CT-derived vertebral bone mineral density is a useful biomarker to predict COVID-19 outcome.

The low vertebral bone computed tomography (CT) Hounsfield unit values measured on CT scans reflect low bone mineral density (BMD) and are known as diagnostic indicators for osteoporosis. The potential prognostic significance of low BMD defined by vertebral bone CT values for the coronavirus disease 2019 (COVID-19) remains unclear. This study aimed to assess the impact of BMD on the clinical outcome in Japanese patients with COVID-19 and evaluate the association between BMD and critical outcomes, such as high-flow nasal cannula, non-invasive and invasive positive pressure ventilation, extracorporeal membrane oxygenation, or death. We examined the effects of COVID-19 severity on the change of BMD over time. This multicenter retrospective cohort study enrolled 1132 inpatients with COVID-19 from the Japan COVID-19 Task Force database between February 2020 and September 2022. The bone CT values of the 4th, 7th, and 10th thoracic vertebrae were measured from chest CT images. The average of these values was defined as BMD. Furthermore, a comparative analysis was conducted between the BMD on admission and its value 3 months later. The low BMD group had a higher proportion of critical outcomes than did the high BMD group. In a subanalysis stratifying patients by epidemic wave according to onset time, critical outcomes were higher in the low BMD group in the 1st-4th waves. Multivariable logistic analysis of previously reported factors associated with COVID-19 severity revealed that low BMD, chronic kidney disease, and diabetes were independently associated with critical outcomes. At 3 months post-infection, patients with oxygen demand during hospitalization showed markedly decreased BMD than did those on admission. Low BMD in patients with COVID-19 may help predict severe disease after the disease onset. BMD may decrease over time in patients with severe COVID-19, and the impact on sequelae symptoms should be investigated in the future.

Investigation of predictors for in-hospital death or long-term hospitalization in community-acquired pneumonia with risk factors for aspiration.

Background: It is known that the mortality of pneumonia in patients with risk factors for aspiration is worse than that in those without these risk factors. However, it is still unknown which risk factors for aspiration predict prognosis. Therefore, we aimed to determine which risk factors for aspiration are associated with death or prolonged hospitalization. Methods: We prospectively followed patients with community-acquired pneumonia at a single hospital providing acute to chronic care in Japan until they died or were discharged. Patients at any risk of aspiration were included. The associations between pneumonia severity, individual risk factors for aspiration, and in-hospital death or prolonged hospitalization were investigated. Overall survival was estimated by the Kaplan - Meier method, and the factors associated with in-hospital death or prolonged hospitalization were investigated by multivariate analysis using factors selected by a stepwise method. Results: In total, 765 patients with pneumonia and risk factors for aspiration were recruited. One hundred and ten patients deceased, and 259 patients were hospitalized over 27 days. In-hospital death increased as the number of risk factors for aspiration increased. In the multivariate analysis, male, impaired consciousness, acidemia, elevated blood urea nitrogen, and bedridden status before the onset of pneumonia were associated with in-hospital death (odds ratio [OR]: 2.5, 2.5, 3.6, 3.1, and 2.6; 95% confidence interval [CI]: 1.6-4.1, 1.4-4.2, 1.6-8.0, 1.9-5.0, and 1.6-4.2 respectively). In the Cox regression analysis, these factors were also associated with in-hospital death. None of the vital signs at admission were associated. Tachycardia, elevated blood urea nitrogen, hyponatremia, and bedridden status were associated with hospitalization for >27 days (OR: 4.1, 2.3, 4.3, and 2.9; 95% CI: 1.3-12.9, 1.5-3.4, 2.0-9.4, and 2.0-4.0, respectively). Conclusions: Blood sampling findings and bedridden status are useful for predicting in-hospital mortality and long-term hospitalization in patients with pneumonia and any risk factor for aspiration.

Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells.

Alveolar type 2 (AT2) epithelial cells are tissue stem cells capable of differentiating into alveolar type 1 (AT1) cells for injury repair and maintenance of lung homeostasis. However, the factors involved in human AT2-to-AT1 cell differentiation are not fully understood. Here, we established SFTPCGFP and AGERmCherry-HiBiT dual-reporter induced pluripotent stem cells (iPSCs), which detected AT2-to-AT1 cell differentiation with high sensitivity and identified factors inducing AT1 cell differentiation from AT2 and their progenitor cells. We also established an "on-gel" alveolar epithelial spheroid culture suitable for medium-throughput screening. Among the 274 chemical compounds, several single compounds, including LATS-IN-1, converted AT1 cells from AT2 and their progenitor cells. Moreover, YAP/TAZ signaling activation and AKT signaling suppression synergistically recapitulated the induction of transcriptomic, morphological, and functionally mature AT1 cells. Our findings provide novel insights into human lung development and lung regenerative medicine.

Successful treatment of lung cancer coexisting with B­cell lymphoma with pembrolizumab following rituximab­included chemotherapy: A case report.

The combined occurrence of lung cancer and B-cell lymphoma, such as mucosa-associated lymphoid tissue (MALT) lymphoma, is rare. The efficacy and safety of immune checkpoint inhibitors (ICIs) remain unknown in this population of patients, and the occurrence of ICI-induced exacerbation of lymphoma is concerning. The present study describes a case of successful treatment with pembrolizumab following rituximab-containing chemotherapy for lung cancer complicated by MALT lymphoma. The patient was a 69-year-old woman diagnosed with MALT lymphoma based on a biopsy of stomach ulcerative lesions, and advanced lung cancer based on a biopsy of a lymph node in the left pulmonary hilum. Complete remission was achieved after one cycle of rituximab and bendamustine therapy for MALT lymphoma. Pembrolizumab monotherapy was subsequently initiated, resulting in a good response for lung cancer without recurrence or exacerbation of the lymphoma. In conclusion, the present study suggested that pembrolizumab, following rituximab-containing therapy, could be a treatment option for patients with lung cancer coexisting with MALT lymphoma.

Quantification of airway structures by persistent homology.

We propose two types of novel morphological metrics for quantifying the geometry of tubular structures on computed tomography (CT) images. We apply our metrics to identify irregularities in the airway of patients with chronic obstructive pulmonary disease (COPD) and demonstrate that they provide complementary information to the conventional metrics used to assess COPD, such as the tissue density distribution in lung parenchyma and the wall area ratio of the segmented airway. The three-dimensional shape of the airway and its abstraction as a rooted tree with the root at the trachea carina are automatically extracted from a lung CT volume, and the two metrics are computed based on a mathematical tool called persistent homology; treeH0 quantifies the distribution of branch lengths to assess the complexity of the tree-like structure and radialH0 quantifies the irregularities in the luminal radius along the airway. We show our metrics are associated with clinical outcomes.

Centrilobular emphysema and airway dysanapsis: factors associated with low respiratory function in younger smokers.

Background: Low respiratory function in young adulthood is one of the important factors in the trajectory leading to the future development of COPD, but its morphological characteristics are not well characterised. Methods: We retrospectively enrolled 172 subjects aged 40-49 years with ≥10 pack-years smoking history who underwent lung cancer screening by computed tomography (CT) and spirometry at two Japanese hospitals. Emphysema was visually assessed according to the Fleischner Society guidelines and classified into two types: centrilobular emphysema (CLE) and paraseptal emphysema (PSE). Airway dysanapsis was assessed with the airway/lung ratio (ALR), which was calculated by the geometric mean of the lumen diameters of the 14 branching segments divided by the cube root of total lung volume on a CT scan. Results: Among the subjects, CLE and PSE were observed in 20.9% and 30.8%, respectively. The mean ALR was 0.04 and did not differ between those with and without each type of emphysema. Multivariable regression analysis models adjusted for age, sex, body mass index and smoking status indicated that CLE and a low ALR were independently associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (estimate -1.64 (95% CI -2.68- -0.60) and 6.73 (95% CI 4.24-9.24), respectively) and FEV1 % pred (estimate -2.81 (95% CI -5.10- -0.52) and 10.9 (95% CI 5.36-16.4), respectively). Conclusions: CLE and airway dysanapsis on CT were independently associated with low respiratory function in younger smokers.

Sleep Restfulness in Patients with Obstructive Sleep Apnea Undergoing Continuous Positive Airway Pressure Therapy.

Objective Sleep restfulness is closely associated with mortality. Thus, it is an important sleep-related symptom in the general population. However, it is rarely evaluated in patients with obstructive sleep apnea (OSA) syndrome. The present study examined the importance of sleep restfulness in patients with OSA receiving continuous positive airway pressure (CPAP) therapy. Materials and Methods We administered sleep-related questionnaires, which included items such as subjective sleep duration and sleep restfulness, to 775 patients with OSA receiving CPAP therapy. Sleep restfulness was rated using a 5-point Likert-type scale, with the score of 5 indicating restfulness. Good adherence to CPAP therapy was defined as the use of CPAP therapy for at least 4 h per night in 70% of nights. Results We excluded 105 patients with lacking data. Thus, 670 patients were finally examined. In total, 29 (4.3%), 124 (18.5%), 139 (20.8%), 235 (35.1%), and 143 (14.3%) patients answered restless (1), somewhat restless (2), neither (3), somewhat restful (4), and restful (5) respectively. A total of 467 (69.7%) patients had good adherence to CPAP therapy. Multivariate logistic regression analysis showed that sleep restfulness was independently and positively associated with subjective sleep duration (≥ 7 hours) and good adherence to CPAP therapy. Conclusion Sleep restfulness was associated with subjective sleep duration and good adherence to CPAP therapy in patients with OSA. Favorable outcomes are significantly correlated with good adherence to CPAP therapy. Thus, sleep restfulness can be an indicator of a subtype that has favorable outcomes in patients after CPAP therapy.

Clinical phenotypes of nontuberculous mycobacterial disease by cluster analysis based on pulmonary function.

BACKGROUND: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often exhibits pulmonary function impairment, such as obstructive or restrictive pattern, with variation among patients according to the damaged lesions in the lung. METHODS: Patients with NTM-PD were consecutively enrolled between September 2019 and December 2020 at the Respiratory Infection Clinic of our hospital. Patients' data were comprehensively collected through laboratory examinations, PFT, chest computed tomography, and questionnaires for the assessment of subjective symptoms and health-related quality of life (HRQOL). Hierarchical cluster analysis was performed using PFT parameters to compare the clinical findings among clusters. RESULTS: Data of 104 patients were analyzed and classified into four clusters. The restrictive pattern with decreased forced expiratory volume in 1 s (FEV1) group showed high serum C-reactive protein and low albumin levels, severe radiological findings, and low HRQOL. In the restrictive pattern with preserved FEV1 group, HRQOL was as low as that in the restrictive pattern with decreased FEV1 group, and bacterial exacerbation was observed relatively frequently. HRQOL in the obstructive impairment group was maintained in comparison with that in the normal group. CONCLUSION: NTM-PD phenotypes were identified using cluster analysis based on PFT. Two different severe phenotypes were also observed. In the early stages of NTM-PD, PFT may be useful in recognizing disease progression.

Integrated assessment of computed tomography density in pectoralis and erector spinae muscles as a prognostic biomarker for coronavirus disease 2019.

BACKGROUND ＆ AIMS: Muscle quantification using chest computed tomography (CT) is a useful prognostic biomarker for coronavirus disease 2019 (COVID-19). However, no studies have evaluated the clinical course through comprehensive assessment of the pectoralis and erector spinae muscles. Therefore, we compared the impact of the areas and densities of these muscles on COVID-19 infection outcome. METHODS: This multicenter retrospective cohort study was conducted by the COVID-19 Task Force. A total of 1410 patients with COVID-19 were included, and data on the area and density of the pectoralis and erector spinae muscles on chest CT were collected. The impact of each muscle parameter on the clinical outcome of COVID-19 was stratified according to sex. The primary outcome was the percentage of patients with severe disease, including those requiring oxygen supplementation and those who died. Additionally, 167 patients were followed up for changes in muscle parameters at three months and for the clinical characteristics in case of reduced CT density. RESULTS: For both muscles, low density rather than muscle area was associated with COVID-19 severity. Regardless of sex, lower erector spinae muscle density was associated with more severe disease than pectoralis muscle density. The muscles were divided into two groups using the receiver operating characteristic curve of CT density, and the population was classified into four (Group A: high CT density for both muscles, Group B: low CT density for pectoralis and high for erector spinae muscle. Group C: high CT density for pectoralis and low for erector spinae muscle, Group D: low CT density for both muscles). In univariate analysis, Group D patients exhibited worse outcomes than Group A (OR: 2.96, 95% CI: 2.03-4.34 in men; OR: 3.02, 95% CI: 2.66-10.4 in women). Multivariate analysis revealed that men in Group D had a significantly more severe prognosis than those in Group A (OR: 1.82, 95% CI: 1.16-2.87). Moreover, Group D patients tended to have the highest incidence of other complications due to secondary infections and acute kidney injury during the clinical course. Longitudinal analysis of both muscle densities over three months revealed that patients with decreased muscle density over time were more likely to have severe cases than those who did not. CONCLUSIONS: Muscle density, rather than muscle area, predicts the clinical outcomes of COVID-19. Integrated assessment of pectoralis and erector spinae muscle densities demonstrated higher accuracy in predicting the clinical course of COVID-19 than individual assessments.

Dual-color live imaging unveils stepwise organization of multiple basal body arrays by cytoskeletons.

For mucociliary clearance of pathogens, tracheal multiciliated epithelial cells (MCCs) organize coordinated beating of cilia, which originate from basal bodies (BBs) with basal feet (BFs) on one side. To clarify the self-organizing mechanism of coordinated intracellular BB-arrays composed of a well-ordered BB-alignment and unidirectional BB-orientation, determined by the direction of BB to BF, we generated double transgenic mice with GFP-centrin2-labeled BBs and mRuby3-Cep128-labeled BFs for long-term, high-resolution, dual-color live-cell imaging in primary-cultured tracheal MCCs. At early timepoints of MCC differentiation, BB-orientation and BB-local alignment antecedently coordinated in an apical microtubule-dependent manner. Later during MCC differentiation, fluctuations in BB-orientation were restricted, and locally aligned BB-arrays were further coordinated to align across the entire cell (BB-global alignment), mainly in an apical intermediate-sized filament-lattice-dependent manner. Thus, the high coordination of the BB-array was established for efficient mucociliary clearance as the primary defense against pathogen infection, identifying apical cytoskeletons as potential therapeutic targets.

Associations of fractional exhaled nitric oxide with airway dimension and mucus plugs on ultra-high-resolution computed tomography in former smokers and nonsmokers with asthma.

BACKGROUND: Associations of fractional exhaled nitric oxide (FeNO) with airway wall remodeling and mucus plugs remain to be explored in smokers and nonsmokers with asthma. Ultra-high-resolution computed tomography (U-HRCT), which allows accurate structural quantification of airways >1 mm in diameter, was used in this study to examine whether higher FeNO was associated with thicker walls of the 3rd to 6th generation airways and mucus plugging in patients with asthma. METHODS: The retrospective analyses included consecutive former smokers and nonsmokers with asthma who underwent U-HRCT in a hospital. The ratio of wall area to summed lumen and wall area was calculated as the wall area percent (WA%). Mucus plugging was visually scored. RESULTS: Ninety-seven patients with asthma (including 59 former smokers) were classified into low (<20 ppb), middle (20-35 ppb), and high (>35 ppb) FeNO groups (n = 24, 26, and 47). In analysis including all patients and subanalysis including nonsmokers or former smokers, WA% in the 6th generation airways was consistently higher in the high FeNO group than in the low FeNO group, whereas WA% in the 3rd to 5th generation airways was not. In multivariable models, WA% in the 6th generation airways and the rate of mucus plugging were higher in the high FeNO group than in the low FeNO group after adjusting for age, sex, body mass index, smoking status, lung volume, and allergic rhinitis presence. CONCLUSIONS: Higher FeNO may reflect the inflammation and remodeling of relatively peripheral airways in asthma in both former smokers and nonsmokers.

Longitudinal changes in respiratory reactance in patients with COPD: associations with longitudinal change in air-trapping, exacerbations, and mortality.

INTRODUCTION: Air-trapping affects clinical outcomes in patients with chronic obstructive pulmonary disease (COPD) and may be detected by reactance at 5 Hz (X5) on respiratory oscillometry because X5 sensitively reflects the elasticity of the chest wall, airway and lung. However, the longitudinal association between X5 and air-trapping remains to be explored. This study aimed to test whether longitudinal changes in X5 could be associated with air-trapping progression, exacerbations, and mortality in patients with COPD. METHODS: In this prospective COPD observational study, the follow-up period consisted of the first 4 years to obtain longitudinal changes in X5 and residual volume (RV) and number of exacerbations and the remaining years (year 4 to 10) to test mortality. Patients were divided into large, middle, and small X5 decline groups based on the tertiles of longitudinal change in X5, and mortality after 4 years was compared between the groups. RESULTS: Patients with COPD (n = 114) were enrolled. The large X5 decline group (n = 38) showed a greater longitudinal change in RV and more exacerbations compared with the small X5 decline group (n = 39) in multivariable models adjusted for age, sex, body mass index, and smoking history. Long-term mortality after the 4-year follow-up was higher in the large X5 decline group than in the small X5 decline group (hazard ratio [95 % confidence interval] = 8.37[1.01, 69.0]) in the multivariable Cox proportional hazard model. CONCLUSION: Longitudinal changes in respiratory reactance could be associated with progressive air-trapping, exacerbation frequency, and increased mortality in patients with COPD.

Artificial intelligence-based analysis of the spatial distribution of abnormal computed tomography patterns in SARS-CoV-2 pneumonia: association with disease severity.

BACKGROUND: The substantial heterogeneity of clinical presentations in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia still requires robust chest computed tomography analysis to identify high-risk patients. While extension of ground-glass opacity and consolidation from peripheral to central lung fields on chest computed tomography (CT) might be associated with severely ill conditions, quantification of the central-peripheral distribution of ground glass opacity and consolidation in assessments of SARS-CoV-2 pneumonia remains unestablished. This study aimed to examine whether the central-peripheral distributions of ground glass opacity and consolidation were associated with severe outcomes in patients with SARS-CoV-2 pneumonia independent of the whole-lung extents of these abnormal shadows. METHODS: This multicenter retrospective cohort included hospitalized patients with SARS-CoV-2 pneumonia between January 2020 and August 2021. An artificial intelligence-based image analysis technology was used to segment abnormal shadows, including ground glass opacity and consolidation. The area ratio of ground glass opacity and consolidation to the whole lung (GGO%, CON%) and the ratio of ground glass opacity and consolidation areas in the central lungs to those in the peripheral lungs (GGO(C/P)) and (CON(C/P)) were automatically calculated. Severe outcome was defined as in-hospital death or requirement for endotracheal intubation. RESULTS: Of 512 enrolled patients, the severe outcome was observed in 77 patients. GGO% and CON% were higher in patients with severe outcomes than in those without. Multivariable logistic models showed that GGO(C/P), but not CON(C/P), was associated with the severe outcome independent of age, sex, comorbidities, GGO%, and CON%. CONCLUSION: In addition to GGO% and CON% in the whole lung, the higher the ratio of ground glass opacity in the central regions to that in the peripheral regions was, the more severe the outcomes in patients with SARS-CoV-2 pneumonia were. The proposed method might be useful to reproducibly quantify the extension of ground glass opacity from peripheral to central lungs and to estimate prognosis.

Aggregated eosinophils and neutrophils characterize the properties of mucus in chronic rhinosinusitis.

BACKGROUND: Airway obstruction caused by viscous mucus is an important pathophysiologic characteristic of persistent inflammation, which can result in organ damage. OBJECTIVE: We investigated the hypothesis that the biophysical characteristics of accumulating granulocytes affect the clinical properties of mucus. METHODS: Surgically acquired nasal mucus samples from patients with eosinophilic chronic rhinosinusitis and neutrophil-dominant, noneosinophilic chronic rhinosinusitis were evaluated in terms of computed tomography density, viscosity, water content, wettability, and protein composition. Isolated human eosinophils and neutrophils were stimulated to induce the formation of extracellular traps, followed by the formation of aggregates. The biophysical properties of the aggregated cells were also examined. RESULTS: Mucus from patients with eosinophilic chronic rhinosinusitis had significantly higher computed tomography density, viscosity, dry weight, and hydrophobicity compared to mucus from patients with noneosinophilic chronic rhinosinusitis. The levels of eosinophil-specific proteins in mucus correlated with its physical properties. Eosinophil and neutrophil aggregates showed physical and pathologic characteristics resembling those of mucus. Cotreatment with deoxyribonuclease and heparin, which slenderizes the structure of eosinophil extracellular traps, efficiently induced reductions in the viscosity and hydrophobicity of both eosinophil aggregates and eosinophilic mucus. CONCLUSIONS: The present study elucidated the pathogenesis of mucus stasis in infiltrated granulocyte aggregates from a novel perspective. These findings may contribute to the development of treatment strategies for eosinophilic airway diseases.

Associations between Nocturnal Hypoxemia and Retinal Nerve Fiber Layer Thinning: The Nagahama Study.

Rationale: There have been meta-analyses that showed reduced retinal nerve fiber layer (RNFL) thickness, which is a surrogate marker of glaucoma, in patients with obstructive sleep apnea (OSA). However, the sample sizes in these reports were small (<300), and the mechanism of RNFL thinning in patients with OSA was not revealed.Objectives: To investigate the relationship of RNFL thickness with nocturnal hypoxemia or hypoxemic burden in a large-scale study.Methods: In this epidemiological study, 8,309 community residents were enrolled. The actigraphy-modified 3% oxygen desaturation index (acti-ODI3%) and cumulative percentage of sleep time with oxygen saturation <90% (acti-CT90) modified by objective sleep duration using actigraphy were measured. The hypoxemic burden is shown as acti-CT90. Circumpapillary RNFL thickness was determined using optical coherence tomography.Results: Multivariable logistic analysis models revealed that an increase in acti-CT90 was significantly associated with mean RNFL thinning after adjusting for several factors in participants without glaucoma diagnosed or treated previously (ß = -0.037; P = 0.009). There were significant differences in mean RNFL thickness among participants stratified according to acti-CT90 (>1.5 vs. ⩽1.5; P = 0.04). Although acti-ODI3% was significantly associated with acti-CT90 (ß = 0.72; P < 0.0001), acti-ODI3% was not significantly associated with mean RNFL thickness in the multivariable logistic analysis (ß = -0.011; P = 0.48). In addition, acti-CT90 was significantly associated with mean RNFL thickness both in the elderly (⩾60 yr; ß = -0.058; P = 0.002) and nonelderly (<60 yr; ß = -0.054; P = 0.007).Conclusions: Acti-CT90, but not acti-ODI3%, was associated with mean RNFL thinning in participants irrespective of age in the elderly or nonelderly. Further prospective studies are required to investigate whether the prevention of hypoxic burden, which was shown as acti-CT90 in this study, is favorable for RNFL thinning.

A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1 (TM5614) in mild to moderate COVID-19.

An inhibitor of plasminogen activator inhibitor (PAI)-1, TM5614, inhibited thrombosis, inflammation, and fibrosis in several experimental mouse models. To evaluate the efficacy and safety of TM5614 in human COVID-19 pneumonia, phase IIa and IIb trials were conducted. In an open-label, single-arm trial, 26 Japanese COVID-19 patients with mild to moderate pneumonia were treated with 120-180 mg of TM5614 daily, and all were discharged without any notable side effects. Then, a randomized, double-blind, placebo-controlled trial was conducted in Japanese COVID-19 patients with mild to moderate pneumonia. The number of study participants was set to be 50 in each arm. Even after extension of the enrollment period, the number of study participants did not reach the initially intended sample size, and 75 patients were enrolled in the study. The total oxygenation scale from Day 1 to Day 14 as the primary endpoint was 1.5 in the TM5614 group vs 4.0 in the placebo group (p = 0.22), and the number of days of oxygen administration required as the secondary endpoint was 2.0 days in the TM5614 group vs 3.5 days in the placebo group (p = 0.34). Further studies will be necessary to verify the efficacy of PAI-1 inhibition for the treatment of COVID-19 pneumonia.Clinical trial registration: Two studies were conducted: a prospective, multicenter, open-label phase II study at https://jrct.niph.go.jp (jRCT2021200018) (First registration date 18/08/2020) and a prospective, multicenter, randomized, double-blind, placebo-controlled, phase II study at https://jrct.niph.go.jp (jRCT2021210006) (First registration date 28/05/2021).

Evaluation of elevated plasma fatty acids as relevant factors for adult-onset asthma: The Nagahama Study.

BACKGROUND: Obesity and increased body mass index (BMI) are the known risk factors for adult-onset asthma. Serum free fatty acid (FFA) and other blood lipid levels are generally elevated in patients with obesity and may be involved in the onset of asthma. However, it remains largely unknown. This study aimed to elucidate the relationship between plasma fatty acids and new-onset asthma. METHODS: This community-based Nagahama Study in Japan enrolled 9804 residents. We conducted self-reporting questionnaires, lung function tests, and blood tests at baseline and 5 years later as follow-up. At the follow-up, plasma fatty acids were measured using gas chromatography-mass spectrometry. Body composition analysis was also measured at the follow-up. The associations between fatty acids and new-onset asthma were evaluated using a multifaceted approach, including targeted partial least squares discriminant analysis (PLS-DA). RESULTS: In PLS-DA for new-onset asthma, palmitoleic acid was identified as the fatty acid most associated with asthma onset. In the multivariable analysis, higher levels of FFA, palmitoleic acid, or oleic acid were significantly associated with new-onset asthma, independent of other confounding factors. The high body fat percentage itself was not the relevant factor, but showed a positive interaction with plasma palmitoleic acid for new-onset asthma. When stratified by gender, the impacts of higher levels of FFA or palmitoleic acid on new-onset asthma remained significant in females, but not in males. CONCLUSIONS: Elevated levels of plasma fatty acids, particularly palmitoleic acid, may be a relevant factor for new-onset asthma.