Grounded on the social exchange theory (SET), social cognitive theory (SCT), and self-determination theory (SDT), this study aims to explore the mediating role of self-efficacy (SE) and work engagement (WE) on the effect of social support (SS) on job satisfaction (JS) among Chinese ethnic minority kindergarten teachers (KTs). The results show that: (1) SS has a directly significant effect on JS; (2) WE mediates the relationship between SS and JS; and (3) SE mediates the relationship between SS and WE. Although the mediation of SE on the relationship between SS and JS is not found, the posited multiple mediations of SE and WE on the relationship between SS and JS are totally accepted. The results reveal that SS mainland Chinese ethnic minority KTs received can not only have a direct effect on JS but also have an indirect impact through the one-path mediating role of WE and the chain mediating role of SE and WE. The results suggest that governments, supervisors, and sponsors should work together to provide ethnic minority KTs with more prioritized SS from both cultural psychology and financial material and opportunities for facilitating professional knowledge and skills in order to enhance their SE, inspire their WE, and eventually accumulate their JS. Job satisfaction (JS) of kindergarten teachers (KTs) has attracted considerable attention from scholars, educators, and policymakers over the past decade . The facIn addition, a few studies have investigated the factors that predict the level of JS of Chinese KTs. For instance, Contrary to the results of the abovementioned research, No doubt, these previous studies have greatly enriched our understanding of KTs’ JS and its antecedents observed. Teachers who are satisfied with their job are often provided with plenty of support from society, supervisors, fellows, and families and feel self-sufficient and engaged in involving work tasks. Effective teachers are essential for an accomplished educational system and a productive institute . HoweverTo bridge this gap and better understand the interaction between SS, SE, WE, and JS, we sought to assess the roles of SE and WE as mediators in the association between SS and JS in a sample composed of mainland Chinese ethnic minority KTs, which provides a specific model of Chinese setting. Constructing the correlation between these four constructs from an ethnical perspective would provide a theoretical reference with a combined evaluation dimension and make a practical contribution to improving national prioritized ethnic policy, promoting educational development in ethnical areas, and facilitating work-related happiness and well-being of ethnic minority KTs, which has valuable implications for other multiple ethnic countries dealing with the same issues.Social support is defined as “the perception that one is cared for, esteemed, and part of a mutually supportive social network” . SS may The concept of JS is multidimensionally defined as what it means and how it impacts and enhances employees’ work performance . SpectorAccording to social exchange theory (SET) e.g., , SS playBased on previous studies, it can be predicted that SS ethnic minority KTs received should play a crucially decisive role in promoting their JS; hence, the following hypothesis was formulated:Hypothesis 1: SS mainland Chinese ethnic minority KTs obtained has a significant and positive impact on their JS.According to social cognitive theory (SCT), SE is initially defined as individuals’ beliefs about their ability to perform a specific behavior successfully . SE has Social support is perceived as an essential aspect to enhance SE. Cross-sectional studies have supported that people’s SE has a significantly positive linkage with the SS they receive . For insIn summary, the more SS KTs receive, the higher SE they recognize, and higher SE further relates to higher JS, suggesting that SE may serve as a mediator in the association between SS and JS. To investigate that prediction, we formulated the following hypothesis:Hypothesis 2: SE plays a significant and positive mediating role in the relationship between SS and JS among mainland Chinese ethnic minority KTs.Work engagement is defined as “a positive, fulfilling, work-related state of mind characterized by vigor, dedication, and absorption” . Vigor rPrevious studies have shown that SS is significantly positively related to employee engagement , leadingUnderpinning these works, we assume that the more SS KTs obtain, the more engaged they are, and resultantly, more engaged work leads to higher JS, indicating that WE may be seen as a mediator in the relationship between SS and JS; hence, the following hypothesis was tested:Hypothesis 3: WE also plays a significant and positive mediating role in the relationship between SS and JS among mainland Chinese ethnic minority KTs.According to self-determination theory SDT; , employeFollowing these studies, we posit that SE is directly related to WE, which subsequently improves job performance. Therefore, the following hypothesis was tested:Hypothesis 4: SE predicts WE and further mediates the relationship between SS and JS among mainland Chinese ethnic minority KTs.The complete hypothesized model is presented in N = 184) of participants come from state-run schools and the remainder (N = 23) work for private-run schools. Ages of participants ranged from 20 to 50 years . More detailed demographical information about their degrees, experiences, and contracts can be found in Participants comprised 207 teachers who work at kindergartens located in the underdeveloped ethnic areas of China, such as Xinjiang, Tibet, Inner Mongolia, Yunnan, Sichuan, Gansu, Guizhou, and Heilongjiang . All participants were recruited from a specific workshop sponsored by local governments and the state-owned enterprise of China Southern Air Holding Company, held by a top-tier teacher education university located in the developed coastal region of China, and taught by the research team consisting of three of the authors , with the obligations to provide poverty alleviation couplet-assistance aimed at promoting job skills and work achievement of ethnic minority KTs and eventually facilitating education equity regionally. Their ethnic identities included Mongol (94), Yi (21), Hui (18), Tibetan (15), Daur (14), Bai (12), Manchu (7), Miao (7), Uyghur (5), Tujia (4), Qiang (3), Zhuang (3), Buyi (1), Chinese Korean (1), Yao (1), and Russian (1). Almost 88.89% . The SSRS was originally developed by Job satisfaction was measured with the Chinese version of Self-efficacy is measured with the Chinese version of the General Self-efficacy Scale (GSES), a 10-item measure that examines an individual’s self-belief in difficulty or dilemma . ResponsWork engagement is measured with the Chinese version of the Utrecht Work Engagement Scale (UWES) , a 17-itN = 207).Before conducting this research, we developed a course on educational research methods to impart the participants the knowledge and skills about how to design and respond a survey in order to obtain high-quality data because of the particularity and rarity of the samples. For the convenience of investigation, we merged the items of four measures into a single sheet, which was inputted into the online survey software Wenjuanxing, known as Chinese Qualtrics, so that participants could respond to them anywhere. Before distributing the survey form, participants were initially provided critical ethics approval and an explanatory statement informing them that they could freely decide whether or not to participate in this research. During the study from 3 August 2019 to 3 September 2019, we delivered the questionnaire link to the participants so that they could fill in online. After participants completed the survey, the data were collected and checked whether there were random or incongruent responses. Benefit from the well-prepared work, we obtained highly valid data from all the participants who enrolled in this workshop   statistical analysis software, to analyze the data. First, we evaluated the psychometric properties of the scales described in Section “SE as a Mediator” by testing reliability, convergent validity, and discriminant validity of the measurement model using confirmatory factor analysis. To improve the model’s satisfactory level, we retained the items with factor loading up to 0.7 for further analysis . Consequ-values) .p = 0.03).r = 0.20; p < 0.01), WE , and JS . Teachers with a high level of SE also obtained high scores for WE . However, the association between SE and JS was found to be non-significant . Moreover, although the Cronbach’s alpha coefficient of SS is 0.67, it can be acceptable  ratio to establish the discriminant validity. The values of the HTMT ratio should be less than 0.85 . Table 5t-values. The SmartPLS 3 provides a current statistical criterion to test the GoF, including standardized root-mean-square residual . Therefore, H2 is not supported.In H2, we proposed that SE significantly mediates the association between SS and JS. The results indicate that there is a relatively significant effect of SS on SE  and for WE to JS . The overall indirect effect of path SS → WE → JS is positively significant . Thus, H3 is fully supported.Regarding H3, we proposed that WE plays a significant role in mediating the relationship between SS and JS. The results indicate that the path coefficients are significant both for SS to WE , and the indirect effect of SS → SE → WE → JS is significant . The total indirect effect of SS on JS is also significant . Therefore, H4 is totally supported.In H4, we posited that SE predicts WE and further mediates the relationship between SS and JS. The results indicate that SE has a significant impact on WE . This result is consistent with the theoretical arguments in the literature  and prevAnother result reveals that despite the significant effect of SS on SE, the mediation role of SE on the relationship between SS and JS is not found, partly rejecting the second hypothesis (H2). Unlike the previous findings reporting that SE has a significant effect on JS , this reMoreover, the mediation role of WE on the association between SS and JS is supported, totally accepting the third hypothesis (H3). This result provides evidence for the previous theoretic arguments  and empiFinally, the result related to the last hypothesis (H4) reveals that SE has a positive effect on WE. In other words, SE mediates the association between SS and WE. At the same time, WE mediates the correlation between SE and JS. This result can be supported by the aforementioned theoretical discussion  and empiWhile reliability and validity issues of the construct were verified in the present study, limitations need to be acknowledged when assessing the results. One limitation is that the participants come from 17 ethnic minority groups (approximately 30% of 56 ethnic groups), which constrains the generalization of the findings; thus, further studies should include more ethnic minority KTs. Another limitation is that we do not consider the differences of all demographical variables that may result in statistical bias; therefore, future works should incorporate more controlled variables, such as gender, degree, and experience, to enhance the statistical power and the model discrimination.This study’s objective was to design a chain mediating model in which SS, SE, WE, and JS among mainland Chinese ethnic minority KTs were tested drawing on the SET, SCT, and SDT. The results reveal that SS from governments, organizations, and institutes is a pivotal antecedent of predicting SE, WE, and JS. The results also reveal that WE mediates the relationship between SS and JS and between SE and JS. In contrast, SE merely mediates the association between SS and WE. Although three posited constructs are accepted, and one is rejected, the proposed multiple mediation constructs are totally supported. This empirical result adds value to the current literature regarding the research on KTs’ job resources and job accomplishment from a perspective of ethnic groups. It also provides an informative insight into how to accelerate ethnic minority KTs’ SE, boost their WE, and ultimately, snowball their JS by offering more and higher quality SS from both cultural psychology and financial material and opportunities to facilitate their professional knowledge and skills for policymakers, governors, sponsors, supervisors, and other providers. This study can be further strengthened and generalized through extending the sample diversity to increase effect size and decrease random errors.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the College of Vocational and Technical Education, South China Normal University Human Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.WC contributed to data curation. SW and MH contributed to conceptualization. SW and GF contributed to formal analysis. MH and HZ contributed to funding acquisition. WZ contributed to investigation. SW contributed to methodology. WC, HZ, and XL contributed to project administration. XL, XZ, and KZ contributed to resources. SW and HZ contributed to software. MH contributed to supervision. SZ and XY contributed to validation. SYW contributed to visualization. SW and XY contributed to writing—original draft. SW, XY, WC, WZ, MH, HZ, XL, and GF contributed to writing—review and editing. All authors contributed to the article and approved the submitted version.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.


Psoriasis vulgaris (PV) is a refractory and relapsing skin disease that affects the physical and mental health of patients and leads to poor quality of life. Current conventional systemic therapy shows a large side effect, which can not be used for a long time, easy to relapse after drug withdrawal, long-term efficacy is poor. At present, traditional Chinese medicine treatment of psoriasis vulgaris effective, can alleviate symptoms, improve the quality of life, stabilize the condition, prolong the remission period. Whereas, there is no related systematic review and meta-analysis. Thus, we intend to conduct a systematic review and meta-analysis to testify autologous blood or autologous serum acupoint injection therapy for Psoriasis Vulgaris.Our systematic review will search all randomized controlled trials for autologous blood therapy of PV, electronically and manually, regardless of publication status and language, until March 19, 2020. Databases include PubMed, EMBASE, Web of Science, Cochrane Controlled Trials Register, China National Knowledge Infrastructure, China Biomedical Literature Database, Chinese Science Journal Database, and Wanfang database. Other sources, including reference lists of identified publications and meeting minutes, will also be searched. Manually search for grey literature, including unpublished conference articles.The main outcomes contain the variation of Psoriasis area and severity index, dermatology life quality index, itching score, the effective rate and adverse events from baseline to the end of studies. This study will provide a comprehensive review of the available evidence for the treatment of PV with this therapy.We will summarize sufficient evidence to confirm the therapeutic effect and safety of autologous blood or autologous serum acupoint injection therapy for PV. Due to the data is not individualized, formal ethical approval is not required.INPLASY202040052. Affecting approximately 2% of the population in the world. About 90% of psoriasis cases are psoriasis vulgaris (PV). Its typical clinical manifestations are clearly demarcated, erythema, pruritus plaque, covered with silver scales. Plaques can merge and cover large areas of the skin. Common locations include the trunk, the extensor surface of the extremities, and the scalp. PV is not life-threatening, but has been shown to have a significant impact on the physical and mental health of patients, who often feel depressed, anxious, ashamed, and even suicidal. Although psoriasis is one of the most studied skin diseases, its pathogenesis has not been fully elucidated.–9 At the same time, the damage of psoriasis to patients’ mental health and quality of life should be highly valued, even comparable to cancer, myocardial infarction, and depression.,11 Mental health comorbidities such as depression, anxiety, suicidal ideation, or suicidal behavior are not uncommon in patients with psoriasis, and sleep difficulties are common.–14 Meanwhile, mental illness may in turn cause and promote the progression of psoriasis, suggesting that there may be an overlapping biological mechanism between psoriasis and psychiatric conditions. Proinflammatory cytokines such as interleukin IL-1 and IL-6 were elevated in patients with psoriasis and depression, suggesting that inflammatory processes may be involved in the progression of both diseases.Some studies and systematic reviews have shown that the prevalence rates of cardiovascular and cerebrovascular diseases, diabetes, breast cancer, inflammatory bowel disease, and chronic kidney diseases are associated with psoriasis. At present, the pathogenesis of psoriasis is still unclear, and the main research focuses on different T cell subsets such as Th1, Th17, and related cytokines such as IL-17, IL-21, IL-22, IL-6, TNF-α, and chemokines. At the same time, the role of IL-23/IL-17 axis in psoriasis is also a hot research topic. In summary, psoriasis is now more recognized as an immune-mediated inflammatory disease.The hallmark of psoriasis is sustained inflammation that leads to uncontrolled keratinocyte proliferation and dysfunctional differentiation. Histological manifestations of psoriasis plaques are echinoderm hyperplasia , which is covered with inflammatory infiltration consisting of dermal dendritic cells, macrophages, T cells, and neutrophils. New blood vessels are also a prominent feature. The choice of treatment for psoriasis depends on the severity of the disease, complications, symptoms, and needs of the patient. Patients with PV are typically divided into 2 categories: mild to moderate to severe plaques, depending on the clinical severity of the lesion, the percentage of affected body surface area, and the patient's quality of life. Clinical disease severity and response to treatment can be graded by many different scores, and the Psoriasis Area and Severity Index (PASI) score has been widely used in PV clinical trials. According to the current US Psoriasis Treatment Guide, there are 5 main therapies for this disease: traditional systemic therapy, biologics, topical therapy, phototherapy, and photochemotherapy. Methotrexate, cyclosporine A and retinoic acid are the traditional systemic treatment options for psoriasis. Although the above drugs are currently used as the most cost-effective first-line drugs, their potential side effects and teratogenic toxicity should not be ignored. Due to the common side effects involving mainly the kidney and the liver, such as nausea, leucopenia, Hypertension, toxicity, and liver transaminase elevation. Topical drugs are currently internationally recognized as topical steroids. Vitamin D analogues and salicylic acid are also recommended in combination with topical steroids. But the side effects of topical steroids are a frequent topic of discussion between doctors and patients. Patients are often most concerned about potential side effects associated with “steroid use”. In the past few years, the accelerated development of the treatment of psoriasis has led to the development of advanced targeted biologic drugs. Currently, drugs targeting TNF-α, IL-23, and IL-17 and signaling pathways such as JAK/STAT are effective in the clinical treatment of PV. However, adverse reactions caused by biological agents have been frequently reported, such as serious infection, hepatitis B and C virus reactivation, interstitial pneumonia, drug-induced lupus erythematosus, etc. More clinical studies are needed on the safety of bio targeted therapy. Moreover, it is expensive and not fully marketed and covered by medical insurance in China, so it is not a good choice for PV patients in China. PV is a complex multifactorial disease. Despite the emergence of many new treatments in recent years, PV is still a treatable but as yet incurable disease. In China, we have been exploring the methods under the guidance of traditional Chinese medicine theory, such as Chinese Herbs, acupuncture, and moxibustion to treat PV patients, with good efficacy, low recurrence rate, and the economy as our pursuit.PV is a chronic recurrent disease that often requires long-term treatment. At present, most of the patients due to the lack of long-term effective treatment, so the disease is serious and prone to relapse, which further increases the medical costs of the patients. A cohort study showed that PV has a significant impact on patients’ income and employment.1.2 As mentioned above, psoriasis is an immune-mediated inflammatory disease. Some systematic reviews have proved that acupoint stimulation has a therapeutic effect on psoriasis, and acupuncture can be used as a complementary and alternative medicine therapies for psoriasis.–25 Zusanli (ST36) is the most commonly used acupoint for AB or AS acupoint injection therapy in clinical practice. And effective stimulation of Zusanli (ST36) has the effect of immune regulation and inhibition of inflammation.,27 AB or AS acupoint injection therapy has been recommended for the treatment of allergies, inflammation, infections, and autoimmune diseases, including acne, chronic urticaria, chronic obstructive pulmonary disease, and diabetes, etc. It can also be used safely in pregnant or lactating patients. The account of it is cheap, easy to use and safe. Therefore, AB or AS acupoint injection therapy may be an option for treating patients with PV in developing countries.Autogenous blood (AB) or autogenous serum (AS) acupoint injection therapy is an acupuncture-related technique that specifically separates the whole blood or serum from the patient's own venous blood and then re-infuses it into the patient's own muscle tissue or acupoint such as Zusanli (ST36) for treatment. According to ancient Chinese medical theory, stimulation of acupuncture points is an effective method of treatment, used to prevent diseases and improve health. Now more and more researches are proving that stimulating acupuncture points can regulate the immune system. The effect of emission on diseases is produced by motivating the inherent regulatory system in the body, having the characteristics of whole regulation, dual-directional regulation, etc. The modern scientific researches show that the body's inherent regulatory system is neuro – endocrine – immune network.2The purpose of this systematic review is to comprehensively collect high-quality randomized controlled trials (RCTs), analyze and summarize the evidence to evaluate the efficacy and safety of AB or AS acupoint injection therapy for PV. To provide evidence for clinical practice by evaluating the efficacy and safety through the Cochrane systematic evaluation. We may recommend an effective treatment that provides clinicians with clinical decision making options to help patients seek further treatment options.33.1https://doi.org/10.37766/inplasy2020.4.0052). The registration number is INPLASY202040052 and the DOI number is 10.37766/INPLASY2020.4.0052. This protocol is developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols (PRISMA-P) statement guidelines. The PRISMA Extension Statement is used to ensure all aspects of methods and findings are reported.The protocol for this systematic review was registered on INPLASY and is available in full on the inplasy.com  clinical trials, case reports, observational study, retrospective studies, animal mechanism studies, self-controlled, random crossover studies.3.2.2The patient must be at least 18 years and less than or equal to 65 years of age. Gender is not restricted. The stage or severity of the disease is not limited. Psoriasis must be diagnosed according to at least 1 internationally or nationally authorized diagnostic criterion. The international standard refers to the diagnostic criteria for psoriasis in the “Cecil Textbook of Medicine”. Domestic standard refers to the diagnostic criteria for psoriasis in “Skins and Venereology”, “Clinical Dermatology”, or “Integrated Chinese, and Western Medicine Skin Dermatology”. The groups were well balanced when they Were enrolled.3.2.3The intervention group will use AB or AS acupoint injection therapy, while the control group adopts the placebo, drugs ), other TCM therapies such as acupuncture, cupping and so on, or other active treatments, no treatment, diet and exercise therapy. The intervention group includes either a single AB or AS acupoint injection therapy or a combination of AB or AS acupoint injection therapy and main therapies . It does not include the combination of AB or AS acupoint injection therapy with different types of TCM adjuvant therapy .3.2.4Primary outcomes1)Measurements were based on the PASI score. Healing: the reduction rate of PASI score after treatment was >90%. Significant effect: the reduction rate of PASI score after treatment was 60% to 89%. Effective: the decline in PASI scores ranged from 20% to 59%. Invalid: PASI score reduction rate <20%. Reduction rate of PASI score = (pretreatment PASI score – post-treatment PASI score)/pre-treatment PASI score × 100%. Total effective rate = (number of recovered cases + number of effective cases + number of effective cases)/total number of cases 100%.2)The proportion of participants with serious adverse effects. We will use the definition of severe adverse effects from the International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, which includes death, life-threatening events, initial or prolonged hospitalization, and adverse events requiring intervention to prevent permanent impairment or damage.Secondary outcomes1)Quality of life measured by a specific scale. Available validated scales are the Dermatology Life Quality Index, Skindex, Psoriasis Disability Index, or Psoriasis Symptom Inventory (PSI).2)Itching score.3)The proportions of participants with adverse effects.3.3The systematic review will search all randomized controlled trials (RCTs) by searching the following database: PubMed, EMBASE, Web of Science, Cochrane Controlled Trials Register, and 4 Chinese databases  with a language limitation of English and Chinese until March 2020. In addition, the related reference lists of identified publications, meeting minutes, gray literature, and unpublished literature for eligible studies which will be searched by us. The search terms included autologous blood, autohemotherapy, self-blood, acupoint, injection, psoriasis, and psoriasis vulgaris.The specific search strategy performed in PubMed is presented in Table 3.43.4.1All potential relevant clinical studies will be screened according to their titles, abstracts, keywords by 2 reviewers (QYW and ML) at the same time independently after removing duplicates and nonclinical trials. And then the intensive reading of full text could authenticate for further assessment if there are studies that could not be clearly included based on both titles and abstracts. Once any disagreement occurs, a decision will be resolved through discussion among the 2 reviewers (QYW and ML), or argument will be adjudicated by a third reviewer (PSH). Details of entire study selection procedure are summarized in flow chart Fig. .3.4.2Before data extraction, a standard data extraction form containing specified outcomes will be created according to the inclusion. Two reviewers (QYW and ML) will extract data independently from each trial: article general information, participants’ characteristics , number of participants on each group, intervention measure of trial and control group, outcomes measures. Any disagreements will be resolved through discussion or consultation between the 2 reviewers if necessary, final determination from a third reviewer (PSH) will be sought. When certain dates are not provided in the paper, we will contact the original author for the needed information.3.4.3Two reviewers (QYW and ML) will evaluate the risk of bias according to the risk of bias (ROB) tool to assess the bias risk of all included studies. We will assess the risk of bias in the following areas: random sequence generation, concealment of allocation sequences, blindness of participants and staff and their result evaluators, incomplete outcome data, selective outcome reports, and other sources of bias. This review will use L, U, and H as the key to these assessments, where L (low) indicates a lower risk of bias, U (unclear) indicates an uncertain risk of bias, and H (high) indicates a higher risk of bias. All reviewers will resolve their differences through discussions. The information contained in the study on the risk of biased assessments will be summarized in a tabular format with a critical discussion of results and impacts. If the information is unclear, we will try to contact the author for the republished articles, and we will only select the original text.3.4.4Data analysis and quantitative data synthesis will be performed using RevMan V.5.3. For continuous data, if there is no heterogeneity, we will use mean difference or standard mean difference to measure the therapeutic effect of 95% CIs. If significant heterogeneity is found, a random-effects model will be used. For the 2-category data, we will use the 95% CIs hazard ratio (RR) for analysis. We will include data from parallel-group design studies for meta-analysis. Only the first phase of the data will be included in the random crossover trial. In these trials, participants were randomly divided into 2 intervention groups and individual measurements for each outcome of each participant were collected and analyzed. The result will be expressed as the RR of the binary data and the standard mean difference of the continuous data.3.4.5Only the first experimental period date will be considered in randomized cross-over trials. In these trials, participants were randomly divided into 2 intervention groups and individual measurements for each outcome of each participant were collected and analyzed.3.4.6Referring to the Cochrane handbook for systematic reviews of intervention, if there are insufficient details or missing data in relation to the characteristics of the studies, 2 reviewers (QYW and ML) will attempt to contact both senior and/or corresponding author of articles through email or telephone for further information about any missing data or unclear information. If it is not possible to contact the original authors or obtain sufficient information, we will exclude such studies and only analyze the available data and describe it in the discussion. The potential impact of insufficient data on the review results will be took into account in the discussion section.3.4.7If our review has a sufficient number of included trials that are available in the meta-analysis. If more than 10 trials are included, the funnel plot will be used to assess the reported bias. If the funnel plot is found to be asymmetrical, analyze the cause using the Egger method. We will include all eligible trials regardless of the quality of the method.3.4.82 test is less than 50%, a fixed-effect model is used for data synthesis. If the I2 test is between 50% and 75%, a random-effects model is used for data synthesis. If the I2 test is higher than 75%, we will investigate the possible causes from a clinical and methodological perspective and provide a descriptive analysis or a subgroup analysis.We will use RevMan V.5.3. for all statistical analyses. If the I3.4.9There is no pre-subgroup plan for this project. When there are significant differences, we will carry out subgroup analysis according to the control group intervention measures and different results.3.4.10When there are enough studies, we will conduct sensitivity analysis of the main results according to the sample size, heterogeneous quality and statistical model (random or fixed effect model) to explore the robustness of the conclusions. Sensitivity analysis will be conducted by removing low-quality studies. If heterogeneity still exists after subgroup analysis, a meta-analysis will be performed again after excluding low-quality tests according to STRICTA checklist. The results of these meta-analyses will be compared and discussed in terms of their sample size, the strength of the evidence, and their impact on the size of the merger effect. However, if there is a high risk of bias in all included studies, we will not conduct sensitivity analysis.3.4.11 The quality of evidence will be classified as “very low”, “low”, “medium” or “high”. Any differences will be resolved by consensus or with the third review author (PSH).We will assess the evidence quality and credibility of the major findings (major outcomes and adverse events) of the studies included in our review, based on recommendations, assessments, development and grading of assessment (GRADE) guidelines.3.5The systematic review and meta-analysis do not require to pass the ethics approval, because we include published articles rather than directly adopt interventions in participants. Ultimately, we will publish the results at a peer-reviewed journal follow as our study is completed.4PV is a refractory and relapsing skin disease that affects the physical and mental health of patients and leads to poor quality of life. Current conventional systemic therapy shows a large side effect, can not be used for a long time, easy to relapse after drug withdrawal, long-term efficacy is poor. At present, traditional Chinese medicine treatment of PV effective, can alleviate symptoms, improve the quality of life, stabilize the condition, prolong the remission period.Domestic and foreign research has proven that alternative treatments such as AB or AS acupoint injection therapy are effective and safe for the treatment of PV, with operability, low-cost, and broad prospects. However, systematic statistical evidence is still lacking. According to the Cochrane method, this study is based on the analysis of clinical RCT evidence at home and abroad, searching and screening the main electronic literature database with evidence-based medical evidence, providing clinicians with more convincing evidence in decision-making, to better guide clinical treatment.Conceptualization: Qiuyue Wang, Pingsheng Hao.Data curation: Qiuyue Wang, Mao Li.Investigation: Qian Luo.Methodology: Qiuyue Wang, Mao Li.Resources: Qiuyue Wang.Software: Qiuyue Wang, Mao Li.Supervision: Pingsheng Hao.Validation: Xingxin Hu.Writing – original draft: Qiuyue Wang.Writing – review & editing: Pingsheng Hao.


Purpose: The aim of this research was to describe, examine, and compare the level of physical fitness, physical activity, and sedentary behaviour in pupils aged 6–13 in the Region of Murcia, Spain, in accordance with weight status. Methods: A total of 370 children (166 girls and 204 boys) aged 6–13  from the Region of Murcia participated in this descriptive and cross-sectional study. Some anthropometric parameters such as body mass index, waist circumference, as well as skinfold measurements were determined. ALPHA-FIT Test Battery was used to evaluate physical fitness. Krece Plus Short Test was used to measure physical activity level and sedentary behaviour. Results: 52.4% of the children presented excess weight . Regarding boys, statistically significant differences were found for cardiorespiratory fitness (p < 0.001), relative handgrip strength (p < 0.001), lower muscular strength (p < 0.001), speed-agility (p < 0.001), as well as sport activities hours (p = 0.001) among the three weight status groups . As for girls, statistically significant differences were found for cardiorespiratory fitness (p = 0.004), relative handgrip strength (p < 0.001), lower muscular strength (p < 0.001), sport activities hours (p = 0.005), as well as physical activity level (assessed by Krece Plus Test) (p = 0.017). A negative statistically significant correlation was found between body mass index and cardiorespiratory fitness (rho = −0.389), lower muscular strength, (rho = −0.340), and relative handgrip strength (rho = −0.547). At the same time, a positive statistically significant relationship between body mass index and the time spent in speed-agility (rho = 0.263) was shown. Regarding waist circumference and body fat percentage, similar relationships were identified. Moreover, a greater probability of having higher cardiorespiratory fitness , relative handgrip strength , more hours of sport activities , and physical activity level (assessed by Krece Plus Test)  was noted in the normal weight group. Conclusions: Children that presented normal weight achieved higher results for health-related physical fitness and physical activity than those with excess weight; this was, however, not found to be the case for sedentary behaviour. The authors emphasise the need for changes in public policies and school-based intervention programmes to develop higher levels of both PF and PA in overweight and obese children. The global prevalence of overweight and obesity in children and adolescents is alarmingly high . In SpaiPhysical fitness (PF) is recognised as an independent predictor of cardiovascular disease and adulthood mortality ,7. Poor On the other hand, obesity has been associated with different behaviours connected with low levels of physical activity (PA)  and sedeIn Spain, studies have been performed to examine the relationship between weight status and PA level ,21, PF ,23, or eOn the other hand, it must not be forgotten that the process of cardiovascular disease begins in childhood, and associated risk factors, including insufficiency of PA and obesity, track through adolescence into adulthood, resulting in an increased risk of premature mortality . In thisAccording to the evidence and the lack of local information in most parts of Spain, particularly in the Region of Murcia, the aim of this study was to describe, compare, and analyse the level of PF, PA, and SB in children aged 6–13 in the Region of Murcia, in accordance with weight status.A descriptive and cross-sectional study was conducted in six primary schools in the Region of Murcia (Spain). A total of 370 children (166 girls and 204 boys) aged 6 to 13  with similar socio-demographic features participated. In terms of age groups, 230 schoolchildren were between 6–9 (118 boys and 112 girls) years of age. In the age group of 10–13, 140 schoolchildren were found (86 boys and 54 girls). Non-probability sampling was the technique used in this study. All children were given the option to take part in the study.In order to enrol a child in the study, parental/legal guardian permission was requested. Both parents and children were duly informed through a document explaining the aim of the study and the procedures involved. Students who were exempted from physical education classes were not included.The present study was approved by the Bioethics Committee of the University of Murcia (ID 2218/2018). It was conducted following the Helsinki Declaration, respecting the human rights of the participants.2). Besides, BMI z-score was computed using the age-specific and sex-specific thresholds provided by the World Health Organization (WHO) [In order to determine the participants’ height, a transportable height rod with a precision of 0.1 cm  was used. Body weight was determined with a body composition analyser with precision of 0.1 kg . Body Mass index (BMI) was computed from the ratio between body weight (kg) and the children’s height squared (mon (WHO)  in orderon (WHO) . To calcon (WHO)  and fat-The ALPHA-FIT Test Battery included PF tests for the youth population , which wTo measure upper body muscular fitness, we measured handgrip strength by means of a hand dynamometer with adjustable grip . To begin with, the children were given a brief explanation. We regulated the dynamometer to meet the child’s hand size as it had been formerly recommended . This teOn the other hand, in order to calculate lower body muscular fitness, a standing broad jump was executed. Subjects were asked to stand with feet together behind the starting line. The subject had to jump forward as far as possible. The distance was measured from the take-off line to the landing point (back of the heels). Two attempts were performed and the best result was recorded (in cm) . Speed-agility was measured with the 4 × 10 m Shuttle Run Test. The test required the participants to run back and forth between two lines (10 m of distance between them) as fast as possible. When the acoustic signal was sounded, the participants ran to the other line and took (the first time) or exchanges (the following times) a sponge that was formerly located behind the lines. The test ended when the participant crossed the finish line with one foot. Two attempts were made and the quickest result was recorded (in seconds) . The Krece Plus Short Test was validated for youths aged 4–14 in the EnKid Study  and was n ≤ 50) or Kolmogorov-Smirnov tests with Lilliefors correction, and the homogeneity of variances by the Levene test.Frequencies and percentages (%) are presented for all qualitative variables and means (M) and standard deviation (SD) are described for all quantitative variables. Data normality was verified by Shapiro-Wilk , according to the normality assumption. Likewise, post hoc analyses were carried out in order to test differences between groups. In the case of variables without assumption of normality, the Mann-Whitney U test with Bonferroni correction was executed. Conversely, for normal variables, Tukey’s HSD or the Dunnett T3 test, depending on the homogeneity of the variances, was used. Effect size was estimated by Cohen’s d . The relationships between quantitative variables were also identified using Spearman’s rho (ρ). Besides, multinomial logistic regression was performed to predict the probability of getting different results according to the weight status. Finally, data analysis was performed using the software SPSS  for Windows (version 24.0). Statistical significance was denoted with a p-value ≤ 0.050.Consequently, the data were examined with the Kruskal-Wallis n = 104), while 24.3% had obesity (n = 90). Furthermore, 52.4% of the pupils presented excess weight (n = 194).Frequencies and percentages of WHO weight status categories are indicated in p < 0.001) between obesity and normal weight peers were found. In the case of girls, the normal weight group had higher CRF, relative handgrip strength, lower muscular strength, sport activity hours, as well as PA level (assessed by Krece Plus Test). Furthermore, post hoc comparisons only showed statistically significant differences among the normal weight group and the two groups with excess weight for relative handgrip strength. Notwithstanding, post hoc analyses only indicated statistically significant differences between the normal weight and obesity groups for CRF, relative handgrip strength, sports activity hours, and PA level (assessed by Krece Plus Test).Data of age, anthropometric characteristics, PF tests, screen time, sport activities hours, and Test Krece Plus score of the sample in accordance with different weight status categories  and sex are shown in rho = −0.389) and standing broad jump, (rho = −0.340) and strong for the relative handgrip strength (rho = −0.547). At the same time, a positive statistically significant relationship between BMI and the time spent in 4 × 10 m Shuttle Run Test (rho = 0.263) was shown. Regarding PA, a negative statistically significant correlation was observed between BMI and sport activity hours (rho = −0.178) and the Krece Plus Test score (rho = −0.141); both correlations being very low. Regarding WC and %BF, relationships similar to those found for BMI and the different variables of PF, PA, and SB were identified.On the other hand, 95% = 1.38–1.82) was observed. In the case of handgrip strength, normal weight group had a lower probability of having higher handgrip strength ; that not being the case for relative handgrip strength . Similarly, normal weight participants had a lower probability of spending more time in the 4x10m Shuttle Run Test  than the obesity group. Regarding PA patterns, the normal weight group presented higher possibilities of doing more hours of sport activities , and a higher score of PA level (assessed by Krece Plus Test)  than their obese counterparts.Lastly, The aim of this study was to describe, examine, and compare the level of PF and PA of pupils aged 6–13 in the Region of Murcia, related to sex and weight status. The results suggest that obese and overweight participants had lower results for health-related PF, sport activity hours, and PA level (measured by Krece Plus Short Test); this was not the case for screen time. Likewise, there were negative relationships between all anthropometric variables  and Krece Plus Short Test, sport activities hours, CRF, upper, and lower muscular fitness and speed-agility. Similarly, normal weight participants were more likely to have superior results on PF tests, as well as more sport activity hours than obese participants.Taking WHO cut-off points for weight status into consideration, in all the sample analysed, it was found that one out of five children had excess weight, obtaining very close values between boys and girls. If we consider the results published in the last ALADINO study in Spain , the datThe results of the PF tests showed that obese subjects presented lower values than normal weight participants on tests that required acceleration of body mass. Hence, obese subjects had lower values of CRF compared to the other groups (in both girls and boys), which is similar to the findings described in former studies ,39,40,41In addition, the Krece Plus Short Test offered higher scores for both boys and girls  for participants with normal weight . These results agree with those attained by Serra et al.  in the EAs a consequence, obesity in youth and the rise in prevalence of excess weight is also related to the increasing amount of screen time . NeverthOur results advocate the need for an increase in both CRF and muscular fitness in children with obesity in order to foster autonomy and engagement in physical activity and programmes designed to raise quality of life . MoreoveThis study has certain limitations. One the one hand, this research had a cross-sectional design. For this reason, it is not possible to conclude that the observed associations reveal causal relationships. Another limitation relates to the lack of information on the physical development of children. For instance, Tanner Stage, as a measure of maturity stage, could have offered a superior adjusted figure of CRF, since evidence of its usage to control for fitness testing has been found . Lastly,Regarding the strengths that characterise our study, even though BMI is generally used to identify overweight and obesity among children, we examined several anthropometric parameters, such as WHtR, WC, or %BF, giving us a better understanding of childhood obesity. This choice was justified on the basis of previously established recommendations, which indicate that BMI assessment should be accompanied by indices of body shape  and other aspects  to effectively determine individual risk . SimilarWhen comparing weight status, children that presented normal weight achieved higher results in health-related PF and PA than children in the other groups (overweight and obese). However, this did not occur in the case of the handgrip strength test, due to the fact that the body weight of the participants was not considered. In terms of adiposity and WC, a negative relation with PF and PA was also verified. Nevertheless, for SB, this was not found to be the case with respect to the anthropometric parameters.The authors emphasise the need for changes in public policies and school-based intervention programmes to develop higher levels of both PF and PA in overweight and obese children so as to counteract the adverse health effects caused by excess weight. Moreover, these results can be implemented in planning structured and tailored intervention programs to prevent overweight issues and obesity in children. These intervention programs should also focus on motor skill improvement, particularly when children do not practise sports in a club environment, because if they do not participate in directed or regulated activities, it will be more difficult for them to engage in PA on a regular basis.


Objectives: Gout is an independent cardiovascular (CV) risk factor with significant morbidity and mortality. We aimed to estimate the prevalence of gout, characteristics and management in a hospitalized population for CV disease, a topic that remains to be defined.Methods: An observational, descriptive, cross-sectional study was carried out in patients admitted for CV events in the Cardiology, Neurology, and Vascular Surgery units of a tertiary center. Patients were selected following a non-consecutive, systematic sampling. Data about CV disease and gout were obtained from face-to-face interviews and patients' records. Gout diagnosis was established using the 2015 ACR/EULAR clinical classification criteria. The registration rate of gout was assessed by auditing patients' records and hospital discharge reports of CV events from the units of interest in the previous 2 years. To predict the presence of gout, multivariate logistic regression models were built to study the possible explanatory variables.Results: Two hundred and sixty six participants were recruited, predominantly males (69.9%) and Caucasians (96.6%) with a mean age of 68 years. Gout was identified in 40 individuals; thus, the prevalence was 15.0% (95% CI 10.9–19.2%). In 35% of cases, the diagnosis was absent from patients' records. Gout was found in 1.4–2.6% of hospital discharge reports of CV events, also indicating under-registration. The disease was long-standing, but with low reported rates of flares, involved joints, and tophi. At admission, only half of the gout patients were on urate-lowering therapy, being 38.5% of them on serum urate <6 mg/dl. The only independent predictor of gout was the existence of previous hyperuricemia (median serum urate in previous 5 years ≥7 mg/dl), with an odds ratio of 2.9 (95% CI 1.2–7.1); if hyperuricemia is not included in the model, the only independent predictor was chronic kidney disease .Conclusion: Gout is highly prevalent among patients admitted for CV events, with significant lack of awareness and suboptimal management, despite being a well-established independent CV risk factor. Gout is a disease of monosodium urate (MSU) crystal deposition. It is the most frequent type of inflammatory arthritis in Western countries, with prevalence rates of up to 1% of the adult population and up to 5% of males aged 65 and over. Concerning Spain, a prevalence rate of 2.4% has been recently announced  or dietary factors, such as elevated intake of fructose, proteins, purines, and alcohol. However, urate underexcretion, especially in the kidneys but also in the gut, constitutes the principal determinant of hyperuricemia . Also inMSU crystals form and deposit in tissues when SU levels remain above its saturation point (7 mg/dl)—the threshold for hyperuricemia . MSU cryThere is a firm association between gout and cardiovascular (CV) disease. Gouty patients develop atherosclerotic complications more frequently than the general population. This association was considered related to the traditional CV risk factors that are common in gout , 15. HowThere is cumulative evidence that hyperuricemia has a pathogenic role in CV disease . BesidesAs with other chronic inflammatory diseases , early aAs the evidence supports the hypothesis that gout is an independent CV risk factor, with derived morbidity and mortality potentially avoidable, we consider it necessary and relevant to gauge the frequency and characterization of gout in patients admitted for CV events. The confirmation of high prevalence with suboptimal management would impact the interpretation and approach to both hyperuricemia-gout and CV disease. The CV risk control strategies initiated at the time of the event (secondary prevention)—usually focused on blood pressure, plasma lipids, and platelet activity—might benefit from proper gout management, based on the available evidence , 44.The primary objective of this study was to estimate the prevalence of gout in patients admitted for CV events. The secondary objectives were (i) to assess the registration rate of gout in patients' records and discharge reports of CV events, (ii) to describe the characteristics and management of gout in this population, and (iii) to identify predictors for the presence of gout in patients with established CV disease. Our hypotheses were (a) that prevalence of gout in patients admitted for CV events would be markedly higher than in the general population, (b) that gout would be under-registered both in patients' records and discharge reports, and (c) that gout management in CV patients would remain suboptimal, with SU levels above the therapeutic target and insufficient use of ULT.We conducted an observational, descriptive, cross-sectional study in patients admitted for CV events in the Cardiology, Neurology, and Vascular Surgery units of our hospital, over 10 months (January to October 2018). It is an academic tertiary public hospital with a population coverage of 267,960 inhabitants (2017), eminently urban and with a slight female predominance (+4.4%). The coverage is broader, as Vascular Surgery and Neurology are reference units for other health departments, precisely in the care of atherosclerotic disease.Adult patients hospitalized for a CV event were eligible. Events were defined by the clinical diagnosis registered in patients' records, as (i) acute coronary syndrome or coronary artery disease that requires revascularization, (ii) new or congestive heart failure, (iii) stroke or transient ischemic attack, or (iv) acute or chronic peripheral artery disease that requires revascularization. Patients were excluded if they presented a background of other inflammatory arthritis to avoid misclassification. Other exclusion criteria were declination or inability to sign the informed consent form. If excluded, minimal data  were collected to ensure representativeness.We followed a non-consecutive, systematic sampling. Screening for enrollment was applied to all patients admitted to the Cardiology unit the second week of odd months, the Neurology unit the fourth week of odd months, and to the Vascular Surgery unit the third week of even months.®) and specialized care (Orion Clinic®) electronic records and face-to-face interviews.Study variables were prospectively collected using a pre-established data collection form. Sources were primary care  at patients' records or defined by a face-to-face interview. For the interview, 2015 ACR/EULAR clinical classification criteria were used . SensitiTo assess the registration rate of gout, we compared the face-to-face interviews with the patients' records. Likewise, we examined discharge reports by CV events from the units of interest in 2016 and 2017 with respect to the inclusion of gout as a secondary diagnosis ; these data were provided by the Admissions and Clinical Documentation unit of our hospital.2 in the previous 2 years or at admission if previous data were missing, estimated according to CKD-EPI formula ; median SU levels in the previous 5 years (mg/dl); hyperuricemia (defined as a median SU level of ≥7 mg/dl in the previous 5 years or the level at admission if previous data were missing); being at the SU target (<6 mg/dl) ; and oth formula .The study complies with the Declaration of Helsinki and was evaluated and approved by the HGUA-ISABIAL Clinical Research and Ethics Committee [2018/07 act]. Informed consent was obtained from all subjects . This investigation is reported according to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement  and goutAt the time of the study design, the prevalence of gout in Spain was undetermined. Later, a general population-based study communicated a prevalence of 2.4% . A formeQuantitative variables are shown as measures of central tendency (mean and median) with dispersion , and qualitative variables such as frequencies and percentages. Age was taken as continuous and categorized by tertiles.t-test, chi-square, and Fisher's exact test were used.For the primary outcome variable , 95% confidence intervals (95% CI) were calculated. For subgroup comparisons , Student's To assess which CV variables predict the presence of gout, a univariate analysis was initially performed for each explanatory variable with a chi-square test, and odds ratios were estimated by simple logistic regression. Those explanatory variables that were statistically significant for gout were included in a multivariate logistic regression model.® Version 25 . For the significance level, a p-value <0.05 was established.Statistical analyses were performed using IBM SPSS Statisticsn = 16), inability to sign the consent (n = 9), and declination of participation (n = 8).Two hundred and ninety nine patients were screened for enrollment. After we excluded 33, the final study sample was 266 participants. The reasons for exclusion were a background of other types of arthritis (n = 126), stroke or transient ischemic attack , acute coronary syndrome , and heart failure .The general characteristics of the study participants are shown in n = 20) or crystal-proven . Thus, in the remaining 14 patients (35.0%), the diagnosis was unregistered but confirmed by interview. Rheumatology had previously seen all crystal-proven gout patients. Regarding discharge reports from the units of interest in 2016 and 2017 , gout was coded as a secondary diagnosis in 19 (1.4%) and 33 (2.6%), respectively, also indicating under-registration.Gout was identified in 40 individuals . Prior gout diagnosis in records was found in 26 patients (65.0%), either clinical-based .The distribution of gout across age groups, gender, and type of CV event is shown in The disease was long-standing though low numbers of flares and involved joints were referred . Tophi wSimple and multivariate logistic regression models are shown in This is the first field study attempting to estimate the prevalence of gout in patients admitted for CV events . Following chart reviews and face-to-face interviews using the ACR/EULAR clinical classification criteria , the disIn Western Europe and North America, the prevalence of gout in adults ranges between 0.3 and 4.8% . In SpaiCompared to population-based or claims databases, a field study ensures high accuracy, here given the good performance that 2015 ACR/EULAR clinical criteria have shown for epidemiological studies in the absence of crystal-proven diagnosis . To reinSecondary CV prevention strategies are initiated when the first clinical event occurs. They aim to make a very high CV risk subside by reaching stricter lipid levels  and greater control of the atherothrombotic process . However, many patients still develop new events. The role of inflammation—measured by high-sensitivity C-reactive protein—as an independent risk factor  and the Gout is not included as a variable of interest in the different guidelines for CV management, which are firmly focused on traditional risk factors. Some of them include recommendations only to check SU levels, and in the case of heart failure following use of diuretics, the management of SU is guided , 61. TheGout was noted as long-standing but with a low number of flares and joints involved. In gout, flares are usually spaced at early stages, and as the crystal deposit grows, they become more frequent. Although a flare is usually intense enough to remember it, the number of subsequent episodes might not be retained in the same way, entailing a potential recall bias. Tophi were detected in 7.7% of patients, a rate considered low for a population with long-standing gout. This is probably an observer bias, as they were assessed by physical exam but not confirmed by imaging or sampling . DedicatUse of ULT and SU levels were inadequate in the sample. When admitted for CV events, patients initiate an intensive control of traditional CV risk factors. However, the poor management of gout observed is an added risk. Pagidipati et al.  found thSome strengths and limitations must be addressed. The sample size of this field study may be considered small. However, the minimal size was pre-calculated with respect to available prevalence estimates. Increasing numbers would add precision to the 95% CI estimation, though the current prediction of one gout patient in every five to ten CV inpatients is relevant and quite above the numbers in the general population . The value of a field study is to make disease diagnoses more correct, in contrast to medical records-based studies. Gout diagnosis by crystals was not feasible due to the epidemiological nature of the study, but the 2015 ACR/EULAR clinical criteria  have shoGout was present in 15% of hospitalized patients for CV events, a prevalence six times higher than in the Spanish adult population and hospital records. A significant rate of under-registration was detected, both in patients' records and discharge reports. Hyperuricemia was the only predictor of gout in admitted CV population; if the SU level is not available, CKD would be taken as a predictor. Gout was long-standing but with a low number of flares and involved joints, and suboptimal management was identified. Therefore, this field study was able to uncover a subpopulation with high CV risk, candidates for both secondary CV prevention strategies and dedicated gout management.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 Alicante Institute of Sanitary and Biomedical Research (ISABIAL) (2018/07 act). The patients/participants provided their written informed consent to participate in this study.IC, MG-G, and MA designed the study project and analyzed and interpreted the results. IC and MG-G acquired the data. MG-G and MA wrote the first draft of the manuscript. All authors contributed, revised, and approved the final version. All authors contributed to the article and approved the submitted version.MA declares consultancies and speaking fees from Menarini, Grünenthal, and Horizon. The remaining 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.


Despite recent studies linking pubertal processes to brain development, as well as research demonstrating the importance of both pubertal and neurodevelopmental processes for adolescent mental health, there is limited knowledge of the full pathways and mechanisms behind the emergence of mental illnesses such as depression and anxiety disorders in adolescence. The Transitions in Adolescent Girls (TAG) study aims to understand the complex relationships between pubertal development, brain structure and connectivity, the behavioral and neural correlates of social and self-perception processes, and adolescent mental health in female adolescents.The TAG study includes 174 female adolescents aged 10.0 to 13.0 years, recruited from the local community in Lane County, Oregon, USA. The participants, along with a parent/guardian, will complete three waves of assessment over the course of 3 years; the third wave is currently underway. Each wave includes collection of four saliva samples (one per week) and one hair sample for the assessment of hormone levels and immune factors; an MRI session including structural, diffusion, resting-state functional and task-based functional scans; the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), a diagnostic interview on current and lifetime mental health; production of a short self-narrative video; and measurement of height, weight, and waist circumference. The functional MRI tasks include a self-evaluation paradigm and a self-disclosure paradigm. In addition, adolescents and their parents/guardians complete a number of surveys to report on the adolescent's pubertal development, mental health, social environment and life events; adolescents also report on various indices of self-perception and social-emotional functioning.The knowledge gained from this study will include developmental trajectories of pubertal, neurological, and social processes and their roles as mechanisms in predicting emergence of mental illness in female adolescents. This knowledge will help identify modifiable, developmentally specific risk factors as targets for early intervention and prevention efforts. Puberty and adolescence represent a time of major change in several domains, including physical, neurological, and social development. These changes are important for adolescents to gain greater independence and develop skills for engagement in peer and romantic relationships. However, the transition into adolescence is also a vulnerable period for mental health, with sharp increases in the incidence of many mental disorders, including depression, anxiety disorders, eating disorders, and substance abuse –3.There is currently only limited knowledge on which mechanisms underlie the increased vulnerability for mental illness, as well as on how to identify those most at risk during this developmental phase. Potential mechanisms include pubertal processes, and also behavioral and neural development related to social processes. Pubertal processes include dramatic increases in levels of adrenal and gonadal hormones, as well as physical changes, both of which unfold in unique ways for male and female adolescents. Research is starting to demonstrate that these pubertal processes are linked with processes of structural and functional brain development, often in sex-specific ways –6. FurthAt the same time, adolescence is a time of social reorientation and shifts in social behavior, proposed to be mediated by changes in social brain function , 10. UndMore knowledge about normative and atypical developmental trajectories and individual differences in the above-mentioned pubertal, neurological, and social processes will help inform prevention and early intervention for mental health issues. It will help to answer key questions about which mechanisms should be targets for prevention and early intervention efforts, as well as which adolescents to focus these efforts on and at which point in development. The Transitions in Adolescent Girls (TAG) study was designed to gain such knowledge, with the broad aim to understand the complex relationships between pubertal development, brain structure and connectivity, the behavioral and neural correlates of social and self-perception processes, and mental health in female adolescents. The study focuses on female adolescents only because pubertal processes, including hormonal and physical changes, differ greatly between the sexes . In addiThe TAG study has four specific aims, as follows.Comprehensively characterize associations within individuals over time in the biological changes associated with puberty. To do so, we will track how indices of pubertal development  covary with changes in task-independent measures of brain development .Describe how indices of pubertal change and changes in social cognition and associated brain function also covary over time. To do so, self-evaluation and affiliation will be assessed at both behavioral and neural levels.Examine how changes in social cognition and associated brain function covary with adolescent-emergent mental health problems, in particular symptoms of depression, anxiety, and deliberate self-harm.Test a set of proposed mediation (path) models whereby correlated changes in task-independent brain structure and connectivity, as well as social cognitive brain functioning and behavior, mediate the relationship between pubertal development and associated mental health problems during early adolescence.174 female adolescents aged 10.0 to 13.0 years were recruited from the community, together with one of their parents/guardians. See Measures below) when there were possible discrepancies. This distribution shows higher racial and ethnic diversity than in the overall population of Lane County, OR, US; for example, 81.2% of the population was non-Hispanic white and 4.6% were multiracial  on a demographic questionnaire and cross-checked with child report during a diagnostic interview  identified as female.At Time 1, 1.7% of participating parents/guardians had less than high school education, 13.8% had completed high school or GED, 8.2% had done some college but without a degree, 5.2% had completed trade, technical or vocational training, 18.4% had an associate's degree, 25.3% had a bachelor's degree, 23.0% had a master's, professional or doctoral degree, and 3.4% did not report their education level.M age 11.64, SD = 0.81), the second wave (T2) took place approximately 18 months after T1 , and the third wave  will take place approximately 18 months after T2. 163 participants completed T2 (retention rate of 94%), the average time between T1 and T2 was 1.57 years (SD = 0.12 years). At each wave participants will complete two laboratory sessions (each 2–3 h in length) 1 month apart, as well as a questionnaire and saliva sampling component at home (see Measures). Sessions were on average 33 days apart at T1 and 32 days at T2.This longitudinal study will take place over the course of approximately 3 years, and includes three testing waves. The first wave (T1) took place when participants were 10.0 to 13.0 years old . At the end of the first session, adolescents and their parents/guardians are given the materials to complete saliva samples at home. Adolescents are asked to collect four saliva samples, one per week, between the two lab sessions. About a month later, participants complete the second session, including the MRI scan, the remaining questionnaires, the self-narrative video (This is me task), and hair sampling and anthropometric measures (see Measures for more details on each component). Procedures described in this paragraph are followed for all three waves, although some questionnaires were added in subsequent waves.Parents/families who showed interest in the study were provided with information about the project and screened for eligibility over the phone. Those eligible were invited to the University of Oregon's Developmental Social Neuroscience laboratory. At the start of the first session parents/guardians provide written informed consent and children assent to participate. In the first session, participants complete a structured diagnostic interview and part of the questionnaires, and they receive instructions for saliva collection and preparation for the magnetic resonance imaging (MRI) scan . These are not described here in full because they are not part of the original protocol and they are presented as opportunities for additional research participation to the adolescents and their families.All scans are acquired using a Siemens Skyra 3.0 Tesla scanner at the Lewis Centre for Neuroimaging at the University of Oregon. Participants go through a mock scanning procedure at every wave, to (re)familiarize them with the scanner and reduce anxiety. At each wave, a T1-weighted structural scan is conducted first, followed by alternating runs of a self-evaluation functional MRI (fMRI) task and a resting-state functional paradigm; two runs of a self-disclosure fMRI task interspersed with a fieldmap; and finally, a diffusion-weighted imaging (DWI) paradigm. See 2, preceded by a non-diffusion-weighted scan (b = 0 s/mm2). The whole sequence is repeated with opposite phase encode direction (left-right and right-left) for the purpose of estimating B0 field offsets. Other parameters for this scan, as well as for the T1-weighted structural scan and resting-state fMRI scan can be found in Participants watch short videos during the structural and diffusion-weighted scans. Participants are asked to close their eyes during the resting-state scan and to not fall asleep (any observations of the participant not following these instructions are noted). Heart rate and breathing are monitored during the resting-state scan using a pulse monitor on the index finger and a breathing monitor across the waist. The sequence for diffusion-weighted images consists of scans in 64 gradient directions at b = 1,000 s/mmThe self-evaluation fMRI paradigm is based on our previous research on self-evaluation in adolescents . In thishttps://github.com/jflournoy/svcwords/tree/tag_protocol_paper).We selected adjectives based on a pilot sample of N = 100 (after exclusions) female Amazon Mechanical Turk (Mturk) participants, paid $1.50 each, who were required to be age 18–25 years , currently living in the United States, and native English speakers. We asked pilot participants to think about when they were in high school and rate themselves on target adjectives based on how well it described them during that time (6 response options from “Very Poorly” to “Very Well”). We also described two different types of high-status or popular adolescents  and asked them to rate themselves on each type using the same response options . Explorahttps://github.com/dsnlab/TAG-fMRI-tasks).Every trait adjective with corresponding question is presented for 4.7 s, participants can respond any time by pressing a button on a button box, and reaction times are recorded. The task uses a mixed event-related design and is split into two runs. Trait adjectives are nested within alternating “self-evaluation” and “change” blocks. Each block begins with a 5 s instruction cue , followed by five adjectives, each separated by a jittered blank screen presented for approximately 0.3 s; participants complete 10 blocks per run, 5 in each condition. Adjectives that were presented in the change condition in run 1, are presented in the self-evaluation condition in run 2 and vice versa. The order of adjectives is randomized. See In this task, participants agree/disagree with short statements about themselves , and subsequently choose either to disclose their answers to their best friend or to keep them private. If participants do not have a best friend they are comfortable sharing with, they are allowed to disclose to a partner or close relative. Half of the items have intimate content , and the other half have more superficial content , see Each statement is presented with the question to agree/disagree for 4.5 s, and with the question about disclosure for 3 s. The evaluative phase was separated from the disclosure phase by an average of 0.18 s, jittered about 0.02 s–0.70 s. A blank screen is shown in between statements for 2.59 s on average (range 1.00 s–14.75 s). Participants' reaction times are recorded. The task is split into 2 runs of 41 statements each. The presentation sequence was optimized to obtain maximal contrast detection between statement depth  and the number of pennies associated with the choices to share versus keep private . See At the end of the task, following the MRI scan, participants will be asked to disclose one of the items that they had chosen to share with their friend during the task. The item to disclose will be randomly chosen by the laboratory computer from a subset of items including both intimate and superficial items. Participants will be informed of this ahead of time. The first name of the friend is reported to check for consistency across waves, as well as their age. Finally, participants complete a short survey about the task  and affective  factors identified from the High Risk Social Challenge  Present and Lifetime Version Interview (K-SADS-PL) will be administered as a measure of mental health symptomatology and as an assessment of current and past episodes of psychopathology according to DSM-IV criteria . TrainedIn addition, self-harm will be examined in detail using an interview-format of the Deliberate Self Harm Inventory  with adAdolescents and parents/guardians are both asked to report on the adolescent's puberty-related physical development, mental health, the family environment, and stressful life experiences. In addition, adolescents complete self-reports on their self-knowledge/self-perception, understanding of mental states, affiliation/self-disclosure, social functioning, and emotion regulation and understanding. See Participants will be asked to collect four saliva samples of 2 ml each at home, in the weeks between the two laboratory sessions. Each sample will be provided through passive drool in the morning, directly after waking, one week apart, on a weekend day. This was done to account for shorter-term variations in the hormones and provide a more stable estimate of basal hormone levels, given that they fluctuate over the day and over the menstrual cycle. This was the preferred method  because menstrual cycles tend to be very irregular in early adolescence. Participants are instructed not to eat or brush their teeth before collecting the sample. Families will store the samples in their home freezer and bring it to their second lab session on ice in a cooler bag. Participants and their parents/guardians will be trained on how to collect and store the samples. They will record the time of day at collection and will report on illnesses and medication use in the 24 h before sample collection. Saliva samples are stored in a -80°C freezer in the lab until they are shipped (overnight on dry ice) to the Stress Physiology Investigative Team at the Iowa State University. There they are assayed in duplicate for dehydroepiandrosterone (DHEA), testosterone, and estradiol using Salimetrics Enzyme-Linked Immunosorbent Assay (ELISA) kits. Samples are rerun if the optical density coefficient of variation (CV) is greater than 7% and enough sample is left over to do so. All hormones for each participant are assayed on the same day to minimize freeze-thaw cycles. Moreover, all saliva samples from each participant are assayed on the same plate, to minimize variation in hormone concentrations that may be attributable to plate differences.via the passive drool method at session 1 of every wave to examine immune markers. Participants are instructed not to eat or drink anything 30 minutes before collection. Samples are stored at -80°C until they are shipped on dry ice to an external laboratory: the Primate Assay Laboratory, University of California, Davis where samples are assayed in duplicate. Saliva samples are first centrifuged twice at 10,000 g at room temperature (24°C) for 10 min each time to remove cells and mucus, but are not diluted. Samples have a total of one freeze/thaw cycle. A multiplex bead array assay technology  is used to assay for C-reactive protein (CRP), interleukin(IL)-2, IL-4, IL-6, IL-10, IL-12p70, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-ɣ) and secretory immunoglobulin A (SIgA) according to manufacturer's instructions.One additional 1.5 ml saliva sample is collected via the passive drool method using DNA Genotek Oragene DISCOVER (OGR-500) collection devices during the second lab session to index telomere length. Participants were instructed not to eat, drink, chew gum, or smoke for 30 min before collection. At T2, a saliva sample for telomere length was collected from the first 109 participants completing this wave using the same instructions. Finally, participants who completed a saliva sample for telomere length during T1 will complete another one at T3. Samples are stored at room temperature until shipped for telomere assay by The Blackburn Lab (http://biochemistry2.ucsf.edu/labs/blackburn/) at the University of California San Francisco where samples are assayed in triplicate. This telomere length measurement assay is adapted from the published original method  in the days before the lab visit.Height, weight, and waist circumference are measured to assess physical development. Measurements will be taken twice at each wave, once at the beginning of the second session and once at the end, to reduce measurement error. Height will be measured using a stadiometer and recorded in centimeters. Weight will be measured using a mechanical column scale with eye level beam and recorded in lbs. Participants are asked to remove shoes, coats and heavy clothing items. Waist circumference will be measured in centimeters using a flexible measuring tape directly on the skin, following the International Society for the Advancement of Kinanthropometry (ISAK) protocols.Adolescents completed the Wechsler Abbreviated Scale of Intelligence, Second Edition  as a meTo determine the sample size for the study, Monte Carlo power analyses were performed in Mplus, with each analysis using 1,000 replications, and an expected attrition rate of 10% per wave. At the time of writing, attrition was only 6.0% between T1 and T2 and 3% between T2 and T3. With the chosen sample size standardized direct effects of 0.235 or larger and moderating effects of 0.15 or larger have at least 80% chance of being statistically significant. For mediation analyses, standardized indirect effects of 0.09 or larger have greater than an 80% chance of statistical significance (assuming the standardized direct effects are at least 0.30).https://nda.nih.gov/edit_collection.html?id=2315. This includes all imaging data, salivary hormone data, most questionnaires, K-SADS-PL interview data, IQ, and anthropometrics.The majority of data collected as part of the study will be uploaded to the Research Domain Criteria database of the National Institute of Health and will be freely available to other researchers: https://github.com/dsnlab/TAG_scripts. However, preprocessing of the imaging data will follow standard pipelines, using fmriprep for fMRI data, freesurfer for structural MRI data, and FSL for diffusion MRI data. The self-evaluation fMRI task will be analyzed as an event-related design, so that both condition (“self” versus “change”) and adjective type can be modeled. The self-disclosure fMRI task will also be analyzed as an event-related design, so that both statement depth  and choice (to share or keep private) can be modeled. Any region-based analyses will be supplemented with whole-brain or network-based analyses. When conducting null hypothesis significance tests we set our statistical thresholds to at least p < .05 while correcting for multiple comparisons, although the precise approaches to do so might vary between empirical papers as standards in the field continue to evolve .Exact procedures used for processing and analysis of the data will depend on the aims and subset of data used in specific empirical papers. Scripts applied to run analyses will be placed on Github: Standardized pipelines have also been developed for the processing of the hormone data. Both salivary and hair samples are assayed in duplicate  and the mean of the duplicates will be used. Salivary hormone concentrations that are non-detectable and too low  will be substituted using the following rules: 1) If other samples from the participant  are also not detectable, the means of all samples are replaced with the lower limit of sensitivity . 2) If other samples from the participant are detectable and 50% or more of the remaining samples are below the lower interval of the inter-quartile range (IQR) for the distribution, the mean of the non-detectable sample is replaced with the lower limit of sensitivity for that assay. 3) If other samples from the participant are detectable and less than 50% of the remaining samples are below the IQR for the distribution, the mean of the non-detectable sample is considered missing. For mean salivary hormone concentrations that were too high , the following rules were applied: 1) If 50% or more of the remaining samples are above the upper IQR, the right censored sample is replaced with the upper limit of the standards for that assay . 2) If less than 50% of the remaining samples are above the upper IQR, the mean of the right censored sample is considered missing. Hair hormone concentrations (mean of the duplicates) that are non-detectable and too low, are substituted with the lower limit of sensitivity. Hair hormone concentrations that are non-detectable and right-censored are substituted with the upper limit of the standards for that assay. Hormone levels will be log-transformed to correct their non-Gaussian distribution.General analytic strategies will include latent growth curve models to examine correlated change among the variables of interest  and mediation models (aim 4). The growth curve models will compare linear and quadratic change over time and dual-process growth models will model relationships among variables of interest over time. Mediating effects will be assessed using mediation models appropriate for longitudinal data, which account for confounds such as trait-stability as well as wave-to-wave autocorrelation. To assess significance of indirect (mediated) effects, we will use bootstrap procedures to construct empirical standard errors to account for the skewed sampling distribution of the indirect path estimate. Where relevant and possible, we will examine the impact of demographic variables (such as gender identity or socioeconomic status) on the investigated associations by comparing models with and without these variables.Despite recent studies linking pubertal processes to brain development  and mentThe use of a community-based sample allows for maximum generalizability to the population of female adolescents.The longitudinal design with three time points per participant provides more power , and allows for the exploration of nonlinear trajectories and of developmentally-specific risk predictions.The focus on social and self-perception processes such as self-evaluation, affiliation, and understanding of mental states better captures adolescent-specific changes and challenges than for example a focus on basic affective processing.The information collected is both comprehensive  and spans several levels . Thereby the data is suitable to apply mediation models and examine mechanisms predicting risk for mental illness.The current study has several strengths:Altogether, this study will help to understand the complex relationships between pubertal development, brain structure and connectivity, the behavioral and neural correlates of social and self-perception processes, and female adolescent mental health. The ultimate goal is to inform novel, developmentally targeted and biologically informed prevention and intervention services that leverage developmental plasticity to help all children, as well as those at higher risk, navigate the transition into and through adolescence with fewer mental health problems.https://nda.nih.gov/edit_collection.html?id=2315. Other data used and/or analyzed during the current study are available from the principal investigator (JP) on reasonable request.The imaging data, salivary hormone data, questionnaires, K-SADS-PL interview data, IQ, and anthropometrics generated as part of this study will be made available through the Research Domain Criteria (RDoC) database: Ethics approval was received from Institutional Review Board of the University of Oregon. Parents/guardians give written informed consent and adolescents assent to participate, and this is repeated at every wave. Research staff have been trained in and follow protocols for confidentiality protection. Following Oregon state law, we have to break this confidentiality in case of non-accidental physical injury to the adolescent, or if we believe a person is in imminent danger of physical harm (including suicide). Risk assessment is done if the participant reports suicidal ideation, self-harm, or information indicating abuse. When risk assessment is done but breaking confidentiality is deemed unnecessary, we provide participants with resources for support.MEAB drafted the manuscript. JP and NA conceptualized the study and wrote the grant funding it. JP, NV, MLB, JEF, TC, JCF, BN, DC, AM, ES, and NA developed the study protocol, including stimulus/paradigm development and identification of surveys. MLB and NA trained K-SADS interviewers. MEAB, NV, MLB, JEF, TC, JCF, BN, DC, AM, SC, LH, BB, HN, and AH collected data. NV, MLB, JEF, TC, JCF, BN, DC, AM, SC, LH, BB, HN, AH, ES, NA, and JP wrote or revised sections of the manuscript. All authors approved the final version of the manuscript.The study described in this manuscript was funded by the National Institute of Mental Health . Author MLB was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number K01MH111951. Author TC was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR002371. Author DC was supported by the National Institutes of Health (F31CA232357). The funding agency had no role in the design of the study or the collection, analysis, and interpretation of data or in writing the manuscript, apart from their financial contribution; the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.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.