Integration of National Health Insurance claims data and animal models reveals fexofenadine as a promising repurposed drug for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common and costly progressive neurodegenerative disease of unclear etiology. A disease-modifying approach that can directly stop or slow its progression remains a major unmet need in the treatment of PD. A clinical pharmacology-based drug repositioning strategy is a useful approach for identifying new drugs for PD. METHODS: We analyzed claims data obtained from the National Health Insurance Service (NHIS), which covers a significant portion of the South Korean population, to investigate the association between antihistamines, a class of drugs commonly used to treat allergic symptoms by blocking H1 receptor, and PD in a real-world setting. Additionally, we validated this model using various animal models of PD such as the 6-hydroxydopmaine (6-OHDA), α-synuclein preformed fibrils (PFF) injection, and Caenorhabditis elegans (C. elegans) models. Finally, whole transcriptome data and Ingenuity Pathway Analysis (IPA) were used to elucidate drug mechanism pathways. RESULTS: We identified fexofenadine as the most promising candidate using National Health Insurance claims data in the real world. In several animal models, including the 6-OHDA, PFF injection, and C. elegans models, fexofenadine ameliorated PD-related pathologies. RNA-seq analysis and the subsequent experiments suggested that fexofenadine is effective in PD via inhibition of peripheral immune cell infiltration into the brain. CONCLUSION: Fexofenadine shows promise for the treatment of PD, identified through clinical data and validated in diverse animal models. This combined clinical and preclinical approach offers valuable insights for developing novel PD therapeutics.

Retinoic Acid Treatment Mitigates PM2.5-Induced Type 2 Inflammation: Insights into Modulation of Innate Immune Responses.

Some studies have demonstrated the effects of particulate matter (PM) on chronic rhinosinusitis with nasal polyps (CRSwNP) development, as well as the therapeutic role of retinoic acid (RA) in nasal polypogenesis. However, the immunologic effect of PM in innate lymphoid cells (ILCs) and the exact mechanism of the therapeutic effect of RA remain unclear. Therefore, the present study investigated the effects of fine-dust-induced inflammation in CRSwNP and the mechanisms of the therapeutic effect of RA. PM2.5 exposure exacerbated pathological damage in the nasal mucosa of mice with nasal polyps (NP) via upregulation of type 2 inflammation. Additionally, PM2.5 exposure increased the expression of type 2 cytokines and epithelial-cell-derived cytokines (IL-33 and IL-25) significantly, as well as the ILC populations in human-NP-derived epithelial cells (HNECs). Moreover, RA supplementation significantly increased the expression of ILCreg in Lin-CD45+CD127+ cells, which in turn increased the levels of the anti-inflammatory cytokine IL-10. The findings suggest that PM2.5 exposures could aggravate the CRSwNP type 2 inflammation, and RA treatment may ameliorate fine-dust-induced inflammation by modulating the innate immune response.

Mid- and Late-Life Chronic Kidney Disease Is Associated with Parkinson's Disease, Not with an Increased Risk of Alzheimer's Disease.

Chronic kidney disease (CKD) is strongly associated with dementia. However, its independent association with Alzheimer's or Parkinson's disease remains unclear. This study investigated the prospective association of patients with CKD aged ≥55 years with an increased risk of Alzheimer's or Parkinson's disease. We conducted a retrospective cohort analysis using a national cohort sample of approximately one million patients. Primary outcome indicators measured included incidence of all-cause dementia, Alzheimer's disease, and Parkinson's disease events using person-years at risk. The hazard ratio was adjusted using the Cox proportional hazards model. We included 952 patients without CKD and 476 with CKD over 55 years using propensity score matching. The CKD group exhibited higher incidences of all-cause dementia, Parkinson's disease, and Alzheimer's disease than the non-CKD group. Furthermore, the CKD group had an elevated risk of all-cause dementia and a significantly increased risk of Parkinson's disease, especially among older women. Notably, the risk of Parkinson's disease was higher within the first 3 years of CKD diagnosis. These findings emphasize the link between CKD in mid- and late-life individuals and a higher incidence of all-cause dementia and Parkinson's disease rather than Alzheimer's disease.

Exploring the Link between Head and Neck Cancer and the Elevated Risk of Acute Myocardial Infarction: A National Population-Based Cohort Study.

Enhanced screening protocols for cancer detection have increased survival in patients with head and neck cancer (HNC), which highlights the need to address the sequelae of therapy-induced cardiovascular complications. This study was conducted to assess the incidence and risk of acute myocardial infarction (AMI) in patients with HNC who have not undergone radiation or chemotherapy using a comprehensive, population-based cohort dataset. A total of 2976 individuals without cancer and 744 individuals with HNC were matched using the propensity score method. The findings indicated that the occurrence rates of AMI were comparable between the HNC (2.19) and non-cancer groups (2.39). Cox regression analysis did not demonstrate a significant increase in the risk of AMI in patients with HNC (hazard ratio: 0.93, 95% confidence interval: 0.50-1.73). No increased risk of AMI was observed in the HNC group compared to the non-cancer group, regardless of the time since the HNC diagnosis. Subgroup analyses showed no notable differences in the AMI risk between the groups when considering sex, age, comorbidities, and cancer type. This study showed that patients with HNC who have not been treated with radiation or chemotherapy did not exhibit an increased incidence or risk of AMI compared to individuals without cancer.

Head and Neck Cancer: A Potential Risk Factor for Parkinson's Disease?

Head and neck cancers (HNC) are frequently associated with neurodegeneration. However, the association between HNC and Parkinson's disease (PD) remains unclear. This study aimed to clarify the relationship between HNC and subsequent PD. This retrospective study used data from a nationally representative cohort. Patients with HNC were identified based on the presence of corresponding diagnostic codes. Participants without cancer were selected using 4:1 propensity score matching based on sociodemographic factors and year of enrollment; 2296 individuals without HNC and 574 individuals with HNC were included in the study. Hazard ratios (HR) for the incidence of PD in patients with HNC were calculated using 95% confidence intervals (CI). The incidence of PD was 4.17 and 2.18 per 1000 person-years in the HNC and control groups, respectively (adjusted HR = 1.89, 95% CI = 1.08-3.33). The HNC group also showed an increased risk of subsequent PD development. The risk of PD was higher in middle-aged (55-69 years) patients with HNC and oral cavity cancer. Our findings suggest that middle-aged patients with HNC have an increased incidence of PD, specifically those with oral cavity cancer. Therefore, our findings provide new insights into the development of PD in patients with HNC.

Exploring the Link between Head and Neck Cancer and Elevated Risk of Rheumatoid Arthritis: A National Population-Based Cohort Study.

An increased risk of cancer among patients with rheumatoid arthritis (RA) has been reported. However, the risk of RA events among patients with head and neck cancer (HNC) is unknown. Therefore, we investigated the incidence and risk of RA among patients with HNC. This study was based on a cohort dataset. Overall, 2824 individuals without HNC and 706 patients with HNC were selected using propensity score matching. The overall RA event rate was 12.19 for patients with HNC and 7.60 for those without HNC. A significantly increased risk of developing RA was also observed among patients with HNC. The risk of developing RA over time was relatively high within the first year after HNC diagnosis; further, it increased significantly during the follow-up period. Moreover, middle-aged male patients with HNC exhibited an increased risk of developing RA compared with the controls; however, no significant difference was noted among female patients or other age groups. Notably, subgroup analysis according to cancer subtype revealed that only oral cancer survivors had an increased risk of developing RA. These results underscore the importance of vigilant monitoring by clinicians to promptly identify the onset of RA in patients with HNC.

Neural-network quantum-state study of the long-range antiferromagnetic Ising chain.

We investigate quantum phase transitions in the transverse field Ising chain with algebraically decaying long-range (LR) antiferromagnetic interactions using the variational Monte Carlo method with the restricted Boltzmann machine employed as a trial wave function ansatz. First, we measure the critical exponents and the central charge through the finite-size scaling analysis, verifying the contrasting observations in the previous tensor network studies. The correlation function exponent and the central charge deviate from the short-range (SR) Ising values at a small decay exponent α_{LR}, while the other critical exponents examined are very close to the SR Ising exponents regardless of α_{LR} examined. However, in the further test of the critical Binder ratio, we find that the universal ratio of the SR limit does not hold for α_{LR}<2, implying a deviation in the criticality. On the other hand, we find evidence of the conformal invariance breakdown in the conformal field theory (CFT) test of the correlation function. The deviation from the CFT description becomes more pronounced as α_{LR} decreases, although a precise breakdown threshold is yet to be determined.

Virtual Golf, "Exergaming", Using Virtual Reality for Healthcare in Older Adults: Focusing on Leisure Constraints, Participation Benefits, and Continuous Participation Intention.

Exergaming, a new type of sport, combined with virtual reality, has provided new opportunities for the aging population. This study analyzed the differences in leisure constraints, participation benefits, and continuous participation intention in virtual golf (represented as an exergame) depending on the participants' ages. Data collection was conducted from August 2023 to November 2023. A quantitative research design and a convenience sampling method were employed, targeting 310 regular virtual golf participants aged 20 years or older in the Republic of Korea. For comparative analysis, the survey participants were segmented into three groups: Group 1, young adults (18-35 years); Group 2, middle-aged adults (36-55 years); and Group 3, older adults (56-69 years). To compare and analyze participation behaviors in virtual golf, the dependent variables were identified: (a) leisure constraints (four factors) to limit formation and participation in leisure; (b) participation benefits (four factors) to encourage participation in leisure; and (c) continuous participation intention (single factor) to show likelihood to participate in leisure in the future. The results revealed that the young adult group showed statistically high results for costs under leisure constraints (F = 14.949, p < 0.001, ηp2 = 0.089), and the older adult group reported statistically high results in physical (F = 9.346, p < 0.001, ηp2 = 0.057) and mental (F = 7.249, p < 0.001, ηp2 = 0.045) participation benefits and continuous participation intention (F = 6.486, p < 0.01, ηp2 = 0.041). This study confirmed that virtual golf using advanced technology brings physical and mental benefits to older people based on reasonable cost and enables continuous participation in physical activity.

Association between Head and Neck Cancer and Increased Risk of Ischemic Heart Disease: A Retrospective Cohort Study Using National Population Data.

Although cancer and ischemic heart disease (IHD) frequently manifest in the same individual, the risk of IHD events in cancer, especially head and neck cancer (HNC), remains unclear. We aimed to examine the incidence and risk of IHD events in patients with HNC using a population-based cohort dataset in South Korea (2002-2013). Through rigorous propensity score matching, we compared data from 2816 individuals without HNC and 704 individuals with HNC. Key independent variables were matched between groups, and the Charlson Comorbidity Index was used to match comorbidities. The Kaplan-Meier method depicted the cumulative probability of IHD throughout the follow-up period for both the study and control groups. The overall IHD incidence was significantly higher (19.93) in patients with HNC than in those without HNC (14.81), signifying an augmented IHD risk in the HNC cohort. Subsequent temporal analysis revealed a significant surge in IHD risk commencing 4 years after HNC diagnosis and persisting throughout the follow-up period. Subgroup analysis revealed an increased IHD risk in men with HNC and patients with cancers affecting the oral and sinonasal regions. This retrospective cohort study provides valuable scientific insights into the nuanced relationship between HNC and IHD, underscoring the need for tailored monitoring protocols and specialized care for susceptible individuals.

Comparison of the Size Measurement of Gallbladder Polyps by Three Different Radiologists in Abdominal Ultrasonography.

BACKGROUND: There is little information regarding the size measurement differences in gallbladder (GB) polyps performed by different radiologists on abdominal ultrasonography (US). AIM: To reveal the differences in GB polyp size measurements performed by different radiologists on abdominal US. METHODS: From June to September 2022, the maximum diameter of 228 GB polyps was measured twice on abdominal US by one of three radiologists (a third-year radiology resident [reader A], a radiologist with 7 years of experience in abdominal US [reader B], and an abdominal radiologist with 8 years of experience in abdominal US [reader C]). Intra-reader agreements for polyp size measurements were assessed by intraclass correlation coefficient (ICC). A Bland-Altman plot was used to visualize the differences between the first and second size measurements in each reader. RESULTS: Reader A, reader B, and reader C evaluated 65, 77, and 86 polyps, respectively. The mean size of measured 228 GB polyps was 5.0 ± 1.9 mm. Except for the case where reader A showed moderate intra-reader agreement (0.726) for polyps with size ≤ 5 mm, all readers showed an overall high intra-reader reliability (reader A, ICC = 0.859; reader B, ICC = 0.947, reader C, ICC = 0.948), indicative of good and excellent intra-reader agreements. The 95% limit of agreement of reader A, B, and C was 1.9 mm of the mean in all three readers. CONCLUSIONS: GB polyp size measurement on abdominal US showed good or excellent intra-reader agreements. However, size changes of approximately less than 1.9 mm should be interpreted carefully because these may be within the measurement error.

Microstructure-Based Modeling of Deformation and Damage Behavior of Extruded and Additively Manufactured 316L Stainless Steels.

In this study, we investigated the micromechanical deformation and damage behavior of commercially extruded and additively manufactured 316L stainless steels (AMed SS316L) by combining experimental examinations and crystal plasticity modeling. The AMed alloy was fabricated using the laser powder bed fusion (LPBF) technique with an orthogonal scanning strategy to control the directionality of the as-fabricated material. Optical microscopy and electron backscatter diffraction measurements revealed distinct grain morphologies and crystallographic textures in the two alloys. Uniaxial tensile test results suggested that the LPBFed alloy exhibited an increased yield strength, reduced elongation, and comparable ultimate tensile strength in comparison to those of the extruded alloy. A microstructure-based crystal plasticity model was developed to simulate the micromechanical deformation behavior of the alloys using representative volume elements based on realistic microstructures. A ductile fracture criterion based on the microscopically dissipated plastic energy on a slip system was adopted to predict the microscopic damage accumulation of the alloys during plastic deformation. The developed model could accurately predict the stress-strain behavior and evolution of the crystallographic textures in both the alloys. We reveal that the increased yield strength in the LPBFed alloy, compared to that in the extruded alloy, is attributed to the higher as-manufactured dislocation density and the cellular subgrain structure, resulting in a reduced elongation. The presence of annealing twins and favorable texture in the extruded alloy contributed to its excellent elongation, along with a higher hardening rate owing to twin-dislocation interactions during plastic deformation. Moreover, the grain morphology and defect state (e.g., dislocations and twins) in the initial state can significantly affect strain localization and damage accumulation in alloys.

Evaluating Aspirin's Efficacy for Primary Prevention in Cardiovascular and Cerebrovascular Disease: Insights from a Nationwide Cohort Study.

BACKGROUND: The effectiveness of aspirin for the primary prevention of cerebro-cardiovascular diseases in Koreans remains unclear. Therefore, we evaluated the preventive effects of low-dose aspirin (equal or less than 100 mg) on cerebro-cardiovascular events. METHOD: We conducted a retrospective cohort study using the National Sample Cohort dataset. From the 1,106,580 individuals eligible in 2004, we selected 200 individuals (47% male and 22.5% aged 65 or older) who consistently received low-dose aspirin from 2004 to 2013 for inclusion in the aspirin cohort. Participants for the control cohort, who did not use aspirin, were selected through propensity score matching based on variables. RESULT: We compared the incidences of endpoints (acute myocardial infarction, cerebral infarction, gastrointestinal hemorrhage, and cerebral hemorrhage) between the aspirin group and the non-aspirin group over the 9-year follow-up period. There was no significant difference in the incidence rates of acute myocardial infarction, cerebral infarction, gastrointestinal hemorrhage, or cerebral hemorrhage between the aspirin and non-aspirin groups. Low-dose aspirin for primary prevention in Koreans did not reduce myocardial or cerebral infarctions and did not increase the risk of gastrointestinal or cerebral hemorrhage. CONCLUSION: Therefore, we suggest that aspirin for primary prevention should be used cautiously and tailored to the individual's baseline cardiovascular risk.

Optimal methodology for percutaneous dilatational tracheostomy: a comparative analysis between conventional and multidisciplinary approaches utilizing ultrasound, flexible bronchoscopy, and microcatheter puncture in critically ill individuals of diminutive stature-a longitudinal single-institutional experience and retrospective analysis.

Background: Percutaneous dilatational tracheostomy (PDT), a bedside procedure in intensive care, enhances respiratory support for critically ill patients with benefits over traditional tracheostomy, such as improved safety, ease of use, cost-effectiveness, and operational efficiency by eliminating patient transfers to the operating room. It also minimizes complications including bleeding, infection, and inflammation. Despite decades of PDT evolution and device diversification, adaptations primarily cater to larger Western patients rather than smaller-statured Korean populations. This study assesses the efficacy and appropriateness of the Ciaglia Blue Rhino (Cook Critical Care, Bloomington, IN, USA), augmented with ultrasound, flexible bronchoscopy, and microcatheter techniques, for Korean patients with short stature. Methods: We conducted PDT on 183 intubated adults (128 male/55 female) with severe respiratory issues at a single medical center from January 2010 to December 2022. Patients were divided into two groups for retrospective analysis: a modified group (n=133) underwent PDT with ultrasound-guided flexible bronchoscopy and microcatheter puncture, and a conventional group (n=50) received PDT using only the Ciaglia Blue Rhino device. We assessed clinical and demographic characteristics, outcomes, and complications such as pneumothorax and emphysema. The study also evaluated the suitability and effectiveness of the devices for Korean patients with short stature. Results: Demographic characteristics including sex, body weight, height, body mass index, obesity status, and underlying diseases showed no significant differences between the two groups. However, the modified group was older (69.5±14.2 vs. 63.5±14.1 years; P=0.01). The sequential organ failure assessment (SOFA) and simplified acute physiology score (SAPS) II score was slightly higher in the modified groups, but no statistically significant differences were observed (7.1±2.3 vs. 6.7±2.3, P=0.31 and 46.7±9.0 vs. 44.0±9.1, P=0.08, respectively). The duration of hospital and ICU stays, as well as days post-PDT, were longer in the conventional group, yet these differences were not statistically significant (P=0.20, P=0.44, P=0.06). Total surgical time, including preparation, ultrasound, bronchoscopy, and microcatheter puncture, was significantly longer in the modified group (25.6±7.5 vs. 19.9±6.5 minutes; P<0.001), and the success rate of the first tracheal puncture was also higher (100.0% vs. 92.0%; P=0.006). Intra-operative bleeding was less frequent in the modified group (P=0.02 for tracheostomy site bleeding and P=0.002 for minor bleeding). Conclusions: PDT, performed at the bedside in intensive care settings, proves to be a swift and dependable method. Utilizing the Ciaglia Blue Rhino device, combined with ultrasound guidance, flexible bronchoscopy, and 4.0-Fr microcatheter puncture, PDT is especially effective for intubated patients who cannot be weaned from ventilation. This technique results in fewer complications than traditional tracheostomy and is particularly beneficial for patients with respiratory issues and smaller-statured Koreans, potentially reducing morbidity and mortality.

Microvilli regulate the release modes of alpha-tectorin to organize the domain-specific matrix architecture of the tectorial membrane.

The tectorial membrane (TM) is an apical extracellular matrix (ECM) in the cochlea essential for auditory transduction. The TM exhibits highly ordered domain-specific architecture. Alpha-tectorin/TECTA is a glycosylphosphatidylinositol (GPI)-anchored ECM protein essential for TM organization. Here, we identified that TECTA is released by distinct modes: proteolytic shedding by TMPRSS2 and GPI-anchor-dependent release from the microvillus tip. In the medial/limbal domain, proteolytically shed TECTA forms dense fibers. In the lateral/body domain produced by the supporting cells displaying dense microvilli, the proteolytic shedding restricts TECTA to the microvillus tip and compartmentalizes the collagen-binding site. The tip-localized TECTA, in turn, is released in a GPI-anchor-dependent manner to form collagen-crosslinking fibers, required for maintaining the spacing and parallel organization of collagen fibrils. Overall, we showed that distinct release modes of TECTA determine the domain-specific organization pattern, and the microvillus coordinates the release modes along its membrane to organize the higher-order ECM architecture.

Artificial intelligence-driven drug repositioning uncovers efavirenz as a modulator of α-synuclein propagation: Implications in Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments for PD remains a major unmet medical need. Notably, drug repositioning is becoming an increasingly attractive direction in drug discovery, and computational approaches offer a relatively quick and resource-saving method for identifying testable hypotheses that promote drug repositioning. We used an artificial intelligence (AI)-based drug repositioning strategy to screen an extensive compound library and identify potential therapeutic agents for PD. Our AI-driven analysis revealed that efavirenz and nevirapine, approved for treating human immunodeficiency virus infection, had distinct profiles, suggesting their potential effects on PD pathophysiology. Among these, efavirenz attenuated α-synuclein (α-syn) propagation and associated neuroinflammation in the brain of preformed α-syn fibrils-injected A53T α-syn Tg mice and α-syn propagation and associated behavioral changes in the C. elegans BiFC model. Through in-depth molecular investigations, we found that efavirenz can modulate cholesterol metabolism and mitigate α-syn propagation, a key pathological feature implicated in PD progression by regulating CYP46A1. This study opens new avenues for further investigation into the mechanisms underlying PD pathology and the exploration of additional drug candidates using advanced computational methodologies.

Epidemiology and Outcomes of Non-Small Cell Lung Cancer in South Korea.

Importance: Valuable evidence regarding clinical characteristics, treatments, and outcomes for non-small cell lung cancer (NSCLC) is limited to individual hospital databases or national-level registries. The common data and federated analysis framework developed through the Extensible Platform for Observational Research in Lung Cancer (EXPLORE-LC) initiative allows for research across multiple high-quality data sources, which may provide a deeper understanding of the NSCLC landscape and identification of unmet needs of subpopulations. Objective: To describe clinical characteristics, initial treatment patterns, subsequent treatment, and overall survival (OS) of patients with NSCLC in South Korea. Design, Setting, and Participants: This multicenter cohort study included patients aged 18 years and older who were diagnosed with NSCLC between 2014 and 2019 and followed up until March 2020 at 3 tertiary hospitals in South Korea. Clinical data were collected using a common data model and clinical data warehouse. Patients who had an initial diagnosis of nonsquamous (NSQ) or squamous (SQ) NSCLC and who had received at least 1 treatment for NSCLC were included in the study. Data were analyzed from June through November 2022. Main Outcomes and Measures: The primary outcome was clinical OS for patients with NSCLC. Secondary outcomes were clinical characteristics and treatment patterns subsequent to the diagnosis of NSCLC. Results: Among 22 101 patients with NSCLC who received anticancer treatment analyzed in this study, 17 350 patients (78.5%) had NSQ and 4751 patients (21.5%) had SQ NSCLC. Clinical characteristics and outcomes and treatment patterns were assessed for 13 084 patients with NSQ cancer who had known EGFR and ALK status (75.4%; mean [SD] 62.2 [10.5] years; 6552 males [50.1%]) and all 4751 patients with SQ cancer (mean [SD] age, 67.1 [8.6] years; 4427 males [93.2%]). More than half of patients with NSQ cancer were never smokers (7399 patients [56.6%]). Patients with SQ cancer were mostly males and former or current smokers (4235 patients [89.1%]) and were diagnosed at a later clinical stage than patients with NSQ cancer (eg, stage I: 1165 patients [24.5%] vs 5388 patients [41.2%]). Patients with EGFR-positive and ALK-positive NSQ cancer diagnosed between 2017 and 2019 had better median OS than similar patients diagnosed between 2014 and 2016 (EGFR-positive: not reached [95% CI, 35.9 months to not reached] vs 28.4 months [95% CI, 25.8 to 30.0 months]; P < .001; ALK-positive: not reached [95% CI, not reached] vs 49.5 months [95% CI, 35.1 months to not reached]; P < .001). No significant difference was observed in OS from first-line treatment for patients with SQ cancer. Conclusions and Relevance: This study, which pooled medical data from multiple clinical data warehouses to produce a large study cohort, may provide meaningful insights into the clinical practice of NSCLC and underscores the value of a common data model approach. The analyzable dataset may hold great promise for future comprehensive identification of subpopulations and unmet needs.

Saturation genome editing maps the functional spectrum of pathogenic VHL alleles.

To maximize the impact of precision medicine approaches, it is critical to identify genetic variants underlying disease and to accurately quantify their functional effects. A gene exemplifying the challenge of variant interpretation is the von Hippel-Lindautumor suppressor (VHL). VHL encodes an E3 ubiquitin ligase that regulates the cellular response to hypoxia. Germline pathogenic variants in VHL predispose patients to tumors including clear cell renal cell carcinoma (ccRCC) and pheochromocytoma, and somatic VHL mutations are frequently observed in sporadic renal cancer. Here we optimize and apply saturation genome editing to assay nearly all possible single-nucleotide variants (SNVs) across VHL's coding sequence. To delineate mechanisms, we quantify mRNA dosage effects and compare functional effects in isogenic cell lines. Function scores for 2,268 VHL SNVs identify a core set of pathogenic alleles driving ccRCC with perfect accuracy, inform differential risk across tumor types and reveal new mechanisms by which variants impact function. These results have immediate utility for classifying VHL variants encountered clinically and illustrate how precise functional measurements can resolve pleiotropic and dosage-dependent genotype-phenotype relationships across complete genes.

Incidence Rates and Risk Ratios of Normal Tension Glaucoma in Patients with Chronic Rhinosinusitis: A Population-Based Longitudinal Follow-Up Study.

Several studies have investigated the association between chronic rhinosinusitis (CRS) and ophthalmological complications. However, it remains uncertain whether CRS is independently associated with the development of normal tension glaucoma (NTG). Therefore, this retrospective cohort study aimed to investigate the prospective association between CRS and the increased incidence and risk of NTG using a representative population-based dataset. The selection of both the CRS and comparison groups was meticulously conducted through the propensity scoring method. The incidence and risk ratios of NTG were measured using person-years at risk and a weighted Cox proportional hazards model. We enrolled 30,284 individuals without CRS (comparison group) and 15,142 individuals with CRS. The NTG incidence rates were 1.19 and 0.81 in the CRS and comparison groups, respectively. The CRS group showed a significantly increased risk of subsequent development for NTG (adjusted hazard ratio = 1.41, 95% confidence interval = 1.16-1.72), regardless of the CRS subtype. Additionally, the risk of developing NTG was relatively higher in the first 2 years after CRS diagnosis. Moreover, a subgroup analysis revealed a higher risk of NTG in elderly female individuals with CRS. The present findings underscore the importance of monitoring and managing NTG risk in individuals with CRS, especially in elderly female patients.

Immunomodulatory Effects of Primed Tonsil-Derived Mesenchymal Stem Cells on Atopic Dermatitis via B Cell Regulation.

Mesenchymal stem cells (MSCs) ameliorate T-and B cell-mediated immune responses. In particular, tonsil-MSCs (T-MSCs) are attractive candidates for practical and clinical applications because of their ease of acquisition and relatively low immunogenicity compared with other MSC sources. The use of MSCs as a therapeutic tool in atopic dermatitis (AD) has been investigated, but that of T-MSCs remains to be explored. Therefore, we investigated the immunomodulatory effects of primed T-MSCs in AD pathogenesis. In our animal study, primed T-MSCs showed greater immunological suppressive effects than naïve T-MSCs. Additionally, in vitro, the proliferation of B cells was downregulated by the addition of primed T-MSCs compared with naïve T-MSCs. The activation of B cells to differentiate into antibody-secreting cells and produce IgE was also reduced when primed T-MSCs were added. Moreover, under CD40-knockdown conditions, we found that CD40 in primed T-MSCs played a critical role as a regulator of B cell activation and was mediated by the non-canonical NF-κB pathway. Therefore, our findings suggest a promising role for primed T-MSCs in the treatment of AD by regulating B cell-mediated inflammatory responses, which are dependent on CD40 expression on primed T-MSCs mediated through the non-canonical NF-κB pathway.