Is Thyroid Dysfunction Associated with Unruptured Intracranial Aneurysms? A Population-Based, Nested Case-Control Study from Korea.

Background: Few risk factors for the development of intracranial aneurysms (IAs) are known. We investigated the potential role of thyroid diseases in IA development using nationwide real-world data. Methods: A nested case-control study within the National Health Insurance Service-National Sample Cohort data from 2002 to 2019 was performed. A total of 5335 patients with unruptured IA were matched by age and sex with 80,025 controls at a ratio of 1:15. We estimated the odds ratios (ORs) and corresponding confidence intervals [CIs] between thyroid diseases and unruptured IA using a multivariable conditional logistic regression model. Results: Tobacco smoking, use of antihypertensive medication, and hypothyroidism were significantly associated with an elevated risk for unruptured IA in univariate analysis. In multivariable analysis, a history of hypothyroidism was associated with unruptured IA (adjusted OR: 1.46 [CI: 1.26-1.69]). Among patients with hypothyroidism, long-term use of thyroid hormone for >5 years was associated with a reduced risk for unruptured IA (adjusted OR: 0.69 [CI: 0.48-0.99]). A history of hyperthyroidism was associated with a reduced risk for unruptured IAs (adjusted OR: 0.71 [CI: 0.54-0.93]). In secondary analyses of the data according to sex, the respective observed associations between hypothyroidism and hyperthyroidism and the risk of IAs were found to be statistically significant in females but not in males. Conclusions: Hypothyroidism is associated with an increased risk of unruptured IAs, whereas hyperthyroidism is associated with a reduced risk. Overall, the findings suggest that thyroid hormones may play a protective role in the development of unruptured IAs. Further studies are needed to clarify potential direct causality and the biologic mechanisms relating thyroid dysfunction and unruptured IA.

A 3 mm Port Reduces Postoperative Pain After Laparoscopic Colon Cancer Surgery: A Case-control Matched Study.

BACKGROUND: Recently, smaller-size trocars and instruments have been developed for laparoscopic colon cancer surgery; however, their effectiveness and safety have not been elucidated. This study aimed to investigate whether 3 mm trocars and instruments have benefits compared with conventional trocars and instruments. PATIENTS AND METHODS: Patients with colon cancer who underwent laparoscopic anterior resection or right hemicolectomy were included. Patients who underwent combined resections of other organs and those with conversion to open surgery were excluded. In the 3 mm group, three 5 mm trocars were replaced by 3 mm trocars. The numeric rating scale (NRS) immediately postoperatively at 24, 48, and 72 hours, respectively, after surgery and the use of additional analgesics and perioperative outcomes were analyzed. Case-control matched analysis was used to reduce bias according to the type of surgery. RESULTS: A total of 207 patients (conventional: n = 158, 3 mm: n = 49) were included. Before matching, NRS 48 hours postoperatively ( P = 0.049), proportion of patients using additional intravenous (IV) analgesics ( P = 0.007), postoperative hospital stay ( P < 0.001), and blood loss ( P < 0.001) were lower in the 3 mm group. In multivariable analysis, trocar type significantly impacted the proportion of patients using additional IV analgesics (odds ratio: 0.330; 95% CI: 0.153-0.712; P = 0.005). After case-control matching, NRS immediately postoperatively ( P = 0.015) and 24 hours postsurgery ( P = 0.043), patients using additional IV analgesics ( P = 0.019), postoperative hospital stay ( P = 0.010), intraoperative blood loss ( P < 0.001), and postoperative complication rate ( P = 0.028) were significantly lower in the 3 mm group compared with the 5 mm group. CONCLUSIONS: The use of 3 mm trocars and instruments in laparoscopic colon cancer surgery can effectively reduce postoperative pain while maintaining perioperative safety.

Operational Definitions of Colorectal Cancer in the Korean National Health Insurance Database.

OBJECTIVES: We reviewed the operational definitions of colorectal cancer (CRC) from studies using the Korean National Health Insurance Service (NHIS) and compared CRC incidence derived from the commonly used operational definitions in the literature with the statistics reported by the Korea Central Cancer Registry (KCCR). METHODS: We searched the MEDLINE and KoreaMed databases to identify studies containing operational definitions of CRC, published until January 15, 2021. All pertinent data concerning the study period, the utilized database, and the outcome variable were extracted. Within the NHIS-National Sample Cohort, age-standardized incidence rates (ASRs) of CRC were calculated for each operational definition found in the literature between 2005 and 2019. These rates were then compared with ASRs from the KCCR. RESULTS: From the 62 eligible studies, 9 operational definitions for CRC were identified. The most commonly used operational definition was "C18-C20" (n=20), followed by "C18-C20 with claim code for treatment" (n=3) and "C18-C20 with V193 (code for registered cancer patients' payment deduction)" (n=3). The ASRs reported using these operational definitions were lower than the ASRs from KCCR, except for "C18-C20 used as the main diagnosis." The smallest difference in ASRs was observed for "C18-C20," followed by "C18- C20 with V193," and "C18-C20 with claim code for hospitalization or code for treatment." CONCLUSIONS: In defining CRC patients utilizing the NHIS database, the ASR derived through the operational definition of "C18-C20 as the main diagnosis" was comparable to the ASR from the KCCR. Depending on the study hypothesis, operational definitions using treatment codes may be utilized.

Operational Definition of Liver Cancer in Studies Using Data from the National Health Insurance Service: A Systematic Review.

Data from the Korean National Health Insurance Service (NHIS) have been widely used to provide real-world evidence. Due to the nature of claims data, researchers use operational definitions to define patients with specific diseases. This study aimed to conduct a systematic review of the operational definitions of liver cancer used in studies based on the NHIS database and to suggest the most appropriate operational definition. Literature search was completed on January 6, 2021, using PubMed and KoreaMed. We applied the most frequently used operational definitions of liver cancer to the NHIS-National Sample Cohort and calculated age-standardized incidence rates (ASRs) of liver cancer by year. The ASRs using each operational definition were compared with the ASR from the Korea Central Cancer (KCCR) data. Among 236 articles, 90 were selected for review, covering histologically various kinds of liver cancer and varied by study subjects. Most studies (n = 79) did not mention whether the codes for the operational definition were from only the main diagnosis or from both the main and sub-diagnosis. The most frequently used operational definition was C22 (n = 39); however, the most similar operational definition was the ASR using "C22.0 or C22.9" for men and "C22.0" for women as the main diagnosis to the ASR from the KCCR. Based on the comparison with KCCR data, we suggest using "C22.0 or C22.9" for men and "C22.0" for women as the main diagnosis for the operational definition of liver cancer when using the NHIS data.

Mechanical activation drives tenogenic differentiation of human mesenchymal stem cells in aligned dense collagen hydrogels.

Tendons are force transmitting mechanosensitive tissues predominantly comprised of highly aligned collagen type I fibres. In this study, the recently introduced gel aspiration-ejection method was used to rapidly fabricate aligned dense collagen (ADC) hydrogel scaffolds. ADCs provide a biomimetic environment compared to traditional collagen hydrogels that are mechanically unstable and comprised of randomly oriented fibrils. The ADC scaffolds were shown to be anisotropic with comparable stiffness to immature tendons. Furthermore, the application of static and cyclic uniaxial loading, short-term (48 h) and high-strain (20%), resulted in a 3-fold increase in both the ultimate tensile strength and modulus of ADCs. Similar mechanical activation of human mesenchymal stem cell (MSC) seeded ADCs in serum- and growth factor-free medium induced their tenogenic differentiation. Both static and cyclic loading profiles resulted in a greater than 12-fold increase in scleraxis gene expression and either suppressed or maintained osteogenic and chondrogenic expressions. Following the 48 h mechanoactivation period, the MSC-seeded scaffolds were matured by tethering in basal medium without further external mechanical stimulation for 19 days, altogether making up 21 days of culture. Extensive cell-induced matrix remodeling and deposition of collagen types I and III, tenascin-C and tenomodulin were observed, where initial cyclic loading induced significantly higher tenomodulin protein content. Moreover, the initial short-term mechanical stimulation elongated and polarized seeded MSCs, and overall cell alignment was significantly increased in those under static loading. These findings indicate the regenerative potential of the ADC scaffolds for short-term mechanoactivated tenogenic differentiation, which were achieved even in the absence of serum and growth factors that may potentially increase clinical translatability.

The impact of COVID-19 on screening for colorectal, gastric, breast, and cervical cancer in Korea.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has affected the utilization of healthcare services, including participation in cancer screening programs. We compared cancer screening participation rates for colorectal, gastric, breast, and cervical cancers among participants in the National Cancer Screening Program (NCSP) in 2019 and 2020 to address the potential distraction effect of COVID-19 on cancer screening. METHODS: Data from the NCSP for 4 cancer types (stomach, colorectal, breast, and cervical) in 2019 and 2020 were used to calculate cancer screening participation rates by calendar month, gender, age group, and geographical region. Monthly participation rates were analyzed per 1,000 eligible individuals. RESULTS: The screening participation rate decreased in 2020 compared to 2019 for all 4 cancers: colorectal (40.5 vs. 35.3%), gastric (61.9 vs. 54.6%), breast (63.8 vs. 55.8%), and cervical (57.8 vs. 52.2%) cancers. Following 2 major COVID-19 waves in March and December 2020, the participation rates in the 4 types of cancer screening dropped compared with those in 2019. The highest decline was observed in the elderly population aged 80 years and older (percentage change: -21% for colorectal cancer; -20% for gastric cancer; -26% for breast cancer; -20% for cervical cancer). CONCLUSIONS: After the 2 major COVID-19 waves, the screening participation rate for 4 types of cancer declined compared with 2019. Further studies are needed to identify the indirect effects of the COVID-19 pandemic on cancer patients, such as delayed diagnoses of cancer or excess cancer deaths.

Preventive Effects of a Human Hematopoietic Mesenchymal Stem Cell (hHMSC) Therapy in Ovalbumin-Induced Food Allergy.

No effective therapeutic strategies have been developed against food allergies. Immunomodulation during early infant period could prevent the development of food allergies. We investigated the preventive effects of human hematopoietic mesenchymal stem cells (hHMSCs) in mice with ovalbumin (OVA)-induced food allergy. BALB/c mice with OVA-induced food allergy were divided into 3 groups, and each group was treated with hHMSCs or hHMSC culture medium (hHMSC-CM) or saline. Ear thickness, allergy score, rectal temperature, and diarrhea occurrence were checked. Total IgE, OVA-specific IgE, and mucosal mast cell protease-1 (mMCP-1) were measured by ELISA. Other allergic parameters were analyzed using histology specimens, RT-PCR, and flow cytometry. Treatment with hHMSCs or hHMSC-CM significantly suppressed the frequency of anaphylactic response and rectal temperature decline, reduced diarrhea, total IgE, OVA-specific IgE, and mMCP-1. While the treatment decreased the level of Th2 cytokines, it enhanced IL-10 and TGF-ß1 mRNA. Exposure to hHMSC or hHMSC-CM did not generate regulatory T cells, but reduced mast cells. The immunomodulatory effect on the Th2 cytokines was greater in hHMSC-CM than in hHMSCs. hHMSC treatment may be a promising preventive intervention against food allergy. Further studies are needed to elucidate the key substances released from hHMSC to induce immune tolerance.

The age-standardized incidence, mortality, and case fatality rates of COVID-19 in 79 countries: a cross-sectional comparison and their correlations with associated factors.

OBJECTIVES: During the coronavirus disease 2019 (COVID-19) pandemic, crude incidence and mortality rates have been widely reported; however, age-standardized rates are more suitable for comparisons. In this study, we estimated and compared the age-standardized incidence, mortality, and case fatality rates (CFRs) among countries and investigated the relationship between these rates and factors associated with healthcare resources: gross domestic product per capita, number of hospital beds per population, and number of doctors per population. METHODS: The incidence, mortality, and CFRs of 79 countries were age-standardized using the World Health Organization standard population. The rates for persons 60 years or older were also calculated. The relationships among the rates were analysed using trend lines and coefficients of determination (R2). Pearson correlation coefficients between the rates and the healthcare resource-related factors were calculated. RESULTS: The countries with the highest age-standardized incidence, mortality, and CFRs were Czechia (14,253 cases/100,000), Mexico (182 deaths/100,000), and Mexico (6.7%), respectively. The R2 between the incidence and mortality rates was 0.852 for all ages and 0.945 for those 60 years or older. The healthcare resources-related factors were associated positively with incidence rates and negatively with CFRs, with weaker correlations among the elderly. CONCLUSIONS: Compared to age-standardized rates, crude rates showed greater variation among countries. Medical resources may be important in preventing COVID-19-related deaths; however, considering the small variation in fatality among the elderly, preventive measures such as vaccination are more important, especially for the elderly population, to minimize the mortality rates.

Mesenchymal Stem Cells Antagonize IFN-Induced Proinflammatory Changes and Growth Inhibition Effects via Wnt/ß-Catenin and JAK/STAT Pathway in Human Outer Root Sheath Cells and Hair Follicles.

Mesenchymal stem cell therapy (MSCT) has been shown to be a new therapeutic option for treating alopecia areata (AA). Outer root sheath cells (ORSCs) play key roles in maintaining the hair follicle structure and supporting the bulge area. In human ORSCs (hORSCs), the mechanism for this process has not been extensively studied. In this study, we aimed to examine the influence of human hematopoietic mesenchymal stem cells (hHMSCs) in the hORSCs in vitro model of AA and determine the mechanisms controlling efficacy. Interferon-gamma (IFN-γ) pretreatment was used to induce an in vitro model of AA in hORSCs. The effect of MSCT on the viability and migration of hORSCs was examined using co-cultures, the MTT assay, and migration assays. We investigated the expression of molecules related to the Wnt/ß-catenin pathway, JAK/STAT pathway, and growth factors in hHMSC-treated hORSCs by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses. hHMSCs increased hORSC viability and migration when they were co-cultured. hHMSCs reverted IFN-γ-induced expression-including NLRP3, ASC, caspase-1, CXCL-9 through 11, IL-1ß, and IL-15-and upregulated several growth factors and hair stem cell markers. hHMSCs activated several molecules in the Wnt/ß-catenin signaling pathway, such as in the Wnt families, ß-catenin, phosphorylated GSK-3ß and cyclin D1, and suppressed the expression of DKK1 induced by IFN-γ in hORSCs. hHMSCs suppressed the phosphorylation of JAK1 to 3, STAT1, and STAT3 compared to the controls and IFN-γ-pretreated hORSCs. These results demonstrate that hHMSCs increased hORSC viability and migration in the in vitro AA model. Additionally, MSCT definitely stimulated anagen survival and hair growth in an HF organ culture model. MSCT appeared to be associated with the Wnt/ß-catenin and JAK/STAT pathways in hORSCs.

Acellular dense collagen-S53P4 bioactive glass hybrid gel scaffolds form more bone than stem cell delivered constructs.

Dense collagen (DC) gels facilitate the osteoblastic differentiation of seeded dental pulp stem cells (DPSCs) and undergo rapid acellular mineralization when incorporated with bioactive glass particles, both in vitro and subcutaneously in vivo. However, the potential of DC-bioactive glass hybrid gels in delivering DPSCs for bone regeneration in an osseous site has not been investigated. In this study, the efficacies of both acellular and DPSC-seeded DC-S53P4 bioactive glass [(53)SiO2-(23)Na2O-(20)CaO-(4)P2O5, wt%] hybrid gels were investigated in a critical-sized murine calvarial defect. The incorporation of S53P4, an osteostimulative bioactive glass, into DC gels led to its accelerated acellular mineralization in simulated body fluid (SBF), in vitro, where hydroxycarbonated apatite was detected within 1 day. By day 7 in SBF, micro-mechanical analysis demonstrated an 8-fold increase in the compressive modulus of the mineralized gels. The in-situ effect of the bioactive glass on human-DPSCs within DC-S53P4 was evident, by their osteogenic differentiation in the absence of osteogenic supplements. The production of alkaline phosphatase and collagen type I was further increased when cultured in osteogenic media. This osteostimulative effect of DC-S53P4 constructs was confirmed in vivo, where after 8 weeks implantation, both acellular scaffolds and DPSC-seeded DC-S53P4 constructs formed mineralized and vascularized bone matrices with osteoblastic and osteoclastic cell activity. Surprisingly, however, in vivo micro-CT analysis confirmed that the acellular scaffolds generated larger volumes of bone, already visible at week 3 and exhibiting superior trabecular architecture. The results of this study suggest that DC-S53P4 scaffolds negate the need for stem cell delivery for effective bone tissue regeneration and may expedite their path towards clinical applications.

3D Printed Polyurethane Scaffolds for the Repair of Bone Defects.

Critical-size bone defects are those that will not heal without intervention and can arise secondary to trauma, infection, and surgical resection of tumors. Treatment options are currently limited to filling the defect with autologous bone, of which there is not always an abundant supply, or ceramic pastes that only allow for limited osteo-inductive and -conductive capacity. In this study we investigate the repair of bone defects using a 3D printed LayFomm scaffold. LayFomm is a polymer blend of polyvinyl alcohol (PVA) and polyurethane (PU). It can be printed using the most common method of 3D printing, fused deposition modeling, before being washed in water-based solutions to remove the PVA. This leaves a more compliant, micro-porous PU elastomer. In vitro analysis of dental pulp stem cells seeded onto macro-porous scaffolds showed their ability to adhere, proliferate and form mineralized matrix on the scaffold in the presence of osteogenic media. Subcutaneous implantation of LayFomm in a rat model showed the formation of a vascularized fibrous capsule, but without a chronic inflammatory response. Implantation into a mandibular defect showed significantly increased mineralized tissue production when compared to a currently approved bone putty. While their mechanical properties are insufficient for use in load-bearing defects, these findings are promising for the use of polyurethane scaffolds in craniofacial bone regeneration.

Rapidly formed stable and aligned dense collagen gels seeded with Schwann cells support peripheral nerve regeneration.

OBJECTIVE: Gel aspiration-ejection (GAE) has recently been developed for the rapid production of dense, anisotropic collagen gel scaffolds with adjustable collagen fibrillar densities. In this study, a GAE system was applied to produce aligned Schwann cells within a type-1 collagen matrix to generate GAE-engineered neural tissues (GAE-EngNT) for potential nerve tissue engineering applications. APPROACH: The stability and mechanical properties of the constructs were investigated along with the viability, morphology and distribution of Schwann cells. Having established the methodology to construct stable robust Schwann cell-loaded engineered neural tissues using GAE (GAE-EngNTs), the potential of these constructs in supporting and guiding neuronal regeneration, was assessed both in vitro and in vivo. MAIN RESULTS: Dynamic mechanical analysis strain and frequency sweeps revealed that the GAE-EngNT produced via cannula gauge number 16 G (∼1.2 mm diameter) exhibited similar linear viscoelastic behaviors to rat sciatic nerves. The viability and alignment of seeded Schwann cells in GAE-EngNT were maintained over time post GAE, supporting and guiding neuronal growth in vitro with an optimal cell density of 2.0 × 106 cells ml-1. An in vivo test of the GAE-EngNTs implanted within silicone conduits to bridge a 10 mm gap in rat sciatic nerves for 4 weeks revealed that the constructs significantly promoted axonal regeneration and vascularization across the gap, as compared with the empty conduits although less effective regeneration compared with the autograft groups. SIGNIFICANCE: Therefore, this is a promising approach for generating anisotropic and robust engineered tissue which can be used with Schwann cells for peripheral nerve repair.

Evaluation of Tumor Blood Flow Using Alternate Ascending/Descending Directional Navigation in Primary Brain Tumors: A Comparison Study with Dynamic Susceptibility Contrast Magnetic Resonance Imaging.

OBJECTIVE: Alternate ascending/descending directional navigation (ALADDIN) is a novel arterial spin labeling technique that does not require a separate spin preparation pulse. We sought to compare the normalized cerebral blood flow (nCBF) values obtained by ALADDIN and dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging (MRI) in patients with primary brain tumors. MATERIALS AND METHODS: Sixteen patients with primary brain tumors underwent MRI scans including contrast-enhanced T1-weighted imaging, DSC perfusion MRI, and ALADDIN. The nCBF values of normal gray matter (GM) and tumor areas were measured by both DSC perfusion MRI and ALADDIN, which were compared by the Wilcoxon signed rank test. Subgroup analyses according to pathology were performed with the Wilcoxon signed rank test. RESULTS: Higher mean nCBF values of GM regions in the bilateral frontal lobe, temporal lobe, and caudate were detected by ALADDIN than by DSC perfusion MRI (p <0.05). In terms of the mean or median nCBF values and the mean of the top 10% nCBF values from tumors, DSC perfusion MRI and ALADDIN did not statistically significantly differ either overall or in each tumor group. CONCLUSION: ALADDIN tended to detect higher nCBF values in normal GM, as well as higher perfusion portions of primary brain tumors, than did DSC perfusion MRI. We believe that the high perfusion signal on ALADDIN can be beneficial in lesion detection and characterization.

Fasting glucose and risk of colorectal cancer in the Korean Multi-center Cancer Cohort.

Previous cohort studies have demonstrated a positive association between diabetes mellitus (DM) and colorectal cancer (CRC). However, there are few comparisons between DM groups categorized by fasting glucose level. This study examined associations between diabetes as defined by fasting glucose level and self-reported history of DM and CRC risk among Korean adults. Data from the Korean Multi-center Cancer Cohort between 1993 and 2005 were analyzed. The study population comprised 14,570 participants aged 20 years or older. Participants were followed until December 31, 2012 (median follow-up: 11.9 years). Among participants with high fasting glucose (≥126mg/dL), the risk of developing CRC was significantly higher (HR: 1.51 [1.02-2.25]) than among participants with low fasting glucose (<126mg/dL). Risk was not significantly higher among participants with self-reported history of DM (HR: 1.34 [0.78-2.31]). When both fasting glucose and history of DM were considered together, the risk of CRC among participants with both high fasting glucose and history of DM was 54% (HR: 1.54 [0.97-2.43]), and the risk of CRC among participants with high fasting glucose and no history of DM was 50% (HR: 1.50 [0.73-3.05]). When the first 5 years of follow-up were excluded, among participants with high fasting glucose, the risk of developing CRC was significantly higher (HR: 1.61 [1.02-2.56]) than among participants with low fasting glucose. Risk of CRC was also significantly higher among participants with high fasting glucose and no history of DM (HR: 1.69 [1.01-2.84]). High fasting glucose and self-reported history of DM were associated with increased risk of CRC in this Korean population.