The AGE levels were observed as an independent predictor of MAC development in a regression analysis . In a ROC-curve analysis, the AUC was 0.79 (95% CI: 0.72–0.85). At a cut-off value of 2.7, 79.7% sensitivity and 69.1% specificity were observed. AGE levels can be used to cheaply, easily and non-invasively identify patients at risk of developing MAC.As a person ages, mitral annular calcification develops in the mitral annulus with increasing frequency. Lipid deposition, inflammation, and aging-related degeneration have been cited as potential causes of this pathophysiology, though there is currently no conclusive evidence to support this. AGEs accumulate in tissues due to the glycation of proteins and lipids, increasing the release of proinflammatory cytokines secondary to oxidative stress through the AGE receptor. The AGE levels increase in diabetic microvascular complications and degenerative aortic valve disease. Our study was planned prospectively as a case–control study involving 94 MAC-positive patients and 94 MAC-negative patients. The demographics, echocardiographic data and AGE levels of the patients were measured and recorded using the skin autofluorescence method. AGE levels were significantly higher in the MAC-positive patient group (3.2 vs. 2.7;  The mitral valve annulus (MVA) is the fibrous skeletal tissue that forms the border between the left atrium (LA) and the left ventricle (LV), to which the anterior (AML) and posterior mitral leaflets (PML) are attached. Mitral annular calcification (MAC) is defined as calcification along the MVA, often extending to the PML and less frequently to the AML, and it is secondary to aging-related degeneration, lipid accumulation, and inflammation in the MVA ,2. HistoNon-enzymatic reactions involving the terminal amino groups of amino acids or the side-chain amino groups of lysine and arginine within proteins, along with carbonyl groups from reducing sugars, lead to the formation of Schiff bases. Under increased oxidative stress conditions, these Schiff bases undergo further glycoxidation reactions, ultimately producing highly reactive 1,2-dicarbonyl compounds. These 1,2-dicarbonyl compounds interact with the amino groups within proteins, leading to the creation of crosslinks both within and between proteins. The intricate series of reactions responsible for the formation of advanced glycation end-products (AGEs) are collectively known as Maillard reactions—chemical processes that occur between the carbonyl groups found in reducing sugars and the N-terminal amine groups found in amino acids, peptides or proteins . BecauseThese data support the hypothesis that AGEs may play a role in the pathophysiology of MAC. Our study investigates the relationship between the amount of AGEs measured using the skin autofluorescence method and MAC.Our study was planned and conducted as a prospective case–control study in accordance with the 1967 Helsinki Declaration. We obtained informed consent from all patients included in the study with the approval of the human research ethics committee of Istinye University . Our study included 94 patients who were screened for MAC. The participants had no history of previous valve or cardiac surgery, no previous invasive intervention to the mitral valve, no history of rheumatic valve disease, no active infection, no end-stage renal failure and no liver failure. People with similar demographic characteristics were included as the control group. The exclusion criteria are summarized in The patient group involved people who had previously been diagnosed with mitral annular calcification and received regular follow-up at our hospital. Demographic characteristics and echocardiographic findings of the patients and control group were obtained from their anamnesis and patient files and recorded, as well as the disease duration of patients diagnosed with DM and the last level of their HbA1c tests. Inter-group comparison of the diabetic patients was also performed.The skin autofluorescence measurements of the participants were the average of 3 measurements made by an individual who did not know which group the subjects belonged to. The AGE reader™  was used to obtain the measurements, which were taken from the inner surface of the forearm of the patients according to the manufacturer’s instructions. No measurements were taken from areas with scars or pigmentation disorders.t-test was applied to the numerical variables, and the data were summarized as median and 25–75% interquartile range (IQR) or mean ± standard deviation. In the regression analysis, univariate regression analysis was performed with all parameters, and multivariate regression analysis was performed using parameters with a p-value < 0.1. Receiver operating characteristic curve (ROC-curve) analysis was performed to evaluate AGE levels and perform MAC prediction, then the cut-off value, sensitivity and specificity were given, and the data were summarized with a 95% confidence interval (CI). A p-value < 0.05 was accepted as the significance level. SPSS 23  and STATA.17  were used for the statistical analysis.In statistical analysis, while analyzing the normality and variance of the parameters, the Kolmogorov–Smirnov test and Shapiro–Wilk tests were used. The chi-square test and Fisher’s exact test were used to analyze the categorical variables, categorical variables were expressed in numbers and percentages. After that, the Mann–Whitney U test or Student’s Our study included 94 MAC-positive patients and 94 MAC-negative patients. Female gender dominance was observed in the MAC-positive group, while male gender dominance was observed in the other group. More than two-thirds of the patients in both groups exhibited signs of hypertension (HT). The statistically significant HT frequency was observed to be higher in the group with MAC. The mean age of both groups was 70 and there was no statistical significance between them. More than half of the patients in both groups had CAD. More than one-third of the patients in both groups were smokers. Patients with MAC have a more frequent history of stroke. The frequency of chronic obstructive pulmonary disease (COPD) was higher in the MAC-positive group. Although the frequency of AF was numerically higher in the MAC-positive group, it failed to reach statistical significance. Approximately half of the patients in both groups had DM; however, no significant difference was observed between the groups in terms of DM frequency and the duration of DM. The hemoglobin A1c (HbA1c) levels of the patients were examined, and the HbA1c levels were significantly higher in the MAC-positive group. The body mass index (BMI) was similar in both groups. The echocardiography data were examined, and the patients’ ejection fractions (EF) were similar. The number of patients with MR > 1 degree was significantly higher in the group with MAC positivity and LA diameter; like MR, it was higher in the MAC-positive group. AGE levels were significantly higher in the MAC positive group. The data are summarized in We used ROC-curve analysis to test the predictive power of AGE levels with regard to MAC positivity. The area under the curve (AUC) was 0.792; 95% CI: 0.728–0.856. Further analysis revealed a sensitivity of 79.7% and specificity of 69.1% at the cut-off value of 2.7 .p-value less than 0.1. The analysis identified LA diameter, AGEs and stroke as independent predictors of MAC. The results of this analysis are summarized in Multivariate regression analysis was performed based on the following parameters: age, female gender, HT, stroke, COPD, HbA1c levels, AGEs, LA diameter and MR > 1, which, in the univariate regression analysis, resulted in a p-value < 0.001. Additionally, in MAC-positive patients without DM, the AGEs values were significantly higher compared to those of MAC-negative patients. There were 55 patients with AGEs of three and above: 9 of them in the control group and 46 in the patient group. The creatinine values of these patients were mean 1.03 ± 0.26.When DM patients were excluded from the analysis, a statistical analysis was performed. The MAC-positive group included 48 patients with DM, while in the MAC-negative group, 47 patients did not have DM. In this analysis, the AGEs values of MAC-positive patients had a median of 2.8 (2.6–3.2 IQR), while in the MAC-negative group, the median was 2.2 (1.8–2.4 IQR), with a Our results show that AGE levels are independent predictors of MAC, with 79% sensitivity and 69% specificity in patients with a cut-off value above 2.7. These findings are indicative of a relationship between AGE levels and MAC. Although we cannot be certain that AGEs accumulate in the MVA, since we did not perform a histological study at the tissue level, it can be concluded that the risk of MAC increases in people with a high accumulation of AGEs in the skin. This demonstrates that non-invasive measurement of AGEs in a very short time in at-risk demographics will enable timely detection of people at a high risk of MAC, allowing further diagnostic and treatment methods to be implemented at an early stage. The presence of inflammatory cell accumulation, calcification, and fibrosis in the valve in the pathophysiology of the development of MAC supports the role of AGEs. The accumulation of AGEs may be the result of increased exogenous uptake, endogenous production and decreased clearance. There was a notable increase in the amount of AGEs in patients who ate a Western diet . As mentPredictors of MAC include advanced age, female gender, end-stage renal disease requiring hemodialysis treatment, high aortic and coronary calcium load, obesity, dyslipidemia and DM. Our study found that LA diameter and stroke were predictors in addition to AGE levels. Our univariate logistic regression analysis identified age, female gender, HT, stroke, COPD, HbA1c levels, AGEs, MR > 1 and LA diameter as predictors of MAC. We believe that the reason for the loss of predictive power in multivariate analysis is the advanced age of our patient groups (mean > 70). In general, we believe that age loses its predictive power in the multivariate analysis due to the inclusion of elderly patients in the study and the case–control study design. We conclude that factors such as obesity, dyslipidemia, DM, age, female gender and HT lose their predictive power in the multivariate analysis due to the presence of such high rates of HT, DM and dyslipidemia patients in the study. We believed that the case–control study design would be the most accurate, since the main purpose of our study was to test the predictive power of AGE levels with regard to MAC. Since LA diameter and stroke are factors that may be caused by MAC, their predictive power has been observed in these patients.When the differences between both groups were observed, it was noted that female gender was significantly more prevalent in the MAC-positive group. This supports the literature, which states that female gender is an independent predictor for MAC. Male gender, on the other hand, is a risk factor for atherosclerosis, which may cause confusion in terms of pathophysiological female gender being a risk factor for MAC. However, abnormal calcium phosphate production and post-menopausal osteoporosis are often blamed for this .As stated by the literature, the presence of HT was higher (greater than 80%) in the MAC-positive group, though it was observed in over 70% of patients in the MAC-negative group. AGEs are catabolized from proximal renal tubules, and apoptosis and inflammation occur in renal proximal cells due to the increase in AGEs. This leads to a subsequent increase in the reabsorption of sodium, which contributes to the development of HT, and increases in AGE levels contribute to the development of HT and, therefore, MAC .The frequency of DM was around 50% in both groups, and the duration of DM was 10 years in both groups. DM is a risk factor for the development of MAC; it is mainly accused of increasing the development of atherosclerosis. Increases in AGE levels are observed in DM patients. The glycation of proteins, nucleic acids and lipids, secondary to a hyperglycemic state or inflammation, plays a fundamental role in the formation of AGEs. Accordingly, these substances begin to accumulate in the tissues, resulting in tissue dysfunction. This leads to an increase in the level of microvascular complications of DM. Rezaei, M. et al. support this assumption; their studies show that AGEs measurements are valuable in the follow-up of DM complications, but they were unable to prove a relationship between HbA1c levels and blood sugar regulation and AGE levels in their work . One reaObesity and hyperlipidemia are risk factors for both CAD and MAC. Obesity contributes to this effect by increasing the frequency of diseases such as hyperlipidemia, HT and DM due to metabolic syndrome. Hyperlipidemia increases lipid deposition in the tissues and thus accelerates plaque development; as a result, the plaque degenerates into an anoxic condition due to malnutrition in the plaque, and ultimately, calcification occurs. MAC development is mainly observed secondary to lipid accumulation and calcification. Hyperlipidemia increases both lipid accumulation and calcification accumulation by creating inflammation and anoxic condition in the tissue . This alCOPD was identified as a risk factor for MAC in univariate analysis, and its frequency was significantly higher in the MAC-positive group. There was no significant difference between the groups in terms of smoking, which is a related condition. We believe that the main effect of smoking and COPD on the development of MAC is that it creates anoxic conditions in the body and increases intra-plaque bleeding and related inflammation. We suggest that as a result of the existing anoxic environment and inflammation, the production of AGEs increases, and their accumulation increases in tissues, especially in cardiovascular structures. Smoking is a risk factor for the development of atherosclerosis and MAC . The mosMAC can lead to increased incidence of HF, MR or MS, AF and stroke. Calcification of the MV cusps due to MAC can cause adhesions and coaptation defects. While adhesions more frequently increase MS, MR also increases as a result of coaptation defects. In one study, 11.7% of 1494 MAC-positive people also had MR; 0.05% had MS; and 8.2% of these people had LA dilatation. . Our stuIn the studies by Nakamura et al., it was demonstrated that the molecule telmisartan reduces soluble advanced glycation end-product receptor (RAGE) levels. Meanwhile, in their research, Matsui et al. showed that the molecule irbesartan decreased AGE-related tubular cell injury. In their study, Ono et al. indicated that the molecule candesartan suppressed AGE levels in individuals with type 2 diabetes and essential hypertension. Additionally, Sebekova et al. suggested that the molecule ramipril potentially improved parameters in non-diabetic nephropathy patients, possibly acting through AGEs. Alagebrium (ALT-711) is known as an AGE-breaker and can reduce AGE levels. Studies have shown conflicting results, with some indicating a reduction in total arterial compliance, a decrease in left ventricular mass, and an improvement in arterial endothelial function, while others have found no significant effect, leading to some confusion in this regard ,37,38,39AGE levels are an independent predictor for MAC, which can predict MAC at the level of 2.7 with 79% sensitivity and 69% specificity. AGE levels can be measured easily, non-invasively and at minimal cost with the AGE-reader device, revealing people at greater risk of MAC development.


Postmenopausal women face a higher risk of depression due to a combination of social and physiological factors. As a beverage rich in a variety of bioactive substances, green tea has significant effects on metabolism, inflammation and endocrine, and may reduce the risk of depression, but few studies have looked at the effects of green tea on postmenopausal women. Therefore, we designed this study to investigate the effects of long-term green tea consumption on inflammation, endocrine and depression levels in postmenopausal women. We investigated a tea-producing village and eventually included 386 postmenopausal women, both in the tea drinking and control groups. The results showed that there were significant differences in the degree of insomnia, degree of depression, BMI, SII and estradiol between the two groups. And, green tea consumption may reduce the risk of depression through the mediating pathway of sleep, SII and estradiol. In summary, long-term green tea consumption can reduce the risk of depression in postmenopausal women by reducing inflammation and increasing estradiol. This kind of living habit deserves further promotion. In recent years, with the rapid development of society, people’s pace of life and pressure are increasing and the incidence of various mental diseases is also rising year by year. Among them, depression is the most common mental illness, and its main characteristics include low mood, loss of interest and decreased motivation, accompanied by physical discomfort, decreased appetite and sleep problems, which not only impair individual function, but also lead to suicide in severe cases. In China, the prevalence of depression among adults is as high as 6.8% . There iGreen tea has always been an important part of the human diet and is widely consumed due to its low price and easy availability, being the second most popular beverage after water. Furthermore, a growing number of studies have shown that green tea is rich in natural bioactive ingredients that not only help enhance cardiovascular and metabolic health ,11,12 buThe relationship between green tea consumption and depression has also received extensive attention from researchers. Although there is substantial evidence that green tea consumption has antidepressant effects ,19,20, tThe study was conducted between June 2023 and August 2023 in a tea-growing village where a large proportion of the population began drinking green tea as adults. We recruited participants through local leaders and conducted questionnaires through trained psychiatrists and nurses. The questionnaire included basic socio-demographic information, green tea consumption, sleep and depression. We defined the tea drinking group as “drinking green tea at least 6 days per week, at least 1 cup (500 mL) per day, for at least 20 years,” while the control group never consumed green tea. People who met the criteria and passed the inclusion and exclusion criteria were asked to sign an informed consent form and then had their blood collected on an empty stomach before 9 a.m. Each person who participated in the survey received a gift. Finally, 386 people met the inclusion criteria and completed the questionnaire and blood collection and were finally included in the study.Inclusion criteria: (1) voluntarily participating in the study and providing written informed consent; (2) participants were able to understand the meaning of the questions in the questionnaire and complete the questionnaire; (3) cooperating with specimen collection.Exclusion criteria: (1) a history of mental illness or a family history of mental illness; (2) recent major setbacks; (3) presence of endocrine or organic diseases.All respondents participated voluntarily under the premise of written informed consent and could quit at any time. All methods during the survey were carried out in accordance with relevant guidelines and regulations. Ethical approval was obtained from the Renmin Hospital of Wuhan University.Basic information includes age, marital status , education level , annual household income , religious belief, smoking and alcohol consumption, residence status, and only child (yes or no). The PSSS  was used to measure the degree of social support. The PSSS has 3 subscales, including 12 items in total, and each item adopts the 1–7 scale scoring method. The higher the score, the higher the social support of an individual. Social support from family, friends, relatives and colleagues can be effectively measured, with good reliability and validity . The greThe insomnia severity index scale was used to screen for insomnia and assess its severity. The scale consists of 7 items, each item 0–4 points a total of 28 points; the higher the score represents the more serious insomnia. A score of 0–7 is rated as no insomnia, a score of 8–14 is rated as mild, a score of 15–21 is rated as moderate, and a score of 22 or above is rated as severe insomnia. The validity and reliability of this scale has been proved, and it has been widely used in investigations and research ,35.The levels of depression were collected using the PHQ-9 , ranging from 0  to 3 . The higher the score, the more severe the symptoms of depression. The reliability and validity of the questionnaire has been proved ,37.Participants were asked to be fasting, and blood was collected in the morning (7–9 a.m.) for hormone and inflammation analysis, using ELISA to measure estradiol, testosterone, TSH (Thyrotropin), FT3(Free Triiodothyronine), FT4(Thyroxine) and inflammation markers. The SII (Systemic Immune Inflammation Index) was used to measure inflammation. The SII is a novel inflammatory biomarker based on lymphocyte, neutrophils and platelet counts, which can reflect the local immune response and systemic inflammation in the whole body. Currently, the SII has been applied in the prediction and correlation studies of a variety of diseases ,39,40. HAnalysis was performed using SPSS Statistics 23.0. Categorical variables were represented by N and percentage, quantitative data were represented by mean and quartile, and differences between groups were measured by Chi-square test and non-parametric test. To test the correlation between green tea consumption and the depression level, univariate analysis takes into account all factors that could influence the depression level, followed by ordered logistic regression analysis. To further explore the indirect effects of tea drinking on depression, path analysis was performed by structural equation model using Amos 26.0. The bootstrapping method (5000 resamples) was employed to estimate the 95% confidence intervals (CI) of the mediators’ indirect effect. When the 95% CI did not contain zero, the indirect effect was considered statistically significant1. The level of significance was set at 0.05, two-tailed .Variables whose sample size did not meet statistical requirements were not included in the analysis or were combined with other groups and then analyzed.p = 0.781), annual income (p = 0.740), type of work (p = 0.336), being an only child and living alone . In addition, there were no significant differences in sleep duration (p = 0.992), systolic blood pressure (p = 0.383), diastolic blood pressure (p = 0.554), TSH (p = 0.792), FT3 (p = 0.219), FT4 (p = 0.984) and testosterone (p = 0.297) between the two groups. However, there were significant differences in the degree of insomnia (p = 0.003), degree of depression (p = 0.002), BMI (p < 0.001), SII (p = 0.033) and estradiol (p < 0.001) between the two groups. . There were no significant differences between the two groups in terms of education level (p = 0.038). In addition, the concentration of SII (p = 0.003) and estradiol (p = 0.029) were also significantly correlated with the degree of depression. , accounting for 45.2% of the total effect. Considering that the direct effect was not significant , tea drinking could majorly influence the degree of depression by the mediating variables including SII, estradiol and the degree of insomnia. The mediating effects of SII, estradiol and the degree of insomnia were all significant, were −0.022 , −0.014  and −0.059 , and accounted for 10.3%, 6.7% and 28.2% of the total effect, respectively. With tea drinking as the independent variable, the degree of depression as the dependent variable, SII, estradiol and the degree of insomnia as the mediating variables, a structural equation model was constructed . The fitpression . The totThe accumulated evidence indicates that a variety of bioactive substances rich in green tea have significant effects on the absorption and secretion of many hormones. For example, green tea consumption has been found to reduce the body’s ability to absorb LT4, and animal studies have shown that its catechins affect thyroid function in rats , resultiSome researchers pointed out in the paper that catechins (the main active substance of green tea) can inhibit aromatase activity so green tea consumption will lead to a decrease in estradiol synthesis, but due to the existence of a feedback mechanism, long-term inhibition of aromatase activity may lead to increased expression of aromatase, which may instead promote an increase in estradiol synthesis  54,55].,55.54,55At the same time, the study also showed that SII in the tea drinking group was significantly lower than that in the control group, which was consistent with the conclusions of previous studies. Green tea can exert its anti-inflammatory effects in a variety of ways, such as being an antioxidant or inhibiting the production of inflammatory factors ,57,58.In addition, the tea drinkers had significantly lower BMIs and less severe insomnia. The improvement of green tea consumption on BMI has been widely confirmed ,60, and The study also showed a significantly lower degree of depression in the green tea drinking group, suggesting that green tea consumption may help reduce depression ,30. HoweIn addition, the pathway model found that green tea consumption may not directly improve the degree of depression but may indirectly reduce the degree of depression by affecting other factors. A pathway analysis showed that tea consumption reduced depression by improving insomnia, increasing estradiol concentration and decreasing SII, with their effects accounting for 28.2%, 6.7% and 10.3%, respectively. Many past studies have provided evidence for this. There is a significant bidirectional relationship between sleep and depression ,69, withThis may be the first study to look at the effects of lifestyle habits (rather than quantity or frequency) of long-term green tea use on behavioral and physiological markers in postmenopausal women, showing that long-term tea consumption can help improve sleep, increase estradiol and reduce depression levels in postmenopausal women. However, this study lacked research on green tea intake, frequency and concentration and could not provide relevant recommendations for the “optimal consumption” of tea drinkers. The subjects of the study were postmenopausal women, and there was no survey of other groups. In addition, the green tea drinking group has a tea drinking history of at least 20 years, so whether the conclusions are still consistent for the people with a shorter tea drinking years needs further investigation. In the future, more standardized observation criteria are needed to improve the consistency of research conclusions.Our study showed that postmenopausal women with long-term green tea consumption had higher estradiol concentrations and lower BMI, SII and insomnia levels. At the same time, they also had lower levels of depression, which may be achieved by green tea consumption by reducing inflammation and increasing estradiol. In conclusion, this lifestyle habit deserves further promotion, which can help improve hormone and inflammation levels in postmenopausal women and reduce the risk of depression. In the future, an exploration of the effects of green tea consumption on men and other age groups is necessary. In addition to hormones and inflammation, the rich active substances in green tea may have a significant effect on both the brain and gut microbiota, which can be used as a potential pathway for green tea to reduce the risk of depression and, thus, deserves further study.


As a traditional fermentation food, red sour soup (RSS) is very popular in China. However, browning is always occurred during the process of fermentation, which influences the sensory quality of RSS and limits its further application. Thus, it is meaningful to elucidate the main factors related to browning during the process of fermentation. Herein, the changes in various factors related to browning from group spontaneous (RSS-SF) and inoculant fermentation (RSS-IF) were determined and analyzed. Firstly, the activity changes of enzymes related to browning indicated that browning of group RSS-SF and RSS-IF during fermentation was not related to enzymatic browning. Secondly, path analysis revealed that the main factors related to non-enzymatic browning of group RSS-SF and RSS-IF were oxidation of polyphenol and degradation of ascorbic acid (Vc). The results of this study not only identifies the main factors associate with browning of RSS, but also provides foundation on how to control the browning of RSS in further study. As a traditional fermentation food of Miao and Dong nationalities, sour soup is very popular in China. Briefly, sour soup mainly includes white and red sour soup , 2. The In summary, there are two types of browning in fruits and vegetables, including enzymatic and non-enzymatic browning. According to previous literature, enzymatic browning is always involved in polyphenoloxidase (PPO) and phenolic compounds . As the As the prevalence of RSS, it has received extensive and increasing attention. To date, the research related to RSS are mainly focused on microorganism communities , 12, andLactobacillus rhamnosus was isolated and identified by 16sRNA and conserved our laboratory. The raw materials for RSS, such as tomatoes, chili pepper, garlic and ginger, were purchased from supermarket . The gallic acid, ascorbic acid, 2, 6-dichlorophenol indophenol, oxophenic acid, methyl catechol, L-phenylalanine, linoleic acid were purchased from Beijing Solarbio Co., Ltd. . All the chemicals used in this study were of analysis grade.The L. rhamnosus. The RSS-SF and RSS-IF both were fermented at 37°C for 28 days. Different samples were randomly withdrawn at 0, 3, 7, 14, 21, and 28 days for subsequent analysis.The process for preparation of RSS was same as our previous study . For spoThe method for determination of browning degree was same as previous study , 10. To 420nm is the absorbance at 420 nm.where AThe activity of PPO , peroxidThe method for determination of amino nitrogen, carbonyl value and Vc were in accordance with previous study . The detThe methods for determination of reducing sugar  and totap ≤ 0.05 of each group.All results were presented as average values from three replications with ± standard deviation (SD). Data was analyzed by one way analysis of variance (ANOVA) of the SPSS 25.0  and mean separations were performed by Duncan’s multiple-range test. Different letters were used to indicate the significant differences at X1), reducing sugar (X2), total polyphenol (X3), Vc (X4), carbonyl value (X5) were taken as the independent variables, and browning degree (Y) was taken as the dependent variable. The direct path coefficients (P1–P5) and indirect path coefficients (Pij) between all these independent variables and dependent variable were analyzed by SPSS 25.0 . The determination coefficients (dij) reflected the degree of independent variables to dependent variable and were calculated by correlation coefficients and path coefficients. The determination coefficient indicated the influence degree of the factor on the result (expressed in d), and it can be determined by formula through correlation coefficient and path coefficient:Path analysis was performed to investigate the main factors related to browning of RSS during fermentation. The content of amino nitrogen .Pij: the influence of one factor Xi on Y through another factor Xj (i ≠ j).di: the influence of single factors on Y.dij: the influence of two factors on Y.Pe: the coefficients of residual factors that not consider during the process of analysis.Generally, browning of food was mainly composed of enzymatic and non-enzymatic browning. For enzymatic browning, those enzymes, such as PPO, POD, and PAL, were considered to be the most important factors associated with browning . PPO shoThe results of changes in total polyphenol during fermentation were depicted in As natural antioxidant, Vc is one of the main nutrition components of different food and also closely related to non-enzymatic browning during the process of food production. According to the previous research, the degradation of Vc could convert to derivative and intermediate to react with other components to lead to browning . In summp < 0.05). Additionally, the amino nitrogen content in group RSS-SF increased after 7 days, and then decreased until 21 days, while the group RSS-IF continually decreased until 21 days, and with a slight increase at 28 days  and Postgraduate Scientific Research Innovation Project of Hunan Province (CX2021SY064).Author JW was employed by Shenzhen Raink Ecology & Environment Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.https://www.frontiersin.org/articles/10.3389/fnut.2023.1092745/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.


The relationship between body composition fat mass (FM) and lean body mass (LBM) and diabetes risk is currently debated, and the purpose of this study was to examine the association of predicted FM and LBM with diabetes in both sexes.The current study was a secondary analysis of data from the NAGALA  cohort study of 15,463 baseline normoglycemic participants. Predicted LBM and FM were calculated for each participant using anthropometric prediction equations developed and validated for different sexes based on the National Health and Nutrition Examination Survey (NHANES) database, and the outcome of interest was diabetes (types not distinguished) onset. Multivariate Cox regression analyses were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of predicted FM and LBM with diabetes risk and further visualized their associations using a restricted cubic spline function.P < 0.05), whereas each kilogram increase in predicted FM increased the diabetes risk by 84% . In contrast, predicted LBM and FM were non-linearly associated with diabetes risk in men , with an L-shaped association between predicted LBM and diabetes risk and a saturation point that minimized the risk of diabetes was 45.4 kg, while predicted FM was associated with diabetes risk in a U-shape pattern and a threshold point with the lowest predicted FM-related diabetes risk was 13.76 kg.The incidence density of diabetes was 3.93/1000 person-years over a mean observation period of 6.13 years. In women, predicted LBM and FM were linearly associated with diabetes risk, with each kilogram increase in predicted LBM reducing the diabetes risk by 65% (HR 0.35, 95%CI 0.17, 0.71; In this Asian population cohort, we found that high LBM and low FM were associated with lower diabetes risk according to anthropometric equations. Based on the results of the non-linear analysis, we believed that it may be appropriate for Asian men to keep their LBM above 45.4 kg and their FM around 13.76 kg. Diabetes, characterized by chronically elevated blood glucose, is a cluster of metabolic disorders due to impaired insulin secretion or insulin resistance (IR) , 2. The N = 15,463), this study further explored and compared the associations between risk for future diabetes and BMI and FM and LBM. Furthermore, due to the high economic and technical costs of dual-energy X-ray absorptiometry (DXA), the gold standard measure of body composition LBM and FM, it is generally used for laboratory examinations rather than for large-scale population measurements. Therefore, consistent with previous studies  is the most commonly used anthropometric parameter to evaluate obesity. However, the limitation that BMI cannot distinguish between fat and lean muscle mass makes it of very limited help in preventing diabetes . In rece studies , the LBM studies .This study used data from the NAGALA cohort study from 1994 to 2016. The cohort study was initiated in 1994 and investigators continuously recruited and followed up with participants who underwent health screening at Murakami Memorial Hospital to evaluate chronic diseases such as diabetes and non-alcoholic fatty liver and their risk factors that affect the health of the general population . Data frn = 863) and data with extreme values (n = 1), fasting plasma glucose (FPG) ≥ 6.1 mmol/L (n = 808) or diagnosis of diabetes at baseline examination (n = 323), taking any medication at baseline (n = 2321), diagnosed liver disease at baseline (except fatty liver) (n = 416), excessive alcohol consumption (n = 739), and unexplained withdrawal from the follow-up cohort (n = 10). We extracted data from 12,498 men and 8,446 women who enrolled in the NAGALA cohort. The follow-up period for each subject was calculated from the date of enrollment in the cohort until the onset of diabetes or missed visits or the study cut-off date, whichever occurred first, using 31 December 2016, as the follow-up cut-off date. For the purposes of the current study, we excluded participants with the following characteristics: incomplete baseline information . As a secondary analysis of NAGALA data, all procedures for this study are in line with the Helsinki Declaration, see STROBE statement , and areR2 = 0.90; woman: R2 = 0.93)] and [LBM ]. Among these predictors, the race variable was a categorical variable that was divided into four categories: Mexican, Hispanic, Black, and Other races, and different race categories were assigned different values in the equations; the Asian population in the current study belongs to Other races, so the assignment values of the race variable for the current study population were −1.007 and 1.050 in the prediction equations for LBM and FM for men, respectively, and −0.34 and 0.325 in the prediction equations for LBM and FM for women, respectively. We calculated the predicted LBM and FM for each participant using the equations presented in 2.The predicted FM and LBM in this study were calculated using the anthropometric prediction equations developed and validated by Lee et al., and the detailed steps for the construction of the equations have been described elsewhere . BrieflyParticipants self-reported information on sex, age, exercise habits, smoking status, and drinking status in a standardized questionnaire. Regarding lifestyle habits, participants who had more than one physical activity per week were considered to have exercise habits; smoking status was defined as none or past or current according to whether subjects smoked in the past or currently; participants’ drinking status was defined as non/small or light or moderate or heavy depending on the type and amount of alcohol they consumed per week during the month before the initial visit . ParticiParticipants’ forearm venous blood samples at fasting (at least 8 h) were drawn by professional medical examiners and then used standard procedures to measure the concentration of biochemical parameters including total cholesterol (TC), γ-glutamyltransferase (GGT), glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), FPG, high-density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST), and triglyceride (TG).Diagnostic criteria for the onset of diabetes include: (1) normoglycemia at baseline but self-reported diabetes diagnosis during follow-up ; (2) normoglycemia at baseline but measured FPG ≥ 7.0 mmol/L or HbA1c ≥ 6.5% during follow-up .P value < 0.05  as the significance criterion; in addition, as the large gender differences in body composition, all analyses were conducted separately in women and men  and used the chi-square test to compare the inter-group difference. Additionally, the inverse probability of treatment weighting method was further used to calculate weighted standardized differences between groups (differences > 10% were considered significant) for visually describing the magnitude of differences between groups  version 2.0, with a  and men . Baselinn groups . Before n groups , we consSensitivity analysis: (1) Excluded participants with less than two years of follow-up, with the aim of avoiding a potential reverse causality from affecting the results. (2) We explored the possibility of unmeasured confounding between predicted LBM and FM and diabetes risk by calculating E-values . The E-vWe also performed subgroup analyses to explore the effects of age, BMI, smoking status, exercise habits, hypertension, and fatty liver on the associations between predicted FM and LBM and diabetes risk and checked for interactions between subgroups using the log-likelihood ratio test.P < 0.001). In addition, compared to the non-diabetic group, the diabetic group had higher predicted LBM  and FM , age, weight, BMI, WC, TC, DBP, SBP, TG, LDL-C, GGT, AST, ALT, and more smokers and fatty liver patients, but had lower height and HDL-C levels ; whereas in exercise habits and drinking status differed significantly only among men . Additionally, by comparing the standardized difference values between groups for both sexes we found that differences in almost all baseline indicators were greater in women than in men.After screening by the exclusion criteria, 15,463 eligible participants were finally included in this study; among them, 8,429 were men, with an average age of 44.09 (9.00); 7,034 were women, with an average age of 43.25 (8.76). During a mean follow-up period of 6.13 years, a total of 373 diabetes cases  occurred. P < 0.05) for women and men, respectively. While the effects of the body composition indicators predicted FM and LBM on the risk of future diabetes showed an opposite trend in women. In women, each kilogram increase in predicted LBM reduced the diabetes risk by 65% ; conversely, each kilogram increase in predicted FM increased the diabetes risk by 84% . However, the overall effect of the association between predicted LBM and diabetes risk was not statistically significant in men , and only predicted FM remained a significant positive association with diabetes risk during multivariate model adjustment .In the collinearity screening, covariates sex, weight, WC, and DBP were excluded from subsequent model adjustment, while there was also collinearity between BMI and predicted FM and LBM, thus BMI was not mutually adjusted with predicted FM and LBM in the subsequent models , 3. Accon = 2,641, 17.08%), and we found that the magnitude and direction of the associations between predicted LBM, FM, and BMI and the risk of diabetes in both sexes remained stable  (P for non-linear < 0.001) (P for non-linear = 0.028)  , 3, but < 0.001) , with an< 0.001) . In addi= 0.028) , with an= 0.028) .P for interaction > 0.05). Moreover, there were no significant interactions in men for all subgroups except for the BMI subgroups and fatty liver  developed and validated by Lee et al.  . Additionally, although BMI was more strongly associated with diabetes risk than predicted FM and LBM in men, we found non-linear associations between predicted FM and LBM and diabetes risk. There was a U-shaped association between predicted FM and diabetes risk in men, with the lowest risk of developing diabetes when the predicted FM was equal to 13.76 kg, and an L-shaped association between predicted LBM and diabetes risk in men, with an increase in predicted LBM helping to reduce diabetes risk when the predicted LBM in men was less than 45.4 kg, but no significant effect on diabetes risk when it was higher than 45.4 kg. These results may be caused by differences in body fat distribution between men and women and the strong correlation between BMI and WC , 41. Men0.8–0.9) . Previou0.8–0.9) , 45 and 0.8–0.9) , 47. TheAs in previous studies, our results also revealed that predicted FM in women was a more important risk factor for diabetes than BMI; however, the difference is that we found for the first time that predicted LBM was a strong protective factor for diabetes in women, and our results remained stable after validation by sensitivity analysis and multiple subgroup analysis. This may be related to the mutual adjustment of the predicted FM and LBM in the current study and the fact that the women in this study were mainly middle-aged. Previous studies have shown that overall body weight in both sexes may keep the same or increase only slightly before reaching old age, but the proportions of FM and LBM will change markedly from midlife, especially in women . In termThe current study had several advantages: (1) Our long follow-up period and large sample size compared to similar studies gave us more adequate statistical efficacy. (2) After a rigorous study design and repeated statistical demonstrations, we found for the first time that predicted LBM was a protective factor for diabetes in women and in men with predicted LBM of less than 45.4 kg, which provided important reference material for diabetes prevention and interventions.R2 > 0.9). Overall, although the anthropometric prediction equations in the current study are cost-effective tools for assessing body compositions, they were not developed in Asian populations, and there may be significant differences in body compositions across ethnic groups, so the applicability of these anthropometric prediction equations to Asian populations requires additional studies for validation, and the results of the current study should be used with caution. (2) The main outcome in the current study was the onset of diabetes, but the diagnostic criteria did not include two-hour postprandial glucose values, which may underestimate the prevalence of diabetes in the current study cohort and thus the extent to which body composition indicators were associated with diabetes risk; in addition, deaths during follow-up were not recorded, which may pose a competing risk to the current findings. (3) Since the current study is a retrospective cohort study, there may be some data on diabetes risk factors that cannot be obtained, resulting in residual confounding; However, in the current study, we further calculated the E-value to quantify the potential impact of unmeasured confounding factors. The results showed that the direct correlation between predicted FM and LBM and diabetes risk in women was stable, while the direct correlation between predicted FM and LBM and diabetes in men may be affected by an unmeasured confounding factor, which needs further study. (4) Since the current study did not differentiate the types of diabetes  that occurred during the follow-up period, it cannot be clearly stated that the analysis of the current study was for type 2 diabetes, but considering that IR caused by obesity is mainly the pathological basis of type 2 diabetes and more than 90% of diabetes is type 2 diabetes  The predicted FM and LBM calculated by the anthropometric prediction equations in this study as alternative indicators of body composition cannot fully and accurately represent the actual FM and LBM. In addition, these predictive equations were developed and validated by Lee et al. in two cohorts of the NHANES database with predominantly US populations, rather than specifically for Asian populations. Although race was considered in these equations, i.e., the differential effects of Mexican American, Hispanic, Black, and Other races, and the equations have been used in previous studies to calculate body compositions in Asian populations , 51, it diabetes , our resPredicted LBM was a protective factor for diabetes and predicted FM was a more important risk factor for diabetes than BMI in Asian women. But, in men, the protective effect of predicted LBM on the risk of diabetes had a saturating effect, and continued increases in predicted LBM above 45.4 kg may not further reduce the risk of diabetes; in addition, we found a U-shaped association between predicted FM and diabetes risk, with the lowest risk of diabetes when the predicted FM reached 13.76 kg. Therefore, taking into account the distribution of LBM and FM levels in both sexes in the current study population, we suggested that Asian adult women should add appropriate muscle-strengthening exercises to traditional lipid-lowering interventions to further reduce the risk of future diabetes, while Asian adult men should actively reduce their fat intake to prevent diabetes based on the prevention of aging-induced LBM loss.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Jiangxi Provincial People’s Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.YZ revised the manuscript and designed the study. All authors conceived the research, drafted the manuscript, did the statistical analysis, and read and approved the final manuscript.


Internet addiction (IA) is becoming a significant public health issue that requires urgent attention, especially for adolescents. Previous studies mainly focused on the risk factors of Internet addiction and drawn some conclusions. The purpose of this study is to investigate the Internet addiction status and concurrent psychological problems in adolescent groups, and explore the differences in the relationship between IA and psychological problems in adolescents from gender and grade.A cross-sectional study was conducted among students of junior and senior high school in 21 prefecture-level cities of Guangdong Province. The Young Diagnostic Questionnaire (YDQ) and the validated Chinese version of the Depression Anxiety Stress Scale-21 (DASS-21) were used to assess participants’ Internet addiction and psychological status. Two-way ANOVA was used to verify the interaction between gender and Internet addiction, grade and Internet addiction on psychological problems. When the interaction was statistically significant, simple effect analysis was further carried out.p < 0.05). Although the prevalence of PIU was the highest in grade 9 (17.29%), the adverse effects of Internet addiction on psychological problems were different in different grades.The prevalence of problematic Internet use (PIU), depression, anxiety, and stress symptoms among adolescents were 16.32%, 30.16%, 35.97% and 18.80% respectively. Although the prevalence of PIU among boys (17.89%) was higher than that of girls (14.86%), girls in PIU group had the highest scores of depression, anxiety and stress. Similarly, the interaction between grade and Internet addiction was also significant (Internet addiction was prevalent among adolescents in Guangdong province, and psychological problems also cannot be ignored. Thus, this study suggests that long-term follow-ups should be included in mental health programs of adolescents to monitor the development of Internet addiction and psychological problems. With the rapid popularity of Internet in the 21st century, the Internet economy and knowledge economy have been keeping on working new wonders . Now we Internet addiction (IA) can be defined as overuse of the Internet leading to impairment of an individual’s psychological state , as well as their scholastic or occupational and social interactions, which is the most common problem among adolescents . InvolviIn recent years, scholars have conducted empirical researches on the related factors of IA and have drawn some conclusions. Consistent with other addictive behaviors, many studies have showed that male adolescents are more prone to IA . For exaBuilding upon previous research in this area, we conducted a cross-sectional study. The purpose of this study is to investigate the phenomenon of IA and concurrent psychological problems in adolescent groups, and explore the differences in the relationship between IA and psychological problems in adolescents from gender and grade, so as to identify any existing associations and theorize as to their causes. We believe that the data from this study will add meaningful information to the field.This is a large sample cross-sectional study that approached students of junior and senior high school in 21 prefecture-level cities of Guangdong Province, jointly carried out by Health Promotion and Education Center and Education Department of Guangdong Province. The survey was conducted from May to June 2020, and the target population comprised school-aged students in Guangdong province. To build our sample, a 10% of junior and senior high schools were randomly selected from each city using the equal probability method, then a cluster sampling method was used to extract students from these schools, and the probability of each student being selected was the same. Owing to the impact of the pandemic (COVID-19), the Chinese version of the electronic questionnaire through an online survey platform—Survey-Star  were distributed to adolescents through their teachers, and the recovered copies were reviewed by professionals. The Survey-Star is a website providing online survey and statistical analysis functions . The queThe inclusion criteria of school-age students were (1) grades 7–12, boy or girl, (2) voluntary participation in this survey, (3) ability to complete the online survey or with the help of parents. Meanwhile, those who were unwilling to participate in the investigation or were diagnosed with cognitive impairment or serious illnesses were excluded. Finally, 154,705 questionnaires were recovered. A total of 140,782 valid questionnaires were collected after removing invalid questionnaires such as wrong filling, random filling and logic errors, with an effective recovery rate of 91.00%. Ethical approval for this study was obtained from Southern Medical University. A parent or guardian assented to student participation before they completed the survey. Due to the heavy workload of written consents from the respondent, the school staff assisted in informing the respondent of the purpose and procedure of this study.α of the scale ranges from 0.68 to 0.79  group, and the participants whose scores ranges from 5 to 8 points were classified as the Problematic Internet Use (PIU) group.The Young Diagnostic Questionnaire (YDQ) was used to assess the status of IA among participants. The 8 items of the YDQ are based on the criteria for pathological gambling in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders , with a  to 0.79 . In the α of the depression, anxiety, stress subscales were 0.911, 0.879 and 0.898, respectively.The psychological problem of the respondents was assessed by the validated Chinese version of the Depression Anxiety Stress Scale-21 (DASS-21) in this research. The scale contains 21 items, which was a set of three self-administered subscales (7 questions each) designed to measure the negative emotional states of depression, anxiety, and stress over the prior week . Each itSociodemographic characteristics include sex, age, school grade, residence, myopia and boarding. Lifestyle behavior involves sleep quality, exercise time and screen time. Sleep quality was assessed by the following questions: “How do you feel about your sleep quality in the past month?” with a possible answer of “Very good,” “Good,” “Bad,” or “Very bad.” For purposes of analysis, “Very good” and “good” were merged into “Good,” and “Bad,” and “Very bad” were merged into “Bad.” Data on exercise time were obtained by self-reported questionnaires. The participants reported exercise time using the following question: “How many hours per day do spend exercising?” The responses included “within 2 h” and “more than 2 h.” Data on screen time were obtained using the following question: “How many hours per day do you spend on electronic devices (besides study)?” All the time spent on screen-based electronic mediums and devices, such as TV, computer, mobile phone, video games, and tablet TV, were included. The responses were classified into “within 2 h” and “more than 2 h.”p < 0.05 was considered as the cutoff value for significance. All data were analyzed using the statistical software SPSS Version 23.0.All study variables were analyzed using descriptive analysis. Proportion with percentage was calculated for categorical variables and mean with standard deviation for continuous scale variables. First, Chi-square tests were used to compare the differences of Internet addiction and psychological problems (DASS-21) among adolescents of different genders and ages. Then, we also compared the differences in the depression, anxiety, and stress scores between NIU group and PIU group by two-sample t-test, and included gender and age for further comparison. Next, two-way ANOVA was used to verify the interaction between gender and Internet addiction, grade and Internet addiction on psychological problems. When the interaction was statistically significant, simple effect analysis was further carried out. The level Among the 140,782 participants, 48.26% were boys and 51.74% were girls. The average age was (14.76 ± 1.44), with a range of 11 to 17 years. About half of the them lived in urban areas (51.72%), and 48.28% lived in rural areas. Myopia was found in 82,637 (58.70%) of the participants. And 52.00% of the participants boarded at school, 75.67% had good sleep quality. In total, the mean YDQ score was (2.01 ± 2.36), with 16.32% of adolescent were classified as belonging to the PIU group. And the prevalence of depression, anxiety, and stress symptoms came in at 30.16% (42466), 35.97% (50640) and 18.80%  according to DASS-21. Others lifestyle information were also presented in p < 0.05). 17.89% of the boys were classified as belonging to the PIU group, which was significantly higher than that of girls (14.86%). Yet, when the grades were divided into junior middle school (7th-9th) and senior high school (10th-12th), there was no significant difference between the two grade groups . Further analysis showed that there were significant differences in the prevalence of PIU among adolescents in six grades , and the highest prevalence of PIU was among adolescents in 9th-grade (17.29%). In addition, this study also found there were statistical differences in the prevalence of depression, anxiety and stress among adolescents of different sex and grade . Similarly, this difference was also statistically significant between different sex (boys and girls) and grade . The results suggested that the mental health problems of adolescents in PIU group were more serious than those in NIU group.p < 0.05), and the interaction between sex and IA was also significant (p < 0.05). The interaction between sex and IA was verified by two-way ANOVA . The resp < 0.05). Specifically, the scores of depression, anxiety and stress of boys in PIU group were 5.619 points, 4.144 points and 5.741 points higher than those in NIU group, respectively. Similarly, this difference exists among girls, the scores of depression, anxiety and stress of girls in PIU group were 7.560 points, 5.886 points and 7.652 points higher than those in NIU group, respectively. The mean difference (PIU-NIU) of depression, anxiety and stress scores of girls in different Internet addiction groups were greater than that of boys . In addition, when the fixed Internet addiction status was in the NIU or PIU group, the scores of depression, stress and anxiety of adolescents of different sex were also different.On the premise of significant interaction, simple effect analysis was conducted . That isp < 0.05), but the interaction between grade and IA was only significant in the dimension of anxiety . However, for the grade, when grade was roughly divided into junior middle school (7th-9th) and senior high school (10th-12th), the main effects of grade on depression, anxiety and stress were significant (p < 0.05). The score of anxiety of junior middle school students in PIU group were 4.771 points higher than those in NIU group. For high school students (grade 10th-12th), the difference was 5.328. Similarly, when the fixed Internet addiction status was in the NIU or PIU group, the score of anxiety of adolescents of different grade were also different  in different Internet addiction states . The anxiety score difference of grade 11 students was the largest .In order to further understand the differences between the six grades of junior high school and senior high school, this study analyzes the grade as a six categories variable. Different from the results of grade as a binary variable, when grade was subdivided, the interaction between grade and IA was significant in depression, anxiety and stress , most countries generally adopt measures of home quarantines and national school closer to maintain social distance. However, Wang et al. pointed out that school closure may cause disruptions in the social interaction, and mental health of children and adolescents . This suConsistent with previous studies , this stp = 0.793). However, when grades were divided into six grades, there were significant differences in the prevalence of PIU among adolescents (p < 0.05). In the stage of junior middle school (7th-9th), with the growth of grade, the prevalence of PIU in adolescents increases gradually (15.61 < 16.57 < 17.29%). But in high school (10th-12th), the prevalence of PIU decreased. This result confirms the views of Widyanto and Mcmurran. The gradual decrease for the prevalence of PIU might be due to increased cognitive maturation and engagement in meaningful activities  and senior high school (10th-12th), there was no significant difference in the prevalence of PIU between different grades  was higher than that in junior high school students . Specifically, the prevalence of depression, anxiety and stress of grade 11 students were the highest, followed by grade 12. This is largely due to the different learning pressures in different grades . In ChinIn view of the differences in the scores of adolescents’ psychological problems under different Internet addiction states , this stWhen grade was roughly divided into junior middle school (7th-9th) and senior high school (10th-12th), the interaction between grade and IA was only significant in the psychological problem of anxiety. But when grades were divided into six grades, the interaction between grade and IA has statistical significance in the three dimensions of psychological problems. Specifically, although the prevalence of PIU was the highest in grade 9, the influence of IA on depression and stress was more obvious in grade 8 and grade 9 students, and the influence of IA on anxiety was more obvious in grade 11 students. Middle school students are in a special stage of physical and mental development. Their self-consciousness is gradually awakening, and the contradictions and psychological conflicts they face are also gradually increasing. The Internet is the most convenient means for them to express themselves. However, once addicted to the Internet and trapped in the virtual world, middle school students will be separated from life and society, lose interest in learning, and easily fall into depression. This phenomenon is more significant among grade 8 and 9 students because for grade 7 students, they have just integrated into the new environment, so they need an adaptation process. At the same time, with the growth of grade, students’ pressure is also increasing. This pressure is largely due to the mismatch between parents’ expectations and adolescents’ own abilities. The reason why high school students have less pressure is that their physical and mental development is relatively mature and they have a certain ability to deal with pressure. For grade 11 students, the learning task at this stage is heavier. On the one hand, students need a process of adaptation after course selection. On the other hand, in order to buy more review time, the curriculum arrangement of some schools is relatively compact. When the temptation of the Internet and heavy learning tasks cannot be balanced, adolescents are likely to fall into anxiety.This study has several strengths: firstly, different from previous studies, this study further analyzes the relationship between Internet addiction and psychological problems in different populations . For example, most previous studies indicated that boy was a risk factor of Internet addiction. But this study further verifies that although the prevalence of PIU was higher in boys, the adverse effect of Internet addiction was more obvious in girls. Secondly, this study is based on a large sample cross-sectional survey in Guangdong Province. Therefore, the results of this study can provide guidance for relevant government departments to formulate adolescent health management and health promotion plans.Several limitations in the present study should be considered. First, this survey was conducted during the COVID-19 pandemic. Li et al. found the prevalence of Internet addiction among the general population in China during the COVID-19 pandemic was remarkably high . This maAdolescents often have strong curiosity and are willing to pursue more autonomy. This makes it particularly important to guide them to cultivate healthy behavior. The present study revealed that IA was prevalent among adolescents in Guangdong province and the prevalence of PIU was 16.32%. In addition, psychological problems such as depression (30.16%), anxiety (35.97%) and stress (18.80%) also cannot be ignored. Although the prevalence of PIU was higher in boys, girls in PIU group had the highest scores of depression, anxiety and stress. Similarly, the influence of IA on depression and stress was more obvious in grade 8 and grade 9 students, and the influence of IA on anxiety was more obvious in grade 11 students. The results suggest that we should not only consider the high prevalence of boys and grade 9 students, but also explore the possible negative effects of Internet addiction on the characteristics of different groups. Thus, we recommend integrating long-term follow-ups into the associated mental health programs of adolescents to monitor the development of Internet addiction and psychological problems. Meanwhile, scholars and health practitioners should consider gender and grade differences when formulating strategies to prevent IA, so that it could offer significative guidance for clinicians, parents and educators.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical approval for this study was obtained from Southern 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.CZ designed this study, participated in its implementation, and served as the lead writer. YX and BX did the data interpretation and co-wrote the article. XZ, LS, and PL were involved in the study design and critically revised the article. SX, FD, and JZ helped to collect the data and research the literature. YC, YL, and ZQ helped with formatting of this manuscript. All authors have seen and approved the final manuscript.This study was funded by the Education Science Planning Project of Guangdong Province in 2022 (Grant number: 2022JKZG048), Special Research Project of Prevention and Control during the COVID-19 pandemic in Universities of Guangdong (Grant number: 2020KZDZX1046); and Key Laboratory of Philosophy and Social Sciences of Guangdong Higher Education Institutions for Health Polices Research and Evaluation (Grant number: 2015WSY0010).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 purpose of this nationwide longitudinal follow-up study is to investigate the relationship between Parkinson’s disease (PD) and congestive heart failure (CHF) patients in Korea. Patient data were collected using the National Health Insurance Service (NHIS) Health Screening (HEALS) cohort. The International Classification of Diseases 10-CM code G-20 distinguished 6475 PD patients who were enrolled in the PD group. After removing 1039 patients who were not hospitalized or attended an outpatient clinic less than twice, the total number of participants was reduced to 5436 individuals. Then, 177 patients diagnosed before 1 January 2004 were removed for relevancy, leaving us with 5259 PD patients. After case–control matching was completed using 1:5 age- and gender-coordinated matching, 26,295 people were chosen as part of the control group. The Cox proportional hazards regression analysis and the Kaplan–Meier technique were used to assess the risk of CHF in patients with Parkinson’s disease. After controlling for age and gender, the hazard ratio of CHF in the PD group was 5.607 , 4.496–6.993). After that, the hazard ratio of CHF in the PD group was modified against for comorbid medical disorders, resulting in a value of 5.696 . In subgroup analysis, CHF incidence rates were significantly increased in the PD group compared to the control group . This nationwide longitudinal study shows a higher incidence rate of CHF in PD patients. Parkinson’s disease (PD) is the second most common neurodegenerative disease that affects human movement over time, affecting 1% to 3% of people aged > 65 years . The maiCurrently, congestive heart failure (CHF) is the leading cause of death. Due to the increase in life expectancy and developments in treatment methods, the number of diagnoses is gradually increasing. Notable symptoms include dyspnea on exertion, peripheral edema, orthopnea, and paroxysmal nocturnal dyspnea .Past studies have found that PD can have critical effects on the heart, as well as the blood vessels ; recent Eight researchers from three different institutions in South Korea gathered data on PD patients from the National Health Insurance Sharing Service (NHIS), a single-payer health system in South Korea, from 2004 to 2015. This particular cohort is credible and reliable as healthcare providers are required to submit medical claims to the NHISS for further review; furthermore, the system itself requires individuals aged ≥ 40 years to take national health examinations, twice every year for office employees and once every year for non-office employees. To elaborate, the data incorporate details about the demographics of individuals, as well as different medical treatments, procedures, and diagnoses they received, as followed by the 10th revised codes of the International Classification of Diseases (ICD-10). We acquired the rights to use the NHIS database from the institutional review board (IRB No. 2020-01-011). Prior consent was not necessary because the data used in this study were anonymous secondary data that were made available for research purposes.Following sex- and age-stratified matching intended to determine the potential dangers of CHF in PD patients, the population incorporating both the PD and control groups comprised 515,547 patients . The KorOut of the 515,547 patients in the NHISS cohort, the number of PD patients was 6475, distinguished by code G20 on the ICD-10 code. Out of these, 5436 patients who went to the outpatient clinic more than twice or who were hospitalized more than once were chosen. Again, the population decreased after those with preexisting PD were removed, leading to a final total of 5259 patients who were recently diagnosed (after 1 January 2004). On the other hand, the population of the control group was determined using the R package match algorithm ‘Match IT’ and 1:5 age- and sex-stratified matching without replacement, which resulted in 26,295 people ,12. Datat-test and the chi-square test. The CHF-free survival rates of both categories were determined through the Kaplan–Meier method, while the differences in disease-free survival were estimated utilizing Wilcoxon’s log rank test. Additionally, approximations on the impact of PD on respective events were tested using multivariate analyses with two Cox proportional hazards regression models. There were three types of Cox proportional hazards regression models that were used: while sex and age were modified in model 1, age, sex, and income were regulated in model 2, and age, sex, income, and other diseases were regulated in model 3. The Cox proportional hazards regression model was used to determine the association between PD and each respective event in each subgroup. The following analyses were deduced using R software (version 3.3.3).The mean differences in the PD and control groups’ demographics and comorbidities were compared through Student’s p = 0.001). However, data for other variables  showed higher prevalence in the control group, with statistical significance . Dyslipidemia was higher in the control group (17.80%) than the PD group (16.77%). However, it was statistically insignificant (p = 0.077).There were 5259 subjects in the PD group and 26,295 in the control group. The incidence rate of CHF was higher in those with PD (7.496) than the control group (1.575). The data were then analyzed through three models. Model 1 was adjusted for age and sex, model 2 was adjusted for age, sex, and income, and model 3 was adjusted for age, sex, income, diabetes, hypertension, and dyslipidemia. After these analyses, the data showed that the PD group was five times more likely to be at risk for CHF. The Cox proportional hazards regression model indicated that the CHF hazard ratio of the PD group for model 1 is 5.607  and other possible confounding variables  are not present in this study, making it more complex to analyze the novel effects on the association between CHF and PD. However, though there are limitations, it is undeniable that this is the first nationwide longitudinal follow-up study that describes the relationship between CHF and PD in South Korea. The results of this research helped to further fathom the association between PD and CHF, as well as its effects. Similar studies are expected to improve patient care in the medical and health sector.This nationwide longitudinal cohort study deduced that PD patients residing in Korea, in general, have an increased risk of CHF. Consequently, this study implies that the risk of CHF should be considered during patient care in those diagnosed with PD.


Adverse childhood experiences (ACEs) are associated with an increased risk of poly-substance use among drug-using adults. However, there is a paucity of literature on a direct or indirect relationship between ACEs and drug use patterns. We thus aimed to identify the pathway of effects of ACEs on drug use patterns in adults by the structural equation model (SEM).A cross-sectional study was conducted by respondent-driving sampling and consecutive sampling among adult drug users in Southwest China in 2021. Descriptive, univariate, and SEM analyses were performed by R software 4.2.1.Of 406 participants recruited from a drug abuse clinic, the average age was 34 years. The majority of the participants were male patients (98.3%) from ethnic minorities (79.6%), who were unmarried (71.6%) and employed (81.2%). Nearly 95.5% experienced ACEs with 46.6% of them reporting four or more ACEs. The median value of self-perception of drug abuse score, friend drug use score, and drug use score was 8.0 , 1.0 , and 1.0  respectively. In the confirmatory analysis part of SEM, the construct of latent variables fitted well with the data. Poly-drug use was significantly and directly affected by three predictors including monthly incomes (β = 0.09), friend drug use (β = 0.50), and ACEs (β = 0.11). The indirect effect of ACEs passing through self-perception of drugs (β = 0.09) was not significant.ACEs have an independent and direct effect on the drug user for poly-drug use apart from the effect of drug-using friends and family income. Drug use could result in a higher risk of negative health outcomes , such asAdverse childhood experiences (ACEs) are associated with an increased risk of substance use, even the development of drug-use disorders . Recent In addition to ACEs, potential risk factors were possibly associated with drug use behaviors including socio-economic characteristics, alcohol  and tobaThis study intended to determine whether and how exposure to adverse experiences during early childhood directly or indirectly predicted the poly-drug use pattern among drug-using adults. We argued that adverse childhood experiences may affect the pattern of drug use by the intermediary variable. Structural equation modeling (SEM), a more advanced form of regression analysis, was an important analytical strategy to disclose the effects of a variable, such as experiences in an early lifetime on the drug use pattern . It was Our general objective was to constitute an extension of previous studies to increase the understanding of the relationship between drug consumption and prior childhood maltreatment. Specifically, we explored the pathways of the influence of ACEs on the drug-use pattern in adulthood and the possible moderating effects of socio-economic characteristics in samples from Southwest China.Our study site was a drug-treatment center in the Jinghong city of Xishuangbanna Autonomous Prefecture, Yunnan Province, where the problem of drug abuse was most prevalent in the province from January to July 2021. Participants were selected by consecutive sampling among drug-using adults who voluntarily came for service. All the participants, the majority of whom local to the province, could communicate in Chinese. An additional sample of participants was obtained from Response Driven Sampling in order to cover participants who were not attending the service. Inclusion criteria were those who had injection drug use in the lifetime and/or used stimulants in the past 6 months, and who were more than 18 years old. Those who could not participate due to physical and psychological reasons were excluded. The 406 eligible participants mainly used self-made questionnaires. The details of the study setting, participants, sampling, and data collection processing can be seen in our previous study .Questionnaires were used to measure sociodemographic data, personal drug use history, family and peer substance use histories, self-perception of drug use, and categories of illegal drug use. The information on the duration of use (in months), frequency of use, dose per use, and mode of administration were also collected. Substance use in our study met the diagnostic criteria for substance dependence in the Psychiatric Diagnostic and Statistical Manual (Fifth Edition) (DSM-V), in which participants were instructed to respond to each question whether they used illegal drugs including opium, heroin, morphine, cannabis, ketamine, crystal meth, meth tab, and ecstasy by giving “no” or “yes” and assigning values from 0 to 1. In addition, family and peer factors included legal  and illegal substance use of the family members and their friends were also measured.The self-perception of drug use questionnaire included 20 items covering contents about stigma perception directly from drug use and psychiatric symptoms caused by substance use based on literature . ACE queThese questions were initially translated into Chinese and modified by the main researcher to suit the Chinese context. A team of experts including two chief physicians from departments of neurology and infectious disease separately and three experts in drug dependence prevention at the Institute of Drug Dependence of Yunnan Province reviewed and finalized the Chinese questions. The finalized version was back-translated into English and compared with the original version to establish the validity of the Chinese version. In-depth interviews were conducted with five border drug users to obtain cultural and contextual relevance. The respondents were asked specific related questions to determine whether the nine questions were understandable and whether the intent of each question was accurately conveyed. They were also asked to elaborate on the reasons why a positive response category was chosen. Based on their suggestions, we modified the questionnaire for clearer comprehensibility and cultural suitability. In January 2021, a pilot study was conducted among 20 border drug users of methadone clinics and detention centers. The participants responded to each question of the questionnaire  by giving “no” or “yes” and similarly assigning values from 0 to 1.The dependent variable was drug use scores ranging from 0 to 8. Socio-demographic variables included age, gender, ethnicity, and marital status. Indicators of socio-economic status (SES) included occupation, education, and monthly income. Among them, age and average income were continuous variables. Ethnic groups were classified into two categories: Han and ethnicity. Marital status was grouped into two categories: (i) unmarried  and (ii) married. For SES factors, education was grouped into two levels: (i) primary school or less and (ii) high school and above. The occupation was grouped into two levels: (i) unemployed and (ii) employed (mainly engaged in agriculture or workers).In addition, ACE scores ranging from 0 to 9 were used to evaluate the cumulative levels of multiple ACEs with a higher score indicating more serious exposure to ACEs. It can be divided into four levels . The friend drug and family member drug use scores were both from 0 to 8, and the scores of self-perception of drug use ranged from 0 to 20.P-value of <0.05 was considered to be statistically significant. Finally, the goodness of fit test was used to examine whether the model fits well with the data.Data management was carried out using Epidata 3.1, and data analyses were conducted using R software 4.2.1. The chi-square test and rank sum test were used for the comparison of risk levels in the univariate analysis. Structural equation model (SEM) analysis was used to explore associations and direct/indirect effects among variables. A 399 of the 406 drug users were male, with an average age of 33 years, 79.5% of ethnic minority, 91.6% of drinking, 71.6% of unmarried and employed accounting for 81.2%. A total of 95.5% of respondents experienced ACEs with 46.4% reporting four or more ACEs. The median values (inter-quartile range) for monthly income, self-perception of drug abuse score, friend drug use score, and drug use score were 3500.0 , 8.0 , 1.0 , and 1.0 , respectively .p < 0.01); friends' drug use was positively associated with the drug use summary score (p < 0.001); the score was negatively correlated with ACEs (p < 0.05); self-perception of drug abuse was positively related to ACEs (p < 0.001), and ACEs were positively related to drinking status (p < 0.05) , RMSEA = 0.000 , AGFI = 0.979, and CFI = 1.000]. From the goodness of fit tests, the final structural model fitted the current data well [chi-square = 10.146 (df = 11, It should be noted that self-perception of drug use was initially treated as an intermediary variable between ACEs and drug use as indicated by one arrow pointing from ACEs to this variable and then from this variable to drug use. However, the coefficient of the latter arrow of −0.09 was not significant. We, therefore, had no evidence that it was an intermediary variable.In this study, exposure to ACEs could predict the drug-use pattern in adulthood with a direct association. In addition, age, income, and friend drug use also have independent effects on the development of drug use in adulthood.ACEs, directly contributed to a risky effect on poly-drug uses, and it is consistent with some studies . It alsoOn the contrary, ACEs were negatively related to self-perception of drug use, but the latter did not significantly link to drug use. An interesting phenomenon found was that a substantive subset of individuals who suffer from ACEs avoid partly or entirely the negative health and social outcomes associated with chronically stressful childhood, a characteristic referred to as resilience . It may Income was a positive factor associated with drug use, and it is similar to other studies. Earlier research has found higher-intensity substance use to be associated with greater sex work income . ObviousFriend drug use contributed to a high score of drug use, but family drug use was not associated with poly-drug use. Prior findings about family influences were contradictory to our results . Family Our study did not identify the association between tobacco and drug abuse, and alcohol usage was not significantly associated with drug use by the SEM model. It is totally contradictory to other studies, which showed that tobacco  and alcoThere were limitations that should be noted. First, the measurement of ACEs relied on self-recall resulting in information bias. Second, the derivation of causality may be restricted due to the cross-sectional design. In addition, pathways suggested by structural equation modeling are not inclusive and barely address directly observed variables without latent variables that may affect the exposure as well as the outcome, which may limit causality explanation. Finally, the study was confined to drug users at the treatment center without a control group who were non-drug users, and the majority of participants were mostly male patients of Dai ethnicity, which limited the generalizability of this study.ACEs could be a predictor for the drug-use pattern in adulthood, as well as friends' drug use and income, in which self-perception of drug use as a mediator between ACEs and poly-drug use could not be confirmed. Strategies on how to build a good family environment, minimize childhood stressful and/or traumatic experiences, and improve teenagers' knowledge of drugs and anti-drug skills would be effective to avoid becoming a drug addict. Meanwhile, a cohort study should be carried out for the further exploration of the causality between ACEs and drug use in adulthood.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional Review Board of Kunming Medical University. The patients/participants provided their written informed consent to participate in this study.JinL and VC designed and developed the study. JH, JinL, PW, and JiaL performed literature reviews, wrote the manuscript, and analyzed and interpreted the data. All authors read and approved the final manuscript.


Necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) are the major contributors to mortality and morbidity in preterm infants. This updated meta-analysis was aimed to assess the effects of mother's milk on the incidence of NEC, LOS, and other clinical outcomes in preterm infants.  PubMed, Embase, and the Cochrane library were searched for papers published up to October 2022. P=0.008). The incidence of proven LOS  and death  was comparable between the two groups. Statistical differences in the incidence of proven or probable LOS  and length of hospitalization  between the intervention group and the control group were observed.  A total of 13 RCTs with 1330 infants were included in the final analysis. Significant difference in NEC (stage 2 or 3) was found between the intervention group and the control group (RR = 0.508, 95% CI: 0.314–0.822, and  The results of this updated meta-analysis showed that compared to the placebo, mother's milk provides better effects in reducing the incidences of NEC, proven or probable LOS, and the length of stay, whereas no significant benefit of mother's milk was observed in reducing the incidence of proven LOS and death. Necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) are the major contributors to mortality and morbidity in premature infants . AccordiMother's milk is the best first immune stimulator in infants, featuring the perfect species-specific nutrition, because it contains many types of protective agents and enhances neurodevelopmental outcomes , 8. ColoWith advancements in neonatal care, the mortality in preterm infants has improved significantly. However, this has been associated with an increase in LOS and NEC. Although many meta-analyses have studied the effect of colostrum therapy on the incidence of NEC and LOS, previous evidence remains uncertain regarding the protective effect of colostrum on infants due to the paucity of sample size –17. In aWe developed the framework of the current systematic review and meta-analysis according to the recommendations issued by the Cochrane Collaboration for the purpose of ensuring the methodological quality because we did not register a formal protocol . We did This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines , patients' characteristics , and outcomes . Any inconsistencies in data extraction were solved based on the consensus principle.The primary outcome was the incidence of NEC  and the application of intervention (mostly received 0.2 ml of their own mothers' milk for 2 to 5 days). We also performed the sensitivity analysis by the random-effect model. For studies that did not present their results as means ± standard deviations, the results were estimated based on the reported parameters  [The risk of bias of all included studies was assessed independently by two authors using the RoB-2 criteria . The lev 95% CI) . Potenti 95% CI) .The assessment for the risk of bias for the included studies is presented in Pheterogeneity=0.391, A total of 12 studies reported the incidence of NEC. One study  did not Pheterogeneity=0.560; death: RR = 0.800, 95% CI: 0.571–1.122, 977 infants from 9 studies, and Pheterogeneity=0.519). However, 8 cohorts of patients reported a statistically difference in the incidence of proven or probable LOS between the intervention group and the control group , proven LOS, proven or probable LOS, and death, without great fluctuation, suggesting that pooled RRs were relatively stable , a trend toward downregulating mortality , and proven sepsis . Despite our study yielding a similar result, it is worth noting that we included 5 newly published studies with over 700 more cases in our study. Moreover, we explicitly include studies comparing mother's milk in the intervention group and sterile water in the control group in order to avoid potential bias due to deviations from intended interventions. Another recent published meta-analysis [I2 = 0%). But compared to the control group, the incidence of NEC  and all-cause mortality  was not significantly reduced in the intervention group. In 2020, Tao et al. [I2 = 94.7%, and P=0.010) was significantly shortened in the intervention group. These results contradicted the results in our analysis. The possible explanation for this difference might also be their relatively small sample size and substantial heterogeneity across their studies.The results of our analysis are partially congruent with those of the previous study. In a previous meta-analysis, Ma et al.  concludeanalysis  investigo et al.  reportedIn addition, it is important to note the feeding type, dose of intervention, and duration of breast milk feeding in this field. Some studies found that colostrum was effective in reducing the rate of NEC, revealing its effect in building up immunity –41. FortI2 and Q-test for heterogeneity, we only found subtle-to-mild heterogeneity across studies. Third, after carefully reviewing the included studies, we found two studies that [The results of this meta-analysis must be considered in light of its strength and limitations. First, to our knowledge, this updated meta-analysis included several newly published studies and approximately doubled the sample size of a previous meta-analysis, therefore providing more reliable results when comparing mother's milk and the placebo in reducing the incidence of severe clinical outcomes among infants. However, according to the quality assessment by the ROB-2 criteria, we found several studies that suffered from a high risk of bias regarding the randomization and blinding process. But the sensitivity analyses showed that the estimated parameters did not affect the conclusions. Second, as the dosage and duration of breast milk feeding might yield distinct heterogeneity between studies, the variation in the inclusion may lead to different clinical outcomes between studies. We decided to use the fixed-effect model throughout the entire analysis, as we realized that the RCTs included in our meta-analysis showed rather small heterogeneity in terms of the population (preterm infants with low birth weight) and intervention (mostly received 0.2 ml of their own mothers' milk for 2 to 5 days). Besides, based on the results of the ies that , 32 usedIn conclusion, the results of this updated meta-analysis showed that, compared to the placebo, mother's milk provides better effects in reducing the incidences of NEC, proven or probable LOS, and the length of stay, whereas no significant benefit of mother's milk was observed in reducing the incidence of proven LOS and death.