Deficiency of S100A8/A9 attenuates pulmonary microvascular leakage in septic mice.

BACKGROUND: We have reported a positive correlation between S100 calcium-binding protein (S100) A8/S100A9 and sepsis-induced lung damage before. However, limited knowledge exists concerning the biological role of S100A8/A9 in pulmonary vascular endothelial barrier dysfunction, as well as the diagnostic value of S100A8/A9 in sepsis. METHODS: Sepsis was induced in C57BL/6J mice and S100A9-knockout (KO) mice through the cecal ligation and puncture (CLP). Pulmonary vascular leakage was determined by measuring extravasated Evans blue (EB). Reverse transcription polymerase chain reaction and the histological score were used to evaluate inflammation and lung injury, respectively. Recombinant S100A8/A9 (rhS100A8/A9) was used to identify the effects of S100A8/A9 on endothelial barrier dysfunction in human umbilical vein endothelial cells (HUVECs). Additionally, the diagnostic value of S100A8/A9 in sepsis was assessed using receiver operating characteristic. RESULTS: S100A8/A9 expression was up-regulated in the lungs of CLP-operated mice. S100A9 KO significantly reversed CLP-induced hypothermia and hypotension, resulting in an improved survival rate. S100A9 KO also decreased the inflammatory response, EB leakage, and histological scores in the lungs of CLP-operated mice. Occludin and VE-cadherin expressions were decreased in the lungs of CLP-operated mice; However, S100A9 KO attenuated this decrease. Moreover, CLP-induced signal transducer and activator of transcription 3 (STAT3) and p38/extracellular signal-regulated kinase (ERK) signalling activation and apoptosis were mitigated by S100A9 KO in lungs. In addition, rhS100A8/A9 administration significantly decreased occludin and VE-cadherin expressions, increased the phosphorylated (p)-ERK/ERK, p-p38/p38, and B-cell leukaemia/lymphoma 2 protein (Bcl-2)-associated X protein/Bcl-2 ratios in HUVECs. CONCLUSION: The present study demonstrated S100A8/A9 aggravated sepsis-induced pulmonary inflammation, vascular permeability, and lung injury. This was achieved, at least partially, by activating the P38/STAT3/ERK signalling pathways. Moreover, S100A8/A9 showed the potential as a biomarker for sepsis diagnosis.

Cytokine Biomarker Phenotype for Early Prediction and Triage of Sepsis in Blunt Trauma Patients.

BACKGROUND: Altered levels of inflammatory markers secondary to severe trauma present a major problem to physicians and are prone to interfering with the clinical identification of sepsis events. This study aimed to establish the profiles of cytokines in trauma patients to characterize the nature of immune responses to sepsis, which might enable early prediction and individualized treatments to be developed for targeted intervention. METHODS: A 15-plex human cytokine magnetic bead assay system was used to measure analytes in citrated plasma samples. Analysis of the kinetics of these cytokines was performed in 40 patients with severe blunt trauma admitted to our trauma center between March 2016 and February 2017, with an Injury Severity Score (ISS) greater than 20 with regard to sepsis (Sepsis-3) over a 14-d time course. RESULTS: In total, the levels of six cytokines were altered in trauma patients across the 1-, 3-, 5-, 7-, and 14-d time points. Additionally, IL-6, IL-10, IL-15, macrophage derived chemokine (MDC), GRO, sCD40 L, granulocyte colony-stimulating factor (G-CSF), and fibroblast growth factor (FGF)-2 levels could be used to provide a significant discrimination between sepsis and nonsepsis patients at day 3 and afterward, with an area under the curve (AUC) of up to 0.90 through a combined analysis of the eight biomarkers (P < 0.001). Event-related analysis demonstrated 1.5- to 4-fold serum level changes for these cytokines within 72 h before clinically apparent sepsis. CONCLUSIONS: Cytokine profiles demonstrate a high discriminatory ability enabling the timely identification of evolving sepsis in trauma patients. These abrupt changes enable sepsis to be detected up to 72 h before clinically overt deterioration. Defining cytokine release patterns that distinguish sepsis risk from trauma patients might enable physicians to initiate timely treatment and reduce mortality. Large prospective studies are needed to validate and operationalize the findings. TRIAL REGISTRATION: Clinicaltrials, NCT01713205. Registered October 22, 2012, https://register. CLINICALTRIALS: gov/NCT01713205.

The Feasibility and Effectiveness of Wearable Sensor Technology in the Management of Elderly Diabetics with Foot Ulcer Remission: A Proof-Of-Concept Pilot Study with Six Cases.

AIMS: Using specials wearable sensors, we explored changes in gait and balance parameters, over time, in elderly patients at high risk of diabetic foot, wearing different types of footwear. This assessed the relationship between gait and balance changes in elderly diabetic patients and the development of foot ulcers, in a bid to uncover potential benefits of wearable devices in the prognosis and management of the aforementioned complication. METHODS: A wearable sensor-based monitoring system was used in middle-elderly patients with diabetes who recently recovered from neuropathic plantar foot ulcers. A total of 6 patients (age range: 55-80 years) were divided into 2 groups: the therapeutic footwear group (n = 3) and the regular footwear (n = 3) group. All subjects were assessed for gait and balance throughout the study period. Walking ability and gait pattern were assessed by allowing participants to walk normally for 1 min at habitual speed. The balance assessment program incorporated the "feet together" standing test and the instrumented modified Clinical Test of Sensory Integration and Balance. Biomechanical information was monitored at least 3 times. RESULTS: We found significant differences in stride length (p < 0.0001), stride velocity (p < 0.0001), and double support (p < 0.0001) between the offloading footwear group (OG) and the regular footwear group on a group × time interaction. The balance test embracing eyes-open condition revealed a significant difference in Hip Sway (p = 0.004), COM Range ML (p = 0.008), and COM Position (p = 0.004) between the 2 groups. Longitudinally, the offloading group exhibited slight improvement in the performance of gait parameters over time. The stride length (odds ratio 3.54, 95% CI 1.34-9.34, p = 0.018) and velocity (odds ratio 3.13, 95% CI 1.19-8.19, p = 0.033) of OG patients increased, converse to the double-support period (odds ratio 6.20, 95% CI 1.97-19.55, p = 0.002), which decreased. CONCLUSIONS: Special wearable devices can accurately monitor gait and balance parameters in patients in real time. The finding reveals the feasibility and effectiveness of advanced wearable sensors in the prevention and management of diabetic foot ulcer and provides a solid background for future research. In addition, the development of foot ulcers in elderly diabetic patients may be associated with changes in gait parameters and the nature of footwear. Even so, larger follow-up studies are needed to validate our findings.

The Chinese consensus for surgical treatment of traumatic rib fractures 2021 (C-STTRF 2021).

Rib fracture is the most common injury in chest trauma. Most of patients with rib fractures were treated conservatively, but up to 50% of patients, especially those with combined injury such as flail chest, presented chronic pain or chest wall deformities, and more than 30% had long-term disabilities, unable to retain a full-time job. In the past two decades, surgery for rib fractures has achieving good outcomes. However, in clinic, there are still some problems including inconsistency in surgical indications and quality control in medical services. Before the year of 2018, there were 3 guidelines on the management of regional traumatic rib fractures were published at home and abroad, focusing on the guidance of the overall treatment decisions and plans; another clinical guideline about the surgical treatment of rib fractures lacks recent related progress in surgical treatment of rib fractures. The Chinese Society of Traumatology, Chinese Medical Association, and the Chinese College of Trauma Surgeons, Chinese Medical Doctor Association organized experts from cardiothoracic surgery, trauma surgery, acute care surgery, orthopedics and other disciplines to participate together, following the principle of evidence-based medicine and in line with the scientific nature and practicality, formulated the Chinese consensus for surgical treatment of traumatic rib fractures (STTRF 2021). This expert consensus put forward some clear, applicable, and graded recommendations from seven aspects: preoperative imaging evaluation, surgical indications, timing of surgery, surgical methods, rib fracture sites for surgical fixation, internal fixation method and material selection, treatment of combined injuries in rib fractures, in order to provide guidance and reference for surgical treatment of traumatic rib fractures.

Emergency Surgery for Blunt Cardiac Injury: Experience in 43 Cases.

BACKGROUND: Blunt cardiac injury (BCI) increases with traffic accidents and is an important cause of death in trauma patients. In particular, for patients who need surgical treatment, the mortality rate is extremely high unless the patient is promptly operated on. This study aimed to explore early recognition and expeditious surgical intervention to increase survival. METHODS: All patients with BCIs during the past 15 years were reviewed, and those who underwent operative treatment were analyzed retrospectively regarding the mechanism of injury, diagnostic and therapeutic methods, and outcome. RESULTS: A total of 348 patients with BCIs accounted for 18.3% of 1903 patients with blunt thoracic injury (BTI). Of 348 patients, 43 underwent operative treatment. The main cause of injury was traffic accidents, with an incidence of 48.8%. Of them, steering wheel injuries occurred in 15 patients. In 26 patients, a preoperative diagnosis was obtained by echocardiography, CT scanning, etc. In the remaining 17, who had to undergo urgent thoracotomy without any preoperative imaging, a definitive diagnosis of BCI was proven during the operation. The volume of preoperative infusion or crystalloid was <1000 ml in 31 cases. Preoperative pericardiocentesis was not used in anyone. In 12 patients, the operation commenced within 1 h. Overall mortality was 32.6%. The death was caused by BCI in 9. CONCLUSIONS: Facing a patient with BTI, a high index of suspicion for BCI must be maintained. To manage those requiring operations, early recognition and expeditious thoracotomy are essential. Preoperatively, limited fluid resuscitation is emphasized. We do not advocate preoperative pericardiocentesis.

Enhancer polymorphism rs10865710 associated with traumatic sepsis is a regulator of PPARG gene expression.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is a major regulator in sepsis. Our previous study identified the enhancer polymorphism rs10865710C/G to be associated with susceptibility to sepsis in trauma patients. We performed two-stage cohort studies integrating biological experiments of potential functional variants that modify susceptibility to traumatic sepsis. METHODS: Improved multiplex ligation detection reaction (iMLDR) was used to genotype rs10865710 in 797 Han Chinese trauma patients in Chongqing. Clinical relevance was validated in 334 patients in Guizhou. The potential function of rs10865710 in transcriptional regulation was explored through a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Expression of PPARγ was assessed by expression quantitative trait locus (e-QTL) and western blot analyses. RESULTS: The association results confirmed rs10865710 to be significantly strongly associated with sepsis risk in trauma patients of the Chongqing and Guizhou cohorts (OR = 1.41 (1.11-1.79), P = 0.004 and OR = 1.45 (1.01-2.09), P = 0.046, both for allele-dose effect, respectively). A meta-analysis of both cohorts and a previous study indicated strong evidence for this association (OR = 1.41 (1.17-1.71), P = 0.0004 for the dominant model, OR = 1.78 (1.34-2.36), P < 0.0001 for the recessive model and OR = 1.38 (1.20-1.58), P < 0.0001 for the allelic model). Functional experiments verified that rs10865710 was a causative variant influencing enhancer activity (G vs. C, 0.068 ± 0.004 vs. 0.096 ± 0.002, P = 0.0005) and CREB2 binding. Expression analysis also indicatevd rs10865710 genotypes to be associated with levels of PPARγ expression (P = 9.2 × 10-5 for dominant effect and P = 0.005 for recessive effect). CONCLUSIONS: Our study provides evidence that the enhancer-region polymorphism rs10865710 might influence transcription factor binding and regulate PPARγ expression, thus conferring susceptibility to traumatic sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01713205. Registered 18 October 2012, retrospectively registered.

China Medical Team: Medical rescue for "4.25" Nepal earthquake.

In recent years, global natural disasters have been frequent and resulted in great casualties and property loss. Since Wenchuan earthquake, the disaster emergency rescue system of China has obtained considerable development in various aspects including team construction, task scheduling, personnel training, facilities and equipments, logistics, etc. On April 25, 2015, an earthquake that measured 8.1 on the Richter scale attacked Nepal. Chinese government firstly organized a medical team, named China Medical Team, and sent it to the attacked region in Nepal to implement medical rescue. The medical team completed the rescue mission successfully and creatively based on their experiences.

Genetic variants of microRNA sequences and susceptibility to sepsis in patients with major blunt trauma.

OBJECTIVE: The objective of this study was to conduct a systematic survey of common precursor microRNA (pre-miRNA) single nucleotide polymorphisms (SNPs) and evaluate their clinical relevance in patients with major blunt trauma. BACKGROUND: Recent evidence indicates that small noncoding RNA molecules known as miRNAs can function as important negative gene regulators and are implicated in the pathogenesis of various diseases. METHODS: We conducted a 2-stage study to examine the impact of 9 selected SNPs with potential functional significance on the susceptibility to sepsis of 1268 trauma patients (1 screening cohort, n = 666) and 2 independent validated cohorts (n = 286 and n = 316, respectively) in China. RESULTS: Among the 9 selected SNPs with potential functional significance, only 1 (miR-608 rs4919510) was found to be strongly associated with a higher risk of developing sepsis and multiple organ dysfunction in all 3 independent study cohorts. An even stronger association was observed for the rs4919510 polymorphism when combining these 3 study cohorts together. In addition, the rs4919510 polymorphism showed a significant correlation with a higher production of proinflammatory cytokines and a lower production of anti-inflammatory cytokines. In vitro experiments further indicated that the G→C variant of this polymorphism could significantly increase the expression of mature miR-608. CONCLUSIONS: Our results indicate that the rs4919510G/C SNP in hsa-mir-608 may be a prognostic biomarker for sepsis in patients with major trauma. Further characterization of miRNA SNPs may open new avenues for studying sepsis and developing novel therapeutic approaches.

Plasma levels of high mobility group box 1 increase in patients with posttraumatic stress disorder after severe blunt chest trauma: a prospective cohort study.

BACKGROUND: High-mobility group box 1 (HMGB1), a key late mediator of systemic inflammation, is a potentially useful biomarker for predicting outcome in patients with severe blunt chest trauma. The purpose of this study was to define the relationship between plasma levels of HMGB1 and posttraumatic stress disorder (PTSD) in patients with severe blunt chest trauma. METHODS: All patients with severe blunt chest trauma (abbreviated injury score ≥3) who were admitted to traumatic surgery department and ultimately survived to follow-up at 6 mo were eligible for the study. HMGB1 was sampled every other day from day 1-day 7 after admission, and plasma concentrations of HMGB1 were measured by a quantitative enzyme-linked immunosorbent assay test. Multivariate regression analysis was used to define the independent contribution of possible risk factors selected by univariate analysis. RESULTS: PTSD was identified in 43 patients including acute PTSD (n = 21), chronic PTSD (n = 18), and delayed-onset PTSD (n = 4) after 6-mo follow-up, in whom significant higher plasma levels of HMGB1 on days three, five, and seven after blunt chest trauma were noted compared with those seen in patients without PTSD (n = 10). Multivariate logistic analysis showed that transfusion, injury severity score, and HMGB1 levels at day 7 were the valuable risk factors for PTSD. CONCLUSIONS: In blunt chest trauma, plasma HMGB1 levels were significantly higher in patients with PTSD compared with patients with non-PTSD. Our data indicate that patients with high plasma levels of HMGB1 may be more prone to develop PTSD including acute and chronic PTSD.

Multi-slice computed tomography for diagnosis of combined thoracoabdominal injury.

PURPOSE: To investigate the diagnostic value of multi-slice computed tomography (MSCT) for combined thoracoabdominal injury. METHODS: A retrospective study was conducted to analyze the clinical data and MSCT images of 68 patients who sustained a combined thoracoabdominal injury associated with diaphragm rupture, and 18 patients without diaphragm rupture. All the patients were admitted and treated in the Chongqing Emergency Medical Center (a level I trauma center) between July 2005 and February 2014. There were 71 males and 15 females with a mean age of 39.1 years (range 13e88 years). Among the 86 patients, 40 patients suffered a penetrating injury, 46 suffered a blunt injury as a result of road traffic accident in 21 cases, fall from a height in 16, and crushing injury in 9. The MSCT images were retrospectively reviewed by two radiologists. The results of CT diagnosis were compared with surgical findings and/or follow-up results. RESULTS: Among the 86 cases, diaphragm discontinuity was found in 29 cases, segmental nonrecognition of the diaphragm in 14, diaphragmatic hernia in 21, collar sign in 14, dependent viscera sign in 18, elevated abdominal organs in 21, bowel wall thickening and/or hematoma in 6, and pneumoperitoneum in 8. CT diagnostic accuracy for diaphragm rupture was 88.4% in the right side and 90.7% in the left side. CT diagnostic accuracy for hemopneumothorax, pulmonary contusion, mediastinal hemorrhage, kidney and adrenal gland injuries was 100%, while for liver, spleen and pancreas injuries was 96.5%, 96.5%, 94.2% respectively. CONCLUSION: To reach an early diagnosis of combined thoracoabdominal injury, surgeons and radiologists should be familiar with all kinds of images which might show signs of diaphragm rupture, such as diaphragm discontinuity, segmental nonrecognition of the diaphragm, dangling diaphragm sign, diaphragm herniation, collar sign, dependent viscera sign, and elevated abdominal organs.

Mobile emergency (surgical) hospital: Development and application in medical relief of "4.20" Lushan earthquake in Sichuan Province, China.

In the 21st century, natural disasters and emergencies occur frequently worldwide, which leads to the loss of hundreds of thousands of lives as well as the direct and indirect economic losses. China has a vast territory frequently struck by natural disasters. However, the reality is not optimistic. Poor organization and management during the rescue actions, the lack of large-scale, systematic medical rescue equipment were all great barriers to the outcomes. Mobile hospitals are expected to provide better health care. We were inspired by the concept of mobile hospital. Chongqing Emergency Medical Center, has set up trauma care system since 1988, in which prehospital care, intensive care, and in-hospital treatment is fully integrated. As a major advantage, such a system provided assurance of "golden hour" rescue treatment. Providing mobile intensive care and prehospital surgical service for severe trauma patients could reduce mortality significantly. Based on the civilian experiences in Chongqing Emergency Medical Center, the mobile emergency (surgical) hospital was developed.

Traumatic diaphragmatic rupture with combined thoracoabdominal injuries: Difference between penetrating and blunt injuries.

PURPOSE: Traumatic diaphragmatic rupture (TDR) needs early diagnosis and operation. However, the early diagnosis is usually difficult, especially in the patients without diaphragmatic hernia. The objective of this study was to explore the early diagnosis and treatment of TDR. METHODS: Data of 256 patients with TDR treated in our department between 1994 and 2013 were analyzed retrospectively regarding to the diagnostic methods, percentage of preoperative judgment, incidence of diaphragmatic hernia, surgical procedures and outcome, etc. Two groups were set up according to the mechanism of injury (blunt or penetrating). RESULTS: Of 256 patients with a mean age of 32.4 years (9-84), 218 were male. The average ISS was 26.9 (13-66); and shock rate was 62.9%. There were 104 blunt injuries and 152 penetrating injuries. Preoperatively diagnostic rate was 90.4% in blunt injuries and 80.3% in penetrating, respectively, P < 0.05. The incidence of diaphragmatic hernia was 94.2% in blunt and 15.1% in penetrating respectively, P < 0.005. Thoracotomy was performed in 62 cases, laparotomy in 153, thoracotomy plus laparotomy in 29, and combined thoraco-laparotomy in 12. Overall mortality rate was 12.5% with the average ISS of 41.8; and it was 21.2% in blunt injuries and 6.6% in penetrating, respectively, P < 0.005. The main causes of death were hemorrhage and sepsis. CONCLUSIONS: Diagnosis of blunt TDR can be easily obtained by radiograph or helical CT scan signs of diaphragmatic hernia. For penetrating TDR without hernia, "offside sign" is helpful as initial assessment. CT scan with coronal/sagittal reconstruction is an accurate technique for diagnosis. All TDR require operation. Penetrating injury has a relatively better prognosis.

Brachiocephalic trunk and left brachiocephalic vein injuries following penetrating right sternoclavicular junction trauma: a case report.

A 46-year-old male sustained severe pe- netrating injury by a sharp instrument to his right upper sternoclavicular junction. The wound tract was from suprasternal notch to mediastinum. Exploratory operation via median sternotomy under general anesthesia found a large mediastinal septum hematoncus, as well as brachiocephalic trunk and left brachiocephalic vein injuries. The perforating vascular wounds were repaired with 5-0 prolene suture. He was recovered uneventfully and discharged 9 days after operation. There was no sequel found during 7 years follow-up.

[Risk factors of mortality in severe chest trauma patients].

OBJECTIVE: To investigate the risk factors of mortality in patients with severe chest trauma (SCT). METHODS: The clinical data of 777 SCT [abbreviated injury scale (AIS) ≥3] patients who were treated in the Chongqing Emergency Medical Center from January 2006 to April 2009 were retrospectively reviewed. Stepwise logistic regression analysis was used to explore 15 possible mortality-related risk factors. RESULTS: Seven factors were found to be correlated with the mortality of SCT: age, hemorrhagic shock, multiple organ dysfunction syndrome (MODS), pulmonary infection, abdominal organ injury, Glasgow coma scale (GCS) score, and thorax AIS score. Among them five factors were the independent factors that might increase the mortality of SCT: hemorrhagic shock (B=1.710, OR=1.291, P=0.001), MODS (B=3.453, OR=1.028, P<0.001), pulmonary infection (B=2.396, OR=10.941, P<0.001), abdominal organ injury (B=1.542, OR=1.210, P=0.005), and thorax AIS score ≥4 (B=0.487, OR=1.622, P<0.001). Two factors showed protective effects: age ≤60 years (B=-0.035, OR=0.962, P=0.01) and GCS score ≥12 (B=-0.635, OR=0.320, P<0.001). CONCLUSIONS: Age, disease severity, and complications (hemorrhagic shock, MODS, and pulmonary infection) are independent risk factors of the mortality of SCT. Effective treatment programs targeting these risk factors may improve the outcomes of SCT patients.

Risk factors of serious postoperative outcomes in patients aged ≥90 years undergoing surgical intervention.

Objective: We aimed to identify preoperative and intraoperative factors associated with serious postoperative outcomes, which may help patients and clinicians make better-informed decisions. Methods: We conducted a retrospective study including all patients aged ≥90 years who underwent surgery between January 1, 2011, and January 1, 2021, at Chongqing University Central Hospital. We assessed 30 pre- and intraoperative demographic and clinical variables. Logistic regression was used to identify the independent risk factors for serious postoperative outcomes in patients aged ≥90 years. Results: A total of 428 patients were included in our analysis. The mean age was 92.6 years (SD ± 2.6). There were 240 (56.1%) females and 188 (43.9%) males. The most common comorbidities were hypertension (44.9%) and arrhythmias (34.8%). The 30-day hospital mortality was 5.6%, and severe morbidity was 33.2%. Based on the multivariate logistic regression classification analysis of the American Society of Anesthesiologists (ASA)≥ Ⅳ [odds ratio (OR), 5.39, 95% confidence interval (CI), 2.06-14.16, P = .001], emergency surgery (OR, 5.02, 95% CI, 2.85-15.98, P = .001) and chronic heart failure (OR, 6.11, 95% CI, 1.93-13.06, P = .001) were identified as independent risk factors for 30-day hospital mortality, and ASA≥ Ⅳ (OR, 4.56, 95%CI, 2.56-8.15, P < .001), Barthel index (BI) < 35 (OR, 2.28, 95%CI, 1.30-3.98, P = .001), chronic heart failure (OR, 3.67, 95%CI, 1.62-8.31, P = .002), chronic kidney disease (OR, 4.24, 95%CI, 1.99-9.05, P < .001), general anesthesia (OR, 3.31, 95%CI, 1.91-5.76, P < .001), emergency surgery (OR, 3.72, 95%CI, 1.98-6.99, P < .001), and major surgery (OR, 3.44, 95%CI, 1.90-6.22, P < .001) were identified as independent risk factors for serious postoperative complications. Conclusions: Patients aged ≥90 years with ASA≥ Ⅳ, BI < 35, combined with chronic heart failure or chronic kidney disease, undergoing emergency surgery, major surgery or general anesthesia have a higher risk of serious postoperative outcomes. Identifying these risk factors in an early stage may contribute to our clinical decision-making and improve the quality of treatments.

Senescent endothelial cells' response to the degradation of bioresorbable scaffold induces intimal dysfunction accelerating in-stent restenosis.

Atherosclerotic cardiovascular disease is a typical age-related disease accompanied by stiffening arteries. We aimed to elucidate the influence of aged arteries on in-stent restenosis (ISR) after the implantation of bioresorbable scaffolds (BRS). Histology and optical coherence tomography showed increased lumen loss and ISR in the aged abdominal aorta of Sprague-Dawley rats, with apparent scaffold degradation and deformation, which induce lower wall shear stress (WSS). This was also the case at the distal end of BRS, where the scaffolds degraded faster, and significant lumen loss was followed by a lower WSS. In addition, early thrombosis, inflammation, and delayed re-endothelialization were presented in the aged arteries. Degradation of BRS causes more senescent cells in the aged vasculature, increasing endothelial cell dysfunction and the risk of ISR. Thus, profoundly understanding the mechanism between BRS and senescent cells may give a meaningful guide for the age-related scaffold design. STATEMENT OF SIGNIFICANCE: The degradation of bioresorbable scaffolds aggravates senescent endothelial cells and a much lower wall shear stress areas in the aged vasculature, lead to intimal dysfunction and increasing in-stent restenosis risk. Early thrombosis and inflammation, as well as delayed re-endothelialization, are presented in the aged vasculature after bioresorbable scaffolds implantation. Age stratification during the clinical evaluation and senolytics in the design of new bioresorbable scaffolds should be considered, especially for old patients.

iNOS aggravates pressure overload-induced cardiac dysfunction via activation of the cytosolic-mtDNA-mediated cGAS-STING pathway.

Background: Sterile inflammation contributes to the pathogenesis of cardiac dysfunction caused by various conditions including pressure overload in hypertension. Mitochondrial DNA (mtDNA) released from damaged mitochondria has been implicated in cardiac inflammation. However, the upstream mechanisms governing mtDNA release and how mtDNA activates sterile inflammation in pressure-overloaded hearts remain largely unknown. Here, we investigated the role of inducible NO synthase (iNOS) on pressure overload-induced cytosolic accumulation of mtDNA and whether mtDNA activated inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Methods: To investigate whether the cGAS-STING cascade was involved in sterile inflammation and cardiac dysfunction upon pressure overload, cardiomyocyte-specific STING depletion mice and mice injected with adeno-associated virus-9 (AAV-9) to suppress the cGAS-STING cascade in the heart were subjected to transverse aortic constriction (TAC). iNOS null mice were used to determine the role of iNOS in cGAS-STING pathway activation in pressure-stressed hearts. Results: iNOS knockout abrogated mtDNA release and alleviated cardiac sterile inflammation resulting in improved cardiac function. Conversely, activating the cGAS-STING pathway blunted the protective effects of iNOS knockout. Moreover, iNOS activated the cGAS-STING pathway in isolated myocytes and this was prevented by depleting cytosolic mtDNA. In addition, disruption of the cGAS-STING pathway suppressed inflammatory cytokine transcription and modulated M1/M2 macrophage polarization, and thus mitigated cardiac remodeling and improved heart function. Finally, increased iNOS expression along with cytosolic mtDNA accumulation and cGAS-STING activation were also seen in human hypertensive hearts. Conclusion: Our findings demonstrate that mtDNA is released into the cytosol and triggers sterile inflammation through the cGAS-STING pathway leading to cardiac dysfunction after pressure overload. iNOS controls mtDNA release and subsequent cGAS activation in pressure-stressed hearts.

A functional variant of lipopolysaccharide binding protein predisposes to sepsis and organ dysfunction in patients with major trauma.

OBJECTIVE: To determine the hypothesis that genetic variations of the lipopolysaccharide-binding protein (LBP) gene influence risk for the development of sepsis and multiple organ dysfunction (MOD) in patients with major trauma. BACKGROUND: Lipopolysaccharide-binding protein plays a central role in innate immune response as the first line of defense and directing the microbial-induced activation of the inflammatory host response. Although a total of 112 single nucleotide polymorphisms (SNPs) have been identified so far within the entire LBP gene, only a few SNPs have been studied. METHODS: Nine haplotype tagging SNPs (htSNPs) were selected from 51 SNPs with a minor allele frequency of ≥5% using the HapMap database for the Chinese Han population. Two independent cohorts of major trauma patients were recruited. The 9 htSNPs were genotyped using pyrosequencing method and analyzed in relation to the risk of development of sepsis and MOD, LBP production, and lipopolysaccharide (LPS)-induced activation of peripheral blood leukocytes. Moreover, the functionality of the rs2232618 polymorphism was assessed by the observation of its effects on the binding and activation of LPS and the LBP-CD14 interaction. RESULTS: Among the 9 htSNPs, only the rs2232618 was significantly associated with higher susceptibility to sepsis and MOD in the 2 independent cohorts of major trauma patients recruited from southwest and eastern China. This SNP was also significantly associated with LPS-induced activation of peripheral blood leukocytes. In addition, the rs2232618 polymorphism could enhance LBP protein activities, showing significant increases in LPS binding to macrophages, LPS-induced cellular activation, and LBP-CD14 interaction at the presence of the variant LBP protein. CONCLUSIONS: The rs2232618 polymorphism is a functional SNP and confers host susceptibility to sepsis and multiple organ dysfunction in patients with major trauma.

Identification of haplotype tag single nucleotide polymorphisms within the receptor for advanced glycation end products gene and their clinical relevance in patients with major trauma.

INTRODUCTION: The receptor for advanced glycation end products (RAGE) has been considered as one of the major pattern recognition receptors and plays an important role in the development of sepsis and multiple organ dysfunction in critical illnesses. Although genetic variants of the RAGE gene have been shown to be well associated with susceptibility to some inflammatory diseases, little is known about their clinical relevance in the development of sepsis in critical ill patients. METHODS: Four genetic variants were selected from the entire RAGE gene and genotyped using pyrosequencing and polymerase chain reaction-length polymorphism methods. Association studies were performed in two independent Chinese Han populations. RESULTS: Among the four genetic variants, only the rs1800625 polymorphism was significantly associated with sepsis morbidity rate and multiple organ dysfunction (MOD) scores in patients with major trauma both in Chongqing (n = 496) and Zhejiang (n = 232) districts, respectively. Results from ex vivo responsiveness of peripheral blood leukocytes indicated that the rs1800625 polymorphism was well associated with decreased production of TNFα. In addition, the rs1800625 polymorphism could significantly inhibit the promoter activities of the RAGE gene. CONCLUSIONS: The rs1800625 polymorphism is a functional variant, which might be used as a relevant risk estimate for the development of sepsis and multiple organ dysfunction syndrome in patients with major trauma.

Management of metallic foreign bodies in the heart.

Management of the metallic foreign body in the heart remains controversial. Evaluation of possible methods for this issue and its possible treatments are discussed, the results of which may lead to a more effective strategy for management of intracardiac foreign bodies.