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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.We retrospectively reviewed all pancreaticoduodenectomies from December 2014 to May 2021. Obesity was defined as body mass index 25 kg/mAmong 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).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.

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. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Microbiota manipulation through preoperative probiotic administration with Clostridium butyricum (CBM588) has shown promising results in reducing surgical site infections, but the resulting changes in gut microbiota are unclear. This study, using 16S ribosomal RNA metagenomic analysis, aimed to observe microbiome changes after CBM588 administration before murine colonic anastomosis. Materials and methods Eighteen C57BL/6 mice were divided into three groups. All mice, including group A as the control group, received oral neomycin and metronidazole before surgery. Group B received six consecutive days of CBM588 before surgery. Group C received kanamycin, gentamycin, colistin, metronidazole, and vancomycin, followed by six consecutive days of CBM588 before surgery. Results Compared with groups A and B, group C had significantly lower adhesion scores (p Clostridiaceae, and genus Clostridium, with low bacterial diversity and composition. Conclusions Using a murine colonic anastomosis model, a preoperative antibiotic cocktail followed by CBM588 supplementation effectively decreased bacterial diversity and increased the percentage of Clostridiaceae. Associated outcomes included lower intra-abdominal adhesion scores, better postoperative performance and anastomotic healing scores, and lower anastomotic necrosis areas.

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

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-1β (IL-1β)-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.

Background Acute exacerbation (AE) of COPD may be accompanied by the deterioration of cardiovascular comorbidities, as evidenced by the increased incidence of acute cardiovascular events. Research Question The goal of this study was to determine whether preceding AE might be associated with mortality of cardiovascular events. Study Design and Methods Using a health insurance research database in Taiwan, patients with COPD were identified who experienced first-time acute myocardial infarction (AMI; n = 26,442), ischemic stroke (n = 54,959), and intracranial hemorrhage (ICH; n = 14,893) over a 13-year period. In each cohort, 4,356, 6,655, and 1,727 patients, respectively, had been hospitalized for AE within the previous year prior to the index cardiovascular events, and patients with COPD but without hospitalization for AEs constituted the control subjects. ORs of 90-day mortality and hazard ratios (HRs) of overall mortality during follow-up in relation to hospitalization for an AE and the frequency of hospitalization for AEs (ie, 1 and ≥ 2 hospitalizations for AEs) were estimated with adjustment for potential confounders. Results Hospitalization for an AE was independently associated with 90-day mortality of AMI (OR, 1.33; 95% CI, 1.24-1.43), ischemic stroke (OR, 1.46; 95% CI, 1.36-1.56), and ICH (OR, 1.19; 95% CI, 1.06-1.32). Hospitalization for an AE was associated with overall mortality of AMI (HR, 1.23; 95% CI, 1.19-1.27), ischemic stroke (HR, 1.29; 95% CI, 1.26-1.33), and ICH (HR, 1.19; 95% CI, 1.13-1.26). In addition, compared with control subjects, patients with more frequent hospitalizations for AEs exhibited significant trends at higher risk of 90-day and overall mortality of AMI, ischemic stroke, and ICH. Finally, these results were consistent with propensity score matching-based estimates. Interpretation Preceding hospitalization for AEs is associated with 90-day and overall mortality of cardiovascular events in COPD.

Objective Evidence suggests that cathepsin S (CTSS), a potent mammalian elastase, participates in abdominal aortic aneurysm (AAA) formation. This study examines the hypothesis that pharmacological inhibition of CTSS with an α-ketoamide based compound 6r might suppress AAA in mice. Methods Experimental study of the CaCl2 induced AAA model in B6 mice and angiotensin II (AngII) infused AAA model in ApoE−/- mice. The effects of intraperitoneal administration of 6r (25 mg/kg) and vehicle every three days since one day after AAA induction were evaluated at 28 days using CaCl2 induced (n = 12 per group) and AngII infused (n = 8 per group) models. Additionally, the effects of post-treatment with 6r and vehicle from seven days or 14 days after AAA induction were evaluated at 28 days using the CaCl2 induced model (n = 6 per group). Aortic samples were harvested for histological and biochemical analyses, including cathepsin levels, Verhoeff Van Gieson staining, TUNEL assay, and immunostaining for macrophages. Results In the CaCl2 induced model, treatment with 6r suppressed aortic dilatation observed in vehicle treated controls (median: 0.58 vs. 0.92 mm; p Conclusion Pharmacological inhibition of CTSS by 6r suppresses AAA formation in mice. Also, post-treatment with 6r retards mouse AAA progression. These findings provide proof of concept validation for CTSS as a potential therapeutic target in AAA.

Background and aims Inflammation, oxidative stress, matrix degradation, medial calcification and vascular smooth muscle cell (VSMC) loss are prominent features in abdominal aortic aneurysm (AAA). VSMC phenotypic switch to a proinflammatory state and VSMC apoptosis could be targetable mechanisms implicated in the pathogenesis of AAA formation. Herein, we investigated the hypothesis that a xanthine derivative (KMUP-3) might suppress AAA through inhibition of VSMC phenotypic switch and apoptosis. Methods In vitro, VSMC calcification was induced using β-glycerophosphate. In vivo, AAA was induced using angiotensin II (1000 ng/kg per minute) infusion for 4 weeks in apolipoprotein E-deficient mice. Results As determined by alizarin red S staining and calcium content measurements, KMUP-3 suppressed VSMC calcification. During VSMC calcification, KMUP-3 inhibited mTOR and β-catenin upregulation, essential for VSMC phenotypic switch, while it enhanced AMP-activated protein kinase (AMPK) activation that protects against VSMC phenotypic switch. Moreover, KMUP-3 attenuated VSMC apoptosis with an increased Bcl-2/Bax ratio and reduced activated caspase-3 expression. During AAA formation, treatment with KMUP-3 inhibited phosphorylated mTOR expression and increased phosphorylated AMPK expression in the medial layer. In addition, KMUP-3 treatment suppressed aortic dilatation together with reduction in proinflammatory cytokines and infiltrating macrophages, attenuation of medial VSMC apoptosis and mitigation of reactive oxygen species generation, matrix-degrading proteinase activities, elastin breakdown and vascular calcification. Conclusions Treatment with KMUP-3 inhibits aneurysm growth possibly through its interference with signaling pathways involved in VSMC phenotypic switch and apoptosis. These findings provide a proof-of-concept validation for VSMC dysfunction as a potential therapeutic target in AAA.

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 (Pi-Dashboard (median 0, IQR 0-0) than with the established EMR (4, IQR 3-5; Pi-Dashboard than with the established EMR (Pi-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. CLINICALTRIAL ClinicalTrials.gov NCT04845698; https://clinicaltrials.gov/ct2/show/NCT04845698

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.

Objectives Patients with RA and SLE have an excess cardiovascular risk. We aimed to evaluate outcomes of acute cardiovascular events in these patients. Methods Using a nationwide database of Taiwan, we identified adult patients who experienced first-time acute myocardial infarction (n = 191 008), intracranial haemorrhage (n = 169 923) and ischaemic stroke (n = 486 890) over a 13-year period. Odds ratios (ORs) of in-hospital mortality and hazard ratios (HRs) of overall mortality and adverse outcomes during long-term follow-up in relation to RA and SLE were estimated with adjustment for potential confounders. Results In each cohort, 748, 410 and 1419 patients had established RA; 256, 292 and 622 patients had SLE. Among acute myocardial infarction patients, RA and SLE were associated with in-hospital mortality (RA: OR 1.61, 95% CI 1.33, 1.95; SLE: OR 2.31, 95% CI 1.62, 3.28) and overall mortality. Additionally, RA (HR 1.28, 95% CI 1.18, 1.38) and SLE (HR 1.46, 95% CI 1.27, 1.69) increased the risk of major adverse cardiac events. After intracranial haemorrhage, patients with RA and SLE had higher risks of in-hospital mortality (RA: OR 1.61, 95% CI 1.26, 2.06; SLE: OR 3.00, 95% CI 2.33, 3.86) and overall mortality. After ischaemic stroke, RA and SLE increased in-hospital mortality (RA: OR 1.45, 95% CI 1.15, 1.83; SLE: OR 2.18, 95% CI 1.57, 3.02), overall mortality and recurrent cerebrovascular events (RA: HR 1.10, 95% CI 1.002, 1.21; SLE: HR 1.31, 95% CI 1.14, 1.51), among which ischaemic stroke (HR 1.39, 95% CI 1.19, 1.62) was more likely to recur in SLE patients. Conclusion Both RA and SLE are consistently associated with adverse outcomes following acute cardiovascular events, highlighting the necessity of integrated care for affected patients.

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.

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.

Background: Lactate is a widely used biomarker for patients with conditions such as infection or trauma. The value of lactate level in risk stratification is rarely investigated for patients admitted to the surgical Intensive Care Unit (ICU), regardless of diagnosis. Purposes: This study examines whether arterial lactate levels at the approximate time of admission can predict short-term mortality in all unscheduled surgical ICU patients. Materials and Methods: A retrospective cohort study of all unscheduled surgical ICU admissions from July 2010 to June 2013 was conducted. Patients were stratified into low (

Thrombomodulin (TM) is a transmembrane glycoprotein that contains five functional domains. Soluble TM (sTM), comprising extracellular domains TMD1 (lectin-like), TMD2 (epidermal growth factor [EGF]-like repeat containing), and TMD3 (serine-threonine rich), can be shed from cells by the intramembrane protease rhomboid-like-2 (RHBDL2). TM is expressed by osteoblasts, yet its role there has not been determined. Herein we aimed to investigate the properties of TM and its domains in osteoblast function and bone repair following injury in diabetes. In response to a scratch injury of cultured osteoblast-like MG63 cells, expression of TM and RHBDL2 was enhanced, with increased release of sTM. Conditioned media from the injured cells promoted osteoblast migration, an effect that was lacking with conditioned media from MG63 cells in which TM was silenced by shRNA. Exogenous recombinant TMD1 had no effect on osteoblast activities or on bone repair in vivo. However, TM domains 2 and 3 (TMD2/3), induced MG63 cell migration, proliferation and mineralization in vitro, and when locally administered in mice, improved in vivo healing of injured calvarium. This beneficial effect of TMD2/3, mediated via fibroblast growth factor receptor (FGFR)/ERK signaling pathways, was also observed in vitro under high glucose conditions where endogenous TM expression was reduced, and in vivo in diabetic mice following tibia fracture or calvarium injury, where the osteoblastic response and healing were otherwise dampened. Taken together, osteoblast TM participates in bone healing, and recombinant TMD2/3 holds promise as a novel therapy for diabetic bone defect healing. © 2020 American Society for Bone and Mineral Research.

Objective To determine whether kidney stone history is associated with adverse outcomes after percutaneous coronary intervention (PCI). Kidney stone formers have an increased risk of developing coronary artery disease; however, whether these patients have worse cardiac outcomes is unknown. Materials and Methods We identified adult patients who underwent first-time PCI in Vanderbilt University Medical Center (VUMC) Synthetic Derivative from 2008 to 2016 (n = 11,289) and in a nationwide database of Taiwan (NHIRD) from 2005 to 2012 (n = 155,762). Odds ratios (ORs) of 30-day in-hospital mortality and hazard ratios (HRs) of 1-year and 3-year adverse outcomes associated with kidney stone history were estimated using a propensity score approach. Results Overall, 294 and 12,286 stone formers undergoing PCI were identified in the VUMC and NHIRD, respectively. After matching, stone formers at VUMC were at higher risks of 30-day in-hospital mortality (OR 2.79, 95% CI 1.15-6.69) and 1-year (HR 1.59, 95% CI 1.13-2.24) and 3-year (HR 1.36, 95% CI 1.02-1.81) myocardial infarction. In the NHIRD, kidney stone history was associated with 1-year (HR 1.12, 95% CI 1.03-1.21) and 3-year (HR 1.14, 95% CI 1.06-1.22) myocardial infarction. In a sensitivity analysis, stone formers undergoing kidney stone surgery were marginally associated with 30-day in-hospital mortality (OR 1.21, 95% CI 0.99-1.48) and were associated with 3-year myocardial infarction (HR 1.13, 95% CI 1.02-1.25). Conclusion Kidney stone history is associated with poorer cardiac outcomes after PCI. Improving secondary cardiac prevention strategies after PCI may be necessary for patients with a history of kidney stone disease.

Wei-Chieh Lin,1 Chang-Wen Chen,1 Chin-Li Lu,2,3 Wu-Wei Lai,4 Min-Hsin Huang,4 Liang-Miin Tsai,1 Chung-Yi Li,2,5,* Chao-Han Lai4,* 1Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Graduate Institute of Food Safety, College of Agriculture and Nature Resources, National Chung Hsing University, Taichung, Taiwan; 4Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan *These authors contributed equally to this work Purpose: COPD is associated with coronary artery disease, and exacerbations are major events in COPD. However, the impact of recent hospitalized exacerbations on outcomes of percutaneous coronary intervention (PCI) remains underdetermined. Patients and methods: Using the National Health Insurance Research Database of Taiwan, we identified 215,275 adult patients who underwent first-time PCI between 2000 and 2012. Among these patients, 15,485 patients had COPD. The risks of hospital mortality, overall mortality, and adverse cardiovascular outcomes after PCI (ie, ischemic events, repeat revascularization, cerebrovascular events, and major adverse cardiac and cerebrovascular events [MACCEs]) in relation to COPD, and the frequency and timing of recent hospitalized exacerbations within 1 year before PCI were estimated. Results: COPD was independently associated with increased risks of hospital mortality, overall mortality, ischemic events, cerebrovascular events, and MACCE during follow-up after PCI. Among cerebrovascular events, ischemic rather than hemorrhagic stroke was more likely to occur. In COPD patients, recent hospitalized exacerbations further increased the risks of overall mortality, ischemic events, and MACCE following PCI. Notably, patients with more frequent or more recent hospitalized exacerbations had a trend toward higher risks of these adverse events (all P-values for trend

Loss of integrity and massive disruption of elastic fibers are key features of abdominal aortic aneurysm (AAA). Peroxisome proliferator–activated receptor γ (PPARγ) has been shown to attenuate AAA through inhibition of inflammation and proteolytic degradation. However, its involvement in elastogenesis during AAA remains unclear. PPARγ was highly expressed in human AAA within all vascular cells, including inflammatory cells and fibroblasts. In the aortas of transgenic mice expressing PPARγ at 25% normal levels ( Pparg C /− mice), we observed the fragmentation of elastic fibers and reduced expression of vital elastic fiber components of elastin and fibulin-5. These were not observed in mice with 50% normal PPARγ expression ( Pparg +/− mice). Infusion of a moderate dose of angiotensin II (500 ng/kg per minute) did not induce AAA but Pparg +/− aorta developed flattened elastic lamellae, whereas Pparg C/− aorta showed severe destruction of elastic fibers. After infusion of angiotensin II at 1000 ng/kg per minute, 73% of Pparg C/− mice developed atypical suprarenal aortic aneurysms: superior mesenteric arteries were dilated with extensive collagen deposition in adventitia and infiltrations of inflammatory cells. Although matrix metalloproteinase inhibition by doxycycline somewhat attenuated the dilation of aneurysm, it did not reduce the incidence nor elastic lamella deterioration in angiotensin II–infused Pparg C/− mice. Furthermore, PPARγ antagonism downregulated elastin and fibulin-5 in fibroblasts, but not in vascular smooth muscle cells. Chromatin immunoprecipitation assay demonstrated PPARγ binding in the genomic sequence of fibulin-5 in fibroblasts. Our results underscore the importance of PPARγ in AAA development though orchestrating proper elastogenesis and preserving elastic fiber integrity.

Background/purpose The comprehensive periodontal treatment project (CPTP) is being implemented in Taiwan since 2010. This retrospective study compared the periodontal status, compliance rates, and influence of risk factors for periodontal recurrence and tooth loss among groups of patients who accepted CPTP and conventional periodontal treatment (CPT). Materials and methods A total of 161 patients who received periodontal therapy were investigated and divided into compliant ( n = 94) and noncompliant ( n = 67) groups. Patients in the compliant group were further assigned to two subgroups: CPT with a postcard recall (PR) system (CPT + PR, n = 48) and CPTP with a PR system (CPTP + PR, n = 46). Demographic characteristics and periodontal parameters, including the probing pocket depth (PPD), bleeding on probing (BOP), and plaque control record (PCR), were collected for comparison between the subgroups. The risk factors for periodontal recurrence and tooth loss were statistically analyzed. Results The 161 patients were followed-up for a mean of 3.8 years. The patients in the CPTP + PR subgroup exhibited shallower PPD, less BOP, improved PCR, and fewer tooth loss. Age, smoking, PPD ≥7 mm, and PCR ≥30% were associated with periodontal recurrence, whereas age, diabetes, BOP ≥30%, and duration of the follow-up period were correlated with tooth loss. PR apparently increased the compliance rate of patients (27.3% vs. 77.7%). Conclusion CPTP with PR led to an optimal and stable periodontal status in patients. Compliant patients maintained a significantly improved periodontal status as compared with noncompliant patients.

Plasminogen (Plg) and thrombomodulin (TM) are glycoproteins well known for fibrinolytic and anticoagulant functions, respectively. Both Plg and TM are essential for wound healing. However, their significance during the reparative process was separately demonstrated in previous studies. Here, we investigate the interaction between Plg and epithelial TM and its effect on wound healing. Characterization of the wound margin revealed that Plg and TM were simultaneously upregulated at the early stage of wound healing and the two molecules were bound together. In vitro, TM silencing or knockout in keratinocytes inhibited Plg activation. Plg treatment enhanced keratinocyte proliferation and migration, and these actions were abolished by TM antibody. Keratinocyte-expressed vascular endothelial growth factor (VEGF), which presented a dose-response relationship with Plg treatment, can be suppressed by TM silencing. Moreover, treatment with VEGF antibody inhibited Plg-enhanced keratinocyte proliferation and wound recovery. In vivo, TM antibody treatment and keratinocyte-specific TM knockout can impede Plg-enhanced wound healing in mice. In high-glucose environments, Plg-enhanced VEGF expression and wound healing were suppressed due at least in part to downregulation of keratinocyte-expressed TM. Taken together, our findings suggest that activation of Plg/TM signaling may hold therapeutic potential for chronic wounds in diabetic or non-diabetic individuals. KEY MESSAGES: Plg binds to TM in cutaneous wound healing. TM facilitates the activation of Plg to Plm in keratinocytes. Epithelial TM regulates Plg-enhanced wound healing through VEGF expression.

Chronic obstructive pulmonary disease (COPD) is associated with increased risk of coronary atherosclerosis. However, its impact on the long-term outcomes in patients undergoing percutaneous coronary intervention (PCI) has not been described. Using the National Health Insurance Research Database of Taiwan, we identified 215275 adult patients who underwent first-time PCI between 2000 and 2012. Among them, the outcomes of patients with COPD (n = 24900) and without COPD (n = 190375) were compared. Baseline demographics and 13-year overall mortality and adverse cardiac outcomes after PCI (i.e., ischemic events, repeat revascularization and major adverse cardiac events (MACE)) in association with COPD were analyzed. Patients with COPD were older (mean age 72.7 vs 64.4 years, P

Tumor endothelial marker 1 (TEM1), also known as endosialin or CD248, is a type I transmembrane glycoprotein containing a C-type lectin-like domain. It is highly expressed in pericytes and fibroblasts. Dermal fibroblasts play a pivotal role during cutaneous wound healing, especially in the proliferative phase. However, the physiological function of TEM1 in wound healing is still undetermined. During the process of wound healing, the expression of both TEM1 and platelet-derived growth factor (PDGF) receptor α was highly upregulated in myofibroblasts. In vivo, fibroblast activation and collagen deposition in granulation tissues were attenuated, and wound healing was retarded in TEM1-deleted mice. In vitro, the migration, adhesion, and proliferation of NIH3T3 cells were suppressed following TEM1 knockdown by short hairpin RNA. In PDGF-BB-treated NIH3T3 cells, the downstream signal and mitogenic, and chemoattractive effects were inhibited by TEM1 knockdown. In addition, TEM1 and PDGF receptor α were colocalized in subcellular organelles in fibroblasts, and the association of TEM1 and PDGF receptor α was demonstrated by coimmunoprecipitation. In summary, these findings suggested that TEM1, in combination with PDGF receptor α, plays a critical role in wound healing by enhancing the mitogenic and chemoattractive effects of PDGF-BB and collagen deposition in myofibroblasts.

To investigate whether recombinant thrombomodulin containing all the extracellular domains (rTMD123) has therapeutic potential against aneurysm development.The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by chronic inflammation and proteolytic degradation of extracellular matrix. Thrombomodulin, a transmembrane glycoprotein, exerts anti-inflammatory activities such as inhibition of cytokine production and sequestration of proinflammatory high-mobility group box 1 (HMGB1) to prevent it from engaging the receptor for advanced glycation end product (RAGE) that may sustain inflammation and tissue damage.The in vivo effects of treatment and posttreatment with rTMD123 on aortic dilatation were measured using the CaCl2-induced AAA model in mice.Characterization of the CaCl2-induced model revealed that HMGB1 and RAGE, both localized mainly to macrophages, were persistently upregulated during a 28-day period of AAA development. In vitro, rTMD123-HMGB1 interaction prevented HMGB1 binding to macrophages, thereby prohibiting activation of HMGB1-RAGE signaling in macrophages. In vivo, short-term treatment with rTMD123 upon AAA induction suppressed the levels of proinflammatory cytokines, HMGB1, and RAGE in the aortic tissue; reduced the infiltrating macrophage number; and finally attenuated matrix metalloproteinase production, extracellular matrix destruction, and AAA formation without disturbing vascular calcification. Consistently, posttreatment with rTMD123 seven days after AAA induction alleviated vascular inflammation and retarded AAA progression.These data suggest that rTMD123 confers protection against AAA development. The mechanism of action may be associated with reduction of proinflammatory mediators, blockade of macrophage recruitment, and suppression of HMGB1-RAGE signaling involved in aneurysm formation and downstream macrophage activation.