Development of a modified 3D region proposal network for lung nodule detection in computed tomography scans: a secondary analysis of lung nodule datasets.

BACKGROUND: Low-dose computed tomography (LDCT) has been shown useful in early lung cancer detection. This study aimed to develop a novel deep learning model for detecting pulmonary nodules on chest LDCT images. METHODS: In this secondary analysis, three lung nodule datasets, including Lung Nodule Analysis 2016 (LUNA16), Lung Nodule Received Operation (LNOP), and Lung Nodule in Health Examination (LNHE), were used to train and test deep learning models. The 3D region proposal network (RPN) was modified via a series of pruning experiments for better predictive performance. The performance of each modified deep leaning model was evaluated based on sensitivity and competition performance metric (CPM). Furthermore, the performance of the modified 3D RPN trained on three datasets was evaluated by 10-fold cross validation. Temporal validation was conducted to assess the reliability of the modified 3D RPN for detecting lung nodules. RESULTS: The results of pruning experiments indicated that the modified 3D RPN composed of the Cross Stage Partial Network (CSPNet) approach to Residual Network (ResNet) Xt (CSP-ResNeXt) module, feature pyramid network (FPN), nearest anchor method, and post-processing masking, had the optimal predictive performance with a CPM of 92.2%. The modified 3D RPN trained on the LUNA16 dataset had the highest CPM (90.1%), followed by the LNOP dataset (CPM: 74.1%) and the LNHE dataset (CPM: 70.2%). When the modified 3D RPN trained and tested on the same datasets, the sensitivities were 94.6%, 84.8%, and 79.7% for LUNA16, LNOP, and LNHE, respectively. The temporal validation analysis revealed that the modified 3D RPN tested on LNOP test set achieved a CPM of 71.6% and a sensitivity of 85.7%, and the modified 3D RPN tested on LNHE test set had a CPM of 71.7% and a sensitivity of 83.5%. CONCLUSION: A modified 3D RPN for detecting lung nodules on LDCT scans was designed and validated, which may serve as a computer-aided diagnosis system to facilitate lung nodule detection and lung cancer diagnosis.

A modified 3D RPN for detecting lung nodules on CT images that exhibited greater sensitivity and CPM than did several previously reported CAD detection models was established.

Early changes in skin surface temperature predict body temperature increases in patients with fever: A pilot study.

OBJECTIVE: To investigate the correlation between body temperature and skin surface temperature in intensive care unit patients and to identify specific indicators of skin surface temperature for early fever detection. RESEARCH METHODOLOGY/DESIGN: This pilot study was a prospective, observational investigation conducted at National Cheng Kung University Hospital in Tainan, Taiwan. A total of 54 patients admitted to the Surgical Intensive Care Unit of a tertiary hospital between April and August 2020 were included. Patients utilized the wearable device HEARThremoTM to continuously monitor skin surface temperature and heart rate. Analysis of Variance was applied to identify the association of skin surface temperature with different body temperature groups. The comparison between skin surface temperature and fever over eight time intervals was studied using a generalized estimating equation. RESULTS: In 34 patients (63 %) with a fever (≥38 °C), skin surface temperature increased (P < 0.001) when body temperature increased. The maximum skin surface temperature was significantly associated with fever 180-210 min before the fever events occurred (OR: 2.22, 95 % CI: 1.30-3.80). The mean skin surface temperature was associated with fever 120-150 min before the fever events (OR: 8.70, 95 % CI: 2.08-36.36). CONCLUSIONS: Skin surface temperature can be an important early predictive sign before the onset of fever. Continuous temperature monitoring can detect fever early and initiate treatment in advance. This study serves as a preliminary exploration in this area, laying the groundwork for future comprehensive research. IMPLICATIONS FOR CLINICAL PRACTICE: Continuous monitoring of skin surface temperature empowers nurses to swiftly detect fever, transcending conventional methods. This proactive approach allows for the early identification of physiological abnormalities, facilitating the prompt initiation of further physical assessments and relevant examinations for early treatment commencement.

TEM1/endosialin/CD248 promotes pathologic scarring and TGF-ß activity through its receptor stability in dermal fibroblasts.

BACKGROUND: Pathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars. METHODS: To investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-ß-mediated responses in pathologic scars. RESULTS: The levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-ß1 signaling through binding with and stabilizing TGF-ß receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids. CONCLUSIONS: Our data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-ß signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars.

Combined model integrating deep learning, radiomics, and clinical data to classify lung nodules at chest CT.

OBJECTIVES: The study aimed to develop a combined model that integrates deep learning (DL), radiomics, and clinical data to classify lung nodules into benign or malignant categories, and to further classify lung nodules into different pathological subtypes and Lung Imaging Reporting and Data System (Lung-RADS) scores. MATERIALS AND METHODS: The proposed model was trained, validated, and tested using three datasets: one public dataset, the Lung Nodule Analysis 2016 (LUNA16) Grand challenge dataset (n = 1004), and two private datasets, the Lung Nodule Received Operation (LNOP) dataset (n = 1027) and the Lung Nodule in Health Examination (LNHE) dataset (n = 1525). The proposed model used a stacked ensemble model by employing a machine learning (ML) approach with an AutoGluon-Tabular classifier. The input variables were modified 3D convolutional neural network (CNN) features, radiomics features, and clinical features. Three classification tasks were performed: Task 1: Classification of lung nodules into benign or malignant in the LUNA16 dataset; Task 2: Classification of lung nodules into different pathological subtypes; and Task 3: Classification of Lung-RADS score. Classification performance was determined based on accuracy, recall, precision, and F1-score. Ten-fold cross-validation was applied to each task. RESULTS: The proposed model achieved high accuracy in classifying lung nodules into benign or malignant categories in LUNA 16 with an accuracy of 92.8%, as well as in classifying lung nodules into different pathological subtypes with an F1-score of 75.5% and Lung-RADS scores with an F1-score of 80.4%. CONCLUSION: Our proposed model provides an accurate classification of lung nodules based on the benign/malignant, different pathological subtypes, and Lung-RADS system.

Do We Need to Administer Fludrocortisone in Addition to Hydrocortisone in Adult Patients With Septic Shock? An Updated Systematic Review With Bayesian Network Meta-Analysis of Randomized Controlled Trials and an Observational Study With Target Trial Emulation.

OBJECTIVES: This systematic review and Bayesian network meta-analysis evaluated the efficacy and safety of hydrocortisone combined with fludrocortisone or hydrocortisone alone, compared with placebo in adult patients with septic shock. DATA SOURCES: By extending a prior Cochrane review, databases, including PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov , along with other relevant websites, were searched until August 31, 2023. STUDY SELECTION: Randomized controlled trials (RCTs) and observational studies using target trial emulation were included. DATA EXTRACTION: The primary outcome was short-term mortality with an emphasis on 28- or 30-day mortality as the main measure and in-hospital or ICU mortality as the nearest surrogate of this measure. Three of the most common adverse events, namely, gastroduodenal bleeding, superinfection, and hyperglycemia, were also considered. DATA SYNTHESIS: A total of 19 studies involving 95,841 patients were included. Hydrocortisone plus fludrocortisone showed the lowest short-term mortality versus placebo (odds ratio [OR]: 0.79; 95% credible interval [CrI], 0.64-0.99; number needed to treat [NNT]: 21, range: 12-500; low certainty of evidence) in terms of informative priors. The surface under the cumulative ranking curve values for hydrocortisone plus fludrocortisone, hydrocortisone alone, and placebo were 0.9469, 0.4542, and 0.0989, respectively. Consistent results were observed in RCTs alone and those using a daily 200-mg dose of hydrocortisone. Although gastroduodenal bleeding or superinfection showed no clear increase, hyperglycemia risk increased. The ORs were 0.53 for placebo versus hydrocortisone plus fludrocortisone and 0.64 for placebo versus hydrocortisone alone, with very low certainty of evidence. CONCLUSIONS: In adults with septic shock, hydrocortisone plus fludrocortisone improved short-term survival with minimal adverse events compared with hydrocortisone alone or placebo. However, these findings are not definitive due to the limited certainty of evidence and wide NNT range. Additional large-scale, placebo-controlled RCTs are needed to provide conclusive evidence.

Soluble CD93 lectin-like domain sequesters HMGB1 to ameliorate inflammatory diseases.

Rationale: CD93, a C-type lectin-like transmembrane glycoprotein, can be shed in a soluble form (sCD93) upon inflammatory stimuli. sCD93 effectively enhances apoptotic cell clearance and has been proposed as an inflammatory disease biomarker. The function of sCD93 involved directly in inflammation remains to be determined. Herein, we attempted to examine the hypothesis that sCD93 might sequester proinflammatory high-mobility group box 1 protein (HMGB1), exerting anti-inflammatory properties. Methods: Different forms of soluble recombinant human CD93 (rCD93) were prepared by a mammalian protein expression system. rCD93-HMGB1 interaction was assessed using co-immunoprecipitation and solid-phase binding assays. Effects of soluble rCD93 were evaluated in HMGB1-induced macrophage and vascular smooth muscle cells (VSMC) activation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, CaCl2-induced and angiotensin II-infused abdominal aortic aneurysm (AAA) formation and ovariectomized-induced osteoporosis in mice. Results: Protein binding studies revealed that soluble rCD93, via the lectin-like domain (D1), can bind to HMGB1 and intercept HMGB1-receptor interaction. Soluble rCD93 containing D1 inhibited HMGB1-induced proinflammatory cytokine production and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation in macrophages and VSMCs, thereby attenuating CaCl2-induced and angiotensin II-infused AAA models. During osteoclastogenesis, RANKL stimulated HMGB1 secretion that promoted RANKL-induced osteoclastogenesis in return. Soluble rCD93 containing D1 impeded RANKL-induced osteoclastogenic marker gene expression and intracellular MAPK/NF-κB signaling, thereby mitigating ovariectomized-induced osteoporosis. Conclusion: These findings demonstrate the therapeutic potential of soluble recombinant CD93 containing D1 in inflammatory diseases. Our study highlights a novel anti-inflammatory mechanism, i.e., sequestration of HMGB1, through which sCD93 prevents HMGB1-receptor interaction on effector cells and alleviates inflammation.

Indoor CO2 monitoring in a surgical intensive care unit under visitation restrictions during the COVID-19 pandemic.

Background: Indoor CO2 concentration is an important metric of indoor air quality (IAQ). The dynamic temporal pattern of CO2 levels in intensive care units (ICUs), where healthcare providers experience high cognitive load and occupant numbers are frequently changing, has not been comprehensively characterized. Objective: We attempted to describe the dynamic change in CO2 levels in the ICU using an Internet of Things-based (IoT-based) monitoring system. Specifically, given that the COVID-19 pandemic makes hospital visitation restrictions necessary worldwide, this study aimed to appraise the impact of visitation restrictions on CO2 levels in the ICU. Methods: Since February 2020, an IoT-based intelligent indoor environment monitoring system has been implemented in a 24-bed university hospital ICU, which is symmetrically divided into areas A and B. One sensor was placed at the workstation of each area for continuous monitoring. The data of CO2 and other pollutants (e.g., PM2.5) measured under standard and restricted visitation policies during the COVID-19 pandemic were retrieved for analysis. Additionally, the CO2 levels were compared between workdays and non-working days and between areas A and B. Results: The median CO2 level (interquartile range [IQR]) was 616 (524-682) ppm, and only 979 (0.34%) data points obtained in area A during standard visitation were ≥ 1,000 ppm. The CO2 concentrations were significantly lower during restricted visitation (median [IQR]: 576 [556-596] ppm) than during standard visitation (628 [602-663] ppm; p < 0.001). The PM2.5 concentrations were significantly lower during restricted visitation (median [IQR]: 1 [0-1] µg/m3) than during standard visitation (2 [1-3] µg/m3; p < 0.001). The daily CO2 and PM2.5 levels were relatively low at night and elevated as the occupant number increased during clinical handover and visitation. The CO2 concentrations were significantly higher in area A (median [IQR]: 681 [653-712] ppm) than in area B (524 [504-547] ppm; p < 0.001). The CO2 concentrations were significantly lower on non-working days (median [IQR]: 606 [587-671] ppm) than on workdays (583 [573-600] ppm; p < 0.001). Conclusion: Our study suggests that visitation restrictions during the COVID-19 pandemic may affect CO2 levels in the ICU. Implantation of the IoT-based IAQ sensing network system may facilitate the monitoring of indoor CO2 levels.

Chondrocyte Thrombomodulin Protects against Osteoarthritis.

Osteoarthritis (OA) is a prevalent form of arthritis that affects over 32.5 million adults worldwide, causing significant cartilage damage and disability. Unfortunately, there are currently no effective treatments for OA, highlighting the need for novel therapeutic approaches. Thrombomodulin (TM), a glycoprotein expressed by chondrocytes and other cell types, has an unknown role in OA. Here, we investigated the function of TM in chondrocytes and OA using various methods, including recombinant TM (rTM), transgenic mice lacking the TM lectin-like domain (TMLeD/LeD), and a microRNA (miRNA) antagomir that increased TM expression. Results showed that chondrocyte-expressed TM and soluble TM [sTM, like recombinant TM domain 1 to 3 (rTMD123)] enhanced cell growth and migration, blocked interleukin-1ß (IL-1ß)-mediated signaling and protected against knee function and bone integrity loss in an anterior cruciate ligament transection (ACLT)-induced mouse model of OA. Conversely, TMLeD/LeD mice exhibited accelerated knee function loss, while treatment with rTMD123 protected against cartilage loss even one-week post-surgery. The administration of an miRNA antagomir (miR-up-TM) also increased TM expression and protected against cartilage damage in the OA model. These findings suggested that chondrocyte TM plays a crucial role in counteracting OA, and miR-up-TM may represent a promising therapeutic approach to protect against cartilage-related disorders.

Feasibility of simultaneous development of laparoscopic and robotic pancreaticoduodenectomy.

Laparoscopic (LPD) and robotic pancreaticoduodenectomy (RPD) are both challenging procedures. The feasibility and safety of simultaneously developing LPD and RPD remain unreported. We retrospectively reviewed the data of patients undergoing LPD or RPD between 2014 and 2021. A total of 114 patients underwent minimally invasive pancreaticoduodenectomy (MIPD): 39 LPDs and 75 RPDs. The learning process of LPD and RPD were similar. The cutoff points of the learning curve were LPD, 13th patient (the 27th patient of MIPD), and RPD, 18th patient (the 31st patient of MIPD) according the cumulative sum analysis of operative time. A decrease in the operative time was associated with the case sequence (p < 0.001) but not with the surgical approach (p = 0.36). The overall surgical outcomes were comparable between both the LPD and RPD groups. When evaluating the learning curve impact on MIPD, LPD had higher major complication (≧ Clavien-Dindo grade III), bile leak and wound infection rates in the pre-learning curve phase than those in the after-learning curve phase, while RPD had similar surgical outcomes between two phases. Simultaneous development of LPD and RPD is feasible and safe for experienced surgeons, with similar learning process and comparable surgical outcomes.

Minimally invasive approaches increase postoperative complications in obese patients undergoing pancreaticoduodenectomy during the initial development period: a propensity score matching study.

BACKGROUND: Obesity increases surgical risks in various abdominal surgeries and its impact on open pancreaticoduodenectomy (OPD) and minimally invasive pancreaticoduodenectomy (MIPD) remains unknown. This study aimed to compare the surgical outcomes of OPD and MIPD in obese and non-obese patients by propensity score matching (PSM) analysis during the implementation of MIPD. METHODS: We retrospectively reviewed all pancreaticoduodenectomies from December 2014 to May 2021. Obesity was defined as body mass index > 25 kg/m2 according to World Health Organization International Obesity Task Force. PSM was used to minimize the selection bias of MIPD. RESULTS: Among 462 pancreaticoduodenectomies (339 OPDs, 123 MIPDs), there were 313 patients in the non-obese group (MIPD: 78, OPD: 235) and 149 patients in the obese group (MIPD: 45, OPD: 104). After PSM, there were 70 MIPD/106 OPD patients in the non-obese group and 38 MIPD/54 OPD patients in the obese group. The obese MIPD patients had more fluid collection (36.8% vs 9.8%, p = 0.002), a higher Clavien-Dindo (CD) grade (p = 0.007), more major complications (42.1% vs 14.8%, p = 0.004), and longer operative times (306 min vs 264 min, p < 0.001) than the obese OPD patients. The non-obese MIPD patients had lower CD grades (p = 0.02), longer operative times (294 vs 264 min, p < 0.001), and less blood loss (100 mL vs 200 mL) than the non-obese OPD patients. MIPD was a strong predictor of major complication (CD ≥ 3) in obese patients (odds ratio 3.11, 95% CI: 1.40-6.95, p = 0.005). CONCLUSIONS: Minimally invasive approaches deteriorate the CD grade, fluid collection, and major complications in obese patients undergoing pancreaticoduodenectomy during the initial development period. Non-obese patients may benefit from MIPD over OPD in terms of less blood loss and lower CD grades. The impact of BMI on MIPD should be considered when assessing the surgical risks.

Interference in melanoma CD248 function reduces vascular mimicry and metastasis.

BACKGROUND: Tumor vascular mimicry is an emerging issue that affects patient survival while having no treatment at the current moment. Despite several factors implicated in vascular mimicry, little is known about stromal factors that modulate tumor microenvironment and shape malignant transformation. CD248, a type-I transmembrane protein dominantly expressed in stromal cells, mediates the interaction between cells and extracellular matrix proteins. CD248 protein expression is associated with the metastatic melanoma phenotype and promotes tumor progression in the stromal cells. This study aimed to explore the cell-autonomous effects of CD248 in melanoma vascular mimicry to aid cancer therapy development. METHODS: Loss-of-function approaches in B16F10 melanoma cells were used to study the cell-autonomous effects of CD248 on cell adhesion, migration, proliferation, and vascular mimicry. A solid-phase binding assay was performed to identify the interaction between CD248 and fibronectin. Horizontal and vertical cell migration assays were performed to analyze cell migration activity, and cell-patterned network formation on Matrigel was used to evaluate vascular mimicry activity. Recombinant CD248 (rCD248) proteins were generated, and whether rCD248 interfered with melanoma CD248 functions was evaluated in vitro. An experimental lung metastasis mouse model was used to investigate the effect of rCD248 treatment in vivo. RESULTS: CD248 protein expression in melanoma cells was increased by a fibroblast-conditioned medium. Knockdown of CD248 expression significantly decreased cell adhesion to fibronectin, cell migration, and vascular mimicry in melanoma cells. The lectin domain of CD248 was directly involved in the interaction between CD248 and fibronectin. Furthermore, rCD248 proteins containing its lectin domain inhibited cell adhesion to fibronectin and slowed down cell migration and vascular mimicry. Treatment with rCD248 protein could reduce pulmonary tumor burden, accompanied by a reduction in vascular mimicry in mice with melanoma lung metastasis. CONCLUSION: CD248 expression in melanoma cells promotes malignant transformation by increasing the activity of cell adhesion, migration, and vascular mimicry, whereas rCD248 protein functions as a molecular decoy interfering with tumor-promoting effects of CD248 in melanoma cells.

Validation of a Deep Learning-based Automatic Detection Algorithm for Measurement of Endotracheal Tube-to-Carina Distance on Chest Radiographs.

BACKGROUND: Improper endotracheal tube (ETT) positioning is frequently observed and potentially hazardous in the intensive care unit. The authors developed a deep learning-based automatic detection algorithm detecting the ETT tip and carina on portable supine chest radiographs to measure the ETT-carina distance. This study investigated the hypothesis that the algorithm might be more accurate than frontline critical care clinicians in ETT tip detection, carina detection, and ETT-carina distance measurement. METHODS: A deep learning-based automatic detection algorithm was developed using 1,842 portable supine chest radiographs of 1,842 adult intubated patients, where two board-certified intensivists worked together to annotate the distal ETT end and tracheal bifurcation. The performance of the deep learning-based algorithm was assessed in 4-fold cross-validation (1,842 radiographs), external validation (216 radiographs), and an observer performance test (462 radiographs) involving 11 critical care clinicians. The performance metrics included the errors from the ground truth in ETT tip detection, carina detection, and ETT-carina distance measurement. RESULTS: During 4-fold cross-validation and external validation, the median errors (interquartile range) of the algorithm in ETT-carina distance measurement were 3.9 (1.8 to 7.1) mm and 4.2 (1.7 to 7.8) mm, respectively. During the observer performance test, the median errors (interquartile range) of the algorithm were 2.6 (1.6 to 4.8) mm, 3.6 (2.1 to 5.9) mm, and 4.0 (1.7 to 7.2) mm in ETT tip detection, carina detection, and ETT-carina distance measurement, significantly superior to that of 6, 10, and 7 clinicians (all P < 0.05), respectively. The algorithm outperformed 7, 3, and 0, 9, 6, and 4, and 5, 5, and 3 clinicians (all P < 0.005) regarding the proportions of chest radiographs within 5 mm, 10 mm, and 15 mm error in ETT tip detection, carina detection, and ETT-carina distance measurement, respectively. No clinician was significantly more accurate than the algorithm in any comparison. CONCLUSIONS: A deep learning-based algorithm can match or even outperform frontline critical care clinicians in ETT tip detection, carina detection, and ETT-carina distance measurement.

Detecting Endotracheal Tube and Carina on Portable Supine Chest Radiographs Using One-Stage Detector with a Coarse-to-Fine Attention.

In intensive care units (ICUs), after endotracheal intubation, the position of the endotracheal tube (ETT) should be checked to avoid complications. The malposition can be detected by the distance between the ETT tip and the Carina (ETT-Carina distance). However, it struggles with a limited performance for two major problems, i.e., occlusion by external machine, and the posture and machine of taking chest radiographs. While previous studies addressed these problems, they always suffered from the requirements of manual intervention. Therefore, the purpose of this paper is to locate the ETT tip and the Carina more accurately for detecting the malposition without manual intervention. The proposed architecture is composed of FCOS: Fully Convolutional One-Stage Object Detection, an attention mechanism named Coarse-to-Fine Attention (CTFA), and a segmentation branch. Moreover, a post-process algorithm is adopted to select the final location of the ETT tip and the Carina. Three metrics were used to evaluate the performance of the proposed method. With the dataset provided by National Cheng Kung University Hospital, the accuracy of the malposition detected by the proposed method achieves 88.82% and the ETT-Carina distance errors are less than 5.333±6.240 mm.

Xanthine Derivative KMUP-1 Attenuates Experimental Periodontitis by Reducing Osteoclast Differentiation and Inflammation.

Periodontitis is an inflammatory disease of gum that may predispose to serious systemic complications such as diabetes and cardiovascular diseases. Activation of macrophages and osteoclasts around periodontal tissue can accelerate gum inflammation. In addition, alteration of cyclic nucleotide levels is associated with the severity of periodontitis. Our previous study has shown that KMUP-1, a xanthine derivative exhibiting phosphodiesterase inhibition and soluble guanylyl cyclase activation, can inhibit lipopolysaccharide (LPS)-induced inflammation and receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclastogenesis. This study was aimed to investigate whether KMUP-1 could attenuate periodontitis both in vitro and in vivo. In vitro, the protective effect of KMUP-1 on inflammation and osteoclastogenesis was investigated in RANKL-primed RAW264.7 cells treated by Porphyromonas gingivalis LPS (PgLPS). The results showed that KMUP-1 attenuated PgLPS-induced osteoclast differentiation as demonstrated by decreased TRAP-positive multinuclear cells and TRAP activity. This reduction of osteoclast differentiation by KMUP-1 was reversed by KT5823, a protein kinase G inhibitor. Similarly, pro-inflammatory cytokine levels induced by PgLPS were inhibited by KMUP-1 in a dose-dependent manner whereas reversed by KT5823. Mechanistically, suppression of MAPKs, PI3K/Akt, and NF-κB signaling pathways and decrease of c-Fos and NFATc1 expression in osteoclast precursors by KMUP-1 may mediate its protective effect. In vivo, two models of periodontitis in rats were induced by gingival injections of PgLPS and ligature placement around molar teeth, respectively. Our results showed that KMUP-1 inhibited alveolar bone loss in both rat models, and this effect mediated at least partly by reduced osteoclastogenesis. In conclusion, our study demonstrated the therapeutic potential of KMUP-1 on periodontitis through suppression of inflammation and osteoclast differentiation.

Integration of an Intensive Care Unit Visualization Dashboard (i-Dashboard) as a Platform to Facilitate Multidisciplinary Rounds: Cluster-Randomized Controlled Trial.

BACKGROUND: Multidisciplinary rounds (MDRs) are scheduled, patient-focused communication mechanisms among multidisciplinary providers in the intensive care unit (ICU). OBJECTIVE: i-Dashboard is a custom-developed visualization dashboard that supports (1) key information retrieval and reorganization, (2) time-series data, and (3) display on large touch screens during MDRs. This study aimed to evaluate the performance, including the efficiency of prerounding data gathering, communication accuracy, and information exchange, and clinical satisfaction of integrating i-Dashboard as a platform to facilitate MDRs. METHODS: A cluster-randomized controlled trial was performed in 2 surgical ICUs at a university hospital. Study participants included all multidisciplinary care team members. The performance and clinical satisfaction of i-Dashboard during MDRs were compared with those of the established electronic medical record (EMR) through direct observation and questionnaire surveys. RESULTS: Between April 26 and July 18, 2021, a total of 78 and 91 MDRs were performed with the established EMR and i-Dashboard, respectively. For prerounding data gathering, the median time was 10.4 (IQR 9.1-11.8) and 4.6 (IQR 3.5-5.8) minutes using the established EMR and i-Dashboard (P<.001), respectively. During MDRs, data misrepresentations were significantly less frequent with i-Dashboard (median 0, IQR 0-0) than with the established EMR (4, IQR 3-5; P<.001). Further, effective recommendations were significantly more frequent with i-Dashboard than with the established EMR (P<.001). The questionnaire results revealed that participants favored using i-Dashboard in association with the enhancement of care plan development and team participation during MDRs. CONCLUSIONS: i-Dashboard increases efficiency in data gathering. Displaying i-Dashboard on large touch screens in MDRs may enhance communication accuracy, information exchange, and clinical satisfaction. The design concepts of i-Dashboard may help develop visualization dashboards that are more applicable for ICU MDRs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04845698; https://clinicaltrials.gov/ct2/show/NCT04845698.

An MRI-Based Clinical-Perfusion Model Predicts Pathological Subtypes of Prevascular Mediastinal Tumors.

This study aimed to build machine learning prediction models for predicting pathological subtypes of prevascular mediastinal tumors (PMTs). The candidate predictors were clinical variables and dynamic contrast-enhanced MRI (DCE-MRI)-derived perfusion parameters. The clinical data and preoperative DCE-MRI images of 62 PMT patients, including 17 patients with lymphoma, 31 with thymoma, and 14 with thymic carcinoma, were retrospectively analyzed. Six perfusion parameters were calculated as candidate predictors. Univariate receiver-operating-characteristic curve analysis was performed to evaluate the performance of the prediction models. A predictive model was built based on multi-class classification, which detected lymphoma, thymoma, and thymic carcinoma with sensitivity of 52.9%, 74.2%, and 92.8%, respectively. In addition, two predictive models were built based on binary classification for distinguishing Hodgkin from non-Hodgkin lymphoma and for distinguishing invasive from noninvasive thymoma, with sensitivity of 75% and 71.4%, respectively. In addition to two perfusion parameters (efflux rate constant from tissue extravascular extracellular space into the blood plasma, and extravascular extracellular space volume per unit volume of tissue), age and tumor volume were also essential parameters for predicting PMT subtypes. In conclusion, our machine learning-based predictive model, constructed with clinical data and perfusion parameters, may represent a useful tool for differential diagnosis of PMT subtypes.

Upregulation of Fibrinogen-Like 1 Expression Contributes to Reducing the Progression of Preeclampsia.

Fibrinogen-like 1 (FGL1) is involved in liver injury and liver regeneration, but its role in placenta and preeclampsia (PE) remains unclear. We assessed FGL1 expression in serum and placenta from L-NAME-induced PE-like mouse and in women with (n = 38) and without (n = 42) PE. For the mouse study, pregnant C57Bl/6 mouse (n = 6/group) were subcutaneously administered L-NAME with or without FGL1 once daily starting on days 7-14 of pregnancy and were sacrificed on gestational day (GD) 20. Maternal body weight, blood pressure, and urinary protein were assessed during GDs 8-20. The weight and length of the placenta and fetus were assessed. The placental structure was evaluated using hematoxylin staining. In the human study, the sera of the pregnant women during the late trimester were assessed with enzyme-linked immunosorbent assays (ELISAs). FGL1 expression in human trophoblast cell lines under L-NAME stimulation was measured using Western blotting and immunofluorescence staining. The detected FGL1 protein levels in serum and placenta were both significantly upregulated in patients and mouse with PE compared with those in the non-PE groups. FGL1 treatment decreased maternal hypertension and proteinuria, decreased fetal weight in mouse with PE, downregulated proinflammatory cytokine (interleukin-1b and interleukin-6) levels, and maintained the balance between antiangiogenic (fms-like tyrosine kinase-1) and proangiogenic (placental growth factor) substances in the placenta. L-NAME-upregulated FGL1 expression was inhibited following overexpression of FoxO3a. In summary, FoxO3a reduction is a potential pathophysiological mechanism leading to upregulated placental FGL1 expression that may play a pivotal role in preventing PE progression.

Role of tumor endothelial marker 1 (Endosialin/CD248) lectin-like domain in lipopolysaccharide-induced macrophage activation and sepsis in mice.

Deleterious hyper-inflammation resulting from macrophage activation may aggravate sepsis and lead to lethality. Tumor endothelial marker 1 (TEM1), a type I transmembrane glycoprotein containing six functional domains, has been implicated in cancer and chronic sterile inflammatory disorders. However, the role of TEM1 in acute sepsis remains to be determined. Herein we explored the functional significance of the TEM1 lectin-like domain (TEM1D1) in monocyte/macrophage activation and sepsis using TEM1D1-deleted (TEM1LeD/LeD) transgenic mice and recombinant TEM1D1 (rTEM1D1) protein. Under stimulation with lipopolysaccharides (LPS) or several other toll-like receptor agonists, TEM1LeD/LeD macrophages produced lower levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 than wild-type TEM1wt/wt macrophages. Compared with TEM1wt/wt macrophages, LPS-macrophage binding and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation were suppressed in TEM1LeD/LeD macrophages. In vivo, TEM1D1 deletion improved survival in LPS-challenged mice with reduction of circulating TNF-α and IL-6 and alleviation of lung injury and pulmonary leukocyte accumulation. In contrast, rTEM1D1 could bind to LPS and markedly suppress LPS-macrophage binding, MAPK/NF-κB signaling in macrophages and proinflammatory cytokine production. Treatment with rTEM1D1 improved survival and attenuated circulating TNF-α and IL-6, lung injury and pulmonary accumulation of leukocytes in LPS-challenged mice. These findings demonstrated differential roles for the TEM1 lectin-like domain in macrophages and soluble TEM1 lectin-like domain in sepsis. TEM1 in macrophages mediates LPS-induced inflammation via its lectin-like domain, whereas rTEM1D1 interferes with LPS-induced macrophage activation and sepsis.

Recombinant thrombomodulin lectin-like domain attenuates Porphyromonas gingivalis lipopolysaccharide-induced osteoclastogenesis and periodontal bone resorption.

BACKGROUND: Evidence demonstrates that the thrombomodulin (TM) lectin domain (TMD1) exerts anti-inflammatory functions. Lipopolysaccharides derived from Porphyromonas gingivalis (Pg-LPS) are considered a major pathogenic factor for chronic periodontitis, promoting inflammation, osteoclastogenesis and alveolar bone resorption. Herein, we aimed to evaluate the potential therapeutic effect of recombinant TMD1 (rTMD1) in suppression of Pg-LPS-induced osteoclastogenesis and periodontal bone loss. METHODS: In vitro, the effects of Pg-LPS, tumor necrosis factor (TNF)-α and rTMD1 on osteoclast differentiation were investigated using receptor activator of nuclear factor-κB ligand (RANKL)-stimulated RAW 264.7 macrophages. In vivo, the effects of rTMD1 treatment were evaluated in a model of experimental periodontitis induced by direct injection of Pg-LPS into the vestibular gingiva. RESULTS: Administration of Pg-LPS to RANKL-stimulated RAW 264.7 macrophages resulted in upregulation of CD86 and osteoclast marker (eg, Dc-stamp and Trap) gene expression and increase of pro-inflammatory cytokine production (e.g., TNF-α) during osteoclast differentiation, and rTMD1 can attenuate these effects. Also, rTMD1 inhibited Pg-LPS-enhanced in vitro bone resorption in a dose-dependent manner. Moreover, TNF-α promoted phosphorylation of p38 and ERK during osteoclast differentiation, and the signal activation can be inhibited by rTMD1. Finally, treatment with rTMD1 hindered Pg-LPS-induced alveolar bone loss in experimental periodontitis in mice. CONCLUSION: Our study demonstrated that rTMD1 attenuates Pg-LPS-enhanced M1 macrophage polarization, osteoclastogenesis and periodontal bone resorption and thus holds therapeutic promise for periodontitis.