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Background. Ferroptosis is a nonapoptotic form of programmed cell death, which may be related to the occurrence and development of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). Mucin 1 (MUC1) is a kind of macromolecule transmembrane glycoprotein. Previous studies have shown that MUC1 could relieve ALI in sepsis and predict whether sepsis patients would develop into ARDS. However, the role of MUC1 in the ferroptosis of sepsis-induced ALI/ARDS remains unclear. Materials and Methods. Sera samples from 50 patients with sepsis/septic shock were used to detect iron metabolism-related markers. Western blot and qRT-PCR were conducted to detect the expression levels of ferroptosis-related genes. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate inflammatory factors. Transmission electron microscopy (TEM) was used to assess morphological changes of cells. Results. The results showed that the iron metabolism-related indicators in sepsis-induced ARDS patients changed significantly, suggesting the iron metabolism disorder. The expression levels of ferroptosis-related genes in lung tissues of sepsis had marked changes, and the lipid peroxidation levels increased, while Ferrostatin-1 (Fer-1) could reverse the above results, which confirmed the occurrence of ferroptosis. In terms of mechanism studies, inhibition of MUC1 dimerization could increase the expression level of Keap1, reduce the phosphorylation level of GSK3β, inhibit the entry of Nrf2 into the nucleus, further inhibit the expression level of GPX4, enhance the lipid peroxidation level of lung tissues, trigger ferroptosis, and aggravate lung injury. Besides, inhibiting MUC1 reversed the alleviating effect of vitamin E on ALI caused by sepsis, increased the aggregation of inflammatory cells in lung tissues, and aggravated alveolar injury and edema. Conclusions. Our study was the first to explore the changes of iron metabolism indicators in ALI/ARDS of sepsis, clarify the important role of ferroptosis in ALI/ARDS induced by sepsis, and reveal the effects and specific mechanisms of MUC1 in regulating ferroptosis, as well as the sensitization on vitamin E.

This study aimed to investigate whether free fatty acids (FFAs) could induce the release of neutrophil extracellular traps (NETs), as well as the mechanism of FFAs-induced NETs in acute lung injury (ALI). FFAs were used to induce NETs production. The reactive oxygen species (ROS) production was detected after FFA and NADPH oxidase inhibitor treatments. The association between FFAs-induced NETs and the activation of p38, ERK, and JNK pathways was investigated. The effect of FFAs-induced NETs on the dendritic cells (DCs) activation and T cell differentiation was investigated. FFAs could induce neutrophils to produce NETs. FFAs significantly promoted ROS production and increased the expression of ERK, p38 and JNK, and treatment of the inhibitors of NAPDH oxidase (DPI), p38 (SB202190), ERK1/2 (U0126) and JNK (SP600125) inhibited FAAs-induced NETs production. FFAs induced NETs could promote DCs activation and consequently led to the differentiation of primary CD4+ T cells into Th1 and Th17 cells and the release of IL-1β, IL-12 and TNF-α. FFAs are capable of inducing NETs via NOX, ERK, p38 and JNK pathways. FFA-induced NETs further lead to DCs activation and T cell differentiation, which can well explain the mechanism of ALI caused by FFAs.

The surgical treatment of massive rotator cuff tears is a clinical challenge for orthopaedic surgeons. Moreover, tendon retraction, adhesions and fatty infiltration after rotator cuff tear will further increase the difficulty of surgical repair. Therefore, it has become a hotspot and difficulty to repair massive rotator cuff tears with a better way in current research. In recent years, with the continuous development of arthroscopic techniques, shoulder arthroscopic surgery has become the gold standard for the treatment of massive rotator cuff tears, but the adaptations, effects and combined application of different surgical methods are still controversial. The author believes that arthroscopic debridement of shoulder joint and acromioplasty or tuberoplasty could relieve shoulder pain in the short-term for elderly patients with lower functional requirements;long biceps tenotomy or tenodesis is effective for patients with biceps long head tendon injury; complete repair is still the first line treatment for massive rotator cuff tears, but partial repair is possible for massive rotator cuff tears that could not be completely repaired;patch augmentation technology could bring good results for young patients with high functional requirements;for patients with limited internal and external rotation of the shoulder joint and high functional requirements, tendon transfers surgery is recommended;superior capsular reconstruction is more advantageous for young patients with no obvious glenohumeral arthritis, better deltoid muscle strength and higher functional requirements. In addition, subacromial spacer implantation has become a current research hotspot due to its advantages of small trauma, low cost and relative safety, and its long-term effect still needs to be further confirmed.

Ning Du,1 En-Qiang Mao,2 Zhi-Tao Yang,2 Hong-Ping Qu,3 Xian Qian,4 Ying Shi,5 Xiao-Lan Bian,6 Juan He,6,* Er-Zhen Chen2,* 1National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, People’s Republic of China; 2Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Critical Care Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China; 5Department of Clinical Pharmacy, Shaoxing Hospital of Traditional Chinese Medicine, Zhejiang, People’s Republic of China; 6Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Er-Zhen Chen, Emergency Intensive Care Unit, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email chenerzhen@hotmail.com Juan He, Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email hejuanwin@126.comPurpose: Infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) is a great challenge. Central nervous system (CNS) infection caused by CRKP is rarely reported, and effective treatment is limited. Thus, this study aimed to assess intrathecal (IT) or intraventricular (IVT) injection of tigecycline for clearing infection with CRKP in CNS.Patients and Methods: Two patients who had intracranial infection with CRKP after craniotomy were treated in our institution and analyzed retrospectively, summarizing their therapeutic schedules.Results: They all had a fever with the positive results of cerebrospinal fluid (CSF) test, and CSF culture showed positive for CPKP, which was sensitive only to tigecycline. In addition, the MIC of polymyxin B was not tested due to the limited laboratory conditions. After IT or IVT injection of tigecycline treatment, the temperature of the patients became normal in 3 days, with normal levels of white blood cells, protein, glucose and chlorine concentrations in the CSF. Crucially, twice CSF cultures also became negative with no clinical symptoms of intracranial infection after IT or IVT injection of tigecycline treatment. Moreover, there were no adverse drug reactions observed.Conclusion: IT or IVT injection of tigecycline may be a bright choice to control intracranial infection with CRKP.Keywords: central nervous system infection, CNS, carbapenem-resistant Klebsiella pneumoniae, CRKP, tigecycline, treatment

To investigate the method and clinical effects of the treatment of recurrent shoulder dislocation with severe glenoid injury by arthroscopic subscapularis augmentation.From March 2019 to August 2020, 16 patients with recurrent dislocation of shoulder with severe glenoid injury underwent arthroscopic subscapularis augmentation, including 10 males and 6 females, aged from 18 to 50 years old with an average of (29.06±10.54) years old, 4 cases of left shoulder and 12 cases of right shoulder.Visual analogue scale (VAS), American Shoulder and Elbow Surgeons (ASES) score and Rowe score were used to evaluate shoulder function and stability before and after operation.All the 16 patients were followed up from 12 to 29 months, with an average of (18.75±7.26) months. VAS score decreased from 5.25±1.13 before operation to 1.37±0.65 at the final follow-up;ASES score increased from 59.44±9.93 before surgery to 90.88±4.00 at the final follow-up; Rowe score of shoulder increased from 51.56±8.89 before surgery to 92.19±7.06 at the final follow-up, and the differences were statistically significant (Arthroscopic subscapularis augmentation in the treatment of recurrent dislocation of shoulder with severe glenoid injury is satisfactory. It is an effective treatment method of recurrent dislocation of shoulder joint with severe glenoid injury, and external rotation function in patients with almost unaffected.

BackgroundGiant cell tumors of the mobile spine invasion of the adjacent vertebrae are an ignored imaging finding.MethodsNine patients with giant cell tumors of the mobile spine with invasion of the adjacent vertebrae confirmed by pathology were enrolled. Eight patients had pure giant cell tumors (GCTs), while one patient also had an aneurysmal bone cyst. All patients underwent conventional computed tomography, three-dimensional reconstruction, and conventional magnetic resonance imaging, while seven patients also underwent post-contrast magnetic resonance imaging.ResultsAll patients showed GCTs of the mobile spine that arose from the vertebral body and extended to the vertebral arch. The tumors showed soft-tissue attenuation with no evidence of a mineralized matrix. Pathological fracture was seen in five patients. The margin of the original tumor showed partial sclerosis in four patients and involved an adjacent vertebral body with a sclerotic rim in two patients. The tumors showed a homogeneous and similar signal intensity to the normal spinal cord on T1WI (T1-weighted image) in five patients. The cystic area of the tumors was hyperintense on T2WI in the remaining four patients, while one patient showed hemorrhage that was hyperintense on T1WI. The solid components of the GCTs show marked enhancement in all cases, while the cystic area of the tumors was observed without enhancement on contrast-enhanced images in four patients. Bone destruction of the adjacent vertebral body showed a homogeneous signal on T1WI and T2WI and marked enhancement on contrast-enhanced images.ConclusionsGiant cell tumors of the mobile spine with invasion into adjacent vertebrae are an unusual imaging finding. Radiologists should be familiar with this imaging characteristic.

To compare difference in clnical efficacy between arthroscopic double posterior internal approach and incisional surgery for acute simple posterior cruciate ligament tibial avulsion fractures.Totally 52 patients with acute simple posterior cruciate ligament tibial avulsion fractures treated from June 2016 to June 2020 were retrospectively analyzed and divided into two groups according to different surgical protocols, 27 patients in arthroscopic group were treated with arthroscopic double posterior internal approach, including 16 males and 11 females, aged from 19 to 52 years old, with an average age of (34.9±9.2) years old;25 patients in open reduction group were treated with posterior medial knee incision, including 14 males and 11 females, aged from 18 to 54 years old , with an average age of(33.7±8.4) years old. Operation time, incision length, intraoperative bleeding, hospitalization days, hospitalization cost, fracture healing, complications, postoperative Lysholm score and IKDC score at 12 months were observed and compared between two groups.All patients in both groups were completed opertaion successfully without vascular or nerve injury, and 52 patients were followed up from 6 to 24 months with an average of (15.0±1.7) months. Operation time and hospitalization cost in arthroscopic group were significantly greater than those in open reduction group(Arthroscopic double posterior internal approach for acute simple posterior cruciate ligament tibial stop avulsion fracture has satisfactory early results and better efficacy than traditional open surgery, which has advantages of less trauma, faster recovery and easier operation.

BACKGROUND: Using standard vancomycin dosage in critically ill patients might lead to therapy failure and worse patient outcomes, augmented renal clearance (ARC) may be the leading risk factor. In this study, we comprehensively investigated the pharmacokinetics-pharmacodynamics (PK-PD) of vancomycin in critically ill patients with ARC, hoping to explore the precise and accurate dose adjustment method for vancomycin. METHODS: All critically ill patients tested for steady-state trough vancomycin serum concentrations during the recent 6 years in a tertiary level hospital were collected retrospectively and divided into ARC and non-ARC groups, respectively, according to creatinine clearance (CLcr). Serum vancomycin concentrations were measured by the fluorescence polarization immunoassay method. PK-PD parameters of vancomycin were recorded or calculated. The desired daily dose successful in achieving the lower target trough levels (10 mg/L) of vancomycin were investigated correspondingly. RESULTS: A total of 280 vancomycin concentrations were eligible for analysis. The ARC group (n=139) contained more male patients (64.7%) with average age and CLcr of 40 years old (P

Objective The aim of this study was to investigate the changes of bile acids in the liver during hemorrhagic shock (HS) and their potential to attenuate liver injury via activation of SIRT1 (sirtuin 1)-FXR (farnesoid X receptor) signaling. Methods A Sprague-Dawley (SD) rat HS model was established, whereas HepG2 cells were hypoxically cultured to simulate HS in vitro. Liver bile acids (BA) were profiled with ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). FXR expression was detected by western blot and immunohistochemistry. The mRNA levels of SIRT1 and FXR were detected by polymerase chain reaction. Protein expression of SIRT1, FoxM1, NF-κB, acetyl-NF-κB, p53, and acetyl-p53 was analyzed by western blot. Hepatocyte apoptosis and proliferation were measured by TUNEL assay and Ki-67 staining, respectively. Serum and supernatant cytokines were analyzed using ELISA assays. Liver injury was also assessed. To investigate the possible mechanisms, SIRT1 agonist (SRT1720), SIRT1 inhibitor (EX527), and FXR inhibitor (Z-guggulsterone) were used. Results Tauroursodeoxycholic acid (TUDCA) in the liver decreased significantly after HS. SIRT1 and FXR expression was time-dependently downregulated by HS or hypoxia condition. TUDCA upregulated SIRT1-FXR activity, which inhibited expression and acetylation of NF-κB and p53 and increased FoxM1 expression, leading to decreased inflammatory response and apoptosis and increased proliferative capacity in hepatocytes, and attenuation of liver injury. EX527 pretreatment reversed the protective effect of TUDCA. Moreover, Z-guggulsterone supplementation decreased the protective effect of TUDCA in vitro. Conclusion TUDCA in the liver decreased during HS. TUDCA supplementation might attenuate HS-induced liver injury by upregulating SIRT1-FXR signaling.

To investigate the early efficacy of arthroscopic autologous osteochondral grafting in the treatment of recurrent anterior shoulder dislocation.From January 2019 to January 2021, 17 patients with recurrent anterior dislocation of shoulder who underwent arthroscopic autologous osteochondral grafting were selected, including 12 males and 5 females, ranging in age from 17 to 55 years old, with a mean of (32.88±12.33) years old. Rowes rating system for Bankart repair(Rowe), Oxford Shoulder Instability Score (OSIS) and Simple Shoulder Test (SST) were compared before operation, 6 months after operation and at the latest follow-up. OSIS and SST used to evaluate shoulder function were recorded before surgery and at the latest follow-up. The shoulder mobility and intraoperative and postoperative complications were also recorded.All 17 patients were followed up, and the duration ranged from 7 to 25 months, with a mean of (18.4±5.4) months. During the follow-up period, there was no re-dislocation, no vascular or nerve injury. Rowe score increased from 26.2±6.0 before operation to 74.4±4.0 and 82.4±3.1 after 6 months and the latest follow-up. There was significant difference in Rowe score between different time points after operation and before operation (This study provides preliminary evidence that arthroscopic autologous osteochondral grafting can achieve satisfactory early clinical outcomes and stability in patients with recurrent anterior shoulder dislocation with glenoid fracture and defect less than20%, which is a reliable and effective procedure.

Purpose It has been reported that approximately 40% of ALI (acute lung injury) incidence resulted from sepsis. Paclitaxel, as a classic anti-cancer drug, plays an important role in the regulation of inflammation. However, we do not know whether it has a protective effect against CLP (cecal ligation and puncture)-induced septic ALI. Our study aims to illuminate the mitigative effects of paclitaxel on sepsis-induced ALI and its relevant mechanisms. Materials and methods The survival rates and organ injuries were used to evaluate the effects of paclitaxel on CLP mice. The levels of inflammatory cytokines were tested by ELISA. MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. The expression levels of MUC1, TLR 4 and p-NF-κB/p65 were detected by Western blot. Results Our results showed that paclitaxel improved the survival rates and ameliorated organ injuries especially lung injury in CLP-induced septic mice. These were accompanied by reduced inflammatory cytokines in sera and BALF (bronchoalveolar lavage fluid). We also found paclitaxel could attenuate TLR 4-NF-κB/p65 activation both in lung tissues of septic mice and LPS-stimulated lung type II epithelial cell line A549. At the upstream level, paclitaxel-upregulated expression levels of MUC1 in both in vivo and in vitro experiments. The inhibitory effects of paclitaxel on TLR 4-NF-κB/p65 activation were reversed in lung tissues of septic mice pre-treated with MUC1 inhibitor and in MUC1-knockdown A549 cells. Protection of paclitaxel on sepsis-induced ALI and decrease of inflammatory cytokines were also abolished by inhibition of MUC1. Conclusion Collectively, these results indicated paclitaxel could significantly alleviate acute lung injury in CLP-induced septic mice and LPS-stimulated lung type II epithelial cell line A549 by activating MUC1 and suppressing TLR-4/NF-κB pathway.

Existing scoring systems have limitations in predicting the in-hospital mortality of adult sepsis patients. We aimed to develop and validate a novel risk score for predicting the in-hospital mortality of adult sepsis patients.The clinical data of 1,335 adult sepsis inpatients were retrospectively analyzed. Enrolled patients were randomly divided into a modeling group and a validation group at a 3:2 ratio. The modeling group (n=801) was used to develop the risk score by univariate and multivariate logistic regression analyses. The score's performance was validated in the validation group (n=534). We classified patients into four risk levels according to the novel risk score.Age, central vein catheterization, mechanical ventilation, vasopressin, Charlson comorbidity index (CCI), respiratory rate (RR), heart rate (HR), Glasgow coma scale (GCS) score, platelet (PLT), hematocrit (HCT), aspartate aminotransferase (AST), and activated partial thrombin time (APTT) were independent risk factors for in-hospital death in adult sepsis patients. Continuous variables were converted into classified variables to develop the risk score, with a total score of 39 points. Adult sepsis patients with low, lower medium, higher medium, and high risk levels had in-hospital mortality rates of 9.8%, 24.7%, 55.8%, and 83.5%, respectively.Compared with the Acute Physiology and Chronic Health Evaluation II scoring system (APACHE II) and the Modified Early Warning Score (MEWS), the novel risk score showed good predictive performance for in-hospital mortality in adult sepsis patients.

The nitrogen doping/infusion of 650 MHz cavities for the circular electron positron collider (CEPC) is investigated in this study. Two 650 MHz 1-cell cavities are first treated via buffered chemical polishing (BCP), followed by nitrogen doping. A “2/6” condition is adopted, similar to that for 1.3 GHz cavities of Linear Coherent Light Source II. The quality factor of both cavities improved to 7 × 1010 in low fields, i.e., higher than that obtained from the baseline test. One 650 MHz two-cell cavity is nitrogen infused at 165 °C for 48 h with a BCP surface base. The intrinsic quality factor (Q0) reached 6 × 1010 at 22 MV/m in the vertical test, and the maximum gradient is 25 MV/m, which exceeds the specification of the CEPC (4 × 1010 at 22 MV/m).

Background The incidence of Candida bloodstream infections (BSIs), has increased over time. In this study, we aimed to describe the current epidemiology of Candida BSI in a large tertiary care hospital in Shanghai and to determine the risk factors of 28-day mortality and the impact of antifungal therapy on clinical outcomes. Methods All consecutive adult inpatients with Candida BSI at Ruijin Hospital between January 1, 2008, and December 31, 2018, were enrolled. Underlying diseases, clinical severity, species distribution, antifungal therapy, and their impact on the outcomes were analyzed. Results Among the 370 inpatients with 393 consecutive episodes of Candida BSI, the incidence of nosocomial Candida BSI was 0.39 episodes/1000 hospitalized patients. Of the 393 cases, 299 (76.1%) were treated with antifungal therapy (247 and 52 were treated with early appropriate and targeted antifungal therapy, respectively). The overall 28-day mortality rate was 28.5%, which was significantly lower in those who received early appropriate (25.5%) or targeted (23.1%) antifungal therapy than in those who did not (39.4%; P = 0.012 and P = 0.046, respectively). In multivariate Cox regression analysis, age, chronic renal failure, mechanical ventilation, and severe neutropenia were found to be independent risk factors of the 28-day mortality rate. Patients who received antifungal therapy had a lower mortality risk than did those who did not. Conclusions The incidence of Candida BSI has increased steadily in the past 11 years at our tertiary care hospital in Shanghai. Antifungal therapy influenced short-term survival, but no significant difference in mortality was observed between patients who received early appropriate and targeted antifungal therapy.

Background No clinical study has investigated the use of ceftazidime-avibactam combination schemes with an in vitro non-susceptible antimicrobial that could be superior to ceftazidime-avibactam monotherapy against carbapenem-resistant Klebsiella pneumoniae. Methods We performed a retrospective cohort study at two tertiary hospitals in China for patients with carbapenem-resistant Klebsiella pneumoniae infection treated with ceftazidime-avibactam for at least 72 h. A Cox proportional hazards regression model was used to evaluate covariates that potentially affected 30-day mortality. Results Sixty-two patients were eligible for our study; 41 (66.1%) received ceftazidime-avibactam combination therapy and 21 (33.9%) received ceftazidime-avibactam monotherapy. The overall 30-day mortality was 33.9% (21 patients): 24.4% (10/41) and 47.6% (11/21), P = 0.028, in combination and monotherapy groups, respectively. Combination therapy was significantly associated with lower 30-day mortality (Hazard ratio, 0.167; 95% Confidence Interval, 0.060–0.465, P = 0.001). At the same time, a higher APACHE II score, use of vasoactive drugs and comorbidity of organ transplantation were considered factors that increased mortality. The propensity score showed no significant alterations with other variables after adding it to the final model. In the subgroup analysis, the protective effect was revealed when combined with carbapenems, tigecycline or fosfomycin were applied, and in the following subgroups of patients: with sepsis, with creatinine clearance > 50 mL/min, stayed in the intensive care unit ≤ 30 days or underwent mechanical ventilation. Conclusions Ceftazidime-avibactam combined with another in vitro non-susceptible antimicrobial, especially carbapenems, fosfomycin and tigecycline, could significantly decrease the 30-day mortality rate for critically ill patients with carbapenem-resistant Klebsiella pneumoniae infection. Further investigation should be carried out to confirm this conclusion and identify autofit antimicrobials in ceftazidime-avibactam combination schemes.

BACKGROUND: The prediction of severe acute pancreatitis (SAP) is the key to providing timely and targeted intensive care for acute pancreatitis (AP). The heart is one of multiple organs involved in the early stage of SAP, but the predictive ability of cardiac dysfunction for SAP remains elusive. We sought to determine if the serum levels of three cardiac indicators (CI) including N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac troponin I (cTNI), and creatine kinase myocardial band (CK-MB) at admission could predict the occurrence of SAP and the development of related organ failure (OF). METHODS: A retrospective, single-center cohort study was conducted on the files of patients presenting to the emergency intensive care unit and medical ward of a regional hospital in Shanghai. Patients diagnosed as having AP and who met the 2012 Atlanta guideline were admitted within 48 hours after disease onset. RESULTS: Of the 670 AP patients screened, 238 were enrolled into the study and divided into mild acute pancreatitis (MAP) (n=59), moderate severe acute pancreatitis (MSAP) (n=123), and SAP (n=56) groups. No significant difference was found in baseline age, gender, duration from disease onset to admission, comorbidity, or substance abuse. As the levels of three CIs were significantly higher in the SAP group than in the MAP and MSAP groups, the enrolled patients were regrouped into non-SAP and SAP groups for predictive evaluation. Multivariate analysis and nomogram modelling showed that CK-MB, but not cTNI or NT-proBNP predicted the occurrence of SAP [area under curve (AUC) =0.805, confidence interval (CI): 0.794–0.905]. Specifically, 89 patients with OF (Modified Marshall score ≥2) upon admission were selected and CK-MB was shown to predict (AUC =0.805, CI: 0.794–0.905) persistent OF (n=48, duration of OF >48 hours) compared to transient organ failure (TOF) (n=41, duration of OF

Background: There is no clinical study investigating if using CAZ-AVI combination schemes with an in vitro non-susceptible antimicrobial could be superior to CAZ-AVI monotherapy against CRKP clinically. Methods: We performed a retrospective, cohort study at two tertiary hospitals in China for patients with CRKP infection who treated by CAZ-AVI at least 72 hours. A Cox-proportional hazards regression model was set up to evaluate covariates which potentially affected 30-day mortality. Results: Sixty-two patients were eligible in our study, 41 (66.1%) received CZA-AVI combination therapy and 21 (33.9%) received CZA-AVI monotherapy. The overall 30-day mortality was 33.9% (21 patients): 24.4% (10/41) and 47.6% (11/21), P=0.028, in combination and monotherapy groups, respectively. Combination therapy was significantly associated with lower 30-day mortality (HR 0.167, 95%CI 0.060-0.465, P=0.001), while higher APACHE II score, use of vasoactive drug and comorbidity of organ transplantation were considered as factors on increasing mortality. The propensity score showed no significant alteration with other variables after adding it into the final model. In the subgroup analysis, the protective effect revealed when combination with carbapenems, tigecycline or fosfomycin were applied, and in the following subgroups of patients: with sepsis, with CrCl > 50 mL/min, stayed in ICU ≤30 days or underwent mechanical ventilation. Conclusions: CAZ-AVI combination with another in vitro non-susceptible antimicrobial, especially carbapenems, fosfomycin and tigecycline, could significantly decrease 30-day mortality rate for critically ill patients with CRKP infection. Further investigation should be carried out to confirm this conclusion and find out the autofit antimicrobials in CAZ-AVI combination schemes.

For patients with sepsis and septic shock, it remains controversial when to restrict fluid intake and achieve a negative fluid balance. The present study aimed to evaluate the effects of the fluid intake volume during the first 24 h as well as fluid balance for 7 days on the prognosis of sepsis or septic shock. A total of 337 patients diagnosed with sepsis or septic shock at Ruijin Hospital (Shanghai, China) were enrolled in the present retrospective study. Patients with a low fluid intake volume during the first 24 h (fluid intake, 28.1±10.6 ml/kg) had lower in-hospital mortality rates (18.0 vs. 27.3%, P=0.043) and a shorter duration of mechanical ventilation [0 (0-6) vs. 3 (0-11), P=0.025] than the high-fluid volume intake group (62.6±17.6 ml/kg). Furthermore, survivors exhibited a daily negative net fluid balance from the second day (48 h), whereas non-survivors had a daily positive net fluid balance for 7 days, where fluid balance volumes were significantly lower in survivors compared with those in non-survivors. Finally, binary logistic regression analysis was used to determine whether the mean daily fluid balance (P

Background: Candida spp. are important opportunist pathogens causing bloodstream infections (BSIs). The present study aims to describe the current epidemiology of Candida BSI in a large Shanghai Tertiary-care Hospital from 2008 to 2018 and to identify the risk factors and the impact of antifungal therapy on clinical outcomes. Methods: From January 2008 to December 2018, all consecutive patients who developed Candida BSI at Ruijin Hospital were enrolled. Underlying diseases, clinical severity, species distribution, antifungal therapy, and its impact on the outcome were analyzed. Results: The incidence of nosocomial Candida BSI was 0.39 episodes/1000 hospitalized patients, and the overall 28-day mortality rate was 28.5%. Among the 393 cases of Candida BSI, 299 cases (76.1%) received antifungal therapy. 247 received early appropriate antifungal therapy (an appropriate drug with adequate dosage was started before the subsequent in vitro susceptibility results), and 52 received target antifungal therapy (appropriate target treatment started after susceptibility results, regardless of whether the inappropriate antifungal treatment has been initialed or not). The 28-day mortality rate was significantly lower in those who received early appropriate antifungal therapy or target antifungal therapy compared with those who did not receive antifungal therapy (25.5% and 23.1% vs. 39.4%,P = 0.012 and P = 0.046). In multivariate Cox regression analysis, age, chronic renal failure, mechanical ventilation, neutropenia were independent risk factors for the 28-day mortality rate, while antifungal therapy was a protective factor for short-term survival rate. Conclusions: The epidemiology of Candida BSI in Shanghai differed from that observed in Western countries. Antifungal therapy did influence the short-term survival, while there was no significant difference between the mortality for those who received early appropriate antifungal therapy and for those who received target antifungal therapy.

Background Evidence implying that metabolism reprogramming plays an important role in the regulation of sepsis is increasing; however, whether it has a similar role in septic organ dysfunction remains unclear. Here we provide evidence to support a new role of uncoupling protein-2 (UCP2)-regulated Warburg effect, i.e., aerobic glycolysis, in promoting mitochondrial injury in the kidney. Methods To imitate sepsis condition, male C57BL/6 mice were operated by the cecal ligation puncture (CLP) in vivo, whereas a normal human kidney cell line (HK-2) was treated with lipopolysaccharide (LPS) in vitro. UCP2 siRNA pretreatment was performed to knock down UCP2 expression in vitro. The glycolysis metabolite was detected by liquid chromatography/tandem mass spectrometry (LC-MS) in vivo and detected by commercial kits in vitro. Oxidative phosphorylation (OXPHOS) level and glycolysis level were monitored by measuring the oxygen consumption rate (OCR, indicative of respiration) and extracellular acidification rate (ECAR, indicative of glycolysis) in vitro. Exogenous lactate was supplied to stimulate HK-2 cells and indicators of mitochondrial dysfunction were also assessed. Results Aerobic glycolysis is enhanced in septic tubular epithelial cells, and the glycolysis inhibitor 2-deoxyglucose (2-DG) can partially restore mitochondrial membrane potential (MMP or ΔΨm) and decrease the reactive oxygen species (ROS) production. With the knockdown of ucp2, the aerobic glycolysis level upregulates, and mitochondrial injury increases. Conclusions These results provide insights on a new mechanism of metabolic regulation of mitochondrial injury and the importance of targeting aerobic glycolysis for the treatment of septic acute kidney injury.

We prove that a topological space is uniform Eberlein compact iff it is homeomorphic to a super weakly compact subset C of a Banach space such that the closed convex hull coC of C is super weakly compact. We also show that a Banach space X is super weakly compactly generated iff the dual unit ball BX* of X* in its weak star topology is affinely homeomorphic to a super weakly compactly convex subset of a Banach space.

Background Nosocomial pneumonia is one of the most common health care–associated infections in intensive care units (ICUs) worldwide, attributing to high morbidity and mortality. Our study aim is to investigate the effectiveness of oral hygiene with 0.2% chlorhexidine gluconate (CHX) and 0.08% metronidazole (MDE) influencing the microbiologic epidemiology and incidence of nonintubation pneumonia (NIP) and ventilator-associated pneumonia (VAP). Methods Patients who stayed >48 hours in the emergency ICU between 2008 and 2012 were enrolled and provided oral hygiene by swabbing with 0.08% MDE twice daily until discharge or death during the first year (period M), whereas CHX was applied during the following 3 years (period C). The incidence and microbiologic epidemiology of NIP and VAP were studied. Results There were 873 patients enrolled. There were 44 episodes of NIP and 25 episodes of VAP that occurred among 212 patients in period M, and 84 episodes of NIP and 49 episodes of VAP occurred among 661 patients in period C. Overall, the rate of NIP and VAP decreased year by year. Acinetobacter baumannii was the most frequently identified bacteria for NIP (22.9%) and VAP (25.3%), with an annual ascent. Few changes were observed on bacteria distribution for NIP and VAP. Conclusions Oral hygiene with CHX, having reduced the incidence of nosocomial pneumonia among critical ill patients, suggests a benefit of oral hygiene in decreasing the incidence of nosocomial pneumonia, including VAP in ICUs, but not bacterial epidemiology.

Background: The expression of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) in renal tubular epithelial cells has been thought to be highly correlated with the occurrence of several kidney diseases, but whether it takes place in renal tissues during hemorrhagic shock (HS) is unknown. The present study aimed to investigate this phenomenon and the inhibitory effect of Vitamin C (VitC). Methods: A Sprague–Dawley rat HS model was established in vivo in this study. The expression level and location of DC-SIGN were observed in kidneys. Also, the degree of histological damage, the concentrations of tumor necrosis factor-μ and interleukin-6 in the renal tissues, and the serum concentration of blood urea nitrogen and creatinine at different times (2–24 h) after HS (six rats in each group), with or without VitC treatment before resuscitation, were evaluated. Results: HS induced DC-SIGN expression in rat tubular epithelial cells. The proinflammatory cytokine concentration, histological damage scores, and functional injury of kidneys had increased. All these phenomena induced by HS were relieved when the rats were treated with VitC before resuscitation. Conclusions: The results of the present study illustrated that HS could induce tubular epithelial cells expressing DC-SIGN, and the levels of proinflammatory cytokines in the kidney tissues improved correspondingly. The results also indicated that VitC could suppress the DC-SIGN expression in the tubular epithelial cells induced by HS and alleviate the inflammation and functional injury in the kidney.

Objective To investigate the roles of epithelial-dendritic cell transformation (EDT) characterized by the expression of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) in the occurrence of tissue inflammation induced by hemorrhagic hypotension (HH), the protective effect of vitamin C (VitC), and the potential mechanisms. Methods We conducted an in vitro study using the rat intestinal epithelial cells (IEC-6). After hypoxic culture with or without VitC for 2, 6, 24, and 48 h (n = 3 per group), the expression levels of DC-SIGN, E-cadherin, and Glycogen synthase kinase-3β-S9 (GSK-3β-S9) in IEC-6 cells, IL-1β, and IL-6 concentrations in the cell culture medium were measured. To investigate the potential mechanism, we inhibited E-cadherin expression by siRNA and GSK-3β activity by TDZD-8, respectively. The in vivo study was conducted by establishing SD rat HH model. We observed the expression levels and location of DC-SIGN in the intestines. We also showed histological damage, TNF-α and IL-6 concentrations, and organ injury scores at 2, 6, and 24 h after HH (n = 6 per group), with or without VitC pretreatment. Results Hypoxia-induced DC-SIGN expression in IEC-6 cells in a time-dependent manner and the inflammatory factors were also increased. VitC inhibited all these phenomena. Hypoxia inhibited GSK-3β activity and E-cadherin expression. VitC could ease these inhibitions. The inhibitory effect of VitC on DC-SIGN was diminished when E-cadherin expression was inhibited in advance. TDZD-8 diminished the protective effect of VitC on E-cadherin and abolished inhibitory effect of VitC on DC-SIGN expression. HH-induced DC-SIGN expression in rat intestine epithelial cells and the histological damage scores and pro-inflammatory cytokine levels were also increased. Conclusions HH induces EDT in rat intestine epithelial cells. VitC maintains GSK-3β activity, attenuates the suppression of E-cadherin caused by hypoxia, and ultimately decreases DC-SIGN expression.

Background Oxidative stress plays a pivotal role in the progress of severe acute pancreatitis (SAP). Vitamin C (VC) is the most important antioxidant in plasma. However, the effects of an intravenous administration of high-dose VC and the mechanisms by which it exerts its antioxidant function in an experimental model of SAP have not been determined. Methods Sodium taurocholate was used to induce rat pancreatic injury and AR42J cells injury. After the establishment of SAP model, SAP rat and injured AR42J cells were treated with VC. For the injured AR42J cells, small interfering RNA-mediated knockdown of NRF2 was conducted after VC treatment. The histopathological characteristics, the apoptosis of pancreatic acinar cells, oxidative stress markers and levels of enzymes, biochemical indicators, and inflammatory cytokines were examined in vivo and in vitro. Furthermore, the mortality of rats was assessed. Results In vivo and in vitro results demonstrated that VC treatment ameliorated apoptosis of pancreatic acinar cells, as evidenced by the increase in Bcl-2, Bcl-XL, and MCL-1 expressions and decrease in Bax and cleaved caspase-3 expression along with decreased TUNEL-positive cells. Also, we found that the elevation of MDA and decrease of SOD, GPx, GSH/GSSG, and T-AOC induced by SAP were reversed by VC treatment in vivo and in vitro, and VC treatment increased expressions of Nrf2, NQO1, and HO-1 in SAP model at protein and gene level, indicating that VC attenuated oxidative stress via the NRF2/NQO1/HO-1 pathway. Meanwhile, it was found that sodium taurocholate significantly induced the release of amylase, lipase, IL-1β, and IL-6 in rat plasma and AR42J cells, which were declined by VC treatment. In vitro results also revealed that these alterations in sodium taurocholate-injured AR42J cells due to VC treatment was attenuated by NRF2 knockdown. In addition, VC at a dose of 500 mg/kg decreased the levels of lactic acid, Cre, NGAL, AST, and ALT in the plasma of SAP rats, suggesting the improvement of renal and pancreatic injury and liver function of SAP rats. Furthermore, the mortality of SAP rats was 50%, which declined to 30% after VC treatment. Conclusions The present study suggests that high-dose of VC ameliorate pancreatic injury of SAP via the NRF2/NQO1/HO-1 pathway to inhibit oxidative stress.

Objective We aimed to investigate whether inhibition of MUC1 would aggravate sepsis-induced ALI, and explore the predictive value of plasma MUC1 for sepsis patients with or without ARDS. Materials and methods MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. Expression levels of MUC1, TLR 4 and HIF-1α were detected by Western blot. In addition, plasma MUC1 levels of enrolled patients were detected by ELISA on the day of admission and on the 3rd day. ROC curve was used to determine the predictive value of MUC1 in sepsis patients with ARDS. Results Our results showed that inhibition of MUC1 could aggravate sepsis-induced acute lung injury and increase the expression of inflammatory cytokines in sera and BALF of sepsis mice. At the same time, we confirmed that inhibition of MUC1 could significantly decrease HIF-1α expression and thereby activate the expression level of TLR4. HIF-1α was a negative regulator of TLR-4. In addition, plasma MUC1 levels of sepsis patients with ARDS were significantly higher than those without ARDS and healthy adults. ROC curve showed that predictive value of plasma MUC1 on sepsis with ARDS on the 3rd day of enrollment was higher than the day of enrollment. Conclusion MUC1 could inhibit the expression of TLR-4 by stabilizing HIF-1α, thereby alleviate sepsis-induced lung injury and protect organ function. At the same time, elevated MUC1 levels in plasma had a good predictive valud on whether patients with sepsis would develop ARDS.

BACKGROUND: Fluid management is crucial to acute respiratory distress syndrome (ARDS) secondary to sepsis. However, choices of fluid resuscitation strategies and fluid input volumes remain a thorny problem. Our study aimed to elucidate the relationship between fluid balance and prognosis of ARDS patients secondary to sepsis. METHODS: Our study included 322 sepsis patients from Ruijin Hospital between 2014 and 2018, and 84 patients were diagnosed as ARDS within 72 hours after onset of sepsis according to Berlin ARDS Definition. RESULTS: Among the 322 sepsis patients, 84 (26.1%) were complicated with ARDS within 72 hours. ARDS patients had a lower oxygenation index (PaO(2)/FiO(2) 166.4±71.0 vs. 255.0±91.2, P

Acute pancreatitis is an acute abdominal disease, with 10-20% of the cases deteriorating rapidly, accompanied by persistent organ failure and further development into severe acute pancreatitis (SAP). The aim of the present study was to investigate the mechanism of fluid resuscitation via the rectum in the early stages of SAP and the role of aquaporins (AQPs). An SAP model was constructed by injection of 5% sterile sodium taurocholate into the biliopancreatic duct of Sprague Dawley rats, and the mean arterial pressure (MAP) was continuously monitored via femoral artery catheterization. At 30 min after the construction of the SAP model, the rats in the fluid resuscitation groups were resuscitated with normal saline at a rate of 4 ml/kg/h through the venous or the rectal route. The AQP and Na+-K+-ATPase levels, and the correlation of the MAP and colon AQPs at the early stages of SAP were analyzed. The results demonstrated that the mRNA level of AQP-3 and AQP-4 in the distal colon decreased significantly in the group subjected to fluid resuscitation via the rectum, while no significant differences were identified in the Na+-K+-ATPase levels of the colon in that group. Furthermore, a negative correlation was identified between the expression of AQPs and the MAP (P

PBS/nano-CaCO3 composites with various nano-CaCO3 weight fractions were prepared by melt blending. The thermal behavior, dynamic mechanical properties and rheological properties of the composites were investigated. DSC measurements revealed that the nano-CaCO3 particles had little influence on the crystallization and melting behavior of PBS. Thermogravimetric analysis showed that the introduction of nano-CaCO3 tended to improve the thermal stability of PBS. Dynamic mechanical analysis showed that the G′ and G″ of the PBS/nano-CaCO3 composites were improved significantly when the nano-CaCO3 content was not more than 3wt%, while the G′ and G″ were mainly decided by the PBS matrix when the nano-CaCO3 content exceeded 3wt%. Rheological results showed that G′

BACKGROUND Blood pressure control is an essential therapy for patients with acute type B aortic dissection (ABAD) and should be maintained throughout the entire treatment. Thus, vast majority current guidelines recommend control the blood pressure to lower than 140/90 mmHg. Theoretically, a much lower target may further decrease the risk of propagation of dissection. However, some argued that too lower blood pressure would compromise the organ perfusion. Thus, there is no unanimous optimal target for blood pressure in patients with ABAD so far. The present study aimed to investigate the optimal blood pressure target for patients with ABAD, in the hope that the result would optimize the treatment of aortic dissection (AD). METHODS The study is a multi-center randomized controlled clinical trial. Study population will include patients with new diagnosed ABAD and hypertension. Blocked randomization was performed where intensive blood pressure control (

In the plastic injection molding (PIM), the optimization of the process parameters is a complex task. The objective of this study is to propose an intelligent approach for efficiently optimizing PIM parameters when multiple objectives are involved, where different objectives, such as minimizing part weight, flash, or volumetric shrinkage, present trade-off behaviors. Multiple objective functions reflecting the product quality are constructed for the optimization model of PIM parameters. The proposed approach integrates Taguchi’s parameter design method, back-propagation neural network (BPNN), grey correlation analysis (GCA), particle swarm optimization (PSO) and multiobjective particle swarm optimization (MOPSO) to locate the Pareto optimal solution for multiobjective optimization problem. PSO and GCA are applied to optimize the network structure of BPNN to establish multiobjective mathematical model (PSO-GCANN) that finely maps the relationship between the input process parameters and output multiresponse. MOPSO is used to fine-tune the Pareto optimal solutions while the approximate PSO-GCANN is utilized to efficiently compute the fitness of every individual during the evolution of MOPSO. The illustrative application and comparison of results show that the proposed methodology outperforms the existing methods and can help mold designers to efficiently and effectively identify optimal process parameters.

Background The fulminant form of hepatitis B-related acute liver failure (FHB-ALF) is a rare but highly fatal outcome of acute hepatitis B virus (HBV) infection. Its related host factors have not been studied to our knowledge. Methods To identify functionally relevant biological pathway(8) in FHB-ALF pathogenesis, pathway enrichment analysis was conducted on a data set of rare case-specific variants derived from exomic sequencing of 10 unrelated cases. Key variants in identified pathways were validated using 312 controls with HBV disease. Mechanistic studies of a recurrent Toll-like receptor (TLR) 2 gene (TLR2) variant were performed in vitro and in vivo. Results The TLR signaling pathway was highly enriched, with associated variants found in 9 of the 10 cases. Notably, a rare heterozygous single-nucleotide variation causing F679I mutation in TLR2 was identified in 2 unrelated cases. In vitro analysis demonstrated F679I to cause loss of function. In both heterozygous and homozygous TLR2 knockout mice, injection of HBV replicon plasmid resulted in more prominent alanine aminotransferase elevations and hepatic necroinflammation than in wild-type mice. Mechanistic analyses demonstrated reduced regulatory T-cell percentages in postexposure TLR2 knockout mice. Conclusions TLR2 signaling is very likely impaired in patients with FHB-ALF. The recurrence of rare case-specific TLR2 variant strongly suggests mechanistic contribution to fulminancy in HBV infection.

Determining optimal process parameter settings critically influences productivity, quality, and cost of production in the plastic injection molding industry. Selecting the proper process conditions for the injection molding process is treated as a multi-objective optimization problem, where different objectives, such as minimizing product weight, volumetric shrinkage, or flash present trade-off behaviors. As such, various optima may exist in the objective space. This paper presents the development of an experiment-based optimization system for the process parameter optimization of multiple-input multiple-output plastic injection molding process. The development integrates Taguchi’s parameter design method, neural networks based on PSO (PSONN model), multi-objective particle swarm optimization algorithm, engineering optimization concepts, and automatically search for the Pareto-optimal solutions for different objectives. According to the illustrative applications, the research results indicate that the proposed approach can effectively help engineers identify optimal process conditions and achieve competitive advantages of product quality and costs.