1H, 13C, and 15N resonance assignments and solution structure of the N-terminal divergent calponin homology (NN-CH) domain of human intraflagellar transport protein 54.

The intraflagellar transport (IFT) machinery plays a crucial role in the bidirectional trafficking of components necessary for ciliary signaling, such as the Hedgehog, Wnt/PCR, and cAMP/PKA systems. Defects in some components of the IFT machinery cause dysfunction, leading to a wide range of human diseases and developmental disorders termed ciliopathies, such as nephronophthisis. The IFT machinery comprises three sub-complexes: BBsome, IFT-A, and IFT-B. The IFT protein 54 (IFT54) is an important component of the IFT-B sub-complex. In anterograde movement, IFT54 binds to active kinesin-II, walking along the cilia microtubule axoneme and carrying the dynein-2 complex in an inactive state, which works for retrograde movement. Several mutations in IFT54 are known to cause Senior-Loken syndrome, a ciliopathy. IFT54 possesses a divergent Calponin Homology (CH) domain termed as NN-CH domain at its N-terminus. However, several aspects of the function of the NN-CH domain of IFT54 are still obscure. Here, we report the 1H, 15N, and 13C resonance assignments of the NN-CH domain of human IFT54 and its solution structure. The NN-CH domain of human IFT54 adopts essentially the α1-α2-α3-α4-α5 topology as that of mouse IFT54, whose structure was determined by X-ray crystallographic study. The structural information and assignments obtained in this study shed light on the molecular function of the NN-CH domain in IFT54.

Structural insights into recognition of SL4, the UUCG stem-loop, of human U1 snRNA by the ubiquitin-like domain, including the C-terminal tail in the SF3A1 subunit of U2 snRNP.

The pre-spliceosomal complex involves interactions between U1 and U2 snRNPs, where a ubiquitin-like domain (ULD) of SF3A1, a component of U2 snRNP, binds to the stem-loop 4 (SL4; the UUCG tetraloop) of U1 snRNA in U1 snRNP. Here, we reported the 1.80 Å crystal structure of human SF3A1 ULD (ULDSF3A1) complexed with SL4. The structural part of ULDSF3A1 (res. 704-785) adopts a typical ß-grasp fold with a topology of ß1-ß2-α1-310a-ß3-ß4-310b-ß5, closely resembling that of ubiquitin, except for the length and structure of the ß1/ß2 loop. A patch on the surface formed by three ULDSF3A1-specific residues, Lys756 (ß3), Phe763 (ß4) and Lys765 (following ß4), contacts the canonical UUCG tetraloop structure. In contrast, the directly following C-terminal tail composed of 786KERGGRKK793 was essentially stretched. The main or side chains of all the residues interacted with the major groove of the stem helix; the RGG residues adopted a peculiar conformation for RNA recognition. These findings were confirmed by mutational studies using bio-layer interferometry. Collectively, a unique combination of the ß-grasp fold and the C-terminal tail constituting ULDSF3A1 is required for the SL4-specific binding. This interaction mode also suggests that putative post-translational modifications, including ubiquitination in ULDSF3A1, directly inhibit SL4 binding.

Adult T-cell leukemia/lymphoma complicated by Pneumocystis pneumonia in a non-endemic area.

Adult T-cell leukemia/lymphoma (ATLL) is a human T-cell leukemia virus type 1-inducing unevenly-distributed T-cell malignancy, which is often complicated by opportunistic infections. Here, we discuss the case of a 75-year-old woman presenting with Pneumocystis pneumonia (PCP) who was subsequently diagnosed with ATLL in Tokyo, a non-endemic area of ATLL. In addition to the elevated soluble interleukin-2 receptor and the detection of flower cells in the screening blood test, the high-resolution computed tomography findings, atypical of PCP, were clues to the diagnosis of ATLL. ATLL should be considered as an underlying disease when patients present with PCP, even in non-endemic areas.

Clinical Utility of Rapid On-Site Evaluation of Touch Imprint Cytology during Cryobiopsy for Peripheral Pulmonary Lesions.

Cryobiopsy enables us to obtain larger specimens than conventional forceps biopsy despite the caution regarding complications. This study aimed to evaluate the clinical utility of rapid on-site evaluation of touch imprint cytology (ROSE-TIC) during cryobiopsy of peripheral pulmonary lesions (PPLs). We retrospectively reviewed the data of consecutive patients who underwent cryobiopsy for solid PPLs between June 2020 and December 2021. ROSE-TIC was performed on the first specimen obtained via cryobiopsy and assessed using Diff-Quik staining. The results of ROSE-TIC for each patient were compared with the histological findings of the first cryobiopsy specimen. Sixty-three patients were enrolled in this study. Overall, 57 (90.5%) lesions were ≤30 mm in size and 37 (58.7%) had positive bronchus signs. The radial endobronchial ultrasound findings were located within and adjacent to the lesion in 46.0% and 54.0% of the cases, respectively. The sensitivity, specificity, and positive and negative predictive values of the ROSE results for histological findings of the corresponding specimens were 69.8%, 90.0%, 93.8%, and 58.1%, respectively. The concordance rate was 76.2%. In conclusion, ROSE-TIC, due to its high specificity and positive predictive value, may be a potential tool in deciding whether cryobiopsy sampling could be finished during bronchoscopy.

Structural basis for the interaction between the first SURP domain of the SF3A1 subunit in U2 snRNP and the human splicing factor SF1.

SURP domains are exclusively found in splicing-related proteins in all eukaryotes. SF3A1, a component of the U2 snRNP, has two tandem SURP domains, SURP1, and SURP2. SURP2 is permanently associated with a specific short region of SF3A3 within the SF3A protein complex whereas, SURP1 binds to the splicing factor SF1 for recruitment of U2 snRNP to the early spliceosomal complex, from which SF1 is dissociated during complex conversion. Here, we determined the solution structure of the complex of SURP1 and the human SF1 fragment using nuclear magnetic resonance (NMR) methods. SURP1 adopts the canonical topology of α1-α2-310 -α3, in which α1 and α2 are connected by a single glycine residue in a particular backbone conformation, allowing the two α-helices to be fixed at an acute angle. A hydrophobic patch, which is part of the characteristic surface formed by α1 and α2, specifically contacts a hydrophobic cluster on a 16-residue α-helix of the SF1 fragment. Furthermore, whereas only hydrophobic interactions occurred between SURP2 and the SF3A3 fragment, several salt bridges and hydrogen bonds were found between the residues of SURP1 and the SF1 fragment. This finding was confirmed through mutational studies using bio-layer interferometry. The study also revealed that the dissociation constant between SURP1 and the SF1 fragment peptide was approximately 20 µM, indicating a weak or transient interaction. Collectively, these results indicate that the interplay between U2 snRNP and SF1 involves a transient interaction of SURP1, and this transient interaction appears to be common to most SURP domains, except for SURP2.

Comparison of Mental Health among Japanese Healthcare Workers at Two Points during the COVID-19 Pandemic.

BACKGROUND: The prolonged pandemic of coronavirus disease 2019 (COVID-19) has resulted in mental burden among healthcare workers (HCWs). This study aimed to conduct a repeated study to assess changes in psychological concerns among Japanese HCWs. METHODS: This study is the second survey involving HCWs at the Japanese Red Cross Medical Center conducted between November 20, 2020 and December 4, 2020. The degree of symptoms of anxiety, depression, and resilience was assessed using the Japanese versions of the 7-item Generalized Anxiety Disorder Scale, Center for Epidemiologic Studies Depression Scale, and 10-item Connor-Davidson Resilience Scale, respectively. RESULTS: The survey included 594 HCWs, comprising 95 physicians, 261 nurses, 150 other co-medical staff, and 88 office workers. Among them, 46 (7.7%) and 152 (25.6%) developed moderate-to-severe symptoms of anxiety and depression, respectively. Compared with those in the initial survey conducted 6 months earlier, the resilience score did not change, whereas the anxiety and depression scores improved significantly (P < 0.001, P = 0.033, respectively). However, the frequency of HCWs developing moderate-to-severe symptoms of anxiety or depression did not significantly improve. Multivariable logistic regression analysis showed that having higher anxiety symptoms was a risk factor for depression symptoms, while older HCWs and those with higher resilience were less likely to develop depression symptoms. CONCLUSIONS: Many HCWs still suffer from psychological concerns during the COVID-19 pandemic.

1H, 13C, and 15N resonance assignments and solution structures of the KH domain of human ribosome binding factor A, mtRbfA, involved in mitochondrial ribosome biogenesis.

Ribosome biogenesis is a complicated, multistage process coordinated by ribosome assembly factors. Ribosome binding factor A (RbfA) is a bacterial one, which possesses a single structural type-II KH domain. By this domain, RbfA binds to a 16S rRNA precursor in small ribosomal subunits to promote its 5'-end processing. The human RbfA homolog, mtRbfA, binds to 12S rRNAs in the mitoribosomal small subunits and promotes its critical maturation process, the dimethylation of two highly conserved consecutive adenines, which differs from that of RbfA. However, the structural basis of the mtRbfA-mediated maturation process is poorly understood. Herein, we report the 1H, 15N, and 13C resonance assignments of the KH domain of mtRbfA and its solution structure. The mtRbfA domain adopts essentially the same α1-ß1-ß2-α2(kinked)-ß3 topology as the type-II KH domain. Comparison with the RbfA counterpart showed structural differences in specific regions that function as a putative RNA-binding site. Particularly, the α2 helix of mtRbfA forms a single helix with a moderate kink at the Ser-Ala-Ala sequence, whereas the corresponding α2 helix of RbfA is interrupted by a distinct kink at the Ala-x-Gly sequence, characteristic of bacterial RbfA proteins, to adopt an α2-kink-α3 conformation. Additionally, the region linking α1 and ß1 differs considerably in the sequence and structure between RbfA and mtRbfA. These findings suggest some variations of the RNA-binding mode between them and provide a structural basis for mtRbfA function in mitoribosome biogenesis.

Efficacy and safety of sotrovimab for vaccinated or unvaccinated patients with mild-to-moderate COVID-19 in the omicron era.

Although sotrovimab, one of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies has been shown to be effective in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) with risk factors, their efficacy in mRNA COVID-19 vaccinated patients in omicron era is unknown. To evaluate the effectiveness of sotrovimab clinical data from both COVID-19 vaccinated and unvaccinated patients who were hospitalized and receiving sotrovimab at the Japanese Red Cross Medical Center were compared. The efficacy and adverse events were evaluated. Of the total 60 patients enrolled in this study, 45 had received the mRNA COVID-19 vaccine and 15 were unvaccinated. The clinical progression with low nasal cannula or face mask was not significantly different between groups (occurring in one patient in each group; p = 0.44), with no further progression in both groups. The duration of hospitalization was eight days for both groups (p = 0.90). Two patients in each group experienced adverse events (7%, p = 0.26). The results suggested that the efficacy and safety of sotrovimab against mild-to-moderate COVID-19 with risk factors in the omicron era might not be different regardless of the vaccination status. The results of the present study are encouraging; however, further randomized clinical studies are needed.

Unilateral Autoimmune Pulmonary Alveolar Proteinosis with Polymyositis-related Interstitial Lung Disease.

A 61-year-old patient with cystic bronchiectasis and bronchial artery hyperplasia in the left lung was diagnosed with polymyositis-related interstitial lung disease. After nine months of immunosuppressive therapy, he developed unilateral autoimmune pulmonary alveolar proteinosis (APAP) in the right lung with respiratory failure. After bronchial artery embolization to prevent massive hemoptysis, whole-lung lavage was performed using veno-venous extracorporeal membrane oxygenation. His respiratory condition improved, and he was discharged from the hospital with supplemental oxygen. Three reported cases of APAP with polymyositis-related interstitial lung disease, including the present case, were all positive for anti-glycyl tRNA synthetase antibody and were under immunosuppressive treatment.

Clinical characteristics of pulmonary hypertension in patients with pleuroparenchymal fibroelastosis.

BACKGROUND: This study aimed to investigate the clinical characteristics and prognosis of patients with pleuroparenchymal fibroelastosis (PPFE) and pulmonary hypertension (PH). METHODS: We retrospectively analyzed the data of patients who were diagnosed with PPFE and underwent transthoracic echocardiography (TTE) for the evaluation of their right heart systems within 3 months of their first visit between 2011 and 2018. Patients were divided into the PH and non-PH groups based on their peak tricuspid regurgitation velocity (TRV) on TTE (cutoff, 2.8 m/s). The clinical characteristics of PH and association between PH and survival among patients with PPFE were investigated. RESULTS: In total, 83 patients were enrolled. Sixteen (19.3%) patients were included in the PH group. The PH group had a lower body mass index, percent predicted forced vital capacity (FVC), 6-min walk distance, and partial pressure of arterial oxygen than the non-PH group. There was no significant difference in the presence of usual interstitial pneumonia patterns in the lower lobes between the two groups. The survival period was significantly shorter in the PH group than in the non-PH group (median survival 16.3 versus 50.2 months, log-rank p < 0.001). The multivariate Cox proportional hazard model showed that male sex (hazard ratio [HR] = 4.83, p < 0.001), Krebs von den Lungen-6 (KL-6) > 550 U/mL (HR = 3.48, p = 0.005), %FVC < 50% (HR = 3.04, p = 0.028), and peak TRV > 2.8 m/s (HR = 3.26, p = 0.038) were independently associated with poor survival. CONCLUSIONS: PH was not rare in patients with PPFE. Male sex, increased KL-6, lower FVC, and PH were independently associated with poor survival in patients with PPFE.

Therapeutic options in thymomas and thymic carcinomas.

INTRODUCTION: Curative-intent surgery is the best therapeutic option for thymic malignancies. However, patients with advanced or recurrent thymic malignancies often require palliative-intent chemotherapy or radiotherapy. Since thymic malignancies are rare cancers, the efficacy and safety of treatments have been verified based on small Phase 2 trials or retrospective studies. AREA COVERED: We comprehensively reviewed the treatment strategies for thymic malignancies, including surgery, radiotherapy, and pharmacotherapy, including cytotoxic chemotherapy, molecular-targeted therapy, and immunotherapy. Additionally, we reviewed specific situations, such as pleural dissemination, central nervous system metastasis, and paraneoplastic syndrome. EXPERT OPINION: Cytotoxic chemotherapy remains the standard option in pharmacotherapy. However, multikinase inhibitors, such as sunitinib and lenvatinib, and immune checkpoint inhibitors including pembrolizumab have been developed to treat thymic carcinomas. Now, a Phase 2 study is evaluating whether lenvatinib plus pembrolizumab benefits patients with type B3 thymoma or thymic carcinoma. Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin inhibitors may contribute to disease control and octreotide scan is only applicable to somatostatin analogues. Although the genomic characteristics of thymic malignancies have been analyzed, few actionable mutations have been detected in general. The development of a treatment strategy using combination pharmacotherapy is anticipated.

An autopsy case of idiopathic pulmonary fibrosis with remarkable honeycomb cyst expansion.

Herein, we report an autopsy case of idiopathic pulmonary fibrosis (IPF) in which remarkable honeycomb cyst expansion appeared in the clinical course. Radiological findings initially showed subpleural predominant reticulation that had progressed to usual interstitial pneumonia with honeycomb cysts, along with a restrictive pattern in the pulmonary function tests. The diameter of honeycomb cysts had gradually increased, and some cysts had abruptly expanded at the end stage. Based on pathological findings of autopsy specimens, bronchiectasis, alveolar collapse due to inflammation, and check-valve mechanism caused by a slit-like orifice of the cysts could have contributed to honeycomb cyst expansion.

1H, 13C and 15N resonance assignments and solution structures of the two RRM domains of Matrin-3.

Matrin-3 is a multifunctional protein that binds to both DNA and RNA. Its DNA-binding activity is linked to the formation of the nuclear matrix and transcriptional regulation, while its RNA-binding activity is linked to mRNA metabolism including splicing, transport, stabilization, and degradation. Correspondingly, Matrin-3 has two zinc finger domains for DNA binding and two consecutive RNA recognition motif (RRM) domains for RNA binding. Matrin-3 has been reported to cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) when its disordered region contains pathogenic mutations. Simultaneously, it has been shown that the RNA-binding activity of Matrin-3 mediated by its RRM domains, affects the formation of insoluble cytoplasmic granules, which are related to the pathogenic mechanism of ALS/FTD. Thus, the effect of the RRM domains on the phase separation of condensed protein/RNA mixtures has to be clarified for a comprehensive understanding of ALS/FTD. Here, we report the 1H, 15N, and 13C resonance assignments of the two RNA binding domains and their solution structures. The resonance assignments and the solution structures obtained in this work will contribute to the elucidation of the molecular basis of Matrin-3 in the pathogenic mechanism of ALS and/or FTD.

Drug-induced hypersensitivity syndrome caused by minodronic acid hydrate.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an important adverse reaction caused by a few drugs. Reactivation of human herpesvirus 6 (HHV-6) is known to be associated with its pathogenesis. DIHS occasionally manifests as pulmonary lesions with a variety of imaging findings. CASE PRESENTATION: An 83-year-old woman started taking minodronic acid hydrate 5 years before admission. She noticed a generalized skin rash 44 days before admission and started oral betamethasone-d-chlorpheniramine maleate combination tablets for allergic dermatitis. She developed a fever and cough in addition to the rash, and was referred to our hospital. Laboratory data showed a high level of eosinophils and liver and biliary enzymes. Computed tomography (CT) studies revealed bilateral diffuse ground-glass opacities with ill-defined centrilobular nodules from the central to peripheral regions of the lungs. Transbronchial lung cryobiopsy specimens showed that lymphocyte infiltration was observed in the alveolar walls and fibrinous exudates and floating macrophages in the alveolar lumina. Immunohistochemistry of biopsy specimens showed more CD4+ lymphocytes than CD8+ lymphocytes, while few Foxp3+ lymphocytes were recognized. The serum anti-HHV-6 immunoglobulin G titer increased at 3 weeks after the first test. Based on these findings, we diagnosed her with DIHS. We continued care without using corticosteroids since there was no worsening of breathing or skin condition. Eventually, her clinical symptoms chest CT had improved. Minodronic acid hydrate was identified as the culprit drug based on the positive results of the patch test and drug-induced lymphocyte stimulation test. CONCLUSIONS: We described the first case of DIHS caused by minodronic acid hydrate. Lung lesions in DIHS can present with bilateral diffuse ground-glass opacities and ill-defined centrilobular nodules on a CT scan during the recovery phase. Clinicians should be aware of DIHS, even if patients are not involved with typical DIHS/DRESS-causing drugs.

Predictive model for the development of critical coronavirus disease 2019 and its risk factors among patients in Japan.

BACKGROUND: This study aimed to examine risk factors associated with critical coronavirus disease 19 (COVID-19) and to establish a risk predictive model for Japanese patients. METHODS: We retrospectively assessed adult Japanese patients diagnosed with COVID-19 at the Japanese Red Cross Medical Center, Tokyo, Japan between February 1, 2020 and March 10, 2021. The patients were divided into critical and non-critical groups based on their condition during the clinical courses. Univariate and multivariate logistic regression analyses were performed to investigate the relationship between clinical characteristics and critical illness. Based on the results, we established a predictive model for the development of critical COVID-19. RESULTS: In total, 300 patients were enrolled in this study. Among them, 86 were included in the critical group. Analyses revealed that age ≥65 y, hemodialysis, need for O2 supplementation upon diagnosis, and an initial serum C-reactive protein level of ≥6.5 mg/dL were independently associated with the development of critical COVID-19. Next, a predictive model for the development of critical COVID-19 was created, and this included the following variables: age ≥65 y, male sex, diabetes, hemodialysis, need for O2 supplementation upon diagnosis, and an initial serum C-reactive protein level of ≥6.5 mg/dL. The area under the receiver operating characteristic curve of the model was 0.86 (95% confidence interval, 0.81-0.90). Using a cutoff score of 12, the positive and negative predictive values of 74.0% and 80.4% were obtained, respectively. CONCLUSIONS: Upon diagnosis, the predictive model can be used to identify adult Japanese patients with COVID-19 who will require intensive treatment.

Clinical impact of combination therapy with baricitinib, remdesivir, and dexamethasone in patients with severe COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide and is also an important disease in Japan. Thus, the optimal treatment strategy for severe COVID-19 should be established urgently. The effects of combination treatment with baricitinib-a Janus kinase inhibitor, remdesivir, and dexamethasone (BRD) are unknown. METHODS: Patients who received combination therapy with BRD at the Japanese Red Cross Medical Center were enrolled in the study. All patients received baricitinib (≤14 d), remdesivir (≤10 d), and dexamethasone (≤10 d). The efficacy and adverse events were evaluated. RESULTS: In total, 44 patients with severe COVID-19 were enrolled in this study. The 28-d mortality rate was low at 2.3% (1/44 patients). The need for invasive mechanical ventilation was avoided in most patients (90%, 17/19 patients). Patients who received BRD therapy had a median hospitalization duration of 11 d, time to recovery of 9 d, duration of intensive care unit stay of 6 d, duration of invasive mechanical ventilation of 5 d, and duration of supplemental oxygen therapy of 5 d. Adverse events occurred in 15 patients (34%). Liver dysfunction, thrombosis, iliopsoas hematoma, renal dysfunction, ventilator-associated pneumonia, infective endocarditis, and herpes zoster occurred in 11%, 11%, 2%, 2%, 2%, 2%, and 2% of patients, respectively. CONCLUSIONS: Combination therapy with BRD was effective in treating severe COVID-19, and the incidence rate of adverse events was low. The results of the present study are encouraging; however, further randomized clinical studies are needed.

Spontaneous Muscle Hematoma in Japanese Patients with Severe COVID-19 Treated with Unfractionated Heparin: Two Case Reports.

In hospitalized coronavirus disease 2019 (COVID-19) patients, anticoagulation therapy is administered to prevent thrombosis. However, anticoagulation sometimes causes bleeding complications. We herein report two Japanese cases of severe COVID-19 in which spontaneous muscle hematomas (SMH) developed under therapeutic anticoagulation with unfractionated heparin. Although the activated partial prothrombin time was within the optimal range, contrast-enhanced computed tomography (CECT) revealed SMH in the bilateral iliopsoas muscles in both cases, which required emergent transcatheter embolization. Close monitoring of the coagulation system and the early diagnosis of bleeding complications through CECT are needed in severe COVID-19 patients treated with anticoagulants.

A case of pulmonary sclerosing pneumocytoma diagnosed preoperatively using transbronchial cryobiopsy.

BACKGROUND: The preoperative diagnosis of pulmonary sclerosing pneumocytoma (PSP) is complicated since PSP has several histological structural patterns in the same neoplasm; hence, it is sometimes pathologically misdiagnosed as adenocarcinoma or carcinoid. In recent years, with the prevalence of transbronchial cryobiopsy (TBLC), we are able to obtain larger specimens than previously. However, to date, there have been no reports describing PSP diagnosed using TBLC. CASE REPORTS: A 43-year-old man was referred to our hospital for an abnormal lesion in the left lung discovered on routine health examination. A computed tomography scan of the chest revealed a 14-mm heterogeneous round nodule with surrounding ground-glass opacity in the left lower lobe. The tumor size increased to 18 mm in three weeks, and he developed bloody sputum. TBLC was performed using radial endobronchial ultrasonography and fluoroscopy. An occlusion balloon and prophylactic epinephrine were used to prevent severe bleeding. Histologically, epithelioid cells with solid proliferation, various papillary lesions, and hemosiderin-laden histiocytes were observed. Immunohistochemical staining revealed the histiocytes positive for thyroid transcription factor-1 and vimentin, and the type II pneumocyte-like-cells positive for cytokeratin 7. The tumor was preoperatively diagnosed as a PSP; the patient underwent left basal segmentectomy and consequently, a final diagnosed of PSP was formulated. CONCLUSION: We report the first case of PSP preoperatively diagnosed using TBLC. Therefore, cryobiopsy could be beneficial in the preoperative diagnosis of PSP.

Side effects and antibody titer transition of the BNT162b2 messenger ribonucleic acid coronavirus disease 2019 vaccine in Japan.

BACKGROUND: The coronavirus disease (COVID-19) has afflicted large populations worldwide. Although vaccines aroused great expectations, their side effects on Japanese people and the antibody titer transition after vaccination are unclear. METHODS: The side effects of the BNT162b2 mRNA COVID-19 vaccine in participants who received vaccination at our center were investigated. Some participants were also surveyed for the antibody titer transition. RESULTS: In this study, 983 and 798 Japanese participants responded to the first and second doses, respectively. Side effects occurred in 757 (77.0%) and 715 participants (90.0%) after the first and second doses, respectively. No Grade 4 side effects occurred. The second dose had significantly more side effects than the first dose (p < 0.001). Side effects occurred after the second dose in 571 female (92.1%) and 178 male participants (80.1%). Female participants had a higher incidence of side effects than the male participants (p < 0.001). A comparison among the age groups showed significant differences (p = 0.018), and the frequency of side effects decreased with age. Twenty-three individuals participated in the survey of antibody titer transition. After the second vaccine dose, the median antibody titers for IgG and IgM were 3.76 and 0.07 AU/mL, respectively. Both IgG and IgM titers showed a significant increase over the study period (p < 0.001). CONCLUSIONS: The BNT162b2 mRNA COVID-19 vaccine might be safe for Japanese people, and the antibody titer increased with two doses of vaccination. Larger nationwide studies are warranted to verify these findings.

Utility of radial endobronchial ultrasonography combined with transbronchial lung cryobiopsy in patients with diffuse parenchymal lung diseases: a multicentre prospective study.

BACKGROUND: Radial endobronchial ultrasonography (R-EBUS) has been used in conjunction with transbronchial lung cryobiopsy (TBLC) to diagnose diffuse parenchymal lung disease (DPLD) and to decrease the risk of bleeding complications. The diagnostic utility of different R-EBUS signs, however, remains unknown. OBJECTIVES: This study aimed to determine whether different R-EBUS signs could be used to more accurately diagnose DPLD and whether bronchial bleeding could be prevented with use of R-EBUS during TBLC. METHOD: Eighty-seven patients with DPLD were included in this multicentre prospective study, with 49 patients undergoing R-EBUS. R-EBUS signals were characterised as displaying either dense or blizzard signs. Pathological confidence of specimens obtained from TBLC was compared between patients with dense versus blizzard signs, and severity of bronchial bleeding was determined based on whether R-EBUS was performed or not. RESULTS: All patients with dense signs on R-EBUS showed consolidation on high-resolution CT (HRCT) imaging. Pathological confidence of lung specimens was significantly higher in patients with dense signs versus those with blizzard signs (p<0.01) and versus those who did not undergo R-EBUS (p<0.05). Patients who underwent TBLC with R-EBUS were more likely to experience no or mild bronchial bleeding than patients who did not undergo R-EBUS (p<0.01), with shorter procedure times (p<0.01). CONCLUSIONS: The dense R-EBUS sign corresponded with consolidation on HRCT. High-quality lung specimens may be obtainable when the dense sign is observed on R-EBUS, and R-EBUS combined with TBLC may reduce risk of bronchial bleeding and shorten procedure times.