Under the background of miniaturization of family size and a growing number of young and middle-aged population outflow in rural China, the study of family pension mechanism in rural China from the perspective of changes in the pension functions of son and daughter will not only help to deepen the understanding of the change rules of China's family system, but also provide important reference for the future design of rural pension system.The data come from the China Family Tracking Survey (CFPS), a nationwide social survey project runs by the Social Science Research Centre of Peking University. After excluding missing data, we obtained a valid sample of 11,207 sons and 2028 daughters in four data periods. We applied a fixed effects model for the analysis.In rural areas, sons mainly provide economic support, while daughters mainly provide life care, thus forming a gender-based division of labor. With increasing off-farm job opportunities for daughters, they provide more economic support for their parents, but the time they spend on housework for their parents is reduced. As the number of children in a family has increased, daughters' role in supporting their parents has decreased. This research shows that although the traditional son-centered pension mode in China has not completely disintegrated, it has changed significantly. The findings reveal that changes in family size and improvements in women's status are important factors in changing family support patterns.Different from the thought research about intergenerational relationship for a whole model, this article from the family internal different subjects role identity, shows the characteristics of the individual in the family, is conducive to theoretically explore the tension in the intergenerational relationship, individual and family which is helpful to understand the contemporary China's rural family generation ethics and intergenerational solidarity model. Families are classified more carefully according to the number, size and gender of children in the family, so as to fully show the heterogeneity and complexity of intergenerational relationships and old-age care models in rural families with different structural types. The discussion of the above issues has refined the description of rural family pension resources in China, which has certain reference significance for improving rural pension policies and actively dealing with the aging population. The concept of “raising sons for old age” exists in traditional rural China. With the aging of China's population and the economic and social changes in rural areas, the role of daughters in the family pension has gradually increased and has become a major trend in modern rural areas. The mode of “daughter support” not only breaks the division of labor in traditional family support, with sons as the core, but also reshapes the division of responsibilities in rural families. An increasing number of studies suggest that daughters are better than sons at providing economic support and life care –3. The nAt present, academic research on rural old-age care in China mainly focuses on family old-age care, family structure, traditional gender concepts and support mechanisms.Due to the lack of social security in traditional rural society, the family has assumed the main function of old-age care. In rural families in China and East Asia, children, especially sons, assume the responsibility of supporting their parents , 5. He eIn practice, the changes in the modern family structure have caused a situation in which daughters support their parents . As famiThe traditional concept of gender has also had a great impact on the ways in which children support their parents; it has been influenced by Confucianism, which holds that the purpose and meaning of having children is to provide “support”; i.e., sons are the most reliable resource for parents . MoreoveOther scholars have found obvious differences between sons and daughters in terms of the support mode, time spent and rules that apply to them ; specifiAs rural areas have modernized, traditional concepts have continuously changed. The process of rural modernization has blurred the differences between genders in social production and narrowed the gender gap in intergenerational support . DaughteIn addition, spiritual support is directly related to elderly people's health, quality of life and happiness. As society has developed, the needs of older people in rural areas have changed from food and clothing to spiritual fulfillment. The needs of elderly people in rural areas are not limited to material needs, such as food, clothing and warmth, but also include spiritual comfort. Studies have found that daughters provide more emotional and functional support to their elderly parents than sons do , 36. TheScholars in China and abroad have widely studied old age in rural areas and obtained relatively rich findings. However, research on rural pensions has fallen short. First, most current research has focused on family pensions as a whole. However, is there any significant difference in the level of support for parents' pensions provided by children within the same family based on gender? How does the gender of children affect the economic support and living care provided to parents in their old age? Second, research on family pensions has focused mainly on economic support, and the difference between genders in how much life care is provided remains unclear. Considering the improvement in women's economic and social status, what is their current status and role in supporting their parents? Can women promote a division of labor among children supporting their parents and improve the level of rural family pensions? In this paper, we use “gender role theory” and “resource endowment theory” to combine economic support with life care and, from the perspective of family support, explore whether and what kinds of differences exist in children's support for their parents as well as the change mechanism that causes gender-based differences in children supporting their parents.Parents' pension benefits are realized in two ways . The firAs the structure of the rural population has changed and rural modernization has accelerated, the gender lines in social production have gradually blurred, and the gender gap in children's intergenerational support has also narrowed . As a reHypothesis 1: In rural families, there is still a traditional pension model based on sons being the main providers, and sons contribute more than daughters to their parents' pensions, but the gap between sons and daughters is narrowing.In rural areas of China, all sectors of society have paid extensive attention to the fact that women are now supporting their parents. Two aspects of the narrowing of the gender gap in how children support their parents have mainly been considered: on the one hand, the role of men in supporting their parents has weakened, and on the other hand, the role of women in supporting their parents has increased. The second aspect is the most important, so this study focuses on socioeconomic status, education level, number of children in the family and other aspects to explore the impact of the gender gap on the ways in which children support their parents.First, we consider the impact of children's socioeconomic status on parental support. Children's socioeconomic status directly affects the level of support they provide to their parents and is generally positively correlated with the economic support that they provide Zhang and Luo . StudiesSecond, the role of education as a relatively scarce resource allowing children to support their parents should not be underestimated. The more resources children have, the more likely they are to provide additional support , 41. StuFinally, the number of children in rural families not only affects the pension resources available to the elderly, but also is the basis for the division of pension responsibilities among children in such families , 43. TheIn summary, in this paper, the following hypotheses are put forward.Hypothesis 2: The higher a daughter's socioeconomic status is, the greater level of support she provides.Hypothesis 3: The more educated a daughter is, the more support she will provide.Hypothesis 4: The proportion of support provided by daughters decreases in families with more children.In this paper, we use data from the Chinese Household Tracking Survey (CFPS), a comprehensive nationwide social survey project organized by the Center for Social Sciences Survey at Peking University. The project adopts a sampling method, covering individual-level, family-level and social-level statistics, and the sample data cover 25 provinces, municipalities and autonomous regions in China . In the survey, 2010 is the baseline, with surveys conducted every 2 years. To date, five periods of data have been published: 2010, 2012, 2014, 2016 and 2018. In this paper, we use four periods of panel data: 2010, 2012, 2016 and 2018. Data for 2014 are excluded because no survey was conducted that year on the parent-child relationship.The CFPS data include information on financial support and household care provided by multiple children to elderly individuals, laying a foundation for in-depth study of variations in the level of support that children provide to their parents. As minor children are not economically able to support their parents, the sample in this research includes rural elderly people who are over 60 years of age and have children who are older than 18. In addition, because the data for each family include rural elderly individuals and their spouses, to avoid repeated calculations, we retain in the sample only one person older than 60 from each family. After eliminating data for which values are missing, we obtain 11,207 valid samples in the four data periods: 9,179 sons and 2,028 daughters.In this paper, the core explained variables are “whether children provide their parents with economic support” and “whether children help their parents with housework and take care of their parents,” both of which are dichotomous. In this paper, the core explanatory variable is children's gender. In addition, the model controls for the children's age, marital status, years of education and type of occupation. The specific index system is shown in Based on our research sample, we perform a descriptive analysis of the main characteristics of daughters and sons in rural families. As shown in The comparison of urban and rural areas indicates that the average number of years of education of urban children is 3.63 years higher than that of rural children, indicating that there is still a certain gap in educational resources and educational levels between urban and rural areas. Although children in cities on average' go to school longer, the proportion of children in cities who do not work is greater than the proportion of rural children who are unemployed by 14.34%. On the one hand, this trend may be due to the pressures of the rural pension system; children leave school early to go work and earn money, thus leading to a lower mean for each education period. Moreover, under life pressures and restricted by the lower number of years spent studying, children in rural areas mostly engage in physical labor; thus, their unemployment rate is low. The parents of children in urban areas are highly educated, and most of them have pensions; therefore, they have a certain ability to provide for old age care and reduce the economic burden of their children. In addition, because children in urban areas are relatively highly educated, they are more resistant to engaging in manual work; instead, they seek work in the “knowledge economy.” These factors combine to cause the proportion of children who are unemployed to be higher in urban areas than in rural areas.As shown in Our objective is to determine whether children's gender within the same family results in significant differences in the ways in which they support their parents. We use the fixed effects model for the analysis because this model can use information about multiple children in rural areas to compare the impact of their gender within the same family on the extent to which they contribute to their parents' support and welfare. When the dependent variable is dichotomous, the fixed effects model is as follows:i denotes the parent and the subscript j denotes the child. Pij is the probability that child j of parent i provides support to his or her parents. xkj is the core explanatory variable for the child's gender, and αi denotes the fixed coefficient of parent i, the heterogeneity of parent i itself.where the subscript i, indicating whether, when both parents are i, there is any difference in children's support behavior. Therefore, through this model, we can more rigorously analyse trends within the same family. Although not for the parents after joining αi level variables , these variables are the same for children within the same family. Therefore, there is no need to control the level variables for parents again.Unlike classical logistic regression, the fixed effect model adds the dummy variable of the fixed coefficient of parent When other variables remain unchanged, the economic support received by parents from their sons is significantly positive at the significance level of 10% , which iIn rural families with both sons and daughters, the sons mainly provide economic support to their parents, while daughters mainly provide household care. The historical principles of traditional rural society in China hold that parents should raise children for security in old age and that “having more children brings more happiness.” However, the son-centered support mechanism has changed when it comes to household care, as daughters perform more of this care, and daughters have also begun to participate in activities that support their parents; hence hypothesis 1 is verified. In rural areas, elderly men are generally supported by their sons and daughters-in-law. However, elderly men and daughters-in-law lack a common emotional foundation, and the subtle “old woman daughter-in-law relation” means that daughters-in-law can meet support requirements only to a certain extent. Elderly men's sons, because they have left the area to seek work, often provide economic support and ignore spiritual care. Therefore, elderly people prefer to receive spiritual care from their daughters. Although daughters are less likely to provide financial support to their parents after marriage, their intimate, sensitive feelings and shared experience of having children enable them to better understand their parents' hardships; thus daughters have an advantage over sons and daughters-in-law in terms of providing spiritual support. When parents need care, daughters play an indispensable role of companionship and spiritual comfort. In other words, people's preference for having boys to secure their old age in rural society is not one-sided but is based on both genders' preferences.According to the above studies, in China's vast rural society, traditional support mechanisms have endured: sons provide “support,” but daughters have begun to be involved in providing support to their parents. Hence, we further analyse the differences between urban and rural areas, changes in the socioeconomic status of women and number of children to understand how children support their parents.To study differences between urban and rural areas in the ways in which children support their parents, we consider the interaction between urban and rural household registration status and children's gender on the basis of our original model, and the results are shown in The interaction between children's gender and household registration is not significant in terms of how much economic support children provide for their parents' pension or household care, which indicates that there is no significant difference between sons and daughters in supporting their parents in the urbanized countryside. As populations in urban and rural areas have become increasingly more mobile, caring for older people is becoming integrated across urban and rural areas. Hence, children support their parents equally in urban and rural areas. However, some studies have shown significant differences between urban and rural areas in the extent to which children support their parents . First, In general, there is a positive correlation between women's socioeconomic status, the number of years they spend in school and their income level. That is, the more educated women are, the higher their status is in their family and society. Moreover, improvements in women's socioeconomic status will raise their income level and help them provide more economic support to their parents. To study whether the socioeconomic status of daughters has an impact on the ways in which they support their parents, we successively include two cross-terms in the model: gender and non-farm work and gender and years of education.As shown in Second, the coefficients of the cross-term of children's gender and years of education for economic support and household care are both positive but non-significant. Generally, children's education level is positively correlated with the extent to which they support their parents; that is, children with higher education levels are more likely to provide support. Previous studies have shown that when children have 17 years of education (college), there is no significant difference in the degree of economic support between sons and daughters, and when children have 8 years of education (junior high school), the difference in the support provided by sons and daughters in the form of household care disappears . One reaThe number of children has a certain impact on their support of their parents. Therefore, the cross-term between the gender of children and the number of children in a family is included in the analytical model. The result of the cross-term represents the impact of the number of children in a family on the ways in which these children support their parents.As shown in To test the robustness of our results, we used the propensity score matching (PSM) method to retest the above model. The PSM method can alleviate the problem of biased estimation caused by the incorrect setting of functional forms by reducing the dependence on functional forms. The scores shown in The coefficient signs and significance of the core explanatory variables in each model in The endogenous problem between the core dependent variable and the independent variable must be avoided. According to the research methods of other scholars , the varOur research not only contributes to an in-depth understanding of the changes taking place in China's rural family pension strategies but also has implications for policy in today's aging China. First, the tradition in rural areas of raising children to gain security in old age has led parents to prefer having boys. However, studies have shown that daughters are playing an increasingly important role in supporting their parents, especially because they perform housework. Will this change lessen the preference for boys in rural families? How will this change affect the gender imbalance in rural areas? These questions are worth further academic attention.Second, in this research, we select rural families with many children, thus avoiding the influence of individual parental differences on children's support behavior, which is consistent with the reality of most families with many children in rural China. Studies have shown that the larger the family, the more financial support sons provide; that is, when there are fewer children, daughters provide more support to their parents. This result is valid mainly when resources are scarce; hence, daughters make a passive choice, leading to more material and spiritual support for elderly individuals. However, as the birth rate continues to decline and the rural population continues to age, causing an increasing number of rural families to have only one child, the burden of family pension will further increase. The adjustment of the number of children in rural families alone is not a long-term solution to the problem of rural family old-age care. New models of old-age care, such as rural home care and community care, can not only meet the needs of elderly people in rural areas but also reduce children's burden of caring for elderly parents.Finally, we consider the role of children's gender in the level of financial support they provide to their parents based on two factors, but due to limitations in the data, this paper has the following deficiencies. First, only in 2010 did the data show how far children live from their parents, and distance greatly affects children's level of support to their parents. Generally, children living close to their parents provide more support. Moreover, we do not consider daughters-in-law and their husbands in the family support system. In rural areas, married daughters traditionally join their husbands' families and, together with their husbands, are required to serve their in-laws, and sons-in-law, to a certain extent, participate in supporting their parents. However, because the data do not investigate the support provided by daughters-in-law and sons-in-law, it is difficult to distinguish the share of support provided by daughters and sons-in-law and sons and daughters-in-law. Therefore, the family support system needs to be further explored.Based on the fourth set of panel data of the Chinese Family Tracking Survey (CFPS), we investigate the differences in the ways in which children support their parents and the mechanisms that influence this support in rural families from the perspectives of economic support and life care. We find that in rural areas, sons mainly provide economic support, while daughters mainly provide life care, thus forming a gender division of labor in rural areas. There is no significant difference between sons and daughters in rural areas and urban areas. Children's education level is positively related to the level of support they provide to their parents, but our regression results are not significant. With the increase in off-farm job opportunities, daughters provide more financial support to their parents but reduce the time they spend on housework for them. With the increase in the number of children in a family, daughters may free-ride, allowing others to support their parents, and their share of support decreases, while sons provide relatively more in terms of both economic support and household care. Our research shows that although the traditional son-centered support system in China has not completely disintegrated, it has changed significantly. In general, changes in the size of the population and improvements in women's status are important factors in explaining the changes taking place in the rural family support model.This work provides three potential contributions. First, different from thought research regarding intergenerational relationships in a whole model, this article focuses on the role identity of internal subjects in a family and shows the characteristics of the individual in the family, which is conducive to theoretically explore tension in intergenerational relationships. Studying individuals and families helps explain contemporary China's model of rural family generation ethics and intergenerational solidarity . Most scSecond, families are classified more carefully here according to the number of children, family size and gender of children to fully show the heterogeneity and complexity of intergenerational relationships and old-age care models in rural families with different structural types. In the multi-child family supporting the elderly shown in this paper, daughters may demonstrate free-riding behaviors in terms of parental support, and their input in parental support is reduced, while sons play a relatively large role in both economic support and household care. Women provide emotional support and do not fully consider the economic ideal of the initiative to pay, reflecting the unique role of women in the family pension. In spite of reduced conventions in rural households, China's rural system is still not similar to the western individual framework, and families still follow traditional Chinese family roles. Sons remain in a dual system of ethics and moral emotion regarding specific financial responsibilities, representing intergenerational ethics and solidarity that differ substantially from western ideals. The change in family social status leads to different pension modes. With the improvement of women's social and economic status and the rationalization trend of “daughter pension” in public opinion and ethics, daughters gradually increase parental economic support and life care, and this support is considered altruistic with the concept of filial piety and gratitude. Sons are more likely to follow the traditional norms in rural areas. Supporting their parents is a reflection of following the traditional theory of filial piety and fulfilling their responsibility to support , 49.Third, the discussion of the above issues has refined the description of rural family pension resources in China, which has certain reference significance for improving rural pension policies and actively dealing with the aging population. With the change in rural fertility concepts, the trend of the family core is enhanced. As for how to increase rural elderly care, the authors believe that the government, the market and the family multi-dimensional main body should coordinate and assistant in a complementary manner . Based oThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SY: conceptualization. WY: methodology, data curation, and writing—original draft preparation. ZJ: formal analysis, writing—review and editing, and supervision. All authors have read and agreed to the published version of the manuscript.


The decision to prepare a review on the state of the art of RAx as a tool for risk assessment for regulatory purposes was taken during a workshop with international experts in Ranco, Italy in July 2018. Three major issues were identified that need optimization to allow a higher regulatory acceptance rate of the RAx procedure: (i) the definition of similarity of source and target, (ii) the translation of biological/toxicological activity of source to target in the RAx procedure, and (iii) how to deal with issues of ADME that may differ between source and target. The use of new approach methodologies (NAM) was discussed as one of the most important innovations to improve the acceptability of RAx. At present, NAM data may be used to confirm chemical and toxicological similarity. In the future, the use of NAM may be broadened to fully characterize the hazard and toxicokinetic properties of RAx compounds. Concerning available guidance, documents on Good Read-Across Practice (GRAP) and on best practices to perform and evaluate the RAx process were identified. Here, in particular, the RAx guidance, being worked out by the European Commission’s H2020 project EU-ToxRisk together with many external partners with regulatory experience, is given.Read-across (RAx) translates available information from well-characterized chemicals to a substance for which there is a toxicological data gap. The OECD is working on case studies to probe general applicability of RAx, and several regulations  already allow this procedure to be used to waive new  Substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group or ‘category’ of substances. Application of the group concept requires that physicochemical properties, human health effects, and environmental effects or environmental fate may be predicted from data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach). This avoids the need to test every substance for every endpoint.”In 2006, the REACH Regulation  was adopted in the EU, starting a new era of chemical assessment and asking for an unprecedented level of effort in collecting toxicological data on chemicals that were already on the market . Under RGenerally speaking, RAx is a technique used to predict endpoint information for one chemical by using data from the same endpoint from (an)other chemical(s) that is considered to be similar in some way. If data are read across from one or only a few source substances, this is often called an “analogue approach”. In contrast, grouping refers to the definition of a set of substances combined in a category, where their known toxicological properties follow a specific trend that can be used to infer the properties of the chemicals belonging to it. The precise border of distinction is not defined, because one-to-one comparison is often supported by evidence gained with other, similar chemicals. For this reason, RAx, as used in this report, represents any approach where a data gap is filled using existing information obtained for other substances .in vitro testing. Among the non-testing approaches, no distinct edge between RAx, WoE or QSAR can be defined, and thus these three techniques may be combined.REACH Annex XI describes also other approaches to waive tests, including quantitative structure activity relationships (QSARs), weight-of-evidence (WoE), and According to the latest ECHA report  on the gin vivo) data from the registrants. Notably, a RAx justification will be rejected when ECHA considers the RAx hypothesis by the registrants implausible but also if the documentation provided is inadequate to allow a reliable assessment of its soundness. Given ECHA’s announcement to substantially increase their dossier evaluation activities, starting already in 20191, it is clear that adequately documenting valid RAx hypotheses in a scientifically sound way is a key issue when trying to avoid unnecessary animal testing under REACH.Under Title VI, Chapter 1  of the REACH Regulation, ECHA must evaluate the submitted dossiers for compliance with regulatory requirements. To that end, ECHA has implemented a system to manually check all dossiers containing waiving of standard information, as is the case when RAx is included in a REACH registration dossier. In this context, rejecting RAx due to inadequate justification has been shown to be one of the main reasons for requesting further  in 2015, which was updated in 2017 to include multi-constituent substances and substances of unknown or variable composition, complex reaction products and biological materials (UVCB) ,c. Origiin vitro testing and adverse outcome pathways (AOPs) could play a role.As far back as 2012, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) published a technical report on the category approach, RAx and QSAR  that rep2 with the collaboration of the US Food and Drug Administration’s Center for Food Safety and Applied Nutrition (FDA-CFSAN) accompanied by a satellite meeting at the Annual Meeting of the Society of Toxicology (SOT) in 2018 relating to the specific topic of regulatory acceptance of RAx  was introduced and taken “in a broad context to include in silico approaches, in chemico and in vitro assays, as well as the inclusion of information from the exposure of chemicals in the context of hazard assessment”. NAMs also embrace other information on toxicodynamics  and toxicokinetics with the aim of improving the understanding of toxic effects .Currently, the EU-ToxRisk project, which is an Integrated European “Flagship” Programme driving mechanism-based toxicity testing and risk assessment for the 21 century , aims toty e.g., , and devty e.g., . One of pothesis . With thThe ongoing general discussion on RAx has confirmed the complexity of the approach and the need to establish suitable rules for its objective application, leading to a broader regulatory acceptance of RAx for the risk assessment of chemicals. With this goal, a group of stakeholders, coming from many different areas, expertise and organizations, including regulatory, validation and government bodies, was convened in Ranco  on July 16–18, 2018. During that workshop, sponsored and co-organized by CAAT-Europe, the EU-ToxRisk project and the Doerenkamp-Zbinden Foundation (DZF), it was decided to prepare an extensive document to present the state-of-the-art of RAx for regulatory purposes with the addition of further comments to foster its applicability for regulatory purposes. The present report, which benefits also from the contribution of experts who did not participate in that meeting, has the ambitious goal to describe the basis for immediate improvement of RAx acceptance as well as to define the strategy for future development in a contribution that may serve as an educational text both for those who are facing the argument for the first time and those who want to deepen it. The concepts and ideas presented here come from the individual participants and do not necessarily reflect the views and opinions of the organizations they represent. The debates were based on scientific discussions among the participants, without a necessarily unanimous final agreement on all issues.1.2in lieu of standard testing, but for proper implementation of the new approach, greater international acceptance is necessary. RAx, and in more general terms in silico methods, are now included and promoted in many regulations across countries and sectors. As an example, the situation in some countries is considered here , whose experience with RAx approaches is relatively mature, has developed the Analogue Identification Methodology4 (AIM) and the Chemical Assessment Clustering Engine (ChemACE)5, specifically designed to assist, review and prioritize large inventories of chemicals and to facilitate RAx and data gap-filling for untested substances. The activity of OPPT started in 2010, with the publication of the New Chemical Categories document  that already have been captured in the current OECD guidance , such as experiences under the Pre-Manufacture Notice (PMN) process or High Production Volume (HPV) program  as well document  that wasAx tools . This pa7, where chemicals began to be assessed as groups based on structural, functional or mechanistic similarities, and is now routinely used in the risk assessment of new and existing substances in Phase 3 (2016–2020). The Government of Canada gained experience in using RAx by contributing to the development of the OECD guidance on the grouping of chemicals and subsequent updates  such as that illustrated by the case study for a group of substituted phenols . RAx was introduced as a key approach to support risk assessment during Phase 2 of the CMP (Substance Groupings Initiative 2011–2015) updates , 2017a a phenols .Other countries have adopted legislations very similar to REACH, but not equally advanced in the promotion of alternative methods. For example, in South Korea the structure of K-REACH resembles that of the EU approach but lacks all reference to the possibility to adapt standard information . This me10. This act contains no details on the toxicological tests that will be in dedicated guidelines still under construction at the time of writing. However, this new law includes the ban on animal tests on cosmetic ingredients.In Australia, the Industrial Chemicals (Notification and Assessment) Act 1989 will be replaced on 1 July 2020 by the Industrial Chemicals Act 2019A candidate country for accession to the EU, Turkey’s program includes the harmonization of its legislation. KKDIK, the Turkish version of REACH, is very similar to the EU’s REACH regulation. However, since KKDIK came into effect only in 2017, with pre-registration and registration deadlines in 2020 and 2023, respectively, it is not yet known to what extent adaptation to standard information requirements will be applied.11, which was started in 2012 and has been updated regularly, is promising with respect to RAx application. HESS supports the evaluation of repeated dose toxicity by category approach and is linked to two databases. The first is a toxicity knowledge database, which contains information on repeated-dose toxicity and toxicity mechanisms. The second is a metabolism knowledge database containing rat metabolism maps and information on absorption, distribution, metabolism and excretion (ADME) in rats and humans. HESS allows chemicals to be categorized on the basis of structural, physicochemical and mechanistic similarities and supports the prediction of repeated-dose toxicity for untested chemicals by means of the category approach. Regarding the legislative framework, chemical substances are regulated by the Chemical Substances of Control Law (CSCL) that may accept a RAx approach for hazard assessment on a case-by-case basis upon the formal approval of a scientific committee. However, so far, the application of RAx for regulatory purposes has been limited.The Japanese Hazard Evaluation Support System (HESS) database and platformin silico models for selection of raw materials in order to avoid the use of unsafe chemicals. It also states that such results must be carefully used and do not fully replace validated in vitro or in vivo models. For drugs and biological products, impurity mutagenesis must be evaluated by two in silico methods (expert rule-based and statistics based). Read-across is not fully acceptable for general toxicity. The Brazilian Center for Validation of Alternative Methods (BraCVAM) encourages the use of the RAx concept, at least at the beginning of a study, as part of the integrated testing strategy (ITS).Regarding Brazil, the Guide for Safety Assessment of Cosmetic Products published by the Brazilian National Health Surveillance Agency  suggests the use of 1.3Given its inherent potential for huge economic savings and scientific innovation, industry is, in general, open to the opportunity of RAx, provided that there are clear rules for its applicability and guarantees for regulatory acceptance. Some key examples are provided here.12, with the final goal of addressing the specific challenge posed by UVCBs such as petroleum chemicals and defining practical strategies for grouping and RAx strategies for a cost-effective solution. The approach is to integrate innovations in (i) in vitro testing, (ii) high-throughput genomics, and (iii) integrative data analyses and visualization into a transparent workflow for RAx assessment. This approach offers interesting perspectives; however, it remains to be seen whether the results produced will ultimately affect the formation of more reliable categories that are acceptable from a regulatory point of view.The petrochemical industry represented by CONCAWE, a division of the European Petroleum Refiners Association, is studying the environmental health and safety of petroleum derivatives. The problem of petroleum products is that they are complex UVCBs with highly variable compositions. Grouping is generally performed through general similarities of analytical characterization and physicochemical characteristics, which are not sufficient in many cases to justify RAx hypotheses. For this reason, CONCAWE has sponsored a new project, called Cat-AppAnother industrial association that is very active in this field is the International Fragrance Association (IFRA). Similar to petroleum products, many fragrances are also UVCBs, often with unclear structures and embracing many different chemical classes. Fragrances are common ingredients of cosmetic products, and their precise toxicological characterization is of the utmost importance. In the case of fragrances, and for the whole cosmetic sector in general, the opportunity of performing risk assessment using the RAx approach is highly appealing . In fact13. They then used this information, together with previously available experimental data, to determine the substances’ biological targets. Also in this area, botanical safety can be evaluated using RAx in combination with the threshold of toxicological concern (TTC), which is the estimated exposure level that is considered of negligible harm , FDA and other governmental institutions with responsibilities in the approval of new drugs declare a willingness to consider any new approach if its scientific validity is demonstrated, but in the end, all substances must undergo extensive aminants . Pharmactests on vertebrate animals shall be undertaken only where no other validated methods are available. Alternative methods to be considered shall include in vitro methods and in silico methods,” and arguably RAx could be considered an in silico method, in particular when supported by in silico tools such as the OECD QSAR Toolbox16. However, for the assessment of pesticide active ingredients, RAx is practically never used, though it is increasingly applied for pesticide impurities, metabolites and degradation products. RAx is also usually considered in the preliminary assessment during the gathering and organization of existing information (The EU Plant Protection Products Regulation (Regulation (EU) 1107/2009), while acknowledging the general principle of avoiding unnecessary animal testing, does not make specific reference to RAx. Article 5 of Regulation (EU) 283/2013 (detailing the data requirements for pesticide active substances) states that “ormation . Only inormation .17.In contrast, Annex IV of the EU Biocidal Products Regulation (Regulation (EU) 528/2012) allows for the adaptation of standard information requirements in the same way as Annex XI of the REACH Regulation, and therefore analogue/grouping approaches are frequently employed. As an example, RAx was used to assess the similarity of 5-chloro-2-(4-chlorophenoxy)phenol (DCCP), a biocide approved for human hygiene, disinfection, food and animal feeds, to Triclosan, based on similar toxicokinetics measured in hamstersRecently, ECHA and EFSA jointly prepared new guidance for the identification of endocrine disruptor properties of pesticides and biocides, in which a RAx opportunity is explicitly mentioned .In conclusion, there are plenty of opportunities for the use of RAx in the different industrial sectors, but they remain substantially underexploited, even though the hope is for a more extensive application in the future .22.1Though this paper is not intended to review all scientific possibilities for RAx justification, it is important to provide the basic principles for the applicability of this approach to facilitate the discussion on validation and acceptance.A RAx hypothesis should start from a proper definition of the target substance(s) by providing the correct molecular structure and purity. In the case of multi-constituent substances, each component should be defined both with respect to its molecular structure and relative content in the target substance or, in general, the composition should be described as much as possible. Ideally, full spectrometry characterization with mass spectrometry (MS) spectra, nuclear magnetic resonance (NMR) spectra of both hydrogen and carbon, if necessary, an infrared (IR) spectrum, and any other techniques that can be useful for the proper definition of the compound should be provided for each substance. This process should be aimed at the characterization of the whole sample rather than a mere definition of the main component. For this aim, the ECHA guidance for substance identification can be very helpful .in silico methodology, e.g., docking simulations or molecular dynamic simulations, may require three-dimensional structural information . In many cases, the first approach is based on expert judgment derived from observation of the chemical structure. In comparatively easy scenarios, the source compound is a stereoisomer of the target compound or a salt with a different counterion or a substance sharing the same scaffold with minor differences in molecular weight. In other cases, the selection of source compounds is not trivial and requires the support of reliable computational tools that may assist in the identification of the proper chemical or group of chemicals. For this, the structure of the target substance should be transferred into a notation for molecular descriptions, for instance Simplified Molecular-Input Line-Entry System (SMILES) strings or the IUPAC International Chemical Identifier (InChI) keys, which are typically used as input into software for the calculation of molecular descriptors and physicochemical properties as well as molecular modelling . Some inormation . The comAfter collecting candidates for source substances, the next step is the collection of all available information to fill the data gap and demonstrate similarity. A possible source compound is useless if there are no data or the available data are not accessible for any reason, such as the study report is proprietary or simply not available. Furthermore, existing information needs to be categorized and, in particular, all data should be analyzed to understand the mechanistic knowledge that they may bring along in order to identify biological pathways responsible for the outcome of an adverse effect that can be combined to substantiate the mechanism of action of target and source substances. If the mechanism behind an endpoint is unknown, chemical similarity and computational tools may still assist the hypothesis, but in this case, the prediction will be associated with a higher degree of uncertainty.After the identification of possible source substances, and collection and categorization of the existing information, the next step is the formulation of a possible RAx hypothesis. Its confirmation may need the identification of a subset of assays and experimental tests to confirm the overlap of biological behavior through the demonstration that relevant key events are fully shared or that a regular trend exists . In factin silico predictions for both the source and the target substance(s). The full set depends on the specific substance and the in vivo endpoint under investigation, but should include as a minimum:Water solubility;Melting and boiling point;o/w);Octanol/water partitioning .The starting point of a strong similarity justification is the definition and characterization of all relevant physicochemical properties. This goal is achieved with the aid of available experimental information or reliable 18. However, as these parameters are fundamental for predicting the biological activity of any substance, it is recommended, in general, to measure physicochemical properties with standard experimental protocols rather than to use prediction models, if possible.Other properties should be considered based on the molecular structure and the endpoint in question. For endpoints such as (DNA-reactive) genotoxicity or skin sensitization parameters, estimating the electrophilicity of certain functional groups or, more generally, the chemical reactivity might be helpful. Other useful further parameters could be, for example, chelating power, surface tension, oxidizing properties, and so on. The scope may include data from related areas, such as environmental fate data, in particular ready biodegradability, because they are indicative of a possible biological similarity, even though not directly relevant to the endpoint of interest. If not possible or too costly to obtain, there are programs that can provide relatively accurate estimations based on quantitative structure-property relationship (QSPR) models. Most of them are collected in the ECHA guidance for the preparation of REACH registration dossiers in the sections on adaptations of the standard testing regime . Others in vivo tests should be considered at the very end of the process and only when all other opportunities have been considered. Gaps or uncertainties should be filled with existing studies or new in vitro tests.When all available data are collected, they must be evaluated to decide whether they provide a clear picture and enough information to conclude whether the comparison between the source substances and the target substance is accurate enough to permit a conclusion and fill the gaps as required. If the approach seems reasonable but not sufficient to demonstrate the similarity, further tests on the category are necessary. The necessity to perform new 19. Where models are used, they should be run also for category members for which experimental data exist. In this way, the applicability of the QSAR/QSPR model(s) to the specific set of chemicals under examination can be demonstrated. Where available, study results should be compared with the output of the computational approach as a reference to assess the accuracy of the prediction and claim better reliability for the output when applied to fill a data gap. Another computational tool developed specifically for RAx purposes is EPA’s Generalized Read Across (GenRA) add-in within the CompTox Chemicals Dashboard18, which uses a similarity-weighted activity algorithm to compute a RAx prediction using both chemical  and biological (in vitro HTS data from the Tox21 program) descriptors.Computational tools assist the identification of source materials and the demonstration of similarity, which would ideally include both toxicokinetic and toxicodynamic (TK/TD) considerations. Computational systems can be applied to analyze the issue globally, for example by defining the bioactivity profile through fingerprint description to feed machine learning models . A usefuad hoc experimental studies.Given that potential selection bias is one of the major issues with respect to the reliability of the RAx approach, it is essential to document selection and deselection as well as chemical and biological characterization of the source chemicals that have been performed according to a clear rationale and in an unbiased way. Whatever the amount and quality of existing information, there will always be some uncertainties that need to be characterized, quantified and accepted. Computational methods may be very useful in providing variance and correlation among features. Uncertainty should be defined for each piece of information and in case of discordant results for the same substance, a conclusion should be drawn carefully by weighing all available information and relevant differences in the experimental protocol of the studies. Missing data and the lack of mechanistic coverage should be overcome with new 2.2As already mentioned, NAMs represent a good opportunity to support the RAx hypothesis by providing data to confirm whether a group of substances shares the same biological mechanism or if they show a specific trend within the category . In the in vitro and in silico techniques are now available and can assist in the purpose of demonstrating similarities within a category. Listing all the opportunities is out of the scope of this paper, and more details are available elsewhere , even though there are still no valid and universally applicable systems , which was implemented in the EU with the Classification Labelling and Packaging (CLP) Regulation (EC) 1272/2008, which explicitly accepts RAx when describing the scope of WoE determination in its Annex I.The difficulty in applying RAx for classification purposes lies in the analysis of potency for the determination of hazard category. Categories of local effects are generally well characterized with defined thresholds, while more concerning endpoints, such as CMRs , have no defined threshold in CLP, and the category is demarcated only by the qualitative probability that a substance may exert that effect. In fact, Category 2 is based on the presumption that the toxicity outcome may result, Category 1B is the proven toxicity in animals, and Category 1A the proven toxicity in humans. In all cases, there is a need to assign a dose to the hazard, which is a defined threshold for local and acute toxicity endpoints and the no-observed-adverse-effect-level (NOAEL) for the systemic endpoints, for risk assessment.The OECD guidance on grouping of chemicals provides some consideration on how a quantitative prediction for target substances can be made by extra- and interpolation within a category for which trend(s) in toxicity or factors influencing toxicity have been identified. When the AOP and quantitative information on the relationship between KE and AO are known, NAMs can be used for the target and source substances to further strengthen the (quantitative) prediction, with the application of a suitable QIVIVE correction. While larger categories might provide the basis for trend analysis and thus a relative potency assessment of their members regarding a specific effect, the situation is much more difficult in one-to-one assessment, and additional reasoning will generally be required to assign the same, or a higher or lower, potency to the target. Depending on the legislative framework, the assignment of additional assessment factors (AF) might be required in such circumstances. A more scientific approach could consider a detailed toxicokinetic assessment with correlation of the exposure and the concentration at the target site.This particular topic clearly needs more discussion and agreement between regulators.2.7The published literature gives an indication of the considerable breadth of RAx studies that have been undertaken and reported. Whilst this is not necessarily representative of all REACH submissions, it does indicate that RAx has been applied in a number of scenarios and with a variety of techniques. Turning some of these into case studies is useful for a number of reasons that go beyond simply providing an illustration for further use .For the illustration of RAx in various forms, the OECD has published case studies on the applicability of IATA including RAx , 2018. TAs part of the SEURAT-1 initiative, RAx case studies were instigated . This re22, and the final report should be published in 2020.The EU-ToxRisk Project has started an initiative in collaboration with regulators from different scientific areas, including experts in the areas of pesticides, food safety, industrial chemicals, etc. Partners have prepared mock submissions to regulators from agencies associated with European regulations in order to learn whether their approaches would be acceptable in a legal context or not. In this way, EU-ToxRisk case studies are treated as if they were real cases with the purpose of challenging the traditional regulatory assessment approach. A dedicated workshop with the active collaboration of ECHA and EFSA has already taken placeIn recent years, also ECHA and the EU Member States have increasingly included grouping approaches into their screening and assessment schemes. In particular, ECHA launched the collaborative approach (COLLA) pilot projects focused on five groups of substances . The aim23, these data mainly derive from the personal experience of some co-authors and are generally not public. Further analysis is not possible and, moreover, the general feedback from the authorities is not known, unless looking for data relative to the submission of the individual substances. Even though it would be interesting, this search is out of the scope of this publication.In the scope of REACH, other simple approaches have been used in the area of metal salts, e.g., for nickel, cobalt, iron chlorides, sulfates, nitrates, etc. More complex RAx categories have been built for petroleum/coal products, fatty acid derivatives, etc. With the exception of a few publications  or indic2.8in vivo test. Rather, the assessment relies on a more global approach that considers a variety of data. Even if the comparison can be between one source and one target, the use in support of many other chemicals in a group or the comparison between other similar substances can be of benefit. Let us consider a very easy example of the RAx of a sodium salt (source) with its acid. If the dissociation constant confirms that the acid is fully dissociated at the physiological pH, such information already might seem enough to justify the read-across. However, the hypothesis would be strengthened further if there is the possibility to compare other experimental endpoints for both substances, highlighting differences that may derive only from the capacity of the acid to alter the pH. It would not be surprising if the acid was classified as an irritant and the salt was not, but they may share identical biological behavior with regard to mutagenicity, developmental toxicity, etc. RAx hypothesis supported by other similar substances, with data on both the acid and the sodium salt, and even other salts, would then appear much stronger.The main potential of RAx lies in its application in an integrated way on several source substances, so it is more than a simple tool to waive a single Similar chemical structure and behavior;QSAR prediction;in vivo studies;Collection and evaluation of existing in vitro tests to confirm the mechanism. If the RAx hypothesis is based on the hypothesis of the same TK/TD profile, strong RAx justification should include, if possible  test, if there is an issue related to developmental toxicity  as observed in traditional 16 supports the user by providing information on alert performance based on the category candidates that are selected  . Althougselected . Recentlselected .Many aspects of RAx are subjective and difficult to quantify. For instance, the evaluation of similarity is very challenging, and minor differences that seem negligible may have a strong impact on the biochemical activity, as illustrated by the problem of activity cliffs. If there was agreement on suitable metrics and on minimum thresholds, this could be used as one of the parameters defining the applicability of a given RAx.A defined endpoint. RAx assessment should be performed for each endpoint for which sufficient data are lacking. Often there is the danger of considering the RAx globally, without a clear definition of the specific activity that it is required.An unambiguous algorithm. This has to be applied to all algorithms that are part of a RAx, e.g., those used for similarity assessment or for weighing information in the context of a WoE decision. The procedure for RAx should be clear, transparent and reproducible, i.e., different experts should arrive at comparable conclusions based on the same set of data.A defined domain of applicability. As noted above, in RAx the applicability domain is characterized by the structural, mechanistic and property space spanned by the category members, while the resulting prediction is subject to the boundaries defined by the regulatory scope of the requested assessment. However, this step should address also the adequacy of the available information. Proper characterization of the applicability domain will also help to identify potential bias in the selection or characterization of the tested substances.Appropriate measures of goodness-of-fit, robustness and predictivity. For the RAx, being an individual and case-specific assessment, performance statistics cannot be obtained, but this should be done for all non-standard methodology, e.g., in vitro and in silico NAMs, used to obtain the overall RAx conclusion  are integrated in AMBIT2. The import and export functions are enhanced in AMBIT2, which allows communication with a variety of additional prediction models such as knowledge-based expert systems for toxicity and metabolism.Another available platform and public tool is AMBIT2tools/databases to search for potential analogues – by structural similarity, experimental data availability for the target-endpoint, combined search  or mechanistic similarity;tools to assess similarity between target and source compounds through structural similarity, mechanistic similarity, physicochemical and ADME similarity;tools to predict potential metabolism and metabolic products;QSAR predictors to predict target endpoint-related properties.The use of several computational tools  can support the different phases of the RAx workflow, e.g.:vice versa. Still, already relatively simple nearest neighbor approaches were reported as quite successful in predicting this hazard . These areas are also known as green toxicology, which is a sector of the green chemistry movement  asking fSpecific use of RAx in academia can go beyond pure research as is the case for industry R&D. RAx should be part of teaching courses in toxicology and other disciplines, with practical sessions on case studies and emphasis on the importance of RAx as a necessary professional qualification. RAx should be a valuable tool in mechanistic understanding as an ideal complement of pure computer modelling systems. Academia should reason in a reverse way, i.e., frame their research questions and present their data in a machine-readable way with reports that contain all useful information to enrich databases for RAx exploitation. Last but not least, the development and optimization of RAx tools represents a thriving research field for academic teams.33 and the associated in silico protocols effort.There are emerging applications also inside regulatory institutions. For example, two EPA Research Centers are engaged in the area of RAx. Within the National Center for Environmental Assessment (NCEA), RAx is routinely applied as part of the Superfund program for provisional peer-reviewed toxicity values (PPRTVs). The workflow is documented in 5Data on analogues,Data on grouping, with identification of trends across a group,QSAR model predictions,In vitro tests, with a focus on AOPs,TK/TD analysis.RAx is potentially a major tool for risk assessment. The power of RAx lies in the possibility of combining data in a global analysis, including:This approach in its more elaborate form is relatively new and requires specific expertise that at the moment is still limited. The roadmap for implementation and confident use of RAx requires actions in many areas with the collaboration of different stakeholders.A very important step is the generation of a template for RAx submission to the authorities with specific instructions on GRAP. In order to increase the confidence in the tool, the creation of examples that would be considered acceptable by regulators is key. Examples should include cases with compounds with high, low or no activity. A detailed analysis of uncertainty is a very important part of this. To this aim, workshops and symposia may contribute in the dissemination of the RAx principles.Simultaneously, other actions should support raising awareness of regulators inside national authorities that RAx is a valid alternative, with the potential to increase confidence in the final outcome as it is based on a reasoned approach with a scientific justification of the mechanism. For this purpose, retrospective examples comparing both the traditional approach and the assessment performed with RAx should be prepared and presented.in vivo studies.On the other side, risk assessors from industry should also learn how to properly apply RAx. There is still much ignorance and apprehension about using RAx in industry, and whilst much guidance and templates for reporting are available, real examples of successful, i.e., accepted, RAx for data gap-filling would be beneficial. The industry needs to be reassured that the effort in preparing a rigorous RAx justification is largely repaid by regulatory acceptance without the need for additional vice versa. It is not surprising that industry is reluctant to invest money into a strategy that is not accepted in other parts of the world. Unfortunately, the problem is not limited to crossing national borders, as sometimes important differences are present among different regulations enforced in the same region. Political action towards harmonization is necessary.Better harmonization of legislation is desirable. That should happen internationally, as it is unacceptable that a good RAx would be, for example, accepted in the EU and rejected in Japan or Another important aspect is education. RAx should be part of the program in university courses in toxicology and other related subjects, in order to provide another useful tool for research and implement NAM approaches.RAx approaches are a dynamic and continually evolving development. The area of mechanistic elucidation of toxicity pathways along with the increase of available information and computational tools is expanding dramatically, and each assessment should be updated in parallel with the commitment to incorporate new evidence into existing RAx packages. These technologies offer the possibility of refinement of RAx justifications, which may lead to greater openness towards acceptance on the regulators’ side. International organizations such as the OECD have a leading role to play in supporting the process definition.in vitro tests, which is desirable to encourage their application to support RAx justification.The fourth sector that is affected by RAx is contract research organizations (CROs) that usually perform new tests on behalf of industry and in many cases provide advice on test strategies. CROs should be aware of RAx possibilities and should implement NAMs in the list of their services. Widespread implementation will facilitate a decrease in the cost of In addition, due to a general lack of strict guidance/rules for GRAP, chances of regulatory failure of a RAx submission are considerably higher compared to, e.g., submitting the “traditional” standard information dataset as required by REACH. Against this background, many companies will prefer higher initial spending with guaranteed regulatory acceptance over an initially smaller investment, which might result in overall much higher costs when a RAx submission is rejected.in vivo test, but considering the limitations of in vivo tests, the future trend is to develop a tool that increases predictivity and reliability by combining RAx approaches with multiple NAMs.Last but not least, there is a need for the development of new tools for building RAx. This part is more complex. First of all, there should be an international agreement for data-sharing and free access to high-quality reports. Then there is the need for new databases with mechanistic information, combined with TK/TD data. In fact, at the moment, the request is to apply RAx simply to waive an extensive


It is recommended that future studies address the subtypes of disorders evaluated using longitudinal designs.Obsessive-compulsive disorder (OCD) and eating disorders (ED) share common causal factors and often represent similar entities. Studies on obsessive-compulsive disorders and eating disorders reveal a significant correlation between maladaptive perfectionism. The objective of this study is to evaluate the predictive variables of perfectionism in patients diagnosed with Anorexia Nervosa (AN), Bulimia Nervosa (BN) and OCD using a structural equation model (SEM). The sample consisted of 187 participants  with a mean age of 26.68 (SD = 10.97). The findings reveal that the model is the same in all the disorders evaluated, achieving an adequate fit: χ2 = 7.95 ( Perfectionism is a maladaptive personality trait when expressed at high levels . HistoriThe increase in studies on maladaptive or negative perfectionism may be supported by the fact that it is a risk factor for mental disorders such as suicidal ideation, depression and anxiety . AccordiSome approaches, such as the trans-diagnostic approach, rescue the relevance of the mediating mechanisms of perfectionism , to explFrom the point of view of these disorders, empirical evidence has identified different mechanisms that have an impact on the symptomatology of maladaptive perfectionism. Among these, the clinical relevance of anxiety about perfectionistic actions , 20.Precisely, it can be pointed out, the mediating character that it obtains by associating it with perfectionism, as an inherent mechanism of modulation and aggravation of symptoms both in EDs –23, and Also, it has been noted that goals, impulses and preoccupation with errors act as pathognomonic criteria of perfectionism, playing a maintaining role in perfectionist symptoms . From thAccordingly, impulsive traits have been identified as increasing the risk of manifesting perfectionist behaviors –36; althMeanwhile, concern over mistakes encompasses cognitive and interpersonal characteristics inherent in the course of perfectionism , which hPhenotypically, certain female gender predilection in the involvement of anxiety course  and emotClearly, OCD and EDs share common causal factors and often represent similar entities. Studies on the relationship between perfectionism, obsessive-compulsive traits and eating disorders reveal a significant correlation with maladaptive perfectionism , 5, 50. The trajectory of these studies has denoted the prediction of maladaptive perfectionism as a psychopathological criterion implicated in the genesis of OCD and ED. Given that these studies have corresponded in analyzing in isolation or partially each of its predictor variables . The present research aims to study the integration of the variables by means of an integrated structural equation model, in order to know the direct and indirect effects between their relationships in a population of patients diagnosed with AN, BN and OCD.n = 71), AN (n = 52), and BN (n = 64) corresponding to the psychiatric outpatient area of the “Ecuadorian Mental Health” Citizen Attention Program of the Ministry of Public Health of Ecuador was included in the study. The diagnosis of the patients was made by psychiatrists in charge of the program. The inclusion criteria for this study were an age of 17 to 40 years, the presence of diagnosis of AN, BN, and OCD according to DSM-V criteria, for the diagnosis of the severity of anorexia nervosa, low body weight defined as a BMI of ≥17 was considered. The study did not consider the subtypes of: anorexia nervosa (restrictive type and binge eating/purging type), and bulimia nervosa (restrictive and purging); exclusion criteria were psychoactive substance dependence, major medical or neurological illness and cognitive impairment. The patients included met the criteria as established by the DSM-5 for the diagnosis of OCD and ED, at least 2 months before entering the study, likewise they did not report being under the effect of any medication or psychotropic, in the development of the tests. The distribution of the participants according to their sociodemographic variants, medical illnesses and psychopathology is reported in The study included a sample of patients diagnosed with OCD .The study was conducted in accordance with the latest version of the Declaration of Helsinki. The Clinical Research Ethics Committee of the Ministry of Public Health of Ecuador approved the study and signed informed consent was obtained from the volunteer participants in the psychiatric outpatient area of the “Ecuadorian Mental Health” Citizen Attention Program.Outpatient physicians and psychiatrists invited patients in the consultation process to participate in the study by informing them that attitudes toward mental health problems were being assessed. The data collection time was 2 months. Those who gave written consent to participate were included in the study. Once this process was completed, the availability of the patients to complete the tests in the regular space of consultations and controls to the patients was scheduled together with the patients. Data collection was performed by the staff psychologist in conjunction with the attending physician. The patients who completed the measures were thanked for their time.Data processing was performed by the Basic Psychology, Behavioral Analysis and Programmatic Development PAD-lab team. After the process of imputation of missing data and the recreation of the final data matrix. Prior to the calculations developed for the fulfillment of the proposed objectives, the fulfillment of the assumptions of: univariate and multivariate normality, homoscedasticity, collinearity and data independence will be analyzed for its corresponding estimator.Quantitative techniques including descriptive statistics, such as means and standard deviations, were used. In developing the proposed multivariable model, a description of each study variable was necessary for theoretical formation and conceptualization. Means with 90% confidence intervals and frequencies were used in the generation of descriptive statistics for continuous and categorical variables, respectively. Structural equation modeling (SEM) is employed in this study as an analytical tool to describe the commonalities among the variables analyzed. By means of maximum likelihood estimation, the covariance matrices extracted from the AMOS results in SPSS were applied. The model was analyzed for goodness-of-fit, residual error and chi-square values within each subsample.Goodness-of-fit is measured on the basis of the Bentler-Bonet normed fit index, the comparative fit index and the standardized residual error estimate . The gooR| > 0.24) to large-high (|R| > 0.37) ranges were considered as relevant. Levels of perfectionism were positively correlated with higher scores on anxiety, emotional regulation, drives, goals, and worry about mistakes.p = 0.000), RMSEA = 0.087 , CFI = 0.991, TLI = 0.951. The overall predictive ability was around 30% (CD = 0.318). The global invariance test showed significant results , suggesting that the underlying processes are similar according to psychiatric disorders. p ≤ 0.05), while dashed lines represent non-significant coefficients (p > 0.05). In patients diagnosed with OCD, AN, and BN, the results indicate that worry about mistakes has a direct predictive effect on perfectionism, as well as an indirect effect mediated by emotional regulation. Goals, on the other hand, have a direct predictive effect on perfectionism and an effect mediated by emotional regulation and anxiety. The effect of female sex and drives is mediated by: a) emotional regulation and b) anxiety, on perfectionism. We manage to denote the mediating role of emotional regulation and anxiety on perfectionism performance in patients diagnosed with OCD, BN and AN.This research aimed to study the integration of predictors of perfectionism by means of a causal integrated model in patients diagnosed with OCD and OCD (AN and BN). In these diagnosed patients, the results indicate that preoccupation with errors has a direct and predictive effect on perfectionism, as well as an indirect effect mediated by emotional regulation. Studies corroborate this endophenotypic criterion in patients with OCD , 59–66, Furthermore, our results corroborate with previous understandings on the following levels: the influence that goals manage to have on perfectionism –89, the Similarly, in our results the effect of female sex and drives act as indirect predictors (mediated) by emotional regulation and anxiety on perfectionism. This manages to denote the mediating role of emotional regulation and anxiety on perfectionism performance in patients diagnosed with OCD, BN and AN. This issue reiterates the importance of gender-specific component analysis when studying perfectionism and associated disorders .The relationships of our results are similar to classic studies mentioning female gender predisposition in the prevalence of psychiatric disorders  such as:The mediating role of emotional regulation and anxiety in mental disorders is denoted. Given that emotion regulation is an important part of daily life, it is not surprising that disturbances in emotions and their regulation can lead to discouragement or even psychopathology. In fact, the revision of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-4]; American Psychiatric Association  reveals As for EDs, our study manages to detonate that perfectionism plays a considerable role in research on the etiology of eating disorders, representing a precursor and a feature of the acute phases of certain eating disorders. For example, research has shown that perfectionism persists after long-term weight regain from AN, and is present in relatives of women with EDs. Additionally, regarding family relationships findings show clinical perfectionism as a mediator between insecure attachment to the mother and ED symptoms . TherefoAlthough perfectionism has been implicated in the etiology of eating disorders, it has been reported to be a specific risk factor for the development of AN and BN but not binge eating disorder (BED). Research examining concurrent factors that discriminate between eating disorders suggests that women with AN tend to have significantly higher levels of perfectionism compared to women with BN. In addition, some studies have found that perfectionism further discriminates between anorexia subtypes, indicating that women with AN are more perfectionistic and rigid than their AN-attracted purging counterparts. For example, some studies of those noted have found no differences in perfectionism between AN subtypes, whereas other studies have found evidence of greater perfectionism in women with the AN-purgecompulsive subtype compared to women with the AN-restrictive subtype. It has been noted, that a propper intervention of ED, requires specifying the way in which perfectionism is presented due to the importance of the role it plays in the dynamic of those disorders .Our research did not involve patients diagnosed with binge eating disorder, however, several studies have noted weak or inconsistent associations between perfectionism and binge eating. It is possible that these inconsistent associations may be explained by the presence of fasting among overeaters. However, to our knowledge, no study has examined these hypotheses directly. This could be done in future research to obtain more consistent results.Regarding perfectionism and OCD, our results are consistent with a number of reports relating perfectionism to obsessive-compulsive symptoms . Gershuny and Sher  found hiOn this point, preoccupation with errors and doubts about actions have also been associated with compulsive indecisiveness , 152, whResearch to date makes it clear that perfectionism is related to OCD. However, as suggested above, high levels of perfectionism may not be unique to OCD. The literature suggests high levels of negative perfectionism in anxious, depressive , eating From the findings presented in this study, we consider that there were also limitations such as: the clarity of the participants' diagnosis, as well as the subtype of psychopathology presented in each of the disorders evaluated and the evaluation of pathognomonic variables of ED  and OCD Another perspective that could be explored in the future is the relevance of gender in ED research; considering the marked theoretical and methodological gap in this field .Finally, we believe that the usefulness of this research is linked to the knowledge of perfectionism as a non-adaptive criterion that exacerbates the symptomatology associated with ED and OCD. So far, no study has examined how different levels of perfectionism act as their own mechanisms within ED and OCD. Thus, our study provides a perspective that may help to deepen the understanding of the psychopathological pictures of the disorders investigated, and consequently to rethink the models of intervention in their patients according to the obtained indicators of perfectionism.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee for Research with Human Beings of the Catholic University of Cuenca CEISH – UCACUE. The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Advantages of hot devices for tonsillectomy, represented by coblation, have been highlighted in recent years. During hot technique tonsillectomy it is important to identify and coagulate the vessels of the tonsillar capsule, especially at the lower pole of the tonsil. Hot technique tonsillectomy under microscope or endoscope has therefore been recommended to achieve accurate identification of the microstructure of the surgical field. We have applied ORBEYE, a three-dimensional surgical exoscope system, to coblation tonsillectomy. Advantages of using ORBEYE include high definition and high magnification images, and flexibility of camera position and angle. This means there is an improved surgical view and working space, particularly at the lower pole during performance of coblation tonsillectomy. Here, we demonstrate that ORBEYE can be an effective surgical instrument in coblation tonsillectomy. Tonsillectomy is one of the most common surgeries in otorhinolaryngology, head and neck surgery. In addition to surgical procedures performed by steel knife or guillotine, the so-called ‘cold method’, some new techniques, known as ‘hot technique’ have been developed and include electrocautery, harmonic scalpel, bipolar diathermy dissection, radiofrequency and coblation. Hot techniques have improved the outcome of tonsillectomy, including achieving lower intraoperative blood loss, shorter operation time and lower postoperative pain . HoweverThe utility of surgical microscopes and endoscopes for precisely identifying anatomy in hot technique tonsillectomy has been reported ,6,7,8,9.We have applied coblation tonsillectomy under a surgical microscope, and introduced ORBEYE, a 3D surgical exoscope system, to coblation tonsillectomy. Here, we report the advantages of ORBEYE in improving the surgical view and working space, particularly in the lower pole of the tonsils, during coblation tonsillectomy in both pediatric and adult patients. To our knowledge, this is the first clinical report on the utility of ORBEYE-assisted coblation tonsillectomy.This is the first case series of three sequential patients that underwent coblation tonsillectomy under ORBEYE performed by a single surgeon (D.M.). Details of the patients are summarized in The ORBEYE 3D surgical exoscope system , with 4K-3D display, Coblator II Surgery System  and Evac70 70 EXTRA HP (Smith & Nephew KK) were used. The operator took position in front of the head of the patient and wore 3D glasses. The main unit of ORBEYE was placed to the patient’s left side, and the camera arm was introduced from the operator’s left side. As the main unit of ORBEYE is smaller than or as small as those of a microscope, it was possible to place ORBEYE without restricting sets of other devices in the operating room. The wireless footswitch of ORBEYE was placed at the left foot of the operator. To allow the operator to perform transoral procedures while looking straight ahead, the 4K-3D monitor was placed at the patient’s feet. The preparation was as simple as covering the exoscope with a drape, and operation could be started immediately. The coblator was placed to the patient’s right, and the foot pedal was placed for use by the operator’s right foot. The scrub nurse stood on the left side because, for the right-handed operator, only the coblator wand was used with the right hand, and forceps or other instruments were used with the left hand. An anesthesiologist stood to the operator’s right side.The anterior palatine arch was incised by ablation mode 7. Connective tissue adhering to the tonsil was ablated along the capsule a. The veFurthermore, a wide working space was obtained, even during dissection of the lower pole a,b. TypiIn tonsillectomy, difficulty and complications can depend on surgical view and working space, especially at the lower pole ,4,5. InaORBEYE facilitated excellent surgical view of the lower pole of the tonsils. Risk factors of postoperative hemorrhage include age of the patient and the level of experience of the surgeon . Wang etExcessive hemorrhage in the surgical field is one of the anxious dificulties during tonsillectomy. It is hard to compare with other devices, as exessive hemorrhage is not a frequent complication among simple adenoid vegetation and tonsillar hypertrophy. However, based on the following points, ORBEYE would be useful even in cases of exessive bleeding. In cases of exessive hemorrhage, if a microscope is used, the operator needs to remove the blood with low magnification, detect the bleeding points, and then perform a rapid hemostasis with high magnification. In contrast, an exoscope can provide high definition and high magnification 3D images even in cases of excessive hemorrhage. In addition, ORBEYE can provide instant switching of the angle of view and the magnification by a footswitch, resulting in an efficient hemostasis. Another type of exoscope represented by VITOM  is fixed by the pneumatic holder, so the operator needs to manually mobilize the microscope and adjust zoom and focus . These rA wider working space could be obtained under ORBEYE. In microscopic tonsillectomy, the operator must stay in a position with their head low and looking up during surgical procedures at the lower pole of the tonsils. Because ORBEYE has an extended focal length of 220 to 550 mm, the lens of the exoscope can be positioned away from the face of the patient. It enables avoidance of interference between the coblator wand and the exoscope. Interference between the long shaft of the coblator wand and the microscope can limit the working space. Interference between the coblator wand and endoscope is inevitable in endoscopic tonsillectomy, in which the endoscope must be positioned inside the patient’s mouth . In addiWe became familiar with ORBEYE-assisted tonsillectomy easily after the introduction. In the field of neuroendoscopic surgery, there are some reports regarding the impact of exoscope on the learning curve. Parihar et al. reported that the learning curve is found initially in pure endoscopic procedures and the video telescope operating monitor system, which is a type of exoscope that effectively reduces the initial learning curve of neuroendoscopy . In thesORBEYE would have some advantages over other exoscopes. Langer et al. recently reported a review about the comparison among some types of exoscope . In the The current report focused on a limited case series without a control group. As the current report is a case series that focused on the introduction of ORBYEYE for adenotonsillectomy using a powered device, it has no control group. To show further safety and feasibility, accumulation of cases and future studies about comparisons between exoscopes and other conventional devices such as microscopes and endoscopes are needed. It is also better to evaluate which surgical techniques  show better compatibility with ORBEYE in future studies. However, we can deduce that this first case series has value with respect to discussing and indicating the utility of ORBEYE-assisted coblation tonsillectomy. The costs for installing ORBEYE  is about the same as those for microscopes. Running costs, such as the cost of surgical drapes, are comparable to those of microscopes. Although the initial costs are expensive, it is considered that ORBEYE provides clear surgical view and wide working space contributing to safe and stressless surgery, and can be applicable for various surgeries in otolaryngologic and head and neck surgery field including otologic surgery, laryngomicrosurgery, and transoral pharyngolaryngeal surgery. The introduction of ORBEYE will have great significance. In addition to the advantages of ORBEYE regarding its superiority over microscopes and endoscopes, its use has significant educational value in surgical training. Instructors and senior surgeons can show residents surgical procedures without interruption and changing positions, and conversely, they can monitor residents’ surgical performance with an extremely fine view.ORBEYE, a high-resolution 3D surgical exoscope system, had various advantages including high definition and high magnification 3D visual images and flexibility of camera position and angle, which provided excellent surgical view and working space in coblation tonsillectomy from early on after the introduction. ORBEYE especially worked well during the procedure at the lower pole of tonsil. Although accumulation of cases and future studies about comparison between exoscope and other conventional devises such as microscope and endoscope are needed, through our three cases, we demonstrated the advantages of ORBEYE-assisted coblation tonsillectomy. The ORBEYE-assisted tonsillectomy is an attractive alternative surgical procedure to conventional procedures. The advantages of ORBEYE should be further evaluated in randomized cohort studies.


Pseudomonas aeruginosa is the most common organism that causes GNS. It is an opportunistic human pathogen that preferentially colonizes moist environments, and thus, it usually affects patients with a history of prolonged exposure to moist environments. Here, we describe a case of GNS in an epidemic prevention volunteer that was caused by wearing personal protective equipment for prolonged durations. The case was reported during the outbreak caused by the SARS-CoV-2 Omicron variant in Shanghai. After receiving information about his condition and proper treatment, the patient was cured.Green nail syndrome (GNS) is an infectious disorder characterized by greenish discoloration of the nail plate.  Pseudomonas aeruginosa is the most common causative pathogen (Green nail syndrome (GNS), also known as chloronychia, is an infectious disorder characterized by greenish discoloration of the nail plate . Pseudompathogen . GNS maypathogen .It is well-known today that various skin disorders are induced by the use of personal protective equipment (PPE) such as facemasks and gloves . Here, wA 34-year-old otherwise healthy male presented with asymptomatic, greenish discoloration of the nail plate that had set in over a period of 4 weeks. The discoloration began at the distal margin extending to the middle of the nail plate. The patient did not report any history of trauma or onychosis. Before the lesions appeared, he was an epidemic prevention volunteer who wore PPE  for at lP. aeruginosa. Subsequently, drug sensitivity tests were performed, which revealed sensitivity to fluoroquinolones including ciprofloxacin and levofloxacin.Physical examination revealed greenish black discoloration from the middle to distal parts of the first and third toenails of the left foot . A whiteGNS was diagnosed based on these findings, and the patient was instructed to stop wearing PPE, to wash his feet daily, and to keep his feet dry. Based on previous literature , 6 and dP. aeruginosa  and the Shanghai Municipal Commission of Health and Family Planning (Grant Number 20194Y0337).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.