Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally; it is valuable to predict its prognosis after treatment. Aspartate aminotransferase-to-platelet index (APRI), a non-invasive biomarker consists of two routine test parameters easily available in all the patients. Our study aimed to investigate whether APRI can serve as an independent prognostic marker in the patients with HCC.Methods: We extensively searched PubMed, Embase, and Web of Science databases on June 20, 2021 to determine all relevant literature. The studies that explored the association between the APRI levels and prognosis of patients with HCC and reported risk estimate data were included. The Newcastle-Ottawa Scale was used to assess the quality of the included studies.Results: A total of 1,097 articles were initially identified, of which 28 studies involving 11,041 patients met the eligibility criteria for the meta-analysis. The pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were 1.77  and 1.59 , respectively, suggesting a significant correlation between the increased APRI levels and poor prognosis in the patients with HCC. In the subgroup analyses, statistical significance of the correlation disappeared in the Korean and Japanese population and in the patients undergoing transarterial chemoembolization (TACE). Of note, the current results may be overestimated due to publication bias, but the conclusion remained unchanged when the bias was adjusted.Conclusion: High APRI levels are associated with poor OS and DFS in the patients with HCC. In most cases, pretreatment APRI can be used as an independent prognostic factor, but it is necessary to incorporate other predictive prognostic systems to ensure accuracy. Further studies are needed to determine the specific beneficiary population and the optimal cutoff value. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide with a poor 5-year survival rate . Despite9/L)] × 100 ] × 100 –10. Meta)] × 100 . Further)] × 100 –15. As tThe studies that explored the association between the APRI levels and the prognosis of HCC have shown inconsistent findings. In addition, these studies tend to come from a single center and are limited to specific populations, such as the patients with hepatitis B virus (HBV)-associated HCC or after hepatectomy. Therefore, to examine the prognostic potential of APRI comprehensively and systematically in the patients with HCC, we extensively reviewed all the cohort studies that explored the association of APRI levels with overall survival (OS) and disease-free survival (DFS) in the patients with HCC. Furthermore, we investigated the effects of multiple host and external factors on the predictive strength, which can help the clinicians fully utilize clinical data for risk stratification and develop personalized monitoring strategies.This meta-analysis was reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA 2020) statement . The proTwo reviewers independently conducted an extensive search of PubMed, Embase, and Web of Science databases to determine all relevant literature on November 15, 2020 and updated on June 20, 2021. The search query was formed by combining the subject words with free words, specifically, that include the following terms: “Carcinoma, Hepatocellular,” “Hepatocellular Carcinoma(s),” “Liver Cancer(s),” “Cell Carcinoma(s), Liver,” “Carcinoma(s), Liver Cell,” “Liver Cell Carcinoma(s),” “Adult Liver Cancer(s),” “Cancer(s), Adult Liver,” “Liver Cancer(s), Adult,” “Hepatoma(s),” “APRI,” “Aspartate aminotransferase-to-platelet ratio index,” and “AST/platelet ratio index.” There were no language restrictions or filters for the search. We also checked the reference lists of relevant reviews and included articles and performed a forward search. The search results discrepancies were resolved by consulting a library search professional.The complete search strategies for each database are available in the HR), risk ratio (RR), or odds ratio (OR) of OS or DFS between the different APRI levels or provided sufficient data to calculate theses risk effects; (4) the study type was a cohort study. The studies were excluded if it met any of the following criteria: (1) pathological type was not HCC; (2) not relevant to the prognosis of HCC; (3) the risk effects and corresponding 95% CI were not provided and available data did not enough to calculate them; (4) studies without original clinical data, such as the reviews, systematic reviews, meta-analysis, expert opinions, editorial, or comment. (5) The articles were not written in full text or the full text was not available, such as the conference abstract. If a patient cohort was included in multiple publications, we selected the study with the largest sample size among the eligible studies to avoid data overlap.The included studies must meet all the following inclusion criteria: (1) the population was patients with HCC; (2) the subjects were divided into low and high APRI level groups; (3) the study investigated the hazard ratio . In studies that provided both adjusted and unadjusted HRs, adjusted HR was preferred.Two authors independently reviewed the titles and abstracts of literature according to the eligibility criteria, initially excluding obvious irrelevant literature, and then re-evaluated the full text of the remaining articles to identify the relevant studies; the reasons for exclusion were recorded. Any disagreements were resolved through the discussion among all the authors. Two reviewers independently extracted the following data from the included literature: first author, publication year, sample size, gender, study region, median/mean age, follow-up time, treatment method, cutoff value of APRI, method of APRI selection, study design, proportion of patients with cirrhosis, vascular invasion, tumor size, number, and stage, hepatitis virus status, and the risk effects of OS and DFS along with corresponding 95% HRs and corresponding 95% CI. Cochran's Q-test and Higgins' I2 statistics were used to assess the heterogeneity between the studies. When I2 < 50% and Pheterogeneity > 0.05, we considered that the heterogeneity was acceptable, and the fixed effects model was used to pool the results; otherwise, significant heterogeneity existed, and the random-effects model was selected  scale (cohort study) was used to assess the quality of the included studies that mainly included selection, comparability, and outcome. When the NOS score ≥ 7, the study was classified as high quality, otherwise considered to be at high risk of bias . We calculated the pooled selected . A univametrical . When pumetrical . If HR < of bias .CI for OS or DFS and the data were insufficient to calculate them, 14 articles did not investigate the effect of APRI levels or analyze APRI separately, 40 articles were not relevant to the prognosis of HCC, two articles included the patients who overlapped with other larger cohorts. The list of articles excluded after a full-text reading is available in the Through the pre-established search strategies, a total of 1,097 records were identified from Embase, PubMed, Web of Science, and reference lists of related papers. Eliminating duplicate literature and screening the titles and/or abstracts resulted in 991 records being excluded. We read the full text of the remaining 106 articles. Among them, 22 articles did not provide the risk effects along with corresponding 95% n = 4), radiotherapy (n = 1), radiofrequency ablation (RFA) (n = 3), or mixed therapy (n = 6), with a median/mean follow-up of 19.8–77.9 months. Some proportions or the entirety of patients in all the studies that reported hepatitis virus status, except one, were complicated with HBV (15.3–100%) and/or HCV (0.9–100%). Similarly, a certain percentage of patients in each evaluated study had cirrhosis (17.9–100%). Most of the studies were dominated by the patients with an early-stage and solitary number of tumors, and the proportion of patients with tumor vascular invasion ranged from 9.8 to 76.3%. The mean/median tumor size in 14 studies exceeded 3 cm. Thirteen studies were grouped with the APRI cutoff values <1, and 12 were ≥1. The APRI test timing in all the studies was before HCC treatment. The determination of the cutoff value was mainly based on an ROC analysis, as well as X-tile plots and other methods, such as experience or reference to the previous research. More detailed characteristics of the included studies are shown in All the included 28 studies were retrospective cohort studies with a sample size ranging from 72 to 1,669, such as a total of 11,041 patients consisting of 8,776 men, 2,159 women, and 106 with unknown gender. Men account for the main proportion in all the studies. The median/mean age of patients in 11 studies was <55 years, 15 studies were >55 years, and the remaining two were unclear. The patients in 18 cohorts were treated with surgery, and the other cohorts included the patients with transarterial chemoembolization (TACE) , so the random-effects model was used for effect size analysis. The pooled HR was 1.77 , indicating that the APRI index had a significant predictive ability for the OS of patients with HCC ; the studies with fewer than 300 subjects and the univariate analysis reported a higher HR. Furthermore, APRI cutoff value (Pinteraction = 0.083) and cutoff determination method (Pinteraction = 0.094) may also be the sources of heterogeneity, while age, treatment, study region, disease stage, hepatitis virus status, cirrhosis, and tumor size were not related to observed substantial heterogeneity. A multivariate analysis showed that APRI could be an independent predictive factor for the OS . Of note, the pooled results from the studies in Japan  and Korea  showed no significant correlation between APRI and OS. In other subgroups, higher APRI levels were consistently associated with poorer OS (P = 0.202).In the subgroup analysis and regression analysis, we found that the sample size and analysis mode were the possible source of heterogeneity , so the fixed-effects model was used. Similar to OS, the pooled HR showed a significant association between the higher APRI levels and poorer DFS   .Pinteraction = 0.037); the studies with the small sample sizes tended to report a higher HR than the large sample sizes. Age (Pinteraction = 0.084) and hepatitis virus status (Pinteraction = 0.081) may also be the sources of heterogeneity. A subgroup analysis showed no statistical correlation between the APRI levels and DFS in the Korean population  and those who received TACE . The statistical significance could be consistently observed in other subgroups. The pooled results of the multivariate analysis indicated that APRI could serve as an independent predictor of DFS in the patients with HCC  .The sample size remained the potential source of heterogeneity (< 0.001) . The regHRs for OS and DFS  and 1.32 , respectively. In DFS analysis, eight unpublished studies were added according to the trim-and-fill method. The re-pooled results showed that the HRs of the fixed-effects model and the random-effects model were 1.48  and 1.50 , respectively.We performed the funnel plots to evaluate the publication bias of included 28 studies, and the results showed obvious asymmetry , 7. The In this study, OS and DFS were used as the endpoints to evaluate whether the APRI levels could predict the prognosis of HCC. The overall pooled results suggested that the patients with HCC with high APRI levels had a significantly increased risk of death and recurrence than the patients with low APRI levels. Although the pooled results may be influenced by publication bias, the significant correlation between the APRI levels and prognosis of HCC remained after adding potentially unpublished literature. Furthermore, we analyzed the impacts of age, treatment, region, sample size, disease stage, hepatitis virus status, APRI cutoff value, cutoff value selection, cirrhosis, analysis mode, and tumor size on the results. Among them, the pooled results from Korea, Japan, and the patients treated with TACE showed no statistical association between the pretreatment APRI levels and prognosis (OS and/or DFS), while a stable correlation could be observed in other subgroups. The results from the multivariate analysis suggested that APRI levels seem to serve as an independent predictive factor for the patients with HCC.In addition to predicting the prognosis of patients with HCC throughout the follow-up period, Liu et al. found that the APRI levels could be an independent risk factor for early recurrence <1 year in the background of cirrhosis/fibrosis, and the study conducted by Allenson et al. showed that a high APRI level was associated with OS <30 days . FurtherLee et al. and Chung et al. also found that the patients who developed HCC death or relapses had persistently higher APRI values than the non-relapsing patients during follow-up , 41. MorAPRI is a non-invasive serum predictor that can be calculated at the bedside using the routine laboratory test parameters. The exact mechanism between APRI and poor prognosis in the patients with HCC after treatment remains unclear. It may be explained by the following reasons. First, the PLT count can promote hepatocyte regeneration and reflect the degree of liver function; thrombopenia is considered a risk factor for cirrhosis, and the patients with cirrhosis generally have decreased the PLT levels due to reduced thrombopoietin and PLT capture by the liver –53. PLT Of note, although current data show that the APRI level can generally reflect the prognosis of patients with HCC, it cannot determine which populations can achieve the best sensitivity and specificity, so it is necessary to combine with other prognostic prediction systems in clinical practice. On the one hand, it can be combined with currently used clinical assessment methods, such as CT, PET-CT, MRI, DSA, ultrasonography, TNM staging system, AFP, or Model for End-Stage Liver Disease score. On the other hand, it is possible to combine other serum markers with prognostic value, such as AST/lymphocyte ratio, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio, to establish a novel prognostic scoring system. For instance, Zhao et al. established a prognostic nomogram involving APRI, AST/lymphocyte ratio, and systemic immune-inflammation index, and Ji et al. found that APRI combined with neutrophil/lymphocyte ratio improved the predictive accuracy , 23.The main limitation of this study was the small number of studies in some subgroups , so it is difficult to draw solid conclusions that are universally applicable to all the regions or all populations. The absence of statistical significance in some subgroups could also be explained by a lack of statistical power due to the small number of included studies. Furthermore, the published studies did not provide sufficient data for a more detailed subgroup analysis to accurately characterize the population that can benefit most from the APRI prediction strategy or is unsuitable for applying APRI scoring. Next, all the included studies were retrospective studies that did not consider scientific research needs in the collection of clinical data and did not guarantee the completeness and homogeneity of data. Third, some factors that may affect the results, such as tumor differentiation, vascular invasion, and tumor number, were not included in the analysis due to a lack of detailed data. In addition, the APRI level was also affected by physical activity, anti-hepatitis virus drugs, and concomitant diseases. Therefore, it will be necessary to proceed with caution when formulating a prognostic risk assessment strategy based on these data. Fourth, although the studies with different APRI cutoff values have shown that high APRI can predict worse OS and DFS, it must be unified before APRI score is widely used in clinical settings. Finally, the current results may be impacted by publication bias. Although the conclusion remains unchanged after adding potentially unpublished studies, the presence of publication bias should be emphasized when determining the APRI optimal cutoff value and evaluating prognostic value in the specific patients.Although APRI is not yet suitable as a single independent prognostic factor for the patients with HCC, we suggest that the clinicians can use the APRI scores combined with other prognostic assessment systems for post-operative risk stratification, which may help to improve the predictive accuracy, leading to more effective clinical decision-making and prolonged survival of patients. Furthermore, more prospective studies with large samples and long-term follow-up from different regions and populations are needed to evaluate the prognostic value and optimal cutoff value of APRI in the patients with different characteristics.The original contributions presented in the study are included in the article/QS contributed to the conception and design of the study. MLiv and ZS searched the database. XZ and MLiu extracted data. ZS and YZ performed the statistical analysis. XZ, MLiv, and ZS wrote the manuscript. ZS contributed to critical revision of the manuscript. All the authors approved the submitted version.The research was supported by the Talent Introduction and Research Start-up Fund of Southwest Medical University (00040056), the Joint Project of the Southwest Medical University-Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University (2018 No. 6-51), Sichuan Provincial Administration of Traditional Chinese Medicine Project (2021 No. 13-130), Science & Technology Department of Sichuan Provincial Project (2021YFH0150), and People's Government of Luzhou City-Southwest Medical University High-level Talent Introduction Special Funding Project (2017RC-002).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 study focused on the clinical application value of artificial intelligence-based computed tomography angiography (CTA) in the diagnosis of orthotopic liver transplantation (OLT) after ischemic type biliary lesions (ITBL). A total of 66 patients receiving OLT in hospital were selected. Convolutional neural network (CNN) algorithm was used to denoise and detect the edges of CTA images of patients. At the same time, the quality of the processed image was subjectively evaluated and quantified by Hmax, Ur, Cr, and other indicators. Then, the digital subtraction angiography (DSA) diagnosis and CTA diagnosis based on CNN were compared for the sensitivity, specificity, positive predictive value, negative predictive value, and patient classification results. It was found that CTA can clearly reflect the information of hepatic aorta lesions and thrombosis in patients with ischemic single-duct injury after liver transplantation. After neural network algorithm processing, the image quality is obviously improved, the lesions are more prominent, and the details of lesion parts are also well displayed. ITBL occurred in 40 (71%) of 56 patients with abnormal CTA at early stage. ITBL occurred in only 8 (12.3%) of 65 patients with normal CTA at early stage. Early CTA manifestations had high sensitivity (72.22%), specificity (87.44%), positive predictive value (60.94%), and negative predictive value (92.06%) for the diagnosis of ITBL. It was concluded that artificial intelligence-based CTA had high clinical application value in the diagnosis of ITBL after OLT. Before the 1990s, the incidence of biliary tract complications after liver transplantation was as high as 30-50%, and the fatality rate was 20-30%, which was one of the main factors affecting the prognosis and long-term survival of liver transplantation patients , 5. The Because of the lack of characteristics of clinical manifestations of biliary tract injury after liver transplantation, generally, the final diagnosis still requires imaging diagnosis . If biliIn recent years, the rapid development of artificial intelligence and big data has gradually penetrated into the medical field. The traditional learning algorithm is weak in feature expression because of the shallow level of training model. As a result, its application in medical image feature extraction is limited. Depth learning algorithm is proposed under the background of advanced CPU, continuous improvement of machine algorithm, and massive medical images. It makes up for the defects of traditional learning algorithm and improves the accuracy of image feature extraction. Based on the above advantages, it has been widely concerned and applied . In partIn this study, patients with ITBL after liver transplantation were selected as the research subjects, and CTA images of the patients were processed. On this basis, the image characteristics of patients' CTA images and the accuracy and sensitivity of CTA diagnosis were analyzed, expected to provide a reference and basis for clinical diagnosis of related diseases.A total of 66 patients receiving OLT in hospital from July 2019 to November 2020 were selected, including 34 females and 32 males, with an average age of 44.8 ± 11.3 years old. All patients underwent DSA and CTA after liver transplantation.Inclusion criteria: patients receiving liver transplants; with postoperative biliary tract complications; able to communicate and normally; and voluntary for the study. Exclusion criteria: patients with hepatic artery stenosis, occlusion, or thrombosis; early cholangiography showed biliary leakage, papillary muscle dysfunction, and abnormal T tube position; the cholangiography quality cannot meet the diagnostic requirements; the two doctors' diagnosis of the cholangiography was inconsistent; and the patient's clinical data was incomplete. All patients signed the informed consent form, and the experiment met the requirements of medical ethics.ITBL diagnostic criteria: post-OLT ITBL can be diagnosed if cholangiography showed damage of hepatobiliary trees at nonanastomotic sites, including biliary stricture/dilation, biliary mud formation/casting, and even biliary damage.Cholangiography was performed on patients using DSA digital contrast machine. All patients underwent T tube cholangiography 10~15 days after OLT to exclude bile leakage, papillary muscle dysfunction, and abnormal T tube position. If the above problems did not occur, the T tube was closed and opened every two weeks. In the interval, patients once appeared abnormal liver enzyme index change or clinical symptoms such as itchy skin and jaundice, and the T tube cholangiography was required again. If there was no abnormality, 3T tube cholangiography was performed 3 months after, and T tube was removed for patients without abnormalities.CTA examination method: the patients were scanned from 2 cm above the top of the diaphragm to the level of the lower poles of both kidneys. In special cases, the scanning range would be enlarged. After plain scanning, contrast agent was injected through the anterior elbow vein, and enhanced scanning was performed. The original data were reconstructed by standard algorithm and processed by postprocessing software. Maximum intensity projection (MIP) and volume rendering (VR) were used for portal vein CTA and biliary system reconstruction.Radiological evaluation: all radiological data were evaluated in complete blindness by two groups of physicians (one senior radiologist and one senior transplant surgeon in each group).The severity of biliary tract injury after liver transplantation is usually graded on the basis of the image and bilirubin level. In the classification process, hilar and intrahepatic lesions are generally described separately. Generally, ITBL after OLT is classified into three levels: mild, moderate, and severe.Patients were mainly observed in the following three aspects. (1) The relationship between ITBL and different manifestations of CTA images was analyzed; (2) the application value of CTA imaging in the diagnosis of ITBL was evaluated; (3) the clinical risk factors related to ITBL were explored.f  is an array of M × N, and the processed image is g , whose gray level is determined by the average gray level of several pixels in the field . The processed image is represented as follows. Denoising: an image x, y = 0, 1, 2 ⋯ , N − 1, S is the domain set centered on point , and M is the total number of coordinate points in S.where  f , and the image noise is n , then, the noisy image g  is expressed as follows. For multiple images, if the original image is If the noise is not correlated with each other and the mean value is zero, thenE[g ] is the expected value of g , and M noisy images after averaging were as follows. where δn2 are the variance of n at the point .where Edge detection:Then, it is definedεGA = 5.0; for the traditional algorithm: err_goal = 0.002, 1r = 0.01. The actual output TT is as follows. TT = −0.0006; 1.0001; -0.0001; -0.0001; 0.003; 0.0148; -0.0007; 0.9971; -0.0056; -0.0038; 0.0241; -0.0009; -0.0046; 0.9911; -0.0060; 0.0283; -0.0007; -0.0055; -0.0105; 0.9925.For the initial population based on CNN algorithm: Pop = 30, The algorithm training target curve is obtained and analyzed to get the running time and iteration times.T test was used, and intergroup comparison adopted χ2 test. The independent sample nonparametric rank and Mann–Whitney U test were used for the descriptive samples, and P < 0.05 was considered statistically significant.All data were analyzed by SPSS 19.0 statistical software. Measurement data were represented by Quantitative analysis results of ultrasonic images processed by traditional methods and CNN algorithm were shown in A total of 66 patients were included in the study, including 34 female patients and 32 male patients. The average age of the patients was 44.8 ± 11.3 years old. X2 = 80.121, P = 0.0001, Pearson column number of connections = 0.51).The relationship between early and late CTA manifestations after OLT was shown in The sensitivity, specificity, and positive and negative predictive values of early CTA in diagnosing ITBL after OLT were shown in ITBL is diagnosed by the radiographic examination. The earliest understanding of this complication was mainly from patients with hepatic artery occlusion/stenosis, and the donor's intrahepatic biliary tract is necrotic due to ischemia, which eventually leads to the dilatation of intrahepatic biliary tract, the formation of bile mud/gallstone, and even the destruction of biliary tract . With moLaboratory examination is important to monitor ITBL after OLT, but in the early stage after transplantation, liver function is in the recovery stage, and the changes of enzyme indexes are very complex, so the serum enzyme changes of ITBL are not specific. Cholangiography is the gold standard for the diagnosis of biliary complications, which can accurately display the size, shape, and distribution of the bile duct lumen, as well as the type, location, and degree of biliary lesions –22. HoweIn recent years, the Internet and information technology have developed vigorously. Corresponding image processing technologies have also achieved rapid development, among which medical image processing technology is a hot research field, such as the proposal of various computer-aided diagnosis systems . The appIn this study, ITBL patients were taken as the research subjects, and the CNN algorithm was used to process CTA images of patients to analyze the application value of the CNN-based CTA in the diagnosis of ITBL patients. It was found that CTA can clearly reflect the information of hepatic aorta lesions and thrombosis in patients with ischemic single-duct injury after liver transplantation. After being processed by neural network algorithm, the image quality was significantly improved, the lesion was more prominent, and the details of the lesion site were also well displayed. Early CTA manifestations had high sensitivity (72.22%), specificity (87.44%), positive predictive value (60.94%), and negative predictive value (92.06%) for the diagnosis of ITBL. Therefore, CTA based on CNN has high clinical application value in the diagnosis of ITBL patients.In this study, ITBL patients were taken as the research subjects, and the CNN algorithm was used to process CTA images of patients to analyze the application value of the CNN-based CTA in the diagnosis of ITBL patients. It was found that CTA can clearly reflect the information of hepatic aorta lesions and thrombosis in patients with ischemic single-duct injury after liver transplantation. After being processed by neural network algorithm, the image quality was significantly improved, the lesion was more prominent, and the details of the lesion site were also well displayed. Additionally, CTA based on CNN algorithm had high sensitivity and specificity for the diagnosis of early biliary tract injury after ITBL. Thus, this study provides a new idea and reference for the treatment and research of related diseases. However, there are still some limitations in this study. For example, the small sample size of the study may lead to certain errors and limitations in the results. Only the CNN algorithm is selected to compare with the traditional algorithm for processing effects. In the follow-up, an expanded sample size is necessary to strengthen the findings of the study, and other popular technologies should also be involved to verify if CNN algorithm is the optimal algorithm for CTA image processing.


Motivations and the organisational frame for volunteering in citizen science projects remain understudied. This study applied a new measurement inventory called Motivational and ORganisational Functions of voluntary ENgagement in Citizen Science (MORFEN-CS), by which established findings of psychology on volunteering in social situations were transferred to volunteering in biodiversity and environmental sciences. It was applied in the citizen science project Insects of Saxony. The results are presented in this article and implications for measuring motivations and for project and volunteer management in citizen science projects are discussed.N = 116), volunteers of the project Insects of Saxony were asked about their current and past volunteering activities, their motivations, their rating of organisational offers, their knowledge, their satisfaction with the project and their personal contribution, and their intended future involvement. Participants in the study were mostly male, well-educated, over 50 years old, and had been volunteering in biodiversity projects for a long time. They were driven by both pro-social  and self-serving (egoistic) motivations, but rated the pro-social functions as more important for their engagement. Communication and feedback were rated the most important organisational offers. Participants also reported a knowledge increase during project participation. While the volunteers were satisfied with the overall project, they were significantly less content with their own contribution. Results from the survey were followed up with a group discussion (N = 60). The anecdotes revealed the participants’ regret of not having more time for their hobby, and they emphasised the challenges that arise from the different scientific approaches of the various disciplines. Most participants indicated that they want to continue their volunteering. Implications for measuring motivations in citizen science projects and for volunteer management are discussed.In a cross-sectional survey study ( In the past ten years, the active participation of citizens in scientific research processes has experienced a considerable boom . Half ofcitizen scientists or CSs) is well established, and they not only contribute data but also help to implement effective conservation measures [Convention on Biological Diversity (CBD) [Action Programme for Insect Protection, started in September 2019 [Red List of Threatened Species [Covering a broad range from all disciplines, most projects still focus on natural sciences, including biodiversity and environmental sciences. Especially in these projects, the involvement of volunteers  , which ober 2019 . Data ga Species ,9. How u Species .citizen science [This type of monitoring requires the help of many experts for very different species, who regularly collect data on a large scale at many different locations. In Germany, as early as 2007, the Federal Ministry for the Environment, Nature Conservation, and Nuclear Safety named this kind of participation  science . Current science .What drives people to contribute actively to a scientific research project in their free time, and which organisational aspects enable and support this volunteering? Very little empirical data are available regarding the reasons driving people to actively contribute to a scientific research project in their free time ,11, as wConsequently, our study will apply a new instrument to measure the motivational and organisational functions of volunteering for citizen science. In doing so, the study contributes to the body of knowledge around environmental volunteering, as well as to the scientific tool kit for studying participation.pro-socially has long been a key question of social psychology. For over two thousand years there has been a debate about whether the drivers for social action are egoistic or altruistic. “The distinction between altruism and egoism is qualitative, not quantitative; it is the ultimate goal, not the strength of the motive, that distinguishes altruistic from egoistic motivation”, Batson and Shaw stated 1991 [empathy-altruism hypothesis), and altruism can lead to prosocial behaviour. Consequently, they advocated a pluralistic model to explain prosocial behaviour, which considers both egoistic and altruistic motivations [functional approach describes that the same volunteering can be based on different motivations and that prosocial behaviour can fulfil more than one function for individuals. The term was coined in 1956 by Smith et al. [values, i.e., expressing values through volunteering, understanding, i.e., learning new things, social, i.e., social relationships, career, i.e., furthering one’s career, protective, i.e., protecting oneself from emotions like guilt, and enhancement, i.e., enhancing positive effect. Interestingly, these six functions are more or less egoistic in nature.When, why and under which circumstances people act ted 1991 . In theiivations . In addih et al.  and 1960h et al.  when meah et al. . They despontaneous, short-term helping behaviour in social contexts. Penner was in 2002 the first to focus on sustained volunteerism, which he defined as “long-term, planned, prosocial behaviours that benefit strangers and occur within an organisational setting”. He found evidence for a multitude of factors that influence sustained volunteering, such as demographic factors, situational factors, and factors related to the organisations, which he transferred to his Conceptual Model of the Causes of Sustained Volunteerism [Most studies on the subject had looked at nteerism  , sustaining the engagement requires both egoistic and altruistic motives [Little empirical data are available on the motivational structures and the organisational framework that promotes sustained volunteering in citizen science projects ,11. Wher motives .Studies investigating motives for volunteering apply a multitude of different methods, such as interviews or focus groups, quantitative questionnaires, or combinations of both. The inventories available, like the VFI  and the N = 38) and expert interviews [Social Motives). The items must all represent the characteristics to be measured appropriately and comprehensively in terms of content, and they must also be formulated clearly and comprehensibly. The items should represent as many degrees of expression of the characteristic to be measured as possible—i.e., low, medium and high characteristic expressions (measured with Pi: item difficulty indices). Each item should as clearly as possible separate persons with a strong characteristic from persons with a weaker characteristic . The number and order of the items should be determined in such a way that the scale can be easily processed by the respondents and at the same time its psychometric quality criteria  optimised.To improve this, a psychometric scale system called Motivational and ORganisational Functions of voluntary ENgagement in Citizen Science (MORFEN-CS) was developed, tested and validated between 2016 and 2018 by Moczek ,27, and N = 11) and in an online-survey using a four-level scale . Respondents of Study 3 were German CSs who had collected hair samples of the European Wildcat over several years. These were genetically analysed and transferred to a nationwide database [prosocial or altruistic, and four self-serving or egoistic functions), and four organisational functions loading on one superior factor [MORFEN-CS was first applied in a pre-test . The multi-factorial structure of MORFEN-CS was replicated by confirmatory factor analyses. Once again, the eight motivational and four organisational functions were found. In sum, there is evidence that different functions of volunteering can be measured with MORFEN-CS. For the resulting factor solutions of MORFEN-CS obtained in these previous studies see the Before being applied in Study 4, the items were revised on the basis of the item analysis to further increase statistical reliability. Some project-specific items of Study 3 were replaced by more general ones. To increase statistical variance, a six-level response scale was presented. Participants in this survey were volunteers from two citizen science projects in Saxony, one of which is iversity   was founded in 2006 by thirteen volunteer members (only one scientist). They dedicated themselves to researching and protecting the highly complex and diverse insect world, in particular to identifying and monitoring the approximately 25,000 insect species occurring in Saxony. Since spring 2011, they have been operating an open access internet platform and database Insects of Saxony [Senckenberg Society for Nature Research joined as a co-operation partner with a module for the collection of historical data from scientific collections as well as the literature and diary entries. Since then, a mobile app has been available. Since 2019, the app has allowed recording of all insects. It contains photos and descriptions for >450 insect species. The group organises two workshops and a yearly excursion of several days, as well as editing the Saxon Entomological Journal [The f Saxony . In 2016 Journal .Insects of Saxony does not provide specified or defined tasks, like focusing on a given selection of insect species, nor clear instructions for the volunteers. This differentiates this project from many other citizen science formats using a more task-led approach [Public Participation in Scientific Research (PPSR) [contributors (primarily of data), (b) as collaborators , (c) as co-creators  and (d) as colleagues (CSs independently conduct research that advances knowledge in a scientific discipline). There were 202 active platform members in 2018, 247 during 2019, 432 in 2020. In total 942 members have registered since project start.approach . CSs areapproach . Some CSh (PPSR) , CSs in Global Biodiversity Information Facility (GBIF) [Lamprohiza splendidula [Xyloscopa violacea) [To ensure data quality, every reported finding is verified by an expert team for accuracy and plausibility. This also includes the technical requirements for species identification. Some can be identified in the field by observation without any technical equipment, for some magnification is needed either by magnification lenses or macro-photography, and few need to be examined with a stereomicroscope or methods such as DNA analysis or statistical analysis of morphometric measurements. Only proofed data are published on the platform, showing the records in an interactive map, the dates in a phenology diagram, and the photos along with the species descriptions. By November 2020, there were >330,000 records for >7000 species and 86,000 photos for 4500 species. Periodically, the data are made available at endidula  and the iolacea) . The proWhat are the main personal circumstances and demographics of the citizen scientists?Which personal motives can be differentiated?Which organisational structures and offers are rated important for the participants’ commitment?Is there an increase in knowledge through voluntary work?How contented are the citizen scientists with the overall project and their personal contribution to the project?Do they want to continue their volunteering in the project?This article extends knowledge from social psychology on volunteering in social situations to volunteering in natural science projects. The following research questions guided us:Model of influences on participation in citizen science projects [Questions 1–3 and 6 were derived from the projects   and thestop investing time to 6 = invest much more time). The 42 items from MORFEN-CS . For a full list of items included in MORFEN-CS, both in German and English, see the The questionnaire was provided between 27 November and 15 December 2018 via an online survey tool  to 202 vN-CS see . were raIn order to evaluate the statistical construct and criterion validity of MORFEN-CS, additional questions and scales were used, but they are not presented in this article, see . ParticiOnly datasets with a finished page 5 (out of 8) and less than 20% missing values were included in the analysis. The net sample consisted of 116 questionnaires (57.4%). Analyses were carried out with Excel (version 15.29.1), RStudio (version 3.3.2) and R-package lavaan .The results of the survey were followed up with a qualitative discussion on 30th March 2019, at the Senckenberg Museum of Zoology in Dresden, during the annual workshop. About sixty people participated, of whom half had completed the online questionnaire. After presenting the main results by the first author we focussed in the discussion on the volunteers’ satisfaction with their own engagement. The many and lively reports were noted down and later categorised by the authors unsystematically, as they were only exploratory in nature.First, we will present the results from the survey, then from the group discussion. The structure will follow the research questions.SD = 13.9). Nearly 70% have an academic degree . A total of 8% are still at university, 24% completed vocational training. Most of the respondents are employed , 24.3% are on pension or in retirement, and all reside in Saxony (Germany). A total of 33% live in one of the two cities of Dresden and Leipzig, which have more than 500,000 inhabitants each. A total of 30% live in places with fewer than 10,000 inhabitants. Nearly 11% have been active in the project since the beginning in 2010. A total of 15% joined in 2016, 13% in 2017 and 23% in 2018. On average, respondents have been active for 43.6 months (SD = 33). A total of 57% volunteered one hour/week, 17% up to 2 h and 4.5% up to 3 h. Almost 10% spend more than 6 h/week. Together they spent 11,605 h volunteering in 2018.Of the 116 respondents, 71.6% are men and 26.7% women (1.7% did not specify). On average they were 52.3 years old . Most of them do not measure or analyse data, nor do they formulate new research questions. Only a few are involved in the quality checking of the reports, as this is reserved for CSs who are qualified as experts .citizen science  and item 15 “contribute to species identification and environmental monitoring” as the second highest , followed by other items from the function nature conservation values . All five items show power indices between Pi 83.9 and 92.2, indicating that they were easy to answer for the respondents of the survey. Because the item-total correlation was within the requested range (rit = 0.4–0.7), they differentiate well between subjects with extreme characteristic values [Looking at the function ence see , item 5 lues see . Overallc values . Note thsocio-political responsibility , citizen science  and social motives  were rated most important for commitment to the project. These four groups of motivational functions are provisionally called pro-social functions , work life balance , and career . With one exception: Qualification , which represents self-organised learning, which was ranked at place 5.The four organisational functions , organisation , and coordination , whereas training was rated as less relevant .Three of the four t (114) = 8.786, p < 0.001, d = 0.508 (medium effect size), 95% CI for d ; single sample t-test, one-sided).The self-assessments of knowledge showed an increase from project start to the time of the survey . A totalM = 79.3%, SD = 17.7; see SD = 25.4; t (113) = −9.918, p < 0.001, d = −1.121 (large effect size), 95% CI for d ; single sample t-test, one-sided).While contentment with the project was high , 68.1% plan to spend (much) more time . A total of 82% would like to know more about the habitats of insects, 79.6% wanted to learn more about individual insects and 80.5% more about different insects. A total of 78.3% aim to contribute to the protection of insects see . No statThe study contributes to our understanding of the motivational and organisational functions of volunteering in biodiversity and environmental sciences projects. The findings expand current knowledge and contribute to the tool kit available for studying participation. This is achieved by applying the new scale system MORFEN-CS.contributors or collaborators [Our survey showed that most of the participants are male, well-educated, and over 50 years old. These profiles perfectly match many other citizen science studies . Most ofborators .pro-social  functions were rated very high  important for the volunteering. In other words, the CSs are looking to support and be part of a community which shares a common research interest. They want to make contact with other like-minded scientists and volunteers to better understand scientific processes and engage in knowledge exchange. These findings parallel those of other studies, which found similar functions of volunteering  motivational functions, such as enhancement, work life balance and career , that the project is well-organised (item 39), and that they can independently determine time and duration of their engagement (item 32). Particularly the high rating of item 38 is in line with a review which showed that citizen scientists highly value the open communication of project findings [qualification  and training . In other words, participants indicated having acquired new skills through the project, despite receiving little training. This matches the project structure, which stipulates some training , but mostly relies on self-directed learning. This maps well onto self-determination theory (SDT) [training and qualification were found [qualification function is also in line with the self-assessed–significant knowledge increase from project start to the time of the survey on expertise on insects and their habitats in Saxony . Similarly, a review article found increases in both general and project-specific knowledge through participation in citizen science projects [We found that multiple motivational and organisational functions are relevant to their volunteering (research questions 2 and 3). All four g e.g., ,41). The. Thepro-findings . Anotherfindings . Interesry (SDT)  which pore found . That prre found . This exprojects . One resprojects .Despite a high response rate, our sample is relatively small and homogeneous with the risk of self-selection bias. During the discussion at the workshop, we received feedback from some that, as a matter of principle, they never take part in surveys. A few of the participants explicitly regretted this in retrospect, as the presentation and discussion of the findings had shown them how valuable such studies can be for the project managers and also their own engagement. It is also conceivable that people tend to take part in such a survey who were more likely to be driven by pro-social motivations. All of this can lead to a bias in the respondent pool and therefore also in the results.Conceptual Model of the Causes of Sustained Volunteerism, Penner models the influences on volunteerism over time [In his ver time . Likewisver time ,23. As wWith MORFEN-CS, Moczek transferred established findings of psychology on volunteering in social situations ,17 to voFuture research should also focus on the effects of collaboration between institutional scientists and volunteers , or on pnature conservation is part of their identity. Given the established community of birders with their distinct identity, which differs from that of environmentalists [insecters? Udall et al. published in 2020 a theoretical framework of how to test identities in relation to other psychological variables relevant for pro-environmental behaviour [When investigating motivations to participate in a citizen science project about rainwater in Mexico, the three top reasons to participate were project-specific . Furthermore, the study found considerable differences in motivations for participants with different personal characteristics  . Consequntalists , we mighehaviour . In addiInsects of Saxony. As we saw in the second group of our Study 4, where volunteers explore the effects of insect-friendly habitats on diversity and which is coordinated by the same project manager, the ratio of men (42%) and women (46%) is much more balanced. From this we conclude that there was no  exclusion of women and that they obviously choose the project that they like better. However, the CSs’ personal contribution to the research should be emphasised and the collaboration with the institutional scientists improved, to prevent drop out due to dissatisfaction [Last, but not least, we derived recommendations to optimise the volunteer management in the project o of men % and wom


To confirm longitudinal changes in 33 subjects, the ratio of follow-up and baseline investigation values was obtained. Correlations and group comparisons were performed for the 8 year change values. PITPNM3, RXFP3, and THRB were hypermethylated in the increased FLI groups, whereas SLC9A2 and FOXI3 were hypermethylated in the decreased FLI groups. DMRs describing NAFLD were determined, and functions related to inflammation were identified. Factors related to longitudinal changes are suggested, and blood circulation-related functions appear to be important in the management of NAFLD.The role of differentially methylated regions (DMRs) in nonalcoholic fatty liver disease (NAFLD) is unclear. This study aimed to identify the role of DMR in NAFLD development and progression using the Korean Genome and Epidemiology Study (KoGES) cohort. We used laboratory evaluations and Illumina Methylation 450 k DNA methylation microarray data from KoGES. The correlation between fatty liver index (FLI) and genomic CpG sites was analyzed in 322 subjects. Longitudinal changes over 8 years were confirmed in 33 subjects. To identify CpG sites and genes related to FLI, we obtained enrichment terms for 6765 genes. DMRs were identified for both high ( The global prevalence of nonalcoholic fatty liver disease (NAFLD) has increased to 25% of the general population and is the main cause of chronic liver disease ,2,3. AltTherefore, screening of NAFLD patients in the general population is important to identify patients with a high risk of disease progression. NAFLD can be diagnosed when patients have hepatic steatosis confirmed by liver biopsy and imaging studies such as ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) without other secondary causes of hepatic fat accumulation . HoweverTo date, several epigenome-wide association studies (EWASs) have been conducted on metabolic traits, including liver diseases ,19,20. EDNA methylation reflects the state of health or chronic diseases. Somatic variants reflect cancer-specific changes and gene expression changes reflect various diseases. However, somatic variants can only be analyzed for carcinoma, and it is difficult to use RNA to identify changes in gene expression. Therefore, it is important to extract factors related to health conditions from DNA obtained from the blood and to extract CpG sites that describe health conditions. Hepatic steatosis is an important factor for liver disease progression and is related to the progression of other metabolic diseases, resulting in cardiovascular disease and malignancies ,30,31. EThe epidemiological and epigenomic datasets of this study were collected from a survey during 2001–2002 and were obtained from the AS-AS cohort of the KoGES released by the Korea Center for Disease Control and Prevention . Particin = 322) and longitudinal (n = 33) analyses. Flowcharts describe the conditions under which the subjects were excluded from the analysis and classified .In this study, genomic DNA extracted from the peripheral blood of subjects was used to evaluate DNA methylation levels. Genomic DNA (500 ng) from each sample was modified by treatment with sodium bisulfite provided in the EZ DNA methylation kit , according to the manufacturer’s instructions. Genome-wide DNA methylation was profiled using the Illumina Infinium Human Methylation 450 k BeadChip , which contains over 485,000 CpG probes covering 99% of the RefSeq genes. Each CpG probe has a beta value ranging from 0 to 1; higher methylation of CpG gives rise to a value closer to 1. We analyzed 364,050 CpG probes in 423 subjects, excluding the missing values. Furthermore, the gene symbol and genomic location corresponding to each CpG probe of the Illumina 450 k methylation chip were obtained using the “getAnnotation” function of the IlluminaHumanMethylationEPICanno.ilm10b2.hg19 library provided by Bioconductor  was re-analyzed. To confirm longitudinal changes, we retrieved 33 subjects, which is the intersection of 50 subjects whose methylation patterns were re-analyzed and 7067 subjects for the filtering criteria. Nineteen demographic and laboratory evaluations, including age, sex, TG, GTP, AST, and ALT, associated with NAFLDs were analyzed. Male participants were classified into the FLI-high group .CD8A, CTU1, TMEM87B, BCL2, AP1M2, PRTFDC1, KIAA1429, cg13188812, and cg08257212). The last two probes were non-annotated (NA) probes (cg13188812) located in the intergenic region (cg08257212).Pearson’s correlation coefficient was calculated using the beta value of each probe and the FLI. From 403,129 correlation results, 15,628 probes with power >0.99 were selected. Nine genes with the top nine r-squared values were selected and are presented a. Nine CAmong the duplicate symbols, probes with a low r-squared value and those located intergenically were excluded. Subsequently 5879 gene symbols were identified. GO terms were extracted for 5258 genes with positive correlations and 621 genes with negative correlations, and the top 20 terms are presented as dot plots b,c. The x-axis represents the fold change (FC), and the y-axis represents the p-value on a −log10 scale. The area that meets the threshold of FC and p-value is represented by two vertical lines and one horizontal line. On the basis of these criteria, differences in methylation levels were confirmed between the high-and low-FLI groups in both sexes .Because of differences in DNA methylation patterns between female and male subjects, the groups were divided according to sex to avoid bias. We examined the demographic variables to classify the subjects on the basis of the FLI 30 and two sexes for methylation analysis, as shown in th sexes a,b. Two th sexes c,d. In eOn the basis of the FCs, GO and KEGG terms were retrieved GO; i,j. A nep-values for all CpG sites. Correlation plots were drawn between FLI and CpG methylation levels in the top nine squares of the correlation coefficients . The four tracks located outside the Circos plot are the results of the correlation and t-test analysis for 322 subjects at baseline. The four tracks located inside are the results of the correlation and t-test analysis for the 33 people included in the longitudinal study.The four analyses were integrated as heatmaps and peaks in one Circos plot . The CirFUT9, GSTA4, L3MBTL3, and CD83. A significant pattern was observed for chromosomes 17 and 19. Meanwhile, in the baseline analysis, a pattern different from the fold-change or correlation coefficient of the autosome was observed on the X chromosome. As a result of the t-test analysis at baseline, a high overall fold-change was observed in the X chromosome, and the correlation coefficient with FLI was negative.In the four analyses, the most statistically significant region was identified in the short arm of chromosome 6. The most significantly differentially expressed genes in each of the four analyses were The relationship between epigenetic patterns and FLI was revealed in 322 samples simultaneously, and longitudinal epigenetic changes in 33 samples were confirmed. Using two approaches on 322 samples, we retrieved enrichment terms for highly correlated genes and genes located on the DMRs and visualized them as dot plots of KEGG and GO analysis and networks.Epigenetics, including DNA methylation, plays an important role in the pathogenesis and progression of metabolic disorders, lifestyles, and cancer . HoweverTHRB gene showed a positive correlation. Hepatic thyroid hormone receptor beta, encoded by the THRB gene, is involved in systemic lipid regulation and is an important factor in the development and progression of NAFLD. In a gene expression study of human liver biopsy samples, THRB expression was negatively correlated with NASH score. This result matches the positive correlation between FLI and THRB methylation shown in our study [In the correlation analysis of the change in FLI with time and gene methylation level, performed in the longitudinal follow-up data, the FLI and the methylation level of the ur study . Hepaticur study . For exaur study . Our stuWe analyzed and selected GO and KEGG enrichment terms from DMRs discovered in 322 subjects, and as a result, various pathways related to FLI were detected. Interestingly, the discovered pathways were hypercholesterolemia and hyperlipidemia. Disruption of cholesterol homeostasis is known to cause hepatocyte damage and steatotic changes and thus contributes to the pathogenesis of NAFLD/NASH . MoreoveMYO18B is related to PI3K/AKT/mTOR, a liver cancer-related pathway, and showed a positive correlation with the increase in methylation as the FLI increased over time.Left ventricular hypertrophy was discovered among the enrichment terms from the 33 samples from a longitudinal study. Interestingly, left ventricular hypertrophy associated with NAFLD has been studied in relation to type 2 diabetes mellitus. In particular, Among the enrichment terms from the two analyses , hypercholesterolemia and essential hypertension were comorbidities of metabolic syndrome with diabetes, and NAFLD was considered the main risk factor for metabolic syndrome. However, in this study, insulin sensitivity was not selected. Insulin sensitivity plays an important role in the development of NAFLD in metabolic syndrome. This is because the FLI was calculated using limited variables when evaluating NAFLD. In addition, the role of hypercholesterolemia may be overestimated because triglycerides are included in the calculation of the FLI. For the induction and maintenance of insulin resistance, studies related to the mechanism of DNA methylation patterns and related pathways should be conducted.Factors related to myocardial reperfusion injury have been identified and are related to necroptosis in the steatotic liver. Terms related to anoxia and hypoxia have been discovered and reported to be related to liver disease related to sleep disturbance . As suchn = 322) and longitudinal (n = 33) cohorts, we extracted FLI-related changes in DNA methylation using t-tests and correlation analyses. The association between THRB and hypercholesterolemia and essential hypertension has been suggested to be associated with NAFLD.In this study, using baseline (A Korea patent application is pending with similar contents to this study.


To identify the relationship between health literacy (HL) and mortality based on a systematic review and meta-analysis.Literature published from database inception until July 2020 was searched using the PubMed and Web of Science databases, using relevant keywords and clear inclusion and exclusion criteria. The search was limited to English language articles. Two reviewers independently selected studies and extracted data. Pooled correlation coefficients and their 95% confidence intervals (CI) between HL and mortality were estimated using Stata 15.0 software. Potential sources of heterogeneity were explored using subgroup analysis, sensitivity analysis, and meta-regression. Quality of the original studies that were included in the meta-analysis was evaluated using the Newcastle–Ottawa Scale. A funnel plot and Egger’s test were used to determine whether significant publication bias was present.Overall, 19 articles were included, reporting on a total of 41,149 subjects. Eleven were prospective cohort studies, and all articles were considered “good” quality. The most used screening instruments were the short Test of Functional Health Literacy (S-TOFHLA) in Adults and the Brief Health Literacy Screen (BHLS). Among 39,423 subjects (two articles did not report the number of patients with low HL), approximately 9202 (23%) had inadequate or marginal HL. The correlation coefficient between HL and mortality was 1.25 (95%CI = 0.25–0.44).Lower HL was associated with an increased risk of death. This finding should be considered carefully and confirmed by further research. Health literacy (HL) is the result of the healthcare and education system, and social, cultural, economic, and other factors. Improving HL is considered to be one of the most fundamental, economical, and effective measures to improve the health level of the whole population . The InsAt present, the status of HL in the world is not optimistic. The European Health Literacy Survey (HLS-EU) Consortium conducted a wide range of HL surveys in eight EU member states between 2009 and 2012, and the results showed that 47% of the 7770 respondents had limited (insufficient or problematic) HL . AccordiAt the patient population level, adequate HL is the basis for disease prevention and management , but in Understanding the impact of HL is a priority for health promotion, prevention and treatment of chronic diseases. Patients with inadequate HL have limited ability to obtain health information and understand disease-related knowledge, lack of correct cognition of disease, and are prone to negative emotions, which affect the treatment effect and lead to adverse outcomes . StudiesWe performed this review according to the recommendations of the Cochrane Collaboration and following the PRISMA Statement. The PROSPERO registration number is CRD42020203347.Relevant studies were identified through the Web of Science Core Collection and PubMed databases by using the following search terms, and the search strategy was specific to each database: 1) health literacy: “health literacy” OR “healthy literacy” OR “literacy”; 2) mortality: “mortality” OR “death” OR “fatal”. The searches were limited to full-length articles published in English, and the results were downloaded into Endnote X9.2 (Thomson Reuters (Scientific) LLC Philadelphia, PA). A more extensive and detailed search strategy is reported in Table Studies were selected if they met the following criteria: 1) the study assessed HL using a previously validated instrument; 2) the main outcome was death, including all-cause mortality and special mortality; and 3) the study assessed the correlation between HL and mortality, and provided hazard ratio (HR), relative risk (RR), or odds ratio (OR) estimates and corresponding 95% confidence intervals (CI). We excluded articles: 1) in languages other than English; 2) that were editorials, conference abstracts, letters, book news, or review articles; 3) in which HL or death was not measured; and 4) in which there was no correlation coefficient between HL and mortality provided. When more than one study reported results from the same cohort, the most recent and detailed studies were included in the analysis.First, two reviewers (Zhaoya F and Yang Y) independently screened the articles by title and abstract. Then, the full-text was read and the remaining articles were filtered again. Any disagreements in the process were resolved by consensus.For each study included in the systematic review, we extracted the following data using a standardized form: first author, year of publication, study design, geographic location, source population, baseline age and sex of participants, subject ethnicity, duration of follow-up, number of deaths, how HL was evaluated, HR RR or OR and the corresponding 95% CI, and adjustments for covariates.The quality of the original studies that were included in the meta-analysis was evaluated using the Newcastle-Ottawa Scale . The quaMost studies divided patients into two categories based on similar cutoff points: adequate and inadequate HL. When the results of adequate, marginal, and inadequate HL were presented, we combined the inadequate and marginal HL categories according to previous studies, which have shown that any inadequate HL is a risk factor for outcomes. HR was used to measure the association between HL and mortality. When studies had not used the highest category as a reference, we recalculated the HRs and their 95% CI relative to the highest category , 20. For2-based Q statistic, and inconsistency was quantified using the I2 statistic. I2 values of 0, 25, 50, and 75% were considered as no, low, moderate, and high degrees of heterogeneity, respectively [2 < 50%) was found, the pooled HR estimate was determined with the fixed effects model; the random effects model was used in the case of significant heterogeneity. Stratification analyses by population, study design, area, time, and the types of HL instruments were conducted as a way of addressing inter-study heterogeneity. Sensitivity analysis was performed to ensure the stability of the results. Meta-regression analysis was used to detect heterogeneity. The dependent variable of meta-regression was the correlation coefficient between HL and mortality, and population, study design, year of publication, and geographic location were independent variables. Publication bias was assessed using Egger’s test [P < 0.05 was assumed to be statistically significant.Inter-study heterogeneity was evaluated using Cochran’s χectively . Accordir’s test . Stata vn = 721) and mortality (n = 256). During the full-text review, 19 articles were selected and included in the systematic review. All the studies included were cohort studies. Specific reasons for exclusion and the selection procedure are shown in Fig. Initially, 1235 articles were identified. Sixty-nine were discarded after the first round screening of title and abstract. The main reason for exclusion was the failure to evaluate HL  and four numeracy items (7 points each) . This teThe BHLS is a subjective measure, which consists of three items, asking patients to report their level of confidence filling out medical forms, need for assistance in reading hospital materials, and understanding of written medical information . The speThe REALM is a word recognition and pronunciation test based on the correct pronunciation of 66 common medical terms designed for use in health care settings. The original REALM was developed in 1991 by Davis and consisted of 125 common medical terms . The tes2 = 78.5%, P < 0.001) showed that there was heterogeneity, using a random effects model to combine effect quantity. Based on the combined results of the 19 cohort studies, compared with the adequate category, inadequate or marginal categories experienced significantly increased risk of death  . Noticeably, the correlation coefficient between HL and mortality was 1.20  based on the prospective cohort study design and 1.38  in the USA.The subgroup analysis included population, study design, area, time, and the types of HL instruments Table . For stuOne study assessed HL using four separate tools, and each provided an association between HL and mortality. When subgroup analysis was conducted according to HL instruments, we used different models for analysis. The asterisk indicates the different tools used in the study, and we chose the results of S-TOFHLA assessment in other subgroup analyses.Sensitivity analyses were used to evaluate the effect of each study on the pooled results by sequentially excluding single studies. The results did not significantly change after excluding each study Table .Table 4To identify the possible sources of heterogeneity, different factors associated with heterogeneity, such as population, study design, year of publication, and geographic location, were computed using meta-regression models, although none of these variables were statistically significant.P < 0.001), and we adjusted for the effect of publication bias by using the Duval and Tweedie’s nonparametric trim-and-fill method, which imputes hypothetical small missing null or negative studies [The publication bias test indicated significant publication bias. A funnel plot Fig.  showed v studies . After iLow HL has important implications for wellness, increasing the risk of negative health outcomes, and is also an invisible barrier to health care services that has profound costs for individual and public health. With the development of medical technology and the increase in life expectancy, people pay more attention to their level of HL. Most researchers believe that HL is an important predictor of health status  . TherefoThis study is a systematic review and meta-analysis of HL levels in the whole population. Among 39,423 subjects  used to measure outcomes. For the present study, using sensitivity analysis, no study was found to significantly contribute to the heterogeneity.Finally, publication bias was detected; the funnel plot revealed an apparent asymmetry that suggested the presence of a potential publication bias, a language bias, inflated estimates by a flawed method logic design in smaller studies, and/or a lack of publication of small trials with opposite results.The strengths of this study that lend weight to our conclusions are the large sample size and the use of validated literacy assessment instruments in almost all studies. The results of the present analysis are intended to provide more robust evidence than any individual study. However, some limitations may have influenced the findings, in that heterogeneity was observed among the included studies and publication bias could not be avoided. Second, the included studies assessed levels of HL with different tools. Although we conducted a stratified analysis based on the type of instrument, it may still affect comparability because subjective and objective measurement tools may have different focuses. Finally, due to the author’s inability to review non-English manuscripts, only English articles were included in this study, which may result in the loss of some studies.Most of the studies were conducted in the USA, which limits the generalizability of the findings to other countries with different healthcare systems and social structures. Future research should be conducted in different countries and regions to increase the generalizability. Second, future studies should consider the use of a more complete measure of HL, one that measures all the dimensions of HL and not only reading comprehension.The prevalence of low HL ranged from 9 to 81% (two articles , 29 did


The odds ratio of hypertension among men with low education was lower than among those with high education . For women, being in the poorest socioeconomic condition increased the risk of hypertension by 1.67 times compared to the richest (95% CI: 1.21–2.32). Gender differences in the prevalence of and factors associated with hypertension were observed among adult populations in Sleman District, Yogyakarta, Indonesia. Therefore, a gender-based approach in the health prevention strategy to control hypertension for men and women is needed.Although hypertension is among the main public health concerns in Indonesia, due to the scarcity of data, few studies have investigated the factors associated with hypertension in men and women. This study aimed to examine the prevalence of and factors associated with hypertension among adult men and women in Indonesia. The 2018 Survey of the Sleman Health Demographic and Surveillance System was utilized, consisting of 4328 individuals aged 18+ years. Multivariable logistic regression analysis was performed to determine the sociodemographic and health behavior factors of hypertension. Overall, the prevalence of hypertension was 40% (42% in men and 38% in women). Age, abdominal obesity and chronic non-communicable diseases were the common predictors of hypertension in men and women ( Non-communicable diseases (NCD) are the leading cause of death globally and have become one of the main health challenges around the world, especially in low- and middle-income countries (LMIC) . In 2016Gender disparities in NCD risk factors have been identified from previous studies in low- or middle-income and high-income countries ,7,8,9. FN = 5640). The complete data for analysis included 4328 individuals, excluding those with missing data.This cross-sectional study was conducted with data from the 2018 Sleman HDSS—a longitudinal and community-based survey established in 2014 through a close collaboration between the Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada, and the Government of Sleman District, Yogyakarta Special Region, Indonesia ,16. DetaThe focus of the study was the prevalence of hypertension. Blood pressure was measured using a Digital Automatic Blood Pressure Monitor HEM-7200  on the right arm with the position aligned with the heart. The measurements were taken three times at home by trained enumerators, in a sitting position after rest for 15 min, with three-minute intervals for each measurement. Hypertension was defined if systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mm Hg or individuals taking blood pressure lowering medication [We included sociodemographic, SES, and health behavior risk factors as potential determinants for hypertension. Sociodemographic factors were derived from individual questionnaires consisting of questions about age group ; location area ; educational level, which was subdivided into four categories—low education , primary school (elementary and junior high school), secondary school (senior high school), and diploma/undergraduate/university); and marital status, which was subdivided into three groups—married/reconciled, unmarried, and divorced/widowed/separated. The SES was derived from a number of questions on household assets and ownership. Principal component analysis (PCA) was used to construct the wealth index, which we later categorized by quintile (1st quintile refers to the poorest group and 5th quintile to the richest group) ,18.For behavioral risk factors, we included physical activity, smoking status, and waist circumference measurement. Smoking status was assessed with the question, “Did you smoke in the past 1 month? ”. Responses were grouped into never smoke (if the respondent answered “never”), current smoker , and former smoker . Physical activity was assessed using a modified short form of the International Physical Activity Questionnaire (IPAQ) for the types and times of physical activities performed in all areas of life: work, home, and exercise. The total duration of activities was transformed to Metabolic Equivalent of Tasks (METs)-minutes and summed to gain an overall estimate of physical activity in a week, and the data were further classified into three categories based on the WHO recommendations  . AbdominThis study received ethical approval from the Medical and Health Research Ethics Committee (MHREC) from the Faculty of Medicine, Public Health, and Nursing at Universitas Gadjah Mada (KE/FK/0434/EC/2018) for routine data collection, and additional ethical consideration for secondary data utilization was received from the same committee (KE/FK/0116/EC/2020).STATA 15.0  was used for the analysis and all analyses were stratified by gender, with a significance value of 0.05. Descriptive analysis of the respondents’ characteristics was presented as frequency distribution and percentage of each variable. Multivariate logistic regression models were used to examine the association of sociodemographic, health risk factors, and hypertension, adjusted for other potential covariates. Estimates of odds ratio (OR) and 95% confidence interval (CI) are presented in total and by gender.We found that individuals who were older, divorced/widowed/separated, had a low education level, had a sedentary lifestyle, had abdominal obesity, and had chronic NCD were more likely to have hypertension .p < 0.05). The odds of hypertension increased with increasing age, with an increase of almost three times higher odds among individuals aged 40–55 years (95% CI: 2.16–3.29) and five times higher odds for the older group (56 years and above) (95% CI = 4.11–6.53) compared to the younger age group (18–39 year). Men had 1.77 times higher odds of developing hypertension than women (95% CI: 1.40–2.23), and the poorest SES group had 1.41 times higher odds of developing hypertension (95% CI: 1.09–1.81) compared to the richest SES group. The odds increased by 1.29 times for those who were divorced/separated, 2.64 times for those with abdominal obesity, and 1.68 times for those with one chronic NCD. However, physical activity and living area were not significantly associated with hypertension (p > 0.05).Findings from the multivariate logistic regression models  showed tp < 0.05). Men with a low education level had a lower risk for hypertension compared to the high-education groups . Among women, being in the poorest SES increased the risk of hypertension by 1.67 times compared to those in the richest SES (95% CI: 1.21–2.32).Findings from the multivariate regression models for men and women are displayed in We calculated the predicted probability of hypertension by abdominal obesity among men and women . The proIn the present study, we revealed gender differences in the prevalence of and factors associated with hypertension observed among adult populations in Sleman District, Yogyakarta, Indonesia. Older age, abdominal obesity, and chronic diseases were the factors most strongly associated with the prevalence of hypertension in both men and women. Socioeconomic status increased the risk of hypertension among women, while, for men, education level had the greatest impact.Abdominal central obesity is a risk factor of hypertension ,20,21,22Smoking has been identified as a health risk factor for cardiovascular diseases and hypertension . In thisSociodemographic factors such as age and SES are well-known risk factors related to hypertension. A study in Indonesia showed that the risk of hypertension increases with age , which iLow SES coupled with low education levels is also associated with a high prevalence of hypertension . HoweverMarital status is also known to play an important role in hypertension . This stThe gender-based approach has been considered an effective strategy for preventing and controlling NCDs , in lineThe strengths of the current study include utilizing HDSS data from an ongoing longitudinal survey that can provide a sampling frame for population-based studies with a high participation rate (95%). HDSS data cover individual and household information on sociodemographic variables, SES, behavioral risk factors, and chronic conditions that provide data complementary to the existing demographic and health information system at the local and national levels. Findings from this study strengthen the scientific evidence on the existing gender differences in risk factors for hypertension among adult populations in Yogyakarta, Indonesia. Some limitations of the study should be noted. The HDSS data used in the current research are from a cross-sectional study, which does not allow direct conclusions on causality to be made. Therefore, future cohort studies are needed to understand the impact of health behavior changes over time on the development of hypertension. Apart from anthropometric and blood pressure measurements, all other information provided in this study was self-reported, which could present some bias. In addition, we observed that more women participated in this study, reflecting how they might exhibit different health behaviors to men. Thus, the estimates might be over-reported or under-reported. However, in this study, we analyzed the data separately for men and women. We are also aware that some health behavior risk factors, such as stress and the consumption levels of salt, alcohol, fatty foods, and fried foods, were not considered in this study but are factors that are closely related to the outcome. Therefore, future studies exploring more health behaviors related to hypertension, as well as social factors, are needed. The prevalence of hypertension among the adult population in Sleman District, Yogyakarta, Indonesia is high, with men having a higher prevalence than women. The most common predictors of hypertension were found to be older age, abdominal obesity, and chronic diseases. Gender differences exist in the prevalence of hypertension in Indonesia, where current hypertension guidelines and management rarely focus on the gender differences. Therefore, a new hypertension control policy should adopt a gender-based approach to health education and surveillance, with strengthened input from a more proactive multisectoral collaboration.


Salvia miltiorrhiza Bunge (SMB) is a kind of traditional Chinese medicine with good efficacy in promoting blood circulation and removing blood stasis, and treatment of CI with it is a feasible strategy. Based on the above analysis, we chose network pharmacology to investigate the feasibility of SMB in the treatment of CI and to study the possible molecular mechanisms by providing some reference for the treatment of CI with TCM.  Cerebral infarction (CI) is a common brain disease in clinical practice, which is mainly due to the pathological environment of ischemia and hypoxia caused by difficult cerebral circulation perfusion function, resulting in ischemic necrosis of local brain tissue and neurological impairment. In traditional Chinese medicine (TCM) theory, CI is mainly due to blood stasis in the brain. Therefore, blood-activating and stasis-dissipating drugs are often used to treat CI in clinical practice.  The active ingredients and related targets of SMB were obtained through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and CI-related targets were obtained from the GeneCards and DisGeNET databases. The target of SMB for the treatment of CI was obtained using Cytoscape software and visualized. GO and KEGG enrichment analysis was performed based on “clusterProfiler” within R, and the prediction results were validated by molecular docking technique.  By constructing a compound-target (C-T) network, it was found that the active components in SMB mainly treated CI by regulating key proteins such as AKT1, IL-6, and EGFR. These key proteins mainly involve in pathways such as immune regulation, cancer and lipid metabolism, such as lipid and atherosclerosis, chemical carcinogenesis-receptor activation pathways, and IL-17 signaling pathway. In the GO term, it mainly regulates the response to steroid hormones, membrane rafts, and G protein-amine receptor coupled activity. Eventually, we verified that the luteolin and tanshinone IIA components in SMB have a good possibility of action with AKT1 and IL-6 by in silico techniques, indicating that SMB has some scientificity in the treatment of CI.  SMB mainly treats CI by regulating 94 proteins involved in lipid and atherosclerosis, chemical carcinogenesis-receptor activation, and IL-17 signaling pathway. Our research strategy provided a template for the drug development of TCM for the treatment of CI. Cerebral infarction (CI), also known as ischemic stroke, is very common in cerebrovascular diseases, and the number of patients with this disease accounts for about 70% of patients with acute cerebrovascular diseases, which indicates that reasonable treatment is important for patients with this disease. The disease is mainly attributed to local tissue ischemia and hypoxia caused by cerebral blood flow disorders, followed by brain tissue necrosis and, in severe cases, neurological impairment . At the With an in-depth understanding of traditional Chinese medicine, people focus on finding appropriate traditional Chinese medicine (TCM) for the treatment of CI. In TCM theory, CI belongs to the category of “stroke,” and the common symptom is blood stasis. Therefore, drugs promoting blood circulation to remove blood stasis can be used to treat CI .Salvia miltiorrhiza Bunge (SMB), a traditional Chinese medicine with the effect of promoting blood circulation and removing blood stasis, is also used as a botanical drug for the treatment of diseases in many Asian countries in addition to its widespread use in China [in China . At the in China .Salvia miltiorrhiza (CSM) injection prepared with SMB as the main raw material is a commonly used drug for promoting blood circulation and removing blood stasis, which has been authorized by the China Food and Drug Administration. CSM is available to treat CI [Compound treat CI . HoweverNetwork pharmacology, as an emerging research tool, can be used to analyze the complex mechanisms of TCM in the treatment of diseases and reveal the route of drug action at the protein level . Therefohttps://tcmspw.com/tcmspsearc-h.php), using “Radix Salviae” as the keyword. Then, we used (OB) ≥30% and (DL) ≥0.18 as the screening criteria to determine the potential active ingredients that may exist.In general, oral bioavailability (OB) is an important measure of drug efficacy and drug-like properties (DL) represent the potential of compounds to become drugs . We firshttps://www.uniprot.org/).We predicted possible targets associated with SMB compounds by searching the TCMSP database for “relevant targets” and normalized the target names by UniProt . Then, using Cytoscape V3.7.1 (https://www.cytoscape.org/) software, we performed a visual analysis of the C-T network.Firstly, we constructed a network of drug compound targets interacting with disease targets by using Venny (https://string-db.org/) [Interaction networks between disease proteins were constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) (db.org/) .Enrichment analysis of GO and KEGG for therapeutic proteins was performed by the “clusterProfiler” package in R  .https://biogps.org/).The drugs refer to TCM and are used under the guidance of the TCM theory, while the medication law of SMB also follows the TCM theory. According to TCM theory, the occurrence of diseases is often due to the imbalance of the overall state of the body, and the lesions of a certain part or organ are often accompanied by abnormalities in other parts of the body. Therefore, during treatment, we need to implement the concept of combining global with local and multidimensional to gain insight into the development and changes of the disease . We wanthttps://www.rcsb.org/), respectively. We performed in silico docking studies by AutoDock Vina software for the two predicted specific compounds and the two targets described above, respectively. We used the fraction of binding energy as a criterion to evaluate the possibility of binding of components to proteins. It is generally accepted that the smaller the binding energy score, the greater the possibility that components act on proteins [To verify the reliability of the previous prediction results, protein structures of AKT1 and IL-6 proteins with PDB codes 4EKL and 1ALU were obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (PDB) proteins .In the TCMSP database, 202 possible chemical constituents of SMB were obtained. According to the screening parameters of OB ≥30% and DL ≥0.18, a total of 59 potential active ingredients corresponding to 113 drug targets were obtained by excluding components without corresponding targets . The 113A total of 3,756 therapeutic targets of CI were obtained from GeneCards and DisGeNET after the removal of duplicated targets , cellular components (CC), and molecular functions (MF) of 94 therapeutic targets for analysis . BP mainAnalysis of the KEGG pathway enrichment, results revealed that SMB may treat CI by regulating 138 pathways. We selected the top 20 pathways for analysis . The resAccording to TCM theory, when lesions occur in local organs or tissues, they often cause reactions in other parts of the body. Therefore, we selected the top 20 proteins of the PPI network to observe their expression in different organs .We can see that most proteins are also highly expressed in the lungs, in addition to higher expression in the brain. This suggests that it may be possible that SMB may also be linked to physiological processes in the lungs when treating CI through these targets. Studies have also shown that lobectomy may cause serious cardioembolic cerebral infarction complications . This alWe selected AKT1, IL-6 and luteolin, and tanshinone IIA, respectively, for docking activity validation by in silico techniques. When the binding energy of protein and active ingredient is <0, it indicates that the active ingredient has the possibility of acting on protein. The lower the binding energy, the more reliable the possibility of action .First, we selected luteolin and AKT1 and IL-6, respectively, for binding validation. The calculated score between luteolin and AKT1 was −8.5 kcal/mol. The calculated score of luteolin with IL-6 was −7.1 kcal/mol, and hydrogen bonds were formed between luteolin and multiple amino acid residues of AKT1 and IL-6, respectively Figures , indicatNext, tanshinone IIA was docked with AKT1 and IL-6, respectively. The docking scores were −9.1 and −7.3 kcal/mol, respectively. Tanshinone IIA can also form hydrogen bonds with multiple amino acid residues of AKT1 and IL-6, respectively Figures . The valFinally, we performed activity validation of AKT1 and IL-6 proteins with their small molecule inhibitors, respectively, for judging the reliability of predicting active components. The calculated scores for the two were -9.1 and -6.8 kcal/mol, respectively. At the same time, both small molecule inhibitors and predicted active components bind to the same active pocket of the corresponding protein, except that the amino acid residues that form hydrogen bonds are different Figures , which wIt is reported that patients who die due to CI account for about 40% of patients with cardiovascular disease each year in China, with the number of people affected being about 1.2 million . For the2 extract of SMB with a cryptotanshinone content of 4.55% can alleviate cerebral ischemic injury by reducing thrombosis and platelet aggregation [Luteolin, tanshinone IIA, miltirone, dihydrotanshinlactone, cryptotanshinone, and isocryptotanshinone and other components may be the main material basis for CI treatment. Modern studies have shown that luteolin can regulate oxidative stress and related proteins on apoptosis pathways , thereby alleviating CI . Tanshinregation . Miltiroregation . Based oProteins such as AKT1, IL-6, EGFR, and MAPK1 occupy an important position in PPI networks. AKT protein plays a key role in the occurrence and development of CI, and AKT protein phosphorylation can play a protective role when brain tissue is ischemic. At the same time, AKT can also regulate the biological activity of many nerve cells . InflammGO enrichment results indicate that CI treatment mainly regulates processes such as response to steroid hormone, membrane raft, and G protein-coupled amine receptor activity. The signaling pathway enrichment results suggest that pathways such as lipid and atherosclerosis, chemical carcinogenesis-receptor activation, and IL-17 signaling pathway are of higher importance in CI therapy.SMB is a commonly used drug in TCM clinical practice and has great application prospects. We predicted the mechanism of action of SMB in the treatment of CI by network pharmacology and validated some of our prediction results using in silico docking techniques. Of course, more evidence is needed to show the effectiveness of SMB in the treatment of CI, which will also be the focus of our later study. Our study provides a reference for TCM treatment of CI.