Trends in the Incidence and Etiology of Non-Traumatic Spinal Cord Injury in Korea: A Nationwide Population-Based Study From 2007 to 2020.

BACKGROUND: Although patients with non-traumatic spinal cord injury (NTSCI) have distinct epidemiological characteristics compared to those with traumatic spinal cord injury, no previous study has reported the incidence of NTSCI on a national scale in Korea. In this study, we examined the trend in incidence of NTSCI in Korea and described the epidemiological characteristics of patients with NTSCI using nationwide insurance data. METHODS: National Health Insurance Service data were reviewed for the period from 2007 to 2020. The International Classification of Diseases, 10th revision, was used to identify patients with NTSCI. Inpatients with newly diagnosed NTSCI on their first admission during the study period were included. Crude incidence was calculated using the annual number of NTSCI cases divided by the mid-year population estimates. Age-specific incidence was calculated by dividing the number of cases in 10-year age groups by the total number of individuals in that age group. Age-adjusted incidence was calculated using direct standardization. Annual percentage changes were calculated using Joinpoint regression analysis. The Cochrane-Armitage trend test was conducted to examine the trends of NTSCI incidence according to the types or etiologies of NTSCI. RESULTS: The age-adjusted incidence of NTSCI increased continuously from 24.11 per million in 2007 to 39.83 per million in 2020, with a significant annual percentage change (4.93%, P < 0.05). The age-specific incidence for those in their 70s and 80s or older was the highest and rapidly increased from 2007 to 2020. According to the types of paralysis in NTSCI, the proportion of tetraplegia decreased, whereas those of paraplegia and cauda equina increased significantly from 2007 to 2020. The proportion of degenerative diseases was the largest among all etiologies and increased significantly during the study period. CONCLUSION: The annual incidence of NTSCI in Korea is increasing significantly, particularly among older adults. As Korea is one of the countries with most rapidly aging population in the world, these results have significant implications, indicating that preventive strategies and sufficient rehabilitation medical services are warranted for the population of older adults.

Comparison of Trends in the Incidence of Traumatic Spinal Cord Injury in Daily Life, Automobile Accidents, and Industrial Accidents: A National Multi-Insurance Study in Korea.

BACKGROUND: To examine the incidence of traumatic spinal cord injury (TSCI) from all etiologies, we measured and compared the incidence of TSCI from three national or quasi-national databases in South Korea, namely, the National Health Insurance Service (NHIS), automobile insurance (AUI), and Industrial Accident Compensation Insurance (IACI). METHODS: We reviewed patients with TSCI reported in the NHIS database between 2009 and 2018, and in the AUI and IACI databases between 2014 and 2018. TSCI patients were defined as those first admitted to the hospital with a diagnosis of TSCI according to the International Classification of Diseases (10th revision) criteria. Age-adjusted incidence was calculated using direct standardization using the 2005 South Korean population or the 2000 US population as the standard population. The annual percentage changes (APC) of TSCI incidence were calculated. The Cochrane-Armitage trend test was performed according to the injured body region. RESULTS: In the NHIS database, age-adjusted TSCI incidence using the Korean standard population increased significantly from 2009 to 2018 (from 33.73 per million in 2009 to 38.14 per million in 2018, APC = 1.2%, P = 0.014). Contrarily, age-adjusted incidence in the AUI database significantly decreased from 13.88 per million in 2014 to 11.57 per million in 2018 (APC = - 5.1%, P = 0.009). In the IACI database, the age-adjusted incidence showed no significant difference, while crude incidence showed a significant increase (from 22.02 per million in 2014 to 28.92 per million in 2018, APC = 6.1%, P = 0.038). According to the age group, all the three databases showed high incidences of TSCI in those in their 60s and 70s or older. Among those in their 70s or older, the incidence of TSCI increased dramatically in the NHIS and IACI databases, while no significant trend was found in AUI database. In 2018, the number of TSCI patients was the highest among those over 70 years of age in the NHIS, whereas among those in their 50s were the highest in both AUI and IACI. The proportion of patients with cervical spinal cord injury was the most common in all these databases. CONCLUSIONS: The differences in trends in the incidence of TSCI may be due to the different etiologies and different characteristics of subjects depending on insurance type. These results imply the need for tailored medical strategies for the different injury mechanisms represented by three national insurance services in South Korea.

Deep Reinforcement Learning for Edge Caching with Mobility Prediction in Vehicular Networks.

As vehicles are connected to the Internet, various services can be provided to users. However, if the requests of vehicle users are concentrated on the remote server, the transmission delay increases, and there is a high possibility that the delay constraint cannot be satisfied. To solve this problem, caching can be performed at a closer proximity to the user which in turn would reduce the latency by distributing requests. The road side unit (RSU) and vehicle can serve as caching nodes by providing storage space closer to users through a mobile edge computing (MEC) server and an on-board unit (OBU), respectively. In this paper, we propose a caching strategy for both RSUs and vehicles with the goal of maximizing the caching node throughput. The vehicles move at a greater speed; thus, if positions of the vehicles are predictable in advance, this helps to determine the location and type of content that has to be cached. By using the temporal and spatial characteristics of vehicles, we adopted a long short-term memory (LSTM) to predict the locations of the vehicles. To respond to time-varying content popularity, a deep deterministic policy gradient (DDPG) was used to determine the size of each piece of content to be stored in the caching nodes. Experiments in various environments have proven that the proposed algorithm performs better when compared to other caching methods in terms of the throughput of caching nodes, delay constraint satisfaction, and update cost.

Deep Learning-Based Subtask Segmentation of Timed Up-and-Go Test Using RGB-D Cameras.

The timed up-and-go (TUG) test is an efficient way to evaluate an individual's basic functional mobility, such as standing up, walking, turning around, and sitting back. The total completion time of the TUG test is a metric indicating an individual's overall mobility. Moreover, the fine-grained consumption time of the individual subtasks in the TUG test may provide important clinical information, such as elapsed time and speed of each TUG subtask, which may not only assist professionals in clinical interventions but also distinguish the functional recovery of patients. To perform more accurate, efficient, robust, and objective tests, this paper proposes a novel deep learning-based subtask segmentation of the TUG test using a dilated temporal convolutional network with a single RGB-D camera. Evaluation with three different subject groups (healthy young, healthy adult, stroke patients) showed that the proposed method demonstrated better generality and achieved a significantly higher and more robust performance (healthy young = 95.458%, healthy adult = 94.525%, stroke = 93.578%) than the existing rule-based and artificial neural network-based subtask segmentation methods. Additionally, the results indicated that the input from the pelvis alone achieved the best accuracy among many other single inputs or combinations of inputs, which allows a real-time inference (approximately 15 Hz) in edge devices, such as smartphones.

Nst1, Densely Associated to P-Body in the Post-Exponential Phases of Saccharomyces cerevisiae, Shows an Intrinsic Potential of Producing Liquid-Like Condensates of P-Body Components in Cells.

Membrane-less biomolecular compartmentalization is a core phenomenon involved in many physiological activities that occur ubiquitously in cells. Condensates, such as promyelocytic leukemia (PML) bodies, stress granules, and P-bodies (PBs), have been investigated to understand the process of membrane-less cellular compartmentalization. In budding yeast, PBs dispersed in the cytoplasm of exponentially growing cells rapidly accumulate in response to various stresses such as osmotic stress, glucose deficiency, and heat stress. In addition, cells start to accumulate PBs chronically in post-exponential phases. Specific protein-protein interactions are involved in accelerating PB accumulation in each circumstance, and discovering the regulatory mechanism for each is the key to understanding cellular condensation. Here, we demonstrate that Nst1 of budding yeast Saccharomyces cerevisiae is far more densely associated with PBs in post-exponentially growing phases from the diauxic shift to the stationary phase than during glucose deprivation of exponentially growing cells, while the PB marker Dcp2 exhibits a similar degree of condensation under these conditions. Similar to Edc3, ectopic Nst1 overexpression induces self-condensation and the condensation of other PB components, such as Dcp2 and Dhh1, which exhibit liquid-like properties. Altogether, these results suggest that Nst1 has the intrinsic potential for self-condensation and the condensation of other PB components, specifically in post-exponential phases.

The Multivalent Polyampholyte Domain of Nst1, a P-Body-Associated Saccharomyces cerevisiae Protein, Provides a Platform for Interacting with P-Body Components.

The condensation of nuclear promyelocytic leukemia bodies, cytoplasmic P-granules, P-bodies (PBs), and stress granules is reversible and dynamic via liquid-liquid phase separation. Although each condensate comprises hundreds of proteins with promiscuous interactions, a few key scaffold proteins are required. Essential scaffold domain sequence elements, such as poly-Q, low-complexity regions, oligomerizing domains, and RNA-binding domains, have been evaluated to understand their roles in biomolecular condensation processes. However, the underlying mechanisms remain unclear. We analyzed Nst1, a PB-associated protein that can intrinsically induce PB component condensations when overexpressed. Various Nst1 domain deletion mutants with unique sequence distributions, including intrinsically disordered regions (IDRs) and aggregation-prone regions, were constructed based on structural predictions. The overexpression of Nst1 deletion mutants lacking the aggregation-prone domain (APD) significantly inhibited self-condensation, implicating APD as an oligomerizing domain promoting self-condensation. Remarkably, cells overexpressing the Nst1 deletion mutant of the polyampholyte domain (PD) in the IDR region (Nst1∆PD) rarely accumulate endogenous enhanced green fluorescent protein (EGFP)-tagged Dcp2. However, Nst1∆PD formed self-condensates, suggesting that Nst1 requires PD to interact with Dcp2, regardless of its self-condensation. In Nst1∆PD-overexpressing cells treated with cycloheximide (CHX), Dcp2, Xrn1, Dhh1, and Edc3 had significantly diminished condensation compared to those in CHX-treated Nst1-overexpressing cells. These observations suggest that the PD of the IDR in Nst1 functions as a hub domain interacting with other PB components.

Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study.

OBJECTIVE: A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10-8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 0.234-0.988]; P=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105-0.868]; P=0.026). CONCLUSIONS: Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.

Pembrolizumab plus GX-188E therapeutic DNA vaccine in patients with HPV-16-positive or HPV-18-positive advanced cervical cancer: interim results of a single-arm, phase 2 trial.

BACKGROUND: Survival outcomes for patients with recurrent or advanced cervical cancer are poor. Pembrolizumab has been approved for the treatment of recurrent or metastatic cervical cancer, with an overall response rate of 14·3%. GX-188E vaccination has been shown to induce human papillomavirus (HPV) E6-specific and E7-specific T-cell responses and cervical lesion regression in patients with cervical precancer. We aimed to investigate whether a combination of GX-188E therapeutic DNA vaccine plus pembrolizumab showed antitumour activity against recurrent or advanced cervical cancer. METHODS: In this open-label, single-arm, phase 2 trial, patients with recurrent or advanced, inoperable cervical cancer, who were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically confirmed recurrent or advanced HPV-positive (HPV-16 or HPV-18) cervical cancer, and who had progressed after available standard-of-care therapy were recruited from seven hospitals in South Korea. Patients received intramuscular 2 mg GX-188E at weeks 1, 2, 4, 7, 13, and 19, with one optional dose at week 46 that was at the investigator's discretion, and intravenous pembrolizumab 200 mg every 3 weeks for up to 2 years or until disease progression. The primary endpoint was the overall response rate within 24 weeks assessed by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 in patients who received at least 45 days of treatment 45 days of treatment with at least one post-baseline tumour assessment, and this is the report of a planned interim analysis. This trial is registered with ClinicalTrials.gov, NCT03444376. FINDINGS: Between June 19, 2018, and March 20, 2020, 36 patients were enrolled and received at least one dose of the study treatment. 26 patients were evaluable for interim activity assessment, with at least one post-baseline tumour assessment at week 10. At the data cutoff date on March 30, 2020, median follow-up duration was 6·2 months (IQR 3·5-8·1). At 24 weeks, 11 (42%; 95% CI 23-63) of 26 patients achieved an overall response; four (15%) had a complete response and seven (27%) had a partial response. 16 (44%) of 36 patients had treatment-related adverse events of any grade and four (11%) had grade 3-4 treatment-related adverse events. Grade 3 increased aspartate aminotransferase, syncope, pericardial effusion, and hyperkalaemia, and grade 4 increased alanine aminotransferase were reported in one patient each. No treatment-related deaths were reported. INTERPRETATION: Treatment with GX-188E therapeutic vaccine plus pembrolizumab for patients with recurrent or advanced cervical cancer was safe and treatment-related adverse events were manageable. This combination therapy showed preliminary antitumour activity in this interim analysis, which could represent a new potential treatment option for this patient population. This trial is ongoing. FUNDING: National OncoVenture.

Registration of digital dental models and cone-beam computed tomography images using 3-dimensional planning software: Comparison of the accuracy according to scanning methods and software.

INTRODUCTION: The registration of cone-beam computed tomography (CBCT) images and digital dental models is required for the design and manufacturing of dental devices such as implant guides and surgical wafers. This study aims to register intraoral scan (IS) models and cast scan (CS) models onto CBCT images using 3-dimensional (3D) planning software and evaluate the registration accuracy according to scanning methods and 3D planning software. METHODS: The CBCT image of an artificial skull model with reference markers was taken. The CS model and the IS model were obtained from the same skull model, registered onto the CBCT image using 3D planning software packages providing manual registration (MR) function and point-based registration (PR) functions, and set as the experimental groups. After registration, shell to shell deviations and positional differences between the reference model and the experimental models were evaluated. RESULTS: The shell to shell deviations ranged from 0.03 to 0.18 mm. Deviations in both the maxilla and mandible were significantly different according to scanning methods and software packages. In the anteroposterior direction, the IS-MR and CS-MR groups showed significantly different positions. In the superoinferior direction, the MR and PR groups showed significantly different positions. CONCLUSIONS: The registration using the PR function of the 3D planning software packages was significantly more accurate than the registration using the MR function. There was no significant difference between the registrations using the IS model and the CS model when using the PR functions.

Bisphenol A exposure and type 2 diabetes mellitus risk: a meta-analysis.

BACKGROUND: This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations. METHODS: The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross-sectional, two case-control and one prospective, were included in the meta-analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random-effects models. RESULTS: A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31). CONCLUSIONS: This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans.

Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor γ in human hepatocytes and increases lipid accumulation.

Monoacylglycerol O-acyltransferase (MGAT) is an enzyme that is involved in triglyceride synthesis by catalyzing the formation of diacylglycerol from monoacylglycerol and fatty acyl CoAs. Recently, we reported that MGAT1 has a critical role in hepatic TG accumulation and that its suppression ameliorates hepatic steatosis in a mouse model. However, the function of MGAT enzymes in hepatic lipid accumulation has not been investigated in humans. Unlike in rodents, MGAT3 as well as MGAT1 and MGAT2 are present in humans. In this study, we evaluated the differences between MGAT subtypes and their association with peroxisome proliferator-activated receptor γ (PPARγ), a regulator of mouse MGAT1 expression. In human primary hepatocytes, basal expression of MGAT1 was lower than that of MGAT2 or MGAT3, but was strongly induced by PPARγ overexpression. A luciferase assay as well as an electromobility shift assay revealed that human MGAT1 promoter activity is driven by PPARγ by direct binding to at least two regions of the promoter in 293T and HepG2 cells. Moreover, siRNA-mediated suppression of MGAT1 expression significantly attenuated lipid accumulation by PPARγ overexpression in HepG2 cells, as evidenced by oil-red-O staining. These results suggest that human MGAT1 has an important role in fatty liver formation as a target gene of PPARγ, and blocking MGAT1 activity could be an efficient therapeutic way to reduce nonalcoholic fatty liver diseases in humans.

Novel insights into paclitaxel's role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment.

BACKGROUND: Triple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed cell death protein-1 (PD-1) blockade in treating TNBC, although the exact mechanisms behind the improved results are unclear. METHODS: We employed an integrated approach, analyzing spatial transcriptomics and single-cell RNA sequencing data from TNBC patients to understand why the combination of PTX and PD-1 blockade showed better response in TNBC patients. We focused on toll-like receptor 4 (TLR4), a receptor of PTX, and its role in modulating the cross-presentation signaling pathways in tumor-associated macrophages (TAMs) within the tumor microenvironment. Leveraging insights obtained from patient-derived data, we conducted in vitro experiments using immunosuppressive bone marrow-derived macrophages (iBMDMs) to validate if PTX could augment the cross-presentation and phagocytosis activities. Subsequently, we extended our study to an in vivo murine model of TNBC to ascertain the effects of PTX on the cross-presentation capabilities of TAMs and its downstream impact on CD8+ T cell-mediated immune responses. RESULTS: Data analysis from TNBC patients revealed that the activation of TLR4 and cross-presentation signaling pathways are crucial for the antitumor efficacy of PTX. In vitro studies showed that PTX treatment enhances the cross-presentation ability of iBMDMs. In vivo experiments demonstrated that PTX activates TLR4-dependent cross-presentation in TAMs, improving CD8+ T cell-mediated antitumor responses. The efficacy of PTX in promoting antitumor immunity was elicited when combined with PD-1 blockade, suggesting a complementary interaction. CONCLUSIONS: This study reveals how PTX boosts the effectiveness of PD-1 inhibitors in treating TNBC. We found that PTX activates TLR4 signaling in TAMs. This activation enhances their ability to present antigens, thereby boosting CD8+ T cell antitumor responses. These findings not only shed light on PTX's immunomodulatory role in TNBC but also underscore the potential of targeting TAMs' antigen presentation capabilities in immunotherapy approaches.

Autotransplantation combined with orthodontic treatment to restore an adult's posttraumatic dentition.

This case report describes the successful treatment of an adult with a skeletal Class II Division 2 posttraumatic dentition with consequential restorations. The extracted maxillary premolar was autotransplanted to replace the hopeless mandibular first molar. The endodontically treated maxillary right canine was extracted instead of the premolar. A multidisciplinary approach including autotransplantation and orthodontic treatment provided a satisfactory outcome.

Epidemiology of Traumatic and Non-Traumatic Spinal Cord Injury in Korea: A Narrative Review.

This review describes the incidence rates and trends of traumatic spinal cord injuries (TSCI) and non-traumatic spinal cord injuries (NTSCI) in South Korea. The incidence of NTSCI has increased more rapidly than that of TSCI in recent years. In 2007, TSCI was more common, but by 2020, NTSCI had surpassed TSCI, particularly in older individuals. While men have a higher incidence of both TSCI and NTSCI, the incidence difference by sex is greater in TSCI. The incidence rates of both TSCI and NTSCI are higher in older individuals, particularly those in their 70s and 80s. For TSCI, falls and traffic accidents are the most common causes, with falls being more prevalent in older adults. Cervical SCIs are the most common TSCI, especially in high-income countries like South Korea. Patients with NTSCI predominantly display paraplegia, which is usually associated with non-traumatic causes such as degenerative disorders and tumors. Higher rates of tetraplegia and paraplegia are observed with TSCI and NTSCI, respectively. The neurological levels of injury also differ between TSCI and NTSCI. Overall, SCIs are a growing concern in South Korea and there is a need for targeted interventions for their management and prevention, especially in older age groups.

Spinal Cord Injury Fact Sheet in Korea.

Spinal cord injury (SCI) has been recognized as a medically complex and life-disrupting condition. As the aging of the population accelerates, the trend of SCI has changed. This review aimed to provide comprehensive statistics and recent epidemiological changes in SCI and rehabilitation in Korea. All three insurance databases (National Health Insurance Service [NHIS], automobile insurance [AUI], and industrial accident compensation insurance [IACI]) were considered. These nationwide databases provide data on the current trends in term of incidence, etiology, and rehabilitation of SCI. Traumatic spinal cord injury (TSCI) was more frequent among the elderly in the NHIS compared to working age individuals in the AUI and IACI. In all three trauma-related insurance databases, male with TSCI outnumbered female. TSCI incidence per year was approximately 17 times higher among males than females, on average, in IACI. In all three insurances, the cervical level of TSCI was the most frequent. Although the ratio of SCI patients receiving rehabilitation treatment at primary and secondary hospitals increased for nine years, the increase in training on activities of daily living (ADL training) was found to be relatively small. This review provides a broader and comprehensive understanding of the incidence, etiology, and rehabilitation treatment of SCI in Korea.

Small Extracellular Vesicles as a New Class of Medicines.

Extracellular vesicles (EVs) are nanovesicles that are naturally released from cells in a lipid bilayer-bound form. A subset population with a size of 200 nm, small EVs (sEVs), is enticing in many ways. Initially perceived as mere waste receptacles, sEVs have revealed other biological functions, such as cell-to-cell signal transduction and communication. Besides their notable biological functions, sEVs have profound advantages as future drug modalities: (i) excellent biocompatibility, (ii) high stability, and (iii) the potential to carry undruggable macromolecules as cargo. Indeed, many biopharmaceutical companies are utilizing sEVs, not only as diagnostic biomarkers but as therapeutic drugs. However, as all inchoate fields are challenging, there are limitations and hindrances in the clinical translation of sEV therapeutics. In this review, we summarize different types of sEV therapeutics, future improvements, and current strategies in large-scale production.

Treatment of skeletal open-bite malocclusion with lymphangioma of the tongue.

Lymphangioma of the tongue causes massive tongue enlargement, leading to difficulties in swallowing and mastication, speech disturbances, airway obstruction, and skeletal deformities such as open-bite malocclusion. Early reduction of tongue volume improved the excessive open bite in a young girl, but it was not sufficient to redirect the original hyperdivergent growth pattern. Orthodontic camouflage treatment was therefore rendered. Long-term evaluation after tongue-reduction surgery and orthodontic treatment is presented.

Incidence of Depression after Traumatic Brain Injury: A Nationwide Longitudinal Study of 2.2 Million Adults.

Although improvements in acute care for traumatic brain injury (TBI) have increased the patient survival rate, many survivors often suffer from neuropsychiatric sequelae such as depression. This study investigated the influence of TBI on the risk of depression using South Korean nationwide data. Data were extracted from the National Health Insurance Service database for patients who experienced TBI from 2010 to 2017 (n = 1,141,593) and for 1:1 matched controls without TBI (n = 1,141,593). Patients under 18 years old or with a history of depression were excluded. TBI was used as a time-varying exposure and a time-dependent Cox regression model was adopted. Age, sex, insurance premium and type, region of residence, past psychiatric diseases, and Charlson Comorbidity Index were adjusted. The incidence of depression in the patients with TBI and matched controls was 34.60 and 21.42 per 1000 person-years, respectively. The risk of depression was higher in the patients with TBI (hazard ratio [HR] 1.19, 95% confidence interval [CI] = 1.18-1.20) than in the matched control group. After stratification by sex and age, the risk was higher in men and the younger age group. In subgroup analyses, patients with skull fracture showed the highest risk of depression. Notably, during the first year after TBI, the depression risk was almost 11 times higher than that in the matched control group (HR 11.71, 95% CI = 11.54-11.87). Our findings highlight a significant association of TBI with an increased risk of subsequent depression. Therefore, continuous awareness with regard to patients' mental health is needed.

Advantage of extracellular vesicles in hindering the CD47 signal for cancer immunotherapy.

The cluster of differentiation 47 (CD47) protein is abundantly expressed on various malignant cells and suppresses the phagocytic function of macrophages and dendritic cells. High CD47 expression levels are correlated with poor cancer survival. Antagonizing CD47 antibodies with potent antitumor effects have been developed in clinical trials, but have critical side effects, inducing anemia and thrombocytopenia. To develop a safe and potent CD47 blockade, we designed extracellular vesicles (EVs) harboring signal regulatory protein alpha (SIPRα)-EV-SIRPα (EVs that express SIPRα). EV-SIRPα showed minimal toxic effects on hematologic parameters and utilized RBCs as delivery vehicles to tumors rather than inducing anemia. EV-SIRPα inhibited ligation of residual CD47 molecules, which attribute to the EV-endocytosis-mediated CD47 depletion and steric hindrance of EV. In an immunologically cold tumor model, EV-SIRPα induced tumor-specific T-cell-mediated antitumor effects. When directly administered to the accessible lesions, EV-SIRPα monotherapy elicited an abscopal effect in the B16F10 tumor model by increasing immune cell infiltration and CD8+-mediated immunity against non-treated tumors. The combinational approach by loading doxorubicin into the EV-SIRPα dramatically reduced the tumor burden and led to 80% complete remission rate. Thus, a potent EV-based CD47 blockade that is hematologically safe, has efficient signaling blocking efficacy, and has systemic antitumor immunity against cancer is recommended.

Safety and immunogenicity of two recombinant DNA COVID-19 vaccines containing the coding regions of the spike or spike and nucleocapsid proteins: an interim analysis of two open-label, non-randomised, phase 1 trials in healthy adults.

BACKGROUND: We assessed the safety and immunogenicity of two recombinant DNA vaccines for COVID-19: GX-19 containing plasmid DNA encoding the SARS-CoV-2 spike protein, and GX-19N containing plasmid DNA encoding the SARS-CoV-2 receptor-binding domain (RBD) foldon, nucleocapsid protein, and plasmid DNA encoding the spike protein. METHODS: Two open-label non-randomised phase 1 trials, one of GX-19 and the other of GX-19N were done at two hospitals in South Korea. We enrolled healthy adults aged 19-49 years for the GX-19 trial and healthy adults aged 19-54 years for the GX-19N trial. Participants who tested positive by serological testing for SARS-CoV-2 were excluded. At 4-week intervals, the GX-19 trial participants received two vaccine doses (either 1·5 mg or 3·0 mg), and the GX-19N trial participants received two 3·0 mg doses. The vaccines were delivered intramuscularly using an electroporator. The participants were followed up for 52 weeks after first vaccination. Data collected up to day 57 after first vaccination were analysed in this interim analysis. The primary outcome was safety within 28 days after each vaccination measured in the intention-to-treat population. The secondary outcome was vaccine immunogenicity using blood samples collected on day 43 or 57 after first vaccination measured in the intention-to-treat population. The GX-19 (NCT044445389) and GX-19N (NCT04715997) trials are registered with ClinicalTrials.gov. FINDINGS: Between June 17 and July 30, 2020, we screened 97 individuals, of whom 40 (41%) participants were enrolled in the GX-19 trial (20 [50%] in the 1·5 mg group and 20 [50%] in the 3·0 mg group). Between Dec 28 and 31, 2020, we screened 23 participants, of whom 21 (91%) participants were enrolled on the GX-19N trial. 32 (52%) of 61 participants reported 80 treatment-emergent adverse events after vaccination. All solicited adverse events were mild except one (2%) case of moderate fatigue in the 1·5 mg GX-19 group; no serious vaccine-related adverse events were detected. Binding antibody responses increased after second dose of vaccination in all groups (p=0·0002 in the 1·5 mg GX-19 group; p<0·0001 in the 3·0 mg GX-19; and p=0·0004 for the spike protein and p=0·0001 for the RBD in the 3·0 mg GX-19N group). INTERPRETATION: GX-19 and GX-19N are safe and well tolerated. GX-19N induces humoral and broad SARS-CoV-2-specific T-cell responses. GX-19N shows lower neutralising antibody responses and needs improvement to enhance immunogenicity. FUNDING: The Korea Drug Development Fund, funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare.