Medication adherence of schizophrenic patients is a growing public health problem. We conducted a meta-analysis on the influencing factors of medication compliance in schizophrenic patients. We searched PubMed, Embase, Cochrane Library, and Web Of Science for relevant articles published up to December 22, 2022. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess influencing factors. Egger’s test, funnel plot, the trim and fill method, and meta-regression analysis were used to assess publication bias. A total of 20 articles were included in the analysis. Twenty influencing factors were divided into seven categories: drug factors , problem behavior , income and quality of life , personal characteristics , disease factors , support level , and positive attitude and behavior . This meta-analysis found that drug factors, disease factors, problem behavior, low income and quality of life, and factors related to personal characteristics appear to be risk factors for medication adherence in people with schizophrenia. And support level, positive attitude and behavior appear to be protective factors. The pathogenesis of schizophrenia is complex and not clear at present. Genetic susceptibility, abnormal neurotransmitter function and external factors may all contribute to the development of schizophrenia3.Schizophrenia is a common severe mental disease with a lifelong prevalence rate of 1%, which is mainly manifested in the disorder of mental and psychological processes such as thinking, perception, self-experience, cognition, will, emotion and behavior, and has the characteristics of high disability rate, repeated illness and prolonged course6. The extent to which patients follow the prescribed time intervals and dosage requirements is defined as medication adherence8. A Low degree is considered as poor medication adherence. Medication non-adherence behaviors include not taking medication on time, not taking more or less medication according to the dose, stopping the medication and reducing medication by themselves.The current treatment of schizophrenia is based on the administration of antipsychotic medication. Medication can control the condition of schizophrenic patients, which has been effective in the alleviation of positive symptoms, prevention of relapse, and extension of life expectancy10. First, low medication compliance will lead to low efficacy and high relapse. Some articles pointed out that the symptoms of schizophrenia developed the fastest in the five years before the onset of schizophrenia, dosing on time and at the right dose is an important factor in the effectiveness of treatment, irregular medication is the key risk factor for relapse11. In a retrospective analysis of 419 psychiatric inpatients readmitted to hospital, Barnett et al. found that patients’ medication non-adherence significantly increased the risk of readmission compared to other factors, with an OR of 3.3312; data from Verdoux et al. show that the most common cause of relapse and readmission in adult studies is the discontinuation of prescription drugs. Patients who do not insist on medication are six times more likely to be admitted to the hospital again than those who insist on medication14. Furthermore, many studies have shown that poor medication adherence is associated with problematic behaviors such as violence, self-harm, and suicide. Buchanan et al. found that there was a significant positive correlation between low drug compliance and harmful violence through 18-month follow-ups of 1435 schizophrenic patients15; Díaz-Fernández et al. pointed out that the lack of treatment compliance of schizophrenic patients is a risk factor for the increase of suicidal behavior16; the results of a multicenter clinical trial in China also show that the aggression risk of schizophrenia patients is related to non-adherence to medication17.Good medication adherence is the key to the effectiveness of drug treatment. Poor medication adherence will cause many problems in schizophrenic patients18. Fenton et al. reported a median non-adherence rate of 55% for oral antipsychotics19 and other data in the literature on medication non-adherence in schizophrenia patients ranging from 20 to 89%22. In recent years, many studies have been reported on the phenomenon of poor medication adherence in patients with schizophrenia, while the factors influencing medication adherence have also become a subject of scholarly interest. Available clinical observations and cohort studies suggest that patients’ age, gender, marital status, insight, other physical illnesses, economic conditions, etc. all have an impact on medication adherence25.Through a review of medication non-adherence behavior in schizophrenia patients, Lacro et al. noted that current medication non-adherence in schizophrenia patients is as high as 40–50%However, the current research lacks uniform predictors and has no clinical implications for interventions for medication adherence in patients with schizophrenia. Understanding the factors that influence medication adherence has practical implications for the identification of patients with low adherence and may assist in the development of clinical interventions for medication adherence. The aim of this study was to analyze the influencing factors of medication adherence of schizophrenic patients, to provide information for the formulation of intervention strategies for medication adherence, and to help patients recover better and reduce recurrence.We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The initial study protocol was preregistered at PROSPERO (CRD42023388661). We searched PubMed, Embase, Cochrane Library, and Web of Science for relevant literature up to 22 December 2022.The search consisted of the following terms as Medical Subject Headings (MSH) and different databases have corresponding modifications. The following search strategy was used: (schizo*) AND (adherence OR compliance OR non-adherence OR non-compliance) AND (relative OR risk*) AND (cohort OR “cohort study”).Two researchers independently assessed the title and abstract that met the potential qualifications of the above search strategy to exclude the following articles: (i) use of long-acting injectable (LAI) antipsychotics; (ii) no relevant diagnosis of schizophrenia; (iii) review articles, comments, case reports, editorials, animal studies, and meta-analysis; (iv) data unextractable or incomplete; (v) language not English. The full text was then further assessed to determine whether the article met the inclusion criteria. The final articles included met the following criteria: (i) patients diagnosed with schizophrenia who are receiving at least one antipsychotic drug, and excluded patients with major medical conditions (such as liver or kidney dysfunction in relationship to cardiovascular disease organic brain disorders), with a history of substance use disorders; (ii) the study was designed as a cohort study or a cross-sectional study; (iii) the hazard ratios (HR), relative risks (RR), and odds ratios (OR) were reported.All data were extracted independently by two investigators and the following data were collected for all articles: author, year of publication, country, sample size, sample age, diagnostic criteria, and influencing factors for medication adherence.26 to assess the cross-sectional studies, and The Newcastle Ottawa Scale (NOS)27 was used to assess the cohort study. For each score, 1 indicates that the study meets this criterion and 0 indicates that the study does not meet this criterion. A total score of no less than 5 will be included in this meta-analysis.In terms of quality assessment, we used the Agency for Healthcare Research and Quality Checklist28. We used the Q-test and I-squared (I2) values to assess heterogeneity. P < 0.1 and I2 > 75% was considered significant heterogeneity. I-squared (I2) values close to 0% and P > 0.1 indicate that heterogeneity is small. Sensitivity analysis was carried out for the parts with large heterogeneity. Given the expected heterogeneity, we adopted the random effect model in advance. The odds ratio (OR) was used as the main index, and a 95% confidence interval (95% CI) was used to reflect the uncertainty of point estimation, with ORs = 1 indicating that the factor was not associated with medication adherence, ORs < 1 considered as protective factors and ORs > 1 as risk factors.In this meta-analysis, Stata 14.0 was used for data analysisP < 0.05) indicated the presence of publication bias. For results showing publication bias, we used the trim and fill method to assess the impact of bias on final outcomes. In addition, to consider potential moderating effects, we used meta-regression to assess the country of study, the type of population (first patients or not), the type of study , and the quality of the literature.For publication bias, we used funnel plots for rough qualitative analysis combined with Egger’s test for quantitative analysis, significant Egger’s test result , and very significant. Therefore, we divided the different influencing factors into seven categories and discussed them respectively  .Data from a total of eight studies containing the number of drugs taken, the therapeutic effect of drugs, and the side effects of drugs are classified as drug factors. Meta-analysis using randomized effects showed that drug factors were the risk factors of medication adherence in schizophrenic patients  Fig. . SensitiI2 = 75. 4, P < 0.05)  Fig. . Subgrou05) Fig. .Fig. 3FoI2 = 86.4%, P < 0.05)  Fig. .I2 = 62.1%, P < 0.05), that is, the higher the level of support, the better the medication adherence , which indicated that positive treatment attitude and behavior were protective factors of medication adherence   Fig. .I2 = 73.5%, P < 0.05)  Fig. .P = 0.538) and positive attitude and behavior (P = 0.204) had publication bias (P < 0.05) (Table P = 0.976 > 0.05), suggesting that there was no publication bias , research type , and literature quality  were not significant sources of heterogeneity. Study countries  may be a source of heterogeneity. Therefore, we conducted a subgroup analysis of the study countries. A total of 12 countries were involved in this meta-analysis, and the results of the subgroup analysis showed that only two countries had low subgroup heterogeneity , while the majority of countries still had high subgroup heterogeneity , study type and literature quality as variables to further explore the possible sources of heterogeneity. The results showed that population type : drug factors , disease factors , personal characteristics , problem behavior , lower income, and lower quality of life. Two categories of factors were protective for medication adherence, with a combined OR of 0.54 : higher levels of support , and positive treatment attitudes and behaviors.This study was based on a meta-analysis of five cross-sectional studies and fifteen cohort studies with an overall sample of 342,408 patients taking antipsychotic medication. The data of meta-analysis showed that a total of five categories of factors were potential risk factors for medication adherence, with a combined OR of 1.31 . The results suggest that the therapeutic effect, dosage, and severity of side effects of drugs will lead to patients’ non-compliance behavior. This is consistent with previous research results46. Also, lower income and quality of life (OR = 1.23), personal attributes including age, gender, and education (OR = 1.21), were all significant in the results of this meta-analysis and were among the risk factors for patient medication adherence. This is different from the results of Lacro et al.18, which may be caused by different inclusion criteria and different data processing methods.In addition to drug factors, the results of our meta-analysis showed that disease-related factors such as problem behaviors of drug and alcohol abuse (OR = 1.77), duration and severity of illness (OR = 1.14) can also influence medication adherence to a large extent. This is consistent with the findings of several previous studies11.In terms of protective factors for medication adherence, we found two significant results: support level (OR = 0.54), positive attitude and behavior (OR = 0.52). Regarding the level of support, both family members  and social support  would increase medication adherence in patients with schizophrenia and also reduce patients’ stigma to a certain extent, especially for patients recovering from the illness. Positive treatment attitude and behavior, including seeing a doctor in time when the disease occurs, insisting on psychological intervention and actively learning related knowledge, etc. These are helpful to the compliance of taking medicine, and at the same time, better guarantee the exertion of drug effect. This is consistent with a previous reanalysis of 38 control studies by Pitsche-l Walz et al., which showed that psychological education can improve the medication compliance of schizophrenia patients, and its one-year recurrence rate can be reduced by 20%Generally speaking, medication adherence is the basic guarantee for schizophrenic patients to obtain the curative effect, which can better help patients recover and reduce recurrence, and then reduce the economic burden on family and society. The results of this meta-analysis may help identify low adherence to medication in patients with schizophrenia and inform the development of prevention protocols. Specifically, the results of the above five risk factors suggest that we have substance abuse behavior, low income, and low life satisfaction, age <25 or age >50, females with low education level are more likely to have drug non-adherence behavior, and we should focus on monitoring the population with the above characteristics. At the same time, combining the results of the two main protective factors we found that interventions targeting the problem of medication adherence can be aimed at improving patients’ life satisfaction, level of support, developing positive attitudes and behaviors, and educating about medication adherence as entry points.SUPPLEMENTAL MATERIAL


Health literacy is crucial for managing pandemics such as COVID-19 and maintaining the health of the population; our goal was to investigate the impact of cultural capital on health literacy during the COVID-19 pandemic among community residents and to further examine the mediating role of social capital in the relationship between cultural capital and health literacy.t-test, and hierarchical linear regression were used to analyze the level of health literacy among community residents and the related elements; the structural equation model (SEM) was used to explore the influential mechanisms of health literacy and explore whether social capital acted as a mediator in the relationship between cultural capital and health literacy.A cross-sectional study was conducted among 1,600 community residents selected in Chongqing, China using a stratified random sampling method. Data were gathered through a questionnaire survey, including sociodemographic characteristics, cultural capital, social capital, and health literacy. Chi-square analysis, one-way ANOVA, β = 0.383, 95% CI = 0.265–0.648), but also indirectly influences health literacy through three types of social capital ; its mediating effect accounting for 50.7% of the overall effect.Cultural capital, community participation, community trust, reciprocity, and cognitive social capital had a significant positive effect on health literacy. In addition, the results of SEM indicated that cultural capital not only directly influences health literacy (Our results highlight the empirical link between cultural capital and health literacy, and suggest that social capital mediates this connection. These findings suggest that governments and communities should focus on the construction of community cultural capital and provide residents with better social capital to improve their health literacy to prepare for future pandemics. In December 2019, the first cases of novel coronavirus pneumonia 2019 (COVID-19) were reported . When anThe concept of health literacy has been applied by relevant scholars in their research fields. In the field of public health, health literacy is defined as the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions, and this degree can make public health decisions that benefit the community . The COVMany studies have researched on health literacy, with majority of them conducted in the United States , 15. StuThree contexts are highlighted in the Institute of Medicine's (IOM) fundamental framework for health literacy—(1) healthcare, (2) education, (3) culture and society—where health literacy can be improved at both the level of the person and the population . Most heA sociological concept, “cultural capital,” was developed by Bourdieu after he summarized Marx's idea of capital. He contends that the allocation of cultural capital among social groupings plays a significant role in the resolution of social issues. After Bourdieu, many scholars critically developed the concept of cultural capital, among which Collins pays attention to the micro level of cultural capital and believes that cultural capital can bring people the micro role of emotional energy under immediate circumstances . CollinsMeanwhile, recent researches have confirmed that social capital and the capacity of social networks, in addition to an individual's abilities, are also associated with health literacy . Social The connection between social capital and health literacy has been the subject of a few studies , 39, andA cross-sectional study was performed among community residents in Chongqing. We used stratified random sampling. First, we stratified according to economic level and used the total GDP of each district as an indicator to measure economic conditions according to the relevant documents published. We selected Yubei and Jiangbei with good economic status, while Fuling and Yongchuan with medium economic status; and Banan with poor economic status. Then, community residents were randomly selected from these districts to conduct the survey. Thus, 355 residents were selected from each district by random sampling. The prerequisites for inclusion were below: (a)being 18–70 years old; (b) being permanent residents; Permanent residents are those who have lived in the community for more than 6 months in the past year; (c) consenting to participate in the survey; (d) having no psychological problems; (e) having the ability to answer questionnaires independently. Finally, we collected 1,600 (96.7%) valid questionnaires .A preliminary investigation was carried out to determine the precise execution of the research and the final questionnaire design before the full-scale survey. From 1 June to 30 September 2021, the formal inquiry was performed by three fellows and seven university and master's-level students with relevant field research experience. Also, the investigators received training on how to employ the same criteria and techniques; prior to the survey, the participants' informed consent was sought, and any relevant justifications were given during the investigation. We have adopted a series of methods to ensure the reliability of data collection. On the one hand, a one-to-one approach was taken throughout the process of the on-site investigation; on the other hand, the questionnaires were uniformly numbered and double entered after the survey was finished to assure the accuracy of the data entry.Based on Collins definition of specific cultural capital, we use three questions to describe cultural capital. The question, “You identify well with the cultural activities in your community,” was used to measure the variable of awareness of identity. The question “Over the past year, you and the residents in your community have shared the same beliefs and goals to fight the pandemic” was used to measure the variable of belief. The question “You follow the core socialist values to mediate interpersonal conflicts and conflicts of interest in your community” was used to measure the variable of values. All items were assessed on a five-point Likert scale . The higher the rating, the greater the cultural capital of community residents. The Cronbach's alpha was 0.956, and confirmatory factor analysis (CFA) reported factor loading was from 0.930 to 0.943, demonstrating high reliability and validity of the scale.The dimensional framework for social capital constructed by Ignacio  was usedThe definition of health literacy involves the ability to acquire, understand and process health information, which corresponds to the theory of knowledge, attitude, and behavior (KAB), so the health literacy evaluation index scale of residents is founded on the theory of KAB. The Communicative and Critical Health Literacy (CCHL) scale developed by Ishikawa et al.  was adopThe first group of covariates considered were demographic and socioeconomic characteristics, including age, gender , political status , education , marital status , and the type of community they live in . The second group consisted of variables of management systems, including risk evaluation management system . Accountability system for public health emergencies . The extent to which smart tools work .P-value of <0.05 was the threshold for significance. Descriptive statistics like frequency and constituent ratio were used to analyze the data. The t-test and one-way ANOVA were used to analyze the distribution differences of the health literacy score in different sociodemographic characteristics.First, SPSS 26.0 was used for statistical analysis. A two-tailed Next, to evaluate the relationship among cultural capital, social capital, and health literacy, the correlation coefficients were estimated, and the main variables affecting the health literacy of community residents were examined using hierarchical multiple regression analysis. To account for any potential confounding, all variables that might have an impact on health literacy were included in the model.Finally, the Structural Equation Model (SEM) was created using AMOS 26.0 to investigate the precise mechanisms underlying the effects of cultural capital, structural social capital, relational social capital, and cognitive social capital on health literacy. We evaluated the fit of the hypothesized model to ensure it fits best with the sample data. The Bootstrap approach was used to estimate both direct and indirect effects in order to calculate confidence ranges for each effect. The corresponding effect is significant if the 95% confidence interval (CI) does not contain 0.P < 0.05) depending on their level of political appearance, education, marital status, risk evaluation management system, accountability system, and the extent to which smart tools work.Univariate analysis showed residents' health literacy ratings varied significantly , since these two variables are highly correlated, we have included a scatter plot in the r = 0.737–0.879, P < 0.01), and the correlation degree of community participation was the highest (r = 0.879); the subdimension of relational social capital was positively correlated with health literacy , among which community trust had the highest correlation degree (r = 0.886); cognitive social capital also had a positive relationship with health literacy .2 was statistically significant when sociodemographic characteristics, cultural capital, structural social capital, relational social capital, and cognitive social capital were entered into the regression equation. By comparing the changes in the ΔR2, the influence of cultural capital on health literacy was greater than that of sociodemographic factors and social capital, making up 51.3% of the variation in health literacy  sociodemographic characteristics; (2) sociodemographic characteristics + cultural capital; (3) sociodemographic characteristics + cultural capital + structural social capital; (4) sociodemographic characteristics + cultural capital + structural social capital + relational social capital; (5) sociodemographic characteristics + cultural capital + structural social capital + relational social capital + cognitive social capital. Results showed that ΔRliteracy .P < 0.001); in the structural social capital dimension, health literacy score increases in direct proportion to community participation score ; in the relational social capital dimension, health literacy increased with increasing community trust and reciprocity score ; the higher the cognitive social capital score, the higher the health literacy score .Specifically, the results of the fifth model's comparison of independent variables showed that health literacy increased with increasing cultural capital score . The model's estimation procedure uses the maximum likelihood approach. χ2/df = 2.281, RMSEA = 0.012, GFI = 0.992, NFI = 0.954, CFI = 0.989, TLI = 0.994, the goodness of fit statistics of the model indicated that the created theoretical models fit the data well , respectively. Cultural capital contributed positive effects on structural social capital, relational social capital, and cognitive social capital, with the coefficients being 0.578, 0.569, and 0.547 (P < 0.001), respectively. Moreover, cultural capital had not only direct effects on health literacy (β = 0.383), but also indirect effects through three types of social capital as the mediators . Besides, three types of social capital had only a direct effect on health literacy . The sizes of the direct effect of cultural capital on health literacy were 0.383 (95% CI: 0.045–0.510); the indirect mediation effects via three types of social capital were 0.175 (95% CI: 0.117–0.465), 0.191 (95% CI: 0.111–0.406), 0.028 (95% CI: 0.031–0.174). The 95% CI did not contain 0, hence these effects are significant. Thus, we can conclude that social capital played the mediating role between cultural capital and health literacy, and the mediation effect of social capital makes up 50.7% of the total effect .The purpose of the study is to explore the association between cultural capital and health literacy during the COVID-19 pandemic among community residents in Chongqing, China; and to examine the mediation role of social capital between cultural capital and health literacy. As far as we know, this work is the first to identify the mediation role of social capital between cultural capital and health literacy among community residents. Our findings indicate that cultural capital not only influences health literacy during the COVID-19 pandemic among community residents directly but also indirectly through social capital.Our results show that during the pandemic, the score for cultural capital (4.198 ± 0.810) was higher than Natalie Ross's findings  conducteThis study found that the influence of cultural capital on health literacy during the COVID-19 pandemic is favorable, the health literacy increased with increased cultural capital, consistent with existing studies , 46. ThiWe distinguished three types of social capital and examined the effect of each type on health literacy separately. Our results indicate that all types of social capital were positively correlated with health literacy. Previous researches have consistently shown that social capital and health literacy are strongly correlated , 59. SpeIn terms of relational social capital, we discovered that, in line with prior research, health literacy rose with higher community trust and reciprocity , 63. TheFinally, we found that cognitive social capital also showed a positive effect on health literacy. Some studies have shown that cognitive social capital can control unhealthy behaviors in an informal way to benefit people's health . During We found that cultural capital promoted health literacy through strengthening social capital. In other words, those with greater cultural capital will also have richer social capital, hence improving their health literacy. This study's findings are explicable by the terror management theory (TMT), which contends that people react favorably to things that uphold their cultural values and that cultural values act as anxiety buffers for people, enabling them to respond positively and having an effect on their cognition and behavior . In addiThe work has a few limitations. First of all, as this was a cross-sectional study, causal conclusions could not be drawn. Cohort follow-up might be used in future studies to acquire longitudinal data, which would provide more conclusive data for causal inference. The second limitation is the representativeness of the sample. Because only Chongqing was conducted for data collection in this study, the results may vary depending on the population or location. Finally, the study's self-reporting and cross-sectional design could have introduced measurement and/or recall bias, which may not reflect the true experiences and perceptions of community residents to a certain extent. In future studies, multiple sources of data can be used to improve the dependability of the questionnaire data, such as paired completion, combinations of self and other ratings, and superior ratings.In summary, our findings demonstrate an empirical connection between cultural capital and health literacy among community residents during the COVID-19 pandemic, indicating that cultural capital can promote health literacy during the COVID-19 pandemic; and showing that social capital mediates this connection. Our results provide directions for improving residents' health literacy and suggest that government and community staff should focus on building cultural capital, actively organize cultural events, strengthen the community of values, enhance the sense of internal beliefs, and provide better social capital to improve residents' health literacy to better protect the health of residents in future pandemics.The original contributions presented in the study are included in the article/Written informed consent was obtained from the individual (s) for the publication of any potentially identifiable images or data included in this article.YL planned the research, designed the programs, conducted the data collection and analysis, and drafted the manuscript. HZ and HC participated in data collection, assisted data analysis, and gave suggestions for the manuscript writing. MX provided ideas and funding to support this study and helped to revise the manuscript. All authors contributed to the article and approved the submitted version.


Sarcoma treatment requires a high level of expertise due to its rarity and heterogeneity. Sarcoma patients should, therefore, be referred to an expert centre as early as possible to ensure optimal treatment. Numerous studies have been carried out to provide evidence for this strategy. In compliance with the 2020 PRISMA guidelines, a systematic search was conducted in PubMed, EMBASE, Ovid Medline, ClinicalTrials.gov and Cochrane Library databases. The subject of these studies was the centralised treatment of adult sarcoma patients at expert centres and the use of interdisciplinary tumour boards. Uncertainty in therapy, delays in referral to expert centres, and limited access to therapeutic modalities continue to be a challenge in sarcoma therapy. At expert centres, diagnostic procedures were more frequently and adequately performed, and treatment was associated with an improvement in outcomes in the majority of studies: patients benefited from longer survival, lower local recurrence rates and a better postoperative outcome. The implementation of an interdisciplinary tumour board was associated with discrepant results. In a greater number of studies, it was associated with a lower local relapse rate, better overall survival and surgical outcome. In two studies, however, a shorter overall survival was observed. The establishment of expert centres and the consistent use of interdisciplinary tumour boards are important structures for ensuring multidisciplinary therapy approaches. There is growing evidence that this holds great potential for optimising sarcoma therapy. In rare and ultra-rare cancers, interdisciplinary and centralized management is considered mandatory for optimal treatment. Accounting for 1% of all cancers, sarcomas belong to rare tumour entities .Centralizing sarcoma treatment in expert centres is not a new concept. For example, in 1994, Gustafson et al. reported a lower local recurrence rate and a reduced need for re-resection in a Swedish cohort with soft tissue sarcomas if they were presented preoperatively to an expert centre . The curIn 1987, a self-proclaimed group of experts was built at Helsinki University Hospital, Finland. The members came from oncology, radiotherapy, orthopaedics, plastic surgery, pathology, and radiology. A treatment protocol was designed based on the current literature at that time. Before starting therapy, all new cases diagnosed with soft tissue sarcoma were discussed in weekly meetings. This approach improved disease-free survival and local control rates . These iAs soon as sarcoma is suspected, further diagnostics and treatment should be performed at an expert centre ,4. The gBefore the therapy, patients should be presented to an interdisciplinary tumour board for careful and individual therapy planning. Further consultation with the multidisciplinary tumour board is also recommended following resection in the case of tumour recurrence or if the therapy regime has to be changed for any reason .In a localized tumour stage, a complete resection of the tumour is warranted regardless of the sarcoma type. As a standard, wide resection is performed by removing the tumour in one part and encapsulating it with healthy tissue. The achievement of free tumour margins (R0 status) is from prognostic significance. If an R0-status is not attained, patients should be referred to an expert centre to evaluate a reresection ,4,7.Prognostic factors such as the tumour characteristic, localisation and diameter, and clinical presentation must be assessed thoroughly to evaluate the necessity of a multimodal therapy concept ,4. DepenAnthracyclines are the most frequently used chemotherapeutic substances in the treatment of sarcomas, either as a monotherapy or in combination with other substances ,4,7. In In a metastasized tumour stage, systemic therapy builds the foundation of the treatment. The resection of metastasis should be decided individually and can improve survival. Radiotherapy and local ablative treatment can also be evaluated if resection of the metastasis is not possible ,4,7.Centralisation and interdisciplinary approaches to therapy are of particular significance in treating sarcomas. There is a consensus that patients can benefit from this strategy. Multiple works and studies were performed to establish evidence for this therapeutic principle and characterize the extent to which this principle is implemented in everyday clinical practice. This review aims to systematically summarize the available literature results and create an overview of their statements.We performed a systematic review that was concordant with the updated guidelines of the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses for non-randomised studies  AND .The registers ClinicalTrials.gov and Cochrane Library were searched by using the term “sarcoma” combined with one of every item used in the MeSH terms mentioned above. The last search was conducted on 12 July 2022 without the application of any limitations. All English and German studies published until 12 July 2022 were considered.The search results were evaluated by the first reviewer (A.S.). Articles that did not correspond to the searched study type, duplicates, incomplete studies, conference abstracts, and studies incoherent to the inclusion and exclusion criteria were excluded .www.osf.io).All primary mono- and multicentric studies addressing the centralized treatment of adult sarcoma patients at expert centres and the involvement of an interdisciplinary tumour board were included. This comprised retro- and prospective studies, with data obtained from cancer registries, databases, structured qualitative interviews, and cross-sectional surveys. Reviews as well as meta-analyses were excluded as the focus of this paper was on primary studies. The review was registered on OSF . The included studies were separated into groups (I and II) for practical reasons regarding the risk of bias assessment, even though the studies overlapped thematically . All stuIn group I, a risk of bias assessment was performed for every study using the Risk of Bias In Non-randomized Studies—of Interventions (ROBINS-I) tool . The CocEach study of group II was individually examined retrospectively for possible limitations and risk of bias. In addition, the reviewers observed the limitations discussed by the study authors . The ROBFollowing the initial evaluation by the first reviewer (A.S.), every study was carefully reassessed by the second reviewer (A.F.) Any discrepancies in the assessment were thoroughly discussed and eventually resolved.For all included studies, the following items were reported: the author, year of publication, study type, the number of patients or participants, and characteristics such as age, sex, and sarcoma type, if applicable. In addition, descriptive data for diagnostics and treatment at an expert centre (EC), respectively, at a non-expert centre (NEC), presentation at an interdisciplinary tumour board (ITB), and compliance to its recommendations were demonstrated. Finally, if valuable for the present review, other results were added in a separate section.The available data for postoperative outcomes, overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), disease-free survival (DFS), local recurrence (LR), local recurrence-free survival (LRFS), recurrence-free survival (RFS), metastatic disease (MD), and hazard ratio (HR) retrospectively odds ratio (OR) were extracted. If the topic was not addressed in the study or data were missing, the respective data were not included.The following PRISMA flow diagram  shows thMultiple efforts have been made to outline the difficulties in accessing specialised diagnostics or consultation at an expert centre. By interviewing 60 Australian patients, relatives, and health professionals, Weaver et al. identified four main problems in sarcoma care: the patient’s perception and symptoms, difficulties in diagnosing sarcomas, the availability of health services, and lack of experience . EichlerSeveral data sets are of interest to elucidate the processes involved in suitable diagnostic procedures. In a prospective cohort study at an Australian centre concerning the biopsies of musculoskeletal tumours, Pollock et al. found that adequate material for diagnosis was better obtained when performed by an expert . A crossTwo consecutive retrospective studies by Thway et al. analysed the discrepancies in the pathological diagnosis of soft-tissue sarcomas and GIST between a British expert and the referring non-expert centre. They found that in 73.4% and 57.8% of cases, the pathological diagnosis of the expert centre was consistent with that of the referring non-expert centre, respectively. However, significant discrepancies between the pathological diagnoses were found in 15.7% and 10.9% of the cases, respectively, resulting in alterations in therapeutic approaches. In the rest of the cases, only minimal or minor discrepancies were observed ,44. In aIt remains an important question whether treatment at specialised centres impacts the prognosis and survival of sarcoma patients. In a retrospective cohort study of the French sarcoma network NETSARC with over 25,000 sarcoma patients by Blay et al., primary surgery at an expert centre was associated with improved overall survival and local recurrence-free survival, stating a hazard ratio of 0.68 and 0.65, respectively . A PortuAdditionally, they observed a lower local relapse rate with treatment at an expert centre . By contSeveral analyses have investigated these effects in retroperitoneal sarcoma. Primary surgery for retroperitoneal soft tissue sarcomas at an expert centre was associated with a better 2-year overall survival and hazard ratio of 0.49 in retrospective analysis based on the French NETSARC database by Bonvalot et al.  Similar Some very rare subtypes have also been evaluated. For example, clear cell sarcomas were analysed in a Polish retrospective cohort study by Ipach et al. The median overall survival was improved, and metastasis occurred later if patients were treated at an expert centre . In PECoFor Ewing sarcomas, Jagodzińska-Mucha et al. observed an improvement in progression-free and 5-year overall survival when patients were referred to a Polish expert centre within three months after the diagnostic biopsy. The hazard ratio for overall survival was 1.6 if this period was longer than three months . AlvarezSeveral data sets are available to assess the influence of surgical outcomes at specialised centres. All of the included studies examining surgical outcomes reported a positive impact on the results when the resection of sarcoma was performed at an expert centre.Many studies demonstrated that high-volume expert centres more often achieved an R0-resection and lower rates of R1/R2-resections compared to non-expert centres ,27,28,38In addition, Sandrucci et al. investigated retroperitoneal sarcomas and found that at an expert centre tumours were more often removed intact and that an R0/R1-status was associated with better overall survival . On the Pollock et al. documented that if an expert had already performed the biopsy, re-resection, and amputations were less likely to be necessary . AdditioSeveral institutions have investigated perioperative therapy’s influence on localised soft tissue sarcoma. Martin-Broto et al. found that patients with high-risk localised soft tissue sarcomas received perioperative chemotherapy more often at an expert centre. In this prospective Spanish study, perioperative chemotherapy in patients with high-risk constellations was independently associated with a reduced risk of recurrence and improved recurrence-free survival . Ray-CoqSnow et al. reported a higher proportion of neoadjuvant radiotherapy when treated at an expert centre regarding the perioperative treatment of retroperitoneal soft tissue sarcomas. In contrast, adjuvant radiotherapy was used more frequently at non-expert centres. Neoadjuvant radiotherapy was also identified as an independent factor of a lower risk of local recurrence . BonvaloWhen analysing relevant factors in treating soft tissue sarcoma patients, interdisciplinary tumour boards are of interest. In the Europe-wide survey by Goedhart et al., 47.1% of participants reported access to a multidisciplinary tumour board. A total of 100% of the participating expert centres held a compulsory interdisciplinary tumour board before starting therapy. In 84%, this took place weekly, and an average of 15 cases were discussed . In the In comparison, in an international survey by Cho et al. to members of the Connective Tissue Oncology Society and the Canadian Association of Radiation Oncology, 96.6% reported having access to a specialised sarcoma board. A total of 85.5% reported presenting every case, and 14.6% only complicated cases . Fayet eIn the analysis by Blay et al., an interdisciplinary tumour board before treatment initiation was associated with an increased risk of death with a hazard ratio of 1.56 for overall survival. By contrast, this approach was a favourable prognostic factor for local recurrence-free survival (hazard ratio: 0.67) and disease-free survival (hazard ratio: 0.80) . A more By contrast, Marec-Bérard et al. and Bonvalot et al. could not identify the use of an interdisciplinary tumour board as an independent prognostic factor in the treatment of sarcomas ,17  formulated a policy statement that focused on patient-centred therapy. For an optimal, evidence-based implementation of diagnostics and treatment, a multidisciplinary team is crucial to accompany the patient from the very first moment of their disease. In addition to the obligatory presentation on a tumour board, this statement especially emphasises a focus on psychosocial aspects, survival, and comorbidities . Among cIn a review, Scott et al. summarised the current evidence on different tumour entities and their treatment by a multidisciplinary team: a large proportion of the reviewed studies conducted between 2020 and 2021 showed an improvement in the outcome and overall survival of patients with breast, prostate, lung, colorectal, oesophageal and breast cancer . BerardiIn treating breast cancer patients, a lot of pioneering work has been conducted on multidisciplinary therapy. For example, as early as 2000, the European Society of Breast Cancer Specialists (EUSOMA) published a paper defining the quality standards for breast cancer centres .Kesson et al. published a retrospective cohort study of more than 13,000 women on implementing a multidisciplinary breast cancer care team that served one region in Scotland. This led to an 18% reduction in mortality compared to the surrounding areas. A retrospective study by Tsai et al. examined more than 18,000 breast cancer patients. Treatment by a multidisciplinary team reduced the risk of local recurrence (hazard ratio of 0.84 (95%-CI 0.70–0.99)) . FinallyA Germany-wide cohort of pancreatic cancer patients was retrospectively studied by Roessler et al. Treatment at a centre certified by the German Cancer Society was associated with the near doubling of median overall survival (4.4 vs. 8 months) and a reduced risk of death (hazard ratio 0.89 (95%-CI 0.85–0.93)) . In addiA comparable, retrospective study of German-certified cancer centres was conducted by Völkl et al. on patients with localised colorectal carcinoma. In an accredited centre, the 3-year survival rate was 71.6% compared to 63.3% in non-certified centres. Overall, reduced risk with a hazard ratio of  was found with treatments at a certified “expert centre” . Peng etThe therapeutic principles investigated in the studies mentioned above also play a significant role in treating rare cancers. For example, European health professionals, patient organisations, and industry members designed the Sarcoma Policy Checklist as a joint venture. In this, the development of national sarcoma centres as centres of high-quality sarcoma treatment and the need for multidisciplinary teams was emphasised as essential principles to optimise sarcoma treatment .A positive example of implementing these principles into sarcoma therapy is the French clinical reference network for soft tissue and visceral sarcomas NETSARC. This implies a comprehensive network of centres, experts, and guideline-based diagnostics and therapy enforcement. Every patient is obligatorily presented in an interdisciplinary sarcoma board and is automatically included in the database registry. Furthermore, the histology of each patient is reviewed by a reference pathologist ,58. BlayAbout 20 years ago, the German Cancer Society’s certification program for cancer centres began to take shape. This program focused on multidisciplinary therapies that followed the highest quality standards and the current guidelines. In 2019, 56% of all cancer patients in Germany were treated at certified cancer centres . In ApriThe studies examined in this review show a high degree of heterogeneity, and their conclusive statements are partly discrepant. However, there is growing evidence that patients benefit from treatment at expert centres and the integration of an interdisciplinary tumour board as a meeting point for all those involved in sarcoma therapy. It appears that these established structures improve the outcomes of sarcoma patients through multidisciplinary action.There have been multiple efforts in establishing these structures toward better networking and the centralisation of treating sarcoma patients to provide access to a standardised, guideline-based therapy. The crucial determinants of multidisciplinary therapy and the development of expert centres for high-quality treatment, among others, have been defined by national and international guidelines as well as reports, such as the Sarcoma Policy Checklist or the Rare Cancer Agenda 2030, but also by national programs, such as the certification program of the German Cancer Society or the NETSARC network in France ,7,28,63.Broad databases will help to unambiguously identify quality indicators, a lack of resources, and where to integrate them into an up-to-date guideline-based therapy. Furthermore, this will increase awareness of interdisciplinary management and cooperation with centres of expertise in sarcoma treatment, aiming to eliminate all treatment uncertainties outside and inside expert centres in the future.


There was also a significant reduction in the intervention group for pain (p < 0.001), tiredness (p = 0.002), sadness (p < 0.001), anxiety (p < 0.001), and appetite (p = 0.001). The Beauty video had the best performance, while the Tranquility video showed no significant improvement in any of the symptoms evaluated. These findings suggest that images of nature may be a valuable tool to help control clinical and psychological symptoms in cancer patients undergoing chemotherapy.The incidence of cancer cases is increasing worldwide, and chemotherapy is often necessary as part of the treatment for many of these cases. Nature-based interventions have been shown to offer potential benefits for human well-being. Objective: This study aims to investigate the outcome of nature images on clinical symptom management related to chemotherapy. Methods: A randomized clinical trial was conducted in an outpatient cancer unit of a private hospital in Brazil, with 173 participants over the age of 18 who were undergoing chemotherapy and had signed an informed consent form. The intervention consisted of the presentation of a 12-min video featuring nature images categorized under the themes of Tranquility, Beauty, Emotions Up, or Miscellany. Images were sourced from the e-Nature Positive Emotions Photography Database (e-NatPOEM), a publicly available collection of affectively rated images. Sociodemographic and clinical data, as well as the participants’ connection to nature, were investigated. The Positive Affect/Negative Affect Scale (PANAS) and the Edmonton Symptom Assessment System (ESAS) were applied pre- and post-intervention. Results: Data showed very strong evidence of a reduction in negative affect for the intervention group ( An estimated 19.3 million new cancer cases occurred worldwide in 2020, according to data from the World Health Organization and the American Cancer Society ,5.Cancer patients often experience negative emotions at diagnosis and throughout treatment . In clinSince Florence Nightingale, there has been a strong emphasis on creating restorative environments in hospitals. Florence recognized the importance of patients being able to see the sky and sunlight through a window, even if nothing else was possible, stating that such measures were of prime importance for patient recovery .A window with a view of a natural landscape has been identified as a potential adjunct in the recovery of surgical patients, resulting in reduced analgesic consumption and shorter hospital stays . HoweverThe growing literature on nature-based interventions in various health settings suggests their potential to alleviate disease-related tension and positively impact patients. However, little is known about the role of human-nature interactions in patients’ health and illness experiences and whether nature contributes to recovery, health, and well-being from their perspective . ResearcA review study has shown that cancer patients appreciate direct contact with nature and benefit from the opportunities of this connection, experiencing consequent tension relief (related to the diagnosis) and feeling aesthetically enriched by nature through the appreciation of its beauty, peace, tranquility, and solitude . AlthougIn this study, we evaluated the therapeutic potential of viewing images of nature on the cancer patients’ positive/negative affect and clinical symptoms related to chemotherapy. For the assessments, we employed the Positive Affect/Negative Affect Scale (PANAS)  and the ClinicalTrials.gov Identifier: NCT03518255 (accessed on 3 May 2023).This randomized clinical trial was conducted in an outpatient care unit for cancer patients at an extra-large private general hospital located in the southern part of Sao Paulo, Brazil. All participants provided written informed consent. The study was approved by the Institutional Research Ethics Review Board in accordance with the Declaration of Helsinki and was registered with The inclusion criteria comprised patients of both sexes, over 18 years old, with preserved clinical conditions and communication functions that allowed them to participate in the study. They were undergoing infusion chemotherapy for any type of cancer. Exclusion criteria comprised patients who received immunotherapy infusion, individuals with visual impairment, and those who experienced any side effects or deterioration in clinical condition  during the interview/intervention period.Since antiemetic medications and certain pain control drugs can affect patients’ psychological state, the control and intervention groups received a similar drug protocol. The institution conducting this study is certified by the American Society of Clinical Oncology (ASCO)  and striThe potential participants were selected from a weekly list of patients scheduled for chemotherapy sessions in the upcoming week. Invitation e-mails were sent to the patients, and those who provided informed consent were included in the screening process.From 22 August 2018 to 13 March 2020, 265 patients underwent screening for eligibility in the study. Among them, 35 were ineligible as they did not meet the inclusion criteria . Additionally, 54 patients declined to participate, and one patient was isolated due to contact precaution procedures. The remaining 175 patients were randomly assigned to one of five groups: the Control group, intervention Beauty group, intervention Emotions Up group, intervention Miscellany group, and intervention Tranquility group. The randomization process was conducted using the Randomizer [We hypothesized that the intervention group, exposed to images of nature, will experience a clinically significant improvement in positive affect and an 80% reduction in negative affect and chemotherapy-related symptoms/adverse events, compared to the control group. To detect a significant difference with 80% power at a 0.05 level of significance (two-sided), we calculated a sample size of at least 30 patients per group.Participants completed a questionnaire that assessed their sociodemographic and clinical variables, including their sex, age, location , marital status, education, profession, urban/rural background, intentional relationship with nature, diagnosis, chemotherapy session, time of diagnosis, and their estimated treatment time for sample characterization.To evaluate the affective aspect of the participants’ relationship with the environment, the Connectedness to Nature Scale (CNS) was used. The CNS consists of 14 items, such as “I think of nature as a community of which I am a part” and “My personal well-being is independent of the well-being of nature”. Participants rated their agreement on a scale ranging from 1  to 5 . This instrument was translated and validated in Brazil and has demonstrated to be a psychometrically adequate measure to assess the general factor of connection with nature in our environment .The Positive Affect/Negative Affect Scale (PANAS) and the Edmonton Symptom Assessment System (ESAS) were administered pre-and post-intervention to all intervention and control groups to assess the primary outcomes. The PANAS consists of 20 items that describe feelings and emotions and assess a person’s positive and negative traits using a 5-point scale . Higher scores on Positive Affect indicate greater intensity of positive emotions, and higher scores on Negative Affect indicate greater intensity of negative emotions . This quThe Edmonton Symptom Assessment System (ESAS) addresses ten common symptoms: pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, sleep, and shortness of breath. The severity at the time of assessment of each symptom is rated from 0 to 10 on a numerical scale; with 0 meaning that the symptom is absent and 10 that it is the worst possible severity. For all items, the higher the score, the worse the symptoms . ESAS isAssessments from the intervention and control groups were collected as follows: participants filled out pre-questionnaires before the session and post-questionnaires after a 20-min interval.The control group did not receive any media or other material. In the intervention group, following the initiation of the chemotherapy infusion procedure, a research team member provided a tablet  exclusively designated for the study and with the other functions restricted. The participant watched a 12-min video on the tablet in a private and comfortable environment, primarily within the room/bed where chemotherapy was administered.The video watched by the participant was randomly selected from four different options: Beauty, Emotions Up, Tranquility, and Miscellany. Each video consisted of 60 images pre-selected from the e-NatPOEM database , which wThe 240 distinct images (60 for each video) were pre-selected from the e-NatPOEM according to the criteria below. The corresponding images can be found in Beauty: related to awe/fascination. Includes white and colorful birds, insects, flowers, and landscapes. Valence range: 6.9–7.8; Arousal range: 3.1–4.2.Emotions Up: related to joy and liveliness. Includes water, pale birds, colorful birds, sky, insects, and sea. Valence range: 5.8–8.0; Arousal range: 3.3–5.6.Tranquility: related to peace and calm. Includes water, sky, and sea. Valence range: 6.6–8.0; Arousal range: 2.8–4.2.Miscellany: includes water, trees, white birds, colorful birds, sky, flowers, insects, and landscapes. Valence range: 5.3–7.5; Arousal range: 3.0–6.1.It is worth emphasizing that both groups received identical standards of care and treatment throughout the study, adhering to the criteria set by the Joint Commission International  and MagnThe calculation of the Connectedness to Nature Scale followed the recommended procedure outlined in a previous study that evaluated the psychometric properties of the Brazilian version . This inVariables were described in total and by groups using absolute frequencies and percentages for qualitative variables, and means, standard deviations, and minimum and maximum values for quantitative variables. Changes in symptoms on the Edmonton Scale were described by individual profile graphs.p-values for moment or group comparisons, which were corrected using the sequential Bonferroni method.To compare between groups and timepoints, we used the generalized estimation equation models , which cTo evaluate the relationship between the Connectedness to Nature Scale and changes in positive and negative affect over timepoints, we used generalized linear models with a quasi-likelihood distribution, in order to adequately fit positive and negative changes, without normal distribution.We analyzed data from 173 individuals: 32 in the Control group (18.5%), 33 in the Miscellaneous group (19.1%), 39 in the Tranquility group (22.5%), 33 in the Emotions Up group (19.1%), and 36 in the Beauty group (20.8%). Overall, 81.5% of the sample received some intervention. Most participants were from Brazil (93.6%), born and currently living in urban areas . Participants’ characteristics are presented in The mean age was 57 years, ranging from 22 to 90 years. The distribution by sex was 56.6% female, and the most frequent marital status was married. Regarding education level, 48.6% had completed undergraduate studies, and 33.5% had completed graduate studies.Intentional contact with nature was reported as daily by 41% of participants, with 6.4% reporting just once a year. The Nature Connection Scale had a concentration in higher scale values, indicating a general high nature connection among participants.A wide range of diagnoses was observed, with the most frequent being digestive system cancer (27.8%), followed by hematologic (21.0%) and reproductive system (20.9%) cancer. The current chemotherapy session number was an average of ten. The chemotherapy session at the time of the study was reported as the first for 41.0% of the participants, while the others were on average in their tenth session.Regarding the time since diagnosis, 25.4% reported knowing about the disease between 3 and 6 months ago, as well as between 1 and 5 years ago. The estimated treatment time exceeded three months for more than 90% of the participants .We compared the intervention groups and control group regarding negative affect at pre- and post-moments, and identified a significant reduction in all groups, including the control group . FeelingThe largest reduction, as indicated by estimated mean values and graphs, was observed in the Miscellany group . When coWe compared the intervention and control groups regarding symptoms at pre- and post-intervention moments and identified a reduction in the intensity of most symptoms .When considering pain, fatigue, sadness, anxiety, and appetite, there is evidence of significant improvement in symptoms across the entire intervention group. When evaluating the groups separately by an intervention video , we obseThe present study assessed the therapeutic potential of nature image viewing in terms of its impact on cancer patients’ positive and negative affect, as well as the clinical symptoms associated with chemotherapy.Anxiety is one of the most prevalent mood states during cancer treatment, related to the diagnosis and treatment itself, fear of metastasis, the unpredictability of physical suffering, and the future. In comparison to the general population, cancer patients exhibit lower levels of positive emotions, as evaluated by PANAS. However, there is no significant difference in the prevalence of negative emotions, indicating similarity in negative emotional experiences . The psyThe PANAS scores for positive affect, as evaluated in our study, were approximately 25% higher both before and after the intervention, compared to patients with advanced cancer, or even the general population [All intervention groups experienced a significant reduction in negative affect. The main negative affect states that showed significant decreases included feelings of fear, nervousness, distress, restlessness, and upset. The control group also showed moderate evidence of reduced negative affect, including anxiety evaluated by the ESAS. This effect can however be expected at the end of a chemotherapy session that has transpired without complications for the study participants.Regarding video content, it is worth noting that the largest reduction in negative affect occurred for the miscellaneous video.The video contents also influenced clinical symptoms in a differentiated manner. The best-performing was the Beauty video, which reduced pain most significantly but also improved sadness and anxiety, and improved well-being and shortness of breath. Beauty is a psychological sensation perceived as a sensory impression; this sensation is pleasant and positive, which can alter the perceptual focus of pain and reduce stress and anxiety by modulating attention as well as higher-order cognitive and emotional processes .The Emotions Up video altered the perception of pain, fatigue, anxiety, and appetite. Surprisingly, the Tranquility video, consisting mainly of images of the sky and sea, with low scores of arousal, had no impact on the participants (note that even the control group showed a reduction in anxiety). This may have occurred because although the images individually evoked feelings of peace and tranquility, but when proposed in the same video, they may have become monotonous in the face of the same predominance of color and theme.Another possibility is that, similarly to what happens with experiments that use music to induce emotions, the ISO  principle may also affect visual stimuli. The ISO principle states the importance of inducing emotional changes gradually. This involves starting with music related to the subject’s initial emotion and smoothly transitioning to subsequent emotion stimuli, ultimately achieving the desired emotion. This implies that abrupt emotional shifts induced by external stimuli are not readily accepted by individuals. Therefore, it is important to modulate the induced emotions . The feeThe Miscellany video reduced fatigue, sadness, and anxiety, and presented the best performance in reducing the negative affect as assessed by PANAS. The miscellany video was compounded by different nature categories, which may confer greater mental fluctuation, without a more specific emotion or experience. Combining these diverse images may have exerted a more realistic and comprehensive result, resembling the broader experience of nature rather than the repetition of a few specific natural elements. The inclusion of elements such as working ants, butterflies, flower-filled paths, and landscapes could promote a sense of proximity and familiarity, while the vibrant colors used in the images might have influenced the perception of fatigue, making them more visually appealing. Additionally, these images presented together also gathered a variety of attributes, such as light, heat, attention, alertness, strength, curiosity, and lightness, among many others mentioned in .In the Emotions Up video, the images also comprised a thematic diversity, which may have favored distraction through the stimulation of visual neurons. Among the mechanisms related to pain relief, distraction and alteration of perceptual focus have been emphasized. These mechanisms can result in the release of endorphins, resulting from both pleasure sensations and positive memories. The brain processing of images permeates all these mechanisms. Positive emotions can help maintain a positive psychological state and neutralize negative situations, including painful experiences . Visual Reduction of the negative affect observed in the control group may have been influenced by the researchers’ contact with the patients during data collection, potentially impacting the patients’ relaxation levels. Social contact provides a sense of connection and support, alleviating loneliness and fear. Additionally, social interactions serve as a distraction from the stress and discomfort associated with treatment, promoting a more positive emotional state. Social contact also provides a sense of normalcy and helps patients maintain a connection with the outside world, offering emotional comfort, and encouragement, and enhancing resilience ,31. An uFatigue is another symptom that is quite prevalent among patients receiving venous or oral chemotherapy. Researchers have shown that viewing nature photos for just six minutes provides a quick and temporary boost, similar to caffeine, improving executive attention in young and old adults, with a restorative influence in older adults who tend to tire more easily and experience more fatigue .A comparative study between forest photos presented on a conventional screen and urban photos presented in 360° format demonstrated that forest photos, regardless of the presentation format, are more effective in preventing mood disturbances compared to urban immersive 360° photos .Photographs, art, and virtual reality (VR) have been recommended in numerous studies as distraction interventions to alleviate patient anxiety in various clinical situations ,34,35. DResearchers investigated two virtual environments that simulated nature scenes, including a blue sky and a green field that participants could explore. During the tour, a voice instructed the user and told stories to evoke specific emotions, significantly decreasing negative mood scores and increasing positive mood after four brief 30-min sessions . Our finNature images offer more than just a distraction technique; they engage mechanisms related to aesthetic appreciation. Aesthetic experiences keep the observers focused on the moment, making room for perceived sensations and emotions provoked by the beauty of what is being observed . This aeThe implication of the presented study for the field of care assistance is the potential to offer patients a low-cost resource that provides both pleasure, through nature-related well-being images, and the ability to increase positive affect and reduce negative affect during chemotherapy. Furthermore, within the education field, it provides an opportunity to foster discussions among healthcare professionals in training about novel care practices characterized by lightweight technologies, such as the one presented in this study.One possible limitation of the findings is that the study was conducted in a single oncology service of a private hospital. Additionally, during data collection the number of refusals to participate was considerable, and many patients reported that this was the moment they had to rest or spend time talking to their companion, or that they preferred to pay attention to the medication infusion process.Future research should focus on applying the proposed intervention in other organizational contexts. The aim is to assess its effectiveness in different patient settings, encompassing various procedures, health facilities, and populations.The videos called Beauty, Emotions Up, and Miscellany, composed of positive emotion-inducing nature images from the e-Nature Positive Emotion Photography Database (e-NatPOEM) , showed The Tranquility video unexpectedly showed no influence on the evaluated clinical and psychological outcomes.


The human leukocyte antigen (HLA) has been linked to the majority of autoimmune diseases (ADs). However, non-HLA genes may be risk factors for ADs. A number of genes encoding proteins involved in regulating T-cell and B-cell function have been identified as rheumatoid arthritis (RA) susceptibility genes.In this study, we investigated the association between RA and single-nucleotide polymorphisms (SNPs) of co-stimulatory or co-inhibitory molecules in 124 RA cases and 100 healthy controls without immune-related diseases .p = 0.038); rs3181096 of CD28 ; rs11571315 , rs733618 , rs4553808 , rs11571316 , rs16840252 , rs5742909 , and rs11571319 of CTLA4 ; and rs10204525 , rs2227982 , rs36084323 , and rs5839828 of PDCD1 .The results showed that there were 13 SNPs associated with RA, including rs181758110 of TNFSF4 (CC vs. CT, Consequently, these SNPs may play an important role in immune regulation, and further research into the role of these SNPs of immune regulatory genes in the pathogenesis of RA is required. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease (AD) in which the immune system attacks the joints as a result of abnormal autoimmunity. The prevalence rate of RA ranges from 0.24% to 1% of the global population  is a common genetic variation that is often used as a genetic marker in the study of genetic diseases. Moreover, genetic polymorphisms can be used as prognostic markers for the prognosis of RA. However, SNP combinations in genomes differ from person to person, particularly among ethnic groups. Although foreign teams have investigated the association between ADs and immune regulatory genes, it is still unclear whether the susceptibility of SNPs applies to Taiwanese people. Therefore, studying disease SNPs for specific ethnic groups remains worthwhile.In this study, 124 patients with RA and 100 subjects without immune abnormalities were recruited. All patients and healthy subjects were asked to sign informed consent forms before we collected their peripheral blood samples, and all procedures were performed in accordance with the applicable guidelines and regulations. The study was approved by the Institutional Review Board (IRB) of Chang Gung Memorial Hospital . The inclusion criteria of RA were based on the RA classification criteria . In addiThe genomic DNA was first extracted from peripheral blood samples using the QIAamp DNA Blood Mini Kit . The concentration and purity of DNA were then determined using a NanoDrop ND-1000 UV–Vis Spectrophotometer  in preparartion for the subsequent PCR. This study focused on the TNFSF4 gene on chromosome 1 and the CTLA4, CD28, and PDCD1 genes on chromosome 2. Because ADs can result from abnormal co-stimulatory and co-inhibitory molecule expression levels  and SNP https://www.broadinstitute.org/haploview/haploview).First, the Hardy–Weinberg equilibrium (HWE) was used to examine the allele frequencies of each SNP in the control group. For statistical analysis, the chi-square test and Fisher’s exact test were performed using SPSS17.0 software. The allele with the highest frequency in the population recruited for this study was designated as major allele “A” and the other as minor allele “a”. In genotype analysis, the homozygous of major allele (AA) was defined as reference, and the homozygous model (AA vs. aa), heterozygote model (AA vs. Aa), additive model (AA vs. Aa vs. aa), dominant model (AA vs. Aa + aa), and recessive model (AA + Aa vs. aa) were evaluated. The significance level was set at α = 0.05, and the odds ratio (OR) with 95% confidence interval (95% CI) was provided. D was used to estimate linkage disequilibrium (LD) by comparing the observed and expected frequency of a haplotype involved in alleles from different loci. Gabriel et al.  defined In this study, 124 patients with RA were recruited, with 101 (81%) women and 23 men (19%). Their onset age was 45.69 ± 1.22 years old. Moreover, 100 people with no immune abnormalities were included in this study, with 74 (74%) women and 26 men (26%), and their average age was 32.1 ± 8.9 years old. The clinical characteristics of all patients are summarized in HWE equilibrium was used to determine whether the control group included could accurately represent the entire population. The findings revealed that rs28718975, rs28541784, rs201801072, rs200353921, and rs1290180288 of CD28 gene and rs945677329, rs56217811, rs980967681, and rs55696217 of CTLA4 gene deviated from HWE. Because subsequent analyses of these SNPs had low confidence, they were not analyzed and discussed Table 4.The genotype frequencies of SNPs located in four genes—TNFSF4, CD28, CTLA4, and PDCD1—were compared between patients with RA and healthy controls in this study. On the basis of the results, 13 SNPs were associated with RA. One was in the TNFSF4 gene, one in the CD28 gene, seven in the CTLA4 gene, and four in the PDCD1 gene Table 5.The genotype frequency of rs181758110 in the TNFSF4 gene differed significantly between RA cases and healthy controls . In rs181758110, all RA cases had the CC genotype. rs3181096 in the CD28 gene was associated with RA in the homozygous model  and recessive model . This meant that people with TT genotype were less likely to develop RA than people with the CC genotype or at least one C allele (CC and CT). Thus, the C allele would be a risk allele for RA.Only one of the seven significant SNPs in the CTLA4 gene, rs11571319, was in the 3′UTR, whereas the other six SNPs were in the promoter region. On the basis of the heterozygous model, rs11571315 was associated with RA . Subjects with the CT genotype in rs11571315 had a lower risk of developing RA. The rs733618 was associated with RA in a recessive model , which meant that subjects carrying the CC genotype had a 1.929 times higher risk of developing RA than subjects carrying at least one T allele (CT and TT). The genotype frequency of rs4553808 was associated with RA based on the additive model . The rs11571316 was associated with RA based on the additive model , heterozygous model , and dominant model . The rs16840252 was associated with RA based on the additive model  and heterozygous model . The genotype frequency of rs5742909 was associated with RA based on the additive model . rs11571319 in the 3′UTR was associated with RA based on all the analysis model. The genotypes of patients with RA and healthy controls differed significantly . In comparison with GG, subjects with AG had a lower risk of developing RA , whereas subjects with AA had a higher risk of developing RA . In addition, when compared with AG + GG, patients with AA had a higher risk of developing RA .Four SNPs in the PDCD1 gene were associated with RA. rs10204525 was associated with RA based on the heterozygous model  and dominant model . In comparison with the AA genotype, subjects with GG at rs2227982 had a 2.171 times increased risk of developing RA . The genotype frequencies of rs36084323 were significantly different between RA cases and healthy controls based on the additive model , dominant model , recessive model , and homozygous model . Furthermore, the genotype frequencies of rs5839828 were significantly different between RA cases and healthy controls based on the additive model , dominant model , recessive model , and homozygous model .RA may be associated with a specific haplotype because of the differences in prevalence and susceptible SNPs in different populations. Therefore, the haplotype analysis was performed after the SNP analysis.In LD analysis, the red color in the box indicates that two SNPs have strong linkage, whereas the less the linkage, the closer to the white color of the box, and the light purple indicates no linkage. In addition, the high LD region is referred to as a haplotype block. According to In addition to investigating the association between SNPs and the development of RA, the association between SNPs and immunological parameters was also been explored. There were three SNPs associated with rheumatoid factor (RF), one SNP associated with anti-cyclic citrullinated peptide antibody (ACCP), and eight SNPs associated with C-reactive protein (CRP) Table 7.The three SNPs associated with the presence of RA were in the CTLA4 gene. rs11571315 was associated with RF based on the recessive model , which meant that the patients with CC genotype in rs11571315 had a lower odds of RF compared to the patients with at least one T-allele (TT and TC). rs4553808 was associated with RF based on the recessive model . rs231775 was associated with RF based on the additive model  and recessive model .rs41386349 of the PDCD1 gene was associated with ACCP based on the dominant model . Compared to the GG genotype, patients with RA with at least one A-allele in rs41386349 had 2.667 times of odds of ACCP.There were three SNPs of the CD28 gene, three SNPs of the CTLA4 gene, and two SNPs of the PDCD1 gene associated with CRP. rs3181096 of the CD28 gene was associated with CRP based on the additive model , dominant model , and heterozygous model . rs3181098 of the CD28 gene was associated with CRP based on the additive model , dominant model , and heterozygous model . rs28688913 of the CD28 gene was associated with CRP based on the dominant model , and heterozygous model . rs733618 of the CTLA4 gene was associated with CRP based on the additive model , recessive model , and heterozygous model . rs11571316 of the CTLA4 gene was associated with CRP based on the additive model , dominant model , and heterozygous model . rs3087243 of the CTLA4 gene was associated with CRP based on the additive model , dominant model , and heterozygous model . rs2227981 of the PDCD1 gene was associated with CRP based on the additive model , dominant model , and heterozygous model . rs6705653 of the PDCD1 gene was associated with CRP based on the dominant model  and heterozygous model .SNP analysis revealed that one SNP of the TNFSF4 gene, seven SNPs of the CTLA4 gene, one SNP of the CD28 gene, and four SNPs of the PDCD1 gene were associated with the onset of RA. We also investigated the association between the SNPs and immunological parameters of patients with RA. It is well known that RF and anti-citrullinated protein antibodies (ACPA) are the characteristic autoantibodies of RA. ACCP is a subset of ACPA, which has been demonstrated that it has 65%–80% sensitivity and up to 98% specificity for RA . CRP plaWe found that rs181758110 in the promoter region of the TNFSF4 gene was associated with RA, and no SNPs of the TNFSF4 gene were associated with the characteristic autoantibodies of RA, which denotes that rs181758110 of the TNFSF4 gene may not be a major SNP that contributed to the pathogenesis of RA. There is currently no relevant research on this SNP, and its function needs to be verified.rs3181096 in the CD28 gene promoter region was associated with RA and CRP in our results. rs3181096 had been previously associated with other ADs and cancers, such as type 1 diabetes  and chilResults showed that rs11571315 was not only associated with the onset of RA but also is RF-positive. However, after a thorough search of the literature, it was found that no other team has yet discovered the correlation between rs11571315 and RA, suggesting that rs11571315 was the RA-associated SNP specific to the Taiwan population. However, rs11571315 was susceptible to other immune disorders, such as transfusion reactions  and polyMoreover, haplotype analysis revealed six SNPs with high LD in the CTLA4 gene, including rs11571316, rs62182595, rs16840252, rs5742909, rs23177, and rs3087243. These six SNPs were found to be significantly associated with RA in several haplotypes. Although rs62182595, rs231775, and rs3087243 did not show a statistically significant association in individual SNP analysis, they did in haplotype analysis. This suggested that there could be an interaction between these SNPs that cause RA. Thus, the function of the RA-predisposing CTLA4 haplotype needs to be investigated further.Following a review of the literature, it was found that these RA-associated SNPs were also related to other ADs and cancers, suggesting that these SNPs play a vital role in the immune response. In addition, we found that the association of several SNPS with RA risk was dependent on RF, ACCP, and CRP status. These immune regulatory genes are involved in the regulation of T-cell activation , and mosIn this study, we did not thoroughly investigate the entire genome. Because T-cell activation is regulated by the additive effect of co-stimulatory and co-inhibitory molecules and promoter SNPs can affect gene expression, the promoter region of genes was extensively discussed in this paper. Furthermore, the hot SNPs from many kinds of literature about ADs or cancers were selected as candidate SNPs for discussion.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The studies involving human participants were reviewed and approved by institutional review board (IRB) of Chang Gung Memorial Hospital . The patients/participants provided their written informed consent to participate in this study.D-PC conceived and designed the experiments. Y-HW reviewed and wrote the final draft. W-TL and FP-H performed the experiments and analyzed and interpreted data. K-HY wrote draft of the manuscript and provided samples. All authors read and approved the final manuscript.