On-chip human lymph node stromal network for evaluating dendritic cell and T-cell trafficking.

The lymph node paracortex, also known as the T-cell zone, consists of a network of fibroblastic reticular cells (FRCs) that secrete chemokines to induce T-cell and dendritic cell trafficking into the paracortex. To model the lymph node paracortex, we utilize multi-channel microfluidic devices to engineer a 3D lymph node stromal network from human cultured FRCs embedded in a collagen I-fibrin hydrogel. In the hydrogel, the FRCs self-assemble into an interconnected network, secrete the extracellular matrix proteins entactin, collagen IV, and fibronectin, as well as express an array of immune cell trafficking chemokines. Although the engineered FRC network did not secrete characteristic CCR7-ligand chemokines (i.e. CCL19 and CCL21), human primary TNF-α matured monocyte-derived dendritic cells, CD45RA+ T-cells, and CD45RA- T-cells migrate toward the lymph node stromal network to a greater extent than toward a blank hydrogel. Furthermore, the FRCs co-recruit dendritic cells and antigen-specific T-cells into the lymph node stromal network. This engineered lymph node stromal network may help evaluate how human dendritic cells and T-cells migrate into the lymph node paracortex via CCR7-independent mechanisms. .

Fire-Resistant and Thermal Stability Properties of Fluorosilicone Adhesives by Incorporation of Surface-Modified Aluminum Trihydrate.

Fluorosilicone was combined with aluminum trihydrate (ATH) to induce synergistic flame-retardant and thermal-resistant properties. The surface of ATH was modified with four different silane coupling agents. The flammability and mechanical properties of the fluorosilicone/ATH composites were assessed using an UL94 vertical test and a die shear strength test. The change in shear strength was investigated under aging for 1000 h at -55 °C and 150 °C. Pure fluorosilicone had inherent fire resistance and thus achieved a V-0 rating even at 20 wt.% ATH loading. Upon addition of ATH treated with 3-glycidoxypropyl trimethoxysilane, the composites exhibited the highest shear strength of 3.9 MPa at 23 °C because of the additional crosslinking reaction of fluorosilicone resin with the epoxide functional group of the coupling agent. Regardless of the types of coupling agents, the composites exhibited similar flame retardancy at the same ATH content, with a slight reduction in shear strength at 180 °C and 250 °C. The shear strength of the adhesives gradually decreased with aging time at -55 °C, but increased noticeably from 3.9 MPa to 11.5 MPa when aged at 150 °C due to the occurrence of the additional crosslinking reaction of fluorosilicone.

Potential value of animal microphysiological systems.

Microphysiological systems (MPS) are designed to recapitulate aspects of tissue/organ physiology in vivo, thereby providing potential value in safety and efficacy assessments of FDA-regulated products and regulatory decision-making. While there have been significant advances in the development, use, and proposals of qualification criteria for human organ MPS, there remains a gap in the development using animal tissues. Animal MPS may be of value in many areas including the study of zoonotic diseases, assessment of the safety and efficacy of animal therapeutics, and possibly reduction of the use of animals in regulatory submissions for animal therapeutics. In addition, the development of MPS from various animal species enables comparison to animal in vivo data. This comparison, while not always critical for all contexts of use, could help gain confidence in the use and application of human MPS data for regulatory decision-making and for the potential identification of species-specific effects. The use of animal MPS is consistent with the replacement, reduction, and refinement (3Rs) principles of animal use by identifying toxic compounds before conducting in vivo studies and identifying the appropriate species for testing.

Microphysiological systems (MPS) mimic aspects of organs in humans or animals. These systems may provide information useful for FDA-regulated products. While there have been significant advances in the development of MPS made from human cells, there remains a gap in the development of MPS using animal cells. FDA believes animal MPS may be of value in many areas including the study of diseases transmitted from animals to humans, assessment of the safety and efficacy of animal drugs, and reduction of the use of animals in regulatory submissions. The development of animal MPS enables comparison to data from studies conducted in animals. This comparison provides confidence in the use of human MPS data for regulatory decision-making. The use of animal MPS is consistent with the 3Rs principles of animal use by allowing identification of toxic compounds before conducting animal studies and by helping select the appropriate species for further testing.

Change in Iridotrabecular Contact and Intraocular Pressure after Phacoemulsification in Primary Angle Closure Disease Spectrum.

Purpose: To compare changes in the swept-source anterior segment optical coherence tomography (SS AS-OCT) parameters and intraocular pressure (IOP) control after lens extraction in various spectra of primary angle closure disease (PACD). Methods: A total 92 eyes from 92 patients with PACD who underwent lens extraction were included in the study. All patients underwent IOP measurement preoperatively and postoperatively at 1 day, 1 week, 1 month, 3 months, and 6 months. SS AS-OCT was performed in all subjects preoperatively and 1 month postoperatively. All participants were divided into two groups depending on the presence of glaucomatous optic disc or visual field damage (group A: primary angle closure suspect or primary angle closure; group B: primary angle closure glaucoma). The changes in IOP and anterior chamber angle (ACA) parameters of SS AS-OCT of each group were compared. Regression analysis was performed to find factors associated with the degree of IOP reduction after lens extraction. Results: Preoperatively, there was no significant difference in IOP (16.3 ± 2.5 vs 16.9 ± 3.2 mmHg, P=0.297) between the two groups, but the number of glaucoma medications used (0.6 ± 1.0 vs 2.0 ± 0.9, P<0.001) was greater in group B. Postoperatively, IOP was not significantly different, but the number of medications used was greater in group B (0.2 ± 0.7, 0.9 ± 0.8, P<0.001). ACA parameters including angle opening distance and trabecular-iris angle had a greater increase in group B after lens extraction. However, the residual iridotrabecular contact (ITC) index (5.6 ± 7.0 vs 10.7 ± 12.1, P=0.014) was significantly greater in group B. A greater change in the ITC index was related to a greater degree of IOP reduction (beta coefficient = 0.429, P<0.001). Conclusions: Eyes with PACG had a greater residual ITC index after lens extraction compared with eyes of other PACD spectrum, and required a greater number of glaucoma medications to maintain a similar level of IOP.

A cohort study of the effects of social support on cerebral cardiovascular disease in subjects with metabolic syndrome.

INTRODUCTION: Previous studies have extensively examined the relationship between social support and various health outcomes. However, little is known about the distinct longitudinal associations between perceived social support and the development of cardiovascular events in patients with metabolic syndrome. In this cohort study, we investigated whether the levels of perceived social support in patients with metabolic syndrome were associated with an increased risk of cerebrovascular and cardiovascular events. METHODS: The level of social support was assessed using the Medical Outcomes Study-Social Support Survey (MOS-SSS) in 2,721 individuals living in Wonju and Pyeongchang, South Korea. The presence of metabolic syndrome was determined by physical measurements and blood tests, and the occurrence of cerebral cardiovascular disease in relation to the presence of metabolic syndrome and the level of social support was analyzed using Cox proportional-hazards models. RESULTS: The median follow-up period was 2,345 days (2,192-2,618). Overall, in the group with metabolic syndrome and low social support, low social support was associated with an increased risk of later cerebral cardiovascular events; in this group, the hazard ratio after adjusting for confounding variables was 1.97 times (95% confidence interval, 1.01-3.85) higher than that in the group without metabolic syndrome and low social support. CONCLUSION: This study shows, for the first time, that the level of social support is a risk factor for preventing cerebral cardiovascular disease in patients with metabolic syndrome and suggests that social support status should be incorporated into multifactorial risk assessment and intervention procedures to prevent metabolic syndrome and cerebral cardiovascular disease.

Anterior Chamber Angle and Intraocular Pressure Control After Phacoemulsification in Primary Angle Closure With Different Mechanisms.

PRCIS: Different mechanisms of angle closure represented distinct aspects of intraocular pressure (IOP) control after phacoemulsification. Classification of angle closure mechanisms is necessary for postoperative IOP management and glaucoma progression in primary angle closure eyes. PURPOSE: To investigate the relationship between the anterior chamber angle (ACA) characteristics, measured by swept-source anterior segment optical coherence tomography (SS AS-OCT), and intraocular pressure (IOP) control after phacoemulsification in eyes with primary angle closure disease (PACD) with different angle closure mechanisms. METHODS: PACD eyes were classified into 3 groups according to angle closure mechanisms using preoperative SS AS-OCT images; pupillary block (PB), plateau iris configuration (PIC), exaggerated lens vault (ELV). This retrospective, clinical cohort study included eighty-five eyes of 85 PACD patients: 34 with PB, 23 with PIC, and 28 with ELV. ACA parameters were measured preoperatively and 1 month postoperatively using SS AS-OCT. IOP measurements were performed preoperatively and during 6 months postoperatively. Postoperative IOP reduction and fluctuation were calculated, and their correlations with SS AS-OCT parameters were analyzed. RESULTS: PIC group showed the lowest postoperative IOP reduction compared with the other groups ( P =0.023). Preoperative ACA measurements were significantly associated with postoperative IOP reduction in ELV and PB groups, while postoperative measurements were in PIC group. Preoperative and postoperative change of iridotrabecular contact (ITC) index and area were correlated with postoperative IOP reduction in PB and ELV groups but not in PIC group. Postoperative ITC index ( P =0.031) and area ( P =0.003) showed significant correlations with postoperative IOP fluctuation only in PIC group. CONCLUSIONS: SS AS-OCT parameters including ITC index and area showed different associations with postoperative IOP control, which should be considered in determination of lens extraction and treatment of PACD eyes.

Colon cancer: the 2023 Korean clinical practice guidelines for diagnosis and treatment.

Colorectal cancer is the third most common cancer in Korea and the third leading cause of death from cancer. Treatment outcomes for colon cancer are steadily improving due to national health screening programs with advances in diagnostic methods, surgical techniques, and therapeutic agents.. The Korea Colon Cancer Multidisciplinary (KCCM) Committee intends to provide professionals who treat colon cancer with the most up-to-date, evidence-based practice guidelines to improve outcomes and help them make decisions that reflect their patients' values and preferences. These guidelines have been established by consensus reached by the KCCM Guideline Committee based on a systematic literature review and evidence synthesis and by considering the national health insurance system in real clinical practice settings. Each recommendation is presented with a recommendation strength and level of evidence based on the consensus of the committee.

The Association between Social Support, Metabolic Syndrome, and Incidence of Cardio-Cerebrovascular Diseases in Older Adults: The ARIRANG Study.

PURPOSE: We investigated the association between social support, metabolic syndrome, and incident cardio-cerebrovascular disease (CCVD) in rural Koreans aged ≥50 years. MATERIALS AND METHODS: We conducted a prospective study using the Korean Genome and Epidemiology Study on Atherosclerosis Risk of Rural Areas in the Korean General Population (KoGES-ARIRANG) dataset. From the baseline of 5169 adults, 1682 participants were finally included according to the exclusion criteria. For outcomes, myocardial infarction, angina, and stroke were included. For independent variables, the social support score and metabolic syndrome were used. Descriptive statistics and multivariate logistic regression were performed to investigate the association among the variables. Paired t-test was conducted to analyze the longitudinal variation of social support scores. RESULTS: During the 6.37 years of median follow-up, 137 participants developed CCVD. The adjusted odds ratio (aOR) of metabolic syndrome with persistently high social support was 2.175 [95% confidence interval (CI): 1.479-3.119]. The aOR of metabolic syndrome with persistently low social support was 2.494 (95% CI: 1.141-5.452). The longitudinal variation of the social support score of persistently high social support group was increased significantly by 4.26±26.32. The score of the persistently low social support group was decreased by 1.34±16.87 with no statistical significance. CONCLUSION: The presence of metabolic syndrome increases the likelihood of developing onset CCVD. Within the metabolic syndrome positive group, when social support was persistently low, the cohort developed more cardio-cerebrovascular disease compared to the persistently higher social support group. The social support score of the persistently low social support group could be improved through proper intervention. To prevent CCVD, metabolic syndrome components and low social support should be improved in the study participants.

Mdivi-1: Effective but complex mitochondrial fission inhibitor.

Mdivi-1, Mitochondrial DIVIsion inhibitor 1, has been widely employed in research under the assumption that it exclusively influences mitochondrial fusion, but effects other than mitochondrial dynamics have been underinvestigated. This paper provides transcriptome and DNA methylome-wide analysis for Mdivi-1 treated SH-SY5Y human neuroblastoma cells using RNA sequencing (RNA-seq) and methyl capture sequencing (MC-seq) methods. Gene ontology analysis of RNA sequences revealed that p53 transcriptional gene network and DNA replication initiation-related genes were significantly up and down-regulated, respectively, showing the correlation with the arrest cell cycle in the G1 phase. MC-seq, a powerful sequencing method for capturing DNA methylation status in CpG sites, revealed that although Mdivi-1 does not induce dramatic DNA methylation change, the subtle alterations were concentrated within the CpG island. Integrative analysis of both sequencing data disclosed that the p53 transcriptional network was activated while the Parkinson's disease pathway was halted. Next, we investigated several changes in mitochondria in response to Mdivi-1. Copy number and transcription of mitochondrial DNA were suppressed. ROS levels increased, and elevated ROS triggered mitochondrial retrograde signaling rather than inducing direct DNA damage. In this study, we could better understand the molecular network of Mdivi-1 by analyzing DNA methylation and mRNA transcription in the nucleus and further investigating various changes in mitochondria, providing inspiration for studying nuclear-mitochondrial communications.

DeepHealthNet: Adolescent Obesity Prediction System Based on a Deep Learning Framework.

The global prevalence of childhood and adolescent obesity is a major concern due to its association with chronic diseases and long-term health risks. Artificial intelligence technology has been identified as a potential solution to accurately predict obesity rates and provide personalized feedback to adolescents. This study highlights the importance of early identification and prevention of obesity-related health issues. To develop effective algorithms for the prediction of obesity rates and provide personalized feedback, factors such as height, weight, waist circumference, calorie intake, physical activity levels, and other relevant health information must be taken into account. Therefore, by collecting health datasets from 321 adolescents who participated in Would You Do It! application, we proposed an adolescent obesity prediction system that provides personalized predictions and assists individuals in making informed health decisions. Our proposed deep learning framework, DeepHealthNet, effectively trains the model using data augmentation techniques, even when daily health data are limited, resulting in improved prediction accuracy (acc: 0.8842). Additionally, the study revealed variations in the prediction of the obesity rate between boys (acc: 0.9320) and girls (acc: 0.9163), allowing the identification of disparities and the determination of the optimal time to provide feedback. Statistical analysis revealed that the performance of the proposed deep learning framework was more statistically significant (p 0.001) compared to the other general models. The proposed system has the potential to effectively address childhood and adolescent obesity.

From animal testing to in vitro systems: advancing standardization in microphysiological systems.

Limitations with cell cultures and experimental animal-based studies have had the scientific and industrial communities searching for new approaches that can provide reliable human models for applications such as drug development, toxicological assessment, and in vitro pre-clinical evaluation. This has resulted in the development of microfluidic-based cultures that may better represent organs and organ systems in vivo than conventional monolayer cell cultures. Although there is considerable interest from industry and regulatory bodies in this technology, several challenges need to be addressed for it to reach its full potential. Among those is a lack of guidelines and standards. Therefore, a multidisciplinary team of stakeholders was formed, with members from the US Food and Drug Administration (FDA), the National Institute of Standards and Technology (NIST), European Union, academia, and industry, to provide a framework for future development of guidelines/standards governing engineering concepts of organ-on-a-chip models. The result of this work is presented here for interested parties, stakeholders, and other standards development organizations (SDOs) to foster further discussion and enhance the impact and benefits of these efforts.

Progress in developing microphysiological systems for biological product assessment.

Microphysiological systems (MPS), also known as miniaturized physiological environments, have been engineered to create and study functional tissue units capable of replicating organ-level responses in specific contexts. The MPS has the potential to provide insights about the safety, characterization, and effectiveness of medical products that are different and complementary to insights gained from traditional testing systems, which can help facilitate the transition of potential medical products from preclinical phases to clinical trials, and eventually to market. While many MPS are versatile and can be used in various applications, most of the current applications have primarily focused on drug discovery and testing. Yet, there is a limited amount of research available that demonstrates the use of MPS in assessing biological products such as cellular and gene therapies. This review paper aims to address this gap by discussing recent technical advancements in MPS and their potential for assessing biological products. We further discuss the challenges and considerations involved in successful translation of MPS into mainstream product testing.

Modulation of TRPV4-mediated TNF-α expression in Müller glia and subsequent RGC apoptosis by statins.

In addition to regulating cholesterol synthesis, statins have neuroprotective effects. Apoptosis of retinal ganglion cells (RGCs) causes a gradual loss of visual function in glaucoma. This study aimed to investigate the neuroprotective effect of statins on the RGC apoptosis induced by activated Müller glia. Primary Müller cells and RGCs were cultured from the retina of C57BL6 mice. Müller cells were activated with GSK101, a transient receptor potential vanilloid 4 (TRPV4) agonist, and tumor necrosis factor-alpha (TNF-α) released to the medium was measured using an enzyme-linked immunosorbent assay. Cells were pretreated with simvastatin or lovastatin before GSK101. RGCs were treated with conditioned media from Müller glia cultures, and apoptosis was determined using flow cytometry. TRPV4 activation through GSK101 treatment induced gliosis of Müller cells, and the conditioned media from activated Müller cells was potent to induce RGC apoptosis. Statins suppress both gliosis in Müller cells and subsequent RGC apoptosis. TNF-α release to the media was increased in GSK101-treated Müller cells, and TNF-α in the conditioned media was the critical factor causing RGC apoptosis. The increase in TRPV4-mediated TNF-α expression occurred through the nuclear factor kappa-light chain enhancer of activated B cell pathway activation, which was inhibited by statins. Herein, we showed that statins can modulate gliosis and TNF-α expression in Müller cells, protecting RGCs. These data further support the neuroprotective effect of statins, promoting them as a potential treatment for glaucoma.

Evaluation of a microphysiological human placental barrier model for studying placental drug transfer.

Understanding drug transport across the placental barrier is important for assessing the potential fetal drug toxicity and birth defect risks. Current in vivo and in vitro models have structural and functional limitations in evaluating placental drug transfer and toxicity. Microphysiological systems (MPSs) offer more accurate and relevant physiological models of human tissues and organs on a miniature scale for drug development and toxicology testing. MPSs for the placental barrier have been recently explored to study placental drug transfer. We utilized a multilayered hydrogel membrane-based microphysiological model composed of human placental epithelial and endothelial cells to replicate the key structure and function of the human placental barrier. A macroscale human placental barrier model was created using a transwell to compare the results with the microphysiological model. Placental barrier models were characterized by assessing monolayer formation, intercellular junctions, barrier permeability, and their structural integrity. Three small-molecule drugs (glyburide, rifaximin, and caffeine) that are prescribed or taken during pregnancy were studied for their placental transfer. The results showed that all three drugs crossed the placental barrier, with transfer rates in the following order: glyburide (molecular weight, MW = 494 Da) < rifaximin (MW = 785.9 Da) < caffeine (MW = 194.19 Da). Using non-compartmental analysis, we estimated human pharmacokinetic characteristics based on in vitro data from both MPS and transwell models. While further research is needed, our findings suggest that MPS holds potential as an in vitro tool for studying placental drug transfer and predicting fetal exposure, offering insights into pharmacokinetics.

Colon cancer: the 2023 Korean clinical practice guidelines for diagnosis and treatment

Colorectal cancer is the third most common cancer in Korea and the third leading cause of death from cancer. Treatment outcomes for colon cancer are steadily improving due to national health screening programs with advances in diagnostic methods, surgical techniques, and therapeutic agents.. The Korea Colon Cancer Multidisciplinary (KCCM) Committee intends to provide professionals who treat colon cancer with the most up-to-date, evidence-based practice guidelines to improve outcomes and help them make decisions that reflect their patients’ values and preferences. These guidelines have been established by consensus reached by the KCCM Guideline Committee based on a systematic literature review and evidence synthesis and by considering the national health insurance system in real clinical practice settings. Each recommendation is presented with a recommendation strength and level of evidence based on the consensus of the committee.

The Association between Social Support, Metabolic Syndrome, and Incidence of Cardio-Cerebrovascular Diseases in Older Adults: The ARIRANG Study

Purpose@#We investigated the association between social support, metabolic syndrome, and incident cardio-cerebrovascular disease (CCVD) in rural Koreans aged ≥50 years. @*Materials and Methods@#We conducted a prospective study using the Korean Genome and Epidemiology Study on Atherosclerosis Risk of Rural Areas in the Korean General Population (KoGES-ARIRANG) dataset. From the baseline of 5169 adults, 1682 participants were finally included according to the exclusion criteria. For outcomes, myocardial infarction, angina, and stroke were included. For independent variables, the social support score and metabolic syndrome were used. Descriptive statistics and multivariate logistic regression were performed to investigate the association among the variables. Paired t-test was conducted to analyze the longitudinal variation of social support scores. @*Results@#During the 6.37 years of median follow-up, 137 participants developed CCVD. The adjusted odds ratio (aOR) of metabolic syndrome with persistently high social support was 2.175 [95% confidence interval (CI): 1.479–3.119]. The aOR of metabolic syndrome with persistently low social support was 2.494 (95%CI: 1.141–5.452). The longitudinal variation of the social support score of persistently high social support group was increased significantly by 4.26±26.32. The score of the persistently low social support group was decreased by 1.34±16.87 with no statistical significance. @*Conclusion@#The presence of metabolic syndrome increases the likelihood of developing onset CCVD. Within the metabolic syndrome positive group, when social support was persistently low, the cohort developed more cardio-cerebrovascular disease compared to the persistently higher social support group. The social support score of the persistently low social support group could be improved through proper intervention. To prevent CCVD, metabolic syndrome components and low social support should be improved in the study participants.

Progressive Changes in the Anterior Segment and Their Impact on the Anterior Chamber Angle in Primary Angle Closure Disease.

PURPOSE: To investigate longitudinal changes in the anterior segment (AS) using serial optical coherence tomography (OCT) images and determine the impact of these changes on the anterior chamber angle (ACA) in eyes with primary angle closure disease (PACD) treated with laser peripheral iridotomy (LPI). DESIGN: Retrospective clinical cohort study. METHODS: This study included 103 patients with PACD who underwent LPI and were followed up by a mean 6.7 ± 1.7 AS-OCT examinations for a mean 6.5 ± 2.9 years. Temporal changes in AS-OCT parameters, including anterior chamber depth (ACD), angle opening distance (AOD750), angle recess area (ARA750), iris thickness (IT750), lens vault (LV), and pupil diameter (PD), were analyzed by multivariate linear mixed effects models (LMEMs). RESULTS: Multivariate LMEMs showed that decrease in AOD750 was not significant (-1.59 µm/y, P = .222); however, ARA750 decreased over time (-2.3 × 103 µm2/y, P = .033) and SSA showed marginal significance (-0.20°/y, P = .098), and LV increased significantly (11.6 µm/y, P < .001) after LPI. Mean LV change was negatively associated with AOD750, ARA750, and SSA, whereas PD was negatively associated with ARA750 (P < .001 each). PD decreased with aging (-13.7 µm/y, P = .036), accompanied by thinning of IT750 (-1.7 µm/y, P = .063). CONCLUSIONS: LV tends to increase with aging, which contributes to the shallowing of the anterior chamber and narrowing of ACA in PACD eyes treated with LPI. In the meantime, pupillary constriction and subsequent peripheral iris thinning associated with aging could possibly offset the effect of ACA narrowing.

Topographic comparison of the retinal microvascular changes between patients with compressive and glaucomatous optic neuropathies.

We investigated the difference in optical coherence tomography angiography characteristics between the patients with compressive optic neuropathy (CON, n = 26) and glaucomatous optic neuropathy (GON, n = 26), who were matched for the severity of visual field defect. The peripapillary retinal nerve fiber layer (pRNFL) thickness in the nasal and temporal sectors was thinner in the CON group, whereas the inferior pRNFL thickness was thinner in the GON group. Accordingly, the CON group had lower peripapillary vessel density (pVD) in the nasal and temporal sectors, and the GON group in the inferior sector. In the macular area, the CON group had a thinner macular ganglion cell-inner plexiform layer in the superior and nasal sectors, whereas the GON group in the inferior sector. However, the CON group did not have a lower macular VD than the GON group in any sector, whereas the GON group exhibited lower superficial capillary plexus VD in the superior, inferior, and temporal sectors. Comparison of the structure-vasculature correlation revealed a significant difference in the nasal and temporal peripapillary areas and superior and nasal macular sectors; a decrease in VD was greater in the GON group than in the CON group when the comparable structural change occurred.