Threshold of hyperglycaemia associated with mortality in critically ill patients: a multicentre, prospective, observational study using continuous glucose monitoring.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) provides comprehensive information on the exposure to dysglycaemia. This study aimed to investigate the threshold of hyperglycaemia related to mortality risk in critically ill patients using CGM technology. METHODS: A total of 293 adult critically ill patients admitted to intensive care units of five medical centres were prospectively included between May 2020 and November 2021. Participants wore intermittently scanned CGM for a median of 12.0 days. The relationships between different predefined time above ranges (TARs), with the thresholds of hyperglycaemia ranging from 7.8 to 13.9 mmol/l (140-250 mg/dl), and in-hospital mortality risk were assessed by multivariate Cox proportional regression analysis. Time in ranges (TIRs) of 3.9 mmol/l (70 mg/dl) to the predefined hyperglycaemic thresholds were also assessed. RESULTS: Overall, 66 (22.5%) in-hospital deaths were identified. Only TARs with a threshold of 10.5 mmol/l (190 mg/dl) or above were significantly associated with the risk of in-hospital mortality, after adjustment for covariates. Furthermore, as the thresholds for TAR increased from 10.5 mmol/l to 13.9 mmol/l (190 mg/dl to 250 mg/dl), the hazards of in-hospital mortality increased incrementally with every 10% increase in TARs. Similar results were observed concerning the associations between TIRs with various upper thresholds and in-hospital mortality risk. For per absolute 10% decrease in TIR 3.9-10.5 mmol/l (70-190 mg/dl), the risk of in-hospital mortality was increased by 12.1% (HR 1.121 [95% CI 1.003, 1.253]). CONCLUSIONS/INTERPRETATION: A glucose level exceeding 10.5 mmol/l (190 mg/dl) was significantly associated with higher risk of in-hospital mortality in critically ill patients.

The combination of lactate level, lactate clearance and APACHE II score better predicts short-term outcomes in critically Ill patients: a retrospective cohort study.

BACKGROUND: The mortality rate is high in critically ill patients due to the difficulty of diagnosis and treatment. Thus, it is very important to explore the predictive value of different indicators related to prognosis in critically ill patients. METHODS: This was a retrospective cohort study of patients in the intensive care unit (ICU) of the Sixth People's Hospital in Shanghai, China. A total of 1465 ICU patients had lactate values > 2.1 mmol/L at least once within 24 h of ICU admission, and arterial blood gas was monitored more than twice during the ICU stay. RESULTS: The predictive value of lactate clearance at 24 h was not high, and the sensitivity and specificity were lower. The predictive value of the lactate level at baseline and the APACHE II score was higher than that of lactate clearance at 24 h in critically ill patients. The predictive value of the lactate level at baseline combined with the APACHE II score was higher than that of the lactate level at baseline or the APACHE II score alone. In addition, the predictive value of lactate clearance at 24 h combined with the APACHE II score was also significantly higher than that of lactate clearance at 24 h or the APACHE II score alone. In particular, the area under the ROC curve reached 0.900, the predictive value was markedly higher than that of the ROC alone, and the sensitivity and specificity were better when these three indicators were combined. CONCLUSIONS: The combination of lactate level, lactate clearance and APACHE II score better predicts short-term outcomes in critically ill patients.

Astragaloside IV enhanced carboplatin sensitivity in prostate cancer by suppressing AKT/NF-κB signaling pathway.

In our study, we explored the effect of astragaloside IV (AgIV) on carboplatin chemotherapy in prostate cancer cell lines in vitro and in vivo. Cell viability assay, colony formation assay, flow cytometry, Western blot, immunohistochemistry, immunofluorescence, and tumor xenograft growth assay were conducted. We found that AgIV significantly decreased the half-maximal inhibitory concentration of carboplatin in prostate cancer cell lines LNCap and PC-3. Moreover, AgIV enhanced the effect of carboplatin in suppressing colony formation and inducing cell apoptosis. A low-dose carboplatin treatment upregulated N-cadherin and Vimentin expression and downregulated E-cadherin expression, but this effect was abolished by combining with AgIV. Carboplatin treatment increased the levels of p-AKT and p-p65 and decreased p-IκBα, but AgIV treatment suppressed this. In addition, AgIV synergized with carboplatin to suppress tumor xenograft growth of PC-3 cells, and decreased pAKT and p-p65 levels in vivo. Our results suggested that AgIV enhanced carboplatin sensitivity in prostate cancer cell lines by suppressing AKT/NF-κB signaling, thus suppressed epithelial-mesenchymal transition induced by carboplatin. Our findings provided a new mechanism for AgIV in overcoming drug resistance of platinum-based chemotherapy and suggested a potential combination therapy of AgIV and carboplatin in prostate cancer.

Risk Factors and Molecular Epidemiology of Complicated Intra-Abdominal Infections With Carbapenem-Resistant Enterobacteriaceae: A Multicenter Study in China.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with poor patient outcomes. Data on risk factors and molecular epidemiology of CRE in complicated intra-abdominal infections (cIAI) in China are limited. This study examined the risk factors of cIAI with CRE and the associated mortality based on carbapenem resistance mechanisms. METHODS: In this retrospective analysis, we identified 1024 cIAI patients hospitalized from January 1, 2013 to October 31, 2018 in 14 intensive care units in China. Thirty CRE isolates were genotyped to identify ß-lactamase-encoding genes. RESULTS: Escherichia coli (34.5%) and Klebsiella pneumoniae (21.2%) were the leading pathogens. Patients with hospital-acquired cIAI had a lower rate of E coli (26.0% vs 49.1%; P < .001) and higher rate of carbapenem-resistant Gram-negative bacteria (31.7% vs 18.8%; P = .002) than those with community-acquired cIAI. Of the isolates, 16.0% and 23.4% of Enterobacteriaceae and K pneumoniae, respectively, were resistant to carbapenem. Most carbapenemase-producing (CP)-CRE isolates carried blaKPC (80.9%), followed by blaNMD (19.1%). The 28-day mortality was 31.1% and 9.0% in patients with CRE vs non-CRE (P < .001). In-hospital mortality was 4.7-fold higher for CP-CRE vs non-CP-CRE infection (P = .049). Carbapenem-containing combinations did not significantly influence in-hospital mortality of CP and non-CP-CRE. The risk factors for 28-day mortality in CRE-cIAI included septic shock, antibiotic exposure during the preceding 30 days, and comorbidities. CONCLUSIONS: Klebsiella pneumoniae had the highest prevalence in CRE. Infection with CRE, especially CP-CRE, was associated with increased mortality in cIAI.

Activating Mas receptor protects human pulmonary microvascular endothelial cells against LPS-induced apoptosis via the NF-kB p65/P53 feedback pathways.

The balance between Ang II/AT1R and Ang-(1-7)/Mas plays a pivotal role in the development of lipopolysaccharides (LPS)-induced acute respiratory distress syndrome. However, the mechanisms underlying the balancing process still remain unclear. Here we investigated the roles of nuclear factor (NF)-κB and p53 in regulating AT1R and Mas expression. The results demonstrated that Ang II pretreatment resulted in downregulation of Mas and upregulation of AT1R, phosphorylated p65, and apoptosis in LPS-treated Human pulmonary microvascular endothelial cells (HPMVECs), but had no effect on p53 expression. Lentiviral vector-mediated P65 knockdown, but not a P53 knockdown, reversed all these effects of Ang II. On the other hand, Ang-(1-7) pretreatment lead to an increased in Mas expression and a decrease in AT1R, p53, and phosphorylated p65 expressions with suppressed apoptosis in LPS-treated cells. P65 knockdown promoted the protein expression of both AT1R and Mas while inhibiting p53 expression. P53 knockdown, but not a p65 knockdown, reversed all these effects of Ang-(1-7). Interestingly, p65 overexpression upregulated p53 and AT1R but downregulated Mas. P53 knockdown activated p65. These results suggest that there is a two-way feedback regulation between AT1R and Mas receptor via the NF-kB p65/P53 pathway, which may play a key role in LPS-induced HPMVECs apoptosis.

Ang-(1-7) treatment attenuates lipopolysaccharide-induced early pulmonary fibrosis.

Early pulmonary fibrosis is the leading cause of poor prognosis in patients with acute respiratory distress syndrome (ARDS). However, whether the renin-angiotensin system (RAS) can serve as a therapeutic target is unknown. In this study, an animal model of early pulmonary fibrosis was established via the LPS three-hit regimen. Afterwards, the animals were treated with intraperitoneal injections of Ang-(1-7), AVE0991, or A779 once per day for 20 days. The plasma and BALF AngII levels of the animals were increased, while there were no significant changes in Ang-(1-7) levels in lung tissue after LPS treatment. Furthermore, the AT1R protein levels were significantly increased and the Mas levels were significantly decreased on days 14 and 21. Administration of Ang-(1-7) downregulated LPS-induced AT1R mRNA expression, which was upregulated by A779. The expression of Mas mRNA responded in the opposite direction relative to AT1R. Moreover, LPS caused decreased levels of Mas and E-cadherin and increased AT1R, Vimentin, and Src phosphorylation levels. Ang-(1-7) or AVE0991 blocked these effects but was counteracted by A779 treatment. Our findings suggested that AngII and AT1R levels exhibit opposite dynamic trends during LPS-induced early pulmonary fibrosis, as do Ang-(1-7) and Mas. Ang-(1-7) exerts protective effects against early pulmonary fibrosis, mainly by regulating the balance between AngII and AT1R and between Ang-(1-7) and Mas and by inhibiting Src kinase activation.

Post-operative delirium associated with metabolic alterations following hemi-arthroplasty in older patients.

BACKGROUND: post-operative delirium (POD) is a common complication in older patients, though a possible link between metabolic changes and POD development has yet to be investigated. METHODS: older patients with hip fracture who underwent hemi-arthroplasty were recruited, and delirious states were assessed for 3 days after surgery using the confusion assessment method-Chinese revision. Simultaneously, fasting blood samples were collected on the morning of surgery and on the first post-operative day. Ultimately, 244 older patients who met the inclusion and exclusion criteria were assessed. Blood samples from 60 patients with POD and 60 matched controls were analysed using metabolomics platforms. RESULTS: sixty patients (24.6%) developed POD. Principal component analysis scores plot and cross-validated scores plots from orthogonal partial least squares-discriminant analysis were implemented to visualise the differences in metabolites between the two groups before and after surgery (P < 0.05). Our data indicate that levels of ω3 and ω6 fatty acids were lower in the POD group than in the NPOD (non-POD) group both before and after surgery; tricarboxylic cycle intermediate levels were lower in the POD group than in the NPOD group, but glycolysis products were higher in the POD group than in the NPOD group after surgery. Furthermore, the branched-chain amino acid (BCAA)/aromatic amino acid ratio was lower in the POD group than in the NPOD group after surgery. CONCLUSIONS: metabolic abnormalities, including deficiencies in ω3 and ω6 fatty acids, perturbations in tricarboxylic cycle and oxidative stress and metabolic imbalances in BCAA and AAA might contribute to POD development.

miR-200b/c attenuates lipopolysaccharide-induced early pulmonary fibrosis by targeting ZEB1/2 via p38 MAPK and TGF-ß/smad3 signaling pathways.

Pulmonary fibrosis triggered during the early stage of acute respiratory distress syndrome (ARDS) contributes to poor prognosis in patients. However, whether microRNAs (miRNAs) can serve as therapeutic targets for early pulmonary fibrosis during ARDS is still largely unknown. In this study, we evaluated the effects and mechanisms of miR-200s and its targets ZEB1/2 in lung tissue. An early pulmonary fibrosis mouse model caused by ARDS was established via a lipopolysaccharide (LPS) three-hit regimen. Lentiviral packaged miR-200b/c cDNA or ZEB1/2 shRNA was intratracheally administered into the lungs of C57BL/6 mice 1 day before an LPS injection was administered. In vitro, following a 30-min pretreatment with miR-200b/c or SB203580/SIS3, RLE-6TN cells were stimulated by LPS or LPS + transforming growth factor-ß (TGF-ß) for 24 h. miR-200b/c and E-cadherin protein expression declined, whereas ZEB1/2 mRNA and protein and vimentin and α-smooth muscle actin (α-SMA) protein levels gradually increased during the development of pulmonary fibrosis. Furthermore, both the overexpression of miR-200b/c and the silencing of ZEB1/2 significantly alleviated pulmonary inflammation and fibrosis, reduced vimentin and α-SMA expression, and increased E-cadherin protein levels. In RLE-6TN cells, LPS combined with TGF-ß exerts synergistic effects of increasing vimentin and α-SMA protein levels, increasing p38 and smad3 phosphorylation and reducing E-cadherin protein levels, which were reversed by pretreatment with miR-200b/c or SB203580/SIS3. Our findings demonstrate that miR-200b/c was downregulated, whereas ZEB1/2 was upregulated in the development of LPS-induced early pulmonary fibrosis. miR-200b/c exerts a protective effect by targeting ZEB1/2, which may be associated with the inhibition of p38 MAPK and TGF-ß /smad3 signaling pathways.

Failure of Isoflurane Cardiac Preconditioning in Obese Type 2 Diabetic Mice Involves Aberrant Regulation of MicroRNA-21, Endothelial Nitric-oxide Synthase, and Mitochondrial Complex I.

BACKGROUND: Diabetes impairs the cardioprotective effect of volatile anesthetics, yet the mechanisms are still murky. We examined the regulatory effect of isoflurane on microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I in type 2 diabetic mice. METHODS: Myocardial ischemia/reperfusion injury was produced in obese type 2 diabetic (db/db) and C57BL/6 control mice ex vivo in the presence or absence of isoflurane administered before ischemia. Cardiac microRNA-21 was quantified by real-time quantitative reverse transcriptional-polymerase chain reaction. The dimers and monomers of endothelial nitric-oxide synthase were measured by Western blot analysis. Mitochondrial nicotinamide adenine dinucleotide fluorescence was determined in Langendorff-perfused hearts. RESULTS: Body weight and fasting blood glucose were greater in db/db than C57BL/6 mice. Isoflurane decreased left ventricular end-diastolic pressure from 35 ± 8 mmHg in control to 23 ± 9 mmHg (P = 0.019, n = 8 mice/group, mean ± SD) and elevated ±dP/dt 2 h after post-ischemic reperfusion in C57BL/6 mice. These beneficial effects of isoflurane were lost in db/db mice. Isoflurane elevated microRNA-21 and the ratio of endothelial nitric-oxide synthase dimers/monomers and decreased mitochondrial nicotinamide adenine dinucleotide levels 5 min after ischemia in C57BL/6 but not db/db mice. MicroRNA-21 knockout blocked these favorable effects of isoflurane, whereas endothelial nitric-oxide synthase knockout had no effect on the expression of microRNA-21 but blocked the inhibitory effect of isoflurane preconditioning on nicotinamide adenine dinucleotide. CONCLUSIONS: Failure of isoflurane cardiac preconditioning in obese type 2 diabetic db/db mice is associated with aberrant regulation of microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I.

Combination of Mean Platelet Volume/Platelet Count Ratio and the APACHE II Score Better Predicts the Short-Term Outcome in Patients with Acute Kidney Injury Receiving Continuous Renal Replacement Therapy.

BACKGROUND/AIMS: Both the Acute physiology and Chronic Health Evaluation (APACHE II) score and mean platelet volume/platelet count Ratio (MPR) can independently predict adverse outcomes in critically ill patients. This study was aimed to investigate whether the combination of them could have a better performance in predicting prognosis of patients with acute kidney injury (AKI) who received continuous renal replacement therapy (CRRT). METHODS: Two hundred twenty-three patients with AKI who underwent CRRT between January 2009 and December 2014 in a Chinese university hospital were enrolled. They were divided into survivals group and non-survivals group based on the situation at discharge. Receiver Operating Characteristic (ROC) curve was used for MPR and APACHE II score, and to determine the optimal cut-off value of MPR for in-hospital mortality. Factors associated with mortality were identified by univariate and multivariate logistic regression analysis. RESULTS: The mean age of the patients was 61.4 years, and the overall in-hospital mortality was 48.4%. Acute cardiorenal syndrome (ACRS) was the most common cause of AKI. The optimal cut-off value of MPR for mortality was 0.099 with an area under the ROC curve (AUC) of 0.636. The AUC increased to 0.851 with the addition of the APACHE II score. The mortality of patients with of MPR > 0.099 was 56.4%, which was significantly higher than that of the control group with of ≤ 0.099 (39.6%, P= 0.012). Logistic regression analysis showed that average number of organ failure (OR = 2.372), APACHE II score (OR = 1.187), age (OR = 1.028) and vasopressors administration (OR = 38.130) were significantly associated with poor prognosis. CONCLUSION: Severity of illness was significantly associated with prognosis of patients with AKI. The combination of MPR and APACHE II score may be helpful in predicting the short-term outcome of AKI.

Bcl-2 silencing attenuates hypoxia-induced apoptosis resistance in pulmonary microvascular endothelial cells.

Pulmonary arterial hypertension (PAH) is a life-threatening disorder that ultimately causes heart failure. While the underlying causes of this condition are not well understood, previous studies suggest that the anti-apoptotic nature of pulmonary microvascular endothelial cells (PMVECs) in hypoxic environments contributes to PAH pathogenesis. In this study, we focus on the contribution of Bcl-2 and hypoxia response element (HRE) to apoptosis-resistant endothelial cells and investigate the mechanism. PMVECs obtained from either normal rats or apoptosis-resistant PMVECs obtained from PAH rats were transduced with recombinant lentiviral vectors carrying either Bcl-2-shRNA or HRE combined Bcl-2-shRNA, and then cultured these cells for 24 h under hypoxic (5% O2) or normoxic (21% O2) conditions. In normal PMVECs, Bcl-2-shRNA or HRE combined with Bcl-2-shRNA transduction successfully decreased Bcl-2 expression, while increasing apoptosis as well as caspase-3 and P53 expression in a normoxic environment. In a hypoxic environment, the effects of Bcl-2-shRNA treatment on cell apoptosis, and on Bcl-2, caspase-3, P53 expression were significantly suppressed. Conversely, HRE activation combined with Bcl-2-shRNA transduction markedly enhanced cell apoptosis and upregulated caspase-3 and P53 expression, while decreasing Bcl-2 expression. Furthermore, in apoptosis-resistant PMVECs, HRE-mediated Bcl-2 silencing effectively enhanced cell apoptosis and caspase-3 activity. The apoptosis rate was significantly depressed when Lv-HRE-Bcl-2-shRNA was combined with Lv-P53-shRNA or Lv-caspase3-shRNA transduction in a hypoxic environment. These results suggest that HRE-mediated Bcl-2 inhibition can effectively attenuate hypoxia-induced apoptosis resistance in PMVECs by downregulating Bcl-2 expression and upregulating caspase-3 and P53 expression. This study therefore reveals critical insight into potential therapeutic targets for treating PAH.

Corrective effect of norepinephrine on hypotension induced by dexmedetomidine in critically ill patients.

PURPOSE: To evaluate the corrective effect of norepinephrine on hypotension induced by dexmedetomidine through monitoring sedation status, hemodynamics as well as oxygen metabolism. METHODS: 100 patients administered standard-dose dexmedetomidine therapy with RASS between -2 and 0 in the intensive care unit (ICU) were included in the study. According to the application of norepinephrine to correct hypotension after dexmedetomidine therapy, the patients were divided into two groups: group A and group B. Group A (dexmedetomidine + norepinephrine group): those who had a systolic arterial pressure < 90 mmHg, a mean arterial pressure < 70 mmHg, or a decline in systolic arterial pressure > 40 mmHg or more than 30% of its base value after dexmedetomidine therapy and then received additional norepinephrine intravenously in order to maintain the arterial pressure at its base value. Group B (dexmedetomidine group): patients received the equivalent dose of dexmedetomidine to maintain the pressure at normal value without extra vasoconstrictor substance. Sedation (CPOT and RASS) and hemodynamic and oxygen metabolism indexes (heart rate, mean arterial pressure, respiratory rate, arterial oxygen saturation, central venous pressure, venous oxygen saturation, arteriovenous carbon dioxide difference, blood lactate level, blood lactate clearance rate, and average hourly urine output) were evaluated in the two groups at baseline, 6th hour, 12th hour, and 24th hour after the administration of intravenous dexmedetomidine. RESULTS: 39 cases were enrolled in group A and 61 cases in group B. Patients of both groups received adequate analgesia and sedation, and there was no significant statistical difference in analgesia and sedation at any point (both p > 0.05). Basal hemodynamic indexes and oxygen metabolism indexes also had no significant statistical difference (both p > 0.05). Central venous pressure (CVP) of group A was significantly higher than that of group B at the 6th hour and 12th hour after administration of intravenous dexmedetomidine (p = 0.005), and the heart rate (HR) of group A was markedly higher than that of group B at the 24th hour after dexmedetomidine therapy (p = 0.017), while the other indexes had no significant difference at any point (both p > 0.05). CONCLUSION: Dexmedetomidine plays an important role in ICU patients due to its pharmacological ability of sedation and analgesia. In our study, dexmedetomidine was successfully applied to ensure goal-directed sedation therapy (GDST). Norepinephrine can correct hypotension and bradycardia induced by intravenous dexmedetomidine. According to the hemodynamic indexes and oxygen metabolism indexes, the application of dexmedetomidine or the combination of dexmedetomidine with norepinephrine are both safe and appropriate to maintain the sedation status and hemodynamic situation in ICU patients.
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The cross talk between cGMP signal pathway and PKC in pulmonary endothelial cell angiogenesis.

Angiogenic proliferation of vascular endothelial cells is believed to play an important role in pulmonary vascular remodeling in pulmonary arterial hypertension. In the present study, we found that c-GMP (cyclic guanosine monophosphate) inhibited the proliferation and tube formation of pulmonary vascular endothelial cells induced by TGF-ß1, and that this process was reversed by PKG (protein kinase G) inhibitor and PKC (protein kinase C) inhibitor. In addition, small interfering RNA (siRNA) targeting ERK also reduced cellular proliferation. Furthermore, western blotting showed that cGMP down-regulated the phosphorylation level of ERK1/2, which was reversed not only by PKG inhibitor but also by PKC inhibitor. Silencing different PKC isoforms showed that PKCΔ, PKCγ and PKCα were involved in ERK phosphorylation, suggesting that PKC kinases have a permissive action. Three subtypes, PKCΔ, PKCγ and PKCα are likely to be involved the phosphorylation suppression of ERK included cGMP. Taken together, these data suggest that ERK phosphorylation mediates the proliferation of pulmonary vascular endothelial cells, and PKC kinases have a permissive action in this process.

A Nomogram Model Containing Genetic Polymorphisms to Predict Risk of Pulmonary Embolism in Pregnant Women.

Introduction: Pulmonary embolism (PE), the most serious presentation of venous thromboembolism (VTE), is associated with a high rate of mortality and expense. Clinical studies on pregnant women with PE are scarce. The aim of this study was to analyze the clinical impact of fibrinolytic enzyme activation inhibitor-1 (PAI-1) 4G/5G genetic polymorphisms, methylenetetrahydrofolate reductase (MTHFR) rs1801131 (A1298C) and rs1801133 (C677T) genetic polymorphisms, and establish a predictive model for pregnant women. Material and Methods: Between September 2022 and August 2023, 53 pregnant women with PE were enrolled. Using the propensity score matching method, 106 consecutive pregnant women without VTE were 1:2 matched. The relevant patient data were collected, and the susceptibility genes for PE were detected to determine genetic polymorphisms, and PE susceptibility in pregnant women, as well as to develop predictive models. Results: Our study showed that 4G/4G homozygous mutations increased the risk of pregnant PE fourfold (OR = 4.46, 95% CI = 1.59-12.50, P = 0.004), whereas the 4G allele mutation increased the risk twofold (OR = 2.33, 95% CI = 1.35-4.04, P = 0.002). A nomogram was established to predict the risk of pregnant women with PE by four predictive features including PAI-1 genetic polymorphisms, international normalized ratio (INR), antithrombin-III (AT-III) activity, and platelet count (PLT). The area under the curve (AUC) of the nomogram was 0.821 (0.744-0.898). The AUC of the internal validation group was 0.822 (0.674-0.971). Decision curve analysis revealed that the nomogram has a higher net benefit in the following threshold: probability interval of ≥15%. Conclusion: The PAI-1 4G/4G genotype is an independent risk factor for pregnant women with PE; furthermore, the presence of the 4G allele can increase the risk of PE. The study established a nomogram to predict the risk of PE in pregnant women.

Bioelectrical Impedance Analysis to Assess Energy Expenditure in Critically Ill Patients: A Cross-Sectional Study.

BACKGROUND: Evaluating energy expenditure is important for establishing optimal goals for nutrition treatment. However, indirect calorimetry, the reference standard for measuring energy expenditure, is difficult to apply widely in clinical practice. OBJECTIVE: To test the consistency of bioelectrical impedance analysis (BIA) relative to indirect calorimetry for evaluating energy expenditure in critically ill patients. METHODS: A cross-sectional study of 140 critically ill adult patients was conducted. Within 24 hours of a patient being transferred to the intensive care unit, trained researchers assessed the patient's energy expenditure by use of BIA and indirect calorimetry simultaneously. Consistency of the 2 measurements was detected by intraclass correlation coefficients with a 2-way random-effects model. Factors affecting consistency were analyzed. RESULTS: Median energy expenditure measured by indirect calorimetry was 1430.0 kcal/d (IQR, 1190.5-1650.8 kcal/d). Median energy expenditure measured by BIA was 1407.0 kcal/d (IQR, 1248.5-1563.5 kcal/d). The correlation coefficient between indirect calorimetry and BIA was 0.813 (95% CI, 0.748-0.862; P < .001). The consistency of the 2 measurements was lower in patients with comorbidities than in those without (P = .004). CONCLUSIONS: Results of BIA were highly consistent with indirect calorimetry assessments of energy expenditure in critically ill patients. Few factors except comorbidity affect the accuracy of BIA when assessing energy expenditure. Therefore, as a low-cost, easy-to-use, and noninvasive method, BIA is a valuable clinical tool for assessing energy expenditure in critically ill patients.

Effectiveness and safety of Shenfu injection in septic patients with hypoperfusion: A multi-center, open-label, randomized, controlled trial.

Background: To evaluate the effectiveness and safety of the Shenfu injection (SFI) combined with standard bundle treatment in septic patients with hypoperfusion. Method: This study was a multi-center, randomized, open-label, controlled trial conducted in four teaching hospitals in China. The septic patients with hypoperfusion and traditional Chinese medicine (TCM) syndrome with Yang-Qi deficiency were enrolled from January 2019, through September 2020. Eligible patients were randomly allocated in a 1:1 ratio to either receive 60 mL of SFI infusion per day plus standard treatment (SFI group) or standard bundle treatment alone (control group). The primary outcome was 28-day all-cause mortality. Secondary outcomes were 90-day all-cause mortality time to weaning from mechanical ventilation, time to weaning from vasopressors, time to discharge from the ICU and hospital, and laboratory results after randomization. Results: A total of 188 patients completed the trail. This study revealed that the results of the SFI group and the control groups were not statistically significant in 28-day all-cause mortality (10.6% vs. 20.2%, respectively; P=0.106). The infusion of SFI was associated with a significant reduction in the duration of vasopressor use (median=4.0 days, interquartile range [IQR]: 2.0 days-6.0 days vs. median=5.0 days, IQR: 3.0 days-8.0 days, respectively; P=0.043). Patients in the SFI group had statistically greater reductions in plasma lactate levels compared with those in the control group at the first 12 h (median=1.1 mmol/L, IQR: 0.3-2.0 mmol/L vs. median=0.0 mmol/L, IQR: -0.2 to 0.8 mmol/L, respectively; P <0.001) and 24 h (median=1.4 mmol/L, IQR: 0.3-2.2 mmol/L vs. median=0.4 mmol/L, IQR: -0.4 to 1.6 mmol/L, respectively; P=0.001). Conclusion: SFI plus standard therapy did not significantly decrease 28-day all-cause mortality for septic patients with hypoperfusion and TCM syndrome with Yang-Qi deficiency.Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR1800020435.

Bone Mesenchymal Stem Cells Origin Exosomes are Effective Against Sepsis-Induced Acute Kidney Injury in Rat Model.

Introduction: The incidence and mortality rates of sepsis-induced acute kidney injury (SAKI) remain high, posing a substantial healthcare burden. Studies have implicated a connection between the development of SAKI and inflammation response, apoptosis, and autophagy. Moreover, evidence suggests that manipulating autophagy could potentially influence the prognosis of this condition. Notably, exosomes derived from bone mesenchymal stem cells (BMSCs-Exo) have exhibited promise in mitigating cellular damage by modulating pathways associated with inflammation, apoptosis, and autophagy. Thus, this study aims to investigate the influence of BMSCs-Exo on SAKI and the potential mechanisms that drive this impact. Methods: The SAKI model was induced in HK-2 cells using lipopolysaccharide (LPS), while rats underwent cecal ligation and puncture (CLP) to simulate the condition. Cell viability was assessed using the CCK-8 kit, and kidney damage was evaluated through HE staining, blood urea nitrogen (BUN), and serum creatinine (SCr) measurements. Inflammatory-related RNAs and proteins were quantified via qPCR and ELISA, respectively. Apoptosis was determined through apoptosis-related protein levels, flow cytometry, and TUNEL staining. Western blot analysis was utilized to measure associated protein expressions. Results: In vivo, BMSCs-Exo ameliorated kidney injury in CLP-induced SAKI rats, reducing inflammatory cytokine production and apoptosis levels. Fluorescence microscope observed the absorption of BMSCs-Exo by renal cells following injection via tail vein. In the SAKI rat kidney tissue, there was an upregulation of LC3-II/LC3-I, p62, and phosphorylated AMP-activated protein kinase (p-AMPK) expressions, indicating blocked autophagic flux, while phosphorylated mammalian target of rapamycin (p-mTOR) expression was downregulated. However, BMSCs-Exo enhanced LC3-II/LC3-I and p-AMPK expression, concurrently reducing p62 and p-mTOR levels. In vitro, BMSCs-Exo enhanced cell viability in LPS-treated HK-2 cells, and exerted anti-inflammation and anti-apoptosis effects which were consistent with the results in vivo. Similarly, rapamycin (Rapa) exhibited a protective effect comparable to BMSCs-Exo, albeit partially abrogated by 3-methyladenine (3-MA). Conclusion: BMSCs-Exo mitigate inflammation and apoptosis through autophagy in SAKI, offering a promising avenue for SAKI treatment.

Fatal multisystem inflammatory syndrome in a 78-year-old adult after severe COVID-19 pneumonia during 2022 Omicron variant epidemic in Shanghai, China.

Multisystem inflammatory syndrome adult type (MIS-A) is a rare type of post-acute COVID-19 syndrome which more frequently occurred in younger population. Here we present a 78-year-old Chinese female, the oldest case reported, diagnosed with MIS-A who had severe SARS-CoV-2 infection. She was diagnosed with severe COVID-19 and experienced an unexpected sudden hemodynamic collapse in the recovery period within three weeks. Her platelet count was sharply dropped, accompanied with sustained cardiac, kidney and liver injury. She was diagnosed with MIS-A according to criteria established by Center of Disease Control and Prevention. Though her condition was improved under administrating with high dose of methylprednisolone and intravenous immunoglobulin, methylprednisolone was unable to withdraw till two weeks as her partial pressure of oxygen/fraction of inspiration oxygen ratio and platelet count dropped on the heels of decreasing dosage. Unfortunately, the patient's condition gradually deteriorated with the development of severe nosocomial pneumonia. We presented this rare case in order to emphasize that MIS-A could occur in the elderly and the management of this population might be more difficult as the condition of the elderly with SARS-CoV-2 infection and MIS-A might be more severe.

HMGB1 mediates lipopolysaccharide-induced macrophage autophagy and pyroptosis.

Autophagy and pyroptosis of macrophages play important protective or detrimental roles in sepsis. However, the underlying mechanisms remain unclear. High mobility group box protein 1 (HMGB1) is associated with both pyroptosis and autophagy. lipopolysaccharide (LPS) is an important pathogenic factor involved in sepsis. Lentivirus-mediated HMGB1 shRNA was used to inhibit the expression of HMGB1. Macrophages were treated with acetylation inhibitor (AA) to suppress the translocation of HMGB1 from the nucleus to the cytosol. Autophagy and pyroptosis-related protein expressions were detected by Western blot. The levels of caspase-1 activity were detected and the rate of pyroptotic cells was detected by flow cytometry. LPS induced autophagy and pyroptosis of macrophages at different stages, and HMGB1 downregulation decreased LPS-induced autophagy and pyroptosis. Treatment with acetylation inhibitor (anacardic acid) significantly suppressed LPS-induced autophagy, an effect that was not reversed by exogenous HMGB1, suggesting that cytoplasmic HMGB1 mediates LPS-induced autophagy of macrophages. Anacardic acid or an anti-HMGB1 antibody inhibited LPS-induced pyroptosis of macrophages. HMGB1 alone induced pyroptosis of macrophages and this effect was inhibited by anti-HMGB1 antibody, suggesting that extracellular HMGB1 induces macrophage pyroptosis and mediates LPS-induced pyroptosis. In summary, HMGB1 plays different roles in mediating LPS-induced autophagy and triggering pyroptosis according to subcellular localization.

Super resolution imaging reconstruction reveals that gold standard methods may not correctly conclude neural/brain functional recovery.

The status of cerebral perfusion and its restoration level play a vital role in the prognosis and clinical decision making of many neurosurgical diseases. As such, gold standard methods including CT, MR and ICP monitoring, which can indicate and measure cerebral perfusion and restoration, have been widely adopted to evaluate whether or not a patient has recovered from neurofunctional disabilities. This robust combination of methods, however, is confronted with a growing number of contradictions in recent years due to its inability to measure the status of cerebral reperfusion in microvasculature level, even though this has been shown to determine neurofunctional restoration as well or even better. To this date, nevertheless, we have very limited imaging methods that could evaluate human cerebral microperfusion both safely and accurately under most neurosurgical conditions. We herein report a new method of acquiring a patient's cerebral microperfusion status noninvasively which could display the precise distribution of microvasculature in deep cerebral regions with a resolution of ∼30 µm, using everyday bed-side ultrasonography combined with a computerized super-resolution reconstruction algorithm. Using this imaging modality, we found that a patient's cerebral microperfusion might not be improved by some routine administrations even though the gold standard method had yielded the opposite conclusions. Our imaging modality retains the safe, portable feature of ordinary ultrasonography while possesses the extraordinary super-resolution nature, which enables an efficient, precise diagnosis of cerebral perfusion. Most importantly, the super resolution nature of this method may also facilitate early-stage evaluation of a patient's neurofunctional restoration level and avoid overoptimistic conclusions from conventional angiography or ICP monitoring.