Association between dynamic fluctuations in triiodothyronine levels and prognosis among critically ill patients within comprehensive intensive care units.

Objective: Decrease in free thyroid hormone T3 (FT3) can be used as an independent prognostic indicator for the risk of death in ICUs. However, FT3 as a predictive marker is hindered by its accuracy. The study introduces the concept of dynamic FT3 data as a means to bolster the value of FT3 as a prognostic tool. Therefore, the aim of this study is to investigate the prognostic value of dynamic FT3 evolution in a comprehensive ICU setting, analyze the consistency between dynamic FT3 changes and variations in disease severity, and explore the feasibility of FT3 as an objective indicator for real-time clinical treatment feedback. Methods: Employing a single-center prospective observational study, FT3 measurements were taken on multiple days following enrollment, corresponding clinical data were collected. To investigated the pattern of dynamic changes of FT3,its prognostic significance in forecasting the risk of 28-day mortality, the alignment between dynamic FT3 changes and variations in the Sequential Organ Failure Assessment (SOFA) score. Results: The survival group exhibited higher last FT3 levels compared to the lowest point (p<0.05), while the death group did not show statistically significant differences (p>0.05). The study also identifies the optimal correlation between FT3 and SOFA score at day 5 (optimal correlation coefficient -0.546).The ROC curve for FT3 at day 5 yielded an optimal AUC of 0.88, outperforming the SOFA score. The study categorizes FT3 curve patterns,Kaplan-Meier survival analysis of these patterns highlighted that the descending-type curve was significantly associated with increased risk of death (P<0.001). Additionally, the research explores the consistency between changes in FT3 and SOFA scores. While overall consistency rates were modest, subgroup analyses unveiled that greater disease severity led to higher consistency rates. Conclusions: This study introduces the concept of dynamic FT3 changes to augment its prognostic utility in comprehensive ICU settings. The research identifies day 5 as the optimal time point for predictive efficacy, the descending FT3 curve as indicative of poor prognosis. While overall consistency with SOFA scores is modest, the correlation strengthens with greater disease severity.

Expression of serum inflammatory cytokines and oxidative stress markers and their correlation with coronary artery calcium score in patients with coronary heart disease.

Introduction: The present study was conducted to explore the expression of serum inflammatory cytokines and oxidative stress markers in patients with coronary heart disease (CHD), with an attempt to analyze their relationship with the coronary artery calcium score (CACS) by coronary computed tomography angiography (CCTA). Material and methods: It total 81 patients with coronary heart disease and 81 healthy adults were included as the observation group and the control group, respectively. The levels of serum interleukin (IL)-6 and IL-12 of the two groups were detected by ELISA, and serum superoxide dismutase (SOD) was detected by the hydroxylamine oxidation method. Micro-RNA-497-5p (miR-497-5p) was screened out as a possible new CHD biomarker and its serum level was measured by real-time fluorescence quantitative PCR. The CACS of patients in the observation group was calculated by the Agatston method to analyze the correlation between the abovementioned indexes and CACS. Results: With increase in the number of CHD lesions, the levels of IL-6, IL-12 and miR-497-5p rose gradually while the level of SOD decreased gradually. In the observation group, IL-6, IL-12 and miR-497-5p were positively correlated with CACS while SOD was negatively correlated with CACS. Conclusions: Abnormal expression levels of serum IL-6, IL-12, SOD and miR-497-5p may be able to reveal the severity of the disease, and the combination with CACS is of potential value in terms of evaluating the condition of patients harboring coronary heart disease.

Prognostic value of serum levels of multiple adhesion factors in patients with sepsis-induced acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is common in patients with sepsis and septic shock. Urine output and serum creatinine (SCr) levels are the criteria for diagnosing AKI. However, the application of these levels in the diagnosis of AKI has limitations. OBJECTIVE: To detect the expression of various adhesion factors in different stages of AKI as defined by Kidney Disease: Improving Global Outcomes (KDIGO) and to analyse their relationship with the prognosis of patients with sepsis-induced AKI (S-AKI). METHODS: Adult patients with sepsis who were admitted to the hospital between June 2019 and May 2020 were included. Of 90 adult patients with sepsis, 58 had S-AKI. Sixty-seven subjects without sepsis were used as controls. Enzyme-linked immunosorbent assay kits were used to measure E-selectin (CD62E), L-selectin (CD62L), P-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and their relationship with the prognosis of patients with S-AKI patients was analysed. Receiver operating characteristic curves were used to analyse the predictive value of different adhesion factors on renal resistance index and renal function recovery. Multivariate logistic regression analysis was used to identify factors associated with renal recovery. RESULTS: The expression of CD62L was significantly higher in S-AKI patients than in non-AKI patients with sepsis. Compared with the non-AKI group, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were significantly higher in the AKI group than in the non-AKI group (P < 0.05). Mean blood pressure, SCr levels and procalcitonin levels were higher in the AKI group than in the non-AKI group (P < 0.05 for all). The CD62L levels decreased with increasing S-AKI stage. The CD62E levels were highest in S-AKI stage 2, and the VCAM-1 levels were highest in S-AKI stage 3. All patients with S-AKI were followed up with for 28 days. The results found that VCAM-1 was the best predictor of renal recovery in patients with S-AKI. CONCLUSION: CD62L is an indicator of S-AKI stage1, and CD62E is an indicator of S-AKI stage 2. In addition, VCAM-I demonstrated satisfactory performance in predicting early recovery of renal function in patients with S-AKI.

The mechanism of low-dose radiation-induced upregulation of immune checkpoint molecule expression in lung cancer cells.

INTRODUCTION: This study explored the effect of low-dose radiation on the expression of immune checkpoint molecules in lung cancer cells and its mechanism, as well as the antitumour effect of combined low-dose radiation and immune checkpoint inhibitors. METHODS: Western blot analysis was used to assess the expression of the immune checkpoint molecules CD47, PD-L1, FGL-1 and CD155 in lung cancer cells after radiation. Western blotting was also used to explore changes in the JAK2/STAT3 pathway. CD8+ T lymphocyte infiltration in tumour tissues were assessed by immunohistochemistry in a mouse model. The inhibitory effect of low-dose radiation combined with PD-L1 or CD47 inhibitors on tumor growth was evaluated by measuring tumor volume. RESULTS: In response to low-dose irradiation, the expression of CD47 and PD-L1 in A549 and LLC cells was increased, the expression of p-JAK2 and p-STAT3 was also increased. AG490-mediated inhibition of the JAK2/STAT3 pathway before irradiation significantly reduced the expression of p-JAK2 and p-STAT3 in lung cancer cells, in the meantime, expression of CD47 and PD-L1 was also reduced. Conventional dose exposure exhibited the same trend. PD-L1 and CD47 protein levels increased after low-dose irradiation in an LLC tumour-bearing mouse model. Low-dose irradiation combined with PD-L1 or CD47 inhibitor treatment reduced levels of PD-L1 or CD47 in tumour tissues, increased the proportion of CD8+ T lymphocytes, and significantly inhibited tumour growth. CONCLUSIONS: Both low-dose and regular-dose irradiation upregulate expression of the immune checkpoint molecules CD47 and PD-L1 in lung cancer cells, and the mechanism may be related to the JAK2/STAT3 pathway. Furthermore, low-dose irradiation combined with PD-L1 or CD47 inhibitors significantly inhibits tumour growth.

Disturbance Rejection and Robustness of Improved Equivalent-Input-Disturbance-Based System.

This article presents an improved equivalent-input-disturbance (EID) approach to handle unknown disturbances and plant uncertainties. The disturbances and uncertainties are treated as a lumped disturbance in an EID-based control system. The effect of the lumped disturbance is compensated by an EID estimator. A constraint between design parameters and uncertainties is imposed on the design of the estimator. In addition, there are insufficient analyses of the influence of uncertainties on the control performance and the stability of the system. A new filter is devised for an improved EID estimator in this article to remove the constraint. This ensures that the sensitivity of the system to disturbances at low frequencies can be freely decreased. An analysis of the system reveals that uncertainties not only influence disturbance-rejection and reference-tracking performance but also affect system stability. A sufficient stability criterion is derived with consideration of uncertainties. The validity of the presented method is demonstrated by simulation and experimental results.

[Consistency comparison of the parameters of the lumbar spine-pelvic sagittal plane between the whole-spine EOS images system and traditional X-ray].

OBJECTIVE: To explore the consistency of the parameters of the lumbar spine pelvic sagittal plane between the whole spine EOS images (EOS) and traditional X-ray imaging. METHODS: A total of 50 patients (26 males and 24 females) hospitalized in the Spine Surgery Department of Beijing Jishuitan Hospital from May to July 2019 were selected for standard standing EOS full-length spine anterolateral and traditional X-ray lumbar pelvic anterior and lateral X-rays. Two attending physicians used Surgimap software to measure the pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL) of the two types of images and repeated these process after two weeks. The consistency test (reliability analysis) was performed on the results measured by two physicians, and the results measured at the two time points were tested for intra-observer consistency (repeatability analysis).The data were combined to perform consistency and difference tests for the parameters between two types of images finally. RESULTS: The mean values of PI measured by EOS imaging and traditional X-ray imaging were(50.5±12.6)° and (51.4±12.2)°, mean difference 0.9, 95% credible interval (0.2-1.6), P=0.020; the mean values of PT were (16.2±8.9)° and (16.9±8.6)°, mean difference 0.7, 95% credible interval (-0.6-2.0), P=0.283; the mean values of SS were (34.3±9.9)° and (34.5±10.4)°, mean difference 0.2, 95% credible interval (-1.2-1.5), P=0.800;the mean values of LL were (42.7±14.9)° and (43.3±15.3)°, mean difference 0.6, 95% confidence interval (-0.8-2.0), P=0.149. The difference in PI between the two imaging methods was statistically significant (P =0.020, P <0.05), but the average difference was small (0.9°), there was no clinical difference. There were no significant differences in PT, SS and LL between the two imaging methods (P>0.05). Inter-group reliability analysis showed excellent agreement between the two physicians in measuring lateral PI, PT, SS and LL using Surgimap software (correlation coefficients within EOS imaging were 0.984, 0.993, 0.980, 0.989;correlation coefficients within X-ray imaging were 0.975, 0.985, 0.976, 0.988). Repeatability analysis showed that PI, PT, SS and LL measured by the two attending physicians at two time points had excellent consistency(ICC within the group was 0.963-0.996). CONCLUSION: In the local lumbar pelvis segment, the PI, PT SS and LL measured by EOS imaging and traditional X-ray imaging had good agreement, and there was no difference in guiding clinical application.

SOX11 and FAK participate in the stretch­induced mechanical injury to alveolar type 2 epithelial cells.

The aim of the present study was to explore the potential role of SOX11 in the stretch­induced mechanical injury to alveolar type 2 epithelial (AT2) cells. A cell stretch (CS) test was used to induce mechanical injury to primary cultured AT2 cells. Wound healing, adhesion, cell viability assays and flow cytometry were performed to evaluate the migration, adhesion, viability and apoptosis of AT2 cells. Changes in the invasive ability of AT2 cells were detected using a Transwell invasion assay. To further explore the underlying molecular mechanisms, reverse transcription­quantitative PCR and western blot analysis were used to assess the expression levels of SOX11, FAK, Akt, caspase­3/8, p65 and matrix metalloproteinase (MMP)7. Co­immunoprecipitation (Co­IP) and luciferase reporter assays were used to detect the interaction between SOX11 and FAK. CS reduced the invasion, migration and adhesion, and increased the apoptosis of AT2 cells. It also resulted in the downregulation of SOX11 and FAK expression in AT2 cells. The overexpression of SOX11 reversed these changes, whereas the knockdown of SOX11 aggravated the deterioration of the aforementioned biological behaviors and the apoptosis of the AT2 cells following CS. The overexpression of SOX11 upregulated the FAK and Akt expression levels, and downregulated caspase­3/8 expression, whereas the silencing of SOX11 reversed these changes following CS. Furthermore, the effects of SOX11 overexpression were inhibited by FAK antagonism. The results of Co­IP demonstrated that SOX11 and FAK were bound together, and that the expression of FAK was significantly increased in the SOX11 overexpression group. Luciferase assays revealed that the luciferase activity and the mRNA expression of FAK were significantly increased following transfection with pcDNA SOX11 and pGL3 FAK promoter. Co­IP and luciferase assays revealed that SOX11 directly regulated the expression of FAK. On the whole, the present study demonstrates that the downregulated expression of SOX11 and FAK are involved in the stretch­induced mechanical injury to AT2 cells. The overexpression of SOX11 significantly alleviates AT2 cell injury through the upregulation of FAK and Akt, and the inhibition of apoptosis. These findings suggest that the activation of SOX11 and FAK may be potential preventive and therapeutic options for ventilator­induced lung injury.

Enhancement of FAK alleviates ventilator-induced alveolar epithelial cell injury.

Mechanical ventilation induces lung injury by damaging alveolar epithelial cells (AECs), but the pathogenesis remains unknown. Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is involved in cell growth and intracellular signal transduction pathways. This study explored the potential role of FAK in AECs during lung injury induced by mechanical ventilation. High-volume mechanical ventilation (HMV) was used to create a mouse lung injury model, which was validated by analysis of lung weight, bronchoalveolar lavage fluid and histological investigation. The expression of FAK and Akt in AECs were evaluated. In addition, recombinant FAK was administered to mice via the tail vein, and then the extent of lung injury was assessed. Mouse AECs were cultured in vitro, and FAK expression in cells under stretch was investigated. The effects of FAK on cell proliferation, migration and apoptosis were investigated. The results showed that HMV decreased FAK expression in AECs of mice, while FAK supplementation attenuated lung injury, reduced protein levels/cell counts in the bronchoalveolar lavage fluid and decreased histological lung injury and oedema. The protective effect of FAK promoted AEC proliferation and migration and prevented cells from undergoing apoptosis, which restored the integrity of the alveoli through Akt pathway. Therefore, the decrease in FAK expression by HMV is essential for injury to epithelial cells and the disruption of alveolar integrity. FAK supplementation can reduce AEC injury associated with HMV.

Transfection of Sox11 plasmid alleviates ventilator-induced lung injury via Sox11 and FAK.

Background Ventilator-induced lung injury (VILI) is the most common complication in the mechanical ventilation in clinic. The pathogenesis of VILI has not been well understood. The SRY related High Mobility Group box group-F family member 11(Sox11) is a protein associated with lung development. The focal adhesion kinase(FAK) is a cytoplasmic tyrosine kinase and is regulated by Sox11. The present study, therefore, was undertaken to explore the potential role of Sox11 and FAK in VILI. Methods High volume mechanical ventilation(HMV) was used to establish mouse VILI model under anesthesia. The lung injury was evaluated by analyzing the lung weight, bronchoalveolar lavage fluid, histopathological changes and apoptosis of the lung. The Sox11 and FAK expressions in the lung were investigated by real-time qPCR, western blot and immunohistochemistry analysis. Results HMV induced VILI simultaneously companied with decreased expressions of Sox11 and FAK in alveolar epithelial and interstitial cells either in gene and protein levels. Transfection of Sox11 plasmid significantly upregulated expressions of Sox11 and FAK in gene and protein levels in the lung and particularly effectively alleviated VILI. Furthermore, FAK antagonism by PF562271(FAK antagonist) blocked the alleviating effect of Sox11 plasmid transfection on the VILI. Conclusion The dysregulation in the Sox11 and FAK after HMV play an important role in the pathogenesis of VILI, and facilitating the activity of Sox11and FAK might be an effective target and potential option in the prevention and treatment of VILI in clinic.

Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer's Disease Mice.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative dementia with the key pathological hallmarks amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau. microRNAs (miRNAs) are small non-coding RNAs that contribute to the pathogenesis of AD. In this study, we investigated the effect of the loss of miR-369 on the phosphorylation of tau protein and the activation of the kinases Fyn and serine/threonine-protein kinase 2 (SRPK2) as the upstream molecules facilitating tau phosphorylation in miR-369 knockout 3xTg-AD mice. METHODS: We generated miR-369 knockout 3xTg-AD mice and investigated their cognitive behaviors by maze tests. Real-time qPCR, western blot, and immunohistochemistry were performed to evaluate the expression of the miR-369 gene, phosphorylation of tau protein, and activation of Fyn and SRPK2. Luciferase reporter assays were applied to confirm the predicted targets of miR-369. RESULTS: Knocking out miR-369 in 3xTg AD mice aggravated cognitive impairment, promoted hyperphosphorylation of tau, and upregulated Fyn and SRPK2. Restoring miR-369 reversed the hyperphosphorylation of tau and downregulated Fyn and SRPK2. Additionally, miR-369 was shown to target the 3'UTRs of Fyn and SRPK2 to regulate their expression levels. CONCLUSION: Loss of miR-369 promotes tau phosphorylation by targeting the Fyn and SRPK2 signaling pathways in AD mice, and supplementation with miR-369 might be a valuable option for AD therapeutic studies.

Blood purification with continuous veno-venous hemofiltration in patients with sepsis or ARDS: a systematic review and meta-analysis.

INTRODUCTION: Severe inflammatory conditions, as severe sepsis/septic shock and acute respiratory distress syndrome (ARDS), are related to high morbidity and mortality. We performed a meta-analysis of randomized trials to assess if blood purification with continuous veno-venous hemofiltration (CVVH) reduces mortality in these settings. EVIDENCE ACQUISITION: Online databases were searched for pertinent studies up to March 2017. We included randomized-controlled trials on the use of CVVH as blood purification technique in comparison to conventional therapy in adult patients with severe sepsis/septic shock or ARDS but no acute kidney injury needing renal replacement therapy. EVIDENCE SYNTHESIS: Eleven studies and 679 patients were included in the analysis. Patients who received CVVH had significantly lower mortality compared to conventional therapy (96 of 351 [27.35%] patients in the CVVH group vs. 129 of 328 [39.33%] in the conventional therapy group, OR=0.58 [95% CI: 0.42, 0.81], P=0.002, I2=10%, number needed to treat: 8) at longest follow-up available. CONCLUSIONS: Overall, low-quality evidence indicates that blood purification with CVVH might be associated with a significant reduction in mortality when performed in patients with sepsis or ARDS. The evidence is still insufficient to support a definitive conclusion of benefit. Further high-quality randomized controlled trials, adequately powered for mortality, are needed to clarify the impact of CVVH on these conditions.

[Effects of levosimendan on hemodynamics and cardiac function in patients with septic shock].

OBJECTIVE: To evaluate the effects of levosimendan on hemodynamics and cardiac function in patients with septic shock. METHODS: A prospective single-center randomized controlled trial was conducted. The patients with septic shock admitted to the Department of Critical Care Medicine of the Third Hospital of Hebei Medical University from June 2011 to October 2013 were enrolled. The patients with septic shock received the conventional treatment according to international guidelines for management of severe sepsis and septic shock. Thirty-six patients received the examination of echocardiography and left ventricular ejection fraction (LVEF)≤ 0.45 after fluid resuscitation were enrolled the study, who were divided into two groups according to random number table, with 18 cases in each group. After the conventional treatment, the patients in dobutamine group received intravenous injection of 5 µg × kg⁻¹ min⁻¹ dobutamine for 48 hours immediately after fluid resuscitation, and those in levosimendan group received a 24-hour infusion of 5 µg × kg⁻¹ min⁻¹ dobutamine followed by a 24-hour infusion of 0.2 µg × kg⁻¹ × min⁻¹ levosimendan. The hemodynamics and cardiac function were evaluated by pulse indicator continuous cardiac output (PiCCO) and ultrasound during treatment. RESULTS: Compared with dobutamine group, after the treatment in the levosimendan group, stroke volume index (SVI), cardiac index (CI) and left ventricular stroke work index (LVSWI) were significantly increased [SVI (mL/m²): 39.8 ± 5.4 vs. 37.5 ± 4.5, t=-2.762, P=0.020; CI (L × min⁻¹ × m⁻²): 4.6 ± 0.7 vs. 3.6 ± 0.7, t=-9.829, P=0.000; LVSWI (kg ×min⁻ ¹ m⁻²): 33.7 ± 2.4 vs. 28.2 ± 1.2, t=-6.307, P=0.000], and central venous pressure (CVP), intrathoracic blood volume index (ITBVI) and extravascular lung water index (EVLWI) were significantly decreased [CVP (mmHg, 1 mmHg=0.133 kPa): 8.2 ± 0.9 vs. 12.1 ± 0.8, t=3.928, P=0.002; ITBVI (mL/m²): 820 ± 42 vs. 978 ± 69, t=9.472, P=0.000; EVLWI (mL/kg): 6.1 ± 1.6 vs. 8.9 ± 1.7, t=4.467, P=0.001]. Cardiac ultrasound showed that compared with dobutamine group, in the levosimendan group, left ventricular end-systolic volume (LVESI) and end-diastolic volume (LVEDI) were significantly lowered [LVESI (mL/m²): 32.7 ± 9.2 vs. 48.2 ± 13.4, t=0.882, P=0.000; LVEDI (mL/m²): 61.7 ± 11.4 vs. 78.6 ± 13.6, t=2.453, P=0.032], and the LVEF was significantly increased (0.463 ± 0.068 vs. 0.383 ± .085, t=-2.439, P=0.035). Levosimendan also could decrease the lactic acid (mmol/L: 3.4 ± 1.1 vs. 5.2 ± 1.2, t=3.346, P=0.007), and increase the lactate clearance rate (mL/min: 73.2 ± 13.5 vs. 47.6 ± 11.8, t=-4.079, P=0.002), 24-hour urinary output (mL: 2 213.4 ± 354.0 vs. 1 533.8 ± 402.0, t=6.342, P=0.000) and 24-hour cumulative intake (mL: 5 746.6 ± 420.0 vs. 4 156.7 ± 215.0, t=7.126, P=0.000). There were no significant differences in total volume of norepinephrine,mortality in intensive care unit (ICU) and 28-day mortality between two groups. CONCLUSIONS: Levosimendan can increase cardiac ejection function, reduce the heart blood and vascular preload, intrathoracic lung water, improve heart function and systemic hemodynamic indexes of patients with septic shock.