Prioritizing causal variants in a regulatory region of the genome remains challenging. Here we introduce the Expression Modifier Score (EMS) v2, allowing prioritization of regulatory variants with high precision. EMSv2 achieves higher prediction performance compared to alternative methods, especially in tissues with low sample size such as brains. We show that the power gain is attributed to implementation of (1) features accounting for long-range DNA sequence interaction, (2) customization of loss-function in training, and (3) multi-task learning framework. We then apply EMSv2 to an independent eQTL data from a Japanese population to demonstrate that EMSv2 outperforms alternative methods in regulatory variant prioritization and can be utilized for functionally-informed fine-mapping in a distinct population. We also show that EMSv2 can be utilized in combination with the gene-level polygenic prioritization score (PoPS) to prioritize complex trait-causal regulatory variants. Our work accelerates regulatory variant prioritization in the human genome. Expression Modifier Score v2 integrates Enformer-derived features and multi-task learning to prioritize regulatory variants and support interpretation of noncoding genetic associations.

We examined changes in smoking cessation service utilization and prescribing patterns under the universal health insurance system during the varenicline supply suspension in Japan. We analyzed publicly available aggregated data from the NDB Open Database, which covers more than 95% of all health insurance claims. Monthly claims for nicotine dependence management fees from April 2019 to March 2024 were evaluated using interrupted time-series analysis, and annual prescription trends for varenicline and nicotine patches were assessed. The varenicline supply suspension was associated with a significant immediate decline in service claims (-6443.5; 95% confidence interval: -8360.2 to -4526.9; p < 0.001). Claims showed a modest downward trend before the suspension, followed by a gradual increase thereafter. Varenicline use declined after 2021, accompanied by increased nicotine patch use. These findings indicate that the supply suspension disrupted smoking cessation services and altered prescribing patterns in Japan, highlighting vulnerability in systems with limited reimbursed therapies.

Primary ciliary dyskinesia (PCD) presents various clinical manifestations, including bronchiectasis, chronic sinusitis, situs inversus, and infertility. PCD is diagnosed through multiple methods, including transmission electron microscopy (TEM), high-speed video microscopy analysis (HSVA), immunofluorescence (IF), and genetic testing. Recent reports show that a homozygous deletion involving exons 1-4 of DRC1 is common in Japanese patients with PCD. We report the case of a 29-year-old male without situs inversus previously diagnosed with diffuse panbronchiolitis, who underwent PCD testing. TEM appeared almost normal, and HSVA showed motile cilia with reduced amplitude. Genetic testing revealed a homozygous deletion involving exons 1-4 of DRC1. Due to lack of a suitable DRC1 antibody for IF, we used the DRC3 antibody as in previous studies. IF showed the absence of DRC3 in the cilia, suggesting a DRC1 deletion affects DRC3 localization in the cilia. To the best of our knowledge, this case represents one of the earliest reports to perform IF and ciliary movement analysis in PCD with a homozygous deletion involving exons 1-4 of DRC1.

Background: CD276 is an immune checkpoint, and immune checkpoint inhibitors (ICIs) targeting CD276 have been tested against various cancers. However, the precise role of CD276 in mesothelioma subtypes is unknown. This study aimed to reveal the prognostic significance of CD276 in various cancers and explore CD276 as a target for ICIs in different mesothelioma subtypes. Methods: We evaluated data from The Cancer Genome Atlas (TCGA) database retrospectively. The Wilcoxon rank-sum test was used to assess CD276 mRNA expression between cancer tissues and the adjacent normal tissues in the context of various cancers. The study involved 86 patients with mesothelioma. The mean number of patients was set as the cutoff value for comparing CD276 mRNA expression. The overall survival (OS) of patients with each mesothelioma subtype was estimated using the Kaplan-Meier method with CD276 mRNA expression. The factors affecting the correlation between OS and high/low CD276 expression in combination with/without a current existing molecular targets of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and vascular endothelial growth factor A (VEGFA) were assessed using a multivariate Cox proportional hazards model. The correlation between the mRNA expression of CD276 and expression of gene markers of tumor-infiltrating immune cells and those of different pathways was evaluated using Spearman's correlation. The factors affecting correlations of CD276 mRNA expression were confirmed using a multivariate linear regression model. Results: Upregulated CD276 mRNA expression was associated with a poor prognosis in various cancers, including epithelioid mesothelioma. The multivariate Cox proportional hazards model demonstrated that upregulated CD276 mRNA expression indicated the worst prognosis, including the combination of CD276 and PD-1, CTLA4, and VEGFA. In addition, using a multivariate linear regression model, CD276 mRNA expression was found to correlate with multiple glycolytic pathway mRNAs in epithelioid mesothelioma, Conclusions: CD276 is an independent prognostic biomarker in patients with epithelioid mesothelioma. It is associated with the glycolytic pathway and may contribute to ATP generation in epithelioid mesothelioma. CD276 inhibitors might contribute to better prognosis in patients with epithelioid mesothelioma.

Predictive models for determining coronavirus disease 2019 (COVID-19) severity have been established; however, the complexity of the interactions among factors limits the use of conventional statistical methods. This study aimed to establish a simple and accurate predictive model for COVID-19 severity using an explainable machine learning approach. A total of 3,301 patients ≥ 18 years diagnosed with COVID-19 between February 2020 and October 2022 were included. The discovery cohort comprised patients whose disease onset fell before October 1, 2020 (N = 1,023), and the validation cohort comprised the remaining patients (N = 2,278). Pointwise linear and logistic regression models were used to extract 41 features. Reinforcement learning was used to generate a simple model with high predictive accuracy. The primary evaluation was the area under the receiver operating characteristic curve (AUC). The predictive model achieved an AUC of ≥ 0.905 using four features: serum albumin levels, lactate dehydrogenase levels, age, and neutrophil count. The highest AUC value was 0.906 (sensitivity, 0.842; specificity, 0.811) in the discovery cohort and 0.861 (sensitivity, 0.804; specificity, 0.675) in the validation cohort. Simple and well-structured predictive models were established, which may aid in patient management and the selection of therapeutic interventions.

Biologics have transformed the management of severe asthma; however, nationwide data on their use in Japan remain limited. We conducted a descriptive analysis using the NDB Open Database from fiscal years 2014-2023 to examine trends in the prescription volumes and costs for five approved biologics. Total prescriptions increased markedly from 81 450 in 2014 to >2 million in 2023, while total costs rose from 24.1 million to 973.3 million U.S. dollars. The proportion of outpatient self-injection prescriptions accounted for more than half of the prescriptions by 2023. These findings reflect the broader adoption of biologics supported by biomarker-driven treatment and expanded access through home administration. Although biologics offer clinical benefits, their growing use highlights the need to monitor their long-term costs and ensure their appropriate utilization. This study provides a nationwide overview of the biologics approved for asthma treatment and highlights key trends relevant to clinicians and policymakers.

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are common viral etiologies of respiratory infections. Although co-infection with other respiratory pathogens is frequently observed, its clinical significance remains unclear. We retrospectively analyzed 57,746 patients who underwent FILMARRAY®, a comprehensive multiplex polymerase chain reaction testing, between November 2020 and March 2023. Clinical features were compared between single infection and co-infection involving RSV or hMPV using χ2 or Fisher’s exact tests. Multiple logistic regression was performed to identify associations with bronchial asthma (BA) exacerbation, adjusting for age, sex, testing period, and RSV co-infection. Among RSV-positive patients, co-infection was associated with higher prevalence of BA history, wheeze, BA exacerbation, combined BA history and exacerbation, systemic steroid use, and age under 6 years compared to that with single infection. RSV co-infection with coronavirus, parainfluenza virus, adenovirus, and rhinovirus/enterovirus was particularly associated with BA exacerbation. Age under 6 years and RSV co-infection were identified as independent risk factors for BA exacerbation using multiple logistic regression. In contrast, no associations were observed in the hMPV co-infection. RSV co-infection with other respiratory viruses increases the risk of BA exacerbation, especially in age under 6 years patients. Given the proven efficacy of RSV vaccine for adults and monoclonal antibody for high-risk children in preventing RSV-related lower respiratory tract disease, RSV-targeted prevention strategies for younger children appear effective in reducing respiratory disease burden.

Bronchoscopy is a widely used diagnostic procedure in respiratory medicine. Despite recent advances in techniques and an ongoing aging population, detailed information regarding current bronchoscopy procedural patterns and practice settings remains limited for Japan. We analyzed bronchoscopic procedure volumes and settings across 47 Japanese prefectures over the 2023 fiscal year, using NDB Open Data. A total of 177,317 procedures were performed, with a nationwide rate of 142.6 per 100,000 population. Of these, 78.8 % were conducted during inpatient care. The procedural rate and proportion of inpatient cases varied substantially by prefecture. No significant correlation was observed between population aging rate and procedure volume, but a moderate positive correlation was identified between procedure volume and the density of board-certified respiratory specialists (Spearman's ρ = 0.517, p < 0.001). This nationwide analysis highlights the substantial regional variations in bronchoscopy practices across Japan and suggests a possible role of specialist distribution in determining access to the procedure.

Antitussive agents are widely prescribed in Japan regardless of the underlying disease, which contradicts clinical guidelines. External factors such as the coronavirus pandemic and subsequent changes may have influenced these prescription patterns; however, the extent remains unclear. In this descriptive study, we used NDB Open Data (2018-2022) to analyze the annual prescription volumes, costs, and drug categories for antitussive agents (including centrally acting and Kampo medicines) and medications for chronic diseases. Prescriptions for both centrally acting agents and Kampo medicines remained stable in 2018-2019, declined in 2020-2021, and partially recovered in 2022. The prescription costs showed a similar trend. These changes were not observed with medications used for chronic diseases. The decline in prescriptions during the pandemic may reflect reduced healthcare use and fewer acute respiratory infections, suggesting that antitussives were likely used for such conditions. These findings highlight the need for more appropriate evidence-based prescription practices.

Background and objectiveThe coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant global morbidity and mortality. This study aimed to investigate the clinical significance of serum vascular endothelial growth factor A (VEGF-A) in COVID-19 patients and its association with disease severity and pulmonary injury.MethodsWe prospectively collected data from 71 hospitalized COVID-19 patients between June 2020 and January 2021. Patients were classified as either mild or severe based on their oxygen requirements during hospitalization. Serum VEGF-A levels were measured using an ELISA kit.ResultsIn comparison to mild cases, significantly elevated serum VEGF-A levels were observed in severe COVID-19 patients. Furthermore, VEGF-A levels exhibited a positive correlation with white blood cell count, neutrophil count, and lymphocyte count. Notably, serum surfactant protein-D (SP-D), an indicator of alveolar epithelial cell damage, was significantly higher in patients with elevated VEGF-A levels.ConclusionThese results suggest that elevated serum VEGF-A levels could serve as a prognostic biomarker for COVID-19 as it is indicative of alveolar epithelial cell injury caused by SARS-CoV-2 infection. Additionally, we observed a correlation between VEGF-A and neutrophil activation, which plays a role in the immune response during endothelial cell injury, indicating a potential involvement of angiogenesis in disease progression. Further research is needed to elucidate the underlying mechanisms of VEGF-A elevation in COVID-19.

Background We recently found that epiplakin 1 (EPPK1) alterations were present in 12% of lung adenocarcinoma (LUAD) cases and were associated with a poor prognosis in early-stage LUAD when combined with other molecular alterations. This study aimed to identify a probable crucial role for EPPK1 in cancer development.Methods EPPK1 mRNA and protein expression was analyzed with clinical variables. Normal bronchial epithelial cell lines were exposed to cigarette smoke for 16 weeks to determine whether EPPK1 protein expression was altered after exposure. Further, we used CRISPR-Cas9 to knock out (KO) EPPK1 in LUAD cell lines and observed how the cancer cells were altered functionally and genetically.Results EPPK1 protein expression was associated with smoking and poor prognosis in early-stage LUAD. Moreover, a consequential mesenchymal-to-epithelial transition was observed, subsequently resulting in diminished cell proliferation and invasion after EPPK1 KO. RNA sequencing revealed that EPPK1 KO induced downregulation of 11 oncogenes, 75 anti-apoptosis, and 22 angiogenesis genes while upregulating 8 tumor suppressors and 12 anti-cell growth genes. We also observed the downregulation of MYC and upregulation of p53 expression at both protein and RNA levels following EPPK1 KO. Gene ontology enrichment analysis of molecular functions highlighted the correlation of EPPK1 with the regulation of mesenchymal cell proliferation, mesenchymal differentiation, angiogenesis, and cell growth after EPPK1 KO.Conclusions Our data suggest that EPPK1 is linked to smoking, epithelial to mesenchymal transition, and the regulation of cancer progression, indicating its potential as a therapeutic target for LUAD.

BACKGROUND:The coronavirus disease 2019, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has become a global epidemic. There are concerns regarding the severity of SARS-CoV-2 infections in kidney transplant (KTx) recipients. However, there is limited data on how the epidemic has affected the treatment and prognosis of these patients. Therefore, we aimed to report the changes in the treatment and outcomes of KTx recipients infected with SARS-CoV-2 during each wave at our institution. METHODS:A total of 282 KTx recipients who were infected with SARS-CoV-2 during the study period were followed up at Tokyo Women's Medical University between March 2020 and August 2022. We investigated the outcomes and treatments of infected KTx recipients. RESULTS:Nineteen (6.7%) patients showed severe outcomes, including eight SARS-CoV-2 infection-related deaths. Risk factors associated with severe outcomes included underlying conditions, such as diabetes mellitus, heart disease, and liver disease (odds ratios, 2.09, 2.88, and 5.52, respectively). Treatment strategies changed throughout the epidemic in response to changes in the SARS-CoV-2 variants. Antiviral drugs were gradually administered as soon as they were approved for use. CONCLUSIONS:Treatment strategies for KTx recipients were gradually established over the course of the epidemic. Although the proportion of infected KTx recipients decreased compared to that of the general population throughout the epidemic, many patients still followed a severe course.

AbstractA 46‐year‐old male was treated with corticosteroids for nonspecific interstitial pneumonia (NSIP). He was referred to our hospital and admitted for worsening dyspnea and diffuse ground‐glass opacity on chest computed tomography (CT) during corticosteroid treatment. Gottron's sign was observed, and the patient was diagnosed with clinically amyopathic dermatomyositis on skin biopsy. We increased the corticosteroid dose and added immunosuppressive agents; however, the opacity on the chest CT worsened. Based on periodic‐acid‐Schiff‐positive granular material in the bronchoalveolar lavage fluid and the presence of anti‐GM‐CSF antibodies, the patient was diagnosed with autoimmune pulmonary alveolar proteinosis (APAP). The concentration of anti‐GM‐CSF antibodies in preserved serum was also elevated when the patient was diagnosed with NSIP. Thus, we assumed that NSIP and APAP coexisted, and that APAP manifested during immunosuppressive therapy. When exacerbation is observed during the treatment of interstitial pneumonia with immunosuppressive agents, it is necessary to consider APAP.

BACKGROUND:Co-detection of respiratory pathogens with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is poorly understood. This descriptive epidemiological study aimed to determine the effect of the interaction of different respiratory pathogens on clinical variables. METHODS:We retrospectively reviewed the results of comprehensive multiplex polymerase chain reaction (PCR) testing from November 2020 to March 2023 to estimate respiratory pathogen co-detection rates in Shinjuku, Tokyo. We evaluated the interactions of respiratory pathogens, particularly SARS-CoV-2, between observed and expected co-detection. We estimated the trend of co-detection with SARS-CoV-2 in terms of age and sex and applied a multiple logistic regression model adjusted for age, testing period, and sex to identify influencing factors between co-detection and single detection for each pathogen. RESULTS:Among 57,746 patients who underwent multiplex PCR testing, 10,516 (18.2%) had positive for at least one of the 22 pathogens. Additionally, 881 (1.5%) patients were confirmed to have a co-detection. SARS-CoV-2 exhibited negative interactions with adenovirus, coronavirus, human metapneumovirus, parainfluenza virus, respiratory syncytial virus, and rhino/enterovirus. SARS-CoV-2 co-detection with other pathogens occurred most frequently in patients of the youngest age group (0-4 years). A multiple logistic regression model indicated that younger age was the most influential factor for SARS-CoV-2 co-detection with other respiratory pathogens. CONCLUSION:The study highlights the prevalence of SARS-CoV-2 co-detection with other respiratory pathogens in younger age groups, necessitating further exploration of the clinical implications and severity of SARS-CoV-2 co-detection.

The severity of chest X-ray (CXR) findings is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). We investigated the clinical and genetic characteristics and prognosis of patients with worsening CXR findings during early hospitalization. We retrospectively included 1656 consecutive Japanese patients with COVID-19 recruited through the Japan COVID-19 Task Force. Rapid deterioration of CXR findings was defined as increased pulmonary infiltrates in ≥ 50% of the lung fields within 48 h of admission. Rapid deterioration of CXR findings was an independent risk factor for death, most severe illness, tracheal intubation, and intensive care unit admission. The presence of consolidation on CXR, comorbid cardiovascular and chronic obstructive pulmonary diseases, high body temperature, and increased serum aspartate aminotransferase, potassium, and C-reactive protein levels were independent risk factors for rapid deterioration of CXR findings. Risk variant at the ABO locus (rs529565-C) was associated with rapid deterioration of CXR findings in all patients. This study revealed the clinical features, genetic features, and risk factors associated with rapid deterioration of CXR findings, a poor prognostic factor in patients with COVID-19.

Abstract Background The severity of chest X-ray (CXR) findings is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). However, the prognostic impact of deterioration of CXR findings and the clinical characteristics of patients with worsening CXR findings remain unclear. We aimed to investigate the clinical and genetic characteristics, as well as the prognosis, of patients with worsening CXR findings during early hospitalisation. Methods We retrospectively included 1656 consecutive Japanese patients with COVID-19 recruited through the Japan COVID-19 Task Force. Rapid deterioration of CXR findings was defined as increased pulmonary infiltrates in ≥ 50% of the lung fields within 48 h of admission. Results Rapid deterioration of CXR findings was an independent risk factor for death, most severe illness, tracheal intubation, and intensive care unit admission. The presence of consolidation on CXR, comorbid cardiovascular and chronic obstructive pulmonary diseases; high body temperature (≥ 37.7°C); and increased levels of serum aspartate aminotransferase (≥ 30 IU/L), potassium (≥ 4.3 mEq/L), and C-reactive protein (≥ 2.53 mg/dL) were independent risk factors for rapid deterioration of CXR findings. The risk variant at the ABO locus (rs529565-C) was associated with rapid deterioration of CXR findings in all patients with COVID-19. Further, the population-specific risk variant at the DOCK2 locus (rs60200309-A) was nominally associated with rapid deterioration of CXR findings in patients aged < 65 years. Conclusions This study revealed the clinical features, genetic features, and risk factors for rapid deterioration of CXR findings in patients with COVID-19. Rapid deterioration of CXR findings is a poor prognostic factor for patients with COVID-19.

Introduction: Transplant recipients (TRs) are at high risk for severe coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibodies (mAbs) are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment without/with mAbs in TRs are limited. We assessed the efficacy of casirivimab/imdevimab against mild-to-moderate COVID-19 in TRs. Methods: Forty-one patients were retrospectively evaluated. The duration until defervescence, oxygen (O2) requirement >= 5 L, and neutralizing antibody levels were compared in TRs with COVID-19 without/with casir-ivimab/imdevimab.Results: Casirivimab/imdevimab was correlated with shorter duration until defervescence and non-requirement of O2 >= 5 L in TRs with COVID-19 [mean: without/with: 6 vs. 2; P = 0.0002, hazard ratio (HR) = 0.3333, 95% confidence interval (CI) = 0.1763-0.6301; 15 vs. 8; P < 0.0001, HR = 0.5333, 95% CI = 0.2878-0.9883; P = 0.0377, HR = 0.1502, 95% CI = 0.02511-0.8980]. Casirivimab/imdevimab was associated with early defer-vescence after adjusting for sex and age (P = 0.013, HR = 0.412, 95% CI = 0.205-0.826). The antibody levels between patients without/with casirivimab/imdevimab on the day of hospitalization were not significantly different (P = 0.1055), including 13 TRs with vaccination. Antibody levels were higher in patients with casir-ivimab/imdevimab at 3-5 days after hospitalization than in those without, at 7-9 days after hospitalization (P < 0.0001, mean, without/with: 414.9/40000 AU/mL).Conclusion: Casirivimab/imdevimab was effective and increased the neutralizing antibody in TRs with mild-to -moderate COVID-19, it may contribute toward preventing the progression.