Prediction models for postoperative delirium in elderly patients with machine-learning algorithms and SHapley Additive exPlanations.

Postoperative delirium (POD) is a common and severe complication in elderly patients with hip fractures. Identifying high-risk patients with POD can help improve the outcome of patients with hip fractures. We conducted a retrospective study on elderly patients (≥65 years of age) who underwent orthopedic surgery with hip fracture between January 2014 and August 2019. Conventional logistic regression and five machine-learning algorithms were used to construct prediction models of POD. A nomogram for POD prediction was built with the logistic regression method. The area under the receiver operating characteristic curve (AUC-ROC), accuracy, sensitivity, and precision were calculated to evaluate different models. Feature importance of individuals was interpreted using Shapley Additive Explanations (SHAP). About 797 patients were enrolled in the study, with the incidence of POD at 9.28% (74/797). The age, renal insufficiency, chronic obstructive pulmonary disease (COPD), use of antipsychotics, lactate dehydrogenase (LDH), and C-reactive protein are used to build a nomogram for POD with an AUC of 0.71. The AUCs of five machine-learning models are 0.81 (Random Forest), 0.80 (GBM), 0.68 (AdaBoost), 0.77 (XGBoost), and 0.70 (SVM). The sensitivities of the six models range from 68.8% (logistic regression and SVM) to 91.9% (Random Forest). The precisions of the six machine-learning models range from 18.3% (logistic regression) to 67.8% (SVM). Six prediction models of POD in patients with hip fractures were constructed using logistic regression and five machine-learning algorithms. The application of machine-learning algorithms could provide convenient POD risk stratification to benefit elderly hip fracture patients.

Insulin alleviates lipopolysaccharide-induced cognitive impairment via inhibiting neuroinflammation and ferroptosis.

Neuroinflammation is regarded to be a key mediator in cerebral diseases with attendant cognitive decline. Ferroptosis, characterized by iron-dependent lipid peroxidation, participates in neuroinflammation and cognitive impairment. Recent studies have revealed insulin's neuroprotective effects and involvement in the regulation of numerous central functions. But the effect of insulin on cognitive impairment induced by neuroinflammation has been rarely explored. In this study, we constructed a cognitive impairment model by intracerebroventricular injection of lipopolysaccharide (LPS) and a single dosage of insulin was mixed in the LPS solution to explore the potential mechanisms through which insulin treatment could improve LPS-induced cognitive dysfunction. At 24 h after treatment, we found that insulin treatment significantly improved LPS-induced cognitive decline, neuronal injuries, and blood-brain barrier (BBB) disruption. Insulin treatment could also inhibit the LPS-induced activation of microglia and astrocytes, and the release of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the hippocampus. Furthermore, insulin treatment inhibited LPS-induced ferroptosis in the hippocampus by decreasing iron accumulation levels, regulating ferroptosis-related proteins including transferrin, glutathione peroxidase 4 (GPX4), ferritin heavy chin 1 (FTH1) and cystine/glutamate antiporter (xCT), inhibiting oxidative stress injuries and lipid peroxidation in the hippocampus. In conclusion, our finding that insulin treatment could alleviate LPS-induced cognitive impairment by inhibiting neuroinflammation and ferroptosis provides a new potential therapeutic method to ameliorate cognitive decline.

Corrigendum: Systemic-immune-inflammation index as a promising biomarker for predicting perioperative ischemic stroke in older patients who underwent non-cardiac surgery.

[This corrects the article DOI: 10.3389/fnagi.2022.865244.].

Preoperative hyperglycemia is associated with elevated risk of perioperative ischemic stroke in type 2 diabetic patients undergoing non-cardiovascular surgery: A retrospective cohort study.

Background: Diabetes mellitus (DM) has been reported to be associated with perioperative stroke, but the effects of preoperative hyperglycemia on the risk of perioperative stroke in diabetic patients undergoing non-cardiovascular surgery remain unclear. This study investigated the association between preoperative hyperglycemia and the risk of perioperative ischemic stroke in type 2 diabetic patients undergoing non-cardiovascular surgery. Methods: This retrospective cohort study screened 27,002 patients with type 2 DM undergoing non-cardiovascular surgery with general anesthesia between January 2008 and August 2019 at The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital. The exposure of interest was preoperative hyperglycemia, defined as a fasting plasma glucose (FPG) ≥ 7 mmol/L. The outcome of interest was a new diagnosis of perioperative ischemic stroke within 30 days after surgery. Residual confounding was minimized by controlling for observable patient and intraoperative factors. Logistic regression was conducted in the total and propensity score matched cohorts. In addition, we stratified patients into six subgroups to investigate whether the association between preoperative hyperglycemia and perioperative ischemic stroke differs in these subgroups. Results: The overall incidence of perioperative ischemic stroke was 0.53% (n = 144) in the current cohort. The odds of perioperative ischemic stroke were significantly increased for patients with preoperative hyperglycemia after adjusting for patient- related variables (OR: 1.95; 95% CI: 1.39-2.75; p < 0.001), surgery-related variables (OR: 2.1; 95% CI: 1.51-2.94; p < 0.001), and all confounding variables (OR: 1.78; 95% CI: 1.26-2.53; p < 0.001). The risk of perioperative stroke was significantly increased in patients with preoperative hyperglycemia (OR: 2.51; 95% CI: 1.66-3.9; p < 0.001) in the propensity score matched cohort. Preoperative hyperglycemia was associated with the outcome for all the subgroups except for patients undergoing neurosurgery. Conclusion: Preoperative hyperglycemia is associated with an elevated risk of perioperative stroke in patients with type 2 DM undergoing non-cardiovascular surgery. The effect could be eliminated for patients undergoing neurosurgery, during which specific risk factors should be considered.

Systemic-Immune-Inflammation Index as a Promising Biomarker for Predicting Perioperative Ischemic Stroke in Older Patients Who Underwent Non-cardiac Surgery.

Objective: This study aimed to investigate the clinical prognostic values of the preoperative systemic-immune-inflammation index (SII) in older patients undergoing non-cardiac surgery, using perioperative ischemic stroke as the primary outcome. Methods: This retrospective cohort study included older patients who underwent non-cardiac surgery between January 2008 and August 2019. The patients were divided into SII < 583 and SII ≥ 583 group according to the optimal SII cut-off value. The outcome of interest was ischemic stroke within 30 days after surgery. Primary, sensitivity, and subgroup analyses were performed to confirm that preoperative SII qualifies as a promising, independent prognostic indicator. Propensity score matching (PSM) analysis was further applied to address the potential residual confounding effect of covariates to examine the robustness of our results. Results: Among the 40,670 included patients with a median age of 70 years (interquartile range: 67, 74), 237 (0.58%) experienced an ischemic stroke within 30 days after surgery. SII ≥ 583 was associated with an increased risk of perioperative ischemic stroke in multivariate regression analysis [odds ratio (OR), 1.843; 95% confidence interval (CI), 1.369-2.480; P < 0.001]. After PSM adjustment, all covariates were well balanced between the two groups. The correlation between the SII and perioperative ischemic stroke remained significantly robust (OR: 2.195; 95% CI: 1.574-3.106; P < 0.001) in the PSM analysis. Conclusion: Preoperative SII, which includes neutrophil, platelet, and lymphocyte counts obtained from routine blood analysis, was a potential prognostic biomarker for predicting perioperative ischemic stroke after non-cardiac surgery in elderly older patients. An elevated SII, based on an optimal cut-off value of 583, was an independent risk factor for perioperative ischemic stroke.

MEF2D Participates in Microglia-Mediated Neuroprotection in Cerebral Ischemia-Reperfusion Rats.

OBJECTIVE: Microglial activation is a vital process in the neuroinflammatory response induced by I/R injury. It has been reported that myocyte enhancer factor (MEF)2D expression in activated microglia is associated with microglia-induced inflammatory responses and plays an important role in neuronal survival. This research aimed to investigate the role and mechanism of MEF2D in microglial activation and neuroinflammation in cerebral I/R in vitro and in vivo. METHODS: A cerebral I/R model was established. In vitro, neuronal, or microglial cells were exposed to oxygen-glucose deprivation and reoxygenation to mimic I/R. MEF2D overexpression was induced, and siRNA was administered in vitro and in vivo. Microglial polarization; MEF2D, nuclear transcription factor (NF)-κb, TLR4, and cytokine levels; neuronal injury; mitochondrial function; brain injury and cognitive function were detected in the different groups in vitro and in vivo. RESULTS: We found that oxygen-glucose deprivation increased MEF2D expression in a time-dependent manner in BV2 cells and primary microglia. MEF2D overexpression inhibited microglial activation, the expression of NF-κb and TLR, cytokine levels, and neuronal injury in microglia exposed to oxygen-glucose deprivation and reoxygenation. In the middle cerebral artery occlusion model, microglial activation, the neuroinflammatory response, mitochondrial dysfunction, brain injury, and cognitive function were improved by MEF2D overexpression and aggravated by MEF2D siRNA treatment. CONCLUSION: These results indicate that MEF2D is a necessary molecule for neuroinflammation regulation and neuronal injury in cerebral ischemia.

miR-217-regulated MEF2D-HDAC5/ND6 signaling pathway participates in the oxidative stress and inflammatory response after cerebral ischemia.

Multiple factors are known to contribute to the pathogenesis of cerebral ischemic injury, including microRNAs (miRNAs). However, the precise mechanism of miRNAs involvement in cerebral ischemia remains largely unclear. In the current study, we found that miR-217 was significantly upregulated in ischemic stroke models, and the upregulation of miR-217 was associated with the development of post-stroke cognitive impairment. Further investigation revealed that myocyte enhancer factor 2D (MEF2D) was the direct target of miR-217. In vitro experiments showed that miR-217 promoted aggregation of histone deacetylase 5 (HDAC5) in cell nuclei by targeting MEF2D, which led to decreased expression of interleukin (IL)-10. In addition, miR-217 inhibited the expression of NADH dehydrogenase subunit 6 (ND6) in a MEF2D-dependent manner. Overexpression of MEF2D can reverse oxygen-glucose deprivation (OGD)-induced downregulation of ND6 and OGD-mediated neuronal apoptosis, and also reduce the elevated generation of reactive oxygen species (ROS) induced by OGD. Additionally, we found that in vivo administration of MEF2D overexpression plasmids increased IL-10 production and ameliorated cognitive impairment after cerebral ischemia. Taken together, these findings reveal a novel pathogenetic mechganism of cerebral ischemia-related brain injury involving the miR-217/MEF2D/HDAC5 axis and the miR-217/MEF2D/ND6 axis.

Kelch-like ECH-associated Protein 1-dependent Nuclear Factor-E2-related Factor 2 Activation in Relation to Antioxidation Induced by Sevoflurane Preconditioning.

BACKGROUND: The authors have reported that antioxidative effects play a crucial role in the volatile anesthetic-induced neuroprotection. Accumulated evidence shows that endogenous antioxidation could be up-regulated by nuclear factor-E2-related factor 2 through multiple pathways. However, whether nuclear factor-E2-related factor 2 activation is modulated by sevoflurane preconditioning and, if so, what is the signaling cascade underlying upstream of this activation are still unknown. METHODS: Sevoflurane preconditioning in mice was performed with sevoflurane (2.5%) 1 h per day for five consecutive days. Focal cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. Expression of nuclear factor-E2-related factor 2, kelch-like ECH-associated protein 1, manganese superoxide dismutase, thioredoxin-1, and nicotinamide adenine dinucleotide phosphate quinolone oxidoreductase-1 was detected (n = 6). The antioxidant activities and oxidative product expression were also examined. To determine the role of kelch-like ECH-associated protein 1 inhibition-dependent nuclear factor-E2-related factor 2 activation in sevoflurane preconditioning-induced neuroprotection, the kelch-like ECH-associated protein 1-nuclear factor-E2-related factor 2 signal was modulated by nuclear factor-E2-related factor 2 knockout, kelch-like ECH-associated protein 1 overexpression lentivirus, and kelch-like ECH-associated protein 1 deficiency small interfering RNA (n = 8). The infarct volume, neurologic scores, and cellular apoptosis were assessed. RESULTS: Sevoflurane preconditioning elicited neuroprotection and increased nuclear factor-E2-related factor 2 nuclear translocation, which in turn up-regulated endogenous antioxidation and reduced oxidative injury. Sevoflurane preconditioning reduced kelch-like ECH-associated protein 1 expression. Nuclear factor-E2-related factor 2 ablation abolished neuroprotection and reversed sevoflurane preconditioning by mediating the up-regulation of antioxidants. Kelch-like ECH-associated protein 1 overexpression reversed nuclear factor-E2-related factor 2 up-regulation and abolished the neuroprotection induced by sevoflurane preconditioning. Kelch-like ECH-associated protein 1 small interfering RNA administration improved nuclear factor-E2-related factor 2 expression and the outcome of mice subjected to ischemia/reperfusion injury. CONCLUSIONS: Kelch-like ECH-associated protein 1 down-regulation-dependent nuclear factor-E2-related factor 2 activation underlies the ability of sevoflurane preconditioning to activate the endogenous antioxidant response, which elicits its neuroprotection.

Neuroprotective gases--fantasy or reality for clinical use?

The neuroprotective properties for certain medical gases have been observed for decades, leading to extensive research that has been widely reported and continues to garner interest. Common gases including oxygen, hydrogen, carbon dioxide and nitric oxide, volatile anesthetics such as isoflurane, sevoflurane, halothane, enflurane and desflurane, non-volatile anesthetics such as xenon and nitrous oxide, inert gases such as helium and argon, and even gases classically considered to be toxic (e.g., hydrogen sulfide and carbon monoxide) have all been supported by the evidence alluding to their use as potential neuroprotective agents. A wide range of neural injury types such as ischemic/hemorrhagic, stroke, subarachnoid hemorrhage, traumatic brain injury, perinatal hypoxic-ischemic brain injuries, neurodegenerative disease as well as spinal cord ischemia have been used as platforms for studying the neuroprotective effects of these gases, yet until now, none of the gases has been widely introduced into clinical use specifically for protection against neural injury. Insufficient clinical data together with contradictory paradigms and results further hinders the clinical trials. However, pre-clinical models suggest that despite the various classes of gases and the broad range of injuries to which medical gases confer, protection, several underlying mechanisms for their neuroprotective properties are similar. In this review, we summarize the literature concerning the neuroprotective effect of each gas and its underlying mechanisms, extract common targets reported for the neuroprotective effects of different gases, highlight the conflicting observations from clinical trials and further discuss the possible hindrances impeding clinical applications in order to propose future research perspectives and therapeutic exploitations.