The Effect of the Mechanical Properties of the 3D Printed Gelatin/ Hyaluronic Acid Scaffolds on hMSCs Differentiation Towards Chondrogenesis

BACKGROUND@#Tissue engineering, including 3D bioprinting, holds great promise as a therapeutic tool for repairing cartilage defects. Mesenchymal stem cells have the potential to treat various fields due to their ability to differentiate into different cell types. The biomimetic substrate, such as scaffolds and hydrogels, is a crucial factor that affects cell behavior, and the mechanical properties of the substrate have been shown to impact differentiation during incubation. In this study, we examine the effect of the mechanical properties of the 3D printed scaffolds, made using different concentrations of cross-linker, on hMSCs differentiation towards chondrogenesis. @*METHODS@#The 3D scaffold was fabricated using 3D bioprinting technology with gelatin/hyaluronic acid (HyA) biomaterial ink. Crosslinking was achieved by using different concentrations of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methlymorpholinium chloride n-hydrate (DMTMM), allowing for control of the scaffold’s mechanical properties. The printability and stability were also evaluated based on the concentration of DMTMM used. The effects of the gelatin/HyA scaffold on chondrogenic differentiation was analyzed by utilizing various concentrations of DMTMM. @*RESULTS@#The addition of HyA was found to improve the printability and stability of 3D printed gelatin/HyA scaffolds.The mechanical properties of the 3D gelatin/HyA scaffold could be regulated through the use of different concentrations of DMTMM cross-linker. In particular, the use of 0.25 mM DMTMM for crosslinking the 3D gelatin/HyA scaffold resulted in enhanced chondrocyte differentiation. @*CONCLUSION@#The mechanical properties of 3D printed gelatin/HyA scaffolds cross-linked using various concentrations of DMTMM can influence the differentiation of hMSCs into chondrocytes.

Role of Klotho and N-acetylcysteine in Oxidative Stress Associated with the Vitrification of Ovarian Tissue Cytoprotective Function of Klotho in Cryopreservation

BACKGROUND@#Cryopreservation can cause mechanical and chemical stress, ultimately leading to the formation of reactive oxygen species (ROS) and oxidative stress. ROS inhibits the expression of antioxidant enzymes in cells, resulting in increased DNA fragmentation and apoptosis. In this paper, we used a vitrification method that has the advantage of producing less ice crystal formation, cost-effectiveness, and time efficiency during cryopreservation. The objective of this paper is to evaluate the degree of protection of ovarian tissue against oxidative stress when N-acetylcysteine (NAC) and Klotho proteins are treated in the vitrification process of ovarian tissue. @*METHODS@#The control group and the cryopreservation groups were randomly assigned, and treated NAC, Klotho, or the combination (NAC ? Klotho). The cell morphological change, DNA damage, senescence, and apoptosis of each group after the freeze–thaw process were compared using transmission electron microscopy, immunohistochemistry, and western blot analysis. @*RESULTS@#Both NAC and Klotho were found to be more effective at protecting against DNA damage than the control;however, DNA damage was greater in the NAC ? Klotho group than in the group treated with NAC and Klotho, respectively. DNA damage and cellular senescence were also reduced during the vitrification process when cells were treated with NAC, Klotho, or the combination (NAC ? Klotho). NAC increased apoptosis during cryopreservation, whereas Klotho inhibited apoptosis and NAC-induced apoptosis. @*CONCLUSION@#This study highlights Klotho’s benefits in inhibiting DNA damage, cell senescence, and apoptosis, including NAC-induced apoptosis, despite its unclear role in vitrification.

Real-World Treatment Intensity and Patterns in Patients With Myopic Choroidal Neovascularization:Common Data Model in Ophthalmology

Background@#A paucity of data addressing real-world treatment of myopic choroidal neovascularization (mCNV) in the era of anti-vascular endothelial growth factor (VEGF) drugs led us to investigate real-world treatment intensity and treatment patterns in patients with mCNV. @*Methods@#This is a retrospective, observational study using the Observational Medical Outcomes Partnership-Common Data Model database of treatment-naïve patients with mCNV over the 18-year study period (2003–2020). Outcomes were treatment intensity (time trends of total/average number of prescriptions, mean number of prescriptions in the first year and the second year after initiating treatment, proportion of patients with no treatment in the second year) and treatment patterns (subsequent patterns of treatment according to the initial treatment). @*Results@#Our final cohort included 94 patients with at-least 1-year observation period. Overall, 96.8% of patients received anti-VEGF drugs as first-line treatment, with most of injections from bevacizumab. The number of anti-VEGF injections in each calendar year showed an increasing trend over time; however, there was a drop in the mean number of injections in the second year compared to the first year from 2.09 to 0.47. About 77% of patients did not receive any treatment in their second year of treatment regardless of drugs. Most of patients (86.2%) followed non-switching monotherapy only and bevacizumab was the most popular choice either in the first-line (68.1%) or in the second-line (53.8%) of treatment. Aflibercept was increasingly used as the first-line treatment for patients with mCNV. @*Conclusion@#Anti-VEGF drugs have become the treatment of choice and second-line treatment for mCNV over the past decade. Anti-VEGF drugs are effective for the treatment of mCNV as the non-switching monotherapy is the main treatment regimen in most cases and the number of treatments decreases significantly in the second year of treatment.

Direct Internal Fixation for Unstable Atlas Fractures

Purpose@#To investigate the radiologic and clinical outcomes of direct internal fixation for unstable atlas fractures. @*Materials and Methods@#This retrospective study included 12 patients with unstable atlas fractures surgically treated using C1 lateral mass screws, rods, and transverse connector constructs. Nine lateral mass fractures with transverse atlantal ligament (TAL) avulsion injury and three 4-part fractures with TAL injury (two avulsion injuries, one TAL substance tear) were treated. Radiologic outcomes included the anterior atlantodental interval (AADI) in flexion and extension cervical spine lateral radiographs at 6 months and 1 year after treatment. CT was also performed to visualize bony healing of the atlas at 6 months and 1 year. Visual Analog Scale (VAS) scores for neck pain, Neck Disability Index (NDI) values, and cervical range of motion (flexion, extension, and rotation) were recorded at 6 months after surgery. @*Results@#The mean postoperative extension and flexion AADIs were 3.79±1.56 (mean±SD) and 3.13±1.01 mm, respectively. Then mean AADI was 3.42±1.34 and 3.33±1.24 mm at 6 months and 1 year after surgery, respectively. At 1 year after surgery, 11 patients showed bony healing of the atlas on CT images. Only one patient underwent revision surgery 8 months after primary surgery due to nonunion and instability findings. The mean VAS score for neck pain was 0.92±0.99, and the mean NDI value was 8.08±5.70. @*Conclusion@#C1 motion-preserving direct internal fixation technique results in good reduction and stabilization of unstable atlas fractures. This technique allows for the preservation of craniocervical and atlantoaxial motion.

Dynamic Interactions of Fully Glycosylated SARS-CoV-2 Spike Protein with Various Antibodies

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein on the viral envelope mediates human angiotensin-converting enzyme 2 (ACE2) binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein models described in our previous work, and performed all-atom molecular dynamics simulations to get insight into the structural dynamics and interactions between S protein and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes, and the influences of antibody on the motion of S protein receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.

Transection of the Common Carotid and Vertebral Arteries Following a Penetrating Neck Injury

A case of a 30-year-old man who was admitted following a penetrating neck injury is presented. A clinical examination and operative findings identified semi-comatose mentality, neck muscle laceration, and transection of the left common carotid and vertebral arteries and the internal jugular vein. During the operation, the carotid arteries were repaired by interposition grafting, and the internal jugular vein was ligated. The vertebral artery was managed by interventional embolization. Although the patient had some neurological deficit, he was discharged on postoperative Day 52. This surgical case prompted a discussion regarding neurological outcomes, and surgical and endovascular treatment following vascular neck injury.

Association between Laterality and Location of Deep Vein Thrombosis of Lower Extremity and Pulmonary Embolism

Purpose@#The aim of this study was to investigate the relationship between the anatomical location of thrombi in the lower extremities and the development of pulmonary embolism (PE). @*Materials and Methods@#We collected and analyzed the data of patients diagnosed with deep vein thrombosis (DVT) of the lower extremities between 2006 and 2015, and included those whose computed tomography (CT) data were available for PE identification. We evaluated the relationship between the laterality and the proximal/distal location of the thrombi in lower extremites and the location of PE. @*Results@#CT images were available for 388/452 patients with DVT. After excluding 32 cases with bilateral involvement, 356 cases were included for analysis in this study. The ratio of DVT in the left:right leg was 232:124. PEs developed in 121 (52.2%) patients with left-sided DVT and in 78 (62.9%) with right-sided DVT (P=0.052). PEs in the main pulmonary arteries developed in 36 (15.5%) patients with left leg DVT and in 30 (24.2%) with right leg DVT (P=0.045). The most frequent site of thrombosis associated with the development of PE was the left iliac vein (59/199, 29.6%). According to the anatomical segment of the leg affected by DVT, patients with DVT in the right femoral vein (50/71, 70.4%; P=0.016) had the highest rate of occurrence of PE. @*Conclusion@#PE develops more frequently in patients with right-sided DVT than in those with left-sided DVT. Therefore, careful observation for the possible development of PE is recommended in cases with right-sided DVT of the lower extremity.

Methodology and Rationale for Ophthalmic Examinations in the Seventh and Eighth Korea National Health and Nutrition Examination Surveys (2017–2021)

This report provides a detailed description of the methodology for ophthalmic examinations according to the Korea National Health and Nutrition Examination Survey (KNHANES) VII and VIII (from 2017 to 2021). The KNHANES is a nationwide survey which has been performed since 1998 in representatives of whole Korean population. During the KNHANES VII and VIII, in addition to the ophthalmic questionnaire, intraocular pressure measurement, visual field test, auto refractometry, axial length and optical coherence tomography measurements were included. This new survey will provide not only provide normative and pathologic ophthalmic data including intraocular pressure, refractive error, axial length, visual field and precise measurement of anterior segment, macula and optic nerve with optical coherence tomography, but also a more accurate diagnosis for major adult blindness diseases, including age-related macular degeneration, diabetic retinopathy, glaucoma, and other ocular diseases, for the national Korean population.

A survey for Management of Drug Safety Evaluation System for Investigational Product

Objective@#To gather the opinions of hands-on workers for successful introduction of the Development Safety Update Report (DSUR) according to a five-year comprehensive plan for clinical trial development [Ministry of Food and Drug Safety, 2019]. @*Methods@#We conducted a survey on considerations that industry stakeholders may have related to the enforcement of the DSUR. A questionnaire was distributed among pharmacovigilance specialists from 13 pharmaceutical companies in South Korea on June 4, 2020. The questionnaire comprised two sections: 1) current status of the Drug Safety Data Management System and 2) considerations on the implementation and management of the DSUR. @*Results@#All respondents have agreed the introduction of DSUR is inevitable for regulatory harmonization and safety of trial subject. However, most respondents (85%) felt concern about additional workload with DSUR implementation. They answered that format and operation system of DSUR should be harmonized with those of international standards and authorities need to minimize double burden due to related report. @*Conclusion@#All respondents asserted that domestic DSUR should be harmonized with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E2F guidelines. Respondents from global companies also suggested regulatory authorities allow DSUR written in English to replace Korean version considering their deadline for submission.Moreover, every respondent agreed regulatory authorities need delicate effort when implementing mandatory submission of DSUR to ensure that even small pharmaceutical companies with no experience in DSUR can comply with the system.

Association between Laterality and Location of Deep Vein Thrombosis of Lower Extremity and Pulmonary Embolism

Purpose@#The aim of this study was to investigate the relationship between the anatomical location of thrombi in the lower extremities and the development of pulmonary embolism (PE). @*Materials and Methods@#We collected and analyzed the data of patients diagnosed with deep vein thrombosis (DVT) of the lower extremities between 2006 and 2015, and included those whose computed tomography (CT) data were available for PE identification. We evaluated the relationship between the laterality and the proximal/distal location of the thrombi in lower extremites and the location of PE. @*Results@#CT images were available for 388/452 patients with DVT. After excluding 32 cases with bilateral involvement, 356 cases were included for analysis in this study. The ratio of DVT in the left:right leg was 232:124. PEs developed in 121 (52.2%) patients with left-sided DVT and in 78 (62.9%) with right-sided DVT (P=0.052). PEs in the main pulmonary arteries developed in 36 (15.5%) patients with left leg DVT and in 30 (24.2%) with right leg DVT (P=0.045). The most frequent site of thrombosis associated with the development of PE was the left iliac vein (59/199, 29.6%). According to the anatomical segment of the leg affected by DVT, patients with DVT in the right femoral vein (50/71, 70.4%; P=0.016) had the highest rate of occurrence of PE. @*Conclusion@#PE develops more frequently in patients with right-sided DVT than in those with left-sided DVT. Therefore, careful observation for the possible development of PE is recommended in cases with right-sided DVT of the lower extremity.

Methodology and Rationale for Ophthalmic Examinations in the Seventh and Eighth Korea National Health and Nutrition Examination Surveys (2017–2021)

This report provides a detailed description of the methodology for ophthalmic examinations according to the Korea National Health and Nutrition Examination Survey (KNHANES) VII and VIII (from 2017 to 2021). The KNHANES is a nationwide survey which has been performed since 1998 in representatives of whole Korean population. During the KNHANES VII and VIII, in addition to the ophthalmic questionnaire, intraocular pressure measurement, visual field test, auto refractometry, axial length and optical coherence tomography measurements were included. This new survey will provide not only provide normative and pathologic ophthalmic data including intraocular pressure, refractive error, axial length, visual field and precise measurement of anterior segment, macula and optic nerve with optical coherence tomography, but also a more accurate diagnosis for major adult blindness diseases, including age-related macular degeneration, diabetic retinopathy, glaucoma, and other ocular diseases, for the national Korean population.

A survey for Management of Drug Safety Evaluation System for Investigational Product

Objective@#To gather the opinions of hands-on workers for successful introduction of the Development Safety Update Report (DSUR) according to a five-year comprehensive plan for clinical trial development [Ministry of Food and Drug Safety, 2019]. @*Methods@#We conducted a survey on considerations that industry stakeholders may have related to the enforcement of the DSUR. A questionnaire was distributed among pharmacovigilance specialists from 13 pharmaceutical companies in South Korea on June 4, 2020. The questionnaire comprised two sections: 1) current status of the Drug Safety Data Management System and 2) considerations on the implementation and management of the DSUR. @*Results@#All respondents have agreed the introduction of DSUR is inevitable for regulatory harmonization and safety of trial subject. However, most respondents (85%) felt concern about additional workload with DSUR implementation. They answered that format and operation system of DSUR should be harmonized with those of international standards and authorities need to minimize double burden due to related report. @*Conclusion@#All respondents asserted that domestic DSUR should be harmonized with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E2F guidelines. Respondents from global companies also suggested regulatory authorities allow DSUR written in English to replace Korean version considering their deadline for submission.Moreover, every respondent agreed regulatory authorities need delicate effort when implementing mandatory submission of DSUR to ensure that even small pharmaceutical companies with no experience in DSUR can comply with the system.

Structure, Dynamics, Receptor Binding, and Antibody Binding of Fully-glycosylated Full-length SARS-CoV-2 Spike Protein in a Viral Membrane

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates host cell entry by binding to angiotensin-converting enzyme 2 (ACE2), and is considered the major target for drug and vaccine development. We previously built fully-glycosylated full-length SARS-CoV-2 S protein models in a viral membrane including both open and closed conformations of receptor binding domain (RBD) and different templates for the stalk region. In this work, multiple s-long all-atom molecular dynamics simulations were performed to provide deeper insight into the structure and dynamics of S protein, and glycan functions. Our simulations reveal that the highly flexible stalk is composed of two independent joints and most probable S protein orientations are competent for ACE2 binding. We identify multiple glycans stabilizing the open and/or closed states of RBD, and demonstrate that the exposure of antibody epitopes can be captured by detailed antibody-glycan clash analysis instead of a commonly-used accessible surface area analysis that tends to overestimate the impact of glycan shielding and neglect possible detailed interactions between glycan and antibody. Overall, our observations offer structural and dynamic insight into SARS-CoV-2 S protein and potentialize for guiding the design of effective antiviral therapeutics.

Modeling and Simulation of a Fully-glycosylated Full-length SARS-CoV-2 Spike Protein in a Viral Membrane

This technical study describes all-atom modeling and simulation of a fully-glycosylated full-length SARS-CoV-2 spike (S) protein in a viral membrane. First, starting from PDB:6VSB and 6VXX, full-length S protein structures were modeled using template-based modeling, de-novo protein structure prediction, and loop modeling techniques in GALAXY modeling suite. Then, using the recently-determined most occupied glycoforms, 22 N-glycans and 1 O-glycan of each monomer were modeled using Glycan Reader & Modeler in CHARMM-GUI. These fully-glycosylated full-length S protein model structures were assessed and further refined against the low-resolution data in their respective experimental maps using ISOLDE. We then used CHARMM-GUI Membrane Builder to place the S proteins in a viral membrane and performed all-atom molecular dynamics simulations. All structures are available in CHARMM-GUI COVID-19 Archive (http://www.charmm-gui.org/docs/archive/covid19), so researchers can use these models to carry out innovative and novel modeling and simulation research for the prevention and treatment of COVID-19.

Dipeptidyl Peptidase-4 Inhibitors versus Other Antidiabetic Drugs Added to Metformin Monotherapy in Diabetic Retinopathy Progression: A Real World-Based Cohort Study

BACKGROUND: To investigate the effects of dipeptidyl peptidase-4 inhibitor (DPP4i) as add-on medications to metformin on progression of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus, compared with sulfonylurea (SU) or thiazolidinedione (TZD). METHODS: We identified 4,447 patients with DPP4i, 6,136 with SU, and 617 with TZD in addition to metformin therapy from the database of Korean National Health Insurance Service between January 2013 and December 2015. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for DR progression. The progression of DR was defined by the procedure code of panretinal photocoagulation, intravitreal injection or vitrectomy; or the addition of diagnostic code of vitreous hemorrhage, retinal detachment, or neovascular glaucoma. RESULTS: The age and sex-adjusted HR of DR progression was 0.74 for DPP4i add-on group compared with SU add-on group (95% confidence interval [CI], 0.62 to 0.89). This lower risk of DR progression remained significant after additional adjustments for comorbidities, duration of metformin therapy, intravitreal injections and calendar index year (HR, 0.80; 95% CI, 0.66 to 0.97). CONCLUSION: This population-based cohort study showed that the use of DPP4i as add-on therapy to metformin did not increase the risk of DR progression compared to SU.

Effect of Statins, Metformin, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers on Age-Related Macular Degeneration

PURPOSE: Statins, metformin, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have been suggested for treating age-related macular degeneration (AMD) due to their pleiotropic effects. Therefore, we investigated whether these drugs prevent AMD. MATERIALS AND METHODS: We conducted a nested case-control study using the Korean National Health Insurance Service database. Using risk-set sampling of age, sex, cohort entry date, and follow-up duration, we identified incident patients with AMD and 10 matching controls in cohorts with diabetes mellitus or cardiovascular diseases. Exposure was assessed within one year before the index date using patient prescription records. We conducted conditional logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between cardiovascular medications and AMD. RESULTS: Our study included 2330 cases and 23278 controls from a cohort of 231274 patients. The ORs (95% CI) for AMD occurrence in users prescribed with statins, metformin, ACE inhibitors, and ARBs were 1.12 (0.94–1.32), 1.15 (0.91–1.45), 0.90 (0.61–1.34), and 1.21 (1.05–1.39), respectively. A duration-response was not observed. CONCLUSION: Statins, metformin, ACE inhibitors, and ARBs did not inhibit AMD in elderly patients. The absence of a duration-response supports the lack of a causal relationship.

Symptomatic Calcific Deposition in Posterior Cruciate Ligament of the Knee / 대한정형외과학회잡지

Calcium deposition disease, including calcific tendinitis, rarely affects the knee joint. Only a few cases can be found in the literatures and there is no case report of symptomatic calcific deposition arising from the posterior cruciate ligament in Korea. The authors encountered a case of symptomatic calcific deposition arising from the posterior cruciate ligament, which was excised arthroscopically and confirmed pathologically. This paper reports this case with a review of the relevant literature.

Nationwide Incidence of Acute Angle Closure Glaucoma in Korea from 2011 to 2015

Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives

Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated and , further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.

Two Cases of Complications during Percutaneous Coronary Intervention for Myocardial Infarction in Patients with Concurrent Chronic Total Occlusion in an Emergency Setting

Morbidity and mortality rates associated with acute myocardial infarction accompanying chronic total occlusion are comparatively high. European guidelines recommend primary intervention for the causative lesion in patient with acute myocardial infarction. Therefore, it is important to identify the culprit lesion. We report two cases of myocardial infarction with concurrent chronic total occlusion in an emergency setting.