Selective targeting of dipeptidyl-peptidase 4 (DPP-4) positive senescent chondrocyte ameliorates osteoarthritis progression.

Senescent cells increase in many tissues with age and induce age-related pathologies, including osteoarthritis (OA). Senescent chondrocytes (SnCs) are found in OA cartilage, and the clearance of those chondrocytes prevents OA progression. However, targeting SnCs is challenging due to the absence of a senescent chondrocyte-specific marker. Therefore, we used flow cytometry to screen and select senescent chondrocyte surface markers and cross-validated with published transcriptomic data. Chondrocytes expressing dipeptidyl peptidase-4 (DPP-4), the selected senescent chondrocyte-specific marker, had multiple senescence phenotypes, such as increased senescence-associated-galactosidase, p16, p21, and senescence-associated secretory phenotype expression, and showed OA chondrocyte phenotypes. To examine the effects of DPP-4 inhibition on DPP-4+ SnCs, sitagliptin, a DPP-4 inhibitor, was treated in vitro. As a result, DPP-4 inhibition selectively eliminates DPP-4+ SnCs without affecting DPP-4- chondrocytes. To assess in vivo therapeutic efficacy of targeting DPP-4+ SnCs, three known senolytics (ABT263, 17DMAG, and metformin) and sitagliptin were comparatively verified in a DMM-induced rat OA model. Sitagliptin treatment specifically and effectively eliminated DPP-4+ SnCs, compared to the other three senolytics. Furthermore, Intra-articular sitagliptin injection to the rat OA model increased collagen type II and proteoglycan expression and physical functions and decreased cartilage destruction, subchondral bone plate thickness and MMP13 expression, leading to the amelioration of OA phenotypes. Collectively, OARSI score was lowest in the sitagliptin treatment group. Taken together, we verified DPP-4 as a surface marker for SnCs and suggested that the selective targeting of DPP-4+ chondrocytes could be a promising strategy to prevent OA progression.

Presentation and management of infection in total disc replacement: A review.

Background: Total disc replacement (TDR) is widely used in the treatment of cervical and lumbar spine pathologies. Although TDR infection, particularly delayed infection, is uncommon, the results can be devastating, and consensus on clinical management remains elusive. In this review of the literature, we asked: (1) What are the reported rates of TDR infection; (2) What are the clinical characteristics of TDR infection; and (3) How has infection been managed for TDR patients? Methods: We performed a search of the literature using PubMed and Embase to identify studies that reported TDR infection rates, the identification and management of TDR infection, or TDR failures with positive cultures. Twenty database studies (17 focusing on the cervical spine and 3 on the lumbar spine) and 10 case reports representing 15 patients were reviewed along with device Summary of Safety and Effectiveness Data reports. Results: We found a lack of clarity regarding how infection was diagnosed, indicating a variation in clinical approach and highlighting the need for a standard definition of TDR infection. Furthermore, while reported infection rates were low, the absence of a clear definition prevented robust data analysis and may contribute to underreporting in the literature. We found that treatment strategy and success rely on several factors including patient symptoms and time to onset, microorganism type, and implant positioning/stability. Conclusions: Although treatment strategies varied throughout the extant literature, common practices in eliminating infection and reconstructing the spine emerged. The results will inform future work on the creation of a more robust definition of TDR infection and as well as recommendations for management.

Mortality Burden Due to Short-term Exposure to Fine Particulate Matter in Korea.

OBJECTIVES: Excess mortality associated with long-term exposure to fine particulate matter (PM2.5) has been documented. However, research on the disease burden following short-term exposure is scarce. We investigated the cause-specific mortality burden of short-term exposure to PM2.5 by considering the potential non-linear concentration-response relationship in Korea. METHODS: Daily cause-specific mortality rates and PM2.5 exposure levels from 2010 to 2019 were collected for 8 Korean cities and 9 provinces. A generalized additive mixed model was employed to estimate the non-linear relationship between PM2.5 exposure and cause-specific mortality levels. We assumed no detrimental health effects of PM2.5 concentrations below 15 µg/m3. Overall deaths attributable to short-term PM2.5 exposure were estimated by summing the daily numbers of excess deaths associated with ambient PM2.5 exposure. RESULTS: Of the 2 749 704 recorded deaths, 2 453 686 (89.2%) were non-accidental, 591 267 (21.5%) were cardiovascular, and 141 066 (5.1%) were respiratory in nature. A non-linear relationship was observed between all-cause mortality and exposure to PM2.5 at lag0, whereas linear associations were evident for cause-specific mortalities. Overall, 10 814 all-cause, 7855 non-accidental, 1642 cardiovascular, and 708 respiratory deaths were attributed to short-term exposure to PM2.5. The estimated number of all-cause excess deaths due to short-term PM2.5 exposure in 2019 was 1039 (95% confidence interval, 604 to 1472). CONCLUSIONS: Our findings indicate an association between short-term PM2.5 exposure and various mortality rates (all-cause, non-accidental, cardiovascular, and respiratory) in Korea over the period from 2010 to 2019. Consequently, action plans should be developed to reduce deaths attributable to short-term exposure to PM2.5.

Coronal vertical fracture of vertebral body following minimally invasive lateral lumbar interbody fusion: risk factor analysis in consecutive case series.

BACKGROUND: To investigate the incidence and risk factors of coronal vertical vertebral body fracture (CV-VBF) during lateral lumbar interbody fusion (LLIF) for degenerative lumbar disease. METHODS: Clinical data, including age, sex, body mass index, and bone mineral density, were reviewed. Radiological assessments, such as facet joint arthrosis, intervertebral disc motion, index disc height, and cage profiles, were conducted. Posterior instrumentation was performed using either a single or staged procedure after LLIF. Demographic and surgical data were compared between patients with and without VBF. RESULTS: Out of 273 patients (552 levels), 7 (2.6%) experienced CV-VBF. Among the 552 levels, VBF occured in 7 levels (1.3%). All VBF cases developed intraoperatively during LLIF, with no instances caused by cage subsidence during the follow-up period. Sagittal motion in segments adjacent to VBF was smaller than in others (4.6° ± 2.6° versus 6.5° ± 3.9°, P = 0.031). The average grade of facet arthrosis was 2.5 ± 0.7, indicating severe facet arthrosis. All fractures developed due to oblique placement of a trial or cage into the index disc space, leading to a nutcracker effect. These factors were not related to bone quality. CONCLUSIONS: CV-VBF after LLIF occurred in 2.6% of patients, accounting for 1.3% of all LLIF levels. A potential risk factor for VBF involves the nutcracker-impinging effect due to the oblique placement of a cage. Thorough preoperative evaluations and surgical procedures are needed to avoid VBF when considering LLIF in patients with less mobile spine.

A case report of torsion of the gravid uterus caused by pelvic adhesion.

Key Clinical Message: In this case, a patient experienced rare uterine torsion during pregnancy, detected by MRI. Diagnosis before Cesarean is helpful to achieve better outcomes, highlighting the importance of attention in high-risk groups. Abstract: Uterine torsion during pregnancy is a rare complication and its risk factors and diagnostic modalities have not yet been clearly defined. Here we present a case of uterine torsion due to unexpected pelvic adhesion. A 34-years-old primigravida patient underwent an emergency cesarean section for aggravated maternal preeclampsia symptoms at 34 + 0 weeks of gestation. Intraoperatively, after the baby was out, it was found that the uterus was rotated about 90 degrees to the right by dense pelvic adhesion in posterior uterine wall. In this patient, a rightward vaginal stretch was represented through a retrospective review of magnetic resonance imaging (MRI) before childbirth. To our knowledge, this is the first reported case of uterine torsion during pregnancy with MRI. Diagnosing uterine torsion in advance or paying attention to incisions during operative delivery will lead to better management in this condition and good perinatal outcomes.

Risk Factors for Reoperation Following Single-Level Cervical Disc Arthroplasty as Utilized in a Representative Sample of United States Clinical Practice: A Retrospective PearlDiver Study.

STUDY DESIGN: Retrospective Cohort. OBJECTIVES: Most data regarding cervical disc arthroplasty (CDA) outcomes are from highly controlled clinical trials with strict inclusion/exclusion criteria. This study aimed to identify risk factors for CDA reoperation, in "real world" clinical practice using a national insurance claims database. METHODS: The PearlDiver database was queried for patients (2010-2020) who underwent a subsequent cervical procedure following a single-level CDA. Patients with less than 2 years follow-up were excluded. Primary outcome was to evaluate risk factors for reoperation. Secondary outcome was to evaluate the types of reoperations. Risk factors were compared using descriptive statistics. Multivariate regression analyses were used to ascertain the association among risk factors and reoperation. RESULTS: Of 14,202 patients who met inclusion criteria, 916 (6.5%) underwent reoperation. Patients undergoing reoperation were slightly older with higher Elixhauser Comorbidity Index (ECI) scores, however both were not risk factors for reoperation. Patients with diagnoses such as smoking, myelopathy, inflammatory disorders, spinal deformity, trauma, or a history of prior cervical surgery were at greater risk for reoperation. No association was found between the year of index surgery and reoperation risk. The most common reoperation procedure was cervical fusion. CONCLUSIONS: As billed for in the United States since 2010, CDA was associated with a 6.5% reoperation rate over a mean follow-up time of 5.3 years. Smoking, myelopathy, inflammatory disorders, spinal deformity, and a history of prior cervical surgery or trauma are risk factors for reoperation following CDA. Though patients who underwent a reoperation were older, age was not found to be an independent risk factor for a subsequent procedure.

Tm4sf19 deficiency inhibits osteoclast multinucleation and prevents bone loss.

BACKGROUND: Multinucleation is a hallmark of osteoclast formation and has a unique ability to resorb bone matrix. During osteoclast differentiation, the cytoskeleton reorganization results in the generation of actin belts and eventual bone resorption. Tetraspanins are involved in adhesion, migration and fusion in various cells. However, its function in osteoclast is still unclear. In this study, we identified Tm4sf19, a member of the tetraspanin family, as a regulator of osteoclast function. MATERIALS AND METHODS: We investigate the effect of Tm4sf19 deficiency on osteoclast differentiation using bone marrow-derived macrophages obtained from wild type (WT), Tm4sf19 knockout (KO) and Tm4sf19 LELΔ mice lacking the large extracellular loop (LEL). We analyzed bone mass of young and aged WT, KO and LELΔ mice by µCT analysis. The effects of Tm4sf19 LEL-Fc fusion protein were accessed in osteoclast differentiation and osteoporosis animal model. RESULTS: We found that deficiency of Tm4sf19 inhibited osteoclast function and LEL of Tm4sf19 was responsible for its function in osteoclasts in vitro. KO and LELΔ mice exhibited higher trabecular bone mass compared to WT mice. We found that Tm4sf19 interacts with integrin αvß3 through LEL, and that this binding is important for cytoskeletal rearrangements in osteoclast by regulating signaling downstream of integrin αvß3. Treatment with LEL-Fc fusion protein inhibited osteoclast function in vitro and administration of LEL-Fc prevented bone loss in an osteoporosis mouse model in vivo. CONCLUSION: We suggest that Tm4sf19 regulates osteoclast function and that LEL-Fc may be a promising drug to target bone destructive diseases caused by osteoclast hyper-differentiation.

Is single-level cervical disc arthroplasty associated with a lower reoperation rate than anterior cervical discectomy and fusion?

OBJECTIVE: Long-term meta-analysis of cervical disc arthroplasty (CDA) trials report lower rates of subsequent cervical spine surgical procedures with CDA compared with anterior cervical discectomy and fusion (ACDF). The objective of this study was to compare the rate of subsequent cervical spine surgery in single-level CDA-treated patients to that of a matched cohort of single-level ACDF-treated patients by using records from 2010 to 2021 included in a large national administrative claims database (PearlDiver). METHODS: This retrospective matched-cohort study used a large national insurance claims database; 525,510 patients who had undergone a single-level ACDF or CDA between 2010 and 2021 were identified. Patients with other same-day spine procedures, as well as those for trauma, infection, or tumor, were excluded, yielding 148,531 patients. ACDF patients were matched 2:1 to CDA patients on the basis of clinical and demographic characteristics. The primary outcome was the overall incidence of all-cause cervical reoperation after index surgery. Secondary outcomes included readmission, any adverse event within 90 days, and overall reintervention after index surgery. Multivariable logistic regression analyses were adjusted for covariates and were employed to estimate the effect of the index ACDF or CDA procedure on patient outcomes. Survival was assessed using Kaplan-Meier estimation, and differences between ACDF- and CDA-treated patients were compared using log-rank tests. RESULTS: After the patients were matched, 28,795 ACDF patients to 14,504 CDA patients were included. ACDF patients had higher rates of 90-day adverse events (18.4% vs 14.6%, adjusted odds ratio [aOR] 0.77, 95% CI 0.73-0.82, p < 0.001) and readmission (11.5% vs 9.7%, aOR 0.87, 95% CI 0.81-0.93, p < 0.001). Over a mean 4.3 years of follow-up, 5.0% of ACDF patients and 5.4% of CDA patients underwent reoperation (aOR 1.09, 95% CI 1.00-1.19, p = 0.059). The rate of aggregate reintervention was higher in CDA patients than in ACDF patients (11.7% vs 10.7%, aOR 1.10, p = 0.002). The Kaplan-Meier 10-year reoperation-free survival rate was worse for CDA than ACDF (91.0% vs 92.0%, p = 0.05), as was the rate of reintervention-free survival (81.2% vs 82.0%, p = 0.003). CONCLUSIONS: Single-level CDA was associated with a similar rate of reoperation and higher rate of subsequent injections when compared with a matched cohort that underwent single-level ACDF. CDA was associated with lower rates of 90-day adverse events and readmissions.

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats.

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.

Biomechanical comparative finite element analysis between a conventional proximal interphalangeal joint flexible hinge implant and a novel implant design using a rolling contact joint mechanism.

BACKGROUND: The rolling contact joint (RCJ) mechanism is a system of constraint that allows two circular bodies connected with flexible straps to roll relative to one another without slipping. This study aims to compare the biomechanical characteristics between the conventional proximal interphalangeal joint (PIPJ) flexible hinge (FH) implant and the novel PIPJ implant adopting a RCJ mechanism during PIPJ range of motion using finite element (FE) analysis. METHODS: The three-dimensional (3D) surface shape of a conventional PIPJ FH implant was obtained using a 3D laser surface scanning system. The configuration and parameters of the novel PIPJ implant were adapted from a previous study. The two implants were assumed to have the same material characteristics and each implant was composed of a hyperelastic material, silicone elastomers. The configuration data for both implants were imported to a computer-aided design program to generate 3D geometrical surface and hyperelastic models of both implants. The hyperelastic models of both implants were imported into a structural engineering software to produce the FE mesh and to perform FE analysis. The FE analysis modeled the changes of mechanics during flexion-extension motion between 0° and 90° of two PIPJ implants. The mean and maximum values of von-Mises stress and strain as well as the total moment reaction based on the range of motion of the PIPJs were calculated. The mean values within the PIPJ's functional range of motion of the mean and maxinum von-Mises stress and strain and the total moment reaction were also determined. RESULTS: The maximum values for the von-Mises stress, and strain, as well as the total moment reactions of the conventional PIPJ FH and novel PIPJ implants were all at 90° of PIPJ flexion. The maximum value of each biomechanical property for the novel PIPJ implant was considerably lower compared with that of the conventional PIPJ FH implant. The mean values within the PIPJ's functional range of motion of the maximum von-Mises stress and strain for the novel PIPJ implant was approximately 6.43- and 6.46-fold lower compared with that of the conventional PIPJ FH implant, respectively. The mean value within a PIPJ's functional range of motion of the total moment reaction of the novel PIPJ implant was approximately 49.6-fold lower compared with that of the conventional PIPJ FH implant. CONCLUSIONS: The novel PIPJ implant with an RCJ mechanism may offer improved biomechanical performance compared with conventional PIPJ FH implant.

Enhanced Cholesterol-Lowering and Antioxidant Activities of Soymilk by Fermentation with Lactiplantibacillus plantarum KML06.

This study aimed to evaluate the cholesterol-lowering and antioxidant activities of soymilk fermented with probiotic Lactobacillaceae strains and to investigate the production of related bioactive compounds. Lactiplantibacillus plantarum KML06 (KML06) was selected for the fermentation of soymilk because it has the highest antioxidant, cholesterol-lowering, and ß-glucosidase activities among the 10 Lactobacillaceae strains isolated from kimchi. The genomic information of strain KML06 was analyzed. Moreover, soymilk fermented with KML06 was evaluated for growth kinetics, metabolism, and functional characteristics during the fermentation period. The number of viable cells, which was similar to the results of radical scavenging activities and cholesterol assimilation, as well as the amount of soy isoflavone aglycones, daidzein, and genistein, was the highest at 12 h of fermentation. These results indicate that soymilk fermented with KML06 can prevent oxidative stress and cholesterol-related problems through the production of soy isoflavone aglycones.

Lumbar Discectomy With Bone-Anchored Annular Closure Device in Patients With Large Annular Defects: One-Year Results.

BACKGROUND: Reherniation rates following lumbar discectomy are low for most patients; however, patients with a large defect in the annulus fibrosis have a significantly higher risk of recurrence. Previous results from a randomized controlled trial (RCT) demonstrated that the implantation of a bone-anchored annular closure device (ACD) during discectomy surgery lowered the risk of symptomatic reherniation and reoperation over one year with fewer serious adverse events (SAEs) compared to discectomy alone. OBJECTIVE: The objective of this prospective, post-market, historically controlled study was to evaluate the use of an ACD during discectomy, and to confirm the results of the RCT that was used to establish regulatory approval in the United States. METHODS: In this post-market study, all patients (N = 55) received discectomy surgery with a bone-anchored ACD. The comparison population was patients enrolled in the RCT study who had discectomy with an ACD (N = 262) or discectomy alone (N = 272). All other eligibility criteria, surgical technique, device characteristics, and follow-up methodology were comparable between studies. Endpoints included rate of symptomatic reherniation or reoperation, SAEs, and patient-reported measures of disability, pain, and quality of life. RESULTS: Fifty-five patients received ACD implants at 12 sites between May 2020 and February 2021. In the previous RCT, 272 control patients had discectomy surgery alone (RCT-Control), and 262 patients had discectomy surgery with an ACD implant (RCT-ACD). Baseline characteristics across groups were typical of the overall population undergoing lumbar discectomy. The proportion of patients who experienced reherniation and/or reoperation was significantly lower in the ACD group compared to RCT-ACD and RCT-Control groups (p < 0.05). In the ACD study, the one-year rate of symptomatic reherniation was 3.7%, compared to 8.5% in the RCT-ACD group and 17.0% in the RCT-Control group. In the ACD group, the risk of reoperation was 5.5%, compared to 6.5% in the RCT-ACD group and 12.5% in the RCT-Control group. There were no device-related SAEs or device integrity failures in the ACD, and there were clinically meaningful improvements in patient-reported measures of disability, pain, and quality of life. CONCLUSION: In this post-market study of bone-anchored ACD in patients with large annular defects, rates of symptomatic reherniation, reoperation, and SAEs were all low. Compared to the RCT, the post-market ACD study demonstrated lower rates of reherniation and/or reoperation and measures of back pain one-year post-surgery.

Comparison of complications between reverse-tapered and nontapered peripherally inserted central catheters.

Purpose of this study was to compare the complication rates between reverse-tapered and nontapered peripherally inserted central catheters (PICCs). In total, 407 patients who had an inpatient clinic-based PICC insertion between September 2019 and November 2019 were retrospectively analyzed. Seven PICC types were used (4 reverse tapered: 4-Fr single-lumen (n = 75), 5-Fr single-lumen (n = 78), 5-Fr double-lumen (n = 62), and 6-Fr triple-lumen (n = 61); 3 nontapered: 4-Fr single-lumen (n = 73), 5-Fr double-lumen (n = 30), and 6-Fr triple-lumen (n = 23)). Complications such as periprocedural bleeding, delayed bleeding, inadvertent removal, catheter obstruction by thrombosis, infection, and leakage were investigated. The overall complication rate was 27.1%. The complication rate was significantly higher for nontapered PICCs than reverse-tapered PICCs (50.0% vs 16.7%, P < 0.001). The overall periprocedural bleeding rate was significantly higher for nontapered PICCs than for reverse-tapered PICCs (27.0% vs 6.2%, P <0.001). The overall inadvertent removal rate was significantly higher for nontapered PICCs than for reverse-tapered PICCs (15.1% vs 3.3%, P < 0.001). There were no other significant differences in complication rates. Nontapered PICCs were associated with higher rates of periprocedural bleeding and inadvertent removal than reverse-tapered PICCs.

High-glutathione mesenchymal stem cells isolated using the FreSHtracer probe enhance cartilage regeneration in a rabbit chondral defect model.

BACKGROUND: Mesenchymal stem cells (MSCs) are a promising cell source for cartilage regeneration. However, the function of MSC can vary according to cell culture conditions, donor age, and heterogeneity of the MSC population, resulting in unregulated MSC quality control. To overcome these limitations, we previously developed a fluorescent real-time thiol tracer (FreSHtracer) that monitors cellular levels of glutathione (GSH), which are known to be closely associated with stem cell function. In this study, we investigated whether using FreSHtracer could selectively separate high-functioning MSCs based on GSH levels and evaluated the chondrogenic potential of MSCs with high GSH levels to repair cartilage defects in vivo. METHODS: Flow cytometry was conducted on FreSHtracer-loaded MSCs to select cells according to their GSH levels. To determine the function of FreSHtracer-isolated MSCs, mRNA expression, migration, and CFU assays were conducted. The MSCs underwent chondrogenic differentiation, followed by analysis of chondrogenic-related gene expression. For in vivo assessment, MSCs with different cellular GSH levels or cell culture densities were injected in a rabbit chondral defect model, followed by histological analysis of cartilage-regenerated defect sites. RESULTS: FreSHtracer successfully isolated MSCs according to GSH levels. MSCs with high cellular GSH levels showed enhanced MSC function, including stem cell marker mRNA expression, migration, CFU, and oxidant resistance. Regardless of the stem cell tissue source, FreSHtracer selectively isolated MSCs with high GSH levels and high functionality. The in vitro chondrogenic potential was the highest in pellets generated by MSCs with high GSH levels, with increased ECM formation and chondrogenic marker expression. Furthermore, the MSCs' function was dependent on cell culture conditions, with relatively higher cell culture densities resulting in higher GSH levels. In vivo, improved cartilage repair was achieved by articular injection of MSCs with high levels of cellular GSH and MSCs cultured under high-density conditions, as confirmed by Collagen type 2 IHC, Safranin-O staining and O'Driscoll scores showing that more hyaline cartilage was formed on the defects. CONCLUSION: FreSHtracer selectively isolates highly functional MSCs that have enhanced in vitro chondrogenesis and in vivo hyaline cartilage regeneration, which can ultimately overcome the current limitations of MSC therapy.

Image Turing test and its applications on synthetic chest radiographs by using the progressive growing generative adversarial network.

The generative adversarial network (GAN) is a promising deep learning method for generating images. We evaluated the generation of highly realistic and high-resolution chest radiographs (CXRs) using progressive growing GAN (PGGAN). We trained two PGGAN models using normal and abnormal CXRs, solely relying on normal CXRs to demonstrate the quality of synthetic CXRs that were 1000 × 1000 pixels in size. Image Turing tests were evaluated by six radiologists in a binary fashion using two independent validation sets to judge the authenticity of each CXR, with a mean accuracy of 67.42% and 69.92% for the first and second trials, respectively. Inter-reader agreements were poor for the first (κ = 0.10) and second (κ = 0.14) Turing tests. Additionally, a convolutional neural network (CNN) was used to classify normal or abnormal CXR using only real images and/or synthetic images mixed datasets. The accuracy of the CNN model trained using a mixed dataset of synthetic and real data was 93.3%, compared to 91.0% for the model built using only the real data. PGGAN was able to generate CXRs that were identical to real CXRs, and this showed promise to overcome imbalances between classes in CNN training.

A novel defined TLR3 agonist as an effective vaccine adjuvant.

Synthetic double-stranded RNA analogs recognized by Toll-like receptor 3 (TLR3) are an attractive adjuvant candidate for vaccines, especially against intracellular pathogens or tumors, because of their ability to enhance T cell and antibody responses. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been limited due to heterogeneous molecular size, inconsistent activity, poor stability, and toxicity. To overcome these limitations, we developed a novel dsRNA-based TLR3 agonist named NexaVant (NVT) by using PCR-coupled bidirectional in vitro transcription. Agarose gel electrophoresis and reverse phase-HPLC analysis demonstrated that NVT is a single 275-kDa homogeneous molecule. NVT appears to be stable since its appearance, concentration, and molecular size were unaffected under 6 months of accelerated storage conditions. Moreover, preclinical evaluation of toxicity under good laboratory practices showed that NVT is a safe substance without any signs of serious toxicity. NVT stimulated TLR3 and increased the expression of viral nucleic acid sensors TLR3, MDA-5, and RIG-1. When intramuscularly injected into C57BL/6 mice, ovalbumin (OVA) plus NVT highly increased the migration of dendritic cells (DCs), macrophages, and neutrophils into inguinal lymph node (iLN) compared with OVA alone. In addition, NVT substantially induced the phenotypic markers of DC maturation and activation including MHC-II, CD40, CD80, and CD86 together with IFN-ß production. Furthermore, NVT exhibited an appropriate adjuvanticity because it elevated OVA-specific IgG, in particular, higher levels of IgG2c (Th1-type) but lower IgG1 (Th2-type). Concomitantly, NVT increased the levels of Th1-type T cells such as IFN-γ+CD4+ and IFN-γ+CD8+ cells in response to OVA stimulation. Collectively, we suggest that NVT with appropriate safety and effectiveness is a novel and promising adjuvant for vaccines, especially those requiring T cell mediated immunity such as viral and cancer vaccines.

Association of long-term exposure to PM2.5 and survival following ischemic heart disease.

BACKGROUND: Numerous studies have suggested that long-term exposure to particulate matter ≤2.5 µm (PM2.5) may cause cardiovascular morbidity and mortality. However, susceptibility among those with a history of ischemic heart disease is less clearly understood. We aimed to evaluate whether long-term PM2.5 exposure is related to mortality among patients with ischemic heart disease. METHODS: We followed up 306,418 patients hospitalized with ischemic heart disease in seven major cities in South Korea between 2008 and 2016 using the National Health Insurance Database. We linked the modeled PM2.5 data corresponding to each patient's administrative districts and estimated hazard ratios (HRs) of cause-specific mortality associated with the long-term exposure to PM2.5 in time-varying Cox proportional hazard models after adjusting for individual- and area-level characteristics. We also estimated HRs by sex, age group (65-74 vs. ≥75 years), and household income. RESULTS: Of the patients with ischemic heart disease, mean age at the discharge was 76.8 years, and 105,913 died during a mean follow-up duration of 21.4 months. The HR of all-cause mortality was 1.10 [95% confidence intervals (CI): 1.07, 1.14] per 10 µg/m3 increase in a 12-month moving average PM2.5. The HRs of cardiovascular, stroke, and ischemic heart disease were 1.17 (95% CI: 1.11, 1.24), 1.17 (95% CI: 1.06, 1.30), and 1.25 (95% CI: 1.15, 1.35), respectively. The subgroup analyses showed that participants aged 65-74 years were more susceptible to adverse effects of PM2.5 exposure. We did not observe any differences in the risk by sex and household income. CONCLUSION: Mortality from all-cause and cardiovascular disease following hospitalization due to ischemic heart disease was higher among individuals with greater PM2.5 exposure in seven major cities in South Korea. The result supports the association of long-term exposure to air pollution with poor prognosis among patients with ischemic heart disease.

Long-term outcomes after endoscopic versus surgical resection of T1 colorectal carcinoma.

BACKGROUND: The long-term outcomes of patients with T1 colorectal cancer (CRC) who undergo endoscopic and/or surgical treatment are not well understood. Invasive CRC confined to the colonic submucosa (T1 CRC) is challenging in terms of clinical decision-making. We compared the long-term outcomes of T1 CRC by treatment method. METHODS: We examined 370 patients with pathological T1 CRC treated between 2000 and 2015 at Seoul St. Mary's Hospital. In total, 93 patients underwent endoscopic resection (ER) only, 82 underwent additional surgery after ER, and 175 underwent surgical resection only. Patients who did not meet the curative criteria were defined as "high-risk." High-risk patients were classified into three groups according to the treatment modalities: ER only (Group A: 35 patients), additional surgery after ER (Group B: 72 patients), and surgical resection only (Group C: 133 patients). The recurrence-free and overall survival (OS) rates, and factors associated with recurrence and mortality, were analyzed. Factors associated with lymph node metastasis (LNM) were subjected to multivariate analysis. RESULTS: Of the 370 patients, 7 experienced recurrence and 7 died. All recurrences occurred in the high-risk group and two deaths were in the low-risk group. In high-risk groups, there was no significant group difference in recurrence-free survival (P = 0.511) or OS (P =0.657). Poor histology (P =0.042) was associated with recurrence, and vascular invasion (P =0.044) with mortality. LNMs were observed in 30 of 277 patients who underwent surgery either initially or secondarily. Lymphatic invasion was significantly associated with the incidence of LNM (P < 0.001). CONCLUSIONS: ER prior to surgery did not affect the prognosis of high-risk T1 CRC patients, and did not worsen the clinical outcomes of patients who required additional surgery. Lymphatic invasion was the most important predictor of LNM.