Galectin-10 in serum extracellular vesicles reflects asthma pathophysiology.

BACKGROUND: Novel biomarkers (BMs) are urgently needed for bronchial asthma (BA) with various phenotypes and endotypes. OBJECTIVE: We sought to identify novel BMs reflecting tissue pathology from serum extracellular vesicles (EVs). METHODS: We performed data-independent acquisition of serum EVs from 4 healthy controls, 4 noneosinophilic asthma (NEA) patients, and 4 eosinophilic asthma (EA) patients to identify novel BMs for BA. We confirmed EA-specific BMs via data-independent acquisition validation in 61 BA patients and 23 controls. To further validate these findings, we performed data-independent acquisition for 6 patients with chronic rhinosinusitis without nasal polyps and 7 patients with chronic rhinosinusitis with nasal polyps. RESULTS: We identified 3032 proteins, 23 of which exhibited differential expression in EA. Ingenuity pathway analysis revealed that protein signatures from each phenotype reflected disease characteristics. Validation revealed 5 EA-specific BMs, including galectin-10 (Gal10), eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and arachidonate 15-lipoxygenase. The potential of Gal10 in EVs was superior to that of eosinophils in terms of diagnostic capability and detection of airway obstruction. In rhinosinusitis patients, 1752 and 8413 proteins were identified from EVs and tissues, respectively. Among 11 BMs identified in EVs and tissues from patients with chronic rhinosinusitis with nasal polyps, 5 (including Gal10 and eosinophil peroxidase) showed significant correlations between EVs and tissues. Gal10 release from EVs was implicated in eosinophil extracellular trapped cell death in vitro and in vivo. CONCLUSION: Novel BMs such as Gal10 from serum EVs reflect disease pathophysiology in BA and may represent a new target for liquid biopsy approaches.

Single-cell multi-omics analysis identifies two distinct phenotypes of newly-onset microscopic polyangiitis.

The immunological basis of the clinical heterogeneity in autoimmune vasculitis remains poorly understood. In this study, we conduct single-cell transcriptome analyses on peripheral blood mononuclear cells (PBMCs) from newly-onset patients with microscopic polyangiitis (MPA). Increased proportions of activated CD14+ monocytes and CD14+ monocytes expressing interferon signature genes (ISGs) are distinctive features of MPA. Patient-specific analysis further classifies MPA into two groups. The MPA-MONO group is characterized by a high proportion of activated CD14+ monocytes, which persist before and after immunosuppressive therapy. These patients are clinically defined by increased monocyte ratio in the total PBMC count and have a high relapse rate. The MPA-IFN group is characterized by a high proportion of ISG+ CD14+ monocytes. These patients are clinically defined by high serum interferon-alpha concentrations and show good response to immunosuppressive therapy. Our findings identify the immunological phenotypes of MPA and provide clinical insights for personalized treatment and accurate prognostic prediction.

A randomized phase 2 study on demeclocycline in patients with mild-to-moderate COVID-19.

Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of demeclocycline in patients hospitalized with mild-to-moderate COVID-19 via an open-label, multicenter, parallel-group, randomized controlled phase 2 trial. Primary and secondary outcomes included changes from baseline (day 1, before the study treatment) in lymphocytes, cytokines, and SARS-CoV-2 RNA on day 8. Seven, seven, and six patients in the control, demeclocycline 150 mg daily, and demeclocycline 300 mg daily groups, respectively, were included in the modified intention-to-treat population that was followed until day 29. A significant change of 191.3/µL in the number of CD4+ T cells from day 1 to day 8 was observed in the demeclocycline 150 mg group (95% CI 5.1/µL-377.6/µL) (p = 0.023), whereas that in the control group was 47.8/µL (95% CI - 151.2/µL to 246.8/µL), which was not significant (p = 0.271). The change rates of CD4+ T cells negatively correlated with those of IL-6 in the demeclocycline-treated groups (R = - 0.807, p = 0.009). All treatment-emergent adverse events were of mild-to-moderate severity. The present results indicate that the treatment of mild-to-moderate COVID-19 patients with demeclocycline elicits immune responses conducive to recovery from COVID-19 with good tolerability.Trial registration: This study was registered with the Japan Registry of Clinical Trials (Trial registration number: jRCTs051200049; Date of the first registration: 26/08/2020).

A Case of Pharyngeal Stenosis Caused by Behçet's Disease Treated With Transoral Videolaryngoscopic Surgery.

Behçet's disease is a refractory inflammatory disease characterized by recurrent oral aphthous ulcers. Ulcers are commonly seen in the oral cavity and the pharyngeal region. In patients with recurrent pharyngeal ulcers, pharyngeal stenosis may occur and leads to dysphagia. Herein, we report a case of pharyngeal stenosis caused by recurrent ulcers due to incomplete Behçet's disease. Prednisolone, colchicine, and infliximab were administered and resolved the pharyngeal ulcers, however, dysphagia persisted. To improve the swallowing function, a pharyngeal dilation surgery and transoral videolaryngoscopic surgery were performed, which resulted in an enlarged pharyngeal cavity. Oral intake of water was initiated the day after surgery, and after six days, the patient was able to take a normal diet. The pharyngeal stenosis had not recurred for one year after the surgery, and a normal diet continued without any dietary restrictions. Therefore, in a case of a severe oropharyngeal lesion, periodic follow-up and surgical interventions by an otolaryngologist are necessary.

Persistence of SARS-CoV-2 neutralizing antibodies and anti-Omicron IgG induced by BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic disease: an explanatory study in Japan.

Background: Autoimmune inflammatory rheumatic disease (AIRD) patients are at high risk of the coronavirus disease 2019 (COVID-19), but the medium-term effects of immunosuppressants on vaccine efficacy are unknown. We investigated the duration of humoral responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type and Omicron variant in AIRD patients administered with two doses of the BNT162b2 (Pfizer-BioNTech) vaccine. Methods: Serum-neutralizing antibody (NAb) and anti-receptor-binding domain (RBD)/spike antibody levels were measured. Short- and medium-term effects of immunosuppressants were analyzed pre-vaccination (Term 1) and 14-42 days (Term 2) and 100-200 days (Term 3) after the second vaccination. Findings: From Feb 1, 2021, to Feb 28, 2022, 439 AIRD patients and 146 healthy controls were investigated. The seropositivity rate and log10-NAb titers were significantly lower in AIRD patients than in controls at Terms 2 and 3. In rheumatoid arthritis patients, tumor necrosis factor-α inhibitors (TNFis) at Term 3, and older age, glucocorticoids, and abatacept at Terms 2 and 3 were risk factors for reduced responses. Anti-Omicron RBD/spike IgG levels strongly correlated with NAb titers. Interpretation: Glucocorticoids, TNFis, and abatacept treatments negatively affect the longevity of humoral responses to SARS-CoV-2, including Omicron, after two vaccine doses. These findings may inform the timing of additional vaccination for AIRD patients. Funding: Cloud Funding of Peace Winds Japan; Center of Innovation Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Science KAKENHI; Japan Agency for Medical Research and Development; Kansai Economic Federation; Mitsubishi Zaidan; and Research Grant from Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology.

Next-generation proteomics of serum extracellular vesicles combined with single-cell RNA sequencing identifies MACROH2A1 associated with refractory COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is widespread; however, accurate predictors of refractory cases have not yet been established. Circulating extracellular vesicles, involved in many pathological processes, are ideal resources for biomarker exploration. METHODS: To identify potential serum biomarkers and examine the proteins associated with the pathogenesis of refractory COVID-19, we conducted high-coverage proteomics on serum extracellular vesicles collected from 12 patients with COVID-19 at different disease severity levels and 4 healthy controls. Furthermore, single-cell RNA sequencing of peripheral blood mononuclear cells collected from 10 patients with COVID-19 and 5 healthy controls was performed. RESULTS: Among the 3046 extracellular vesicle proteins that were identified, expression of MACROH2A1 was significantly elevated in refractory cases compared to non-refractory cases; moreover, its expression was increased according to disease severity. In single-cell RNA sequencing of peripheral blood mononuclear cells, the expression of MACROH2A1 was localized to monocytes and elevated in critical cases. Consistently, single-nucleus RNA sequencing of lung tissues revealed that MACROH2A1 was highly expressed in monocytes and macrophages and was significantly elevated in fatal COVID-19. Moreover, molecular network analysis showed that pathways such as "estrogen signaling pathway," "p160 steroid receptor coactivator (SRC) signaling pathway," and "transcriptional regulation by STAT" were enriched in the transcriptome of monocytes in the peripheral blood mononuclear cells and lungs, and they were also commonly enriched in extracellular vesicle proteomics. CONCLUSIONS: Our findings highlight that MACROH2A1 in extracellular vesicles is a potential biomarker of refractory COVID-19 and may reflect the pathogenesis of COVID-19 in monocytes.

Chronic Pulmonary Disease Caused by Tsukamurella toyonakaense.

Unidentified Mycobacterium species are sometimes detected in respiratory specimens. We identified a novel Tsukamurella species (Tsukamurella sp. TY48, RIMD 2001001, CIP 111916T), Tsukamurella toyonakaense, from a patient given a misdiagnosis of nontuberculous mycobacterial pulmonary disease caused by unidentified mycobacteria. Genomic identification of this Tsukamurella species helped clarify its clinical characteristics and epidemiology.

Longitudinal alterations of the gut mycobiota and microbiota on COVID-19 severity.

BACKGROUND: The impact of SARS-CoV-2 infection on the gut fungal (mycobiota) and bacterial (microbiota) communities has been elucidated individually. This study analyzed both gut mycobiota and microbiota and their correlation in the COVID-19 patients with severe and mild conditions and follow-up to monitor their alterations after recovery. METHODS: We analyzed the gut mycobiota and microbiota by bacterial 16S and fungal ITS1 metagenomic sequencing of 40 severe patients, 38 mild patients, and 30 healthy individuals and reanalyzed those of 10 patients with severe COVID-19 approximately 6 months after discharge. RESULTS: The mycobiota of the severe and mild groups showed lower diversity than the healthy group, and in some, characteristic patterns dominated by a single fungal species, Candida albicans, were detected. Lower microbial diversity in the severe group was observed, but no differences in its diversity or community structure were detected between the mild and healthy groups. The microbiota of the severe group was characterized by an increase in Enterococcus and Lactobacillus, and a decrease in Faecalibacterium and Bacteroides. The abundance of Candida was positively correlated with that of Enterococcus in patients with COVID-19. After the recovery of severe patients, alteration of the microbiota remained, but the mycobiota recovered its diversity comparable to that of mild and healthy groups. CONCLUSION: In mild cases, the microbiota is stable during SARS-CoV-2 infection, but in severe cases, alterations persist for 6 months after recovery.

Targeting GGT1 Eliminates the Tumor-Promoting Effect and Enhanced Immunosuppressive Function of Myeloid-Derived Suppressor Cells Caused by G-CSF.

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells that accumulate in tumor-bearing hosts. Since MDSCs suppress anti-tumor immunity and promote tumor progression, they are promising targets for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF) is an agent used for the treatment of chemotherapy-induced febrile neutropenia (FN) in patients with cancer. However, several reports have revealed that G-CSF plays crucial immune-related adverse roles in tumor progression through MDSCs. In this study, we showed that MDSCs differentiated in the presence of G-CSF in vitro exhibited enhanced proliferation and immunosuppressive activity compared to those differentiated without G-CSF. RNA sequencing analysis demonstrated that G-CSF enhanced the immunosuppressive function of MDSCs by upregulating gamma-glutamyltransferase (GGT) 1. Moreover, in the EL4 lymphoma-bearing neutropenic mouse model, administration of recombinant G-CSF increased the number of MDSCs and attenuated the anti-cancer effect of chemotherapy. We showed that the combination of GGsTop, a GGT inhibitor, could prevent G-CSF-induced tumor growth, without affecting the promotion of myelopoiesis by G-CSF. These results suggest that targeting GGT1 can mitigate G-CSF-induced enhanced immunosuppressive functions of MDSCs and can eliminate the tumor-promoting effect of G-CSF. Furthermore, GGsTop could be an attractive combination agent during G-CSF treatment for FN in patients with cancer.

The Diagnosis of Nontuberculous Mycobacterial Pulmonary Disease by Single Bacterial Isolation Plus Anti-GPL-Core IgA Antibody.

Although serum anti-glycopeptidolipid (GPL)-core IgA antibody is a highly specific test for infection with Mycobacterium avium complex (MAC), Mycobacterium abscessus, and its subspecies abscessus, subsp. massiliense, and subsp. bolletii (MAB), its use for the definitive diagnosis of MAC pulmonary disease (PD) and MAB-PD are unknown. To clarify the diagnostic accuracy of the anti-GPL-core IgA antibody test among patients with radiologically suspected MAC-PD or MAB-PD who already have a single positive sputum culture test. The first isolations of MAC and MAB from patients with radiologically suspected MAC-PD or MAB-PD at the Osaka Toneyama Medical Center between January 2006 and December 2020 were collected. Patients were enrolled when their serum anti-GPL-core IgA antibody was measured during the 3 months before and after the first isolation. We retrospectively compared the results of anti-GPL-core IgA antibody testing with the final diagnoses based on the current guidelines. We included 976 patients for analysis. The serum anti-GPL-core IgA antibody was positive in 699 patients (71.6%). The positive predictive value of anti-GPL-core IgA antibody for the diagnosis of MAC-PD or MAB-PD was 97.4%. The median time required for the second positive culture after the first isolation was 51 days (interquartile range 12 to 196 days). The positive serum anti-GPL-core IgA antibody test allowed an early and definitive diagnosis of MAC-PD or MAB-PD in those who already had a single positive sputum culture test. IMPORTANCE To satisfy the microbiologic criteria of the current diagnostic guideline for nontuberculous mycobacterial pulmonary disease (PD), at least two positive sputum cultures of the same species of mycobacteria from sputum are required to avoid the casual isolation of mycobacteria. This study showed that the positivity of a serum anti-glycopeptidolipid (GPL)-core IgA antibody test has an excellent diagnostic ability among patients with radiologically suspected Mycobacterium avium complex (MAC)-PD or Mycobacterium abscessus (MAB)-PD who already had a single positive sputum culture test. The usage of single culture isolation plus anti-GPL-core IgA antibody as another diagnostic criterion has a time, cost, and effort-saving effect. Furthermore, it will facilitate the diagnosis of MAC-PD or MAB-PD in the early stage of disease because serum anti-GPL-core IgA antibody becomes high in these patients. Therefore, we proposed adding single culture isolation plus anti-GPL-core IgA antibody as "combined microbiological and serological criteria" to the diagnostic guidelines for MAC-PD and MAB-PD.

Impact of bronchial wall thickness on airflow obstruction in bronchiectasis.

The association between airflow obstruction and bronchial dilation has been researched in bronchiectasis. However, the impact of bronchial wall thickening on airflow obstruction has not been thoroughly investigated. This study assessed the underlying mechanism of airflow obstruction in bronchiectasis due to abnormal bronchial wall thickening using oscillometry. A total of 98 patients with bronchiectasis were retrospectively reviewed. At the time of diagnosis, spirometric and oscillometric parameters, high-resolution computed tomography scores, and clinical characteristics were collected. The bronchial diameter, bronchial wall thickness, and extent of emphysema were evaluated semi-quantitatively. Correlations between patient data and characteristics were analyzed. Thirty-three patients with airflow obstruction showed higher respiratory resistance, more negative respiratory reactance (Xrs) at 5 Hz (X5), and higher bronchial wall thickness score than those without airflow obstruction. The bronchial wall thickness score negatively affected forced expiration volume in 1 s /forced vital capacity and X5. Abnormal bronchial wall thickening might make Xrs more negative and progress airflow obstruction in bronchiectasis.

Influence of one-wall remaining coronal tooth with resin abutment and fiber post on static and dynamic fracture resistance.

The objective of this study was to determine the influence of height and thickness of the one wall remaining coronal tooth structure on the fracture resistance of an endodontically treated root with resin abutment build-up using resin composite and fiber-reinforced resin composite post. Static and dynamic fracture tests were performed by placing the remaining tooth wall on the tensile side and applying loads at an angle of 30° from the tooth axis. Superior static fracture resistance was observed when the wall remaining on the tooth had a height and thickness greater than 1.0 mm. The dynamic fatigue test showed high loading capacity or fracture resistance in specimens with large height and thickness. The dynamic fatigue test showed the influence of the remaining tooth structure on fracture resistance clearly. In conclusion, the static and dynamic fracture resistances increased with the height and thickness of the one wall remaining tooth structure.

Pulmonary eosinophilia may indicate onset stage of allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) and chronic eosinophilic pneumonia (CEP) both display peripheral eosinophilia as well as pulmonary infiltration, together described as pulmonary eosinophilia, and differentiation is sometimes problematic. This study therefore examined the distinctions between ABPA with and without CEP-like shadows. METHODS: This retrospective cohort study from a single center included 25 outpatients (median age, 65 years) with ABPA diagnosed between April 2015 and March 2019, using criteria proposed by the International Society of Human and Animal Mycology (ISHAM), which focuses on positive specific IgE for Aspergillus fumigatus. Patients were assigned to either the eosinophilic pneumonia (EP) group or Non-EP group, defined according to findings on high-resolution computed tomography (HRCT). The EP group included patients with HRCT findings compatible with CEP; i.e., the presence of peripheral consolidation (p-consolidation) or ground-glass opacities (GGO), with no evidence of high-attenuation mucus. The Non-EP group comprised the remaining patients, who showed classical findings of ABPA such as mucoid impaction. Differences between the groups were analyzed. RESULTS: Baseline characteristics, frequency of a history of CEP (EP, 50% vs. Non-EP, 26%) and tentative diagnosis of CEP before diagnosis of ABPA (67% vs. 16%) did not differ significantly between groups. Although elevated absolute eosinophil count and Aspergillus-specific immunoglobulin E titers did not differ significantly between groups, the Non-EP group showed a strong positive correlation between these values (R = 0.7878, p = 0.0003). The Non-EP group displayed significantly higher levels of the fungal marker beta-D glucan (median, 11.7 pg/ml; interquartile range, 6.7-18.4 pg/ml) than the EP group (median, 6.6 pg/ml; interquartile range, 5.2-9.3 pg/ml). Both groups exhibited frequent recurrence of shadows on X-rays but no cases in the EP group had progressed to the Non-EP group at the time of relapse. CONCLUSIONS: The ABPA subgroup with imaging findings resembling CEP experienced frequent recurrences, as in typical ABPA. In pulmonary eosinophilia, even if there are no shadows indicating apparent mucous change, the Aspergillus-specific immunoglobulin E level is important in obtaining an accurate diagnosis and in the selection of appropriate therapies for this type of ABPA.

Corrigendum: Oxygen Extraction Based on Inspiratory and Expiratory Gas Analysis Identifies Ventilatory Inefficiency in Chronic Obstructive Pulmonary Disease.

[This corrects the article DOI: 10.3389/fphys.2021.703977.].

Oxygen Extraction Based on Inspiratory and Expiratory Gas Analysis Identifies Ventilatory Inefficiency in Chronic Obstructive Pulmonary Disease.

Aims: In contrast to cardiovascular disease, low rather than high ventilatory inefficiency, evaluated by the minute ventilation-carbon dioxide output (V'E-V'CO2)-slope, has been recognized as being related to greater disease severity in chronic obstructive pulmonary disease (COPD). To better care for patients with cardiopulmonary disease, understanding the physiological correlation between ventilatory inefficiency and exercise limitation is necessary, but remains inadequate. Given that oxygen uptake (V'O2) evaluated by cardiopulmonary exercise testing (CPET) depends on both the ventilatory capability and oxygen extraction, i.e., the difference between inspiratory and expiratory oxygen concentration (ΔFO2), the aim of this study was to investigate the correlations between V'E-V'CO2-slope and the ΔFO2 during exercise and their physiological implications in patients with COPD. Methods: A total of 156 COPD patients (mean age, 70.9 ± 7.2 years) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV and 16 controls underwent CPET with blood gas analysis. Results: With the progression of COPD, mechanical ventilatory constraints together with a slower respiratory frequency led to exertional respiratory acidosis. In GOLD IV cases, (1) decrease in the dependence of reduced peak V'O2 on V'E led to an increase in its dependence on peak ΔFO2 during exercise; and (2) the ΔFO2-V'CO2-slope became steeper, correlating with the severity of exertional respiratory acidosis (r = 0.6359, p < 0.0001). No significant differences in peak exercise ΔFO2 or V'E-V'CO2-slope were observed among the various GOLD stages. In all subjects, including controls, peak exercise ΔFO2 had the strongest correlation with the V'E-V'CO2-slope (r = -0.8835, p < 0.0001) and correlated well with body mass index (r = 0.3871, p < 0.0001), although it did not correlate with the heart rate-V'CO2-relationship and V'E. Conclusions: Ventilatory efficiency related to CO2 clearance might depend on exertional oxygen extraction in the body. Measuring ΔFO2 might be a key component for identifying ventilatory inefficiency and oxygen availability. Increasing ΔFO2 would help to improve ventilatory inefficiency and exercise tolerance separately from cardiac and ventilatory capability in COPD patients.

Serum GPL core antibody levels are associated with disease activity and treatment outcomes in Mycobacterium avium complex lung disease following first line antibiotic treatment.

BACKGROUND: No objective serum biomarkers of disease course or treatment outcome of Mycobacterium avium complex lung disease (MAC-LD) presently exist. Serum IgA antibody levels against the glycopeptidolipid (GPL) core have good diagnostic accuracy for MAC-LD. However, their usefulness for monitoring and predicting disease course and outcome of MAC-LD following first-line antibiotic treatment remains unclear. METHODS: We conducted a single-center retrospective cohort study to investigate the utility of serial measurements of GPL core IgA antibodies for monitoring disease course in 133 patients with MAC-LD following first-line antibiotic treatment. RESULTS: Patients were classified into treatment failure [n = 46 (34.6%)], recurrence [n = 19 (14.3%)], or treatment success [n = 68 (51.1%)] groups according to bacteriological outcomes after chemotherapy. Pretreatment serum anti-GPL core IgA levels in the treatment success group were similar to those in the treatment failure and recurrence groups (P = 0.6431 and P = 0.9045, respectively). In the treatment success group, serum anti-GPL core IgA levels were significantly and continuously reduced after initiating antibiotic treatment. No significant reductions in anti-GPL core IgA levels were observed in either the treatment failure or recurrence groups. Reduced levels of GPL core antibodies following antibiotic treatment correlated well with treatment outcomes (P = 0.0045). CONCLUSION: In this study, by performing serial measurements, we found that GPL core antibody levels were associated with disease activity and treatment outcomes in patients with MAC-LD. Time course analysis of anti-GPL core IgA levels clearly differentiated between patients who achieved treatment success and those who experienced treatment failure or disease recurrence.

Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD/emphysema) is a life-threatening disorder and there are few effective therapies. Cigarette smoke-induced oxidative stress, airway inflammation, and apoptosis of lung cells have been reported to be involved in the pathogenesis of COPD/emphysema and lead to alveolar septal destruction. Here we show that the expression level of FCH and double SH3 domains 1 (FCHSD1) was drastically increased in mice in response to elastase instillation, an experimental model of COPD. FCHSD1 is a member of the F-BAR family with two SH3 domains. We found that Fchsd1 knockout (Fchsd1-/-) mice were protected against airspace enlargement induced by elastase. Elastase-instilled lungs of Fchsd1-/- mice showed reduced inflammation and apoptosis compared with WT mice. We also found that elastase-induced reduction of Sirtuin 1 (SIRT1) levels, a histone deacetylase reported to protect against emphysema, was attenuated in the lungs of Fchsd1-/- mice. Furthermore, FCHSD1 deficiency enhanced nuclear translocation of nuclear factor-like 2 (NRF2), a redox-sensitive transcription factor, following H2O2 stimulation. Conversely, Fchsd1 overexpression inhibited NRF2 nuclear translocation and increased the reduction of SIRT1 levels. Notably, FCHSD1 interacted with NRF2 and SNX9. Our results show that FCHSD1 forms a multicomplex with NRF2 and SNX9 in the cytosol that prevents NRF2 from translocating to the nucleus. We propose that FCHSD1 promotes initiation of emphysema development by inhibiting nuclear translocation of NRF2, which leads to down-regulation of SIRT1.

Pleuroparenchymal fibroelastosis in Mycobacterium avium complex pulmonary disease: clinical characteristics and prognostic impact.

The association between Mycobacterium avium complex pulmonary disease (MAC-PD) and pleuroparenchymal fibroelastosis (PPFE) has been reported previously, and interstitial pneumonia as a comorbidity is associated with a worse prognosis. However, no study has thoroughly reported on PPFE associated with MAC-PD. The present study investigated the prevalence, clinical characteristics, and prognostic impact of PPFE in patients with MAC-PD. A total of 224 patients, newly diagnosed with MAC-PD, were retrospectively reviewed. At the time of diagnosis, chest high-resolution computed tomography (HRCT), sputum examination, and clinical characteristics were collected. The extent of PPFE and MAC-PD was evaluated semi-quantitatively using HRCT scores. Risk factor analysis for clinical or radiological deterioration necessitating multidrug antimicrobial treatment within 3 years, and all-cause mortality within 5 years, from the initial diagnosis was performed based on the PPFE score. PPFE was observed in 59 out of 224 patients (26.3%). A higher PPFE score was a risk factor for dyspnoea, fatigue, and lower body mass index (BMI) (p<0.05). Although PPFE score did not correlate with clinical or radiological deterioration within 3 years (p=0.576), a higher PPFE score (adjusted OR 1.66, 95% CI 1.06-2.60, p=0.028) and lower BMI (adjusted OR 0.61, 95% CI 0.39-0.94, p=0.028) increased the risk of 5-year mortality. PPFE is a relatively common complication and an independent poor prognostic factor of MAC-PD. This study highlights the need for further studies investigating whether the presence of PPFE can be a clinical indicator for initiating treatment of MAC-PD.

Oscillometry and computed tomography findings in patients with idiopathic pulmonary fibrosis.

Although the utility of oscillometry for predicting disease severity in idiopathic pulmonary fibrosis (IPF) had been researched, little has been reported on the mechanism of why respiratory impedance reflects disease severity. In addition, traction bronchiectasis has been considered to reduce respiratory resistance and correlate negatively with airflow obstruction, but this hypothesis has not been validated. The present study aimed to investigate the correlations between oscillometric parameters and fibrosis-related lung abnormalities in IPF and to assess the utility of oscillometry as a surrogate marker for traction bronchiectasis and airflow obstruction. Eighty Japanese patients with IPF underwent high-resolution computed tomography (HRCT), spirometry, and oscillometry and were retrospectively investigated. Fibrosis-related HRCT findings were scored regarding airspace consolidation, honeycombing, architectural distortion, traction bronchiectasis, and fibrosis. Correlations between the HRCT scores, spirometric parameters, and oscillometric parameters were analysed. Respiratory reactance correlated positively with all fibrosis-related HRCT scores. Vital capacity and forced vital capacity (FVC) correlated negatively with oscillometric parameters and HRCT scores, reflecting the severity of restrictive ventilatory deficiency. Respiratory resistance was not related to any of the HRCT scores or forced expiratory volume in 1 s/FVC. However, forced expiratory volume in 1 s/FVC correlated positively with HRCT scores, which showed that airflow obstruction became milder as the disease progressed. In conclusion, respiratory reactance reflects fibrosis and restrictive ventilatory deficiency in IPF. Moreover, respiratory resistance is independent of traction bronchiectasis and airflow obstruction in patients with IPF, which implies that respiratory resistance might reflect different properties of the airways.

Pulmonary disease caused by a newly identified mycobacterium: Mycolicibacterium toneyamachuris: a case report.

BACKGROUND: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient. CASE PRESENTATION: A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly. CONCLUSION: We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.