simulated. Mutual verification was carried out using the results obtained from field monitoring, numerical and theoretical. The findings are as follows: the established equations for calculating pipe jacking force are highly applicable across various conditions of pipe–slurry–soil contact, and the outcomes derived from theoretical formulas align remarkably well with those obtained through field monitoring and numerical simulation. During the jacking process, the sidewalls exhibit initial partial sliding followed by a complete movement as the jacking force intensifies and subsequently diminishes, eventually attaining stability during the behavior adjustment phase. Moreover, the bottom pipe–soil contact is the most common situation in actual construction.In practical engineering, whilst estimating the jacking force of rectangular pipe jacking using an empirical formula, the results obtained from said formula deviate from reality and manifest inadequate engineering guidance. The equations governing the applied force during the installation of rectangular pipe jacking have been derived for various contact states involving the interaction between the pipe, slurry, and soil. The distinct stress conditions in the pipe jacking process as well as the shear-friction mechanism between the pipe and the surrounding soil have been taken into account. The displacement control method is introduced to simulate the pipe–slurry–soil contact friction during the pipe jacking process in FLAC Pipe jacking represents a frequently utilized trenchless technology extensively applied in underground passageways and municipal engineering projects. The jacks are required to provide jacking force in the pipe jacking process, the estimation of jacking force largely depends on engineering experience. The magnitude of the jacking force is directly proportional to both the precast strength of the pipe section and the design strength of the reaction wall. The accuracy of predicted jacking force is closely tied to the project's safety and cost-efficiency.5. In the subsequent phase, exclusive attention was directed towards pipe–slurry contact, involving an assessment of thixotropic slurry as a power-law fluid and utilizing a fluid flat model to compute the pipe–slurry shear stress7. The final part encompassed both pipe–soil and pipe–slurry contact analyses, presuming that thixotropic slurry could not entirely envelop the pipe sections, thus maintaining contact with both soil and slurry during pipe jacking12. Nonetheless, these studies face two challenges: (1) Most investigations have centered on circular jacking pipes, with limited exploration of rectangular jacking pipes; (2) The consideration of thixotropic slurry in jacking force analyses has been oversimplified and diverges from practicality, rendering it unfeasible.Frictional resistance around the pipe constitutes the primary factor influencing jacking force. Numerous studies have been undertaken to elucidate the correlation between jacking force and frictional resistance. By contemplating the potential impact of pipe–soil friction and pipe–slurry frictional resistance, the jacking force calculation model was divided into three distinct parts. The initial segment solely analyzed pipe–soil contact, asserting that frictional resistance equated to the earth pressure on the pipe jacking multiplied by the pipe–soil friction coefficientThe utilization ratio of rectangular pipe jacking is 20% higher than that of circular pipe jacking for the same cross-sectional area, which makes rectangular pipe jacking more widely used in engineering. However, there is currently no suitable method to calculate the jacking force of rectangular pipe jacking tunnels. The design calculations for actual engineering projects mainly rely on circular tunnel pipe jacking methods, which lack accurate predictions for jacking force due to poor construction guidance.3D finite element software and displacement control method were adopted to simulate pipe jacking by studying the jacking posture and jacking force of the pipe jacking, after which the simulation results were compared with the theoretical results. Then, using these cases, the formula derived from this study was compared with the existing formula. Finally, this formula was applied to other pipe jacking projects to verify its universality.In this study, considering the different contact states of pipe–slurry–soil in practical engineering, a jacking force calculation model and formula were proposed based on the analyses of pipe–slurry and pipe–soil contacts. The FLAC13.Jacking pipe jacked in the soil was subjected to the vertical and horizontal pressure of the soil, as illustrated in Fig. 3 to estimate the jacking force of the rectangular pipe jacking, as expressed by the following equation:a represents the average frictional resistance per pipe joint, recommended to be within the range of 7–12 kN/m2. NF represents the frontal resistance. D and L represent the diameter of the pipe segment and the jacking distance, respectively. k represents the safety factor, which is determined based on the actual situation and is generally in the range of 1.2 to 1.5.The Chinese standard adopts the calculation formula of the circular pipe jacking force14, and it is also applied to calculate the jacking force of the rectangular pipe jacking.NF represents the frontal resistance, which can be calculated using Eq.  is the area of excavation head, a (m) and b (m) indicate the cross-sectional parameters of the pipe jacking. 14.Considering the influence of the thixotropic slurryd in Eq. .6\documeBy conducting a comparative analysis of the calculation formulas, the following deductions can be made: 1) There is no formula for rectangular pipe jacking in the code of Asian countries, and the circular pipe jacking calculation formula is still used to calculate the rectangular jacking force, which is of poor applicability. 2) Both calculation formulas , the earth pressure 18).17\doFigure 22 presents the parameter characteristics of the contact surface.To simulate the pipe–slurry–soil interaction, a contact surface was established between the pipe and soil, and the contact parameters were altered to simulate different pipe–soil contacts, including the full pipe–slurry contact, the full pipe–soil contact and bottom pipe–soil contact. Table 323. However, this method requires the input of actual or theoretical jacking forces into the numerical model, followed by multiple iterations to adjust the forces until the pipe reaches the intended position. Consequently, it becomes time-consuming. In response to the limitations of the force control method, a refined simulation approach for pipe jacking has been developed, based on the principles of the displacement control method.The force control method is frequently used in simulating the jacking process, enabling the analysis of interactions between the pipe, mud, and soil, which offers valuable guidance for constructionIn the displacement control method, the required time step is determined by considering the known parameters of jacking distance and speed. During the simulation, the pipe's velocity is assigned, and the time steps of the solution are adjusted until the pipe jacking reaches the predetermined location, as shown in Fig. In order to determine the sliding tendency and mechanical behavior of the contact surface during jacking, the pipe–soil contact is taken as an example. The distribution of the shear stress of the contact surface is shown in Fig. The material properties of the jacking pipe, such as its stiffness, strength, and flexibility, directly affect the jacking force. Stiffer and stronger pipes can resist deformation and may require higher jacking forces. If the pipe experiences bending or deformation due to uneven soil conditions or misalignment, it can increase the jacking force. The maximum deformation of the jacking pipe in this calculation is only 10 mm, so its influence on the jacking force is small.Figure The numerical simulation results are compared with the field monitoring data for the jacking force, as shown in Fig. The passageway of the Juhua Station on Kunming Metro Line 4 were constructed using pipe jacking techniques. The jacking distance extended approximately 50 m, with a burial depth of 5.0 m. The soil layers traversed by the pipe jacking project predominantly consist of silty clay. The dimensions of the pipe and the computational parameters are comprehensively detailed in Table Figure The passageway of the subway Station on Shanghai Metro Line 18 were constructed using pipe jacking techniques. The jacking distance extended approximately 25 m, with a burial depth of 3.5 m. The soil layers traversed by the pipe jacking project predominantly consist of silty clay. The dimensions of the pipe and the computational parameters are comprehensively detailed in Table Based on an analysis of various contact conditions, a formula for calculating the rectangular jacking force was proposed. In comparison with existing formulas, the formulation introduced in this paper is more realistic and comprehensively accounts for actual jacking force fluctuations.Taking into account the pipe–slurry–soil contact, the displacement control method was used to accurately simulate the jacking process. The simulation outcomes were found to align with the actual scenario.The results gleaned from numerical simulations depicted the pipe jacking process with initial partial and complete sliding of the side-walls. Meanwhile, the jacking force exhibited an increase surpassing the maximum static frictional force, followed by a subsequent decrease before eventually stabilizing.By comparing the jacking force monitored on site, which was calculated by theory and simulated by the numerical method, the bottom pipe–soil contact is the most common situation in actual construction.The priority of the pipe jacking project is the estimation of the jacking force. This estimation is interconnected with factors such as the design strength of the reaction wall, the strength of prefabricated pipe, the selection of jacks, and the jacking force during construction. To achieve precise jacking force estimation, the influence of thixotropic slurry was taken into account, leading to the proposal of a prediction model. This model is founded on the principles of earth pressure in pipe jacking, as well as the friction at the interfaces of pipe–soil and pipe–slurry contacts. Consequently, the following conclusions can be drawn:


The future education and training for HCPs should focus on private community health centers (CHCs), HCPs whose license type is other than a doctor, and HCPs with low after-tax annual income.No research has been conducted to explore the variables associated with healthcare providers’ (HCPs) knowledge and attitudes toward the human papillomavirus vaccine (HPV) since the vaccine was approved for free use in some Chinese cities. In Shenzhen, southern China, a convenience sample strategy was used to distribute questionnaires to HCPs involved in the government’s HPV vaccination program from Shenzhen. There were 828 questionnaires collected in total, with 770 used in the analysis. The mean HPV and HPV vaccine knowledge score was 12.0 among HCPs involved in the government HPV vaccination program . the average scores for HPV and HPV vaccine knowledge varied among different types of medical institutions. District hospitals had the highest mean score of 12.4, while private hospitals ranked fourth with a mean score of 10.9. Multivariate logistic regression results revealed significant disparities in the type of license and after-tax annual income across HCPs ( Cervical cancer is the only cancer with a known cause that is both preventable and treatable, yet it is the world’s fourth most common gynecologic cancer, with a significant disease burden in China ,2. In 20We conducted a survey of HCPs involved in the free HPV vaccination program for schoolgirls in Shenzhen to describe their current state overall, as well as their knowledge and attitudes toward the HPV vaccine. The survey also aimed to assess the factors that may impact their knowledge and recommended behaviors regarding the vaccine.A cross-sectional study on HPV vaccine knowledge and attitudes among HCPs in Shenzhen was conducted between June 2022 and November 2022. Convenience sampling was used to cover all districts in Shenzhen. The inclusion criteria for the study population included HCPs involved in the governmental free HPV vaccination program in Shenzhen who voluntarily participated in the survey. The exclusion criterion was a refusal to participate in the questionnaire. The survey for this study was collected by sending electronic questionnaires to HCPs who attended training for the free HPV vaccination program in Shenzhen.https://www.wjx.cn/ (accessed on 1 April 2023)) was utilized to collect the data for this study. Respondents were directed to complete the electronic questionnaire by scanning a QR code or clicking on the link generated by the “Questionnaire Star”. The questionnaire was devised through a collaborative process involving epidemiologists and (HCPs), utilizing the previous literature and extensive discussions. To ensure its validity and effectiveness, the questionnaire was initially tested on a group of 90 HCPs, and adjustments were made to the content and language based on their feedback. The questionnaire was ultimately divided into three sections to cover different aspects of HPV awareness and knowledge. The questionnaire mainly consisted of the following three parts: (1) Socio-demographic data such as age, gender, degree of education, marital status, and income level. (2) Knowledge of HPV and HPV vaccines, such as HPV transmission channels, HPV transmission targets, HPV infection symptoms, and the best time for HPV vaccination. (3) Behavior for recommending HPV vaccination. To calculate the knowledge score, the questionnaire was assigned one point for each correct answer and no points for each incorrect answer. The questionnaire was administered electronically, and it was sent to project training sessions and working groups related to the free HPV vaccination program for schoolgirls in Shenzhen.The Chinese online survey application “Questionnaire Star”  was performed for analysis.HCPs involved in the governmental HPV vaccination program were classified into four groups based on their medical institution and type of employment: Level I/Regional community health center (CHC), Level II CHC, Private CHC, and District Hospitals. The HCPs mainly included obstetricians, gynecologists, general practitioners, public health doctors, and nurses. Chi-square tests were used to compare sociodemographic information between the subgroups, while Kruskal–Wallis H tests and Kruskal–Wallis 1-way ANOVA (k samples) were used to compare knowledge levels. To investigate the characteristics associated with levels of HPV vaccine knowledge, dichotomous logistic regression and multi-variable logistic regression were used. The Mann–Whitney U test was used to compare disparities in the HPV and HPV vaccine knowledge scores among healthcare professionals who recommended the HPV vaccine and those who did not make such recommendations. The Odds Ratio (OR), 95% confidence interval (CI), and n = 115), Level II CHC  and Private CHC  were between the ages of 31 and 40. The female respondents’ population was extremely high (94.1%). HCPs from various healthcare institutions differed significantly in age, gender, education level, Major, type of license, job title, employment type, after-tax annual income, and years of work, indicating significant differences (p < 0.05) .  < 0.05) .p < 0.001), while the other three types of medical institutions did not differ significantly from each other (adjusted p = 1.000)  and a total knowledge score of 15.0. However, there were several knowledge items that had a correct rate of less than 70%, including: “The body naturally creates high quantities of HPV antibodies to prevent re-infection?” and “HPV can be spread by contact with the skin, oral mucosa, and others” “Who is eligible to receive the HPV vaccine?” This study found that the average scores for HPV and HPV vaccine knowledge varied among different types of medical institutions. District hospitals had the highest mean score of 12.4, while private hospitals ranked fourth with a mean score of 10.9. Further analysis revealed significant differences in the knowledge scores between private community health centers (CHCs) and other medical institution types (adjusted = 1.000) .p < 0.05). Nurses  and other HCPs  were lower than physicians. This study found that HCPs with higher after-tax annual incomes had higher HPV and HPV vaccine knowledge scores. Using an after-tax annual income of 100,000 RMB as a reference, HCPs with incomes of 100,000–200,000 RMB , 200,000–300,000 RMB , and >300,000 RMB  had higher adjusted odds ratios for higher knowledge scores  reported recommending the HPV vaccine to others. This included 259 (94.9%) in Level I/Regional CHCs, 292 (94.8%) in Level II CHCs, 86 (94.5%) in Private CHCs, and 92 (93.9%) in district hospitals. However, some respondents reported a reluctance to recommend the HPV vaccine to others, citing several reasons. The main three reasons for this included: “Vaccine promotion is not my responsibility,” “Fear of trouble caused by recommending self-pay vaccines to service recipients” and “Uncertainty of the HPV vaccination process” .p < 0.001).In addition, the Mann–Whitney U test was used to analyze the differences in HPV and HPV vaccine knowledge scores between healthcare professionals who recommended the HPV vaccine and those who had not recommended it. The results showed that the distribution of HPV and HPV vaccine knowledge scores between the two groups of healthcare professionals was inconsistent. The average knowledge score of healthcare professionals who recommended the HPV vaccine was 12.09 ± 2.02, while that of healthcare professionals who did not recommend the HPV vaccine was 10.76 ± 2.67. The average rank of knowledge scores for healthcare professionals who had recommended the HPV vaccine was 392.15, while that of healthcare professionals who had not recommended the HPV vaccine was 267.30. The Mann–Whitney U test results indicated that there was a statistically significant difference in HPV and HPV vaccine knowledge scores between healthcare professionals who had recommended the HPV vaccine and those who had not recommended it  HPV and HPV vaccine knowledge score among participants in Shenzhen was 12.02 (2.08) out of 15 ,28,29; tA comparison of the four types of medical institutions revealed that there was no difference in the level of knowledge between the three types of public medical institutions but there was a significant difference between private CHC and the other three types of public medical institutions. This disparity could be attributed to the lower overall quality of medical staff in private CHCs compared to public medical institutions. Therefore, it is critical to increase HCPs’ knowledge of HPV and HPV vaccines, improve access to HPV and HPV vaccine information in private CHCs, and strengthen HPV education for HCPs in CHCs. These efforts are necessary to ensure that HCPs are equipped with the information and skills required to offer effective HPV prevention and treatment to patients. Overall, targeted education and training programs, as well as increased access to information and resources, are essential for improving HCPs’ knowledge and understanding of HPV and the HPV vaccine. In doing so, we can strive towards reducing the incidence of HPV-related diseases and improving the overall health outcomes of patients in Southern China. Consistent with previous studies ,32, our The present study has several strengths that are worth noting. Firstly, it is the first survey conducted in China that specifically explores HPV and HPV vaccine knowledge and attitudes among HCPs involved in the government’s HPV vaccination program in Shenzhen. This contributes to the existing literature and fills an important knowledge gap in this field. Secondly, our sample size was relatively large, with 770 HCPs participating in this study. This allowed for a more comprehensive analysis of the knowledge and attitudes of HCPs towards HPV and HPV vaccines. Lastly, we conducted a detailed analysis of the factors influencing HCPs’ knowledge levels and recommended behaviors, which could provide valuable insights for improving HCPs’ education and training programs in relation to HPV vaccination.Several limitations of our study should be acknowledged. Firstly, the questionnaire used in this study was only implemented in Shenzhen and was developed based on the national setting of China. Secondly, the findings are restricted to the specific data obtained from Shenzhen. Therefore, caution should be taken when applying these results to other regions where legislative and health-related implementations differ from those in Shenzhen. However, the results are still valuable for promoting the implementation of the free HPV vaccination program in Shenzhen. Lastly, as the study adopted a convenience sample instead of a probability sample, there may be variation in the level of access among participants. Therefore, future studies are recommended to use random sampling and perform rigorous analyses.This study provides an overview of Shenzhen, southern China, where HCPs exhibit a higher level of knowledge and recommended behaviors for the HPV vaccine. The knowledge that HCPs have on HPV infection routes and modes of transmission, as well as some of the reasons for non-recommended behaviors, needs to be improved. The significantly lower scores of HCPs in private CHCs compared to public medical institutions, as well as the factors influencing knowledge levels, indicate that future education and training for HCPs should focus on private CHCs, HCPs whose license type is other than a doctor, and HCPs with a low after-tax annual income.


Women with HSIL typically undergo conization/LEEP to remove cervical lesions, but the risk of HSIL lesions returning after surgical treatment remains higher than in the general population. HPV vaccination is essential to prevent cervical cancer. However, the effect of prophylactic HPV vaccination on reducing the risk of recurrent cervical lesions after surgical treatment remains unclear. This review aims to analyze and summarize the latest literature on the role of prophylactic HPV vaccine in reducing the recurrence of cervical lesions after surgery in patients with HSIL, and to review and update the history, efficacy, effectiveness and safety of HPV vaccine, focusing on the current status of global HPV vaccine implementation and obstacles. The majority > 95%) of cervical cancers are associated with persistent infection with high-risk human papillomavirus (HPV) . In 2020% of cervThere are two grades of squamous intraepithelial lesions in the 5th edition of WHO Classification of Tumors of female reproductive organs: low-grade squamous intraepithelial lesion (LSIL), including ervical intraepithelial neoplasia(CIN) 1, high-grade squamous intraepithelial lesions (HSIL), including ervical intraepithelial neoplasia2, 3 . The primary objective of the cervical screening program is the early detection and treatment of precancerous lesions, namely low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Women with high-grade squamous intraepithelial lesions(HSIL) typically undergo cervical conization to remove cervical lesions and prevent progression . AlthougHPV is a small, non-encapsulated, double-stranded DNA virus that can infect mucosal and skin epithelial cells. The DNA genome of HPV encodes approximately eight open reading frames (ORFs). ORF is divided into three functional areas, including early area (E), late area (L), and non-coding part or long control area (LCR). The E region gene encodes proteins E1–E7 necessary for viral replication and is involved in the pathogenicity of the virus. The L region genes encode the capsid proteins L1 and L2 required for virion assembly, and the long control region (LCR) regulates gene expression and replication . Most geMost women infected with HPV rely on their own immunity to clear the virus within a few years, and approximately 10–20% of women continue to be infected . The perThe prophylactic HPV vaccine is effective in reducing the incidence of HPV infection and HPV-related diseases, and there are currently three licensed vaccines available . The bivTherapeutic vaccines differ from preventive vaccines in that they rely on T-cell-mediated immune responses  that target the elimination of infected HPV and lesions rather than the production of neutralizing antibodies. Therapeutic HPV vaccines are facilitated by antigen-presenting cells (APCs), such as dendritic cells (DC). DC present HPV antigens via major histocompatibility class I (MHC-I) and class II (MHC-II) molecules, respectively activating HPV antigen-specific CD8 + and CD4 + T cells, targeting the killing of infected and/or transformed cells. E6 and E7 are not only near ideal targets for cervical cancer immunotherapy, but also the best targets for the development of therapeutic HPV vaccines. E6 and E7 are expressed in precancerous and invasive lesions and participate in cell cycle arrest, while they are not expressed in healthy cells. They are necessary to initiate and sustain HPV-related malignancies , 48. Thup = 0.014). At follow-up 6 months after surgery, the persistence/recurrence rates were found to be very low in both groups, 1.1% in the vaccinated group and 1.5% in the non-vaccinated group (p > 0.05) [p = 0.006). The surgery reduced the overall risk of new or persistent CIN 2 + by 65 percent.The pooled estimated OR was 0.35  [Continuous infection with high-risk HPV is the primary and only modifiable factor leading to the development of cervical lesions into HSIL and cervical cancer. Therefore, it has been proposed to vaccinate patients undergoing HSIL surgery with the preventive HPV vaccine. To date, no therapeutic HPV vaccine has been approved for HSIL. Attempting to vaccinate patients with advanced cervical lesions with the preventative HPV vaccine may be another simple and effective way to reduce recurrent HSIL and prevent cervical cancer. Del Pino et al. reported that 153 (57.7%) women in HSIL who underwent cervical conization received vaccination and 112 (42.3%) women refused vaccination. The incidence of persistent/recurrent HSIL was lower in vaccinated women compared to unvaccinated women . Casajua 0.0001) .However, vaccination does not eliminate HPV that already exists in women –57, and Vaccination can be used as a primary preventive measure against new HPV infections in previously unvaccinated patients, but no large-scale, multidisciplinary clinical trial has investigated the efficacy of the HPV vaccine for secondary prevention in patients with active HPV-related disease. The mechanism of action of the HPV vaccine in patients with pre-existing cervical lesions is not fully understood, and several hypotheses have been proposed so far to explain the exact protective mechanism of HPV vaccination in infected individuals. (1) The HPV vaccine induces the production of neutralizing antibodies against HPV capsid protein L1 virus particles. Neutralizing antibodies bind to newly acquired virus particles or virus particles produced by infected cells to inhibit infection of new cells by residual viruses, prevent HPV from entering host cells, and reduce the spread of existing infections. These vaccines do not effectively clear pre-existing infections because viral antigens are not expressed on the surface of infected cells and therefore cannot be targeted by antibodies after vaccination , 60. (2)Immunogenicity is the ability to generate an immune response and can be measured by antibody formation or cell-mediated immunity through cytotoxic T lymphocytes . Long-teSeveral studies have shown that 9- and 15-year-old women have higher specific antibody titers than 16- and 26-year-old women who have been vaccinated –75. A loThe addition of adjuvants improves the strength and persistence of the immune response. The bivalent vaccine contains the proprietary adjuvant ASO4, which consists of 500 mg of aluminum hydroxide and 50 mg of the Toll-like receptor 4 agonist, 3-O-desacyl-4 'phospholipid A, as an additional immune stimulant. 225 mg amorphous aluminum hydroxyphosphate sulfate (AAHS) as an adjuvant for tetravalent vaccines. Both vaccines have been reported to show effective safety and immunogenicity. However, bivalent vaccines yield higher immunogenicity against HPV infection than tetravalent vaccines –81.The concentration of each L1 VLPs and the antigen to adjuvant ratio are important differences between different prophylactic HPV vaccines, including Gardasil and Ceravix. Clinical studies have shown that the immunogenicity of three different doses of the preventative vaccine against HPV infection and cervical cancer is similar. However, levels of anti-PV16 and anti-PV18 antibodies were significantly reduced after vaccination with Gardasil compared to Cervarix . GardasiTwo doses of HPV vaccine are more protective than one, but different studies have not found statistically significant differences between two and three doses , 81, 83.These results suggest that boosting vaccine doses and using appropriate adjuvants can improve the immune response and increase levels of neutralizing antibodies.The prophylactic HPV vaccine type elicits a specific immune response, and the structure of the L1 gene is similar to that of the non-vaccinated HPV type, resulting in long-term cross-reactive immunogenicity against the HPV type not included in the vaccine. Previous studies reported cross protection against HPV31 and HPV45 types after vaccination with a bivalent (HPV16/HPV18) vaccine. In addition, the cross-reactive immunogenicity of the quadrivalent HPV vaccine against HPV45 has been detected . FUTURE Post-operative HPV vaccination in women with HSIL can reduce the recurrence rate of lesions , 90. HowContinuous HPV infection after treatment, regardless of residual HSIL/CIN2-3, is the most significant identified risk factor for cervical cancer . AnotherDoes the HPV vaccine benefit women who remain infected after treatment? Although the HPV vaccine stimulates local antibodies in the cervix that prevent the virus from entering the basal layer of the cervix, the effectiveness of prophylactic HPV vaccination in preventing widespread HPV infection has not been proven , 30, 100WHO initially recommended a three-dose regimen for HPV vaccination in 2009. A three-dose regimen is typical for infant vaccines based on inactivated proteins .The second dose is given 1–2 months after the first dose, and the third dose is given 6 months after the first dose. The first two doses stimulate the production of immunological memory B cells in bone marrow, so they are called "initial dose". The second dose had an increased affinity for the antigen, resulting in a larger antibody response than the first dose. Due to this "affinity maturation" process, high affinity B lymphocytes are produced and differentiated into B memory cells that can quickly respond to antigens and produce NAbs . SchilleReducing vaccination doses due to financial and infrastructure constraints has significant public health implications, alleviating financial and logistical barriers to the introduction of HPV vaccination programmes. Single dose regimens will significantly reduce supply and storage issues and improve compliance. In recent years, multiple studies have evaluated the efficacy of shortening vaccination time in adolescents –114. TheAs a result, in 2014 the European Medical Association recommended only two doses of HPV vaccine for adults, , 115. InAccording to the WHO Global Advisory Committee on Vaccine Safety (GACVS), HPV vaccines are classified as extremely safe . The mosHPV is transmitted between men and women through sexual intercourse, and female patients may be re-infected by a man after the HPV has subsided. Sexual intercourse with condoms can reduce the risk of transmission, and the most appropriate method is to vaccinate both men and women against HPV to reduce the risk of infection . The HPVSince the HPV vaccine was first approved in the United States in June 2006, a large amount of real-world data has proven that HPV vaccination is safe and effective in preventing and treating HPV infection and related diseases , 138. HoHPV vaccination rates have an important impact on cervical lesions and cervical cancer rates. Thus, addressing barriers to vaccination is key to achieving the full benefits of vaccines. Currently, there are still multiple barriers to HPV vaccination programs, including the following:The cost of vaccines is a significant barrier, especially in low- and middle-income countries. Recommendations to address this are to add HPV vaccination to the childhood immunization schedule and/or in combination with other vaccines, but this approach is not sustainable without external support .Another huge obstacle to HPV vaccination in low- and middle-income countries is the cold chain preservation of HPV vaccines, which requires high costs for preservation and transportation. Cold chain supply alone accounts for 80 percent of the cost of the vaccine. One solution to this problem is to dehydrate the vaccine ingredients and freeze them in powder form for storage and transportation at higher temperatures . AnotherIn most low- and middle-income countries, the public is unaware of HPV-related diseases and national vaccination programmes . Due to Globally, the COVID-19 pandemic in 2019 and the closure of schools and suspension of routine immunization schedules between 2019 and 2022 disrupted health systems around the world. Twenty-five million children missed the 2021 vaccination, a 30 percent increase from 2019. Many schemes are still recovering from the effects of the pandemic .A shortage of HPV vaccines, lack of insurance coverage , the neeThere is increasing evidence that HPV vaccination reduces the risk of recurrent cervical lesions in women with surgically treated HSIL, and prospective studies are needed to assess the effect of the prophylactic vaccine on recurrent cervical lesions.The best time for perioperative HPV vaccination is before or shortly after LEEP/ conization (up to 1 month after LEEP). Vaccination as soon as possible can better prevent reinfection in women at risk for HPV infection.The HPV vaccine is highly safe with few side effects and excellent immunogenicity. A single-dose administration regimen showed significant protection in susceptible populations, but its cross-over protection was limited. Existing HPV vaccines do not prevent all types of HPV, eliminate previous HPV infections, and treat related cervical diseases. As a result, significant numbers of people remain infected with HPV despite receiving the vaccine. In addition, multiple barriers to HPV vaccination currently keep global coverage low, particularly in low- and middle-income countries. There is an unmet need for therapeutic HPV vaccination, and HPV-associated malignancies will remain high for many years to come.With our continuous in-depth understanding of the specific pathological mechanism of HPV and the molecular biological mechanism of tumors, the development of HPV therapeutic vaccines for various types of HPV immunogenicity, cheaper, less cold chain tolerance can be expected, and the goal of improving the coverage rate and success rate of the global HPV vaccine and eliminating cervical cancer will be achieved.


The same trend was observed for the average hospital stay, which declined from 9 to 7 days, with an AAPC of −1.33 . An undulating but overall slightly declining pattern was observed for the inpatient mortality . We observed a reduction in the hospitalization rates for invasive and non-invasive cervical cancer, which was observed in almost all age groups and in all German federal states. Conclusion: Our study provides a comprehensive analysis of the trends in HPV-related hospitalizations over the past two decades. The decline in hospitalization rates for cervical cancer and dysplasia suggests the potential efficacy of the HPV vaccination and screening programs.HPV has been linked to the development of precancerous and cancerous lesions. The aim of this study was to evaluate the burden of HPV-related hospitalization in Germany from 2000 to 2021 and the potential impact of the COVID-19 pandemic on it. Methods: We performed a retrospective query using data from the German Statistical Office from 2000 to 2021, including hospital admission, inpatient mortality and hospital stay length data on cervical cancer/dysplasia, female genitourinary tract, anal, penile, head and neck cancers. Results: The HPV-attributable hospitalization rate per 100,000 inhabitants in Germany has decreased over time, from 89 cases in 2000 to 60 in 2021, with an average annual percent change (AAPC) of −1.93 (CI −2.08–−1.79,  Human papillomaviruses (HPV) are a family of viruses that can cause benign and malignant cutaneous and mucosal lesions and have been linked to various diseases, including anogenital dysplasia, cancer and upper aerodigestive tract neoplasms. Man is the only known natural reservoir. They are transmitted through skin or mucosa contact through micro-injuries, in most cases through person-to-person contact. The virions infect the epithelial cells of the basal cell layer. Sexual contact is the main mode of transmission. Vaginal or anal sexual intercourse is the transmission route for infections in the anogenital area, while transmission into the oral cavity or the oropharynx is possible via orogenital sexual practices. Condom use does not entirely negate the risk of transmission. Rarely, HPV can also be transmitted through a smear infection or from mother to newborn peripartum. Most HPV infections produce no symptoms ,2.More than 200 HPV genotypes have been identified. However, the most clinically important classification within the HPV family is that of high vs. low risk, according to the oncogenic potential of each type. Twelve high-risk subtypes are currently classified as definitely carcinogenic: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. The most important one, from an epidemiological point-of-view, is the high-risk HPV type 16, which can be detected in the majority of HPV-related carcinomas [HPV infection has been linked to considerable morbidity and mortality due to its carcinogenic potential and was estimated to have caused almost half a million cases and 250,000 deaths from cervical cancer in 2002 . Of 14 mData from 2010 indicate that 38% of young German women are infected with HPV of any type, most 90%) of which are at a high-risk for cancer type . Accordi0% of whiThe aim of this study was to evaluate the burden of HPV-related hospitalization in Germany from 2000 to 2021 and the potential impact of the COVID-19 pandemic on it.We performed a retrospective query using data from the German Statistical Office (Statistisches Bundesamt Deutschland) . The datAccording to published literature, the following attributable fractions (AFs) were used to quantify the proportion of hospitalizations attributable to HPV for each disease group: 100% for cervix cancer, 88% for anal cancers, 77% for female genitourinary tract cancers, 50% for penile cancers and 26% for oral and pharyngeal cancers ,13,14. Op < 0.05. The term “stable” was used in the event that the APC was between −0.5 and 0.5. Below this interval, trends were deemed “decreasing”; above this interval, they were deemed “increasing”. Ethical review and approval were waived for this study, since it involved aggregated, publicly available data.The hospitalization rate was calculated per 100,000 people based on the German population size each year. Statistical analyses were performed using SPSS 19.0. The time trends were analyzed using the Joinpoint model  to evaluate the direction and the intensity of the (linear) trend, estimating an annual percent change (APC) and the average annual percent change (AAPC). AAPC is a summary measure of the trend over a pre-specified fixed interval, describing the average annual percent change (APC) over a period of multiple years. It is computed as a weighted average of the APCs from the Joinpoint model, with the weights equal to the length of the APC interval. The final model is based on linear segments connected at joinpoints, representing the best fit of the observed data ,16. The p < 0.05) (p < 0.05) for cervical cancer/dysplasia, 1.76  for female genitourinary tract cancer, 0.1  for anal cancer, 2.03  for penile cancer and 0.31  for head and neck cancers. Additionally, the percentage of HPV-related cases to the total number of hospitalizations decreased over time from 2000 to 2018, but demonstrated a sharp rising tendency during the COVID-19 pandemic. The AAPC was −1.77   A. As see < 0.05) C.p < 0.05). After an initial decrease in HPV-attributable inpatient mortality from 2000–2004, the rate increased again from 2004 to 2007 and remained stable from 2007 to 2016. Another increase was seen from 2016 to 2019 with an accompanying decrease during the pandemic, from 2019 to 2021 (p < 0.05) for cervical cancer/dysplasia, 1.39  for female genitourinary tract cancer, −0.84  for anal cancer, 0.59  for penile cancer and −0.61  for head and neck cancers (p < 0.05) (p < 0.05)  C, while  < 0.05) D.p < 0.05). The time decreased from 9 to 7 days in 2000 and 2021, respectively. For reference, the AAPC for all hospitalized cases was −1.44 . The decrease was steady from 2000 to 2014, and entered a stable phase from 2014 to 2019, followed by a steep decrease in the pandemic period from 2019 to 2021, as seen in p < 0.05) for cervical cancer/dysplasia, −2.3  for female genitourinary tract cancer, −1.45  for anal cancer, −1.93  for penile cancer and −1.63  for head and neck cancers (p < 0.05)  and decreased over time with an AAPC of −1.33  C.The hospitalization rates for invasive cervical cancer have decreased over time, with the age group of 40–69 years presenting consistently with the highest rates. In the 20–29 age group, which contains individuals who have been vaccinated against HPV, we observed a steep decreasing trend for the years 2018 to 2021, with an APC of −17.8 A. FurtheThe hospitalization rate of HPV-related diseases in Germany has declined over the studied period, from 89 cases per 100,000 inhabitants in 2000 to 60 cases per 100,000 inhabitants in 2021. This decline in hospitalization rates could be mainly attributed to a significant reduction in cervical cancer and dysplasia cases. This decreasing trend is consistent with previous studies from other European countries ,18,19,20The HPV-related inpatient mortality decreased slightly from 2000 to 2021. After an initial decrease from 2000–2004, the rate had an undulating course over time. While an overall declining trend could be observed for cervical cancer/dysplasia, anal, head and neck cancer, the opposite was true for female genitourinary and penile cancer. Additionally, the percentage of HPV-attributable fatal inpatient cases to the total number of HPV-attributable hospitalizations showed an increasing tendency over time. Data on inpatient mortality are limited in the literature, but the overall mortality rates  for cervical cancer have been consistently decreasing in Western Europe . In contThe average hospital stay for HPV-related cases decreases over time from 9 to 7 days, aligned harmoniously with the overall trajectory of average hospital stay, irrespective of admission cause. The decrease for the former was steady from 2000 to 2014, entered a stable phase from 2014 to 2019, followed by a steep decrease during the COVID-19 pandemic, from 2019 to 2021. This trend could be observed in all evaluated HPV-related diseases. Interestingly, the average hospital stay for female genitourinary tract cancer was the highest (9–15 days), twice as high as that for cervical cancer/dysplasia (5–8 days). The decline in average hospital stay can be attributed to a large degree to the implementation of the diagnostic-related group (DRG) system , but mayFocusing on invasive and non-invasive cervical cancer, we observed a reduction in the hospitalization rates of both conditions. This reduction was observable in almost all age groups and in all German federal states, albeit at a varied degree. The increase in participation in screening programs in the 1990s and the implementation of vaccination programs since 2007 have probably contributed to the significant reduction in hospital admission rates . The estWhile the paper provides valuable insights into the burden of HPV-related hospitalization in Germany, it is important to acknowledge its limitations. Our analysis is based on health insurance data and thus includes only individuals who sought medical advice and were diagnosed with the relevant pathologies. Furthermore, the HPV attributable rate in different pathologies is calculated according to bibliographic estimates and not a direct examination of biological materials. The overall burden of HPV-related disease is surely underestimated, since our analysis does not include ambulatory care data, which are not available. Due to the limited resolution (three-character-ICD-10-GM) of the available data, our analysis could not include diagnoses such as genital warts, although HPV plays a central role in their pathology. That being said, the rarity of genital warts as a primary diagnosis in hospitalized patients makes their exclusion insignificant for our analysis see . HPV hasThis study has important implications for public health policymakers and healthcare providers in Germany. The decline in hospitalization rates for HPV-related diseases, particularly cervical cancer and dysplasia, suggests the potential efficacy of HPV vaccination and screening programs. The authors’ exploration of the impact of the COVID-19 pandemic on hospitalization rates highlights the need for adaptable healthcare strategies during unforeseen events.In conclusion, our study provides a comprehensive analysis of the trends in HPV-related hospitalizations over the past two decades. The findings shed light on the changing landscape of HPV-related diseases in Germany and offer insights into the effectiveness of preventive measures such as screening and vaccination. This study contributes to the understanding of the burden of HPV-related diseases and can be of value to future public health initiatives in Germany and beyond.


For insecticide treatments, we established an untreated check, a positive control insecticide with known negative effects on the arthropod community and a selective insecticide. We investigated how plot size impacts the estimation of treatment effects relative to community structure (27 taxa), community diversity, individual abundance, effect sizes, biological control function of arthropod taxa with a wide range of mobility, including Collops spp., Orius tristicolor, Geocoris spp., Misumenops celer, Drapetis nr. divergens and Chrysoperla carnea s.l.. Square 144 m2 plots supported similar results for all parameters compared with larger plots, and are thus sufficiently large to measure insecticidal effects on non-target arthropods in cotton.Plot size is of practical importance in any integrated pest management (IPM) study that has a field component. Such studies need to be conducted at a scale relevant to species dynamics because their abundance and distribution in plots might vary according to plot size. An adequate plot size is especially important for researchers, technology providers and regulatory agencies in understanding effects of various insect control technologies on non-target arthropods. Plots that are too small might fail to detect potential harmful effects of these technologies due to arthropod movement and redistribution among plots, or from untreated areas and outside sources. The Arizona cotton system is heavily dependent on technologies for arthropod control, thus we conducted a 2-year replicated field experiment to estimate the optimal plot size for non-target arthropod studies in our system. Experimental treatments consisted of three square plot sizes and three insecticides in a full factorial. We established three plot sizes that measured 144 mOur results are applicable to cotton systems with related pests, predators or other fauna with similar dispersal characteristics. Moreover, these results also might be generalizable to other crop systems with similar fauna. Plot size is of practical importance for anyone designing experiments involving mobile species, regardless of the study purpose. Because natural arthropod communities range freely over large agricultural areas, observations from small areas could be quite different from the dynamics and patterns that occur in large areas. Thus, plots need to be as large as practically possible for experiments to be applicable to commercial scales –3.Bt crops. Several authors have demonstrated that the distribution and abundance of arthropods in plots varies according to plot size [Choosing an adequate plot size is particularly important in non-target arthropod assessments involving insect control technologies, e.g. insecticides and transgenic lot size –6. This lot size .However, larger plots necessarily result in higher costs associated with land rental, water, labor and equipment, and might not be tenable when there is a limited amount of seed in the case of regulated trials. Plots need to be as large as practically possible while balancing the goals of accurately measuring gross effects on non-target arthropods and using on an area suitable for the ecological attributes of the arthropod community, especially mobility , 7.Some authors have suggested that few studies have been conducted in field plots of sufficient size to understand potential disruptions of insecticidal technologies on biological control agents and other non-target organisms , 8–10. SLygus hesperus Knight and whiteflies, Bemisia argentifolii Bellows and Perring (= B. tabaci MEAM1) [We conducted a 2-year field experiment to estimate the optimal plot size for non-target arthropod studies in the Arizona cotton system. Our IPM program is heavily dependent on selective insecticides and the conserved biological control provided by key predators of our two key pests, i MEAM1) –17. We iGossypium hirsutum L., was planted on 1 June 2017 and 4 May 2018, and grown in accordance with agronomic practices for the area. The variety planted in both years, DP1549B2XF, was a Bollgard II® XtendFlex® variety , which provides resistance to lepidopteran insects and tolerance to dicamba, glyphosate and glufosinate herbicides.Experiments were conducted at the University of Arizona’s Maricopa Agricultural Center, Maricopa, AZ, United States, in 2017 and 2018. Cotton, A randomized complete block design was used in both years. Plots were established in a single field site about 3 ha in size, subdivided into four blocks. Within blocks, treatments were randomly assigned to plots.2); “medium” plot: 18 m long by 18 m ; “large” plot: 24 m long by 24 m  with ca. 1 m row spacing, and 3 m unplanted alleys. Two controls were established, a negative control, an untreated check , and a positive control (a broad-spectrum insecticide) with known negative effects on the arthropod community [L. hesperus, but essentially no effect on B. argentifolii. A third treatment consisted of a selective insecticide that targets B. argentifolii and with proven non-effects on the arthropod community [Experimental treatments consisted of plot sizes and insecticides in a full factorial. Three square plot sizes were established: a “small” plot: 12 m long by 12 m  tractor-mounted boom sprayer  at a volume of 112.5 l/ha. To avoid drift, insecticides were sprayed directly to plots during calm weather conditions, using low spray boom heights and reduced sprayer ground speed.Calendar sprays with acephate and flupyradifurone treatments were made every 14 days for a total of 3 sprays at their highest labeled rates during the flowering period. These were scheduled sprays for the purposes of non-target evaluations, and therefore they were not based on needs dictated by action thresholds for pest control. Spray dates were 1 August, 15 August and 29 August in 2017, and 2 August, 16 August and 30 August in 2018. A plant growth regulator  was sprayed in 2017 according to cotton commercial guidelines to manage the balance between vegetative and reproductive growth for cotton production. These plant growth regulator sprays were not necessary in 2018.L. hesperus and B. argentifolii) as much as possible among insecticidal treatments by spraying other insecticides that selectively targeted either whiteflies or Lygus [L. hesperus) and the other one is selective (flupyradifurone controls B. argentifolii), we anticipated that there would be disparities among major arthropod prey. Thus, we tried to maintain comparable levels of B. argentifolii and L. hesperus in all plots as much as possible with these “maintenance sprays”. The most convenient metric for those levels is the action threshold for each pest. Thus, these sprays targeted L. hesperus and B. argentifolii, and were deployed at economic threshold levels based on standard sampling methods for these pests [Ideally, pest levels should be comparable among insecticidal treatments as pests can change plot conditions  that might affect arthropod dynamics, thereby causing gross changes across treatments that could potentially mask the effects of the intended treatments on arthropods . Bordinior Lygus . Since ise pests , 19.L. hesperus control were deployed in the untreated check and flupyradifurone treatments, but not in the positive control as acephate has commercial activity against Lygus  applied twice in 2017 (10 and 24 August) and three times  in 2018. Maintenance sprays for B. argentifolii control were deployed once in the positive control and once in the untreated check in both years. We sprayed the selective insecticides, pyriproxyfen  on 24 August 2017, and buprofezin  on 30 August 2018. As flupyradifurone has whitefly activity, no maintenance sprays were required against whiteflies; density levels there never exceeded the threshold.Maintenance sprays for L. hesperus and predator sampling in our system [Lygus (nymphs and adults) and other arthropods were sampled concurrently with a standard 38 cm diameter sweep net. Sampling was done at three, seven and 13 days after each spray . Twenty-five sweeps per plot were used in the small plot, 2 sets of 25 sweeps (50 sweeps) in medium plots, and 4 sets of 25 sweeps (100 sweeps) in large plots. This intensity of sampling was similar across different plot sizes to ensure similar removal of arthropods. All data were standardized to 100 sweeps, because this is the unit of measurement used for r system , 18.B. argentifolii were sampled at three and seven days after each spray, for a total of six samples each year. Ten leaves from the fifth mainstem node below the terminal per plot were randomly selected to estimate adult density and collected to estimate egg and nymph density in the laboratory. Adult density was estimated by counting individuals on the underside of leaves in situ [2 disk taken from these leaves [Densities of  in situ . Nymph ae leaves , 21.Collops quadrimaculatus (Fabricius), C. vittatus (Say), Orius tristicolor (White), Geocoris punctipes (Say), G. pallens Stål, Misumenops celer (Hentz), Drapetis nr. divergens Loew and Chrysoperla carnea s.l. (Stephens). Samples were frozen and later counted in the laboratory using a dissecting microscope. These are all generalist predators. Collops spp. are soft-winged flower beetles from the family Melyridae. The hemipterans Geocoris spp. (family: Geocoridae) and Orius spp. (family: Anthocoridae) are piercing-sucking predators. M. celer are commonly known as “crab spiders” and belong to the family Thomisidae. C. carnea is a species of green lacewing from the Chrysopidae family.Densities of 27 additional arthropod taxa were estimated, including key arthropod predators in our system ; B. argentifolii adults per leaf or large nymphs per leaf disc. We estimated eight predator to prey ratios as follow: M. celer/B. argentifolii adults, M. celer/B. argentifolii large nymphs, D. nr divergens/B. argentifolii adults, D. nr divergens/B. argentifolii large nymphs, O. tristicolor/B. argentifolii adults, C. carnea larvae/B. argentifolii adults, Collops spp./B. argentifolii large nymphs and G. punctipes/B. argentifolii large nymphs. For Geocoris spp., evaluations were done only with G. punctipes because G. pallens Stål densities were very low throughout the years of these trials. We chose these ratios because at certain levels they independently indicate functioning whitefly biological control in our system [The key predators mentioned above were used to calculate predator to prey ratios as the quotient of each species per 100 sweeps to the number of r system , 22, 23.r system .in situ sentinel prey method was developed to measure biological control function along with other sources of in-field mortality for B. argentifolii eggs and fourth instar nymphs based on procedures developed for life tables of sessile insects [O. tristicolor; Geocoris spp. and C. carnea larvae) feed on whitefly eggs [A novel  insects , 25. Whi insects , 4) insefly eggs .Three cohorts of at least 25 newly-laid live eggs (< 1 day old) per plot were established on 1, 16 and 29 August in 2018. The first two cohorts were established the same day of the sprays, and the third cohort was established the day before the last spray. Two cohorts of at least 25 newly molted fourth instar live nymphs, appearing flat and translucent, per plot were established on 2 August in three replicate plots, and 29 August in all plots in 2018. The first cohort was established the same day of the first spray, and the second cohort was established the day before the last spray.Collops spp. or Coccinelidae. This type of predation usually removes all trace of the individual. However, in rare cases we could observe partial nymphal cadavers or egg pedicels still anchored on leaves [Geocoris spp., Orius spp. and C. carnea larvae as shown in previous studies [Leaves with nymphs were collected 4–5 days and leaves with eggs at 7 days after establishment and taken to the laboratory for inspection. These intervals correspond with developmental times for these stages in a typical Arizona summer. Eggs and nymphs were examined to determine in-field mortality sources using a dissecting scope in the laboratory. A single observer made all determinations within a single block. Mortality was recorded as due to predation, parasitism, inviability or eggs that failed to hatch, dislodgement and unknown. Dislodgement can be due to weather like rain and/or wind or to chewing predation by beetles mainly from n leaves . Predati studies . These pB. argentifolii mortality occur simultaneously and so there is no obvious temporal sequence of mortality. Thus, mortality from one factor can conceal the action of a previous factor [Different factors that affect s factor . To accos factor –28; see s factor  for formArthropods (43 taxa) collected from sweep samples were used to calculate Species Richness (S), the Shannon-Wiener Diversity Index (H), the Effective Number of Species associated with the Shannon Diversity Index (ENS) and the Shannon Evenness Index (J). These metrics were calculated for every treatment plot.We used a mixed-model, repeated measures analysis of variance  to test for treatment differences (insecticide and plot size) affecting the abundance of the six key predators and key pests over the season in both years. We also used this model to test for treatment differences in diversity metrics. The model included fixed effects of plot size, insecticide, year and sampling date (repeated measure) and their interactions. Block and associated interaction terms were considered random effects. The covariance structure used was AR(1). We used the proportion of maximum scaling method (POMS), which transforms each scale  to a common metric running from 0 (= minimum possible) to 1 (= maximum possible) , to miniAnalyses were done for all sample dates after the first application of insecticides. Before insecticidal application, pre-counts of arthropod densities were not statistically different. To facilitate the visualization of patterns, we graphically represented pest and predator abundance using cumulative arthropod-days over the season using the trapezoidal rule .We calculated the proportion of dates that each key predator to prey ratio was above functioning biological control levels in our system . These dF type test based on sample permutation to test for statistical significance in patterns. Principal response analyses were done in CANOCO v5 .We examined the main effects of plot size on the entire arthropod predator community through Principal Response Curves (PRC), a time-dependent, multivariate analysis that depicts arthropod community trends over time for each treatment relative to a control –34. We eLygus spp. and B. argentifolii) in each insecticidal treatment (positive control and flupyradifurone) relative to means in the untreated check for each plot size.Finally, we estimated Hedge’s d effect sizes between means from arthropod abundance . The negative control, acephate, supported much lower predator densities as expected. The results from the negative control provide strong evidence that the experimental design was robust enough to measure the known destructive effect of this insecticide.Plot size and its interactions were not significant for key predator abundance  depicts the effect of small and medium plot sizes relative to the large plot size for the untreated check, positive control and flupyradifurone separately . PRCs baB. argentifolii adults and large nymphs (P > 0.05) . These are not ecologically relevant interactions as temporal effects were expected due to yearly and weekly changes in abundance, and the second interaction was due to only one contrast over twelve dates   and only in one dates in 2018 , medium (0.5) to large (0.8) effects sizes using Cohen’s scale . However2) are sufficiently large to measure insecticidal effects on non-target arthropods in Arizona cotton. We were able to clearly measure the known destructive effects of the positive control (acephate), and detected effects of the selective insecticide flupyradifurone in small plots, including improved predation and arthropod abundance. Small plots supported arthropods for all parameters compared to medium and large plots based on several metrics: 1) individual species abundance and effect sizes of key predators and pests; 2) community structure (PRCs) and diversity (indices); and 3) biological control function  and success (predator to prey ratios).We investigated how plot size impacts the estimation of treatment effects relative to density, diversity and biological control function for arthropod taxa with a wide range of mobility . We found no effect of plot size and concluded that “small” square plots , and effects on community structure and diversity that included 43 taxa.Previous plot size research done in Texas cotton found that “small” plots were sufficiently large for non-target arthropod studies. Harding et al.  studied g et al.  only spr2 in corn [2 in soybeans [2 in quinoa [2 in cotton [2. This finding was recently supported by a comprehensive meta-analysis of Bt maize [Plot size in non-target arthropod studies varies considerably . For exa in corn , and somsoybeans , 21 m2 in quinoa  and 170 n cotton , 41. In n cotton  found noBt maize . In contBt maize .Our small plot here was the smallest practical plot that we could use without compromising sample unit size and over-sampling the fauna in our system. In our small plots, almost the entire length of two middle rows is needed to complete 25 sweeps and still avoid sampling the plot edges. It also was important to have a significant number of interior rows designated for sampling so that one could use alternate rows over time and minimize plant damage caused by sweeps. The minimal plot size is also a factor of the sampling method. Thus, systems that use other sampling methods  could potentially be subjected to smaller plots whereas other sampling methods might dictate the need for a larger plot. Plot geometry also needs to be considered. Our plots were square, however; long rectangular plots of the same area might not perform well because the distance between field edges of the longest side of rectangular plots would be reduced, which could influence arthropod movement and behavior differently. Distance between plots, plot isolation by alternate crops or bare ground and surrounding vegetation can impact arthropod movement as well [2 to 20,000 m2 [At the other end of the spectrum, there were practical constraints to testing even larger plot sizes, including significant increases in costs of land rental, irrigation costs, labor, etc. Previous research done in larger plots in Arizona cotton found no effect of plot size in a long-term study testing the effects of transgenic Bt cotton on non-target arthropod abundance between plots ranging from 1200 m0,000 m2 . Larger 0,000 m2 . Another2) are sufficiently large for non-target arthropod studies in Arizona cotton. Small plots allowed us to detect treatment differences, and supported similar individual predator abundance, arthropod community structure and diversity, and biological control function and success compared with larger plot sizes. Therefore, our results are applicable to cotton systems with related pests, predators or other fauna with similar dispersal characteristics. These findings can be applied to target and non-target organism studies in cotton, including studies involving transgenic cotton with insecticidal properties. Moreover, these results also might be generalizable to other crop systems with similar fauna.This study investigated the effect of plot size on several taxa with a wide range of mobility in Arizona cotton. We demonstrated that “small” square plots Click here for additional data file.


Contradictory results regarding the safety of human papillomavirus (HPV) vaccination during pregnancy have been obtained, which has cast doubt on the use of this method. This review and meta-analysis were conducted to evaluate the safety of HPV vaccination during pregnancy.Complying with the inclusion and exclusion criteria, we searched Web of Science, Scopus, Medline, EMBASE, PubMed and Google Scholar databases for articles published in the past decade using the following keywords: ‘papilloma human virus’, ‘HPV vaccine’, ‘pregnancy’ and ‘safety and prevention’. The minimum report quality of the articles was 16 based on the STROBE checklist.Seven articles were included in the study, three of which were included in the meta-analysis, and the rest were reviewed systematically. The results of the meta-analysis showed that vaccination against HPV during pregnancy or around this period does not increase the risk of miscarriage  and stillbirth (RR=2.02: 95% CI: 0.65–6.27). No significant difference between miscarriage and stillbirth was observed in women vaccinated against HPV versus those not vaccinated.The study of 1380424 individuals showed that HPV vaccination during pregnancy is better postponed until after this period. However, no significant evidence was found to indicate that vaccination was dangerous and unsafe during pregnancy. Further studies are needed to draw a more definitive conclusion. HPV is the most prevalent sexually transmitted infection globally2, it is often asymptomatic and is self-limiting. The virus has double-stranded DNA that infects the skin and mucous membranes and can cause extensive symptoms3. The majority of HPV infected cases cure spontaneously. Evidence indicates that virus is not detectable within two years in more than 90% of cervical HPV infection cases. However, infection with one of thirteen types of oncogene HPV types can be carcinogenous5. HPV has a strong association and is the main cause of cervical cancer, a cancer with a high fatality rate among women6. Other than cervical cancer, it is known as a cause of vaginal, vulvar, penile, rectal, as well as oropharyngeal cancers4.HPV is one of the largest families of infectious viruses and the most common type of sexually transmitted infection7. Mesher et al.8 in their study in England, showed that among positive swab samples, 19% were positive for HPV type 16 and 6.5% for HPV type 18. Similarly, So et al.9 in South Korea, examined 986 healthy women and identified that the prevalence of HPV was 33.7%9. Results of the study by Mbulawa et al.10, revealed that HPV prevalence among healthy South African women was approximately 37%. This prevalence was higher among young (18–25 years) women.HPV primarily affects youth aged <25 years. The prevalence of HPV infection is estimated to be nearly 12% among young adult women with normal cervical cytology1. According to the World Health Organization (WHO), the target group for HPV vaccination is adolescent girls (aged 9–14 years). Vaccination has been recommended for girls aged <15 years as two doses (0 and 6 months). For girls aged ≥15 years, three doses  have been recommended. The upper age limit for HPV vaccination is 26 years12.Because of the significant side effects that the virus may have on women and even on men, it is recommended that women aged 9–26 years be vaccinated against the virus13, but since pregnancy tests are not routinely performed before vaccination, some pregnant women may inadvertently be vaccinated against HPV14. A 2009 community-based clinical trial showed a link between spontaneous miscarriage in women who had been vaccinated against HPV15. Due to the adverse effects of HPV vaccination, screening programs on individuals receiving the vaccination are being conducted in some countries14. On the other hand, in some other studies, no adverse effects of HPV vaccination have been observed, and it is only recommended that this vaccination be postponed until after pregnancy16. To date, there is inconclusive evidence of the impact of HPV vaccination during pregnancy17; therefore, some researchers vaccinate patients during pregnancy18. Thus, this systematic review and meta-analysis were conducted to review studies on HPV vaccination in pregnant women.HPV vaccination is not recommended during pregnancyThis study was conducted during 2020 in Tabriz University of Medical Sciences, Iran. The review looked at the safety of the HPV vaccine in pregnant women. It was searched in databases including Web of Science, Scopus, Medline, EMBASE, PubMed, and Google Scholar; all articles published during 2009 to 2019 were entered into this review study by observing the inclusion and exclusion criteria. Keywords used to search these databases included ‘human papillomavirus’ or ‘HPV vaccine’ and ‘pregnancy’, ‘immunity’, and ‘prevention’ and ‘abortion’ or ‘miscarriage’ and ‘stillbirth’. The criteria for entering the study included the keywords mentioned in the title and the keywords of the article, and the criteria for excluding the study comprised studies without full text, abstracts presented at conferences (without full text), and articles not fully related to the subject. References of the retrieved articles were also reviewed.Vaccinated women were women who had been injected with at least one dose of one of the two types of HPV vaccine  six weeks before the last menstrual period (LMP) or during pregnancy. In this study, miscarriage and stillbirth were the two studied outcomes. Miscarriage was considered fetal loss up to 23 weeks of gestation, and stillbirth was defined as intrauterine death after 23 weeks of gestation.19. Out of the 22 items on this checklist, 18 items are generally used in all types of studies, and four items are considered professionally depending on the type of study. Accordingly, articles unrelated to the purpose of the study, duplicate articles, and abstracts without sufficient evidence and having a score <16, according to the STROBE criterion, were excluded from the study.The quality of article reporting was assessed based on the STORBE checklist. This checklist has 22 items that consist of six general sections; these six sections include the title and abstract (1 item) Introduction (2 items), Methods (9 items), Results (5 items), Discussion (4 items) and other data includes the source of funding (1 item)All steps were performed by two researchers (RD and SH) at a time interval of two weeks so that after searching for articles and combining them in one system, RD examined the articles individually and SH after two weeks from the completion of the first researcher’s work began reviewing the articles. If there was a disagreement between the two researchers in entering or leaving out the article or articles, RN assisted them. Risk ratio was calculated for cohort articles that were entered into the meta-analysis. Risk ratio was calculated separately for the outcomes of miscarriage and stillbirth.2 statistics were used to calculate heterogeneity. The significance level was considered to be 0.05. Statistical analysis was performed using the Review Manager (Revman) version 5.2. Significant heterogeneity was observed for both miscarriage and stillbirth outcomes.Chi-squared and IIn the initial search, the total number of articles found was 121, of which 81 were duplicate articles, and 40 articles were reviewed based on the STORBE checklist, of which only ten articles remained and were reviewed. Three of those articles were clinical trials and seven articles were descriptive (cohort) studies. Finally, six articles were entered into this systematic review and meta-analysis .20, in their retrospective cohort study of 2800 pregnancies between 2008 and 2014, found that 35% had received at least one dose of the quadrivalent vaccine around pregnancy (6 weeks before LMP), and 32% of them had received it during pregnancy. The risk of miscarriage did not increase in women who had received the vaccine during pregnancy  and around pregnancy 1.07 (95% CI: 0.81–1.41). In general, the results of this study showed that vaccination during or around pregnancy does not increase the risk of miscarriage.Kharbanda et al.21 conducted a prospective study involving 1752 pregnant women. The results showed that pregnancy outcomes were above 96% without any abnormalities or complications; the overall rate of spontaneous miscarriage was 6.7 per 100 outcomes (95% CI: 5.5–8.2). The mortality rate was 0.8 per 100 outcomes (95% CI: 0.4–1.4). Although the prevalence of spontaneous miscarriage and stillbirth in the population receiving the quadrivalent HPV vaccine during pregnancy did not differ from the general population, researchers do not recommend HPV vaccination during pregnancy.Goss et al.22 in a cohort study examining the results (517 pregnancies) of HPV vaccination in women and infants in the United States, Canada, and France, found that the overall rate of spontaneous miscarriage was 6.9 per 100 outcomes. They concluded that although the incidence of spontaneous miscarriage was not higher in those who were vaccinated during pregnancy than in those who were not vaccinated, it was better to postpone HPV vaccination until after pregnancy.Dana et al.23 in a long-term cohort study, assessed the potential effect of the HPV vaccine on miscarriage in Costa Rica. Of 7466 women, 3727 received three doses of bivalent HPV or hepatitis A vaccines. The results of the study showed no evidence of an increased risk of miscarriage.Panagiotou et al.25. Among the studies evaluated, three articles had the necessary criteria to enter the meta-analysisThis review study aimed to investigate the effects of vaccination against HPV on spontaneous miscarriage and stillbirth. Our review revealed that none of the studies showed an increase in spontaneous miscarriage and stillbirth following vaccination; studies have even shown no statistically significant differences between vaccinated and non-vaccinated groups regarding these two outcomes.26. HPV vaccination is recommended for all girls/women aged 9–26 years through national immunization programs. Moreover, a ‘catch-up vaccine’ for unvaccinated adults with high-risk behaviors has also been suggested27. At present, three types of HPV vaccine are available, the bivalent vaccine is an effective vaccine against HPV types 16 and 18. Quadrivalent vaccine can cover types 6, 11, 16, 18 and the nonavalent vaccine covers even more types of HPV: 6, 11, 16, 18, 31, 33, 45, 52, and 5828. The bivalent, quadrivalent and the nonavalent HPV vaccines are recombinant. They contain virus-like particles which promote an immune response more severe than natural infection29.Cervical cancer is the 4th most prevalent cancer among women cancers in the world, with a high fatality rate. Implementation of the HPV vaccine is probably the most effective way to reduce the burden of cervical cancer32. WHO and some vaccine manufactures recommend avoiding vaccination during pregnancy33.While a considerable proportion of vaccine recipients are women in reproductive age, HPV vaccination may be given during or immediately prior to pregnancy for a variety of reasons. Current guidelines indicate that HPV vaccination during pregnancy, along with its benefits, may be associated with side effects and, therefore, recommend postponing it to the postpartum period23 and Skinner et al.34 did not find any relation between HPV vaccine and miscarriage among women who received HPV vaccine between 4 weeks before and 45 days after conception. Moro et al.35 carried out a pooled analysis consisting of five randomized trials in which 1796 women were vaccinated with HPV quadrivalent during pregnancy and did not identify differences for miscarriage between vaccinated and unvaccinated women. Moreira et al.36, conducted a study to assess the safety of nonavalent HPV vaccine. The study was a phase III clinical trial on men and non-pregnant women in which the frequency of miscarriage in the group of women who received the nonavalent HPV vaccine did not different with women who take quadrivalent one. Miscarriage rate was in normal range within the two groups36. Lipkind et al.37 in their study showed that administration of quadrivalent HPV vaccine during preconception time or within pregnancy is not related with increased preterm birth and birth defects.However, studies examining the results of vaccinations during pregnancy in different countries have not confirmed the reported complications of HPV vaccination, to which our study results are in accordance. Angelo et al.12.Evidence suggests that the risk of complications in the vaccine recipient group is higher (not significant). By assessment of the results of various studies that included 1380424 pregnant vaccinated women, we found that vaccination during pregnancy is not dangerous. Vaccination during pregnancy has been reported to be without any problems; however, in all these studies, it has been recommended to delay the vaccination to the postpartum period. WHO in its position paper about HPV vaccination, has recommended avoiding it during pregnancy. It also notes that, if a woman becomes pregnant after injection with a HPV vaccine, completion of vaccination should be postponed until after pregnancy. Termination of pregnancy is not necessarily due to HPV vaccinationOur results are restricted by a number of limitations. The number of studies that could be included in the meta-analysis was small, and the research team was forced to analyze the rest of the studies systematically and not perform subgroup analyses. The results of the meta-analysis showed high heterogeneity of studies, while publication bias was not assessed. Different populations and different definitions from the time of miscarriage and stillbirth are the possible causes of high heterogeneity, especially in results regarding spontaneous miscarriage.The results of the study showed that miscarriage and stillbirth after receiving HPV vaccine during pregnancy were not significantly higher than in comparison populations, however, it is recommended to pause vaccination until the post-pregnancy period, until further research becomes available. Considering the burden of HPV, it is essential to stress the need for vaccination among young adults.