Integrated proteomic and genomic analysis to identify predictive biomarkers for valproate response in bipolar disorder: a 6-month follow-up study.

BACKGROUND: Several genetic studies have been undertaken to elucidate the intricate interplay between genetics and drug responses in bipolar disorder (BD). However, there has been notably limited research on biomarkers specifically linked to valproate, with only a few studies investigating integrated proteomic and genomic factors in response to valproate treatment. Therefore, this study aimed to identify biological markers for the therapeutic response to valproate treatment in BD. Patients with BD in remission were assessed only at baseline, whereas those experiencing acute mood episodes were evaluated at three points (baseline, 8 ± 2 weeks, and 6 ± 1 months). The response to valproate treatment was measured using the Alda scale, with individuals scoring an Alda A score ≥ 5 categorized into the acute-valproate responder (acute-VPAR) group. We analyzed 158 peptides (92 proteins) from peripheral blood samples using multiple reaction monitoring mass spectrometry, and proteomic result-guided candidate gene association analyses, with 1,627 single nucleotide variants (SNVs), were performed using the Korean chip. RESULTS: The markers of 37 peptides (27 protein) showed temporal upregulation, indicating possible association with response to valproate treatment. A total of 58 SNVs in 22 genes and 37 SNVs in 16 genes showed nominally significant associations with the Alda A continuous score and the acute-VPAR group, respectively. No SNVs reached the genome-wide significance threshold; however, three SNVs (rs115788299, rs11563197, and rs117669164) in the secreted phosphoprotein 2 gene reached a gene-based false discovery rate-corrected significance threshold with response to valproate treatment. Significant markers were associated with the pathophysiological processes of bipolar disorders, including the immune response, acute phase reaction, and coagulation cascade. These results suggest that valproate effectively suppresses mechanisms associated with disease progression. CONCLUSIONS: The markers identified in this study could be valuable indicators of the underlying mechanisms associated with response to valproate treatment.

Interpersonal sensitivity and childhood trauma in patients with major depressive disorder, bipolar I, and II disorder.

Childhood trauma and interpersonal sensitivity impact the development of mood disorders. In this study, we investigate the association between childhood trauma and interpersonal sensitivity in patients with mood disorders. A total 775 patients (major depressive disorder [MDD, n = 241], bipolar I disorder [BD I, n = 119], and bipolar II disorder [BD II, n = 415]) and 734 controls. For evaluation, we used the Childhood Trauma Questionnaire-Short Form (CTQ) and Interpersonal Sensitivity Measure (IPSM). We examined between-group differences for each subscale in the CTQ and IPSM. Patients with BD II had significantly higher IPSM total scores than patients with MDD, BD I, or controls. The CTQ total score was related to the IPSM total score in all participants and subgroups. Among the CTQ subscales, emotional abuse showed the highest correlation with the IPSM total score, while separation anxiety and fragile inner self showed higher positive correlations with CTQ than the other subscales of IPSM in all patient groups and the control group, respectively. The findings reveal that childhood trauma and interpersonal sensitivity are positively correlated among patients with MDD, BD I, and BD II, and that interpersonal sensitivity is higher in patients with BD II than those with BD I or MDD. Childhood trauma is associated with interpersonal sensitivity, and each trauma type has a different impact on mood disorders. We expect that this study will encourage future research on interpersonal sensitivity and childhood trauma in mood disorders to improve treatment approaches.

Validation of the Short Form of the Mood Instability Questionnaire-Trait (MIQ-T-SF) in the Korean General Population.

OBJECTIVE: Mood instability (MI) is a clinically significant trait associated with psychiatric disorders. However, there are no concise measurements to evaluate MI. The initial Mood Instability Questionnaire-Trait (MIQ-T) was developed to fill this gap. The current study aimed to create a short form of MIQ-T (MIQ-T-SF) that measures MI with high validity and reliability in the Korean general population. METHODS: Of the 59 items in the MIQ-T, 17 items were chosen for the MIQ-T-SF following the factor analysis process. In total, 540 participants completed the MIQ-T-SF. Cronbach's alpha and McDonald's omega were used to evaluate reliability. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to determine construct validity. Concurrent validity was confirmed via comparisons with Personality Assessment Inventory-Borderline Features Scale. Measurement invariance across gender and age groups was confirmed before analyzing differences in scores using Kruskal-Wallis test. RESULTS: The MIQ-T-SF displayed expected correlations and high internal consistency (α=0.71-0.90, Ωt=0.72-0.92). Using EFA and CFA, a five-factor structure was confirmed. Measurement invariance was supported, and gender differences were observed. CONCLUSION: The MIQ-T-SF is an accurate and reliable method to detect MI in the Korean general population. The study's results offer new perspectives for future studies on MI.

DEVELOPMENT OF SCORE SYSTEM BASED ON POINT-OF-CARE ULTRASOUND TO PREDICT VASOPRESSOR REQUIREMENT FOR EMERGENCY PATIENTS WITH CARDIOPULMONARY SYMPTOMS.

ABSTRACT: Objectives : Patients with cardiopulmonary symptoms admitted to the emergency department (ED) have high mortality and intensive care unit admission rates. We developed a new scoring system comprising concise triage information, point-of-care ultrasound, and lactate levels to predict vasopressor requirements. Methods : This retrospective observational study was conducted at a tertiary academic hospital. Patients with cardiopulmonary symptoms who visited the ED and underwent point-of-care ultrasound between January 2018 and December 2021 were enrolled. The influence of demographic and clinical findings on the requirement for vasopressor support within 24 h of ED admission was investigated. A new scoring system was developed using key components after stepwise multivariable logistic regression analysis. Prediction performance was evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results : A total of 2,057 patients were analyzed. A stepwise multivariable logistic regression model showed high predictive performance in the validation cohort (AUC, 0.87). Eight key components were selected: hypotension, chief complaint, and fever at ED admission, and way of ED visit, systolic dysfunction, regional wall motion abnormalities, inferior vena cava status, and serum lactate level. The scoring system was developed based on the ß coefficients of each component: accuracy, 0.8079; sensitivity, 0.8057; specificity, 0.8214; PPV, 0.9658; and NPV, 0.4035, with a cutoff value according to the Youden index. Conclusions : A new scoring system was developed to predict vasopressor requirements in adult ED patients with cardiopulmonary symptoms. This system can serve as a decision-support tool to guide efficient assignment of emergency medical resources.

Effect of emergency physician-operated emergency short-stay ward on emergency department stay length and clinical outcomes: a case-control study.

BACKGROUND: We hypothesized that an emergency short-stay ward (ESSW) mainly operated by emergency medicine physicians may reduce the length of patient stay in emergency department without expense of clinical outcomes. METHODS: We retrospectively analysed adult patients who visited the emergency department of the study hospital and were subsequently admitted to wards from 2017 to 2019. We divided study participants into three groups: patients admitted to ESSW and treated by the department of emergency medicine (ESSW-EM), patients admitted to ESSW and treated by other departments (ESSW-Other) and patients admitted to general wards (GW). The co-primary outcomes were ED length of stay and 28-day hospital mortality. RESULTS: In total, 29,596 patients were included in the study, and 8,328 (31.3%), 2,356 (8.9%), and 15,912 (59.8%) of them were classified as ESSW-EM, ESSW-Other and GW groups, respectively. The ED length of stay of the ESSW-EM (7.1 h ± 5.4) was shorter than those of the ESSW-Other (8.0 ± 6.2, P < 0.001) and the GW (10.2 ± 9.8, P < 0.001 for both). Hospital mortality of ESSW-EM (1.9%) was lower than that of GW (4.1%, P < 0.001). In the multivariable linear regression analysis, the ESSW-EM was independently associated with shorter ED length of stay compared with the both ESSW-Other (coefficient, 1.08; 95% confidence interval, 0.70-1.46; P < 0.001) and GW (coefficient, 3.35; 95% confidence interval, 3.12-3.57; P < 0.001). In the multivariable logistic regression analyses, the ESSW-EM was independently associated with lower hospital mortality compared with both the ESSW-Other group (adjusted P = 0.030) and the GW group (adjusted P < 0.001). CONCLUSIONS: In conclusion, the ESSW-EM was independently associated with shorter ED length of stay compared with both the ESSW-Other and the GW in the adult ED patients. Independent association was found between the ESSW-EM and lower hospital mortality compared with the GW.

Korean Validation of the Short Version of the TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire) in Patients with Mood Disorders.

BACKGROUND AND OBJECTIVES: The Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) is designed to assess affective temperaments. The short version of the TEMPS-A (TEMPS-A-SV) has been translated into various languages for use in research and clinical settings. However, no research has been conducted to validate the Korean version of the TEMPS-A-SV in patients with mood disorders. The goal of this study is to evaluate the reliability and validity of the TEMPS-A-SV in Korean mood disorder patients. MATERIALS AND METHODS: In this cross-sectional retrospective study, a total of 715 patients (267 patients with major depressive disorder, 94 patients with bipolar disorder I, and 354 patients with bipolar disorder II) completed the Korean TEMPS-A-SV. Cronbach's alpha and McDonald's omega were used to assess the reliability. Exploratory factor analysis (EFA) was also performed. Spearman's correlation coefficient was used to examine associations between the five temperaments. The difference in five temperament scores between the gender or diagnosis groups was analyzed, and the correlation between five temperament scores and age was tested. RESULTS: The Korean TEMPS-A-SV displayed good internal consistency (α = 0.65-0.88, ω = 0.66-0.9) and significant correlations between the subscales except one (the correlation between hyperthymic and anxious). Using EFA, a two-factor structure was produced: Factor I (cyclothymic, depressive, irritable, and anxious) and Factor II (hyperthymic). The cyclothymic temperament score differed by gender and the anxious temperament score was significantly correlated with age. All the temperaments, except for irritable temperament, showed significant differences between diagnosis groups. CONCLUSIONS: Overall, the results show that the TEMPS-A-SV is a reliable and valid measurement that can be used for estimating Koreans' affective temperaments. However, more research is required on affective temperaments and associated characteristics in people with mood disorders.

Relationship between childhood trauma and resilience in patients with mood disorders.

BACKGROUND: Childhood trauma has lasting negative impacts on individuals' psychological functioning. However, there is limited empirical evidence on the association between childhood trauma and resilience and none examining such relationship among diverse clinical populations. This study aimed to investigate the relationship in patients with major depressive disorder, bipolar I disorder, bipolar II disorder, and a comparison group. METHODS: In total, 787 psychiatric patients and 734 people from the general population participated in the study. The Childhood Trauma Questionnaire-Short Form and Connor-Davidson Resilience Scale were used to assess childhood trauma and resilience, respectively. RESULTS: Individuals with childhood trauma showed lower levels of resilience in all subjects; among them, those who experienced emotional abuse and emotional neglect exhibited even stronger associations than other types of childhood trauma. There was a significant difference in the negative relationship between childhood trauma and resilience by group, where the association was more prominent in the comparison group than in MDD and BD II patient groups. LIMITATIONS: The generalizability of our results may be limited due to unproportionate patient sample size. Also, we could not examine the causal relationship between childhood trauma and resilience. CONCLUSION: Childhood trauma and resilience had a significantly negative association. Our results suggest that people who have experienced emotional abuse and emotional neglect should be closely assisted to develop resilience. Interventions that promote resilience should be provided to individuals predisposed to psychological risks as a result of childhood trauma.

Borderline Personality Pathology in Major Depressive Disorder, Bipolar I and II Disorder, and Its Relationship With Childhood Trauma.

OBJECTIVE: Mood disorder and borderline personality pathology (BPP) are frequently comorbid and relate to childhood trauma. We investigated the relationship between childhood trauma and BPP features in mood disorder patients versus controls. METHODS: A total of 488 mood disorder patients, particularly major depressive disorder (MDD), bipolar I disorder (BD I), and bipolar II disorder (BD II), and 734 controls were included. We examined between-group BPP-related differences and correlated between BPP and childhood trauma using the Childhood Trauma Questionnaire-Short Form (CTQ) and the Personality Assessment Inventory-Borderline Features Scale. RESULTS: BD II patients showed significantly higher BPP. Emotional abuse and neglect were prominently associated with BPP, while affective instability and negative relationships exhibited a stronger association with childhood trauma. We also found a positive relationship between childhood trauma and BPP in MDD, BD I, and BD II patients. CONCLUSION: The findings of the present study imply that BPP features are more likely to be found in patients with BD II than BD I or MDD. Mood disorder patients with severe childhood trauma may have higher BPP features. Thus, further study of the relationship between childhood trauma and BPP features could improve the therapeutic approaches and help understand patients with mood disorders.

Korean Validation of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire.

OBJECTIVE: The Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) has been validated in more than 30 languages and is noted for its broad application in research and clinical settings. This study presents the first attempt to examine the reliability and validity of the TEMPS-A in Korea. METHODS: A total of 540 non-clinical participants completed the Korean TEMPS-A, which was adapted from the original English version via a comprehensive translation procedure. Reliability was assessed using Cronbach's α, and associations between temperaments were examined using Spearman's correlation coefficient. Exploratory factor analysis (EFA) was performed, and differences in TEMPS-A scores between the gender- and age-based groups were examined using Kruskal-Wallis analysis. RESULTS: The Korean TEMPS-A exhibited excellent internal consistency (0.70-0.91) and significant correlations between subscales. EFA resulted in a two-factor structure: Factor I (depressive, cyclothymic, irritable, and anxious) and Factor II (hyperthymic). Gender and age group differences were observed. CONCLUSION: Overall, our results suggest that TEMPS-A is a reliable and valid measure of affective temperaments for the Korean population. This study opens new possibilities for further research on affective temperaments and their related traits.

Efficacy and safety of daily home-based transcranial direct current stimulation as adjunct treatment for bipolar depressive episodes: Double-blind sham-controlled randomized clinical trial.

Background: Although transcranial direct current stimulation (tDCS) is known to be a promising therapeutic modality for unipolar depression, the efficacy and safety of tDCS for bipolar depressive episodes (BD) are still unknown and clinical trials of home-based tDCS treatment are scarce. As a result, we set out to investigate the efficacy and safety of home-based tDCS for the treatment BD. Methods: Participants (n = 64), diagnosed as bipolar disorder as per the diagnostic and statistical manual of mental disorders (DSM-5), were randomly assigned to receive tDCS. Hamilton Depression Rating Scale (HDRS-17) scores were measured at the baseline, week 2, 4, and 6, and home-based tDCS (for 30 min with 2 mA) was self-administered daily. Results: Of the 64 patients (15.6% bipolar disorder I, 84.4% bipolar disorder II), 41 patients completed the entire assessment. In the intention-to-treat analysis, time-group interaction for the HDRS-17 [F (3, 146.36) = 2.060; p = 0.108] and adverse effect differences between two groups were not statistically significant, except the pain score, which was higher in the active group than the sham group (week 0-2: p < 0.01, week 2-4: p < 0.05, and week 4-6: p < 0.01). Conclusion: Even though we found no evidence for the efficacy of home-based tDCS for patients with BD, this tool was found to be a safe and tolerable treatment modality for BD. Clinical trial registration: [https://clinicaltrials.gov/show/NCT03974815], identifier [NCT03974815].

Development and Validation of the Mood Instability Questionnaire-Trait (MIQ-T).

Background and objectives: Mood instability (MI) is a stable trait associated with psychiatric disorders, yet there is a lack of tools to measure MI. The purpose of this study was to develop and validate the Mood Instability Questionnaire-Trait (MIQ-T) to evaluate MI in mood disorder patients. Material and methods: Items were taken from various established questionnaires to create an initial list of MIQ-T questions. Data from 309 psychiatric patients (n = 309; 62 major depressive disorder, 58 bipolar I disorder, and 189 bipolar II disorder) were gathered from their medical records and were utilized in an exploratory factor analysis to clarify the underlying components of MI. Then, anonymous survey data from 288 individuals from the general population were included in the analysis as a comparison group. Associations between MIQ-T and other previously validated clinical instruments for mood disorders were examined to test external validity. Results: The exploratory factor analysis demonstrated that the five-factor structure (Lability, Upward Tendency, Downward Tendency, Childhood Instability, and Seasonality) of 59 items was the most appropriate with clear, cohesive features. MIQ-T exhibited high internal consistency (α = 0.96) and moderate to strong correlations with other previously validated clinical instruments, which were consistent with theoretical predictions, providing evidence of criterion validity. Short forms were also created to address the high internal consistency value, which can indicate redundancy, and to increase the approachability of the measure. We found that the patients with bipolar II disorder had higher MIQ-T scores than the patients with bipolar I disorder or major depressive disorder and the comparison group. Conclusion: Together, these findings validate the newly developed MIQ-T as an instrument of mood instability. MIQ-T can be a potential research tool for mood disorder.

A clinical prediction tool to predict urinary tract infection in pediatric febrile patients younger than 2 years old: a retrospective analysis of a fever registry.

OBJECTIVE: Urinary tract infection (UTI) is a significant issue in young febrile patients due to potential long-term complications. Early detection of UTI is crucial in pediatric emergency departments (PEDs). We developed a tool to predict UTIs in children. METHODS: Clinical data of patients <24 months of age with a fever and UTI or viral infection were extracted from the fever registry collected in two PEDs. Stepwise multivariate logistic regression was performed to establish predictors of identified eligible clinical variables for the derivation of the prediction model. RESULTS: A total of 1,351 patients were included in the analysis, 643 patients from A hospital (derivation set) and 708 patients from B hospital (validation set). In the derivation set, there were more girls and a lower incidence of a past history of UTI, older age, less fever without source, and more family members with upper respiratory symptoms in the viral infection group. The stepwise regression analysis identified sex (uncircumcised male), age (≤12 months), a past history of UTI, and family members with upper respiratory symptoms as significant variables. CONCLUSION: Young febrile patients in the PED were more likely to have UTIs if they were uncircumcised boys, were younger than 12 months of age, had a past history of UTIs, or did not have families with respiratory infections. This clinical prediction model may help determine whether to perform urinalysis in the PED.

The Role of Interleukin-22 and Its Receptor in the Development and Pathogenesis of Experimental Autoimmune Uveitis.

IL-22 is a pro- and anti-inflammatory cytokine that is mainly produced by T cells and NK cells. Recent studies have reported the increased number of IL-22 producing T cells in patients with autoimmune noninfectious uveitis; however, the correlation between IL-22 and uveitis remains unclear. In this study, we aimed to determine the specific role of IL-22 and its receptor in the pathogenesis of uveitis. Serum concentration of IL-22 was significantly increased in uveitis patients. IL-22Rα was expressed in the retinal pigment epithelial cell line, ARPE-19. To examine the effect of IL-22, ARPE-19 was treated with recombinant IL-22. The proliferation of ARPE-19 and the production of monocyte chemoattractant protein (MCP)-1 from ARPE-19 were clearly elevated. IL-22 induced MCP-1 which facilitated the migration of inflammatory cells. Moreover, IL-22 increased the IL-22Rα expression in ARPE-19 through the activation of PI3K/Akt. Experimental animal models of uveitis induced by interphotoreceptor retinoid binding protein 1-20 (IRBP1-20) exhibited elevation of hyperplasia RPE and IL-22 production. When CD4+ T cells from the uveitis patients were stimulated with IRBP1-20, the production of IL-22 definitely increased. In addition, we examine the regulatory role of cysteamine, which has an anti-inflammatory role in the cornea, in uveitis through the down-regulation of IL-22Rα expression. Cysteamine effectively suppressed the IRBP1-20-induced IL-22Rα expression and prevented the development of IRBP1-20-induced uveitis in the experimental animal model. These finding suggest that IL-22 and its receptor have a crucial role in the development and pathogenesis of uveitis by facilitating inflammatory cell infiltration, and that cysteamine may be a useful therapeutic drug in treating uveitis by down-regulating IL-22Rα expression in RPE.