Comparative analysis of salivary cortisol measurements using different assay methods in relation to serum-free cortisol measurement.

Objectives: Salivary cortisol reflects the biologically active form of serum cortisol, offering a noninvasive evaluation method for the diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis. While liquid chromatography-tandem mass spectrometry (LC-MS/MS) is known for its specificity, immunoassays (IA) are commonly used because of their simplicity. This study aimed to assess the performance of salivary cortisol measurement using both IA and LC-MS/MS in comparison to serum-free cortisol measurement. Methods: Assay results for 188 saliva and 94 serum samples from 47 participants were analyzed. Salivary samples collected at different time points were analyzed using IA and LC-MS/MS. Serum samples were analyzed for cortisol, cortisol-binding globulin, and free cortisol. The statistical analyses included correlations and method comparisons. Results: The diurnal salivary cortisol profiles exhibited a comparable circadian rhythm pattern; however, the concentrations measured using IA were consistently higher than those measured using LC-MS/MS. The correlation analysis revealed robust associations among salivary cortisol (IA), salivary cortisol (LC-MS/MS), and serum-free cortisol levels (LC-MS/MS). However, the method comparison revealed a systematic bias between IA and LC-MS/MS in salivary cortisol measurement. Conclusions: This study contributes to the ongoing debate on assay techniques by affirming the suitability of IA and LC-MS/MS for salivary cortisol measurement to assess dynamic changes in HPA axis activity. The identified systematic bias emphasizes the importance of selecting methods based on specific research or clinical requirements.

Exploratory Clinical Trial of a Depression Diagnostic Software That Integrates Stress Biomarkers and Composite Psychometrics.

OBJECTIVE: This study evaluated the clinical effectiveness of Minds.NAVI, a depression screening kit combining psychometric measures and stress hormone biomarkers, in a prospective clinical trial. The objective was to assess its potential as a depression screening tool and investigate the associations between psychological assessments, salivary hormone staging, and depression severity. METHODS: Thirty-five participants with major depressive disorder and 12 healthy controls (HCs) were included. The Minds.NAVI software, utilizing the PROtective and Vulnerable factors battEry Test (PROVE) and salivary cortisol/dehydroepiandrosterone (DHEA) analysis, was employed. The PROVE test is a comprehensive self-report questionnaire that assesses depressive symptoms, suicide risk, attachment style, adverse childhood experiences, mentalization capacity, and resilience. In addition, salivary cortisol and DHEA levels were measured to evaluate the functional stage of the hypothalamic-pituitary-adrenal (HPA) axis. RESULTS: Minds.NAVI exhibited 100% sensitivity, 91.7% specificity, and 97.9% accuracy in distinguishing depression from HCs within an exploratory small group. Salivary stress hormone phases showed changes with depression stage (p=0.030), and the proportion of patients with "adrenal exhaustion stage" was higher in the moderate/severe depression group (p=0.038). Protective/vulnerable factors differed significantly between controls and depressed groups (p<0.001). Cortisol awakening response inversely correlated with depressive symptom severity (r=-0.31, p=0.034). CONCLUSION: This study suggested possible clinical effectiveness of Minds.NAVI, a depression screening tool that integrates psychometric measures and stress hormone biomarkers. The findings support the potential association between depression, chronic stress, and HPA axis hyporesponsiveness.

Incidence, Prevalence, and Mortality of Eosinophilic Granulomatosis With Polyangiitis in Korea: A Nationwide Population-Based Study.

PURPOSE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of vasculitis with multiorgan involvement. The incidence and prevalence of EGPA vary geographically and ethnically. This study investigated the incidence, prevalence, and mortality of EGPA in a nationwide population-based cohort in Korea. METHODS: This retrospective cohort study used data from the National Health Insurance database that covers almost all Korean residents. EGPA was identified using relevant diagnostic codes from 2007 to 2018. Newly diagnosed EGPA cases since 2007 and patients who visited outpatient clinics for EGPA at least three times were included. Age- and sex-adjusted standardized incidence and prevalence rates were analyzed. RESULTS: A total of 843 patients with EGPA were identified. The mean annual standardized incidence between 2007 and 2018 was 1.2 (per 1,000,000 individuals). The incidence of EGPA has increased from 1.1 (per 1,000,000 individuals) in 2007 to 1.6 (per 1,000,000 individuals) in 2017. The standardized prevalence of EGPA has increased from 1.1(per 1,000,000 individuals) in 2007 to 11.2 (per 1,000,000 individuals) in 2018. The incidence and prevalence of EGPA were higher in women than in men. The standardized mortality rate was 1.61 (95% confidence interval [CI], 1.34-1.93) in total population, 1.59 (95% CI, 1.23-2.02) in males, and 1.63 (95% CI, 1.22-2.13) in females. CONCLUSIONS: The incidence of EGPA has increased over the past decade. Incidence and prevalence rates were higher in females than in males. The overall mortality rate associated with EGPA was higher than that in the general population.

Inhaled Corticosteroids May Not Affect the Clinical Outcomes of Pneumonia in Patients with Chronic Obstructive Pulmonary Disease.

Background: Although inhaled corticosteroids (ICS) is reportedly associated with a higher risk of pneumonia in chronic obstructive pulmonary disease (COPD), the clinical implications of ICS have not been sufficiently verified to determine their effect on the prognosis of pneumonia. Methods: The electronic health records of patients hospitalized for pneumonia with underlying COPD were retrospectively reviewed. Pneumonia was confirmed using chest radiography or computed tomography. The clinical outcomes of pneumonia in patients with COPD who received ICS and those who received long-acting bronchodilators other than ICS were compared. Results: Among the 255 hospitalized patients, 89 met the inclusion criteria. The numbers of ICS and non-ICS users were 46 and 43, respectively. The CURB-65 scores at the initial presentation of pneumonia were comparable between the two groups. The proportions of patients with multilobar infiltration, pleural effusion, and complicated pneumonia in the radiological studies did not vary between the two groups. Additionally, the defervescence time, proportion of mechanical ventilation, intensive care unit admission, length of hospital stays, and mortality rate at 30 and 90 days were not significantly different between the two groups. ICS use and blood eosinophils count were not associated with all pneumonia outcomes and mortality in multivariate analyses. Conclusion: The clinical outcomes of pneumonia following ICS use in patients with COPD did not differ from those in patients treated without ICS. Thus, ICS may not contribute to the severity and outcomes of pneumonia in patients with COPD.

Successful robotic kidney transplantation for surgeons with no experience in minimally invasive surgery: a single institution experience.

BACKGROUND: Robotic kidney transplantation (RKT) is a novel and welcomed innovation yielding good surgical outcomes. However, data on the feasibility and safety of performing RKT by surgeons with a lack of prior minimally invasive surgery (MIS) experience are limited. The authors aimed to evaluate the surgical and functional results of RKT and present the learning curves (LC) of RKT by a single surgeon with no prior experience in MIS. MATERIALS AND METHODS: This was a retrospective study of all RKT performed between November 2019 and April 2023 at Severance Hospital in Seoul, South Korea. The authors analyzed surgical and functional outcomes, as well as complication rates of RKT in comparison to open kidney transplantation (OKT). The authors evaluated LCs using the cumulative summation method to describe the number of cases associated with the competency of a single surgeon. RESULTS: A total of 50 patients who underwent RKT and 104 patients who underwent OKT were included in this study. In RKT group, the median surgical console time was 193 min (interquartile range, 172-222) and the median vascular anastomoses time was 38 min (35-44). Total operation time was 323 min (290-371) and rewarming time was 62.5 min (56.0-70.0) in RKT group compared to 210 min (190-239) and 25 min (21-30), respectively, in OKT group. Despite extended surgical durations with a robotic technique, both groups had comparable intraoperative and postoperative outcomes, as well as renal function. Estimated blood loss and post-transplant hospital stays were significantly lower in RKT group than in OKT group. LC analysis of RKT by the single surgeon revealed that surgical competence was achieved after 15 cases. CONCLUSION: Even if surgeons do not have prior experience with MIS, they can rapidly overcome the LC and safely perform RKT with adequate preparation and acquisition of basic robotic surgical techniques.

Resting-state functional connectivity and cognitive performance in aging adults with cognitive decline: A data-driven multivariate pattern analysis.

BACKGROUND: Cognitive impairments occur on a continuous spectrum in multiple cognitive domains showing individual variability of the deteriorating patterns; however, often, cognitive domains are studied separately. METHODS: The present study investigated aging individual variations of cognitive abilities and related resting-state functional connectivity (rsFC) using data-driven approach. Cognitive and neuroimaging data were obtained from 62 elderly outpatients with cognitive decline. Principal component analysis (PCA) was conducted on the cognitive data to determine patterns of cognitive performance, then data-driven whole-brain connectome multivariate pattern analysis (MVPA) was applied on the neuroimaging data to discover neural regions associated with the cognitive characteristic. RESULTS: The first component (PC1) delineated an overall decline in all domains of cognition, and the second component (PC2) represented a compensatory relationship within basic cognitive functions. MVPA indicated rsFC of the cerebellum lobule VIII and insula with the default-mode network, frontoparietal network, and salience network inversely correlated with PC1 scores. Additionally, PC2 score was related to rsFC patterns with temporal pole and occipital cortex. CONCLUSIONS: The featured primary cognitive characteristic depicted the importance of the cerebellum and insula connectivity patterns in of the general cognitive decline. The findings also discovered a secondary characteristic that communicated impaired interactions within the basic cognitive function, which was independent from the impairment severity.

Development and validation of a machine learning-based fall-related injury risk prediction model using nationwide claims database in Korean community-dwelling older population.

BACKGROUND: Falls impact over 25% of older adults annually, making fall prevention a critical public health focus. We aimed to develop and validate a machine learning-based prediction model for serious fall-related injuries (FRIs) among community-dwelling older adults, incorporating various medication factors. METHODS: Utilizing annual national patient sample data, we segmented outpatient older adults without FRIs in the preceding three months into development and validation cohorts based on data from 2018 and 2019, respectively. The outcome of interest was serious FRIs, which we defined operationally as incidents necessitating an emergency department visit or hospital admission, identified by the diagnostic codes of injuries that are likely associated with falls. We developed four machine-learning models (light gradient boosting machine, Catboost, eXtreme Gradient Boosting, and Random forest), along with a logistic regression model as a reference. RESULTS: In both cohorts, FRIs leading to hospitalization/emergency department visits occurred in approximately 2% of patients. After selecting features from initial set of 187, we retained 26, with 15 of them being medication-related. Catboost emerged as the top model, with area under the receiver operating characteristic of 0.700, along with sensitivity and specificity rates around 65%. The high-risk group showed more than threefold greater risk of FRIs than the low-risk group, and model interpretations aligned with clinical intuition. CONCLUSION: We developed and validated an explainable machine-learning model for predicting serious FRIs in community-dwelling older adults. With prospective validation, this model could facilitate targeted fall prevention strategies in primary care or community-pharmacy settings.

Safety and efficacy of remimazolam compared with midazolam during bronchoscopy: a single-center, randomized controlled study.

Although remimazolam is an ultra-short-acting benzodiazepine with a shorter elimination half-life and faster recovery time than midazolam, studies evaluating its safety and efficacy during bronchoscopy are limited. This study aimed to compare the safety and efficacy of remimazolam with those of midazolam for bronchoscopy. This prospective randomized parallel-group study was conducted at a single institution. The primary outcome was the time from the end of the procedure to full alertness. Other procedural time parameters, satisfaction profiles, and adverse effects were thoroughly evaluated. The time taken to reach peak sedation and the time from the end of the procedure to full alertness was significantly shorter in the remimazolam group than in the midazolam group (median [interquartile range], 2 min [1-4] vs. 3 min [2-5], P = 0.006; and median, 2 min [1-5] vs. 5 min [1-12], P = 0.035, respectively). In patients with non-biopsy procedures (n = 79), participant satisfaction was significantly higher in the remimazolam group than in the midazolam group (median rated scale, 10 vs. 7, P = 0.042). Physician satisfaction and willingness to repeat the procedure were similar between groups. Although the incidence of adverse effects was similar between the groups and there was no significant difference, the midazolam group had a higher antidote administration rate than the remimazolam group (15.7% vs. 4.1%, P = 0.092). Remimazolam is effective and safe for achieving adequate sedation, with a shorter onset time and faster neuropsychiatric recovery than midazolam. It may be a new option for sedation during bronchoscopy.Trial registration: The trial registration number is NCT05994547, and the date of first registration is 16/08/2023.

Association and interaction between clinician-rated measures of depression and anxiety with heart rate variability in elderly patients with psychiatric disorders.

Background: Older adults are vulnerable to comorbid depression and anxiety symptoms; however, these conditions are widely underrecognized and often untreated. Understanding their combined manifestation using objective measurements, such as clinician-rated scales and heart rate variability (HRV), can help refine the diagnosis and select a treatment strategy for geriatric patients. Methods: This study included patients over 65 years who were mainly diagnosed with either category of depressive or anxiety disorders from the psychiatric outpatient clinic in a university hospital. A total of 114 patients met eligibility with a completed collection of electrocardiograms, the Hamilton Depression Rating Scale (HDRS; clinician-rated depression), and the Hamilton Anxiety Scale (HAS; clinician-rated anxiety) to assess the severity of symptoms. Both main and interaction effects between HDRS and HAS on HRV parameters were examined. Results: Significant interaction effects between clinician-rated depression and anxiety (HDRS × HAS) on HRV reduction in frequency parameters (i.e., nuLF, nuHF, LF/HF ratio) were found, which consistently indicated autonomic nervous system dysregulation. Findings imply that HRV could reflect synergistic effects of comorbid depressive and anxiety symptoms, perhaps due to the amplification of individual symptoms in geriatric patients. Conclusions: The results imply that using objective measurements can improve diagnostic accuracy, particularly in geriatric patients with comorbid status, and the normalization of the autonomic nervous system might be a candidate target for prevention and treatment.

The Prevalence and Clinical Characteristics of Borderline Personality Disorder in South Korea Using National Health Insurance Service Customized Database.

PURPOSE: The purpose of the present study was to identify the prevalence and clinical characteristics of borderline personality disorder (BPD) in South Korea using the Korean National Health Insurance database (DB). MATERIALS AND METHODS: We used the National Health Insurance Service (NHIS)'s research DB (NHIS-2021-1-790) from January 1, 2010 to December 31, 2019, to make customized DB including sociodemographic information and absence or presence of BPD and other psychiatric disorders. The prevalence and the age of onset of BPD was estimated. To compare medical service utilization between the BPD group and the control group, a 1:1:1 propensity score matching was employed, and the regression analysis was conducted. RESULTS: The prevalence of BPD per 10000 people was 0.96 in 2010 and 1.06 in 2019. The prevalence ratio of males to females was 1:1.38 in 2010 and 1:1.65 in 2019, showing that BPD was more prevalent in females. The patients' overall average age of onset was 33.19±14.6 years, with the highest prevalence shown in 8503 people in their 20s. By administrative district, the highest prevalence of BPD per 10000 people was shown in Seoul with 8.71 and the lowest in Jeollanam-do with 2.35. The BPD patients showed a pattern of extensive use of general and mental healthcare services. CONCLUSION: This study identified the prevalence of BPD on a national DB set in South Korea. Although the prevalence of BPD in South Korea was relatively low compared to other countries, there was a steady increase in the number of BPD patients over a decade, which may be possibly due to an increased awareness of mental health and campaigns among healthcare providers and users in the country.

Inhaled Corticosteroids and the Risk of Nontuberculous Mycobacterial Pulmonary Disease in Chronic Obstructive Pulmonary Disease: Findings from a Nationwide Population-Based Study.

Studies have shown increased nontuberculous mycobacterial pulmonary disease (NTM) incidence with inhaled corticosteroid (ICS) use in patients with chronic respiratory diseases; however, this association in chronic obstructive pulmonary disease (COPD) remains insufficiently studied. Using a nationwide population-based database of the Korean National Health Insurance Service, newly diagnosed COPD patients (2005-2018) treated with inhaled bronchodilators were selected. An NTM case was defined by the presence of the first diagnostic code following inhaled bronchodilator use. Results indicated that ICS users did not have an increased risk of NTM disease compared to non-ICS users (hazard ratio (HR), 1.121; 95% confidence interval (CI), 0.950-1.323; p = 0.176). However, in a subgroup analysis, the highest quartile of the cumulative ICS dose was associated with the development of NTM (1.200, 0.950-1.323, p = 0.050). Medium (1.229, 1.008-1.499, p = 0.041) and high daily doses of ICS (1.637, 1.241-2.160, p < 0.001) were associated with an increased risk of NTM disease. There was no difference in the risk of NTM according to ICS type. ICS use may increase the risk of developing NTM disease in patients with COPD. Physicians should weigh the potential benefits and risks of ICS, especially when using high doses and prolonged durations.

Outstanding Characteristics of Birt-Hogg-Dube Syndrome in Korea.

Birt-Hogg-Dube (BHD) is a rare genetic disorder characterized by multiple lung cysts, typical skin manifestations, and renal tumors. We prospectively enrolled thirty-one subjects from four South Korean institutions with typical lung cysts, and next-generation sequencing was conducted. We prospectively enrolled thirty-one subjects from four Korean institutions with typical lung cysts. Next-generation sequencing was performed to investigate mutations in the following genes: FLCN, TSC1, TSC2, CFTR, EFEMP2, ELN, FBLN5, LTBP4, and SERPINA1. BHD was diagnosed in 11 of the 31 enrolled subjects (35.5%; FLCN mutations). Notably, we identified three novel mutations (c.1098G>A, c.139G>T, and c.1335del) that have not been previously reported. In addition to FLCN mutations, we also observed mutations in CFTR (16.1%), LTBP4 (9.7%), TSC2 (9.7%), TSC1 (3.2%), ELN (3.2%), and SERPINA1 (3.2%). According to a systematic review of 45 South Korean patients with BHD, the prevalence of pneumothorax (72.7%) was greater in South Korea than in the rest of the world (50.9%; p = 0.003). The prevalence of skin manifestations (13.6%) and renal tumors (9.1%) was lower in Korea than in the rest of the world, at 47.9% [p < 0.001] and 22.5% [p = 0.027], respectively). This study confirmed a significant prediction model for BHD based on age, number of lung cysts (>40), and maximal diameter of lung cysts (>2 cm) regardless of skin manifestations and renal tumors. Importantly, three novel mutations (c.1098G>A, c.139G>T, and c.1335del) were identified. In conclusion, South Korean patients with BHD display characteristics that are different from those observed in patients of other nationalities. Detailed characterization of lung cysts is needed to define BHD, especially in South Korea, even if patients do not present with skin or renal lesions.

The Profile of Early Sedation Depth and Clinical Outcomes of Mechanically Ventilated Patients in Korea.

BACKGROUND: Current international guidelines recommend against deep sedation as it is associated with worse outcomes in the intensive care unit (ICU). However, in Korea the prevalence of deep sedation and its impact on patients in the ICU are not well known. METHODS: From April 2020 to July 2021, a multicenter, prospective, longitudinal, noninterventional cohort study was performed in 20 Korean ICUs. Sedation depth extent was divided into light and deep using a mean Richmond Agitation-Sedation Scale value within the first 48 hours. Propensity score matching was used to balance covariables; the outcomes were compared between the two groups. RESULTS: Overall, 631 patients (418 [66.2%] and 213 [33.8%] in the deep and light sedation groups, respectively) were included. Mortality rates were 14.1% and 8.4% in the deep and light sedation groups (P = 0.039), respectively. Kaplan-Meier estimates showed that time to extubation (P < 0.001), ICU length of stay (P = 0.005), and death (P = 0.041) differed between the groups. After adjusting for confounders, early deep sedation was only associated with delayed time to extubation (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.55-0.80; P < 0.001). In the matched cohort, deep sedation remained significantly associated with delayed time to extubation (HR, 0.68; 95% CI, 0.56-0.83; P < 0.001) but was not associated with ICU length of stay (HR, 0.94; 95% CI, 0.79-1.13; P = 0.500) and in-hospital mortality (HR, 1.19; 95% CI, 0.65-2.17; P = 0.582). CONCLUSION: In many Korean ICUs, early deep sedation was highly prevalent in mechanically ventilated patients and was associated with delayed extubation, but not prolonged ICU stay or in-hospital death.

Isolation of Bovine Milk Exosome Using Electrophoretic Oscillation Assisted Tangential Flow Filtration with Antifouling of Micro-ultrafiltration Membrane Filters.

Tangent flow-driven ultrafiltration (TF-UF) is an efficient isolation process of milk exosomes without morphological deformation. However, the TF-UF approach with micro-ultrafiltration SiNx membrane filters suffers from the clogging and fouling of micro-ultrafiltration membrane filter pores with large bioparticles. Thus, it is limited in the long term, continuous isolation of large quantities of exosomes. In this work, we introduced electrophoretic oscillation (EPO) in the TF-UF approach to remove pore clogging and fouling of with micro-ultrafiltration SiNx membrane filters by large bioparticles. As a result, the combined EPO-assisted TF (EPOTF) filtration can isolate large quantities of bovine milk exosomes without deformation. Furthermore, several morphological and biological analyses confirmed that the EPOTF filtration approach could isolate the milk exosomes in high concentrations with high purity and intact morphology. In addition, the uptake test of fluorescent-labeled exosomes by the keratinocyte cells visualized the biological function of purified exosomes. Hence, compared to the TF-UF process, the EPOTF filtration produced a higher yield of bovine milk exosomes without stopping the filtering process for over 200 h. Therefore, this isolation process enables scalable and continuous production of morphologically intact exosomes from bovine milk, suggesting that high-quality exosome purification is possible for future applications such as drug nanocarriers, diagnosis, and treatments.

Differential relationship of observer-rated and self-rated depression and anxiety scales with heart rate variability features.

Heart rate variability (HRV) is a known psychophysiological marker for diverse psychiatric symptoms. In this study, we aimed to explore the potential for clinical use of HRV by investigating the interrelationship between HRV indices and clinical measures mainly used to assess depressive and anxious symptoms. Participants who reported depressive and anxious symptoms were designated into the following groups: group 1, clinician-rated and self-rated depression; group 2, only self-rated depression; group 3, clinician-rated and self-rated anxiety; group 4, only self-rated anxiety. Statistical comparisons were performed between these groups to investigate the association between HRV and clinical measures. As a result, HRV variables showed significant correlations only with the clinician-rated assessments. Moreover, both time and frequency domain HRV indices were significantly different between groups 1 and 2, but groups 3 and 4 showed significant differences only in frequency domain HRV indices. Our study showed that HRV is an objective indicator for depressive or anxious symptoms. Additionally, it is considered a potential indicator for predicting the severity or state of depressive symptoms rather than of anxious symptoms. This study will contribute to increasing the diagnostic utility of discriminating those symptoms based on HRV in the future.

Robotic ureter reconstruction using the native ureter to treat long-segment ureteral stricture of the transplant kidney utilizing Indocyanine green: The first Korean experience.

PURPOSE: Ureteral strictures are a common complication after kidney transplantation. Open reconstruction is preferred for long-segment ureteral strictures that cannot be resolved endoscopically; however, it is known to have the potential to fail. We report 2 successful cases of robotic reconstruction surgery of a transplant ureter using the native ureter with the aid of intraoperative Indocyanine green (ICG). MATERIALS AND METHODS: Patients were placed in semi-lateral position. Using Da Vinci Xi, the transplant ureter was dissected, and the stricture site was identified. End-to-side anastomosis of the native ureter to the transplant ureter was performed. ICG was utilized to identify the course of the transplant ureter and confirm the vascularity of the native ureter. RESULTS: Case 1: A 55-year-old female underwent renal transplantation at another hospital. She had recurrent febrile urinary tract infections (UTIs) and a ureteral stricture requiring percutaneous nephrostomy (PCN). The PCN and ureteral stent were removed successfully after surgery. The patient had only 1 febrile UTI episode after surgery. Case 2: A 56-year-old female underwent renal transplantation at another hospital. She had acute pyelonephritis 1-month post-transplantation, and a long-segment ureteral stricture was identified. She developed a UTI with anastomosis site leakage in the early postoperative period, which resolved with conservative treatment. The PCN and ureteral stent were removed 6 weeks after surgery. CONCLUSIONS: Robotic surgery for managing long-segment ureteral stricture after kidney transplantation is safe and feasible. The use of ICG during surgery to identify the ureter course and its viability can improve the success.

Effect of developmental stress on the in vivo neuronal circuits related to excitation-inhibition balance and mood in adulthood.

Introduction: Traumatic events in early life have a deleterious effect on the development of normal brain developments, which may be a cause of various psychiatric disorders in adulthood. Most prior studies focused on molecular biological aspects, and research on functional changes in neural circuits is still limited. We aimed to elucidate the effect of early life stress on in vivo excitation-inhibition and serotonergic neurotransmission in the adulthood using non-invasive functional molecular imaging (positron emission tomography, PET). Methods: To compare the effect of stress intensity, early life stress animal models were divided into single trauma (MS) and double trauma groups (MRS). MS was derived from maternal separation, whereas MRS was derived from maternal separation and restraint stress after birth. And to evaluate the stress vulnerability on the sex, we used male and female rats. Results: The MRS group showed greater weight loss and more severe depressive/anxiety-like behaviors than the MS and control groups. Corticosterone levels in MRS showed a greater extent of decline than in the MS group; however, there was no significant difference in the change of T3 and T4 between MS and MRS. In the PET, the stress exposure groups showed lower brain uptake for GABAergic, glutamatergic, and serotonergic systems compared with the control group. The excitatory/inhibitory balance, which was derived by dividing glutamate brain uptake into GABAergic uptake, increased as stress intensity increased. Neuronal degeneration in the stress exposure groups was confirmed by immunohistochemistry. In the sex comparison, female showed the greater changes of body weight, corticosterone level, depressive/anxiety-like behavior, and neurotransmission systems than those in male. Conclusion: Taken together, we demonstrated that developmental stress induces dysfunction of neurotransmission in vivo, and that females are more vulnerable to stress than males.

Risk of Secondary Cancer after Adjuvant Tamoxifen Treatment for Ductal Carcinoma In Situ: A Nationwide Cohort Study in South Korea.

Endocrine therapy is the mainstay treatment for hormone receptor-positive ductal carcinoma in situ. The aim of this study was to examine the long-term secondary malignancy risk of tamoxifen therapy. The data of patients diagnosed with breast cancer between January 2007 and December 2015 were retrieved from the database of the Health Insurance Review and Assessment Service of South Korea. The International Classification of Diseases, 10th revision, was used to track all-site cancers. Age at the time of surgery, chronic disease status, and type of surgery were considered covariates in the propensity score matching analysis. The median follow-up duration was 89 months. Forty-one patients in the tamoxifen group and nine in the control group developed endometrial cancer. The Cox regression hazard ratio model showed that tamoxifen therapy was the only significant predictor of the development of endometrial cancer (hazard ratio, 2.791; 95% confidence interval, 1.355-5.747; p = 0.0054). No other type of cancer was associated with long-term tamoxifen use. In consonance with the established knowledge, the real-world data in this study demonstrated that tamoxifen therapy is related to an increased incidence of endometrial cancer.

Marked Reduction in the Risk of Dementia in Patients with Breast Cancer: A Nationwide Population-Based Cohort Study.

PURPOSE: An inverse relationship between cancer and neurodegenerative disease, which presents the possibility of a reduced risk of dementia in cancer patients, has been suggested previously. However, a nationwide longitudinal population-based study of specific types of cancer with due consideration of treatment effects has not been conducted. Materials and Methods: This nationwide population-based cohort study used data obtained in a 12-year period (January 2007- December 2018) in the Korean National Health Insurance claims database. All female breast cancer patients (age ≥ 50 years) diagnosed between 2009 and 2010 were included after excluding those with physician visits for any cancer during a 2-year period (2007-2008). Patients with senile cataract constituted the control group. The main study outcome was the risk of developing dementia. RESULTS: From a total of 90,396 and 85,906 patients with breast cancer and cataract, respectively, patients without behavior codes were excluded. Data for 15,407 breast cancer patients and 7,020 controls were analyzed before matching. After matching for comorbidities and age, either group comprised 2,252 patients. The median follow-up time was 104.1±24.0 months after matching. After matching, breast cancer was a predictor of a lower risk of for dementia (hazard ratio, 0.091; 95% confidence interval, 0.075 to 0.111; p < 0.001). In breast cancer patients, receiving chemotherapy and endocrine therapy did not significantly affect the incidence of dementia. CONCLUSION: Breast cancer was associated with a remarkably decreased risk of dementia. The findings strongly suggest an inverse relationship between cancer and neurodegeneration, regardless of the adverse effects of cancer treatment on cognitive function.

Advancing ecological validity and clinical utility in virtual reality-based continuous performance test: exploring the effects of task difficulty and environmental distractors.

Introduction: Researchers have highlighted concerns regarding the limited diagnostic utility and ecological validity of the Continuous Performance Test (CPT). Recent advancements in VR-based CPTs have attempted to address these concerns by simulating real-life scenarios and enhancing attention deficit hyperactivity disorder (ADHD) diagnosis; however, certain areas require improvement for obtaining reliable data from both healthy individuals and those with ADHD. To tackle these issues, we developed an enhanced VR-based CPT program featuring four distinct difficulty levels, advancing toward home-based assessment. Method: Our feasibility study involved subjects without ADHD to establish a normative profile for VR-based CPT before extending it to ADHD assessment. Our sample included 20 Korean adults. They received a VR device with the VR-based CPT program installed and were asked to perform 1-2 blocks per day at home. Participants were instructed to complete 12 blocks over the subsequent 2 weeks. Psychological assessments and electroencephalograms (EEGs) were administered before and after the program. Post-study usability measures were also collected. Result: Higher commission errors were notably evident in the "very high" difficulty level which featured complex stimuli and increased distraction. A notable correlation emerged between the overall distraction level and CPT accuracy, along with a significant link between intensity scores and commission errors. No significant differences were found in psychological assessment and there were no significant changes in the Theta-Beta Ratio (TBR) index before and after the program. The usability of our program was fair. Discussion: The study reveals that the newly designed VR-CPT program, simulating diverse real-life environments and offering varying task difficulty levels, proved acceptable and feasible. The key point of our study was that the adjustment and segmentation of difficulty levels in the VR-based CPT were achieved, and that this effort was validated by examining the impact of different levels of difficulty on CPT measures. Implementing this experimental setup in a home-based environment increased ecological validity, as well as clinical utility. Limitations and suggested directions for further investigation are described in detail.