Multiparameter spectral CT-based radiomics in predicting the expression of programmed death ligand 1 in non-small-cell lung cancer.

AIM: To explore the value of radiomics for predicting the expression of programmed death ligand 1 (PD-L1) in non-small-cell lung cancer (NSCLC) based on multiparameter spectral computed tomography (CT) images. MATERIALS AND METHODS: A total of 220 patients with NSCLC were enrolled retrospectively and divided into the training (n=176) and testing (n=44) cohorts. The radiomics features were extracted from the conventional CT images, mono-energy 40 keV images, iodine density (ID) maps, Z-effective maps, and electron density maps. The logistic regression (LR) and support vector machine (SVM) algorithms were employed to build models based on radiomics signatures. The prediction abilities were qualified by the area under the curve (AUC) obtained from the receiver operating characteristic (ROC) curve. Internal validation was performed on the independent testing dataset. RESULTS: The combined model for PD-L1 ≥1%, which consisted of the radiomics score (rad-score; p<0.0001), white blood cell (WBC; p=0.027) counts, and air bronchogram (p=0.003), reached the highest performance with the AUCs of 0.873 and 0.917 in the training and testing dataset, respectively, which was better than the radiomics model with the AUCs of 0.842 and 0.886. The combined model for PD-L1 ≥50%, which consisted of rad-score (p<0.0001) and WBC counts (p=0.027), achieved the highest performance in the training and testing dataset with AUCs of 0.932 and 0.903, respectively, which was better than the radiomics model with AUCs of 0.920 and 0.892, respectively. CONCLUSION: The radiomics model based on the multiparameter images of spectral CT can predict the expression level of PD-L1 in NSCLC. The combined model can obtain higher prediction efficiency and serves as a promising method for immunotherapy selection.

[Efficacy of first generation EGFR-TKIs and chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations].

Objective: To investigate the clinical effects of first generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) compared with platinum-based chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations. Methods: Clinical data of 4 276 patients diagnosed as advanced lung adenocarcinoma (ⅢB/Ⅳ) underwent EGFR gene detection at the Affiliated Cancer Hospital of Zhengzhou University from January 2012 to February 2018 were collected and 99 cases with uncommon EGFR mutations were selected. The clinical pathological features, treatment outcomes, treatment options and prognosis after first-line treatment of the 99 cases were analysed and compared with other patients with common EGFR mutations. Results: The objective response rates of patients with uncommon EGFR mutations receiving EGFR-TKIs or platinum-based chemotherapy were 33.0% and 27.1%, respectively. The disease control rates were 76.5% and 87.5%, respectively. The progression-free survival (PFS) of patients treated with EGFR-TKIs was 7.2 months, significantly superior than 4.9 months of patients receiving chemotherapy (P=0.009). The overall survival of patients treated with EGFR-TKIs was 14.3 months, significantly worse than 20.7 months of patients receiving chemotherapy (P=0.034). Multivariate analysis showed that distant metastases (P=0.001) and smoking history (P=0.013) were independent prognostic factors for OS of lung adenocarcinoma patients with EGFR uncommon mutations. Conclusions: Compared with chemotherapy, the usage of first generation of EGFR-TKIs as first-line therapy can improve the short-term efficacy of advanced lung adenocarcinoma patients with EGFR uncommon mutations. However, platinum-based chemotherapy shows a longer overall survival.

[Relationship between weight change and the changes in blood pressure, blood glucose and blood lipid profiles in middle-aged and elderly Chinese people: a cohort study].

Objective: To explore the relationship between weight change and the changes in blood pressure, blood glucose and blood lipid profiles in middle-aged and elderly Chinese people. Methods: All participants were from the Dongfeng-Tongji cohort study. The study included 16 606 middle-aged and elderly Chinese people with complete information in the baseline survey in 2008 and the first follow-up survey in 2013. We collected the data on demographic characteristics, lifestyle, history of diseases and medication, and the results of medical health examinations, including height, weight, blood pressure, fasting blood glucose and lipid profiles. We divided the weight change into five groups, moderate or above weight loss (<-8.0%), slight weight loss (-8.0%, -3.1%), weight maintenance (-3.0%, 3.0%), slight weight increased (3.1%, 8.0%), and moderate or above weight increased (>8.0%). Generalized linear regression model was used to analyze the relationship between weight change and the changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride (TG). Subgroup analyses were used to explore the influences of gender, age and baseline BMI level on the relationship between weight change and the above-mentioned metabolic indicators. Results: The average age of participants in baseline survey was (62.19±7.28) years with a range of 45 to 89 years. During the five-year period, there were 18.86% (2 633), 28.03% (4 655), 35.87% (5 956), 13.96% (2 319), 6.28% (1 043) people with moderate or above weight loss, slight weight loss, weight maintenance, slight weight increased, and moderate or above weight increased, respectively. Regression analyses showed that body weight change were positively correlated with changes in SBP, DBP, FBG, TC, LDL-C and TG, and negatively correlated with change in HDL-C (all linear trend P values were<0.05); As every 10% of weight changed, the ß (95%CI) of changes in SBP (mmHg) (1 mmHg=0.133 kPa), DBP (mmHg), FBG (mmol/L), TC (mmol/L), LDL-C (mmol/L), HDL-C (mmol/L) and TG (mmol/L) were 4.94 (4.32, 5.55), 2.50 (2.11, 2.88), 0.05 (0.02, 0.08), 0.13 (0.11, 0.16), 0.14 (0.12, 0.16), -0.05 (-0.07, -0.04) and 0.16 (0.14, 0.18), respectively. Furthermore, subgroup analyses showed that weight change can lead to greater changes in blood pressure in older and overweight or obesity elderly people (all P for interaction<0.05). Conclusion: Weight loss was beneficial for middle-aged and elderly people to improve the blood pressure, blood glucose and blood lipid profiles, regardless of the weight at the baseline, while weight gain was not.

[Atrial fibrillation in patients with obstructive hypertrophic cardiomyopathy: clinical characteristics and risk factors].

Objective: To evaluate the clinical characteristics and risk factors for atrial fibrillation(AF)in patients with obstructive hypertrophic cardiomyopathy(OHCM). Methods: Patients with OHCM hospitalized in Fuwai Hospital from March 2011 to January 2016 were enrolled in the present study. Each patient underwent examinations including transthoracic echocardiography, body surface electrocardiograph or dynamic electrocardiogram (Holter). Cardiac troponin I (cTNI) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP)levels were tested and clinical profiles were collected.The subjects were divided into two groups (the AF group and non-AF group). Risk factors for AF in patients with OHCM were assessed by multivariate logistic regression analysis. Results: A total of 309 patients were evaluated in the study. Among them, 17.5%( 54/309) patients were with AF.Age[(51.2±10.1)years vs (43.1 ± 14.4)years], New York Heart Association class(NYHA class)(2.8±0.5 vs 2.6±0.6), disease duration[6.0(4.0, 10.0)years vs 3.0(1.0, 6.0)years], left atrial (LA) dimension[(45.1±7.0)mm vs(42.6 ± 7.4)mm]and NT-pro-BNP levels[2 007(1 565, 3 199)pmol/L vs 1 509(729, 2 921)pmol/L]in the AF group were significantly higher than those in the non-AF group (all P<0.05). Multivariate logistic regression analysis indicated that advanced age(OR=1.04, 95% CI 1.01-1.08, P<0.01), higher NYHA class(OR=2.00, 95% CI 1.08-3.70, P<0.05)and longer disease duration(OR=1.08, 95% CI 1.01-1.15, P<0.05)were independent risk factors for AF in patients with OHCM, in which advanced age(OR=1.05, 95% CI 1.02-1.09, P<0.01), higher NYHA class(OR=3.39, 95% CI 1.53-7.54, P<0.01), LA dimension(OR=1.06, 95% CI 1.01-1.12, P<0.05)and longer clinical course(OR=1.12, 95% CI 1.04-1.20, P<0.01)were associated with AF in male patients, and advanced age (OR=1.05, 95% CI 1.01-1.09, P<0.05)and longer disease duration(OR=1.14, 95% CI 1.01-1.28, P<0.01)were associated with AF in female patients when stratified by gender. Conclusion: Advanced age , higher NYHA class and longer clinical duration are independent risk factors for AF in OHCM patients.

[Comparison of two quantitative methods of endobronchial ultrasound real-time elastography for evaluating intrathoracic lymph nodes].

Objective: To compare the clinical value of two quantitative methods in analyzing endobronchial ultrasound real-time elastography (EBUS-RTE) images for evaluating intrathoracic lymph nodes. Methods: From January 2014 to April 2014, EBUS-RTE examination was performed in patients who received EBUS-TBNA examination in Shanghai Chest Hospital. Each intrathoracic lymph node had a selected EBUS-RTE image. Stiff area ratio and mean hue value of region of interest (ROI) in each image were calculated respectively. The final diagnosis of lymph node was based on the pathologic/microbiologic results of EBUS-TBNA, pathologic/microbiologic results of other examinations and clinical following-up. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were evaluated for distinguishing malignant and benign lesions. Results: Fifty-six patients and 68 lymph nodes were enrolled in this study, of which 35 lymph nodes were malignant and 33 lymph nodes were benign. The stiff area ratio and mean hue value of benign and malignant lesions were 0.32±0.29, 0.62±0.20 and 109.99±28.13, 141.62±17.52, respectively, and statistical differences were found in both of those two methods (t=-5.14, P<0.01; t=-5.53, P<0.01). The area under curves was 0.813, 0.814 in stiff area ratio and mean hue value, respectively. The optimal diagnostic cut-off value of stiff area ratio was 0.48, and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 82.86%, 81.82%, 82.86%, 81.82% and 82.35%, respectively. The optimal diagnostic cut-off value of mean hue value was 126.28, and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 85.71%, 75.76%, 78.95%, 83.33% and 80.88%, respectively. Conclusion: Both the stiff area ratio and mean hue value methods can be used for analyzing EBUS-RTE images quantitatively, having the value of differentiating benign and malignant intrathoracic lymph nodes, and the stiff area ratio is better than the mean hue value between the two methods.

[Analysis on clinical characteristics and prognosis of patients with mitral valve prolapse].

Objective: To evaluate the clinical characteristics and prognosis of patients with mitral valve prolapse (MVP). Methods: We retrospectively analyzed the clinical characteristics and prognosis of 148 MVP patients who underwent mitral valve surgery in Fuwai hospital from January 2012 to December 2015.The patients were divided into mucoid degeneration group (52 cases) and without mucoid degeneration group(19 cases) according to pathological examination of leaflets and chordate. Results: The clinical symptoms of MVP patients included dyspnea (59.5%(88/148)), chest distress and pain (52.7%(78/148)), and palpitations (36.5% (54/148)). Mitral valve repair was performed in 144 cases (97.3%), and mitral valve replacement was performed in 4 cases (2.7%). Posterior leaflet prolapse was the most common form of MVP (68.9%, 102/148). Pathological examination revealed myxomatous degeneration in 73.2% patients (52/71), fibrosis in 8.5% patients (6/71), and fibrinoid necrosis in 8.5% patients (6/71). Patients with mucoid degeneration had less atrial fibrillation before surgery (5.8%(3/52) vs. 42.1%(8/19), P<0.01), smaller preoperative left atrium diameter ((43.2±6.5) mm vs. (48.2±8.9) mm, P<0.05), more posterior leaflet prolapse (94.2%(49/52) vs. 63.2%(12/19), P<0.01), redundant chordae (26.9%(14/52) vs. 0, P<0.05) and leaflet thickening (76.9%(40/52) vs. 52.6%(10/19), P<0.05) when compared with patients without mucoid degeneration.Echocardiography examination at the postoperative follow-up of 39.0(22.3, 57.0) months revealed smaller left atrium diameter((38.5±7.1) mm vs. (45.3±8.3) mm, P<0.01), left ventricular end-diastolic diameter ((48.9±6.2) mm vs. (57.5±7.6) mm, P<0.01), reduced left ventricular ejection fraction ((61.2±7.1)% vs. (65.1±6.2)%, P<0.01) and less moderate or severe mitral regurgitation (1.4%(2/148) vs. 100.0%(148/148), P<0.01) compared with the corresponding preoperative values. Conclusions: Dyspnea is the main symptom, and mucoid degeneration characterized by redundant chordae and leaflet thickening are the main pathological features of MVP patients.The surgical treatment of MVP patients is related with satisfactory outcome results.

Combined Anti-CD154/CTLA4Ig Costimulation Blockade-Based Therapy Induces Donor-Specific Tolerance to Vascularized Osteomyocutaneous Allografts.

Tolerance induction by means of costimulation blockade has been successfully applied in solid organ transplantation; however, its efficacy in vascularized composite allotransplantation, containing a vascularized bone marrow component and thus a constant source of donor-derived stem cells, remains poorly explored. In this study, osteomyocutaneous allografts (alloOMCs) from Balb/c (H2(d) ) mice were transplanted into C57BL/6 (H2(b) ) recipients. Immunosuppression consisted of 1 mg anti-CD154 on day 0, 0.5 mg CTLA4Ig on day 2 and rapamycin (RPM; 3 mg/kg per day from days 0-7, then every other day for 3 weeks). Long-term allograft survival, donor-specific tolerance and donor-recipient cell trafficking were evaluated. Treatment with costimulation blockade plus RPM resulted in long-term graft survival (>120 days) of alloOMC in 12 of 15 recipients compared with untreated controls (median survival time [MST] ≈10.2 ± 0.8 days), RPM alone (MST ≈33 ± 5.5 days) and costimulation blockade alone (MST ≈45.8 ± 7.1 days). Donor-specific hyporesponsiveness in recipients with viable grafts was demonstrated in vitro. Evidence of donor-specific tolerance was further assessed in vivo by secondary donor-specific skin graft survival and third-party graft rejection. A significant increase of Foxp3(+) regulatory T cells was evident in tolerant animals. Donor cells populated peripheral blood, thymus, and both donor and recipient bone marrow. Consequently, combined anti-CD154/CTLA4Ig costimulation blockade-based therapy induces donor-specific tolerance in a stringent murine alloOMC transplant model.

Combined PCR and Q-RT-PCR technique for detecting chimerism in a non-human Primate vascularized osteomyocutaneous allografts model.

Face transplantation and other composite tissue transplantation (CTA) are permissive to transplantation tolerance. The real reason, that composite tissue containing bone achieves transplantation immune tolerance more easily than the composite tissue without the bone is not clear. The chimerism may be the main mechanism in the progress of inducing the transplantation tolerance by CTA. We currently have established a non-human Primate Vascularized Osteomyocutaneous Allografts Model. To test the chimerism which comes from donor after the transplantation, we developed a method which combined reverse transcription polymerase chain reaction (RT-PCR) and real-time quantitative PCR (qRT-PCR) technique using primers specific for Macaca fascicularis sex determination region on the Y chromosome (SRY) gene. With the method, we estimated the level of the chimerism.

Development and characterization of Rift Valley fever virus-like particles.

Rift Valley fever (RVF) is an acute, febrile zoonotic disease that is caused by the RVF virus (RVFV) and spread by arthropod vectors. RVF is currently prevalent in Africa and the Arabian Peninsula, and causes substantial economic losses. Furthermore, this disease poses a serious threat to animal and human health in regions worldwide, making it a serious public health concern. However, RVFV vaccines for human use are still unavailable, and hence there is an urgent need for novel efficient vaccines against RVFV. Vaccine preparation techniques have become a crucial factor in developing new vaccines. In the current study, the N and G protein genes of RVFV were inserted into the pFastBacDual baculovirus expression vector downstream of the pP10 and pPH promoters. The resultant recombinant vector, pFastBacDual-S-M, was transfected into Sf9 insect cells by lipofection. The recombinant baculovirus, named rBac-N-G, was retrieved and infected into Sf9 insect cells to generate RVFV virus-like particles (VLPs). Using polyclonal antibodies against RVFV proteins in immunofluorescence and western blot analyses, we positively identified the presence of the RVFV proteins in VLP preparations. Sucrose density gradient centrifugation and transmission electron microscopy revealed that the morphology of the RVFV VLPs was consistent with previous reports of RVFV virions. This study describes a technique for efficient production of RVFV VLPs, and has laid the foundation for future VLP-based RVFV vaccines.

Spontaneous resolution of acute rejection and tolerance induction with IL-2 fusion protein in vascularized composite allotransplantation.

Vascularized composite allotransplantation (VCA) has emerged as a treatment option for treating nonlife-threatening conditions. Therefore, in order to make VCA a safe reconstruction option, there is a need to minimize immunosuppression, develop tolerance-inducing strategies and elucidate the mechanisms of VCA rejection and tolerance. In this study we explored the effects of hIL-2/Fc (a long-lasting human IL-2 fusion protein), in combination with antilymphocyte serum (ALS) and short-term cyclosporine A (CsA), on graft survival, regulatory T cell (Treg) proliferation and tolerance induction in a rat hind-limb transplant model. We demonstrate that hIL-2/Fc therapy tips the immune balance, increasing Treg proliferation and suppressing effector T cells, and permits VCA tolerance as demonstrated by long-term allograft survival and donor-antigen acceptance. Moreover, we observe two distinct types of acute rejection (AR), progressive and reversible, within hIL-2/Fc plus ALS and CsA treated recipients. Our study shows differential gene expression profiles of FoxP3 versus GzmB, Prf1 or interferon-γ in these two types of AR, with reversible rejection demonstrating higher Treg to Teff gene expression. This correlation of gene expression profile at the first clinical sign of AR with VCA outcomes can provide the basis for further inquiry into the mechanistic aspects of VCA rejection and future drug targets.

ROS, MAPK/ERK and PKC play distinct roles in EGF-stimulated human corneal cell proliferation and migration.

Cornea is at the outermost surface of eye globe, and it easily receives damage from ultraviolet light exposure, physiology wounding, and infections. It is essential to understand the mechanisms controlling human corneal epithelial (HCE) cell proliferation and wound healing. Epidermal growth factor (EGF) could stimulate cell proliferation and migration in various cell types. Therefore, we investigated the roles and mechanisms of EGF on HCE cell proliferation and migration. CCK-8 kit and wound healing experiment were used to investigate HCE cell proliferation and cell migration, respectively. ROS activity was quantified by DCFDA and flow cytometry. Western blot and Q-PCR were performed to examine protein and RNA levels. EGF could promote HCE cell proliferation and migration in both physiology status and UV irradiation conditions, which is used to mimic the disease condition in human corneal epithelial cells. Interestingly, the promotion effect of EGF on HCE cell proliferation is mainly mediated by activated ROS signaling under disease condition. However, the EGF function is mediated by ROS and MAPK/ERK pathway in EGF-treated corneal epithelial cells in physiology status, in which ROS and MAPK/ERK pathway have no mutual influence on the other signaling pathway in EGF-stimulated corneal epithelial cells. We also revealed that MAPK/ERK pathway instead of ROS mediates EGF-stimulated HCE cell migration. Interestingly, we found that PKC proteins were downregulated by EGF in HCE cells that is partially mediated by ROS signaling, while PKC pathway was not involved in EGF-stimulated corneal cell proliferation and migration. EGF promotes human corneal cell proliferation and migration both in physiology and disease conditions, and ROS, MAPK/ERK and PKC pathways play different roles in these processes.

Potential role of high-mobility group box 1 protein in the pathogenesis of influenza H5N1 virus infection.

During influenza A virus (IAV) (H5N1) infection, the levels of inflammatory cytokines are markedly elevated in the lungs of infected hosts. One of them, high-mobility group box 1 protein (HMGB1) functions in regulation of cellular transcription and activation of proinflammatory responses, but little is known about its role in viral infection. In this study, we attempted to address this question. Using an IAV (H5N1) - mouse model, lung tissues were analyzed for virus titer, expression of HMGB1 and other inflammatory cytokines and histopathological changes. Moreover, the effect of administration of HMGB1-specific antibody to the infected mice on these parameters was investigated. The results showed that the HMGB1 expression was induced on days 3-7 post infection (p.i.) and primarily localized to epithelial cells of alveoli and bronchioles. The HMGB1-specific antibody reduced the levels of inflammatory cytokines and chemokines and the survival rate, but did not influence the virus titer. Summing up, these data suggest that HMGB1 contributes to the pathogenesis of IAV (H5N1) infection in mice by inducing extensive inflammatory responses and severe pneumonia.

[Analysis of epidemiological characteristics and risk factors of catheter-associated urinary tract infections in patients with perineal and/or hip burns].

Objective: To explore the epidemiological characteristics and risk factors of catheter-associated urinary tract infections in patients with perineal and/or hip burns. Methods: This study was a retrospective case series study. From January 2018 to December 2022, 260 patients with perineal and/or hip burns and urinary catheters indwelling who met the inclusion criteria were admitted to the Department of Burns and Wound Repair of the Second Affiliated Hospital of Zhejiang University School of Medicine, including 192 males and 68 females, aged 20-93 years. The total incidence of catheter-associated urinary tract infections in patients with perineal and/or hip burns, the detection of pathogenic bacteria, and the resistance of major Gram-negative and Gram-positive bacteria to commonly used antimicrobial drugs in clinic were recorded. According to whether catheter-associated urinary tract infection occurred or not, the patients were divided into infection group (43 cases) and non-infection group (217 cases). The basic conditions including gender, age, total burn area, depth of perineal burn, depth of hip burn, and burn site on admission, complications of diabetes mellitus, inhalation injury, and hypoproteinaemia, invasive operations including tracheotomy and non-perineal/hip debridement/skin transplantation surgery, duration of catheter retention, number of urethral catheterization, and bladder irrigation of patients between the two groups were compared, and the independent risk factors influencing the occurrence of catheter-associated urinary tract infections in patients with perineal and/or hip burns were screened. Results: The total incidence of catheter-associated urinary tract infections in patients with perineal and/or hip burns in this study was 16.5% (43/260). The pathogens detected were predominantly Gram-negative, followed by fungi; the main Gram-negative bacterium was Klebsiella pneumoniae, and the main Gram-positive bacterium was Enterococcus faecalis. The resistance rates of Klebsiella pneumoniae to amoxicillin/clavulanic acid, amitraz, amikacin, ciprofloxacin, ceftriaxone, and levofloxacin were higher than 70.0%, the resistance rates of Klebsiella pneumoniae to cefoxitin, cefoperazone/sulbactam, cefepime, meropenem, imipenem, and piperacillin/tazobactam ranged from 56.3% to 68.8%, and the resistance rates of Klebsiella pneumoniae to ceftazidime and tigecycline were lower than 50.0%. The resistance rates of Enterococcus faecalis to ciprofloxacin and penicillin were both 85.7%, the resistance rates of Enterococcus faecalis to erythromycin, clindamycin, moxifloxacin, and tetracycline ranged from 14.3% to 57.1%, and the resistance rates of Enterococcus faecalis to linezolid, tigecycline, and vancomycin were all 0. The differences were statistically significant between the two groups in terms of gender, status of complication of hypoproteinaemia, depth of perineal burn, status of non-perineal/hip debridement/skin transplantation surgery, status of bladder irrigation, number of urethral catheterization, and duration of catheter retention of patients (with χ2 values of 7.80, 4.85, 10.68, 9.11, and 16.48, respectively, and Z values of -4.88 and -5.42, respectively, P<0.05). There were no statistically significant differences in the age, total burn area, complications of diabetes mellitus and inhalation injury, burn site, depth of hip burns, and status of tracheotomy of patients between the two groups (P>0.05). Multifactorial logistic regression analysis showed that gender, deep partial-thickness perineal burns, non-perineal/hip debridement/skin transplantation surgery, bladder irrigation, and duration of catheter retention were the independent risk factors for catheter-associated urinary tract infections in patients with perineal and/or hip burns (with odds ratios of 2.86, 2.63, 2.79, 2.34, and 1.04, respectively, with 95% confidence intervals of 1.21-6.73, 1.03-6.71, 1.03-7.59, 1.05-5.22, and 1.02-1.06, respectively, P<0.05). Conclusions: The incidence of catheter-associated urinary tract infections is high in patients with perineal and/or hip burns, with Klebsiella pneumoniae as the predominant pathogenic bacteria having a high resistance rate to commonly used antimicrobial drugs in clinic. Gender, deep partial-thickness perineal burns, non-perineal/hip debridement/skin transplantation surgery, bladder irrigation, and duration of catheter retention are the independent risk factors for catheter-associated urinary tract infections in patients with perineal and/or hip burns.

Vascularized osteomyocutaneous allografts are permissive to tolerance by induction-based immunomodulatory therapy.

Vascularized composite allografts (VCAs) are unique among transplanted organs in that they are composed of multiple tissues with disparate antigenic and immunologic properties. As the predominant indications for VCAs are non-life-threatening conditions, there is an immediate need to develop tolerance induction strategies and to elucidate the mechanisms of VCA rejection and tolerance using VCA-specific animal models. In this study, we explore the effects of in vitro induced donor antigen-specific CD4(-) CD8(-) double negative (DN) Treg-based therapy, in a fully MHC mismatched mouse VCA such as a vascularized osteomyocutaneous as compared to a non-VCA such as a full thickness skin (FTS) transplantation model to elucidate the unique features of VCA rejection and tolerance. We demonstrate that combined therapy with antigen-induced CD4 derived DN Tregs and a short course of anti-lymphocyte serum, rapamycin and IL-2/Fc fusion protein results in donor-specific tolerance to VCA, but not FTS allografts. Macrochimerism was detected in VCA but not FTS allograft recipients up to >60 days after transplantation. Moreover, a significant increase of CD4(+) Foxp3(+) Tregs was found in the peripheral blood of tolerant VCA recipients. These data suggest that VCA are permissive to tolerance induced by DN Treg-based induction therapy.

[Current status and research advances on catheter-associated urinary tract infection in burn patients].

Catheter-associated urinary tract infection (CAUTI) is one of the common nosocomial infections in burn patients. It not only extends the length of hospital stay of patients, increases the economic burden on family and society, but also seriously affects the prognosis and quality of life of patients, increases the risk of death of patients. In this paper, the epidemiological characteristics, influencing factors, and prevention measures of CAUTI in burn patients are reviewed to draw high attention of clinical medical staff and to provide some reference for clinical practice.

[Research progress on moderate and deep sedation during wound dressing change in pediatric burn patients].

Moderate and deep sedation can effectively relieve or eliminate the pain and body discomfort during wound dressing change in pediatric burn patients, relieve anxiety, agitation, and even delirium of the children, reduce the metabolic rate of the children, make them in a quiet, comfortable, and cooperative state, which is conducive to the smooth completion of dressing change. This paper summarized the three aspects of moderate and deep sedation in pediatric burn patients, including the overview, main points of implementation, and effects, and further introduced the moderate and deep sedation medication regimens for different routes of administration, as well as the content of evaluation and monitoring. Suggestions on the prevention and management of related complications and the management of moderate and deep sedation implementation procedures were put forward, in order to provide references for the development of moderate and deep sedation for wound dressing change in pediatric burn patients in China.

Prolonged survival of allogeneic islets in cynomolgus monkeys after short-term triple therapy.

Preclinical studies in nonhuman primates (NHP) are particularly useful to evaluate the safety and efficacy of new therapeutic proteins developed for use in clinical transplantation. We hypothesized that a treatment that selectively destroys activated cytopathic donor reactive T cells while sparing resting and immunoregulatory T cells in a mouse model might also produce long-term drug-free engraftment and tolerance without the hazards of lymphopenia in the challenging nonhuman primate islet allograft model. Short-term treatment with a regimen consisting of rapamycin, and IL-2.Ig plus mutant antagonist-type IL-15.Ig cytolytic fusion proteins (triple therapy) posttransplantation results in prolonged, drug-free engraftment of cynomolgus islet allografts. Moreover slow progressive loss of islet function in some recipients was not associated with obvious pathologic evidence of rejection.

Adoptive cell therapy using antigen-specific CD4⁻CD8⁻T regulatory cells to prevent autoimmune diabetes and promote islet allograft survival in NOD mice.

AIMS/HYPOTHESIS: A new differentiation pathway for CD4(-)CD8(-) (DN) T cells has recently been identified that exhibits the potent function of peripheral converted DN T cells in suppressing immune responses and provides the potential to treat autoimmune diseases. The aim of this study was to determine if the DN T cells converted from CD4(+) T cells of NOD mice retain the antigen-specific regulatory capacity and prevent autoimmune diabetes in vivo. We also sought to determine if the combination of DN T cells with rapamycin promotes islet allograft survival in autoimmune diabetic NOD recipients. METHODS: NOD CD4(+) T cells were converted to DN T cells in an in vitro mixed-lymphocyte reaction, with or without GAD65 peptide, as previously reported. The antigen-specific DN T cells were adoptively transferred to NOD/SCID mice, new-onset diabetic NOD mice or islet-allograft-recipient NOD mice as the part of cell-based therapy. The development of diabetes and allograft survival was assessed by monitoring blood glucose levels. RESULTS: NOD CD4(+) T cells were converted in vitro to DN T cells at a rate of 50% and expressed unique cell features. The DN T cells from NOD donors blocked autoimmunity and prevented diabetes in NOD models, and these effects were even greater for GAD65-peptide-primed DN T cells. DN T cells acted in conjunction with rapamycin to suppress alloantigen-triggered T cell proliferation, promoted apoptosis and prolonged islet allograft survival in NOD recipients. CONCLUSIONS/INTERPRETATION: Administration of the islet beta cell antigen-specific DN T cells can prevent the development of autoimmune diabetes and promote islet allograft survival in NOD mice.

Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance.

The alloimmune response against fully MHC-mismatched allografts, compared with immune responses to nominal antigens, entails an unusually large clonal size of alloreactive T cells. Thus, induction of peripheral allograft tolerance established in the absence of immune system ablation and reconstitution is a challenging task in transplantation. Here, we determined whether a reduction in the mass of alloreactive T cells due to apoptosis is an essential initial step for induction of stable allograft tolerance with non-lymphoablative therapy. Blocking both CD28-B7 and CD40-CD40 ligand interactions (co-stimulation blockade) inhibited proliferation of alloreactive T cells in vivo while allowing cell cycle-dependent T-cell apoptosis of proliferating T cells, with permanent engraftment of cardiac allografts but not skin allografts. Treatment with rapamycin plus co-stimulation blockade resulted in massive apoptosis of alloreactive T cells and produced stable skin allograft tolerance, a very stringent test of allograft tolerance. In contrast, treatment with cyclosporine A and co-stimulation blockade abolished T-cell proliferation and apoptosis, as well as the induction of stable allograft tolerance. Our data indicate that induction of T-cell apoptosis and peripheral allograft tolerance is prevented by blocking both signal 1 and signal 2 of T-cell activation.