Assessment of Concerning Behavior (ACB) was introduced by Tarver et al. (2021) to evaluate mental health and problematic/risky behaviors in children and young people with autism spectrum disorder (ASD).This study examined the psychometric validation of the Assessment of Concerning Behavior (ACB) in an Iranian sample of parents of children and young people with ASD. Confirmatory factor analysis was conducted to examine the structure of ACB in a sample of 303 parents.The data supported the two factor structure, all factor loadings were significant and scale structure was confirmed similar to the original scale. The results supported the two-factor structure for ACB that included internalizing and externalizing problems scales. The two factors of ACB are positively correlated with Aberrant Behavior Checklist scores which showed that the validity of two factors is satisfactory. The reliability of the two subscales was reasonable as well.The study suggests that the ACB could be an operational tool to assess the mental health and problematic/risky behaviors in Iranian children and young people with ASD. Autism Spectrum Disorder (ASD) is characterized by impaired communication and social skills, as well as repetitive behaviors and restrictive interests, according to the American Psychiatric Association . It is eResearch has shown that individuals with ASD often exhibit concerning behaviors that can have negative impacts on their individual and social functioning in the long term . ConcernIn addition to the core symptoms of ASD, many children with ASD present with broader behavioral, emotional, and affective problems that require clinical evaluation and intervention. Lindor et al.  reportedSeveral studies in the literature have used Aberrant Behavior Checklist (ABC)  and the To the best of our knowledge, there is currently no informant-based questionnaire available in Iran to evaluate concerning behaviors in individuals with ASD. This study aimed to validate the parent/caregiver version of the Assessment of Concerning Behavior (ACB) questionnaire for parents of children and adolescents with autism. Tarver et al.  reportedIn our study conducted in Iran, we investigated the Persian version of the Assessment of Concerning Behavior (ACB) questionnaire as a new and favorable tool for clinical and research purposes in autism. The ACB is a mental health assessment scale designed for individuals with ASD and can be used for therapeutic, educational, and research purposes. It has diagnostic value, which can aid psychologists and clinical specialists in diagnosing and designing therapeutic interventions for individuals with ASD. We chose to examine the ACB questionnaire for several reasons. Firstly, it is a relatively new scale, developed in 2022, with good psychometric characteristics in the original sample, despite having fewer questions compared to other accessible scales. Moreover, the ACB questionnaire is capable of measuring a more comprehensive range of high-risk behaviors and coexisting symptoms compared to other questionnaires. Additionally, the ACB questionnaire is easy to use by parents and caregivers.We validated the parental version of the ACB questionnaire because, in the original study, the parental version had better validity and reliability compared to other versions. Additionally, parents are more accessible than children and adolescents with ASD, and they are the most reliable source for reporting psychological problems and seeking treatment for their children. By examining the reliability and validity of the ACB questionnaire in a sample of Iranian parents of individuals with autism, we established the psychometric properties of the ACB questionnaire in our studied population.In this study, the psychometric properties of the ACB questionnaire were investigated by translating the original version into Persian using a standardized translation procedure . Data weIn this study, the Assessment of Concerning Behavior (ACB) Scale  was usedParticipants were asked to match each item on the ACB questionnaire to their child/adolescent’s behavior over the past month, using a five-point Likert scale ranging from 1 (never true) to 5 . The ACB questionnaire includes two dimensions of internalizing and externalizing problems. Externalizing problems (items 1–19) include aggressiveness, control, and impulsivity, while internalizing behaviors (items 20–35) include withdrawal, depression, and anxiety. In Tarver et al.’s study, the Alpha values were 0.86 and 0.88 for the internalizing problems and externalizing problems subscale, respectively . Demographic information, including age, marriage age, socioeconomic status (SES), and the age of the child/adolescent, was collected. Six schools in four cities were purposefully selected to recruit parents of children with ASD, and these schools specialized in providing educational services to children with autism. The age range of the students whose parents participated in the study was between 6 and 15 years, with 41 girls (13%) and 263 boys (87%). Of the students, 223 (73.59%) were classified as requiring support, 73 (24.09%) as requiring substantial support, and 7 (2.31%) as requiring very substantial support. Children and adolescents with ASD who participated in this study were enrolled in schools dedicated to the education of individuals with autism. Before enrolling in these schools, all participants had received a diagnosis of ASD from a psychiatrist and a psychologist. The selected schools provided the parents’ information to the research team, who then contacted the parents and provided information about the purpose of the study. Informed consent was obtained from the participants before they completed the questionnaires, and they were informed that the data would only be used for academic purposes, and their personal information would be kept confidential.The participants in this study were parents of individuals with ASD who were selected through purposive sampling. Informed consent and questionnaires were completed in Persian. A total of 376 parents participated in the study. We excluded cases with inappropriate responses to the questionnaire and distorted questionnaires from the analysis. Inappropriate responses included those with missing or incomplete answers, and distorted questionnaires referred to responses that were highly inconsistent or contradictory. These criteria were applied based on established guidelines for data cleaning and quality control in psychological research. A total of 73 cases were excluded based on these criteria, resulting in a final sample size of This study was conducted in accordance with the ethical standards of the institutional research committee of the University of Hormozgan, Bandar Abbas, Iran, and with the 1964 Helsinki Declaration and its later amendments. No animal studies were conducted as part of this research. Informed consent was obtained from all participants involved in the study.α = 0.86–0.94) and test–retest correlation  were reported across the subscales (Aberrant behavior checklist (ABC) was developed by Aman et al.  to measuubscales , 25. Theχ2/df, approximation mean square error (RMSEA), and comparative fit index (CFI) were used as fit indices. The model fit was considered good based on the following criteria: a ratio of χ2 to degrees of freedom greater than 3, a Comparative Fit Index (CFI) of at least 0.90, an SRMR below 0.08, which is a commonly used cut-off for a good fit  was performed with the original 2-dimensional (2D) version of the ACB scale using Amos 24.0. The ratio good fit . ConvergThe means scores of the ACB items and other variables are presented in In this study, a confirmatory factor analysis (CFA) with maximum likelihood estimation was conducted to examine the factor structure of the ACB questionnaire. In confirmatory factor analysis (CFA), maximum likelihood (ML) is commonly used and assumes that the observed indicators follow a continuous and multivariate normal distribution. We tested three models: one factor, two factors, internalizing and externalizing models. The results indicated that all factor loadings were significant and that the scale structure was consistent with the original scale, with two dimensions of internalizing and externalizing problems subscales. The model fit indices, presented in To assess the reliability of the ACB questionnaire and its two dimensions, Cronbach’s alpha coefficients were calculated. Convergent validity was examined by investigating the correlation between ACB scores and ABC scores. The results showed a significant correlation between the internalizing and externalizing subscale subscales and ABC scores. The correlation coefficients and Cronbach’s alpha values are presented in The objective of the current study was to evaluate the psychometric properties of the ACB questionnaire in a sample of Iranian parents of individuals with ASD, and to establish an appropriate solution for this population. Additionally, we examined the association between ACB scores and a source of convergent validity (ABC scores). The research findings confirmed the validity and reliability of the ACB questionnaire. The results of the confirmatory factor analysis (CFA) supported the two-factor structure of the ACB, consisting of internalizing and externalizing problems subscales. This structure aligns with the current conceptualization of concerning behaviors, which includes both intrapersonal and interpersonal aspects, such as worrying  and hitting or hurting others  . The chaMoreover, the reliability of the internalizing and externalizing subscales was assessed through the calculation of Cronbach’s alpha coefficient, which indicated that these subscales had appropriate alpha coefficients. Additionally, the correlation of the internalizing and externalizing subscales with ABC scores provided evidence of convergent validity. The results showed a significant relationship between the ABC scores and the internalizing and externalizing problems subscales of the ACB. Overall, the analyses in our study confirmed the reliability and validity of the internalizing and externalizing subscales, which is consistent with previous research , 32.Despite the ACB being a valid tool for assessing the psychological problems of children and adolescents with ASD, there are some limitations to its use, particularly in versions designed for teachers and individuals with autism. The reliability and validity of the autistic children and young people version of the scale have been reported as less satisfactory, and low completion rates on the child and teacher versions are significant limitations. Autistic individuals may have difficulty understanding the scale items due to cognitive and communication limitations, making it difficult to obtain accurate responses. Conversely, parents and caregivers of individuals with ASD spend the most time with them and are a credible source of information for evaluating their mental health. The Persian version of the ACB has the potential to provide a comprehensive assessment of concerning behaviors in individuals with ASD, which can assist psychologists and clinical professionals in developing treatment and educational interventions to improve their mental health.The developers of the ACB conducted analyses to explore the relationships between scores on the ACB scales and the sex and age of individuals with ASD and found no differences in parent-reported externalizing behavior on the ACB based on sex. Similar to the original developers of the scale, we believe that the ACB is suitable for use across the age-span, particularly for individuals between 7 to 29 years old. However, it is recommended that future studies investigate the appropriateness of the ACB for different age and IQ groups.The findings of our study have significant implications for scholars and practitioners as it provides a simple and psychometrically comprehensive tool for measuring concerning behaviors in children and young people with ASD. Additionally, this scale can be used to examine the relationship between concerning behaviors and other psychological and emotional constructs in individuals with ASD. Future studies could investigate the relationship between concerning behaviors and parenting stress, self-regulation problems, and academic outcomes. Furthermore, the ACB can be used to assess the effectiveness of interventions aimed at improving the mental health of individuals with ASD. To increase the generalizability of our findings, future studies could examine the validity of the ACB using exploratory factor analysis (EFA).Although significant information is provided in this study, however, there are some limitations to our study. Firstly, our sample comprised Iranian parents of individuals with ASD, and caution should be exercised when generalizing the findings to other populations. Secondly, data collection was conducted online, and participants answered the questionnaire voluntarily, which may introduce bias. Finally, our study only examined the ACB’s convergent validity with ABC scores, and future studies could investigate its divergent validity by studying its correlation with variables such as social skills, well-being, and happiness.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Hormozgan University. The patients/participants provided their written informed consent to participate in this study.KM, AS, FZ, and SAS: conception and design. SAS and FZ: data collection, KM, AS, FZ, and SAS drafting manuscript, and agreeing final submission. SAS: data analysis. KM and AS: interpretation of results. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The reviewer KH declared a past co-authorship with the author AS to the handling editor.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 aim of the ‘Pathways to Independence’ study was to gain knowledge of how to facilitate a healthy development for unaccompanied refugee minors (URMs) after settling in Norwegian municipalities.The project is located in the URM child welfare services (URM CWS) of the Bergen municipality. We invited 101 URMs older than 15 years connected to the URM CWS to participate in a comprehensive survey. Of the invited, 81 consented to participate. The survey included questions on the user’s experiences and satisfaction with the URM CWS, and questions related to schooling, social support and activities after settlement. We also included standardized and validated questionnaires on potential traumatic events, mental and somatic health, protective factors and quality of life. These questionnaires have previously been used in two Norwegian epidemiological studies, the ‘Youth@Hordaland’ and ‘Young in Foster care’, facilitating comparison of the results with other youth populations in Norway.Results from the project will be valuable in the process of reaching knowledge-based recommendations for successful settlement of URMs. The large number of refugees seeking asylum in Norway in 2015 led to a mobilization of the Norwegian municipalities to increase the rate of settlements. A large portion of these refugees was unaccompanied minors, with 5480 applying for asylum in Norway in 2015 .URM refers to children younger than 18 years at arrival that have fled their country of origin without their parents or other legal guardians to seek protection and asylum in a new country . URMs arThere has been an increasing number of studies into the mental health of URMs settled in high-income countries. Results suggest that the URMs are particularly vulnerable in terms of a high burden of mental health problems such as depression, anxiety and post-traumatic stress, and that these mental health problems persist after settlement –11. A loA recent systematic review finds that supportive living arrangements and less restrictive settings are important factors to promote psychological resilience and improved mental health in URMs after settlement . MoreoveIn Norway, municipalities differ in how they organize the settlement work with the URMs. Most organize this work within the child welfare services (CWS) but some lay the responsibility at other agencies, such as refugee agencies. It is reasonable to believe that the content and quality of the services will be important determinants of a successful transition for the URMs to an independent life in Norwegian society. Still, many point to the fact that there is a lack of systematic knowledge of how municipalities can contribute to a healthy development for URMs during settlement ,3. In thThe overall aim of the ‘Pathways to Independence’ study was to gain knowledge on how to facilitate a healthy development for URMs after settling in Norwegian municipalities. We conducted a comprehensive survey in URMs settled in Bergen municipality including questions related to experiences and satisfaction with the URM CWS, schooling, social support, and activities after settlement, in addition to standardized and validated questionnaires on potential traumatic events, mental and somatic health, protective factors and quality of life. Based on the results from the survey and subsequent processes in the URM CWS, the overall purpose was to make knowledge-based adjustments to the services provided to the URMs. The main objective of the current paper was to describe the design and procedures of the survey.The ‘Pathways to Independence’ study consist of a comprehensive survey conducted among URMs settled in Bergen municipality and co-ordinated by the URM CWS in the municipality. The city of Bergen is the second largest city in Norway, with close to 300,000 inhabitants. Settlement of refugees has over time been a prioritized area in the municipality, and settlement of URMs has been a part of the municipal CWS for the last 20 years. The URM CWS has the sole responsibility for settlements of URMs in the city of Bergen. Their services include both case work and placements in foster homes, institutions, joint homes, host families and private housing with or without follow up. Each URM has close contact with their case worker at the URM child welfare agency, and services may be offered until the URM turns 25 years.All URMs 15 years or more associated with the URM CWS in Bergen municipality were invited to participate in the study, and we included all who were 15 years or older and consented to participate in the study. For participants younger than 16, consent was also obtained from their legal guardian. From the target population of 116 URMs, 10 were considered ineligible to participate due to evasive behaviour and poor mental health, three were excluded due to inability to provide the participants with proper follow-up after the survey (participants living in other parts of the country), and two were excluded due to lack of capacity of the case worker. Hence, the number of invited URMs was 101 of which 81 consented, yielding a participation rate of 80%. Demographic information of the participants is provided in The enrolment and data collection lasted from December 2018 to January 2019. The case workers at the URM CWS were responsible for inviting the URMs to participate in the study and to schedule a time to complete the comprehensive survey administrated online using Qualtrics Survey Software. The URMs completed the online questionnaire at the case worker’s office. URMs were first provided with written and oral information about the study and consented to participate on the first page of the questionnaire, after going through the information thoroughly with the case workers. The case workers were present and available for questions and queries while the URMs filled in the survey but were instructed to not look at the participants’ responses. Six of the participants used an interpreter due to lack of knowledge of the Norwegian language. Case workers clarified words and sentences that the URMs found difficult to understand if an interpreter was not used. Participants used between 1.5 to 3.5 hours to complete the survey.https://www.norceresearch.no/prosjekter/barn-i-bergen) and ‘Young in Foster care’ (https://www.norceresearch.no/prosjekter/fosterbarns-psykiske-helse), thus facilitating comparisons of the URMs’ responses to youth from a general population and youth in foster care in Norway.The survey was developed particularly for this study and included a total of 213 questions. These questions were related to background information  and the number of times the URM had moved after settlement), the URMs’ experience and satisfaction with the URM CWS, their schooling experiences, perceptions of social support and participation in activities after settlement. In addition, we included standardized and validated questionnaires measuring exposure to potential traumatic events, symptoms of mental health problems and somatic complaints, sleep patterns and problems, protective factors, quality of life and acculturation strategies  as a compensation for their participation.The project was approved by the Regional Committee for Medical and Health Research Ethics of Western Norway (REK-Vest) (2018/966) and conducted in accordance with recommendations from the Norwegian Data Protection Services. Participation in the study was voluntarily, and the participants could withdraw from the project at any time. All participants received a gift certificate of 300 NOK . Still, a notable weakness is the relatively few participants, in particular females, which restricts the potential for doing bi- and multivariate analyses and subgroup analyses to identify specific associations with, for example, country of origin and sex. Moreover, questionnaires were in Norwegian and many of the topics could have a culturally specific character that may be difficult to transfer across cultures. Using common questionnaires with that of other studies in important comparison groups in Norway is a unique asset of this study. It could be argued that the presence of the case workers whilst conducting the study, particularly during the completion of the survey, could bias responses to some questions. Still, through close discussion in the project group and with the ethical board, it was decided that the case workers were important measures to secure a safe situation for the URMs when answering potentially emotionally challenging questions.The dataset is administered by Regional Centre for Child Mental Health and Welfare, West (RKBU-Vest), NORCE Norwegian Research Centre. Researchers are invited to contact the project leader (first author) for enquires regarding collaboration. Approval from a Norwegian regional committee for medical and health research ethics and the Norwegian data protection services is a pre-requirement.


Diagnosis-Related-Group (DRG) payment is considered a crucial means of addressing the rapid increases of medical cost and variation in cost. This paper analyzes the impact of DRG payment on variation in hospitalization expenditure in China.Z were selected. Patients in the fee-for-service (FFS) payment group and the DRG payment group were used as the control group and intervention group, respectively, and propensity-score-matching (PSM) was conducted. Interquartile distance (IQR), standard deviation (SD) and concentration index were used to analyze variation and trends in terms of hospitalization expenditure across the different groups.Patients with chronic obstructive pulmonary disease (COPD), acute myocardial infarction (AMI) and cerebral infarction (CI) in a Chinese City Z decreased by 11,094, 4,833 and 4,987 CNY, respectively. The concentration indices of hospitalization expenditures for three diseases are all below 0 , with the absolute value tending to increase year by year.After DRG payment reform, the SD of hospitalization expenditure in respect of the COPD, AMI and CI patients in City DRG payment can be seen to guide medical service providers to provide effective treatment that can improve the consistency of medical care services, bringing the cost of medical care closer to its true clinical value. Poor.  analyzed. [.  report t. [. . Such hi. [. –10.It can be observed that medical costs in China have increased at a very high rate and in a way that has also given rise to significant variation in medical costs. Between 2007 and 2012, China’s real per capita health expenditure grew by 14.9% annually, with per capita GDP growing by only 10.2% . The resAt present, many low-and middle-income countries (LMICs) are actively introducing Diagnosis-Related-Group (DRG) payment as a means of controlling medical costs and helping more patients to receive standardized medical care service. Since 2010, DRG payment pilot programs have been carried out in a number of cities in China. Theoretically, under the DRG payment model, doctors are more motivated to implement necessary treatment in accordance with clinical guidelines, which will have an impact on the incentive to save on medical costs , 18, inhThis paper aims to analyze the impacts of DRG payment on variation in medical costs in China, and evaluate the role of DRG payment system design in regulating medical care service. Consequently, practical evidence will be provided for other LMICs introducing models grounded in DRG payment.Z began to implement DRG payment reform in 2012. Six tertiary first-class public hospitals were selected as the pilot, in which all discharged cases were in DRG payment, while the remaining hospitals were still in FFS payment. In addition, during the period 2010–2016 that this study focused on, there were no other policies implemented that might affect hospitalization expenditure. The data were collected from a medical insurance database relating to policyholders of the urban employee basic medical insurance (UEBMI) in City Z. These data included information on variables such as patients’ basic demography (age and gender), primary diagnosis, secondary diagnosis, and hospitalization expenditures . The reform of this city’s DRG payment system was implemented in 2012. In order to avoid being influenced by the introduction of another policy affecting medical expenses, which was named the cancelling of drug mark-up costs issued in 2017, only data from 2010 to 2016 were considered. In terms of how this seven-year period can be broken down, 2010–2011 was the period before reform of the DRG payment, and the period 2012–2016 represents the situation following reform in DRG payment. In terms of research objects, we select patients with chronic obstructive pulmonary disease (COPD), acute myocardial infarction (AMI) and cerebral infarction (CI) to reflect the variation in hospitalization expenditure for both internal and surgical diseases on the basis that these conditions have clear clinical guidelines, feature in a high number of cases, and tend to incur high medical costs . The Charlson Comorbidity Index (CCI) was used to evaluate the severity of each given patient’s condition, with CCI ≤ 1 indicating a low level of severity. All cost data were used to eliminate the impact of inflation through the urban consumer price index (CPI) given on the official website of the Chinese Bureau of Statistics.City Z have implemented DRG payment, and all other medical institutions in this city continue to operate using pay on FFS payment. The intervention group was taken to comprise patients with COPD, AMI and CI in the six former hospitals, while the control group was taken to comprise patients from the other hospitals. The intervention group and the control group were matched by 1:1 propensity-score-matched (PSM) year after year. To exclude the influence of individual differences on the outcome, the propensity score was obtained by logistic regression of the patients’ age, gender, and CCI. The Caliper value of the matching accuracy was 0.02.Six hospitals in City The study was conducted to compare the variation in the trend of hospitalization expenditure in respect of the intervention and control groups before and after the implementation of the DRG payment. The degree of variation was taken to be represented by the interquartile range (IQR) and standard deviation (SD). The smaller the value, the more concentrated the distribution of hospitalization expenditures. The calculation formulas of IQR and SD are shown in  and 2)..2).1\docQ3, x.75andQ1, x.25 respectively represent the hospitalization expenditure of the third and first quartile, P values were calculated. The calculation formula for concentration index is shown in , being 5972 CNY more than that in the control group.In relation to AMI patients, following the DRG payment policy reform, the SD of hospitalization expenditures in the intervention group decreased by 2,483 CNY more than that of the control group. And, in 2013, the magnitude of the decrease grew to 4,112 CNY more than the control group. Although the SD of hospitalization expenditure in the intervention group increased year on year from 2014 to 2016, the absolute value was still smaller than that of the control group.Finally, in relation to CI patients, there was no corresponding main diagnosis in the database in 2010, and only the results from 2011 to 2016 could be considered. It can be seen that the SD of hospitalization expenditures in the intervention group continued to decline following the DRG payment policy reform, with all decreasing more than the control group in other years except 2014.Figure For COPD patients, after the DRG payment reform, the IQR of the intervention group can be seen to be smaller than that for the control group in each year. The declining trend of the IQR was the most obvious in the first year after the reform, and the median of hospitalization expenditure can be seen to be lower than the fixed level of DRG payment. In the control group, there is no obvious decreasing trend in terms of the IQR, and there is little difference between the median hospitalization expenditure and the fixed amount, which is higher than the intervention group.For CI patients, the IQR of hospitalization expenditure in the intervention group decreased significantly following the DRG payment reform, and the IQR in all years can be observed to be smaller than those relating to the control group. From 2013, the median hospitalization expenditure is lower than the fixed level of DRG payment. For the control group, the IQR of hospitalization expenditure shows no downward trend, and the median hospitalization expenditure is always higher than the fixed level of DRG payment.For AMI patients, following the DRG payment reform, the IQR of hospitalization expenditure for the intervention group is smaller than that of the control group, most markedly in 2012 and 2013. The median expenditures of the two groups are both lower than the fixed level of DRG payment. The median hospitalization expenditure of the intervention group is lower than that of the control group and demonstrate a continuous downward trend.Table The results of this study show that, variation in hospitalization expenditures of both internal diseases (represented by COPD and CI) and surgical diseases (represented by AMI) decreased year by year after the implementation of the DRG payment system, while variation in hospitalization expenditures in FFS payment are witnessed to be significantly higher during the same period. This suggests that China’s DRG payment reform can motivate doctors to provide more standardized medical care service in a manner that may have contribution to reduce variation in medical care costs and improving the consistency of medical care service.Previous studies have shown that doctors’ behavior is a key factor in variation in medical costs. The average cost of a single type of surgical operation varies among different surgeons , and the. [Previous studies from developed countries have also provided evidence that variation in hospitalization expenditure decreases following the implementation of DRG payment, thus providing supporting evidence for the conclusions drawn in this study. In the United States, McMahon L and Newbold R  used a M.  analyzedThe present study also found that patients with AMI were associated with the smallest decrease in the degree of variation in terms of hospitalization expenditure both before and after DRG payment reform. This can be explained in terms of the point that the treatment of AMI is now relatively mature as a medical procedure, accompanied by an industry consensus and universal clinical guidelines as a means of standardizing doctors’ behaviors . It is oThe findings of this study illustrate the effectiveness and advantages of the DRG payment reform, and fully demonstrate its necessity. Most importantly, this study can provide convinced practical evidence and experience for LMICs which are trying to reform payment system to address the rapidly rising of medical care costs.There are two main limitations to highlight. First, due to the nature of the data, it is not possible to describe which specific services might have changed during the treatment process. Second, given the lack of data on quality of care, it is unclear whether the reductions in cost variability highlighted are also accompanied by a change in quality of care. These are points of interest that might be taken up in further studies.The Chinese data considered in this study provide evidence that DRG payment can help reduce variation in medical care costs, suggesting that providers are more likely to follow clinical guidelines and conduct effective treatment after taking the risk of overspending, with DRG payment bringing the cost of care closer to its true clinical value in a way that is not observed for FFS. This practical evidence from China gives confidence to other LMICs that seek to introduce DRG payment reform and proves advantages of DRG payment, which can help them design more scientific and efficient payment system. It should be borne in mind, however, that even with the introduction of DRG payment, quality monitoring will be necessary to prevent providers going to the other extreme of squeezing costs to the detriment of healthcare quality.


West Nile virus (WNV) is a flavivirus with an enzootic cycle between birds and mosquitoes; humans and horses are incidental dead-end hosts. In 2020, the largest outbreak of West Nile virus infection in the Iberian Peninsula occurred, with 141 clusters in horses and 77 human cases.We analysed which drivers influence spillover from the cycle to humans and equines and identified areas at risk for WNV transmission.Based on data on WNV cases in horses and humans in 2020 in Portugal and Spain, we developed logistic regression models using environmental and anthropic variables to highlight risk areas. Models were adapted to a high-resolution risk map.Cases of WNV in horses could be used as indicators of viral activity and thus predict cases in humans. The risk map of horses was able to define high-risk areas for previous cases in humans and equines in Portugal and Spain, as well as predict human and horse cases in the transmission seasons of 2021 and 2022. We found that the spatial patterns of the favourable areas for outbreaks correspond to the main hydrographic basins of the Iberian Peninsula, jointly affecting Portugal and Spain.A risk map highlighting the risk areas for potential future cases could be cost-effective as a means of promoting preventive measures to decrease incidence of WNV infection in Europe, based on a One Health surveillance approach. What did you want to address in this study?West Nile fever is a viral infection transmitted to humans and other animals via mosquitoes. Infections of West Nile virus are increasing in Europe and the disease has a considerable impact on human and animal health. We wished to explore the environmental conditions that influence the transmission of the virus to humans and horses and test the role of horses as indicators of the disease in humans.What have we learnt from this study?Data on West Nile virus infection in horses can be useful indicators of risks of human cases. In addition, river basins play an important role as places where outbreaks occur and spread.What are the implications of your findings for public health?Horses can be used as part of an integrated surveillance system focused on reducing the number of people and animals infected with the virus. Decision-making would be more efficient using river basins as management units, instead of political administrative units, for example to alert the health facilities after infected horses have been detected.West Nile virus (WNV) is a mosquito-borne arbovirus of the family Flaviviridae . The virEquines are particularly sensitive to WNV infection. In horses, neurological disorders are more common than in humans . NeuroloBased on data of 77 human cases and 141 clusters in horses notified in the 2020 season, we aimed to analyse the geographical distribution of cases of WNV infection in horses and humans and create a risk map of the Iberian Peninsula to visualise environmental and spatial patterns from a macroecological perspective. We wanted to test if equine WNV infection cases could predict risk areas for human cases, which could be useful to implement early warning mechanisms, improve planning of surveillance measures and develop prevention policies in at-risk areas before outbreaks occur.2, while the average surface area of parishes was approximately 20 km2. For the modelling, municipalities and parishes were considered the operational geographic units (OGUs) in the Iberian Peninsula.Spain and Portugal report cases of WNV infection in humans to the European Surveillance System (TESSy) operated by the European Centre for Disease Prevention and Control (ECDC). We listed all areas in Spain and Portugal where cases of WNV infection in horses and humans occurred during the transmission season of 2020. We used cases that were detected during passive and active surveillance: clinical cases that were serologically positive (IgM) or with the virus identified using reverse transcription (RT) . For datSupplementary table.We elaborated separate risk models for cases of WNV infection in horses and in humans. First, using univariate score tests for the presence or absence of cases of WNV infection, we assessed the capacity of different environmental variables to explain the distribution of cases. Variables were selected on the basis of their potential predictive power and were assumed to be at least correlated with more proximal causal factors. Mosquito data were not available, therefore we used water availability and temperature as proxies of mosquito presence. The variables used comprised different factors, such as density of the human and animal population, distance to roads, production of crops, forests, river, altitude and precipitation. A list of all factors considered can be seen in the We controlled multicollinearity among variables by calculating pairwise Spearman correlation coefficients. If two variables belonging to the same factor were correlated by more than 0.8, the least explanatory variable, according to the score tests, was deleted. Moreover, we controlled the false discovery rate to avoid an increase in type I errors due to the number of variables used in the analysis . TherefoWe evaluated the classification and discrimination capacity of the horse and human risk model. The classification power of the models, using a value of F = 0.5 as classification threshold, was estimated using the sensitivity, specificity, Cohen’s kappa and correct classification rate (CCR)  and the 2 squares using a direct downscaling approach [2 squares according to the variable values for the same spatial resolution. In this way, we elaborated a risk map covering the entire Iberian Peninsula uniformly and at a high spatial resolution. Spatial analyses and the map display were elaborated using the geographic information systems QGIS 3.4 (www.qgis.org) and ArcGIS Desktop 10.7 (www.desktop.arcgis.com). Statistical analyses were performed using SPSS Statistics 26 (https://www.ibm.com).To increase the potential utility of the cartographic model, we downscaled the model from its original OGU  to 4 kmapproach . We used2). Agricultural land use also influenced the localisation of outbreaks. Infections in horses were more common in areas with rice fields and irrigated land, such as permanently irrigated land, fruit trees and pastures, while human cases were more common in areas with irrigation systems.The occurrence of cases in horses and humans was affected by several factors . TemperaRisk areas for WNV infection in humans were concentrated in the southern part of the Iberian Peninsula: along the coast, throughout the Guadalquivir River Basin and in two patches inland along the rivers Tagus and Guadiana . The higCartographically, risk models of horses and humans were very similar, although the high-risk areas for horses were more widespread. The risk areas identified by the horse model highlighted the main river basins in the Iberian Peninsula . All humWe evaluated the classification and discrimination capacity of the models. Both models showed high sensitivity, correctly detecting the cases in horses (sensitivity (Se) = 0.87) and humans (Se = 1). Equally, both models identified with high precision the absence of cases, showing a high specificity: 0.88 for horses and 0.95 for humans. Discrimination of the models was outstanding: 0.96 in horses and 0.99 in humans . The horDuring the last decades, the situation with WNV infection in Europe has progressed from sporadic cases to yearly outbreaks that affect both equines and humans ,32,33. TThe horse model could be used to predict high-risk areas for equine and human cases. Evaluation of the models showed that the horse model could correctly classify risk areas for WNV infection in humans. This means that equids can be used as identifiers of risk areas where the virus could occur. Equids are normally more exposed to mosquito bites than humans due to their management conditions. Therefore, if an area experiences a spillover of WNV from the enzootic cycle, equines may be the first exposed. In humans, WNV infection is usually asymptomatic and there are no specific signs; cases may go unnoticed if neurological symptoms are not seen. Diagnosed cases in humans are only the tip of the iceberg: 80% of individuals infected with WNV are estimated to be asymptomatic and less than 1% develop a severe form of the disease. In that case, WNV infection may be a life-threatening condition, leading to serious complications in people over 50 years and in immunocompromised patients . HoweverIn Europe, a relationship between the occurrence of cases in equines and in humans has been observed . In otheFurther studies are needed to determine the extent to which equine data can be used as indicators of a prospective outbreak risk. Maintaining surveillance on horses is crucial, and it should be combined with surveillance in mosquitoes, birds and the human population to allow a more integrated and comprehensive approach in endemic countries , and proThe role of river basins in outbreaks of WNV infection in the Iberian Peninsula is also noteworthy, as has been reported in other countries ,56 such Based on our results, we propose river basins as-public health management units, rather than administrative units . If cases are detected in horses, all health care centres within the same river basin should be alerted, as the spread can occur in neighbouring territories, even across countries like Portugal and Spain, if they share the same river basin. Decision-making would be more efficient from an ecosystem perspective, considering the environment and animal health as a whole, using in this case equines as identifiers of risk areas to ensure public health, i.e. the One Health approach. This biogeographic characterisation of the disease may help in the early identification of areas with a high potential risk, where cases in humans have not yet been detected. Our aim was to contribute to the knowledge of the viral ecology of this re-emerging pathogen in Europe and facilitate the development of surveillance programmes and preventive measures such as fumigation plans in sensitive areas or citizen awareness campaigns to reduce exposure and mosquito bites to reduce the impact of the disease and the number of people exposed to this virus.


Rare diseases affect a small number of people compared to prevalent diseases. The vast majority of these diseases are of genetic origin, have no cure, are chronic and can lead to death. Although the right to access medicines is included in the constitutionally guaranteed right to health in Brazil, problems in the supply of medicines for rare diseases are reported in the country. This study aimed to describe and analyse the initiatives to promote access to medicines for treating rare diseases in the Unified Health System, Brazil, after the publication of the Brazilian Policy on the Comprehensive Care of People with Rare Diseases. Based on the model published by the WHO Regional Office for Europe, which described access to medicines in prelaunch, perilaunch and postlaunch policies, the initiatives referring to each category were summarized based on documentary research searched in online databases from January 2014 to December 2020.Different actions and policy interventions were identified, which went through the expansion of resources for research and development, health regulations, incorporation of new drugs, review and publication of clinical guidelines, and expansion of the network of care facilities by the Ministry of Health. On the other hand, aspects related to care policies, pricing methods, technological development, and development of pharmaceutical service processes were not implemented.Although it is impossible to determine the explicit motivation of such actions concerning the Policy, its publication certainly was a landmark in Brazilian society, allowing greater recognition of the needs of rare disease patients and the specificities of treatment’. However, this study suggests that the steps that make up the life cycle of medicines are not linked, lacking articulation and integration of the care network, and consequently, there is no evidence that rare disease policy publication has generated a broad impact on the promotion of access to medicines to treat rare diseases in Brazil.The online version contains supplementary material available at 10.1186/s13023-023-02881-5. Rare diseases affect a small number of people compared to prevalent diseases. However, there is no global consensus regarding their definition, and the prevalence threshold is the most commonly used descriptor .Individually, these diseases have a low prevalence rate; on the other hand, collectively, they affect a substantial proportion of the population. For example, a recent study based on the European definition of rare diseases estimated between 6,000 and 8,000 types of rare diseases that affect at least 3.5–5.9% of the world population; 71.9% of those diseases are genetic and inherited, and 69.9% begin to manifest during childhood . The refIn 2014, Brazil published a rare disease policy stating that rare diseases affect up to 65 people per 100,000 inhabitants .The Brazilian Policy on the Comprehensive Care of People with Rare Diseases (BPCCPRD) is organized in structuring axes according to the common characteristics of the diseases: Axis I includes rare genetic diseases, and Axis II includes rare nongenetic diseases. Among the principles of the BPCCPRD are the incorporation and use of technologies aimed at promotion, prevention, and comprehensive care in the Health Care Network (HCN). Such care includes medicinal treatment and nutritional formulas when recommended within the scope of the Brazilian Unified Health System , whose incorporations should result from the recommendations made by the National Committee for Health Technology Incorporation (CONITEC) and the subsequent drafting of clinical guidelines , 4. In tFurthermore, the BPCCPRD proposed two complementary structural components to the HCN: the Specialized Healthcare Center  and the Rare Diseases Reference Center (Portuguese: Serviço de Referência em Doenças Raras). It also created financial incentives for accredited centres and incorporated genetic and biochemical tests .In the SUS, pharmaceutical services pose a considerable challenge for managers and professionals, mainly due to the financial resources involved and the need for technical and organizational improvement. On the one hand, advances in structuring public health policies have allowed greater access to medicines and SUS services; on the other hand, there is still a need for continuous improvements, mainly regarding the population with specific needs. For example, many sufferers from rare diseases face barriers in accessing care, and a decade ago, less than 10% received specific treatment for the diseases, according to estimates .In low- or middle-income countries, such as Brazil, the availability in the market of medicines for treating rare diseases does not guarantee that patients will have access to them, given the gaps in the country’s integrated solutions to ensure universal health coverage . Some ofAccording to the Brazilian Constitution, access to medicines can be understood as part of the right to health. However, problems in medicine provision are broadly reported , 14, andIn this sense, this study aimed to describe and analyse the initiatives to promote access to medicine for treating rare diseases in the SUS after the publication and implementation of the BPCCPRD.Brazilian government initiatives were summarized considering the WHO model for access to new medicines . The proThe analysed data are in the public domain and were researched through a documentary assessment of online databases previously defined by the researchers. The sources and searches performed are described in Additional files Clinical trials and scientific research related to medicines or nutritional supplementation to treat rare diseases conducted between 2014 and 2020 were searched. To this end, all clinical trial registries were searched in the Brazilian Registry of Clinical Trials (ReBEC). After individual surveys, all studies involving new medicine research or improvement/assessment of existing treatments were selected.On Plataforma Brasil, a search for research involving developing medicines and/or nutritional formulas for rare diseases was performed using the keyword “rare diseases” . On ClinicalTrials.gov, a search was performed among all studies registered in Brazil with the keyword “rare diseases”.A systematic search of the CONITEC website  website.In the database, a search was conducted for medicines registered in the following regulatory categories: biological  ; new , and applicant type .The time elapsed to make the medication available at the SUS was evaluated. First, the time elapsed between proposal submission and recommendation decision publication was evaluated. Then, the time elapsed between the recommendation decision for incorporation and the publication of the clinical guideline was evaluated.The technologies were categorized according to the recommendation decision publication year, with the axes defined by the BPCCPRD.The SUS management sphere responsible for financing each medicine on the list of incorporated medicines for rare diseases between January 2014 and December 2020 was identified. Searches of the agendas and summaries of the CIT meetings and the Brazilian National List of Medicines were conducted .Additionally, we assessed the time elapsed between CONITEC publication of the incorporation decision and agreement on financing responsibility at the CIT.The listings of strategic products to the SUS eligible for submitting proposals for Partnership for Productive Development (PDP) projects in 2014–2020 were searched. In addition, the listing of products with partnerships in force in December 2020 was searched and is described in this study.Based on the code system provided by the legislation, the accredited services to people with rare diseases within the National Register of Health Facilities were searched. Data concerning the geographic location and types of rare diseases treated for each accredited service were described.Different initiatives were identified in the prelaunch, perilaunch, and postlaunch categories from 2014 to 2020.The establishment of the National Policy for Technological Innovation in Health, regulatory procedures related to research involving human beings, and clinical trials with medicines were identified. Furthermore, the methods by which the industry could offer experimental medicines to patients suffering from diseases hitherto untreated in the country were defined, and the right to poststudy access to clinical research protocols was granted to patients with ultrarare diseases.The search on research registration platforms identified some studies involving medicines. In ReBEC, most of the trials registered referred to therapeutic alternatives for medicines already in use in the country, with the involvement of higher education institutions and publicly traded corporations/private legal entities. On the other hand, research with new medicines had the pharmaceutical industry as the entity responsible for the study and involvement of private equity , in partnership with the Ministry of Health of Brazil, issued a call for research to obtain epidemiological information on rare diseases in Brazil .The promotion and incentives for research on rare diseases are goals of the federal public administration and the work of the Interministerial Committee on Rare Diseases. In addition, 30% of the resources destined for the Health Research Promotion Program for the technological development of medicines, immunobiological products, health products, and other therapeutic modalities are now allocated to treat rare or neglected diseases  of the Federal University of Rio de Janeiro and the Support Program for the Institutional Development of the Brazilian Public Health System (PROADI-SUS) .Furthermore, a systematic search on the CONITEC website showed that four alerts , three reports , and 19 sections in recommendation reports of studied medicines  were published while this study was being conducted.In Brazil, the sanitary registration of medicines for rare diseases was standardized in 2017 with the publication of the Collegiate Board Resolution (RDC) 205  and its Thirty-seven rare disease medicines were identified in the following regulatory categories: biological n = 21); new (n = 13); advanced therapy products (n = 2); and specific (n = 1)  held several events: a discussion on multicriteria decision analysis (MCDA) in HTAs; a workshop in partnership with the National Institute for Health and Care Excellence (NICE) to address methodological aspects of HTAs and strategies for the involvement of patients, industry sectors, and other stakeholders; and a congress on patient involvement in the HTA process.In October 2020, CONITEC launched on its website an area designed for public and patient involvement called Patient’s Perspective (Portuguese: Perspectiva do Paciente), where patients or caregivers can write about their experiences concerning the disease they are facing. Additionally, rare diseases were the subject of two public calls for medicine analysis between October and December 2020.This study identified 64 incorporation requests of medicines for rare diseases. External applicants submitted most proposals , and the Ministry of Health submitted 23 requests (35.9%). There was agreement in the recommendations in 32 decisions . The incorporation or non-incorporation recommendations are described in Table To obtain the 32 incorporation recommendations, the time elapsed to achieve a result was 233 days . In Brazil, legislation  establisad experimentum use reports.In Brazil, in 2018, the recommendations to incorporate some medicines for rare diseases  started to require patient follow-up in reference centres to collect evidence of clinical effectiveness in real-world situations. Then, within three years, a subsequent reassessment by CONITEC must be conducted, which in the reports is called An innovative approach to financing the purchase occurred in April 2019, when the Ministry of Health decided to incorporate nusinersen for spinal muscular atrophy types 2 and 3 through a risk-sharing agreement. This project was an alternative measure to produce additional evidence about the therapeutic value of these medicines and observe the real impacts on patients’ health and quality of life. However, this agreement failed due to the lack of detailed regulations and legal standards for implementation within the SUS scope .A bill related to the cost and supply of medicines and therapies for treating rare or neglected diseases is in progress in the Chamber of Deputies and awaits conclusive consideration  to discuss aspects in the initial phase of clinical guideline (Portuguese: Protocolos Clínicos e Diretrizes Terapêuticas (PCDT)) drafting. During this study, four polls addressed rare diseases.In the study period, 31 PCDTs for rare diseases were updated, and 16 new PCDTs were implemented, for a total of 51 PCDTs.After the recommendation for incorporating the medicines into the SUS, the technical areas have 180 days to provide the population with the medicines. Establishing clinical protocols is one of the requirements for access .In investigating the time elapsed between the decision to recommend incorporation and the publication of the clinical guideline for the 11 rare diseases for which there was no prior treatment available in the SUS and whose medicines were recommended during the study period, eight protocols did not comply with the period established by law. Thus, the data obtained in this study were for 292 days .Regarding the responsibility for financing, most of the medicines incorporated for rare diseases are procured and financed by the Ministry of Health (Group 1A CEAF). Table When assessing the period required for the financial agreement, in 15 situations, the timeframe did not comply with the law . The datFor national public medicine manufacturing, as of 2015, some medicines for treating rare diseases were on the SUS list of strategic products and eligible for Partnership for Productive Development (PDP) project proposal submissions. The partnerships in force in 2020  includedThe service offer was evaluated by identifying qualified reference centres after the BPCCPRD. By 2020, 19 reference services for rare diseases had been enabled in the country, according to the data described in Table Many medicines for treating rare diseases are listed in the CEAF strategy. In 2020, a change was identified in its execution model, increasing from three to six months the expiry period of the Report for the Request, Evaluation, and Authorization of Medicines from the Specialized Component of Pharmaceutical Assistance (Portuguese: LME).Due to the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) emerged, special criteria for implementing the CEAF strategy related to documentation renewal and dispensing anticipation were advocated. Additionally, patients with Gaucher disease, assisted by the Ministry of Health through the provision of enzymatic therapy by Bio-Manguinhos/Fiocruz, started to be given medicine infusions via home care service .Searches on the Legislative Power websites identified social demands in the scope of rare diseases, which were discussed in the Special Subcommittee on Rare Diseases of the Chamber of Deputies and in the Temporary Subcommittee on Rare Diseases of the Senate. Topics included scientific research conducted in Brazil, incorporating technologies by the SUS considering specificities, expanding diagnostic methods, defending rights and social inclusion, and improving specific legislation.The analysis model chosen in this study clearly showed that a set of interconnecting policies determines access to medicines for treating rare diseases. Furthermore, this study showed that since the publication of the BPCCPRD, actions to promote access to such medicines have been developed in Brazil, including all phases of development, dispensation, and use of medicines. Although it is impossible to determine the explicit motivation of such actions concerning the BPCCPRD, its publication certainly is a landmark in Brazilian society, allowing greater recognition of the needs of rare disease patients and the specificities of treatment. Therefore, expanding and guaranteeing access to pharmacological treatment is fundamental to provide a better quality of life for people affected by a rare disease.Among prelaunch activities, the development of research for new medicines, the expansion of financial resources forecast by the federal government, and the sanitary regulation of access to innovative treatments indicate that there are concrete initiatives to expand access. According to Gomes et al. , aspectsAmong prelaunch actions, different aspects can be considered drivers of access, such as regulating the sanitary registration of rare disease medicines, which can expand the supply of new medicines in the SUS Table . In thisad experimentum) as a possibility for reassessing better technological alternatives based on evidence; however, the country does not have structural conditions  for its successful development.There is a growing demand for incorporating rare disease medicines both by SUS internal and external requests, as also described by Biglia et al. . DespiteIn postlaunch interventions, the reassessment of norms related to good health practices and pharmacovigilance of medicines and updates to clinical guidelines are essential actions to promote the proper and efficient use of these medicines. Furthermore, the Rare Diseases Reference Centres Table , accrediAs already found by Mayrides et al.  and descThere was also no update in the financial resources for funding passed on to Rare Diseases Reference Centres. In addition, Brazil’s data systematization should be discussed in managing rare diseases. In Brazil, there was no development of a system to register clinical data, which hindered the integration between the different components of the HCN. According to Félix et al. , the RarWithin the scope of national manufacturing, PDPs reduce the acquisition cost of medicines that are currently imported. They also boost local manufacturing involving technology transfer to the Brazilian market . NeverthLogistical issues remained unchanged. The processes of planning, acquisition, distribution network improvement and expansion of the Secretary of State for Health’s role in promoting the rational use of medicines need broader discussions to avoid gaps in patient treatment . NoncompThe lack of alignment between the actions for access to medicines implies the occurrence of judicialization. Consequently, it burdens the system and may restrict the support of health needs while not ensuring adequacy in the administration of medicines, continuity of treatment, and follow-up by a trained health team in addition to favouring particular groups over others , 43.According to Gammie et al. , the natThis study has severe limitations related to the perilaunch phase, since it was not possible to perform a deeper analysis of the impact of the study being financed by public, private, or mixed capital, having a national or international scope. We performed only a simple search to identify the presence or absence of clinical research initiatives in the country. Another limitation considered is that the material consulted does not present data related to the effective offer of medicines to patients, so future investigations on effective access are pertinent.The enactment of the BPCCPRD acknowledged the importance of discussing rare diseases in Brazil. The BPCCPRD also created a regulatory framework for service accessibility, increasing the demands for medicine incorporation, PCDT updates, and licensing of reference centres. However, these efforts were not aligned with care policies, pricing methods, technological development, or process management in pharmaceutical assistance, lacking articulation in the care network. Consequently, there is no evidence that its publication has generated a broad impact on promoting access to medicines to treat rare diseases in Brazil. Furthermore, it is believed that integrating the life cycle stages and usage cycle stages of medicines can improve the quality and speed of the processes, thus avoiding progressive losses in the quality of life of patients suffering from a rare disease and contributing to comprehensive care. Finally, this can also prevent increased judicialization related to medicine access.Additional file 1: Search about prelaunch, perilaunch and postlaunch activities to promote access to medicines for treating rare diseases, Brazil, 2014–2020.Additional file 2: Regulations, norms or guidelines related to rare diseases after publication and implementation of the BPCCPRD, Brazil, 2014–2020.Additional file 3: Research and clinical trials related to medicines for treating rare diseases conducted in Brazil, 2014–2020.


An immune system of varying complexity in different species serves both to defend against harmful molecules (toxins) and pathogenic agents that have overcome the host’s natural barriers and to maintain cellular homeostasis by eliminating degenerated and dead cells. Interestingly, the immune system is characterized by great plasticity. By being able to distinguish between self- and non-self-substances, it forms a memory that continues to develop throughout the entire life span. The great challenge for the immune system in the Anthropocene era is to preserve these evolutionarily acquired skills in a permanently changing environment through the release of unnatural anthropogenic xenobiotics and through human activity itself. The risk of adverse effects from single xenobiotics or xenobiotics occurring in a mixture results not only from their released quantity but also from their chemical properties, which contribute to the fact that individual substances and groups of substances are hardly degradable in nature and cannot be metabolized by organisms. This can lead to the lifelong accumulation of these substances, the consequences of which are not yet predictable. To gain a better understanding of the immunomodulatory role of anthropogenic xenobiotics in agriculture, aquaculture, ecology, and conservation, studies on wild and domesticated animals are essential. However, great efforts are still needed to understand the evolutionary range of immunological defense mechanisms against stressors.via respiration or ingestion. A physiological function for Cd has not yet been identified, but it poses long-term health risks. Its immunomodulating effects under experimental conditions in vivo and in vitro in different species has been well summarized in the review by Wang et al. Accumulating also in immune cells, Cd modulates the function of cells of both the innate and adaptive immune systems. The species- and immune cell type-independent adverse effect of Cd on the immune system is mainly immunosuppression with all its consequences. With respect to the half-life time of Cd of decades, the review also emphasized the need to have strategies for the detoxification of living systems from incorporated Cd. Antioxidative bioactive compounds or trace elements, such as zinc or selenium, can be promising candidates for application as supplementation. Although they can prevent the harmful effects of Cd to some extent, they do not promote its excretion. Thus, there is a further urgent need to develop effective immunotherapies to alleviate the immunosuppressing effects of Cd.One of the substances accumulating in living organisms, as mentioned above, is cadmium (Cd). The intake after occupational or non-occupational exposure to Cd happens unconsciously Baranska et al. described a genotoxic effect of four members of BFR in immune cells, underscoring the immunosuppressing effects of BFR. The compound-dependent genotoxic effect was induced by partially repairable strand-breaks formation and oxidative-damaged pyrimidines in mononuclear cells. This effect was initiated indirectly by DNA-damaging agents, such as reactive oxygen species (ROS) and other reactive species, but not by DNA adducts with BFR. How the genotoxic effect could be prevented was not examined. However, due to the formation of ROS, similar protecting effects by antioxidative compounds, as in the case of damage by Cd, are conceivable.Another class of substances of great concern are synthetic brominated flame retardants (BFR) applied to reduce the flammability of products containing them. They are effective in plastics and textile applications such as electronics, clothes, and furniture. They have been detected in animal tissues and in water and sediment samples far from their source of origin, raising concerns about their global impact because of their persistence and bioaccumulation. Qing et al. have given a convincing example. In pullets, a combination of the two natural feed contaminants, the mycotoxins ochratoxin A (OTA) and aflatoxin B1 (AFB1), evoked pro-inflammatory cytokines in serum as a sign of pathological changes, including enhanced apoptosis in the kidney and liver. Although OTA and AFB1 are known to be toxic to the kidney and hepatotoxic, respectively, the consumption of both toxins additionally influenced the composition of the gut microflora. They stimulated more the growth of pernicious bacteria, from which an additional risk may be posed. Because a permanent interaction between immunocompetent cells and microorganisms in the course of evolution has presumably led to the formation of robust signaling networks that protect the organism, analyzing the effect of xenobiotics or natural toxins on the microbiome is of great importance. If this interaction is disturbed, the immune system is less able to eliminate harmful pathogens.Apart from the direct immunosuppressing effects of xenobiotics, such as Cd and BFR, an indirect activation of the immune system by a stressor may indicate its detrimental effect. In this respect, Caenorhabditis elegans, a free-living nematode, Mello et al. analyzed the effect of the pesticide and inhibitor of the electron transport chain in mitochondria rotenone in C. elegans embryos under mild mitochondrial stress. They demonstrated that the mitotoxicant rotenone affected the defense toward individual pathogen species in both directions. The nematodes were more protective against some pathogen species but more unprotected against others.Immunocompetent cells from germ-free animals show a disturbed cell metabolism and are thus not able to initiate immune responses. Proteins of the mitochondrial respiratory chain seem to play a decisive role in this. Thus, mitochondria represent a key modulator of immune responses (mitoimmunity). Since mitochondria can be particularly vulnerable targets to several classes of environmental toxicants, including metals, polycyclic aromatic hydrocarbons, and pesticides, it can therefore be assumed that these substances can have an immunomodulatory effect by influencing the immune metabolism. As the key role of mitochondria is conserved in vertebrates and Due to the diversity of species with their specific immune systems and specific interacting factors (microbiota), it is clear from the outset that this Research Topic can only present examples of studies highlighting the different focuses of the analysis of the immunomodulatory effects of xenobiotics or natural toxins in animals. However, the studies listed above are the most important Research Topics that assess the effects of single stressors and, far more importantly, the mixtures of stressors on the immune system, such as direct and indirect immune modulation, interaction between the immune system and microbiota, and the immune metabolism.The author confirms being the sole contributor of this work and has approved it for publication.


Patient-reported outcome measures (PROMs) are questionnaires that measure patient outcomes related to quality of life, health, and functioning, and are increasingly used to assess important outcomes from the patient’s perspective. For PROMs to contribute to better health and better care, it is vital that their content validity be adequate. This requires patient involvement in various steps of PROM development. PROM developers not only recognize the benefits of patient involvement but also report difficulties in recruiting patients and experience patient involvement as time-consuming, logistically challenging, and expensive.This study seeks to explore different strategies for disclosing the experiential knowledge of patients, namely through analyzing patient stories on the web and social media. The research questions are as follows: (1) how do bloggers living with a disease experience their health-related quality of life? (2) How are these experiences reflected in the domains and items of PROMs related to their disease?First, a qualitative analysis of blogs written by patients was performed. Second, subthemes and underlying codes resulting from this qualitative analysis were systematically compared with the domains and items in PROMs for the respective diseases that the bloggers write about. Blogs were identified via the Google search engine between December 2019 and May 2021.Bloggers describe a wide range of experiences regarding their physical functioning and health; mental well-being; social network and support; daily life, education, work, and leisure; coping; and self-management. Bloggers also write about their positive and negative experiences with health care delivery, the organization of health care, and health care professionals. In general, patients’ experiences as described in blogs were reflected in the domains and items of the PROMs related to their disease. However, except for diabetes mellitus, in all the sets of PROMs, potentially missing topics could be identified. Similarly, with the exception of Parkinson disease, all PROMs address issues that patients did not write about in their blogs and that might therefore be redundant.Web-based patient stories in the form of blogs reveal how people living with a certain disease experience their health-related quality of life. These stories enable analyses of patients’ experiences that can be used to assess the content validity of PROMs. This can be a useful step for researchers who are looking for sets of measuring instruments that match their purposes. Value-based health care (VBHC) has globally been embraced as a concept that guides innovation and improvement in health care delivery -4. In VBPROMs are questionnaires that measure patient outcomes related to quality of life, health, and functioning, and are increasingly used to assess important outcomes from the patient’s perspective . PROMs cFor PROMs to contribute to better health and better care, it is vital that their content validity be adequate and that, in other words, they truly measure outcomes that matter to patients. To assure the content validity of PROMs, the content of PROMs needs to be examined by the targeted patient group ,12. ThisTherefore, it is interesting to explore different interpretivist strategies for disclosing the experiential knowledge of patients, namely through analyzing patient stories on the web and social media. van de Bovenkamp et al  argue thMcCarrier et al  showed tBuilding on these suggestions, therefore, this study aims to explore the use of patient stories in the form of blogs published on the web for assessing the content validity of PROMs. The research questions are as follows: (1) how do bloggers living with a disease experience their health-related quality of life? (2) How are these experiences reflected in the domains and items of PROMs related to their disease?The research questions are addressed first through a qualitative analysis of blogs written by patients. Second, subthemes and underlying codes resulting from this qualitative analysis are systematically compared with the domains and items in PROMs for the respective diseases that the bloggers write about.To demonstrate the feasibility of using blogs to assess the content validity of PROMs, blogs on 3 different chronic disease are used, namely rheumatoid arthritis, Parkinson disease, and diabetes mellitus. In addition, blogs of patients with breast cancer and its survivors have been analyzed. Blogs were identified between December 2019 and May 2021 in separate research projects coordinated by the first author (DMJD). The individual studies took place as master thesis projects of the master programs Health Economics, Policy and Law and Health Care Management of the Erasmus School of Health Policy & Management. The choice of the diseases was made by the individual students, who were free to pick a topic of interest provided that an ICHOM standard set of outcome measures was available for the chosen disease category.ICHOM standard sets include recommendations about which PROMs to use. Data on recommended PROMs were derived from ICHOM Connect -23, specThe analyses for breast cancer and diabetes mellitus included all the PROMs that are recommended by ICHOM. However, the list of PROMs that ICHOM recommends for inflammatory arthritis is very long. Therefore, for practical reasons, we choose to focus on the 2 PROMs from that list, which are most frequently used by Dutch physicians to measure outcomes of care in patients with rheumatoid arthritis, namely the Health Assessment Questionnaire and the Short-Form 36 (SF-36) . AlternaThe data on breast cancer blogs were collected and coded by MD and DMJD, rheumatoid arthritis by LK and DMJD, Parkinson disease by JS and DMJD, and diabetes mellitus by SS and DMJD. Blogs were identified using Google’s search engine, and bloggers’ contributions were entered into the analysis in batches. For example, the analysis of bloggers with breast cancer started with the 5 most recent blog posts of 20 different bloggers. This process continued until data saturation was reached .All projects included blogs written by Dutch patients in order to be able to draw conclusions on the validity of the respective PROMs in the context of the Dutch health care system. We used blogs that were available in the public domain . Furthermore, for patients living with rheumatoid arthritis, data collected from blogs were complemented with patient stories based on interviews, to account for potential bias caused by the fact that patients with severe rheumatoid arthritis cannot write blogs anymore .See Full texts of blogs were imported into the ATLAS.ti software (ATLAS.ti Scientific Software Development GmbH) using identification numbers or names of bloggers, depending on whether a blogger chose to be quoted as an author . In ATLAS.ti, unstructured, raw data from blogs were analyzed using open inductive coding in an iterative process. This analysis resulted in the identification of themes and subthemes that have been used to explore how bloggers experience their health-related quality of life. Health-related quality of life is a broad concept relating to the effect of a particular health status on a person’s well-being . This inAs the initial coding process took place in separate research projects and data were inductively coded from the perspective of the bloggers, separate codebooks exist for the 4 disease categories. For the purpose of summarizing the findings in this paper , diseaseAs a consequence of the nature of the primary research projects, which were relatively small master thesis studies, the check of the supervising author (DMJD) on the coding conducted by each of the other authors  focused on (1) obtaining consensus about the inclusion of text fragments based on the broad and subjective definition of health-related quality of life, (2) reaching consensus about the way in which codes have been grouped into subthemes and themes, and (3) consistent application of the codes within each of the separate data sets. The unique codes themselves have not been applied by 2 of the authors separately in order to be able to calculate the level of agreement. Furthermore, it is important to note that the coding took place before and separate from the comparison with the various PROMs because we wanted to interpret themes and subthemes in the qualitative data without being influenced by domains and items in the PROMs. In all the research projects, data collection and analysis continued until no new topics were extracted from the data, implying that data saturation had occurred.The comparison with the PROMs was guided by the criteria for content validity described by Terwee et al . SpecifiResults section.In the Erasmus School of Health Policy & Management, research conducted by students for their master thesis is exempt from review by the internal ethical committee. The ethical assessment is the responsibility of the supervisor. We handled this as follows: all the blogs that have been used were published in the public domain on the web platform. The first research project focused on bloggers with Parkinson disease and took place in 2020. In that specific case, we argued that blogs were made public by their authors and therefore could be used for the purpose of academic quality of life research. However, in subsequent projects that took place in 2021 on rheumatoid arthritis, diabetes mellitus, and breast cancer, discussions within our research team led us to take a different viewpoint. Following the line of reasoning described by Snee , it is pAlthough bloggers from all 4 patient groups cover this broad range of topics, their specific experiences differ. Bloggers writing about rheumatoid arthritis frequently discuss topics concerning limitations in physical functioning, for example, pain, that cause inconveniences in daily life. Some patients with rheumatoid arthritis are not able to walk for a long time or to lift heavy objects; in other patients, the limitations manifest themselves in smaller everyday activities: “For example, because of my limited hand function, I am a little nervous with every new toilet outside the home about whether I can open the locked toilet door again. Yes, I sometimes fail” . DespiteBloggers with Parkinson disease often write about how they feel. Although they do mention positive attitudes, like staying hopeful and enjoying life, they also say to be struggling with feelings of sadness, depression, anxiety, mood changes, and negative thoughts. Living with the disease provokes emotions such as feeling insecure, vulnerable, and ashamed. With respect to physical problems, bloggers with Parkinson disease write, for example, about “fatigue.” One blogger describes how she struggles:I always have a low energy level. On a good day I have about 50 per cent of the energy of a woman that isn’t sick. So that isn’t much. I get tired easily and after an intensive day I need a whole day to recover and I won’t be able to work at all.Parkinson disease blogger 7, anonymousOther health issues described include symptoms like rigidity, postural instability, bradykinesia, tremor, pain, dyskinesia, the so-called freezing, loss of balance, and hypomimia.For patients with breast cancer and its survivors, feelings are an important issue too. For example, bloggers mention feelings of sadness; anxiety or fear; depressive feelings; and feelings of frustration, anger, loneliness, shame, guilt, and insecurity. Several bloggers write about trust in their own body and about fear for relapses: “I am terrified that it will return” . ConcernBloggers writing about diabetes mellitus describe how their condition forms an integral part of daily life. Diabetes is “a continuous presence, a presence that is just as normal as eating, drinking, and sleeping” . Self-management and controlling blood sugar levels never stop. Patients have to take responsibility all the time, for example, to make sure to be prepared for a hypo- or hyperglycemia.When I go for a walk, I always make sure I have some important items with me. It seems terrible to me to get a hypo while being on the way and not having anything to eat or drink with me.Diabetes mellitus blogger 7, anonymousThe results of the comparison for breast cancer show that the majority of topics addressed in the BREAST-Q and in the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) are also mentioned in the blogs. Only a minority of items in those 2 PROMs are not matched by issues discussed in the blogs. However, 18 of the items that the EORTC Quality of Life Questionnaire—Breast Cancer (EORTC QLQ-BR45) addresses are not described by bloggers with breast cancer. Vice versa, coping strategies and problems with fertility and pregnancy support are mentioned by bloggers but are not covered by any of the 3 breast cancer PROMs that are recommended by ICHOM.For rheumatoid arthritis, the comparison of the Health Assessment Questionnaire and SF-36 shows that many of the topics addressed in those PROMs were also coded in the qualitative analyses of the blogs. There is one exception: both PROMs address personal care; however, this issue is not mentioned in the blogs. Alternatively, there are 3 topics that are discussed in blogs but are missing in the PROMs, namely side effects of drugs, flares, and experiences with treatment.All the items covered in the PDQ-39 and PDQ-8 for Parkinson disease are also mentioned in the blogs written by patients with Parkinson disease. However, bloggers writing about Parkinson disease discuss a whole range of issues that are missing in the PROMs, namely fulfilment, impact on social life, perceived quality of care, personality change, relationship, self-management, and sleep disorder.Finally, the 5-item World Health Organization Well-Being Index, the 9-item Patient Health Questionnaire, and the Problem Areas in Diabetes together cover all the issues that are discussed by bloggers writing about diabetes mellitus. There are no missing domains. However, all 3 of the diabetes PROMs contain questions about topics that bloggers have not mentioned, for example, whether daily life is filled with interesting things ; having little interest or pleasure in doing things, trouble concentrating on things, and moving or speaking slowly, or being fidgety or restless ; and not having clear and concrete goals for diabetes care, feeling discouraged with diabetes treatment plan, feelings of deprivation regarding food and meals, or not knowing if mood or feelings are related to diabetes (Problem Areas in Diabetes).This study aimed to explore the use of patient stories in the form of blogs to assess the content validity of PROMs. Our first research question was: How do bloggers living with a disease experience their health-related quality of life? The blogs cover a broad set of themes that reflect common domains of health-related quality of life  such as The second research question was: How are these experiences reflected in the domains and items of PROMs related to their disease? The analyses showed that, in general, patients’ experiences as described in blogs were reflected in the domains and items of the PROMs related to their disease. However, with the exception of PROMs for diabetes mellitus, for all the patient groups, potentially missing topics could be identified, that is, issues that were raised in blogs but are not addressed in PROMs. Similarly, with the exception of the PROMs for Parkinson disease, PROMs address issues that patients did not write about in their blogs. This is particularly the case for the ICHOM breast cancer and diabetes mellitus PROMs.The finding that bloggers with rheumatoid arthritis or Parkinson disease write about the limitations experienced in daily life might reflect the disabling, progressive course of rheumatoid arthritis and Parkinson disease and the effect this has on daily life -37. SimiIn the scientific literature, there are many reports of qualitative research aimed at understanding how patients experience their lives with chronic diseases -41. AccoOur comparison with PROMs shows that it is probably more relevant to assess content validity at the level of an ICHOM set as a whole rather than for single PROMs in those sets. Content validity refers to the relevance of items for the construct of interest. If the construct of interest is outcomes that matter to patients, as is the case with the ICHOM, a set of PROMs need to be chosen that together will address all these outcomes. Even so, however, it remains questionable whether it is possible to capture the full range of patient experiences in a meaningful way. For example, in a discourse analysis, Steinmann et al  reportedNonetheless, this explorative study has shown the potential of using patient stories in the form of blogs for assessing the content validity of PROMs. Health-related quality of life themes could be identified in the blogs of all patient groups. This supports the use of generic PROMs such as the SF-36, the EuroQol 5D, or other global measures in ICHOM standard sets . SimilarAlthough some missing topics could be identified, overall, patients’ experiences as described in blogs are reflected in PROMs. However, the PROMs in the ICHOM breast cancer set and in the ICHOM diabetes mellitus set also address issues that were not identified in the blogs. This indicates that some of the questions are potentially redundant, depending perhaps on the stage of the patient journey in which the surveys are administered. The breast cancer PROMs, for example, contain questions that are relevant during treatment but maybe less relevant for patients who are long-term breast cancer survivors.So, blogs provide a rich source of data as argued by van de Bovenkamp et al . AccordiDespite these challenges and the limitations described above, blogs have some advantages over using interviews or focus groups in the development of PROMs. Conducting interviews too is time-consuming, and interviews are a co-constructing method in which both interviewer and participant contribute to the conversation . This imAll in all, in developing new PROMs from scratch, the use of more traditional methods such as interviews or focus groups is probably preferable because they offer better options to control the selection of participants and minimize bias. However, in many cases, researchers do not aim at developing a new PROM but at choosing the right PROMs from the large number of questionnaires that are available . In thisThe strength of our study lies in the systematic use of qualitative research to analyze the content validity of PROMs that included in ICHOM standard sets. Even though these standard sets aim to measure outcomes that matter, our analysis has shown that the sets may still miss topics that are potentially relevant for patients and address issues that might be redundant from the patient perspective.A possible limitation of our study is that the initial coding of blogs took place in separate projects in which data were inductively coded from the perspective of the bloggers. This increases the internal validity of the codes per patient group, but it limits the possibilities of comparing codes across groups. However, comparison across patient groups was not the purpose of our study. Instead, we aimed to use the results of the qualitative analyses per patient group to assess the content validity of the PROMs that are used for that specific population.In addition, it is difficult to verify the accuracy of the information that bloggers provide. It is possible that bias occurs because bloggers are more inclined to try to appeal to their readers rather than alienate them . An inheApart from that, the use of blogs also leaves a group of patients unheard of, for example, the group of older patients who are often not very comfortable with using the internet . A bloggWeb-based patient stories in the form of blogs reveal how people living with a certain disease experience their health-related quality of life. These blogs enable a rich description of patients’ experiences with their health and physical functioning, their feelings, side effects of treatment, and their coping with the disease in daily live. Similarities in these experiences support the use of generic PROMs. However, the qualitative analysis also revealed differences between patient groups that may be better captured by disease-specific PROMs.Although for the development of completely new PROMs more traditional methods such as interviews or focus groups offer more controlled conditions, blogs can be used to assess the content validity of PROMs. This study showed that the experiences of bloggers living with breast cancer, Parkinson disease, rheumatoid arthritis, and diabetes mellitus are reflected in the domains and items of the PROMs that ICHOM recommends for these patient groups. However, potentially missing topics and potentially redundant topics could also be identified when comparing the content of PROMs with issues that were raised in blogs. Therefore, an analysis of web-based patient stories can be a useful step for researchers who are looking for PROMs that match their purposes.