Nirmatrelvir and ritonavir for inpatients with severe or critical COVID-19 beyond five days of symptom onset: a propensity score-matched, multicenter, retrospective cohort study.

BACKGROUND: There is an urgent need for therapeutic strategies for inpatients with severe or critical COVID-19. The evaluation of the clinical benefits of nirmatrelvir and ritonavir (Nmr/r) for these patients beyond five days of symptom onset is insufficient. METHODS: A new propensity score-matched cohort was constructed by using multicenter data from 6695 adult inpatients with COVID-19 from December 2022 to February 2023 in China after the epidemic control measures were lifted across the country. The severity of disease of the inpatients was based on the tenth trial edition of the Guidelines on the Diagnosis and Treatment of COVID-19 in China. The symptom onset of 1870 enrolled severe or critical inpatients was beyond five days, and they received either Nmr/r plus standard treatment or only standard care. The ratio of patients whose SOFA score improved more than 2 points, crucial respiratory endpoints, changes in inflammatory markers, safety on the seventh day following the initiation of Nmr/r treatment, and length of hospital stay were evaluated. RESULTS: In the Nmr/r group, on Day 7, the number of patients with an improvement in SOFA score ≥ 2 was much greater than that in the standard treatment group (P = 0.024) without a significant decrease in glomerular filtration rate (P = 0.815). Additionally, the rate of new intubation was lower (P = 0.004) and the no intubation days were higher (P = 0.003) in the first 7 days in the Nmr/r group. Other clinical benefits were limited. CONCLUSIONS: Our study may provide new insight that inpatients with severe or critical COVID-19 beyond five days of symptom onset benefit from Nmr/r. Future studies, particularly randomized controlled trials, are necessary to verify the above findings.

Dual-targeting tigecycline nanoparticles for treating intracranial infections caused by multidrug-resistant Acinetobacter baumannii.

Multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) is a formidable pathogen responsible for severe intracranial infections post-craniotomy, exhibiting a mortality rate as high as 71%. Tigecycline (TGC), a broad-spectrum antibiotic, emerged as a potential therapeutic agent for MDR A. baumannii infections. Nonetheless, its clinical application was hindered by a short in vivo half-life and limited permeability through the blood-brain barrier (BBB). In this study, we prepared a novel core-shell nanoparticle encapsulating water-soluble tigecycline using a blend of mPEG-PLGA and PLGA materials. This nanoparticle, modified with a dual-targeting peptide Aß11 and Tween 80 (Aß11/T80@CSs), was specifically designed to enhance the delivery of tigecycline to the brain for treating A. baumannii-induced intracranial infections. Our findings demonstrated that Aß11/T80@CSs nanocarriers successfully traversed the BBB and effectively delivered TGC into the cerebrospinal fluid (CSF), leading to a significant therapeutic response in a model of MDR A. baumannii intracranial infection. This study offers initial evidence and a platform for the application of brain-targeted nanocarrier delivery systems, showcasing their potential in administering water-soluble anti-infection drugs for intracranial infection treatments, and suggesting promising avenues for clinical translation.

Impairment of antigen-presenting function of peripheral γδ T cells in patients with sepsis.

Impairment of antigen-presenting functions is a key mechanism contributing to sepsis-induced immunosuppression. Recently, γδ T cells have been demonstrated as professional antigen-presenting cells (APCs); however, their role in sepsis remains unknown. In this in vitro study, the APC function of human peripheral γδ T cells was assessed using samples collected from 42 patients with sepsis and 27 age-matched healthy controls. The APC-related markers HLA-DR, CD27, CD80, and CCR7 on fresh γδT cells were significantly higher in patients with sepsis compared with matched controls; however, they responded poorly to 4-hydroxy-3-methyl-2-butenyl pyrophosphate (HMBPP) stimulation, characterized by the deactivation of these APC markers and impaired proliferation. Furthermore, the adhesion function of γδ T cells, essential for antigen presentation, was greatly reduced in patients with sepsis; for instance, in co-cultures with green fluorescent protein-expressing Escherichia coli, HMBPP-activated γδT cells from healthy individuals adhered to E. coli efficiently, whereas no such phenomenon was observed with respect to γδT cells from patients with sepsis. In line with these results, in co-cultures with isolated CD4+ αß T cells, HMBPP-activated γδT cells of healthy individuals promoted the efficient proliferation of CD4+ αß T cells, whereas γδT cells from patients with sepsis did not do so. In conclusion, our findings show that the antigen-presenting function of γδT cells is severely impaired in patients with sepsis and the mechanisms behind need further study.

Sequential use of midazolam and dexmedetomidine for long-term sedation may reduce weaning time in selected critically ill, mechanically ventilated patients: a randomized controlled study.

BACKGROUND: Current sedatives have different side effects in long-term sedation. The sequential use of midazolam and dexmedetomidine for prolonged sedation may have distinct advantages. We aimed to evaluate the efficacy and safety of the sequential use of midazolam and either dexmedetomidine or propofol, and the use of midazolam alone in selected critically ill, mechanically ventilated patients. METHODS: This single-center, randomized controlled study was conducted in medical and surgical ICUs in a tertiary, academic medical center. Patients enrolled in this study were critically ill, mechanically ventilated adult patients receiving midazolam, with anticipated mechanical ventilation for ≥ 72 h. They passed the spontaneous breathing trial (SBT) safety screen, underwent a 30-min-SBT without indication for extubation and continued to require sedation. Patients were randomized into group M-D (midazolam was switched to dexmedetomidine), group M-P (midazolam was switched to propofol), and group M (sedation with midazolam alone), and sedatives were titrated to achieve the targeted sedation range (RASS - 2 to 0). RESULTS: Total 252 patients were enrolled. Patients in group M-D had an earlier recovery, faster extubation, and more percentage of time at the target sedation level than those in group M-P and group M (all P < 0.001). They also experienced less weaning time (25.0 h vs. 49.0 h; HR1.47, 95% CI 1.05 to 2.06; P = 0.025), and a lower incidence of delirium (19.5% vs. 43.8%, P = 0.002) than patients in group M. Recovery (P < 0.001), extubation (P < 0.001), and weaning time (P = 0.048) in group M-P were shorter than in group M, while the acquisition cost of sedative drug was more expensive than other groups (both P < 0.001). There was no significant difference in adverse events among these groups (all P > 0.05). CONCLUSIONS: The sequential use of midazolam and dexmedetomidine was an effective and safe sedation strategy for long-term sedation and could provide clinically relevant benefits for selected critically ill, mechanically ventilated patients. TRIAL REGISTRATION: NCT02528513 . Registered August 19, 2015.

Association between glucocorticoids treatment and viral clearance delay in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Evidence of glucocorticoids on viral clearance delay of COVID-19 patients is not clear. METHODS: In this systematic review and meta-analysis, we searched for studies on Medline, Embase, EBSCO, ScienceDirect, Web of Science, Cochrane Library, and ClinicalTrials.gov from 2019 to April 20, 2021. We mainly pooled the risk ratios (RRs) and mean difference (MD) for viral clearance delay and did subgroup analyses by the severity of illness and doses of glucocorticoids. RESULTS: 38 studies with a total of 9572 patients were identified. Glucocorticoids treatment was associated with delayed viral clearance in COVID-19 patients (adjusted RR 1.52, 95% CI 1.29 to 1.80, I2 = 52%), based on moderate-quality evidence. In subgroup analyses, risk of viral clearance delay was significant both for COVID-19 patients being mild or moderate ill (adjusted RR 1.86, 95% CI 1.35 to 2.57, I2 = 48%), and for patients of being severe or critical ill (adjusted RR 1.59, 95% CI 1.23 to 2.07, I2 = 0%); however, this risk significantly increased for patients taking high doses (unadjusted RR 1.85, 95% CI 1.08 to 3.18; MD 7.19, 95% CI 2.78 to 11.61) or medium doses (adjusted RR 1.86, 95% CI 0.96 to 3.62, I2 = 45%; MD 3.98, 95% CI 3.07 to 4.88, I2 = 4%), rather those taking low doses (adjusted RR 1.38, 95% CI 0.94 to 2.02, I2 = 59%; MD 1.46, 95% CI -0.79 to 3.70, I2 = 82%). CONCLUSIONS: Glucocorticoids treatment delayed viral clearance in COVID-19 patients of taking high doses or medium doses, rather in those of taking low doses of glucocorticoids.

Individualized resuscitation strategy for septic shock formalized by finite mixture modeling and dynamic treatment regimen.

BACKGROUND: Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. METHODS: Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. RESULTS: A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. CONCLUSIONS: Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.

Takotsubo cardiomyopathy following pericardiectomy: A case report.

BACKGROUND: Takotsubo cardiomyopathy (TC) is defined as a temporary and reversible systolic abnormality of the left ventricle's apical area resembling myocardial infarction in the nonexistence of coronary artery disease. Only a few cases have been reported after cardiac operations or after pericardiocentesis. AIM: To emphasize the need to be aware of the possibility of the occurrence of this potentially fatal complication after cardiac surgery. MATERIALS AND METHODS: A 66-year-old man underwent a pericardiectomy. He progressed to exacerbation of hemodynamic instability postoperatively and was diagnosed with TC, finally, he had to be supported by an intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO). RESULTS: Patient's left ventricle function recovered fully in 2 weeks. DISCUSSION: We discussed the pathogenesis and treatment of postoperative TC. CONCLUSION: TC has to be carefully considered in the differential diagnosis in case of acute left ventricle dysfunction following cardiac surgery.

Cancer Targeted Gene Therapy for Inhibition of Melanoma Lung Metastasis with eIF3i shRNA Loaded Liposomes.

Eukaryotic translation initiation factors 3i (eIF3i) is a proto-oncogene that is overexpressed in various tumors, reducing its expression by eIF3i shRNA is a promising strategy to inhibit tumor growth or metastasis. Tumor cell is the target of eIF3i shRNA so that tumor-site accumulation could be important for fulfilling its therapeutic effect. Thus, the iRGD modified liposome (R-LP) was rationally synthesized to enhance the antitumor effect by active targeted delivery of eIF3i shRNA to B16F10 melanoma cells. R-LP encapsulating eIF3i shRNA gene (R-LP/sheIF3i) were prepared by a film dispersion method. The transfection experiment proves that R-LP could effectively transfect B16F10 cells. R-LP/sheIF3i notably restrained the migration, invasion, and adhesion of melanoma cells in vitro. In a mouse model of lung metastasis, R-LP/sheIF3i administered by intravenous injection suppressed pulmonary metastasis of melanoma by dramatically downregulated eIF3i expression and subsequently inhibiting tumor neovascularization and tumor cells proliferation in vivo. Our results provide a basis for tumor cells targeting strategies to reduce the expression of eIF3i by RNAi in the treatment of tumor metastasis.

High-density lipoprotein cholesterol to low-density lipoprotein cholesterol ratio in early assessment of disease severity and outcome in patients with acute pancreatitis admitted to the ICU.

BACKGROUND: Patients with acute pancreatitis usually exhibit dyslipidemia and oxidative stress. However, the significance of high-density lipoprotein cholesterol (HDL-C) level, low-density lipoprotein cholesterol (LDL-C) level and the HDL-C/LDL-C ratio (H/L ratio) as markers for disease progression remain unknown. AIM: The aim of this study was to evaluate the role of HDL-C levels, LDL-C levels and the H/L ratio as markers of disease progression in patients admitted to the intensive cate unit with acute pancreatitis. METHODS: This retrospective study was conducted at a tertiary critical care center in China. Plasma HDL-C and LDL-C levels were measured in 166 patients with acute pancreatitis. The associations between HDL-C, LDL-C, H/L ratio, as well as other inflammatory index and mortality, were analyzed. Multivariate cox analysis based on two models was used to determine the independent prognostic factor. Predictive ability of in-hospital mortality for variables was determined using the receiver operating characteristics curves. RESULTS: Significantly higher H/L ratios at admission were observed in patients with acute pancreatitis who died compared with survivors (0.93 vs. 0.64, p < 0.001). The area under the ROC curve for H/L ratio-based prediction of mortality was 0.658. When clinical confounders were included in multivariable cox regression analysis, the association was preserved (Model A HR = 1.587, p = 0.011; Model B HR = 1.332, p = 0.032). The mortality risk in different groups defined by an H/L ratio cutoff value was significantly different, based on survival curve analysis. CONCLUSION: The H/L ratio at the time of admission to the ICU appears to be a biomarker of disease progression in patients with acute pancreatitis.

Neutrophil-to-lymphocyte ratio as a predictive biomarker for moderate-severe ARDS in severe COVID-19 patients.

TRIAL REGISTRATION: ChiCTR, ChiCTR2000029758. Registered 12 February 2020 - Retrospectively registered.

Elevated cardiac biomarkers may be effective prognostic predictors for patients with COVID-19: A multicenter, observational study.

PURPOSE: The coronavirus disease 19 (COVID-19) has become a global health event. Cardiac biomarkers like creatine kinase isoenzyme (CK-MB), myoglobin, and high-sensitivity troponin T were usually elevated in early stages. This study aimed to investigate whether the elevated cardiac biomarkers could become effective prognostic predictors for COVID-19 patients. METHODS: The present study involved 357 COVID-19 patients. The potential predictors for two study outcomes (in-hospital death and recovery status) in 28 days were selected by LASSO regression analysis. Prognostic values of cardiac biomarkers selected were evaluated using the receiver operating characteristic curve (ROC) and the area under ROC (AUC). RESULTS: After 28-day follow-up, overall 357 patients were divided into death group (n = 25) and survival group (n = 332), or non-recovery group (n = 43) and recovery group (n = 314). The LASSO regression analysis showed elevated CK-MB and myoglobin were independent risk predictors for in-hospital death, and CK-MB and myoglobin were also independent risk predictors for non-recovery. The AUC of CK-MB and myoglobin for in-hospital death were 0.862 (95%CL: 0.804-0.920, p < 0.001) and 0.838 respectively (95%CL: 0.729-0.947, p < 0.001). The AUC of CK-MB and myoglobin for non-recovery were 0.839 (95%CL: 0.786-0.892, p < 0.001) and 0.841 (95%CL: 0.765-0.918, p < 0.001) respectively. We also found AUC of combined use of CK-MB and myoglobin for in-hospital death and non-recovery were 0.883 (95CL: 0.813-0.952, p < 0.001), and 0.873 (95%CL: 0.817-0.930, p < 0.001) respectively. CONCLUSIONS: In patients with COVID-19, elevated CK-MB and myoglobin on admission may be effective predictors for adverse outcomes, and combined use of CK-MB and myoglobin had a better performance for prediction.

The Prognostic Nutritional Index is associated with mortality of COVID-19 patients in Wuhan, China.

BACKGROUND: Declared as pandemic by WHO, the coronavirus disease 2019 (COVID-19) pneumonia has brought great damage to human health. The uncontrollable spread and poor progression of COVID-19 have attracted much attention from all over the world. We designed this study to develop a prognostic nomogram incorporating Prognostic nutritional index (PNI) in COVID-19 patients. METHODS: Patients confirmed with COVID-19 and treated in Renmin Hospital of Wuhan University from January to February 2020 were included in this study. We used logistic regression analysis to find risk factors of mortality in these patients. A prognostic nomogram was constructed and receiver operating characteristics (ROC) curve was drawn to evaluate the predictive value of PNI and this prognostic model. RESULTS: Comparison of baseline characteristics showed non-survivors had higher age (P < .001), male ratio (P = .038), neutrophil-to-lymphocyte ratio (NLR) (P < .001), platelet-to-lymphocyte ratio (PLR) (P < .001), and PNI (P < .001) than survivors. In the multivariate logistic regression analysis, independent risk factors of mortality in COVID-19 patients included white blood cell (WBC) (OR 1.285, P = .039), PNI (OR 0.790, P = .029), LDH (OR 1.011, P < .015). These three factors were combined to build the prognostic model. Area under the ROC curve (AUC) of only PNI and the prognostic model was 0.849 (95%Cl 0.811-0.888) and 0.950 (95%Cl 0.922-0.978), respectively. And calibration plot showed good stability of the prognostic model. CONCLUSION: This research indicates PNI is independently associated with the mortality of COVID-19 patients. Prognostic model incorporating PNI is beneficial for clinicians to evaluate progression and strengthen monitoring for COVID-19 patients.

[Association of Glucose Variability and ICU Delirium of Patients after Liver Transplantation].

OBJECTIVE: To study the association of glucose variability and ICU delirium of patients after liver transplantation. METHODS: This was a retrospective, single-center cohort study. Patients who admitted to ICU after liver transplantation during Aug. 2016 to Dec. 2018 were enrolled. They were divided into two groups accoding to whether they had delirium in ICU. Multivariate logistic regression analysis model was used to analyze the relationship between glucose variability and ICU delirium, and Cochran-Armitage trend test was used to analyze the linear relationship between blood glucose variability levels and the incidence of delirium. RESULTS: A total of 242 patients were enrolled, among them, 36 patients had delirium. The occurrence rate of delirium was 14.9% (36/242). Results indicated that glucose variability was an independently risk factor of ICU delirium for liver transplant patients ( P=0.045), and delirium was more common in patients with higher glucose variability (fourth quartile vs. first quartile, odds ratio =5.283, 95% confidence interval: 1.092～25.550, P=0.038). Results of Cochran-Armitage trend test indicated that there was a linear relationship between blood glucose variability level and ICU delirium rate, with the increase of glucose variability level, the risk of ICU delirium was increased too ( P<0.001). CONCLUSION: Glucose variability was an independently risk factor of ICU delirium in liver transplantation patients.

Compare the effect of noninvasive ventilation and tracheotomy in critically ill mechanically ventilated neurosurgical patients: a retrospective observe cohort study.

OBJECTIVE: Patients with severe brain injury is usual at high risk of extubation failure, despite of those with no/minor primary respiratory problem, majority of them still needs long term respiratory support and has severe pulmonary complications. This retrospective study aimed to compare the effect of noninvasive ventilation (NIV) and tracheotomy on the prognosis in critically ill mechanically ventilated neurosurgical patients. METHODS: This is a single center, retrospective observe cohort study. Postoperative patients with brain injury consecutively admitted to ICU from November 1st, 2015 through February 28th, 2017, who had received invasive mechanical ventilation more than 48 h were screened, those who received NIV or tracheotomy procedure, meanwhile with Glasgow Coma Scale (GCS) score between 8 and 13 points before using NIV or undergoing tracheotomy, were retrospectively included in this study. The demographic data and clinical main outcomes such as ICU and hospital mortality, time of mechanical ventilation, length of ICU and hospital were collected. The primary outcome was the incidence of postoperative pulmonary infection between two groups. RESULTS: 77 patients were included in this study. 33 patients received NIV, and 44 patients received tracheotomy through the ICU duration. The incidence of postoperative pulmonary infection in NIV group was significantly lower than that in tracheotomy group (54.5% VS 84.1%, P < 0.05), Application of NIV was associated with shorter duration of invasive mechanical ventilation ([median 123.0 h VS 195.0 h, P < 0.05). Moreover, GCS score at ICU discharge, as well as the difference of GCS score between at admission to ICU and ICU discharge were also better than the tracheotomy group (P < 0.001). CONCLUSION: Compared with tracheotomy, use of NIV after extubation in critically ill mechanically ventilated neurosurgical patients may be associated with lower incidence of postoperative pulmonary infection, shorter duration of invasive mechanical ventilation and better improvement in brain function. Further studies need to verify the effect of NIV in this kind of patients.

Vitamin A deficiency in critically ill children with sepsis.

BACKGROUND: Data that indicate vitamin A status in critically ill children with sepsis are sparse. The association between serum vitamin A levels and the clinical outcomes of sepsis has not been well assessed. The aim of this study was to assess the prevalence of vitamin A deficiency in critically ill children with sepsis and its association with clinical outcomes. METHODS: Critically ill children with sepsis admitted to the pediatric intensive care unit were engaged in this prospective study. Sex- and age-matched approximate-health children from the Department of Pediatric Surgery were enrolled as the control group. Blood samples were collected from all patients in the first 24 h of admission for the measurement of serum vitamin A status. We compared vitamin A status between the sepsis group and the control group. In addition, we compared the clinical characteristics of the two subgroups of septic patients with vitamin A deficiency and those without vitamin A deficiency. Univariate and multivariable methods were used to evaluate the association between vitamin A deficiency and septic shock. RESULTS: One hundred sixty septic children and 49 approximate-health children were enrolled in this study. Vitamin A deficiency was found in 94 (58.8%) subjects in the study group and 6 (12.2%) subjects in the control group (P < 0.001). In septic patients, 28-day mortality and hospital mortality in patients with vitamin A deficiency were not significantly higher than that in patients without vitamin A deficiency (P > 0.05). However, vitamin A levels were inversely associated with higher PRISM scores in septic children with VAD (r = - 0.260, P = 0.012). Vitamin A deficiency was associated with septic shock with an unadjusted odds ratio (OR) of 3.297 (95% confidence interval (CI), 1.169 to 9.300; P = 0.024). In a logistic model, vitamin A deficiency (OR, 4.630; 95% CI, 1.027-20.866; P = 0.046), procalcitonin (OR, 1.029; 95% CI, 1.009-1.048; P = 0.003), and the Pediatric Risk of Mortality scores (OR, 1.132; 95% CI, 1.009-1.228; P = 0.003) were independently associated with septic shock. CONCLUSION: The prevalence of vitamin A deficiency was high in children with sepsis. Vitamin A deficiency may be a marker of mortality in critically ill children with sepsis. TRIAL REGISTRATION: Clinicaltrials.gov , NCT03598127.

[The Construction of ROR1 Targeting Chimeric Antigen Receptor Modified T Cells and Its Killing Effect for ROR1-positive Tumor Cells].

OBJECTIVE: To test the killing effect of type Ⅰ receptor tyrosine kinase-like orphan receptor (ROR1) chimeric antigen receptor T cell (CAR-T) on several ROR1-expressing tumor cells in vitro. METHODS: The CAR gene was designed and synthesized by constructing the lentiviral vector plasmid, and BamHⅠ/EcoRⅠ was used to identify the plasmid. The expression levels of ROR1 among a variety of tumor cell lines were compared using flow cytometry (FCM). The killing effect of CAR-T on positive cells was detected by FCM, the LDH assay and ELISA. RESULTS: The double enzyme digestion identified CAR gene was successfully constructed to the lentivirus vector plasmid. FCM detection showed that the efficiency of CAR-T infection was about 47.23%. Multiple tumor cells expressed ROR1 in varying degrees. The FCM and the LDH assay indicated that CAR-T specifically killed ROR1-positive tumor cells. On positive target cells, more interferonI-γ (FN-γ) could be released during the CAR-T killing process than control T (P<0.05). CONCLUSION: We successfully constructed ROR1 CAR-T. CAR-T can specifically kill ROR1-positive tumor cells and cause the release of large amounts of IFN-γ, providing an experimental basis for clinical application.

PSME3 induces epithelial-mesenchymal transition with inducing the expression of CSC markers and immunosuppression in breast cancer.

Proteasome activator subunit 3 (PSME3) plays a key role in breast cancer by regulating the cell cycle. However, its role in other pathogenesis-related features of breast cancer is unclear. In this study, we found that overexpression of PSME3 induced the epithelial-mesenchymal transition and contributed to induce the expression of cancer stem cell markers of the MDA-MB-231 cell line, thus increasing the migration, and invasion of the cells. Moreover, overexpression of PSME3 reduced the chemotaxis of CD8+ T cells and induced the apoptosis of T cells in vitro. Furthermore, PSME3 knockdown increased the number of CD8+ T cells in vivo and reduced the subcutaneous tumor growth rate. These findings revealed that PSME3 induces epithelial-mesenchymal transition with inducing the expression of CSC markers and influencing the tumor immune microenvironment in breast cancer.

Role of using two-route ulinastatin injection to alleviate intestinal injury in septic rats.

PURPOSE: Early application of protease inhibitors through the intestinal lumen could increase survival following experimental shock by blocking the pancreatic digestive enzymes. Hence, it was hypothesized that two-route injection (intraintestinal + intravenous) of ulinastatin (UTI), a broad-spectrum protease inhibitor, could better alleviate intestinal injury than single-route injection (either intravenous or intraintestinal). METHODS: A sepsis model induced by lipopolysaccharide on rats was established. The rats were randomly divided into five groups: sham, sepsis, UTI intravenous injection (Uiv), UTI intraintestinal injection (Uii), and UTI intraintestinal + intravenous injection (Uii + Uiv) groups. The mucosal barrier function, enzyme-blocking effect, levels of systemic inflammatory cytokines, and 5-day survival rate were compared among groups. The small intestinal villus height (VH), crypt depth (CD), and two components of mucosal barrier (E-cadherin and mucin-2) were measured to evaluate the mucosal barrier function. The levels of trypsin and neutrophil elastase (NE) in the intestine, serum, and vital organs were measured to determine the enzyme-blocking effect. RESULTS: Compared with the single-route injection group (Uiv or Uii), the two-route injection (Uii + Uiv) group displayed: (1) significantly higher levels of VH, VH/CD, E-cadherin, and mucin-2; (2) decreased trypsin and NE levels in intestine, plasma, and vital organs; (3) reduced systemic inflammatory cytokine levels; and (4) improved survival of septic rats. CONCLUSION: Two-route UTI injection was superior to single-route injection in terms of alleviating intestinal injury, which might be explained by extensive blockade of proteases through different ways.

[Predictors of Long-term Mortality and Health Related Quality of Life for Elderly Patients with Sepsis].

OBJECTIVE: To explore the predictors of long-term mortality and healthy related quality of life (HR-QoL) for elderly patients with sepsis. METHODS: Two hundred and thirty-eight septic patients older than 60 years old admitted to intensive care unit (ICU) were enrolled in the study,and were followed up by telephone interview one year after ICU discharge. The hospital mortality and cumulative one-year mortality were analyzed,single and multiple factors analysis were used to for the risk factors of 1-year mortality. Quality of life (QoL) was evaluated by the Euro QoL-5 Dimensions (EQ5D) questionnaire,and the influential factors of long-term QoL were also analyzed. RESULTS: A total of 238 patients were enrolled,58 patients of them(24.4%) died during hospitalization and one-year accumulative mortality was 59.7% (142 cases). Single factor analysis showed that acute physiology and chronic health evaluation (APACHE Ⅱ),continuous renal replacement therapy (CRRT),fungal infection,sepsis,tracheal extubation and use of vasopressor within 24 h,the length of mechanical ventilation were correlated with one-year mortality. Multivariate regression analysis showed that APACHE Ⅱscore,CRRT and fungal infection were independent risk factors for one-year mortality,while tracheal extubation within 24 h and shorter length of ICU stay were related to better quality of life. CONCLUSION: One-year mortality of elderly patients with sepsis was high. Tracheal extubation in 24 h and length of hospital stay were predictor of long-term QoL.

Relationship Between Short-Term Blood Pressure Variability and Incidence of Acute Kidney Injury in Critically Ill Patients.

BACKGROUND/AIMS: Blood pressure (BP) variability is associated with cardiovascular events, and cerebral and renal damage. The aim of this study was to investigate any potential relationship between short-term BP variability and incidence of acute onset conditions, such as acute kidney injury (AKI), in critically ill patients. METHODS: BP was monitored to analyze its variability in critically ill patients in present study. Short-term BP variability was assessed as average real variability (ARV), standard deviation (SD) and coefficient of variation (CV) of 24-hour BP. RESULTS: A total of 565 patients were included, 41.2% (n=233) of which presented with AKI after admission (AKI stage I, n = 94; stage II, n = 37; stage III, n = 102). The mean APACHE II score was 21.5 for all patients. ARV of 24 h systolic BP was significantly higher in patients with AKI (p<0.001). This association remained (p=0.006) after adjustment for potential confounders. The incidence of AKI increased with the ARV from 14.0% (ARV ≤6 mmHg) to 73.9% (ARV >14 mmHg). A weak association was also found between BP variability and hospital mortality in critically ill patients. CONCLUSION: BP variability is correlated with the incidence of AKI in critically ill patients.