Background: and Purpose: To assess the long-term effectiveness, safety, and economic viability of recently approved Alzheimer’s disease (AD) therapies, as well as to evaluate the real-world application of novel diagnostics among AD patients with diverse comorbidities, comprehensive real-world data (RWD) analysis is essential. The Korean JOint RegistrY for ALZheimer’s Treatment and Diagnostics (JOY-ALZ) endeavors to create a registry of RWD derived from clinical practice on new diagnostic methods and therapeutic agents for AD introduced in Korea since 2021. Methods: Participants must fulfill all the following: 1) be at least 19 years old; 2) be actively receiving, scheduled to initiate, or undergoing evaluation for any AD disease-modifying treatment; 3) have completed amyloid positron emission tomography or cerebrospinal fluid AD immunoassay (a positive result is not essential for participation); 4) have a clinical classification of cognitively unimpaired, mild cognitive impairment, or probable AD dementia. Data generated during routine care is segmented into a minimum dataset, extended dataset, and research-only dataset requiring extra consent. Assessments encompass clinical, cognitive, functional, neurobehavioral, neuroimaging, and biomarker evaluations, in addition to systematic monitoring of new AD treatments and their safety.Data are collected and monitored at baseline, at semiannual intervals during the initial 2 years, and then annually up to 2034. To date, 46 medical centers will participate in JOY-ALZ. Conclusions JOY-ALZ is expected to promote understanding of the long-term clinical outcomes, safety, and cost-effectiveness of recently introduced diagnostics and treatments for AD, thereby supporting the progress of precision medicine in AD care and diagnosis.

Janus kinase (JAK) inhibitors are an important treatment option for ulcerative colitis, providing rapid onset of action, oral administration, and efficacy even after biologic failure. The 3 approved agents—tofacitinib, filgotinib, and upadacitinib—differ in JAK isoform selectivity, leading to clinically meaningful differences in efficacy and safety. Evidence from network meta-analyses, clinical trials, and real-world studies consistently shows that upadacitinib provides the highest efficacy for induction and maintenance of remission, whereas filgotinib demonstrates the most favorable safety profile. The strong efficacy of upadacitinib and tofacitinib is particularly relevant in patients with severe disease, including acute severe ulcerative colitis, and upadacitinib maintains high efficacy regardless of prior advanced therapy exposure. JAK inhibitors also benefit extraintestinal manifestations. Although risks such as herpes zoster, serious infection, thromboembolism, and major cardiovascular events differ among agents, long-term data suggest generally acceptable safety when used appropriately. Intraclass JAK-to-JAK cycling is feasible, with about half of patients achieving steroid-free clinical remission in retrospective cohorts. Based on mechanistic, clinical, and real-world evidence, filgotinib may be a first-line option for patients with lower disease activity or when safety is a priority, whereas upadacitinib or tofacitinib may be preferred in higher disease activity. Strategically selecting agents may improve durability and outcomes.

Background: Despite widespread vaccination efforts against severe acute respiratory syndrome coronavirus 2, variants with increased transmissibility or immune evasion continue to emerge, posing a considerable challenge. Understanding the immunological factors associated with coronavirus disease (COVID-19) progression is essential for improving patient management and treatment strategies. We explored the dynamic changes in the peripheral white blood cell (WBC) profile, including T lymphocyte subsets, to assess their potential as predictors of disease severity and progression. Methods: Two hundred fifty-eight patients hospitalized for confirmed COVID-19 were classified into four sub-cohorts based on changes in disease severity over 7 days. WBC parameters, including absolute neutrophil, total lymphocyte, and T cell subset counts, and the neutrophil-to-lymphocyte ratio (NLR) were assessed at admission and after 7 days. Results: Patients with persistent mild-to-moderate illness exhibited a marked increase in the lymphocyte count and a decrease in the NLR over time. In contrast, patients with sustained severe-to-critical illness showed an increasing WBC count without a corresponding increase in the lymphocyte count, in addition to a marked elevation in the NLR. Patients whose condition improved from severe-to-critical to mild-to-moderate illness showed increased cluster of differentiation (CD)3+ and CD4+ T cell counts and an elevated CD4/CD8 ratio, whereas the NLR did not significantly change. Conclusions The early-phase dynamics of T cell subsets may serve as a useful biomarker of disease severity and recovery in patients with COVID-19. Monitoring these immunological changes may help support clinical decision-making and inform the timing of therapeutic interventions.

BACKGROUND/OBJECTIVES: Obesity is a complex metabolic disorder characterized by excessive adipose tissue accumulation, dysregulated lipid metabolism, and insulin resistance, leading to an increased risk of metabolic disease. While Withania somnifera (AS) and Chrysanthemum zawadskii Herbich var. latilobum (Maxim.) Kitamura (C) have traditionally been used for their metabolic regulatory properties, their combined effects on adipogenesis, lipogenesis, lipolysis, and insulin signaling remain unexplored. Therefore, this study aimed to evaluate the anti-obesity effects of AS, C, and their optimal combination (ASC) in 3T3-L1 adipocytes by investigating their impact on lipid metabolism and glucose homeostasis.MATERIALS/METHODS: Following adipogenic differentiation, 3T3-L1 adipocytes were treated with AS, C, and ASC at different concentrations. RESULTS: AS, C, and ASC significantly inhibited adipogenesis by downregulating cyclic adenosine monophosphate (cAMP) response element-binding protein, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding proteins alpha and beta phosphorylation, thereby reducing lipid accumulation in adipocytes. They also suppressed lipogenesis by downregulating the expression of dephosphorylated acetyl-CoA carboxylase, fatty acid synthase, and lipoprotein lipase. In contrast, they markedly enhanced lipolysis, as evidenced by increased hormone-sensitive lipase and protein kinase A expression, along with elevated glycerol release and cAMP levels. Furthermore, AS, C, and ASC activated energy metabolism pathways, as indicated by the upregulation of AMP-activated protein kinase, uncoupling protein 1, and carnitine palmitoyltransferase 1A, suggesting a transition toward enhanced mitochondrial fatty acid oxidation. Notably, AS, C, and ASC significantly improved insulin signaling by restoring insulin receptor substrate 1, phosphoinositide 3-kinase, and Akt phosphorylation, while upregulating glucose transporter type 4 expression, indicating enhanced glucose uptake. Among all treatments, ASC showed relatively greater efficacy compared to AS or C alone, suggesting a potential additive effect. CONCLUSION These findings demonstrate that ASC effectively modulates multiple metabolic pathways in adipocytes, including adipogenesis, lipogenesis, lipolysis, energy metabolism, and insulin signaling, to exert its anti-obesity effects.

Background: To investigate the fracture risks associated with anti-diabetic drugs in older women with type 2 diabetes mellitus (T2DM), who are particularly susceptible to skeletal fragility. Methods: Using data from the Korean National Health Insurance Service, this nested case-control study included 10,104 older women with T2DM and osteoporotic fractures (aged 66.5±3.4 years) matched in a 1:3 ratio with controls by birthdate, Charlson Comorbidity Index, and cohort entry date. We analyzed the odds of major osteoporotic fracture (MOF), vertebral fracture (VF), and non-VF (NVF) in users of sulfonylurea, thiazolidinedione (TZD), dipeptidyl peptidase-4 inhibitor, and sodium-glucose cotransporter 2 inhibitor (SGLT2i), compared to metformin (Met)-only users using multivariable logistic regression. Results: During a follow-up period of 3.8±2.8 years, TZD users had a higher risk of MOF than Met-only users (odds ratio [OR], 1.35; 95% confidence interval [CI], 1.19-1.53; P<0.001). Risks of VF and NVF were also increased in the TZD group (OR, 1.21; 95% CI 1.03-1.42; P=0.022 and OR, 1.32; 95% CI 1.14-1.52; P<0.001, respectively). No significant differences were observed in other drug groups. The increased risk of VF and NVF in the TZD group were particularly pronounced in patients with normal or osteopenic bone mineral density (BMD) and in those with normal body mass index (BMI), respectively. Conclusions In older women with T2DM, TZD use was associated with increased VF and NVF risks, particularly among those with normal or osteopenic BMD and normal BMI. SGLT2i showed no increased risk, but further large-scale studies are needed to confirm its skeletal safety.

Objective: This study aimed to develop a reliable and valid Mixed State Severity Index (MSSI) to assess mood instability in patients with mood disorders and determine cutoff scores. Methods: Twenty-one items were selected based on Koukopoulos’ criteria for mixed depressive episode, historically referred to as agitated depression, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision mixed features criteria. The MSSI was administered to 242 patients (major depressive disorder [n=92], bipolar disorder [BD] I [n=78], and BD II [n=72]) and 726 controls. Results: The MSSI demonstrated high internal consistency (α=0.78–0.90). Exploratory factor analysis revealed a stable four-factor structure. Based on receiver operating characteristic analysis, optimal cutoff scores were identified to distinguish mood disorder groups from controls, ranging from 19.5 to 27.5 depending on diagnosis. Conclusion The MSSI is a reliable and valid instrument for assessing the severity of mixed features in patients with mood disorders. The established cutoff scores enhance its clinical utility, providing robust diagnosis and treatment planning support.

Schwann cells are the most abundant cells in the peripheral nervous system, maintaining the development, function and regeneration of peripheral nerves. Defects in these Schwann cells injury response potentially contribute to the pathogenesis of diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus. The protein p66shc is essential in regulating oxidative stress responses, autophagy induction and cell survival, and is also vital in the development of DPN. In this study, we hypothesized that p66shc mediates high glucose-induced oxidative stress and autophagic dysfunction. In Schwann cells treated with high glucose; p66shc expression, levels of reactive oxygen species, autophagy impairment, and early apoptosis were elevated. Inhibition of p66shc gene expression by siRNA reversed high glucose-induced oxidative stress, autophagy impairment, and early apoptosis. We also demonstrated that the levels of p66shc was increased, while autophagy-related proteins p62 and LC3 (LC3-II/I) were suppressed in the sciatic nerve of streptozotocin-induced diabetes mice. P66shc-deficient mice exhibited the improvement in autophagy impairment after diabetes onset. Our findings suggest that the p66 plays a crucial role in Schwann cell dysfunction, identifying its potential as a therapeutic target.

Purpose: To evaluate the relationship between distal fusion level in correction and fusion surgery for adolescent idiopathic scoliosis (AIS) and radiologic changes in the sacroiliac (SI) joint. Materials and Methods: This retrospective cohort study evaluated patients who underwent correction and fusion for AIS between 2005 and 2017 with at least 5 years of follow-up. We categorized patients into two groups: Group 1 (distal fusion above L2, 74 patients) and Group 2 (distal fusion at L3 and below, 52 patients). Radiologic parameters and SI joint changes were evaluated on plain radiographs obtained from preoperative to 5 years postoperatively. We also investigated other risk factors for SI joint change. Results: Analysis of demographic factors revealed no significant difference between the two groups. There was a significant difference in the incidence of SI joint change between Group 1 (5 patients, 6.75%) and Group 2 (18 patients, 34.61%), with Group 2 showing a faster increase in incidence according to the Kaplan-Meier method (p<0.0001). Preoperative lumbar lordosis (LL) and ΔLL had a significant relationship with SI joint changes [preoperative LL, hazard ratio (HR)=0.77, 95% confidence interval (CI)=0.64– 0.93, p=0.008; ΔLL, HR=0.79, 95% CI=0.67–0.95, p=0.01). Conclusion After AIS surgery, patients who had fusion to the lower lumbar vertebrae (L3 or L4) experienced a higher incidence and faster progression of degenerative changes in the SI joint. Low preoperative LL and inadequate correction of LL during the operation were also risk factors for SI joint degeneration.

Background: Cardiovascular diseases are the leading cause of mortality after liver transplantation (LT). Although the impact of secondary tricuspid regurgitation (TR) with severe pulmonary hypertension (PH) is well investigated, the impact of primary TR with tricuspid valve incompetence (TVI) on LT outcomes remains unclear. We aimed to investigate the prevalence and impact of primary TR with TVI on LT outcomes in a large-volume LT center. Methods: We retrospectively examined 5 512 consecutive LT recipients who underwent routine pretransplant echocardiography between 2008 and 2020. Patients were categorized based on the presence of anatomical TVI, specifically defined by incomplete coaptation, coaptation failure, prolapse, and flail leaflets of tricuspid valve (TV). Propensity score (PS)-based inverse probability weighting (IPW) was used to balance clinical and cardiovascular risk variables. The outcomes were one-year cumulative all-cause mortality and 30-day major adverse cardiovascular events (MACE). Results: Anatomical TVI was identified in 14 patients (0.3%). Although rare, these patients exhibited significantly lower post-LT one-year survival rates (64.3% vs. 91.5%, P < 0.001) and higher 30-day MACE rates (42.9% vs. 16.9%, P = 0.026) than patients without TVI. They also had worse survival irrespective of echocardiographic evidence of PH (P < 0.001) and exhibited higher one-year mortality (IPW-adjusted hazard ratio: 4.09, P = 0.002) and increased 30-day MACE rates (IPW-adjusted odds ratio: 1.24, P = 0.048). Conclusions Primary TR with anatomical TVI was associated with significantly reduced one-year survival and increased post-LT MACE rates. These patients should be prioritized similarly to those with secondary TR with severe PH, with appropriate pretransplant evaluations and treatments to improve survival outcomes.

Background: Despite the necessity of long-term management for fracture risk reduction, adherence to osteoporosis pharmacotherapy remains poor. We investigated the factors influencing adherence to pharmacotherapy among Korean patients with osteoporosis, with a particular focus on treatment with bisphosphonates (BPs). Methods: Data from 725,313 osteoporosis patients newly prescribed BPs or selective estrogen receptor modulators (SERMs) between 2012 and 2014, obtained from the Korean National Health Insurance Service, were analyzed. Adherence was assessed based on compliance and persistence over a two-year period, with factors associated with adherence identified using multivariable logistic regression. Results: Only 14.8% of the patients who started BPs or SERMs sustained medication compliance, with 15.8% persisting with treatment over the two-year follow-up. Compared with BPs, patients receiving SERMs showed better compliance and persistence (odds ratios [ORs], 1.44 and 1.48, respectively; P < 0.001); while patients receiving intravenous administration showed higher compliance and persistence (ORs, 2.08 and 1.76, respectively; P < 0.001) compared with those taking oral medications. Patients placed on a quarterly dosing schedule showed improved compliance and persistence (ORs, 1.55 and 1.31, respectively; P < 0.001) compared with those on other dosing intervals. Male gender, advanced age, living outside metropolitan areas, receiving treatment in non-general hospitals, and a history of previous fractures were associated with poorer two-year adherence. Conclusion This study underscores the complex nature of medication adherence among Korean osteoporosis patients, particularly those treated with BPs. These findings accordingly indicate that medication with more convenient administration regimens and fewer side effects, coupled with suitable follow-up durations, could contribute to enhancing treatment adherence.