Scaling of the strange-metal scattering in unconventional superconductors.

Marked evolution of properties with minute changes in the doping level is a hallmark of the complex chemistry that governs copper oxide superconductivity as manifested in the celebrated superconducting domes and quantum criticality taking place at precise compositions1-4. The strange-metal state, in which the resistivity varies linearly with temperature, has emerged as a central feature in the normal state of copper oxide superconductors5-9. The ubiquity of this behaviour signals an intimate link between the scattering mechanism and superconductivity10-12. However, a clear quantitative picture of the correlation has been lacking. Here we report the observation of precise quantitative scaling laws among the superconducting transition temperature (Tc), the linear-in-T scattering coefficient (A1) and the doping level (x) in electron-doped copper oxide La2-xCexCuO4 (LCCO). High-resolution characterization of epitaxial composition-spread films, which encompass the entire overdoped range of LCCO, has enabled us to systematically map its structural and transport properties with unprecedented accuracy and with increments of Δx = 0.0015. We have uncovered the relations Tc ~ (xc - x)0.5 ~ (A1□)0.5, where xc is the critical doping in which superconductivity disappears and A1□ is the coefficient of the linear resistivity per CuO2 plane. The striking similarity of the Tc versus A1□ relation among copper oxides, iron-based and organic superconductors may be an indication of a common mechanism of the strange-metal behaviour and unconventional superconductivity in these systems.

Unveiling the potent effect of vitamin D: harnessing Nrf2/HO-1 signaling pathways as molecular targets to alleviate urban particulate matter-induced asthma inflammation.

BACKGROUND: Asthma is the most common allergic disease characterized by an inflammatory response in the airways. Mechanismly, urban particulate matter (PM) is the most widely air pollutant associated with increased asthma morbidity and airway inflammation. Current research found that vitamin D is an essential vitamin with anti-inflammatory, antioxidant and other medical efficacy. Inadequate or deficient vitamin D often leads to the pathogenesis and stability of asthma. NGF exacerbates airway inflammation in asthma by promoting smooth muscle cell proliferation and inducing the Th2 immune response. Activation of the Nrf2/HO-1 signaling pathway can exert a protective effect on the inflammatory response in bronchial asthma. However, the specific mechanism of this pathway in PM-involved asthmatic airway smooth muscle cells remains unclear. METHODS: Mice were sensitized and challenged with Ovalbumin (OVA) to establish an asthma model. They were then exposed to either PM, vitamin D or a combination of both, and inflammatory responses were observed. Including, acetylcholine stimulation at different concentrations measured airway hyperresponsiveness in mice. Bronchoalveolar lavage fluid (BALF) and serum were collected for TNF-α, IL-1ß, IL-6, and Nerve growth factor (NGF) analysis. Additionally, lung tissues underwent histopathological examination to observe alveolar structure and inflammatory cell infiltration. Specific ELISA kits were utilized to determine the levels of the inflammatory factors TNF-α, IL-1ß, IL-6, and Nerve growth factor (NGF). Nrf2/HO-1 signaling pathways were examined by western blot analysis. Meanwhile, we constructed a cell system with low HO-1 expression by lentiviral transfection of airway smooth muscle cells. The changes of Nrf2, HO-1, and NGF were observed after the treatment of OVA, PM, and Vit D were given. RESULTS: The in vivo results showed that vitamin D significantly alleviated pathological changes in lung tissue of PM-exposed mice models. Mechanismly, vitamin D decreased substantial inflammatory cell infiltration in lung tissue, as well as the number of inflammatory cells in BALF. Furthermore, vitamin D reduced the heightened inflammatory factors including of TNF-α, IL-1ß, IL-6, and NGF caused by PM exposure, and triggered the activity of nucleus Nrf2 and HO-1 in PM-exposed asthmatic mice. Notably, knockdown HO-1 weakens the Vitamin D- mediated inhibition to pollution toxicity in asthma. Importantly, in vitro experiments on OVA-stimulated mice airway smooth muscle cells, the results showed that OVA and PM, respectively, reduced Nrf2/HO-1 and increased NGF's expression, while vitamin D reversed the process. And in the HO-1 knockdown cell line of Lenti-si-HO-1 ASMCs, OVA and PM reduced Nrf2's expression, while HO-1 and NGF's expression were unchanged. CONCLUSIONS: The above results demastrate that vitamin D downregulated the inflammatory response and the expression of NGF by regulating the Nrf2/HO-1 signaling pathways in airway smooth muscle cells, thereby showing potent anti-inflammatory activity in asthma.

Clinical significance of hemoglobin level and blood transfusion therapy in elderly sepsis patients: A retrospective analysis.

INTRODUCTION: The clinical significance of hemoglobin level and blood transfusion therapy in elderly sepsis patients remains controversial. The study investigated the relationship between mortality, hemoglobin levels, and blood transfusion in elderly sepsis patients. METHODS: Elderly sepsis patients were included in the Marketplace for Medical Information in Intensive Care (MIMIC-IV) database. A multivariate regression model analyzed the relationship between the Hb level and the 28-day mortality risk. Logistic Multivariate analysis, Propensity Matching (PSM) analysis, an Inverse Probabilities Weighting (IPW) model and doubly robust estimation were applied to analyze the 28-day mortality risk between transfused and non-transfused patients in Hb at 7-8 g/dL, 8-9 g/dL, 9-10 g/dL, and 10-11 g/dL groups. RESULTS: 7473 elderly sepsis patients were enrolled in the study. The Hb level in the ICU and the 28-day mortality risk of patients with sepsis shared a non-linear relationship. The patients with Hb levels of <10 g/dL(p < 0.05) and > 15 g/dL(p < 0.05) within 24 h had a high mortality risk in multivariate analysis. In the Hb level 7-8 g/dL and 8-9 g/dL subgroup, the Multivariate analysis (p < 0.05), PSM (p < 0.05), IPW (p < 0.05) and doubly robust estimation (p < 0.05) suggested that blood transfusion could reduce the mortality risk. In the subgroup with a Hb level of 10-11 g/dL, IPW (p < 0.05) and doubly robust estimation (p < 0.05) suggested that blood transfusion could increase the mortality risk of elderly sepsis patients. CONCLUSION: A non-linear relationship between the Hb level and the 28-day mortality risk and Hb levels of <10 g/dL and > 15 g/dL may increase the mortality risk, and blood transfusion with a Hb level of <9 g/dL may minimize mortality risk in elderly sepsis patients.

Early administration of hydrocortisone, vitamin C, and thiamine in adult patients with septic shock: a randomized controlled clinical trial.

BACKGROUND: The combination therapy of hydrocortisone, vitamin C, and thiamine has been proposed as a potential treatment in patients with sepsis and septic shock. However, subsequent trials have reported conflicting results in relation to survival outcomes. Hence, we performed this randomized controlled trial (RCT) to evaluate the efficacy and safety of early combination therapy among adult patients with septic shock. METHODS: This single-center, double-blind RCT enrolled adult patients with diagnosis of septic shock within 12 h from Northern Jiangsu People's Hospital between February 2019 and June 2021. Recruited patients were randomized 1:1 to receive intervention (hydrocortisone 200 mg daily, vitamin C 2 g every 6 h, and thiamine 200 mg every 12 h) or placebo (0.9% saline) for 5 days or until ICU discharge. The primary endpoint was 90-day mortality. The secondary endpoints included mortality at day 28, ICU discharge, and hospital discharge; shock reversal; 72-h Delta SOFA score; ICU-free days, vasopressor-free days, and ventilator support -free days up to day 28; ICU length of stay (LOS) and hospital LOS. RESULTS: Among 426 patients randomized, a total of 408 patients with septic shock were included in the per-protocol (PP) analysis, of which 203 were assigned to the intervention group and 205 to the placebo group. In the PP population, the primary outcome of 90-day mortality was 39.9% (81/203) and 39.0% (80/205) in the intervention and the placebo groups, respectively, and was not significantly different (P = 0.86). There was no significant difference between two groups in 28-day mortality (36.5% vs. 36.1%, P = 0.94) or the ICU mortality (31.5% vs. 28.8%, P = 0.55) and hospital mortality (34.5% vs. 33.2%, P = 0.78). No other secondary outcomes showed significant differences between two groups, including shock reversal, vasopressor-free days, and ICU LOS. Intention-to-treat analysis included all the 426 patients and confirmed these results (all P > 0.05). CONCLUSION: Among adult patients with septic shock, early use of hydrocortisone, vitamin C, and thiamine combination therapy compared with placebo did not confer survival benefits. Trial registration ClinicalTrials.gov: NCT03872011 , registration date: March 12, 2019.

[Establishment of a predictive model of septic myocardiopathy based on left ventricular global longitudinal strain].

Objectives: To explore the risk factors associated with septic cardiomyopathy and establish a predictive model of the disease based on left ventricular global longitudinal strain (LV GLS). Methods: Data from sepsis patients without a history of cardiac dysfunction who were treated in the Critical Care Department of the Northern Jiangsu People's Hospital from September, 2019 to January, 2021 were included in the analysis. The LV GLS was measured by echocardiography within 72 hours and the patients were divided into a septic myocardiopathy group (LV GLS>-17%) and a normal cardiac function group (LV GLS≤-17%). Clinical data from two groups of patients were collected for univariate analysis. The receiver operating characteristic (ROC) curves of the factors that were statistically different were drawn for exploring the diagnostic and cut-off values. The continuous variable was converted to a dichotomous variable according to the cut-off value. Multivariate logistic regression analysis of sepsis cardiomyopathy was performed to screen the risk factors and create a predictive model. The predictive model was evaluated by ROC curve analysis and the Bootstrap method and shown as a nomograph. Results: Patients in the sepsis cardiomyopathy group had higher levels of high sensitive troponin I (Hs-TnI), procalcitonin (PCT), lactate (Lac), N-terminal pro-brain atriuretic peptide (NT-proBNP), vasopressor dosing intensity (VDI) and sequential organ failure assessment (SOFA) when compared to those in the normal cardiac function group (all P<0.05). The multivariate logistic regression analysis showed that Hs-TnI≥0.131 µg/L (OR=6.71, 95%CI:2.67-16.88, P<0.001), PCT≥40 µg/L (OR=3.08, 95%CI:1.10-8.59, P=0.032), Lac≥4.2 mmol/L (OR=2.80, 95%CI:1.02-7.69, P=0.045), NT-proBNP≥3 270 ng/L (OR=2.67, 95%CI:1.06-6.74, P=0.038) were independent risk factors for septic myocardiopathy. The area under the ROC curve of the predictive model based on the four indexes up-mentioned was 0.838 (95%CI:0.766-0.910), and the C-index was 0.822 (95%CI:0.750-0.894) which indicated the utility of the nomogram. The model had a good predictive ability, accuracy and discrimination. Conclusions: Hs-TnI≥0.131 µg/L, PCT≥40 µg/L, Lac≥4.2 mmol/L and NT-proBNP≥3 270 ng/L are independent risk factors for septic myocardiopathy, and the septic cardiomyopathy predictive model constructed based on these factors has a good diagnostic performance.

Initial fluid resuscitation (30 mL/kg) in patients with septic shock: More or less?

OBJECTIVES: The 2018 Surviving Sepsis Campaign (SSC) recommends rapid administration of 30 mL/kg crystalloid fluids for hypotension or lactate ≥4 mmol/L in patients with septic shock; however, there is limited evidence to support this recommendation. The purpose of this study was to examine the relationship between initial fluid resuscitation doses and prognosis in patients with septic shock. METHODS: This was a multicenter prospective observational study of adult patients with septic shock who were admitted to four intensive care units (ICUs) in a total of three Jiangsu Province teaching hospitals over a 3-year span from May 8, 2018, to June 15, 2021. Each enrolled patients with septic shock was categorized into the low-volume (below 20 mL/kg fluid), medium-volume (20-30 mL/kg fluid) or high-volume (above 30 mL/kg fluid) fluid group according to the initial infusion dose given for fluid resuscitation. Various demographic attributes and other variables were collected from medical records. Logistic regression and Kaplan-Meier curve analysis were used to determine the relationship between initial fluid resuscitation doses and patient outcomes. MEASUREMENTS AND MAIN RESULTS: A total of 302 patients who presented to the ICU were diagnosed with septic shock. The 28-day mortality was highest in the high-volume group (48.3%) and lowest in the medium-volume group (26.3%, P < 0.05). Patients who completed 30 mL/kg initial fluid resuscitation in the first 1-2 h had the lowest 28-day mortality rate (22.8%, P < 0.05). Logistic regression showed that a medium initial fluid volume dose was an independent protective factor, with the odds ratio (OR) indicating significantly decreased mortality (OR, 0.507; 95% confidence interval, 0.310-0.828; P = 0.007; P < 0.05). A Kaplan-Meier curve stratified by initial fluid resuscitation dose was constructed for the probability of 28-day mortality. The medium-volume fluid group showed a significantly lower 28-day mortality rate than the high-volume group or the low-volume group (log-rank test, P = 0.0016). CONCLUSION: In septic shock patients, an initial fluid resuscitation rate of 20-30 mL/kg within the first hour may be associated with reduced 28-day mortality; however, this result needs to be confirmed by further high-quality randomized controlled clinical trials. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-OOC-17013223. Registered 2 November 2017, http://www.chictr.org.cn/showproj.aspx?proj=22674.

Full superconducting dome of strong Ising protection in gated monolayer WS2.

Many recent studies show that superconductivity not only exists in atomically thin monolayers but can exhibit enhanced properties such as a higher transition temperature and a stronger critical field. Nevertheless, besides being unstable in air, the weak tunability in these intrinsically metallic monolayers has limited the exploration of monolayer superconductivity, hindering their potential in electronic applications (e.g., superconductor-semiconductor hybrid devices). Here we show that using field effect gating, we can induce superconductivity in monolayer WS2 grown by chemical vapor deposition, a typical ambient-stable semiconducting transition metal dichalcogenide (TMD), and we are able to access a complete set of competing electronic phases over an unprecedented doping range from band insulator, superconductor, to a reentrant insulator at high doping. Throughout the superconducting dome, the Cooper pair spin is pinned by a strong internal spin-orbit interaction, making this material arguably the most resilient superconductor in the external magnetic field. The reentrant insulating state at positive high gating voltages is attributed to localization induced by the characteristically weak screening of the monolayer, providing insight into many dome-like superconducting phases observed in field-induced quasi-2D superconductors.

Pharmacokinetics and tissue distribution of cantharidin after oral administration of aqueous extracts from Mylabris in rats.

A sensitive gas chromatography-mass spectroscopy method was established for the determination of cantharidin (CTD) in rat plasma and liver homogenates. During the experiment, rats were randomly divided into two groups (low, high) and were administered aqueous extract of Mylabris compound for 7 days. Then, plasma and tissue samples were taken at different time points to study the pharmacokinetics and tissue distribution of CTD in rats. The selected reaction monitoring transitions for CTD and clofibrate (internal standard) were m/z 128 → 85 and m/z 169 → 141, respectively. The calibration curve ranged from 10.26 to 3,078 ng/ml for plasma and from 10.26 to 246.24 ng/ml for liver homogenates. The lower limits of quantification were 10.26 ng/ml for both plasma and liver. The intra- and inter-day precision and accuracy were <20% for both plasma and liver homogenates. Extraction recovery ranged from 89.21 to 103.61% for CTD in rat plasma and liver and from 83.79 to 102.74% for IS in rat plasma and liver. Matrix effects ranged from 93.06 to 110.44% for CTD and from 91.65 to 110.80% for IS.

Effect of Low-Dose Hydrocortisone Therapy in Adult Patients With Septic Shock: A Meta-Analysis With Trial Sequential Analysis of Randomized Controlled Trials.

BACKGROUND: The efficacy of low-dose hydrocortisone therapy in the management of septic shock remains controversial in critical care for many years. Hence, we performed this meta-analysis of randomized controlled trials (RCTs) with trial sequential analysis (TSA) to evaluate its effect on clinical outcome among adult patients with septic shock. METHODS: We identified relevant RCTs published from inception to March 7, 2018 comparing low-dose hydrocortisone with placebo or no intervention in adults admitted to the intensive care unit (ICU) for septic shock. Meta-analyses were performed for the primary and secondary outcomes. The risk of bias was assessed using the Cochrane Collaboration's instrument. Trial sequential analysis was used to pool the results from the included studies for the primary outcomes. RESULTS: Thirteen studies were retrieved by our literature search strategy. There were no significant differences in 28-day mortality (odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.81-1.00; P = .05) and hospital mortality (OR = 0.91, 95% CI = 0.82-1.02; P = .09) between the 2 groups, which were confirmed by TSA. However, there was a significant improvement in shock reversal in the hydrocortisone group (OR = 1.33, 95% CI = 1.02-1.72; P = .03). Furthermore, subgroup analyses revealed that hydrocortisone plus fludrocortisone statistically reduced the rate of 28-day mortality (OR = 0.79, 95% CI = 0.64-0.97; P = .03), ICU mortality (OR = 0.77, 95% CI = 0.63-0.95; P = .02), and hospital mortality (OR = 0.77, 95% CI = 0.63-0.95; P = .01) in comparison with the placebo, the results were also confirmed by TSA. CONCLUSION: Among adult patients with septic shock, the use of low-dose hydrocortisone compared with control did not confer overall survival benefits, albeit improving shock reversal rate. The benefit of reducing 28-day mortality, ICU mortality, and hospital mortality was observed in combination use of hydrocortisone and fludrocortisone.

Study on the mechanism of cantharidin-induced hepatotoxicity in rat using serum and liver metabolomics combined with conventional pathology methods.

Cantharidin (CTD), a compound secreted from Mylabris species, exhibits strong antitumor properties; however, hepatotoxicity restricts its clinical application. The mechanism by which CTD induces toxicity remains unclear. In the present study, the hepatotoxicity of CTD in the rat was investigated using a metabolomic approach combined with conventional pathology methods. A total of 30 rats were intragastrically treated with two doses of CTD (0.75 and 1.5 mg/kg) for 15 days to evaluate hepatotoxicity. Serum and liver samples were collected for biochemical dynamics analyses, histopathological examination and metabolomic analysis. It was found that liver index and serum biochemical indices were significantly increased. Furthermore, the pathology results showed that hepatocytes and subcellular organelles were damaged. Metabolomics analysis found 4 biomarkers in serum and 15 in the liver that were associated with CTD-induced hepatotoxicity. In addition, these were responsible for CTD hepatotoxicity by glycerophospholipid metabolism, sphingolipid metabolism, and steroid hormone biosynthesis. In conclusion, conventional pathology and metabolomics for exploring hepatotoxicity can provide useful information about the safety and potential risks of CTD.

Highly Conductive Metallic State and Strong Spin-Orbit Interaction in Annealed Germanane.

Similar to carbon, germanium exists in various structures such as three-dimensional crystalline germanium and germanene, a two-dimensional germanium atomic layer. Regarding the electronic properties, they are either semiconductors or Dirac semimetals. Here, we report a highly conductive metallic state in thermally annealed germanane (hydrogen-terminated germanene, GeH), which shows a resistivity of ∼10-7 Ω·m that is orders of magnitude lower than any other allotrope of germanium. By comparing the resistivity, Raman spectra, and thickness change measured by AFM, we suggest the highly conductive metallic state is associated with the dehydrogenation during heating, which likely transforms germanane thin flakes to multilayer germanene. In addition, weak antilocalization is observed, serving as solid evidence for strong spin-orbit interaction (SOI) in germanane/germanene. Our study opens a possible new route to investigate the electrical transport properties of germanane/germanene, and the large SOI might provide the essential ingredients to access their topological states predicted theoretically.

A meta-analysis of the effects of therapeutic hypothermia in adult patients with traumatic brain injury.

PURPOSE: Therapeutic hypothermia management remains controversial in patients with traumatic brain injury. We conducted a meta-analysis to evaluate the risks and benefits of therapeutic hypothermia management in patients with traumatic brain injury. METHODS: We searched the Web of Science, PubMed, Embase, Cochrane (Central) and Clinical Trials databases from inception to January 17, 2019. Eligible studies were randomised controlled trials that investigated therapeutic hypothermia management versus normothermia management in patients with traumatic brain injury. We collected the individual data of the patients from each included study. Meta-analyses were performed for 6-month mortality, unfavourable functional outcome and pneumonia morbidity. The risk of bias was evaluated using the Cochrane Risk of Bias tool. RESULTS: Twenty-three trials involving a total of 2796 patients were included. The randomised controlled trials with a high quality show significantly more mortality in the therapeutic hypothermia group [risk ratio (RR) 1.26, 95% confidence interval (CI) 1.04 to 1.53, p = 0.02]. Lower mortality in the therapeutic hypothermia group occurred when therapeutic hypothermia was received within 24 h (RR 0.83, 95% CI 0.71 to 0.96, p = 0.01), when hypothermia was received for treatment (RR 0.66, 95% CI 0.49 to 0.88, p = 0.006) or when hypothermia was combined with post-craniectomy measures (RR 0.69, 95% CI 0.48 to 1.00, p = 0.05). The risk of unfavourable functional outcome following therapeutic hypothermia management appeared to be significantly reduced (RR 0.78, 95% CI 0.67 to 0.91, p = 0.001). The meta-analysis suggested that there was a significant increase in the risk of pneumonia with therapeutic hypothermia management (RR 1.48, 95% CI 1.11 to 1.97, p = 0.007). CONCLUSIONS: Our meta-analysis demonstrated that therapeutic hypothermia did not reduce but might increase the mortality rate of patients with traumatic brain injury in some high-quality studies. However, traumatic brain injury patients with elevated intracranial hypertension could benefit from hypothermia in therapeutic management instead of prophylaxis when initiated within 24 h.

Effects of restrictive red blood cell transfusion on the prognoses of adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.

PURPOSE: Restrictive red blood cell transfusion strategies remain controversial in patients undergoing cardiac surgery. We performed a meta-analysis to assess the prognostic benefits of restrictive red blood cell transfusion strategies in patients undergoing cardiac surgery. METHODS: We identified randomized clinical trials through the 9th of December 2017 that investigated a restrictive red blood cell transfusion strategy versus a liberal transfusion strategy in patients undergoing cardiac surgery. Individual patient data from each study were collected. Meta-analyses were performed for the primary and secondary outcomes. The risk of bias was assessed using the Cochrane Risk of Bias Tool. A trial sequential analysis (TSA)-adjusted random-effects model was used to pool the results from the included studies for the primary outcomes. RESULTS: Seven trials involving a total of 8886 patients were included. The TSA evaluations suggested that this meta-analysis could draw firm negative results, and the data were sufficient. There was no evidence that the risk of 30-day mortality differed between the patients assigned to a restrictive blood cell transfusion strategy and a liberal transfusion strategy (odds ratio (OR) 0.98; 95% confidence interval (CI) 0.77 to 1.24; p = 0.87). Furthermore, the study suggested that the restrictive transfusion strategy was not associated with significant increases in pulmonary morbidity (OR 1.09; 95% CI 0.88 to 1.34; p = 0.44), postoperative infection (OR 1.11; 95% CI 0.95 to 1.3; p = 0.58), acute kidney injury (OR 1.03; 95% CI 0.92 to 1.14; p = 0.71), acute myocardial infarction (OR 1.01; 95% CI 0.80 to 1.27; p = 0.78), or cerebrovascular accidents (OR 0.97; 95% CI 0.72 to 1.30; p = 0.66). CONCLUSIONS: Our meta-analysis demonstrates that the restrictive red blood cell transfusion strategy was not inferior to the liberal strategy with respect to 30-day mortality, pulmonary morbidity, postoperative infection, cerebrovascular accidents, acute kidney injury, or acute myocardial infarction, and fewer red blood cells were transfused.

Effect of levosimendan on prognosis in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: Small trials suggest that levosimendan is associated with a favorable outcome in patients undergoing cardiac surgery. However, recently published larger-scale trials did not provide evidence for a similar benefit from levosimendan. We performed a meta-analysis to assess the survival benefits of levosimendan in patients undergoing cardiac surgery and to investigate its effects in subgroups of patients with preoperative low-ejection fraction (EF). METHODS: We identified randomized clinical trials through 20 April 2017 that investigated levosimendan therapy versus control in patients undergoing cardiac surgery. Individual patient data from each study were compiled. Meta-analyses were performed for primary outcomes, secondary outcomes and serious adverse events, and subgroup analyses according to the preoperative EF of enrolled patients were also conducted. The risk of bias was assessed using the Cochrane risk-of-bias tool. RESULTS: Seventeen studies involving a total of 2756 patients were included. Levosimendan therapy was associated with a significant reduction in 30-day mortality (RR 0.67; 95% CI, 0.49 to 0.93; p = 0.02) and reduced the risk of death in single-center trials (RR 0.49; 95% CI, 0.30 to 0.79; p = 0.004) and in subgroup trials of inferior quality (RR 0.39; 95% CI, 0.17 to 0.92; p = 0.02); however, in multicenter and in high-quality subgroup-analysis trials, no significant difference in mortality was observed between patients who received levosimendan therapy and controls (p > 0.05). However, in high-quality subgroup trials, levosimendan therapy was associated with reduced mortality in patients in a preoperative low-EF subgroup (RR 0.58; 95% CI, 0.38 to 0.88; p = 0.01). Similarly, only patients in the preoperative low-EF subgroup benefited in terms of reduced risk of renal replacement therapy (RR 0.54; 95% CI, 0.34 to 0.85; p = 0.007). Furthermore, levosimendan therapy was associated with a significant reduction in intensive care unit (ICU) length of stay (MDR -17.19; 95% CI, -34.43 to -2.94; p = 0.02). CONCLUSIONS: In patients undergoing cardiac surgery, the benefit of levosimendan in terms of survival was not shown in multicenter or in high-quality trials; however, levosimendan therapy was associated with reduced mortality in patients with preoperative ventricular systolic dysfunction.

Global end-diastolic volume index vs CVP goal-directed fluid resuscitation for COPD patients with septic shock: a randomized controlled trial.

PURPOSE: This study aimed to investigate the clinical effects of early goal-directed therapy according to the global end-diastolic volume index (GEDI) on chronic obstructive pulmonary disease (COPD) patients with septic shock. METHODS: A total of 71 COPD patients with septic shock were randomly assigned to 2 groups. In the control group (n = 37), fluid resuscitation was performed based on the central venous pressure. In the study group (n = 34), fluid resuscitation was performed until GEDI reached 800 mL/m2. The following indices were observed for the 2 groups: 6- and 24-hour fluid volumes, norepinephrine dosage, 24-hour blood lactate clearance rate, duration of mechanical ventilation, intensive care unit (ICU) length of stay, ICU mortality, and 90-day survival rate. RESULTS: At both 6- and 24-hour measurements, the fluid volume was lower and norepinephrine dosage was higher in the control group than in the study group (P < .05). The blood lactate clearance rate was lower, the duration of mechanical ventilation was longer, and the length of stay in the ICU was longer in the control group than in the study group (P < .05). No significant difference in mortality or 90-day survival rate was found between the 2 groups. CONCLUSIONS: The GEDI goal-directed fluid resuscitation shows better clinical effects than that shown by central venous pressure for COPD patients with septic shock; however, it cannot reduce the mortality rate.

Early initiation of low-dose hydrocortisone treatment for septic shock in adults: A randomized clinical trial.

BACKGROUND: Physiologic dose hydrocortisone is part of the suggested adjuvant therapies for patients with septic shock. However, the association between the corticosteroid therapy and mortality in patients with septic shock is still not clear. Some authors considered that the mortality is related to the time frame between development of septic shock and start of low dose hydrocortisone. Thus we designed a placebo-controlled, randomized clinical trial to assess the importance of early initiation of low dose hydrocortisone for the final outcome. METHODS: A total of 118 patients with septic shock were recruited in the study. All eligible patients were randomized to receive hydrocortisone (n=58) or normal saline (n=60). The study medication (hydrocortisone and normal saline) was initiated simultaneously with vasopressors. The primary end-point was 28-day mortality. The secondary end-points were the reversal of shock, in-hospital mortality and the duration of ICU and hospital stay. RESULTS: The proportion of patients with reversal of shock was similar in the two groups (P=0.602); There were no significant differences in 28-day or hospital all-cause mortality; length of stay in the ICU or hospital between patients treated with hydrocortisone or normal saline. CONCLUSION: The early initiation of low-dose of hydrocortisone did not decrease the risk of mortality, and the length of stay in the ICU or hospital in adults with septic shock. TRIAL REGISTRATION: www.clinicaltrials.govNCT02580240.

The Effect of Early Goal-Directed Therapy on Outcome in Adult Severe Sepsis and Septic Shock Patients: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Whether early goal-directed therapy (EGDT) improves outcome in severe sepsis and septic shock remains unclear. We performed a meta-analysis of existing clinical trials to examine whether EGDT improved outcome in the resuscitation of adult sepsis patients compared with control care. METHODS: We searched for eligible studies using MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials, and Web of Science databases. Studies were eligible if they compared the effects of EGDT versus control care on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Data including mortality, sample size of the patients with severe sepsis and septic shock, and resuscitation end points were extracted. Data were analyzed using methods recommended by the Cochrane Collaboration Review Manager 4.2 software. Random errors were evaluated by trial sequential analysis (TSA). RESULTS: Nine studies compared EGDT with control care, and 5202 severe sepsis and septic shock patients were included. A nonsignificant trend toward reduction in the longest all-cause mortality was observed in the EGDT group compared with control care (relative risk, 0.89; 99% confidence interval, 0.74-1.07; P = 0.10). However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients (relative risk, 0.72; 99% confidence interval, 0.57-0.90; P = 0.0002). TSA indicated lack of firm evidence for a beneficial effect. CONCLUSIONS: In this meta-analysis, a nonsignificant trend toward reduction in the longest all-cause mortality in patients resuscitated with EGDT was noted. However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients. TSA indicated a lack of firm evidence for the results. More powered, randomized controlled trials are needed to determine the effects.

MSCs modified with ACE2 restore endothelial function following LPS challenge by inhibiting the activation of RAS.

Angiotensin (Ang) II plays an important role in the process of endothelial dysfunction in acute lung injury (ALI) and is degraded by angiotensin-converting enzyme2 (ACE2). However, treatments that target ACE2 to injured endothelium and promote endothelial repair of ALI are lacking. Mesenchymal stem cells (MSCs) are capable of homing to the injured site and delivering a protective gene. Our study aimed to evaluate the effects of genetically modified MSCs, which overexpress the ACE2 protein in a sustained manner via a lentiviral vector, on Ang II production in endothelium and in vitro repair of lipopolysaccharide (LPS)-induced endothelial injury. We found that the efficiency of lentiviral vector transduction of MSCs was as high as 97.8% and was well maintained over 30 passages. MSCs modified with ACE2 showed a sustained high expression of ACE2 mRNA and protein. The modified MSCs secreted soluble ACE2 protein into the culture medium, which reduced the concentration of Ang II and increased the production of Ang 1-7. MSCs modified with ACE2 were more effective at restoring endothelial function than were unmodified MSCs, as shown by the enhanced survival of endothelial cells; the downregulated production of inflammatory mediators, including ICAM-1, VCAM-1, TNF-α, and IL-6; reduced paracellular permeability; and increased expression of VE-cadherin. These data demonstrate that MSCs modified to overexpress the ACE2 gene can produce biologically active ACE2 protein over a sustained period of time and have an enhanced ability to promote endothelial repair after LPS challenge. These results encourage further testing of the beneficial effects of ACE2-modified MSCs in an ALI animal model.

Stable genetic alterations of ß-catenin and ROR2 regulate the Wnt pathway, affect the fate of MSCs.

The Wnt pathways have been shown to be critical for the fate of mesenchymal stem cells (MSCs) in vitro, but their roles in MSCs in vivo remain poorly characterized due to the lack of stable alterations in their signaling. In the present study, we constructed long-term and stable mMSCs lines with activated and inactivated ß-catenin (the key molecule of the canonical Wnt signaling pathway) or ROR2 (the key molecule of the noncanonical Wnt5a/ROR2 signaling pathway) modifications with lentiviral vectors. We found that the transduction efficiencies mediated by the lentiviral vectors were 92.61-97.04% and were maintained over 20 passages of mMSCs. Transfection by lentiviral vectors not only regulated the mRNA and protein expression of ß-catenin or ROR2 but also regulated nuclear ß-catenin accumulation or the Wnt5a/JNK and Wnt5a/PKC pathways belonging to the canonical Wnt and noncanonical Wnt5a/ROR2 pathways, respectively. ß-Catenin or ROR2 gene overexpression promoted mMSC proliferation, migration and differentiation into osteoblasts, while inhibiting the adipogenic differentiation of mMSCs. In contrast, inactivation of the ß-catenin or ROR2 genes resulted in the opposite effects. Therefore, these results confirm that lentiviral vector transduction can facilitate sustained and efficient gene modification of the Wnt pathway in mMSCs. This study provides a method to investigate the effects of the Wnt pathway on the fate of mMSCs in vivo and for the further improvement of MSC-based therapies.

The effect of glutamine therapy on outcomes in critically ill patients: a meta-analysis of randomized controlled trials.

INTRODUCTION: Glutamine supplementation is supposed to reduce mortality and nosocomial infections in critically ill patients. However, the recently published reducing deaths due to oxidative stress (REDOX) trials did not provide evidence supporting this. This study investigated the impact of glutamine-supplemented nutrition on the outcomes of critically ill patients using a meta-analysis. METHODS: We searched for and gathered data from the Cochrane Central Register of Controlled Trials, MEDLINE, Elsevier, Web of Science and ClinicalTrials.gov databases reporting the effects of glutamine supplementation on outcomes in critically ill patients. We produced subgroup analyses of the trials according to specific patient populations, modes of nutrition and glutamine dosages. RESULTS: Among 823 related articles, eighteen Randomized Controlled Trials (RCTs) met all inclusion criteria. Mortality events among 3,383 patients were reported in 17 RCTs. Mortality showed no significant difference between glutamine group and control group. In the high dosage subgroup (above 0.5 g/kg/d), the mortality rate in the glutamine group was significantly higher than that of the control group (relative risk (RR) 1.18; 95% confidence interval (CI), 1.02 to 1.38; P = 0.03). In 15 trials, which included a total of 2,862 patients, glutamine supplementation reportedly affected the incidence of nosocomial infections in the critically ill patients observed. The incidence of nosocomial infections in the glutamine group was significantly lower than that of the control group (RR 0.85; 95% CI, 0.74 to 0.97; P = 0.02). In the surgical ICU subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.70; 95% CI, 0.52 to 0.94; P = 0.04). In the parental nutrition subgroup, glutamine supplementation statistically reduced the rate of nosocomial infections (RR 0.83; 95% CI, 0.70 to 0.98; P = 0.03). The length of hospital stay was reported in 14 trials, in which a total of 2,777 patients were enrolled; however, the patient length of stay was not affected by glutamine supplementation. CONCLUSIONS: Glutamine supplementation conferred no overall mortality and length of hospital stay benefit in critically ill patients. However, this therapy reduced nosocomial infections among critically ill patients, which differed according to patient populations, modes of nutrition and glutamine dosages.