Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming.

Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. The increased astrocyte proliferation by hyperglycemia was reduced by Glut1 inhibitor BAY-876. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreERT2;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, and proinflammatory phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. In line with findings from mouse experiments, a high-glucose environment intensified the LPS-triggered production of proinflammatory molecules in primary astrocyte cultures. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.

Use of artificial intelligence in triaging of chest radiographs to reduce radiologists' workload.

OBJECTIVES: To evaluate whether deep learning-based detection algorithms (DLD)-based triaging can reduce outpatient chest radiograph interpretation workload while maintaining noninferior sensitivity. METHODS: This retrospective study included patients who underwent initial chest radiography at the outpatient clinic between June 1 and June 30, 2017. Readers interpreted radiographs with/without a commercially available DLD that detects nine radiologic findings (atelectasis, calcification, cardiomegaly, consolidation, fibrosis, nodules, pneumothorax, pleural effusion, and pneumoperitoneum). The reading order was determined in a randomized, crossover manner. The radiographs were classified into negative and positive examinations. In a 50% worklist reduction scenario, radiographs were sorted in descending order of probability scores: the lower half was regarded as negative exams, while the remaining were read with DLD by radiologists. The primary analysis evaluated noninferiority in sensitivity between radiologists reading all radiographs and simulating a 50% worklist reduction, with the inferiority margin of 5%. The specificities were compared using McNemar's test. RESULTS: The study included 1964 patients (median age [interquartile range], 55 years [40-67 years]). The sensitivity was 82.6% (195 of 236; 95% CI: 77.5%, 87.3%) when readers interpreted all chest radiographs without DLD and 83.5% (197 of 236; 95% CI: 78.8%, 88.1%) in the 50% worklist reduction scenario. The difference in sensitivity was 0.8% (95% CI: - 3.8%, 5.5%), establishing noninferiority of 50% worklist reduction (p = 0.01). The specificity increased from 86.7% (1498 of 1728) to 90.4% (1562 of 1728) (p < 0.001) with DLD-based triage. CONCLUSION: Deep learning-based triaging may substantially reduce workload without lowering sensitivity while improving specificity. CLINICAL RELEVANCE STATEMENT: Substantial workload reduction without lowering sensitivity was feasible using deep learning-based triaging of outpatient chest radiograph; however, the legal responsibility for incorrect diagnoses based on AI-standalone interpretation remains an issue that should be defined before clinical implementation. KEY POINTS: • A 50% workload reduction simulation using deep learning-based detection algorithm maintained noninferior sensitivity while improving specificity. • The CT recommendation rate significantly decreased in the disease-negative patients, whereas it slightly increased in the disease-positive group without statistical significance. • In the exploratory analysis, the noninferiority of sensitivity was maintained until 70% of the workload was reduced; the difference in sensitivity was 0%.

Evaluation of the synergistic impact of needle and forceps biopsy with electromagnetic navigation bronchoscopy: the CONFIDENT-ENB trial design.

BACKGROUND: Electromagnetic navigation bronchoscopy (ENB) is an emerging advanced imaging-guided bronchoscopy technique for diagnosing peripheral lung lesions. However, the selection strategy for the optimal biopsy device and whether adopting a multi-tool strategy increases the diagnostic yield remains undetermined. The CONFIDENT-ENB trial (NCT05110131) is a prospective randomized study on ENB, performed in a least-invasive setting. The primary aim is to evaluate whether a combination of needle aspiration and forceps biopsy improves the diagnostic performance, and assess the comparative diagnostic value and discordance of the two devices. METHODS: The trial will recruit 142 participants with lung lesions suspected of malignancy who are eligible for an elective ENB procedure under moderate sedation. Participants will undergo ENB-guided needle aspiration and forceps biopsy in a randomized order without the use of any complementary techniques. All participants will be followed up subsequently for up to 12 months to conclude the final diagnosis of the biopsied lesions. Primary outcomes include the diagnostic yield and sensitivity of each biopsy modality and the diagnostic yield of the combined modalities. DISCUSSION: The CONFIDENT-ENB trial will prospectively evaluate the synergistic effectiveness and comparative accuracy of ENB-guided needle aspiration and forceps biopsy in a least-invasive setting. The results are expected to improve our understanding of the optimal tool-selection strategy for ENB. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05110131). Prospectively registered on 5 November 2021.

Application of N Descriptors Proposed by the International Association for the Study of Lung Cancer in Clinical Staging.

Background Patients with N1 or N2 non-small cell lung cancer exhibit prognostic heterogeneity. To refine the current N staging system, new N stages were proposed by the International Association for the Study of Lung Cancer. However, those proposed new N stages have not been validated. Purpose To evaluate the prognostic performance of the proposed N descriptors for clinical staging. Materials and Methods Participants with non-small cell lung cancer without distant metastasis from January 2010 to December 2014 were retrospectively included. Each patient's clinical N (cN) stage was assigned to one of seven categories (cN0, cN1a, cN1b, cN2a1, cN2a2, cN2b, cN3). The 5-year overall survival rates were estimated with the Kaplan-Meier method. The adjusted hazard ratios (HRs) and their 95% CIs were estimated by using a multivariable Cox proportional hazard model. Ad hoc analyses according to lymph node (LN) size were performed. Results A total of 1271 patients (median age, 66 years; interquartile range, 59-73 years; 812 men) were included. The 5-year overall survival rates were 77.3%, 53.7%, 36.0%, 29.2%, 34.4%, 18.0%, and 12.4% for stages cN0, cN1a, cN1b, cN2a1, cN2a2, cN2b, and cN3, respectively. Patients with cN2b disease had a worse prognosis than patients with cN2a disease (HR, 1.53; 95% CI: 1.06, 2.22; P = .02). There was no prognostic difference between cN1b and cN1a (HR, 1.13; 95% CI: 0.61, 2.09; P = .71); however, there was a difference between cN1 subgroups when stratified by LN size (≥2 cm; HR, 2.26; 95% CI: 1.16, 4.44; P = .02). Within cN2a disease, there were no differences between cN2a1 and cN2a2 (HR, 0.98; 95% CI: 0.61, 1.56; P = .93) or between subgroups according to LN size (HR, 0.74; 95% CI: 0.40, 1.37; P = .34). Conclusion A survival difference was observed between single- and multistation involvement among cN2 disease. The number of involved lymph node stations in patients with cN1 disease and the presence of skip metastasis in patients with cN2 disease were not associated with survival differences. © RSNA, 2021 Online supplemental material is available for this article.

Interobserver variability in Lung CT Screening Reporting and Data System categorisation in subsolid nodule-enriched lung cancer screening CTs.

OBJECTIVES: To assess interobserver agreement in Lung CT Screening Reporting and Data System (Lung-RADS) categorisation in subsolid nodule-enriched low-dose screening CTs. METHODS: A retrospective review of low-dose screening CT reports from 2013 to 2017 using keyword searches for subsolid nodules identified 54 baseline CT scans. With an additional 108 negative screening CT scans, a total of 162 CT scans were categorised according to the Lung-RADS by two fellowship-trained thoracic radiologists in consensus. We randomly selected 20, 20, 10, and 10 scans from categories 1/2, 3, 4A, and 4B CT scans, respectively, to ensure balanced category representation. Five radiologists classified the 60 CT scans into Lung-RADS categories. The frequencies of concordance and minor and major discordance were calculated, with major discordance defined as at least 6 months of management discrepancy. We used Cohen's κ statistics to analyse reader agreement. RESULTS: An average of 60.3% (181 of 300) of all cases and 45.0% (90 of 200) of positive screens were correctly categorised. The minor and major discordance rates were 12.3% and 27.3% overall and 18.5% and 36.5% in positive screens, respectively. The concordance rate was significantly higher among experienced thoracic radiologists. Overall, the interobserver agreement was moderate (mean κ, 0.45; 95% confidence interval: 0.40-0.51). The proportion of part-solid risk-dominant nodules was significantly higher in cases with low rates of accurate categorisation. CONCLUSION: This retrospective study observed variable accuracy and moderate interobserver agreement in radiologist categorisation of subsolid nodules in screening CTs. This inconsistency may affect management recommendations for lung cancer screening. KEY POINTS: • Diagnostic performance for Lung-RADS categorisation is variable among radiologists with fair to moderate interobserver agreement in subsolid nodule-enriched CT scans. • Experienced thoracic radiologists showed more accurate and consistent Lung-RADS categorisation than radiology residents. • The relative abundance of part-solid nodules was a potential factor related to increased disagreement in Lung-RADS categorisation.

Accuracy and complications of percutaneous transthoracic needle lung biopsy for the diagnosis of malignancy in patients with idiopathic pulmonary fibrosis.

OBJECTIVES: To determine the accuracy of CT-guided percutaneous transthoracic needle lung biopsy (PTNB) for the diagnosis of malignancy and the associated complication rates in patients with idiopathic pulmonary fibrosis (IPF). METHODS: This retrospective study included 91 CT-guided PTNBs performed in 80 patients with IPF from April 2003 through December 2016. Data regarding patients, target lesions, procedures, complications, and pathological reports were collected, and the final diagnosis was made. The diagnostic accuracy, sensitivity, specificity, percentage of nondiagnostic results, and complication rates were determined. Multivariable logistic regression analyses were performed to identify risk factors for nondiagnostic results and major complications. RESULTS: Three biopsies (technical failure [n = 2] and undetermined final diagnosis [n = 1]) were excluded from the diagnostic accuracy calculation. The diagnostic accuracy, sensitivity, and specificity were 89% (78/88), 90% (62/69), and 84% (16/19), respectively. The percentage of nondiagnostic results was 34% (30/88). Lesion size ≤ 3 cm (odds ratio [OR], 8.8; 95% confidence interval [CI], 2.5-31.2; p = 0.001) and needle tip placement outside the target lesion (OR, 13.7; 95% CI, 1.4-132.2; p = 0.02) were risk factors for nondiagnostic results. The overall and major complication rates were 51% (46/91) and 12% (11/91), respectively. The presence of honeycombing along the path of the needle (OR, 11.2; 95% CI, 1.4-89.1; p = 0.02) was an independent risk factor for major complications. CONCLUSIONS: CT-guided PTNB shows a relatively reasonable accuracy in diagnosing malignancy in patients with IPF. The complication rate may be high, especially when the needle passes through honeycomb lesions. KEY POINTS: • In patients with idiopathic pulmonary fibrosis (IPF), CT-guided percutaneous transthoracic needle lung biopsy (PTNB) showed a relatively reasonable accuracy for the diagnosis of malignancy. • Target lesion size ≤ 3 cm and biopsy needle tip placement outside the target lesion were risk factors for nondiagnostic results of CT-guided PTNB. • The complication rate may be high, especially in cases where the biopsy needle passes through honeycomb lesions.

Effectiveness of radiologist training in improving reader agreement for Lung-RADS 4X categorization.

OBJECTIVES: To identify the agreement on Lung CT Screening Reporting and Data System 4X categorization between radiologists and an expert-adjudicated reference standard and to investigate whether training led to improvement of the agreement measures and diagnostic potential for lung cancer. METHODS: Category 4 nodules in the Korean Lung Cancer Screening Project were identified retrospectively, and each 4X nodule was matched with one 4A or 4B nodule. An expert panel re-evaluated the categories and determined the reference standard. Nineteen radiologists were asked to determine the presence of CT features of malignancy and 4X categorization for each nodule. A review was performed in two sessions, and training material was given after session 1. Agreement on 4X categorization between radiologists and the expert-adjudicated reference standard and agreement between radiologist-assessed 4X categorization and lung cancer diagnosis were evaluated. RESULTS: The 48 expert-adjudicated 4X nodules and 64 non-4X nodules were evenly distributed in each session. The proportion of category 4X decreased after training (56.4% ± 16.9% vs. 33.4% ± 8.0%; p < 0.001). Cohen's κ indicated poor agreement (0.39 ± 0.16) in session 1, but agreement improved in session 2 (0.47 ± 0.09; p = 0.03). The increase in agreement in session 2 was observed among inexperienced radiologists (p < 0.05), and experienced and inexperienced reviewers exhibited comparable agreement performance in session 2 (p > 0.05). All agreement measures between radiologist-assessed 4X categorization and lung cancer diagnosis increased in session 2 (p < 0.05). CONCLUSION: Radiologist training can improve reader agreement on 4X categorization, leading to enhanced diagnostic performance for lung cancer. KEY POINTS: • Agreement on 4X categorization between radiologists and an expert-adjudicated reference standard was initially poor, but improved significantly after training. • The mean proportion of 4X categorization by 19 radiologists decreased from 56.4% ± 16.9% in session 1 to 33.4% ± 8.0% in session 2. • All agreement measures between the 4X categorization and lung cancer diagnosis increased significantly in session 2, implying that appropriate training and guidance increased the diagnostic potential of category 4X.

Brefeldin A-sensitive ER-Golgi vesicle trafficking contributes to NLRP3-dependent caspase-1 activation.

Endoplasmic reticulum (ER)-Golgi vesicle trafficking plays a pivotal role in the conventional secretory pathway of many cytokines; however, the precise release mechanism of a major inflammasome mediator, IL-1ß, is not thought to follow the conventional ER-Golgi route and remains elusive. Here, we found that perturbation of ER-Golgi trafficking by brefeldin A (BFA) treatment attenuated nucleotide-binding oligomerization domain-like receptor family, pyrin-domain-containing 3 (NLRP3) inflammasome activation in mouse bone marrow-derived macrophages (BMDMs). BFA treatment inhibited NLRP3-mediated inflammasome assembly and caspase-1 activation but did not block IL-1ß secretion from BMDMs following BFA administration after NLRP3 inflammasome activation. Consistently, short-hairpin RNA-dependent knockdown of BFA-inhibited guanine nucleotide-exchange protein 1 (BIG1), a molecular target of BFA and an initiator of Golgi-specific vesicle trafficking, abolished NLRP3-dependent apoptosis-associated speck-like protein containing a caspase-recruitment domain oligomerization and caspase-1 activation in BMDMs. Similarly, knockdown of Golgi-specific BFA-resistance guanine nucleotide exchange factor 1, another target of BFA, clearly attenuated NLRP3-mediated caspase-1 activation in BMDMs. Mechanistically, inhibition of BIG1-mediated vesicle trafficking did not impair NLRP3-activating signal 2-promoted events, such as potassium efflux and mitochondrial rearrangement, but caused significant impairment of signal 1-triggered priming steps, including NF-κB-mediated pathways. These data suggest that BFA-targeted vesicle trafficking at the Golgi contributes to activation of the NLRP3 inflammasome signaling.-Hong, S., Hwang, I., Gim, E., Yang, J., Park, S., Yoon, S.-H., Lee, W.-W., Yu, J.-W. Brefeldin A-sensitive ER-Golgi vesicle trafficking contributes to NLRP3-dependent caspase-1 activation.

Fusion rate according to mixture ratio and volumes of bone graft in minimally invasive transforaminal lumbar interbody fusion: minimum 2-year follow-up.

OBJECTIVES: Hydroxyapatite (HA) is commonly used as bone substitute in clinical practices. However, only few studies have compared the relationship between the mixture ratio of bone graft in the actual clinical field and fusion rate according to bone graft volume. The study aimed to analyze the fusion rate according to the mixture ratio and the amount of bone graft in minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). METHODS: A total number of 88 subjects who completed a 2-year follow-up after MI-TLIF participated in this study. Subjects were divided into three groups: Group 1 with local autograft, Group II with a mixture of HA and autobone of over 50%, and Group III with a mixture of HA and autobone of less than 50%. Subjects were also grouped into two groups: Group A with a graft volume of less than 12 ml and Group B with more than 12 ml. The correlation of mixture ratio and the graft volume with fusion rate was analyzed. For clinical analysis, visual analogue scale for pain and Oswestry Disability Index were used. Bone integration was evaluated based on the classification methods described in the Burkus study. RESULTS: Fusion rates are increased according to the ratio of autograft in all groups: 90.9% in Group I, 87.8% in Group II, and 85.7% in Group III. However, there were no significant differences between groups (p = 0.22). The fusion rates significantly increased as the amount of bone graft increased to over 12 ml, showing 81.5% in Group A and 92.0% in Group B (p = 0.03). CONCLUSIONS: A high rate of fusion was achieved in MI-TLIF in graft volume of more than 12 ml. We therefore recommend at least 12 ml of bone graft volume for successful fusion.

Comparison of Clinical and Radiological Outcomes after Vertebroplasty and Balloon Kyphoplasty in the Treatment of Osteoporotic Vertebral Compression Fractures.

BACKGROUND: Vertebroplasty (VP) and balloon kyphoplasty (KP) are effective means with which to improve pain and function in osteoporotic vertebral compression fractures. However, the risk of complications after these procedures is poorly understood, with concerns regarding adjacent vertebral fractures. This study retrospectively investigated the clinical and radiological outcomes of these procedures. METHODS: A total of 115 patients who experienced their first vertebral fracture were treated with VP (N=63) or KP (N=52) at the Dankook University Hospital between January 2013 and December 2022. The clinical outcomes were evaluated using the visual analog scale (VAS) preoperative and at 1-year follow-up. Radiological comparisons were performed for kyphosis correction, vertebral height restoration, and postoperative cement leakage. RESULTS: KP was more effective than VP, especially for vertebral body height restoration and kyphotic angle reduction (P<0.05). However, the incidence of cement leakage, new adjacent vertebral fractures, and improvement in pain assessed by VAS did not differ statistically between the 2 groups (P>0.05). CONCLUSIONS: Considering that KP was performed on fractures with severe deformity, no differences were observed in the clinical outcomes and incidence of adjacent vertebral fractures compared Considering that KP was performed for fractures with severe deformity, there was no difference in clinical outcomes and incidence of adjacent vertebral fractures compared to VP. Improvements in radiological measurements were demonstrated. Therefore, KP may be a good treatment option for pain relief and long-term prognosis in patients with high-compressive-rate vertebral fractures.

Usefulness of longitudinal nodule-matching algorithm in computer-aided diagnosis of new pulmonary metastases on cancer surveillance CT scans.

Background: Detecting new pulmonary metastases by comparing serial computed tomography (CT) scans is crucial, but a repetitive and time-consuming task that burdens the radiologists' workload. This study aimed to evaluate the usefulness of a nodule-matching algorithm with deep learning-based computer-aided detection (DL-CAD) in diagnosing new pulmonary metastases on cancer surveillance CT scans. Methods: Among patients who underwent pulmonary metastasectomy between 2014 and 2018, 65 new pulmonary metastases missed by interpreting radiologists on cancer surveillance CT (Time 2) were identified after a retrospective comparison with the previous CT (Time 1). First, DL-CAD detected nodules in Time 1 and Time 2 CT images. All nodules detected at Time 2 were initially considered metastasis candidates. Second, the nodule-matching algorithm was used to assess the correlation between the nodules from the two CT scans and to classify the nodules at Time 2 as "new" or "pre-existing". Pre-existing nodules were excluded from metastasis candidates. We evaluated the performance of DL-CAD with the nodule-matching algorithm, based on its sensitivity, false-metastasis candidates per scan, and positive predictive value (PPV). Results: A total of 475 lesions were detected by DL-CAD at Time 2. Following a radiologist review, the lesions were categorized as metastases (n=54), benign nodules (n=392), and non-nodules (n=29). Upon comparison of nodules at Time 1 and 2 using the nodule-matching algorithm, all metastases were classified as new nodules without any matching errors. Out of 421 benign lesions, 202 (48.0%) were identified as pre-existing and subsequently excluded from the pool of metastasis candidates through the nodule-matching algorithm. As a result, false-metastasis candidates per CT scan decreased by 47.9% (from 7.1 to 3.7, P<0.001) and the PPV increased from 11.4% to 19.8% (P<0.001), while maintaining sensitivity. Conclusions: The nodule-matching algorithm improves the diagnostic performance of DL-CAD for new pulmonary metastases, by lowering the number of false-metastasis candidates without compromising sensitivity.

The Effect of Denosumab in Elderly Patients Regarding Bone Density and Fracture Risk.

BACKGROUND: With an aging population, the importance of treating and diagnosing osteoporosis is increasing. Osteoporosis, previously known as a resorptive change primarily related to endocrinological mechanisms, is also being approached as a phenomenon of senile change. Denosumab is gaining popularity among osteoporosis medications due to its ability to increase bone mineral density (BMD) and the economic benefit arising from the 6-month cycle. In line with previous literature, this study aimed to examine the BMD-augmenting effect of denosumab through which it reduces fracture risk in individuals aged over 80 years. METHODS: We reviewed patients who received denosumab between 2018 and 2022 with a minimum clinical observation period of 12 months. BMD was measured every 12 months, and patients were classified per their period of denosumab use. Fracture risk was evaluated using the fracture risk assessment tool (FRAX) and fracture incidence during the observation period were assessed. RESULTS: Among 155 patients, a significant increase in BMD was observed at 3 sites: the lumbar spine, femoral neck, and total hip (p<0.001, p<0.001, and p=0.001, respectively). The patients were divided according to the length of clinical follow-up they received, and similar results were found in all subgroups. Fracture risk assessment was performed using FRAX and the incidence of fracture events during follow-up. FRAX significantly decreased in all subgroups except those who received 24 months of follow-up (p=0.003, p=0.41, p=0.001 in the 12, 24, and ≥36 months groups, respectively). CONCLUSIONS: Denosumab use resulted in long-term BMD increase and reduced fracture risk in individuals aged 80 and above.

Change of Symptoms after Total Hip Arthroplasty in Patients with Hip-Spine Syndrome.

Purpose: Elderly patients with degenerative diseases undergo treatment for the hip and spine; these patients present with various symptoms. This study focused on patients with residual symptoms, predominantly pain, even after receiving treatment for their spinal lesions. Materials and Methods: Patients who underwent total hip arthroplasty (THA) between 2016 and 2022 at a single tertiary hospital were included in the study. Of the 417 patients who underwent primary THA, a retrospective review of 40 patients with previous lesions of the spine was conducted. Patients were stratified to two cohorts: Patients with symptoms related to the spine (Group A), and those with hip-related symptoms (Group B). Pre- and postoperative comparisons of groups A and B were performed. Results: Improvements in patients' symptoms were observed in groups A and B after THA. In Group A, the mean preoperative visual analog scale (VAS) score was 5.10±0.876, which showed a postoperative decrease to 2.70±1.767. In Group B, the mean preoperative VAS score was 5.10±1.539, which showed a postoperative decrease to 2.67±1.493. Conclusion: According to the findings, promising results were achieved with THA in treatment of debilitating diseases of the hip for both the prognosis of the disease, as well as the patients' symptoms. In addition, in some cases elderly patients with dual pathologies underwent treatment for spinal lesions without performance of any evaluation related to the hip. Thus, evaluation of a patient's hip must be performed and performance of THA in patients with symptoms even after treatment of spinal lesions is recommended.

Electromagnetic Navigation Bronchoscopy Versus Radial Endobronchial Ultrasound for Diagnosing Lung Cancer: A Propensity Score-Matched Analysis.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) and radial endobronchial ultrasound (R-EBUS) are advanced imaging-guided bronchoscopy techniques for diagnosing pulmonary lesions. This study aimed to determine the comparative diagnostic yield of sole ENB and R-EBUS under moderate sedation. METHODS: We investigated 288 patients who underwent sole ENB (n=157) or sole R-EBUS (n=131) under moderate sedation for pulmonary lesion biopsy between January 2017 and April 2022. After a 1:1 propensity score-matching to control for pre-procedural factors, the diagnostic yield, sensitivity for malignancy, and procedure-related complications between both techniques were compared. RESULTS: The matching resulted in 105 pairs/procedure for analyses with balanced clinical and radiological characteristics. The overall diagnostic yield was significantly higher for ENB than for R-EBUS (83.8% vs. 70.5%, p=0.021). ENB demonstrated a significantly higher diagnostic yield than R-EBUS among those with lesions>20mm in size (85.2% vs. 72.3%, p=0.034), radiologically solid lesions (86.7% vs. 72.7%, p=0.015), and lesions with a class 2 bronchus sign (91.2% vs. 72.3%, p=0.002), respectively. The sensitivity for malignancy was also higher for ENB than for R-EBUS (81.3% vs. 55.1%, p<0.001). After adjusting for clinical/radiological factors in the unmatched cohort, using ENB over R-EBUS was significantly associated with a higher diagnostic yield (odd ratio=3.45, 95% confidence interval=1.75-6.82). Complication rates for pneumothorax did not significantly differ between ENB and R-EBUS. CONCLUSION: ENB demonstrated a higher diagnostic yield than R-EBUS under moderate sedation for diagnosing pulmonary lesions, with similar and generally low complication rates. Our data indicate the superiority of ENB over R-EBUS in a least-invasive setting.

Volumetric analysis of pulmonary nodules: reducing the discrepancy between the diameter-based volume calculation and voxel-counting method.

Background: When assessing the volume of pulmonary nodules on computed tomography (CT) images, there is an inevitable discrepancy between values based on the diameter-based volume calculation and the voxel-counting method, which is derived from the Euclidean distance measurement method on pixel/voxel-based digital image. We aimed to evaluate the ability of a modified diameter measurement method to reduce the discrepancy, and we determined a conversion equation to equate volumes derived from different methods. Methods: Two different anthropomorphic phantoms with subsolid and solid nodules were repeatedly scanned under various settings. Nodules in CT images were detected and segmented using a fully automated algorithm and the volume was calculated using three methods: the voxel-counting method (Vvc ), diameter-based volume calculation (Vd ), and a modified diameter-based volume calculation (Vd+ 1), in which one pixel spacing was added to the diameters in the three axes (x-, y-, and z-axis). For each nodule, Vd and Vd +1 were compared to Vvc by computing the absolute percentage error (APE) as follows: APE =100 × (V - Vvc )/Vvc . Comparisons between APEd and APEd+1 according to CT parameter setting were performed using the Wilcoxon signed-rank test. The Jonckheere-Terpstra test was used to evaluate trends across the four different nodule sizes. Results: The deep learning-based computer-aided diagnosis (DL-CAD) successfully detected and segmented all nodules in a fully automatic manner. The APE was significantly less with Vd+1 than with Vd (Wilcoxon signed-rank test, P<0.05) regardless of CT parameters and nodule size. The APE median increased as the size of the nodule decreased. This trend was statistically significant (Jonckheere-Terpstra test, P<0.001) regardless of volume measurement method (diameter-based and modified diameter-based volume calculations). Conclusions: Our modified diameter-based volume calculation significantly reduces the discrepancy between the diameter-based volume calculation and voxel-counting method.

Therapeutic effect of NLRP3 inhibition on hearing loss induced by systemic inflammation in a CAPS-associated mouse model.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is an inherited autoinflammatory disease caused by a gain-of-function mutation in NLRP3. Although CAPS patients frequently suffer from sensorineural hearing loss, it remains unclear whether CAPS-associated mutation in NLRP3 is associated with the progression of hearing loss. METHODS: We generated a mice with conditional expression of CAPS-associated NLRP3 mutant (D301N) in cochlea-resident CX3CR1 macrophages and examined the susceptibility of CAPS mice to inflammation-mediated hearing loss in a local and systemic inflammation context. FINDINGS: Upon lipopolysaccharide (LPS) injection into middle ear cavity, NLRP3 mutant mice exhibited severe cochlear inflammation, inflammasome activation and hearing loss. However, this middle ear injection model induced a considerable hearing loss in control mice and inevitably caused an inflammation-independent hearing loss possibly due to ear tissue damages by injection procedure. Subsequently, we optimized a systemic LPS injection model, which induced a significant hearing loss in NLRP3 mutant mice but not in control mice. Peripheral inflammation induced by a repetitive low dose of LPS injection caused a blood-labyrinth barrier disruption, macrophage infiltration into cochlea and cochlear inflammasome activation in an NLRP3-dependent manner. Interestingly, both cochlea-infiltrating and -resident macrophages contribute to peripheral inflammation-mediated hearing loss of CAPS mice. Furthermore, NLRP3-specific inhibitor, MCC950, as well as an interleukin-1 receptor antagonist significantly alleviated systemic LPS-induced hearing loss and inflammatory phenotypes in NLRP3 mutant mice. INTERPRETATION: Our findings reveal that CAPS-associated NLRP3 mutation is critical for peripheral inflammation-induced hearing loss in our CAPS mice model, and an NLRP3-specific inhibitor can be used to treat inflammation-mediated sensorineural hearing loss. FUNDING: National Research Foundation of Korea Grant funded by the Korean Government and the Team Science Award of Yonsei University College of Medicine.

Neutrophils Facilitate Prolonged Inflammasome Response in the DAMP-Rich Inflammatory Milieu.

Aberrant inflammasome activation contributes to various chronic inflammatory diseases; however, pyroptosis of inflammasome-active cells promptly terminates local inflammasome response. Molecular mechanisms underlying prolonged inflammasome signaling thus require further elucidation. Here, we report that neutrophil-specific resistance to pyroptosis and NLRP3 desensitization can facilitate sustained inflammasome response and interleukin-1ß secretion. Unlike macrophages, inflammasome-activated neutrophils did not undergo pyroptosis, indicated by using in vitro cell-based assay and in vivo mouse model. Intriguingly, danger-associated molecular patterns (DAMP)-rich milieu in the inflammatory region significantly abrogated NLRP3-activating potential of macrophages, but not of neutrophils. This macrophage-specific NLRP3 desensitization was associated with DAMP-induced mitochondrial depolarization that was not observed in neutrophils due to a lack of SARM1 expression. Indeed, valinomycin-induced compulsory mitochondrial depolarization in neutrophils restored inflammasome-dependent cell death and ATP-induced NLRP3 desensitization in neutrophils. Alongside prolonged inflammasome-activating potential, neutrophils predominantly secreted interleukin-1ß rather than other proinflammatory cytokines upon NLRP3 stimulation. Furthermore, inflammasome-activated neutrophils did not trigger efferocytosis-mediated M2 macrophage polarization essential for the initiation of inflammation resolution. Taken together, our results indicate that neutrophils can prolong inflammasome response via mitochondria-dependent resistance to NLRP3 desensitization and function as major interleukin-1ß-secreting cells in DAMP-rich inflammatory region.

Antimicrobial Peptide LL-37 Drives Rosacea-Like Skin Inflammation in an NLRP3-Dependent Manner.

Rosacea is a chronic inflammatory skin disease characterized by immune response-dependent erythema and pustules. Although the precise etiology of rosacea remains elusive, its pathogenesis is reportedly associated with an increased level of antimicrobial peptide LL-37. However, molecular mechanisms underlying the progression of rosacea via LL-37 remain poorly understood. Here, we examined the potential role of LL-37 in rosacea-like skin inflammatory phenotypes at a molecular level. Our in vitro data demonstrated that LL-37 promotes NLRP3-mediated inflammasome activation in lipopolysaccharide-primed macrophages, indicated by the processing of caspase-1 and IL-1ß. LL-37 was internalized into the cytoplasm of macrophages through P2X7 receptor-mediated endocytosis. Intracellular LL-37 triggered the assembly and activation of NLRP3-ASC inflammasome complex by facilitating lysosomal destabilization. Consistent with these in vitro results, intradermal LL-37 administration induced in vivo caspase-1 activation and ASC speck formation in the skin of Nlrp3-expressing, but not in Nlrp3-deficient, mice. Intradermal injection of LL-37 elicited profound recruitment of inflammatory Gr1+ cells and subsequent skin inflammation. However, LL-37-induced rosacea-like skin inflammation was significantly abrogated in Nlrp3-deficient mice. Furthermore, an NLRP3-specific inhibitor, MCC950, markedly reduced LL-37-triggered rosacea-like phenotypes. Taken together, our findings clearly indicate that NLRP3 inflammasome activation plays a crucial role in LL-37-induced skin inflammation and rosacea pathogenesis.

The anterior translation of the humeral head leads to a decrease in the coracohumeral distance in subscapularis tear.

A total of 297 patients who classified as subscapularis (SC) tears through arthroscopic evaluation were retrospectively enrolled, and Fifty-seven patients with impingement syndrome were also enrolled as the control group for normal-population comparison. The coracohumeral distance (CHD) and humeral head anterior translation (HHAT) were measured on magnetic resonance imaging. Our study demonstrated that the anterior translation of the humeral head is related with a decrease in the coracohumeral distance in subscapularis tear. Although, correlation between radiologic parameters (coracohumeral distance and anterior translation of the humeral head) and severity of subscapularis tear was note detected. LEVEL OF EVIDENCE: Level IV, retrospective study.

Irreducible posterior fracture and dislocation of shoulder with massive rotator cuff tear due to incarceration of biceps tendon: A case report.

Acute traumatic posterior glenohumeral dislocation in association with a massive rotator cuff tear is rare. Moreover, only few cases with interposition of the long biceps head of the tendon has been described to prevent reduction in posterior dislocation of the shoulder. In addition, combined scapula fracture with posterior shoulder dislocation also extremely rare. We present a case of Irreducible posterior fracture and dislocation of shoulder with massive rotator cuff tear due to incarceration of biceps tendon. For the treatment arthroscopic in situ superior capsule reconstruction was performed using the long head of the biceps tendon with rotator cuff repair.