NRP1 antagonism as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis.

BACKGROUND: Neuropilin-1 (NRP1) is expressed on the surface epithelium of respiratory tract and immune cells, demonstrating its possible function in regulating the immune response in airway disease. However, its role in patient with chronic rhinosinusitis (CRS) remains unknown. This study aimed to elucidate the role of NRP1 in CRS with nasal polyps (CRSwNP). METHODS: Sinonasal biopsy specimens were immunohistochemically stained to investigate NRP1 expression. Double immunofluorescence, immunoblotting, and real-time polymerase chain reaction were performed to evaluate NRP1 in primary human nasal epithelial cells (hNECs). An NRP1 inhibitor was administered to a murine nasal polyp (NP) model. RESULTS: NRP1 was highly expressed in the epithelium in patients with CRSwNP compared to nasal tissue from controls and CRS without NP patients. NRP1 and vascular endothelial growth factor were upregulated in hNECs under hypoxia. Treatment with NRP1 inhibitor (EG00229) reduced the secretion of interleukin (IL)-1ß, IL-6, IL-8, and IL-33 cytokines, as well as inducible nitric oxide synthase, cyclooxygenase-2, and prostaglandin E2 in hNECs. We found that NRP1 was highly expressed in the airway epithelium in the murine NP model. The group treated with the NRP1 inhibitor had significantly fewer nasal polypoid lesions and reduced accumulations of immune cells. CONCLUSIONS: These findings reveal that NRP1 is upregulated in CRS and NP epithelium, and the inhibition of NRP1 may lead to a reduction in NP growth and immune cell infiltration. Our results suggest that NRP1 inhibition could be a novel possibility for treating nasal polyposis.

Factors Affecting Adherence to National Colorectal Cancer Screening: A 12-Year Longitudinal Study Using Multi-Institutional Pooled Data in Korea.

BACKGROUND: Consistent uptake of colorectal cancer (CRC) screening is important to reduce the incidence and mortality from advanced-stage CRC and increase the survival rate of the patients. We conducted a longitudinal study to determine the factors affecting CRC screening compliance in Korean adults using individual-level linked data from the Korean National Health and Nutrition Examination Survey, Korean National Health Insurance Service, and Korean Health Insurance Review and Assessment Service. METHODS: We selected 3,464 adults aged 50-79 years as the study population and followed them for 12 years (January 2007-December 2018). The outcome variable was the level of adherence to CRC screening, categorized as nonadherent, intermittently adherent, and consistently adherent. An ordinal logistic regression model was designed to determine the socioeconomic factors, family history of CRC, and medical conditions that could facilitate the consistent uptake of CRC screening. RESULTS: The results showed a significant and positive association between consistent uptake of CRC screening and the 100-150% income category (odds ratio [OR], 1.710; 95% confidence interval [CI], 1.401-2.088); clerical, sales and service job category (OR, 1.962; 95% CI, 1.582-2.433); residency at medium-sized cities (OR, 1.295; 95% CI, 1.094-1.532); high-school graduation (OR, 1.440; 95% CI, 1.210-1.713); married status (OR, 2.281; 95% CI, 1.946-2.674); use of employment-based national health insurance (OR, 1.820; 95% CI, 1.261-2.626); use of private insurance (OR, 2.259; 95% CI, 1.970-2.589); no disability (OR, 1.428; 95% CI, 1.175-1.737); family history of CRC (OR, 2.027; 95% CI, 1.514-2.714); and history of colorectal neoplasm (OR, 1.216; 95% CI; 1.039-1.422). CONCLUSION: The lack of regular participation in CRC screening programs in the Republic of Korea was found to be an issue that requires attention. Policies on CRC screening must place increased emphasis on strengthening educational and public relations initiatives.

Ganglioside GD3 Regulates Inflammation and Epithelial-to-Mesenchymal Transition in Human Nasal Epithelial Cells.

Chronic sinusitis with nasal polyps (CRSwNP) is one of the most common chronic inflammatory diseases, and involves tissue remodeling. One of the key mechanisms of tissue remodeling is the epithelial-mesenchymal transition (EMT), which also represents one of the pathophysiological processes of CRS observed in CRSwNP tissues. To date, many transcription factors and forms of extracellular stimulation have been found to regulate the EMT process. However, it is not known whether gangliosides, which are the central molecules of plasma membranes, involved in regulating signal transmission pathways, are involved in the EMT process. Therefore, we aimed to determine the role of gangliosides in the EMT process. First, we confirmed that N-cadherin, which is a known mesenchymal marker, and ganglioside GD3 were specifically expressed in CRSwNP_NP tissues. Subsequently, we investigated whether the administration of TNF-α to human nasal epithelial cells (hNECs) resulted in the upregulation of ganglioside GD3 and its synthesizing enzyme, ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialytransferase 1 (ST8Sia1), and the consequently promoted inflammatory processes. Additionally, the expression of N-cadherin, Zinc finger protein SNAI2 (SLUG), and matrix metallopeptidase 9 (MMP-9) were elevated, but that of E-cadherin, which is known to be epithelial, was reduced. Moreover, the inhibition of ganglioside GD3 expression by the siRNA or exogenous treatment of neuraminidase 3 (NEU 3) led to the suppression of inflammation and EMT. These results suggest that gangliosides may play an important role in prevention and therapy for inflammation and EMT.

A Data-Driven Reference Standard for Adverse Drug Reaction (RS-ADR) Signal Assessment: Development and Validation.

BACKGROUND: Pharmacovigilance using real-world data (RWD), such as multicenter electronic health records (EHRs), yields massively parallel adverse drug reaction (ADR) signals. However, proper validation of computationally detected ADR signals is not possible due to the lack of a reference standard for positive and negative associations. OBJECTIVE: This study aimed to develop a reference standard for ADR (RS-ADR) to streamline the systematic detection, assessment, and understanding of almost all drug-ADR associations suggested by RWD analyses. METHODS: We integrated well-known reference sets for drug-ADR pairs, including Side Effect Resource, Observational Medical Outcomes Partnership, and EU-ADR. We created a pharmacovigilance dictionary using controlled vocabularies and systematically annotated EHR data. Drug-ADR associations computed from MetaLAB and MetaNurse analyses of multicenter EHRs and extracted from the Food and Drug Administration Adverse Event Reporting System were integrated as "empirically determined" positive and negative reference sets by means of cross-validation between institutions. RESULTS: The RS-ADR consisted of 1344 drugs, 4485 ADRs, and 6,027,840 drug-ADR pairs with positive and negative consensus votes as pharmacovigilance reference sets. After the curation of the initial version of RS-ADR, novel ADR signals such as "famotidine-hepatic function abnormal" were detected and reasonably validated by RS-ADR. Although the validation of the entire reference standard is challenging, especially with this initial version, the reference standard will improve as more RWD participate in the consensus voting with advanced pharmacovigilance dictionaries and analytic algorithms. One can check if a drug-ADR pair has been reported by our web-based search interface for RS-ADRs. CONCLUSIONS: RS-ADRs enriched with the pharmacovigilance dictionary, ADR knowledge, and real-world evidence from EHRs may streamline the systematic detection, evaluation, and causality assessment of computationally detected ADR signals.

Time to surgery and survival in breast cancer.

BACKGROUND: This study aimed to investigate the effect of the time from diagnosis to breast cancer surgery on breast cancer patients' prognosis. METHODS: Of the 1900 patients diagnosed with invasive (stage 1-3) breast cancer who underwent surgery in KUH between 2012 and 2019, 279 patients were enrolled in this study. All patients, including those who received neoadjuvant chemotherapy, were classified as Model 1 subjects, and those who received immediate surgical treatment were classified as Model 2 subjects. We conducted a Cox regression analysis to identify prognostic factors of breast cancer associated with the time from diagnosis to surgery. RESULTS: The univariate results indicated a sharp drop in both groups' survival rates when the time to surgery was delayed for more than 8 weeks (Model 1 p = 0.000; Model 2 p = 0.001). In the multivariate analysis, the hazard ratio (HR) of Model 1increased (HR = 6.84, 95% CI 1.06-44.25) in response to a delay in surgery of more than 8 weeks. Smoking and the American Joint Committee on Cancer (AJCC) staging system had a negative effect on breast cancer prognosis, while hormone therapy had a positive effect. CONCLUSION: For all patients, a delay in breast cancer surgery of more than 8 weeks was inversely associated with survival.

Columellar Wound Immediately After Open Rhinoseptoplasty Treated With Application of DuoDERM Extra Thin.

ABSTRACT: Most patients who undergo open rhinoseptoplasty do not develop any wound at the transcolumellar incision site. However, some patients require wound care immediately post-operation. Dressing is difficult to perform in the columellar region because of the location. Here, we report 2 cases of columellar wound as a complication of open rhinoseptoplasty. A patient developed mild wound dehiscence immediately after primary rhinoseptoplasty, whereas another developed partial columellar skin necrosis after the revision operation. We applied DuoDERM Extra Thin dressing (ConvaTec Group, Deeside, UK) for columellar wound and achieved healing. DuoDERM Extra Thin can be a simple and easy dressing material for immediate care of transcolumellar wounds.

Association between Air Pollutants and Initial Hospital Admission for Ischemic Stroke in Korea from 2002 to 2013.

OBJECTIVES: There is limited information regarding the association between air pollution exposure and stroke incidence. Therefore, this study aimed to assess the associations between short-term exposure to ambient air pollutants and initial hospital admission for ischemic stroke. MATERIALS AND METHODS: From the Korea National Health Insurance Service-National Sample Cohort 2002-2013 database in South Korea, 55,852 first hospital admissions for ischemic stroke were identified. A generalized additive Poisson model was used to explore the association between air pollutants, including particulate matter, sulfur dioxide, nitrogen dioxide, and carbon monoxide and admissions for ischemic stroke. RESULTS: All air pollutant models showed significant associations with ischemic stroke in the single lag model. In all air pollutant models excluding particulate matter 10 µm, a significant association was found between nitrogen dioxide exposure and initial admission for ischemic stroke after adjusting for other pollutants. An increment of 10 µg/m3 in nitrogen dioxide concentration at lag 0 and 14 days corresponded to a 0.259% (95% confidence interval, 0.231-0.287%) and 0.110% (95% confidence interval, 0.097-0.124) increase in initial admission for ischemic stroke, respectively. CONCLUSIONS: The exposure-response relationship between nitrogen dioxide and initial admissions for ischemic stroke was approximately linear, with a sharper response at higher concentrations. Short-term exposure to nitrogen dioxide was positively associated with initial hospital admission for ischemic stroke.

Prevalence of Intracranial Aneurysms in Patients With Systemic Vessel Aneurysms: A Nationwide Cohort Study.

Background and Purpose- Most aneurysms are a focal manifestation of a systemic condition. Some reports have suggested genetic and environmental factors may play a role in pathogenesis. The aim of the present study was to evaluate the prevalence of intracranial aneurysms (IA) in a large cohort of patients with other systemic vessel aneurysms and dissections (OVAD) and identify potential risk factors for IA in this population. Methods- We defined OVAD as systemic vessel aneurysms, excluding aortic dissections and aneurysms. A cohort of 1.1 million patients was extracted from the population-based cohort from the Korea National Health Insurance Service, which holds almost all medical data including diagnostic codes, procedures, and personal information. Using χ2 or Fisher exact test, the prevalence of the IA concerning OVAD status was analyzed. Results- In OVAD individuals, 25.7% (261/1017) of patients had been concurrently diagnosed with IA. The odds ratios for having concurrent IA in patients with OVAD were 56.31 (95% CI, 48.821-64.949; P=0.000). OVAD patients with dyslipidemia were >7× likely to be affected by IA (adjusted odds ratio, 7.7 [95% CI, 6.59-9.01]; P=0.000). Hypertension, diabetes mellitus, old age (>60 years), and male sex had increased odds for having concurrent IA by 5.89, 3.48, 1.83, and 1.35, respectively. Subgroup analysis with socioeconomic or disability revealed that the prevalence of IA was significantly higher in all groups. Uncertainty regarding the temporal sequence of onset and lack of detail on disease severity and subtype prevented more conclusive results. Conclusions- Patients with OVAD have a higher prevalence of IA than control groups. Therefore, we may approach aneurysms as systemic disease, and further investigations about their pathophysiology must follow.

Preoperative latent medial laxity and correction angle are crucial factors for overcorrection in medial open-wedge high tibial osteotomy.

PURPOSE: This study aimed to determine which preoperative factors affect the postoperative change in the joint line convergence angle (JLCA) by preoperatively quantifying soft tissue laxity. METHODS: Thirty-four patients who underwent medial open-wedge high tibial osteotomy (HTO) with a navigation were analysed. The JLCA change after HTO was calculated using standing long-bone anteroposterior radiographs taken preoperatively and 6 months postoperatively. Latent soft tissue laxity was defined as the amount of soft tissue that can be extended to valgus or varus from the weight-bearing position, and calculated by subtracting the JLCA on weight-bearing standing radiographs from that on stress radiographs. Multiple linear regression was performed to determine the preoperative factors that statistically correlated with the postoperative JLCA change. RESULTS: In multiple linear regression, JLCA change had a statistically significant correlation with latent medial laxity (R = 0.6) and a statistically borderline significant correlation with correction angle (R = 0.2). These imply that the postoperative JLCA change increased by 0.6° per 1° increase in latent medial laxity, and increased by 0.2° per 1° increase in correction angle. Latent medial laxity was the most crucial factor associated with postoperative JLCA changes. CONCLUSION: The JLCA change could be larger in patients with large latent medial laxity or severe varus deformity requiring a large correction, which could lead to unexpected overcorrection in HTO. Postoperative JLCA change should be considered in preoperative surgical planning. Target point shifting within the hypomochlion point could be a strategy to prevent overcorrection, especially in patients with large latent medial laxity. LEVEL OF EVIDENCE: Level IV.

Ganglioside GM3 Up-Regulate Chondrogenic Differentiation by Transform Growth Factor Receptors.

Mesenchymal stem cells, also known as multipotent stromal progenitor cells, can differentiate into cells of mesodermal lineage. Gangliosides are sialic acid-conjugated glycosphingolipids that are believed to regulate cell differentiation and several signaling molecules. These molecules are localized in glycosphingolipid-enriched microdomains on the cell surface and are regulated by glycosphingolipid composition. Transforming growth factor-beta (TGF-ß) signaling plays a critical role in chondrogenic differentiation. However, the role of gangliosides in chondrogenesis is not understood. In this study, the relationship between the ganglioside GM3 and TGF-ß activation, during chondrogenic differentiation, was investigated using an aggregate culture of human synovial membrane-derived mesenchymal stem cells. We showed that the gangliosides GM3 and GD3 were expressed after the chondrogenic differentiation of hSMSC aggregates. To test whether GM3 affected the chondrogenic differentiation of hSMSC aggregates, we used GM3 treatment during chondrogenic differentiation. The results showed that the group treated with 5 µM GM3 had higher expression of chondrogenic specific markers, increased toluidine blue, and safranin O staining, and increased accumulation of glycosaminoglycans compared with the untreated group. Furthermore, GM3 treatment enhanced TGF-ß signaling via SMAD 2/3 during the chondrogenic differentiation of hSMSC aggregates. Taken together, our results suggested that GM3 may be useful in developing therapeutic agents for cell-based articular cartilage regeneration in articular cartilage disease.