Abstract Background The associations between serum uric acid and osteoporosis or osteopenia remain controversial, and few studies have explored whether BMI acts as a mediators in the association between the SUA and OP/ osteopenia. Objective To explore the relationship between serum uric acid and osteoporosis or osteopenia among US adults. Methods A cross-sectional study was conducted to examine the association between serum uric acid and osteoporosis or osteopenia from four cycles of NHANES. Binary logistic regression models and restricted cubic spline models were used to evaluate the association between serum uric acid and osteoporosis or osteopenia, and interaction analysis was used to test the differences between subgroups. Mediation analysis was utilized to investigate whether BMI acts as a mediator in the association between SUA and OP/ osteopenia. Results 12581 participants aged ≥ 18 years were included. A U-shape nonlinear relationship between SUA and osteoporosis or osteopenia in all people was found (P < 0.0001, P for nonlinear = 0.0287). There were significant interactions in age subgroups (P for interaction = 0.044), sex subgroups (P for interaction = 0.005), and BMI subgroups (P for interaction = 0.017). We further assessed the subgroups and found the optimal range of serum uric acid levels with a lower risk of osteoporosis or osteopenia was 357–535 µmol/L in males, 327–417 µmol/L in people aged ≥ 50 years, above 309 µmol/L in people aged < 50 years, 344–445 µmol/L in people with BMI ≥ 30, and above 308 µmol/L in people with BMI < 30. BMI fully mediated the association of SUA and OP/osteopenia, with a value of -0.0024(-0.0026–-0.0021). These results were robust in sensitivity analyses. Conclusions A complicated relationship between SUA and bone health in different populations was observed. Maintaining SUA within a specific range may be beneficial to bone health. In addition, BMI may play an important role in the association between SUA and bone health, but considering the limitations of this study, further prospective research is required.

Purpose: We investigated the risk factors and characteristic clinical features of peripartum cardiomyopathy (PPCM) to lay the groundwork for early identification, screening, diagnosis, and intervention in high-risk pregnant women. Patients and methods: A retrospective case-control study was conducted to analyze data from 44 patients with PPCM and 226 normal pregnant women from a Chinese population. Results: Significant differences were found between the groups in terms of various factors such as age, body mass index (BMI), heart rate, and medical history. Logistic regression models identified abnormal electrocardiography (OR=18.852), upper respiratory tract infection (OR=41.822), gestational hypertension (OR=18.188), and cesarean section ( OR=8.394) as risk factors for PPCM. Common clinical features observed in patients with PPCM included cough, wheezing, and chest tightness (68.18%), left heart enlargement (56.82%) and valvular insufficiency (81.82%). Additionally, cardiotropic virus was detected in a subset of patients (43.18%) and NT-proBNP was elevated >= 400 pg/mL (81.82%). Conclusion: In the Chinese population, the presence of abnormal electrocardiograms during pregnancy, history of upper respiratory tract infection, gestational hypertension, and maternal choice of cesarean section suggest the possibility of PPCM development. Factors such as advanced age, family history of cardiovascular disease, gestational diabetes mellitus, eclampsia, anemia, and hypoproteinemia should be considered. Clinically, patients present with cough, wheezing, chest tightness, enlarged left heart, valvular insufficiency and NT-proBNP elevated >= 400 pg/mL. This study could serve as a valuable reference for medical practitioners for the early identification and screening of patients with PPCM.

This research aimed to systematically uncover the metastatic characteristics and survival rates of lung cancer subtypes and to evaluate the impact of surgery at the primary tumor site on cancer-specific survival in DM lung cancer. We used the Surveillance, Epidemiology, and End Results (SEER) database (2010-2019) to identify primary lung cancers with DM at presentation (M1). Kaplan-Meier (KM) survival curves were generated and compared utilizing log-rank tests. Cox regression methods were employed to determine hazard ratios (HR) and 95% confidence intervals related to CSS factors. Inverse probability of treatment weighting (IPTW) was applied to reduce bias. We analyzed 77,827 M1 lung cancer cases, with 41.22% having DM at presentation. Bone metastasis was most common in ADC, ASC, SCC, LCC; brain in LCNEC; liver in SCLC. Lung was common in TC + AC and SCC. Long-term survival was best in TC + AC and worst in SCLC (p < 0.001). Male gender, age < 50, primary tumor site (main bronchus, lower lobe), large tumor diameter, ADC/SCLC/SCC pathology, and regional lymph node involvement were significant risk factors for multiorgan metastasis. Age >= 50, male, large tumor diameter, positive lymph nodes, and multiorgan metastases were associated with lower CSS. In contrast, radiotherapy, chemotherapy, systemic therapy, and surgery were associated with higher CSS rates. Primary tumor resection improved survival in lung cancer patients (excluding small cell lung cancer, SCLC) with single organ metastases (KM log rank p < 0.001, HR = 0.6165; 95% CI (0.5468-0.6951)), especially in brain (p < 0.001, HR = 0.6467; 95% CI (0.5505-0.7596)) and bone (p = 0.182, HR = 0.6289; p < 0.01), but not in liver or intrapulmonary metastases after IPTW. Significant differences in DM patterns and corresponding survival rates exist among lung cancer subtypes. Primary tumor resection improves survival in lung cancer patients (excluding small cell lung cancer, SCLC) with single organ metastases, with better outcomes in patients with brain and bone metastases, while no significant benefit was seen in patients with liver and intrapulmonary metastases.

Background:Coronary artery disease (CAD) is a complex disease and the leading cause of death worldwide. It is caused by genetic and environmental factors or their interactions. Candidate gene association studies are an important genetic strategy for the study of complex diseases, and multiple variants of inflammatory cytokines have been found to be associated with CAD using this method. Interleukin-5 (IL-5) is an important inflammatory immune response factor that plays a role in a various inflammatory disease. Clinical tests and animal experiments indicated that IL-5 is involved in CAD development, but the exact mechanisms are unclear. This study investigated the genetic relationship between the single nucleotide polymorphisms (SNPs) in IL5 and CAD.Materials and Methods:Based on the Chinese Han population, we collected 1,824 patients with CAD and 1,920 control subjects and performed a two-stage case-control association analysis for three SNPs in IL5 (rs2057687, rs78546665, and rs2069812) using the high resolution melt (HRM) technology. Logistic regression analyses were applied to adjust for traditional risk factors for CAD and to perform haplotype and gene interaction analyses. Multiple linear regression analyses were used to study relationships between the selected SNPs and serum lipid levels.Results:In this study, two-stage case-control association analysis revealed that the allele and genotype frequency distributions of the three IL5 SNPs were not statistically significant between the case and control groups. In addition, none of the IL5 haplotypes were associated with CAD. Further stratified analyses were conducted by sex, age, hypertension, and disease status, respectively, and the results revealed that the rs2057687 and rs2069812 of IL5 were associated with CAD in the male group (p adj = 0.025, OR, 0.77 (95% CI, 0.62-0.97); p adj = 0.016, OR, 0.82 (95% CI, 0.70-0.97), respectively); the rs2057687 and rs78546665 of IL5 were associated with late-onset CAD (p adj = 0.039, OR, 0.78 (95% CI, 0.62-0.99); p adj = 0.036, OR, 1.46 (95% CI, 1.02-1.53), respectively); the rs2069812 of IL5 was associated with CAD in the hypertension group (p adj = 0.036, OR, 0.84 (95% CI, 0.71-0.99)); and none of the SNPs in IL5 were associated with different CAD states (anatomical CAD and clinical CAD). In addition, the association between SNPs and the serum lipid levels indicated that rs78546665 was positively correlated with triglyceride levels (p = 0.012). Finally, SNP-SNP interaction analyses revealed that interactions of rs2057687 and rs2069812 were associated with CAD (p adj = 0.046, OR, 0.77 (95% CI, 0.13-4.68)).Conclusion:This study suggested that the common variants of IL5 might play a role in CAD by affecting the risk factors for CAD and through SNP-SNP interactions, which provides a new target for specific treatment of CAD patients and a theoretical basis for personalized medicine.

Esophageal squamous cell carcinoma (ESCC) consistently ranks as one of the most challenging variants of squamous cell carcinomas, primarily due to the lack of effective early detection strategies. We herein aimed to elucidate the underlying mechanisms and biological role associated with A-kinase anchoring protein 12 (AKAP12) in the context of ESCC. Bioinformatic analysis had revealed significantly lower expression level of AKAP12 in ESCC tissue samples than in their non-cancerous counterparts. To gain deeper insights into the potential role of AKAP12 in the progression of ESCC, we conducted a single-gene set enrichment analysis of AKAP12 on ESCC datasets. Our findings suggested that AKAP12 exhibits functions inhibiting cell cycle progression, tumor proliferation, and epithelial-mesenchymal transition. To further validate our findings, we subjected ESCC cell lines to AKAP12 overexpression using CRISPR/Cas9-SAM. In vitro analyses demonstrated that increased expression of AKAP12 significantly reduced cell proliferation, migration, and cell cycle progression. Simultaneously, genes associated with this biological role undergo corresponding regulatory shifts. These observations provided valuable insights into the biological role played by AKAP12 in ESCC progression. In summary, AKAP12 shows promise as a new potential biomarker for early ESCC diagnosis, offering potential advantages for subsequent therapeutic intervention and disease management.

BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is fibrotic lung disease with no effective treatment. It is characterized by destruction of alveolar structure and pulmonary interstitial fibrosis, leading to dyspnea and even asphyxia death of patients. Epithelial-mesenchymal transition (EMT) is considered to be a driving factor in the pathogenesis of IPF. Osteopontin (OPN) is a secreted protein widely present in the extracellular matrix and involved in the occurrence and development of a variety of diseases.METHODS:The original datasets were obtained from NCBI GEO databases analyzed with the online tool GEO2R and EasyGEO. Bleomycin induced mouse pulmonary fibrosis model and OPN/OPN-biotin treated mouse model were established to investigate the role of OPN in mouse pulmonary fibrosis and the target cells of OPN. A549 cells and HBE cells were used to explore the mechanism of OPN-induced epithelial-mesenchymal transition (EMT) in epithelial cells and mass spectrometry was used to detect OPN downstream receptors. Precision-cut lung slices and lentivirus-treated mice with pulmonary fibrosis were used to examine the therapeutic effect of OPN and its downstream pathways on pulmonary fibrosis.RESULTS:We demonstrate that the content of OPN in IPF bronchoalveolar lavage fluid (BALF) is high compared to the normal groups, and its expression level is correlated with prognosis. At the animal level, OPN was highly expressed at all stages of pulmonary fibrosis in mice, and the bronchoalveolar lavage fluid (BALF) could accurately reflect its expression in the lung. Next, we reveal that OPN was mainly expressed by macrophages and the main target cells of OPN were epithelial cells. Mice developed pulmonary fibrosis accompanied after treating the mice with OPN. Both in vitro and in vivo experiments confirmed that OPN could induce EMT of alveolar epithelial cells. Mechanistically, OPN binding triggered phosphorylation of FAK by CD44, thus activating snail1-mediated profibrotic protein synthesis. Inhibition of FAK phosphorylation and its downstream pathways can effectively alleviate pulmonary fibrosis in precision sections of lung tissue (PCLS) assay. OPN knockdown in bleomycin-induced lung fibrosis mice led to significantly less fibrosis.CONCLUSION:Our data suggest that OPN mediates lung fibrosis through EMT, implicating its potential therapeutic target and prognostic indicator role for IPF. OPN may be a target for the diagnosis and treatment of IPF.

Objective Sarcopenia has been recognized as a third category of complications in people with diabetes. However, few studies focus on the reduction of skeletal muscle mass in young people with diabetes. The aim of this study was to investigate risk factors of pre-sarcopenia in young patients with diabetes and establish a practical tool to diagnose pre-sarcopenia in those people. Methods Patients ( n = 1246) enrolled from the National Health and Nutrition Examination Survey (NHANES) cycle year of 2011 to 2018 were randomly divided into the training set and validation set. The all-subsets regression analysis was used to select the risk factors of pre-sarcopenia. A nomogram model for the prediction of pre-sarcopenia in the diabetic population was established based on the risk factors. The model was evaluated by the area under the receiver operating characteristic curve for discrimination, calibration curves for calibration, and decision curve analysis curves for clinical utility. Results In this study, gender, height, and waist circumference were elected as predictive factors for pre-sarcopenia. The nomogram model presented excellent discrimination in training and validation sets with areas under the curve of 0.907 and 0.912, respectively. The calibration curve illustrated excellent calibration, and the decision curve analysis showed a wide range of good clinical utility. Conclusions This study develops a novel nomogram that integrates gender, height, and waist circumference and can be used to easily predict pre-sarcopenia in diabetics. The novel screen tool is accurate, specific, and low-cost, highlighting its potential value in clinical application.

BackgroundSunburn is a common problem for outdoor workers and casual outdoor walkers. Carotenoids are important elements in normal function of skin tissue and skin metabolism and are critical in the development of some cancers. However, the possible relationships between sunburn sensitivity, carotenoids and the risk of cancers remain unknown.ObjectivesTo explore the associations of serum carotenoids with sunburn severity and the risk of cancers.MethodsA cross-sectional study from the National Health and Nutrition Examination Survey from 1999 to 2018 were conducted. The relationship between sunburn and serum carotenoids, cancers were investigated by unconditional or ordinal logistic regression. Mediation analysis was used to explore the effect of carotenoids on the relationship between sunburn and cancers.ResultsA total of 25,440 US adults from 1999 to 2018 were enrolled in this study. There were significant differences in sex, race and natural hair color between the sunburn and non-sunburn people. The severity of sunburn was significantly associated with serum trans-β-carotene, cis-β-carotene, combined lutein, and vitamin A. The odds ratios of severe reactions were 5.065 (95% CI: 2.266–11.318) in melanoma patients, 5.776 (95% CI: 3.362–9.922) in non-melanoma patients, and 1.880 (95% CI: 1.484–2.380) in non-skin cancers patients. Additionally, serum carotenoids were partially attributable to the effect of sunburn on skin and non-skin cancers.ConclusionSunburn severity was associated with cancers, and severer sunburn was related with higher risk of cancers. Serum carotenoids were also associated with sunburn severity. Moreover, the relationship between sunburn and cancers was mediated by some serum carotenoids.

目的:探讨免疫吸附疗法应用于扩张型心肌病（DCM）患者的有效性和安全性。方法:本研究在国内首次报道免疫吸附疗法成功应用于1例DCM患者，并通过荟萃分析系统性评价免疫吸附疗法在DCM患者中的有效性与安全性。荟萃分析中，我们检索PubMed、Embase、Web of Science-MEDLINE、Cochrane Library、CENTRAL和ClinicalTrials.gov等数据库，查找2000年1月1日—2021年11月26日以英文发表的免疫吸附疗法治疗DCM的临床研究。应用Stata MP Version 15.0和GraphPad Prism Version 7.0软件进行荟萃分析和统计分析。结果:该例DCM患者接受单疗程的免疫吸附治疗后，在18个月随访期间，N末端脑钠肽原下降，左室射血分数增加以及左室舒张末期内径减低。荟萃分析最终纳入11篇文献，包括313例DCM患者，其中免疫吸附组167例，对照组146例，平均随访时间为3～30个月。与对照组相比，免疫吸附组DCM患者NYHA心功能分级得到明显改善（P＜0.000 1）,伴左室射血分数升高（WMD=6.70,95%CI:5.28～8.12）和左室舒张末期内径减低（WMD=-3.65,95%CI:-4.12～-3.19）。免疫吸附组患者未见感染、大出血、肾功能恶化等严重并发症的报道。结论:免疫吸附疗法可明显改善DCM患者的心功能和逆转心脏重构。

Wound healing is closely related to immunity and inflammation. As one of the main effector cells of inflammation, neutrophils have been proved to play an important role in the pathophysiological process of diabetic foot and other types of wound healing. Recent studies have proven that neutrophils can inhibit or hinder wound healing by releasing neutrophil extracellular trap(NET) under the stimulation of inflammation and injury, and play an important role in the process of wound healing. However, the role of NET in different types of wound healing has not been fully elucidated. This article will focus on the latest research progress of immune response and inflammatory response in wound healing, combined with the role of NET in the wound healing of different types to make a review.

Interleukin-9 (IL-9) plays important role in coronary artery disease (CAD). However, the exact relationship between them is not explored yet. Here, four tag SNPs covering IL9 (rs31563, rs2069868, rs2069870 and rs31564) were selected to conduct case-control association analyses in a total of 3704 individuals from Chinese Han population (1863 CAD vs 1841 control). Results showed that: first, rs2069868 was associated with CAD combined with hypertension (P-adj = 0.027); second, IL9 haplotype (CGAT) was associated with CAD (P-adj = 0.035), and the combination genotype of "rs31563_CC/rs31564_TT" would remarkably decrease the risk of CAD (P-adj = 0.001); third, significant associations were found between rs2069870 and decreased LDL-c levels and decreased total cholesterol levels, and between rs31563 and increased HDL-c levels (P-adj < 0.05). Therefore, we conclude that IL9 might play a causal role in CAD by interacted with CAD traditional risk factors, which might confer a new way to improve the prevention and treatment of CAD.

Xie, Tian1; Wang, Shikai1; Zhang, Xiangda2; Ou, Sihua3; Mo, Xiaoqiao4 Author Information

Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p < 0.01). Histopathological analysis showed decreased injury in lung, liver, and intestine in de-escalation therapy compared with escalation therapy (p < 0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p < 0.01), however, no significant difference was found between de-escalation and escalation group (p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.

BACKGROUND:To assess the efficacy and safety of corticosteroids in COVID-19 patients compared with standard care or placebo. METHODS:Electronic databases were searched to identify relevant studies. The mortality, adverse events, and other data from studies were pooled for statistical analysis. RESULTS:Ten randomized clinical trials were eligible for inclusion. Corticosteroid treatment in COVID-19 patients did not significantly reduce the risk of death (RR: 0.93; CI: 0.82, 1.05) and the need for mechanical ventilation (RR: 0.82; CI: 0.62, 1.08). No mortality reduction was also observed in the subgroup of patients requiring mechanical ventilation (RR: 0.90; CI: 0.79-1.03). The use of corticosteroids increased mortality in the subgroup of patients not requiring oxygen support (RR: 1.24; CI: 1.00-1.55). The survival benefit was observed in a low dosage of corticosteroids (RR: 0.90; CI: 0.84-0.97) and dexamethasone (RR: 0.90; 95% CI: 0.79-1.04). There was no difference in the rates of adverse events (RR: 1.13; CI: 0.58, 2.20) and secondary infections (RR: 0.87; CI: 0.66, 1.15). CONCLUSION:Corticosteroid treatment did not convincingly improve survival in severe COVID-19 patients. Low-dose dexamethasone could be considered as a drug for the treatment of COVID-19 patients. More high-quality trials are needed to further verify this conclusion.Expert Opinion: The effect of corticosteroids on patient survival highly depended on the selection of the right dosage and type and in a specific subgroup of patients. This meta-analysis, which included more RCTs, evaluated the safety and efficacy in severe COVID-19 patients and analyzed the effects of different types of corticosteroid treatments. Corticosteroid treatment did not convincingly improve survival in severe COVID-19 patients. But the low dose dexamethasone appear to have a role in the management of severe COVID-19 patients.

在美国建国后,本土医生逐渐形成一个独特的利益集团,美国医学会是医生利益集团的载体.罗斯福新政时期,以美国医学会为代表的医生利益集团为维护自身利益,采取一系列的措施成功阻止了全民医疗保障制度的建立.伟大社会时期,美国出现新一轮医疗保障制度建设呼声,美国医学会对此依然保持消极与抵制态度.由于一些主观因素和客观因素,美国医学会最终没能阻止医疗照顾法案和医疗救助法案的诞生.美国医学会的影响使美国医疗保障制度具有鲜明的特色.

OBJECTIVE:To establish a prognostic Nomogram model for predicting the risk of early death in polytrauma patients. METHODS:Data extracted from a polytrauma study on Dryad, an open access database, was selected for secondary analysis. Patients from 18 to 65 years old with polytrauma in the original data were included. All patients with missing variables, such as blood lactic acid (Lac), Glasgow coma score (GCS) and injury severity score (ISS) at admission, were excluded. The differences of gender, age, Lac, ISS and GCS scores between the patients who died within 72 hours and those who survived were analyzed. The risk factors for 72-hour death were analyzed by Logistic regression, and the Nomogram prediction model was established using R software. The receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of the model, and the Bootstrap method was used for internal verification by repeating sample for 1 000 times. Decision curve (DCA) was applied to analyze the clinical practical value of the model. RESULTS:A total of 2 315 polytrauma patients were included. Logistic regression analysis showed that Lac, GCS score and age > 55 years old were the risk factors for early death in polytrauma patients [Lac: odds ratio (OR) = 1.36, 95% confidence interval (95%CI) was 1.29-1.42, P < 0.001; GCS score: OR = 0.76, 95%CI was 0.73-0.79, P < 0.001; age > 55 years old: OR = 1.92, 95%CI was 1.37-2.66, P < 0.001]. The prediction model was established by using the above risk factors and displayed by Nomogram. ROC curve analysis showed that the area under the ROC curve (AUC) of Nomogram model to predict the risk of death within 72 hours was 0.858, and the predictive ability of Nomogram model was significantly higher than that of Lac (AUC = 0.743), GCS score (AUC = 0.774) and ISS score (AUC = 0.699), all P < 0.05. The model calibration chart showed that the predicting probability was consistent with the actual occurrence probability, and the DCA showed that Nomogram model presented excellent clinical value in predicting the 72-hour death risk for polytrauma patients. CONCLUSIONS:The prognostic Nomogram model presents significantly predictive value for the risk of death within 72 hours in polytrauma patients. Prognostic Nomogram model could offer individualized, visualized and graphical prediction pattern, and provide physicians with practical diagnostic tool for triage system and management of polytrauma according to precision medicine.

BACKGROUND:Some biotics, like β-Lactams, have shown immunomodulation effects during sepsis, but the detailed mechanism was still unclear. Here we postulated that neutrophils play an essential role and β-Lactams exert immunomodulation effects through modulating neutrophil extracellular traps (NETs) formation. METHODS:NETs formation induced by two β-Lactams, Meropenem (MEM) and ceftazidime/tazobactam (CAZ/TB) in neutrophils from healthy donors and HL-60 cells was performed. Reactive oxygen species (ROS) generation and the activity of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase were examined. Additionally, the upstream signal pathway of NETs formation, including protein kinase C (PKC), protein kinase B (Akt) and mammalian target of rapamycin (mTOR), were detected. RESULTS:MEM and CAZ/TB modulate NETs formation in activated PMNs, not resting PMNs. Both reduced ROS generation in resting PMNs and increased in activated PMNs. To test the activity of NADPH oxidase, we detected NADPH in MEM and CAZ/TB pre-cultivated activated PMNs, which showed that MEM and CAZ/TB modulates NETs formation through activation of NADHP oxidase by affecting the subunits of key enzymes. However, MEM reduced levels of phosho-PKC-Akt-mTOR, with no changes in CAZ/TB. CONCLUSIONS:We firstly demonstrate that β-Lactams showed the definitive immunomodulation effects through modulating NETs formation, which is depended on PKC-Akt-mTOR signal pathway.

19世纪中期,英国开始实施疾病救济、儿童救济以及劳动救济等区别性救济.19世纪后期到20世纪初,英国的区别救济有了进一步的发展,老年救济、疾病救济和失业救济的发展成为突出的表现.区别性救济的实施改变了英国济贫法的综合性救济传统与特征,成为19世纪后期英国济贫法改革的重要内容之一,不仅为不同人群以及不同原因所造成的贫困提供了更加直接、更有针对性的救济,也为英国现代社会保险制度的出现提供了条件.

Background: Early intravenous administration of tranexamic acid has been shown to protect the intestinal barrier after a model of trauma-hemorrhagic shock in the rat, but the potential mechanism remains unclear. Our previous studies have demonstrated that neutrophil extracellular traps contribute to the intestinal barrier dysfunction during sepsis and other critical conditions. Meanwhile, there are high levels of neutrophil infiltration in the intestine during trauma-hemorrhagic shock. Here, we hypothesized that neutrophil extracellular trap formation played a vital role during trauma-hemorrhagic shock-induced intestinal injury and that tranexamic acid, a serine protease inhibitor, may inhibit neutrophil extracellular trap formation and protect intestinal barrier function in trauma-hemorrhagic shock. Methods: A model of trauma-hemorrhagic shock in male rats was established. The rats were divided into 6 groups: (1) sham group; (2) trauma-hemorrhagic shock group; (3) trauma-hemorrhagic shock + DNase I group; (4) trauma-hemorrhagic shock + tranexamic acid group; (5) trauma-hemorrhagic shock + tranexamic acid (different time) group; and (6) trauma-hemorrhagic shock + tranexamic acid (different doses) group. The DNase I solution was injected intravenously to disrupt neutrophil extracellular traps immediately after the trauma-hemorrhagic shock model was completed. After 24 hours, the small intestine and blood were collected for analysis. Human neutrophils were harvested and incubated with phorbol-12-myristate-13-acetate or tranexamic acid, generation of reactive oxygen species, and key proteins expression were detected. Results: Trauma-hemorrhagic shock induced the formation of intestinal neutrophil extracellular traps and disrupted the intestinal tight junction proteins. Clearing of neutrophil extracellular traps by DNase I resulted in increased expression of tight junction proteins and alleviated the intestinal injury. Early intravenous tranexamic acid administration (1 hour after trauma-hemorrhagic shock) decreased neutrophil extracellular trap formation and prevented tight junction protein disruption compared to the non-tranexamic acid group; however, after delayed administration of tranexamic acid (6 hours), there were no changes in neutrophil extracellular trap formation and intestinal injuries compared to the non-tranexamic acid group. Furthermore, tranexamic acid inhibited neutrophil extracellular trap formation and protected the intestinal barrier in a dose-dependent manner and high-dose (20 mg/kg) treatment of tranexamic acid showed a better effect compared with the therapeutic dose (10 mg/kg). The results of thromboelastography demonstrated that the R and K values in the high-dose group decreased (R, 1.85 +/- 0.14 vs 3.87 +/- 0.16 minutes, P < .001; K, 0.95 +/- 0.04 vs 1.48 +/- 0.07 minutes, P < .001), accompanied by a decrease in LY3O, indicating that treatment with a high dose of tranexamic acid may cause hypercoagulability and shutdown of fibrinolysis. In addition, less neutrophil extracellular trap formation was detected in neutrophils incubated with neutrophils via an reactive oxygen species-dependent pathway. Conclusion: We first demonstrated a novel role of neutrophil extracellular traps in the pathophysiology of intestinal barrier dysfunction during trauma-hemorrhagic shock. Notably, early but not delayed intravenous administration of tranexamic acid effectively inhibits neutrophil extracellular trap formation and protects intestinal barrier function. Therefore, these results suggested a potential theoretic intervention for the protection of the intestinal barrier during trauma-hemorrhagic shock. In such a process, tranexamic acid appears to regulate neutrophil extracellular trap formation via the classic reactive oxygen speciesimitogen-activated protein kinase pathway. (C) 2019 Elsevier Inc. All rights reserved.