Using an ensemble machine learning technique that incorporates the results of multiple machine learning algorithms, the study’s objective is to build a reliable model to predict the early mortality among hepatocellular carcinoma (HCC) patients with bone metastases.We extracted a cohort of 124,770 patients with a diagnosis of hepatocellular carcinoma from the Surveillance, Epidemiology, and End Results (SEER) program and enrolled a cohort of 1897 patients who were diagnosed as having bone metastases. Patients with a survival time of 3 months or less were considered to have had early death. To compare patients with and without early mortality, subgroup analysis was used. Patients were randomly divided into two groups: a training cohort  and an internal testing cohort . In the training cohort, five machine learning techniques were employed to train and optimize models for predicting early mortality, and an ensemble machine learning technique was used to generate risk probability in a way of soft voting, and it was able to combine the results from the multiply machine learning algorithms. The study employed both internal and external validations, and the key performance indicators included the area under the receiver operating characteristic curve (AUROC), Brier score, and calibration curve. Patients from two tertiary hospitals were chosen as the external testing cohorts (n = 98). Feature importance and reclassification were both operated in the study.The early mortality was 55.5% (1052/1897). Eleven clinical characteristics were included as input features of machine learning models: sex (p = 0.019), marital status (p = 0.004), tumor stage (p = 0.025), node stage (p = 0.001), fibrosis score (p = 0.040), AFP level (p = 0.032), tumor size (p = 0.001), lung metastases (p < 0.001), cancer-directed surgery (p < 0.001), radiation (p < 0.001), and chemotherapy (p < 0.001). Application of the ensemble model in the internal testing population yielded an AUROC of 0.779 , which was the largest AUROC among all models. Additionally, the ensemble model (0.191) outperformed the other five machine learning models in terms of Brier score. In terms of decision curves, the ensemble model also showed favorable clinical usefulness. External validation showed similar results; with an AUROC of 0.764 and Brier score of 0.195, the prediction performance was further improved after revision of the model. Feature importance demonstrated that the top three most crucial features were chemotherapy, radiation, and lung metastases based on the ensemble model. Reclassification of patients revealed a substantial difference in the two risk groups’ actual probabilities of early mortality . Patients in the high-risk group had significantly shorter survival time than patients in the low-risk group (p < 0.001), according to the Kaplan–Meier survival curve.The ensemble machine learning model exhibits promising prediction performance for early mortality among HCC patients with bone metastases. With the aid of routinely accessible clinical characteristics, this model can be a trustworthy prognostic tool to predict the early death of those patients and facilitate clinical decision-making. Primary liver cancer is the most frequent cause of cancer-related death in most regions of the world, and it is predicted to be the sixth most prevalent cancer worldwide in terms of incidence and mortality in 2020, with up to 906,000 new cases and 830,000 deaths . HepatocWith the improvement of prognosis among HCC patients in recent years due to novel imaging techniques and multidisciplinary therapies, extrahepatic metastases now occur more frequently . The bonA number of risk factors, including marital status , primaryWe extracted data from the Surveillance, Epidemiology, and End Results (SEER) Program. SEER is a large oncologic database which collects information on cancer diagnoses and survival for about 30% of the US population with the effort to reduce the cancer burden. We completed the registration form to obtain SEER*Stat (version 8.4.0.1) after reading and signing the Terms of Use Agreement. This software provides us with interface to access to the SEER database and download corresponding data.Between January 1, 2000, and December 31, 2019, patients with histologically confirmed HCC were included for the analysis. The exclusive criteria were as follows (1): Patients did not have bone metastases (2); Patients younger than 18 years old (3); Patients did not have the histological diagnosis of adenomas and adenocarcinomas (4); Patients whose causes of death were missing or unknown (5); Patients were alive or dead of other reason (not attributable to liver cancer) with a follow-up interval of only three or less months; and (6) Patients whose survival time was unknown. Complete data were required for stage and liver cancer-specific mortality, and censoring was derived from the vital status recode.All enrolled patients from the SEER database were divided into two groups: a model training cohort  and a model testing cohort . The model testing cohort was regarded as the internal testing cohort, and the eligible patients from Hainan Hospital of Chinese PLA General Hospital (Sanya) and Hainan Cancer Hospital (Haikou) were served as the external testing cohort (n = 98). When users access to the SEER database, it is unnecessary to obtain formal ethics approval, since it is covered by its open access policy. This study was approved by the Hainan Hospital of Chinese PLA General Hospital and patients gave informed oral consent prior to data collection.Age, sex, race, marital status, tumor (T) stage, node (N) stage, fibrosis score, alpha fetoprotein (AFP) level, tumor size, brain metastases, liver metastases, lung metastases, surgery of lymph, cancer-directed surgery, radiation, and chemotherapy were all taken out of the SEER database. Patients having a survival interval of three months or less were considered to have experienced early mortality. Cancer-specific death was recorded and used in the study. In terms of American Joint Committee on Cancer and Extent of Disease classification, T and N stages were used for analysis. Race was divided into black, white, others, and unknown, the others of race included American Indian, AK Native, Asian, and Pacific Islander.Selection of model features was determined by subgroup analysis of clinical characteristics in the training group, and significant variables were included as the input features of model building. Five machine learning techniques, including an artificial neural network, gradient boosting decision tree, eXGBoosting machine, decision tree, and support vector machine, were investigated in the study to construct an ensemble machine learning model. Each model received the same input features. These models are widely used for binary classification issues in the field of medicine, and this study chose a wide range of models to reflect this. To further explain, gradient boosting decision tree frequently conducts well with risk classification, but an ensemble was introduced to further improve model robustness in the study. Combining the outputs of the artificial neural network, gradient boosting decision tree, eXGBoosting machine, decision tree, and support vector machine, ensemble machine learning can use models created by numerous machine learning techniques to make predictions. Particularly, ensemble models frequently produce superior predicting performance than individual machine learning models , 21. BroThe AUROC was calculated for model discrimination during model evaluation. The models’ capacity for discrimination refers to their power to discern between favorable and unfavorable outcomes. The density probability curve and discrimination slope were used in the analysis as additional indicators showing model discrimination. Brier score and visual examination of calibration plots were used to evaluate model calibration, which reflects the consistency between anticipated and observed outcomes. The predicted risk of an event developing vs. the observed risk were plotted in calibration plots, and the calibration slope and intercept-in-large were derived for each plot. For each machine learning model, a clinical net benefit was also calculated using decision curve analysis; this measure of value was accomplished by making decisions based on model predictions. For each model, other key performance measures included specificity, sensitivity, and accuracy.t-test for continuous variables and chi-square test or adjusted continuity chi-square test for proportional variables, the clinical characteristics between patients in the training and testing groups were compared. In order to interpret feature contributions, in terms of the ensemble machine learning model, Shaley Additive Explanation (SHAP) was utilized. Patients were categorized into two risk groups using the ensemble machine learning model, stratified by the ideal cut-off value (threshold). The chi-square test was used to compare the difference of the actual probability of developing early mortality among patients in the high- and low-risk groups. The Kaplan–Meier method and log-rank test were conducted to create the survival curve among patients stratified by risk groups. The statistical tools used for these analyses included the R statistical software  and Python (version 3.9.7). Statistical significance was defined as a two-sided p-value of 0.05.Using the The study included 124,770 people with liver cancer in total. A cohort of 1,897 individuals from the SEER database who had been histologically determined to have HCC with bone metastases were included based on the screening criteria Figure 1A comparison of clinical characteristics was operated between patients in the training and internal testing cohort, and it demonstrated that the two cohorts were comparable because no significant difference was found in the distribution of the clinical characteristics Table 2.via subtracting 20.0% in each predicted risk of early mortality. Thus, the new revised calibration plot was provided . To be specific, patients in the high-risk group were 2.37 times more likely to suffer early death as compared to patients in the low-risk group. The Kaplan–Meier survival curve also demonstrated that patients in the high-risk group had significant shorter survival time in comparison to patients in the low-risk group. Patients in the high-risk group may therefore require greater care. Surgery may not be advised for those individuals because they were at a high danger of passing away within 3 months, would not have enough time to recuperate from surgery, and had slim prospects of ever benefiting from it. In addition, a multidisciplinary cooperation was recommended to manage HCC patients with bone metastases due to its complexity , and if The restrictions of this study are outlined below: (1) Because some clinical criteria, such as Child-Pugh grade, are not available in the SEER database, this study’s selection of variables is constrained. (2) The information that was taken from the SEER database was on the condition at the time of the initial diagnosis, suggesting that bone metastases that occur in the later stages may not have been documented. (3) The model showed positive predictive performance in both the internal and external validation, but additional external validation is still needed to increase the model’s generalizability.In conclusion, the ensemble machine learning model shows promising prediction performance for early mortality among HCC patients with bone metastases. This model can be a prognostic tool to predict the survival outcome of those patients and facilitate clinical decision-making. Surgery might not be advised for patients in the high-risk group because they had a high chance of passing away within 3 months. For a subset of patients, chemotherapy, radiation therapy, and the avoidance or treatment of lung metastases are advised due to their positive effects on survival.https://seer.cancer.gov/. External testing data are available under reasonable request to the corresponding authors.Publicly available datasets were analyzed in this study. Training and internal testing data are available at This study was approved by Hainan Hospital of Chinese PLA General Hospital and patients gave informed written consent prior to data collection. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors conceived and designed the analysis; ZL, SW, XC, and QY oversaw data collection, YQ and ML performed the analysis, and all authors provided clinical interpretation of the findings. MY and ML drafted the manuscript. The corresponding author has full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors contributed to the article and approved the submitted version.


Parathyroid carcinoma (PC) is an extremely rare malignant tumor with an incidence of about 6 new cases per 10 million inhabitants per year. While several papers have been published on treatments and outcomes of PC patients with loco-regional disease, little is known about the prognosis, treatment strategies, and prognostic factors of patients with distant metastasis.We performed a systematic review and a pooled analysis of histopathologically confirmed PC cases published in literature using the following keywords: “metastasis–metastatic–secondary nodes” AND “parathyroid carcinoma”. Original case reports and case series reporting metastatic parathyroid carcinoma were included. Data from 58 articles were extracted in a piloted form by five reviewers on a shared database.Seventy-nine patients with metastatic PC were identified between 1898 and 2018. Ten (13%) patients had synchronous metastases, while metachronous metastases occurred in 43 (54%) patients. The remaining 26 patients developed metastatic disease concomitantly to local recurrence. Primary hyperparathyroidism guided the diagnosis of metastatic recurrence in 58 (73%) patients. Surgery was the main primary approach adopted, as it was performed in 43 (54%) patients. Twenty (25%) patients underwent systemic antineoplastic therapy, consisting of chemotherapy, immunotherapy, tyrosine kinase inhibitors, and hexestrol therapy. Bone resorption inhibitors had a limited efficacy in the long-term control of hypercalcemia. After a median follow-up of 37.5 months, 43 (55%) patients died, 22 (51%) due to the consequences of uncontrolled PHPT. The median overall survival was 36 months (range: 1–252). Surgery was associated with a better OS , whereas bone metastases represented a negative prognostic factor .Metastatic PC has a relatively poor prognosis. The main goals of treatment are to counteract tumor growth and control hypercalcemia. Surgery of metastases is the best approach to achieve rapid control of PHPT and longer survival. Target therapies and immunotherapy deserve to be extensively tested in metastatic PC and strategies to better control hypercalcemia should be implemented. Parathyroid carcinoma (PC) is an extremely rare malignant tumor with an incidence in the US SEER registry of about 6 new cases per 10 million population per year –4. UnlikApproximately 90% of PC patients have symptomatic primary hyperparathyroidism (PHPT) . The mosDue to the early onset of PHPT, PC is usually diagnosed as a local disease and the definitive diagnosis is based on pathological features of capsular invasion, vascular invasion, and mitotic activity , 14. MolSurgery is the mainstay of PC management. The gold standard is en bloc resection of all involved tissues and should include at least the PC and the ipsilateral thyroid lobe; the role of the central lymph node dissection is still debated. Surgery must be performed with care to avoid spillage of tumor cells into the surgical field .Survival of PC patients is reportedly heterogeneous , 13. TheThe estimated risk of recurrence is 50%–60% at 2–5 years, more frequently in the case of a non-radical surgical approach , 22, 23.While several papers have been published on the outcome of patients with early-stage disease, little is known about the prognosis, treatments, and prognostic factors of patients with relapsed and metastatic disease.It has been reported that morbidity and mortality associated with metastatic PC is in many cases due to PHPT and related complications rather than to tumor progression . HoweverWe systematically reviewed all cases of metastatic PC described in the literature, with the aim to perform a pooled analysis to obtain information on clinicopathological features, treatment strategies, patient outcome, and prognostic factors. Based on the results obtained, we provided some suggestions on possible clinical approaches.PRISMA checklist was used to present the results of this systematic reviewTo the extent of the best published literature on metastatic PC, a four-step search strategy was planned. First, we identified the following keywords and MeSH terms in PubMed: “metastasis–metastatic–secondary nodes” AND “parathyroid carcinoma”. Secondly, the terms were searched in PubMed. Third, based on our objective, case reports and case series reporting metastatic parathyroid carcinoma were included in this review. Fourth, references to the included articles were scrutinized for additional papers. The last search was performed on 15 December 2021. Only articles that described the clinical history and treatment of individual patients with metastatic parathyroid carcinoma were selected. All articles that did not describe treatments for metastatic disease or did not report outcome or survival were excluded. No restrictions were imposed on publication date or publication status and only English-language articles were selected. The eligibility assessment was performed in an independent and unblinded standardized manner by five reviewers. Disagreements among reviewers were resolved by consensus.Data were extracted by five reviewers on a shared database with collection and coding rules for the variables explained. After the first data extraction from a sample of included studies, the consistency of the extracted data was assessed to ensure that the reviewers who extracted the data interpreted the forms and draft instructions well. Each reviewer completed data extraction from each article independently. The following data were reported: (1) general information of the paper ; (2) patient-disease data at first diagnosis ; (3) recurrence data ; (4) metastasis data ; (5) hypercalcemia data ; and (6) follow-up data . If a full paper could not be retrieved, information was extracted from the abstract.in vitro, or animal). The full text of the remaining 122 articles was evaluated, and from the references of these studies, 15 additional articles were identified. Seventy-eight articles were excluded because they contained no data on treatment of metastatic disease, outcomes, or follow-up or because of possible duplicate use of data. Finally, data from 59 papers were included in this pooled analysis. The search revealed 1,225 potentially relevant articles on metastatic parathyroid carcinoma. Reading the title or abstract, 1,103 studies were excluded for various reasons  for continuous variables. Normal distribution of continuous variables was assessed by Kolmogorov–Smirnov and Shapiro–Wilk tests, when applicable. Cox proportional hazards models were introduced to investigate possible prognostic factors for overall survival. We accepted a type I error of maximum 5%. All analyses were performed with SPSS .We identified 79 patients diagnosed with metastatic PC between 1898 and 2018. Data of 59 of them (74%) were derived from case reports, 14 (18%) from single-institution case series, and 6 (8%) from multicenter series. Surgery was the primary approach for metastatic disease, as it was performed in 43 patients (54%). Thirty-five of them (81%) underwent resection of lung metastasis, while in six and four patients, surgery was performed on brain and liver metastases, respectively. In nine patients, surgery was followed by radiotherapy. No patients received adjuvant systemic therapy. Radiotherapy alone was the primary approach in 9 patients (12%); 20 patients (25%) underwent a systemic antineoplastic therapy, 11 (55%) of which as a primary approach Table 2.The diagnosis of metastatic disease was associated with PHPT in 58 patients (73%), while 10 (13%) patients reported symptoms caused by tumor invasion  and 3 patients both. In the remaining eight patients (10%), the diagnosis was incidental during follow up. The median calcium level was 14.5 mg/dl . As reported in After a median follow-up of 37.5 months, 43 patients (55%) died. The causes of death were as follows: uncontrolled PHPT in 22 patients (51%), tumor progression in 14 patients (32%), and other causes in 3 patients (7%). The cause of death was not specified for four patients. The median overall survival from diagnosis of metastasis to death or last follow-up (OS) was 36 months . These data have important implications on the follow-up of operated patients, which is based on prospective evaluation of blood levels of calcium and parathyroid hormone but should also include periodic radiological evaluations. Since, in the present series, the most frequent site of metastasis was lung, followed by bone, liver, and lymph nodes, a CT scan of the abdomen and thorax may be considered adequate in the follow-up. However, 9% of patients developed brain metastases; thus, a brain CT and/or MR should be considered in case of appearance of suspicious neurological symptoms. Noteworthy, in 26 patients (33%), distant metastases occurred together with local recurrence; this emphasizes the need to include accurate clinical examination and neck ultrasound in the follow-up. With regard to nuclear medicine techniques, the case series presented in literature suggest that a total body acquisition with 99mTc-sestaMIBI and 18F-FDG PET/CT can be complementary to conventional imaging in the initial staging, especially in more aggressive and rapidly evolving forms , 26. HowThe main goals of treating metastatic PC are to counteract tumor growth and control hypercalcemia. The control of hypercalcemia is of paramount importance, since in this series it was the cause of death in half of the patients. All PC patients with PHPT had at least one metastatic site; however, the extent of disease did not correlate with the severity of hypercalcemia. Therefore, surgery of metastasis with radical intent was effective in controlling hypercalcemia and should be pursued whenever possible, as it allowed rapid control of PHPT and a longer survival. This is relevant as many patients present an oligo metastatic disease at first relapse, and this observation, together with the predilection of the lung as a site of metastasis, favors surgery. If complete excision of all metastases is not possible, local regional treatments, such as radio-frequency ablation, similarly to what is adopted in other tumors, could reasonably be considered, although data on the efficacy of these treatments could not be obtained in this series.With regard to systemic therapies, long-term control of hypercalcemia in malignancies can be achieved with the use of bone resorption inhibitors such as bisphosphonates and denosumab. In patients with PC-related hypercalcemia, however, the effect of these drugs was transient, and the syndrome was invariably resistant after initial control. Denosumab appears to be effective in patients with zoledronic acid resistance , but ourThe prognosis of patients with metastatic PC was relatively poor, with a median survival of 36 months, but with considerable variability over a range of 1 to 255 months. The independent prognostic parameters were surgery as a favorable factor, underlining the importance of this therapeutic modality in this setting, and bone metastases as a worsening factor. This latter finding is in contrast with what has been observed in other metastatic malignacies , 49, in Data on the efficacy of systemic anticancer therapies are scarce and sometimes anecdotal. The few cases treated with chemotherapy have shown activity of alkylating drugs and anthracyclines. Target therapy could be a suitable option and several potentially actionable genomic alterations have been described, including PTEN, NF1, KDR, PIK3CA, and TSC242 , 16. In In this study, we included the largest number of metastatic PC cases. Previous studies were mostly case reports or case series, and mostly included PC with and without recurrence. We focused on metastatic status, overall survival, and treatment, which were not highlighted in previous studies. To reduce potential bias in the analyses, we undertook a systematic review with the independent application of pre-defined inclusion criteria and data extraction. However, our study has some limitations. Demographics data were only derived from secondary data without standard protocols and from a long period; hence, there was high heterogeneity. Moreover, the study suffered from publication bias.Metastatic parathyroid carcinoma arises in the fourth decade of age and has a poor prognosis. Increased calcemia and parathormone values lead to diagnosis in most patients, although some report only symptoms caused by the growth of the tumor mass. Oligometastatic lung disease is the most frequent pattern of recurrence, and in about one-third of patients, local recurrence occurs together with distant metastases. The main goals of the treatment are to counteract tumor growth and control hypercalcemia. The latter challenge is of paramount importance, as it is the cause of death in at least half of patients. Surgery of metastases is the best approach to achieve rapid control of PHPT and longer survival. When surgery cannot be radical, other complementary local–regional approaches can be used. Systemic therapies should be considered when the disease could not be managed with local ablative treatments. According to the few data in the literature, dacarbazine, anthracyclines, sorafenib, and other antiangiogenetic drugs provided some positive results in the management of metastatic PC. Also, immunotherapy with vaccines based on bovine PTH-like immunogenic fragments seems promising, and this strategy deserves to be tested in association with modern immune checkpoint inhibitors. Based on the results of this systematic review and pooled analysis, we propose a list of suggestions for the management of patients with metastatic PC Table 4.The original contributions presented in the study are included in the article/AA, AB, SG, and PB contributed to conception and design of the study. AA, DS, AT, LL, and CM contributed to the research and extraction of data. MZ performed the statistical analysis. AA, DS, AT, LL, and CM wrote the first draft of the manuscript. MZ wrote a section of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted versionThe 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.


Currently, little is known about the mechanism of how university students’ attitudes toward entrepreneurship education (ATEE) affect entrepreneurial self-efficacy (ESE) in the post-pandemic entrepreneurial environment. Based on the existing research, this study explores the relationship between ATEE, the post-pandemic entrepreneurship environment, and ESE through a questionnaire survey. A total of 910 university students from three universities in Zhejiang Province, China participated, with an effective rate of 92.9%. The data collection focused on the period from August to December 2020. In this study, Stepwise Multiple regression analysis was used to analyze university students' ATEE and its impact on ESE, as well as the moderating effect of the post-pandemic entrepreneurial environment. The results show that the gender of university students and the entrepreneurial experience of their family members exist significant differences in their ATEE and also on their ESE. Furthermore, ATEE exert a significant and positive impact on their entrepreneurial self-efficacy, while the post-pandemic entrepreneurial environment plays a positively moderating role in this influential process. Entrepreneurship education has always been an important program of colleges and universities to cultivate innovative and entrepreneurial talents. A variety of entrepreneurship courses, projects, and competitions have been emerging . AdminisAmong the various influencing factors associated with university students' ESE, entrepreneurship education had been proven to have a considerable impact . PlanninAt present, most countries in the world remain in the stage of containing the novel coronavirus outbreak. While people are working hard to control the spreading of the virus, epidemic prevention and control had also brought profound changes to styles of people's learning, work, and life . These uIn summary, this study not only examines the influence of university students' ATEE on ESE, but also further explores the regulatory role of the post-epidemic entrepreneurial environment on this influence. There are two major questions in this study: First, whether university students' ATEE positively affect ESE? Second, whether the post-epidemic entrepreneurial environment can effectively adjust the impact of university students' ATEE on ESE? This will enable to further understand the critical factors affecting the university students' ESE, thus providing a new direction for the effectiveness of implementing entrepreneurship education in universities, and also offering guidance significance for improving ESE of university students.Empirical studies had shown that university students' ATEE significantly positively affected entrepreneurial intentions , and so Hypothesis 1: University students’ ATEEs can significantly affect their ESEs.The entrepreneurial environment has been playing an important role in the development of entrepreneurship. Bandura proposed a social cognitive theory, which emphasized the “individual–environment–behavior” interaction . The conHypothesis 2: The post-pandemic entrepreneurial environment performs a moderating role in the relationship between university students’ ATEE and ESE.In this study, the relationship between ATEE and entrepreneurial self-efficacy (ESE) and the moderating effect of the Post-pandemic Entrepreneurial Environment (PEE) in this relationship were investigated using ATEE as the independent variable, ESE is the dependent variable, and PEE as the moderator .Each questionnaire involved in this study consists of four sections, namely, basic information about the participants, a scale of university students’ ATEE, a scale of their ESE, and a scale of post-pandemic entrepreneurial environment. Two English majors were asked to conduct translation and back translation for each of the three scales from the original questionnaire to narrow down cross-cultural differences.Before the formal test, this study applied the convenience sampling method to select 119 volunteers from a comprehensive university in Zhejiang Province to conduct the pilot test. According to their feedback and the reliability and validity analysis of the pilot test data, some items that did not meet the standard were deleted, and a formal questionnaire was finally formed. This study and these questions do not pose any potential risks to participants. The study applied a 5-point Likert scale to measure each item, ranging from 1 to 5, with 1 meaning totally disagree and 5 meaning totally agree.This study conducted anonymous surveys on ATEEs, PEEs, and ESEs of three universities respectively. Three universities in Zhejiang Province were selected as the target, which are provincial model ones for entrepreneurship education with a relatively integral major setup. The major considerations for this choice are outlined below. First, the three universities offer a comprehensive popular course of entrepreneurship “Career Planning and Entrepreneurship” for most of their junior students, while some of their senior students receive a hierarchical and categorical entrepreneurship education with elective courses, such as “Fundamentals of Entrepreneurship for University Students,” in addition to entrepreneurship projects, competitions, and practices. Second, all three universities are located in Zhejiang Province, a relatively economically developed area in China with a solid humanistic foundation and strong policy support for entrepreneurship. Finally, Zhejiang Province implemented a good control program against the COVID-19 pandemic so that people returned to work and school quite early. These are favorable factors for the creation of an entrepreneurial environment. Therefore, these three universities have been selected for this study, and their samples are both typical and pioneering in the sense of entrepreneurship education.In the formal test, convenience sampling method was adopted to sample students from different majors of the above three universities in Zhejiang Province of China. First, we contacted the teachers responsible for entrepreneurship in universities and selected 1,050 students as the subjects of the questionnaire. Second, we conducted data collection. Data collection was mainly concentrated between August and December 2020. Participants were informed by trained researchers that participation was voluntary and anonymous and that data collected were protected by the Declaration of Helsinki . The resAmong the respondents, 220 were male and 690 were female students; The subjects of this study were university students ranging in ages from 18 to 24 years old. 560 people were juniors, and 350 people were at the undergraduate level and above. 240 had family members with experiences in entrepreneurship and 670 did not. In terms of receiving entrepreneurship education, 67.3% of the students had attended entrepreneurship courses, 62% had attended entrepreneurship lectures, 16% had participated in entrepreneurship competitions or projects, 16.8% had participated in entrepreneurship practices, and 12.1% had participated in other forms of entrepreneurship education.This study was approved by the Ethics Committee of Ningbo University and the test was conducted with the informed consent of the participants.This part of the questionnaire focuses on participants’ gender, major, grade, educational background, family members with or without entrepreneurship experience, and the form of entrepreneurship education they have participated in.This study adopts a revised version of the ATEE scale created by Jena, Cronbach’s α for the cognitive component, affective component, behavioral component, were 0.76, 0.79, 0.81 respectively, AVE values for the three components were 0.69,0.72,0.67 separately. CR values for CA, AA, BA, were 0.89,0.89,0.83 individually, which all showed good validity and reliability . The resThis scale, developed by This scale was developed by Confirmatory Factor Analysis see  was perfConfirmatory Factor Analysis was performed on the formal test data of PEE, and the results showed: RMR=0.029 (less than 0.08), NFI=0.893 (close to 0.9), IFI=0.895 (close to 0.9), TLI=0.842 (close to 0.9), CFI=0.895 (close to 0.9), RMSEA=0.062 (less than 0.08), and SRMR=0.043 (less than 0.08), indicating that the measurement model basically fitted the observed data . The AveConfirmatory Factor Analysis was performed on the formal test data of ESE, and the results showed: RMR=0.011 (less than 0.08), GFI=0.983 (more than 0.9), NFI=0.991 (more than 0.9), IFI=0.992 (more than 0.9), TLI=0.984 (more than 0.9), CFI=0.992 (greater than 0.9), SRMR=0.013 (less than 0.08), showing that the measurement model fitted the observed data well . The AveThe data analysis and statistics in this study fall into the following steps: First, SPSS and AMOS are used to test the reliability and validity of the scale of university students’ attitudes toward entrepreneurship education, the scale of post-pandemic entrepreneurial environment, and the scale of entrepreneurial self-efficacy; next, a correlation analysis is made to explore the correlations among the three main variables; finally, if the correlations among the three variables were significant, a hierarchical regression analysis would be applied to explore the mechanisms of action between the variables and the environment moderating effect of post-pandemic entrepreneurship.χ2 = 7733.281, df = 275, GFI = 0.481, RMSEA = 0.173); the hypothetical model  significantly outperforms the one-factor model . Although the above tests fail to rule out the threat of common method biases, they have provided evidence that the problem of common method biases in this study is not serious.According to the result of the confirmatory factor analysis of the one-factor model in this study, however, the one-factor model is found not to fit the data well ; male students perceive the post-pandemic entrepreneurial environment significantly higher than do female students ; male students have significantly higher entrepreneurial self-efficacy than do female students ; students whose family members have entrepreneurship experience have significantly higher attitudes toward entrepreneurship education than students whose family members have no such experience ; entrepreneurial self-efficacy is significantly higher among students whose family members have entrepreneurship experience than among students whose family members have no such experience ; students whose family members have entrepreneurship experience perceive the post-pandemic entrepreneurial environment significantly higher than students whose family members have no such experience .The results of t-tests on the independent samples  and 4 haStepwise multiple regression analysis was conducted to the study. Assumption of regression analysis was tested including Independence, Normality, and Homogeneity of Variables. First, having autocorrelation means the scores can be repeating patterns or scores of a sample are not independent. Durbin–Watson value of 1.970 indicated no autocorrelation as Durbin Watson test value between 1.5-2.5 denotes no autocorrelation . Second,Therefore, this study used multiple regression analysis to examine whether university students’ attitudes toward entrepreneurship education affect entrepreneurial self-efficacy and whether the post-pandemic entrepreneurial environment has a moderating effect on this, after controlling for demographic variables (gender and family members with or without entrepreneurship experience) that can also have an effect on university students’ attitudes toward entrepreneurship education and entrepreneurial self-efficacy. Convert the control variables into dummy variables , turn the control variables into independent variables , and conduct a linear regression analysis;Step 1: Using the forced entry method, put the attitudes toward entrepreneurship education into independent variables, and conduct regression analysis to examine the effect of attitudes toward entrepreneurship education on entrepreneurial self-efficacy, the results are as Model 1 ;Step 2: Use moderating variables of the post-pandemic entrepreneurial environment as third-level independent variables, and conduct the regression analysis, the results are as Model 2 ;Step 3: By calculating the variables to obtain the results of the interaction term, standardize the interaction term as the fourth-level independent variable, and then and conduct the regression analysis including this variable to examine the impact of interaction on entrepreneurial self-efficacy. The results are as Model 3 .β = 0.758, p < 0.001), indicating the higher university students’ attitudes toward entrepreneurship education, the higher their entrepreneurial self-efficacy. Therefore, Hypothesis 1 is supported.Finally, Create β = 0.060, p < 0.001). The variance inflation factor (VIF) is used as a pointer to test for multicollinearity. And the VIF values are all less than 10, which mean that there is no significant multicollinearity problem between the variables. Therefore, it can be concluded from Model 3 that the post-pandemic entrepreneurial environment performs a positive moderating role in the influence of attitudes toward entrepreneurship education on entrepreneurial self-efficacy. Therefore, Hypothesis 2 is supported.As shown in the column “Model 3” of To further examine how the post-pandemic entrepreneurial environment moderates the impact of university students’ attitudes toward entrepreneurship education on ESE, an interaction diagram is drawn between high and low scores in the post-pandemic entrepreneurial environment, that is, one standard deviation above and one standard deviation below the mean score of the post-pandemic entrepreneurial environment, respectively. First off, the findings of the study indicate that male university students have a stronger sense of entrepreneurial self-efficacy than do female university students. The findings are in line with the study by Second, the findings indicate that university students’ attitudes toward entrepreneurship education have a positive and significant effect on their entrepreneurial self-efficacy. That is, the higher the university students’ attitudes toward entrepreneurship education, the higher their entrepreneurial self-efficacy. This is in line with the previous research . EntreprThird, the findings show that the post-pandemic entrepreneurial environment positively moderates the relationship between attitudes toward entrepreneurship education and entrepreneurial self-efficacy. This means the higher the score of perceived post-pandemic entrepreneurial environment, the more significant the positive effect of students’ attitudes toward entrepreneurship education on entrepreneurial self-efficacy. The results of this study may partially validate the social cognitive theory, which emphasizes that human behavioral intentions are influenced by the interaction between individual and environmental factors . In thisFirst, it is suggested that entrepreneurship education in universities allow for the individual differences between students. On the one hand, entrepreneurship education should allow for gender differences. On the other hand, entrepreneurship education should allow for the differences in resource base of students’ families.Second, we suggest that entrepreneurship education in universities focus on students’ attitudes toward it. This suggestion can be implemented in the following three aspects: Firstly, in the cognitive aspect, the teaching contents covered in entrepreneurship education should be more inclusive of the instruction of basic common sense about entrepreneurship, entrepreneurial expertise training courses, and new paths for students to practice entrepreneurship, so that an all-round entrepreneurship education system can be built; secondly, in the emotional aspect, entrepreneurship education should be staffed with an outstanding teaching faculty that demonstrate good teaching styles and personal charms, keep track of students’ satisfaction with instructors and courses, and focus on students’ interest in entrepreneurship courses; finally, in the aspect of behavior tendency, students’ attitudes toward entrepreneurship education in universities can be promoted by vivifying entrepreneurship courses, so that students are more willing to attend and learn more from the classes.Third, it is therefore recommended that the government further optimize the post-pandemic entrepreneurial environment. The government can formulate entrepreneurship incentive policies to create better platforms and favorable conditions for entrepreneurs, such as tax breaks for university students who are ready to start their own business and free business sites for entrepreneurship through university business parks.Overall, this study has explored the relationship between university students’ attitudes toward entrepreneurship education and entrepreneurial self-efficacy, and the moderating effect of the post-pandemic entrepreneurial environment on their relationship. The findings have confirmed the positive predictive effect of university students’ attitudes toward entrepreneurship education and entrepreneurial self-efficacy, and revealed the positive moderating effect of the post-pandemic entrepreneurial environment on their relationship, carrying certain implications on how the government and universities can improve their entrepreneurial self-efficacy in the post-pandemic era. Nevertheless, we should also admit some limitations of this study. First, this study has adopted a cross-sectional design so that future longitudinal research can confirm the causal relationships in this study. Second, the samples in this study have been collected from exemplary universities in innovation and entrepreneurship education, and it is expected that the type of universities and sample size can be expanded in subsequent studies to obtain more evidence. Finally, this study overlooks the sociocultural factors in the entrepreneurial process , 2020, aThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Human Ethics Committee of the Ningbo University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JZ designed the study, analyzed the data, and drafted the manuscript. JH assisted in analyzing and interpreting the data and participated in the revision of the manuscript. YH participated in the revision of 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.


A retrospective study was conducted on the clinical records of 148 children diagnosed with severe beta thalassemia who were admitted to our hospital between October 2018 and September 2021. The patients were separated into two groups, a control group and an intervention group, with 74 cases in each group, according to the various care approaches. The basic treatment regimen was given to all of the children: deferoxamine mesylate combined with deferiprone. During treatment, the control group received routine care, and the intervention group adopted the FCC model based on a mobile app. The quality of life scale for children and adolescents (QLSCA) score, the family assessment device (FAD) score, the exercise of self-care agency scale (ESCA) score, and the medication compliance scale score were compared between the two groups. F = 198.400, 259.200, and 129.800, all P < 0.001). Scores in both groups increased over time , and there was an interaction effect between grouping and time . The P values were 0.020, <0.001, and 0.007. The FAD score of the intervention group was significantly lower than that of the control group . The FAD scores of both groups decreased over time . There was an interaction effect between groups and time .  The QLSCA score, ESCA score, and medication compliance scale score of the intervention group were significantly higher than those of the control group and showed a significant difference (intergroup effect:  The application effect of the mobile app-based FCC model combined with the comprehensive iron removal treatment program in children with severe beta thalassemia is significant, which can significantly improve the quality of life, family function, self-care ability, and medication compliance of children, and has high clinical application value. Heavy beta thalassemia has a prolonged time of treatment, and the illness causes complications repeatedly. In general, infants born during the first stage of the disease display no clinical symptoms. However, between 3 and 6 months of birth, children may develop life-threatening symptoms such as hemolytic anemia, hepatosplenomegaly, low body resistance, growth retardation, and a particularly poor appearance [Thalassemia is a recessive genetic disorder characterized by the suppression of globin chain synthesis caused by a malfunction or deletion of globin genes, resulting in a change in hemoglobin composition . In Baisup to 1‰ . Iron ovpearance . TherefoFamily-centered care (FCC) is a medical care strategy based on a cooperative connection between medical service providers, patients, and their mutually beneficial families. It emphasizes the role of the family in the treatment and rehabilitation of children, encourages the participation of children and their parents, and collaborates with medical staff to jointly promote children's health. It is an effective mode of pediatric nursing . CurrentThis study developed a mobile app based on the Omaha System to identify health issues in children with severe beta thalassemia at home, provide reasonable therapies based on evidence, and produce a mobile app based on this knowledge. The FCC mode of three-tier A hospital-primary hospital-family connection, which was mediated by grassroots health institutions or school doctors, was also developed using the mobile app, and the effect was assessed. This mode included technology transfer, remote diagnosis and treatment, and home visits.μg/L.The clinical data of children with severe beta thalassemia admitted to our hospital between October 2018 and September 2021 were analyzed retrospectively. Inclusion criteria are as follows: severe beta thalassemia was determined according to Rome III diagnostic criteria , ages 6 Following their hospitalization, all of the children received complete iron removal treatment (deferoxamine mesylate with deferiprone). Specific methods are as follows: oral deferidone tablets , 75 mg/kg each time, 3 times a day, and dermal injection of deferoxamine mesylate , 5 d/week, once/d, 40 mg/kg each time, with the portable infusion pump utilized for continuous and gradual infusion for 8-12 h. All patients were treated for 12 weeks.The control group implemented routine nursing, specifically telephone follow-up after discharge. Specific methods are as follows: within 1 week after discharge, the responsible nurse conducted a telephone follow-up for the children once. During the 4th, 8th, and 12th week after discharge, the nurse in charge continued to follow-up with each child by telephone once, understood their recovery status, and provided routine guidance, requesting that children and their parents contact the pediatric department of the hospital whenever they experience difficulties.Based on the control group, the intervention group implemented a mobile app-based FCC model. Specific measures include the following: (1) establishing a professional guided intervention team. Establish professional guidance and consulting team consisting of 2 chief physicians, 2 chief superintendent nurses, 1 deputy chief nurse, 3 supervisor nurses, and 3 nurses before the nursing begins. There is 1 doctor, 2 nurses, or 2 medical staff at the village health facility in the registered community or township of the child and 1 school doctor at the school where the child is enrolled. (2) Professional education is as follows. All team members received training from the Baise Health and Family Planning Commission and passed the evaluation, which included health management knowledge and technology and intervention plan needs. (3) On the day the child was discharged, the practitioner assisted poor families in installing the mobile app center type nursing home end while also teaching parents how to use the mobile app. Simultaneously, the patient's discharge information will be transferred to the primary health service station where the patient lives via the medical terminal to interact with other appropriate medical staff . (4) Community health care personnel should visit the children within one week of their hospital discharge, with supervision content including an assessment of the environment , physical function, psychosocial status, health behavior, and the cognition of the child and its parents, as well as targeted guidance to the children and their parents. If the children and their parents encounter difficulties, they can use the mobile app to contact the medical staff at grade A hospital for support and assistance. (5) Basic health service professionals continue to visit the children at home on the 4th, 8th, and 12th weeks after they were discharged from the hospital to understand their compliance behavior and to conduct medication guidance, care guidance, and health behavior inspection and supervision. Children and their parents can contact medical personnel at any time via a mobile app and apply for remote diagnosis and treatment. (6) Implementing FCC intervention via network mobile app: nurses provide online counseling services. Every week, a senior nurse in charge is designated as the WeChat group manager. She used the app every day from 8 : 30 to 09 : 30 and 16 : 30 to 17 : 30 to conduct online consultations for family members, answer queries, provide extensive instructions, and conduct weekly assessment of children's quality of life and implementation of nursing interventions with a specific focus. Team members received feedback from parents through communication. Parents provided feedback on their children's food, activities, quality of life, and other information to the WeChat group in the form of photographs or videos, allowing team members to intuitively evaluate the children's circumstances and deliver more targeted health education. Every week, team members used pictures, documents, videos, and other formats to spread awareness about poverty and provide popularization knowledge for children and encourage family involvement. Parents communicate with one another, share care experiences, and offer emotional support. The team members disclosed relevant information. To increase the ability of family members to care for themselves at home, team members provided hospital information on the app regularly, such as presenting “Home for the Poor” and “International Day for the Poor” health lectures.All of the study's outcomes were assessed at discharge (before intervention), 12 weeks after discharge (12 weeks after intervention), and 24 weeks after discharge (24 weeks after intervention). (1) The quality of life scale for children and adolescents (QLSCA)  was usedT-test was performed for comparison between the two groups, and repeated measures analysis of variance was used for comparison of data at different time points between groups. The counting data was represented by n (%), and a χ2 test was performed. When P < 0.05, the difference was considered statistically significant.SPSS 17.0 statistical software was used to analyze the data, and the measurement data that conformed to a normal distribution were represented as “P > 0.05), showing that they were comparable. There were a total of 148 cases included. All patients were separated into a control group and an intervention group (each containing 74 patients) based on their respective care methods. There were no statistically significant differences between the two groups in terms of gender, age, disease course, body weight, stage of iron overload degree, and serum ferritin at discharge baseline . Scores in both groups showed a trend of increasing over time , and there was an interaction effect between grouping and time . The P values were 0.020, <0.001, and 0.007, respectively. The QLSCA score, ESCA score, and medication compliance scale score are provided in Tables 21The QLSCA score, ESCA score, and medication compliance scale score of the intervention group were significantly higher than those of the control group, indicating a significant difference . The FAD score of both groups decreased over time . There was an interaction effect between groups and time   .Currently, there is no effective treatment for severe beta thalassemia; however, regular blood transfusions and iron removal are used clinically to prolong the lives of children. Despite these interventions, it is still difficult to avoid direct death due to liver and kidney damage as well as heart failure before puberty . The majThis study investigated the impact of a mobile app-based FCC model in conjunction with a comprehensive iron removal treatment on children with severe beta thalassemia. Following the completion of the basic treatment of the comprehensive iron removal treatment plan, the children in the two groups received routine care and app-based FCC mode intervention, respectively. The findings demonstrated that the QLSCA score, ESCA score, and medication compliance scale score all increased, while the FAD score decreased for the children who received intervention based on the app-based FCC model. This suggests that the app-based FCC model can improve the children's quality of life, family function, self-care ability, and medication compliance. The FCC is a medical service provider based on a cooperative relationship between the patient and the family health care plan that is mutually beneficial. Its primary objective is to support children, families, and medical professionals. It highlights the importance of family care in the rehabilitation of children with the disease and encourages children and parents to participate, work with medical staff, and improve children's health . The funIn conclusion, the mobile app-based FCC model in conjunction with comprehensive iron removal therapy has a large application effect in children with severe beta thalassemia, which can considerably enhance their quality of life, family function, self-care ability, and medication compliance. It has significant clinical use. There is a chance of some bias in the result data, which must be proven by larger sample size research. Because this study utilized a small sample size, additional research with larger sample sizes is required.


Previous studies found that remnant cholesterol (RC) is a risk factor for cardiovascular diseases and childhood obesity is associated with cardiometabolic diseases. This study aimed to explore the relationship between RC and abdominal obesity in children.A total of 5,959 children, aged 6−12 years old, were selected from a cross-sectional study in urban-rural areas of Chongqing, China. RC was calculated by total cholesterol (TC)—high-density lipoprotein (HDL-C) cholesterol—low-density lipoprotein (LDL-C) cholesterol and was divided into four groups by quartiles (Q1–Q4).p < 0.05; Q3: OR = 2.127, 95% CI: 1.632−2.772, p < 0.001; Q4: OR = 2.386, 95% CI: 1.819−3.130, p < 0.001). In the stratified analyses by urban-rural areas, the odds ratios were greater in rural areas  than in urban areas .Compared to children with the lowest RC (Q1), children with higher RC had significantly higher odds of abdominal obesity (Q2: OR = 1.450, 95% CI: 1.131−1.859, Our study found that RC was positively correlated with abdominal obesity in children, and this association was higher for children living in rural areas. Remnant cholesterol (RC) is the amount of cholesterol in triglyceride (TC)-rich lipoproteins produced by the liver and the intestine. It can also be considered as the sum of all non-low-density lipoprotein (LDL) and non-high-density lipoprotein (HDL) cholesterol levels . RC is aThis study hypothesized that RC is correlated with abdominal obesity in children and an urban-rural difference may exist. A large cohort from Chongqing, China was used to test the hypothesis. The results could provide a basis for the prevention of early dyslipidemia in children with obesity and to reduce the cardiovascular risk in adulthood.n = 89) or without data on waist circumference and height (n = 11)  sampling. Details of participant recruitment and questionnaire collection were described in a previously published article . The basshown in . The MedDemographic data included age, gender, and residing in rural/urban areas. Socioeconomic status (SES) including parents' occupation, fathers' education level, household income, living situation, people living with a child, and medical insurance were collected. Parental education level was represented by a 4-point scale  , 17. Dat2 (kg/m2). Waist circumference was measured two times at the center of the umbilicus, and the average value was taken to calculate the waist-to-height ratio (WHtR) as a measure of abdominal obesity.Physical examination was conducted by trained pediatric nurses, as previously described . In brieBlood pressure (BP) and heart rate were measured on three different occasions using an OMRON arm-mounted electronic sphygmomanometer (HEM7051). Children were diagnosed with hypertension if all three BP measurements met the criteria for hypertension according to the diagnostic criteria for Chinese children .Blood samples were taken after at least 12 h of fasting for the measurement of biochemical indexes, including fasting blood glucose (FBG), TC, TG, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). TC was measured by the Cholesterol Determination - Peroxidase and 4-Aminoantipyrine substrate method. The mixture of cholesteryl esters and free cholesterol was reacted with cholesteryl esterase and cholesterol oxidase to produce hydrogen peroxide, which reacted with 4-aminoantipyrine and produced quinone imine compounds. HDL cholesterol was measured by the direct peroxidase clearance method in two steps. In the first step, reagent one (buffer 2-ethanesulfonic acid and surfactant 1) and serum lipid compositions , and LDL) were reacted to expose the cholesterol in the serum. After cholesterol esterase and cholesterol oxidase catalyzed the cholesterol, hydrogen peroxide was produced. In the second step, similarly, another surfactant was used to expose the cholesterol in HDL, which would react with cholesterol enzymes for chromogenic reaction, and the shade of color was proportional to the amount of HDL cholesterol. LDL cholesterol was measured by the direct surfactant removal method. Except for LDL, surfactant 1 was used to alter the structure of lipoproteins , and the metabolite would react with cholesterol esterases and cholesterol oxidases. As a result, all lipoproteins, except LDL, were eliminated. Then, a chromogenic reaction of LDL occurred with surfactant 2. The shade of color was proportional to the amount of LDL cholesterol. The details were described in a previous study , and RC A threshold of WHtR ≥0.480 for boys and WHtR ≥ 0.456 for girls were identified for abdominal obesity in childhood .t-test. Skewed distribution continuous variables  were reported as medians (interquartile range), and the Mann–Whitney U test was used for comparison between the two groups. The Chi-square test was used to compare categorical variables. A linear regression model was used to evaluate the association between RC and WHtR, and a logistic regression model was used to assess the relationship between abdominal obesity and quartile range increase of RC.Normally distributed continuous variables were expressed as mean ± standard deviation, and the differences between rural and urban areas were assessed with Student's © 2016 SAS Institute Inc., Cary, NC, USA). A p-value <0.05 was considered statistically significant.Statistical analysis was performed using SAS 9.4 software (CopyrightThe demographic characteristics of the participants are presented in p < 0.05) (p for trend <0.05), which was found in both urban and rural areas.The prevalence of abdominal obesity was higher in children with increased total RC, and the RC of children living in urban areas was higher than those living in rural areas  . The pre < 0.05) –4. Additp < 0.001, in Compared to the normal-weight children, the RC levels were higher in children with abdominal obesity, and the difference was significant both in urban and rural areas . In the subgroup analyses, the RC level was significantly positively associated with WHtR in children living in both urban  and rural  areas.A linear regression model was used to examine the relationship between RC and WHtR in p < 0.05; Q3: OR = 2.127, 95% CI: 1.632−2.772, p < 0.001; Q4: OR = 2.386, 95% CI: 1.819−3.130, p < 0.001). In the stratified analyses by urban-rural areas, the odds ratios were greater in rural areas  than in urban areas .A logistic regression model was used to investigate the relationship between RC by quartiles and abdominal obesity in Our study showed a significant positive association between RC and abdominal obesity in children. Children living in urban areas had a higher level of RC than children living in rural areas. However, the prevalence of abdominal obesity among children in rural areas was higher than that in urban areas. The association between RC and abdominal obesity was higher for children living in rural areas.Similarly, previous studies found that, both in children and adults, RC was positively correlated with waist circumference and BMI , 13, 22.The dietary structure of children had changed greatly during the past decades, and accompanying it, the incidence of childhood obesity had increased dramatically , 28, 29.Remnant cholesterol (RC) had been found as an independent risk factor for cardiovascular disease, similar to LDL, and the RC in the bloodstream passed through the endothelium and collected within the arterial wall, where it was absorbed by macrophages and smooth muscle cells, forming foam cells that eventually became part of the atherosclerotic plaque . AtherosFasting RC was not only a risk factor for cardiovascular diseases such as atherosclerosis and myocardial infarction but was also associated with diabetes, kidney disease, and carotid artery intima-media thickness in adolescents , 35–37. Obesity in children is mainly subcutaneous fat, so the use of abdominal obesity indicators is more appropriate than using general obesity diagnosed by BMI . Our stuThere are several limitations to this study. First, the RC calculated from the standard lipid profile as TC minus LDL-C minus HDL-C is different from the RC measured by nuclear magnetic resonance , as therIn our study, RC was positively associated with childhood abdominal obesity both in urban and rural areas. Moreover, the association was higher for children living in rural areas. Our findings provided a theoretical basis for cardiovascular prevention in children with abdominal obesity. Further cohort studies are needed to confirm the causal relationship between RC and abdominal obesity in children.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Medical Research Ethics Committee of the Research Division of the Children's Hospital of Chongqing Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.XiaohL: conceptualization, planning the methodology, and writing—review and editing. SL, DH, and LZ: investigation and supervision. FT, YF, YR, and XP: validation and obtaining resources. JT, XiaoyL, XinggL, and GH: writing—original draft and writing—review and editing. All authors critically reviewed and approved the final draft of the manuscript.This work was supported by the Basic Research Project of Key Laboratory of the Ministry of Education of China in 2021 (GBRP-202106), the Major Health Project of Chongqing Science and Technology Bureau (CSTC2021jscx-gksb-N0001), the Research and Innovation Team of Chongqing Medical University (W0088), the Joint Medical Research Project of Chongqing Municipal Health Commission and Chongqing Science and Technology Bureau (2020MSXM062), the National Key Research and Development Project (2017YFC0211705), the Education Commission of Chongqing Municipality (KJQN201900443), and the National Natural Science Foundation of China (82003521). The funders had no role in the study design, data collection and analysis, the decision to publish, or the preparation of 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.


Ictal panic (IP) can be observed occasionally in patients with temporal lobe epilepsy (TLE). Such descriptions can be found in previous studies, but the mechanism is still not clear and often confused with panic attacks in patients with panic disorder (PD). We try to use imaging methods  to study the mechanism of this psychiatric comorbidity in patients with TLE.t-tests were used to compare differences between the TLEIP, TLE without IP, and healthy control(HC)groups. The relationship between brain abnormalities and patient characteristics was explored by correlation analyses.Forty right-onset TLE patients were observed, including 28 patients with TLE but without IP and 12 patients with TLEIP along with 30 gender-age matched healthy controls were included. We collected clinical/physiological/neuropsychological and rs-fMRI data. Degree centrality (DC) and functional connectivity (FC) were calculated. For the DC and FC values, analysis of covariance (ANCOVA) was used to find different areas and No significant differences in gender and age were found among the three groups, and no significant differences in education level, Montreal Cognitive Assessment (MOCA), Hamilton Depressive Scale (HAMD), Hamilton Anxiety Scale (HAMA), and epilepsy duration (years) between the TLEIP and TLE without IP groups. In addition to fear, other symptoms were observed, including nausea, palpitations, rising epigastric sensation, and dyspnea. There was no correlation between the duration of IP and HAMA. Moreover, all IP durations were <2 min. Compared to the HCs and TLE without IP group, the DC value of the TLEIP group in the left middle temporal gyrus (LMTG) was significantly increased. Compared to the HCs, FC could be found between the LMTG and left inferior temporal gyrus (LITG) in the TLEIP group. In addition, there was FC between the LMTG and cerebellum in the TLEIP group. The difference in the magnitude of FC between the TLEIP vs. HC group was greater than the difference between the TLE vs. HC group.This study describes brain abnormalities in patients with TLEIP. These results will help to preliminarily understand the mechanism of ictal panic and abnormal functional connection in patients with TLE, and further explore the neuroimaging mechanism of ictal panic in patients with TLE. Fear is a very distinct and recognized emotion caused by exposure to real or imagined threats , 2. The Temporal lobe epilepsy (TLE) is a partial form of epilepsy that originates in one or several of the anatomic locations of the temporal lobe, and which can spread through a network of neuronal interconnections to adjacent brain tissue . OccasioResting-state functional magnetic resonance imaging (rs-fMRI) is now widely used in studies of the human brain. It is an advantageous tool that allows the mapping of regional interactions in the subject's brain when explicit cognitive tasks are not being performed , 34. LocDegree centrality is proposed to map the degree of functional connectivity inherent in the brain in order to reflect the stability of cortical network structure at the voxel level. FC is the mechanism for the coordination of activity between different neural assemblies in order to achieve a complex cognitive task or perceptual process . The twoDegree centrality describes the importance of individual voxels in the whole brain and can help find areas with abnormal connections with other brain regions. FC can further find the abnormal connection. In this study, we employed an rs-fMRI to explore the brain-functional abnormalities in patients with right-onset TLEIP from different perspectives. Compared to control subjects, we sought to determine whether patients with TLEIP have specific brain-functional abnormalities by using the DC metrics and whether they have abnormal FC. Further, we sought to determine whether these abnormalities were associated with the clinical/physiological/neuropsychological characteristic scores of these patients.All participants were recruited from the epilepsy clinic of the First Affiliated Hospital of Guangxi Medical University. This study was approved by the hospital's Medical Research Ethics Committee. Written informed consent was provided by all participants. Forty patients with TLE were diagnosed by two neuropsychologists according to clinical characteristics, EEGs, and imaging examination. Patients were divided into two groups, TLEIP and TLE without IP groups. In order to reduce the impact on the results, we selected patients with epileptogenic focus on the right as the research subjects.The inclusion criteria for the TLEIP group involved: (1) Patients with epilepsy who satisfy any two or more of the following conditions: a. The epileptogenic focus was located in the right temporal lobe. b. MRI showed unilateral or bilateral hippocampal atrophy/sclerosis, or other abnormalities in the unilateral or bilateral temporal lobe. c. EEG examination revealed that epileptic discharges originated from the right temporal lobe; (2) Mini-mental state examination (MMSE) scores more than 24, right-handed, 18–50 years, and; (3) TLE history with ictal panic, as a precursor of seizures or as a symptom of seizures.The following exclusion criteria were used in the TLEIP group: (1) Structural MRI showed other brain structural lesions besides hippocampal atrophy or hippocampal sclerosis; (2) A diagnosis of severe mental or neurological diseases except for ictal panic history; (3) People with alcohol abuse or drug abuse , and; (4The inclusion criteria for the TLE without IP group involved: (1) Patients with epilepsy who satisfy any two or more of the following conditions: a. The epileptogenic focus was located in the right temporal lobe. b. MRI showed unilateral or bilateral hippocampal atrophy/sclerosis, or other abnormalities in the unilateral or bilateral temporal lobe. c. EEG examination revealed that epileptic discharges originated from the right temporal lobe; (2) MMSE scores more than 24, right-handed, 18–50 years, and; (3) TLE history without ictal panic.The following exclusion criteria were used in the TLE without IP group: (1) Structural MRI showed other brain structural lesions besides hippocampal atrophy or hippocampal sclerosis; (2) A diagnosis of severe mental or neurological diseases; (3) People with alcohol or drug abuse , and;  without a history of mental or neurological diseases were enlisted from the community. Gender, age, and MMSE scores were matched with those of patients.MRI data were acquired using an Achieva 3.0-T MRI scanner with a 12-channel head coil . Prior to scanning, each subject was asked to rest for 20 min. During MRI scanning, subjects were instructed to close their eyes, remain conscious, and avoid active thinking. Foam padding was utilized for noise mitigation and to limit head movements. For each subject, resting-state functional imaging was obtained using the echo-planar image (EPI) technique with the following parameters: repetition time (TR) = 2,000 ms, echo time (TE) = 30 ms, 31 slices and 180 volumes, slice thickness = 5 mm, slice gap = 1 mm, voxel size = 3.44 × 3.44 × 6.00 mm, field of view = 220 × 220 mm, flip angle = 90°, scanning time = 360 s.http://restfmri.net/forum/restplus) based on SPM12 (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/), including (1) removing the first 10 time points to make the longitudinal magnetization reach steady state and to let the participant adapt to the scanning environment; (2) slice-timing to correct the differences in image acquisition time between slices; (3) head motion correction; (4) spatial normalization to the Montreal Neurological Institute (MNI) space via the deformation fields derived from tissue segmentation of structural images (resampling voxel size = 3 mm × 3 mm × 3 mm); (5) spatial smoothing with an isotropic Gaussian kernel with a full width at half maximum (FWHM) of 6 mm; (6) removing linear trend of the time course; (7) regressing out the head motion effects (using Friston 24 parameter) from the fMRI data, and; (8) band-pass filtering (0.01–0.08 Hz). No participants were excluded from further analysis due to large head motion (DC omits step 5).Image preprocessing was performed using the Resting-State fMRI Data Analysis Toolkit plus V1.24 (RESTplus V1.24) toolbox  represents the degree centrality of node i, CD(Ni) is simply to sum the cell values of the corresponding row or column of node i in the network matrix   .P < 0.0005, cluster level P < 0.025). Second, (if found) the difference region was made to be a mask and the mask was used to conduct two-sample t-tests between each two of the three groups, with the results corrected by GRF . Gender, age, and education level were applied as covariates to minimize their potential effects on the analysis.First, in the DC analysis, the processed data of three groups were analyzed by one-way analysis of covariance (ANCOVA) to find the significant difference regions among groups . Third, (if found) the difference region was made to be a mask and the mask was used to conduct two-sample t-tests between each two of the three groups, with the results corrected by GRF . Gender, age, and education level were applied as covariates to minimize their potential effects on the analysis.In the FC analysis, first, through the comparison of DC values, the region with a significant difference between TLEIP and the other two groups is regarded as a region of interest (ROI). In order to explore the difference between TLEIP and TLE without IP, the main parts of the fear circuit: amygdala, hippocampus, parahippocampal gyrus, and thalamus are also taken as ROIs, then voxel-wise FC was performed on the whole brain to calculate the FC between the ROIs and the whole brain. Second, the processed data of the three groups were analyzed by one-way ANCOVA to find the significant difference regions among groups  . First, the Shapiro-Wilk test was conducted to determine whether the quantitative data conformed to a normal distribution. Second, if data conformed to a normal distribution, the data of the three groups were statistically analyzed by one-way ANCOVA test, and the data of the two groups were statistically analyzed by an independent There were no significant differences in gender and age among the TLEIP, TLE without IP, and HC groups. There were no significant differences in education level, MOCA, HAMD, HAMA, and epilepsy duration (years) between the TLEIP and TLE without IP groups .p = 0.659, For TLEIP patients, in addition to fear, other symptoms were also observed, including nausea, palpitations, rising epigastric sensation, and dyspnea . There wP < 0.001, cluster level P < 0.05)  was significantly increased  .P < 0.001, cluster level P < 0.05)  in the TLEIP group, we also found that there were FCs between the LMTG and cerebellum in the TLEIP group. Although compared to the HC group, we found that there was FC between the LMTG and LITG in the TLE without IP group, the area of LITG in the TLEIP vs. HC group was larger than those in the TLE without IP group vs. HC group. In addition, the difference in the magnitude of FC between the TLEIP vs. HC group was greater than the difference between the TLE without IP vs. HC group.  .In this study, we found that there were no significant differences in HAMA scores between the TLEIP and TLE without IP groups, and there was no significant correlation between the duration of IP symptoms and HAMA scores in the TLEIP group. Therefore, we speculate that there is no correlation between IP and anxiety in patients with TLEIP, which is different from previous studies describing the relationship between anxiety and panic , 31, 44.Degree centrality reflects the role and status of voxels in the brain network and represents the most local and directly quantifiable centrality measure. In this study, we found the LMTG exhibited increased DC, which indicated increased importance of this region in the brain of patients with TLEIP. The LMTG was involved in several functions, including semantic processing, sentence understanding, word generation, action observation, complex sound processing, logical reasoning, and dynamic facial expression recognition –52. GeneP < 0.00001, uncorrected for multiple testing) in the LMTG and cerebellum. In contrast, random-effects group analysis for placebo and anticipatory anxiety (AA) using the same level of significance generated no significant results. In this study, we found that the FC between the LMTG and the cerebellum was strengthened in patients with TLEIP, which also verified this result. Although no local brain and FC abnormalities were found in the amygdala, hippocampus, parahippocampal gyrus, and thalamus, we speculate that the mechanism of TLEIP may not be completely the same as the mechanism of PD. This may mainly be due to the transient and recoverable incomplete activation of the fear circuits caused by the epileptiform discharge of the local epileptogenic focus in the temporal lobe it was difficult to collect patients with TLEIP, a large number of samples were not included in this studylack of horizontal comparison with patients with PDparticipants are patients with right-onset TLE, more patients with left-onset TLE need to be collected to have a further study.In the future, we will collect more patients with left-onset TLE and patients with PD for study to further explore the mechanism of fear in the functional brain network.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the First Affiliated Hospital's Medical Research Ethics Committee of Guangxi Medical University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.WC is responsible for experimental design. JZ is responsible for providing overall ideas. ZL is responsible for instrument operation. XP is responsible for data analysis. JL and LN is responsible for data collection. All authors contributed to the article and approved the submitted version.This research is supported by the National Natural Science Foundation of China (contract authorization number: 81560223) and Guangxi Postgraduate Education Innovation Plan (authorization number: YCBZ2019042).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.