To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

To investigate the relationship between depression and AD, water avoidance stress (WAS) was induced for 10 days in both Tg2576 mice and wild-type (WT) mice. After WAS, memory function and depressive-like behavior were investigated in Tg2576 mice. Tg2576 WAS mice exhibited more depressive-like behaviors than WT WAS and Tg2576 control (CON) mice. Strikingly, Tg2576 CON mice showed more depressive-like behaviors than WT mice. Moreover, corticosterone and phospho-glucocorticoid receptor (p-GR) levels were also higher in Tg2576 WAS mice in comparison to Tg2576 CON mice. Spinster homologue 2 (SPNS2) is a member of non-ATP-dependent transporter. The role of SPNS2 was widely known as a sphingosine-1-phosphate (S1P) transporter, which export intracellular S1P from cells. Using GEO database to analyze SPNS2 gene expression changes in patients with AD and depression, we show that SPNS2 gene expression correlates with AD and depression. Interestingly, Tg2576 WAS mice displayed significantly increased levels of SPNS2 w1hen compared to Tg2576 CON counterparts. SPNS2 levels were also higher in Tg2576 CON mice in comparison with WT CON mice. Remarkably, we found a decrease in S1P brain levels and an increase in S1P serum levels of Tg2576 WAS mice in comparison with Tg2576 CON mice. Accordingly, WAS induced group further decreased S1P levels in the brains. However, the level in the serum further increased in comparison with non-induced group. Therefore, these results suggest that AD and depression could be associated, and that Tg2576 transgenic mice are more susceptible to stress-induced depression through the release of S1P by SPNS2 up-regulation.

Purpose: The aim of this study was to investigate the occurrence of dry eye syndrome (DES) in children under 18 years old before and during the COVID-19 pandemic using nationwide population-based cohort analysis. Methods: This study utilized the database provided by the Korea Disease Control and Prevention Agency and the Korean National Health Insurance Service. We used claims-based data for patients diagnosed with COVID-19 between October 8, 2020, and December 31, 2021, and those without a diagnosis of COVID-19. DES cases were defined as having at least one diagnosis of H0411 or H1621 based on the International Classification of Diseases, 10th Revision codes. The primary outcome was the evaluation of the hazard ratio for DES between the COVID-19 season and the non–COVID-19 season. Results: A total of 198,486 individuals from the COVID-19 season cohort and 211,828 individuals from the non–COVID-19 season cohort were included in the study. There were no differences in characteristics between the COVID-19 season cohort and the non–COVID-19 season cohort (all standardized mean difference, <0.1). The cumulative incidence of DES during the COVID-19 season was significantly higher than that during the non–COVID-19 season. The COVID-19 season DES incidence rate was 6,419.64 per 100,000 person-years and non–COVID-19 season DES incidence rate was 5,804.88 per 100,000 person-years. In addition, children aged 13 to 18 years, female sex, those living in metropolitan areas, and those with diabetes mellitus had a higher risk of DES. Conclusions The prevalence of diagnosed DES in children increased during the COVID-19 pandemic compared to previous years. Children aged 13 to 18 years, female sex, those living in metropolitan areas, and those with diabetes mellitus had a higher risk of DES. Further studies are needed to directly analyze the potential factors associated with the increased prevalence of DES.

Severe bone defects pose a clinical challenge in total ankle arthroplasty (TAA) and are frequently considered contraindicated. We introduce an innovative approach that utilizes a structural tibial cut autograft to address anterior distal tibia bone defects during TAA. This technique is a viable alternative to employing revision TAA systems or resorting to excessively high tibial cuts. Furthermore, it facilitates achieving favorable sagittal alignment and ensures adequate fixation strength of the tibial component.

Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. −0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (−55.20% vs. −7.69%, P<0.001) without previously unknown adverse drug events. Conclusion The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin’s preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Background: Worldwide, sepsis is the leading cause of death in hospitals. If mortality rates in patients with sepsis can be predicted early, medical resources can be allocated efficiently. We constructed machine learning (ML) models to predict the mortality of patients with sepsis in a hospital emergency department. Methods: This study prospectively collected nationwide data from an ongoing multicenter cohort of patients with sepsis identified in the emergency department. Patients were enrolled from 19 hospitals between September 2019 and December 2020. For acquired data from 3,657 survivors and 1,455 deaths, six ML models (logistic regression, support vector machine, random forest, extreme gradient boosting [XGBoost], light gradient boosting machine, and categorical boosting [CatBoost]) were constructed using fivefold cross-validation to predict mortality. Through these models, 44 clinical variables measured on the day of admission were compared with six sequential organ failure assessment (SOFA) components (PaO 2 /FIO 2 [PF], platelets (PLT), bilirubin, cardiovascular, Glasgow Coma Scale score, and creatinine).The confidence interval (CI) was obtained by performing 10,000 repeated measurements via random sampling of the test dataset. All results were explained and interpreted using Shapley’s additive explanations (SHAP). Results: Of the 5,112 participants, CatBoost exhibited the highest area under the curve (AUC) of 0.800 (95% CI, 0.756–0.840) using clinical variables. Using the SOFA components for the same patient, XGBoost exhibited the highest AUC of 0.678 (95% CI, 0.626–0.730). As interpreted by SHAP, albumin, lactate, blood urea nitrogen, and international normalization ratio were determined to significantly affect the results. Additionally, PF and PLTs in the SOFA component significantly influenced the prediction results. Conclusion Newly established ML-based models achieved good prediction of mortality in patients with sepsis. Using several clinical variables acquired at the baseline can provide more accurate results for early predictions than using SOFA components. Additionally, the impact of each variable was identified.

Purpose: The aim of this study was to investigate the occurrence of dry eye syndrome (DES) in children under 18 years old before and during the COVID-19 pandemic using nationwide population-based cohort analysis. Methods: This study utilized the database provided by the Korea Disease Control and Prevention Agency and the Korean National Health Insurance Service. We used claims-based data for patients diagnosed with COVID-19 between October 8, 2020, and December 31, 2021, and those without a diagnosis of COVID-19. DES cases were defined as having at least one diagnosis of H0411 or H1621 based on the International Classification of Diseases, 10th Revision codes. The primary outcome was the evaluation of the hazard ratio for DES between the COVID-19 season and the non–COVID-19 season. Results: A total of 198,486 individuals from the COVID-19 season cohort and 211,828 individuals from the non–COVID-19 season cohort were included in the study. There were no differences in characteristics between the COVID-19 season cohort and the non–COVID-19 season cohort (all standardized mean difference, <0.1). The cumulative incidence of DES during the COVID-19 season was significantly higher than that during the non–COVID-19 season. The COVID-19 season DES incidence rate was 6,419.64 per 100,000 person-years and non–COVID-19 season DES incidence rate was 5,804.88 per 100,000 person-years. In addition, children aged 13 to 18 years, female sex, those living in metropolitan areas, and those with diabetes mellitus had a higher risk of DES. Conclusions The prevalence of diagnosed DES in children increased during the COVID-19 pandemic compared to previous years. Children aged 13 to 18 years, female sex, those living in metropolitan areas, and those with diabetes mellitus had a higher risk of DES. Further studies are needed to directly analyze the potential factors associated with the increased prevalence of DES.

Peripheral neurodegenerative diseases induced by irreversible peripheral nerve degeneration (PND), such as diabetic peripheral neuropathy, have a high prevalence worldwide and reduce the quality of life. However, there is no agent effective against the irreversible PND. After peripheral nerve injury, Schwann cells play an important role in regulating PND. However, because PND involves multiple biochemical events in Schwann cells, a one-drug-single-target therapeutic strategy is not feasible for PND. Here, we suggested that fascaplysin (Fas), a compound with multiple targets (CDK4/6), could overcome these problems. Fas exerted a significant inhibitory effect on axonal degradation, demyelination, and Schwann cell proliferation and dedifferentiation during in vitro and ex vivo PND. To discover the most likely novel target for PND, a chemo-bioinformatics analysis predicted the other on-targets of Fas and identified androgen receptor (AR) which were involved in Schwann cell differentiation and proliferation.AR interacted with Fas, and nuclear import of the AR/Fas complex was inhibited in Schwann cells, altering the expression patterns of transcription factors during PND. Therefore, Fas may have therapeutic potential for irreversible peripheral neurodegenerative diseases.

Purpose: The aim of this study was to investigate the occurrence of dry eye syndrome (DES) in children under 18 years old before and during the COVID-19 pandemic using nationwide population-based cohort analysis. Methods: This study utilized the database provided by the Korea Disease Control and Prevention Agency and the Korean National Health Insurance Service. We used claims-based data for patients diagnosed with COVID-19 between October 8, 2020, and December 31, 2021, and those without a diagnosis of COVID-19. DES cases were defined as having at least one diagnosis of H0411 or H1621 based on the International Classification of Diseases, 10th Revision codes. The primary outcome was the evaluation of the hazard ratio for DES between the COVID-19 season and the non–COVID-19 season. Results: A total of 198,486 individuals from the COVID-19 season cohort and 211,828 individuals from the non–COVID-19 season cohort were included in the study. There were no differences in characteristics between the COVID-19 season cohort and the non–COVID-19 season cohort (all standardized mean difference, <0.1). The cumulative incidence of DES during the COVID-19 season was significantly higher than that during the non–COVID-19 season. The COVID-19 season DES incidence rate was 6,419.64 per 100,000 person-years and non–COVID-19 season DES incidence rate was 5,804.88 per 100,000 person-years. In addition, children aged 13 to 18 years, female sex, those living in metropolitan areas, and those with diabetes mellitus had a higher risk of DES. Conclusions The prevalence of diagnosed DES in children increased during the COVID-19 pandemic compared to previous years. Children aged 13 to 18 years, female sex, those living in metropolitan areas, and those with diabetes mellitus had a higher risk of DES. Further studies are needed to directly analyze the potential factors associated with the increased prevalence of DES.