Learning burnout affects the positive development of college students. The present study aimed to investigate the relationship between family socioeconomic status (FSES) and learning burnout, as well as the mediation effect of subjective well-being and the moderation effect of resilience in this relation.A total of 550 Chinese college students from Yunnan completed a questionnaire measuring the research variables in this study.(1) After controlling for participants’ gender and age, FSES negatively, and significantly predicted learning burnout; (2) subjective well-being partially mediated the relationship between FSES and learning burnout; and (3) the direct effect of FSES on learning burnout and the mediation effect of subjective well-being was moderated by resilience. The level of learning burnout of individuals with low resilience increased significantly with the decrease of FSES, and the level of learning burnout of individuals with high resilience decreased significantly with the increase in subjective well-being.The present findings support the moderated mediation model underlying the relationship between FSES and learning burnout. This also has significant implications for formulating prevention and intervention measures on learning burnout among college students.First of all, this study used the cross-sectional study design, which cannot make a causal inference. In addition, the sample in this study is university students from Kunming, which may affect the popularity of the results. Learning burnout is a stress response that students are unable to cope with academic stress, and is an emotional, attitude, and behavioral failure that occurs when students are unable to meet their learning needs . LearninThe Family Stress Model shows that parents with high FSES have less mental and financial stress, more harmonious family relationships, and are more able to raise their children positively, giving them higher subjective well-being and life satisfaction so that there are more positive emotions toward study and life, which has an important impact on reducing students’ learning burnout . SubjectThe Resilience Framework Theory believes that the individual’s protective factors can reduce the negative impact of the risk factors in the external situation on the individual’s development through some means such as selective perception, reconstruction, changing the environment, and active coping . ResilieTo sum up, some studies have shown that FSES is an important factor affecting college students’ learning burnout, but the relationship between FSES and college students’ learning burnout and “how and when” FSES affects learning burnout still need to be further explored see . The indH1: Subjective well-being plays a mediating role between FSES and learning burnout among college students;H2: Resilience plays a moderating role in the mediating model of “FSES—subjective well-being—learning burnout” of college students.In the convenient sampling method, 600 college students were randomly selected for a cross-sectional questionnaire survey at a university in Kunming, Yunnan Province, and a total of 586 paper questionnaires were recovered. There were 550 valid questionnaires obtained after excluding incomplete questionnaires and gender-missing questionnaires with an effective rate of 93.86%. The sample included 200 boys (36.4%) and 350 girls (63.6%). Participants ranged in age from 17 to 26 years of age, with an average age of 19.927 years (SD = 1.559). Other demographic characteristics of the sample were shown in The questionnaire and methodology for this study were approved by the Human Research Ethics Committee of the Kunming Medical University .Scholars generally use the three variables of household income, parents’ education level, and occupation to synthesize the FSES index . The hou2/df = 1.428, p < 0.001, SRMR = 0.032, RMSEA = 0.055, GFI = 0.980, and TLI = 0.961, the Cronbach’s alpha coefficients of three weight scales were 0.793, 0.825, and 0.899.The Subjective Well-Being Questionnaire was compiled by Diener including life satisfaction  , positiv2/df = 4.146, p < 0.001, SRMR = 0.038, RMSEA = 0.058, GFI = 0.944, and TLI = 0.909, and both the absolute and value-added adaptation indexes were in the acceptable range. The Cronbach’s alpha coefficient for the Connor-Davidson Resilience Scale was 0.835.The Learning Burnout Scale (LBS) comprises 20 items including three dimensions: dejection , improper behavior strength , reduced personal accomplishment . The questionnaire used a five-point Likert scale ranging from 1 (completely disagree) to 5 (completely agree). Responses across the 20 items were averaged to obtain the score, with higher scores indicating a higher degree of learning burnout . In this2/df = 4.299, p < 0.001, SRMR = 0.057, RMSEA = 0.052, GFI = 0.914, and TLI = 0.948, and both the absolute and value-added adaptation indexes were in the acceptable range. The Cronbach’s alpha coefficient for the Connor-Davidson Resilience Scale was 0.912.The Connor-Davidson Resilience Scale consists of 25 items and measures three aspects of resilience: (1) tenacity , (2) strength , (3) optimism . The questionnaire uses a five-point Likert scale ranging from 1 (completely disagree) to 5 (completely agree). Responses across the 25 items were averaged to obtain the score, with higher scores indicating a higher capacity for resilience . StudiesPrevious studies have shown that gender and age have a significant effect on learning burnout . To exclOrganize and analyze data using SPSS 23.0 and SPSS macro program PROCESS compiled by 2 and normed-χ2 (NC), where a non-statistically significant χ2 value and NC values of under 3.0 indicate a good fit  were adopted: absolute fit and relative fit measures. The formerly included χgood fit . The latgood fit .2/df = 6.937, CFI = 0.325, NFI = 0.297, TLI = 0.281, RMSEA = 0.104. Therefore, there is no serious common method deviation in this study  Harman single-factor method is used for common method deviation testing. After principal component analysis, 16 eigenvalues greater than 1 were extracted. The first factor explaining the variance is 20.483%, which was lower than the 40% required by the critical standard , indicatis study .M = 2.829, SD = 0.478) was significantly higher than that of girls , t(548) = 2.203, p < 0.05, d = 0.087. The gender difference in subjective well-being is not significant , t(548) = −1.497, p > 0.05; gender difference in resilience is not significant , t(548) = 0.760, p > 0.05. The results of the correlation analysis (see p < 0.001). Among them, FSES is significantly positively correlated with subjective well-being and resilience, and significantly negatively correlated with learning burnout; subjective well-being is significantly negatively correlated with learning burnout, and resilience is significantly negatively correlated with subjective well-being and learning burnout.The results of the gender difference test showed that boys’ learning burnout score  and positively predicting subjective well-being . When FSES and subjective well-being both predict learning burnout, subjective well-being has a significant negative predictive effect on learning burnout , and the negative predictive effect of FSES on learning burnout is still significant . The results of the mediating effect test show that subjective well-being plays a mediating role in FSES’ prediction of learning burnout, with an effect size value of −0.068 and a 95% Bootstrap confidence interval of  (excluding 0), the mediating effect accounts for 35.052% of the total effect. H1 was validated.The mediating effect of subjective well-being between FSES and learning burnout was tested under the condition of controlling gender and age using model 4 of PROCESS. The results are shown in β = 0.104, p < 0.01) and predicts subjective well-being insignificantly , and the product of subjective well-being and resilience significantly negatively predicts learning burnout . This indicates that the predictive effects of FSES and subjective well-being on learning burnout are both regulated by resilience. H2 was validated. The simple slope test is further used to analyze the moderating effect of resilience in FSES and learning burnout, as well as subjective well-being and learning burnout. The mental resilience score is higher than M + SD as the high group, and the lower than M − SD as the low group, and the group regression is performed. The results are shown in β = −0.204, p < 0.001 to β = −0.001, p = 0.993), which is also shown in β = −0.113, p = 0.063) to significant . Based on that, the present study shows the mediating effect of subjective well-being in M − SD, M, and M + SD.Under the condition of controlling gender and age, the moderating effect of resilience is tested using model 59. The results are shown in To sum up, subjective well-being plays a mediating role between FSES and learning burnout, and the direct effect of FSES on learning burnout and the mediating effect of subjective well-being are moderated by resilience in the second half. Specifically, with the increase in resilience level, the direct effect of FSES on learning burnout is decreasing, and the mediating effect of subjective well-being is increasing.Based on previous research and the family stress model and psychological resilience framework theory, the present study constructs a moderated mediation model based on subjective well-being as a mediating variable and resilience as a moderating variable, which not only clarifies the problem of FSES “how to affect” college students’ learning burnout (the mediating role of subjective well-being) but also responses what conditions for FSES did the more significant effects of learning burnout (the moderating effect of resilience). The results of the study have some theoretical and practical significance for deepening the relationship between FSES and individual psychological and behavioral adaptation, guiding college students with poor family conditions to cultivate subjective well-being and alleviating learning burnout.Consistent with previous studies, the results of the study show that the FSES is significantly negative in predicting college students’ learning burnout . FamilieThe study found that FSES affected college students’ learning burnout by partially mediating role of subjective well-being, and generally supported the family stress model that high FSES college students were more able to be satisfied in material and life, experience higher subjective well-being, and therefore more active in learning, self-efficacy and achievement , which sBased on the psychological resilience framework theory, the present research investigates the moderating role of resilience in the relationship between FSES, subjective well-being, and college students’ learning burnout. The results found that resilience can not only moderate the relationship between FSES and learning burnout but also moderate the mediating model of “FSES—subjective well-being—learning burnout,” which supports H2. Specifically, compared with individuals with high resilience, the direct predictive effect of FSES on learning burnout is more significant for individuals with low resilience. This result not only shows that there are individual differences in the process of resilience causing learning burnout (the mediating role of subjective well-being) but also shows that resilience is a protective factor against other factors to cause individuals to emerge with social maladjustment, which is consistent with the results of previous studies . AccordiIn addition, the study found that subjective well-being had a positive effect on the learning burnout of high resilience college students compared to low resilience individuals. The results show that resilience, as a cognitive factor, can regulate the influence of emotional factors (subjective well-being) on individual problem behavior, that is, the negative predictive effect of subjective well-being on learning burnout requires a higher resilience of individuals. The psychological resilience framework theory suggests that subjective well-being and resilience, as the process of interaction between internal psychological elasticity factors and negative environmental factors in the body, form a process of psychological resilience and determine the behavioral outcome of individuals . CollegeThe present study had important theoretical and practical implications for developing interventions for learning burnout. On the theoretical aspect, this result enriches the complex mechanism of interaction between emotional and cognitive factors and individual development results in the existing psychological resilience framework theory, and on the other hand, it provides a theoretical basis and a new perspective for the intervention of positive emotions to promote individual learning adaptation in the practice of real mental health education. The main findings of this study are important for the development of interventions for learning burnout. FSES can indirectly play a role in college students’ learning burnout through the mediating path of subjective well-being, while resilience can regulate the predictive effect of FSES and subjective well-being on learning burnout. This also suggests that learning burnout intervention for college students from different family backgrounds needs to pay attention to the combination of individual cognitive factors and emotional factors for educators and parents through the cultivation of good resilience to increase the positive effect of subjective well-being on learning burnout.The following limitations exist in this study. First of all, this study uses the cross-sectional study design, which cannot make a causal inference. This moderated mediation model proposed by the present study can be further tested by longitudinal research in the future. Secondly, this study measures resilience through The Connor-Davidson Resilience Scale, preferring to regard resilience as a trait and neglecting to pay attention to the process of mental resilience. Future research can manipulate different ways of psychological resilience by the experimental method, thus inducing different forms of psychological resilience process of individuals, to examine the moderating effect of resilience on the relationship between FSES, subjective well-being, and learning burnout. Thirdly, the variables in this study are self-reporting. Future studies can measure the main variables of this study using a variety of methods . In addition, the sample in this study is university students from Kunming, which may affect the popularity of the results. Future researchers can select college students from different regions, majors, and ages to conduct surveys to further test the main results of this study.(1)After controlling for participants’ gender and age, FSES negatively, and significantly predicted learning burnout;(2)Subjective well-being partially mediated the relationship between FSES and learning burnout;(3)The direct effect of FSES on learning burnout and the mediation effect of subjective well-being was moderated by resilience. The level of learning burnout of individuals with low resilience increased significantly with the decrease of FSES, and the level of learning burnout of individuals with high resilience decreased significantly with the increase in subjective well-being.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The questionnaire and methodology for this study was approved by the Human Research Ethics Committee of the Kunming Medical University . Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.WW, YZ, and XL: research idea and study design. ZCG, XC, XW, XZ, and FT: data collection. WW, YL, XM, and LY: data analysis and manuscript writing. ZYG, SL, YC, and QL: supervision, project administration, and funding acquisition. 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.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.


To investigate the link between genetic variants associated with plasma homocysteine levels and risk of intracranial aneurysm (IA) using two-sample Mendelian randomization.We used single-nucleotide polymorphisms associated with human plasma homocysteine levels as instrumental variables for the primary analysis in a genome-wide association study of 44,147 subjects of European ancestry. Summary-level statistics were obtained for 79,429 individuals, including 7,495 IA cases and 71,934 controls. To enhance validity, five different Mendelian randomization methods  were used for the analyses.P-values of 0.398 for aneurysmal subarachnoid hemorrhage , 0.246 for IA , and 0.644 for unruptured IA . The MR-Egger analysis showed no association between IAs and homocysteine, with all P > 0.05.The inverse variance weighted analysis method produced Using gene-related instrumental variables, the Mendelian randomization analyses demonstrated a lack of an association between plasma homocysteine levels and IAs or aneurysmal subarachnoid hemorrhage. Intracranial aneurysm (IA) is confined, pathological dilatations of the walls of intracranial arteries that are at risk of rupture. About 85% of spontaneous subarachnoid hemorrhage (SAH) is due to ruptured IA . The incHyperhomocysteinemia has been widely reported to be associated with the development of cerebrovascular disease –8. ExcesRecent studies have shown an association between IAs and hyperhomocysteinemia in the Chinese Han population , 15. In Mendelian randomization (MR) is the use of genetic variation in non-experimental data to estimate the causal link between exposure and outcome, and it can reduce the impact of behavioral, social, psychological, and other factors . And in We used single-nucleotide polymorphisms (SNPs) associated with human plasma homocysteine levels as instrumental variables (IVs) for the primary analysis in a GWAS of 44,147 subjects of European ancestry .n = 7,495), UIA-only , and aSAH-only  vs. controls  in individuals of European ancestry.We extracted SNPs associated with IA from a large GWAS involving 7,495 IA cases and 71,934 controls . The MR P < 5 × 10−8) SNPs were used as IVs. Second, linkage disequilibrium (LD) must not exist between the selected IVs, because it can lead to interpretation bias. Among the selected SNPs, we performed a clumping step  to reduce the LD during our MR analysis. Third, guaranteeing that the impact of SNPs on outcome and exposure is related to only one allele during MR analysis is an important condition, and in accordance, SNPs with a palindromic structure were removed.The following steps were applied to select the best IVs to guarantee the accuracy and validity of the inferences on the causal relationship between the risk of IA and plasma homocysteine. The first step was to select SNPs with thresholds of significant association with the plasma homocysteine levels as IVs. A set of genome-wide statistically significant , MR-Egger, weighted median, simple mode, and weighted mode methods to evaluate the causal link between IAs and plasma homocysteine. The IVW method is characterized by an analysis that does not take into account the presence of an intercept term and uses the inverse of the outcome variance (quadratic of the standard error) as a weight to provide a comprehensive estimate of the impact of the plasma homocysteine on the incidence of IA. Ensuring these SNPs are not pleiotropic when using the IVW method is important, otherwise, the results will be highly biased. The MR-Egger method can provide causal estimates that are unaffected by breaches of standard IV assumptions and can detect whether standard IV assumptions are violated . The weiQ-statistic was applied to examine whether heterogeneity was present among the selected SNPs. We calculated MR power through a web-based tool (https://shiny.cnsgenomics.com/mRnd/)  . The stam/mRnd/) . For them/mRnd/) . The MR P < 5 × 10−8) from a GWAS of plasma homocysteine levels (P < 5 × 10–8) . When homocysteine was analyzed against IAs and aneurysmal subarachnoid hemorrhage, two SNPs (rs838133 and rs548987) were found to be absent in the IA and aneurysmal subarachnoid hemorrhage datasets, and when homocysteine was analyzed with unruptured aneurysms, four SNPs  were absent in the unruptured aneurysm dataset. None of these SNPs have a proxy SNP. The SNPs we used and their association with IAs are shown in First, we screened 18 SNPs as IVs . Furthermore, there were no weak instrumental variables . The Chochran's Q-statistics showed no significant heterogeneity . The limited number of SNPs included prevented examination of horizontal pleiotropy and heterogeneity.The MR-Egger regression indicated no horizontal pleiotropy in the analysis of the relationship between homocysteine and aneurysms , and UIA  showed no association between IAs and homocysteine.The results of all MR analyses showed no association between IAs and homocysteine, with all P > 0.05 . The resThis MR study provides evidence that IAs are not associated with homocysteine in Europeans. To our knowledge, this is the first MR study on the association between plasma homocysteine levels and IAs.https://www.healthdata.org), stroke is the second leading cause of disability and mortality worldwide  and the Natural Science Foundation of Jiangsu Province (No. H2017022).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.


The sudden outbreak of COVID-19 has made blended learning widely accepted, followed by many studies committed to blended learning outcomes and student attitudes. Few studies have, however, focused on the summarized effect of blended learning. To complement this missing link, this study meta-analytically reviews blended learning outcomes and student attitudes by including 30 peer-reviewed journal articles and 70 effect sizes. It concludes that blended learning outcomes are significantly higher than the traditional learning outcomes with a medium effect size, and learners hold significantly more positive attitudes toward blended learning than traditional learning with a medium effect size. Blended learning may be promising, and information technology scientists may focus on the development of more advanced and effective devices to improve blended learning effectiveness. Therefore, blended learning could involve distributed, decentralized, hybrid, and flexible learning  education held more positive attitudes toward the blended approach CPR than the control group who received traditional education  What differences in learning outcomes can be established between blended learning and the traditional face-to-face approach? (2) What differences in learner attitudes can be established between blended learning and the traditional face-to-face approach? Research hypotheses tend to be proposed and tested in meta-analyses in the field of education  into EBSCOhost for academic search ranging from 2000 to 2020, and 508 results returned (25 August 2020). They reduced the results to 137 by limiting them to fulltext, academic peer-reviewed journal, academic theoretical journal, journal, and English. Finally, they selected 4 peer-reviewed articles of high quality.via “” AND TI “blended learning OR hybrid learning” within the field of Educational Technology, ranging from 2000 to 2020. After removing 47 results, we selected 5 articles of high quality. We obtained 8 results from Web of Science (WOS) and selected 4 of them.Additionally, they obtained 52 results by searching Springer By keying in [Publication Title: blended learning OR hybrid learning] AND [[All: control] OR [All: treatment] OR [All: experimental]] in Taylor & Francis, they obtained 205 results, ranging from 2000 to 2020. By selecting the subject “education”, we reduced the results to 142. They selected 6 high-quality peer-reviewed articles after perusing the articles.By keying in “Title abstract, keywords: control OR treatment OR experimental, and Title: blended learning OR hybrid learning” in the database Elsevier ScienceDirect, they obtained 56 results, ranging from 2000 to 2020. After careful reading and screening, they selected 11 of them. Besides, we selected results based on both inclusion and exclusion criteria, as well as The STARLITE tool Booth, .via controlled and randomized comparative design; (2) divide the participants into both control and treatment groups and the control group receives traditional face-to-face learning, while the treatment group receives blended learning; (3) include student attitudes toward blended learning or blended learning outcomes such as test scores, satisfaction, and conceptual understanding; (4) are published in English.; (5) belong to peer-reviewed journal articles.The studies will be considered eligible if they: (1) focus on blended learning effect The studies will be excluded if they: (1) are not related to the comparison between blended and traditional learning; (2) are conference abstracts, editorial articles, review articles or meta-analyses; (3) focus on online learning technologies rather than the use of them in education; (4) cannot provide enough information for meta-analysis even after we correspond with the authors.We also used University of West England Framework for Critically Appraising Research Articles , so we apply a random-effect model to the analysis. Means, standard deviations, total numbers of participants and mean differences between blended groups and control groups are indicated, as well as a forest plot on the right. The values of weights indicate the power of an individual study influencing the summarized results. The higher the weight is the more powerful influence an individual study will exert on a summarized result. The studies conducted by Baepler et al. , ranging from 0.41 to 0.63 in 95% CI, which indicates that the result has a strong confidence. This result does not touch the no-effect line. The diamond is placed on the right side of the no-effect line, indicating the mean of blended learning outcomes is larger than that of the traditional learning. Therefore, we accept the first research hypothesis that the blended learning outcomes are significantly higher than the traditional learning outcomes.In the middle of the forest plot, the vertical line is referred to as a no-effect line. The result will be considered insignificantly different if the line is touched. The diamond at the bottom of the forest line indicates the summarized result. The former is negatively correlated with the latter. The narrower the diamond is, the stronger confidence the result will have. As shown in t = 4.02, p = 0.00; Begg's test z = 4.02, p = 0.00). The sensitivity analysis . We retrieved the data from four studies to address the question, where the data provided by Chang et al. , ranging from 0.19 to 0.96 in 95% CI. This indicates that the summarized result is reliable and convincing. The summarized result does not touch the vertical no-effect line and the result is placed on the right side. This implies that the mean of blended learning is significantly larger than that of the traditional learning. Therefore, we accept the second research hypothesis that learners hold significantly more positive attitudes toward blended learning than traditional learning.The diamond summarizing the final result is narrow . We also carried out a sensitivity analysis ], while the study of Monteiro and Morrison ]. Most of the other studies obtained medium effect size, e.g., Baepler et al. ], Hill et al. ], and Botts et al. ]. The total effect size is at the medium level [d = 0.522 ].As for blended learning outcomes, the study of Gordon et al.  obtainedMorrison  gained tr et al.  [d = 0.5l et al.  [d = 0.5s et al.  [d = 0.5d = 1.42 ], while McCutcheon et al. ], and Chang et al. ]. So did Shorey et al. ]. The total effect size is at the medium level [d = 0.63 ] ] .via a one-way pedagogical approach, which adopts traditional tools such as radio, television, broadcaster, and mail. The second generation develops into distance education with the help of traditional instructional technologies, e.g., multimedia projecting systems and computer software assisted boards. The third generation, conducive to higher education  (Important) Introduction to Linguistics; Introduction to Linguistics of online and offline mixed courses in Beijing Language and Culture University in 2020; Special fund of Beijing Co-construction Project-Research and reform of the Undergraduate Teaching Reform and Innovation Project of Beijing higher education in 2020-innovative multilingual + excellent talent training system (202010032003); The research project of Graduate Students of Beijing Language and Culture University Xi Jinping: The Governance of China (SJTS202108).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.


In recent years, the role of metformin in girls with precocious puberty (PP) has been increasingly frequently studied. The objective of this present study is to assess the effect of metformin on low birth weight girls with precocious puberty (LBW-PP girls).We search the confirmed studies about circulating metformin and PP from the databases of EMBASE, PubMed, and Web of Science. Data were reported as weighted mean difference (WMD) and associated 95% confidence intervals (CIs). Analysis was performed by Review Manager 5.3 and Stata version 12.0.P = .001), androstenedione (P = .022), bone mineral density , triglycerides (P ≤ .001), body mass index Z score , dehydroepiandrosterone-sulfate , sex hormone-binding globulin , high-density lipoprotein (HDL) cholesterol (P ≤ .001), low-density lipoprotein (LDL) cholesterol (P = .021), fat mass (P ≤ .001), lean mass (P = .025), and fasting insulin (P = .002).A total of 205 cases  were included in this study. The meta-analysis of randomized controlled trials (RCTs) suggested that metformin had statistically significant effects on testosterone (This meta-analysis provided evidence of the efficacy of metformin in girls with LBW-PP girls, which proved that metformin could improve metabolism and reduce weight. Metformin had a positive effect on preventing LBW-PP girls from developing into obesity and polycystic ovarian syndrome. In addition, this meta-analysis provided important reference opinions and directions for the treatment of LBW-PP girls. PP is classified into 2 major categories based on the etiology: central PP (gonadotropin-releasing hormone [GnRH] dependent) and peripheral precocious puberty .,2,6,7 PPP is due to the production of sex steroids from endogenous or exogenous sources.,6,7 Precocious development of secondary sexual characteristics is independent of the GnRH pulsatile secretion.,7 Some important causes include congenital adrenal hyperplasia, McCune Albright syndrome, gonadal tumors, adrenal tumors, familial male, exogenous exposure to sex steroids, Van Wyk, and Grumbach syndrome.,6,7 It is reported that some low birth weight girls with PP (LBW-PP) girls tend to start puberty earlier with too large adrenarcheal hormone profile due to excessive catch-up of growth.,4 PP may lead to some physical and psychological changes, for the growth plate is obviously sensitive to the effects of estrogen and the nutritional consequences of PP tend to precede the signs of sexual maturity, which may result in premature fusion of the growth plate, thus leading to short stature in adults. In recent years, the incidence of PP has increased year by year. In addition, low birth weight girls would eventually develop polycystic ovary syndrome (PCOS). In this process, girls at risk for development of an adipose body composition, with early onset of puberty and rapid progression to menarche, exaggerated their weight catch-up in early childhood and showed development of PP.–10Female precocious puberty (PP) represents a girl’s development of secondary sexual characteristics before the age of 8. Metformin seems to function mainly through activation of adenosine monophosphate–activated protein kinase, a conserved regulator of the cellular response to low energy in the liver. This activation is catalyzed by serine-threonine-kinase (LKB1).–14 In addition, metformin is widely used in the treatment of tumors, diabetes, and other diseases.,16 Recent studies have shown that early treatment with metformin was able to reduce central obesity and normalize circulating concentrations of insulin and adipokines, due to its positive effect on glucose, lipid, and corticosteroid metabolism.Metformin, dimethylbiguanide, is an oral glucose-lowering agent.,19 but few on the treatment of LBW-PP girls with metformin. In this regard, it is of paramount importance to explore the effect of metformin on PP. This study hypothesized that the use of metformin may have a positive effect of LBW-PP girls. And the earlier it is used, the better the effect. Therefore, we evaluated the effect of metformin on girls with LBW girls with PP by using a systematic review and meta-analysis.There are many reports on the treatment of PP with GnRH or GnRHa,A comprehensive literature search was conducted to identify all potentially relevant articles by using the PUBMED, Web of Science, and EMBASE from their inception to June 2021. All search methods were based on a systematic approach. This is consistent with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P).Searches for terms PP OR low birth weight girls with PP AND metformin were performed.https://pubmed.ncbi.nlm.nih.gov/), and ethical approval was waived or not necessary.The involved articles in this study were from public databases .The literature search was performed by 2 reviewers, all potentially eligible studies for inclusion and assessment and the data have been independently extracted. Differences were also resolved by consulting a third reviewer as required. The present study obtained additional data, if necessary, by getting in touch with the authors of the original studies.The main inclusion criteria are as follows:a. Randomized controlled clinical trials. Girls were randomly assigned to receive metformin or untreated.2 or BMI Z score 0.9 to 1.8; testosterone ≥25 ng/dL;  levels. All the variables studied , low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, fat mass, lean mass, and gaseous insulin) were adequately described and measured in the included studies.b. Girls in the control and treatment group should meet the following conditions: age 7 to 13 years; body mass index (BMI) 18 to 22 kg/mc. Studies reported standard mean difference (SMD) or weighted mean difference (WMD) with corresponding 95% confidence intervals (CIs) provided adequate data to calculate these values.This form was made by 2 researchers used to extract data from the eligible studies independently. Discussions around these data were conducted to resolve discrepancies. The collected information included the author, age at study start, year of publication, sample size, treatment method, weighted mean difference  or SMD (95% CI), and variables controlled for matching or multivariable models. The data were inputted into the Review Manager software (RevMan 5.3). The Cochrane score was used to evaluate the quality of the selected literature as per the quality standards of the Cochrane scale. Two reviewers resolved their differences through discussion. Differences could be resolved by consulting a third reviewer when necessary.P values were 2-sided, and P < .05 was considered as the limit of statistical significance. Six studies were used to estimate the heterogeneity. According to the heterogeneity standard of I² statistic, the I² statistic was used to assess the heterogeneity between studies. As I² ≥ 50%, heterogeneity was considered significant. Thus, random effects estimates were performed to calculate. If I² < 50%, fixed effects model was performed. The WMD for continuous variables were used to explain results with the 95% CI. In addition, in-depth research on subgroup (or regression) analysis and sensitivity analysis were conducted against some data with significant heterogeneity.According to each study, 12 variables were extracted as mean ± standard deviation (SD). Some researches provided 95% CI of means and standard error of means (SEM), and then 95% CIs and SEM were converted to SD values. Our study used Stata (version 12.0) to analyze data. The research selection process is summarized in Figure  The precise of bias risk for each study included is shown in Figure For each selected randomized, prospective and non-randomized clinical study, the risk of bias was assessed as per the standards described in the Cochrane Reviewers Handbook.Testosterone was reported in 5 studies. A complete of 171 girls were included, of whom 85 had been in the metformin group and 86 had been in the untreated group. Testosterone decreased significantly in the metformin group Table ; Fig. 3.Androstenedione was reported in 4 studies. A complete of 133 girls were included, of whom 66 had been in the metformin group and 67 had been in the untreated group. Androstenedione decreased significantly in the metformin group  include few studies. Therefore, the results provided by subgroup analysis are not as reliable as the whole, and sensitivity analysis shows that the studies Ibáñez et al,22 have significant sensitivity . Besides, metformin can improve the oxidative stress status of girls to reduce the level of androgen and DHEAS.,32 Due to the limitation of the number of included articles, further verification is required for the present research results.The data showed that there was no significant difference in DHEAS between the metformin group and the untreated group. The results of the present study does not support the evidence that metformin can reduce DHEAS levels. Nonetheless, some researches have shown that metformin has a certain regulatory effect on DHEAS. Metformin can regulate the sensitivity of insulin levels. Hence, early medication can adjust over-excited adrenal function and reduce the level of DHEAS. PCOS girls have missed this window period. As human body develops, it is difficult to get fundamental improvement after the window period is missed.Associated research reports showed that metformin has little effect on DHEAS in girls with PCOS of childbearing age.–37 By reducing insulin resistance in the liver, decreasing androgen secretion by adrenal glands and ovaries, and increasing the production of SHBG in the liver, metformin takes effect in girls, thus reducing free testosterone concentrations.–40In addition, the data showed that the levels of SHBG in the metformin intervention group were significantly lower than those in the untreated group. Based on the results above, the effect of metformin on testosterone, androstenedione, and SHBG can be judged: metformin has a positive effect on reducing the risk of LBW-PP girls developing into PCOS. The effect of metformin on the bone development of LBW-PP girls requires further studies. Our meta-analysis also showed the metformin-treated group presented consistent improvements in all biochemical and body composition variables when compared to the untreated group. According to the results in this present study, LDL cholesterol, BMI Z score, fat mass, and fasting insulin significantly reduced. HDL cholesterol and lean mass significantly increased, indicating that metformin can effectively reduce the risk of LBW girls with PP women developing obesity and hyperlipidemia. In addition, it has been found that lean mass in the metformin intervention group increased significantly when compared to the untreated group. This contradicted the conclusion that metformin had no effect on lean mass in the present study. However, the sample size is small, which is not sufficient to draw a definite conclusion.The results of this meta-analysis show that there was no significant difference in BMD between metformin group and untreated group, which is consistent with the conclusions in the study by de Zegher et al. Using metformin at this phase can reduce the risk of obesity and hyperlipidemia in LBW-PP girls more effectively, regulate the secretion of androgens in the adrenal glands, and reduce the future the risk of developing into PCOS. Regarding the timing of medication, it may be demarcated by menarche, which requires further study.The result of meta-analysis showed that early and adequate use of metformin has a more significant effect on girls with LBW-PP girls. Its mechanism may be as follows: The adolescence provides an opportunity to reprogram the wrong programming that occurred in early life. For PP girls, a catch-up growth after birth showed up, thus resulting in the wrong coding of early life planning. Adolescence may be a critical window in which the epigenetic settings may be changed.Z score, and fasting insulin was the result of high probability of publication bias, as indicated by their Egger test P values of .040, .002, .005, and .048. Although this present study has certain limitations, results have shown that metformin can have positive effects. It is suggested that more scientifically designed, randomized, double-blind controlled clinical trials are required to support the results of this research.Some limitations should be considered before the results of this meta-analysis were examined. The number of girls included in each group of randomized controlled trial (RCT) is relatively small. In addition, the dose of metformin ranged from 425 to 825 mg in different studies and the treatment time varied from as short as 6 months to as long as 5 years. In addition, significant heterogeneity in eligible studies adversely affected the meaningful results of the current meta-analysis. Besides, the very low quality for testosterone, triglycerides, BMI This evidence of the efficacy of metformin in girls with low birth weight PP has been provided in meta-analysis, which proved that metformin was able to boost metabolism and weight loss. Metformin has been proven positive in preventing low birth weight precocious puberty from developing into obesity and polycystic ovarian syndrome.ZL and XS conceived and designed the study; ZL and YW searched the related articles; ZL, XS, YW, and LL analyzed the data; ZL, XS, and LL wrote the manuscript. JZ supervised the whole process. All authors read and approved the final manuscript.


Psychological trauma in childhood can lead to post-traumatic disorder (PTSD) with protracted comorbid depression, which responds poorly to conventional antidepressants. Previous studies have shown that prazosin, an α1-adrenergic receptor antagonist, can help eliminate nightmares and improve sleep quality and suicidal ideation in PTSD patients. This case report presents that prazosin had a rapid antidepressant effect in a female adolescent PTSD patient with treatment-resistant depression (TRD). Prazosin improved not only depression symptoms but also sleep quality, suicidal ideation, and cognitive function. Prazosin was well tolerated without obvious adverse effects. Our preliminary study suggests that further clinical trials are needed to determine the efficacy and safety of prazosin in treating PTSD patients with comorbid TRD. Physical and psychological trauma in childhood is a common precipitating and perpetuating factor for post-traumatic stress disorder (PTSD). Depression is the most common comorbidity of PTSD and often responds poorly to available antidepressants –3. MilliMany clinical studies have shown that prazosin, an α1-adrenergic receptor antagonist, significantly improves nightmares in PTSD . HoweverWe here present a case of a female adolescent PTSD patient with comorbid TRD who was previously treated with a wide range of antidepressants, antipsychotics, and electroconvulsive therapy (ECT) but without achieving remission. During this admission, the patient was given low-dose prazosin as an augmenting treatment and showed remarkable improvements in PTSD and TRD symptoms.Miss A, a 16-year-old female with a history of sexual abuse in childhood, has been hospitalized multiple times in the past two years with the diagnosis of depression and PTSD. Patient reported as a victim of sexual assault by a male neighbor when she was 8 years older. She began to suffer from depression, anxiety, and sleep problem 2 years ago. Since then, she has been hospitalized 6 times with major complaints of depression and anxiety. She also complained of sleep disturbance, nightmares, irritation, and memory loss. She often re-experienced the scenario of childhood sexual assault. She thought of killing herself and felt extremely disgusted with adult men. To manage PTSD and depression, she first was on sertraline (100 mg/day) and was late on venlafaxine XR, but with little improvement. Her anxiety was managed with diazepam (10 mg/day) and lorazepam (0.5 mg qn). One year ago, her intimate friend committed suicide from a drug overdose, and she was blamed and threatened by her friend's parents and relatives, and her symptoms worsened. She was augmented with olanzapine (2.5 mg after lunch and 5 mg at bedtime) and co-treated with four MECT and Venlafaxine XR (150 mg/d) but did not get complete remission.Before this admission, the patient broke up with her partner and attempted to commit suicide multiple times. The patient was hospitalized with the diagnosis of PTSD with comorbid TRD. TRD was diagnosed according to DSM-5 and the failure with two successive antidepressants with adequate dose and duration. Physical exams and image studies were not remarkable. The patient was put on venlafaxine XR (up to 225 mg/day), bupropion XR (up to 300 mg/d), olanzapine (up to 10 mg/day) for 3 weeks, and also received eight sessions of modified electroconvulsive therapy (MECT), but achieved no significant improvement. After informed consent, the patient was first put on prazosin at a low dosage of 0.25 mg at bedtime for 3 days with blood pressure monitored. The dose was then increased to 0.5 mg/day on day 4 and 1 mg/day on day 14 . The patDepression is a common comorbid complication in PTSD. Like that for depression, selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs for the treatment of PTSD. However, around a half percent of patients respond poorly to the treatment , 5. PrazPrevious work mainly investigated the effect of prazosin on PTSD symptoms, especially nightmares , 13; lesWe used low doses of prazosin (0.25 to 1 mg daily), which gave marked improvements in both PTSD and depression symptoms without adverse effects. Previous studies showed that prazosin might improve nightmares in children and adolescents with PTSD with rare adverse events, and there was no significant change in blood pressure with the initiation of prazosin –19. The Combining low-dose prazosin and SSRIs may effectively improve PTSD symptoms and the comorbid TRD. The use of low-dose prazosin is also safe and well tolerable. However, large-scale clinical studies are warranted to study the findings in this case further.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical approval was obtained from the 3rd Hospital in Huzhou Municipal, Zhejiang, China . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.PG: funding acquisition and writing-original draft. YF and XZ: investigation and software. MF: data curation, investigation, and software. MQ: project administration, resources, supervision, and visualization. JH: validation and visualization. SW: conceptualization, methodology, and writing-review & editing. HC: organizing this research and writing and revising this manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Project of Health Department in Zhejiang Province (2019KY681), Huzhou Municipal Science and Tech Commission (No. 2018GYB16). The funding body had no role in the design of the study and collection, analysis and interpretation of data and in writing the manuscript.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.


Based on the social and psychological capital framework, this study aimed to investigate the direct effect of bullying on adolescents’ subjective well-being and to reveal the potential psychosocial mechanisms in this relationship. Through the multi-stage cluster random sampling procedure, a cross-sectional survey was conducted among 728 adolescents from Hebei Province in China. Structural equation modeling was adopted for data analysis. After controlling for sociodemographic variables, the results indicated that only relational bullying had a significant negative effect on adolescents’ subjective well-being. Moreover, social capital and psychological capital mediated the relationship between relational bullying and adolescents’ subjective well-being. This study expands our understanding of the influencing mechanisms from bullying victimization to subjective well-being and also provides practical implications for future social policy development and relevant interventions. School bullying occurs widely around the world and has become a significant social concern ,2. AccorThe Research Report on School Violence Cases issued by the Supreme People’s Court of China illustrates that adolescents in high school are most likely to experience school bullying compared with children in other stages of their life [However, in the social context of China, there remain several research gaps. Firstly, empirical studies that focus on exploring the potential influencing paths of school bullying by using quantitative methods are relatively lacking. Secondly, previous studies have shown that the impact of school bullying has significant differences among different age groups, and it normally achieves its peak during adolescence . The higeir life . Howevereir life ,14. MoreIn this study, school bullying is defined as aggressive behavior that occurs on and off campus between students, in which the perpetrator intentionally bullies the victim in various ways. School bullying can manifest in various ways and is mainly divided into overt and relational bullying, depending on the nature of the bullying . Overt bAccording to previous studies, both types of bullying styles can cause harm to the growth of adolescents. However, previous studies have found inconsistent effects , with soHypothesis 1a.Overt bullying is negatively related to adolescents’ subjective well-being,Hypothesis 1b.Relational bullying is negatively related to adolescents’ subjective well-being.Guided and inspired by prior research that attempted to explain the complex mechanisms between school bullying and adolescent well-being, another purpose of this study is to further explore and validate potential pathways that may help to expand the current understanding in academia ,26,27. TAccording to Bourdieu’s 1986) definition, social capital is deemed as the resources and support that adolescents can obtain from their social network system . From th986 definIt is noteworthy that the majority of the current research focuses on only one dimension of social or psychological capital but lacks an integrated analysis and validation of the two types of capital. Moreover, the conceptual framework of social and psychological capital was proposed mainly in the context of workplace bullying in Western culture. Although some studies have validated the theoretical applicability in the context of school bullying , it stilHypothesis 2a.Social capital mediates the relationship between overt bullying and subjective well-being.Hypothesis 2b.Social capital mediates the relationship between relational bullying and subjective well-being.Hypothesis 3a.Psychological capital mediates the relationship between overt bullying and subjective well-being.Hypothesis 3b.Psychological capital mediates the relationship between relational bullying and subjective well-being.Based on the above analysis, the literature review illustrates that even though the interrelationship between school bullying and subjective well-being has been widely tested in different cultural settings, research addressing the controversies between the impacts of different types of bullying is lacking. Furthermore, the potential mediating role of social capital and psychological capital has yet to be validated in an integrated framework focused on a group of high-school-aged adolescents. This study aims to address the research gaps and provide solid empirical evidence for future studies and practices. Accordingly, this study proposes the following theoretical framework see .Based on multi-stage cluster random sampling, which requires researchers to divide the population into groups (clusters) at various stages for better data collection, firstly, a list of schools in one city of Hebei Province in China was obtained by the research team, and four high schools were randomly selected. Secondly, one class was randomly selected from each grade (Grades 10–12) in each selected school. Then, all students in each selected class were invited to participate in our survey. Overall, we finally recruited 728 school-aged adolescents from four high schools as the research sample for this cross-sectional study. The study strictly followed various research ethics, such as anonymity, confidentiality, and voluntary participation. Research ethics approval of this study was received from the Research Ethics Committee of The Zhejiang Gongshang University, where the first author is affiliated. Before starting the survey, the researcher gave a detailed introduction to the student participants, their parents, and the school authorities about the purpose and content of the study and informed them of their right to participate voluntarily or to withdraw at any time. In the sample of this study, there were 345 males (47.4%) and 383 females (52.6%). Their average age was 16.33 years old (SD = 1.00). The proportions of junior (n = 157), sophomore (n = 359), and senior (n = 152) high-school students were 21.6%, 49.3%, and 20.9%, respectively. Most participants (719) were of Han ethnicity (98.8%). Slightly more than half of all participants (482) were from rural households (66.2%), and the remaining 246 teenagers were from urban households (33.8%). As for their family economic status, 9 teenagers were from extreme-poverty families (1.2%), 50 teenagers were from poor families (6.9%), 471 participants were from general families (64.7%), 177 teenagers were from wealthy families (24.3%), and 21 participants were from very well-off families (2.9%).The present study was conducted by using the Overt Victimization and Relational Victimization subscales of the Problem Behavior Frequency Scale developed by Farrell et al. . The OveThe mediating variables in this study were social capital and psychological capital. The Multidimensional Scale of Perceived Social Support developed by Zimet et al.  was usedIn the present study, psychological capital was operationalized as the sense of self-worth, self-efficacy, and hope. Self-worth was measured through the Self-Concept Scale developed by Shevlin et al. . The scaThe dependent variable in this study was subjective well-being, which was measured by the WHO Well-Being Index (WHO-5) . The scaThe confounding variables in this study included gender , age, household registration , ethnicity , and family economic status .2), comparative fit index (CFI), and root mean square error of approximation (RMSEA) were used to verify the fit of the measurement model and the structural model. Due to the sensitivity of the chi-square values to the sample size, a good model fit is achieved if CFI > 0.90 and RMSEA < 0.08 [Firstly, this study conducted a descriptive statistical analysis and correlation analysis among key variables in SPSS 24.0 . To verify the three research hypotheses mentioned above, this study used structural equation modeling in Amos 25.0  to validate the mechanisms of school bullying on adolescents’ subjective well-being. The validation of the structural equation model was conducted in two specific steps: the measurement model and the structural model. The measurement model was tested based on confirmatory factor analysis (CFA) to explore whether each latent variable  in this study could be constructed by its corresponding indicators. Further, to test the direct effect of school bullying on subjective well-being and the mediating effect of social capital and psychological capital, this study tested hypotheses through two structural models. To test Hypotheses 1a and 1b, a “direct effect model” was developed to verify the direct effects of the two types of bullying on adolescents’ subjective well-being after controlling for the covariates. To test Hypotheses 2a and 2b and Hypotheses 3a and 3b, a “mediated effect model” was developed to verify the significant effects of the two mediating variables: social capital and psychological capital. The Sobel test and bootstrap analysis were used to determine the significance of the mediating effects. The chi-square . Specifically, overt bullying and relational bullying showed significant negative correlations with all indicators of social and psychological capital; both types of bullying were also significantly and negatively correlated with adolescents’ subjective well-being. In addition, social capital and psychological capital showed significant positive correlations with subjective well-being.As shown in 2 = 443.687, df = 98, p < 0.001, CFI = 0.940, and RMSEA = 0.070. In addition, all observed variables loaded significantly on their corresponding latent variables. The factor loadings of the scale items on the latent variables of overt bullying and relational bullying ranged from 0.700 to 0.815 and 0.789 to 0.879, respectively; family support, peer support, and teacher support, as the three indicators of the latent variable of social capital, had factor loadings of 0.708, 0.569, and 0.505, respectively. Self-worth, self-efficacy, and hope, as the three indicators of the latent variable of psychological capital, had factor loadings of 0.708, 0.569, and 0.505, respectively. The factor loadings of all observed variables were higher than 0.50, which met the criteria for acceptable factor loadings of the measurement model, indicating that the measurement instruments used in this study could accurately measure the concepts and variables related to them.The measurement model results showed a positive model fit: χ2 = 397.941, df = 82, p < 0.001, CFI = 0.939, and RMSEA = 0.073. As shown in p < 0.001); however, overt bullying did not have a significant effect on adolescents’ subjective well-being . In the direct model, only two confounding variables, gender  and family economic status , were significantly associated with adolescents’ subjective well-being. Thus, Hypothesis 1b was supported according to the empirical results, while Hypothesis 1a was rejected.The direct-effect model was designed to validate distinct bullying typologies’ direct effects on adolescents’ subjective well-being. The direct-effect model reported a good model fit: χ2 = 621.645, df = 194, p < 0.001, CFI = 0.933, and RMSEA = 0.055. The analysis results and model parameters of the mediated-effect model are detailed in Based on the analysis of the direct model described above, the mediating-effect model further incorporated two mediating variables: social capital and psychological capital. The model fit indicators of the mediated-effect model also showed a good model fit: χp < 0.05). The Sobel test for the path “relational bullying → psychological capital → subjective well-being” also indicated that relational bullying indirectly affected adolescents’ subjective well-being through the mediating mechanism of psychological capital . After including mediating variables, the direct effect of relational bullying on subjective well-being was not significant . Thus, social and psychological capital played a fully mediating role. Specifically, relational bullying reduced adolescents’ social capital  and psychological capital , and decreases in social capital  and psychological capital  further negatively affected adolescents’ subjective well-being. In addition, the results of the bootstrap analysis also demonstrated the total indirect effects of relational bullying on subjective well-being via social capital and psychological capital , and these effects were significant. Based on these results, both Hypotheses 2b and 3b were supported.We adopted the Sobel test and bootstrap analysis to verify whether the mediating effects of social capital and psychological capital were significant. The results of the Sobel test for the path “relational bullying → social capital → subjective well-being” showed that social capital played a significant mediating role in the relationship between relational bullying and subjective well-being  and intraindividual resources . This study demonstrated that although relational bullying had a direct negative effect on adolescent well-being, the direct effect of relational bullying on subjective well-being was not significant when the mediating variables of social capital and psychological capital were included, indicating that social capital and psychological capital fully mediated the relationship between relational bullying and subjective well-being. In the cultural context of collectivism, intergroup interdependence becomes an important way to acquire social and psychological capital. When adolescents are isolated from their peer groups, their perceived social resources will decrease along with their psychological capital, which is mainly reflected in the form of lower levels of self-efficacy, self-worth, and hope. The reduction in external social support and the strengthening of internal psychological vulnerability further impair adolescents’ evaluation of their own state of well-being and reduce their subjective well-being.First, grounded in the analytical framework of social and psychological capital theories, the current study reveals the differences in the effects of overt and relational bullying on adolescents’ subjective well-being. Second, our study verifies the mediating effects of social and psychological capital in the relationship between school bullying and adolescents’ subjective well-being. In general, the findings enrich the theoretical explanation of the influencing pathways and provide empirical evidence for the future development of social policy and practical interventions.The Notice on Special Treatment of School Bullying issued by the Education Supervision Commission of the State Council of China in 2016 provides clear guidance on the prevention and treatment of school bullying, requiring schools around the country to strictly manage and punish this problem. This indicates that school bullying has become an important issue of concern at the national policy level. However, due to the hidden nature of relational bullying, the “perpetrators” of relational bullying are not easily screened by relevant disciplines, and it is also hard for educators to notice the “recipients” of relational bullying. The emotional and psychological damage and abuse caused by this kind of hidden violence may be more traumatic to students’ growth and development. Therefore, in the “blind spot” of policy coverage, school social workers and educational practitioners should work together to intervene with young victims of relational bullying to reduce the negative impact of hidden bullying on their well-being.The above findings provide important empirical evidence and practical insights for future school bullying prevention. In recent years, China has issued a series of policies and regulations to deal with the problem of school bullying. For example, Furthermore, concerning the mediating roles of social and psychological capital, social-work-practice interventions need to take both the social environment and the individual’s own developmental characteristics into account. On the one hand, school social workers could use resource linkage to help isolated and excluded adolescents to obtain more external support from the multidimensional social system. On the other hand, school social workers could also help empower students through casework or group work, enhance their recognition of their own value and ability, improve their psychological capital, and realize “helping others to help themselves”. Therefore, enhancing social and psychological capital is a key breakthrough to cut off the negative effects of school bullying, and it could be one of the important practical strategies to enhance adolescents’ subjective well-being and psychological health.There are still some limitations in this study, which need to be further considered for future studies. Firstly, the cross-sectional research design adopted in this study only allows for a preliminary exploration of the relationships between variables and does not allow for causal inferences. Future studies are encouraged to conduct a longitudinal research design to further validate the theoretical model proposed in this study. Moreover, the sample in this study is only from Hebei Province in China, which might not be nationally representative. Future studies could enhance the generalizability of the findings through a larger sampling size. In addition, although the current study examined the distinct nature of overt bullying and relational bullying with systematic analyses of their influencing pathways on adolescents’ subjective well-being, we only measured bullying between peer groups and ignored bullying and violence between teachers and students. Future research could further explore how teacher bullying affects the development of adolescents. Finally, when experiencing negative interpersonal problems , adolescents in collectivist cultures may be more cognitively and emotionally vulnerable than those from Western individualist cultures ,49. TherThis study tested the differences in the effects of overt and relational bullying on adolescents’ subjective well-being and confirmed that only relational bullying had a significant direct effect on adolescents’ subjective well-being among high-school-aged adolescents. Moreover, guided by the framework of social and psychological capital theories, this study further explored the mediating mechanisms of external environmental resources  and intraindividual resources . In line with our expectations, we found that social capital and psychological capital fully mediated the relationship between relational bullying and subjective well-being. Taken together, this study deepens the current understanding of the relationship between school bullying and subjective well-being among adolescents in academia. More essentially, based on the strong empirical evidence, this study further encourages continuous efforts for the future prevention of school bullying and provides practical suggestions on this issue.


The aim is to explore the intakes of dietary nutrients and the changes of gut microbiota composition among patients with hypertensive disorders of pregnancy (HDP) and provide a theoretical basis for the prevention and treatment of HDP.This study was conducted at the Maternal and Child Health Care Hospital of Changzhou. A total of 170 pregnant women  in the third trimester were enrolled. Dietary nutrient intakes were assessed through a food frequency questionnaire survey. Fresh fecal samples were aseptically collected, and 16S rDNA sequencing was conducted. The intakes of dietary nutrients and the diversity and relative abundance of gut microbiota were compared between pregnant women with and without HDP. A logistic regression model was used to investigate the association between differential gut microbial genera and the risk of HDP.Bacteroides were increased, and the relative abundances of Actinobacteriota, Lachnospiraceae, Prevotellaceae, Bifidobacteriaceae, Blautia, Prevotella, and Bifidobacterium were decreased in women with HDP compared with those in the controls. In addition, the relative abundance of Bifidobacterium was positively correlated with dietary intakes of vitamin C and vitamin E in patients with HDP. After adjustment for confounding factors, the odds ratio  of HDP for the relative abundance of Bifidobacterium was 0.899 .The daily dietary intakes of vitamin A and vitamin C in pregnant women with HDP were significantly lower than those in the control group. The relative abundances of Bacteroidota, Bacteroidaceae, and Bifidobacterium was negatively associated with HDP. Moreover, dietary vitamin C and gut Bifidobacterium may cooperatively contribute to reduce the risk of HDP.The composition of gut microbiota in pregnant women with HDP was significantly changed compared with that of healthy controls. The relative abundance of  Hypertensive disorders of pregnancy (HDP) is mainly divided into gestational hypertension (GH), preeclampsia (PE), chronic hypertension complicated with PE, and pregnancy complicated with chronic hypertension . A meta-The pathogenesis of HDP has not been fully understood, but it is believed to be caused by the combined maternal, placental, and fetal effects. The occurrence and development of HDP are accompanied by a series of pathophysiological changes, such as immune maladjustment, chronic uterine placental ischemia , oxidatiBacteroides spp. and Clostridium spp.  . Lutein,ium spp. . On the ium spp. . These soperties . In receoperties . Howeveroperties . Liu et uangzhou , which mThe aforementioned studies of gut microbiota in patients with HDP showed inconsistent results. In addition, multiple confounding factors, such as race, region, diet, and lifestyle, limit the extrapolation of these results. To date, very few studies have considered nutrient intakes in the study of gut microbiota differences between women with and without HDP. Here, we hypothesize that dietary nutrition and gut microbiota cooperatively contribute to HDP. We explored the intakes of dietary nutrients and the changes in gut microbiota composition among patients with HDP in the third trimester in Changzhou. We also analyzed the correlations of blood pressure and gut microbiota with clinical characteristics and dietary nutrients. The current work would provide a theoretical basis for the prevention and treatment of HDP.Pregnant women with HDP in the third trimester who planned to deliver in the Maternal and Child Health Care Hospital of Changzhou from October 2019 to October 2020 were selected as the case group, and healthy pregnant women hospitalized during the same period (±1 week) were selected as the control group. The inclusion criteria for patients with HDP were based on “Hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice” , triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), total bilirubin, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid, and C-reactive protein (CRP), by an automatic biochemical analyzer (AU5800).Serum vitamin levels, including vitamin A, vitamin E, and beta-carotene, were detected by high-performance liquid chromatography (Agilent 1260). The standard was dissolved in anhydrous ethanol to prepare the standard reserve solution. A total amount of 200 μl of serum samples stored in dark was added to anhydrous ethanol to remove proteins and then extracted with n-hexane. After centrifugation, the supernatant was blow-dried with nitrogen at ambient temperature, redissolved in methanol, and detected after filtration. Finally, the standard curve was drawn to calculate the content of vitamins.Dietary intake during the previous 4 weeks was assessed using a food frequency questionnaire (FFQ), which was conducted face-to-face by trained dietitians. The questionnaire was modified on the basis of the questionnaire used in the Chinese nutrition and health surveillance. Participants were asked to report the consumption frequency and the average consumption of food items per time according to food pictures labeled with standard portion sizes. The daily average consumption of each item was calculated by the consumption frequency and the average consumption per time. Finally, the data were imported and computed to obtain the nutrient intakes by using NCCW 12.0 , which is primarily based on China Food Composition 2002 and 2004.At least 500 mg of fresh feces from each participant was aseptically collected, then transferred and stored at a −80°C freezer within 2 h. Fecal bacterial genomic DNA was extracted using MagPure Stool DNA KF kit B , and 16S rDNA V4-region sequencing was conducted based on Illumina HiSeq 2500 by Huada Medical Laboratory Co., Ltd. . DNA samples were amplified with the primers 515F (5'-GTGCCAGCMGCCGCGGTAA-3') and 806R (5'-GGACTACHVGGGTWTCTAAT-3'). The pairs of reads obtained by paired-end sequencing were joined to obtain Tags by using FLASH 1.2 . The Tagt-test or Mann–Whitney U-test was used to compare the mean levels of continuous variables with normal distributions or with non-normal distributions between pregnant women with and without HDP. Chi-square test was used to compare the distribution of categorical variables between groups by using SPSS 23.0. The alpha-diversity  and relative abundance of gut microbiota were estimated online , and GraphPad Prism 8.0 and ggplot2 package in R 4.0.3 were used for visualization. The beta-diversity of gut microbiota was estimated using R package vegan based on Bray-Curtis distance, principal coordinate analysis (PCoA) was plotted with R package ggplot2 for visualization, and permutational MANOVA was used for comparison among groups. LEfSe analysis was performed online  based on linear discriminant analysis (LDA). The default value of LDA was 2. Correlation analysis was performed based on Spearman's ranking, and heat map was used for visualization by HemI 1.0. A logistic regression model was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of the association between differential gut microbial genera and HDP risk. Model 1 was a crude model, and model 2 was adjusted for covariates as follows: age, gestational week, pre-pregnancy body mass index (BMI), and parity . Moreover, bootstrap method was used to evaluate the stability of regression model. All p values were two-sided and p < 0.05 was considered significant.Student's p < 0.05). Subjects with HDP had significantly elevated serum levels of AST, uric acid, and CRP, and significantly lower serum levels of total bilirubin, albumin, and vitamin A than those without HDP (p < 0.05).The clinical characteristics of the case group and the control group are summarized in p < 0.05). No significant differences in other dietary nutrient intakes were detected between the two groups (p > 0.05).A total of 91 FFQs were collected. As shown in Systolic blood pressure and DBP were both positively correlated with pre-pregnancy BMI, uric acid, and CRP, and negatively correlated with total bilirubin in all subjects. For all participants, albumin was negatively correlated with SBP. Among patients with HDP, SBP was positively correlated with CRP and dietary intakes of sodium and calcium .2 = 0.009, p = 0.094). As shown in p = 0.076) and Chao1 index (p = 0.058) of gut microbiota in the case group had a decreasing trend compared with those in the control group, though the difference was not statistically significant. The Simpson index (p = 0.126) and Observed species index (p = 0.101) were not significantly different between the two groups.A total of 129 fecal samples were collected (55 from the case group and 74 from the control group). A total of 5,306,609 reads were obtained by 16S rDNA sequencing and clustered into 4,622 OTUs. As shown in p < 0.05). The relative abundances of Firmicutes and Proteobacteria showed no significant difference between the two groups (p > 0.05)  .p < 0.05)   . At the  < 0.05) , 5. . At theThe differential microbiota and their contribution at five levels from phylum to genus between the case group and the control group were identified by LEfSe analysis . A totalBacteroides was positively correlated with pre-pregnancy BMI and serum beta-carotene, and negatively correlated with LDL-C, ALT, AST, and DBP. The relative abundance of Blautia was positively correlated with ALT, AST, and dietary energy intake in the case group. Among subjects with HDP, the relative abundance of Prevotella was positively correlated with ALT and DBP. The relative abundance of Bifidobacterium was positively correlated with albumin and dietary intakes of energy, vitamin C, and vitamin E in patients with HDP  of HDP indicated that the relative abundance of Bacteroides was positively related to HDP , and the relative abundance of Bifidobacterium was negatively associated with HDP . After adjustment for age, gestational week, pre-pregnancy BMI, and parity (model 2), the relative abundance of Bifidobacterium remained significantly negatively associated with HDP . The results of Bootstrap indicated a good stability of these associations (p < 0.05). However, the association between the relative abundance of Bacteroides and HDP was no longer statistically significant in model 2 (In the unadjusted model (model 1), the  model 2 .Bifidobacterium was significantly negatively associated with HDP.Hypertensive disorders of pregnancy is a complication of pregnancy that severely threatens maternal and infant health, and is the second leading cause of maternal death worldwide . The preWe found a significant reduction in dietary intakes of vitamin A and vitamin C among women with HDP compared with healthy controls. A cross-sectional study found that women with PE tended to intake lower vitamin A compared to non-PE women . The serOur study showed that there was no significant difference in alpha-diversity between the two groups, but the Shannon index and Chao1 index in the case group had a decreasing trend compared with the control group, suggesting a lower richness and uniformity of gut microbiota in patients with HDP compared with that in the control group. Similarly, previous studies found that the alpha-diversity of pregnant women with PE in the third trimester also showed a decreasing trend compared with the controls, though the difference was not statistically significant , 33, 34.Bacteroides were enriched in pregnant women with HDP. Bacteroidota is a gram-negative bacteria that produces lipopolysaccharide (LPS)  , and thede (LPS) . In addirtension . Studiesrtension , 34.Prevotella was revealed among patients with HDP in this study. Prevotella may produce SCFAs using fiber and polysaccharides  BioProject, The studies involving human participants were reviewed and approved by the Ethics Committee of Changzhou Maternal and Child Health Care Hospital (QNRC2016302). The patients/participants provided their written informed consent to participate in this study.JY and YS conceived and designed the study. JY, BZ, TM, and HH recruited clinical participants, collected samples, and conducted the questionnaire survey. JY drafted the manuscript. YS critically revised the manuscript. All authors read and approved the final manuscript.This study was supported by the Young Talents Science and Technology Project of Changzhou Health Commission (No. QN202050).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.


Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract, with a 5-year survival rate of 5%. The prognostic models to predict the prognosis of patients with GBC remain controversial. Therefore, to construct a prognosis prediction of GBC, a retrospective cohort study was carried out to investigate the prognostic nutritional index and histological grade in the long-term outcome of patients with GBC after radical surgery (RS).A retrospective study of a total of 198 patients with GBC who underwent surgical treatment were enrolled. The hematological indicators, imageological data, and perioperative clinical data were acquired for statistical analysis and poor prognosis model construction.p < 0.05), but there was no significant difference in prognosis for patients with non-poorly differentiation (NPD) or low-risk scores after RS (p > 0.05).Prognostic nutrition index (PNI) < 45.88, maximum tumor diameter (MTD) > 2.24 cm, and jaundice (JD) were all associated with a poor prognosis in multivariate logistic regression analysis. The prognosis prediction model was based on the three risk factors, which indicated a superior predictive ability in the primary cohort [area under the curve (AUC) = 0.951] and validation cohort (AUC = 0.888). In multivariate Cox regression analysis, poorly differentiation (PD) was associated with poor 3-year survival. In addition, Kaplan–Meier (KM) survival analysis suggested that GBC patients with high-risk scores and PD had a better prognosis after RS (Our prediction model for GBC patients with prognosis evaluation is accurate and effective. For patients with PD and high-risk scores, RS is highly recommended; a simple cholecystectomy can also be considered for acceptance for patients with NPD or low-risk score. The significant findings provide a new therapeutic strategy for the clinical treatment of GBC. The surs routes –6. The ms routes , 8. TherAlthough various scoring systems are used in clinical practice, the preoperative prognostic models to predict the prognosis of patients with GBC remain controversial –11. ThesWe conducted a retrospective study on a total of 198 patients with GBC who underwent surgery in the Department of Hepatobiliary Surgery of Fujian Medical University Union Hospital between January 2008 and December 2017. The study was carried out in accordance with the protocol approved by the Ethics Committee of the Medical Faculty of Fujian Medical University, according to the Declaration of Helsinki.All the patients included in the present study fit the following criteria: (1) patients with GBC underwent surgery [radical surgery (RS) or non-radical surgery (NRS)]; and (2) neither radiotherapy nor chemotherapy was administered prior to or posterior to the surgery. The histological diagnosis of the tumors was based on the criteria of the World Health Organization (WHO), and the TNM stage was determined according to the American Joint Committee on Cancer . The patients with the following characteristics were excluded: (1) the medical history, operation records, and auxiliary examination are incomplete; (2) death occurred during and after the operation; (3) patients are not willing to cooperate with the investigation during the follow-up; and (4) patients with coexisting or previous cancers. Based on the hospital database, the following data were collected for each patient, such as age, gender, T stage, and other miscellaneous clinical characteristics.9/L) and serum albumin (ALB) (g/L) within 1 week before surgery as follows (9/L). Jaundice was defined as yellow staining of the sclera of the patients (serum bilirubin > 34 mmol/L). Patients with postoperative recurrence/metastasis/death time less than 36-months were considered to have poor prognosis. The obtained hematological index and imageological index were established with a receiver operating characteristic (ROC) curve of poor prognosis. The cut-off values of these variables were obtained according to the best Youden index when these areas under the curve (AUC) were more than 0.6, and then classified into two categories; the classification criteria for each potential index were determined through the literature when the AUC was less than 0.6.The prognostic nutrition index was calculated from the baseline clinical peripheral lymphocyte count (PLC) , and pectoral and abdominal computed tomography (CT) or magnetic resonance imaging (MRI) were performed during the follow-up period. The median follow-up duration was 17.5 months (range 1–36 months). The follow-up rate of this study was 87.9%.t-test was used to compare the groups of continuous, normally distributed variables. Pearson’s χ2 test was used to determine the significance of the differences for the dichotomous variables. Univariate analysis and multivariate analyses with the logistic/Cox regression proportional hazard model were performed to evaluate the prognostic factors. OS survival and overall recurrence were defined as the time from operation until death or censoring, which were calculated by the Kaplan–Meier (KM) analysis, and the difference in groups was assessed by the log-rank test. All values of ps were two-sided, with statistical significance set at p less than 0.05.The statistical analyses were performed by standard SPSS . The categorical variables were presented as numeric values and percentages, and the continuous variables with normal distributions were presented as means and standard deviations (mean ± SDs). An independent n = 138) and validation cohort (n = 60) in a ratio of 7:3. A poor prognosis prediction model was built and validated based on the clinical and laboratory indicators. According to the best Youden index, all patients were divided into high-risk and low-risk groups based on an optimal cut-off value. Subsequently, survival analyses were compared between high-risk and low-risk groups and their subgroups.The flowchart of the manuscript design is presented in p > 0.05).The baseline hematological, imageological, and pathological characteristics in the primary cohort and validation cohort are shown in The ROC curve of poor prognosis established with the candidate factors of PNI and MTD is shown in OR]: 3.508, p < 0.001), MTD > 2.24 cm , PD , Jaundice , liver invasion . After multivariate analysis, the positive results were, respectively,: PNI < 45.88 , MTD > 2.24 cm , JD . The multivariable analysis of these risk factors of poor prognosis and measurement of the risk scores are presented in The eighteen candidate risk factors related to poor prognosis were screened by univariate logistic regression analysis in the primary cohort which are shown in OR and a nomogram plot for predicting poor prognosis risk were presented in To further verify the validity of this model, a forest plot of independent predictors of poor prognosis with the p was 0.090 in the primary cohort and was 0.192 in the validation cohort) indicate a reliable calibration. The decision curve shown in A calibration analysis of this poor prognosis prediction model was presented in p < 0.001; p < 0.001; p < 0.001) and validation cohort . The overall recurrence rate between the low-risk and high-risk groups in the primary cohort was 36.50 and 83.19%, respectively, and the difference was statistically significant  and NRS (stands for simple cholecystectomy), the patients in the poor prognosis low-risk and high-risk groups were classified into RS and NRS subgroups, respectively, and the KM survival analysis was conducted between RS and NRS subgroups. In the high-risk group, the OS rate in the RS and NRS subgroup were, respectively, 32.99 and 12.21%, indicating a significant statistical difference (p < 0.05). However, no statistical difference existed between RS and NRS subgroups in the NPD group , so there may be some deviations in the results. In addition, our prediction model is established by PNI, MTD, and jaundice, but other clinical characteristic parameters, such as tumor margins, invasion, and metastasis, have not been comprehensively evaluated. Hence, the issues mentioned above need to be further verified by more and larger participants, multicenter randomized controlled studies, and this is also the research plan that we need to carry out further in the future.In summary, we have developed and validated a novel poor prognosis prediction model based on PNI, MTD, and jaundice for patients with GBC, which shows superior practicability and availability. Due to a high-risk score of early tumor recurrence, our findings demonstrate that RS is necessary for those preoperative or intraoperative diagnosis of patients with GBC. Nevertheless, for those postoperative accidental diagnosis of GBC, whereas for patients with PD and a high-risk score, RS is highly recommended; while for the patients with high and moderate differentiation or a low-risk score, rather than a traumatic RS, a simple cholecystectomy can be considered for acceptance. These findings demonstrate important guiding significance for the next treatment strategy of accidental GBC which occasionally appears in clinic.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 Ethics Committee of the Medical Faculty of Fujian Medical University. The patients/participants provided their written informed consent to participate in this study.SQ and PC contributed to the conception of the study. HH, ZY, and GC contributed to the data collection and audit. SQ and PC performed the data analyses and wrote the manuscript. 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.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.