Orientia tsutsugamushi, is a serious public health problem in the Asia-Pacific region, threatening the health of more than one billion people. China is one of the countries with the most serious disease burden of scrub typhus. Previous epidemiological evidence indicated that meteorological factors may affect the incidence of scrub typhus, but there was limited evidence for the correlation between local natural environment factors dominated by meteorological factors and scrub typhus. This study aimed to evaluate the correlation between monthly scrub typhus incidence and meteorological factors in areas with high scrub typhus prevalence using a distributed lag non-linear model (DLNM). The monthly data on scrub typhus cases in ten provinces from 2006 to 2018 and meteorological parameters were obtained from the Public Health Science Data Center and the National Meteorological Data Sharing Center. The results of the single-variable and multiple-variable models showed a non-linear relationship between incidence and meteorological factors of mean temperature (Tmean), rainfall (RF), sunshine hours (SH), and relative humidity (RH). Taking the median of meteorological factors as the reference value, the relative risks (RRs) of monthly Tmean at 0°C, RH at 46%, and RF at 800 mm were most significant, with RRs of 2.28 (95% CI: 0.95–5.43), 1.71 (95% CI: 1.39–2.09), and 3.33 (95% CI: 1.89–5.86). In conclusion, relatively high temperature, high humidity, and favorable rainfall were associated with an increased risk of scrub typhus.Scrub typhus, caused by  Orientia tsutsugamushi  as the main source of infection. Chigger larvae are the vectors, and are transmitted to humans through the bite of chigger mite larvae carrying rickettsia  , 6. ThroFirstly, the relationship between scrub typhus and meteorological factors has not been fully extrapolated. Secondly, previous studies have rarely considered the lag effect of meteorological factors, and the time unit setting of the lag effect research is not detailed. Most of them selected some old models, and the results obtained are not reliable. Inconsistent results due to differences in models and regions, do not provide good predictive power, and cannot be used as a decision-making tool. A more suitable prediction model for scrub typhus has not been found. One of the key reasons is that changes in meteorological factors in different regions and degrees have different effects on the occurrence and development of diseases.This study covered the epidemiological characteristics of scrub typhus from January, 2006 to December, 2018. On the basis of historical data, the DLNM was used to predict the relationship between meteorological factors and the incidence of scrub typhus in 10 provinces. To our knowledge, this is the largest epidemiological study of scrub typhus to date, covering the largest number of provinces and the longest period.tsutsugamushi in multiple ways, take targeted prevention and control measures more effectively. We aimed to investigate the potential impact of various climatic variables on disease transmission opportunities in areas with high tsutsugamushi prevalence, taking into account the lag time. This will provide a new insight into the potential impact of climate change on scrub typhus transmission to help develop early warning systems.Humans generally lack immunity to scrub typhus and no effective vaccine is available. Therefore, exploring the relationship between climate change and scrub typhus will help the public health department to grasp the pattern of https://www.phsciencedata.cn/Share/en/index.jsp). Population data were obtained from the National Bureau of Statistics of the People's Republic of China (http://data.stats.gov.cn). All clinical diagnosis cases met the criteria for scrub typhus (http://www.chinacdc.cn) issued by the Chinese Center for Disease Control and Prevention in 2009.During the period from 2006 to 2018, monthly data of scrub typhus of 31 provinces in China, including the number of cases and incidence, were obtained from the National Notifiable Disease Report System. These data are available from the China Public Health Science Data Center (http://data.cma.cn/wa) , average RF (mm), average SH (h), average RH (%) were obtained from 272 sites enclosed in meteorological monitoring stations in China (a.cn/wa) .P25, median, 75), minimum, and maximum were used to describe the distribution of incidence of scrub typhus and meteorological variables. Analysis of variance (ANOVA) test was applied to analyze the values of meteorological among the four seasons: spring (March to May), summer (June to August), autumn (September to November), and winter (December to February). A Kruskal-Wails test was used to examine the scrub typhus incidences among the four seasons. The significance level of all these analyses was set at 0.05 in two-tailed tests.Although some provinces have large increasement in scrub typhus incidence, the actual incidence was very low, so we did not include them in the model. Finally, we selected top 10 average annual incidence provinces as study region in this study. In the descriptive analysis, mean, standard deviation, quartiles  in the multiple-variable DLNM. Finally, 7 months were set as the maximum number of lag months. Long-term cumulative risk referred to the cumulative 7-month risk.In the single-variable model, in addition to the weather conditions, we further considered the factors of season, temporal trends, quantile groups for average incidence and previous month incidence.The added variables in the multiple-variable model were used to control the significant confounders including Tmean, RH, RF, temporal trend, season factors, quantile groups for average incidence and previous month incidence.https://cran.r-project.org/web/package/dlnm/index.html) was used to specify the intersection of quadratic splines of three meteorological variables, predict and plot the results of the fitted model   . DLNM wahttps://www.rdocumentation.org/packages/splines/versions/4.1.3). Regarding the space of lags, we evaluated the time lag from 0 to 7 months. The knots for the spline for lags were placed at equally spaced value on the log scale of lags, using the function lognots. The prediction values here were centered at the median of each meteorological variable.We defined the cross-basis matrices when building DLNM. The cross-basis for weather factors was specified by B-spline using the function bs from the package SPLINES in R software  per year to control for long-term trends in meteorological factors across provinces. All statistical analyses were performed by two-tailed tests with a significance level of 0.05, using the Joinpoint Regression Program (version 4.9.0.0) developed by the National Cancer Institute (NCI), ArcGIS 10.2  and R software  .P < 0.001), and the annualized average incidence was 0.641 per 100,000 (P < 0.001), then increased to 1.93 per 100,000 in 2018, with an APC of 12.8%  (P < 0.001) and 58.9% , respectively.This study consisted of 142,849 scrub typhus cases between January 1, 2006 and December 31, 2018. The annual incidence showed a significant upward trend  . Among tFrom 2006 to 2018, scrub typhus predominantly circulated in the south, southeast and southwest of China . At leasA heat map was used to show seasonal patterns, which displayed that the national incidence was lower in winter (December to February) and higher in autumn (September to November) .The national monthly Tmean and average RH were 13.29°C and 66.30%. The RF was 77.63 mm, and the SH was 174.68 h . In the Pearson's correlation analysis of ten high incidence provinces revealed that the incidence of scrub typhus was significantly positively correlated with three weather conditions, including monthly Tmean (r = 0.19), RF (r = 0.19) and RH (r = 0.26) ( = 0.26) .In the DLNM, exposure-response curves showed a substantial linear association between scrub typhus and meteorological conditions with a lag of 0–7 months. In the single-variable models, three meteorological conditions were associated with scrub typhus incidence . The RR We used the median of weather factor as a reference and calculated the relative variable in different lag months . In lag We found that the cumulative risks of meteorological factors with a lag of 0–7 months were associated with scrub typhus incidence. In the single-variable models, the Tmean at 19–23°C, the RH at 62–76%, and the RF at 0–8 mm, 29–90 mm and 612–800 mm were all positively associated with scrub typhus risk . In the China is one of the regions where the incidence of scrub typhus is relatively obvious, with cases mainly distributed in Yunnan, Guangdong, Hainan, Fujian and other regions south of the Yangtze River. Since 1986, the epidemic focus has begun to appear in the area north of the Yangtze River. The distribution of scrub typhus incidences varied among provinces and cities in China, and the number of cases was uneven, which may be caused by socioeconomic factors such as population density and the difference in land use types or natural environments such as temperature, precipitation, and vegetation. This study conducted an epidemiological analysis on the top ten provinces with scrub typhus incidence, and explored the relationship between meteorological factors and the incidence through the DLNM.This study revealed that scrub typhus mainly existed in the economically underdeveloped areas of southern China, such as Yunnan, Guangxi, and Jiangxi, which led us to doubt whether economic and social factors would affect scrub typhus . Shah etL.deliense with a 3-month life cycle , Through Poisson regression model and DLNM, Wei et al. found that the risk of scrub typhus increased by 3.8% for every 1°C increase in monthly surface temperature; the risk of scrub typhus increased by 5.3% for every 1°C increase in daily temperature, with a lag of 7 weeks . Currently, many vector-borne infectious diseases  are found to be positively correlated with precipitation, and disease transmission may be affected by the growth and development of pathogens and vectors/hosts –36. WhenThe lag analysis of humidity in this study displayed the different results between the single-variable and multiple-variable models. Results of single-variable model showed that high humidity could increase the scrub typhus risk, but when the humidity exceeded the critical value, it became an inhibitory effect on the risk. High humidity was also thought to increase the risk of scrub typhus. Yang et al. found that every 1% increase in monthly relative humidity in the first two months was associated with a 12.6% increase in monthly cases, which was consistent with our results . MoreoveIn conclusion, (relatively) high temperature, high humidity and sufficient rainfall were all associated with the incidence of scrub typhus, and there was a certain cumulative lag effect. Changes in natural and socioeconomic factors would have a huge impact on the habitat of rodents and chiggers, thereby affecting the population distribution of rodents and chiggers. Therefore, in areas with high incidence of scrub typhus such as Yunnan and Guangdong, targeted prevention and control measures should be carried out during the epidemic season, and health education and personal protection awareness should be strengthened for vulnerable groups such as the middle-aged and elderly, farmers and diaspora children. The health department should strengthen local scrub typhus monitoring to detect and treat in time. At the same time, further studies should be conducted to find out the key risk factors affecting the rise of scrub typhus incidence, so as to provide a theoretical basis for scientific and effective prevention and control of scrub typhus.This study has several limitations. First, we lack the epidemiological data of scrub typhus after 2018, and we cannot analyze the prevalence of scrub typhus in recent years. Second, we cannot extrapolate the short-term impact of meteorological factors on scrub typhus from monthly data. Third, data on some socioeconomic factors, including GDP, urbanization level, etc., are not collected. In future, the impact of meteorological factors and socioeconomic environment on scrub typhus needs to be comprehensively considered.The original contributions presented in the study are included in the article/This study obtained the permission of the Ethics Committee of the Nanjing Bioengineering (Gene) Technology Center for Medicines (Ethics Committee Batch No: 2018001003). Our study did not involve any private and personal information about scrub typhus cases. The data was anonymous.YL and LoZ: data curation, conception, software, and writing—original draft. HL, YQ, NY, LA, and CZ: conception, methodology, and software. LoZ and JW: data curation and software. LoZ: supervision. YL and WT: data collection, visualization, and writing—review and editing. All authors contributed to the article and approved the submitted version.This study was supported by the Jiangsu Social Development Project (BE2017620) and National Natural Science Foundation of China (U1602223).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Current evidence of interprofessional collaboration suggests the importance of measuring and identifying the current state of the health professions’ interprofessional competencies. Therefore, this study was aimed at measuring the interprofessional competencies of health professionals in the Global South context using the validated CICS29.This was a cross-sectional study involving 300 healthcare professionals of a newly established teaching hospital. Prior to the measurement of interprofessional competencies, the 29-items CICS29, which has been translated into Indonesian language, was revalidated using a confirmatory factor analysis (CFA). The 29 items of CICS29 were grouped into six subscales and each item was measured using a 5-point Likert scale. Data on gender, age, type of profession, and the length of working experience was also collected to identify whether discernible differences between grouping variables exists.Prior to measuring the interprofessional competencies, the validity of the instrument was established. Based on the CFA, the same six-factor model was found in the current study. The Indonesian CICS29 was reliable, with Cronbach alpha values of 0.921 for the whole instrument and that of each subscale ranged between 0.656 and 0.726. The mean total score of CICS29 was 128.53 (out of 145), ranged from 123 to 133.40 obtained by pharmacists and dentists respectively. No significant differences of CICS29 scores were found between grouping variables.The current study has revealed relatively good interprofessional competencies of healthcare professionals working in a newly established teaching hospital in the Global South healthcare context. Measuring the interprofessional competencies serves as baseline for further intervention to nurture and maintain collaborative practice. In addition, the current study has further proven the cross-cultural validity of CICS29, thus appropriate to be utilized in different setting and context. The World Health Organization asserts the importance of interprofessional collaboration (IPC) practice to ensure safe and optimum patient care . IPC, asDespite the impact of interprofessional education (IPE) on patient care that has started to emerge, Reeves et al. argued that understanding of the collaboration process is still lacking, including how such collaboration affects clinical outcomes and processes . The autAside from understanding the nature of the collaborative practice, it is also important to learn about the interprofessional competencies of health care professionals. Measuring the interprofessional competencies of health care professionals is necessary given the role of health care professionals, especially those working in the academic health setting, as interprofessional role models for students . In a syn = 304) was considered relatively inadequate for a factor analysis  participated in this study. The details of the participants are provided in To ensure the validity of the instrument, the data first underwent CFA using Stata 14 software to confirm the CICS29 model as compared with the original one. Following the confirmation of the CICS29 model, the internal consistency of the instrument was calculated. Further analysis was then conducted using SPSS 22.0 to examine the distribution of CICS29 scores and to identify whether discernible differences in the measurement results existed in relation to several variables such as age, gender, types of professions, educational background , working status (full time/part time), and length of working experience.The descriptive analysis was performed first to examine the validity of each CICS29 item by identifying the item-total correlation and Cronbach’s alpha of each item . A CFA wThe validity of the instrument was further established by determining the reliability of the instrument as a whole and of each subscale. The Cronbach alpha value of the whole instrument was 0.921, and the value for each of the subscales was as follows: attitudes and beliefs as a professional (ABP), 0.732; team-management skills (TMS), 0.621; actions for accomplishing team goals (ATG), 0.726; providing care that respects patients (PCRP), 0.669; attitudes and behaviors that improve team cohesion (ABTC), 0.657; and fulfilling one’s role as a professional (FRP), 0.656.F = 0.644, p = 0.666. The scores of each subscale also did not significantly differ between profession groups, ABP, F = 1.470, p = 0.200; TMS, F = 1.147, p = 0.336; ATG, F = 0.239, p = 0.945; PCRP, F = 1.751, p = 0.123; ABTC, F = 1.624, p = 0.154; and FRP, F = 1.048, p = 0.389. Complete results of the mean scores of the total CICS29 and its subscales are presented in Using the validated CICS29, we examined the interprofessional competencies of the participants. The mean total CICS29 score was 128.53 , ranging from 123 (mean CICS29 score of pharmacist profession) to 133.40 (mean CICS29 score of dentist profession). Based on a one-way ANOVA, we found that there were no significant differences between the total mean score of each profession group, t-test analysis demonstrated no significant correlations on gender, t(298) = 1.881, p = 0.061, and working status, t(298) = 0.582, p = 0.561. Similar results were found using the one-way ANOVA on the variable of participants’ educational background, F = 0.908, p = 0.437. A significant regression equation was not found between mean total CICS29 scores with age and length of working experiences, F = 0.534, p = 0.660, with an R2 of 0.005. The predicted mean CICS29 total score is equal to 127.506–0.040 (length of working experiences) + 0.146 (age).The analysis also included the differences in the mean total CICS29 scores based on the grouping variables using the appropriate statistical analysis. The independent The findings of the CFA have demonstrated the validity of the CICS29 as an instrument to measure health professionals’ interprofessional competencies. The original CICS29 has also been validated in the Italian setting , where tSince the CICS29 has undergone several CFAs in different settings and countries and still retains its original six-factor model, we argue for the strength and quality of the instrument, which further support the suitability of its use in measuring interprofessional competencies in the current setting. Peltonen et al.  in theirUsing the valid Indonesian version of the CICS29, the interprofessional competencies of health professionals in this study were measured. Despite the unavailability of clear guidelines on how to categorize and interpret the CICS29 scores, the interprofessional competencies of the study participants are considered satisfactory because the mean total score of the CICS29 was around 88.6% of the maximum possible score. Other studies in the healthcare professional setting measured the perceptions of health care professionals toward IPC practice. For example, Soemantri et al.  conducteBased on the breakdown of subscales, the relatively high CICS29 subscale scores indicated that most participants in this study have what it takes to become effective interprofessional team members. Since the CICS29 subscales represent the essential abilities and attitudes for effective IPC, summarized by Reeves  in his eThe study findings also demonstrate that there are no statistically significant differences in the CICS29 scores based on professions and other discerning variables such as age, gender, working status, and length of working experiences. Older age and longer working experiences have been found to be the factors that influence IPC . BecauseBased on the study findings, several implications can be outlined. First, measuring healthcare professionals’ interprofessional competencies is important to serve as baseline for assessing the effectiveness of any interventions to improve collaborative practice. Second, the CICS29 is proven to be one of the instruments with cross-cultural validity, thus using the same instrument results from different countries can be directly compared to further inform IPC practice throughout the world, including within the Global South healthcare context. This is perhaps even more important for the Global South healthcare context since the hierarchical professional boundaries can be more prominent . Third, We acknowledge the limitation of the study in that it only involved one hospital in Indonesia. Therefore, the study might not be directly generalizable. As with other self-administered scales, there is a possibility for participants to provide socially desirable responses, which might not reflect the real situation. Despite these limitations, we believe that our study has contributed to the understanding of healthcare professionals’ interprofessional competencies in a Global South healthcare context. Measuring health care professionals’ interprofessional competencies could serve as the basis for intervention programs to further improve interprofessional competencies and enable more patient-centered and collaborative care. Our study has also established the construct validity of the Indonesian version of the CICS29, including cross-cultural validity. Further study is necessary to include more study sites and explore each of the factors which influence collaborative practice in more depth, which can lead to an understanding of how IPC can be further nurtured and maintained, especially in the Global South healthcare context. Moreover, a study to examine the relationships between interprofessional competencies and certain healthcare outcomes is also worthwhile.Measuring the interprofessional competencies of healthcare professionals in this study, using the CICS29 which has been proven to have cross-cultural validity, has advanced our understanding in terms of how they perceive their competencies, especially in a newly established hospital in the Global South healthcare context. The current study has identified relatively good interprofessional competencies and moreover, no differences in the competencies based on professions, age, and length of working experiences were found. Thus, an effective collaborative practice is to be expected, along with continued awareness that collaborative practice is indeed a complex construct that requires further in-depth exploration and observation.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 Research Ethics Committee, Faculty of Medicine, Universitas Indonesia. The patients/participants provided their written informed consent to participate in this study.DS led the study from the concept development, data collection, data analysis, and manuscript development and wrote the first draft of the manuscript. AF, RW, SK, and DD contributed to data collection, analysis, reviewed, edited, and finalized the manuscript. All authors have read and approved the final version of the manuscript.


Orthorexia nervosa (ON) is defined as an exaggerated, obsessive, pathological fixation on healthy food, healthy eating, or health-conscious eating behaviors. In the literature, there is an ongoing debate over whether ON should be considered simply a lifestyle phenomenon or a psychiatric disorder. In this vein, ON seems to share psychopathological characteristics with both eating disorders (EDs) and obsessive-compulsive disorder (OCD). However, there are insufficient data to reconcile the debate. The present study aimed at consolidating evidence on the clinical significance of ON and its relationship with EDs and OCD. A selective review of the literature published between January 2015 and March 2022 was conducted, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Ten studies were included. Some of these studies suggested that ON might follow a full-syndrome DSM-5 ED. Other studies proposed that ON and DSM-5 EDs may co-occur. Finally, only two studies suggested a relationship between ON and OCD. To date, the clinical significance of ON and its relationship with EDs and other DSM-5 psychiatric disorders  appears complicated and unclear. Future longitudinal research on the possible clinical course of ON is needed. In 1997, the physician Steven Bratman first described orthorexia nervosa (ON) as a condition characterized by a pathological obsession with healthy or “pure” eating and proper nutrition.In everyday life, individuals with ON avoid eating with other people and spend significant time planning and preparing healthy meals, using “pure food”. Notably, they exclude foods from their diets that they consider impure because they have pesticides or artificial substances, and they worry in excess about the materials used in the food elaboration. This specific attention to food purity and healthiness becomes an obsession that significantly interferes with global life functioning and may also lead to physical impairments such as malnutrition and excessive weight loss ,2,3. At ON is typically characterized by a desire to enhance one’s health and prevent or treat disease through the consumption of healthy food and the elimination of foods perceived as impure and unhealthy; this generally results in severe food intake restriction and the elimination of specific food groups, such as meat, dairy, grain, cooked food, and non-seasonal produce ,6. AnothSeveral instruments exist for the evaluation of ON, but the most widely used in the literature is the ORTO-15. The ORTO-15 is a self-report questionnaire  and madePrevious research ,14,15 haHowever, other studies  have sugResearch has also investigated the relationship between ON and OCD. Similar to patients with OCD, individuals with ON spend most of their time practicing strict and effortful procedures to choose, prepare, and eat healthy food. Indeed, orthorexic tendencies have been found in patients with OCD symptoms. In addition, some individuals with ON present recurrent, intrusive thoughts related to food, health, and contamination, which cause marked distress and anxiety. Most likely, these thoughts are similar to the obsessions experienced by OCD patients. Furthermore, the ritualistic processes of food preparation and consumption observed in individuals with ON resemble compulsions. Similar to the obsessions and compulsions of OCD patients, orthorexic thoughts and behaviors generate significant wasted time and limitations to social life resulting in high distress and worsening of quality of life . Overall, there is limited systematic research on ON, its clinical significance, and its relationship with psychiatric disorders . The studies and reviews described so far have specifically considered the relationship between ON and eating disorders or that between ON and OCD.Thus, the present review aims to summarize the literature over the last seven years on the clinical significance of ON and its relationship with both EDs and OCD. The present study comprised a selective review of the literature published between January 2015 and March 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.All included studies were obtained from a literature search of the electronic databases PubMed, CINAHL, PsycInfo, MedLine, and Cochrane Library. The algorithm used for the literature research was a combination of the terms: (orthorexia nervosa) AND . We purposely added “mental disorders” as a keyword in order to balance the sensitivity and specificity of our search strategy.Twelve articles were included. The last update of the search was in March 2022. The included studies investigated the clinical significance of ON and its relationship with EDs and OCD. Reviews, meta-analyses, comments, and letters were excluded. No language restrictions or study design restrictions were applied.The reference lists of the most important articles of interest were examined. Data on efficacy, acceptability, and tolerability were extracted by three authors independently . Article selection was completed by other authors . The search algorithm retrieved a total of 175 articles, of which 140 were excluded prior to screening. Of the 35 records screened, 10 referred to eligible studies, and the remaining 25 were excluded for the reasons listed in In terms of evidence-based medicine, the quality of the included studies was moderate. Ten studies on the clinical significance of ON and its relationship with DSM-5 EDs and OCD were analyzed. Due to the number and heterogeneity of the included studies, a narrative synthesis was conducted to describe, organize, explore, and interpret their findings while examining their methodological adequacy. Recently, Strahler et al.  examinedp < 0.001). A major risk of developing ON in adolescents aged 13–16 years was also found. Comparing the results of the ORTO-15 and the Maudsley Obsessional-Compulsive Inventory (MOCI), the authors found no significant relationship between the severity of obsessive-compulsive symptomatology and ON.Łucka et al.  examinedp = 0.001; ANO vs. control: p = 0.001). Finally, regarding the fulfillment of basic psychological needs, the ANO group scored significantly higher on the Basic Psychological Needs Scale [BPNS-E] competence (p < 0.017) and autonomy (p < 0.017) subscales relative to the AN group. Barthels et al.  investign = 43) of subjects presented a strong preoccupation with healthy food intake. Additionally, ON was negatively predicted by eating pathology, weight concern, health orientation, and appearance orientation. In fact, eating pathology and orthorexic behaviors showed a negative association, whereby lower levels of eating pathology were associated with more frequent orthorexic behaviors.Brytek-Matera et al.  assessedp < 0.01). Furthermore, correlations of the FMPS total score with scores on the OCI-R and EDE-Q were significantly greater than those of the FMPS total score with that of the rBOT (p < 0.05). Similarly, the association between the FMPS total score with that of the OCI-R was significantly greater than the association between the FMPS total score with that of the EDE-Q (p < 0.01). Bartel et al.  investigp = 0.005), followed by appearance orientation (p = 0.002) and overweight preoccupation (p < 0.001). Barnes and Caltabiano  investigNovara et al.  examinedp = 0.0005). Vaccari et al.  analyzedp < 0.05). No relationship was found between the severity of obsessive-compulsive symptoms and ON in patients with OCD (p > 0.05). Additionally, orthorexic tendencies were higher in participants who regularly engaged in physical exercise and patients with OCD (p < 0.05). When the groups were compared according to scores on the ORTO-11, the orthorexic symptoms of participants who regularly engaged in physical exercise were higher than those of the OCD patients and the healthy individuals who did not regularly engage in physical exercise (p < 0001).Yilmaz et al.  investigRania et al.  describeThe present selective review aimed at summarizing the recent findings on the clinical significance of ON and its relationship with EDs and other DSM-5 psychiatric disorders . Within the literature, there is an ongoing debate regarding two important clinical issues. The first consists of verifying whether ON is a behavioral/lifestyle phenomenon or a mental disorder. In this respect, Strahler et al.  found thThe second clinical issue about ON that is highly debated in the literature relates to whether or not ON should be classified as a distinct disorder, an ED, or a variant of another psychiatric disorder . As regards the clinical relationship between ON and DSM-5 EDs, Barnes and Caltabiano  showed tBarthels et al.  showed tIn anorexia, according to Fairburn , a feeliFurther research is needed to assess orthorexic-eating behaviors during treatment for anorexia, applying several follow-up measurements  to investigate orthorexic and anorexic eating behaviors over time.Regarding the clinical relationship between ON and OCD, previous studies ,61,62 haIn our review, Novara et al.  focused Similarly, Vaccari et al.  aimed atOverall, these results seem to support the idea that a correlation exists not only between ON and EDs but also between ON and OCD.Despite this, we point out a crucial difference between ON and OCD. In individuals with ON, ritual food preparation is not aimed at reducing distress like in OCD compulsions.Indeed, the repetitiveness and permanence of food-related thinking might suggest an excessive concern over the healthiness and preparation of food rather than an obsession followed by a compulsion to neutralize it. Finally, an individual with ON experiences his eating behavior as being in harmony or consistent with his ideal self-image. We propose that considering this egosyntonicity is a crucial target in improving the diagnostic definition of orthorexia and the implementation of effective psychotherapeutic treatments. Even if obsessive-compulsive characteristics may be associated with or mediate orthorexic behaviors, these two conditions could be treated with different approaches. For example, a psychoeducational intervention, focused on improving awareness of distress and the decrease in quality of life associated with orthorexic eating behaviors, could be useful in order to enhance compliance of individuals with ON with any other therapeutic intervention. Some limitations should be considered in our review. Firstly, the included studies featured a variety of study designs and ON measures. In addition, the review included both general population and clinical population studies. This limits the interpretability of the findings.The present selective review synthesized the recent literature on the prevalence and clinical significance of ON. The results suggest that ON should be considered a condition with clinical significance and not simply a behavioral/lifestyle phenomenon. In addition, while ON may be related to EDs and OCD, these relationships are not yet clear and should be clarified in future research. In particular, longitudinal studies should be conducted to collect data at the onset and during the clinical course of ON. This might improve our ability to determine whether ON precedes or follows the onset of EDs, OCD, or both.This knowledge could help the better diagnostic definition of orthorexia and the development of adequate therapeutic interventions.


Ammodaucus leucotrichus Coss. & Dur., a small annual species that grows in the Saharan and sub-Saharan countries. In the present study, we investigated whether the standardized ethanolic extract of A. leucotrichus fruits and R-perillaldehyde, a monoterpenoid isolated from A. leucotrichus fruits, are able to affect different processes involved in different phases of cancer development. In particular, we explored their genoprotective, proapoptotic, antiproliferative, and cytodifferentiating potential on different human cell models. We analyzed the genoprotective and proapoptotic activity on human lymphoblast cells (TK6) using the micronucleus test, and the cytodifferentiation effects on human promyelocytic cells (HL60) through the evaluation of different markers of differentiation forward granulocytes or monocytes. The results showed that the extract and perillaldehyde were able to induce apoptosis and protect from clastogen-induced DNA damage. To our best knowledge, this is the first report on the ability of A. leucotrichus and perillaldehyde to induce apoptosis and protect DNA from the toxicity of different compounds. Data reported in this work are the starting point for their pharmacological use. Going forward, efforts to determine their effects on other events associated with cancer development, such as angiogenesis and metastasization, will provide important information and improve our understanding of their potential in cancer therapy.Little is known about the pharmacological activity of  Current pharmacological approaches for cancer treatment include the use of a plethora of chemotherapeutic drugs, which are characterized by multiple adverse and toxic effects . RecentlAmmodaucus leucotrichus Coss. & Dur. (Apiaceae), known in Algeria as “Kammûn es-sofi”, is an aromatic small annual species that grows in the Saharan and sub-Saharan countries of North Africa, including Morocco, Algeria, and Tunisia extending to Egypt and tropical Africa  assay for adherent cells. The viability percentage recorded in the treated cultures was normalized on that recorded in the concurrent negative control cultures, considered equal to 100%. IC50 was calculated by interpolation from the dose–response curve.After treatment with PD):The number of cells seeded at time 0  and that measured at the end of the treatment time (post-treatment cell number) were evaluated using the Guava ViaCount Reagent. From those values, we derived the population doubling , containing PI for 30 min in the dark. The analysis of samples was performed via flow cytometry.After treatment, cells were incubated with 100 µL of Guava Nexin Reagent (Merck), containing 7-AAD and annexin V-phycoerythrin, for 20 min at room temperature in the dark, and analyzed by flow cytometry. The apoptotic cell percentage recorded in the treated cultures was normalized on that recorded in the concurrent negative cultures, considered equal to 1, and expressed as apoptotic fold increase .A. leucotrichus or perillaldehyde with or without the clastogen CYT and the aneugen VINB, used as positive controls [MNi frequency was evaluated in cultures treated with controls . The anacontrols  already controls ,52,53,54Briefly, at the end of the treatment time, cells were collected, lysed, and stained with SYTOX Green. The discrimination between nuclei and MNi was performed based on the different sizes analyzed by forward scatter (FSC) and the different intensities of green fluorescence. The MNi frequency, calculated as the number of MNi per 10,000 nuclei deriving from living and proliferating cells and recorded in treated cultures at all concentrations tested, was normalized on those recorded in the untreated cultures.A. leucotrichus or perillaldehyde for 72 h, as previously described [The cytodifferentiation potential was evaluated in HL60 cells treated with escribed . After iThe activity of α-naphthyl acetate esterase was assessed using the cytochemical 91-A kit , accordiv/v) was used as the positive control. Results were expressed as percentages of positive cells over total cells.The NBT assay evaluates the ability of a compound to generate superoxide when exposed to TPA . BrieflyAfter 72 h of treatment, the medium was removed and the non-adherent cells were gently removed, washing with PBS 1x. Dish-anchored cells were counted using the inverted microscope Nikon ECLIPSE Ts2 . TPA 50 p values below 0.05 were considered significant.Results are expressed as the mean ± SEM of at least three independent experiments. Statistical analyses were performed using one-way or two-way ANOVA test and Dunnett or Bonferroni as post-test, using GraphPad InStat 6.0 version ; A. leucotrichus to induce apoptosis and protect DNA from the toxicity of different compounds. Data reported in this work are the starting point for its pharmacological use. Going forward, efforts to determine its effects on other events associated with cancer development, such as angiogenesis and metastasization, and to analyze its activity in association with conventional chemotherapeutic drugs will provide important information and improve our understanding of its potential in cancer therapy. To our best knowledge, this is the first report on the ability of


Patients using immunosuppressive drugs may have unfavorable results after infections. However, there is a lack of information regarding COVID-19 in these patients, especially in patients with rheumatoid arthritis (RA). Therefore, the aim of this study was to evaluate the risk factors associated with COVID-19 hospitalizations in patients with RA.This multicenter, prospective cohort study is within the ReumaCoV Brazil registry and included 489 patients with RA. In this context, 269 patients who tested positive for COVID-19 were compared to 220 patients who tested negative for COVID-19 (control group). All patient data were collected from the Research Electronic Data Capture database.P < 0.001) and current use of glucocorticoids  were the risk factors associated with hospitalization. In addition, anosmia was associated with a lower chance of hospitalization .The participants were predominantly female (90.6%) with a mean age of 53 ± 12 years. Of the patients with COVID-19, 54 (20.1%) required hospitalization. After multiple adjustments, the final regression model showed that heart disease (OR = 4.61, 95% CI 1.06–20.02. Our results demonstrated that heart disease and the use of glucocorticoids were associated with a higher number of hospital admissions for COVID-19 in patients with RA.Trial registration: Brazilian Registry of Clinical Trials - RBR-33YTQC.The online version contains supplementary material available at 10.1186/s42358-022-00244-5. The COVID-19 pandemic has raised additional concerns for rheumatologists, especially related to health care for patients with immune-mediated rheumatic diseases (IMRDs) . NotablyAlthough some evidence on the course of SARS-CoV-2 infections in patients with IMRDs has already been demonstrated, such as a similar COVID-19 prevalence to that of the general population , there aConsidering the rheumatoid arthritis (RA) treatment scenario, which includes disease activity, low-dose prednisone, methotrexate, TNF blockers, IL-6 antagonists, JAK inhibitors, and anti-CD20 therapy, as a prototype for these findings, this study had the main aim of evaluating the risk factors associated with COVID-19 hospitalizations in patients with RA.This was a cross-sectional analysis performed only in patients with RA who were enrolled in the ReumaCoV-Brazil Registry, a multicenter, prospective cohort study, used to evaluate and monitor patients with IMRDs during the COVID-19 pandemic. The complete methodology and initial data were published previously , 16. EliThe following inclusion criteria were considered: (a) an age older than 18 years; (b) a diagnosis of COVID-19, according to the Ministry of Health; and (c) a previous diagnosis of RA, according to the American College of Rheumatology or the European League against Rheumatism criteria. The exclusion criteria were patients with HIV or other immunodeficiency diseases, previous organ or bone marrow transplants, neoplasms in the last five years, current chemotherapy treatment and diseases of the thymus.https://www.project-redcap.org/) electronic database was used to collect and record the patients’ sociodemographic aspects and information on RA ). Information was obtained by telephone or a face-to-face consultation, according to the local recommendations due to the pandemic, and through medical records in the event of hospitalization.The Research Electronic Data Capture (REDCap)  were presented. For associations among categorical variables, the chi-square test was used, or Fisher’s exact test was used when cells had expected values of less than five counts. In cases of discrepancies, the standardized adjusted residue was used to identify local differences–cells with absolute values above 1.96 indicated significant deviations from expected values assignable only to random variations.The comparisons of the means between two groups and more than two groups were performed using Student’s t-test for independent samples and analysis of variance (ANOVA), respectively. Normality in data distribution was verified by the Kolmogorov–Smirnov test. In the event of assumption violations to Student’s t-test and ANOVA, the Mann–Whitney and Kruskal–Wallis nonparametric tests were used, respectively. Once the Kruskal–Wallis test was significant, the location of paired differences was determined by Dunn Bonferroni tests, maintaining an overall significance level of 5%.To assess the simultaneous effects of the demographic and clinical characteristics  on hospitalizations , univariate and multivariate logistic regressions were adjusted. For the initial multivariate models, predictor variables whose associations with the dependent variable were significant at 10% in the univariate logistic regression were selected. Then, a backward procedure was conducted by excluding the variables one by one in order of significance that were not found to be more significant at 5% in the multivariate regression than those in the final model. The final model fit was then evaluated by a Hosmer and Lemeshow test. Due to the large number of predictor variables and the small number of events, the variables whose associations with the dependent variable were significant amounted to 10% in the univariate logistic regression. Then, the variables that were not significant to 5% were excluded one by one in order of significance (backward method). In addition, the adjustment adequacy of the final model was evaluated by the Hosmer and Lemeshow test.For all statistical tests, a significance level of 5% was used. Statistical analyses were performed using SPSS 20.0 statistical software.This study was approved by the Brazilian Committee of Ethics in Human Research on April 5, 2020,  and registered on the Brazilian Registry of Clinical Trials (RBR-33YTQC) on June 1, 2020. All patients signed informed consent forms, and the results of the study are presented in an aggregated form, guaranteeing confidentiality and ensuring that there are no risks to patients’ well-being and care.From May 24, 2020, to January 31, 2021, 489 patients with RA were included: 269 tested positive for COVID-19, and 220 tested negative for COVID-19 (control group). There was a female predominance  with a mean age of 53 ± 12 years. Considering only the patients with COVID-19, 54 (20.1%) patients required hospitalization.Comparing hospitalized patients with COVID-19 with outpatients, patients with COVID-19 were older, and had one, two or more comorbidities present. Diabetes mellitus and hypertension were significantly more prevalent in those who required hospital care Table .Table 1Considering specific findings related to RA, including autoantibody status and cumulative damage (erosions), extra-articular manifestations, withdrawal therapy, and the current use of azathioprine and corticosteroids were associated with hospitalization. On the other hand, patients on TNF inhibitors had a significantly lower frequency of hospitalization Tables  and 4.TaP < 0.001), vomiting , heart disease , and the current use of glucocorticoids . Moreover, anosmia was associated with a lower chance of hospitalization    but simiThe main advantage of our study was the inclusion of a large sample of patients with RA. In addition, all data were preparametrized, prestandardized and captured by a trained rheumatologist and with laboratory test confirmation for those who tested positive for COVID-19.Considering the traditional risk factors related to COVID-19 severity, our results did not find a significant association with age after multiple adjustments for cofounders, which is contrary to other studies from the general population and IMRD cohorts , 18–21.However, heart disease, as a comorbidity, was significantly associated with hospitalization, which is in accordance with the current literature –33.These results suggest that the comorbidity burden seems to be similar to several reports from the general population, regardless of underlying rheumatic disease , 31–41.Although some clinical findings were associated with hospitalization in our cohort, such as shortness of breath and vomiting, these findings may be redundant because they are considered red flags or parameters for hospitalization –48. TherInterestingly, anosmia, an important specific clinical marker for COVID-19 , had a pIt is worth emphasizing that the clinical and laboratory characteristics of RA and DMARDs  were not associated with hospitalization in the final analysis, except for the current use of glucocorticoids . This is a recurrent finding among the studies , 13.Patients with RA on TNF inhibitors had a lower rate of hospitalizations in the initial analysis but this finding was not confirmed after multivariate analysis which is contrary to own findings when considering the entire sampling of patients with IMRDs  and the In addition, the second analysis of the GRA database that involved 2869 patients with RA found that rituximab  and JAK inhibitors  were significantly associated with COVID-19 severity . Our datOur study has some limitations, such as the convenience sample and small number of patients, cross-sectional analysis of an ongoing prospective cohort, the low number of rituximab users and specific DMARD targets and the lack of information on disease activity. On the other hand, our study included a national sample with a more homogeneous rate of community viral transmission, social distancing measures and immunization.Our data showed traditional risk factors, including heart disease as a comorbidity, and the current use of glucocorticoids are more involved with hospitalizations for COVID-19 in patients with RA than the underlying IMRDs alone.Additional file 1. Results of univariate logistic regression models - hospitalization in patients with rheumatoid arthritis.


Epilepsy is one of the most frequent serious brain disorders. Approximately 30,000 of the 150,000 children and adolescents who experience unprovoked seizures are diagnosed with epilepsy each year. Magnetic resonance imaging is the method of choice in diagnosing and monitoring patients with this condition. However, one very effective tool using MR images is volBrain software, which automatically generates information about the volume of brain structures. A total of 57 consecutive patients (study group) suffering from epilepsy and 34 healthy patients (control group) who underwent MR examination qualified for the study. Images were then evaluated by volBrain. Results showed atrophy of the brain and particular structures—GM, cerebrum, cerebellum, brainstem, putamen, thalamus, hippocampus and nucleus accumbens volume. Moreover, the statistically significant difference in the volume between the study and the control group was found for brain, lateral ventricle and putamen. A volumetric analysis of the CNS in children with epilepsy confirms a decrease in the volume of brain tissue. A volumetric assessment of brain structures based on MR data has the potential to be a useful diagnostic tool in children with epilepsy and can be implemented in clinical work; however, further studies are necessary to enhance the effectiveness of this software. Epilepsy is one of the most frequent serious brain disorders. It is a combination of somatic, vegetative, and psychiatric symptoms resulting from both morphological and metabolic changes in the brain. It is characterized by a persistent predisposition to generate seizures. The prevalence of epilepsy among the pediatric population is the highest during the first year of life . ApproxiChildren show cognitive impairment, possibly due to changes in the brain structures following seizures or epileptic dysfunction. Discrete changes in the brain architecture, function or biochemistry can be assessed by imaging studies, which detect focal changes in 21–37% of patients with epileptic seizures ,5.Magnetic resonance (MR) is the method of choice for diagnosing epilepsy. The detection of structural changes in the central nervous system (CNS) in this examination, correlating with other diagnostic findings, significantly increases the chance of successful surgical treatment of epilepsy and could possibly help to define or to clarify the etiology of epileptic seizures. MR imaging performed in accordance with a standard protocol enables the detection of focal lesions , while the use of appropriate MR protocols  significHowever, chronic epilepsy may be associated with the occurrence of structural and volumetric changes in the brain both within and beyond the epileptogenic zone. Cross-sectional MR imaging studies in patients with intractable epilepsy have reported significant cerebellar and cerebral volume reduction as well as atrophy of the hippocampus or brain cortex in children and adults ,11. AtroBy following this thought, it was our aim to evaluate the volume of selected brain structures in the pediatric population and assess whether differences exist between individuals with epilepsy and healthy volunteers in terms of brain atrophy.Four hypotheses were formulated:Hypothesis 1 (H1).During epilepsy, there is an atrophy of brain tissue that reflects in the decrease in volume of particular brain structures.Hypothesis 2 (H2).There is a significant difference in particular structures’ volumes between the study and control group.Hypothesis 3 (H3).There is a relationship between the volume of individual CNS structures and the presence of comorbidities in a group of children with epilepsy.Hypothesis 4 (H4).VolBrain software is a tool for parameterization of brain lesions in the course of epilepsy.n = 91). The process of obtaining the required data consisted of several steps. Initially, images of certain patients were exported from the local Picture Archiving and Communication System (PACS). Then, the scans in DICOM format (.dcm) were converted into NIFTI format (.nii), using free MRIcron software. Further steps involved creating a free account and registering on the volBrain website (www.volbrain.upv.es/ accessed on 1 May 2022). Then, individual scans in NIFTI format were uploaded to the volBrain. The software rendered an automatic, quantitative analysis of the MR data. Processing time for a single image averaged 14 min (depending on how occupied the servers were at the particular time). The volBrain pipeline is designed to enhance the quality of the input images and set them in a geometric space and intensity to segment and distinguish the various structures and tissues. The segmentation process consists of the following steps: spatially adaptive non-local means denoising, rough inhomogeneity correction, affine registration to MNI space, fine SPM-based inhomogeneity correction, intensity normalization, non-local Intracranial Cavity Extraction (NICE), tissue classification, non-local hemisphere segmentation (NABS) and non-local subcortical structure segmentation, respectively . The final phase was based on a comparative analysis of the structures’ volume differences between the S group and the C group.In our retrospective study, the study (S) consisted of 57 consecutive patients  suffering from epilepsy, regardless of its type and disease duration, who underwent head MR examination without contrast agent administration between 2018 and 2021 at the Children’s Hospital of the Medical University of Lublin in Poland. Their mean age was 8.94 ± 4.72 years . The exclusion criteria included the most common causes of secondary epilepsies such as post-traumatic, hemorrhagic, ischemic-hypoxic lesions and brain structure deformations such as hydrocephalus, tumors, arteriovenous malformation or developmental disorders. The control (C) group included 34 healthy patients F = 15, M = 19) without epilepsy with mean age 9.24 ± 5.44 years  who underwent head MR examination for reasons other than epilepsy. All examinations were performed using Siemens Aera 48-channel 1.5T MRI scanner according to a dedicated protocol (epilepsy-specific protocol) . The study was based on assessment with the use of T1-weighted ISO 3D MRI images , there were no relevant lesions in the brain in the MR examination  the non-parametric Mann–Whitney U test was applied to test the difference between the two groups .1.BrainThe statistically significant differences between the S and the C group were found for:p = 0.029 *)  than for the S group (Mdn = 90.53%),  .2.Laterap = 0.001 *)  than for the control group (Mdn = 0.55%),  .3.Putamep = 0.044 *)  than for the studied group (Mdn = 0.62%)  .The results for the other tested factors indicated non-significant differences between the groups (S and C). Nevertheless, there is a definite declining trend in the volume of remaining structures in patients with epilepsy as compared to healthy patients.Next, the results from the volBrain program were analyzed according to the presence of comorbidities in a group of children with epilepsy. The following comorbidities/conditions were included in the analysis: prematurity, delayed development, cerebral palsy, the presence of arachnoid cyst, Recklinghausen’s disease, undefined CNS defects, mental disability, speech disorders, hearing loss and factor XII deficiency; however, due to the small number of distributed variables, the analysis was based on two variables—the absence or presence of comorbidities.Although no significant differences were observed between the groups, patients with comorbidities showed bigger brain atrophy (90.11 vs. 90.55% of the IC), and greater volume of the lateral ventricles (0.98 vs. 0.69% of the IC) .In addition, EEG examinations of patients with epilepsy were also included in the analysis. Four groups were selected: normal EEG, paroxysmal lesions, generalized lesions and localized lesions. The results showed that there were no significant differences for all quantitative variables  relative to normal EEG or EEG deviations. The study group was also divided according to the duration of the disease , which was then confronted with changes in volumes of the particular intracranial structures. Similarly, no significant relationships were found between disease duration and quantitative variables.The etiology of epileptic seizures is multifactorial: genetic, metabolic, and dependent on triggering immune factors . ChromosMany studies support the hypothesis that the cause of epileptic seizures might be attributed to an imbalance between excitatory and inhibitory currents that include: gliosis, uncontrolled inflammation, an impaired blood–brain barrier (BBB), neurodegeneration, aberrant neurogenesis, axonal and dendritic plasticity, changes in neural circuits, structural and functional changes in receptors, ion channels, transporters and enzymes implicated in excitatory and inhibitory neurotransmission, reorganization of the extracellular matrix (ECM) and epigenetic reprogramming . There iIn a single study from the Institute of Neurology in London, postmortem examinations revealed macroscopic abnormalities in 70% of epilepsy cases. These included: contusions, old infarcts, hippocampal sclerosis, cortical dysgenesis, vascular malformations, oligodendrogliomas, neurodegenerative brain diseases, and microcephaly . The aboFor several years, the effect of epilepsy on the volume of the brain structures has begun to be considered. To date, the volumetry of individual parts has been assessed based on post-mortem examinations, pneumoencephalography, computed tomography and magnetic resonance imaging. Studies in which traditional methods of measurement were used were analyzed ,11,13.The most common MR techniques to evaluate the abnormalities of the entire brain comprise the assessment of the anatomical structure (volumetric and morphometric MRI), white matter tissue properties (diffusion MRI), neuronal activation  and metabolite concentrations (MRSI) ,25. FuncThe study, carried out with MR imaging-based volume measurements, proves that multiple brain regions beyond the hippocampus are volumetrically affected in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE + HS). Patients displayed significant volume reduction in the ipsilateral amygdala, thalamus, and cerebral WM. In addition, patients with left MTLE + HS displayed volume loss in the contralateral hippocampus and cerebellar GM bilaterally .Another analysis of optimized voxel-based morphometry results showed a significantly smaller size of structures such as the rostrum and rostral body of corpus callosum and the left hippocampus compared to the C group. The left frontal lobe was significantly larger in the epilepsy group . Our stuBased on our study, in which we used VolBrain software to analyze the volume of each CNS structure, we found that there is also a slight reduction in hippocampus and thalamus volume, but no difference in amygdala and globus pallidus volume in the S and C group.There are a few studies in the literature that analyzed the volume of specific CNS structures in patients with epilepsy using VolBrain software, which is emphasized by the fact that it is an extremely innovative method. Contrary to our study, other authors included adult and pediatric patients in their analysis.The first study involved an analysis that investigated the cerebellar substructure alterations and the association with clinical factors and cognitive scores among refractory unilateral TLE patients. The study included 48 patients aged 14 to 60 years who suffered from drug-resistant unilateral temporal epilepsy. The total volumes of crus I, crus II, and IX were significantly smaller on both sides; however, the GM volumes of cerebellar lobules showed a reduction in crus III and IX ipsilateral and crus II contralateral. The duration of epilepsy has no effect on the GM volumes of contralateral crus II. A decrease in the volume of the GM volumes of contralateral crus II resulted in significant deviations in the cognitive scores .Subsequent studies were devoted to the analysis of the volume of the hippocampus and the subfield of the hippocampus in patients with TLE. Based on the analysis, it was found that the volume of the hippocampus decreased in the course of TLE. Moreover, hippocampal volumes ipsilateral to the hippocampal sclerosis side were significantly reduced compared with controls and also with the non-lesional side . Additiop = 0.99), but Neuroquant had lower sensitivity  [It is worth mentioning that there are not many similar types of software to volBrain. One of them is Neuroquant, which automatically measures the volume of brain structures. It has found application in observing changes in the course of Alzheimer’s disease, traumatic brain injury and multiple sclerosis . There w< 0.001) . Several< 0.001) . Some ev< 0.001) . Similar< 0.001) . Our resOur study validates H1, H2 and H4 hypotheses. Healthy patients do not have any significant brain changes in comparison to children with epilepsy. The S group has lower values of cerebrum, cerebellum, brainstem, hippocampus, putamen, thalamus and nucleus accumbens, which indicates atrophy of the brain. Signs of atrophy were evident in the visual MR assessment (performed by an experienced radiologist) and then quantitatively confirmed by automated volumetric evaluation. Statistical analysis based on volBrain software is the basis for creating a parameterization. However, the H3 hypothesis is not fully validated due to the fact that there were no significant differences between the groups with and without the presence of comorbidities. Nonetheless, a declining trend was observed in the volumes of the majority of evaluated structures in patients with epilepsy in relation to healthy controls. In the case of lateral ventricles, the observed volumes were bigger in the epileptic subjects.The data obtained have important clinical and prognostic significance; however, there are some limitations. First of all, they need to be confirmed in a large study group as this could significantly affect the results. In the study group, the presence of comorbidities was not significantly correlated, but there was a trend showing greater brain atrophy among patients with comorbidities. Other variables could be considered, such as disease duration and EEG abnormalities . Moreover, the interpretation of volumetry results is challenging due to the inherent methodological differences. Furthermore, normal morphometric differences are recognized in diverse populations that may need consideration. Our study did not assess the impact of the volume of individual parts of the CNS on cognitive functions. In addition, in the cited analyses, the research group consisted of only patients with specific types of epilepsy , while our study included all patients with symptoms of epilepsy regardless of the location.Structural changes in people with epilepsy in the form of brain atrophy are well known; however, this is not assessed visually—there is a lack of parameterization. To our best knowledge, there are only a few studies that analyze the volumetry of particular brain structures, especially by using VolBrain software.In our study, signs of atrophy were evident in the visual MR assessment (performed by an experienced radiologist) and then quantitatively confirmed by automated volumetric evaluation. Significant differences were evident, especially for structures such as brain tissue, lateral ventricles and putamen. Volumetric assessment of brain structures based on MR data can potentially be a useful diagnostic tool in children with epilepsy and can be implemented in clinical work for monitoring patients and the progression of the disease. In addition, it is a time-saving program and appears to be an effective, objective and accurate method; however, further studies are necessary to enhance the effectiveness of this software.


Prunus spinosa, Taraxacum spp., Rosa canina, Urtica dioica, Juglans regia and Fragaria vesca. In the Lovinac region, people used fewer species of plants (76 species mentioned). The most common species used there are: Rosa canina, Achillea millefolium, Cornus mas, Crataegus monogyna, Sambucus nigra and Prunus domestica. In the town of Gospić, the collection and use of plants was not so widespread, with only 61 species mentioned, the most common being: Achillea millefolium, Cornus mas, Sambucus nigra, Viola sp., Prunus domestica and Rosa canina. The medicinal use of herbal tea Rubus caesius and Cydonia oblonga against diarrhea was well known in the study area and is used medicinally, mainly in the rural parts of the Gospić area. The consumption of the Sorbus species  is an interesting local tradition in Perušić and Lovinac. Species that are difficult to find in nature today and are no longer used include: Veratrum sp., Rhamnus alpinum ssp. fallax, Gentiana lutea and Ribes uva-crispa. The use of Chenopodium album has also died out. We can assume that the differences in ethnobotanical knowledge between the three studied areas are partly due to minor differences in climate and topography, while other causes lie in the higher degree of rurality and stronger ties to nature in the Lovinac and Perušić areas. The most important finding of the study is the use of the parasitic fungus Taphrina pruni (Fuckel) Tul. as a snack. The use of Helleborus dumetorum for ethnoveterinary practices is also worth noting. The traditional use of plants in the study area shows many signs of abandonment, and therefore efforts must be made to maintain the knowledge recorded in our study.This study analyzed the use of plants and fungi, some wild and some cultivated, in three municipalities of Lika-Senj County . The range of the study area was about 60 km. Forty in-depth semi-structured interviews were performed. The use of 111 plant taxa from 50 plant families and five taxa of mushrooms and fungi belonging to five families was recorded (on average 27 taxa per interview). The results showed quite large differences between the three studied areas in terms of ethnobotanical and ecological knowledge. In the Perušić area, (101 taxa mentioned), some people still use wild plants on a daily basis for various purposes. The most commonly noted plants are  Traditionalist societies seek to preserve their traditional and cultural values, aiming to transfer them to posterity. Ethnobotanical studies can help in this task ,2,3. In Most botanical studies conducted in Croatia are focused on exploring floristic composition, vegetation and threatened and endemic species . To dateAccording to Łuczaj et al. ,15,16, tThe evolving dynamics of ethnobotanical knowledge transmission have been found to be affected by different drivers, including political , historiThe western regions of the Dinarides were inhabited by the so-called White Vlachs, whose name is derived from the white woolen clothes they wore.The related Black Vlachs lived in the eastern areas of the Dinarides and wore black woolen clothes. Croats differed from the Vlach population in never having engaged in nomadic cattle breeding but always having lived in permanent settlements. White Vlachs, who lived around Velebit and Dinara in the Middle Ages, were Roman Catholics, while the Black Vlachs were partly Bogumili, and partly members of the Orthodox church. This situation was disrupted by the Ottomans, who reached Lika in the 16th century. Until the beginning of the 18th century, there were no major settlements located where the town of Gospić is today. The settlers who arrived here were mostly craftsmen and farmers of diverse origin: Christianized Muslims, Bunjevci and Catholics from the coast and upper Pokuplje (Bosnia and Herzegovina). During the period of Turkish settlement, Perušić enjoyed the reputation of an advanced and rich district center, a fortress guarded by soldiers and surrounded by populous villages. At the beginning of the 18th century, the Bunjevci and the Vlachs were settled in Lovinac and engaged in animal husbandry ,26.The people of Lika have always been poor and humble, surviving on “proja” , sheep’s milk, cheese, potatoes, beans, cabbage, onions and bacon. Due to the high birth rate in the 19th century, Lika became the province with the most visible degree of emigration in Croatia, both to richer regions and overseas . Since the traditional consumption of useful plants in the central Lika region has never been documented, the general aim of this study is focused on edible food and feed, medicinal plants, and ethnoveterinary uses, but also includes plants used for religious or traditional ceremonies and tools. The aim was also to contribute to the knowledge of plant biodiversity in the area.During the surveys, 1082 valid use records were collected, in which the respondents identified 111 plant species from 50 plant families and five taxa of mushrooms and fungi belonging to five families . As manySD = ±8.3940). The most recorded taxa belong to Rosaceae (21) and Compositae (13) plant families. Some of the families were represented by only one or two species, but those species were frequently mentioned among respondents, such as the families Cornaceae , Urticaceae  and Juglandaceae . The number of taxa per interview was between 15 and 49, with a mean of 27 taxa per interview  and Cornus mas (RFC = 0.825). A total of 10 taxa have absolute frequencies of 30 or more, while 40 were mentioned at least 10 times.The most frequently mentioned taxon in the survey is olium L. , with reJI = 57.14% for the pair Gospić–Lovinac, JI = 55.86% for the pair Lovinac –Perušić and JI = 54.37% for the pair Gospić–Perušić.Of the total of 111 plant taxa recorded, 47 were mentioned in all three survey localities, while 28 occurred in at least two localities. Some taxa were recorded only in one particular locality: Perušić—28 taxa, Lovinac—9 and Gospić—1. The similarity or correspondence (Jaccard Index) between the pairs of areas is Rosa canina L. (Sj = 0.6725), Achillea millefolium (Sj = 0.6670), Cornus mas (Sj = 0.5627), Sambucus nigra L. (Sj = 0.5236) and Urtica dioica (Sj = 0.5050). The most important plant species in relation to Smith’s S saliency indicator values are eCV), we find that the three taxa with the highest cultural value are Cornus mas (CVe = 0.812), Taraxacum spp. (eCV = 0.380) and Achillea millefolium (eCV = 0.356)  .SD = ±4.682) and seven for medicinal purposes . In addition, plants were used as livestock feed (33 species), to make alcoholic beverages (15 species), for ceremonial purposes  and for medicinal purposes (46 taxa) . They usCornus mas has the largest number of recorded uses (UR = 63), followed by Prunus domestica L. (UR = 49), Juglans regia (UR = 46), Urtica dioica (UR = 41) and Achillea millefolium (UR = 41) (The average number of use reports per plant is 11.24 for the whole study area. The taxon UR = 41) . Cornus mas is not only the most commonly used plant; together with Tilia platyphyllos, it also has the most different uses, namely five. However, for the latter plant, the total number of uses is only UR = 30. On average, the number of uses, i.e., use categories, is 1.72 per plant.Prunus domestica has the highest UR in the food and drink category (UR = 31) and Achillea millefolium in the medicine category (UR = 37). In alcoholic beverages, Juglans regia L. (UR = 19) is used most for the production of sweet walnut liqueur. Taraxacum sect. Ruderalia is mostly used as livestock feed (UR = 21), and Corylus avellana L. is the most commonly used plant in the category of building and making useful items (UR = 11) (UR = 11) .Fic), respondents showed the highest level of agreement in the food and beverage  and ceremonial purpose  use categories  and Cornus mas (FLs = 90.91) , followed by Prunus domestica (FLs = 56.25) and Cornus mas (FLs = 51.52). In the animal feed use category, agreement is highest for the taxa Taraxacum spp. (FLs = 65.62) and Urtica dioica (FLs = 45.16). A large proportion of respondents indicated that the taxon Corylus avellana is, or has been, used in construction or for making useful items for the home or farm. Of the ten taxa with the highest UR, only Cornus mas is used for ceremonial purposes (FLs = 42.42).Regarding use as food or beverage, interviewees have the highest agreement regarding = 90.91) . In the The most commonly used plant parts are fruits , leaves (23%), and flowers (21%) . Fruits A total of 284 uses of plants for medicinal purposes were recorded, most of which were for treating stomach aches (44), colds (25), and coughs (21). The greatest variety of plant species is used to treat diarrhea (6), open wounds (5) and coughs (5). The most frequently reported unique medicinal uses were the treatment of heart problems in humans (six use reports) and the treatment of erysipelas in pigs (four use reports). We found high fidelity levels regarding the use of certain plants for medicinal purposes with respect to treatment of stomach pains, colds, coughs, wounds, abdominal cramps and pain, diarrhea, earache, anemia and warts .Agaricus sp. (20 times) and Boletus sp. (6 times) were mentioned most frequently. Mushrooms are used as food, usually fried with eggs. A more recent method of preparation is in risottos or sauces . Three respondents mentioned eating the fruits of Prunus domestica infected with Taphrina pruni (Fuckel) Tul. fungus as children.Mushrooms or fungi were mentioned a total of 34 times by 21 of the 40 respondents (mean = 0.85). Therefore, on average, 1.6 taxa were mentioned per interview. Rumex spp. or a decoction of Cydonia oblonga L., R. pulcher L., and oak bark (Quercus sp.), which is sometimes even combined with Hypericum perforatum L. A decoction of St. John’s wort (H. perforatum) or juice squeezed from raw green bean leaves (Phaseolus vulgaris L.) is also used to wash wounds and scratches in cattle and to stop bleeding. Hellebore  has long been used for cattle and horses to treat inflammation of the larynx or ears. The affected area is pierced with a cleaned hellebore root, which leads to irritation and the formation of an abscess that draws out the inflammation. Danewort (Sambucus ebulus L.) has been used to treat swine ersypelas in pigs, reduce swelling from snake bites in cows, and when extracting fever from the body.The results show the most frequently mentioned plant species used to treat various diseases and ailments in animals. In both people and animals , diarrhea is treated with dried fruits of Silene vulgaris (Moench) Garcke is used in religious ceremonies, brought to church for blessing, later salted and given to cattle to eat.F = 3.5, p = 0.038, Scheffe post hoc test p = 0.008). The average number of records per respondent is significantly higher in the Perušić locality than in the Gospić locality  = 3.5, p = 0.038, Scheffe post hoc test p = 0.008). One possible reason for this difference is the larger proportion of the population in the Perušić locality employed in activities related to agricultural and forestry resources. Most of the population of Gospić is not employed in the primary sector and lives in urban conditions.The largest number of taxa (101) and the highest mean number of taxa listed per respondent (27.05) were recorded in the locality of Perušić. Seventy-three taxa were recorded in the locality of Lovinac (25.31 per respondent) and 59 in Gospić (average 22.09). The average number of taxa per subject is statistically significantly higher in the Perušić locality than in the Gospić locality (ANOVA RFC = 1.00). In Perušić, there is no such instance for any taxon. The decrease in ethnobotanical knowledge of people moving to urban settings (like Gospić) can be expected and was even recorded in the Balkans from Kosovo [Considering the entire study area, 40 of the total 111 taxa recorded have absolute frequencies of 10 or more, and 10 have frequencies of 30 or more. The frequencies of taxa in individual areas range from zero to 15, and are highest in the Perušić locality (16 respondents). In the Gospić locality (11 respondents), there are four taxa with frequencies of 10 or more; in the Lovinac locality (13 respondents) there are eight; and in the Perušić locality there are 15. These data confirm the difference in ethnobotanical knowledge in the three studied areas could be due to the greater degree of urbanization around Gospić. The relative frequencies indicate a higher concentration around a lower number of known taxa around Gospić and Lovinac compared to Perušić. Namely, in the former two areas, three taxa are mentioned by all respondents . Their diet is based on crops that they can grow themselves in the garden, such as cabbage that can be lacto-fermented in the fall for the winter, potatoes, beans, garlic, onions, and corn for flour or polenta. This is in contrast with, e.g., the Zadar region of Dalmatia on the other side of the Velebit range, where a large number of wild vegetable taxa is used .Rosa canina 90% (Lika) vs. 65% (Knin), Sambucus nigra 82.5% (Lika) vs. 72.5% (Knin), Cornus mas 82.5% (Lika) vs. 65% (Knin), Taraxacum 80% (Lika) vs. 40% (Knin) and Prunus spinosa 82.5% (Lika) vs. 35% (Knin).The five wild plant species with the highest frequency of mentions from the area of central Lika (this research) are also commonly used in the area of Knin : Rosa caRubus caesius (UR 24), Carum carvi (UR 21), and Pyrus communis (UR 8) were not recorded in Knin. Comparing the most frequently mentioned species with studies from other countries, we found some different uses, e.g., Juglans regia and Mentha spicata L. leaves with salt were used as traditional insect repellents in Bulgaria [Achillea millefolium is used in tea to treat stomach pain in South Kosovo [Comparing this research and the neighboring area of Knin , we noteBulgaria . In addih Kosovo .rakija spirits in the study area, including Prunus domestica, Pyrus spp., Cydonia oblonga, Juniperus communis and—nowadays quite rarely, due to longer collection time—Cornus mas. Plum brandy, so-called lička šljivovica (“Lika plum brandy”), is used most commonly.A large number of fruit species are still used to distil Pyrus communis “Tepka”) is also commonly used in the area —it must be bletted to be tasty for consumption, and in the past, it was cut, strung on twine, dried and eaten on Christmas Eve. A dish called oša consists of a thick compote of dried pears or prunes/fresh plums with homemade bread. However, this tradition has been forgotten in the last 50 years. According to Hećimović-Seselja [The local cultivar of pears  Tul. The food use of this fungus has never been recorded in ethnobiological literature. The situation is comparable to the use of corn smut Ustilago maydis (DC.) Cordacalled in the Mexican huitlacoche [The observed number of wild mushrooms used for food is relatively low for the habitat of Lika, which is very rich in fungi species due to the presence of mixed deciduous forests. Here only a few species of mushrooms are used for food, but harvesting and selling mushrooms  has been an important contribution to the household budget of the inhabitants of Lika for many years; they are very widespread, and about 15 kg can be harvested in one afternoon . For comparison, in the Romanian Carpathians, 24 species are used by a similar sample of the local population of Ukrainians (on average 9.7 per respondent) . A largetlacoche —a gall fTaphrina, they used to nibble on young Fagus sylvatica leaves and young Rosa canina shoots. They also state that they sucked the flower of Primula vulgaris or juice from the stem of Rumex acetosa. In the municipality of Lovinac, there is also mention of sucking juice from the root of Scorzonera villosa. A large number of children’s snacks should be noted. Some of the respondents state that as children, apart from Sambucus ebulus has been used to treat swine erisypelas in pigs or to reduce swelling from snake bites in cows as well as to extract fever from the body. Similar uses were recorded in an earlier study by Hećimović-Seselja from 1985 [S. ebulus was used to treat tuberculosis [As shepherding has been the basis for the local economy for centuries, it must be noted that some knowledge on plants used to cure and feed animal persists in the area. In Lika, rom 1985 . In Polarculosis , and Akbrculosis .Helleborus dumetorum Waldst. & Kit. ex Willd is an exception. Although Helleborus species have been known to be used in human and animal medicinal practices, they are highly toxic. Therefore, their use has been decreasing. Their application in veterinary practices in the area is an archaic feature. Helleborus species are still used in other parts of south-eastern Europe, but relatively rarely, e.g., in Transylviania Helleborus purpurascens Waldst. & Kit. is known for its use in immunotherapy, treatment of wounds, and as an antiemetic drug in ethnoveterinary medicine [Helleborus odorus Waldst. & Kit. ex Willd is used for medicinal purposes for humans, in the form of a decoction and infusion for liver and skin disease [The majority of food and medicinal plants used in the area are ubiquitous species of widely known and documented use. medicine . In the  disease .Helleborus is the children’s game “titra”, which uses the plant’s stems and is still remembered by the local population. Several players can participate in the game. According to the rules, each player can have 5 to 10 “titre”—stems of Helleborus. The stems are arranged in a bundle. The first player holds them in the palm of his right hand, transfers them to the upper side of the same hand, catches them and counts how many pairs of stems he has caught. If the player counts an odd number, then he takes one “titra”, puts it aside, and throws the rest of the stems one more time, palm facing down. If the player has an odd number of stems the second time, he sets two stems aside. If the player catches an even number during their next turn, they lose, and the next person follows the same procedure until all her credits are used up. The player with the most “titre” is the winner [Another use of e winner .The effect of the ex-Yugoslav war between 1991–1995 may have also had a strong effect on plant knowledge in the area. The region was highly depopulated both by heavy fighting with the Serbian army and by the exodus of local inhabitants to cities and other countries. Additionally, a large percentage of the Orthodox  population left the region.The field research study was conducted in a continental, mountainous part of Croatia, in three municipalities  of Lika-Senj County . 2 with a total of 16,390 inhabitants, most of whom live in Gospić . Perušić and Lovinac are typical rural areas with a very low population density of 6.89 and 2.95 inhabitants per km2, respectively. The municipality of Gospić has the status of a town and is the seat of Lika County. Gospić is the only settlement with more than 10,000 inhabitants in the county, but even this administrative area is sparsely populated, with only 13.18 inhabitants per km2. The percentage of inhabitants aged 65 years or above is over 35% in the locality of Perušić and Lovinac, and 21% in the locality of Gospić.The areas of the municipalities extend from NW to SE and have a range of ca. 60 km, with an elevation of mainly 550–600 m above sea level. The study area covers 1692 kmAccording to its current population density, Lika is a sub-ecumenical area. From the beginning of the 20th century, Lika lagged far behind in terms of agricultural and economic development, and there was not enough food for the population, so some of the inhabitants moved to other parts of Croatia or abroad . These pThe cessation of animal husbandry and the abandonment of pastures and meadows has led to progressive succession, causing pastures to disappear and be replaced by scrubland and eventually forest, which is the climax  of vegetation in Croatia.In the area of central Lika, the proportion of fertile land is small due to the domination of karstic rocks, which, along with unfavorable climatic conditions , significantly affects the characteristics of agricultural production (the choice of crops for cultivation is narrowed).Aremonio-Fagion) predominate in Lika, and in the highest areas the beech forest transitions into low forms of coniferous trees, where Pinus mugo Turra is dominant. Downy oak and sessile oak (Quercion pubescenti-petraeae) predominate in fields, forests and thickets, where white hornbeam  is also present [According to the Köppen climate classification, the area of Lika is dominated by a moderately warm humid climate with hot summers (Cfb), and only the highest mountain areas of Velebit, Plješivica and Mala Kapela have a snow-forest climate (Df) . Accordi present .The landscape of Lika includes characteristic slopes bounded by the longest Croatian mountain Velebit—the highest peak of Lika —in the west-southwest, by Velika Kapela and Mala Kapela in the northwest, and by Plješivica  in the east .The Velebit mountain range separates the continental and coastal parts of the Lika-Senj County, and the Northern Velebit National Park, the Paklenica National Park and the Velebit National Park lie on its territory . PlitvičData were collected through a survey of the local population conducted during the period February–May 2020. The second author of this paper is originally from the investigated area and helped with the selection of the interviewees. In-depth semi-structured interviews and the free listing method were used. The principles of the American Anthropological Association Code of Ethics  and the http://herbarium.agr.hr/ (accessed on: 14 October 2022)). Fungi were placed in the Croatian National Fungarium (CNF) in Zagreb ).Seven non-exclusive modalities or categories were available for various uses: food or drink, medicine, alcoholic beverages, animal feed, construction and handicrafts, ceremonial uses, and other. For plant identification, standard floras for this area of Europe were used, such as: Nikolić’s guide to the identification of the flora of Croatia , PignattThe main variables of the dataset were: the informant’s code number, the place of the survey, the order of mention of the plants, the local plant name, the types of use and the preparation method for each type of use, i.e., the use category. In addition, for each taxon recorded, the following information was provided: scientific plant name and plant parts used.All taxa mentioned two or more times were included in the analyses performed. Taxa that were mentioned only once were included only if we considered the information to be particularly relevant and provided by the most trusted informants.RFC is the relative frequency of citation, FC is the absolute frequency or number of mentions of a single taxon, and N is the total number of informants [To determine the level of awareness of a single taxon among respondents, relative frequencies were calculated using the following formula:formants .Sj) [Sj:L is the length of the plant list per informant, Rj is the rank of taxon j in the list, and N is the total number of lists in the survey.The importance of a single taxon with respect to the entire study area and each of its three subregions was first evaluated using Smith’s S salience measure (Sj) . This inCV) [CV depends on the number of respondents who report using a taxon and the number of use categories. The following formula was used to calculate CV:Uce represents the number of uses of taxon e divided by the number of possible uses . The symbol Ice represents the number of respondents who indicated that taxon e is used, relative to the total number of respondents, and IUce is the quotient of the sum of respondents for each of the 7 uses and the total number of respondents. For example, if taxon e was used for food by 35 respondents and for medicinal purposes by 4 respondents, IUce = (35 + 4)/40 [We assessed the practical importance of taxa to the community using the cultural value coefficient (CV) . This in + 4)/40 .Fic) function. This indicator is based on the number of use reports (urn) and the number of taxa (taxan) per specific use category [The respondents’ consensus regarding the use of plants for a specific purpose was quantified using the informant consensus factor  per species is the number of mentions of use of a specific plant species in all use categories [The use report indicator  were performed using the program Microsoft Excel, Version 2013, Microsoft Corporation, Redmond, WA, USA. A comparison of results by location was performed using ANOVA in the program IBM SPSS Statistics for Windows, Version 21, IBM Corp., Armonk, NY, USA. Other calculations and analyzes were performed using packages “ethnobotanyR”  and “AntThe list of plant taxa used is largely typical for central Europe. Like in other central European regions, few wild vegetables are used, and mainly fruits and medicinal herbs are collected from the wild. Similarly to coastal parts of Croatia, surprisingly few taxa of edible fungi are collected, in spite of the presence of large areas of woodland.We can assume that the differences in ethnobotanical knowledge between the three studied areas are partly due to minor differences in climate and topography, while other causes lie in the higher degree of rurality and stronger ties to nature in the Perušić and Lovinac areas.Based on the observed situation and results, we propose actions to preserve the remaining traditional plant knowledge, primarily in the form of activities and workshops to promote the use and preparation of local wild plant food products and herbal teas among the local population.