Persistent acute kidney injury biomarkers: A systematic review and meta-analysis.

BACKGROUND: Various biomarkers reportedly predict persistent acute kidney injury (AKI) despite their varying predictive performance across clinical trials. This study aims to compare the accuracy of various biomarkers in predicting persistent AKI in different populations and regions. METHODS: In this meta-analysis, we searched for urinary C-C motif chemokine ligand 14 (CCL14), Tissue inhibitor of metalloproteinase-2&insulin-like growth factor-binding protein-7 (TIMP-2&IGFBP7), Neutrophil Gelatinase-Associated Lipocalin (NGAL), plasma Cystatin C (pCysC), Soluble urokinase plasminogen activator receptor (suPAR), Proenkephalin (PenK) and urinary dickkopf-3:urinary creatinine (uDKK3:uCr) from various databases including Medline, PubMed, Embase, and Cochrane. This was geared towards predicting persistent AKI in adults (>18 years). Hierarchically summarized subject work characteristic curves (HSROC) and diagnostic odds ratio (DOR) values were used to summarize the diagnostic accuracy of the biomarkers. Further, meta-regression and subgroup analyses were carried out to identify sources of heterogeneity as well as evaluate the best predictive biomarkers in different populations and regions. RESULTS: We screened 31 studies from 2,356 studies and assessed the diagnostic value of 7 biomarkers for persistent AKI. Overall, CCL14 had the best diagnostic efficacy with an AUC of 0.79 (95 % CI 0.75-0.82), whereas TIMP-2 & IGFBP7, NGAL, and pCysC had diagnostic efficacy of 0.75 (95 % CI 0.71-0.79),0.71 (95 % CI 0.67-0.75), and 0.7007, respectively. Due to a limited number of studies, PenK, uDKK3:uCr, and suPAR were not subjected to meta-analysis; however, relevant literature reported diagnostic efficacy above 0.70. Subgroup analyses based on population, region, biomarker detection time, AKI onset time, and AKI duration revealed that in the intensive care unit (ICU) population, the AUC of CCL14 was 0.8070, the AUC of TIMP-2 & IGFBP7 was 0.726, the AUC of pCysC was 0.72, and the AUC of NGAL was 0.7344; in the sepsis population, the AUC of CCL14 was 0.85, the AUC of TIMP-2&IGFBP7 was 0.7438, and the AUC of NGAL was 0.544; in the post-operative population, the AUC of CCL14 was 0.83-0.93, the AUC of TIMP-2&IGFBP7 was 0.71, and the AUC of pCysC was 0.683. Regional differences were observed in biomarker prediction of persistent kidney injury, with AUCs of 0.8558 for CCL14, 0.7563 for TIMP-2 & IGFBP7, and 0.7116 for NGAL in the Eurasian American population. In the sub-African population, TIMP-2 & IGFBP7 had AUCs of 0.7945, 0.7418 for CCL14, 0.7097 for NGAL, and 0.7007 for pCysC. for TIMP-2 & IGFBP7 was 0.7945, AUC for CCL14 was 0.7418, AUC for NGAL was 0.7097, and AUC for pCysC was 0.7007 in the sub-African population. Duration of biomarker detection, AKI onset, and AKI did not influence the optimal predictive performance of CCL14. Subgroup analysis and meta-regression of CCL14-related studies revealed that CCL14 is the most appropriate biomarker for predicting persistent stage 2-3 AKI, with heterogeneity stemming from sample size and AKI staging. CONCLUSION: This meta-analysis discovered CCL14 as the best biomarker to predict persistent AKI, specifically persistent stage 2-3 AKI.

The chemokine receptor type 5 inhibitor maraviroc alleviates sepsis-associated liver injury by regulating MAPK/NF-κB signaling.

Sepsis-related organ damage, as the most intractable problem in intensive care units (ICUs), receives a great deal of attention from healthcare professionals. Sepsis-associated liver injury (SALI) often leads to poor clinical outcomes due to its complex physiological mechanism. In previous studies, chemokine receptor 5 (CCR5) inhibitors were shown to exert unique anti-inflammatory effects. As the therapeutic effect of maraviroc (MVC) on SALI is still unclear, we aimed to explore whether MVC is effective in treating SALI. We established a model of SALI by cecal ligation and puncture (CLP) and intraperitoneally injected 20 mg/kg MVC 2 h after CLP. The results showed that MVC could significantly ameliorate liver injury after CLP. Furthermore, we demonstrated that MVC reduced inflammatory infiltration and apoptosis after SALI. In addition, we found that the function of MVC in reducing inflammation was obtained through the inhibition of the two inflammatory signaling pathways mentioned above. Finally, the JNK agonist AN was chosen for reverse research. As shown by the results, the therapeutic effects of MVC disappeared after AN treatment, indicating that MVC exerted anti-inflammatory and antiapoptotic effects through JNK. Our study revealed that MVC could reduce liver injury after SALI by inhibiting liver inflammation and hepatocyte apoptosis induced by CLP and that MVC exerted diminish inflammatory effects by inhibiting the NF-κB and MAPK signaling pathways.

Protective effect of intravenous amino acid on kidney function: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Acute kidney injury (AKI) is a common complication in critically ill and cardiac surgery patients. Intravenous amino acids can increase renal perfusion and replenish renal functional reserves. However, the exact therapeutic efficacy of intravenous amino acids in reducing the incidence of AKI remains uncertain. Therefore, this study aims to comprehensively review the existing evidence to assess the potential of intravenous amino acids in kidney protection. METHODS: EMBASE, PubMed, MEDLINE, and the Cochrane Library were searched for randomized controlled trials published on or before July 2, 2024, that examined the relationship between Intravenous amino acids and renal function. We extracted population characteristics and outcome variables related to renal function from randomized controlled trials comparing intravenous amino acid supplementation with no supplementation. We assessed this evidence using the Risk of Bias 2 (RoB2) tool for randomized controlled trials. Data were synthesized using a random-effects model. RESULTS: This review included 7 randomized controlled trials with a total of 505 patients. The results showed that compared with the control group, intravenous amino acid administration significantly reduced the incidence of AKI (RR: 0.81, 95 % CI: 0.68-0.97, P = 0.02) and increased urine output (MD: 308.87, 95 % CI: 168.68-449.06, P < 0.0001). However, intravenous amino acids did not reduce mortality or the incidence of kidney replacement therapy, with no statistical difference in 30-day mortality (RR: 0.93, 95 % CI: 0.65-1.34, P = 0.71), 90-day mortality (RR:1.00, 95 % CI: 0.77-1.29, P = 0.98), or need for kidney replacement therapy (RR: 0.92, 95 % CI: 0.41-2.06, P = 0.83). Subgroup analysis suggested that, regardless of sample size, intravenous amino acid administration reduced the incidence of AKI and was particularly significant in patients undergoing cardiac and major vascular surgery. Furthermore, intraoperative intravenous amino acid therapy demonstrated a significant reduction in the incidence of AKI compared to postoperative administration. CONCLUSIONS: Intravenous amino acids protect renal function in patients at high risk of AKI, particularly after cardiac surgery. It reduces the incidence of AKI and increases urine output, but has no significant effect on KRT and mortality.

Post-translational modifications in sepsis-induced organ dysfunction: mechanisms and implications.

As a grave and highly lethal clinical challenge, sepsis, along with its consequent multiorgan dysfunction, affects millions of people worldwide. Sepsis is a complex syndrome caused by a dysregulated host response to infection, leading to fatal organ dysfunction. An increasing body of evidence suggests that the pathogenesis of sepsis is both intricate and rapid and involves various cellular responses and signal transductions mediated by post-translational modifications (PTMs). Hence, a comprehensive understanding of the mechanisms and functions of PTMs within regulatory networks is imperative for understanding the pathological processes, diagnosis, progression, and treatment of sepsis. In this review, we provide an exhaustive and comprehensive summary of the relationship between PTMs and sepsis-induced organ dysfunction. Furthermore, we explored the potential applications of PTMs in the treatment of sepsis, offering a forward-looking perspective on the understanding of infectious diseases.

[Research progress on the relationship between the gut microbiota dysbiosis and sepsis-induced cardiomyopathy].

Sepsis is a life-threatening organ dysfunction caused by the host's dysfunctional response to infection. Sepsis-induced cardiomyopathy (SICM), as a serious complication of sepsis, is an acute reversible cardiac dysfunction syndrome unrelated to myocardial ischemia, which affects the outcome and prognosis of sepsis. As a complex microbial system, gut microbiota has been confirmed to be involved in the development of coronary heart disease, hypertension, heart failure and other cardiovascular diseases, and is also related to the occurrence and development of sepsis. However, there are few studies on the relationship between gut microbiota and SICM. This paper reviews the current research progress on gut microbiota and SICM, aiming at provide a new idea for clinical treatment of SICM.

[Research progress in the mechanism of intestinal environmental disturbance on the occurrence and development of sepsis-associated liver injury].

Sepsis-associated liver injury (SALI) is a common complication of sepsis, which is characterized by systemic immune disorders induced by sepsis leading to liver damage. Currently, there are no effective treatments for SALI, which is related to its complex pathophysiological mechanisms. In recent years, the disorder of intestinal environment after sepsis has been considered as an important factor for SALI, but the specific molecular mechanism of the above process is still unclear. This article will review the pathological role and molecular mechanisms between intestinal environmental disturbance and SALI, aiming to analyze the potential research direction of SALI and identify potential therapeutic targets for its treatment.

[Construction of a risk predictive model of acute kidney injury based on urinary tissue inhibitor of metalloproteinase 2 and insulin-like growth factor-binding protein 7 and its early predictive value in critically ill patients].

OBJECTIVE: To establish a risk predictive model nomogram of acute kidney injury (AKI) in critically ill patients by combining urinary tissue inhibitor of metalloproteinase 2 (TIMP2) and insulin-like growth factor-binding protein 7 (IGFBP7), and to verify the predictive value of the model. METHODS: A prospective observational study was conducted. The patients with acute respiratory failure or circulatory disorder admitted to the intensive care unit (ICU) of Northern Jiangsu People's Hospital from November 2017 to April 2020 were enrolled. The patients were enrolled within 24 hours of ICU admission, and their general conditions and relevant laboratory test indicators were collected. At the same time, urine was collected to determine the levels of biomarkers TIMP2 and IGFBP7, and TIMP2×IGFBP7 was calculated. Patients were divided into non-AKI and AKI groups according to whether grade 2 or 3 AKI occurred within 12 hours after enrollment. The general clinical data and urinary TIMP2×IGFBP7 levels of patients between the two groups were compared. The indicators with P < 0.1 in univariate analysis were included in the multivariate Logistic regression analysis to obtain the independent risk factors for grade 2 or 3 AKI within 12 hours in critical patients. An AKI risk predictive model nomogram was established, and the application value of the model was evaluated. RESULTS: A total of 206 patients were finally enrolled, of whom 54 (26.2%) developed grade 2 or 3 AKI within 12 hours of enrollment, and 152 (73.8%) did not. Compared with the non-AKI group, the patients in the AKI group had higher body mass index (BMI), pre-enrollment serum creatinine (SCr), urinary TIMP2×IGFBP7 and proportion of using vasoactive drugs, and additional exposure to AKI (use of nephrotoxic drugs before enrollment) was more common. Multivariate Logistic regression analysis showed that BMI [odds ratio (OR) = 1.23, 95% confidence interval (95%CI) was 1.10-1.37, P = 0.000], pre-enrollment SCr (OR = 1.01, 95%CI was 1.00-1.02, P = 0.042), use of nephrotoxic drugs (OR = 2.84, 95%CI was 1.34-6.03, P = 0.007) and urinary TIMP2×IGFBP7 (OR = 2.19, 95%CI was 1.56-3.08, P = 0.000) was an independent risk factor for the occurrence of grade 2 or 3 AKI in critical patients. An AKI risk predictive model nomogram was constructed based on the independent risk factors of AKI. Bootstrap validation results showed that the model had good discrimination and calibration in internal validation. Receiver operator characteristic curve (ROC curve) analysis showed that the area under the ROC curve (AUC) of urinary TIMP2×IGFBP7 alone in predicting grade 2 or 3 AKI within 12 hours in critical patients was 0.74 (95%CI was 0.66-0.83), the optimal cut-off value was 1.40 (µg/L) 2/1 000 (sensitivity was 66.7%, specificity was 85.0%), and the predictive performance of the model incorporating urinary TIMP2×IGFBP7 was significantly better than that of the model without urinary TIMP2×IGFBP7 [AUC (95%CI): 0.85 (0.79-0.91) vs. 0.77 (0.70-0.84), P = 0.005], net reclassification index (NRI) was 0.29 (95%CI was 0.08-0.50, P = 0.008), integrated discrimination improvement (IDI) was 0.13 (95%CI was 0.07-0.19, P < 0.001). CONCLUSIONS: The AKI risk predictive model based on urinary TIMP2×IGFBP7 has high clinical value and is expected to be used to early predict the occurrence of AKI in critically ill patients.

Case report: Inhaled nitric oxide rescued a hypoxemia patient caused by dermatomyositis complicated with interstitial pneumonia.

Interstitial pneumonia is the most common and serious secondary lesion of dermatomyositis. In some cases, patients may develop severe acute pneumonia that can quickly progress to respiratory failure, resulting in high mortality rates. A 57-year-old woman with dermatomyositis and interstitial pulmonary fibrosis experienced severe hypoxemia due to pulmonary infection. Despite receiving various treatments after entering the intensive care unit (ICU), such as anti-infection therapy, lung recruitment, prone position ventilation, sedative and muscle relaxation, the patient's oxygen saturation continued to decline. Electrical impedance tomography (EIT) monitoring revealed that prone position could not improve ventilation homogeneity. However, the patient's ventilation/perfusion (V/Q) matching significantly improved 10 min after initiation of supine position ventilation combined with inhalation of nitric oxide (iNO). The patient's PaO2/FiO2 (P/F) ratio increased from 86 mmHg to 150 mmHg at 30 min post-treatment. iNO treatment continued for 2 days. Then the patient's condition improved and she was successfully weaned off the ventilator with rigorous monitoring and symptomatic care. The implementation of mechanical ventilation combined with iNO therapy rapidly improved V/Q matching and oxygenation in a patient with hypoxemia caused by dermatomyositis complicated with interstitial pneumonia. This approach successfully avoided the need for invasive extracorporeal membrane oxygenation (ECMO) support.

The influence of gender on the epidemiology of and outcome from sepsis associated acute kidney injury in ICU: a retrospective propensity-matched cohort study.

PURPOSES: The influence of gender on the epidemiology of and outcome from SA-AKI in ICU has not been fully clarified. Our aim is to elucidate these differences. METHODS: This study included adult patients with sepsis in MIMIC IV (V 2.2), and propensity matching analysis, cox regression and logistic regression were used to analyze gender differences in incidence, mortality and organ support rate. RESULTS: Of the 24,467 patients included in the cohort, 18,128 were retained after propensity score matching. In the matched cohort, the incidence of SA-AKI in males is higher than that in females (58.6% vs. 56.2%; P = 0.001).males were associated with a higher risk of SA-AKI (OR:1.07(1.01-1.14), P = 0.026;adjusted OR:1.07(1.01-1.14), P < 0.033).In SA-AKI patients, males were associated with a lower risk of ICU mortality(HR:0.803(0.721-0.893), P < 0.001;adjusted HR:0.836(0.746-0.937), P = 0.002) and in-hospital mortality(HR: 0.820(0.748-0.899), P < 0.001;adjusted HR:0.853(0.775-0.938), P = 0.003).there were no statistically significant differences between male and female patients in 1-year all-cause mortality (36.9% vs. 35.8%, P = 0.12), kidney replacement therapy rate (7.8% vs.7.4%, P = 0.547), mechanical ventilation rate 64.8% vs.63.9%, P = 0.369), and usage of vasoactive drugs (55.4% vs. 54.6%, P = 0.418). CONCLUSIONS: Gender may affect the incidence and outcomes of SA-AKI, further research is needed to fully understand the impact of gender on SA-AKI patients.

Low HDL-C can be a biomarker to predict persistent severe AKI in septic patients? A retrospective cohort study.

PURPOSES: Low HDL-C is associated with an increased risk of sepsis-associated AKI and subsequent decline in eGFR. HDL-C possesses anti-inflammatory, antioxidant, and endothelial repair-promoting properties. The use of Apo A-I mimetic peptides, which are the main structural components of HDL-C, has been shown to improve renal function in animal models of sepsis. However, the diagnostic value of low HDL-C in persistent sepsis-associated AKI remains unclear. METHODS: This is a retrospective cohort study based on MIMIC IV (V 2.2). The study population consisted of all adult septic patients admitted to the Beth Israel Deaconess Medical Center Intensive Care Unit from 2008 to 2019, with plasma HDL-C measured within 24 h of ICU admission. The primary endpoint was persistent severe sepsis-associated acute kidney injury (SA-AKI) and the secondary endpoint is kidney replacement therapy (KRT). Logistic regression was used to assess the correlation between HDL-C and persistent severe SA-AKI and KRT, and receiver operating characteristic (ROC) curve analysis was performed to evaluate predictive ability. RESULTS: A total of 604 cases of SA-AKI patients were included in the analysis, among which 88 cases (14.5%) experienced persistent severe SA-AKI. The median (IQR) HDL-C level in the group with persistent severe SA-AKI was lower (33.0 [24.0-45.5]) compared to the non-persistent severe SA-AKI group (42.0 [31.0-53.0]). However, HDL-C showed poor discriminatory ability with an AUROC [95%CI] of 0.62 [0.56-0.69]. Clinical prediction models based on serum creatinine concentration, 24-h creatinine change, APSIIIscore, lactate levels, APTT, and heart rate performed well in predicting persistent severe SA-AKI with an AUROC [95%CI] of 0.876 [0.84-0.91]. However, adding HDL-C to this model did not improve predictive performance. CONCLUSIONS: The plasma HDL-C measured within 24 h after admission to the ICU does not provide a good prediction for persistent severe SA-AKI, and it does not improve the clinical predictive ability compared to conventional variables.

[A nonlinear relationship between the hemoglobin level and prognosis of elderly patients with sepsis: an analysis based on MIMIC-IV].

OBJECTIVE: To investigate the correlation of hemoglobin (Hb) level with prognosis of elderly patients diagnosed as sepsis. METHODS: A retrospective cohort study was conducted. Information on the cases of elderly patients with sepsis in the Medical Information Mart for Intensive Care-IV (MIMIC-IV), including basic information, blood pressure, routine blood test results [the Hb level of a patient was defined as his/her maximum Hb level from 6 hours before admission to intensive care unit (ICU) and 24 hours after admission to ICU], blood biochemical indexes, coagulation function, vital signs, severity score and outcome indicators were extracted. The curves of Hb level vs. 28-day mortality risk were developed by using the restricted cubic spline model based on the Cox regression analysis. The patients were divided into four groups (Hb < 100 g/L, 100 g/L ≤ Hb < 130 g/L, 130 g/L ≤ Hb < 150 g/L, Hb ≥ 150 g/L groups) based on these curves. The outcome indicators of patients in each group were analyzed, and the 28-day Kaplan-Meier survival curve was drawn. Logistic regression model and Cox regression model were used to analyze the relationship between Hb level and 28-day mortality risk in different groups. RESULTS: A total of 7 473 elderly patients with sepsis were included. There was a "U" curve relationship between Hb levels within 24 hours after ICU admission and the risk of 28-day mortality in patients with sepsis. The patients with 100 g/L ≤ Hb < 130 g/L had a lower risk of 28-day mortality. When Hb level was less than 100 g/L, the risk of death decreased gradually with the increase of Hb level. When Hb level was ≥ 130 g/L, the risk of death gradually increased with the increase of Hb level. Multivariate Logistic regression analysis revealed that the mortality risks of patients with Hb < 100 g/L [odds ratio (OR) = 1.44, 95% confidence interval (95%CI) was 1.23-1.70, P < 0.001] and Hb ≥ 150 g/L (OR = 1.77, 95%CI was 1.26-2.49, P = 0.001) increased significantly in the model involving all confounding factors; the mortality risks of patients with 130 g/L ≤ Hb < 150 g/L increased, while the difference was not statistically significant (OR = 1.21, 95%CI was 0.99-1.48, P = 0.057). The multivariate Cox regression analysis suggested that the mortality risks of patients with Hb < 100 g/L [hazard ratio (HR) = 1.27, 95%CI was 1.12-1.44, P < 0.001] and Hb ≥ 150 g/L (HR = 1.49, 95%CI was 1.16-1.93, P = 0.002) increased significantly in the model involving all confounding factors; the mortality risks of patients with 130 g/L ≤ Hb < 150 g/L increased, while the difference was not statistically significant (HR = 1.17, 95%CI was 0.99-1.37, P = 0.053). Kaplan-Meier survival curve showed that the 28-day survival rate of elderly septic patients in 100 g/L ≤ Hb < 130 g/L group was significantly higher than that in Hb < 100 g/L, 130 g/L ≤ Hb < 150 g/L and Hb ≥ 150 g/L groups (85.26% vs. 77.33%, 79.81%, 74.33%; Log-Rank test: χ2 = 71.850, P < 0.001). CONCLUSIONS: Elderly patients with sepsis exhibited low mortality risk if their 100 g/L ≤ Hb < 130 g/L within 24 hours after admission to ICU, and both higher and lower Hb levels led to increased mortality risks.

Effect of the Timing of Amubarvimab/Romlusevimab (BRII-196/198) Administration on Progression to Severe Disease in Elderly Patients with COVID-19 Infection: A Retrospective Cohort Study.

Objective: Early intervention with neutralizing antibodies is considered to be effective in preventing disease progression in patients with mild to moderate COVID-19 infection. Elderly patients are the most susceptible and at a higher risk of COVID-19 infection. The present study aimed to assess the necessity and possible clinical benefits of the early administration of Amubarvimab/Romlusevimab (BRII-196/198) in the elderly population. Methods: The present study was designed as a retrospective, multi-center cohort study conducted with 90 COVID-19 patients aged over 60, who were divided into two groups based on the timing of the administration of BRII-196/198 (administration at ≤ 3 days or > 3 days from the onset of infection symptoms). Results: The ≤ 3 days group exhibited a greater positive effect (HR 5.94, 95% CI, 1.42-24.83; P < 0.01), with only 2 patients among 21 patients (9.52%) exhibiting disease progression, compared to the 31 patients among the 69 patients (44.93%) of the > 3 days group who exhibited disease progression. The multivariate Cox regression analysis revealed low flow oxygen support prior to BRII-196/198 administration (HR 3.53, 95% CI 1.42-8.77, P < 0.01) and PLT class (HR 3.68, 95% CI 1.37-9.91, P < 0.01) as independent predictors of disease progression. Conclusions: In elderly patients with mild or moderate COVID-19 disease, who do not require oxygen support and had the risk factors for disease progression to severe COVID-19 disease, the administration of BRII-196/198 within 3 days resulted in a beneficial trend in terms of preventing disease progression.

Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

Development and validation of a nomogram for predicting in-hospital mortality of elderly patients with persistent sepsis-associated acute kidney injury in intensive care units: a retrospective cohort study using the MIMIC-IV database.

OBJECTIVES: To identify the clinical risk factors that influence in-hospital mortality in elderly patients with persistent sepsis-associated acute kidney injury (S-AKI) and to establish and validate a nomogram to predict in-hospital mortality. DESIGN: Retrospective cohort analysis. SETTING: Data from critically ill patients at a US centre between 2008 and 2021 were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database (V.1.0). PARTICIPANTS: Data from 1519 patients with persistent S-AKI were extracted from the MIMIC-IV database. PRIMARY OUTCOME: All-cause in-hospital death from persistent S-AKI. RESULTS: Multiple logistic regression revealed that gender (OR 0.63, 95% CI 0.45-0.88), cancer (2.5, 1.69-3.71), respiratory rate (1.06, 1.01-1.12), AKI stage (2.01, 1.24-3.24), blood urea nitrogen (1.01, 1.01-1.02), Glasgow Coma Scale score (0.75, 0.70-0.81), mechanical ventilation (1.57, 1.01-2.46) and continuous renal replacement therapy within 48 hours (9.97, 3.39-33.9) were independent risk factors for mortality from persistent S-AKI. The consistency indices of the prediction and the validation cohorts were 0.780 (95% CI: 0.75-0.82) and 0.80 (95% CI: 0.75-0.85), respectively. The model's calibration plot suggested excellent consistency between the predicted and actual probabilities. CONCLUSIONS: This study's prediction model demonstrated good discrimination and calibration abilities to predict in-hospital mortality of elderly patients with persistent S-AKI, although it warrants further external validation to verify its accuracy and applicability.

Predictability performance of urinary C-C motif chemokine ligand 14 and renal resistive index for persistent sepsis-associated acute kidney injury in ICU patients.

OBJECTIVES: The performance of renal resistance index (RRI) in predicting persistent sepsis-associated acute kidney injury (S-AKI) remains debatable, and the value of urinary C-C motif chemokine ligand 14 (CCL14) in predicting persistent S-AKI has not been validated yet. Therefore, we aimed to determine the applicability of a urinary biomarker CCL14 for the early detection of persistent S-AKI. Furthermore, the use of RRI obtained from renal Doppler ultrasonography was applied to differentiate transient from persistent S-AKI. Finally, we aimed to evaluate the use of these techniques in predicting different subtypes of S-AKI. METHODS: This prospective observational study was conducted at the internal medicine intensive care unit (ICU) of a university hospital. The RRI was determined within 12 h of ICU admission and the urinary CCL14 was evaluated at T0, T6, T12, and T24. The reversibility of renal dysfunction was assessed within 48 h. The receiver operating characteristic curves were then plotted to assess the diagnostic efficacy of the RRI and urinary CCL14 in predicting persistent S-AKI. RESULTS: Out of 48 patients, 23 developed persistent S-AKI upon admission. The RRI was higher in the persistent S-AKI group (P = 0.02) and the RRI ≥ 0.679 could predict persistent S-AKI with an area under the receiver operating characteristic curve of 0.79 (95% CI 0.65-0.93), a sensitivity of 91.30% (95% CI 70-98%), and a specificity of 65.20% (95% CI 43-83%). Urinary CCL14 was not significantly different between the two groups at the tested period, showing poor diagnostic performance at T0, T6, T12, and T24, with areas under the receiver operating characteristic curves of 0.56 (95% CI 0.38-0.73), 0.62 (95% CI 0.46-0.79), 0.52 (95% CI 0.35-0.68), and 0.60 (95% CI 0.43-0.77), respectively. CONCLUSIONS: The RRI obtained from renal Doppler ultrasound is extremely effective in predicting persistent S-AKI in critically ill patients, and urinary CCL14 could not distinguish between transient and persistent S-AKIs.

Immunomodulatory effect of IL-2 induced bone marrow mononuclear cell therapy on control of allergic asthma.

Asthma is a chronic airway disease. Allergic reactions and T helper (h)2 immune response play a key role in asthma occurrence. Cell therapy can control inflammation and remodeling responses in allergic asthma, and cytokines can change this effect. Therefore, in this study, the effect of treated cell therapy with IL-2 to control allergic asthma was studied. Bone marrow cells were extracted and co-cultured with IL-2 and the cells were used via intra-tracheal administration in allergic asthma mice. Levels of IL-4, IL-5, IL-13, Leukotriene B4 and C4, and remodeling factors were measured. At least, a histopathology test of lung tissue was done. Type2 cytokines, leukotrienes, remodeling factors, mucus secretion, goblet cell hyperplasia, peri-bronchial and peri-vascular inflammation were significantly (p˂0.05) decreased by treating with bone marrow-derived mononuclear cells (BMDMCs) and IL-2-BMDMCs. Treatment with IL-2-BMDMCs could significantly decrease IL-13, transforming growth factor (TGF)-ß, HP levels, and mucus secretion (p˂0.05) compared to BMDMCs treatment. In this study, BMDMCs and IL-2-BMDMCs therapy could decrease inflammation, allergic, and remodeling factors in allergic asthma. Cell therapy with BMDMCs had a strong and notable effect on the control of allergic asthma pathophysiology when co-cultured and used with IL-2.

Ranging pattern development of a declining delphinid population: A potential cascade effect of vessel activities.

It is generally accepted that vessel activity causes various behavioral responses of cetaceans and undermines individual fitness. Whether or how it can lead to a demographic response of populations remains rarely examined. In the northern Beibu Gulf, China, vessel activities have sharply increased in the past two decades, while abnormal demographic dynamics was recently noted for the resident Indo-Pacific humpback dolphins. The present study first examined the humpback dolphins' utilization distribution (UD) from 2003 to 2019. Habitat suitability was then modeled with the sighting data collected before the most recent population reduction. Finally, we tried to disentangle the anthropogenic driver of dolphin demography by cross-referring the spatiotemporal development of dolphins' UD, vessel activities, and habitat suitability. Our results showed that the dolphins' UD shrank substantially during the port expansion in the early 2010s, and we suggest that the consequential increase in vessel activities might impose extra marine stressors on the resident humpback dolphins. To reduce the boat interaction, the dolphins steadily shifted their core area to a less suitable area in the east during 2015-2017, when unnaturally low survivals were recorded. Afterward, the dolphin core area partially shifted back to the more suitable area in the west, which corresponded to the improving dolphin survival in 2018. Our finding suggested that the vessel activity may be responsible for the dolphin displacement, while staying in the less suitable area may further lead to a more severe and acute demographic consequence on the population. The underlying and indirect impact of vessel activities as disclosed by the present study is particularly important for port management, marine planning, and conservation practice regarding coastal cetaceans, especially for those resident and endangered populations inhabiting the urbanized coastal areas.

Patient-Level Meta-Analysis of Low-Dose Hydrocortisone in Adults with Septic Shock.

BACKGROUND: Trials and study-level meta-analyses have failed to resolve the role of corticosteroids in the management of patients with septic shock. Patient-level meta-analyses may provide more precise estimates of treatment effects, particularly subgroup effects. METHODS: We pooled individual patient data from septic shock trials investigating the adjunctive use of intravenous hydrocortisone. The primary outcome was 90-day all-cause mortality, and it was also analyzed across predefined subgroups. Secondary outcomes included mortality at intensive care unit and hospital discharge, at 28 and 180 days, and vasopressor-, ventilator-, and organ failure­free days. Adverse events included superinfection, muscle weakness, hyperglycemia, hypernatremia, and gastroduodenal bleeding. RESULTS: Of 24 eligible trials (n=8528), 17 (n=7882) provided individual patient data, and 7 (n=5929) provided 90-day mortality. The marginal relative risk (RR) for 90-day mortality of hydrocortisone versus placebo was 0.93 (95% confidence interval [CI], 0.82 to 1.04; P=0.22; moderate certainty). It was 0.86 (95% CI, 0.79 to 0.92) for hydrocortisone with fludrocortisone and 0.96 (95% CI, 0.82 to 1.12) without fludrocortisone. There was no significant differential treatment effect across subgroups. Hydrocortisone was associated with little to no difference in any of the secondary outcomes except vasopressor-free days (mean difference, 1.24 days; 95% CI, 0.74 to 1.73; high certainty). Hydrocortisone may not be associated with an increase in the risk of superinfection (RR, 1.04; 95% CI, 0.95 to 1.15; low certainty), hyperglycemia (RR, 1.05; 95% CI, 0.98 to 1.12; low certainty), or gastroduodenal bleeding (RR, 1.11; 95% CI, 0.83 to 1.48; low certainty). Hydrocortisone may be associated with an increase in the risk of hypernatremia (RR, 2.01; 95% CI, 1.56 to 2.60; low certainty) and muscle weakness (n=2647; RR, 1.73; 95% CI, 1.49 to 1.99; low certainty). CONCLUSIONS: In this patient-level meta-analysis, hydrocortisone compared with placebo was not associated with reduced mortality for patients with septic shock. (Funded by "Programme d'Investissements d'Avenir," a research Professorship from the National Institute of Health and Care Research, Leadership Fellowships from the National Health and Medical Research Council of Australia, and Emerging Leaders Fellowship from the National Health and Medical Research Council of Australia; PROSPERO registration number, CRD42017062198.)

[Effects of vaccination status on the disease severity of patients with coronavirus disease 2019].

OBJECTIVE: To evaluate the effect of 2019 novel coronavirus inactivated vaccine on the disease severity of patients with Delta variant of coronavirus disease 2019. METHODS: A retrospective analysis was performed on 704 patients with coronavirus disease 2019 infected with Delta variant who were older than 18 years old and admitted in the coronavirus disease 2019 designated hospital of Yangzhou (Subei Hospital New Area Branch) from July 2021 to September 2021. They were divided into severe (severe, critical) group and non-severe (light, ordinary) group according to the clinical characteristics of patients. According to the vaccination status, they were divided into 0-dose group, 1-dose group and 2-dose group. We evaluated the effects of vaccination on the severity of the disease and the production of antibodies, and analyzed the influencing factors leading to the severe group of coronavirus disease 2019. RESULTS: The proportion of severe group in the 2-dose vaccinated group was significantly lower than that in the 1-dose vaccinated group and 0-dose vaccinated group [3.02% (7/232) vs. 9.48% (22/232), 15.83% (38/240), P < 0.05]. The time from onset to admission (day: 1.97±1.66 vs. 2.66±2.70), age (years: 45.3±12.2 vs. 63.6±17.0), direct bilirubin [DBil (µmol/L): 3.70±1.83 vs. 5.30±5.13], lactate dehydrogenase [LDH (U/L): 240.69±74.29 vs. 256.30±85.18], creatinine [SCr (µmol/L): 63.38±19.86 vs. 70.23±25.43], interleukin-6 [IL-6 (ng/L): 7.32 (1.54, 17.40) vs. 18.38 (8.83, 33.43)], creatine kinase [CK (U/L): 66.00 (43.00, 99.75) vs. 78.00 (54.50, 144.00)] and D-dimer [mg/L: 0.30 (0.08, 0.49) vs. 0.41 (0.23, 0.69)] of patients in the 2-dose group were significantly lower than those in the 0-dose group (all P < 0.05), while platelet [PLT (×109/L): 176.69±60.25 vs. 149.25±59.07], white blood cell count [WBC (×109/L): 5.43±1.77 vs. 5.03±1.88] and lymphocyte [LYM (×109/L): 1.34±0.88 vs. 1.17±0.50] were significantly higher than those in the 0-dose group (all P < 0.05). The titer of immunoglobulin G (IgG) in the 2-dose group was significantly higher than those in the 1-dose group and 0-dose group on the 10th day after admission [U/L: 130.94 (92.23, 326.31), 113.18 (17.62, 136.20), 117.85 (33.52, 156.73), both P < 0.05], and higher than 0-dose group on the 16th day [U/L: 156.12 (120.32, 167.76) vs. 126.52 (61.34, 149.57), P < 0.05]. The proportion of complete 2-dose vaccination [10.45% (7/67) vs. 35.32% (225/637)], LYM (×109/L: 1.09±0.32 vs. 1.25±0.56) and PLT (×109/L: 138.55±68.03 vs. 166.93±59.70) in the severe group were significantly lower than those in the non-severe group (P < 0.05), while the time from onset to admission (day: 3.01±2.99 vs. 2.25±2.09), the length of hospital stay (day: 28±18 vs. 16±6), male proportion [77.61% (52/67) vs. 34.54% (220/637)], age (years: 69.13±12.63 vs. 52.28±16.53), DBil [µmol/L: 4.20 (3.18, 6.65) vs. 3.60 (2.80, 4.90], LDH (U/L: 310.61±98.33 vs. 238.19±72.14), SCr (µmol/L: 85.67±38.25 vs. 65.98±18.57), C-reactive protein [CRP (µmol/L): 28.12 (11.32, 42.23) vs. 8.49 (2.61, 17.58)], IL-6 [ng/L: 38.38 (24.67, 81.50) vs. 11.40 (4.60, 22.07)], CK [U/L: 140.00 (66.00, 274.00) vs. 72.80 (53.00, 11.00)] and the D-dimer [mg/L: 0.46 (0.29, 0.67) vs. 0.35 (0.19, 0.57)] in the severe group were significantly higher than those in the non-severe group (all P < 0.05). Multivariate regression analysis showed that the odds ratio (OR) of severe group was 0.430 (P = 0.010) in the 1-dose group and the 2-dose group compared with the 0-dose group. However, the risk of severe group was 0.381-fold in the 2-dose group compared with the 0-dose group [OR = 0.381, 95% confidence interval (95%CI) was 0.121-1.199] which was not statistically significant, when the age was included in the regression analysis (P > 0.05). PLT (OR = 0.992, 95%CI was 0.986-0.998) were protective factors, but older than 60 years old (OR = 3.681, 95%CI was 1.637-8.278), CK (OR = 1.001, 95%CI was 1.000-1.001), IL-6 (OR = 1.006, 95%CI was 1.002-1.010), SCr (OR = 1.020, 95%CI was 1.007-1.033) were risk factors for severe group (all P < 0.05). CONCLUSIONS: Compared with the 0-dose vaccinated patients, the coronavirus disease 2019 patients infected with delta variant and fully vaccinated with 2-dose 2019 novel coronavirus inactivated vaccine had lower level of IL-6, SCr, CK and D-dimer, and higher PLT, LYM and IgG titer, who were not easy to develop into the severe condition.

[Research progress of ferroptosis in sepsis].

Sepsis is a systemic disease with severe health consequences, and it was redefined in 2016 as a life-threatening organ dysfunction caused by an abnormal host response to infection and is a global public health priority. In recent years, there has been increasing recognition of the role of dysregulated micronutrient iron metabolism in the pathogenesis of sepsis. The concept of ferroptosis, an iron-dependent, non-apoptotic mode of cell death characterized by the accumulation of lipid reactive oxygen species (ROS), was first proposed by Dixon et al. in 2012. As a novel mode of programmed cell death, ferroptosis differs in morphological and biochemical characteristics from various forms of cell death, such as apoptosis, autophagy, necrosis and lysis. Recent studies have shown that ferroptosis plays an important regulatory role in the development of sepsis and has become a research focus and highlight for the diagnosis and prognosis of related diseases. Therefore, this paper reviews the latest developments in ferroptosis in sepsis, in order to further understanding its pathogenesis and providing new therapeutic targets for sepsis-related organ dysfunction.