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Sorting spikes from extracellular recordings, obtained by sensing neuronal activity around an electrode tip, is essential for unravelling the complexities of neural coding and its implications across diverse neuroscientific disciplines. However, the presence of overlapping spikes, originating from neurons firing simultaneously or within a short delay, has been overlooked because of the difficulty in identifying individual neurons due to the lack of ground truth. In this study, we propose a method to identify overlapping spikes in extracellular recordings and to recover hidden spikes by decomposing them. We initially estimate spike waveform templates through a series of steps, including discriminative subspace learning and the isolation forest algorithm. By leveraging these estimated templates, we generate synthetic spikes and train a classifier using their feature components to identify overlapping spikes from observed spike data. The identified overlapping spikes are then decomposed into individual hidden spikes using a particle swarm optimization. Results from the testing of the proposed approach, using the simulation dataset we generated, demonstrated that employing synthetic spikes in the overlapping spike classifier accurately identifies overlapping spikes among the detected ones (the maximum F1 score of 0.88). Additionally, the approach can infer the synchronization between hidden spikes by decomposing the overlapped spikes and reallocating them into distinct clusters. This study advances spike sorting by accurately identifying overlapping spikes, providing a more precise tool for neural activity analysis., Competing Interests: Declarations. Ethics approval and consent to participate: The animal experimentation was conducted at Center for Neuroscience Imaging Research within the Institute for Basic Science (IBS), Sungkyunkwan University and approved by its Institutional Animal Care and Use Committee (SKKUIACUC2023-10-21-1), as part of a collaboration with Catholic Kwandong University. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Abnormal posture is known to affect the efficacy of exercise therapy for musculoskeletal diseases. However, no studies to date have examined the effect of exercise programs should take into account the posture of the upper body in patients with rotator cuff disease. This study aimed to assess how rotator cuff and corrective exercises impact shoulder function and muscle strength post-arthroscopic rotator cuff repair surgery, providing tailored rehabilitation programs for patients with forward posture., Methods: Ninety male patients who underwent arthroscopic rotator cuff repair participated in this study. The patients were randomly divided into three groups corrective exercise group (CEG, n = 29), rotator cuff exercise group (REG, n = 27), and control group (CG, n = 28). Each group was instructed to apply different exercise programs to correct posture and enhance rotator cuff strength. All patients were checked by the American Shoulder and Elbow Surgeons (ASES) score, Constant score and muscle strength, and range of motion preoperatively and postoperatively at 6 months and 1 year., Results: ASES shoulder function scores showed significant difference between the three groups (p = 0.002, F = 7.03), indicating that the corrective exercise program was more beneficial than rotator cuff exercises (p = 0.009, F = 3.78). A significant intergroup difference in mean Constant score was also noted (p = 0.025, F = 3.86), while a statistically significant interaction between time and group was observed (p = 0.032, F = 2.96)., Conclusions: These results suggested that a corrective exercise program can improve shoulder muscle strength and function after rotator cuff repair in male patients with a forward shoulder posture., (© 2024. The Author(s).)

Background: The increasing complexity of the healthcare environment and the necessity of multidisciplinary teamwork have highlighted the importance of interprofessional education (IPE). IPE aims to enhance the quality of patient care through collaborative education involving various healthcare professionals, such as doctors, nurses, and pharmacists. This study sought to analyze how game-based IPE activities influence students' perceptions and reflective thinking. It also aimed to identify the shifts in perception and effectiveness caused by this educational approach., Methods: The study is based on a game-based IPE program conducted at University A, involving medical and nursing students in structured learning and team-based activities. Data were collected using essays written by the students after they had participated in IPE activities. Text network analysis was conducted by extracting key terms, performing centrality analysis, and visualizing topic modeling to identify changes in students' perceptions and reflective thinking., Results: Keywords such as "patient," "thought," "group," "doctor," "nurse," and "communication" played a crucial role in the network, indicating that students prioritized enhancing their communication and problem-solving skills within the educational environment. The topic modeling results identified three main topics, each demonstrating the positive influence of game-based collaborative activities, interprofessional perspectives, and interdisciplinary educational experiences on students. Topic 3 (interdisciplinary educational experience) acted as a significant mediator connecting Topic 1 (game-based collaborative activity experience) and Topic 2 (interprofessional perspectives)., Conclusion: This study demonstrates that game-based IPE activities are an effective educational approach for enhancing students' team building skills, particularly communication and interprofessional perspectives. Based on these findings, future IPE programs should focus on creating collaborative learning environments, strengthening communication skills, and promoting interdisciplinary education. The findings provide essential insights for educational designers and medical educators to enhance the effectiveness of IPE programs. Future research should assess the long-term impacts of game-based IPE on clinical practice, patient outcomes, and participants' professional development., (© 2024. The Author(s).)

Background: Asians and Asian Americans have the lowest rate of mental health service utilization (25%) in the US compared to other racial/ethnic groups (39 - 52%), despite high rates of depression, anxiety, and suicidal ideation. The lack of culturally-responsive mental health trainings hinders access to mental health services for these populations. We assessed the mental health priorities of Asian communities in Greater Boston and evaluated cultural responsiveness of the Mental Health First Aid (MHFA), a first-responder training teaching participants skills to recognize signs of mental health and substance use challenges, and how to appropriately respond., Methods: This is community-based participatory research with the Boston Chinatown Neighborhood Center (BCNC), Asian Women For Health (AWFH), and the Addressing Disparities in Asian Populations through Translational Research (ADAPT) Coalition. We conducted focus groups with community-based organization staff and community members to assess mental health priorities of Asian populations in Boston, MA. We then evaluated the utility and cultural-responsiveness of the English-language MHFA for Asian populations through pre- and post-training questionnaires and focus groups with community participants. Paired t-tests were used to evaluate questionnaire responses. Thematic analysis was used to analyze interviews., Results: In total, ten staff and eight community members participated in focus groups, and 24 community members completed the MHFA and pre- and post-training questionnaires. Common mental health challenges in the Asian communities reported by participants were loneliness, high stigma around mental illnesses, academic pressure, and acculturation stress. Compared to pre-training, MHFA participants demonstrated lower personal mental health stigma (p < 0.001) and higher mental health literacy (p = 0.04) post-training. Participants also noted the lack of data statistics and case studies relevant to Asian populations in the training, and desired the training be offered in languages spoken by Asian ethnic subgroups (e.g., Chinese, Vietnamese)., Conclusion: Cultural-responsiveness of the MHFA for Asian populations could be improved with the inclusion of data and case studies that capture common mental health challenges in the Asian communities and with translation of the MHFA to non-English languages predominant in Asian communities. Increasing the cultural relevance and language accessibility of the MHFA could facilitate wider adoption of these trainings across communities and help to reduce mental health stigma and gaps in literacy and service utilization., (© 2024. The Author(s).)

Background: Hyperuricemia could be a risk for various chronic diseases, and it could be largely corrected by diet control. This study was a nationwide cross-sectional study to investigate the association between serum uric acid level and dietary fiber intake., Methods: This study analyzed data based on the Korean National Health and Nutrition Examination Survey conducted from 2016 to 2018. Adults over 20 years of age with normal renal function, defined as an estimated glomerular filtration rate (eGFR) over 30mL/min/1.73m 2 , were included. The criteria for hyperuricemia were ≥ 7 mg/dL in men and ≥ 6 mg/dL in women. Data regarding dietary intake were obtained using the 24-hour recall method., Results: A total of 15,278 subjects (6,455 males/8,823 females) were analyzed. The prevalence of hyperuricemia was 19.3% in men and 6.8% in women. There were significant, negative associations between serum uric acid and total fiber intake in both men and women. Consuming more than 27.9 g of dietary fiber in men and 20.7 g in women reduced the risk of hyperuricemia by approximately 30% with odds ratios of 0.72 (0.62-0.83) and 0.71 (0.56-0.88) in men and women, respectively. With regard to the risk reduction by the type of dietary fiber, cereal fiber was significantly identified in both men and women, while fruit fiber was only significant in men. In the subgroup analysis, this association remained significantly in young and metabolically healthy populations with normal weight., Conclusions: Dietary fiber intake was inversely associated with serum uric acid levels. This relationship was particularly significant in metabolically healthy young adults., (© 2024. The Author(s).)

Background: To evaluate the therapeutic effects of topical RCI001 (RCI) and compare its efficacy with that of 1% prednisolone acetate (PDE) and 5% Lifitegrast in a modified mixed dry eye disease (DED) model., Methods: The environmental DED model was induced in BALB/c mice in a dry chamber with scopolamine. The eyes of the mice were treated topically with phosphate buffered saline (PBS), PDE, Lifitegrast or RCI twice daily for 1 week. Ocular surface staining (OSS), tear secretion, inflammatory cytokines in the ocular surface and lacrimal gland, and immunofluorescence staining in the conjunctiva and cornea(CC) were assessed., Results: The RCI group demonstrated better improvement of OSS and tear secretion than the PBS group (OSS, PBS: 13.0 ± 1.6, RCI: 9.4 ± 3.0; tear secretion, PBS: 5.0 ± 0.4 mm, RCI: 7.0 ± 0.3 mm, each P < 0.001) and better clinical efficacy than PDE and Lifitegrast groups on Day 7 (improvement rate of OSS, RCI: 32.45%, Lifitegrast: 13.13%, PDE: 12.25%). The RCI group resulted in significantly lower expression of oxidative stress markers in the CC than the PBS group (4-HNE, NOX2, and NOX4 in the conjunctiva; NOX2 in the cornea, each P < 0.05). However, the PDE and Lifitegrast groups did not show significant differences compared with the PBS group. There were no significant differences of inflammatory cytokines in the ocular surface and lacrimal gland between all groups., Conclusion: Topical RCI001 showed excellent therapeutic effects in environmental DED models by stimulating tear secretion, modulating oxidative stress and improving corneal epithelial healing compared to 1% PDE and 5% Lifitegrast., (© 2024. The Author(s).)

Background: This study aimed to investigate the impact of tobacco industry interference on the implementation and management of tobacco control and the tobacco epidemic using the Tobacco Industry Interference Index (TIII) and MPOWER-a package of measures for tobacco control-and adult daily smoking prevalence in 30 countries., Methods: The TIII was extracted from the Global Tobacco Industry Interference Index 2019 and Global Center for Good Governance in Tobacco Control (GGTC). MPOWER measures and adult daily smoking prevalence rate were extracted from the World Health Organization (WHO) report on the global tobacco epidemic in 2021. We assessed the ecological cross-lagged association between TIII and MPOWER scores and between TIII and age-standardized prevalence rates for adult daily tobacco users., Results: Tobacco industry interference was inversely correlated with a country's package of tobacco control measures (β = -0.088, P = 0.035). The TIII was correlated with weaker warnings about the dangers of tobacco (β = -0.016, P = 0.078) and lack of enforcement of bans on tobacco advertising promotion and sponsorship (β = -0.023, P = 0.026). In turn, the higher the TIII, the higher the age-standardized prevalence of adult daily tobacco smokers for both sexes (β = 0.170, P = 0.036). Adult daily smoking prevalence in males (β = 0.417, P = 0.004) was higher in countries where the tobacco industry received incentives that benefited its business., Conclusion: Where the interference of the tobacco industries was high, national compliance with the Framework Convention on Tobacco Control (FCTC) was lower, and the prevalence of adult daily smokers higher. National governments and global society must work together to minimize the tobacco industry's efforts to interfere with tobacco control policies., (© 2023. The Author(s).)

Backgrounds: Remdesivir (RDV) is an antiviral agent approved for the treatment of coronavirus disease 2019 (COVID-19); however, is not recommended for patients with renal impairment. Due to limitations associated with prospective clinical trials, real-world data on the safety and efficacy of RDV in patients with renal impairment are necessary., Methods: Propensity score-matched (PSM) retrospective analysis was conducted between March 2020 and September 2022 in COVID-19 patients with an eGFR < 30 mL/min in four Korean hospitals. The RDV treatment group was matched to the untreated control group. The safety and clinical outcomes in patients who received RDV were analyzed., Results: A total of 564 patients were enrolled; 229 patients received RDV either for treatment or prophylaxis. On day 5, no difference in nephrotoxicity was observed between the two groups, and liver enzyme levels were within the normal range. In multivariate analysis for new dialysis, RDV treatment was not a risk factor for new dialysis. Among the 564 patients, 417 were indicated for a 5-day course of RDV treatment and 211 patients were treated with RDV. After PSM, no differences in the clinical outcomes were observed between the two groups., Conclusion: RDV use in COVID-19 patients with renal impairment did not result in significant nephrotoxicity or hepatotoxicity., (© 2023. The Author(s).)

Background: The emergence of carbapenem-resistant Enterobacterales (CRE) infections is rapidly increasing and represents a serious public threat. In 2020, a total of 16,883 carbapenemase-producing Enterobacterales strains were collected; among these isolates, 21 strains were repeatedly isolated in a local tertiary care hospital., Methods: Antimicrobial susceptibility testing was performed using the broth microdilution method. All 21 strains of CRKP were analyzed by PFGE after XbaI digestion. The 21 CRKP strains were sequenced on the Illumina Miseq and Oxford Nanopore GridION platforms., Results: These 21 CRKP isolates showed an identical antimicrobial resistance profile, including resistance to ampicillin, carbapenems, cephems, chloramphenicol, fluoroquinolone, macrolides and trimethoprim/sulfamethoxazole. Based on whole-genome analysis, these 21 CRKP isolates shared a common genetic structure (ISAba125-IS630-bla NDM-1 -ble MBL ) and harbored additional resistance determinants (bla OXA-1 , bla CTX-M-15 , bla SHV-11 , bla SHV-67 , aac(6')-Ib-cr, qnrS1, OqxA, OqxB, catB3, mph(A), sul1, and dfrA12) and mutations in the quinolone resistance-determining regions of gyrA (S83I) and parC (S80I). These isolates belonged to the ST147 and KL64 capsular types, which were carried on IncFIB replicon plasmids. The 21 CRKP strains collected from one hospital were divided into five PFGE patterns, and they were closely related with a minimum similarity value of 95.2%. These isolates were found to be highly related based on the presence of between 2 and 27 SNPs., Conclusions: These findings indicate that NDM-1-producing K. pneumoniae ST147 may have been introduced via a common source, implying nosocomial transmission; furthermore, continuous monitoring is necessary to prevent endemic transmission., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: To evaluate the efficacy of 1% and 2% rebamipide clear solution in the treatment of dry eye disease (DED)., Methods: Two hundred twenty patients with DED were randomly assigned to one of three groups: the 1% rebamipide, 2% rebamipide, or placebo (eye drops containing the same ingredients, except for the active components). Each eye drop was instilled four times daily for 12 weeks. Changes in tear film break-up time (TBUT), corneal and conjunctival staining score, Schirmer 1 test, and the Ocular Surface Disease Index (OSDI) from baseline to 12-week visit between the study groups were compared for efficacy assessment., Results: The mean age of study patients was 43.8±14.2 years. The 1% and 2% rebamipide groups showed greater improvement in TBUT (1.99±1.87 and 2.02±2.21 s) at 12 weeks from baseline than the placebo group (1.25±2.93 s). The 2% rebamipide group showed greater improvement in the corneal staining score (- 3.15±2.00) at 12 weeks from baseline than the placebo group (- 2.85±1.80). The 1% and 2% rebamipide groups showed improvement in Schirmer 1 test (1.27±3.86 and 1.50±4.14 mm) at 12 weeks of treatment, but not the placebo group (0.55±2.99 mm). Both the rebamipide groups and the placebo group showed significantly improved OSDI after treatment for 12 weeks; however, there was no significant difference among the three groups., Conclusions: 1% and 2% rebamipide clear solutions are an effective therapeutic option for improving TBUT and tear volume, and stabilizing the corneal staining score in DED., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Metabolic syndrome is associated with type 2 diabetes and its prevalence is increasing worldwide in young adults. We aimed to determine whether cumulative exposure to metabolic syndrome is associated with type 2 diabetes risk in young adults., Methods: Data of 1,376,540 participants aged 20-39 years without a history of type 2 diabetes and who underwent four annual health check-ups were collected. In this large-scale prospective cohort study, we evaluated the incidence rates and hazard ratios (HRs) of diabetes according to cumulative frequencies of metabolic syndrome over 4 years of consecutive annual health check-ups (burden score 0-4). Subgroup analyses were performed by sex and age., Results: During 5.18 years of follow-up, 18,155 young adults developed type 2 diabetes. The incidence of type 2 diabetes increased with burden score (P < 0.0001). The multivariable-adjusted HRs for type 2 diabetes were 4.757, 10.511, 18.288, and 31.749 in participants with a burden score of 1 to 4, respectively, compared to those with 0. In subgroup analyses, the risk of incident diabetes was greater in women than men and in the 20-29 years age group than the 30-39 years age group. The HRs were 47.473 in women and 27.852 in men with four burden scores., Conclusion: The risk of type 2 diabetes significantly increased with an increase in the cumulative burden of metabolic syndrome in young adults. Additionally, the association between cumulative burden and diabetes risk was stronger in women and the 20s age group., (© 2023. The Author(s).)

Background: Desflurane is not recommended during anesthesia induction because of its sympathetic stimulation effect, particularly in patients with myocardial ischemic disease. To date, the hemodynamic response to 1 MAC desflurane inhalation in combination with remifentanil infusion during anesthesia induction has rarely been reported., Methods: This investigation was designed to compare hemodynamic responses to 1 MAC desflurane (group D, n = 200) with sevoflurane (group S, n = 200) during anesthesia induction and endotracheal intubation in adult patients undergoing elective spine surgery. Subgroup analysis of the different age subgroups was also performed. With continuous infusion of remifentanil 0.1 μg/kg/min, anesthesia was induced with propofol bolus, and endotracheal intubation was performed after muscle relaxation. Heart rate (HR) and mean arterial blood pressure (MAP) were measured every minute for 5 min after anesthesia induction (T1-5) and after endotracheal intubation (T6-10)., Results: HR was significantly higher in group D (n = 182) than in group S (n = 173) at T3-10 except at T6 (1 min after intubation) (all P < 0.05). In the age-based subgroup analyses, which subdivided the group D and S into four subgroups based on patient's age, the changes in HR from baseline values were significantly different between the coeval subgroups of patients in their 20-29 years and 30-39 years of age (all P < 0.05). MAP was reduced from baseline value, irrespective of group and age., Conclusion: Inhalation of 1 MAC desflurane during anesthesia induction with propofol bolus and remifentanil continuous infusion and during endotracheal intubation was more likely to induce elevations in HR more likely than 1 MAC sevoflurane, especially in younger patients., Trial Registration: This study was registered in the Clinical Research Information Service (CRIS, http://cris.nih.go.kr ) of the Republic of Korea on Feb 12, 2016 (Registration No. KCT 0,001,813)., (© 2023. The Author(s).)

Background: Cancer cells have developed molecular strategies to cope with evolutionary stressors in the dynamic tumor microenvironment. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a metabolic rheostat that regulates diverse cellular adaptive behaviors, including growth and survival. However, the mechanistic role of PGC1α in regulating cancer cell viability under metabolic and genotoxic stress remains elusive., Methods: We investigated the PGC1α-mediated survival mechanisms in metabolic stress (i.e., glucose deprivation-induced metabolic stress condition)-resistant cancer cells. We established glucose deprivation-induced metabolic stress-resistant cells (selected cells) from parental tumor cells and silenced or overexpressed PGC1α in selected and parental tumor cells., Results: Several in vitro and in vivo mouse experiments were conducted to elucidate the contribution of PGC1α to cell viability in metabolic stress conditions. Interestingly, in the mouse xenograft model of patient-derived drug-resistant cancer cells, each group treated with an anti-cancer drug alone showed no drastic effects, whereas a group that was co-administered an anti-cancer drug and a specific PMCA inhibitor (caloxin or candidate 13) showed marked tumor shrinkage., Conclusions: Our results suggest that PGC1α is a key regulator of anti-apoptosis in metabolic and genotoxic stress-resistant cells, inducing PMCA expression and allowing survival in glucose-deprived conditions. We have discovered a novel therapeutic target candidate that could be employed for the treatment of patients with refractory cancers., (© 2023. The Author(s).)

Background: Canine cloning technology based on somatic cell nuclear transfer (SCNT) combined with genome-editing tools such as CRISPR-Cas9 can be used to correct pathogenic mutations in purebred dogs or to generate animal models of disease., Results: We constructed a CRISPR-Cas9 vector targeting canine DJ-1. Genome-edited canine fibroblasts were established using vector transfection and antibiotic selection. We performed canine SCNT using genome-edited fibroblasts and successfully generated two genome-edited dogs. Both genome-edited dogs had insertion-deletion mutations at the target locus, and DJ-1 expression was either downregulated or completely repressed., Conclusion: SCNT successfully produced genome-edited dogs by using the CRISPR-Cas9 system for the first time., (© 2022. The Author(s).)

Background: Stevens-Johnson syndrome (SJS) is an abnormal immune-response causing extensive exfoliation of the mucocutaneous tissue including conjunctiva. While several factors are associated with the alteration of conjunctival microbiota, the conjunctiva of SJS patients are found to harbor a different microbiota compared to healthy subjects. We investigated the conjunctival microbiota of Korean SJS patients, and identified factors associated with the conjunctival microbiota and its positive culture., Methods: Medical records were retrospectively reviewed in 30 chronic SJS patients who had undergone conjunctival swab culture sampling. Demographic factors, chronic ocular surface complications score (COCS), tear break-up time (TBUT), tear secretion, tear matrix metalloproteinase 9 (MMP9), and results of conjunctival swab culture were assessed., Results: Positive culture was seen in 58.1%. Gram positive bacteria was most commonly isolated, among which Coagulase-negative Staphylococci (45.5%) and Corynebacterium species (40.9%) were predominantly observed. Tear MMP9 positivity was observed significantly more in the positive culture group (100%) compared to the negative culture group (70%) (P = 0.041). Topical cyclosporine and corticosteroid were not associated with repetitive positive cultures. No significant differences in COCS, TBUT, and tear secretion were found between culture-positive and culture-negative groups., Conclusion: Our study suggests that tear MMP9 positivity may be related with the presence of an abnormal ocular surface microbiota in chronic SJS patients., (© 2022. The Author(s).)

Background: Ovarian "seromucinous carcinoma" has been recently removed in 2020 5 th Edition of WHO classification of Female Genital Tumors and is considered as a subtype of endometrioid carcinoma with mucinous differentiation, while "seromucinous borderline tumor" remains and exists as a distinct entity. Both diseases may be considered as no more same lineage. However, ovarian seromucinous borderline tumor (SMBT) is also one of the endometriosis-related neoplasm of ovary similar to endometrioid tumor, featuring that about 50% of ovarian SMBTs combine endometriosis. The present study was aimed to investigate whether the ovarian SMBTs are different in clinical features and molecular patterns, according to the presence of combined endometriosis., Results: There were no statistical differences in clinical findings between two groups. There was also no significant difference in pregnancy outcomes and recurrence between two groups. In immunohistochemical patterns, there was a statistically significant difference in PAX2 and PAX8 expression between in ovarian SMBT with or without endometriosis (P = 0.016, P < 0.001). Only a few cases of ovarian SMBT with endometriosis showed expression of PAX2 and conversely, most of the cases showed expression of PAX8. PR positivity was more prominent in ovarian SMBT with endometriosis than without endometriosis (P = 0.018), although there was no difference in positive ER expression. There were no statistical differences in WT1, CK20 and CDX2 expressions between two groups., Conclusions: Ovarian SMBT with endometriosis did not clinically differ from that without endometriosis. However, the molecular patterns were different between two groups and ovarian SMBT with endometriosis is close to endometrioid tumor types unlike SMBT without endometriosis. Further, a direct comparison study between seromucinous borderline tumor and endometrioid borderline tumor is needed with a gene profiling study to prove their relationship., (© 2022. The Author(s).)

Background: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance., Method: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss., Result: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011., Conclusion: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income., (© 2022. The Author(s).)

Background: To evaluate the effects of pretreatment for dry eye disease (DED) on the accuracy of intraocular lens (IOL) power calculation., Methods: Patients who underwent uneventful cataract surgery were included in the study. IOL power was determined using the SRK/T and Barrett Universal II (Barrett) formulas. The patients were divided into non-pretreatment and pretreatment groups, and those in the pretreatment group were treated with topical 0.5% loteprednol etabonate and 0.05% cyclosporin A for 2 weeks prior to cataract surgery. Ocular biometry was performed in all groups within 2 days before surgery. The mean prediction error, mean absolute error (MAE), and proportions of refractive surprise were compared between the non-pretreatment and pretreatment groups at 1 month postoperatively. Refractive surprise was defined as MAE ≥ 0.75D., Results: In a total of 105 patients, 52 (52 eyes) were in the non-pretreatment group and 53 (53 eyes) in the pretreatment group. The MAE was 0.42 ± 0.33, 0.38 ± 0.34 (SRK/T, Barrett) and 0.23 ± 0.19, 0.24 ± 0.19 in the non-pretreatment and pretreatment groups, respectively (p < 0.001/=0.008). The number of refractive surprises was also significantly lower in the pretreatment group. [non-pretreatment/pretreatment: 9/2 (SRK/T); 8/1 (Barrett); p = 0.024/0.016]. Pretreatment of DED was related to a reduction in postoperative refractive surprise. [SRK/T/Barrett: OR = 0.18/0.17 (95% CI: 0.05-0.71/0.05-0.60), p = 0.014/0.006]., Conclusions: The accuracy of IOL power prediction can be increased by actively treating DED prior to cataract surgery., (© 2021. The Author(s).)

Background: Assessment of the optical outcome and adverse events in post-epikeratopathic eyes after removal of the epikeratoplasty lenticule (EKPL)., Methods: This was a retrospective case-series study of patients who underwent EKPL removal between 2002 and 2020. Ten eyes were included in the analysis. We compared the clinical characteristics of the patients before surgery, 6 months after surgery, before lenticular removal, and after removal, and reported optical or ocular surface complications., Results: We removed EKPL due to the lenticular opacity in five eyes (50%), intraocular lens (IOL) insertion (n = 4, 40%) after cataract surgery (n = 3) or in aphakic eyes (n = 1), and lenticule-induced irregular astigmatism in one eye (10%). After EKPL removal, the mean refractive power of the cornea (Km) revealed a tendency to increase. Out of nine cases, six cases showed corneal steepening and three cases revealed corneal flattening. When the keratometric readings of pre-epikeratoplasty and post-lenticular removal were compared within the same case, the average difference was 5.1 D ± 4.0 (n = 8). Complications were observed in 3 of 10 cases (excessive corneal flatness, ectatic change, and abnormal epithelial cell ingrowth) after removal., Conclusions: The surgeon should expect the corneal refractive power to steepen or flatten in some cases with abnormal astigmatism and irregularity. Epikeratophakic eyes may exhibit serious ectatic changes, and abnormal epithelial cell ingrowth after removal of epikeratophakic lenticules., (© 2021. The Author(s).)

Background: Recent resting-state fMRI studies demonstrated functional dysconnectivity within the central pain matrix in migraineurs. This study aimed to investigate the spatial distribution and amplitude of low-frequency oscillations (LFOs) using fractional amplitude of low-frequency fluctuation (fALFF) analysis in migraine patients without aura, and to examine relationships between regional LFOs and clinical variables., Methods: Resting-state fMRI data were obtained and preprocessed in 44 migraine patients without aura and 31 matched controls. fALFF was computed according to the original method, z-transformed for standardization, and compared between migraineurs and controls. Correlation analysis between regional fALFF and clinical variables was performed in migraineurs as well., Results: Compared with controls, migraineurs had significant fALFF increases in bilateral ventral posteromedial (VPM) thalamus and brainstem encompassing rostral ventromedial medulla (RVM) and trigeminocervical complex (TCC). Regional fALFF values of bilateral VPM thalamus and brainstem positively correlated with disease duration, but not with migraine attack frequency or Migraine Disability Assessment Scale score., Conclusions: We have provided evidence for abnormal LFOs in the brainstem including RVM/TCC and thalamic VPM nucleus in migraine without aura, implicating trigeminothalamic network oscillations in migraine pathophysiology. Our results suggest that enhanced LFO activity may underpin the interictal trigeminothalamic dysrhythmia that could contribute to the impairments of pain transmission and modulation in migraine. Given our finding of increasing fALFF in relation to increasing disease duration, the observed trigeminothalamic dysrhythmia may indicate either an inherent pathology leading to migraine headaches or a consequence of repeated attacks on the brain., (© 2021. The Author(s).)

Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases; however, there has been little research into its impact on gestational diabetes mellitus (GDM)., Methods: This study included 308,095 women registered in the Korean National Health Insurance Service database, who delivered between 2011 and 2015 and received a health examination within 52 weeks before pregnancy. Insulin-requiring GDM was defined as no insurance claims for diabetes mellitus and a fasting blood glucose level of < 126 mg/dL before pregnancy, and initiation of insulin treatment during pregnancy. A fatty liver index (FLI) was calculated using body mass index, waist circumference, and blood triglyceride and γ-glutamyl transferase levels. FLI scores < 30 ruled out hepatic steatosis, while FLI scores ≥ 60 indicated NAFLD., Results: The prevalence of NAFLD was 0.8% (2355/308,095) and 1984 (0.6%) subjects developed insulin-requiring GDM. FLIs of 30-59 and ≥ 60 were significantly associated with increased risk of insulin-requiring GDM (odds ratio [OR] 3.50; 95% confidence interval [CI] 2.99-4.10; OR 4.19; 95% CI 3.37-5.23), respectively. Further exploration of the association of FLI with GDM across FLI decile categories revealed a steady increase in OR across the categories. The association was more prominent among those without metabolic syndrome., Conclusion: NAFLD in women is an independent risk factor for insulin-requiring GDM., (© 2021. The Author(s).)

Background: Endometrial cancer is often the sentinel cancer in women with Lynch syndrome, among which endometrioid endometrial cancer is the most common. We found a Korean case of uterine carcinosarcoma associated with Lynch syndrome. And we reviewed 27 Korean women with endometrial cancer associated with Lynch syndrome already released in case report so far., Case Presentation: The proband, a 45-year-old Korean woman received treatment for endometrioid adenocarcinoma. Her older sister and niece were treated for endometrioid adenocarcinoma and carcinosarcoma, respectively. Family history met the Amsterdam II criteria and immunohistochemical analysis revealed a loss of MLH1 and PMS2. They all harbored a previously unreported germline likely pathogenic variant in c.1367delC in MLH1. They underwent staging operations including total hysterectomy, bilateral salpingo-oophorectomy, pelvic/paraaortic lymph node dissection, and washing cytology. All three women were healthy without evidence of relapse for over 4 years., Conclusion: This report indicates a novel germline c.1367delC variant in MLH1, and presents a Korean case of uterine carcinosarcoma associated with Lynch syndrome. Furthermore, the c.1757&#95;1758insC variant in MLH1 was suggested as a founder mutation in Lynch syndrome in Korean women.

Background & Aims: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous neoplasms. Although some have a relatively benign and indolent natural history, others can be aggressive and ultimately fatal. Somatostatin analogues (SSAs) improve both quality of life and survival for these patients once they develop metastatic disease. However, these drugs are costly and their cost-effectiveness is not known., Methods: A decision-analytic model was developed and analyzed to compare two treatment strategies for patients with Stage IV GEP-NETs. The first strategy had all patients start SSA immediately while the second strategy waited, reserving SSA initiation until the patient showed signs of progression. Sensitivity analysis was performed to explore model parameter uncertainty., Results: Our model of patients age 60 with metastatic GEP-NETs suggests empiric initiation of SSA led to an increase 0.62 unadjusted life-years and incremental increase in quality-adjusted life years (QALYs) of 0.44. The incremental costs were $388,966 per QALY and not cost-effective at a willingness-to-pay threshold of $100,000. Death was attributed to GEP-NETs for 94.1% of patients in the SSA arm vs. 94.9% of patients in the DELAY SSA arm. Sensitivity analysis found that the model was most sensitive to costs of SSAs. Using probabilistic sensitivity analysis, the SSA strategy was only cost-effective 1.4% of the time at a WTP threshold of $100,000 per QALY., Conclusions: Our modeling study finds it is not cost-effective to initiate SSAs at time of presentation for patients with metastatic GEP-NETs. Further clinical studies are needed to identify the optimal timing to initiate these drugs.

Background: While aging is a potent risk factor of dry eye disease, age-related gut dysbiosis is associated with inflammation and chronic geriatric diseases. Emerging evidence have demonstrated that gut dysbiosis contributes to the pathophysiology or exacerbation of ocular diseases including dry eye disease. However, the relationship between aging-related changes in gut microbiota and dry eye disease has not been elucidated. In this pilot study, we investigated the association between aging-dependent microbiome changes and dry eye severity in C57BL/6 male mice., Results: Eight-week-old (8 W, n = 15), one-year-old (1Y, n = 10), and two-year-old (2Y, n = 8) C57BL/6 male mice were used. Dry eye severity was assessed by corneal staining scores and tear secretion. Bacterial genomic 16 s rRNA from feces was analyzed. Main outcomes were microbiome compositional differences among the groups and their correlation to dry eye severity. In aged mice (1Y and 2Y), corneal staining increased and tear secretion decreased with statistical significance. Gut microbiome α-diversity was not different among the groups. However, β-diversity was significantly different among the groups. In univariate analysis, phylum Firmicutes, Proteobacteria, and Cyanobacteria, Firmicutes/Bacteroidetes ratio, and genus Alistipes, Bacteroides, Prevotella, Paraprevotella, and Helicobacter were significantly related to dry eye severity. After adjustment of age, multivariate analysis revealed phylum Proteobacteria, Firmicutes/Bacteroidetes ratio, and genus Lactobacillus, Alistipes, Prevotella, Paraprevotella, and Helicobacter to be significantly associated with dry eye severity., Conclusions: Our pilot study suggests that aging-dependent changes in microbiome composition are related to severity of dry eye signs in C57BL/6 male mice.

Background: Medical centers with varying levels of expertise treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which are relatively rare tumors. This study assesses the impact of center volume on GEP-NET treatment outcomes., Methods: We used the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare claims data. The data includes patients diagnosed between 1995 and 2010 who had no health maintenance organization (HMO) coverage, participated in Medicare parts A and B, were older than 65 at diagnosis, had tumor differentiation information, and had no secondary cancer. We identified medical centers at which patients received GEP-NET treatment (surgery, chemotherapy, somatostatin analogues, or radiation therapy) using Medicare claims data. Center volume was divided into 3 tiers - low, medium, and high - based on the number of unique GEP-NET patients treated by a medical center over 2 years. We used Kaplan-Meier curves and Cox regression to assess the association between volume and disease-specific survival., Results: We identified 899 GEP-NET patients, of whom 37, 45, and 18% received treatment at low, medium volume, and high-volume centers, respectively. Median disease-specific survival for patients at low and medium tiers were 1.4 years and 5.3 years, respectively, but was not reached for patients at high volume centers. Results showed that patients treated at high volume centers had better survival than those treated in low volume centers (HR: 0.63, 95% CI: 0.4-0.9), but showed no difference in outcomes between medium and high-volume centers., Conclusions: Our results suggest that for these increasingly common tumors, referral to a tertiary care center may be indicated. Physicians caring for GEP-NET patients should consider early referral to high volume centers.

Background: Prostate cancers frequently metastasize to bone, where the best microenvironment for distant colonization is provided. Since osteotropic metastasis of prostate cancer is a critical determinant of patients' survival, searches for preventive measures are ongoing in the field. Therefore, it is important to dissect the mechanisms of each step of bone metastasis, including the epithelial-mesenchymal transition (EMT) and cross-talk between metastatic niches and cancer cells., Methods: In this study, we established a highly bone-metastatic subline of human prostate cancer cells by selecting bone-homing population of PC3 cells after cardiac injection of eight-week-old male BALB/c-nude mice. Then we assessed the proliferation, EMT characteristics, and migration properties of the subline (mtPC3) cells in comparison with the parental PC3 cells. To investigate the role of S100A4, we performed gene knock-down by lentiviral transduction, or treated cells with recombinant S100A4 protein or a S100A4-neutralizing antibody. The effect of cancer cells on osteoclastogenesis was evaluated after treatment of pre-osteoclasts with conditioned medium (CM) from cancer cells., Results: The mtPC3 cells secreted a markedly high level of S100A4 protein and showed elevated cell proliferation and mesenchymal properties. The increased proliferation and EMT traits of mtPC3 cells was inhibited by S100A4 knock-down, but was not affected by exogenous S100A4. Furthermore, S100A4 released from mtPC3 cells stimulated osteoclast development via the cell surface receptor RAGE. Down-regulation or neutralization of S100A4 in the CM of mtPC3 cells attenuated cancer-induced osteoclastogenesis., Conclusion: Altogether, our results suggest that intracellular S100A4 promotes cell proliferation and EMT characteristics in tumor cells, and that secreted S100A4 activates osteoclastogenesis, contributing to osteolytic bone metastasis. Thus, S100A4 upregulation in cancer cells highly metastatic to bone might be a key element in regulating bone metastasis.

Background: Precise measurement of ocular biometry is critical for determining intraocular lens power. Newly developed swept-source optical coherence tomography (SS-OCT) - based ocular biometric devices, ANTERION and CASIA2 provide ocular biometric measurements as IOLMaster 700. This study aimed to assess agreement between three devices., Methods: This retrospective comparative study includes patients with cataract who underwent ocular biometric measurements with three devices, ANTERION, CASIA2, and IOLMaster 700, at Seoul National University Hospital, in April 2020. Anterior keratometry, total keratometry, central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) were the main parameters for the comparison. To assess the agreement between the devices, intraclass coefficient (ICC) and Bland-Altman analysis with 95% limits of agreement (LoA) were used., Results: A total of 47 eyes of 29 patients were measured with three devices. Average anterior keratometry showed excellent agreement (ICC ≥ 0.989), and the mean difference was less than 0.1 D. However, the ICC of the total average keratometry ranged from 0.808 to 0.952, and the difference was more than 0.43 D. The AL measured by ANTERION and IOLMaster 700 showed excellent agreement (ICC = 0.999), and the mean difference was 0.005 mm. The ANTERION and IOLMaster 700 did not obtain AL in six (12.8%) and three (6.4%) cases, respectively (P = 0.001 by Fisher's exact test). The CCT, ACD, and LT also showed excellent agreement (ICC > 0.9)., Conclusions: The new SS-OCT-based devices, ANTERION, and CASIA2 showed a good agreement with IOLMaster 700 in measuring ocular biometry except for the total keratometry. The AL of ANTERION and IOLMaster 700 showed excellent agreement.

Background: Some sea anemone toxins cause renal injuries resembling hemolytic uremic syndrome (HUS). To date, only a few cases of HUS caused by sea anemone stings have been reported. In this case report, we have described an HUS case caused by a sea anemone sting., Case Presentation: In November 2019, a 37-year-old man with no underlying disease was admitted to our hospital. He presented with intense pain, a rash on, and swelling in his right thigh. Two days prior, he had been stung by a sea anemone while scuba diving in Cebu, Philippines. His blood tests revealed renal dysfunction, and his platelet count was normal. However, on day three, the platelet count decreased rapidly. His blood haptoglobin level decreased, and schistocytes were identified on the peripheral blood smear. We suspected thrombotic microangiopathy and started the conventional treatment, comprising hemodialysis, blood transfusion, and antibiotic administration. ADAMTS-13 and genetic test results associated with atypical HUS were normal. Therefore, the patient was diagnosed with HUS caused by a sea anemone toxin., Conclusions: HUS caused by a sea anemone toxin is rare, but it is a serious medical disease. Clinicians should consider HUS in patients with such clinical presentations, and they should make prompt treatment-related decisions.

Background: Metabolic syndrome (MetS) status changes over time, but few studies have investigated the relationship between the extent or duration of exposure to MetS and the risk of cardiovascular disease (CVD). We investigated the cumulative effects of MetS and its components on the risk of myocardial infarction (MI) and stroke., Methods: From the Korean National Health Insurance database, 2,644,851 people who received annual health examinations from 2010 to 2013 were recruited. Exposure-weighted scores for MetS during this 4-year period were calculated in two ways: cumulative number of MetS diagnoses (MetS exposure score, range: 0-4) and the composite of its five components (MetS component exposure score, range: 0-20). The multivariable Cox proportional-hazards model was used to assess CVD risk according to the exposure-weighted scores for MetS., Results: MetS was identified at least once in 37.6% and persistent MetS in 8.2% of subjects. During the follow-up (median, 4.4 years), 10,522 cases of MI (0.4%) and 10,524 cases of stoke (0.4%) occurred. The risk of MI and stroke increased gradually with increasing exposure scores of MetS and its components (each P for trend < 0.0001). The hazard ratio [(HR) (95% CI)] of MI and stroke were 5.27 (4.20-6.62) and 3.90 (3.09-4.93), respectively, in those with a score of 20 compared with those with a MetS component exposure score of 0. People fulfilling only two MetS components out of 20 already had 22% increased risk of MI, and those with three MetS components had 24% increased risk of stroke. These associations were consistent in the subgroup and sensitivity analyses., Conclusions: A dose-response relationship between the cumulative exposure to metabolic disturbances and incident MI or stroke was evident. Even minimal exposure to MetS components was sufficient to increase the risk of CVD significantly, highlighting the importance of intensive risk management for the prevention of CVD.

Background: This study aimed to evaluate the benefit of brachial-ankle pulse wave velocity (baPWV) as a noninvasive marker of arterial stiffness for the prediction of all-cause and cause-specific mortality in patients with type 2 diabetes., Methods: This multicenter prospective observational study analyzed 2308 patients with type 2 diabetes between 2008 and 2018. The patients were categorized according to the quartiles of baPWV. Cause of mortality was determined using death certificates and patient clinical records. We estimated proportional mortality rates from all causes, cardiovascular, cancer, and other causes among adults with diabetic status according to their baPWV. Cox regression models were used to estimate hazard ratios (HRs)., Results: There were 199 deaths (8.6%) in the study population during a median follow-up duration of 8.6 years. When baPWV was assessed as quartiles, a significantly higher risk of all-cause mortality (HR = 5.39, P < 0.001), cardiovascular-mortality (HR = 14.89, P < 0.001), cancer-mortality (HR = 5.42, P < 0.001), and other-cause mortality (HR = 4.12, P < 0.001) was found in quartile 4 (Q4, ≥ 1830 cm/s) than in quartiles 1-3 (Q1-3). Adding baPWV to baseline model containing conventional risk factors such as age, sex, diabetes duration, body mass index, glycated hemoglobin, systolic blood pressure, glomerular filtration rate, smoking, and insulin improved the risk prediction for all-cause (net reclassification index (NRI) = 49%, P < 0.001) and cause-specific (cardiovascular NRI = 28%, P = 0.030; cancer NRI = 55%, P < 0.001; other-cause NRI 51%, P < 0.001) mortality., Conclusion: This long-term, large-scale, multicenter prospective observational cohort study provide evidence that increased arterial stiffness, as measured by baPWV, predicts the risk of all-cause and cause-specific mortality in type 2 diabetes, supporting the prognostic utility of baPWV. Trial registration Clinical Research Information Service (CRIS), KCT 0005010. Retrospectively Registered May 12, 2020. https://cris.nih.go.kr/cris/search/search&#95;result&#95;st01.jsp?seq=16677.

Background: By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice., Methods: This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care., Results: A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24-89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620)., Conclusions: In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.

Background: Dyslipidemia is a well-known risk factor for cardiovascular disease (CVD). Recently, atherogenic index of plasma (AIP) has been proposed as a novel predictive marker for CVD, and few cross sectional studies have demonstrated a relationship between AIP and coronary artery disease. The present study investigated the association between AIP and the progression of coronary artery calcification (CAC) in Korean adults without CVD., Methods: A total of 1124 participants who had undergone CAC measurement at least twice by multi-detector computed tomography (CT) at a health check-up center were enrolled. Their anthropometric measurements and various cardiovascular risk factors were assessed. AIP was defined as the base 10 logarithm of the ratio of the concentration of triglyceride (TG) to high-density lipoprotein-cholesterol (HDL-C). CAC progression was defined as either incident CAC in a CAC-free population at baseline, or an increase of ≥2.5 units between the square roots of the baseline and follow-up coronary artery calcium scores (CACS) in subjects with detectable CAC at baseline., Results: CAC progression was observed in 290 subjects (25.8%) during the mean follow-up of 4.2 years. All subjects were stratified into three groups according to AIP. There were significant differences in cardiovascular parameters among groups at baseline. The follow-up CAC and the incidence of CAC progression increased gradually with rising AIP tertiles. In logistic regression analysis, the odds ratio for CAC progression was 2.27 when comparing the highest to the lowest tertile of AIP (95% CI: 1.61-3.19; P for trend < 0.01). However, this association was attenuated after adjustment for multiple risk factors (P for trend = 0.67)., Conclusions: There is a significant correlation between AIP and the progression of CAC in subjects without CVD. Although AIP was not an independent predictor of CAC progression, AIP should be considered when estimating the current as well as future CVD risk, along with other traditional risk factors.

An amendment to this paper has been published and can be accessed via the original article.

Background: Poor quality obstetric and newborn care persists in sub-Saharan Africa and weak provider competence is an important contributor. To be competent, providers need to be both knowledgeable and confident in their ability to perform necessary clinical actions. Confidence or self-efficacy has not been extensively studied but may be related to individuals' knowledge, ability to practice their skills, and other modifiable factors. In this study, we investigated how knowledge and scope of practice are associated with provider confidence in delivering obstetric and newborn health services in Uganda and Zambia., Methods: This study was a secondary analysis of data from an obstetric and newborn care program implementation evaluation. Provider knowledge, scope of practice (completion of a series of obstetric tasks in the past 3 months) and confidence in delivering obstetric and newborn care were measured post intervention in intervention and comparison districts in Uganda and Zambia. We used multiple linear regression models to investigate the extent to which exposure to a wider range of clinical tasks associated with confidence, adjusting for facility and provider characteristics., Results: Of the 574 providers included in the study, 69% were female, 24% were nurses, and 6% were doctors. The mean confidence score was 71%. Providers' mean knowledge score was 56% and they reported performing 57% of basic obstetric tasks in the past 3 months. In the adjusted model, providers who completed more than 69% of the obstetric tasks reported a 13-percentage point (95% CI 0.08, 0.17) higher confidence than providers who performed less than 50% of the tasks. Female providers and nurses were considerably less confident than males and doctors. Provider knowledge was moderately associated with provider confidence., Conclusions: Our study showed that scope of practice (the range of clinical tasks routinely performed by providers) is an important determinant of confidence. Ensuring that providers are exposed to a variety of services is crucial to support improvement in provider confidence and competence. Policies to improve provider confidence and pre-service training should also address differences by gender and by cadres.

Background: The differentiation of human mesenchymal stem cells (hMSCs) into osteoblasts (OBs) is a prerequisite for bone formation. However, little is known about the definitive surface markers for OBs during osteogenesis., Methods: To study the surface markers on OBs, we generated and used monoclonal antibodies (MAbs) against surface molecules on transforming growth factor-β1 (TGF-β1)-treated cancer cells. The generated MAbs were further selected toward expression changes on hMSCs cultured with TGF-β1/bone morphogenetic protein-2 (BMP-2) or osteogenic differentiation medium (ODM) by flow cytometry. Immunoprecipitation and mass spectrometry were performed to identify target antigens of selected MAbs. Expression changes of the target antigens were evaluated in hMSCs, human periodontal ligament cells (hPDLCs), and human dental pulp cells (hDPCs) during osteogenic and adipogenic differentiation by quantitative polymerase chain reaction (qPCR) and flow cytometry. hMSCs were also sorted by the MAbs using magnetic-activated cell sorting system, and osteogenic potential of sorted cells was evaluated via Alizarin Red S (ARS) staining and qPCR., Results: The binding reactivity of MR14-E5, one of the MAbs, was downregulated in hMSCs with ODM while the binding reactivity of ER7-A7, ER7-A8, and MR1-B1 MAbs was upregulated. Mass spectrometry and overexpression identified that MR14-E5, ER7-A7/ER7-A8, and MR1-B1 recognized integrin α2, α3, and αV, respectively. Upon osteogenic differentiation of hMSCs, the expression of integrin α2 was drastically downregulated, but the expression of integrin α3 and αV was upregulated in accordance with upregulation of osteogenic markers. Expression of integrin α3 and αV was also upregulated in hPDLCs and hDPCs during osteogenic differentiation. Cell sorting showed that integrin αV-high hMSCs have a greater osteogenic potential than integrin αV-low hMSCs upon the osteogenic differentiation of hMSCs. Cell sorting further revealed that the surface expression of integrin αV is more dramatically induced even in integrin αV-low hMSCs., Conclusion: These findings suggest that integrin α3 and αV induction is a good indicator of OB differentiation. These findings also shed insight into the expression dynamics of integrins upon osteogenic differentiation of hMSCs and provide the reason why different integrin ligands are required for OB differentiation of hMSCs.

Background: Functional communication is vital in many areas of daily life, and modifying dysfunctional communication has been emphasized in various social areas, including family and school. The present preliminary study addressed the feasibility of a virtual reality (VR)-based interactive feedback program for the modification of dysfunctional communication., Methods: Thirty-seven healthy young males completed psychological assessments associated with functional communication and participated in the VR-based program, consisting of the three tasks of 'exploring the communication style,' 'practicing functional communication,' and 'expressing empathy.' Behavioral parameters were recorded based on the participants' choices among available options and the visual analog scale scores that resulted in responses to questions in the tasks., Results: Participants completed the program without dropping-out and reported 10.76 (SD, 9.66) in the Simulator Sickness Questionnaire and 106.97 (SD, 16.66) in the Presence Questionnaire. In exploring the communication style, there was no difference between the dysfunction level-with family and dysfunction level-with a friend, but only the dysfunction level-with family showed significant correlations with the level of communication with parents. In practicing functional communication, the communication scores with the placating, blaming, and computing styles significantly increased according to the repetition of trials. In expressing empathy, the empathetic feeling score was negatively correlated with the perspective-taking score, whereas the emotional intensity score was positively correlated with the level of differentiation of the self., Conclusion: These results suggest that the program may have a tolerable level of cybersickness, an adequate level of presence, an improvement in the behavioral parameters that may reflect the important aspects of communication, and a proper reflection of psychological states or interpersonal characteristics. The use of this program can be an important starting point for the development of a more convenient method for delivering VR programs designed to modify dysfunctional communication, which can further increase computerized dissemination.

Background: Currently, various types of toric intraocular lenses (IOL) have been manufactured and can be divided into three types according to the location of correction component; front-toric IOL (correction on anterior IOL surface), back-toric IOL (correction on posterior IOL surface), and bi-toric IOL (correction on both anterior and posterior IOL surfaces). In this study, we aimed to investigate the effectiveness of reducing corneal astigmatism of either normal or post-penetrating keratoplasty (PKP) corneas according to the type of implanted toric IOLs., Methods: Medical records were retrospectively reviewed in 370 patients who had undergone phacoemulsification with posterior chamber toric IOL insertion (front-toric IOL, back-toric IOL or bi-toric IOL). Subjects were divided into 2 groups; subjects who had no history of corneal disease with corneal astigmatism more than 1.00 diopters (D) (G1) and subjects who received previous PKP with all corneal sutures removed and had corneal astigmatism more than 1.25 D (G2). Preoperatively intended target from SRK/T was evaluated. Refractive astigmatism and its vector analysis (J0, J45), mean numerical error (MNE) and mean absolute error (MAE) were assessed at least a month after cataract surgery., Results: Mean preoperative corneal astigmatisms were 2.2 D and 4.0 D in G1 and G2, respectively. There was significant reduction of mean postoperative refractive astigmatism to 0.89 D in G1 and to 2.33 D in G2. In G1, bi-toric IOL showed significantly more improved refractive astigmatism than back-toric IOL. In G2, no difference in refractive astigmatism according to toric IOL type was observed. While G2 showed no difference in MNE among toric IOLs, in G1, bi-toric IOL showed significant hyperopic shift compared to back-toric IOL. In both groups, there was no significant difference in MAE according to type of IOL. No postoperative complications were observed., Conclusion: Our study suggests that all types of toric IOL are beneficial in correcting astigmatism of normal and post-PKP corneas. Noticeably, bi-toric IOL showed significantly better results in refractive astigmatism than back-toric IOL in normal cornea. However, bi-toric IOL showed a more hyperopic shift compared to back-toric IOL. Among post-PKP corneas, all types of toric IOL showed similar results.

Background: The aim of this study was to characterize the mechanical and physio-biological properties of peptide-coated stent (PCS) compared to commercialized drug-eluting stents (DESs)., Methods: WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met), a stimulating peptide for homing endothelial colony-forming cell was specially synthesized and coated to bare metal stent (BMS) by dopamine-derived coordinated bond. Biological effects of PCS were investigated by endothelial cell proliferation assay and pre-clinical animal study. And mechanical properties were examined by various experiment., Results: The peptide was well-coated to BMS and was maintained and delivered to 21 and 7 days in vitro and in vivo, respectively. Moreover, the proliferation of endothelial cell in PCS group was increased (approximately 36.4 ± 5.77%) in PCS group at 7 day of culture compare to BMS. Although, the radial force of PCS was moderated among study group. The flexibility of PCS was (0.49 ± 0.082 N) was greatest among study group. PCS did not show the outstanding performance in recoil and foreshortening test (3.1 ± 0.22% and 2.1 ± 0.06%, respectively), which was the reasonable result under the guide line of FDA (less than 7.0%). The nominal pressure (3.0 mm in a diameter) of PCS established by compliance analysis was 9 atm. The changing of PCS diameter by expansion was similar to other DESs, which is less than 10 atm of pressure for the nominal pressure., Conclusions: These results suggest that the PCS is not inferior to commercialized DES. In addition, since the PCS was fabricated as polymer-free process, secondary coating with polymer-based immunosuppressive drugs such as -limus derivatives may possible., Competing Interests: Competing interestsThe authors declare that they have no competing interest., (© The Author(s). 2020.)

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer that develops in the pleural and outer layer of tissues surrounding the lungs. MPM is primarily caused by occupational exposure to asbestos and results in a poor prognosis. Effective therapeutics as well as early diagnostics for the MPM are still lacking. To identify potential diagnostic biomarkers for MPM, we performed bioinformatics analysis of public database., Methods: Utilizing databases from Cancer Cell Line Encyclopedia (CCLE) and Gene Expression Omnibus (GEO), we identified several potential candidates that could act as MPM biomarkers. We carried out additional molecular analyses of these potential markers using MPM patient tissue samples via quantitative polymerase chain reaction., Results: We identified Lysyl oxidase (LOX), Lysyl oxidase homologs 1&2 (LOXL1& LOXL2) Zinc Finger Protein, FOG Family Member 2 (ZFPM2) as potential diagnostic biomarkers for MPM. In this study, we found that the LOX family and ZFPM2 showed comparable diagnostic ability to Fibulin-3 or mesothelin (MSLN) and would be better potential biomarkers than Sulfatase 1 (SULF1), Thrombospondin 2 (THBS2) and Cadherin 11 (CDH11)., Conclusions: LOX family and ZPFM2 were identified as novel MPM diagnostic biomarkers which could strengthen MPM clinical diagnostic capabilities., Competing Interests: Competing interestThe authors have no conflict of interest., (© The Author(s). 2020.)

Background: The aim of the present study was to identify a threshold for the cholesterol level at which the risk of cardiovascular disease (CVD) begins to increase in people with type 2 diabetes mellitus (DM)., Methods: Using the Korean National Health Insurance Service database, 2,077,135 people aged ≥ 40 years with type 2 DM who underwent regular health checks between 2009 and 2012 were included. Subjects with previous CVD were excluded. Cox regression analyses were performed to estimate the risk of CVD for each low-density lipoprotein cholesterol (LDL-C) group using the < 70 mg/dL as the reference group., Results: There were 78,560 cases of stroke (3.91%), and 50,791 myocardial infarction (MI, 2.53%) during a median follow-up of 7.1 years. Among participants not taking statins, LDL-C levels of 130-159 mg/dL and ≥ 160 mg/dL were significantly associated with the risk of MI: the hazard ratios (HRs) (95% confidence interval) were 1.19 (1.14-1.25) and 1.53 (1.46-1.62), respectively. Among participants taking statins, all categories of LDL-C level ≥ 70 mg/dL were significantly associated with increased risk of stroke and MI., Conclusions: We identified an increased risk of CVD in people with an LDL-C level ≥ 130 mg/dL among individuals with type 2 DM not taking statins. The risk of CVD was significantly higher in those taking statins with an LDL-C level ≥ 70 mg/dL.

Background: The guidelines to correct the mechanical axis in high tibial osteotomy (HTO) have changed recently, and some studies have suggested that the correction of the mechanical axis should be based on the severity of cartilage defect. The purpose of this study was (1) to evaluate the radiographic and clinical outcomes of HTO with concomitant cartilage procedures and (2) to compare our method with conventional method regarding the mechanical axis correction., Methods: Sixty-six knees which underwent opening wedge HTO with cartilage procedures were evaluated retrospectively. The mean age was 56.0 ± 8.3 years, and the average follow-up period was 35.9 ± 22.0 months (range, 24-93 months) with a minimum follow-up of 2 years. All patients were divided into two groups regarding the method of mechanical axis correction; the postoperative mechanical axis was shifted to 50-55% of the tibial plateau width in group I (n = 46) and to 62-66% according to the conventional method in group II (n = 20). Concomitant cartilage procedures were performed, and each technique of those was determined according to the cartilage status., Results: The functional scores and visual analog scale for pain in all patients showed a significant improvement at the final follow-up, but there was no significant difference between two groups. The postoperative mechanical axis was the valgus axis of 0.7° in group I with average mechanical axis deviation (MAD) of 51.7%, whereas the valgus axis of 4.2° in group II with average MAD of 64.0%. In patients who underwent second-look arthroscopy, the cartilaginous regeneration could be obtained by cartilage procedures., Conclusion: In HTO with concomitant cartilage procedures, the method to correct postoperative mechanical axis to the neutral or valgus axis less than 3° could be an effective and safe method to obtain reliable clinical outcomes without complications. Therefore, our method can be used as a selective technique to prevent complications related to the postoperative valgus alignment in patients who are needed much correction angle due to the preoperative severe varus alignment., Study Design: Retrospective comparative study, level III.

Background: This study is aim to compare the clinical effectiveness between the two most prominent dry eye disease (DED)-specific eye drops, 0.05% cyclosporine (CN) and 3% diquafosol (DQ)., Methods: This is a multi-centered, randomized, masked, prospective clinical study. A total of 153 DED patients were randomly allocated to use CN twice per day or DQ six times daily. Cornea and conjunctival staining scores (NEI scale), tear break-up time (TBUT), Schirmer test scores, and ocular surface disease index (OSDI) score were measured at baseline, 4 and 12 weeks after treatment., Results: At 12 weeks after treatment, NEI scaled scores were significantly reduced from the baseline by - 6.60 for CN and - 6.63 for DQ group (all P < 0.0001, P = 0.9739 between groups). TBUT and Schirmer values for CN were significantly improved from the baseline at 4 and 12 weeks (P = 0.0034, P < 0.0001 for TBUT, P = 0.0418, P = 0.0031 for Schirmer test). However, for DQ, TBUT showed significant improvement at 12 weeks only (P = 0.0281). Mean OSDI score differences from the baseline to 12 weeks were improved by - 13.03 ± 19.63 for CN and - 16.11 ± 20.87 for DQ, respectively (all P < 0.0001, P = 0.854 between groups). Regarding drug compliance, the mean instillation frequency of CN was less than that of DQ (P < 0.001). There were no statistically significant intergroup differences in safety evaluation., Conclusions: The level of improvement regarding NEI, TBUT, and OSDI scores were not significantly different between the two treatment groups. However, with regards to the early improvement of TBUT and patient compliance, patients using CN improved faster and with greater adherence to drug usage than did those treated with DQ., Trial Registration: KCT0002180 , retrospectively registered on 23 December 2016.

Background: Actinomycosis is a rare, chronic granulomatous disease caused by Gram-positive anaerobic bacteria that colonize the oral cavity. Cervicofacial actinomycosis is the most frequent clinical presentation of actinomycosis, but hematogenous osteomyelitis at distant sites can occur in rare instance in immunocompromised or pediatric patients, only a few cases have been reported in healthy patients. Here we described a new case of distal femur osteomyelitis caused by Actinomyces in an adult patient who was immunocompetent and had no predisposing factors., Case Presentation: A woman aged 52 years with no history of trauma presented with severe pain, swelling, and increased local heat in the proximal area of the right knee 3 weeks after she first noticed discomfort. Magnetic resonance imaging showed persistent osteomyelitis of the distal metaphysis and diaphysis of the femur with a multifocal intraosseous abscess pocket. An incision and drainage of the abscess were conducted. The tissue culture, fungus culture, acid fast bacillus (AFB) culture, AFB smear, and tuberculosis polymerase chain reaction test results were negative. A pathologic examination confirmed the presence of actinomycosis. The patient was successfully treated with intravenous penicillin G for 8 weeks followed by oral amoxicillin-clavulanate for 6 weeks with repeated surgical debridement and drainage. After a 5-year follow up, the patient had no signs of recurring infection or complications and she had full range of movement in the affected knee., Conclusions: Although rare, actinomycotic osteomyelitis can occur in healthy people. Furthermore, actinomycotic osteomyelitis is easily misdiagnosed as tuberculosis in areas with a high prevalence of tuberculosis. To detect and identify the bacteria accurately, pathologic examination should be performed as well as culture tests, because the probability for culture confirmation of actinomycosis is quite low. The initial treatment is vital to a successful outcome without ostectomy or amputation.

Background: Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib., Methods: This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients., Results: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes., Conclusion: Pretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib.

Background: Because weight control is a cornerstone of diabetes management, it is important to understand the relationship of weight change to risk of cardiovascular disease (CVD) among patients with type 2 diabetes mellitus (DM). We aimed to investigate whether changes in weight early after diagnosis influence the incidence of CVD and all-cause mortality in patients with type 2 DM., Methods: Using nationally representative data from the Korean National Health Insurance System, 173,246 subjects with new-onset DM who underwent health examinations during 2007-2012 were included. Weight was measured at the time of diabetes diagnosis and 2 years later. Weight change over 2 years was divided into five categories of 5% weight change, from weight loss ≥ - 10% to weight gain ≥ 10%., Results: There were 3113 deaths (1.8%), 2060 cases of stroke (1.2%), and 1767 myocardial infarctions (MIs) (1.0%) during a median follow-up of 5.5 years. Subjects with weight gain ≥ 10% had a significantly higher risk of stroke (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.23-1.84), compared with the group with stable weight. There was no significant association between weight change after diagnosis of DM and incident MI. All-cause mortality showed a U-shaped curve according to weight change. The group with weight loss ≥ - 10% had the highest HR for all-cause mortality (HR 1.86; 95% CI 1.61-2.14) and the HR for weight gain ≥ 10% was 1.61 (95% CI 1.37-1.89)., Conclusions: Weight changes of more than 10% after diabetes diagnosis were associated with higher mortality and over 10% weight gain was associated with increased risk of stroke.

Background: To investigate the efficacy and safety of the retention ring-assisted continuous application of 0.1% riboflavin in pulsed-light accelerated corneal collagen cross-linking on the progression of keratoconus., Methods: The medical records of 20 eyes of 18 patients with progressive keratoconus who received collagen cross-linking at Seoul National University Hospital were retrospectively reviewed. Isotonic 0.1% riboflavin was continuously applied for 10 min using an 8.0-mm retention ring before the irradiation and accelerated cross-linking was applied with 30-mW pulsed-ultraviolet light at a wavelength 365 nm for eight minutes (1 s on/1 s off; 30 mW/cm 2 , cumulative dose of 7 .2J/cm 2 ) without further intermittent application of riboflavin. Visual acuity, refractive error, topographic index, corneal thickness, and endothelial cell density were evaluated before the operation and at 1, 3, 6, and 12 months., Results: The best corrected visual acuity in logMAR improved from preoperative 0.43 to 0.17 in 12 months (p = 0.050). Maximum keratometry decreased from 51.8 D to 50.4 D at 6 months (p = 0.015) and 50.1 D at 12 months (p = 0.0003). Astigmatism decreased from preoperative 5.5 D to 4.1 D at 12 months (p < 0.0001). Thinnest corneal thickness decreased at three and 6 months but recovered in 12 months (p > 0.05). Endothelial cell density decreased at postoperative 1 month (p = 0.02) but gradually recovered in 12 months (p > 0.05)., Conclusions: Retention ring-assisted continuous application of riboflavin for 10 minutes in pulsed-light accelerated cross-linking is a comparably safe and effective treatment for halting the progression of keratoconus in 12 months when compared to outcomes of the standard Dresden protocol shown in previous reports.

Background: Degenerative knee osteoarthritis is a leading cause of disability in the elderly. If patients do not respond to pharmacological or nonpharmacological intervention, total knee replacement surgery is recommended. However, owing to the contraindications and adverse effects of surgery, the need for a new treatment strategy is emerging. Traditional herbal medicine is a widely used intervention in east Asia to treat knee osteoarthritis. Gyejigachulbutang is one of the frequently prescribed herbal formulae. The aim of our study is to evaluate the efficacy and safety of gyejigachulbutang for knee osteoarthritis., Methods: This study is a randomized, placebo-controlled, patient and assessor blinded, superiority clinical trial. A total of 80 patients with knee osteoarthritis will be enrolled. The participants will be randomly assigned to the gyejigachulbutang or placebo group in a 1:1 ratio in two Korean medical hospitals. Every participant will take gyejigachulbutang or placebo at a dose of 2.5 g three times a day for 4 weeks. Additional follow-up will be conducted 4 weeks after treatment completion. Any concomitant treatment to relive knee pain will not be allowed except for rescue medicine (acetaminophen). The primary outcome will be a comparison of the change in the visual analogue scale score for knee pain from baseline to visit 3 (week 4) for both the treatment and placebo groups. Secondary outcomes include clinical relevance, minimal clinically important difference, disability, quality of life, and safety., Discussion: This protocol presents a research methodology for clinical trials of gyejigachulbutang for knee osteoarthritis. Various secondary outcomes make this trial more informative. Our trial will provide fundamental evidence for knee osteoarthritis management via herbal medicine treatment., Trial Registration: Clinical Research Information Service (CRIS), KCT0003024 . Registered on 25 July 2018.

Background: The purpose of this study is to compare the biometric parameters and intraocular lens (IOL) power calculation by a new swept-source optical coherence tomography (SS-OCT) biometer with those by a partial coherence interferometry (PCI) biometer., Methods: Medical records of 175 eyes from 175 patients were retrospectively reviewed. One of two monofocal IOLs (Tecnis ZCB00 or Acrysof SA60AT) were implanted in the eyes. Axial length (AL), mean keratometry (Km), J0, J45 and anterior chamber depth (ACD) were compared between PCI and SS-OCT biometers. The refractive mean error (ME) and refractive mean absolute error (MAE) were also compared. Examination failure rates were calculated in each device., Results: Out of 175 eyes, 150 eyes were successfully examined by both devices. AL was measured slightly shorter when using SS-OCT than PCI biometer, while Km was measured higher (P < .0001, P = .03, respectively, paired t-test). J0, J45 and ACD were not significantly different between two devices. ME and MAE calculated using SRK-T, Hoffer Q, and Haigis formula were not significantly different except MAE calculated with Haigis formula for Tecnis ZCB00 IOLs (P = .03, paired t-test). The examination failure rates were 14.29 and 1.14% when using the PCI and SS-OCT biometers, respectively., Conclusions: AL and Km don't seem to be comparable between two devices, while J0, J45 , and ACD do. IOL power calculation using SRK-T and Hoffer Q was correlated between the devices. The penetration ability of a SS-OCT biometer is superior.