Empathy is hypothesized to have several components, including affective, cognitive, and somatic contributors. The only validated, self-report measure to date that assesses all three forms of empathy is the Cognitive, Affective, and Somatic Empathy Scale (CASES), but no current study has reported the psychometric properties of this scale outside of the initial U.S. sample. This study reports the first psychometric analysis of a non-English translation of the CASES.Confirmatory factor analysis was used to assess the factor structure of CASES as well as its associations with callous-unemotional traits in 860 male and female children (mean age 11.54± .64 years) from the China Jintan Child Cohort Study.Analyses supported a three-factor model of cognitive, affective, and somatic empathy, with satisfactory fit indices consistent with the psychometric properties of the English version of CASES. Construct validity was established by three findings. First, females scored significantly higher in empathy than males. Second, lower scores of empathy were associated with lower IQ. Third, children with lower empathy also showed more callous-unemotional attributes.We established for the first time cross-cultural validity for Cognitive, Affective, and Somatic Empathy Scale (CASES). Our Chinese data supports the use of this new instrument in non-Western samples, and affirms the utility of this instrument for a comprehensive assessment of empathy in children. Empathy has become an increasingly popular target of study for understanding neurobiological mechanisms underlying child aggression, antisocial behavior, and future conduct problems ,2. ThereCognitive empathy (drawn from theory-of-mind perspectives) reflects mental awareness of another person’s internal state, while affective empathy reflects the ability to experience another person’s internal state vicariously . Motor eIn an attempt to address this problem, Raine and Chen  recentlyAs such, the purpose of this study is to examine the validity and reliability of a Chinese translation of the CASES measure. Psychometric analyses of empathy assessments to date have largely focused on their validation in Western samples, but investigation into other populations is warranted given the universality of empathy as a common human experience. Expressions of emotion and interpersonal behaviors are culture-bound, underscoring the need for translations of these assessment tools to account for cross-cultural diversity in empathy as a construct and to accurately capture its presence and correlates in non-Western populations. Valid and reliable assessments for empathy in Chinese youth are lacking and would be valuable for research to better understand risk factors and potential interventions for child internalizing and externalizing behaviors. Furthermore we are aware of only two studies to date ,14 that The Jintan Child Cohort Study is an ongoing longitudinal study made up of three waves. This Cohort Study looks at early health factors in relationship to later physical and psychosocial wellbeing of children and adolescents, including cognitive, emotional, and behavioral outcomes in a representative sample of children living in Jintan city . This stSigned consent forms for children’s participation were obtained from the parents. IRB approval was obtained from the University of Pennsylvania and the Ethical Committee for Research at Jintan Hospital in China.Raine and Chen  developeThe Inventory of Callous–Unemotional Traits (ICU) is a 24 item self-report scale designed to assess CU traits such as limited empathy and a lack of guilt . ExampleIQ was assessed using the Chinese version and norms of The Wechsler Intelligence Scale for Children-IV (WISC-IV)  22]. Th. Th22]. Analyses were conducted using SPSS version 24.0 and R. Mean, SD, skewness and kurtosis were calculated. To test internal consistency, Cronbach’s alpha coefficient was calculated.2/df < 3.0, CFI >.95, RMSEA < .06 and SRMR < .08, which suggest a good fit . Chi. Chi2/dfuate fit . The χ2 2 difference test. For example, if the χ2 difference test is not significant moving from the configural to the metric level, then metric invariance is established.We also used multigroup CFA to test invariance of this instrument across gender. We assessed a series of nested models with increasingly strict constraints on parameters to establish configural, metric, and scalar invariance . ConfiguGender differences were tested using Student’s t test as it has been found that boys are less empathic than girls on average when using self-report questionnaires . The partial correlations between the scales of CASES and ICU, IQ were conducted to test construct validity whilst controlling for age.CFA with maximum likelihood estimation was used to examine the three first-order models. The fit indices of the models are presented in Model 2 consisted of the two factors of positive and negative valence. The standardized factor loadings were all significant and ranged from .34 to .70, with a mean loading of .54, demonstrating that the items generally converged meaningfully to the scale.Model 3 consisted of the three factors: cognitive, affective and somatic aspects of empathy. The standardized factor loadings were all significant and range from .34 to .68, with a mean loading of .54, demonstrating that the items generally converged meaningfully to the scale.The overall results suggest that three models have χ2/df< 5.0, RMSEA < .06 SRMR < .08, and CFI was .86∼.88, demonstrating all three models was adequate, but not optimal because CFI<0.90. The RMSEA of the three-factor model improved to .053, and the CFI improved to .88, suggesting a satisfactory model fit –27.2 (1) = 44.22, p < .001). The three-factor structure  was also found to have a significantly better fit, compared to the one-factor model (Δχ2 (3) = 179.59, p < .001).In addition, A two-factor structure  was found to have a significantly better fit, compared to the one-factor model  and in the direction of lower empathy being associated with high CU traits. The “ICU total score” column in As indicated in The purpose of this study was to assess the validity and reliability of the Chinese version of the CASES for assessment of children’s cognitive, affective, and somatic empathy. Results of our CFA support a three-factor model consisting of cognitive, affective, and somatic empathy and a two-factor model consisting of positive and negative aspects of empathy, with both sets of results producing satisfactory model fits. Acceptable reliability indices, including Cronbach’s alpha and item-total correlations, were obtained for each of the three main factors as well as for positive and negative empathy. Construct validity was supported by results indicating that females scored significantly higher than males, with lower empathy being associated with lower IQ. Construct validity was also reflected in findings showing that children with lower empathy also showed more CU attributes. This study utilized a relatively large sample that is representative of both rural and urban populations, lending support to the generalizability of these findings.The CFA results revealed that the Chinese CASES possesses a stable three-factor structure with satisfactory loadings on each factor. This is consistent with that of the original English version . FurtherWe found a negative association between different aspects of empathy and total ICU score, which is consistent with past studies and recent reviews ,30,31. DAnother aspect of construct validity was evidenced by lower empathy being associated with lower IQ. While several previous studies have found no direct linkage between empathy and IQ, they have found that emotional intelligence has been positively correlated to both IQ  and empathy . Although we did not measure emotional intelligence, it is possible that the positive association between empathy and IQ that was found in this study could be mediated, at least in part, by emotional intelligence. It is also noteworthy that our findings of gender differences across all aspects of empathy—also evidence of construct validity—is consistent with other well-established findings that girls are more empathic than boys, on average ,42.Finally, the successful translation of CASES into Chinese has potentially important implications for child developmental and mental health outcome research in Chinese populations. Over the past few decades, China has experienced an increase in numerous social and public health problems, including gambling , cigaretAlthough we believe that findings from our novel analysis are potentially important for advancing our understanding of empathy in child developmental and mental health outcomes, some limitations exist. For example, this study is restricted to children no older than 12 years. Future research is needed to extend our understanding of empathy measurement in different age groups. This is an appropriate next step given that CASES is designed for a wide range of ages and development stages, from children to adults.This study is the first psychometric analysis of the only non-English translation of CASES to date. Results of CFAs reflect a successful translation from its original English version into Chinese which is consistent with reliability and validity analyses from Raine & Chen , therebyS1 Table(DOCX)Click here for additional data file.


Differences in domain-specific vocational knowledge were predicted by crystallized and fluid intelligence in the course of VET. A multiple matrix design with 3 year-specific booklets was used for the vocational knowledge tests of the medical assistants. The unique and joint contributions of the predictors were investigated with structural equation modeling. Crystallized intelligence emerged as the strongest predictor of vocational knowledge at every stage of VET, while fluid intelligence only showed weak effects. The present results support the knowledge-is-power hypothesis, even in a broad and more naturalistic setting. This emphasizes the relevance of general knowledge for occupations, such as medical assistants, which are more focused on learning hands-on skills than the acquisition of academic knowledge.Medical education research has focused almost entirely on the education of future physicians. In comparison, findings on other health-related occupations, such as medical assistants, are scarce. With the current study, we wanted to examine the knowledge-is-power hypothesis in a real life educational setting and add to the sparse literature on medical assistants. Acquisition of vocational knowledge in vocational education and training (VET) was examined for medical assistant students ( Research regarding medical education has mainly focused on medical students in different phases of their education by examining admission to medical schools and universities , performIn Germany, VET is characterized by a combination of traditional education in vocational schools and training of hands-on skills in medical practice. The regular training period for medical assistants is 3 years with an interim exam after the second year and the final graduation exam at the end of the third year. The curriculum of medical assistants in the German federal state Baden-Wuerttemberg comprises (a) medical terminology, (b) assistance with diagnostic and therapeutic actions for various diseases, (c) attending patients during preventive treatments, (d) how to maintain patient confidentiality, (e) medical data protection, (f) legal regulations relevant for their profession, and (g) occupational safety and health . Early dConsidering the relevance of VET success from the perspective of educational and labor market policy, empirical findings on individual differences in vocational education are surprisingly scarce. With the current study, we add to the research literature by analyzing the joint and unique effects of gf and gc in explaining individual differences in vocational knowledge of future medical assistants. The implemented research design allows us to estimate these effects at different phases of VET and to elaborate regarding the extent to which the knowledge-is-power hypothesis holds true in a real-life educational setting.The predictive validity of cognitive abilities, such as intelligence, for school and vocational success is one of the best established findings in social sciences. Numerous studies suggest that fluid and crystallized intelligence are crucial in various academic and occupational settings . Fluid iBesides gf, crystallized intelligence (gc) is another prominent factor in consensual theories on the structure of intelligence . Gc is dSuch findings corroborate with the knowledge-is-power hypothesis stating that cognitive endeavors in a specific domain are best predicted by domain-specific knowledge rather than more general cognitive abilities such as fluid intelligence . AccordiInconsistent findings reported in the research literature regarding the respective influence of gf or g and gc can be linked to several factors. First, the specificity of the learning situation, that is to say, gf is more important for learning outcomes in restricted environments , whereas it is less important for self-directed learning at home . In the # factor  as predictor variables and compare results to the gf-gc-model. If the knowledge-is-power hypothesis holds true, gc# should still have a stronger impact on vocational knowledge than g. Even though the study was cross-sectional, the research design allowed for an evaluation of vocational knowledge acquisition at the different stages of VET, thus, providing a rough estimation of learning trajectories. In terms of mean changes, we expect strong changes in VET knowledge as the education progresses, whereas we predict smaller changes in gc and no changes in gf.In summary, the contributions of gf and gc to vocational knowledge depend on several factors. For the present study, we expected a positive influence of both gf and gc on vocational knowledge for medical assistant VET students. In accordance with the knowledge-is-power hypothesis, we expected gc to show a greater impact on vocational knowledge than gf. As an alternative way of modeling, individual differences in vocational knowledge acquisition during VET of medical assistants might also be explained by a general intelligence factor (g)  that accn = 448 medical assistant students  was recruited from five out of 24 vocational schools that provide VET for medical assistants in the German federal state of Baden-Wuerttemberg. The high proportion of female students is similar to the overall percentage of female medical assistant students in Germany . Cohorts of VET students were recruited from all 3 years of education. Detailed information on the demographics is provided in Table 1. Medical VET students attended courses with the same curriculum irrespective of their previous education. Informed consent was obtained from all participants and individual feedback was offered to all participants. The students were tested in groups of 10–30 people, depending on the class size, who worked on the whole test battery for approximately 100 min.A sample of 98%; see . Age of Chamber of Industry and Commerce [Industrie- und Handelskammer (IHK)] from the years 2010–2014 and official sample questions for exam preparation . To keep the individual workload to a minimum, a multiple matrix design with three training-year specific booklets was used. More specifically, each test consisted of 30 items with 10 items being equal in all booklets, and another 10 items shared between adjacent test forms (see Table 2). We used a vertical linking design in order to connect the different training-year specific test forms and to estimate students’ abilities on a common scale  = 8.17, p = 0.04. Therefore, medical knowledge, laboratory knowledge, and organizational knowledge were used as subtests for the domain-specific knowledge test.Vocational knowledge of medical assistant students was assessed with a domain-specific knowledge test covering the different relevant topics of the VET course. The following sources were used for item development: (1) the curriculum of medical assistants , (2) staon e.g., , and (3)on e.g., . Items hon scale . FurtherBerlin Test of Fluid and Crystallized Intelligence for Grades 8–10  HF, (b) HBR, (c) HCI, (d) HI), (2) humanities  a historian, (b) a philosopher, (c) a mathematician, (d) a chemist), and (3) social studies ? GNP is a... (a) measure of the tax revenue of the government, (b) measure of the states’ social expenditure, (c) measure of the income of residents in a national economy, (d) measure of the export volume of a national economy). The gc test consists of 64 items covering the “breadth and depth” of the declarative knowledge (Gc was assessed in three broad domains: (1) natural sciences  with the Weighted Least Squares Mean and Variance adjusted (WLSMV) estimator which is appropriate for dichotomous variables (Comparative Fit Index (CFI) ≥ 0.95, Root Mean Square Error of Approximation (RMSEA) ≤ 0.06, and Weighted Root Mean Square Residual (WRMR) ≤ 1.0. In subsequent analysis, items of the intelligence measures were parceled to keep the number of indicators within a reasonable range and to get reliable and robust parameter estimates. The parceling approach is viable in the case that the construct is unidimensional and the residual correlations are negligible  between latent variables across groups, scalar invariance is necessary for the comparison of the mean structure.In order to make valid comparisons of students’ performance across years of VET, it is necessary to ensure measurement invariance for gf and gc. Invariance testing with s MGCFA;  is a seq2(77) = 93.5, p = 0.09, CFI = 0.982, RMSEA = 0.02, WRMR = 0.854. For gf, five parcels with equal difficulty were built. For the gc scale, the four medicine items were excluded from all further analysis due to a substantial overlap with the curriculum of medical assistants. Although the CFI for the gc model was slightly below the cut-off value suggested by 2 = 1,725.8, p < 0.01, CFI = 0.942, RMSEA = 0.02, WRMR = 0.993. For subsequent analysis indicators were parceled in order to reduce the number of estimated parameters and to allow for robust parameter estimation with moderate sample size. Gc items were aggregated to parcels according to three broad content areas. To ensure the comparability of the intelligence scales across the 3 years of VET, the measurement models were tested for measurement invariance. The models were compared based on the deterioration in the CFI between consecutive models with ΔCFI ≤ 0.01 indicating invariance (Table 3), which allows us to examine the relative contribution of gf and gc on vocational knowledge across years of education.One-dimensional measurement models were estimated for gf and gc with individual items as indicators. For the gf scale, one item had to be deleted due to a technical problem. The measurement model with 15 gf items showed good fit to the data: χvariance . For allFor the vocational knowledge test, three-dimensional 2PL models were estimated separately for each year of VET and subsequently linked on a common scale . Five ofd1/2 = 0.45; d2/3 = 0.99; d1/3 = 1.51). In contrast, the means of gf and gc remained stable across the 3 years of education , since domain-general knowledge and fluid intelligence are not specifically promoted through VET. The almost identical means of the intelligence scales across VET in this cross-sectional data, also advocate for the comparability of the subsamples.There were significant increases in vocational knowledge, which indicates the successful acquisition of job-relevant knowledge over the course of VET. The standardized mean differences, according to Figure 2). Constraining the factor loadings and intercepts to equality across years of education , the model still provided good model fit  as compared to a model constrained to metric measurement invariance . In the correlated factor model, gc turned out to be the strongest predictor of vocational knowledge in all 3 years of VET. Interestingly, in this model, gf showed no impact on vocational knowledge for the first 2 years of education and only a small influence in the last year of VET.Structural equation modeling was used to predict individual differences in health knowledge of medical assistants with gc and gf (#) below an overarching g factor . This allows us to estimate the effect of a general cognitive ability factor and an independent  knowledge factor. Model fit of the nested factor model was good: χ2(155) = 207.9, p < 0.01, CFI = 0.956, RMSEA = 0.04, SRMR = 0.07. As for the nested factor model, the overarching g factor showed a significant influence on health knowledge with a slight increase for the third year students. However, the predictive power for gc# was higher than the impact of g, with the exception of the third year. And even for third year students, the influence of an overarching g factor did not exceed that of gc#.To further examine the unique effects of gf and gc on vocational knowledge acquisition, we modeled gc as a nested factor  and complex problem solving , rather than focusing on declarative knowledge . HoweverThe current findings provide support for the notion that a comprehensive knowledge base is a crucial prerequisite for knowledge acquisition in educational environments , 2012. TThe current results support the notion that knowledge tests might be a useful selection tool in the context of career counseling of high school students. While non-cognitive constructs such as vocational interests contribute to dropout intention, job change, or job satisfaction e.g., , the actAll subjects gave written informed consent. The protocol was approved by the “Ministerium für Kultus, Jugend und Sport Baden-Württemberg.”OW and US conceived and designed the study. AM performed data collection, pre-processing and analysis of the data. US helped with the data analysis. AM wrote and OW and US critically commented on the manuscript. AM, US, and OW gave final approval of the manuscript to be published.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.


Lower quality of life, especially in the physical domain , is common in patients after hematopoietic stem cell transplantation (HSCT). However, few studies explore changes in the Physical-QOL, i.e., physical symptoms, in everyday life of patients following HSCT. The present study addresses this gap by examining patient daily physical symptoms and their predictors in terms of demographic and clinical characteristics.Physical symptoms were reported by 188 patients  for 28 consecutive days after post-HSCT hospital discharge. Multilevel modeling was used to investigate fixed and random effects for physical symptom changes over time.β = 0.09, p < .01) and baseline depressive symptoms  were associated with the initial level of physical symptoms. Patients with more depressive symptoms before HSCT and with more adverse treatment effects presented with more physical symptoms immediately after hospital discharge. The type of transplant, diagnosis, and conditioning regimen differentiated the course of physical symptoms. Patients with leukemias and other myeloid neoplasms , after allogeneic HSCT , and with non-myeloablative conditioning  showed a significant lower decrease in symptoms over time. Patients with multiple myeloma presented with the most rapid improvement .The results indicated that the initial level of physical symptoms  systematically decreased over 28 days. Treatment toxicity (WHO scale; The findings suggest a heterogeneous and rather positive response to HSCT. Treatment-related conditions occurred to be a significant predictor of the intensity of change in physical functioning after HSCT. Although high dose-therapy (chemotherapy and radiotherapy) and hematopoietic stem cell transplantation (HSCT) lead to an improved long-term survival of patients treated by these methods , 2, suchdynamics of changes in physical symptoms or physical HRQOL over time after HSCT and the determinants of these changes. The present study addresses this gap.Adverse physical symptoms are common indicators of the health-related quality of life (HRQOL) physical domain . Earlierchanges in symptoms or the growth curve of physical symptoms over time. In fact, improvements in physical HRQOL and regression of treatment-related side effects occur shortly after HSCT  covariance structure was used for the models, given the common proximal autocorrelation in the daily data .A total of 437 patients met the study criteria between November 2014 and November 2016. Of the 437 eligible patients, 238 gave their written informed consent and filled in the baseline measurement questionnaire . The final sample included 188 participants who participated in the daily study for at least 7 days . Most participants were in a stable relationship, had at least a secondary education, were professionally inactive, and assessed their economic status as average and underwent autologous HSCT (autoHSCT) and myeloablative conditioning , and type of transplant . Higher treatment toxicity according to the WHO Toxicity Scale and allogeneic HSCT  were associated with an increased likelihood of belonging to the non-completers group.Of the remaining 50 participants, 6 were disqualified from HSCT, 16 died at the time of isolation, 28 resigned from the daily assessment. Sample attrition analyses  indicated that the daily study completers and non-completers did not differ in terms of sociodemographic , health-related variables , or depressive symptoms at baseline, except treatment toxicity , with 61% of fully completed diaries. There were no significant associations between missing data and demographic characteristics, clinical variables, daily physical symptoms, and belonging to the paper or an email group. The data were missing at random. MLM leads to unbiased estimates in that case . The find effect size = 1.28); −2LL = 15365.59, AIC = 155375.59, BIC = 15407.95. Besides, there was evidence of between-person  variability in both the intercept  and slope  of physical symptoms. The intraclass correlation coefficient (ICC) was 0.72, also indicating between-person differences in the physical symptoms.Descriptive statistics of daily physical symptoms are presented in Table B = 0.11, SE = 0.04, p = .008) and pre-HSCT depressive symptoms  were significantly associated with the intercept of physical symptoms, but did not differentiate the slope of physical symptoms . The remaining variables and their interactions with time were not statistically significant. Final model 1 included treatment toxicity and depression, controlling for the age, gender, and comorbidities. Patients with more depressive symptoms before HSCT and with more adverse treatment effects had more physical symptoms immediately after hospital discharge. The results from MLM  examining associations between level two variables as predictors of time course of physical symptoms are given in Table Preliminary results of MLM indicated that only treatment toxicity  showed that there were no group differences in the initial level of physical symptoms. The autoHSCT-by-day interaction indicated group differences in time course of physical symptoms. AlloHSCT group did not show physical symptom change over 28 days of the study (non-significant 0.02 unit decrease), whereas the autoHSCT group showed their 0.08 unit decrease over time , controlling for the age, gender, comorbidities, treatment toxicity, and pre-HSCT depression, indicated no group difference in the intercept of physical symptoms. However, there was a significant leukemias-by-day interaction i.e., patients with leukemias and other myeloid neoplasms showed only a 0.02 unit decrease in physical symptoms in time compared to other patients with a significant 0.07 unit decrease , controlling for the age, gender, comorbidities, treatment toxicity, and pre-HSCT depression, revealed significant group differences in the growth curve of physical symptoms see Fig. . The decFinally, the result of model 6 examining the moderator effect of conditioning , controlling for the age, gender, comorbidities, treatment toxicity, and pre-HSCT depression, indicating a significant difference in the growth curve of physical symptoms between MA and non-MA group see Fig. . MA patiNo moderator effect of lymphomas was found (see model 5). Besides, as it was expected, there was evidence of autocorrelation in the level 1 residuals in all models.Due to the lack of longitudinal research on the time course of physical HRQOL in post-HSCT patients, the aim of this study was to examine the time-based trajectory of their physical symptoms over 28 days and trajectory determinants. The findings revealed a significant systematic decrease in physical symptoms in time, moderated by the type of disease, transplant, and preparatory treatment (conditioning).Immediately after hospital discharge patients reported on average 4 out of 22 possible symptoms and their number decreased in time. This indicates a relatively good physical adaptation to HSCT as evidenced by few treatment-related side effects and symptom resolution within the first month after hospital discharge. Such results are consistent with the current longitudinal studies conducted in a similar time period and in the traditional mode –5, 17. TSince the group was heterogeneous in terms of physical symptoms, we tested for the moderator responsible for this variability. Significant independent predictors of the initial level of physical symptoms were treatment toxicity and baseline depression, after adjusting for the effects of age, gender, and comorbidities.The more toxic the treatment as measured by the WHO scale, the more symptoms were reported by patients on Day 1 of the study. These important findings were not previously reported in the literature. Moreover, a higher initial level of physical symptoms was also related to higher pre-HSCT depressive symptoms. Positive relationships between these variables were observed in previous studies , 27, 28.Interestingly, neither treatment toxicity nor baseline depression determined the further course of symptoms in time. Significant moderators of change were type of disease, type of transplant, and conditioning regimen, after controlling for the age, gender, comorbidities, treatment toxicity, and baseline depression. Patients with autoHSCT, MA conditioning, and with MM were characterized by a significant higher decrease in symptoms over time. In turn, patients with leukemias and other myeloid neoplasms demonstrated a significantly lower decrease in symptoms over time as compared to the remaining patients. A better physical HRQOL among autoHSCT recipients as compared to alloHSCT patients was reported in previous studies . A novelPatients with leukemias and other myeloid neoplasms experienced lower decrease in treatment-related adverse symptoms. Previous studies also reported poorer functioning of patients with leukemias as compared to MM and lymphoma patients . Poorer Patients with MM experienced the most rapid improvement in adverse physical symptoms. The similar result was reported in another study . Faster Patients with lymphomas were similar to patients with leukemias, other myeloid neoplasms, and MM in terms of the level and time course of physical symptoms. Our findings highlight the difference in adverse symptom change among and between various disease groups and awareness about the diversity of recovery of patients which can prevent stereotyping and routine approaches to their physical problems.Somewhat surprisingly, our results show conditioning regimen associated with higher toxicity (MA)  also resOur study has a number of limitations. First, significant disproportions in the number of members in the compared groups (MA vs. non-MA) could have introduced bias into our results. One of the remaining factors such as type of transplant may be the cause of the MA effect. The issue of MA-related long-term adverse symptoms requires further investigation. Second, there were a disproportionate number of patients who received autoHSCT in the study group. Hence, larger groups of patients with different conditioning regimen and type of transplant should be enrolled in future studies. Third, depressive symptoms were not controlled on a daily basis, which could have the interpretative significance. Fourth, depressive symptoms were based on self-report assessments rather than clinical diagnosis. Finally, we tested only the moderator effect of demographic and clinical factors on the initial level at discharge and the time course of physical symptoms.Due to the heterogeneity of the group, it would also be reasonable to examine whether it is possible to identify in the study group the patient subgroups with the similar baseline level and trajectory of symptoms in time, in accordance with the person-centered approach . Despite


Schistosomiasis is a neglected infection affecting millions of people, mostly living in sub-Saharan Africa. Morbidity and mortality due to chronic infection are relevant, although schistosomiasis is often clinically silent. Different diagnostic tests have been implemented in order to improve screening and diagnosis, that traditionally rely on parasitological tests with low sensitivity. Aim of this study was to evaluate the accuracy of different tests for the screening of schistosomiasis in African migrants, in a non endemic setting.A retrospective study was conducted on 373 patients screened at the Centre for Tropical Diseases (CTD) in Negrar, Verona, Italy. Biological samples were tested with: stool/urine microscopy, Circulating Cathodic Antigen (CCA) dipstick test, ELISA, Western blot, immune-chromatographic test (ICT). Test accuracy and predictive values of the immunological tests were assessed primarily on the basis of the results of microscopy (primary reference standard): ICT and WB resulted the test with highest sensitivity , with a high NPV (98%). CCA showed the highest specificity (93%), but low sensitivity (48%). The analysis was conducted also using a composite reference standard, CRS  and Latent Class Analysis (LCA). The latter two models demonstrated excellent agreement (Cohen’s kappa: 0.92) for the classification of the results. In fact, they both confirmed ICT as the test with the highest sensitivity (96%) and NPV (97%), moreover PPV was reasonably good . ELISA resulted the most specific immunological test (over 99%). The ICT appears to be a suitable screening test, even when used alone.The rapid test ICT was the most sensitive test, with the potential of being used as a single screening test for African migrants. Schistosoma mansoni, S. haematobium and less frequently by other species, affects more than 200 million people, mostly in Africa, and may chronically cause irreversible damage of the liver (S. mansoni) or of the kidneys and the urinary tract, including cancer of the bladder (S. haematobium). As in chronic infections eggs of both species are often missed by microscopy of faeces and urine, with this retrospective study we evaluate the accuracy of different, alternative diagnostic tests, for the screening of schistosomiasis in African migrants and asylum seekers, of whom many thousands reach the Italian coast every year proceding from the most endemic areas. The most interesting finding of our study is that a rapid diagnostic test for antibody detection in blood, easy to use as a point-of-care tool, resulted the most sensitive of the five tests evaluated, and thus is very promising as a screening tool even when used without any additional test.Schistosomiasis is probably the most important of the neglected tropical diseases (NTD) caused by helminthes (worms). It is acquired bathing in freshwater in endemic areas. The life cycle is complex and involves freshwater snails. Schistosomiasis, caused by  Schistosomiasis is a fluke worm infection affecting at least 78 countries and more than 200 million people worldwide, and causing an estimated burden of 3.3 million disability-adjusted life-years (DALYs) ,2.Ninety-three percent of the global cases occur in sub-Saharan Africa, mostly caused by the species Schistosoma mansoni and S. haematobium. In this area, approximately 300,000 deaths due to schistosomiasis are estimated annually [S. mansoni and S. haematobium [annually . A huge annually . The heamatobium –12, and matobium ,14, adeqmatobium , originamatobium ,17, is amatobium ,19.S. mansoni) is more sensitive than microscopy, particularly in light infections [S. haematobium infections (ranging from 21.4% to 71.4%) [The estimated prevalence of schistosomiasis in African migrants, reported from a scarce European literature, ranged from 9–15% if based on use of microscopy ,21 to 5.fections ,28. Howeo 71.4%) . The como 71.4%) ,30.S. haematobium and S. mansoni soluble antigens was used on a limited number of subjects exposed to the recent outbreak of urinary schistosomiasis in Corsica, where a hybrid form between human S. haematobium and animal S. bovis was identified [S. mansoni antigens only, had showed for this species a good accuracy (sensitivity 89.5% and specificity 100%) [Other diagnostic techniques have been implemented more recently ,31,32. Aentified ,33. Howety 100%) ,35.S. haematobium infection. In a Cochrane meta-analysis of studies conducted in endemic areas, the CCA test, compared to microscopy, showed an average sensitivity and specificity of 39% and 78%, respectively, for S. haematobium infection, and of 89% and 55%, respectively, for S. mansoni. This test has been utilized only recently with immigrants in Europe [S. mansoni cercarial transformation fluid for detection of antibodies in blood showed a sensitivity and specificity of 100% and 39.5%, respectively, in a schistosome-endemic area [The urine Circulating Cathodic Antigen (CCA) is a rapid test, based on the identification in the urine of the genus-specific proteoglycan antigen of the schistosomal gut epithelium, regurgitated by the live adult worm only . The CCAn Europe ,38. A raThe main purpose of our study was to identify the more accurate screening strategy for schistosomiasis in a non endemic area.S. mansoni, S. haematobium, or both) rather than the infection by either species. The rationale is that, with the exception of microscopy , the other techniques are not able to discriminate between the two species. Furthermore, the treatment of both infections is with the same drug praziquantel.The target condition was schistosomiasis  and is based on the principle of the homogeneous sandwich . b) the tests routinely used at CTD, namely: the circulating cathodic antigen (CCA) urine dipstick test for S. mansoni , an enzyme-linked immunosorbent assay , and the microscopic examination of stool and urine.The main objective was to assess the accuracy of a series of diagnostic tests for the screening of schistosomiasis, including: a) the new, commercially available RDT (Schistosoma ICT IgG-IgM), and the Western Blot (Schisto II Western Blot IgG) , both aimed at detecting th, 2016. At the Centre for Tropical Diseases, all subjects submitted to any serological exam are asked to sign an informed consent for the anonymous storage of a serum specimen for any future research purpose. Parents’ or legal guardians’ consent is obtained for individuals of less than 18 years of age.Ethical clearance from Comitato Etico Provinciale di Verona e Rovigo: protocol n 33909 of July 13Retrospective, comparative diagnostic study, intended to estimate the sensitivity, specificity, positive and negative predictive values of the tests examined.The study was carried out at the Centre for Tropical Diseases (CTD) of Sacro Cuore Hospital , a referral center for tropical and parasitic diseases in the country. The study population was retrieved from the CTD patient database and was mostly composed by African recent asylum seekers that were routinely screened for schistosomiasis, regardless if symptomatic or not, in the context of a regional, pilot programme. The study was meant to include all consecutive subjects screened in the 2-year period considered . The study was carried out at the reference laboratory for parasitic diseases of CTD by experienced professionals.st March, 2014 to 28th February, 2016.The results of the routine screening tests  were retrieved from the patient database, while the new tests (ICT and WB) were performed for the study purpose on fully anonymized, coded serum samples, routinely stored and cryo-preserved at CTD. The archived specimens were kept frozen at -80°C from the day of the sample collection and the tests were executed within 24 hours of unfreezing. The study covered the two-year period from 1Inclusion criteria. Subjects of all ages submitted to routine screening for schistosomiasis with CCA urine dipstick, ELISA serology and microscopy of the stools and urine.Exclusion criteria. a) Lack of informed consent for usage of biological samples for study purpose; b) Missing result for one of the routine screening tests ; c) Unavailability of ICT and/or WB result.The assessment of accuracy of all tests for schistosomiasis is hampered by the lack of a gold standard. In particular, microscopy (of stools and urine) is virtually 100% specific but lacks sensitivity –27. On tTherefore, the test accuracy was evaluated using three different standards:Primary reference standard based on microscopy (see below for details)Composite reference standard (CRS) (see below for details) ,41.Latent Class Analysis (LCA) (see below for details) .Sensitivity, specificity, odds ratio, positive and negative predictive values of the index tests according to the primary reference standard.a) Sensitivity, specificity, odds ratio, positive and negative predictive values of the index tests according to CRS and LCA, respectively; b) Concordance between CRS and LCA in identifying true positive and true negative cases.Primary Reference standard: direct detection of S. mansoni or S. haematobium eggs in stools or urine. Composite Reference Standard. The subjects were classified as: Infected (denominator for sensitivity): positive microscopy OR (negative microscopy AND at least 2 concordant positives of the four index tests). Not infected (denominator for specificity): negative microscopy AND < 2 positives of the four index tests.Index tests included four commercial tests: Urine CCA dipstick test , Bordier ELISA , Schisto II Western Blot IgG  and Schistosoma ICT IgG-IgM .A brief description of all the methods follows.S. haematobium egg count on the day of the sample collection [From one to three urine samples were obtained (from 10 a.m. to 12 a.m) over consecutive days for each patient. The urine were subjected to CCA dipstick test and to filtration method for llection ,43.One drop of urine sample was added to the CCA urine cassette, following the manufacturer's instructions. Once absorbed, one drop of buffer was added and the result was read 20 minutes after. Valid tests were scored as positive or negative depending on whether or not a colored band appeared. The reading was done independently by two observers, and, in case of discordance, by a third observer. In case a result was judged equivocal by two observers , it was reported as indeterminate.The remaining urine was shaken and filtered through a 25-mm diameter small meshed filter (12 μm Nucleopore), which was then placed on a labeled slide and examined under a microscope (100x) for Schistosoma eggs.Three stool samples per patient were collected in formol on consecutive days. Each sample was submitted to formol-ether concentration and examined (100x) .Up to 10 ml of venous blood was collected from each patient in silica-coated tubes without anticoagulant. The serum was separated by centrifugation at 3000 rpm for 5 min. Bordier ELISA was executed on 10 μl of serum, and remaining aliquots were stored at -80°C. Both Schisto II Western Blot IgG and Schistosoma ICT IgG-IgM were performed using the latter serum. Cutoffs for each test were pre-determined prior to testing.S. mansoni. Briefly, 10 μl of serum were diluted with 2 ml of buffer before adding 100 μl to each ELISA microwell. According to the manufacturer's instructions, the result is positive when the absorbance of the analyzed sample is higher than the absorbance of the weak positive control (provided with the kit). In order to be able to compare results from different runs, we defined as positive samples those with: optical density (OD) of study sample/OD of weak positive serum ≥ 1 . The test was carried out in double and, in case of discordant results, it was further repeated on another blood sample, in order to avoid indeterminate results.The test detects Schistosoma IgG antibodies by using antigens from adult of S. mansoni + S. haematobium antigen strips (supplied with the kit) were incubated with 25 μl of sera diluted in Tris-NaCl sample buffer for 90 minutes. Then, a first washing step with Tris-NaCl washing buffer permitted to remove any unbound sample components. Later, the strips were incubated with an alkaline phosphates—anti human IgG conjugate for 60 minutes. After a second washing step, the whole complex was revealed by the corresponding substrate-chromogenic solution containing nitroblue tetrazolium and 5-bromo-4-chloro-3-indolylphosphate as a dark blue-purple color. The color development was stopped after 60 minutes by washing the strips with distilled water. The strips were dried and glued to paper for reading. The Schistosoma-specific IgG, if present in the sample, appeared as violet colored bands. Valid tests were read as positive depending on the presence of one of the following: 1) band P22-24; 2) a large band P30-34; 3) a thin band P30-34 plus at least one among bands P8, PP9, P10, P12-13, P14-15, P18. The strips were read independently by two observers, and, in case of discordance, by a third observer. In case a result was judged equivocal by two observers , it was reported as indeterminate.The test was carried out according to the manufacturer's instructions. Briefly, the This immune-chromatographic test (ICT) was carried out according to the manufacturer's instructions. Briefly, 30 μl of serum were added to a cassette, followed by 2 drops of the eluent (supplied with the kit). The result was read after 20 minutes. The tests were read as positive or negative depending on whether or not a colored band had appeared. The reading and the interpretation were carried out the same way as for CCA (see above).The approximate cost per test  is € 7 for ELISA, € 9 for CCA, € 14 for ICT and € 33 for WB.For the analysis, all indeterminate results were classified as positive. All reference and index tests were executed and read by highly trained, senior staff of the CTD laboratory. Four senior staff members performed and read all the tests, according to the procedures outlined above.Microscopy, serology and urine CCA dipstick test were carried out at CTD by different laboratory personnel. The staff performing the tests carried out on the frozen specimens (ICT and WB) had no access to the source codes and therefore were blinded as of the results of the previous tests, as well as of the results of either test.For both the primary and secondary endpoints, the sensitivity of each index test was calculated as the proportion of positive results over all infected subjects according to the primary and composite reference standards, respectively. Uncertainty was quantified using the 95% confidence intervals. Similarly, the specificity was calculated as the proportion of negative results over all not infected subjects according to the primary and composite reference standard, respectively. Uncertainty was quantified the same way as above.A further analysis was performed using the method of Latent Class Analysis (LCA).Latent class models (LCMs) combine the results of multiple diagnostic tests through a probabilistic model to obtain estimates of disease prevalence and diagnostic test accuracy in situations where there is no single, accurate reference standard .Diagnostic studies that apply LCMs treat the target disease status as an unmeasured (”latent”) categorical variable with K classes, reflecting the levels of the underlying disease. The manifest variables, the outcomes of T (binary) diagnostic tests, are considered to be imperfect classifiers of the disease status. The LCM describes a statistical model relating the manifest variables to the latent disease status.When K = 2, it is assumed that the two latent classes correspond to a class of subjects in which the target disease is present and a class of subjects in which the target disease is absent. Parameter estimates obtained from the 2-class LCM are interpreted as estimates of the sensitivity and specificity of each test and the prevalence of the target disease .We assumed the conditional independence among the tests.The analysis was performed by using LCA, random LCA and extended LCA R’s libraries.Predictive values  were then estimated, based on the prevalence of the infected subjects obtained with the three methods .We also assessed the concordance between CRS and LCA in classifying the study subjects. Considering as cases all subjects classified in Class 1 by LCA, and negatives (non-cases) all subjects classified in Class 2 by LCA, we compared the proportion of subjects classified as cases and non-cases by CRS and LCA, respectively.Cohen’s Kappa measure  was used to assess the agreement as follows: K ≤ 0, no agreement; K = 0–0.20, poor agreement; K = 0.21–0.40, fair agreement; K = 0.41–0.60, moderate agreement; K = 0.61–0.80, substantial agreement; and K = 0.81–1.00, nearly perfect agreement ,45.th, 2016).Samples were anonymously coded, unlinked from any information identifying the source individuals. At the Centre for Tropical Diseases, all subjects submitted to any serologic exam are asked to sign an informed consent for the anonymous storage of a serum specimen for any future research purpose. Parents’ or legal guardians’ consent is obtained in case of individuals of less than 18 years of age. Specimens lacking the consent are immediately discarded. Although the study was retrospective and no action on patients was involved, the study protocol was nevertheless submitted to the Ethics Committee of the Coordinating Site  for approval. The latter acknowledged the study protocol and formally authorized the study (protocol n. 33909 of July 13The flow of participants is described in S. mansoni eggs were found in the stools of 32/373 subjects (8.6%) and S. haematobium eggs in the urine of 40/373 subjects (10.7%). Seven subjects (1.9%) had both the infections.The proportion of positive microscopic results in the population under study was 65/373 (17.4%). In particular, The results of the 4 index tests according to microscopy are reported in S. mansoni only, CCA sensitivity increased to 72% (23/32), while that of the other tests resulted similar, in particular: ELISA, 84% (27/32); WB, 91% (23/32); and ICT, 94% (29/32).Considering S. haematobium and negative for S. mansoni, CCA sensitivity dropped to 24% (8/33), while that of the other tests, again, resulted similar, in particular: ELISA, 79% (26/33); WB, 94% (31/333); and ICT, 94% (31/33).Considering samples with positive microscopy for We also assessed if the presence of haematuria significantly influenced the proportion of CCA positivity. This data was available for about half of the study subject (185/373 or 49.6%). Considering subjects who resulted microscopically negative to both species, CCA resulted positive in 6/43 subjects with haematuria  and in 9/73 subjects without haematuria .The proportion of positive results according to the CRS was 38.6% (144/373). According to LCA modeling, the proportion of subjects classified in Class 1 was 35.6%. The results are detailed in ICT confirmed the highest sensitivity (96% for both models), followed by WB. CCA was again the test with the lowest sensitivity, that resulted very low . On the other hand, although the specificity of CCA was confirmed to be higher than 90%, both CRF and LCA identified ELISA as the indirect test with the highest specificity, being over 99%.The accuracy and predictive values, according to the three reference standards used, is summarized in Subjects with at least 2 concordant positive results of the index tests OR with a positive microscopy (irrespective of the other results) had 91.1% probability of being classified as cases by LCA, while all the others (negative microscopy and <2 positive index tests) had 99.5% probability of being classified as non-cases by LCA.The concordance between the two methods of classification was excellent .Assuming using ICT as a screening test , we assessed, using the LCA model, the positive and negative predictive values of a combination of a positive ICT (the test with the highest sensitivity) with a positive or a negative second test, respectively. The results are reported in Schistosomiasis prevalence was very important in the study population, composed for the vast majority of asylum seekers. Even when considering microscopy only, that is not sufficiently sensitive, the proportion of positives was higher than 17%. According to CRS and LCA, this proportion was very similar, 38.6% and 35.6%, respectively.S. mansoni) when the goal is to identify infections in an endemic country, but, according to our results, its sensitivity in non-endemic settings should be better assessed, before considering it as a potential screening tool, considering that the goal is to find and treat any infection, including chronic infections with a low egg output.The urinary, rapid antigen test CCA was unsatisfactory: its sensitivity was poor, and this, with any reference standard used, makes it inadequate for screening purpose. The higher sensitivity found by other studies  probablyWB showed an excellent combination of sensitivity and specificity, although the latter was not as high as one might expect by this technique. According to the manufacturer, a single band is sufficient to define a positive result. It is possible that a more conservative definition (i.e. requiring at least two positive bands) would bring the test specificity closer to 100%, though, expectedly, at the expense of some loss of sensitivity. We plan to investigate this with the next, longitudinal study (see below).ELISA was the test providing the most surprising results, as it was found to be virtually 100% specific according to both CRS and LCA. This result was not expected, as serologic tests in general are held to give a variable proportion of false positive results, due to cross-reaction with other pathogens and to other reasons . We trieAccording to both CRS and LCA, the sensitivity of microscopy was poor, thus confirming that finding schistosome eggs in the stools or urine is diagnostic, but their absence does not by any mean rule out the infection.All the main results, both of the infection prevalence in the study population and of the accuracy of the different tests, were very similar between the two models, indicating a satisfactory robustness of the (independent) methods used. The agreement between the two models in classifying the study subjects was nearly perfect (Cohen’s kappa test = 0.92).Should a screening program be planned, it should rely on a sensitive approach, that minimizes the risk of leaving infected subjects without the necessary treatment.Regardless the reference standard used, the ICT resulted the most sensitive test, with the potential of being used as a single screening test . The PPV of ICT was low when using the primary reference standard (reflecting the low specificity when a poorly sensitive test is used as reference), but reasonably high according to both the composite reference standard and the LCA, thus probably justifying a treatment, in a screening context, even without a confirmation test.Would a second test necessary/useful? The answer to this question depend on the context. Newly arrived immigrants/asylum seekers are often a very mobile group, and it is crucial to be able to screen (and treat the positives) at the first visit. The ICT appears to be sufficiently accurate for this purpose. On the other hand, in a clinical context, a confirmatory test would be obviously indicated. A positive microscopy would be the only test providing the certainty of infection, but a negative result would by no mean rule out the infection . ELISA iIn a screening context, this test can be used alone as a tool to decide the treatment, the only reasonable alternative being, in a high prevalence population such as our study population, a presumptive treatment of all immigrants coming from high prevalence countries, considering the potential severity of the chronic infection and the relatively harmless and highly effective treatment available (praziquantel). The cost-effectiveness of either approach was beyond the scope of this research and should be planned as a further study.We believe that a major strength of our study is the reference standard used. Direct demonstration of eggs in stools and/or urine is of course diagnostic, but this technique is also known to lack sensitivity, as infections with a low parasitic load are easily missed –27. It iWe acknowledge also some limitations of the models used. As far as the CRS is concerned, it may be argued that it is not correct to include an index test among the tests composing the reference standard. Moreover, the latter tests should not be conditionally dependent, while in fact three of them were based on the same principle, that is, antibody detection, and therefore conditional independence cannot be assumed. Besides, antibody detection does not necessarily reflect an active infection.In our retrospective, real-life study, we aimed at estimating the accuracy of all available tests, and this is the reason why all the index tests were also part of the reference standard. This was the only way of obtaining the same denominator of infected/not infected for all the tests examined. Precisely because we were aware of the limitations of the CRF used, we decided to also use a third, alternative method, namely the LCA.More in general, the main weakness of our study was the retrospective design. Although most of the tests were carried out for screening purpose and not because of clinical suspicion, some selection bias cannot be ruled out. Moreover not all the tests were always available during the study period, and the subjects lacking any of the tests under study had to be excluded from the analysis. Finally, the estimation of the prevalence in a hospital setting may not be representative of the general population, although in this case, as explained above, most tests were carried out on subjects submitted to a pilot screening, regardless the presence/absence of symptoms.Both ICT and CCA tests imply the visual reading by the observer of a band appearing within 15 minutes on the device. Theoretically, a classification of positive results (e.g. “strong positives” and “weak positives”) would be possible, based on the band intensity, also considering that the few results originally classified as undetermined obviously concerned faint positives for which an agreement was not reached). Unfortunately the test results were only classified as positive, negative or undetermined, therefore this distinction was not possible and will be certainly taken into account in a prospective study (see below). Automatic readers could possibly improve the use of these and other qualitative diagnostic tools in the future.We are planning an extensive, multi centre, longitudinal diagnostic study in order to assess the best diagnostic and screening strategy for schistosomiasis. Bio-molecular methods (that were not included in this study) will be also assessed. We are also planning to compare the results of the ICT performed after finger prick with those on serum obtained according to the standard procedure. If they are concordant, the use of ICT will be greatly facilitated outside health facilities.The new, rapid diagnostic test ICT is a suitable screening tool for schistosomiasis. A positive result should ideally be confirmed by a second test. ELISA and of course microscopy are the best confirmers of a positive ICT. Nevertheless, neither second test, if negative, is sufficient to rule out the infection. In a screening context, the ICT should probably used alone as a decision tool about treating or not the infection, the only practical alternative being a presumptive treatment of the population at risk.S1 File(XLSX)Click here for additional data file.


P < 0.0001). The TE and SY types showed higher forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) values than the SE type (P < 0.0001). An increase in IRV and a decrease in expiratory reserve volume (ERV) in TE type males remained even after adjusting for covariate factors. These results indicate that young adults with the TE type have weaker lung function than those with the other constitutional types, suggesting its innate physiological pulmonary features.The purpose of this study was to determine the differences in pulmonary function among Sasang constitutional types in young adults. The Sasang Constitutional Analysis Tool (SCAT), pulmonary function tests (PFTs), and cardiopulmonary exercise tests were conducted in 417 participants from 2009 to 2015. Subjects with the Tae-Eum (TE) type had significantly higher inspiratory capacity (IC) and inspiratory reserve volume (IRV) values than those with the So-Yang (SY) and So-Eum (SE) types ( Sasang Constitutional Medicine (SCM) is a traditional Korean medicine created by Lee Je-ma 1837–1900) at the end of the 19th century 837–1900 . Several1), are decreased, it is defined as pulmonary dysfunction [The pulmonary function test (PFT) is widely used in clinical practice to screen for the presence or absence of pulmonary dysfunction . If measfunction . Severalfunction , 17 and function , diabetefunction , and dysfunction . Recent function , 22. Howfunction , impairefunction , and thefunction .The relationship between Sasang constitution and pulmonary dysfunction has not yet been clarified. There have been few attempts at scientific and comprehensive pathological interpretation. As the risk of metabolic diseases increases, the importance of the TE type's physiological interpretation also increases.This cross-sectional study was conducted from 2009 to 2015. All of the questionnaire data and clinical data, including Sasang constitutional type (SCT) and PFT, were compiled from the Korea Constitutional Multicenter Bank (KCMB) of the Korea Institute of Oriental Medicine (KIOM). Using this resource, we collected questionnaire data on 417 subjects who were recruited at Asan Medical Center. The present study population comprised a population-based sample selected from healthy subjects recruited through advertisements at Asan Medical Center. Twenty-six subjects who did not complete the PFT were excluded from the analysis. After applying these exclusions, a total of 391 individuals were analyzed. This study was approved by the Institutional Review Board of Asan Medical Center (IRB number: 2009-0566). All participants agreed to join this study, and written informed consent for participation was obtained.The determination of SCT was performed using the SCAT developed by the KIOM . Facial 1 were measured at rest. FEV1/FVC was calculated as FEV1 divided by FVC. Total lung capacity and its subdivisions were measured by the nitrogen washout method with the Vmax 229. PFT was performed in accordance with recommended standards [2max, mL/kg/min), a measure of cardiorespiratory fitness, was recorded using a Vmax ENCORE 29c indirect calorimeter (SensorMedics) during exercise testing on a treadmill following a standard Bruce protocol [The PFT was performed using a Vmax 229 Pulmonary Function/Cardiopulmonary Exercise Testing Instrument . FVC and FEVtandards . MaximumBMI was calculated as weight divided by height squared. Waist circumference (cm) was measured at the narrowest point between the lower rib and the iliac crest. Blood pressure was measured with a standard mercury sphygmomanometer on the nondominant arm. Blood samples were analyzed at Seoul Clinical Laboratories  to determine the levels of fasting plasma glucose, insulin, triglycerides (TGs), and high-density lipoprotein (HDL) cholesterol.P values < 0.05 were considered statistically significant.All statistical analyses were performed with SPSS Statistics® version 23 . One-way analysis of variance (ANOVA) was conducted to evaluate differences in the general characteristics and cardiorespiratory values across SCTs. Bonferroni's post hoc test was performed for multiple comparisons. The PFT and cardiopulmonary fitness data were compared among SCTs using analysis of covariance (ANCOVA) while adjusting for sex, age, height, weight, and presence of diabetes mellitus . The participants were defined as having diabetes mellitus if a fasting glucose level exceeded ≥126 mg/dL or 2-hour plasma glucose exceeded ≥200 mg/dL. All The general characteristics of the participants are shown in 1 were lower in subjects with the SE type than in those with the TE and SY types. When stratified by gender, male TE participants had higher inspiratory capacity (IC) and inspiratory reserve volume (IRV) values and lower expiratory reserve volume (ERV) values than those with the other types. Female TE and SY participants had higher VC, inspiratory capacity (IC), and FVC values than those with the SE types.Overall, the results of the PFT showed that subjects with the TE type had significantly higher IC and IRV values than those with the SE and SY types. Vital capacity (VC), FVC, and FEV1 showed a similar trend in the TE and SY groups despite the difference in BMI and TE groups were higher in the SE group. When stratified by gender, IC, ERV, and IRV showed a similar trend despite the difference in BMI; male TE participants had higher IC and IRV values and lower ERV values than the SE type. In females, this tendency was maintained; TE and SY participants had similar VC, IC, and FVC values, which were higher than in the SE participants  that can affect the PFT were adjusted, the influence of the significant variables from the ANOVA almost disappeared.1, although there was a trend towards higher IRV and lower ERV and FVC values in subjects with the TE than in other types.ANCOVA revealed no significant difference in any PFT variables except for FEVAccording to the analysis stratified by gender, there was no significant difference in any variable in males. However, although statistical significance was not achieved among the constitutional types, there was a tendency for male TE participants to have lower tidal volume (VT), VC, ERV, and FVC values and higher IC and IRV values than the other constitutional types.In females, VC and exercise time were significantly lower in SE participants than in SY participants. Additionally, ERV was higher and IRV was lower in TE participants, in contrast to the total and male results .Among the SCTs, the constitution that is profoundly related to pulmonary function is the TE type. Subjects with the TE type have weak pulmonary function and strong liver function compared to the other constitutions . The purGender, age, and height are the major determinants of pulmonary function in normal adults , 31. It When comparing the general characteristics according to constitution, participants with the TE type had a higher body weight, BMI, and waist circumference than the other constitutions; thus, high blood pressure, fasting insulin, TGs, and low HDL were confirmed. This is consistent with previous studies that reported that subjects with the TE type are prone to obesity and are therefore vulnerable to metabolic syndrome, hypertension, and diabetes , 9. The 1 values, consistent with previous research that TE type males had a large PFT value [1 values of subjects with the SE type were the smallest among the SCTs. It is presumed that this result is because the height of SE subjects is significantly smaller than those with the TE and SY types.The present study found that, in general, subjects with the TE type exhibit increased pulmonary function and lung volume compared with the other types. Because lung function is mostly affected by height , a relatFT value . AdditioAfter adjusting for age, height, weight, and presence of diabetes mellitus as covariates, there was a tendency towards lower FVC values in TE type males than other constitutions, although the tendency was not significant. These results indicate that innate pulmonary function of the TE type is weaker than that of the other constitutions and that the lung function characteristics of the TE type are not the same as those of a general obese group .1 [Previous studies have shown that an increase in BMI is associated with a decrease in FVC and FEV1 . The TE 1 . Obesity1 , 37, 38.1 . In addi1 .2max and exercise time also showed the characteristic of decreased cardiopulmonary function in TE type participants compared to the other types. This result suggests that subjects with the TE type exhibit characteristics of obesity; thus, their cardiorespiratory function is reduced [In addition, changes in respiratory function in the TE type reflect altered lung volume caused by obesity. It is reported that obesity causes a reduction in the ERV as a result of a reduction in diaphragm mobility and pulmonary compliance . Obesity reduced .The current study is an analysis of young adult participants. In the case of middle-aged adults reported previously, a reduction of FVC in the TE types had a stronger tendency than in the present study . Taken tThe following points are limitations to present study. First, we recruited participants who were considered healthy and did not perform any other chest X-rays. Second, variables such as factors affecting pulmonary function  were not considered together. Thus, a more accurate comparison of pulmonary function was limited. In addition, considering the fact that pulmonary function reaches its maximum value in the mid-20's and declines as age increases , it is nAs mentioned above, subjects with the TE type have the highest prevalence of metabolic syndrome and hypertension than those with the other constitutions , 6. BothIn conclusion, our data suggest that subjects with the TE type, especially males, exhibit weaker pulmonary function, in terms of lung capacity and volume than those with the SE and SY types.


Burkholderia pseudomallei as a contaminant or another organism. Disease awareness is low, and people in rural areas neither wear boots nor boil water before drinking to protect themselves from acquiring B. pseudomallei. Previously, about 10 melioidosis deaths were formally reported to the National Notifiable Disease Surveillance System (Report 506) each year, thus limiting priority setting by the MoPH. In 2015, the formally reported number of melioidosis deaths rose to 112, solely because Sunpasithiprasong Hospital, Ubon Ratchathani province, reported its own data (n = 107). Melioidosis is truly an important cause of death in Thailand, and currently reported cases (Report 506) and cases diagnosed at research centers reflect the tip of the iceberg. Laboratory training and communication between clinicians and laboratory personnel are required to improve diagnosis and treatment of melioidosis countrywide. Implementation of rapid diagnostic tests, such as a lateral flow antigen detection assay, with high accuracy even in melioidosis-endemic countries such as Thailand, is critically needed. Reporting of all culture-confirmed melioidosis cases from every hospital with a microbiology laboratory, together with final outcome data, is mandated under the Communicable Diseases Act B.E.2558. By enforcing this legislation, the MoPH could raise the priority of this disease, and should consider implementing a campaign to raise awareness and melioidosis prevention countrywide.A recent modelling study estimated that there are 2800 deaths due to melioidosis in Thailand yearly. The Thailand Melioidosis Network (formed in 2012) has been working closely with the Ministry of Public Health (MoPH) to investigate and reduce the burden of this disease. Based on updated data, the incidence of melioidosis is still high in Northeast Thailand. More than 2000 culture-confirmed cases of melioidosis are diagnosed in general hospitals with microbiology laboratories in this region each year. The mortality rate is around 35%. Melioidosis is endemic throughout Thailand, but it is still not uncommon that microbiological facilities misidentify  Burkholderia pseudomallei [B. pseudomallei, respectively, countrywide [n = 386; mortality 50%), Ubon Ratchathani , Bangkok (n = 91), Chiang Mai (n = 61), Nakhon Ratchasima (n = 30), Nonthaburi (n = 11), and Songkla (n = 6) [Indigenous melioidosis was first reported in Thailand by Chittivej et al. in 1955 [domallei . A totaldomallei . Subsequntrywide . By 1985 (n = 6) .B. pseudomallei as a contaminant or other organism [B. pseudomallei identified in 46 hospitals from four regions of Thailand in 1995 (Northeast (n = 19), Central (n = 11), North (n = 9) and South (n = 7)) [In Thailand, underrecognition and misdiagnosis of melioidosis have been major obstacles to saving lives from this disease. Worldwide, untrained laboratory personnel commonly misidentify organism . Leelara(n = 7)) . B. pseudomalleii identification for laboratory personnel is still needed countrywide.From 1995 to 2015, melioidosis was heavily reported from Northeast Thailand ,8 and raThe case fatality rate (CFR) of melioidosis in general hospitals in Thailand decreased markedly from 60–70% to 35–40% after the landmark study comparing ceftazidime with ‘conventional’ treatment was published in 1989 . UnfortuIt is still unknown how many patients die of melioidosis in Thailand yearly. A recent modeling study estimated that there are 7572 human melioidosis cases per year in Thailand, of whom 2838 (37%) die . At NakhThe Thailand Melioidosis Network was formed in 2012, and has been working closely with the MoPH to investigate the burden, solve the problems of underreporting by Report 506, and develop initiatives on melioidosis. Here, we review the current guidelines for diagnosis, treatment and prevention of melioidosis in Thailand, explore how to improve the official data and increase awareness of melioidosis. We discuss the needs and future challenges to save lives from melioidosis in Thailand.B. pseudomallei from 1910 to 2015 in Thailand  , could bironment ,30. n = 12) and South (n = 12) regions, followed by the East (n = 3), North (n = 1), and Central (n = 1) areas [A number of captive zoo animals  and dome1) areas . A descr1) areas .B. pseudomallei could be found in soil in North Thailand, but the details of locations were not reported, and an updated study has not been conducted [North Thailand is composed of 9 provinces, some of which share a border with Myanmar and Laos. Its geography is comprised of several mountain ranges and the basins of four major rivers, which are tributaries of the Chao Phraya River in Central Thailand. Melioidosis has occasionally been reported from Chiang Mai, the largest province in the region ,38,39. Fonducted .B. pseudomallei and diagnosis of melioidosis to laboratory staff from 17 hospitals in North Thailand and other regions. The immediate result was that Chiangkom Hospital, Phayao, North Thailand, diagnosed 20 culture-confirmed cases in 2017 [B. pseudomallei, and misidentification as Pseudomonas spp. or contaminants was common. A recent study from Chiangrai Prachanukroh Hospital, Chiang Rai, also found that B. pseudomallei was commonly misidentified as Acinetobacter spp. [In September 2017, a workshop organized by the MoPH, MRC, and Thailand Melioidosis Network was conducted at the Faculty of Associated Medical Sciences, Chiang Mai University, to provide information on melioidosis, the potential pitfalls in the identification of  in 2017 . During ter spp. . Lack ofB. pseudomallei, in this same study [P = 0.1) among patients with known outcomes from bacteremic melioidosis. These figures are likely to underestimate the true burden of B. pseudomallei, as the surveillance was focused on hospitalized cases. This study shows that the incidence of bacteremic melioidosis in Eastern Thailand is much higher than the figures reported to Report 506 of MoPH, Thailand suggest.East Thailand is characterized by short mountain ranges alternating with alluvial plains. This region was historically not considered an endemic area for melioidosis; however, population-based surveillance activities by TUC in Sa Kaeo province, located on the Cambodian border about 200 kilometers from Bangkok, indicated otherwise . Estimatme study . The CFRB. pseudomallei to be highly prevalent in all six provinces  in East Thailand [A descriptive study of animal melioidosis between 2006–2010 also reported a high number of culture-confirmed human melioidosis in two Eastern provinces, Chachoengsao (151 human cases and 2 goats), and Chonburi (76 human cases and 1 goat), where goat cases were diagnosed [Thailand .The geography of West Thailand is characterized by high mountains and steep river valleys along the border with Myanmar. Diagnosis of culture-confirmed melioidosis was rare within West Thailand until recently . A descrB. pseudomallei in soil samples collected from Prachuap Khiri Khan, West Thailand [During the workshop conducted at Chiang Mai University, North Thailand, in September 2017, laboratory staff from Somdejphrajaotaksin Maharaj Hospital, Tak, West Thailand, also participated. After the workshop, 3 culture-confirmed cases were diagnosed at the hospital that year . TUC conThailand . These rThailand . TraininB. pseudomallei was widely found in water supplies on Koh Phangan [B. pseudomallei in all 14 provinces in South Thailand [South Thailand is famous for its beautiful beaches. The western part has steeper coastlines and is on the Andaman Sea, while the east side is mainly river plains and on the Gulf of Thailand. Melioidosis is increasingly recognized as endemic in South Thailand. One of the most striking phenomena was a number of culture-confirmed cases reported from tsunami survivors in 2004 in Phangnga ,47,48, o Phangan . Churang Phangan . Overall Phangan . The low Phangan , compareThailand . TherefoThailand .B. pseudomallei outside the region, and that melioidosis is not endemic in Central Thailand. However, recent evidence in 2014 showed the presence of culture-confirmed melioidosis in ten goats in Bangkok, suggesting that B. pseudomallei might be covertly present in the environment in the central region and in Bangkok  or national guidelines for identification of n = 107 and 87, respectively) [The National Communicable Disease Surveillance system (Report 506) was established in Thailand in 1968. Melioidosis has been one of the diseases for notification since 2002. However, until 2014, only about 10 fatal melioidosis cases per year were voluntarily reported in Report 506 ,25,26,27ctively) ,58. It iB. pseudomallei in their Report 506. By enforcing this legislation, the MoPH could raise the priority of the disease, and should also consider implementing a large campaign to raise awareness and implement melioidosis-prevention measures countrywide. Since June 2016, reporting of culture-confirmed melioidosis cases from every hospital with a microbiology laboratory, together with final outcome, has been mandated under the Communicable Diseases Act B.E.2558 (A.D. 2015) . Melioidn = 1000) and the model-predicted fatal cases (n = 2838) [We believe that the main cause for the discrepancy between the estimated number of fatal cases  should not be used to diagnose melioidosis in endemic countries due to the high background seropositivity ,25,26,27The Thailand Melioidosis Network has proposed revising the reporting system to cover only culture-confirmed cases so that the true burden and true mortality (and CFR) could be demonstrated to the MoPH. Nonetheless, due to the problem of maintaining diagnostic capacity for melioidosis at community hospitals, the proposal was not accepted. The community hospitals require affordable rapid diagnostic tests (RDT) with high accuracy  to justify replacement of the IHA. Therefore, such an RDT is critically needed for Thailand.B. pseudomallei were reported to Report 506, and how many of those died countrywide. These activities will support the MoPH to improve understanding of the burden of melioidosis and the discrepancies between cases diagnosed by attending physicians, microbiologically-confirmed cases, and those reported to Report 506.Currently, the MoPH is working to rectify the underreporting of deaths caused by melioidosis in Report 506 by using (1) the hospital database known as ‘43 files reports’ and (2) existing microbiological databases. The 43 file reports include International Statistical Classification of Diseases 10 (ICD-10). According to ICD-10, melioidosis is coded as A24. The MoPH is evaluating how many patients with the ICD-10 code of A24 were reported to Report 506, and how many of those died countrywide. Other work has used laboratory microbiological databases, and will evaluate how many patients with cultures positive for Awareness of melioidosis in the general Thai population is very low. A recent study showed that 74% of lay adults had never heard of melioidosis, and 19% had heard of the disease, but had no further knowledge . InformaA contributing factor to poor awareness of the disease is that many melioidosis patients die quickly before the microbiological results have been reported to the doctors caring for the patient. Even for culture-confirmed cases of melioidosis, doctors and healthcare workers are often too busy to explain to patients and their families what melioidosis is. This is because the relatives have usually never heard of this disease, and the explanation would take time. Most relatives in such scenarios are informed that the cause of death was sepsis, septic shock, or bacteremia, without explaining about melioidosis. They are also not informed about how to prevent other people in the family, or in the community, from acquiring the same disease. Although those who survive melioidosis are educated about the disease and receive oral eradicative treatment for up to 20 weeks, knowledge about the importance of the disease is not effectively shared with their relatives, friends, or communities. This is shown by the fact that most have never heard of the disease.The Thailand Melioidosis Network was formed during a meeting in March 2012 . The meeThe first international congress devoted to melioidosis held in Thailand, entitled ‘International Congress on Melioidosis’ with the theme ‘State of the art discoveries and trends towards the 21st century’, took place at the Siam City Hotel in Bangkok in 1998. The congress was organized by the Chulabhorn Research Institute and the chairperson was Prof. StitayaSirisinha. There were 150 delegates from Thailand and several other countries. The meeting was later referred to as ‘The 2nd World Melioidosis Congress’, which has since been held every three years and rotated through melioidosis-endemic countries. The international melioidosis meeting held in Kuala Lumpur, Malaysia in 1994 and chaired by Prof. Savithiri Puthucheary was regarded as the first World Melioidosis Congress (WMC). The 3rd and 4th WMC were held in 2001 in Perth, Australia, and 2004 in Singapore, respectively. In 2007, the 5th World Melioidosis Congress was again held in Thailand at Khon Kaen province and hosted by MRC, with Prof. Surasak Wongratanacheewin as chairperson , followeHosting these meetings in Thailand has helped to raise the profile of melioidosis in the Thai medical, scientific, and political communities, as well as attracting media attention for the general public. During the meetings of the Thailand Melioidosis Network in 2012, four priority areas were identified . These iFirst, the problem of underreporting by Report 506 must be solved. Although the rise in the reported number of deaths in 2015 occurred, more needs to be done. Only one provincial hospital  reported its melioidosis cases and their mortalities to Report 506. This was partially supported by the research unit in Sunpasitthiprasong Hospital. In future, the personnel who are responsible for the system might change jobs, and the system is not automated. Although a lot of discussion with many hospitals has taken place, the data from these hospitals have not yet been submitted to the national reporting system. An immediate need is educating and supporting all hospitals with microbiological facilities to report their culture-confirmed melioidosis cases and their mortalities to Report 506. A long-term solution is to automate the reporting system, similar to the systems in the Netherlands and China . AnotherSecondly, in order to raise public awareness of melioidosis, a large national campaign led by the MoPH is needed. Based on multiple studies in Thailand ,19, lay B. pseudomallei selective culture media, and (4) a lack of RDTs for melioidosis diagnosis direct from clinical specimens, obviating the need for bacterial culture. Major university hospitals in Thailand could use instruments such as the Vitek 2 system  or matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOFMS), if the appropriate databases for B. pseudomallei are available [B. pseudomallei to identify the organism within available resources, for example, using standard biochemistry and drug susceptibility tests. All technicians should be trained to recognize B. pseudomallei colonies, and not discard them as contaminants. All oxidase-positive Gram-negative bacilli should be tested to see whether they are B. pseudomallei [Pseudomonas spp. should include a note that the organism was tested and confirmed not to be B. pseudomallei. A simple three-disc susceptibility testing method  are not available. All uncertain isolates should be sent for confirmation to the Department of Medical Science, MoPH, Thailand, university hospital laboratories, or any research organizations in the area willing to receive bacterial isolates for confirmation of identity. Third, the problem of misdiagnosis and bacterial misidentification in hospital microbiological laboratories outside Northeast Thailand has been described above. This is very likely due to the fact that (1) most laboratory technicians erroneously believe that melioidosis is endemic only in Northeast Thailand, (2) laboratory training around diagnostic testing is not adequate, (3) there is a lack of rapid bacterial identification tests, along with poor usage of vailable . Howeverdomallei . Reportsnic acid ,68) shouB. pseudomallei has been available in Thai research organizations for more than 17 years [B. pseudomallei countrywide [A latex agglutination assay using a monoclonal antibody specific for 17 years . The tesntrywide .A lateral flow immunoassay (LFI) using a similar monoclonal antibody to the latex agglutination assay has been developed by InBIOS , and is currently being evaluated in several countries ,71. LFI Fourth, recommendations for melioidosis prevention should be promoted thoroughly and intensively. Thailand is a hotspot for melioidosis, but only a small proportion of people in Thailand follow recommended behaviors that can prevent melioidosis ,19. ThesIn the long term, an effective vaccine against melioidosis, targeting at-risk groups, such as people with diabetes and agriculture workers, would be the ideal strategy for reducing the burden of disease and number of deaths from melioidosis in Thailand , and couIn conclusion, we strongly believe that a prevention campaign should be undertaken now by the MoPH, together with enhancing disease surveillance systems, raising awareness of the disease and its true mortality, and improving the diagnosis of melioidosis. We believe that formal campaigns from the MoPH would enhance the usage of free boots that MoPH regularly provides to farmers. More lives could be saved, not only from leptospirosis, but also from melioidosis.