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Background: Women are less likely to receive left ventricular assist devices and are more likely to experience poor outcomes. However, how gender impacts LVAD decision-making regarding LVAD implantation and the effects of that decision remains unknown., Methods: We performed a sub-group analysis from the stepped-wedge DECIDE-LVAD trial, which tested a decision-support intervention for patients considering LVAD therapy., Results: Excluding 9 patients who withdrew from assessments, of the 239 patients analyzed, 203 (85%) were men and 36 (15%) were women. More men received LVADs (70%) than women (61%) and more men were alive at 6 months compared to women, both among those who received LVADs (87% vs 82%) and those who did not (74% vs 50%) (p = 0.002). Compared to men, women were more likely to have decision regret, depressive symptoms and perceived stress at baseline but not at follow-up. At 6-month follow-up, men experience improvements in decisional conflict, acceptance of illness, struggle with illness, and perceived stress-none of those improvements were noted amongst women. Compared to men who received LVADs, women receiving LVADs had worse decision regret and depressive symptoms at baseline and worse acceptance of illness and perceived stress at six months. Men who received LVADs experienced improvement in decisional conflict and perceived stress, while women did not experience these improvements. Both men and women who received LVADs experienced improvement in depressive symptoms. Quality of life as assessed by EuroQol visual analog scale improved for both men and women who received LVADs but not for those who did not receive LVADs; no gender differences in quality of life were noted., Conclusion: Women require greater decisional support at time of decision to undergo LVAD implantation and subsequently might benefit from more intensive psychosocial support., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JMK: non-financial compensation from Pfizer Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Over the last few decades, there has been growing evidence of earlier onset and progression of puberty worldwide. This population-based longitudinal cohort study aimed to analyze the change in the annual incidence rate of central precocious puberty (CPP) among Korean children over the most recent decade, using the national registry data., Method: The International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) and insurance claims for gonadotropin-releasing hormone agonist (GnRHa) treatment were used to identify CPP patients who were using the Korean Health Insurance Review & Assessment Service (HIRA) database between 2008 and 2020. Patients who began GnRHa therapy before the age of 9 and 10 for girls and boys, respectively, were included in the study., Results: A total of 6,906 boys and 126,377 girls were diagnosed with CPP between 2008 and 2020. The annual incidence of CPP increased by 83.3 times in boys (from 1.2 to 100 per 100,000 persons) and by 15.9 times in girls (from 88.9 to 1414.7 per 100,000 persons). The age-specific annual incidence of CPP increased remarkably more in older children than in younger ones; the 2020 CPP incidence among 9-year-old boys and 8-year-old girls reached 705.2 and 7,967.3 per 100,000 persons, respectively. The annual prevalence of CPP in boys and girls increased from 2.7 to 206.5 (76.5 times) and from 141.8 to 3439.9 (24.3 times) per 100,000 persons, respectively., Conclusion: Based on GnRHa treatment insurance claims, our study suggests that the annual incidence of CPP has substantially increased in Korea during the past 13 years. These findings highlight the importance of meticulous judgment by doctors in determining GnRHa treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Previous studies have shown that, thread carpal tunnel release (TCTR), an ultrasound-guided transverse carpal ligament (TCL) transection procedure through needle and thread, to be a safe and effective technique for carpal tunnel release, compared to an open and endoscopic technique. We developed a newly improved thread (Smartwire-01, 0.27mm in diameter, Korea). This pilot study was performed to propose the effectiveness of TCTR with Smartwire-01 compared to the commercial thread in clinical settings., Methods: A total of 22 TCTR procedures have been performed on 19 patients by one physiatrist during a 42-month period. The diagnosis of carpal tunnel syndrome was based on standard clinical criteria including electromyography (EMG). Patients were divided into two groups, one dissected with commercial thread and the other with Smartwire-01. The technique was standardized by keeping the entry point at the middle of the palm and the exit point at just medial to the palmaris longus tendon. The Numeric Rating Scale and Boston Carpal Tunnel Syndrome Questionnaire (BCTQ) were used to assess monthly outcomes for 6 months following the procedure. The Wilcoxon signed rank test and the Mann-Whitney-U test were performed to analyze the above variables in the two groups., Results: There was no definite evidence that the two groups have significant differences for any of the surveyed variables. The TCTR procedure with our newly developed thread also had significant improvements for all variables, showing its effectiveness in both pain and functional ability. The NRS and BCTQ severity and functional scales showed significant decreases just after the dissection and progressive improvement during each monthly follow-up of our study until the last assessment at 6 months., Conclusion: The study suggests that, our newly developed thread is as safe and effective as the commercial thread in TCTR, we therefore recommend a randomize controlled trial with above methodology., Competing Interests: The authors have declared that no competing interests exist.

A novel stent retriever device for in vivo mechanical thrombectomy for acute cerebral infarction has been developed. In this study, we compared the thrombus removal capacity, potential complications, and extent of vessel wall damage of this novel device with those of the Solitaire FR device by performing a histopathologic analysis using an autopsied canine model. Through this experimental evaluation, we aimed to assess the safety and efficacy of the newly developed thrombus removal device for cerebral infarction. Blood clots (autologous thrombus) were injected into 12 canines. Mechanical thrombectomy was performed in six canines using the newly developed Tromba thrombectomy device (experimental group) and in the other six canines using the Solitaire FR thrombectomy device (control group). Angiographic and histopathologic evaluations were performed 1 month after the blood vessels underwent mechanical thrombectomy. In the experimental group, the reperfusion patency was classified as "no narrowing" in five cases and "moderate narrowing (25%-50% stenosis)" in one case. In the control group, the reperfusion patency was classified as "no narrowing" in four cases, "moderate narrowing (25%-50% stenosis)" in one case, and "slight narrowing (less than 25% stenosis)" in one case. In the experimental group, intimal proliferation was observed in only two cases, endothelial loss was observed in two cases, and device-induced medial injury was observed in one case. In the control group, intimal proliferation was observed in two cases, endothelial loss was observed in one case, and thrombosis (fibrin/platelet) was observed in one case. The Tromba thrombectomy device showed no significant difference to the conventional Solitaire device in angiographic and histopathologic evaluations after thrombus removal. The stability and efficiency of the newly developed Tromba device are considered to be high and comparable to those of Solitaire., Competing Interests: We have declared that no competing interests exist.

We investigated the effect of the coronavirus disease-2019 (COVID-19) pandemic on suicide trends in Korea via a time-series analysis. We used Facebook Prophet to generate forecasting models based on the monthly numbers of suicide deaths in Korea between 1997 and 2018, validated the models by comparison with the 2019 numbers, and predicted the numbers of suicides in 2020. We compared the expected and observed numbers of suicides during the COVID-19 pandemic. The total numbers of suicides during the COVID-19 pandemic did not deviate from projections based on the pre-pandemic period. However, the number of suicides among women and those under the age of 34 years significantly exceeded the expected level. The COVID-19 pandemic did not increase the overall suicide rate significantly. However, suicides among women and young people increased, suggesting that the pandemic might drive more members of these groups to suicide. Further studies are needed to verify the long-term impact of the COVID-19 pandemic on suicide., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Head rotation is thought to have an effect on obstructive sleep apnea (OSA) severity. However, keeping the head rotated fully during sleep is difficult to maintain, and the effect of head rotation is not the same in all OSA patients. Thus, this study aimed to identify whether less head rotation has an effect on airway patency and determine the responder characteristics to the head rotation maneuver (HRM)., Methods: We recruited 221 patients who underwent overnight polysomnography and drug-induced sleep endoscopy (DISE) in a tertiary hospital from June 2019 to July 2020. Airway patency and the site of airway collapse were determined in the supine position with the head at 0, 30, and 60 degrees of rotation (HRM0°, HRM30°, and HRM60°, respectively) during DISE. The site of collapse was determined using the VOTE classification system: the velum (palate), oropharyngeal lateral walls, tongue base, and epiglottis. Each structure was labeled as 0, 1, or 2 (patent, partially obstructed, and completely obstructed, respectively). Airway response to the HRM30° and 60° and the clinical characteristics associated with airway opening were analyzed., Results: The study population had a median age of 52 (25-61) years, a body mass index of 26.7(24.6-29.4) kg/m2, and the apnea-hypopnea index (AHI) of 28.2(13.7-71.9) events/h. HRM influenced airway patency positively not only with HRM60° (p<0.001) but also following limited rotation (HRM30°, p<0.001). Patients with tongue base (40.0% with HRM 60°) and epiglottic (52.6% with HRM 60°) collapse responded particularly well to HRM. Multivariate analysis revealed that lower AHI (p<0.001) and an absence of oropharyngeal lateral walls collapse (p = 0.011) were significant predictors of responders to HRM., Conclusion: Head rotation improved airway obstruction in OSA patients, even with a small degree of rotation, and should be further explored as a potential form of therapy in appropriately selected patients., Competing Interests: Andrew Wellman works as a consultant for Apnimed, Nox, Inspire, and Somnifix. He has received grants from Regeneron and Somnifix. He also has a financial interest in Apnimed Corp., a company developing pharmacologic therapies for sleep apnea. Dr. Wellman’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials. DPW is the Director of Medical Affairs for Apnimed and is a consultant for Cryosa, Cerebra Health, Philips Respironics, and LinguaFlex. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background and Purpose: Peritumoral brain edema (PTBE) is a common complication in meningioma and disruption of the tumor-brain barrier in meningioma is crucial for PTBE formation. To evaluate the association between meningioma size and PTBE, we measured meningioma volumes using the 3D slicer in patients with convexity and parasagittal meningiomas., Methods: Receiver operating characteristic curve analysis was used to determine the optimal cut-off meningioma volume values for predicting PTBE occurrence. Logistic regressions were used to estimate the odds ratios for PTBE occurrence in patients with convexity and parasagittal meningiomas according to several predictive factors., Results: A total of 205 convexity or parasagittal meningioma patients with no other brain disease who underwent one or more contrast-enhanced brain MRIs were enrolled in this 10-year analysis in two hospitals. The optimal cut-off meningioma volume value for prediction of PTBE in all study patients was 13.953 cc (sensitivity = 76.1%; specificity = 92.5%). If a meningioma is assumed to be a complete sphere, 13.953 cc is about 2.987 cm in diameter., Conclusions: Our study suggests a cut-off value of 3 cm meningioma diameter for prediction of PTBE in patients with convexity and parasagittal meningiomas. We believe that we have revealed why the meningioma diameter of 3 cm is clinically meaningful., Competing Interests: The authors have declared that no competing interests exist.

The dramatic changes in people's daily lives caused by the 2019 coronavirus (COVID-19) pandemic have had a huge impact on their emotions and behaviors. This study aimed to examine psychosocial responses to COVID-19 using network analysis. A total of 1,500 urban residents of South Korea, selected from an online public panel, were surveyed using self-rating questionnaires addressing daily life changes, fear of infection, and distress related to COVID-19. Participants also completed a 10-item Perceived Stress Scale survey. We constructed regularized partial correlation networks, estimated global and local network metrics, tested network accuracy and stability, and compared the estimated networks between men and women. The network of the psychosocial responses consisted of 24 nodes that were classified into five groups: 'fear of infection', 'difficulty with outside activities', 'economic loss', 'altered eating and sleeping', and 'adaptive stress'. The node centralities indicated that 'distress in obtaining daily necessities' and 'concern about harming others' were the most important issues in people's responses to COVID-19. These nodes were connected by a negative edge, reflecting individual- and community-level issues, respectively. The overall level of perceived stress was linked to the network by the connection node 'anger toward others or society', which was associated with economic problems in men, but with distress from changes in daily activities in women. The results suggest that two contrasting feelings-personal insecurity regarding basic needs and a collectivistic orientation-play roles in the response to unusual experiences and distress due to COVID-19. This study also showed that public anger could arise from the psychological stress under the conditions imposed by COVID-19., Competing Interests: The authors have declared that no competing interests exist.

Objective: To find preoperative screening criteria for dry eye syndrome (DES) that present after successful endoscopic dacryocystorhinostomy (EDCR)., Methods: We retrospectively analyzed medical records of 110 patients who underwent EDCR for nasolacrimal duct obstruction. DES diagnostic criteria were defined as tear break-up time (TBUT) less than 10 seconds, and ocular surface disease index (OSDI) score greater than 13 points. After EDCR, patients were divided into DES group and control group according to the DES diagnostic criteria. Preoperative OSDI score alone or in combination of preoperative TBUT and OSDI score were used to find screening criteria, which could discriminate the two groups preoperatively with a high positive predictive value (PPV). Criteria A was set same as the diagnostic criteria of DES, and Criteria B and C were set to improve PPV by increasing specificity while maintaining similar sensitivity to Criteria A., Results: Thirty patients (27.3%) were diagnosed with DES after EDCR, while 80 patients (72.7%) were normal. In patients with DES, preoperative TBUT was not different (p = 0.851), but OSDI score was significantly higher (p<0.001). Criteria A showed a sensitivity of 73.3%, specificity of 55.0%, and PPV of 38.0%. Criteria B and C excluded preoperative TBUT, which had no difference between the two groups, and set screening criteria with preoperative OSDI score alone. Criteria B (preoperative OSDI score of 19.6 points or more) showed a sensitivity of 75.0%, specificity of 60.6%, PPV of 41.7% and AUC of 0.739 (p < 0.001). Criteria C was consisted of 5 out of 12 OSDI items that showed significant differences between the two groups; blurred vision, reading, working with a computer, low humidity, and air conditioning. Criteria C (preoperative 5-item OSDI score of 24.4 points or more) was a better predictability, with a sensitivity of 75.0%, specificity of 71.3%, PPV of 49.5%, and AUC of 0.804 (p < 0.001). The AUC of Criteria C was significantly higher than that of Criteria B (p = 0.0037)., Conclusion: DES occurred after successful EDCR in 27.3% of patients, and an OSDI questionnaire helped to screen DES. The predictability could improve using the modified OSDI score which showed noticeable difference in five OSDI items before and after EDCR., Competing Interests: The authors have declared that no competing interests exist.

Diabetic retinopathy (DR) is a common complication of diabetes, and it is the consequence of microvascular retinal changes due to high glucose levels over a long time. Metabolomics profiling is a rapidly evolving method used to identify the metabolites in biological fluids and investigate disease progression. In this study, we used a targeted metabolomics approach to quantify the serum metabolites in type 2 diabetes (T2D) patients. Diabetes patients were divided into three groups based on the status of their complications: non-DR (NDR, n = 143), non-proliferative DR (NPDR, n = 123), and proliferative DR (PDR, n = 51) groups. Multiple logistic regression analysis and multiple testing corrections were performed to identify the significant differences in the metabolomics profiles of the different analysis groups. The concentrations of 62 metabolites of the NDR versus DR group, 53 metabolites of the NDR versus NPDR group, and 30 metabolites of the NDR versus PDR group were found to be significantly different. Finally, sixteen metabolites were selected as specific metabolites common to NPDR and PDR. Among them, three metabolites including total DMA, tryptophan, and kynurenine were potential makers of DR progression in T2D patients. Additionally, several metabolites such as carnitines, several amino acids, and phosphatidylcholines also showed a marker potential. The metabolite signatures identified in this study will provide insight into the mechanisms underlying DR development and progression in T2D patients in future studies., Competing Interests: The authors have declared that no competing interests exist.

We sought to investigate the association between consumption of coffee, tea, or soft drinks and risk of open-angle glaucoma (OAG) among Koreans using nationwide population-based data. This cross-sectional survey was performed through the Korea National Health and Nutrition Examination Survey 2010 to 2011. Participants older than 19 years were included in the sample for analysis after excluding those with any missing data. The diagnosis of OAG was based on the International Society of Geographical and Epidemiological Ophthalmology criteria, and participants without glaucomatous optic neuropathy served as controls. The frequency of beverage consumption during the past 12 months was obtained through a questionnaire. Multivariate logistic regression models were used to determine the relationship between consumption of each type of beverage and prevalence of OAG. A total of 6,681 participants was included in the analysis. The prevalence of OAG was 4.4% (n = 323), including 5.4% (n = 169) among men and 3.5% (n = 154) among women. After adjusting for multiple covariates, coffee consumption was significantly associated with OAG, while no significant association was found between consumption of tea or soft drinks and OAG. Participants who drank coffee had a higher risk of having OAG compared with those who did not drink coffee (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.22-4.72; p = 0.011). In sex-stratified analyses, the robust association of coffee consumption with OAG was observed in men (OR, 3.98; 95% CI, 1.71-9.25; p = 0.001) but not in women. Our results suggest that coffee consumption may affect the risk of OAG, particularly in men., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To investigate significant intraocular pressure (IOP) levels associated with the risk of open-angle glaucoma (OAG) in the treatment-naïve Korean population., Methods: Participants ≥20 years of age in Korea National Health and Nutrition Examination Survey 2010-2011 were divided into two groups, those with higher and lower IOP values, compared with the reference IOP value. We compared the risk of OAG in each group using regression analyses. The IOP value that yielded the highest statistical significance was determined as an IOP significantly associated with the OAG risk., Results: A total of 7,650 participants (7,292 control, 358 OAG) were included. The mean IOP was significantly higher in OAG group (14.4 ± 2.9 mmHg), compared to control group (13.9 ± 2.7 mmHg, P = 0.022). In association with an increased risk of OAG, the significant IOP value was 18 mmHg (Odds ratio [OR] = 1.79, 95% confidence interval [CI] 1.14-2.80, P = 0.011). Additionally, sex-difference was identified and they were 19 mmHg (OR = 2.79, 95% CI 1.27-6.16, P = 0.011) in men and 18 mmHg (OR = 2.65, 95% CI 1.32-5.33, P = 0.006) in women. The IOP values associated with significantly decreased risk of glaucoma were determined to be 14 mmHg in men (OR = 0.68, 95% CI 0.47-0.99, P = 0.042) and 16 mmHg in women (OR = 0.47, 95% CI 0.27-0.81, P = 0.007)., Conclusions: In consideration of the risk to benefit ratio, the reference IOP level for screening or setting the target IOP for treatment could be considered different from traditional 21 mmHg in Korean population., Competing Interests: The authors have declared that no competing interests exist.

We sought to evaluate the relationship between adult body height and risk of age-related macular degeneration (AMD) among healthy Koreans using nationwide population-based data. We analyzed data derived from the Korea National Health and Nutrition Examination Survey 2008-2011. Participants over 40 years of age were included in the sample after excluding individuals with systemic comorbidities or missing relevant data. The presence and severity of AMD were graded using fundus photographs. The relationship between body height and risk of AMD was determined using multiple logistic regression analyses. Among a total of 8,435 participants, 544 (6.45%) had AMD: 502 (5.95%) with early AMD and 42 (0.5%) with late AMD. In multivariate-adjusted analyses, taller body height was significantly associated with a lower prevalence of AMD (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.81-0.99), while body mass index (BMI) was not associated with AMD. An inverse association between body height and risk of AMD was observed most frequently in participants under 65 years of age (OR, 0.81; 95% CI, 0.70-0.94). Furthermore, body height showed an inverse association with risk of AMD among obese participants (BMI ≥25.0 kg/m2) (OR, 0.75; 95% CI, 0.60-0.93). Subgroup analysis by AMD type disclosed a significant inverse association between body height and early AMD (OR, 0.87; 95% CI, 0.79-0.97) but not late AMD. Our results suggest that shorter body height is independently associated with increased risk of AMD, especially early AMD, in a dose-response manner in people who are obese or under 65 years of age., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: Posttraumatic hydrocephalus affects 11.9%-36% of patients undergoing decompressive craniectomy (DC) after traumatic brain injury and necessitates a ventriculo-peritoneal shunt placement. As bone and arachnoid trabeculae share the same collagen type, we investigated possible connections between the skull Hounsfield unit (HU) values and shunt-dependent hydrocephalus (SDHC) in patients that received cranioplasty after DC for traumatic acute subdural hematoma (SDH)., Methods: We measured HU values in the frontal bone and internal occipital protuberance from admission brain CT. Receiver operating characteristic curve analysis was performed to identify the optimal cut-off skull HU values for predicting SDHC in patients receiving cranioplasty after DC due to traumatic acute SDH. We investigated independent predictive factors for SDHC occurrence using multivariable logistic regression analysis., Results: A total of 162 patients (>15 years of age) were enrolled in the study over an 11-year period from two university hospitals. Multivariable logistic analysis revealed that the group with simultaneous frontal skull HU ≤797.4 and internal occipital protuberance HU ≤586.5 (odds ratio, 8.57; 95% CI, 3.05 to 24.10; P<0.001) was the only independent predictive factor for SDHC in patients who received cranioplasty after DC for traumatic acute SDH., Conclusions: Our study reveals a potential relationship between possible low bone mineral density and development of SDHC in traumatic acute SDH patients who had undergone DC. Our findings provide deeper insight into the association between low bone mineral density and hydrocephalus after DC for traumatic acute SDH., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Though elevated ferritin level and decreased lung function both predispose people to cardio-metabolic disease, few reports have investigated the association between them. Furthermore, it remains unclear whether the association reflects a change in iron stores or an epiphenomenon reflecting metabolic stress. Therefore, we looked for possible associations between ferritin, iron, and transferrin saturation (TSAT) and lung function to clarify the role of iron-related parameters in healthy men., Methods: We conducted a cohort study of 42,927 healthy Korean men (mean age: 38.6 years). Percent predicted forced expiratory volume in one second (FEV1%) and forced vital capacity (FVC%) were categorized into quartiles. Adjusted odds ratios (aORs) and 95% confidence intervals (using the highest quartile as reference) were calculated for hyperferritinemia, high iron, and high TSAT after controlling for potential confounders., Results: The median ferritin level was 199.8 (141.5-275.6) ng/mL. The prevalence of hyperferritinemia (defined as >300 ng/mL) was 19.3%. Subjects with hyperferritinemia had lower FEV1% and FVC% than those with normal ferritin level with a slight difference, but those were statistically significant (99.22% vs.99.61% for FEV1%, p = 0.015 and 98.43% vs. 98.87% for FVC, p = 0.001). However, FEV1/FVC ratio was not significantly different between groups (P = 0.797). Compared with the highest quartile, the aORs for hyperferritinemia across decreasing quartiles were 1.081 (1.005-1.163), 1.100 (1.007-1.200), and 1.140 (1.053-1.233) for FEV1% (p for trend = 0.007) and 1.094 (1.018-1.176), 1.101 (1.021-1.188), and 1.150 (1.056-1.252) for FVC% (p for trend = 0.001). However, neither FEV1% nor FVC% was associated with iron or TSAT., Conclusions: Hyperferritinemia was associated with decreased lung function in healthy Korean men, but iron and TSAT were not. Longitudinal follow-up studies are required to validate our findings., Competing Interests: NO authors have competing interests.

Background and Purpose: Disruption of the tumor-brain barrier in meningioma plays a critical role in the development of peritumoral brain edema (PTBE). We hypothesized that osteoporotic conditions may be associated with PTBE occurrence after radiation in patients with intracranial meningioma., Methods: We measured Hounsfield units (HU) of the frontal skull on simulation brain CT in patients who underwent linear accelerator (LINAC)-based radiation treatment for intracranial meningioma. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off values for several predictive factors. The cumulative hazard for PTBE was estimated and classified according to these factors. Hazard ratios were then estimated to identify independent predictive factors associated with the development of PTBE after radiation in intracranial meningioma patients., Results: A total of 83 intracranial meningiomas in 76 patients who received LINAC-based radiation treatment in our hospital over an approximate 5-year period were included for the study. We found mean frontal skull HU ≤630.625 and gross tumor volume >7.194 cc to be independent predictors of PTBE after radiation treatment in patients with meningioma (hazard ratio, 8.41; P = 0.019; hazard ratio, 5.92; P = 0.032, respectively). In addition, patients who were ≥65 years showed a marginally significant association with PTBE., Conclusions: Our study suggests that possible osteoporotic conditions, large tumor volume, and older age may be associated with PTBE occurrence after LINAC-based radiation treatment for intracranial meningioma. In the future we anticipate that these findings may enhance the understanding of the underlying mechanisms of PTBE after radiation in meningioma patients., Competing Interests: The authors have declared that no competing interests exist.

Background: The prognostic role of BDNF val66met polymorphism on long-term cardiac outcomes in acute coronary syndrome (ACS) has been unclear. Environmental factors may modify the association, but these have not been investigated to date. This study aimed to investigate the potential interactive effects of BDNF val66met polymorphism and personality traits, one of the main environmental prognostic factors of ACS, on major adverse cardiac events (MACEs) in patients with ACS., Methods: A total of 611 patients with recent ACS were recruited at a university hospital in Korea. Baseline evaluations from 2007 to 2012 assessed BDNF val66met polymorphism and personality using the Big Five Inventory, which yielded two personality clusters (resilient and vulnerable) and five dimensions (extraversion, agreeableness, conscientiousness, neuroticism, and openness). Over a 5~12 year follow-up after the index ACS, times to MACE were investigated using Cox regression models after adjustment for a range of covariates., Results: The BDNF val66met polymorphism modified the associations between vulnerable personality type and worse long-term cardiac outcomes in ACS patients with significant interaction terms, in that the associations were statistically significant in the presence met allele. Similar findings were observed for the individual personality dimensions of agreeableness and neuroticism., Conclusions: Gene (BDNF val66met polymorphism) x environment (personality traits) interactions on long-term cardiac outcomes were found in ACS., Competing Interests: Prof R Stewart reports research funding from Janssen and Roche, and co-supervision of a PhD with GSK. The other authors have no conflict to report related to this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Glycated hemoglobin (HbA1c) is an indicator of the average blood glucose concentration. Failing to control HbA1c levels can accelerate the development of complications in patients with diabetes. Although metabolite profiles associated with HbA1c level in diabetes patients have been characterized using different platforms, more studies using high-throughput technology will be helpful to identify additional metabolites related to diabetes. Type 2 diabetes (T2D) patients were divided into two groups based on the HbA1c level: normal (HbA1c ≤6%) and high (HbA1c ≥9%) in both discovery and replication sets. A targeted metabolomics approach was used to quantify serum metabolites and multivariate logistic regression was used to identify significant differences between groups. The concentrations of 22 metabolites differed significantly between the two groups in the discovery set. In the replication set, the levels of 21 metabolites, including 16 metabolites identified in the discovery set, differed between groups. Among these, concentrations of eleven amino acids and one phosphatidylcholine (PC), lysoPC a C16:1, were higher and four metabolites, including three PCs (PC ae C36:1, PC aa C26:0, PC aa C34:2) and hexose, were lower in the group with normal HbA1c group than in the group with high HbA1c. Metabolites with high concentrations in the normal HbA1c group, such as glycine, valine, and PCs, may contribute to reducing HbA1c levels in patients with T2D. The metabolite signatures identified in this study provide insight into the mechanisms underlying changes in HbA1c levels in T2D., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Osteoporotic vertebral compression fractures (OVCFs) have a serious impact on people's health and quality of life. The purpose of this study was to analyze brain volume in patients with osteoporosis using brain magnetic resonance imaging (MRI) and to investigate the relationship with osteoporotic vertebral compression fractures., Materials and Methods: We included 246 patients with osteoporosis who underwent thoracolumbar radiographs and brain MRI at our hospital. Clinical data on age, sex, bone mineral density, height, weight, osteoporosis medication, hypertension, diabetes, alcohol drinking, and smoking were collected. Intracranial cavity, brain parenchyma, and lateral ventricles volumes were measured using brain MRI with a semiautomated tool., Results: We founded an independent correlation between age and volume percentages of the brain parenchyma and lateral ventricles. We observed a statistically significant decrease in volume percentage of the brain parenchyma and an increase in volume percentage of the lateral ventricles with increasing age. In addition, we confirmed that patients with OVCF showed a significantly lower volume percentage of brain parenchyma than patients without OVCF., Conclusion: We observed a significant association between OVCF and volume percentage of brain parenchyma. Degeneration of the brain may lead to a high incidence of falls, and OVCF may occur more frequently in patients with osteoporosis., Competing Interests: The authors have declared that no competing interests exist.

The criterion for the remission period of chronic cluster headache (CCH) was recently revised from < 1 month to < 3 months in the third edition of the International Classification of Headache Disorders (ICHD-3). However, information on the clinical features of CCH based on the ICHD-3 criteria is currently limited. The present study aimed to investigate the clinical features of CCH based on ICHD-3 using data from the Korean Cluster Headache Registry (KCHR). The KCHR is a multicentre prospective registry of patients with cluster headache (CH) from 15 hospitals. Among the 250 participants with CH, 12 and 176 participants were classified as having CCH and episodic cluster headache (ECH), respectively. Among 12 participants with CCH, 6 (50%) had remission periods of < 1 month, and the remaining 6 (50%) had a remission period of 1-3 months. Six participants had CCH from the time of onset of CH, and in the other 6 participants, CCH evolved from ECH. CCH subjects had later age of onset of CH, developed the condition after a longer interval after CH onset, and had more migraine and less nasal congestion and/or rhinorrhoea than ECH subjects. Clinical features of CCH with remission periods < 1 month were not significantly different from those of CCH with remission periods of 1-3 months, except for the total number of bouts. More current smoking and less diurnal rhythmicity were observed in participants with CCH evolved from ECH compared to those with ECH. In conclusion, the number of subjects with CCH doubled when the revised ICHD-3 criteria were used. Most of clinical characteristics of CCH did not differ when the previous and current version of ICHD was applied and compared. Some clinical features of CCH were different from those of ECH, and smoking may have a role in CH chronification., Competing Interests: SJ Cho was involved as a site investigator of a multicentre trial sponsored by Otsuka Korea, Eli Lilly and Company, and Novartis, worked as an advisory member for Teva, and received research support from Hallym University Research Fund 2016 and a grant from the Korean Neurological Association (KNA-16-MI-09). MK Chu was a site investigator for a multi-centre trial sponsored by Otsuka Korea, Novartis International AG, and Eli Lilly and Company. He worked as an advisory member for Teva, and received lecture honoraria from Allergan Korea, Handok-Teva, and Yuyu Pharmaceutical Company in the past 24 months. The other authors, except for SJ Cho and MK Chu, declare no potential conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background and Purpose: Low body mass index (BMI) at presentation has been reported to be associated with higher incidence and mortality of lung cancer, but studies on the relationship between brain metastasis and BMI at presentation are lacking. This study aimed to evaluate the association between brain metastasis and BMI and bone mineral density (BMD) in NSCLC., Methods: We retrospectively enrolled patients with non-small cell lung cancer who underwent brain magnetic resonance imaging with contrast within 3 months of diagnosis. The BMI was collected, and the BMD was measured in Hounsfield unit (HU) on initial staging computed tomography scans. The independent relationship between BMI and BMD was assessed using multivariable linear regression according to the presence of brain metastasis., Results: A total of 356 consecutive NSCLC patients were enrolled in the study over a 8-year period in a single institution. Lower BMI with higher BMD was an independent predictive factor for brain metastasis in patients with NSCLC, relative to the other group (HR, 2.03; 95% CI, 1.21 to 3.40; P = 0.007). We also found a significant negative correlation between BMI and BMD among patients with NSCLC with brain metastases (B, -3.343; 95% confidence interval, -6.352 to -0.333; P = 0.030)., Conclusions: Brain metastasis may possibly be associated with lower BMI and higher BMD in NSCLC patients. We expect that these results may facilitate future predictions of brain metastases during the clinical course of NSCLC and enhance our understanding of the underlying mechanisms that link brain metastases and lung cancer., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the correlation between dyspeptic symptoms and gastric motility parameters measured by magnetic resonance imaging (MRI) using volumetry and motility indices in patients with Parkinson's disease (PD)., Materials and Methods: In this IRB-approved study, MRI datasets obtained from August 2014 to May 2016 in 38 PD patients were retrospectively analyzed. Patients underwent a 120-minute-long MRI study using a liquid test meal and 8 sets of scans. Gastric content volume (GCV) and total volume (TGV), gastric half emptying time (T1/2), motility index (GMI), accommodation (GA), and emptying (GE) values were acquired. These measurements were compared between patients according to the presence of gastric symptoms: early satiety (n = 25), epigastric pain (n = 13), and dyspepsia (n = 28)., Results: Patients with early satiety showed significantly decreased GE of GCV and TGV (p < 0.001 and p = 0.017). Dyspeptic patients had significantly decreased GE of GCV and GMI (p = 0.001 and p = 0.029). GE of GCV at 90 and 120 minutes were significantly lower in patients with early satiety (p = 0.001 and p = 0.002). GE of GCV and GMI at 90 minutes were significantly decreased in patients with dyspepsia (p = 0.004 and p = 0.002). T1/2 of GCV was prolonged in patients with early satiety, epigastric pain, and dyspepsia (p = 0.004, p = 0.041, and p = 0.023). T1/2 of TGV also delayed in patients with early satiety (p = 0.023). GMI at 90 minutes was significantly correlated with dyspepsia on multivariable analysis (p = 0.028)., Conclusions: Gastric motility can be quantitatively assessed by MRI, showing decreased GMI, delayed GE, and prolonged T1/2 in PD patients with early satiety or dyspepsia., Competing Interests: The authors have declared that no competing interests exist.

Air pollution is well-known as a major risk to public health, causing various diseases including pulmonary and cardiovascular diseases. As social concern increases, the amount of air pollution data is increasing rapidly. The purpose of this study is to statistically characterize dependence between major cities in China based on a measure of directional dependence estimated from PM2.5 measurements. As a measure of the directional dependence, we propose the so-called copula directional dependence (CDD) using beta regression models. An advantage of the CDD is that it does not rely on strict assumptions of specific probability distributions or linearity. We used hourly PM2.5 measurement data collected at four major cities in China: Beijing, Chengdu, Guangzhou, and Shanghai, from 2013 to 2017. After accounting for autocorrelation in the PM2.5 time series via nonlinear autoregressive models, CDDs between the four cities were estimated to produce directed network structures of statistical dependence. In addition, a statistical method was proposed to test the directionality of dependence between each pair of cities. From the PM2.5 data, we could discover that Chengdu and Guangzhou are the most closely related cities and that the directionality between them has changed once during 2013 to 2017, which implies a major economic or environmental change in these Chinese regions., Competing Interests: The authors have declared that no competing interests exist.

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease. NAFLD begins with excessive lipid accumulation in the liver and progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is closely linked to dysregulated hepatic lipid metabolism. Although recent studies have reported that epidermal growth factor receptor (EGFR) signaling regulates lipid metabolism, the roles of EGFR and EGFR inhibitors as modulators of lipid metabolism are largely unknown. Here, we investigated whether inhibiting EGFR using the EGFR tyrosine kinase inhibitor (TKI) PD153035 improves NAFLD. Our results demonstrate that EGFR was activated in liver tissues from high fat diet (HFD)-induced NAFLD mice. Inhibiting EGFR using PD153035 significantly reduced phosphatidylinositol-3-kinase/protein kinase B signaling and sterol responsive elementary binding protein 1 and 2 expression, which prevented HFD-induced hepatic steatosis and hypercholesterolemia by reducing de novo lipogenesis and cholesterol synthesis and enhancing fatty acid oxidation. Additionally, inhibiting EGFR improved HFD-induced glucose intolerance. In conclusion, these results indicate that EGFR plays an important role in NAFLD and is a potential therapeutic target., Competing Interests: The authors have declared that no competing interests exist.

Background: Given the complexity of managing hepatocellular carcinoma (HCC), a multidisciplinary approach (MDT) is recommended to optimize management of HCC patients. However, evidence suggesting that MDT improves patient outcome is limited., Methods: We performed a retrospective cohort study of all patients newly-diagnosed with HCC between 2005 and 2013 (n = 6,619). The overall survival (OS) rates between the patients who were and were not managed via MDT were compared in the entire cohort (n = 6,619), and in the exactly matched cohort (n = 1,396)., Results: In the entire cohort, the 5-year survival rate was significantly higher in the patients who were managed via MDT compared to that of the patients who were not (71.2% vs. 49.4%, P < 0.001), with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval [CI]; 0.41-0.53). In the exactly matched cohort, the 5-year survival rate was higher in patients who were managed via MDT (71.4% vs. 58.7%, P < 0.001; HR [95% CI] = 0.67 [0.56-0.80]). The survival benefit of MDT management was observed in most pre-defined subgroups, and was especially significant in patients with poor liver function (ALBI grade 2 or 3), intermediate or advanced tumor stage (BCLC stage B or C), or high alphafetoprotein levels (≥200 ng/ml)., Conclusion: MDT management was associated with improved overall survival in HCC patients, indicating that MDT management can be a valuable option to improve outcome of HCC patients. This warrants prospective evaluations., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: Osteoporosis is one of the most common chronic metabolic diseases, but detection and treatment rates are low. The aim of the current study was to evaluate the correlation between frontal skull Hounsfield unit (HU) values from brain computed tomography (CT) scans and T-scores of the lumbar spine and femoral neck from dual-energy X-ray absorptiometry (DXA) scans., Methods: Patients with < 1 year between brain CT and DXA scans were included in the study. The average frontal skull HU value used for analysis was defined as the average of four HU values of the frontal bone. A receiver operating characteristic curve was generated, and area under the curve (AUC) was used to determine the HU values of the frontal skull for predicting osteoporosis. The frontal skull HU value with the highest sensitivity and specificity was considered the optimal cutoff value., Results: In total, 899 patients who underwent both brain CT and DXA scans at a single institution were enrolled. Average skull HU values differed significantly among patients in different bone mineral density categories (p < 0.001). There was a positive correlation between skull HU value and T-score (β = 105.06, p < 0.001, R2 = 0.343). The mean HU value in subjects with osteoporosis was 515, and the optimal cutoff value for the prediction of osteoporosis was 610 HU (AUC = 0.775, 95% CI 0.744-0.806, p < 0.001)., Conclusions: Clinical brain CT scans can assist in the detection of osteoporosis, and patients with an HU value < 610 as determined via brain CT may be considered for further evaluation for possible osteoporosis.

Importance: This review provides a comprehensive comparison of treatment outcomes between robot-assisted laparoscopic surgery (RLS) and conventional laparoscopic surgery (CLS) based on randomly-controlled trials (RCTs)., Objectives: We employed RCTs to provide a systematic review that will enable the relevant community to weigh the effectiveness and efficacy of surgical robotics in controversial fields on surgical procedures both overall and on each individual surgical procedure., Evidence Review: A search was conducted for RCTs in PubMed, EMBASE, and Cochrane databases from 1981 to 2016. Among a total of 1,517 articles, 27 clinical reports with a mean sample size of 65 patients per report (32.7 patients who underwent RLS and 32.5 who underwent CLS), met the inclusion criteria., Findings: CLS shows significant advantages in total operative time, net operative time, total complication rate, and operative cost (p < 0.05 in all cases), whereas the estimated blood loss was less in RLS (p < 0.05). As subgroup analyses, conversion rate on colectomy and length of hospital stay on hysterectomy statistically favors RLS (p < 0.05)., Conclusions: Despite higher operative cost, RLS does not result in statistically better treatment outcomes, with the exception of lower estimated blood loss. Operative time and total complication rate are significantly more favorable with CLS.

The prevalence of cytotoxic tumor infiltrating lymphocytes (TILs) has demonstrated prognostic value in multiple tumor types. In particular, CD8 counts (in combination with CD3 and CD45RO) have been shown to be superior to traditional UICC staging in colon cancer patients and higher total CD8 counts have been associated with better survival in breast cancer patients. However, immune infiltrate heterogeneity can lead to potentially significant misrepresentations of marker prevalence in routine histologic sections. We examined step sections of breast and colorectal cancer samples for CD8+ T cell prevalence by standard chromogenic immunohistochemistry to determine marker variability and inform practice of T cell biomarker assessment in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Stained sections were digitally imaged and CD8+ lymphocytes within defined regions of interest (ROI) including the tumor and surrounding stroma were enumerated. Statistical analyses of CD8+ cell count variability using a linear model/ANOVA framework between patients as well as between levels within a patient sample were performed. Our results show that CD8+ T-cell distribution is highly homogeneous within a standard tissue sample in both colorectal and breast carcinomas. As such, cytotoxic T cell prevalence by immunohistochemistry on a single level or even from a subsample of biopsy fragments taken from that level can be considered representative of cytotoxic T cell infiltration for the entire tumor section within the block. These findings support the technical validity of biomarker strategies relying on CD8 immunohistochemistry.

Background and Purpose: Hydrocephalus is a frequent complication following subarachnoid hemorrhage. Few studies investigated the association between laboratory parameters and shunt-dependent hydrocephalus. This study aimed to investigate the variations of laboratory parameters after subarachnoid hemorrhage. We also attempted to identify predictive laboratory parameters for shunt-dependent hydrocephalus., Methods: Multiple imputation was performed to fill the missing laboratory data using Bayesian methods in SPSS. We used univariate and multivariate Cox regression analyses to calculate hazard ratios for shunt-dependent hydrocephalus based on clinical and laboratory factors. The area under the receiver operating characteristic curve was used to determine the laboratory risk values predicting shunt-dependent hydrocephalus., Results: We included 181 participants with a mean age of 54.4 years. Higher sodium (hazard ratio, 1.53; 95% confidence interval, 1.13-2.07; p = 0.005), lower potassium, and higher glucose levels were associated with higher shunt-dependent hydrocephalus. The receiver operating characteristic curve analysis showed that the areas under the curve of sodium, potassium, and glucose were 0.649 (cutoff value, 142.75 mEq/L), 0.609 (cutoff value, 3.04 mmol/L), and 0.664 (cutoff value, 140.51 mg/dL), respectively., Conclusions: Despite the exploratory nature of this study, we found that higher sodium, lower potassium, and higher glucose levels were predictive values for shunt-dependent hydrocephalus from postoperative day (POD) 1 to POD 12-16 after subarachnoid hemorrhage. Strict correction of electrolyte imbalance seems necessary to reduce shunt-dependent hydrocephalus. Further large studies are warranted to confirm our findings.

Background and Purpose: Although the effect of weather and air pollution on the occurrence of subarachnoid hemorrhage (SAH) has been investigated, results have remained inconsistent. The present study aimed to determine the seasonality of aneurysmal subarachnoid hemorrhage occurrence and mortality., Methods: We used the National Inpatient Sample database to evaluate the effect of meteorological factors and air pollutants on patients with subarachnoid hemorrhage in Korea between 2011 and 2014. Monthly variations in SAH occurrence and mortality were analyzed using locally weighted scatter plot smoothing curves. Multivariate Poisson generalized linear regression models were used to evaluate potential independent meteorological and pollutant variables associated with SAH occurrence and mortality., Results: In total, 21,407 patients who underwent clip or coil treatment owing to aneurysmal SAH in Korea from January 1, 2011, to December 31, 2014, were included. The crude incidence rate of SAH in Korea was 10.5 per 100,000 people per year. An approximately 0.5% lower risk of SAH was observed per 1°C increase in mean monthly temperature (relative risk, 0.995; 95% confidence interval [CI], 0.992-0.997; p < 0.001), while an approximately 2.3% higher risk of SAH was observed per 1°C increase in mean monthly diurnal temperature., Conclusions: We showed distinct patterns of seasonal and monthly variation in the occurrence and mortality of SAH. Our findings suggest that meteorological factors may play an important role in monthly variations in the occurrence of aneurysmal SAH.

Cerebral white matter hyperintensities (WMHs) are central MRI markers of the brain aging process, but the mechanisms for its progression remain unclear. In this study, we aimed to determine whether the baseline serum cystatin C level represented one mechanism underlying WMH progression, and whether it was associated with the long-term progression of cerebral WMH volume in MRI. 166 consecutive individuals who were ≥50 years of age and who underwent initial/follow-up MRI evaluations within an interval of 34-45 months were included. Serum cystatin C level, glomerular-filtration rate (GFR), and other laboratory parameters were measured at their initial evaluation and at the end of follow-up. Cerebrovascular risk factors, medications, and blood-pressure parameters were also reviewed. WMH progression rate was measured by subtracting WMH volume at baseline from that at the follow-up using volumetric analysis, divided by the MRI intervals. At baseline, WMH volume was 9.61±13.17 mL, mean GFR was 77.3±22.8 mL/min, and mean cystatin C level was 0.92±0.52 mg/L. After 37.9±3.4 months, the change in WMH volume was 3.64±6.85 mL, the progression rate of WMH volume was 1.18±2.28 mL/year, the mean ΔGFR was 2.4±7.9 mL/min, and the mean Δcystatin C was 0.03±0.34 mg/L. The progression rate of WMH volume was linearly associated with cystatin C level (B coefficient = 0.856; 95% confidence interval [CI] 0.174-1.538; P = 0.014), along with the baseline WMH volume (B = 0.039; 95% CI 0.019-0.059; P<0.001), after adjusting for the conventional vascular risk factors, laboratory parameters, medication profiles, and GFR. Especially, patients with a baseline level of cystatin C ≥1.00 mg/L exhibited a much higher progression rate of WMH as compared with those with a baseline level of cystatin C <1.00 mg/L (1.60±1.91 mL/year vs. 0.82±1.63 mL/year, P = 0.010). We concluded that serum cystatin C level is independently associated with the long-term progression rate of the cerebral WMH volume. Therefore, serum cystatin C level might predict the progression of cerebral WMH.

Glycemic variability (GV) is reportedly a predictor for poor outcome in various clinical conditions. We aimed to assess whether GV during hospital admission is associated with poor outcomes in patients with acute ischemic stroke (AIS) and diabetes. We prospectively enrolled consecutive patients with AIS from the registry of 6 tertiary hospitals between January 2013 and December 2014. For the GV index, we used a glucose level range that was divided into 4 quartiles. Multivariable binary and ordinal logistic regression analyses were performed to determine the association between GV and the modified Rankin Scale score (3-6) at 3 months. We enrolled 1,504 patients with AIS and diabetes (mean age, 68.1 years; male, 57.2%), of which 35.1% had poor outcomes at 3 months. An increasing glucose range quartile was positively associated with initial neurologic severity and development of hypoglycemia during hospital admission. Multivariable analysis showed that the glucose level range quartile was associated with poor outcomes, even after adjusting for the number of glucose measurement and hypoglycemia (odds ratio [OR] Q2 vs. Q1: 1.50, 95% confidence interval [CI]: 1.02-2.18; OR Q3 vs. Q1: 2.01, 95% CI: 1.34-3.01; OR Q4 vs. Q1: 1.98, 95% CI: 1.22-3.23). These associations remained significant after dichotomization according to glycated hemoglobin levels at admission. An increasing glucose level range as a GV index during hospital admission was associated with poor functional outcomes at 3 months in patients with AIS and diabetes.

Background: This study aimed to evaluate the psychometric properties of the Korean version of the Clinically Useful Anxiety Outcome Scale (CUXOS) and to examine the current diagnostic comorbidity and differential severity of anxiety symptoms between major depressive disorder (MDD) and anxiety disorders., Methodology: In total, 838 psychiatric outpatients were analyzed at their intake appointment. Diagnostic characteristics were examined using the structured clinical interview from the DSM-IV because the DSM5 was not available at the start of the study. The CUXOS score was measured and compared with that of 3 clinician rating scales and 4 self-report scales., Principal Findings: The CUXOS showed excellent results for internal consistency (Cronbach's α = 0.90), test-retest reliability (r = 0.74), and discriminant and convergent validity. The CUXOS significantly discriminated between different levels of anxiety severity, and the measure was sensitive to change after treatment. Approximately 45% of patients with MDD were additionally diagnosed with anxiety disorders while 55% of patients with anxiety disorders additionally reported an MDD. There was a significant difference in CUXOS scores between diagnostic categories (MDD only, anxiety only, both disorders, and no MDD or anxiety disorder). The CUXOS scores differed significantly between all categories of depression (major, minor, and non-depression) except for the comparison between minor depression and non-depression groups., Conclusions: The Korean version of the CUXOS is a reliable and valid measure of the severity of anxiety symptoms. The use of the CUXOS could broaden the understanding of coexisting and differentiating characteristics of anxiety and depression.

Aims: To evaluate the relationships between open-angle glaucoma (OAG) and various anthropometric measurements., Design: Korea National Health and Nutrition Examination Survey (KNHANES), a population-based cross-sectional study using a complex, stratified, multistage, probability-cluster survey., Methods: A total of 5,255 participants including 247 glaucoma patients, aged ≥ 19 years were included from the KNHANES V database. Glaucoma diagnosis was based on International Society of Geographical and Epidemiological Ophthalmology criteria. Various anthropometric data regarding obesity were analyzed including body mass index (BMI), total body fat mass, total body muscle mass (lean body mass, non-bone lean body mass, and appendicular skeletal muscle (ASM) mass), and waist circumference (WC). The differences in OAG prevalence with respect to anthropometric parameter quartiles were examined., Results: In males, the multivariate general linear model adjusted for age, alcohol, smoking, exercise, systemic hypertension, diabetes, and intraocular pressure (IOP) showed the quartiles for the anthropometric parameters BMI, fat mass/weight ratio and fat mass/muscle mass ratio were negatively associated with OAG. However, muscle mass parameter/BMI ratio was significantly positively associated with OAG (P for trend<0.05). In females, height and fat mass/BMI showed a significant relationship with the risk of OAG. (P value<0.05)., Conclusions: In the present study, high fat mass was associated with low OAG risk. Body composition seemed to affect the prevalence of OAG, but further evaluation is needed.

Purpose: To explore the pathogenesis of peripheral reticular pigmentary degeneration (PRPD) and its clinical significance., Methods: This cross-sectional, observational study (conducted between January 2010 and May 2015) enrolled 441 eyes of 229 subjects, including 35 eyes with PRPD and 406 eyes without PRPD, which was identified by ultra-wide-field fluorescein angiography (UWFA). The distribution and angiographic circulation time of PRPD were assessed by UWFA. The frequencies of systemic and ophthalmologic comorbidities were compared between groups. Univariate and multivariate generalized estimation equation methods were used to determine the risk factors for PRPD., Results: The patients with PRPD had a mean age of 75.7 ± 8.5 years (range, 59-93 years), whereas the patients without PRPD had a mean age of 60.1 ± 14.9 years (range, 9-92 years). All eyes with PRPD manifested the lesion in the superior nasal periphery with or without circumferential extension. Among those, only 16 eyes (45.7%) in the PRPD group showed distinctive features in the same location on fundus photographs. There was significant choroidal filling delay in the PRPD group when compared with the control group (1.42±1.22 vs. -0.02±1.05 seconds, P < 0.001). Multivariate regression analysis revealed that older age (P < 0.001), stroke (P = 0.018), ischemic optic neuropathy (P < 0.001), and age-related macular degeneration (P = 0.022) were significantly associated with PRPD., Conclusions: UWFA may enhance the diagnostic sensitivity of PRPD. Choroidal vascular insufficiency with compromised systemic circulation in the elderly was related to the manifestation of PRPD. These results help to better understand the pathophysiology of PRPD. Co-existence of systemic and ophthalmic circulatory disorders should be considered in patients with PRPD., Competing Interests: The authors have declared that no competing interests exist

Background: To investigate the association between heavy metal levels and open-angle glaucoma (OAG) with low- and high-teen baseline intraocular pressure (IOP) using a population-based study design., Methods: This cross-sectional study included 5,198 participants older than 19 years of age who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) from 2008 to 2012 and had blood heavy metal levels available. The OAG with normal baseline IOP (IOP ≤ 21 mmHg) subjects were stratified into low-teen OAG (baseline IOP ≤ 15 mmHg) and high-teen OAG (15 mmHg < baseline IOP ≤ 21 mmHg), and the association between blood lead, mercury, and cadmium levels and glaucoma prevalence was assessed for low- and high-teen OAG., Results: The adjusted geometric mean of blood cadmium levels was significantly higher in subjects with low-teen OAG than that of the non-glaucomatous group (P = 0.028), whereas there were no significant differences in blood lead and mercury levels. After adjusting for potential confounders, the low-teen OAG was positively associated with log-transformed blood cadmium levels (OR, 1.41; 95% confidence interval (CI), 1.03-1.93; P = 0.026). For high-teen OAG, log-transformed blood levels of the three heavy metals were not associated with disease prevalence. The association between log-transformed blood cadmium levels and low-teen OAG was significant only in men (OR, 1.65; 95% CI, 1.10-2.48; P = 0.016), and not in women (OR, 1.10; 95% CI, 0.66-1.85; P = 0.709)., Conclusions: The results of this study suggest that cadmium toxicity could play a role in glaucoma pathogenesis, particularly in men and in OAG with low-teen baseline IOP., Competing Interests: The authors have declared that no competing interests exist.

Despite the clinical impact of non-motor symptoms (NMS) in Parkinson's disease (PD), the characteristic NMS in relation to the motor subtypes of PD is not well elucidated. In this study, we enrolled drug-naïve PD patients and compared NMS between PD subtypes. We enrolled 136 drug-naïve, early PD patients and 50 normal controls. All the enrolled PD patients were divided into tremor dominant (TD) and non-tremor dominant (NTD) subtypes. The Non-Motor Symptom Scale and scales for each NMS were completed. We compared NMS and the relationship of NMS with quality of life between normal controls and PD patients, and between the PD subtypes. Comparing with normal controls, PD patients complained of more NMS, especially mood/cognitive symptoms, gastrointestinal symptoms, unexplained pain, weight change, and change in taste or smell. Between the PD subtypes, the NTD subtype showed higher total NMS scale score and sub-score about weight change. Weight change was the characteristic NMS related to NTD subtype even after controlled other variables with logistic regression analysis. Even from the early stage, PD patients suffer from various NMS regardless of dopaminergic medication. Among the various NMS, weight change is the characteristic NMS associated with NTD subtype in PD patients., Competing Interests: The authors have declared that no competing interests exist.

The single nucleotide polymorphism rs9939609 of the gene FTO, which encodes fat mass and obesity-associated protein, is strongly associated with obesity and type 2 diabetes (T2D) in multiple populations; however, the underlying mechanism of this association is unclear. The present study aimed to investigate FTO genotype-dependent metabolic changes in obesity and T2D. To elucidate metabolic dysregulation associated with disease risk genotype, genomic and metabolomic datasets were recruited from 2,577 participants of the Korean Association REsource (KARE) cohort, including 40 homozygous carriers of the FTO risk allele (AA), 570 heterozygous carriers (AT), and 1,967 participants carrying no risk allele (TT). A total of 134 serum metabolites were quantified using a targeted metabolomics approach. Through comparison of various statistical methods, seven metabolites were identified that are significantly altered in obesity and T2D based on the FTO risk allele (adjusted p < 0.05). These identified metabolites are relevant to phosphatidylcholine metabolic pathway, and previously reported to be metabolic markers of obesity and T2D. In conclusion, using metabolomics with the information from genome-wide association studies revealed significantly altered metabolites depending on the FTO genotype in complex disorders. This study may contribute to a better understanding of the biological mechanisms linking obesity and T2D.

Background: HIV-associated neurocognitive disorder (HAND) can occur in patients without prior AIDS defining illness and can be debilitating. This study aimed to evaluate the difference in the patterns of intrinsic brain activity between patients with or without HAND for deepening our understanding of HAND., Methods: We evaluated 24 HIV-infected individuals, 12 with previously diagnosed HAND and 12 previously diagnosed without HAND, and 11 seronegative individuals. These individuals then underwent repeat NP testing and a functional brain MRI scan. For functional MRI analysis, seed-based analysis with bilateral precuneus cortex seed was applied., Results: Among the 12 individuals with previously diagnosed HAND, 3 showed improvement of their neurocognitive function and 1 was excluded for worsening liver disease. Among the 12 patients who previously had normal neurocognitive function, 2 showed neurocognitive impairment. Overall, the HAND group, who had impaired cognitive function at the time of MRI scan, showed significant decrease of resting status functional connectivity between bilateral precuneus and prefrontal cortex (PFC) compared with nonHAND group, those who had normal neurocognitive function (Corrected P<0.05). The functional connectivity with the right inferior frontal operculum and right superior frontal gyrus was positively correlated with memory and learning ability., Conclusions: This cross-sectional study found a significant difference in fMRI patterns between patients with and without HAND. Decreased functional connectivity between precuneus and PFC could be possible functional substrate for cognitive dysfunction in HIV patients, which should be characterized in a longitudinal study.

The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.

Osteoclasts seem to be metabolic active during their differentiation and bone-resorptive activation. However, the functional role of lactate dehydrogenase (LDH), a tetrameric enzyme consisting of an A and/or B subunit that catalyzes interconversion of pyruvate to lactate, in RANKL-induced osteoclast differentiation is not known. In this study, RANKL treatment induced gradual gene expression and activation of the LDH A2B2 isotype during osteoclast differentiation as well as the LDH A1B3 and B4 isotypes during osteoclast maturation after pre-osteoclast formation. Glucose consumption and lactate production in growth media were accelerated during osteoclast differentiation, together with enhanced expression of H+-lactate co-transporter and increased extracellular acidification, demonstrating that glycolytic metabolism was stimulated during differentiation. Further, oxygen consumption via mitochondria was stimulated during osteoclast differentiation. On the contrary, depletion of LDH-A or LDH-B subunit suppressed both glycolytic and mitochondrial metabolism, resulting in reduced mature osteoclast formation via decreased osteoclast precursor fusion and down-regulation of the osteoclastogenic critical transcription factor NFATc1 and its target genes. Collectively, our findings suggest that RANKL-induced LDH activation stimulates glycolytic and mitochondrial respiratory metabolism, facilitating mature osteoclast formation via osteoclast precursor fusion and NFATc1 signaling.

This study investigated the relationship between erythrocyte membrane fatty acid (FA) levels and the severity of symptoms of individuals at ultra-high risk (UHR) for psychosis. Subjects of the present study consisted of 80 neuroleptic-naïve UHR patients. Partial correlation coefficients were calculated between baseline erythrocyte membrane FA levels, measured by gas chromatography, and scores on the Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning Scale, and Montgomery-Asberg Depression Rating Scale (MADRS) after controlling for age, sex, smoking and cannabis use. Subjects were divided into three groups according to the predominance of positive or negative symptoms based on PANSS subscale scores; membrane FA levels in the three groups were then compared. More severe negative symptoms measured by PANSS were negatively correlated with two saturated FAs (myristic and margaric acids), one ω-9 monounsaturated FA (MUFA; nervonic acid), and one ω-3 polyunsaturated FA (PUFA; docosapentaenoic acid), and were positively correlated with two ω-9 MUFAs (eicosenoic and erucic acids) and two ω-6 PUFAs (γ-linolenic and docosadienoic acids). More severe positive symptoms measured by PANSS were correlated only with nervonic acid. No associations were observed between FAs and MADRS scores. In subjects with predominant negative symptoms, the sum of the ω-9 MUFAs and the ω-6:ω-3 FA ratio were both significantly higher than in those with predominant positive symptoms, whereas the sum of ω-3 PUFAs was significantly lower. In conclusion, abnormalities in FA metabolism may contribute to the neurobiology of psychopathology in UHR individuals. In particular, membrane FA alterations may play a role in negative symptoms, which are primary psychopathological manifestations of schizophrenia-related disability.

Background: Various stimuli can trigger migraines in susceptible individuals. We examined migraine trigger factors by using a smartphone headache diary application., Method: Episodic migraineurs who agreed to participate in our study downloaded smartphone headache diary application, which was designed to capture the details regarding headache trigger factors and characteristics for 3 months. The participants were asked to access the smartphone headache diary application daily and to confirm the presence of a headache and input the types of trigger factors., Results: Sixty-two participants kept diary entries until the end of the study. The diary data for 4,579 days were analyzed. In this data set, 1,099 headache days (336 migraines, 763 non-migraine headaches) were recorded; of these, 772 headache events had with trigger factors, and 327 events did not have trigger factors. The common trigger factors that were present on headache days included stress, fatigue, sleep deprivation, hormonal changes, and weather changes. The likelihood of a headache trigger was 57.7% for stress, 55.1% for sleep deprivation, 48.5% for fatigue, and 46.5% for any trigger. The headaches with trigger factors were associated with greater pain intensity (p<0.001), headache-related disability (p<0.001), abortive medication use (p = 0.02), and the proportion of migraine (p < 0.001), relative to those without trigger factors. Traveling (odd ratios [OR]: 6.4), hormonal changes (OR: 3.5), noise (OR: 2.8), alcohol (OR: 2.5), overeating (OR: 2.4), and stress (OR:1.8) were significantly associated with migraines compared to non-migraine headaches. The headaches that were associated with hormonal changes or noise were more often migraines, regardless of the preventive medication. The headaches due to stress, overeating, alcohol, and traveling were more often migraines without preventive medication, but it was not evident with preventive medication., Conclusion: Smartphone headache diary application is an effective tool to assess migraine trigger factors. The headaches with trigger factors had greater severity or migraine features. The type of triggers and the presence of preventive medication influenced the headache characteristics; hence, an investigation of trigger factors would be helpful in understanding migraine occurrences.

Importance: Intraocular pressure (IOP) reduction or stabilization is the only proven method for glaucoma management. Identifying risk factors for IOP is crucial to understand the pathophysiology of glaucoma., Objective: To examine the associations of change in body mass index (BMI), waist circumference, and percent fat mass with change in intraocular pressure (IOP) in a large sample of Korean adults., Design, Setting and Participants: Cohort study of 274,064 young and middle age Korean adults with normal fundoscopic findings who attended annual or biennial health exams from January 1, 2002 to Feb 28, 2010 (577,981 screening visits)., Exposures: BMI, waist circumference, and percent fat mass., Main Outcome Measure(s): At each visit, IOP was measured in both eyes with automated noncontact tonometers., Results: In multivariable-adjusted models, the average increase in IOP (95% confidence intervals) over time per interquartile increase in BMI (1.26 kg/m2), waist circumference (6.20 cm), and percent fat mass (3.40%) were 0.18 mmHg (0.17 to 0.19), 0.27 mmHg (0.26 to 0.29), and 0.10 mmHg (0.09 to 0.11), respectively (all P < 0.001). The association was stronger in men compared to women (P < 0.001) and it was only slightly attenuated after including diabetes and hypertension as potential mediators in the model., Conclusions and Relevance: Increases in adiposity were significantly associated with an increase in IOP in a large cohort of Korean adults attending health screening visits, an association that was stronger for central obesity. Further research is needed to understand better the underlying mechanisms of this association, and to establish the role of weight gain in increasing IOP and the risk of glaucoma and its complications.

Purpose: To evaluate the pathological effect of the duration of arm swelling on the shoulder pathology in patients with breast cancer-related lymphedema., Methods: Forty seven breast cancer patients with unilateral arm lymphedema were assessed. The duration of the arm swelling and shoulder pain were recorded. Ultrasound examination of the shoulder joint was performed in all patients to detect any lesions., Results: Abnormalities were detected by ultrasound in 41/47 (87.2%) study participants. Subacromial subdeltoid bursal thickening was found in 26/47 (55.3%) participants, distension of the biceps brachii tendon sheath was found in 14/47 (29.8%) and a supraspinatus tendon tear was found in 13/47 (27.7%). Patients with a supraspinatus tendon tear were found to have a significantly longer duration of lymphedema (1310 days vs. 398 days, p = 0.032)., Conclusions: The duration of arm lymphedema has a progressive pathological effect on rotator cuff. Clinicians should adopt an early management approach of shoulder pain in patients with breast cancer-related lymphedema.

Introduction: SCA17 is an autosomal dominant cerebellar ataxia with expansion of the CAG/CAA trinucleotide repeats in the TATA-binding protein (TBP) gene. SCA17 can have various clinical presentations including parkinsonism, ataxia, chorea and dystonia. SCA17 is diagnosed by detecting the expanded CAG repeats in the TBP gene; however, in the literature, pathologic repeat numbers as low as 41 overlap with normal repeat numbers., Methods: The subjects in this study included patients with involuntary movement disorders such as cerebellar ataxia, parkinsonism, chorea and dystonia who visited Seoul National University Hospital between Jan. 2006 and Apr. 2014 and were screened for SCA17. Those who were diagnosed with other genetic diseases or nondegenerative diseases were excluded. DNA from healthy subjects who did not have a family history of parkinsonism, ataxia, psychiatric symptoms, chorea or dystonia served as the control. In total, 5242 chromosomes from 2099 patients and 522 normal controls were analyzed., Results: The total number of patients included in the analysis was 2099 (parkinsonism, 1706; ataxia, 345; chorea, 37; and dystonia, 11). In the normal control, up to 44 repeats were found. In the 44 repeat group, there were 7 (0.3%) patients and 1 (0.2%) normal control. In 43 repeat group, there were 8 (0.4%) patients and 2 (0.4%) normal controls. In the 42 repeat group, there were 16 (0.8%) patients and 3 (0.6%) normal controls. In 41 repeat group, there were 48 (2.3%) patients and 8 (1.5%) normal controls. Considering the overlaps and non-significant differences in allelic frequencies between the patients and the normal controls with low-expansions, we could not determine a definitive cutoff value for the pathologic CAG repeat number of SCA17., Conclusion: Because the statistical analysis between the normal controls and patients with low range expansions failed to show any differences so far, we must consider that clinical cases with low range expansions could be idiopathic movement disorders showing coincidental CAG/CAA expansions. Thus, we need to reconsider the pathologic role of low range expansions (41-42). Long term follow up and comprehensive investigations using autopsy and imaging studies in patients and controls with low range expansions are necessary to determine the cutoff value for the pathologic CAG repeat number of SCA17.

Background: Sepsis, including severe sepsis and septic shock, is a major cause of morbidity and mortality. Albumin and C-reactive protein (CRP) are considered as good diagnostic markers for sepsis. Thus, initial CRP and albumin levels were combined to ascertain their value as an independent predictor of 180-day mortality in patients with severe sepsis and septic shock., Materials and Methods: We conducted a retrospective cohort study involving 670 patients (>18 years old) who were admitted to the emergency department and who had received a standardized resuscitation algorithm (early goal-directed therapy) for severe sepsis and septic shock, from November 2007 to February 2013, at a tertiary hospital in Seoul, Korea. The outcome measured was 180-day all-cause mortality. A multivariate Cox proportional hazard model was used to identify the independent risk factors for mortality. A receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive accuracy of the CRP/albumin ratio at admission., Results: The 180-day mortality was 28.35% (190/670). Based on the multivariate Cox proportional hazard analysis, age, the CRP/albumin ratio at admission (adjusted HR 1.06, 95% CI 1.03-1.10, p<0.001), lactate level at admission (adjusted HR 1.10, 95% CI 1.05-1.14, p<0.001), and the Sequential Organ Failure Assessment (SOFA) score at admission (adjusted HR 1.12, 95% CI 1.07-1.18, p<0.001) were independent predictors of 180-day mortality. The area under the curve of CRP alone and the CRP/albumin ratio at admission for 180-day mortality were 0.5620 (P<0.001) and 0.6211 (P<0.001), respectively., Conclusion: The CRP/albumin ratio was an independent predictor of mortality in patients with severe sepsis or septic shock.

Recent studies have suggested that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) increases macrophage phagocytosis through adenosine monophosphate-activated protein kinase (AMPK). However, little information is available on the effects of AICAR on the clearance of apoptotic cells by macrophages, known as efferocytosis, which is essential in maintaining tissue homeostasis and resolving inflammation. AICAR increased p38 MAPK activation and the phagocytosis of apoptotic cells by macrophages, which were inhibited by the p38 MAPK inhibitor, SB203580, the TGF-beta-activated kinase 1 (TAK1) inhibitor, (5Z)-7-oxozeaenol, and siRNA-mediated knock-down of p38α. AICAR increased phosphorylation of Akt, but the inhibition of PI3K/Akt activity using LY294002 did not affect the AICAR-induced changes in efferocytosis in macrophages. CGS15943, a non-selective adenosine receptor antagonist, did not affect AICAR-induced changes in efferocytosis, but dipyridamole, an adenosine transporter inhibitor, diminished the AICAR-mediated increases in efferocytosis. AICAR-induced p38 MAPK phosphorylation was not inhibited by the AMPK inhibitor, compound C, or siRNA-mediated knock-down of AMPKα1. Inhibition of AMPK using compound C or 5'-iodotubercidin did not completely block AICAR-mediated increases in efferocytosis. Furthermore, AICAR also increased the removal of apoptotic neutrophils or thymocytes in mouse lungs. These results reveal a novel mechanism by which AICAR increases macrophage-mediated phagocytosis of apoptotic cells and suggest that AICAR may be used to treat efferocytosis-related inflammatory conditions.