BACKGROUND: Bone defects are commonly encountered due to accidents, diseases, or aging, and the demand for effective bone regeneration, particularly for dental implants, is increasing in our aging society. Mesenchymal stem cells (MSCs) are promising candidates for regenerative therapies; however, obtaining sufficient quantities of these cells for clinical applications remains challenging. DW-MSCs, derived from embryonic stem cells and developed by Daewoong Pharmaceutical, exhibit a robust proliferative capacity even after extensive culture. METHODS: This study explores the therapeutic potential of DW-MSCs in various animal models of bone defects. DWMSCs were expanded for over 13 passages for in vivo use in rat and canine models of bone defects and osteomyelitis. The research focused on the in vivo osteogenic differentiation of DW-MSCs, the establishment of a fibrin-based system for bone regeneration, the assessment of bone repair following treatment in animal models, and comparisons with commercially available bone grafts. RESULTS: Results showed that DW-MSCs exhibited superior osteogenic differentiation compared to other materials, and the fibrinization process not only preserved but enhanced their proliferation and differentiation capabilities through a 3D culture effect. In both bone defect models, DW-MSCs facilitated significant bone regeneration, reduced inflammatory responses in osteomyelitis, and achieved effective bone healing. The therapeutic outcomes of DW-MSCs were comparable to those of commercial bone grafts but demonstrated qualitatively superior bone tissue restructuring. CONCLUSION Our findings suggest that DW-MSCs offer a promising approach for bone regeneration therapies due to their high efficacy and anti-inflammatory properties.

Background: The development of frailty at hospital discharge affects the clinical outcomes in severe coronavirus disease 2019 (COVID-19) survivors who had no frailty before hospitalization. We aimed to describe the prevalence of new frailty using the clinical frailty scale (CFS) and evaluate its associated factors in patients with severe COVID-19 without pre-existing frailty before hospitalization. Methods: We performed a secondary analysis of clinical data from a nationwide retrospective cohort collected from 22 hospitals between January 1, 2020 and August 31, 2021. The patients were at least 19 years old and survived until discharge after admission to the intensive care unit (ICU) because of severe COVID-19. Development of new frailty was defined as a CFS score ≥5 at hospital discharge. Results: Among 669 severe COVID-19 survivors without pre-existing frailty admitted to the ICU, the mean age was 65.2±12.8 years, 62.5% were male, and 50.2% received mechanical ventilation (MV). The mean CFS score at admission was 2.4±0.9, and new frailty developed in 27.8% (186/483). In multivariate analysis, older age, cardiovascular disease, CFS score of 3–4 before hospitalization, increased C-reactive protein level, longer duration of corticosteroid treatment, and use of MV and extracorporeal membrane oxygenation were identified as factors associated with new-onset frailty. Conclusion Our study suggests that new frailty is not uncommon and is associated with diverse factors in survivors of severe COVID-19 without pre-existing frailty.

Background: This study aimed to determine whether a shorter high-dose rifampicin regimen is non-inferior to the standard 6-month tuberculosis regimen. Methods: This multicenter, randomized, open-label, non-inferiority trial enrolled participants with respiratory specimen positivity by Xpert MTB/RIF assay or Mycobacterium tuberculosis culture without rifampicin-resistance. Participants were randomized at 1:1 to the investigational or control group. The investigational group received high-dose rifampicin (30 mg/kg/day), isoniazid, and pyrazinamide until culture conversion, followed by high-dose rifampicin and isoniazid for 12 weeks. The control group received the standard 6-month regimen. The primary outcome was the rate of unfavorable outcomes at 18 months post-randomization. The non-inferiority margin was set at <6% difference in unfavorable outcomes rates. The study is registered with ClinicalTrials.gov (NCT04485156) Results: Between 4 November 2020 and 3 January 2022, 76 participants were enrolled. Of these, 58 were included in the modified intention-to-treat analysis. Unfavorable outcomes occurred in 10 (31.3%) of 32 in the control group and 10 (38.5%) of 26 in the investigational group. The difference was 7.2% (95% confidence interval, ∞ to 31.9%), failing to prove non-inferiority. Serious adverse events and grade 3 or higher adverse events did not differ between the groups. Conclusion The shorter high-dose rifampicin regimen failed to demonstrate non-inferiority but had an acceptable safety profile.

Background: Colorectal carcinomas (CRCs) with caudal-type homeobox 2 (CDX2) loss are recognized to pursue an aggressive behavior but tend to be accompanied by a high density of tumor-infiltrating lymphocytes (TILs). However, little is known about whether there is an interplay between CDX2 loss and TIL density in the survival of patients with CRC. Methods: Stage III CRC tissues were assessed for CDX2 loss using immunohistochemistry and analyzed for their densities of CD8 TILs in both intraepithelial (iTILs) and stromal areas using a machine learning-based analytic method. Results: CDX2 loss was significantly associated with a higher density of CD8 TILs in both intraepithelial and stromal areas. Both CDX2 loss and a high CD8 iTIL density were found to be prognostic parameters and showed hazard ratios of 2.314 (1.050–5.100) and 0.378 (0.175–0.817), respectively, for cancer-specific survival. A subset of CRCs with retained CDX2 expression and a high density of CD8 iTILs showed the best clinical outcome (hazard ratio of 0.138 [0.023–0.826]), whereas a subset with CDX2 loss and a high density of CD8 iTILs exhibited the worst clinical outcome (15.781 [3.939–63.230]). Conclusions Altogether, a high density of CD8 iTILs did not make a difference in the survival of patients with CRC with CDX2 loss. The combination of CDX2 expression and intraepithelial CD8 TIL density was an independent prognostic marker in adjuvant chemotherapy-treated patients with stage III CRC.

Background and Objectives: The Korean Organ Transplant Registry (KOTRY) provided data for this third official report on adult heart transplantation (HT), including information from 709 recipients. Methods: Data from HTs performed at seven major centers in Korea between March 2014 and December 2020 were analyzed, focusing on immunosuppression, acute rejection, cardiac allograft vasculopathy (CAV), post-transplant survival, and mechanical circulatory support (MCS) usage. Results: The median ages of the recipients and donors were 56.0 and 43.0 years, respectively.Cardiomyopathy and ischemic heart disease were the most common preceding conditions for HT. A significant portion of patients underwent HT at waiting list status 1 and 0. In the multivariate analysis, a predicted heart mass mismatch was associated with a higher risk of 1-year mortality. Patients over 70 years old had a significantly increased risk of 6-year mortality. The risk of CAV was higher for male donors and donors older than 45 years. Acute rejection was more likely in patients with panel reactive antibody levels above 80%, while statin use was associated with a reduced risk. The employment of left ventricular assist device as a bridge to transplantation increased from 2.17% to 22.4%. Pre-transplant extra-corporeal membrane oxygenation was associated with worse post-transplant survival. Conclusions In this third KOTRY report, we analyzed changes in the characteristics of adult HT recipients and donors and their impact on post-transplant outcomes. The most notable discovery was the increased use of MCS before HT and their impact on post-transplant outcomes.

Background and Objectives: The risk profiles, procedural characteristics, and clinical outcomes for women undergoing bifurcation percutaneous coronary intervention (PCI) are not well defined compared to those in men. Methods: COronary BIfurcation Stenting III (COBIS III) is a multicenter, real-world registry of 2,648 patients with bifurcation lesions treated with second-generation drug-eluting stents.We compared the angiographic and procedural characteristics and clinical outcomes based on sex. The primary outcome was 5-year target lesion failure (TLF), a composite of cardiac death, myocardial infarction, and target lesion revascularization. Results: Women (n=635, 24%) were older, had hypertension and diabetes more often, and had smaller main vessel and side branch reference diameters than men. The pre- and post-PCI angiographic percentage diameter stenoses of the main vessel and side branch were comparable between women and men. There were no differences in procedural characteristics between the sexes. Women and men had a similar risk of TLF (6.3% vs. 7.1%, p=0.63) as well as its individual components and sex was not an independent predictor of TLF. This finding was consistent in the left main and 2 stenting subgroups. Conclusions In patients undergoing bifurcation PCI, sex was not an independent predictor of adverse outcome.

Purpose: Methacholine bronchial provocation tests (MBPTs) are commonly used to assess airway hyperresponsiveness, but some patients show no significant response. This study aimed to compare the clinical characteristics of asthmatic patients based on their sensitivity to MBPTs. Methods: We conducted a retrospective cross-sectional study involving adult asthmatic patients from 6 university hospitals in South Korea. Patients were categorized into 2 groups: those with MBPT sensitivity (the provocative concentration of methacholine that leads to a 20% reduction in forced expiratory volume in 1 second [PC20]≤ 16 mg/mL) and those with lower sensitivity (PC 20 > 16 mg/mL). Clinical characteristics were compared between the 2 groups. Results: Among 346 patients, 213 had PC 20 ≤ 16 mg/mL and 133 had PC 20 > 16 mg/mL. The PC20> 16 mg/mL group had a higher prevalence of late-onset asthma (P= 0.024) and obesity (P= 0.045). While no significant differences in immunoglobulin E (≥ 200 IU/mL) were found, the PC 20 ≤ 16 mg/mL group had greater T2-high inflammation, such as elevated eosinophil counts and fractional exhaled nitric oxide (P< 0.001 and P= 0.004, respectively). Asthma exacerbations requiring emergency visits or hospitalizations were more frequent in the PC 20 > 16 mg/mL group, despite a lower proportion of patients on higher-step treatments according to Global Initiative for Asthma guidelines. Conclusion Asthmatic patients with PC 20 > 16 mg/mL tend to present with late-onset asthma, less T2-high inflammation, and higher rates of asthma exacerbations. Further studies are needed to clarify the clinical features of asthma patients with PC 20 > 16 mg/mL and assess the long-term significance of these findings.

Purpose: Methacholine bronchial provocation tests (MBPTs) are commonly used to assess airway hyperresponsiveness, but some patients show no significant response. This study aimed to compare the clinical characteristics of asthmatic patients based on their sensitivity to MBPTs. Methods: We conducted a retrospective cross-sectional study involving adult asthmatic patients from 6 university hospitals in South Korea. Patients were categorized into 2 groups: those with MBPT sensitivity (the provocative concentration of methacholine that leads to a 20% reduction in forced expiratory volume in 1 second [PC20]≤ 16 mg/mL) and those with lower sensitivity (PC 20 > 16 mg/mL). Clinical characteristics were compared between the 2 groups. Results: Among 346 patients, 213 had PC 20 ≤ 16 mg/mL and 133 had PC 20 > 16 mg/mL. The PC20> 16 mg/mL group had a higher prevalence of late-onset asthma (P= 0.024) and obesity (P= 0.045). While no significant differences in immunoglobulin E (≥ 200 IU/mL) were found, the PC 20 ≤ 16 mg/mL group had greater T2-high inflammation, such as elevated eosinophil counts and fractional exhaled nitric oxide (P< 0.001 and P= 0.004, respectively). Asthma exacerbations requiring emergency visits or hospitalizations were more frequent in the PC 20 > 16 mg/mL group, despite a lower proportion of patients on higher-step treatments according to Global Initiative for Asthma guidelines. Conclusion Asthmatic patients with PC 20 > 16 mg/mL tend to present with late-onset asthma, less T2-high inflammation, and higher rates of asthma exacerbations. Further studies are needed to clarify the clinical features of asthma patients with PC 20 > 16 mg/mL and assess the long-term significance of these findings.

Purpose: Regenerative medicine is expected to offer an alternative to liver transplantation for treating liver diseases in the future, with one significant challenge being the establishment of an effective stem cell administration route. This study assessed the antifibrogenic effects of adipose-derived stem cells (ASCs) in a liver fibrosis mouse model, focusing on 2 methods of delivery: intravenous injection and scaffold implantation. Methods: An extracellular matrix mimic scaffold was utilized for culturing peroxisome proliferator-activated receptor gamma coactivator 1-alpha–overexpressing ASCs (tASCs). These scaffolds, laden with tASCs, were then implanted subcutaneously in mice exhibiting liver fibrosis. In contrast, the Cell groups received biweekly intravenous injections of tASCs for 4 weeks. After 4 weeks, tissue samples were harvested from the euthanized mice for subsequent analysis. Results: Real-time PCR and Western blot analyses on liver tissues, focusing on markers like alpha-smooth muscle actin (α-SMA), matrix metalloproteinase-2, and transforming growth factor-beta 1 (TGF-β1), showed that both delivery routes substantially lowered fibrotic and inflammatory markers compared to controls (P < 0.05), with no significant differences between the routes. Histological examinations, along with immunohistochemical analysis of α-SMA, collagen type I alpha, and TGF-β1, revealed that the scaffold implantation approach resulted in a greater reduction in fibrosis and lower immunoreactivity for fibrotic markers than intravenous delivery (P < 0.05). Conclusion These findings indicate that delivering tASCs via a scaffold could be more effective, or at least similarly effective, in treating liver fibrosis compared to intravenous delivery. Scaffold implantation could offer a beneficial alternative to frequent intravenous treatments, suggesting its potential utility in clinical applications for liver disease treatment.