Clozapine and Antipsychotic Monotherapy

Background: Although clozapine is effective for treatment-resistant schizophrenia (TRS), the rate of clozapine prescription is still low. Whereas antipsychotic monotherapy is recommended in clinical practice guidelines, the rate of antipsychotic polypharmacy is still high. There is little evidence on whether a clozapine prescription influences changes in the rate of monotherapy and polypharmacy, including antipsychotics and other psychotropics. We therefore hypothesized that the rate of antipsychotic monotherapy in patients with TRS who were prescribed clozapine would be higher than that in patients with schizophrenia who were not prescribed clozapine. Methods: We assessed 8306 patients with schizophrenia nationwide from 178 institutions in Japan from 2016 to 2019. We analyzed the psychotropic prescription data at discharge in patients diagnosed with TRS and with no description of TRS (ND-TRS) based on the diagnosis listed in the discharge summary. Results: The rate of antipsychotic monotherapy in the TRS with clozapine group (91.3%) was significantly higher than that in the TRS without clozapine group (45.9%; P < 2.0 × 10−16) and the ND-TRS without clozapine group (54.7%; P < 2.0 × 10−16). The rate of antipsychotic monotherapy without any other concomitant psychotropics in the TRS with clozapine group (26.5%) was significantly higher than that in the TRS without clozapine group (12.6%; P = 1.1 × 10−6) and the ND-TRS without clozapine group (17.0%; P = 5.9 × 10−6). Conclusions: Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Case of uncontrolled asthma with Ceriporia lacerata-related broncholithiasis

An 81-year-old Japanese male patient was treated for asthma. He complained of persistent cough and wheezing. Chest computed tomography scan revealed atelectasis in the right middle lobe. Fiberoptic bronchoscopy was performed. Results showed a calcified stone with filamentous fungi with septa in the right middle lobe bronchus, which was subsequently removed. Ceriporia lacerata was detected repeatedly on sputum culture. Thus, the filamentous fungi were suspected as C. lacerata. Broncholithiasis possibly caused mucous membrane damage owing to C. lacerata colonization, resulting in allergic airway inflammation. Herein, we report a rare case of C. lacerata-related broncholithiasis associated with asthma exacerbation

Predictors of radiological aggravations of pulmonary MAC disease.

Background and objectivesThe number of patients with pulmonary Mycobacterium avium complex (MAC) disease is increasing worldwide, especially among middle-aged women and never-smokers. However, little is known about the factors causing exacerbations of pulmonary MAC disease in untreated patients. The aim of the present study was to identify the predictors of radiological aggravations of pulmonary MAC disease.MethodsFrom April 2011 to December 2018, 238 MAC patients at our institute were newly diagnosed with pulmonary MAC disease according to the 2007 American Thoracic Society/Infectious Disease Society guideline. Their medical records were examined retrospectively for their clinical findings. The radiological findings at the time of the diagnosis and 1 year later were evaluated. To identify the predictors of radiological aggravation, multivariable analysis was performed with the data of 167 treatment-naïve patients.ResultsFemale, never-smoker, and nodular/bronchiectatic (NB) type were predominant in patients with pulmonary MAC disease. Univariate analysis of data from treatment-naïve subjects showed that no lung diseases other than MAC, extensive radiological findings, and a positive acid-fast bacilli (AFB) smear were significantly associated with radiological aggravations. On multivariate analysis, the radiological factor (larger affected area) and absence of other lung disease were significantly associated with radiological aggravations. In particular, the presence of abnormal shadows in more than 3 lobes was significantly associated with radiological aggravations.ConclusionsIn this study, the presence of extensive radiological findings and the absence of lung diseases other than MAC were predictors of radiological aggravations of treatment-naïve pulmonary MAC disease. In particular, the presence of abnormal shadows in more than 3 lobes was significantly associated with radiological aggravations

Therapeutic modality of plasmacytoid dendritic cells in a murine model of <em>Aspergillus fumigatus</em> sensitized and infected asthma

Aspergillus fumigatus (Af) is a representative pathogen for severe asthma with fungal sensitization (SAFS), which has been coined to define a particular phenotype of severe asthma despite the use of high-dose inhaled corticosteroids and long-acting bronchodilators. Since current therapies cannot adequately control SAFS, a new therapeutic modality is required. Focusing on the immunoregulatory profile of plasmacytoid dendritic cells (pDCs), the purpose of the present study was to investigate the effects of intranasal transfer of pDCs to a murine model of Af sensitized and infected asthma mimicking SAFS on airway inflammation and cytokine profiles. Splenic pDCs were obtained from Af sensitized and infected donor mice. Thereafter, these pDCs were intranasally transferred into the airway of Af sensitized and infected recipient mice. pDCs inhibited both eosinophilic and neutrophilic airway inflammation. Analysis of cytokine profiles in lung tissue revealed that pDCs significantly inhibited proinflammatory cytokines, MIP-2, IL-5 and IL-17, and significantly increased an immunoregulatory cytokine, IL-10. In contrast, pDCs did not significantly modulate IFN-γ, a critical cytokine for antifungal immunity, suggesting the absence of immunosuppressive effects. Transfer of pDCs into the airway could be an effective and safe therapeutic modality for SAFS

Analysis of predictive parameters for the development of radiation-induced pneumonitis

Introduction: Prevention and effective treatment of radiation-induced pneumonitis (RP) could facilitate greater use of radiation therapy (RT) for lung cancer. The purpose of this study was to determine clinical parameters useful for early prediction of RP. Methods: Blood sampling, pulmonary function testing, chest computed tomography, and bronchoalveolar lavage (BAL) were performed in patients with pathologically confirmed lung cancer who had completed ≥60 Gy of RT, at baseline, shortly after RT, and at 1 month posttreatment. Results: By 3 months post-RT, 11 patients developed RP (RP group) and the remaining 11 patients did not (NRP group). RT significantly increased total cell counts and alveolar macrophages in BAL of the NRP group, whereas lymphocyte count was increased in both groups. Matrix metallopeptidase-9 (MMP-9) increased and vascular endothelial growth factor decreased significantly in the BAL fluid (BALF) of the RP group following RT. Serum surfactant protein D (SP-D) increased significantly in the NRP group. SP-D in BALF from the RP group increased significantly with a subsequent increase in serum SP-D. Pulmonary dilution decreased similarly in both groups of patients. Conclusions: Increased SP-D in BALF, rather than that in serum, could be useful biomarkers in predicting RP. The MMP-9 in BALF might play a role in the pathogenesis of RP. Pulmonary dilution test may not be predictive of the development of RP