R = 0.6, p = 0.02). Conclusions: The majority of Australian adolescents with ME/CFS continue to fulfil diagnostic criteria at follow-up, with fatigue, pain, and health-related quality of life representing domains particularly relevant to perpetuation of ME/CFS symptoms in the early years following diagnosis. This has direct clinical impact for treating clinicians in providing a more realistic prognosis and highlighting the need for intervention with young people with ME/CFS at the initial diagnosis and start of treatment.Background: The purpose of this study was to follow-up an Australian cohort of adolescents newly-diagnosed with ME/CFS at a tertiary paediatric ME/CFS clinic and healthy controls over a mean period of two years (range 1–5 years) from diagnosis. Objectives were to (a) examine changes over time in health and psychological wellbeing, (b) track ME/CFS symptomatology and fulfillment of paediatric ME/CFS diagnostic criteria over time, and (c) determine baseline predictors of ME/CFS criteria fulfilment at follow-up. Methods: 34 participants aged 13–18 years  completed standardised questionnaires at diagnosis (baseline) and follow-up assessing fatigue, sleep quality and hygiene, pain, anxiety, depression, and health-related quality of life. ME/CFS symptomatology and diagnostic criteria fulfilment was also recorded. Results: ME/CFS patients showed significant improvement in most health and psychological wellbeing domains over time, compared with controls who remained relatively stable. However, fatigue, pain, and health-related quality of life remained significantly poorer amongst ME/CFS patients compared with controls at follow-up. Sixty-five percent of ME/CFS patients at baseline continued to fulfil ME/CFS diagnostic criteria at follow-up, with pain the most frequently experienced symptom. Eighty-two percent of patients at follow-up self-reported that they still had ME/CFS, with 79% of these patients fulfilling criteria. No significant baseline predictors of ME/CFS criteria fulfilment at follow-up were observed, although pain experienced at baseline was significantly associated with criteria fulfilment at follow-up ( Paediatric myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling condition of unknown etiology. It causes significant and well-documented adverse effects in physical and psychological functioning, school attendance and participation, and quality of life ,2,3,4. LSignificant change in emotional, social, hormonal, and physical functioning is typical in the transition from childhood to early adulthood . Onset oWhile there are relatively few longitudinal studies assessing follow-up of adolescent patients with ME/CFS, the limited evidence available suggests that improvement and recovery are more likely in paediatric ME/CFS compared with adult ME/CFS . To dateSurprisingly few studies have focused on the health factors that may predict longer-term outcomes such as persistence of diagnostic symptoms, with studies tending to focus on risk factors for new-onset ME/CFS ,31. The There were three mains aims for this study. First, we aimed to examine the change over time in factors associated with health and psychological wellbeing  in newly-diagnosed adolescents with ME/CFS relative to healthy adolescents, across a mean follow-up period of two years from diagnosis (and study enrolment). Second, we aimed to track patients’ ME/CFS symptomatology over time to determine the type and frequency of symptoms experienced, and fulfilment of paediatric ME/CFS diagnostic criteria at follow-up . Finally, the third aim was to determine which aspects of health and psychological wellbeing at diagnosis best predicted ME/CFS criteria fulfilment at follow-up.This study represents a follow-up of a wider study that investigated brain structure and function, cognition, and psychological wellbeing in adolescents first diagnosed with ME/CFS and healthy adolescent controls . A totalAll 48 participants were invited to participate in the follow-up study approximately two years after their participation in the original study when they were first diagnosed with ME/CFS. Ten participants (7 ME/CFS and 3 controls) could not be contacted despite multiple attempts, and 4 participants withdrew at follow-up (1 ME/CFS and 3 controls). Therefore, 34 participants  took part in both the original and follow-up studies and were included as part of the current investigation. Informed consent was obtained from all participants and their parents, and no compensation or incentives were offered to participate in the research. The study was approved by The Royal Children’s Hospital Human Research Ethics Committee .Original study at diagnosis (Baseline). Participants completed standardised questionnaires via REDCap Software . The quFollow-up study. Participants completed the same questionnaires administered at baseline. In addition, the adolescents originally diagnosed with ME/CFS were also asked to complete a health questionnaire about symptoms experienced over the past 3 months.Health and psychological wellbeing measures across five domains were collected at both baseline and follow-up, and shown in A short researcher-designed health questionnaire for the ME/CFS cohort was administered at baseline and follow-up, based on the diagnostic criteria for the paediatric case definition of ME/CFS and developed by the Pediatric ME/CFS Case Definition Working Group ,37,52. ATwo main measures were obtained from the health questionnaire: (a) fulfilment of ME/CFS diagnostic criteria : Two-subtest Full Scale Intellectual Quotient (Vocabulary and Matrix Reasoning subtests) at baseline and follow-up to obtain an estimation of their general intellectual ability, or FSIQ [M = 100, SD = 15).Finally, participants completed the  or FSIQ . Standart-tests and chi-square tests were used to assess group differences at baseline and follow-up.All data were analysed using the statistical analysis program Stata 16.0 , and screened for violations of statistical assumptions. The sample characteristics were summarised using descriptive statistics. Independent samples b) with their 95% confidence intervals (CIs), and associated standard errors (SE). A significance level of 0.05 was used for all models, and rather than relying solely on p values, Cohen’s d was calculated to determine the magnitude of the effect and interpreted according to Cohen’s [For the first aim, analysis of group differences in aspects of health and psychological wellbeing over time involved a single linear mixed-effects regression model for each outcome (dependent variable). Models included time (baseline vs. follow-up) and group (ME/CFS vs. control) as predictors, an interaction term between group and time, a random intercept for each participant to allow for clustering of observations within a participant, and follow-up time interval in years as a covariate . The linear mixed-effects regression results were presented as estimated mean differences (fixed main effects and pairwise contrasts of the dependent variable); that is, unstandardised regression coefficients  the proportion that fulfilled paediatric ME/CFS diagnostic criteria ,37, (b) p values. ORs were used as the magnitude of the effect and were interpreted according to Rosenthal’s [For the third aim, multiple logistic mixed-effects regression models were performed to determine which baseline variables of health and psychological wellbeing best predicted fulfilment of ME/CFS diagnostic criteria at follow up , via unstandardised regression coefficients, 95% CIs, and enthal’s  guidelinAs shown in Estimated mean group differences (ME/CFS vs. control) over the approximate two-year period (baseline vs. follow-up) are shown in p < 0.001, d = 1.47). This group difference diminished over time, with the ME/CFS group reporting significant improvement in fatigue levels from baseline to follow-up , and the control group remaining relatively stable . At follow-up, the ME/CFS group still reported significantly greater fatigue than controls, although the magnitude of this effect was reduced compared to baseline .Fatigue. A significant main effect of group, time, and group by time interaction effect was observed. At baseline, the ME/CFS group had a significantly greater level of problems related to fatigue than controls . This magnitude of change over time in sleep quality differed between the groups, with the ME/CFS group reporting significant improvement from baseline to follow-up , and the control group remaining stable . At follow-up, there was no significant difference in sleep quality between the two groups .Sleep quality. A significant main effect of group, time, and group by time interaction effect was observed. At baseline, the ME/CFS group reported significantly poorer sleep quality than controls .Sleep hygiene. A significant time by group interaction effect was observed, however the individual effects of time and group were very small and did not reach significance. The groups showed similar levels of sleep hygiene at both baseline and follow-up, and the interaction effect appeared to be driven by a small decline in sleep hygiene in the control group over time . Over time, the ME/CFS group reported a significant decline in pain from baseline to follow-up , and the control group remained stable . At follow-up, the ME/CFS group continued to report significantly greater pain than controls, although the magnitude of this effect was reduced compared to baseline .Pain. A significant effect of group, time, and group by time interaction effect was observed. At baseline, the ME/CFS group reported significantly greater severity of present pain than controls . Over time, anxiety levels significantly decreased for the ME/CFS group , but did not significantly change for controls , such that at follow-up there was no significant difference in anxiety levels between the two groups .Anxiety. A significant main effect of group, time, and group by time interaction effect was observed. At baseline, the ME/CFS group reported significantly greater levels of anxiety than the control group . Mean group differences in depression from baseline to follow-up were associated with negligible effect sizes for both groups .Depression. No significant main effects of time or group, nor a significant time by group interaction effect was observed . Over time, this magnitude of this group difference diminished, whereby HRQOL significantly improved for the ME/CFS group  but did not significantly change for the control group . At follow-up, the ME/CFS group still reported significantly worse HRQOL than controls, although the magnitude of the effect was reduced compared to baseline .HRQOL. A significant main effect of group, time, and group by time interaction effect was observed. At baseline, the ME/CFS group reported significantly poorer HRQOL than controls . At follow-up, 65% (n = 11) of participants fulfilled criteria for ME/CFS . Of the 4 participants who met criteria for ‘atypical ME/CFS’  at follow-up, all 4 met criteria for the classic criteria of fatigue, sleep problems, and pain. Six of the 17 (35%) did not fulfil ME/CFS criteria at follow-up, and none of these endorsed persistent and unrelenting fatigue as a symptom.At baseline, all 17 adolescents diagnosed with ME/CFS by their consultant ME/CFS specialist paediatrician fulfilled criteria for ME/CFS , a greater proportion fulfilled criteria for ME/CFS than not . Nine of the 14 participants reported that their ME/CFS had impacted ‘a lot’ on their participation in school, studies or employment, while 5 reported that it impacted ‘a little’. All three participants who self-reported as not having ME/CFS at follow-up did not fulfill criteria for ME/CFS. Breakdown of participants who fulfilled paediatric ME/CFS diagnostic criteria at both time points is summarised in Of the majority that self-reported as having ME/CFS at follow-up in response to the question ‘do you still have ME/CFS?’ . Pain was the most endorsed symptom at follow-up (100%), closely followed by sleep problems (94.1%) and one or more autonomic/neuroendocrine/immune problems (94.1%).p > 0.05, d range = 0.02–0.33, OR range = 0.83–2.54). Pain experienced at baseline was close to reaching significance  and was associated with a moderate effect size (d = 0.33), but a small OR  = 0.02). For the Pearson correlation analysis, only pain experienced at baseline was significantly associated with ME/CFS criteria fulfilment at follow-up, with moderate effect . The Pearson correlation matrix for this analysis can be found in None of the baseline variables of health and psychological wellbeing were significant predictors of fulfilment of ME/CFS diagnostic criteria at follow-up  two-year period in adolescents diagnosed with ME/CFS compared with their healthy peers. It also aimed to track patients’ ME/CFS symptomatology and fulfillment of paediatric ME/CFS diagnostic criteria at follow-up, and determine whether ME/CFS criteria fulfilment at follow-up could be predicted by aspects of health and psychological wellbeing at diagnosis.Greater levels of fatigue, pain, and anxiety, and lower levels of sleep quality and HRQOL were observed amongst adolescents with ME/CFS at baseline compared with their healthy peers. This is consistent with previous cross-sectional findings in adolescents with ME/CFS from our own team ,9,43,58 A positive finding from this study was that with significant improvement over time, adolescents with ME/CFS became comparable to their healthy peers at follow-up in their level of anxiety and sleep quality. The lack of follow-up studies assessing anxiety in paediatric ME/CFS make the reasons for this improvement in anxiety level unclear. It is possible that anxiety experienced at baseline related to the diagnosis itself and/or diagnostic and prognostic uncertainty, all of which may have reduced in impact over time. Gradual acceptance and better management of their chronic condition may also have played a role in improving anxiety and sleep quality, including multi-disciplinary input in the post-diagnosis period. Certainly, many participants with ME/CFS continued to be managed by a general practitioner (47% of the ME/CFS cohort), paediatrician (41%), psychologist (29%) and/or physiotherapist (29%) for more than 3 visits (71%) over the course of the study period. Inter-relatedness of the domains studied would also suggest that management, rehabilitation and improvement in one area would likely lead to symptom reduction in related domains .More concerning was the finding that despite significant and clinically-meaningful improvement over time (with moderate to large effect sizes), adolescents with ME/CFS continued to show significantly greater fatigue, pain and poorer health-related quality of life than their healthy peers at follow-up. This observation is important for the treating clinician to understand so that a more realistic prognosis and need for intervention can be discussed with the young person and their family at the initial diagnosis and start of treatment. Van Geelen et al.  found coUnlike previous studies ,31,62,66The main finding from the second aim of our study was that approximately two thirds (65%) of participants continued to fulfill paediatric ME/CFS diagnostic criteria at follow-up, which included cases of severe, moderate, and atypical severity. The remaining third (35%) were not classified as meeting criteria and more likely reflected a sub-clinical sample of individuals that had improved considerably since diagnosis, given that none reported unexplained, persistent fatigue that represented a substantial reduction in previous functioning. This 35% of participants could be interpreted as having improved clinical status since diagnosis, which would fall within the observed ‘recovery’ range in Moore et al.’s  systematConsistent with the majority of patients fulfilling paediatric ME/CFS criteria at follow-up, the majority of patients (82%) self-identified as continuing to have the condition at follow-up. Of these patients, 79% did indeed fulfil criteria for ME/CFS, while 21% did not. On one hand, the disparity could be an issue of construct validity. Whilst the Canadian consensus criteria for paediatric ME/CFS is considered an improvement upon previous case definitions , greaterThe main finding from the third aim of our study was that no aspects of baseline health and psychological wellbeing were found to significantly predict ME/CFS criteria fulfilment at follow-up, with any great effect. However, despite not reaching significance as a predictor (with moderate effect), pain at baseline was significantly and positively associated with meeting criteria at follow-up, and was also the most commonly endorsed symptom by patients at follow-up. This would suggest that the experience of pain early in illness course may be relevant to later diagnostic status in the wider paediatric ME/CFS population, which is supported by previous research ,75.new onset chronic fatigue, they found no association between baseline anxiety/depression and persistent chronic fatigue. Rowe [have found associations between baseline health/psychological wellbeing—e.g., sleep quality [Although many reports imply that the presence of poor health at ME/CFS onset influences future recovery ,63,76, eue. Rowe  and Rimeue. Rowe  findingsue. Rowe ,15,24,76 quality , depress quality ,78, anxi quality —and folln = 8) may potentially have been more functionally impaired than those who participated at follow-up, thereby influencing the representativeness of our sample. Importantly, analysis comparing baseline data for those involved in and those lost to follow-up revealed no significant differences in demographic characteristics  or intellectual ability (FSIQ), which suggests these influences were minimal. Our study would also have benefited from the inclusion of a comparison group such as adolescents with fibromyalgia, and with a larger sample size, would have been powered to separate the cohort into subgroups of mild, moderate, and severe ME/CFS for analysis. This would have helped to offset any influence of regression toward the mean when evaluating change over time [It is important to acknowledge the possibility that those adolescents with ME/CFS who were lost to follow-up , the current study highlights the need for early identification and targeted and intensive treatment in these domains that continues at least two years post-diagnosis, but ideally longer. The symptom domain of pain may be a particularly pertinent area of focus in the management of paediatric ME/CFS, given pain was most frequently endorsed at follow-up, and pain at baseline was significantly associated with fulfilment of ME/CFS criteria at follow-up. Clinical multidisciplinary strategies targeting pain relief and management including medication, physiotherapy, cognitive and behavioural techniques , and regular follow-up with the treating physician will be essential in this regard. The use of standardised and consistent measurement of symptomatology across illness course, including evidence-based consensus criteria, and person-centred measurements of recovery will also be important in tracking patients’ clinical outcomes and wellbeing over time in a meaningful way. Based on our findings, future research must employ multiple follow-up time points over a longer time period  to accommodate and record the fluctuating nature of symptoms and illness severity over the ME/CFS illness course. Such information would be invaluable for understanding the different types of illness trajectories experienced by patients, and best predictors of recovery. It would also help clinicians, adolescent patients, and their families in preparing young people with ME/CFS for the potential transition from family-oriented paediatric health services to more independently-oriented adult health services if required.


Lower serum levels of low-density lipoprotein cholesterol (LDL-C) have been suggested to indicate higher suicide risk and various psychiatric symptoms. Previously, we reported that lower serum LDL-C levels are associated with loneliness, social phobia, isolated life with little social support, and lower trust in others among young non-clinical females. Thus, we hypothesize that schizoid personality traits may be associated with lower serum LDL-C. We here verified this hypothesis using non-clinical data and clinical data with schizophrenia. Using the database from the Midlife in Japan (MIDJA), a cohort of residents living in Tokyo, we analyzed whether schizoid-related interpersonal characteristics were associated with LDL-C. In addition, we assessed the association between blood biomarkers including LDL-C and schizoid personality traits in 101 adult non-clinical volunteers. Finally, we evaluated the interaction between LDL-C and social decision making of patients with schizophrenia. In female non-clinical volunteers, serum LDL-C level was a predictive factor and negatively correlated with schizoid personality traits. Female patients with schizophrenia, whose serum LDL-C levels were lower, tended not to trust other females. The present findings suggest that LDL-C may influence schizoid personality traits in females, which provide a basis for further investigation into the biological aspects of schizoid personality disorder. Schizoid personality disorder is known as one of the personality disorders that are often seen before the onset of schizophrenia . SchizoiMore than a quarter of a century ago, Lindberg et al. reported that there was an association between increased suicide risk and lower serum levels of low-density lipoprotein cholesterol (LDL-C) , and thaIn the present study, we verified this hypothesis using non-clinical data from volunteers and clinical data from patients with schizophrenia. We first examined the relationship of serum LDL-C levels to schizoid personality by gender using database from the Midlife in Japan (MIDJA), which is a cohort of residents living in Tokyo. The results of the examination showed that the interpersonal characteristics associated with low serum LDL-C levels in females were most likely to reflect their schizoid personality traits. Each personality disorder has a biological pathophysiological basis , and schN = 1027, 505 males and 522 females, aged 30 to 79). The questionnaire was administered to the participants from April to September 2008. Data were collected regarding socio-demographic characteristics  and a self-rated questionnaire  completed by participants. From January 2009 to April 2010, biomarker data including blood assays were obtained from a portion of participants  at a clinic near the University of Tokyo (Biomarker Project). The results of these surveys are publicly available by the Inter-university Consortium for Political and Social Research (ICPSR), and the following analysis was conducted using the published MIDJA survey data.In the MIDJA survey, 1027 adults were randomly recruited from residents of 23 wards in Tokyo ’; ‘agreeableness’; and ‘agency’) and various problems of close interpersonal relationships with friends, spouse/partner, and family as follows: (1) problems with friends , (2) problems with spouse/partner , and (3) problems with family  for each gender.We selected the university campus as an appropriate place to recruit participants and advertise our study. Participants mostly consisted of university students and were recruited by print advertisement, “CALL FOR MENTALLY AND PHYSICALLY HEALTHY VOLUNTEERS”, on the campus of Kyushu University from February to May 2014. Socio-demographic information of all participants was collected; then, a medical doctor assessed whether the participants were healthy or not. The inclusion criteria of the present study were as follows: (1) proficient in Japanese and (2) more than 17 years old. The exclusion criteria were participants with severe heart, liver, or kidney diseases.After obtaining written informed consent, we administered self-rating questionnaires including the Structured Clinical Interview for DSM-IV Personality Disorders Personality Questionnaire (SCID-II/PQ), and the following blood tests using non-fasting venous blood samples: serum LDL-C and high-density lipoprotein cholesterol (HDL-C), serum total bilirubin and uric acid (UA), and serum high-sensitivity C-reactive protein (hsCRP) and plasma fibrin degradation products (FDP). We adopted these biomarkers as measured items because of their easy measurement in normal clinical settings and comparison with the MIDJA survey, in which some of the biomarkers were also adopted.The serious interpersonal problems that characterize schizoid personality disorder are mainly related to isolation and loneliness, which are naturally related to the sense of trust and fear of others, social phobia, and the social networks actually built with others. In addition, in today’s Information Technology society, isolated living and the degree of dependence on the Internet are considered to have an important relationship. Therefore, in this study, we measured the following psychological rating scales, which are probably related to the mentality of patients with schizoid personality disorder and their real lives. SCID-II/PQ includes a 119-item questionnaire version of the SCID-II, on which items are answered using a “yes” (1) or “no” (0) response format . Items cWe recruited patients diagnosed and treated for schizophrenia by an experienced psychiatrist in a community psychiatric hospital as participants in the study. The inclusion criteria of the present study were as follows: (1) proficient in Japanese and (2) more than 17 years old. The exclusion criteria were participants with severe heart, liver, or kidney diseases.After obtaining written informed consent, all participants played a PC-based trust game and provided a non-fasting venous blood sample. We measured the same blood biomarkers as on the second study on student-age non-clinical volunteers.Based on our previous research, we assessed participants’ trusting behavior toward others by a PC-based trust game . In thisp = 0.05.We performed statistical analyses by using SPSS, version 22 . All analyses were stratified by participant gender. First, we analyzed the data from the MIDJA. Correlation analyses were performed between serum LDL-C levels and six personality traits and various problems of close interpersonal relationships with friends, spouse/partner, and family to calculate Spearman’s correlation coefficient (ρ). Second, correlation analyses were performed between schizoid personality scores of SCID-II/PQ, self-administered questionnaires, and blood biomarkers to calculate Spearman’s correlation coefficient (ρ) on student-age non-clinical samples. Third, regression analyses were performed with the stepwise method for efficient biomarker detection and determination of whether serum LDL-C levels predicted schizoid personality scores. We included six independent variables: LDL-C, HDL-C, total bilirubin, UA, FDP, and hsCRP. The dependent variable was schizoid personality score. To avoid the issue of multicollinearity, we chose the stepwise option and confirmed that the scores of condition indices were below fifteen for each final model. Finally, correlation analyses were performed between serum LDL-C levels and three types of social decision making  in a trust game to calculate Pearson’s correlation coefficient (r) or Spearman’s correlation coefficient (ρ) on patients with schizophrenia. We used a two-tailed significance level of p = 0.014; and ρ = −0.159, p = 0.039, respectively). In females, the results of correlation analysis showed that serum LDL-C levels were negatively correlated with ‘spouse/partner disagreement’ , and positively correlated with ‘affectual solidarity given to spouse/partner’ and ‘support given to family’ . These results suggest that low serum LDL-C levels are related to poor and problematic interpersonal relationships in females. Schizoid personality disorder is known as a personality disorder characterized by scarcity and problems in interpersonal relationships, and the above aspects of MIDJA are often observed in persons with schizoid personality. The relationships between serum LDL-C levels, six personality traits, and “problems of close interpersonal relationships” were shown in p = 0.010; and ρ = −0.311, p = 0.035, respectively). We conducted multiple regression analysis using the stepwise method, with schizoid personality score as the dependent variable and blood biomarkers as independent variables for efficient biomarkers detection; however, no statistically significant independent variables were detected . We conducted multiple regression analysis using the stepwise method in the same way as for males. Regression analyses with the stepwise method revealed that schizoid personality score was predicted by only serum LDL-C levels   .p = 0.043) = 36.3–44.8) and 14 females  participated in the PC-based trust game. In male participants with schizophrenia, the results of correlation analysis did not show any statistically significant correlation between serum LDL-C levels and each decision in a trust game. In female participants with schizophrenia, the results of correlation analysis showed that serum LDL-C levels were positively correlated with the trustworthiness of female partners  .In the present study, we first analyzed the MIDJA data by gender, and we found that low serum LDL-C levels are associated with poor and problematic interpersonal relationships. Based on this analysis, we hypothesized that poor and problematic interpersonal relationships reflect the characteristics of schizoid personality disorder. Next, we conducted an analysis of the data for student-age non-clinical volunteers and found that female participants with lower serum LDL-C levels tended to have higher schizoid personality scores. On the other hand, no such association between serum LDL-C levels and schizoid personality scores was found in male participants. Finally, we conducted a PC-based trust game with patients with schizophrenia and examined the correlation with serum LDL-C levels, and we found that female patients with lower serum LDL-C levels tended not to trust their female partners.To our knowledge, this is the first study showing the association between serum LDL-C levels and schizoid personality traits in young non-clinical females and between serum LDL-C levels and the decision-making tendencies of female patients with schizophrenia. Boundaries between normal and abnormal personality are artificial and a matter of controversy ; thus, pIn spite of evidence that individuals with schizoid personality disorder are characterized by serious social, psychiatric, and socioeconomic dysfunction , the bioThe relationship between schizoid personality traits and blood biomarkers shown in the present study has a gender difference. A previous study has shown that schizoid personality disorder is a predictor of whether psychotherapy is effective in only female patients , suggestSeveral limitations exist in the present study. First, the subjects who participated in this study as student-age non-clinical volunteers were recruited from only a certain region and an institution, and their number is small. The number of patients with schizophrenia participated in the study was also small. The possibility of selection bias cannot be ruled out. However, no previous study has reported that serum LDL-C levels are associated with schizoid personality traits and social decision making in a PC-based trust game, and we believe that this study has strong importance. Second, because structured diagnostic interviews were not conducted with the non-clinical volunteers, we cannot rule out the possibility that some of the participants in this study may have suffered from some kind of psychiatric disorder. Similarly, the participants in study 2 were not diagnosed with schizoid personality disorder by structured diagnostic interviews. Instead, they were assessed for schizoid personality traits by taking the SCID-II/PQ. In future studies, it will be necessary to assess the comorbidity of psychiatric disorders by conducting structured interviews such as the Structured Clinical Interview for the DSM. Third, the present cross-sectional study could not evaluate the causal relationship between schizoid personality traits and serum LDL-C levels. In addition, this pilot study suggests that LDL-C may be a biological marker of schizoid personality traits among females, and even though schizoid personality traits are one of the premorbid personality traits of schizophrenia, it does not necessarily directly imply that females with low serum LDL-C are at higher risk of developing schizophrenia. To clarify this point, it is necessary to consider that the further long-term longitudinal observations of females with low serum LDL-C will be needed. Fourth, there may also be confounding factors such as comorbid physical diseases such as thyroid dysfunction, tobacco, alcohol, and dietary and exercise habits. Hence, further research is needed to validate the present results and to clarify the role of LDL-C in various interpersonal relationships and schizoid personality.In conclusion, based on the significant findings in the present study, we propose the hypothesis that low LDL-C is a possible blood biomarker of schizoid personality traits among young female adults. To elucidate the role of LDL-C in the development of schizoid personality traits and schizophrenia, further studies are required.


OUTBREAK has the potential to guide and help health authorities to intervene and minimize the effects of outbreaks.The current COVID-19 pandemic has already claimed more than 3.7 million victims and it will cause more deaths in the coming months. Tools that track the number and locations of cases are critical for surveillance and help in making policy decisions for controlling the outbreak. However, the current surveillance web-based dashboards run on proprietary platforms, which are often expensive and require specific computational knowledge. We developed a user-friendly web tool, named OUTBREAK, that facilitates epidemic surveillance by showing in an animated graph the timeline and geolocations of cases of an outbreak. It permits even non-specialist users to input data most conveniently and track outbreaks in real-time. We applied our tool to visualize the SARS 2003, MERS, and COVID19 epidemics, and provided them as examples on the website. Through the zoom feature, it is also possible to visualize cases at city and even neighborhood levels. We made the tool freely available at  Effective epidemiological surveillance is essential to ensure a timely and adequate response to infectious disease outbreaks. Communicable disease surveillance provides requisite information to monitor, evaluate, and model the preventive and control measures. The primary goal of the process is to monitor the spread of an ongoing infectious disease outbreak and geographically detect disease hotspots. Moreover, it assists in tracking emerging diseases that pose a threat to public health across the globe. Integrated disease surveillance enables health authorities to (i) identify populations at risk, (ii) implement prevention and control strategies, (iii) detect unusual disease patterns, and (iv) contain the re-emergence or emergence of communicable diseases .The coronavirus epidemics  and the COVID-19 pandemic have displayed the capacity of an infectious disease to spread rapidly. The SARS epidemic 2003–2004) infected over 8000 people in 17 countries with a mortality rate of 9.6% 003–2004 . The highttps://coronavirus.jhu.edu/map.html) by the Johns Hopkins University [http://nssac.bii.virginia.edu/covid-19/dashboard/) by the University of Virginia, the World Health Organization’s (WHO) dashboard (https://who.maps.arcgis.com/apps/opsdashboard/index.html), and COVID-19 local dashboards from Bing-Microsoft (https://www.bing.com/covid) and Google (https://news.google.com/covid19/map). HealthMap , operated since 2006, developed by Harvard University and Boston Children’s Hospital, also tracks other infectious diseases such as influenza, dengue, tuberculosis, and measles. Although most of these dashboards use open-source data, they run on Esri ArcGIS web services which are often expensive or hard to build since it demands a specific knowledge of GIS-based software and programs. In addition, these dashboards are limited to monitor only from a spatial epidemiological perspective and usually lack a time axis to track the evolution of an outbreak. Moreover, these dashboards do not allow the user to input data, restricting non-GIS specialists to utilize the dashboard features for their research or decision-making, who usually lack access to such software or services. To overcome these issues, we developed a new web-based tool that allows the user to input epidemiological data in a user-friendly way to track, study and visualize the outbreaks in real-time.The current COVID-19 pandemic led several research teams to develop web-based dashboards that display surveillance datasets generated across the globe. Examples include COVID-19-Map , the ongoing COVID-19 pandemic with infected and death cases, and another with deaths and vaccines data from January 1, 2020, to May 31, 2021 .OUTBREAK facilitates epidemic surveillance by visualizing user-defined geographical coordinates (geolocations of cases) on an interactive map and generating an animated timeline graph (case numbers). The tool is available for access through a website at https://outbreak.sysbio.tools/. The software includes a text and video tutorial with a detailed description of how to use it. OUTBREAK uses Flask, a Python-based web framework on the server-side [https://hub.docker.com/r/integrativebioinformatics/outbreak) together with the information on how to install and run the software locally.OUTBREAK online tool is freely available under MIT license at ver-side . The usever-side . The intOUTBREAK's input file consists of geographical (latitude and longitude) and temporal (date) information. Users are required to provide this information in a tab-delimited (.txt) file format. The file needs at least four columns with fixed column names as Label, Latitude, Longitude, and Date; representing respectively the row identifier (first column), geographical coordinates  and temporal information (fourth column). The optional columns include the color, size, and number of occurrences for each point  as a hypothetical epidemic, where each type of incident is shown in a different color (https://outbreak.sysbio.tools/animation/EXAMPLE).Epidemiologists and decision-makers may need to classify the cases by multiple criteria such as incoming cases, ethnicity, sex, and age, among others, to implement comprehensive disease surveillance. For such classification purposes, OUTBREAK enables the users to apply different colors for each variable of interest Fig. . FinallyOUTBREAK is a web-based tool that permits easy surveillance of any epidemiological data. The tool enables the user to monitor epidemic data at various geographical levels – global, country, city, neighborhood, street, or a building. Moreover, the tool allows viewing the change in daily and cumulative case numbers in a graphical format. The input file needs to consist of only geographical coordinates  and dates (dd/mm/yyyy) to generate the graphics. Besides epidemic surveillance, other potential applications include animal migration and population studies. In summary, OUTBREAK aims to enable user-friendly interactive and dynamic maps that can help in the spatial and temporal exploration of an epidemic. We hope this tool will guide the health authorities and decision-makers in making effective interventions to minimize the undesirable impacts of the current and future outbreaks.


Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication associated with a high mortality. However, evidence and guidance on management is sparse. The aim of this international survey was to assess differences in prevention, diagnostic and treatment strategies for AE-IPF in specialised and non-specialised ILD centres worldwide.Material and Methods: Pulmonologists working in specialised and non-specialised ILD centres were invited to participate in a survey designed by an international expert panel. Responses were evaluated in respect to the physicians' institutions.Results: Three hundred and two (65%) of the respondents worked in a specialised ILD centre, 134 (29%) in a non-specialised pulmonology centre. Similarities were frequent with regards to diagnostic methods including radiology and screening for infection, treatment with corticosteroids, use of high-flow oxygen and non-invasive ventilation in critical ill patients and palliative strategies. However, differences were significant in terms of the use of KL-6 and pathogen testing in urine, treatments with cyclosporine and recombinant thrombomodulin, extracorporeal membrane oxygenation in critical ill patients as well as antacid medication and anaesthesia measures as preventive methods.Conclusion: Despite the absence of recommendations, approaches to the prevention, diagnosis and treatment of AE-IPF are comparable in specialised and non-specialised ILD centres, yet certain differences in the managements of AE-IPF exist. Clinical trials and guidelines are needed to improve patient care and prognosis in AE-IPF. Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrosing interstitial lung disease associated with a poor prognosis with a five-year survival rate of 20–40% and a median survival time of 2–5 years , 2. An awww.theipfproject.com)  . Nationap-values are solely to be interpreted descriptively and no adjustment for multiple testing was conducted. p-values smaller than 0.05 were regarded as statistically significant. All analyses were conducted using R v.3.4.2 (http://r-project.org).For questions with categorical answers, absolute and relative frequencies were calculated and chi-squared tests were used to assess differences between specialised and non-specialised ILD centres. For questions with answers on a continuous scale, median, first and third quartile, minimum and maximum were determined and differences between continents were assessed using Kruskal–Wallis tests. Due to the exploratory nature of this survey, all resulting Overall, 509 pulmonologists from 66 countries responded. Three hundred and thirty four (65.9%) of the participants worked in a specialised ILD centre, 142 (28.0%) in non-specialised ILD centres i.e. in a general pulmonology department, 4 (0.8%) on an intensive care unit and 27 (5.3%) did not indicate their institution. Physicians working on an intensive care unit or who did not indicate their institution were excluded from the analysis. A total of 436 pulmonologists working in a specialised or non-specialised ILD centre were included in this analysis. On average 331 cases of AE-IPF were seen in specialised ILD centres and 139 in non-specialised ILD centres. p = 0.0106). Conversely, pathogen testing in urine was performed significantly more often in specialised ILD centres than in non-specialised ILD centres . 50% of specialised ILD centres screened for RSV , compared to only 33% in non-specialised ILD centres (p = 0.0024). The use of biomarker KL-6 was higher in non-specialised ILD centres than in specialised ILD centres . The most relevant diagnostic procedures applied for AE-IPF are shown in Most diagnostic tools, including multi-slice thin-section computer tomography without contrast media (HRCT), CT with contrast media in the absence of clinical suspicion of pulmonary embolism, bronchoalveolar lavage (BAL), echocardiography, assessment for pathogens, NT-proBNP/BNP, D-Dimer and troponins were used similarly between specialised and non-specialised ILD centres. The main difference was the sampling of sputum for microbiology (induced sputum) which was more frequent in non-specialised ILD centres .p = 0.0288).Other immunosuppressive therapies such as cyclosporine, cyclophosphamide (i.v. bolus), tacrolimus and rituximab were rarely used in both specialised and non-specialised ILD centres, but cyclosporine was significantly more frequently used in non-specialised ILD centres .Other therapies such as polymyxin B hemoperfusion (7 vs. 10%), and plasmapheresis/plasma exchange (4 vs. 5%) were also less commonly used in specialised and non-specialised ILD centres. However, significantly more pulmonologists treated their patients with recombinant thrombomodulin in non-specialised ILD centres than in specialised ILD centres .The choice of the antifibrotic drug did also not differ significantly between specialised and non-specialised centres .p = 0.0513) and 7% discontinuing therapy (p = 0.5491) in non-specialised ILD centres. The dose was reduced by 1 % in specialised ILD centres compared to 5% in non-specialised ILD centres (p = 0.0301), 9% would switch to the alternative antifibrotic therapy in specialist ILD centres and similarly 10% would switch in non-specialised ILD centres (p = 0.999).For patients already on antifibrotic therapy at the time of AE-IPF, there was no significant difference in the approach: 80% of respondents in specialised ILD centres would continue and 5% would discontinue antifibrotic therapy, compared to 70% continuing . Only a minority in both institutions would perform right heart catheterization in AE-IPF in suspected PH (6 vs. 7%). Seven percentage would start a PH specific treatment after an established PH diagnosis in a specialised ILD centre, significantly more (14%) would do so in a non-specialised ILD centre (p = 0.0494). Only 3% of physicians in a specialised ILD centre and 1% in a non-specialised centre would start a PH specific treatment without a confident diagnosis. After stabilisation of AE-IPF, more than 50% of physicians would evaluate a PH specific treatment by subsequently performing right heart catheterization (56 vs. 55%). A quarter of all participating pulmonologists in specialised and non-specialised ILD centres saw no indication for a PH treatment during or after AE-IPF  during an AE-IPF, significantly more physicians in specialised ILD centres would start diuretic therapy than in non-specialised ILD centre  and non-invasive ventilation (NIV) (72 vs. 77%). 9% of specialised and 11% of non-specialised ILD centres use invasive ventilation for all critical ill patients, whereas 48 vs. 39% respectively would only use invasive ventilation in patients suitable for lung transplantation (LTX) as a bridge to LTX or in very selected cases.p = 0.0287).Significantly more physicians in specialised ILD centres offered extracorporeal membrane oxygenation (ECMO) to patients suitable for LTX as a bridge to LTX than in non-specialised ILD centres .Institutional differences in these approaches are shown in p = 0.0438) in all IPF patients. Long-term azithromycin, low dose steroids (≤10 mg) and anticoagulation (to prevent AE-IPF) were only used by a minority in both types of institutions.Measures aimed at preventing the occurrence of AE-IPF was equal amongst specialised and non-specialised ILD centres and included vaccinations, antifibrotic therapy and pulmonary rehabilitation or other forms of structured exercise therapy. Antacid drugs were prescribed significantly more in non-specialised ILD centres than in specialised ILD centres .See alsoInstitutional differences in preventive strategies are shown in p = 0.0101). There were more pulmonologists in non-specialised ILD centres who saw a need of improvement in multidisciplinary strategies for diagnosing and discussions than in specialised ILD centres .Pulmonologists in both specialised and non-specialised ILD centres advocate more intensive collaboration between different ILD specialists; improved education and training of physicians; education of patients and caregivers as well as enhanced research to improve the understanding of the pathophysiology, diagnosis and management of AE-IPF. Physicians working in specialised ILD centres saw a stronger need for intensified research and projects on the treatment of AE-IPF .Other immunosuppressants and strategies are used less frequently. Very few pulmonologists never use immunosuppression for AE-IPF. Although there is only low evidence base for the use of more potent anti-inflammatory treatment approaches such as cyclosporine A, intravenous cyclophosphamide or tacrolimus –24, theyThe international guidelines recommend avoiding ICU in patients with AE-IPF (weak recommendation)  because In non-specialised and specialised ILD centres prevention strategies towards AE-IPF were performed to the same extent. Vaccinations were most frequently used; although their use is recommended by the international guideline, there is a lack of evidence to support this recommendation .post-hoc analyses , a more recent study did not support this . This isBesides many similarities in the approach towards AE-IPF, there are also some differences in ILD specialised and non-specialised ILD centres.PH is common in patients with IPF . Its preMany physicians use antacid drugs as a preventive strategy for AE-IPF, significantly more in non-specialised ILD centres. Lee et al. reported a higher pepsin level in the BAL of patients with AE-IPF compared to patients with stable disease  and a reOnly a few pulmonologists use low dose steroids as a preventive strategy for AE-IPF, most of them in non-specialised ILD centres. This approach is in line with the international guideline where it is not recommended to use steroids beyond AE-IPF , 25. FurBoth pulmonologists in specialised and non-specialised ILD centres saw a high requirement for improved research strategies for AE-IPF. Significantly more non-specialised ILD centres saw the need for improvement in multidisciplinary strategies for diagnosing and discussion compared to pulmonologists in specialised ILD centres. Multidisciplinary team (MTD) meetings are widely used in the process of diagnostic and patient management  and theyMany of the differences observed underscore the high and still unmet need for intensive research in AE-IPF. However, others might be associated with strategies applied outside current evidence. This demonstrates how important education in rare diseases and their complications is.Our survey has some limitations: The survey was not designed for a data driven assessment of management practises but mainly to evaluate attitudes towards different aspects of AE-IPF. Participation was voluntarily and biased by involvement i.e. non-participating centres may have answered differently. Additionally, there was an imbalance between the number of specialised and non-specialised ILD institutions. Moreover, the number of ILD centres and patient numbers and thus experiences of diagnosis and management of AE-IPF may vary from country to country. Arguably, the number of IPF patients and cases of AE-IPF are higher in Japan as an example, than in other countries . TherefoIn conclusion, specialised and non-specialised ILD centres throughout the world do only differ in some aspects in the management of AE-IPF. Due to scant evidence and missing focused guidelines basic research and clinical trials have to be performed to establish optimal approaches to this deadly complication.The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants was not required to participate in this study in accordance with the national legislation and the institutional requirements.MP and MK contributed mainly to the conception and design of the study. MP wrote the first draft of the manuscript. JK performed the statistical analysis. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Background: Several previous studies have revealed a negative impact of perceived stress on post-stress growth. Nevertheless, the potential mediating and moderating mechanisms are unclear, particularly for left-behind children in China. Therefore, this study aims to investigate the negative relationship between perceived stress and post-stress growth, the mediating effect of social support, as well as the moderating effect of emotional intelligence in a sample of Chinese left-behind children. Methods: A sample of 837 Chinese students in elementary and middle school was collected for this study. The Perceived Stress Scale, the Social Support Scale, the Emotional Intelligence Scale, and the Post-Stress Growth Scale were employed to examine them. The data were analyzed using SPSS 25.0 software. Results: The results indicate a significant negative association between perceived stress and post-stress growth. Among perceived stress and social support, the former acted as a mediator, while the latter as a moderator. This study sheds light on the post-stress growth of Chinese left-behind children. The findings validated a model of moderated mediation that shows the relationship between perceived stress, emotional intelligence, social support, and post-stress growth. Conclusion: This study confirmed that social support is one of the most important factors among left-behind children, from perceived stress to post-stress growth. Furthermore, the study reveals that emotional intelligence can adjust the relationship between perceived stress and social support to post-stress growth. Therefore, for both family education and school education, the result provides a new direction. China has undergone an enormous internal migration ever since the 1980s as a result of the rapid economic urbanization process. As a consequence, a new subgroup known as left-behind children has emerged in China, comprising mainly children who have been abandoned in the rural areas while their parents, also called migrant parents, relocate for employment ,3. In 20These negative implications, however, do not truly represent the health consequences of parental departure on left-behind children , becauseAccording to Tedeschi and Calhoun’s cognitive theory , social Additionally, previous research indicated that in the link between social support and adolescent cognition, emotional intelligence can operate as a moderator. Adolescents with high emotional intelligence value the interactive experience of social support more than those with low emotional intelligence, resulting in greater positive cognition and decreased negative cognition ,24. BaruTo date, numerous studies have investigated the factors that lead to PTG in children and teens who have undergone various types of trauma. There has been no research on post-stress growth and the factors that lead to it in left-behind children thus far. Despite this, few researchers have looked at the potential mediating and moderating mechanisms, and even fewer have studied children who are left behind as a vulnerable group. Against this backdrop, the current study aims to conduct a moderated mediation model to clarify through what experiences  and under what conditions  perceived stress is negatively associated with post-stress growth in a sample of Chinese left-behind children. Perceived stress refers to an individual’s perceptions or ideas about the amount of stress they are experiencing at any particular time or during a specified period. Stress does not always result in negative health repercussions . Chen anHypothesis 1.There is a negative relationship between perceived stress and post-stress growth.Social support, as a critical social element in child development, is associated with left-behind children’s PTG ,39. The Hypothesis 2.Social support mediates the relationship between perceived stress and post-stress growth.Emotional intelligence (EI) is a well-known concept, and the studies that focus on EI indicate that it is strongly associated with PTG  and percHypothesis 3.Emotional intelligence moderates the relationship between perceived stress and perceived social support.Hypothesis 4.Social support mediates the relationship between perceived stress, emotional intelligence, and post-stress growth. A cross-sectional study was used to examine the moderating and mediating effects of social support and emotional intelligence on the association between perceived stress and post-stress growth. This type of design was introduced using a survey to simultaneously investigate and describe the study variables .A group of 837 rural left-behind children was considered from five elementary and middle schools in Nanning city, Liuzhou city, Qinzhou city, Hezhou city, and Baise city in the Guangxi Zhuang Autonomous Region in China, wherein a large population of migrating laborers reside. The adolescents were from grades eight to twelve. The informed consent of each participant and their guardian was obtained. In addition, accompanied by the class teacher, students answered the questionnaires in the classroom for approximately 30 min, and the questionnaires were collected on-site. Perceived stress. The Chinese version of the Perceived Stress Scale (PSS) has been used in prior research to assess perceived stress in Chinese left-behind children [children . Chinesechildren  translatSocial support. The youth social support scale was prepared by Yuemei and Dai [ and Dai . This scEmotional intelligence. The Chinese version of the Emotional Intelligence Scale (EIS) [le (EIS) ,56 contaPost-stress growth. Qin and Wu’s [and Wu’s  Post-Strt-test, and one-way analysis of variance (ANOVA) were obtained. Pearson’s coefficient was then computed for every variable. SPSS 25.0 and Hayes’s [For the basic sociodemographic parameters, a descriptive analysis, an independent sample  Hayes’s  PROCESS  Hayes’s  suggesteIn this study, the common method deviation was controlled procedurally by adopting anonymous measurement and partial item reverse measures. Nevertheless, common method bias might exist in the results collected from the self-reported questionnaires . Therefot-tests, as well as one-way ANOVA, were employed to assess the demographic variables considered. p = 0.027). Furthermore, left-behind children’s post-stress growth (p = 0.000) from middle schools was significantly higher than those from elementary schools. The post-stress growth of mother-only migration children was significantly lower than that of father-only migration and both-parent migration (p = 0.020).The study surveyed 837 left-behind children in China. The sample was composed of 376 (44.9%) males and 461 (55.1%) females, out of which 223 participants (26.6%) were in elementary school and 614 (73.4%) were in middle school. Furthermore, 248 (29.6%) were experiencing father-only migration, 134 (16%) were experiencing mother-only migration, and 455 (54.4%) were experiencing both-parent migration. Independent sample p < 0.01). According to p < 0.01), and emotional intelligence was positively correlated with post-stress growth .Perceived stress was significantly negatively correlated with post-stress growth . Nevertheless, the negative effects of perceived stress on social support were significant , as were the positive effects of social support on post-stress growth .After adjusting the items for gender, grade, and left-behind status, the SPSS PROCESS Macro Model 4 (30) was used to evaluate the mediation model of social support on the relationship between perceived stress and post-stress growth see . PerceivThe indirect impact of social support on the relationships between perceived stress and post-stress growth was relatively significant (95% CI = −0.338 and −0.183), since 95% CI did not comprise 0. The direct effect was 95% CI = −0.096 and 0.135, since 95% CI included 0. Therefore, the results suggested that the mediation was complete.p < 0.001). Moreover, perceived stress interacted with emotional intelligence and was negatively associated with social support . Gender, grade, and left-behind status were selected as control factors depending on the outcomes of the preceding analyses, in agreement with a previous study . The SPSp < 0.001). When the emotional intelligence level was lower , perceived stress still had a negative effect on social support ; however, the effect was lower than that of the high-emotional-intelligence group. Specifically, left-behind children in both the high- and low-emotional-intelligence groups could significantly improve their social support, as long as they were good at using emotional intelligence after experiencing perceived stress. Nevertheless, this effect was more obvious in those with high emotional intelligence. The results of Model 2 (p < 0.001). These results concluded that the relationships between perceived stress and social support were significantly moderated by the levels of emotional intelligence, and the model of moderated mediation for post-stress growth was also significant.In addition, to further verify this, a simple slopes test was conducted. More detailed information is shown in  Model 2  revealed1 was accepted). Furthermore, perceived social support mediated the relationship between perceived stress and post-stress growth, and that emotional intelligence might act as a moderator between perceived stress and social support, implying that left-behind children with higher emotional intelligence could seek social support more effectively than left-behind children with lower emotional intelligence (these results accepted H2 and H3). Finally, the results revealed that perceived stress affected post-stress growth via social support with the increment of emotional intelligence (these results accepted H4).The current study focused on Chinese left-behind children and sought to investigate the moderated mediation roles of social support and emotional intelligence in the association between perceived stress and post-stress growth. The findings indicated that perceived stress was negatively associated with post-stress growth . Third, this study concentrated mainly on the associations between perceived stress, emotional intelligence, social support, and post-stress growth. More studies are needed to explore the influencing factors for the post-stress growth of Chinese left-behind children. This study examined the relationship between perceived stress and post-stress growth in Chinese left-behind elementary and middle school students. Social support was one mechanism by which perceived stress contributed to post-stress growth improvement. In addition, social support entirely buffered the effect of perceived stress on post-stress growth. Moreover, emotional intelligence contributed to the moderating relationship of perceived stress on social support. The findings indicated that social support was a critical component affecting left-behind children’s post-stress growth in the relationship between perceived stress and post-stress growth and that emotional intelligence acted as a moderator in the path between perceived stress and social support.


OBJECTIVES/GOALS: The goal of this project was to develop and evaluate a pilot mentor training program for clinical research professionals. This project presents an evidence- and theory-based mentoring program that has been developed, implemented, and evaluated for this group of translational research professions. METHODS/STUDY POPULATION: The curriculum for the program was designed for aspiring mentors and aligned with the topics of existing Entering Mentoring curriculum for translational workforce . Eleven experienced CRPs participated in the pilot training program. The training was delivered in two-hour meetings over eight weeks. Qualitative e-mail interviews and a validated mentoring competency assessment  and mentor role assessment  tool were used for process and outcome evaluation. Cases studies specific to the CRPs work environment were developed and used to facilitate discussions throughout the training. RESULTS/ANTICIPATED RESULTS: Pre- and post-training scores for mentoring competency assessment were compared across six sub-indexes. Paired t-tests showed a significant difference for the maintaining effective communication competency, p = 0.0202. Comparisons of individual items also showed positive changes in the promoting professional development competency, p = 0.0161). Qualitative assessment revealed that most mentor trainees recognized a distinction between a mentor and a supervisor or on-the-job-trainer. Furthermore, most have been informal mentors without a formal role assignment, the need for ongoing mentoring, and potential of mentoring networks. DISCUSSION/SIGNIFICANCE OF IMPACT: CRPs is a diverse group of research support professionals who may hold the roles of research study coordinators, research nurses, regulatory and compliance specialists. Tailored mentoring can provide essential infrastructure for ongoing professional development and support talent retention.


EyeDiseases (https://eyediseases.bio-data.cn/), the first database for multi-omics data integration and interpretation of human eyes diseases. It contains 1344 disease-associated genes with genetic variation, 1774 transcription files of bulk cell expression and single-cell RNA-seq, 105 epigenomics data across 185 kinds of human eye diseases. Using EyeDiseases, we investigated SARS-CoV-2 potential tropism in eye infection and found that the SARS-CoV-2 entry factors, ACE2 and TMPRSS2 are highly correlated with cornea and keratoconus, suggest that ocular surface cells are susceptible to infection by SARS-CoV-2. Additionally, integrating analysis of Age-related macular degeneration (AMD) GWAS loci and co-expression data revealed 9 associated genes involved in HIF-1 signaling pathway and voltage-gate potassium channel complex. The EyeDiseases provides a valuable resource for accelerating the discovery and validation of candidate loci and genes contributed to the molecular diagnosis and therapeutic vulnerabilities with various eyes diseases.Eye diseases are remarkably common and encompass a large and diverse range of morbidities that affect different components of the visual system and visual function. With advances in omics technology of eye disorders, genome-scale datasets have been rapidly accumulated in genetics and epigenetics field. However, the efficient collection and comprehensive analysis of different kinds of omics data are lacking. Herein, we developed  Eye diseases encompass a large and diverse range of morbidities that affect different components of the visual system and visual function . In the Genetic variation also plays important roles in eye diseases in both children and adults. Over 60% of cases of childhood blindness are caused by genetic factors, such as congenital glaucoma, ocular malformations, atrophy of the optic nerve and retinitis pigmentosa . AlthougDisease-specific databases are useful for researchers to find and retrieve the appropriate information. However, a gene–disease association database dedicated to eye diseases is still unavailable. With the next-generation sequencing technologies providing even more power for gene discoveries , it has Eyediseases integrates multi-omics data from 1138 projects. The main diseases include Refractive error, Myopia, Retinitis, Glaucoma, Cataract, Age-related macular degeneration. There are 2509 records of single nucleotide variants (SNVs) and 1344 records of genes, and the corresponding annotation are based on hg19 and hg38. There are 710 and 1056 records in the microarray and bulk cell RNA-seq expression data, respectively. The single-cell RNAseq data includes six normal eye tissues and two disease samples. There are 105 records in the epigenomics which contain DNA methylation, ATAC-seq, H3K27ac, H3K27me3, H3K4me1, H3K4me3, H3K9me3 data from 15 normal tissues and 12 disease tissues , cross-referenced with the list of diseases included in NCBI. Consequently, total 185 eye diseases were retained, which gene associations can be found by our data collection process (see below).The disease list was obtained from the Medical Subject Headings (MeSH) (https://omim.org/) to get the official disease names and linked all the disorders to OMIM, and searched PubMed for additional citations using the query ‘disease name’. All citations were double-checked manually. For association, we first searched and collected data with MeSH and OMIM name from the established GWAS catalog (https://www.ebi.ac.uk/gwas/) and GWAS Central . To obtain a complete resource of multi-omics relevant to eye disorders, comprehensive searches were performed for eye studies.One important feature of EyeDiseases is comprehensive collection of data from major genetic studies for most eye disorders. For gene linked with syndromic eye disorder, we searched Online Mendelian Inheritance in Man databases  and EMBL-EBI (https://www.ebi.ac.uk/) database with the following query terms: ‘(eye OR disease name) AND (microarray OR transcriptome OR RNAseq)’ for expression profiling studies, ‘(eye OR disease name) AND (single cell RNA-seq OR scRNA-seq)’ for single cell profiling studies and ‘(eye OR disease name) AND (DNA methylation OR histone OR ATAC-seq)’ for epigenomic datasets. Each type of data includes normal tissues and disease tissues. We also achieved the datasets from ENCODE (https://www.encodeproject.org/), and TCGA  database.We searched the GEO  using the affy package in R. Agilent microarrays were normalized using the limma package in R . To provide a systematic nomenclature for assessment of gene expression across platforms, microarray probes were re-mapped to Ensembl gene IDs and gene symbol using the biomaRt package in R, taking the maximum mean signal across all probes available for each gene, using the collapseRows function. The collapseRows MaxMean function was explicitly developed to perform cross-platform microarray meta-analysis and has been extensively validated in its ability to increase between-study consistency and enhance reproducibility . Strict https://satijalab.org/seurat) to cluster the cells and find cell markers that define clusters via differential expression  in disease and normal samples, respectively. We used the soft threshold method for pearson correlation analysis of the expression profiles to determine the connection strengths between two genes. To select and prioritize candidate genes for complex eye diseases, we calculated the gene significance (GS) of a gene as the Pearson correlation coefficient for testing the association of the gene expression to the disease type. Generally, if GS were highly associated, it implied that genes were most significantly correlated with the disease. Furthermore, to systematic characterize candidate causal genes for AMD, we observed the assay for transposase-accessible chromatin with sequencing (ATAC-Seq) peak in AMD associated genes and find the extent to which epigenetic changes regulate AMD.https://flask.palletsprojects.com) framework. PostgreSQL (12–12.1–2) is used to store and manage the data information of the database. EyeDiseases uses Vue (2.6.11) for most of its front-end components and adopts. The UI that is compatible with PC and mobile terminals is completed through Bulma (https://bulma.zcopy.site). All drawing functions in the EyeDiseases are realized by using D3 (5.16.0) and Plotly (http://chart-studio.plotly.com), The tables of the database are visualized using ag-gird. The entire web application is deployed on CentOS  operating system. All the data and code used is publicly available at https://github.com/sulab-wmu/eyediseases.EyeDiseases codes were developed using an integrated development environment, the server is implemented based on the Flask (https://eyediseases.bio-data.cn/). To support facilitating access to genetic and epigenetic data in Eyediseases, five main search and explore approaches have been provided in home page: search by disease, search by gene, search by variant, explore by transcriptomics and explore by epigenomics  clicking one of the three data categories  on the home page; or (ii) selecting expression or single-cell RNAseq of ‘Browse’ on the function bar on the top of the web page. The expression search section, multi-gene query visualization allows users to select platform, species and datasets, and enter a list of genes of interest.P-value, (v) average log2 fold change; (v) PC1 and (vi) PC2. In the Epigenomics view, Eyediseases provides a user-friendly and configurable genome browser through which multiple genomic and epigenomic resources can be visualized simultaneously. The genomic viewer connecting to a PostgreSQL backend is used to show the landscape for normal and disease tissue epigenomic information. Features of the viewer include the ability to zoom through the given regions, to enter a region by specifying the genomic coordinates, to change the order of tracks and to show and hide certain feature tracks and configure the appearance of the displayed information.Next, users can click submit to view the expression of those genes in a table and a heat map that shows expression level across all normal or disease tissues. By default, the genes and tissues are clustered using hierarchical clustering. You can download the expression matrix and figure for further analysis. In the single-cell RNA-seq section, the results are showed by project. The view shows t-SNE plots of all cell type as well as a computed matrix table of cell markers with columns (i) cluster ID, (ii) cell type, (iii) cell marker, (iv) COVID-19 runs rampant around the world . Ocular P-value = 0.01 and OR = 5.1, Fisher's P-value = 0.004, respectively)  is the leading cause of blindness in the elderly with limited therapeutic options . Genetic) Figure . To more) Figure .−7) and positive regulation of angiogenesis (FDR = 1.73 × 10−4), which have been associated with choroidal neovascularization and the progression of AMD into the neovascular clinical phenotype (nAMD). Regard to nAMD, HIFs regulate the expression of multiple growth factors and cytokines involved in angiogenesis and inflammation, hallmarks of neovascular AMD. HIFs also increase RPE apoptosis and autophagy, similarly to the choriocapillaries, which stimulates the endothelial proliferation observed in nAMD. Additionally, we found that the module 7 was enriched for voltage-gate potassium channel complex (FDR = 0.022) and postsynaptic density (FDR = 0.024), which imply neuronal processes are essential elements in human retinal tissues in response to AMD. Another way to infer the function of the modules is based on the known function of highly connected genes with central positions within the modules (‘‘hub’’ genes). We explored the strongest connections in module 6 and 9 using Cytoscape software  enrichments to determine function of the genes between module 7 and 9 Figure . Notablye Figure . These rEyeDiseases is a first comprehensive database that has been developed for the integration of multiple omics and interactive analysis in eye diseases. The data in EyeDiseases are from GWAS catalog, GWAS Central, OMIM, the GEO database, the EMBL-EBI, ENCODE, TCGA and Drugbank database with thousands of samples included. Data type consisting of the genome, transcriptome, epigenome, single-cell and targeted drug. EyeDiseases is a time-saving, free, and intuitive tool for tapping the full potential of publicly available genomics big data, which enables biologists and clinicians without any programming experience to obtain ready-to-use multi-omics data and perform a diverse range of data analyses. It also has the potential to become a one-stop service for data query and analysis for the scientific and clinical community associated with the eye disorder field.The majority of genetic variants potentially associated with eye diseases (e.g. AMD) that are identified by GWAS are located in non-coding sequences, suggesting that their functions, if any, may be exerted through regulating the expression of genes producing proteins or non-coding RNAs . Thus, iTo better serve the research community of eye diseases, we will not only continuously update multi-omics data from both eye disease and normal samples, but also develop new analytical features for further exploration of the available big genomic data. Our next plan is to obtain more public multi-omics data on eye diseases, such CNV, proteomics, ocular image and metagenomics, and build an enhanced database based on comprehensive genome-level data for the effective visualization and analysis of all human genes in the future. We believe Eyediseases could serve as a very useful public resource for both bench scientists and computational biologists, and contribute to clinical and translational studies.


Objective: Sexual dimorphism has been investigated in schizophrenia, although sex-specific differences among individuals who are at clinical high-risk (CHR) for developing psychosis have been inconclusive. This study aims to characterize sexual dimorphism of language areas in the brain by investigating the asymmetry of four white matter tracts relevant to verbal working memory in CHR patients compared to healthy controls (HC). HC typically show a leftward asymmetry of these tracts. Moreover, structural abnormalities in asymmetry and verbal working memory dysfunctions have been associated with neurodevelopmental abnormalities and are considered core features of schizophrenia.Methods: Twenty-nine subjects with CHR  for developing psychosis and twenty-one HC  matched for age, sex, and education were included in the study. Two-tensor unscented Kalman filter tractography, followed by an automated, atlas-guided fiber clustering approach, were used to identify four fiber tracts related to verbal working memory: the superior longitudinal fasciculi (SLF) I, II and III, and the superior occipitofrontal fasciculus (SOFF). Using fractional anisotropy (FA) of tissue as the primary measure, we calculated the laterality index for each tract.Results: There was a significantly greater right>left asymmetry of the SLF-III in CHR females compared to HC females, but no hemispheric difference between CHR vs. HC males. Moreover, the laterality index of SLF-III for CHR females correlated negatively with Backward Digit Span performance, suggesting a greater rightward asymmetry was associated with poorer working memory functioning.Conclusion: This study suggests increased rightward asymmetry of the SLF-III in CHR females. This finding of sexual dimorphism in white matter asymmetry in a language-related area of the brain in CHR highlights the need for a deeper understanding of the role of sex in the high-risk state. Future work investigating early sex-specific pathophysiological mechanisms, may lead to the development of novel personalized treatment strategies aimed at preventing transition to a more chronic and difficult-to-treat disorder. Sexual dimorphisms in schizophrenia have been well-documented in a range of areas including symptomatology, treatment response, and outcome. However, one of the most robust findings is the earlier onset of illness in males . More spA promising indicator of a CHR state for psychosis is working memory impairments –7. SpeciVerbal memory impairments in patients with schizophrenia have also been linked to white matter tract asymmetries. Tract asymmetries in this study are defined as the relative ratio of white matter microstructural measurements, such as fractional anisotropy (FA), a measure of the directionality of white matter fiber bundles, in white matter tracts in the left hemisphere compared to the right hemisphere . Since tWhile white matter tract asymmetries have also been reported to increase with a longer duration of illness , it has Sex has also been shown to be a major influence on the development of white matter tracts , 38. ForGiven that verbal working memory deficits have been shown in patients with schizophrenia and are a promising symptom criterion for CHR conversion to psychosis, we investigated possible alterations in sexually dimorphic asymmetry in four white matter tracts in CHR for psychosis individuals compared to healthy controls (HC). The tracts of interest were central components of the verbal working memory circuit, including the SLF with its three subcomponents , in addition to the SOFF. In this study, we employed a novel data-driven fiber clustering approach based on diffusion magnetic resonance imaging (dMRI), and an anatomically curated white matter fiber clustering atlas . We hypowww.sfb936.net) investigating functional and structural connectivity in schizophrenia. Parts of this data were already published  and 25 HC. The participants' handedness was verified with the empirically validated Edinburgh Handedness Inventory . Four HCThe inclusion criteria for CHR for psychosis were defined in line with the criteria of the Early Detection and Intervention Program of the German Research Network on Schizophrenia (GNRS) , includiAll CHR individuals underwent the Mini Neuropsychiatric Interview  to recor2 matrix = 108 × 128, 30 non-colinear gradient directions with b = 1,000 s/mm2 collected twice and 10 images with b = 0 s/mm2. The quality control steps comprised visual inspection of the images for movement artifacts, EPI distortions and structural abnormalities using 3D Slicer  (http://fsl.fmrib.ox.ac.uk/fsl/). The gradient vector table was updated accordingly. A relative motion parameter was obtained for each scan from the transforms by calculating the average displacement between adjacent volumes. Finally, brain masks for skull stripping were generated automatically within 3D Slicer using Otsu's method and then manually edited to ensure anatomical accuracy. After preprocessing, each gradient was averaged from both acquisitions using an in-house developed script (All images were obtained using a Siemens 3T scanner (Magnetom Trio) at the University Medical Center Hamburg-Eppendorf with a 12-channel head coil. Diffusion-weighted images (DWI) were acquired using an echo-planar imaging sequence (EPI) with the following parameters: TR = 7.7 s, TE = 85 ms, flip angle = 90°, 32 interleaved slices, slice thickness = 2 mm, field of view (FOV) = 216 × 256 mmcer.org) . Gradiend script .https://github.com/pnlbwh/ukftractography). The UKFt fits a mixture model of compartments to the dMRI data while tracking fibers, taking advantage of information from the previous step along the fiber to help stabilize model fitting , as implemented in the open-source software package . Recent studies have shown that this fiber clustering approach enables reliable fiber quantification and three-dimensional visualization , as well as tractography visualization with anatomical hierarchies in 3D Slicer via the SlicerDMRI project (dmri.slicer.org)  , 65.Next, hemispheric asymmetry was calculated for all four tracts of interest using the laterality index (LI) based on the following formula: LI = (Right FA – Left FA)/(Right FA + Left FA) of the average FA across each tract. This index yields positive values for right-lateralized, negative values for left-lateralized white matter tracts, and zero values for absolute symmetry.t-tests or Mann-Whitney-U-tests .Group differences were compared by means of independent A linear mixed-effects (LMEs) model was used to analyse the effects of group, sex, white matter tracts and any group-related interactions on LI. LMEs have several advantages over traditional repeated-measures designs, as they can accommodate departures from assumptions of homogeneity of regression slopes and independence, and thus are better suited to model inter-individual variability . Moreovep > 0.09), nor between the sex-specific subgroups . Additionally, there were no significant differences in PANSS sub-scores, nor in SOPS sub-scores, between CHR males and CHR females . There were also no significant differences between group (CHR or HC) and gender  in working memory performances .Sociodemographic and clinical variables of the sample are shown in  = 4.099, p = 0.048], indicating that there are sex-related differences in terms of hemispheric asymmetry across the two groups . Specifically, subsequent post-hoc pairwise comparisons within each group (HC or CHR) revealed a greater hemispheric asymmetry in healthy males than healthy females, but that did not reach the significance threshold . There was no such difference between CHR males and CHR females (p = 0.45). Moreover, post-hoc pairwise comparisons within each sex demonstrated a significantly different LI between HC and CHR females , but not between HC and CHR males (p = 0.91). To determine which tract was driving the effect in females, post-hoc pairwise comparisons between each white matter tract's LI revealed a significantly greater rightward asymmetry of the SLF-III in CHR females compared to HC females  (p > 0.1).The interaction of Group × Sex had a significant effect on LI [F = 0.92) . There wp = 0.047), indicating that in females, a greater degree of rightward asymmetry was related to poorer performance , while few have investigated the role that sex may play. For example, Di Biase and colleagues suggest that increases in FA in early stage psychosis patients may compensate for cortical thinning that occurs with longer durations of illness . SimilarMoreover, we found no significant difference in white matter asymmetry in CHR males compared to HC males, which aligns well with another DTI study which also reports no significant white matter asymmetry differences in ultra-high-risk males who later developed psychosis . Thus, oConcerning methodological aspects of the study, the present study demonstrates the efficacy and sensitivity of using and automatically annotating fiber clustering method for white matter tract parcellation across different populations. This method has been increasingly and successfully applied to clinical studies , 60, 61 Several potential limitations of our study should be mentioned. Due to difficulty in recruiting CHR individuals, the sample size is not large, especially considering the sex-specific subgroups, thus limiting statistical power. This translates into another limitation concerning our lack of findings with respect to correlations with prodromal symptoms. It would have been promising to find a correlation between altered laterality and specific symptoms. Single shell data is another limitation. Multi-shell data would make the multi-compartmental fit more robust . Lastly,Finally, one empirical next step to elucidate the association between a putative sex-specific neurodevelopmental disturbance in the frontoparietal network and verbal working memory dysfunction in the CHR state might be the inclusion of a sufficient number of individuals with a schizotypal tendency. In schizophrenia, as well as in individuals with schizotypy, atypical brain laterality is considered a potential underlying basis for the excess of non-right-handedness  . FurtherIn conclusion, the present study demonstrates that CHR females show greater rightward asymmetry of the SLF-III which we believe highlights the underappreciated role of sex in understanding white matter asymmetry and alterations in the pathophysiology of a high-risk state for developing psychosis. Thus, improving our understanding of both the sexual dimorphism of white matter asymmetry and the factors that influence these neurodevelopmental maturational processes, as well as the factors they influence, such as clinical and cognitive symptoms, may help to promote the development of novel interventions aiming to prevent transition into a chronic and difficult-to-treat disorder.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 Ethik-Kommission - Ärztekammer Hamburg. The patients/participants provided their written informed consent to participate in this study.CM and SS designed the study. JR, FN, and MM collected data. SS and ML analyzed data. TB, YR, and SC-K wrote codes. AL, GL, MK, FZ, LO'D, OP, and MS gave methodological support. SS, CM, and MS supervised the project. SS and AL worte the paper. All authors discussed the results and commented on the manuscript at all stages.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.


Pain is one of the most common symptoms among patients with cancer. Pain significantly debilitates cancer patients’ health-related quality of life (QOL), and it can persist as one of the independent prognostic factors for survival. When the World Health Organization (WHO) recently reformed the International Classification of Diseases, “cancer-related pain” was appended to be defined as chronic pain attributable to either the cancer itself or its treatments. Opioid analgesics are critical to the effective relief of cancer-related pain. Opioid analgesics were originally recommended by the WHO in 1986 as part of the cancer pain relief guidelines for improving QOL among patients with cancer. Further, the WHO in 2018, extended the indications for strong opioids from conventional moderate-to-severe cancer-related pain to include mild-to-moderate cancer-related pain. Thus, the administration of opioid analgesics has persisted as a mainstay analgesic therapy for cancer-related pain. To expand universal access to effective palliative care and cancer-related pain relief, the problem of supply has been identified as one of the barriers for adequate opioid availability by the International Narcotics Control Board.The Lancet Regional Health – Western Pacific, Wu and colleaguesIn ,Their previous studyThe present study determines that conventional opioids were merely replaced by newly launched strong opioids, suggesting that resolving supply problems alone was not sufficient to improve adequate opioid availability. In fact, lack of training and awareness of healthcare professionals has been identified as the primary barrier for adequate opioid availability.The author received funding from Shionogi & Co. Ltd., Nippon Zoki Pharmaceutical, Heartfelt Inc., Nipro Corporation, Eisai Co. Ltd., and Fureasu Co. Ltd; payments from Daiichi-Sankyo, Shionogi & Co. Ltd., Nippon Zoki Pharmaceutical, Mundipharma K.K., Eisai Co. Ltd., MSD, and GlaxoSmithKline K.K.