Aneurysm and Artery Dissection After Oral VEGFR-TKI Use in Adults With Cancer.

Importance: The association of tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR-TKIs) with aneurysm and artery dissection (AAD) has been frequently reported in spontaneous reporting databases. Objective: To investigate the risk and incidence of AAD occurrence in patients with cancer treated with oral VEGFR-TKIs, with capecitabine as an active comparator. Design, Setting, and Participants: This national, historical cohort study was conducted using national claims data from the National Health Insurance Service in Korea from 2007 to 2020, with a 1-year follow-up. Patients with cancer aged 40 years or older prescribed oral VEGFR-TKIs or capecitabine were enrolled. Data were analyzed from September 2022 through April 2023. Exposure: Oral VEGFR-TKIs (sorafenib, regorafenib, vandetanib, sunitinib, lenvatinib, axitinib, and pazopanib) or capecitabine as a comparator. Main Outcomes and Measures: Hazard ratios (HRs) were used to investigate the association between VEGFR-TKI use and AAD after propensity score matching. The primary outcome was AAD, and secondary outcomes were aortic aneurysm and dissection and AAD with rupture. Outcomes were defined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes. Results: Among 127 710 patients with cancer eligible for the study (80 386 males [62.9%]; mean [SD] age, 62.6 [10.9] years), 37 308 patients received VEGFR-TKIs and 90 402 patients received capecitabine. Among 27 535 matched patients receiving VEGFR-TKIs, the incidence of AAD within 1 year of treatment initiation was 6.0 per 1000 person-years. The median (IQR) time to AAD onset in the matched AAD group was 114 (67-257) days after treatment initiation, with the highest incidence observed during the first 3 months (45 incidents vs 31, 17, and 16 incidents during 3- to 6-month, 6- to 9-month, and 9- to 12-month periods, respectively). Cox regression modeling showed that the risk of AAD occurrence was significantly higher among patients prescribed VEGFR-TKIs than those receiving capecitabine (HR, 1.48; 95% CI, 1.08-2.02); similar results were obtained among females (HR, 2.08; 95% CI, 1.26-3.42), older adults (aged ≥65 years; HR, 1.42; 95% CI, 1.01-1.99), and patients with dyslipidemia (HR, 1.58; 95% CI, 1.11-2.24). Conclusions and Relevance: In this study, the use of oral VEGFR-TKIs was associated with an increased risk of AAD occurrence. These findings elucidate vascular toxic effects and may provide a substantial reference for reducing the socioeconomic burden of adverse events associated with VEGFR-TKI use.

Depression risk associated with the use of 5α-reductase inhibitors versus α-blockers: A retrospective cohort study in South Korea.

BACKGROUND: One of the most prescribed treatments for benign prostatic hyperplasia (BPH) is 5α-reductase inhibitors (5ARI). Europe experienced recent safety issues involving 5ARI and depression symptoms, with similar findings being seen in Western countries. The South Korea has updated the drug label in accordance with European recommendations, but the relevant evidence was insufficient. This study compared the use of 5ARI versus α-blocker (AB) as a treatment for BPH and related risks of depression to provide evidence based on the Korean population. METHODS: This was a retrospective cohort study using South Korea's Health Insurance Review & Assessment Service claim data from 2011 to 2017. New patients diagnosed in men with BPH and taking medications that contained either 5ARI or AB between July 1, 2013, and June 30, 2015, were included (n = 1,461 5ARI; n = 18,650 AB). The primary outcome was depression defined per the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10: F32-34, F38, F412, F432). Logistic regression was used to implement 1:1 propensity score (PS) matching of patients taking 5ARI to those taking AB to adjust for confounding. Cox proportional hazard models were used to compare the risk of depression associated with 5ARI versus AB. RESULTS: Balance in baseline characteristics between the treatment groups were achieved within PS matched pairs (1,461 pairs). Compared to the AB medication group, the 5ARI group had lower depression (HR: 0.69, 95% CI: [0.51-0.92]). However, we could not find a clinically relevant, statistical difference after PS matching (HR: 0.91, 95% CI: [0.61-1.36]). CONCLUSIONS: The risk of depression associated with 5ARI was not meaningfully different from AB in Korea, which suggests that medical officials should provide the most appropriate medication for BPH patients by considering both treatment benefits and depression risk.

Sex Disparity in Survival of Patients With Uveal Melanoma: Better Survival Rates in Women Than in Men in South Korea.

Purpose: The purpose of this study was to determine the survival rate of patients with uveal melanoma and sex disparity in this rate in South Korea. Methods: We extracted incident uveal melanoma patients using the Korea Central Cancer Registry (KCCR) database, which covered the entire population from 1999 to 2012 in South Korea. We estimated all-cause survival probabilities and cancer-specific survival probabilities of patients with uveal melanoma and compared these probabilities between subgroups (sex, tumor site, age at diagnosis, etc.) using Kaplan-Meier methods and log-rank tests. We fitted the Cox-proportional hazards models for all-cause death and cancer death to determine sex disparities in survival. Results: A total of 344 uveal melanoma patients (175 women, 51%) were ascertained. They comprised 283 patients with choroidal melanoma (82%) and 61 patients with ciliary body/iris melanoma (18%). The observed 5-year survival probability from all-cause death was 75% (95% confidence interval [CI]: 69%-79%); women with uveal melanoma showed higher survival probability (83% [95% CI: 76%-89%]) compared with men (66% [95% CI: 58%-73%], P < 0.01). After adjusting for age, year of diagnosis, tumor sites, and diagnostic verification method, the hazards for all-cause death and cancer death in women with uveal melanoma were lower than those in men (hazards ratio for cancer death = 0.50 [95% CI: 0.30-0.81]; hazards ratio for all-cause death = 0.39 [95% CI: 0.25-0.61]). Conclusions: Women with uveal melanoma have better survival probabilities relative to men with uveal melanoma. Our findings show a comprehensive picture of survival probability in uveal melanoma cancer patients in Korea, which requires further investigation of mechanism of the sex disparity in uveal melanoma.

Suicide Risk Assessments: Which Suicide Risk Factors Psychiatric Residents Consider Significant?

OBJECTIVE: Patients visiting the emergency department (ED) after a suicide attempt are generally assessed for suicide risk by psychiatric residents. Psychiatric residents' competence in evaluating the risk posed by the patients who attempted suicide is critical to preventing suicide. METHODS: We investigated factors considered important by psychiatric residents when evaluating suicide risk. This study included 140 patients admitted to the ED after attempting suicide. Psychiatric residents rated patients' severity of current and future suicide risk as low/moderate/high using the Brief Emergency Room Suicide Risk Assessment (BESRA). The association between each BESRA variable and level of suicide risk was analyzed. RESULTS: Many factors were commonly considered important in evaluating the severity of current and future suicide risk. However, the following factors were only associated with future suicide risk: female gender, having no religion, family psychiatric history, history of axis I disorders, having a will, harboring no regrets, and social isolation. CONCLUSION: Psychiatric residents use diverse factors when assessing suicide risk. Psychiatric residents might put more emphasis on non-modifiable demographic and clinical factors, concrete evidence showing suicide determination, and social isolation to assess the risk of future suicide.

Analysis of pharmacogenomic variants associated with population differentiation.

In the present study, we systematically investigated population differentiation of drug-related (DR) genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB) database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA) F-test, Fst, and Nearest Shrunken Centroid Method (NSCM). Fst showed high sensitivity with stable specificity among varying sample sizes; thus, we selected Fst for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with a high level of differentiation (HD gene group) and genes with a low level of differentiation (LD gene group). Last, we conducted a gene ontology (GO) analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. "Cell communication" and "cell-cell signaling" had the lowest Benjamini-Hochberg's q-values (0.0002 and 0.0006, respectively), and "drug binding" was highly enriched (16.51) despite its relatively high q-value (0.0142). Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5. Specifically, the Fst values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was "Wnt signaling pathway," which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding.

Risk and protective factors predicting multiple suicide attempts.

This study compared demographical and clinical variables between first and multiple suicide attempters and investigated risk and protective factors predicting multiple attempts. 228 patients visiting emergency department after attempting suicide were divided into two groups: first attempter (n=148, 64.9%) and multiple attempter (n=80, 35.1%). Demographic variables, clinical characteristics, factors related with suicide behavior, and psychiatric resources between two groups were compared. Multivariate logistic regression analysis was conducted to investigate risk and protective factors predicting multiple attempts. The results showed that multiple attempters were younger, not married, more severe in psychopathology (e.g., psychiatric disorder, personality disorder, lower function, and suicide family history) and suicidality (e.g., repetitive/severe/continuous suicide ideation), and lower in psychiatric resources (e.g., interpersonal stress/conflict, conflicting interpersonal relationship, socially isolated, lower personal achievement, and lower ability to control emotion) than first attempters. Suicide ideation severity and conflicting interpersonal relationships predicted multiple suicide attempts, whereas past year's highest global functioning score and age over 45 protected against multiple suicide attempts. This study demonstrated that multiple suicide attempters have more severe clinical profile than first suicide attempters. Moreover, decreasing severity of suicide ideation, improving interpersonal relationships, and enhancing functioning level of suicide attempters might be important in preventing them from re-attempting suicide.

3D culture of adipose-tissue-derived stem cells mainly leads to chondrogenesis in poly(ethylene glycol)-poly(L-alanine) diblock copolymer thermogel.

Poly(ethylene glycol)-b-poly(L-alanine) (PEG-L-PA)s with L-PA molecular weights of 620, 1100, and 2480 Da and a fixed molecular weight of PEG at 5000 Da were synthesized to compare the thermosensitive behavior, and to investigate their potential as a three-dimensional (3D) culture matrix of adipose-tissue-derived stem cells (ADSCs). The sol-to-gel transition temperature and the concentration ranges where the transition was observed decreased as the L-PA molecular weight increased. ADSCs were cultured in the 3D matrixes of in situ formed PEG-L-PA hydrogels, which were produced by increasing the temperature of cell-suspended PEG-L-PA aqueous solutions. The spherical morphology was maintained in the PEG-L-PA hydrogel, while the cells underwent fibroblastic morphological changes in the Matrigel over 14 days of incubation. ADSCs exhibited high expression of type II collagen in the PEG-L-PA thermogel. In addition, they also moderately expressed the biomarker of myogenic differentiation factor 1 as the same mesodermal lineages, as well as the type III ß-tubulin as a cross-differentiation biomarker. Similar to the in vitro study, the ADSCs predominantly exhibited chondrogenic biomarkers in the in vivo study. The study demonstrates that the polypeptide thermogel of PEG-L-PA is promising as a 3D culture matrix of ADSCs and as an injectable tissue engineering biomaterial.

Threat-induced autonomic dysregulation in panic disorder evidenced by heart rate variability measures.

OBJECTIVE: The objective was to compare autonomic response to threatening stimuli between patients with panic disorder (PD) and healthy volunteers by using 5-min recordings of heart rate variability (HRV). METHODS: Twenty-seven patients with PD and 20 healthy controls were recruited. The first 5-min measurement of HRV was conducted at resting state. HRV measurement during threatening stimuli was conducted while participants were viewing 15 threatening pictures. Spectral analyses measures included high-frequency (HF; 0.15-0.4 HZ) component, low-frequency (LF; 0.04-0.15 Hz) component and LF/HF ratio. RESULTS: There was no significant HRV difference between the two groups at the resting state. During threatening stimuli, the PD group had significantly higher LF power and LF/HF ratio and significantly lower HF power than the healthy controls (for all, P<.01). A two-way analysis of variance was employed to determine the effect of group (patient and control) and condition (threatening and resting) on all three HRV measures. The analysis showed a significant main effect of group (F=12.21; P<.01), condition (F=14.21; P<.001) and interaction effect between group and condition (F=4.83; P<.05) on LF/HF ratio. CONCLUSIONS: The findings from the present study suggest that patients with PD exhibit a sympathetic predominance when faced with threatening stimuli compared with normal control subjects.

Development and Standardization of Extended ChaeLee Korean Facial Expressions of Emotions.

OBJECTIVE: In recent years there has been an enormous increase of neuroscience research using the facial expressions of emotion. This has led to a need for ethnically specific facial expressions data, due to differences of facial emotion processing among different ethnicities. METHODS: FIFTY PROFESSIONAL ACTORS WERE ASKED TO POSE WITH EACH OF THE FOLLOWING FACIAL EXPRESSIONS IN TURN: happiness, sadness, fear, anger, disgust, surprise, and neutral. A total of 283 facial pictures of 40 actors were selected to be included in the validation study. Facial expression emotion identification was performed in a validation study by 104 healthy raters who provided emotion labeling, valence ratings, and arousal ratings. RESULTS: A total of 259 images of 37 actors were selected for inclusion in the Extended ChaeLee Korean Facial Expressions of Emotions tool, based on the analysis of results. In these images, the actors' mean age was 38±11.1 years (range 26-60 years), with 16 (43.2%) males and 21 (56.8%) females. The consistency varied by emotion type, showing the highest for happiness (95.5%) and the lowest for fear (49.0%). The mean scores for the valence ratings ranged from 4.0 (happiness) to 1.9 (sadness, anger, and disgust). The mean scores for the arousal ratings ranged from 3.7 (anger and fear) to 2.5 (neutral). CONCLUSION: We obtained facial expressions from individuals of Korean ethnicity and performed a study to validate them. Our results provide a tool for the affective neurosciences which could be used for the investigation of mechanisms of emotion processing in healthy individuals as well as in patients with various psychiatric disorders.

Symptom severity of panic disorder associated with impairment in emotion processing of threat-related facial expressions.

AIM: To compare emotion recognition patterns between patients with panic disorder (PD) and healthy volunteers and to analyze the correlation between the degree of emotion recognition impairment and symptom severity in patients with PD. METHODS: Twenty-four patients with PD and 20 healthy controls were tested with a facial emotional expression recognition task involving four basic emotions (i.e. happiness, sadness, anger, and fear). Emotion recognition measures included the recognition threshold, response time, response time of correctly classified emotions (response time_crt), and recognition error. An average of all four emotions for each emotion recognition measure was compared between the two groups and then a comparison of recognition measures for each specific emotion was conducted. The correlations between severity of the State-Trait Anxiety Inventory, Beck Depression Inventory (BDI), and Panic Disorder Severity Scale with emotion recognition indices were also analyzed. RESULTS: Average recognition threshold was significantly higher in the PD group compared to the control group. In the PD group, there was a non-significant trend of increase in the emotion recognition threshold for fear and the response time for anger compared with the control group. In the correlation analysis, higher trait anxiety was associated with slower response time_crt for anger and a higher BDI score was associated with slower response times and response time_crt for happiness and anger. CONCLUSION: This study suggests that symptom severity of PD might be associated with impairment in emotion processing of threat-related facial expressions.

Ethnic variability in the allelic distribution of pharmacogenes between Korean and other populations.

OBJECTIVE: We examined the differences in allele frequencies for pharmacogenes among the Korean (KOR), Chinese (CHB), Japanese (JPT), Caucasian (CEU), and Nigerian (YRI) populations. METHODS: Fifty-seven pharmacogenes were selected from the imputed Korean Association REsource and HapMap databases. Minor allele frequencies were analyzed using the sample size-modified single nucleotide polymorphism-specific fixation index (FST) and the χ-test with Bonferroni's correction. Geneset analysis was also carried out to identify pharmacogenes that have significantly different allele frequencies among the various populations tested. RESULTS: The KOR population was the most divergent group from the YRI population (FST: 0.079) but very similar to the CHB and JPT populations (FST: 0.003). VKORC1 showed a large population divergence in the KOR-YRI (0.439) comparison. CYP3A4 was also highly divergent in the KOR-YRI (FST: 0.361) comparison. The calcium signaling pathway gene set was divergent in all pairwise population comparisons. CONCLUSION: In terms of the 57 pharmacogenes studied, there were no significant differences among the KOR, CHB, and JPT populations. However, the YRI and CEU populations were significantly differentiated from the three Eastern Asian groups. Future pharmacogenomics studies can utilize the polymorphisms identified in this study, as these variants may have important implications for the selection of highly informative single nucleotide polymorphisms for future clinical trials.

The impact of personality traits on emotional responses to interpersonal stress.

OBJECTIVE: The aim of the present study was to examine the impact of personality traits on emotional responses to interpersonal stress. METHODS: Thirty-two healthy college students (18 men, 14 women; age 25.2±2.7 years) participated in the study. Mood and anxiety were assessed with the Beck Depression Inventory and the State Trait Anxiety Inventory. Personality traits were assessed with the Interpersonal Sensitivity Measure (IPSM). The subjective emotional responses of participants to different (i.e., negative, neutral, and positive) interpersonal feedback were measured. RESULTS: Subject responses were positive to positive interpersonal feedback and negative to negative interpersonal feedback. The IPSM fragile inner self subscore was negatively correlated with the subjective emotional ratings in response to interpersonal feedback. No correlation was found between validation measures (i.e., the degree of attention in the task and task difficulty) and subjective emotional responses. CONCLUSIONS: Taken together, emotional responses to interpersonal stress may be modulated by personality traits and may impact health and psychological outcomes. Therefore, proper screening and stress management programs that focus on personality traits may improve the mental health of college students.

Characteristics of drug overdose in young suicide attempters.

OBJECTIVE: Few studies have focused on the characteristic features of drug overdose in children and adolescents who have attempted suicide in Korea. The present study examined the characteristics of drug overdose in children and adolescents who visited the emergency room following drug ingestion for a suicide attempt. METHODS: The medical records of 28 patients who were treated in the emergency room following a drug overdose from January 2008 to March 2011 were analyzed. Demographic and clinical variables related to the suicide attempts were examined. RESULTS: The mean age of the patients was 16.6±1.7 years (range 11-19 years), and 20 of the patients (71.4%) were female. Most of the patients (n=23, 82.1%) overdosed on a single drug; acetaminophen-containing analgesics were the most common (n=12, 42.9%). Depression was the most common psychiatric disorder (n=22, 78.6%), and interpersonal conflict was the most common precipitating factor of the suicide attempts (n=11, 39.3%). This was the first suicide attempt for approximately 80% of the patients. About one fourth of the patients (n=7, 25%) had follow-up visits at the psychiatric outpatient clinic. CONCLUSION: Early screening and psychiatric intervention for depression may be an important factor in preventing childhood and adolescent suicide attempts. Developing coping strategies to manage interpersonal conflicts may also be helpful. Moreover, policies restricting the amount and kind of drugs purchased by teenagers may be necessary to prevent drug overdose in this age group.