Ferroptosis contributes to airway epithelial E-cadherin disruption in a mixed granulocytic asthma mouse model.

Aberrant expression of airway epithelial E-cadherin is a key feature of asthma, yet the underlying mechanisms are largely unknown. Ferroptosis is a novel form of regulated cell death involved in asthma pathogenesis. This study was aimed to evaluate the role of ferroptosis and to investigate whether ferroptosis mediates E-cadherin disruption in mixed granulocyte asthma (MGA). Two murine models of MGA were established using toluene diisocyanate (TDI) or ovalbumin with Complete Freund's Adjuvant (OVA/CFA). Specific antagonists of ferroptosis, including Liproxstatin-1 (Lip-1) and Ferrostatin-1 (Fer-1) were given to the mice. The allergen-exposed mice displayed markedly shrunk mitochondria in the airway epithelia, with decreased volume and denser staining accompanied by down-regulated GPX4 as well as up-regulated FTH1 and malondialdehyde, which are markers of ferroptosis. Decreased pulmonary expression of E-cadherin was also observed, with profound loss of membrane E-cadherin in the airway epithelia, as well as increased secretion of sE-cadherin. Treatment with Lip-1 not only showed potent protective effects against the allergen-induced airway hyperresponsiveness and inflammatory responses, but also rescued airway epithelial E-cadherin expression and inhibited the release of sE-cadherin. Taken together, our data demonstrated that ferroptosis mediates airway epithelial E-cadherin dysfunction in MGA.

Soluble E-Cadherin Contributes to Airway Inflammation in Severe Asthma.

Impaired airway epithelial barrier and decreased expression of E-cadherin are key features of severe asthma. As a gatekeeper of the mucosa, E-cadherin can be cleaved from the cell surface and released into the apical lumen as a soluble form (sE-cadherin).This study was aimed to investigate the role of sE-cadherin in severe asthma.Induced sputum was obtained from healthy subjects and patients with asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). The role of sE-cadherin in severe asthma was evaluated by intraperitoneal injection of DECMA-1, a neutralizing antibody against sE-cadherin. Mice or THP-1-derived macrophages were treated with recombinant sE-cadherin to explore the pro-inflammatory mechanism of sE-cadherin.Severe asthma patients had a significantly higher sputum sE-cadherin level than the health subjects with mild to moderate asthma, which were positively correlated with sputum HMGB1 level and glucocorticoid dosage required for daily control. Allergen exposure markedly increased sE-cadherin level in the bronchoalveolar lavage fluid in mice. Treatment of DECMA-1 significantly attenuated allergen-induced airway inflammation and hyperresponsivenes in both models of severe asthma. While exposure to recombinant sE-cadherin dramatically up-regulated VEGF expression in THP-1-derived macrophages, and increased neutophlil and eosinophil infiltration into the airway as well as the release of VEGF and IL-6 in mice, both of which can be suppressed by pharmacological inhibition of ERK signaling.Taken together, our data indicated that sE-cadherin contributed to the airway inflammation of severe asthma in an ERK-depedent pathway.

Causal role of lipid metabolism in pulmonary alveolar proteinosis: an observational and mendelian randomisation study.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterised by the accumulation of lipoprotein material in the alveoli. Although dyslipidaemia is a prominet feature, the causal effect of lipid traits on PAP remains unclear. This study aimed to explore the role of lipid traits in PAP and evaluate the potential of lipid-lowering drug targets in PAP. METHODS: Clinical outcomes, lipid profiles and lung function tests were analysed in a clinical cohort of diagnosed PAP patients and propensity score-matched healthy controls. Genome-wide association study data on PAP, lipid metabolism, blood cells and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. FINDINGS: Observational results showed that higher levels of total cholesterol (TC), triglycerides and low-density lipoprotein (LDL) were associated with increased risks of PAP. Higher levels of TC and LDL were also associated with worse PAP severity. In MR analysis, elevated LDL was associated with an increased risk of PAP (OR: 4.32, 95% CI: 1.63 to 11.61, p=0.018). Elevated monocytes were associated with a lower risk of PAP (OR 0.34, 95% CI: 0.18 to 0.66, p=0.002) and mediated the risk impact of LDL on PAP. Genetic mimicry of PCSK9 inhibition was associated with a reduced risk of PAP (OR 0.03, p=0.007). INTERPRETATION: Our results support the crucial role of lipid and metabolism-related traits in PAP risk, emphasising the monocyte-mediated, causal effect of elevated LDL in PAP genetics. PCSK9 mediates the development of PAP by raising LDL. These finding provide evidence for lipid-related mechanisms and promising lipid-lowering drug target for PAP.

Ferroptosis mediates airway epithelial E-cadherin dysfunction in LPS-induced acute lung injury.

BACKGROUND: Loss of E-cadherin in the airway epithelial cells is a critical contributor to the development of ALI/ARDS. Yet the underlying mechanisms are largely unknown. Increasing evidences have revealed the significance of ferroptosis in the pathophysiological process of ALI/ARDS. The aim of this study was to investigate the role of ferroptosis in dysregulation of airway epithelial E-cadherin in ALI/ARDS. METHODS: BALB/c mice were subjected to intratracheal instillation of lipopolysaccharide (LPS) to establish an ALI model. Two inhibitors of ferroptosis, liproxstatin-1 (Lip-1, at the dose of 10 mg/kg and 30 mg/kg) and ferrostatin-1 (Fer-1, at the dose of 1 mg/kg and 5 mg/kg), were respectively given to the mice through intraperitoneal injection after LPS challenge. The expression of ferroptotic markers, full-length E-cadherin and soluble E-cadherin (sE-cadherin) were both detected. RESULTS: LPS exposure dramatically down-regulated pulmonary expression of E-cadherin in mice, with profound loss of membrane E-cadherin in the airway epithelial cells and increased secretion of sE-cadherin in the airway lumen. At the same time, we found that the mitochondrial of airway epithelial cells in LPS-exposed mice exhibited significant morphological alterations that are hallmark features of ferroptosis, with smaller volume and increased membrane density. Other makers of ferroptosis were also detected, including increased cytoplasmic levels of iron and lipid peroxidates (MDA), as well as decreased GPX4 expression. 30 mg/kg of Lip-1 not only showed potent protective effects against the LPS-induced injury, inflammation, edema of the lung in those mice, but also rescued airway epithelial E-cadherin expression and decreased the release of sE-cadherin through inhibiting ferroptosis. While no noticeable changes induced by LPS were observed in mice treated with Lip-1 at 10 mg/kg nor Fer-1 at 1 mg/kg or 5 mg/kg. CONCLUSIONS: Taken together, these data demonstrated that ferroptosis mediates airway epithelial E-cadherin dysfunction in LPS-induced ALI.

Impact of diabetes on COVID-19 and glucocorticoids on patients with COVID-19 and diabetes during the Omicron variant epidemic: a multicenter retrospective cohort study in South China.

BACKGROUND: To explore the impact of diabetes on the clinical features and prognosis of COVID-19 and assess the influence of glucocorticoid use on the prognosis of patients with COVID-19 and diabetes. METHODS: This retrospective multicenter cohort study included patients admitted between December 2022 and January 2023. The patients were grouped according to diabetes and glucocorticoid use. The primary outcome was in-hospital mortality. RESULTS: Among 400 patients with glucocorticoid data, 109 (27.3%) had diabetes. The inflammatory cytokines were higher in patients with diabetes, manifested by higher IL-6 (25.33 vs. 11.29 ng/L, p = 0.011), CRP (26.55 vs. 8.62 mg/L, p = 0.003), and PCT (0.07 vs. 0.04 ng/ml, p = 0.010), while CD4+ (319 vs. 506 /mL, p = 0.004) and CD8+ (141 vs. 261 /mL, p < 0.001) T lymphocytes were lower. The overall mortality rate of hospitalized COVID-19 patients with diabetes was 13.46%. The diabetic patients who received glucocorticoids vs. those who did not receive glucocorticoids had a similar mortality (15.00% vs. 11.39%, p = 0.591). CONCLUSIONS: Patients with COVID-19 and diabetes are more likely to experience hyperinflammatory response and T cell reduction, especially those with severe/critical disease. Glucocorticoid use was not associated with the prognosis of COVID-19 in patients with diabetes. Still, glucocorticoids should be used cautiously in diabetic patients with severe/critical COVID-19.

Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin.

Cross-species transmission of viruses from wildlife animal reservoirs poses a marked threat to human and animal health 1 . Bats have been recognized as one of the most important reservoirs for emerging viruses and the transmission of a coronavirus that originated in bats to humans via intermediate hosts was responsible for the high-impact emerging zoonosis, severe acute respiratory syndrome (SARS) 2-10 . Here we provide virological, epidemiological, evolutionary and experimental evidence that a novel HKU2-related bat coronavirus, swine acute diarrhoea syndrome coronavirus (SADS-CoV), is the aetiological agent that was responsible for a large-scale outbreak of fatal disease in pigs in China that has caused the death of 24,693 piglets across four farms. Notably, the outbreak began in Guangdong province in the vicinity of the origin of the SARS pandemic. Furthermore, we identified SADS-related CoVs with 96-98% sequence identity in 9.8% (58 out of 591) of anal swabs collected from bats in Guangdong province during 2013-2016, predominantly in horseshoe bats (Rhinolophus spp.) that are known reservoirs of SARS-related CoVs. We found that there were striking similarities between the SADS and SARS outbreaks in geographical, temporal, ecological and aetiological settings. This study highlights the importance of identifying coronavirus diversity and distribution in bats to mitigate future outbreaks that could threaten livestock, public health and economic growth.

Comparison of Effects of Sugammadex and Neostigmine on Postoperative Neuromuscular Blockade Recovery in Patients with Interstitial Lung Diseases Undergoing Transbronchial Cryobiopsy: A Randomized Trial.

BACKGROUND While many studies have been conducted on sugammadex sodium and neostigmine in patients undergoing general anesthesia, few have explored their effects in patients with interstitial lung diseases (ILDs). MATERIAL AND METHODS Sixty-three patients who underwent transbronchial cryobiopsy under general anesthesia were enrolled in a prospective randomized study. The patients were randomly divided into 2 groups: neostigmine combined with atropine group (group C, n=32) and sugammadex group (group S, n=31). Induction and maintenance of anesthesia were the same in both groups. Patients received rocuronium during anesthesia. At the end of the procedure, when the T2 of the train-of-four stimulation technique (TOF) monitoring appeared, neostigmine 0.04 mg/kg combined with atropine 0.02 mg/kg was injected intravenously in group C, and sodium sugammadex 2 mg/kg was injected intravenously in group S. Time from administration of muscle relaxant antagonist to recovery of TOF ratio (TOFr) to 0.9 and extubation time were recorded. The residual rate of neuromuscular blockade at 1, 3, 5, 7, and 10 min after extubation was calculated. RESULTS Compared to group C, group S had a significantly shorter recovery time of TOFr to 0.9 (4.0[2.0] min vs 14.0[11.0] min, P<0.001) and extubation time (4.0[3.0] min vs 11.0[7.0] min, P<0.001). The residual rate of neuromuscular blockade was remarkably lower in group S than in group C at 3, 5, and 7 min after extubation (3.2% vs 31%, 0% vs 25%, 0% vs 6%, P<0.05). CONCLUSIONS Sugammadex is more effective than neostigmine in reversing the muscle-relaxant effect of rocuronium bromide in patients with ILDs.

First in vivo Experiment with PulmValve Endobronchial Valve: Feasibility, Efficiency, and Safety.

INTRODUCTION: Endoscopic lung volume reduction with endobronchial valves has been widely recognized for treating hyperinflation in advanced chronic obstructive pulmonary disease and emphysema patients. The main challenges include the technical complexity of upper lobe implantation and the number of endobronchial valves required. These issues might be addressed by placing larger diameter valves in the lobar bronchus. This study evaluated the feasibility, efficiency, and safety of the new valve PulmValve (model PV-13) in porcine models. METHODS: Six PV-13 valves were bronchoscopically implanted into the caudal lobe bronchus of six healthy pigs. The procedure time, valve deployment, and removability were recorded. Follow-up examinations included blood tests, chest CT scans, and bronchoscopy at 30 min, 14 days, 28 days, and 84 days post-procedure, with necropsy and pathological evaluations after the final follow-up examination. RESULTS: The successful in vivo deployment and removal of PV-13 valves was established, with a median procedure time of 6.5 min. The distal lung volume reduction was evident at 30 min post-operation and was persistently monitored on day 84. No migration or malfunction of any PV-13 valves was detected, but a mild angle deviation was found in 3 cases. Coughing was observed in four pigs within the first 7 days and localized granulation tissue was observed in all pigs. No cases of pneumothorax, diffuse pneumonia, or hemoptysis were detected. CONCLUSIONS: In this study, we report the successful implantation and removal of a new valve PulmValve in a short operation time. Complete lobar atelectasis was induced without device migration, malfunction, or severe complications. Further studies are warranted to evaluate the long-term, sustained effects and potential benefits in human patients.

The Wound Healing of Autologous Regenerative Factor on Recurrent Benign Airway Stenosis: A Canine Experimental and Pilot Study.

INTRODUCTION: Benign airway stenosis (BAS) is a severe pathologic condition. Complex stenosis has a high recurrence rate and requires repeated bronchoscopic interventions for achieving optimal control, leading to recurrent BAS (RBAS) due to intraluminal granulation. METHODS: This study explored the potential of autologous regenerative factor (ARF) for treating RBAS using a post-intubation tracheal stenosis canine model. Bronchoscopic follow-ups were conducted, and RNA-seq analysis of airway tissue was performed. A clinical study was also initiated involving 17 patients with recurrent airway stenosis. RESULTS: In the animal model, ARF demonstrated significant effectiveness in preventing further collapse of the injured airway, maintaining airway patency and promoting tissue regeneration. RNA-seq results showed differential gene expression, signifying alterations in cellular components and signaling pathways. The clinical study found that ARF treatment was well-tolerated by patients with no severe adverse events requiring hospitalization. ARF treatment yielded a high response rate, especially for post-intubation tracheal stenosis and idiopathic tracheal stenosis patients. CONCLUSION: The study concludes that ARF presents a promising, effective, and less-invasive method for treating RBAS. ARF has shown potential in prolonging the intermittent period and reducing treatment failure in patients with recurrent tracheal stenosis by facilitating tracheal mucosal wound repair and ameliorating tracheal fibrosis. This novel approach could significantly impact future clinical applications.

Prevention of postoperative nausea and vomiting after orthognathic surgery: a scoping review.

INTRODUCTION: Postoperative nausea and vomiting (PONV) is one of the most common adverse events following orthognathic surgery. It's a distressing feeling for patients and continues to be the cause of postoperative complications such as bleeding, delayed healing, and wound infection. This scoping review aims to identify effective PONV prophylaxis strategies during orthognathic surgery that have emerged in the past 15 years. METHODS: We searched Pubmed, Cochrane Controlled Register of Trials, and Embase from 2008 to May 2023. Studies meeting the following criteria were eligible for inclusion: (1) recruited patients undergo any orthognathic surgery; (2) evaluated any pharmacologic or non-pharmacologic method to prevent PONV. Studies meeting the following criteria were excluded: (1) case series, review papers, or retrospective studies; (2) did not report our prespecified outcomes. RESULTS: Twenty-one studies were included in this review. Pharmacological methods for PONV prevention include ondansetron and dexamethasone (3 studies), peripheral nerve block technique (4 studies), dexmedetomidine (1 study), pregabalin (2 studies), nefopam (2 studies), remifentanil (1 study), propofol (2 studies), and penehyclidine (1 study). Non-pharmacologic methods include capsicum plaster (1 study), throat packs (2 studies) and gastric aspiration (2 studies). CONCLUSIONS: Based on current evidence, we conclude that prophylactic antiemetics like dexamethasone, ondansetron, and penehyclidine are the first defense against PONV. Multimodal analgesia with nerve block techniques and non-opioid analgesics should be considered due to their notable opioid-sparing and PONV preventive effect. For the non-pharmacological methods, throat packs are not recommended for routine use because of their poor effect and serious complications. More prospective RCTs are required to confirm whether gastric aspiration can prevent PONV effectively for patients undergoing orthognathic surgery.

HO-1 upregulation promotes mitophagy-dependent ferroptosis in PM2.5-exposed hippocampal neurons.

Fine particulate matter (PM2.5) has been extensively implicated in the pathogenesis of neurodevelopmental disorders, but the underlying mechanism remains unclear. Recent studies have revealed that PM2.5 plays a role in regulating iron metabolism and redox homeostasis in the brain, which is closely associated with ferroptosis. In this study, the role and underlying mechanism of ferroptosis in PM2.5-induced neurotoxicity were investigated in mice, primary hippocampal neurons, and HT22 cells. Our findings demonstrated that exposure to PM2.5 could induce abnormal behaviors, neuroinflammation, and neuronal loss in the hippocampus of mice. These effects may be attributed to ferroptosis induced by PM2.5 exposure in hippocampal neurons. RNA-seq analysis revealed that the upregulation of iron metabolism-related protein Heme Oxygenase 1 (HO-1) and the activation of mitophagy might play key roles in PM2.5-induced ferroptosis in HT22 cells. Subsequent in vitro experiments showed that PM2.5 exposure significantly upregulated HO-1 in primary hippocampal neurons and HT22 cells. Moreover, PM2.5 exposure activated mitophagy in HT22 cells, leading to the loss of mitochondrial membrane potential, alterations in the expression of autophagy-related proteins LC3, P62, and mTOR, as well as an increase in mitophagy-related protein PINK1 and PARKIN. As a heme-degradation enzyme, the upregulation of HO-1 promotes the release of excess iron, genetically inhibiting the upregulation of HO-1 in HT22 cells could prevent both PM2.5-induced mitophagy and ferroptosis. Furthermore, pharmacological inhibition of mitophagy in HT22 cells reduced levels of ferrous ions and lipid peroxides, thereby preventing ferroptosis. Collectively, this study demonstrates that HO-1 mediates PM2.5-induced mitophagy-dependent ferroptosis in hippocampal neurons, and inhibiting mitophagy or ferroptosis may be a key therapeutic target to ameliorate neurotoxicity following PM2.5 exposure.

N-Containing Porous Carbon-Based MnO Composites as Anode with High Capacity and Stability for Lithium-Ion Batteries.

MnO has attracted much attention as the anode for Li-ion batteries (LIBs) owing to its high specific capacity. However, the low conductivity limited its large application. An effective solution to solve this problem is carbon coating. Biomass carbon materials have aroused much interest for being low-cost and rich in functional groups and hetero atoms. This work designs porous N-containing MnO composites based on the chemical-activated tremella using a self-templated method. The tremella, after activation, could offer more active sites for carbon to coordinate with the Mn ions. And the as-prepared composites could also inherit the special porous nanostructures of the tremella, which is beneficial for Li+ transfer. Moreover, the pyrrolic/pyridinic N from the tremella can further improve the conductivity and the electrolyte wettability of the composites. Finally, the composites show a high reversible specific capacity of 1000 mAh g-1 with 98% capacity retention after 200 cycles at 100 mA g-1. They also displayed excellent long-cycle performance with 99% capacity retention (relative to the capacity second cycle) after long 1000 cycles under high current density, which is higher than in most reported transition metal oxide anodes. Above all, this study put forward an efficient and convenient strategy based on the low-cost biomass to construct N-containing porous composite anodes with a fast Li+ diffusion rate, high electronic conductivity, and outstanding structure stability.

Clinical Characteristics of Coronavirus Disease 2019 in China.

BACKGROUND: Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. METHODS: We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. RESULTS: The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. CONCLUSIONS: During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.).

Mechanical stretch promotes apoptosis and impedes ciliogenesis of primary human airway basal stem cells.

BACKGROUND: Airway basal stem cells (ABSCs) have self-renewal and differentiation abilities. Although an abnormal mechanical environment related to chronic airway disease (CAD) can cause ABSC dysfunction, it remains unclear how mechanical stretch regulates the behavior and structure of ABSCs. Here, we explored the effect of mechanical stretch on primary human ABSCs. METHODS: Primary human ABSCs were isolated from healthy volunteers. A Flexcell FX-5000 Tension system was used to mimic the pathological airway mechanical stretch conditions of patients with CAD. ABSCs were stretched for 12, 24, or 48 h with 20% elongation. We first performed bulk RNA sequencing to identify the most predominantly changed genes and pathways. Next, apoptosis of stretched ABSCs was detected with Annexin V-FITC/PI staining and a caspase 3 activity assay. Proliferation of stretched ABSCs was assessed by measuring MKI67 mRNA expression and cell cycle dynamics. Immunofluorescence and hematoxylin-eosin staining were used to demonstrate the differentiation state of ABSCs at the air-liquid interface. RESULTS: Compared with unstretched control cells, apoptosis and caspase 3 activation of ABSCs stretched for 48 h were significantly increased (p < 0.0001; p < 0.0001, respectively), and MKI67 mRNA levels were decreased (p < 0.0001). In addition, a significant increase in the G0/G1 population (20.2%, p < 0.001) and a significant decrease in S-phase cells (21.1%, p < 0.0001) were observed. The ratio of Krt5+ ABSCs was significantly higher (32.38% vs. 48.71%, p = 0.0037) following stretching, while the ratio of Ac-tub+ cells was significantly lower (37.64% vs. 21.29%, p < 0.001). Moreover, compared with the control, the expression of NKX2-1 was upregulated significantly after stretching (14.06% vs. 39.51%, p < 0.0001). RNA sequencing showed 285 differentially expressed genes, among which 140 were upregulated and 145 were downregulated, revealing that DDIAS, BIRC5, TGFBI, and NKX2-1 may be involved in the function of primary human ABSCs during mechanical stretch. There was no apparent difference between stretching ABSCs for 24 and 48 h compared with the control. CONCLUSIONS: Pathological stretching induces apoptosis of ABSCs, inhibits their proliferation, and disrupts cilia cell differentiation. These features may be related to abnormal regeneration and repair observed after airway epithelium injury in patients with CAD.

Virtual bronchoscopic navigation and endobronchial ultrasound with a guide sheath without fluoroscopy for diagnosing peripheral pulmonary lesions with a bronchus leading to or adjacent to the lesion: A randomized non-inferiority trial.

BACKGROUND AND OBJECTIVE: Transbronchial sampling of peripheral pulmonary lesions (PPLs) is routinely performed under fluoroscopy. However, advanced ancillary techniques have become available, such as virtual bronchoscopic navigation (VBN) and radial endobronchial ultrasound with a guide sheath (rEBUS-GS). This study was performed to determine whether the diagnostic utility of VBN and rEBUS with a GS is similar with or without fluoroscopy. METHODS: This multicenter non-inferiority trial randomized patients to a VBN-rEBUS-GS with or without fluoroscopy group at three centres. The primary endpoint was the diagnostic yield. The secondary endpoints were the time for rEBUS, GS, and the total operation. Complications were also recorded. RESULTS: Four hundred and ninety-six subjects were assessed and 426 subjects were included in the analysis (212 in non-fluoroscopy-guided-group and 214 in fluoroscopy-guided-group). The diagnostic yield in the non-fluoroscopy-guided-group (84.0%) was not inferior to that in the fluoroscopy-guided-group (84.6%), with a diagnostic difference of -0.6% (95% CI: -6.4%, 5.2%). Multivariable analysis confirmed that bronchus sign and lesion nature were valuable diagnostic predictors in non-fluoroscopy-guided-group. The non-fluoroscopy-guided-group had shorter rEBUS, GS, and total operation time. No severe complications occurred in either group. CONCLUSION: Transbronchial diagnosis of PPLs suspicious of malignancy and presence of a bronchus leading to or adjacent to lesions using VBN-rEBUS-GS without fluoroscopy is a safe and effective method that is non-inferior to VBN-rEBUS-GS with fluoroscopy. Bronchus leading to lesions and malignant nature are associated with high diagnostic yield in VBN-rEBUS-GS without fluoroscopy for the diagnosis of PPLs.

5G-Based Remote Virtual Bronchoscopic Navigation-Guided Transbronchial Lung Biopsy for Diagnosis of Lung Cancer: Description of 2 Cases.

INTRODUCTION: Bronchoscopic navigation combined with endobronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) is an important approach for the diagnosis of peripheral pulmonary lesions (PPL). The fifth-generation (5G) network, characterized by low latency and high stability, has shown promising possibilities in telemedicine for remote areas. METHODS: We present two cases of PPL in primary hospitals without navigation equipment. The EBUS-TBLB was performed with the guidance of remote augmented reality virtual bronchoscopic navigation (VBN) based on a 5G network. In practice, the 5G network could enable the matching of actual/virtual bronchoscopic images and navigation paths in real time, as well as high-speed transmission at long distances (>20 km), without any visual delay (<500 ms). CONCLUSION: Both patients were successfully diagnosed with lung cancer after accurate positioning and obtaining biopsies of target lesions. This 5G-based remote VBN-guided EBUS-TBLB appears to be safe with reliable connections in both cases and shows potential for cost-effectiveness. It would be an optimal resource for undeveloped regions and/or regions lacking endoscopists with extensive experience in navigation-related procedures.

The Novel Application of Robotic-Assisted Bronchoscopy Combined with Photodynamic Therapy for Adenoid Cystic Carcinoma of the Trachea.

Robotic platforms have been widely used in the various fields of clinical diagnosis and therapy of diseases in the past decade. Robotic-assisted bronchoscopy (RAB) demonstrates its advantages of visibility, flexibility, and stability in comparison to conventional bronchoscopic techniques. Improving diagnostic yield and navigation yield for peripheral pulmonary lesions has been defined; however, RAB platform of treatment was not reported. In this article, we report a case of a 52-year-old woman who was diagnosed with the tracheal adenoid cystic carcinoma and recurred in the second postoperative year, leading to the involvement of the entire tracheal wall and lumen obstruction. Since the lesion was inoperable, we combined RAB and photodynamic therapy (PDT) for the patient. The potential advantages of using RAB for PDT delivery include precise light irradiation of target lesions and stable intra-operative control over the long term. This is a novel application of RAB combined with PDT for airway diseases. The case report may provide a new insight into the diagnosis and treatment of pulmonary diseases. In addition to improving the diagnostic rates, the RAB platform may also play an important role in the treatment of airway and lung disease in the future.

Deep Learning-Based Segmentation of Airway Morphology from Endobronchial Optical Coherence Tomography.

BACKGROUND: Manual measurement of endobronchial optical coherence tomography (EB-OCT) images means a heavy workload in the clinical practice, which can also introduce bias if the subjective opinions of doctors are involved. OBJECTIVE: We aim to develop a convolutional neural network (CNN)-based EB-OCT image analysis algorithm to automatically identify and measure EB-OCT parameters of airway morphology. METHODS: The ResUNet, MultiResUNet, and Siamese network were used for analyzing airway inner area (Ai), airway wall area (Aw), airway wall area percentage (Aw%), and airway bifurcate segmentation obtained from EB-OCT imaging, respectively. The accuracy of the automatic segmentations was verified by comparing with manual measurements. RESULTS: Thirty-three patients who were diagnosed with asthma (n = 13), chronic obstructive pulmonary disease (COPD, n = 13), and normal airway (n = 7) were enrolled. EB-OCT was performed in RB9 segment (lateral basal segment of the right lower lobe), and a total of 17,820 OCT images were collected for CNN training, validation, and testing. After training, the Ai, Aw, and airway bifurcate were readily identified in both normal airway and airways of asthma and COPD. The ResUNet and the MultiResUNet resulted in a mean dice similarity coefficient of 0.97 and 0.95 for Ai and Aw segmentation. The accuracy Siamese network in identifying airway bifurcate was 96.6%. Bland-Altman analysis indicated there was a negligible bias between manual and CNN measurements for Ai (bias = -0.02 to 0.01, 95% CI = -0.12 to 0.14) and Aw% (bias = -0.06 to 0.12, 95% CI = -1.98 to 2.14). CONCLUSION: EB-OCT imaging in conjunction with ResUNet, MultiResUNet, and Siamese network could automatically measure normal and diseased airway structure with an accurate performance.

The Association Between Insulin Use and Asthma: An Epidemiological Observational Analysis and Mendelian Randomization Study.

BACKGROUND: Asthma is a common respiratory disease caused by genetic and environmental factors, but the contribution of insulin use to the risk of asthma remains unclear. This study aimed to investigate the association between insulin use and asthma in a large population-based cohort, and further explore their causal relationship by Mendelian randomization (MR) analysis. METHODS: An epidemiological study including 85,887 participants from the National Health and Nutrition Examination Survey (NHANES) 2001-2018 was performed to evaluate the association between insulin use and asthma. Based on the inverse-variance weighted approach, MR analysis were conducted to estimate the causal effect of insulin use on asthma from the UKB and FinnGen datasets, respectively. RESULTS: In the NHANES cohort, we found that insulin use was associated with an increased risk of asthma [odd ratio (OR) 1.38; 95% CI 1.16-1.64; p < 0.001]. For the MR analysis, we found a causal relationship between insulin use and a higher risk of asthma in both Finn (OR 1.10; p < 0.001) and UK Biobank cohorts (OR 1.18; p < 0.001). Meanwhile, there was no causal association between diabetes and asthma. After multivariable adjustment for diabetes in UKB cohort, the insulin use remained significantly associated with an increased risk of asthma (OR 1.17, p < 0.001). CONCLUSIONS: An association between insulin use and an increased risk of asthma was found via the real-world data from the NHANES. In addition, the current study identified a causal effect and provided a genetic evidence of insulin use and asthma. More studies are needed to elucidate the mechanisms underlying the association between insulin use and asthma.

Safety and efficacy of cryobiopsy for the diagnosis of lymphangioleiomyomatosis compared with forceps biopsy and surgical lung biopsy.

BACKGROUND: Transbronchial lung forceps biopsy (TBFB) is recommended before a surgical lung biopsy (SLB) when a definitive diagnosis of lymphangioleiomyomatosis (LAM) is required for patients without any additional confirmatory features. Transbronchial lung cryobiopsy (TBCB) has been suggested as replacement test in patients considered eligible to undergo SLB for the diagnosis of interstitial lung diseases. The efficacy and safety of TBCB were compared with that of TBFB and SLB in the diagnosis of LAM. METHODS: A retrospective analysis was conducted on 207 consecutive patients suspected with LAM in the First Affiliated Hospital of Guangzhou Medical University from 2005 to 2020. RESULTS: The difference in diagnostic rate of patients suspected with LAM between TBCB (20/30, 66.7%) and TBFB (70/106, 66.0%) groups was not significant (p = 0.949). One patient performed TBCB with negative pathological results could be diagnosed exclusively after SLB. LAM diagnosis was confirmed by surgical pathological findings in 3 TBFB-negative patients. More patients with minimal cystic profusion were diagnosed with LAM by TBCB (5/19, 26.3%) and SLB (11/39, 28.2%) than by TBFB (3/61, 4.9%) (TBCB vs TBFB: p = 0.04, SLB vs TBFB, p < 0.001). The difference between the severity of cystic lung disease in patients diagnosed with LAM through TBCB and SLB was not significant (p > 0.05). One pneumothorax, 8 mild bleeding and 1 moderate bleeding were observed in TBCB. One pneumothorax, 15 mild bleeding and 1 moderate bleeding occurred after TBFB. CONCLUSION: Compared to TBFB, TBCB is safe and effective in diagnosing LAM at a higher diagnostic rate in patients with minimal cystic profusion.