Metformin monotherapy versus predominantly older non-metformin antidiabetic medications for cerebrovascular risk in early type 2 diabetes management.

AIM: Choosing the initial treatment for type 2 diabetes (T2D) is pivotal, requiring consideration of solid clinical evidence and patient characteristics. Despite metformin's historical preference, its efficacy in preventing cerebrovascular events lacked empirical validation. This study aimed to evaluate the associations between first-line monotherapy (metformin or non-metformin antidiabetic medications) and cerebrovascular complications in patients with T2D without diabetic complications. METHODS: We analysed 9090 patients with T2D without complications who were prescribed either metformin or non-metformin medications as initial therapy. Propensity score matching ensured group comparability. Cox regression analyses, stratified by initial metformin use, assessed cerebrovascular disease risk, adjusting for multiple covariates and using competing risk analysis. Metformin exposure was measured using cumulative defined daily doses. RESULTS: Metformin users had a significantly lower crude incidence of cerebrovascular diseases compared with non-users (p < .0001). Adjusted hazard ratios (aHRs) consistently showed an association between metformin use and a lower risk of overall cerebrovascular diseases (aHRs: 0.67-0.69) and severe events (aHRs: 0.67-0.69). The association with reduced risk of mild cerebrovascular diseases was significant across all models (aHRs: 0.73-0.74). Higher cumulative defined daily doses of metformin correlated with reduced cerebrovascular risk (incidence rate ratio: 0.62-0.94, p < .0001), indicating a dose-dependent effect. CONCLUSION: Metformin monotherapy is associated with a reduced risk of cerebrovascular diseases in early-stage T2D, highlighting its dose-dependent efficacy. However, the observed benefits might also be influenced by baseline differences and the increased risks associated with other medications, such as sulphonylureas. These findings emphasize the need for personalized diabetes management, particularly in mitigating cerebrovascular risk in early T2D stages.

S-ketamine as an adjuvant in patient-controlled intravenous analgesia for preventing postpartum depression: a randomized controlled trial.

BACKGROUND: Postpartum depression (PPD) is a common complication of cesarean section. S-ketamine given intravenously during surgery can help prevent PPD. However, whether S-ketamine in patient-controlled intravenous analgesia (PCIA) can reduce the incidence of PPD is unknown. This study assessed the effect of S-ketamine as an adjuvant in PCIA for preventing PPD in women undergoing cesarean delivery. METHODS: A total of 375 parturients scheduled to undergo cesarean section and then receive PCIA were recruited from a single center and were randomly assigned to control (C) group (sufentanil 2 µg/kg + tropisetron 10 mg) or S-ketamine (S) group (S-ketamine 0.5 mg/kg + sufentanil 2 µg/kg + tropisetron 10 mg). The primary outcome was the incidence of PPD measured by the Edinburgh postnatal depression scale (EPDS) after surgery. The secondary outcomes were EPDS scores, visual analog scale (VAS) scores, Ramsay sedation scale (RSS) scores, and the rate of adverse events, including headache, nausea, dizziness, drowsiness, and vomit. RESULTS: A total of 275 puerperal women were included in the study. The rate of depression in parturient on postoperative days 3, 14, 28 in the C group and S group were 17.6 and 8.2% (p < 0.05), 24.2 and 9.8% (p < 0.05), and 19.0 and 17.2% (p = 0.76) respectively. EPDS scores in the C group and S group on postoperative days 3,14, and 28 were 7.65 ± 3.14 and 6.00 ± 2.47 (p < 0.05), 7.62 ± 3.14 and 6.38 ± 2.67 (p < 0.05), and 7.35 ± 3.17 and 6.90 ± 2.78 (p = 0.15), respectively. The rate of adverse events in the C group and S group were headache 3.3 and 4.1% (p = 0.755), nausea 5.9 and 8.2% (p = 0.481), dizziness 9.2 and 12.3% (p = 0.434), drowsiness 6.5 and 10.7%(p = 0.274), and vomit 5.9 and 5.7% (p = 0.585). CONCLUSIONS: S-ketamine (0.01 mg/kg/h) as an adjuvant in PCIA significantly reduces the incidence of PPD within 14 days and relieves pain within 48 h after cesarean delivery, without increasing the rate of adverse reactions. TRIAL REGISTRATION: Registered in the Chinese Clinical Trial Registry ( ChiCTR2100050263 ) on August 24, 2021.

Inhaled nitric oxide and acute kidney injury risk: a meta-analysis of randomized controlled trials.

PURPOSE: There are conflicting results as to the effect of inhaled nitric oxide (iNO) therapy on the risk of acute kidney injury (AKI). The aim of this study was to perform a meta-analysis to assess the updated data. METHODS: We systematically searched Web of Science, the Cochrane Library, Wanfang, and PubMed for relevant randomized control trials between database inception and 9/07/2020. Relative risks (RRs) with 95% confidence intervals (CIs) predicting the risk of AKI were extracted to obtain summary estimates using fixed-effects models. The Trim and Fill method was used to evaluate the sensitivity of the results and adjust for publication bias in meta-analysis. RESULTS: 15 randomized controlled studies from 14 articles involving 1853 patients were included in the study. Analyzing the eligible studies we found: (1) iNO therapy significantly increased the risk of AKI in acute respiratory distress syndrome patients (RR 1.55, 95% CI 1.15-2.10, p = 0.004; I 2 for heterogeneity 0%; P het = 0.649). (2) The use of iNO was associated with reduced AKI risk in patients undergoing cardiac surgery (RR 0.80, 95% CI 0.64-0.99, p = 0.037; I 2 for heterogeneity 0%; P het = 0.528). (3) For organ transplantation recipients, there was no effect of iNO administration on the risk of AKI (RR 0.50, 95% CI 0.16-1.56, p = 0.233; I 2 for heterogeneity 0%; P het = 0.842). The Trim and Fill analysis showed that the overall effect of this meta-analysis was stable. CONCLUSIONS: The effect of iNO on AKI risk might be disease-specific. Future RCTs with larger patient populations should aim to validate our findings.

Efficacy of Flurbiprofen for Postoperative Pain in Chinese Surgical Patients: A Meta-Analysis.

BACKGROUND: The objective of this meta-analysis is to assess the analgesic effect of flurbiprofen on postoperative pain in Chinese surgical patients. METHODS: The primary outcome was acute postoperative pain scores; the secondary outcomes included total opiate consumption during surgery and adverse effects, such as nausea, vomiting, and dizziness. Results were expressed as weighted mean difference (WMD) or odds ratio with 95% confidence intervals (95% CIs). We evaluated heterogeneity by visually examining the forest plots and quantified it by using the I2 statistic. We used random-effects models to pool the data. RESULTS: Of 573 abstracts reviewed, 19 studies involving 1628 participants met the inclusion criteria. Pooled results showed that the intravenous administration of flurbiprofen had a beneficial effect in reducing pain scores at 2 (WMD, -0.78; 95% CI, -1.22 to -0.34; P = 0.001), 6 (WMD, -0.93; 95% CI, -1.40 to -0.46; P = 0.000), 12 (WMD, -1.09; 95% CI, -1.93 to -0.24; P = 0.011), 24 (WMD, -1.08; 95% CI, -1.48 to -0.68; P = 0.000), and 48 (WMD, -0.62; 95% CI, -1.19 to -0.05; P = 0.032) h after surgery. In addition, flurbiprofen administration significantly decreased the incidence of postoperative nausea and vomiting (odds ratio, 0.39; 95% CI, 0.26-0.58; P = 0.000) but had no effects on opiate consumption and dizziness. CONCLUSIONS: The perioperative administration of flurbiprofen is effective in reducing postoperative pain, nausea, and vomiting in Chinese surgical patients. Future studies with adequate power should evaluate the ideal flurbiprofen regimen for postoperative pain.

BIS index monitoring and perioperative neurocognitive disorders in older adults: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Perioperative neurocognitive disorders (PND) are common in elderly patients after surgery. It has been reported that BIS-guided anesthesia potentially influenced the occurrence of PND. Therefore, we conducted this systematic review and meta-analysis to explore the associations between bispectral index (BIS) monitoring and PND. METHODS: Two researchers independently searched for relevant randomized controlled trials (RCTs) in PubMed, EMBASE, and the Cochrane Library (CENTRAL) using keywords related to the BIS and PND from inception to April 22, 2019. Odds ratios (OR) with 95% CI were calculated using a random effects model. RESULTS: Nine RCTs involving 4023 participants aged 60 years or older were included into this meta-analysis. BIS-guided anesthesia was not associated with lower incidence of POD (random effects; OR: 0.69; 95% CI 0.48, 1.01), delayed neurocognitive recovery (DNR) at 1 day, 7 days (random effects; OR: 0.14; 95% CI 0.02, 1.23; random effects; OR: 0.97; 95% CI 0.57, 1.63), and postoperative neurocognitive disorder (NCD) at 90 days and 1 year after surgery in older adults (random effects; OR:0.72; 95% CI 0.52, 1.00; random effects; OR: 0.26; 95% CI 0.03, 2.47). CONCLUSIONS: No definite evidence demonstrated that BIS-guided anesthesia decreased the incidence of POD, DNR and postoperative NCD in older patients. More homogeneous RCTs assessing the efficacy of BIS monitoring on reducing the occurrence of these perioperative cognitive disorders are needed.

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders.

In recent years, sevoflurane and isoflurane are the most popular anesthetics in general anesthesia for their safe, rapid onset, and well tolerant. Nevertheless, many studies reported their neurotoxicity among pediatric and aged populations. This effect is usually manifested as cognitive impairment such as perioperative neurocognitive disorders. The wide application of sevoflurane and isoflurane during general anesthesia makes their safety a major health concern. Evidence indicates that iron dyshomeostasis and ferroptosis may establish a role in neurotoxicity of sevoflurane and isoflurane. However, the mechanisms of sevoflurane- and isoflurane-induced neuronal injury were not fully understood, which poses a barrier to the treatment of its neurotoxicity. We, therefore, reviewed the current knowledge on mechanisms of iron dyshomeostasis and ferroptosis and aimed to promote a better understanding of their roles in sevoflurane- and isoflurane-induced neurotoxicity.

Association between vitamin D concentration and delirium in hospitalized patients: A meta-analysis.

BACKGROUND: Now the occurrence of delirium is more concerning to clinicians and psychiatrists. It has been reported that vitamin D deficiency may be a relevant factor in the development of delirium in hospitalized patients. STUDY OBJECTIVE: To investigate the association between vitamin D concentration and delirium in hospitalized patients. DESIGN: Meta-analysis. METHODS: A systematic literature search was conducted using PubMed, EMBASE, and the Cochrane Library. The primary outcome was the occurrence of delirium in the inpatient setting. Odds ratios (OR) were calculated with random or fixed effects models. RESULTS: In this article, we define the normal range of vitamin D concentrations as greater than 75 nmol / L, 50-75 nmol / L as vitamin D insufficiency, 25-50 nmol / L as vitamin D deficiency, and less than 25 nmol / L as vitamin D severe deficiency. The Results showed that severe vitamin D deficiency (OR: 1.98 [1.41-2.79], P<0.001) and vitamin D deficiency (OR: 1.50 [1.12-2.00], P = 0.006) were more likely to develop delirium than normal vitamin D levels. Subgroup analysis also revealed that low vitamin D concentrations were associated with a higher incidence of delirium, whether the cutoff point was 25 nmol/L (OR: 1.52 [1.40-1.64], P<0.001), 50 nmol/L (OR: 1.47 [1.19-1.82], P<0.001), or 75 nmol/L (OR: 1.54 [1.21-1.96], P<0.001). The included studies scored medium and high on the Newcastle-Ottawa quality assessment scale. CONCLUSION: Compared with normal vitamin D levels, severe vitamin D deficiency and vitamin D deficiency, but not vitamin D insufficiency, are associated with a higher incidence of delirium in hospitalized patients. TRIAL REGISTRATION: This review was registered in the PROSPERO database under identifier CRD42021271347. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021271347.

Prevalence of preoperative cognitive impairment among elderly thoracic surgery patients and association with postoperative delirium: a prospective observational study.

Background: Preoperative cognitive impairment (PCI) may increase the incidence of postoperative delirium (POD), yet screening for cognitive impairment is rarely performed. This study hypothesized that Mini-Cog for preoperative cognitive impairment screening predicts postoperative delirium. Methods: The prospective observational study recruited 153 elderly patients presenting for elective thoracic surgery. Cognitive function of these patients was screened using Mini-Cog preoperatively. We considered that patients with Mini-Cog scores ≤ 3 had cognitive impairment. Delirium was assessed using the Short CAM scale on postoperative days 1-5. Results: Of the 153 participants, 54 (35.3%) were assigned to the PCI group, and 99 (64.7%) were assigned to the Normal group. Place of residence, education level, and history of hypertension were significantly different between the two groups (P < 0.05). 51 (33.3%) patients developed POD. Multifactorial analysis revealed that PCI (OR = 2.37, P = 0.028), older age (OR = 1.13, P = 0.009), ASA grade III (OR = 2.75, P = 0.012), and longer duration of anesthesia (OR = 1.01, P = 0.007) were associated with POD. Conclusion: Preoperative cognitive impairment is strongly associated with POD. Mini-Cog could be recommended for screening PCI. Clinical trial registration: ClinicalTrials.gov, identifier NCT05798767.

Bicuculline and Bumetanide Attenuate Sevoflurane-Induced Impairment of Myelination and Cognition in Young Mice.

Sevoflurane (Sevo) is one of the most commonly used general anesthetics for infants and young children. We investigated whether Sevo impairs neurological functions, myelination, and cognition via the γ-aminobutyric acid A receptor (GABAAR) and Na+-K+-2Cl- cotransporter (NKCC1) in neonatal mice. On postnatal days 5-7, mice were exposed to 3% Sevo for 2 h. On postnatal day 14, mouse brains were dissected, and oligodendrocyte precursor cell line level lentivirus knockdown of GABRB3, immunofluorescence, and transwell migration assays were performed. Finally, behavioral tests were conducted. Multiple Sevo exposure groups exhibited increased neuronal apoptosis levels and decreased neurofilament protein levels in the mouse cortex compared with the control group. Sevo exposure inhibited the proliferation, differentiation, and migration of the oligodendrocyte precursor cells, thereby affecting their maturation process. Electron microscopy revealed that Sevo exposure reduced myelin sheath thickness. The behavioral tests showed that multiple Sevo exposures induced cognitive impairment. GABAAR and NKCC1 inhibition provided protection against Sevo-induced neurotoxicity and cognitive dysfunction. Thus, bicuculline and bumetanide can protect against Sevo-induced neuronal injury, myelination impairment, and cognitive dysfunction in neonatal mice. Furthermore, GABAAR and NKCC1 may be mediators of Sevo-induced myelination impairment and cognitive dysfunction.

General anesthetic action profile on the human prefrontal cortex cells through comprehensive single-cell RNA-seq analysis.

The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2 h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.

The research landscape of ferroptosis in the brain: A bibliometric analysis.

Background: Ferroptosis is a newly proposed concept of programmed cell death and has been widely studied in many diseases during the past decade. However, a bibliometric study that concentrates on publication outputs and research trends of ferroptosis related to the brain is lacking. Methods: We retrieved publication data in the field of ferroptosis in the brain from the Web of Science Core Collection on 31 December 2021. A bibliometric analysis was performed using VOSviewer and CiteSpace software. Results: Six hundred fifty-six documents focusing on ferroptosis in the brain were published from 2012 to 2021. The number of publications in this field has shown a steady increase in recent years. Most publications were from China (338) and the United States (166), while the most productive organizations were at the University of Melbourne (34) and University of Pittsburgh (23). Ashley I. Bush was the most productive author, while Scott J Dixon was the most co-cited author. The journal Free Radical Biology and Medicine published the most articles in this field, while Cell was the most cited journal. Among 656 publications, top 10 cited documents were cited at least 300 times. Among the top 20 references with the strongest citation bursts, half of the papers had a burst until 2021. The keywords analysis suggests that the top 20 keywords appeared at least 40 times. Additionally, "amyloid precursor protein" was the keyword with strongest bursts. Conclusion: Research on ferroptosis in the brain will continue to be highly regarded. This study analyzed the research landscape of ferroptosis in the brain and offers a new reference for researchers in this field.

Epileptiform EEG discharges during sevoflurane anesthesia in children: A meta-analysis.

OBJECTIVE: To investigate the overall incidence and associated factors of epileptiform discharges in children during sevoflurane anesthesia. METHODS: Our group systematically searched the PubMed, Cochrane library (Central) and EMBASE for the relevant trials from their inception until September 2020. The primary endpoint was the incidence of epileptiform discharges during sevoflurane induction. The secondary endpoints were the incidence of different types of epileptiform discharges, factors associated with these epileptiform events, and other adverse events such as seizure-like movements. RESULTS: After screening of 713 records, eleven studies involving 448 participants were included into the final analysis. Meta-analysis indicated that the overall incidence of Epileptiform EEG discharges was 38.1% (95%confidence interval [CI], 19.1%-59.2%) during sevoflurane anesthesia in children. Subgroup analysis showed that the incidence of these EEG patters was lower when participants were inducted by using the low initial concentration of sevoflurane, compared with the high initial concentration sevoflurane (1.7%, 95%CI, 0.0% to 8.4% versus 47.7%, 95%CI, 25.5% to 70.3%, P < 0.05). The longer exposure (>3 min) of high concentration sevoflurane during induction showed higher rate of epileptiform discharges than a shorter exposure (≤3 min) (48.4%, 95%CI, 20.1% to 77.3% versus 5.7%, 95%CI, 0.00% to 23.5%; P < 0.05). No significant difference for the incidence of epileptiform discharges was observed in subgroup analysis of addition of nitrous oxide (69.2%, 95%CI, 34.0% to 95.7% versus 41.3%, 95%CI, 15.6% to 69.7%, Pï¹¥0.05) and type of EEG monitoring (26.9%, 95%CI, 3.8% to 60.7% versus 53.1%, 95%CI, 25.4% to 79.8%, Pï¹¥0.05). CONCLUSIONS: The incidence of epileptiform EEG events in children during sevoflurane anesthesia varied from 19.1%-59.2%. The low initial concentration technique and shorter exposure time of high concentration sevoflurane may be associated with a decreased incidence of these epileptiform discharges in EEG. SIGNIFICANCE: Epileptiform EEG discharges during sevoflurane anesthesia in children should arouse clinicians' attention. The use of low initial concentration technique and shorter exposure time of high concentration sevoflurane may be associated with a lower occurrence of these paradoxical events.

High flow nasal cannula for patients undergoing bronchoscopy and gastrointestinal endoscopy: A systematic review and meta-analysis.

Background: High flow nasal cannula is gaining increasingly used in patients undergoing endoscopic procedures. We undertook this systematic review and meta-analysis to determine whether high flow nasal cannula (HFNC) could effectively minimize the risk of hypoxemia as compared with conventional oxygen therapy (COT). Methods: We performed a comprehensive search of Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Web of Science. Studies involving the application of HFNC during endoscopic procedures were identified. Results: We included 15 randomized controlled trials (7 bronchoscopy, 8 gastrointestinal endoscopy). Patients receiving HFNC during endoscopic procedures had a significantly lower risk of hypoxemia (defined as SpO2 < 90%) versus COT group (risk ratio = 0.32; 95%CI (0.22-0.47), 13 studies, 4,093 patients, moderate-quality evidence, I 2 = 48.82%, P < 0.001). The lowest SpO2 was significantly higher in HFNC group (mean difference = 4.41; 95%CI (2.95-5.86), 9 studies, 1,449 patients, moderate-quality evidence, I 2 = 81.17%, P < 0.001) than those receiving COT. No significant difference was detected between groups in end-procedure partial pressure of CO2 (standard mean difference = -0.18; 95%CI (-0.52-0.15), 5 studies, 238 patients, moderate-quality evidence, I 2 = 42.25%, P = 0.29). Patients receiving HFNC were associated a lower need for airway intervention (risk ratio = 0.45; 95%CI (0.24-0.84), 8 studies, 2,872 patients, moderate-quality evidence, I 2 = 85.97%, P = 0.01) and less procedure interruption (risk ratio = 0.36; 95%CI (0.26-0.51), 6 studies, 1,562 patients, moderate-quality evidence, I 2 = 0.00%, P < 0.001). The overall intubation rate after endoscopy was 0.20% in both group, with no difference detected (risk ratio = 1.00; 95%CI (0.30-3.35), 7 studies, 2,943 patients, low-quality evidence, I 2 = 0.00%, P = 1.00). Conclusion: This systematic review and meta-analysis found moderate to low evidence that the application of HFNC was associated with improved oxygenation, decreased need for airway intervention, and reduced procedure interruption in patients undergoing endoscopic procedures. Future larger sample and high-quality studies are warranted to confirm our result and further investigate the effectiveness of HFNC in patients at risk. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022298032.

EEG-Parameter-Guided Anesthesia for Prevention of Emergence Delirium in Children.

Background: Emergence delirium (ED) usually occurs in children after surgery with an incidence of 10−80%. Though ED is mostly self-limited, its potential injuries cannot be ignored. Whether electroencephalography (EEG)-parameter-guided anesthesia could reduce the incidence of ED in pediatric surgery has not been fully discussed to date. Methods: Fifty-four boys aged 2−12 years undergoing elective hypospadias surgery under sevoflurane anesthesia were selected. In the EEG-parameter-guided group (E group), sevoflurane was used for anesthesia induction and was maintained by titrating the spectral edge frequency (SEF) to 10−15 and combining the monitoring of density spectral array (DSA) power spectra and raw EEG. While in the control group (C group), anesthesiologists were blinded to the SedLine screen (including SEF, DSA, and raw EEG) and adjusted the intraoperative drug usage according to their experience. Patients with a Pediatric Anesthesia Emergence Delirium (PAED) score > 10 were diagnosed with ED, while patients with a PAED score > 2 were diagnosed with emergence agitation (EA). Results: Finally, a total of 37 patients were included in this trial. The incidence of ED in the E group was lower than in the C group (5.6% vs. 36.8%; p = 0.04), while the incidence of EA was similar in the two groups (61% vs. 78.9%; p = 0.48). Intraoperative parameters including remifentanil dosage and the decrease in mean arterial pressure (MAP) were not different between the two groups (p > 0.05), but the mean end-tidal sevoflurane concentration (EtSevo) was lower in the E group than in the C group (p > 0.05). Moreover, during PACU stay, the extubation time and discharge time of the groups were similar, while the PAED scores within 5 min from extubation and the Face, Legs, Activity, Cry, and Consolability (FLACC) scores within 30 min from extubation were lower in the E group than in the C group. Conclusion: EEG-parameter-guided anesthesia management reduced the incidence of ED in children. Studies with larger sample sizes are needed to obtain more convincing results.

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity.

Background: Sevoflurane is one of the most popular inhalational anesthetics during perioperative period but presenting neurotoxicity among pediatric and aged populations. Recent experiments in vivo and in vitro have indicated that ferroptosis may contribute to the neurotoxicity of sevoflurane anesthesia. However, the exact mechanism is still unclear. Methods: In current study, we explored the differential expressed genes (DEGs) in HT-22 mouse hippocampal neuronal cells after sevoflurane anesthesia using RNA-seq. Differential expressed ferroptosis-related genes (DEFRGs) were screened and analyzed by Gene Ontology (GO) and pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING). Significant modules and the hub genes were identified by using Cytoscape. The Connectivity Map (cMAP) was used for screening drug candidates targeting the identified DEFRGs. Potential TF-gene network and drug-gene pairs were established towards the hub genes. In final, we validated these results in experiments. Results: A total of 37 ferroptosis-related genes (18 upregulated and 19 downregulated) after sevoflurane exposure in hippocampal neuronal cells were finally identified. These differentially expressed genes were mainly involved into the biological processes of cellular response to oxidative stress. Pathway analysis indicated that these genes were involved in ferroptosis, mTOR signaling pathway, and longevity-regulating pathway. PPI network was constructed. 10 hub genes including Prkaa2, Chac1, Arntl, Tfrc, Slc7a11, Atf4, Mgst1, Lpin1, Atf3, and Sesn2 were found. Top 10 drug candidates, gene-drug networks, and TFs targeting these genes were finally identified. These results were validated in experiments. Conclusion: Our results suggested that ferroptosis-related genes play roles in sevoflurane anesthesia-related hippocampal neuron injury and offered the hub genes and potential therapeutic agents for investigating and treatment of this neurotoxicity after sevoflurane exposure. Finally, therapeutic effect of these drug candidates and function of potential ferroptosis targets should be further investigated for treatment and clarifying mechanisms of sevoflurane anesthesia-induced neuron injury in future research.

Sevoflurane exposure induces neurotoxicity by regulating mitochondrial function of microglia due to NAD insufficiency.

Developmental neurons received with sevoflurane, the commonly used inhalational anesthetic agent in clinical surgery, several times tend to be destroyed. Microglia, the resident immune cells of the central nervous system (CNS), are activated after sevoflurane exposure, accompanied by releasing proinflammatory cytokines that damage developing neurons. The sevoflurane-induced neurotoxicity could be attributed to activated microglia presenting proinflammatory and anti-inflammatory functions. Proinflammatory microglia release cytokines to impair the CNS, while anti-inflammatory microglia engulf damaged neurons to maintain CNS homeostasis. Sevoflurane exposure promotes the secretion of proinflammatory cytokines by microglia, inhibiting the microglial phagocytic function. Microglia with poor phagocytic function cannot engulf damaged neurons, leading to the accumulation of damaged neurons. The mechanism underlying poor phagocytic function may be attributed to mitochondrial dysfunction of microglia induced by sevoflurane exposure, in which affected mitochondria cannot generate adequate ATP and NAD to satisfy the energy demand. We discovered that sevoflurane treatment impaired the mitochondrial metabolism of microglia, which resulted in NAD deficiency and couldn't produce sufficient energy to clear damaged neurons to maintain CNS development. Our findings provide an explanation of a new mechanism underlying sevoflurane-induced neurotoxicity.

The role of depolarizing activation of Na+-Ca2+ exchanger by oligodendrocyte progenitor cells in the effect of sevoflurane on myelination.

AIMS: The aim of this study was to investigate the role of depolarizing activation of Na+-Ca2+ exchanger (NCX) by oligodendrocyte progenitor cells (OPC) in the effect of sevoflurane on myelination. MAIN METHODS: On postnatal days 7, 8, and 9, mice were exposed to 3 % sevoflurane for 2 h per day. The proliferation, differentiation, and myelin sheath of OPC were observed with immunofluorescence, quantitative real-time polymerase chain reaction (QRT-PCR), and transmission electron microscopy (TEM) at various time points. The open field, Y maze, and new object recognition tests were used to measure spatial learning and memory. siRNA was used for the knockdown NCX1 in human OPC (HOPC) before sevoflurane exposure; the Transwell migration assay was used to measure cell migration ability and Fluo 4-AM was used to measure intracellular Ca2+ concentration. KEY FINDINGS: Pretreatment with an NCX inhibitor attenuated the proliferation and differentiation of OPC induced by sevoflurane and induced a remarkable increase in platelet-derived growth factor receptor-alpha (PDGFRα), 2, 3-cyclic nucleotide 3-phosphodiesterase (CNPase), oligodendrocyte transcription factor 2 (Olig2), and homeodomain protein NK2 homeobox 2 (NKX2.2) levels. Pretreatment with an NCX inhibitor alleviated the sevoflurane-induced myelination disorder and cognitive impairment. The decreased cell migration and increased intracellular Ca2+ concentration observed in the siRNA-negative control group was reversed in the sevoflurane plus siRNA-NCX1 group. SIGNIFICANCE: This study suggests that repeated sevoflurane exposure in newborn mice leads to depolarization of OPC, which leads to Ca2+ influx through NCX and affects OPC proliferation, migration, differentiation, and myelination, ultimately leading to cognitive impairment.

Post-COVID pain and quality of life in COVID-19 patients: protocol for a meta-analysis and systematic review.

INTRODUCTION: During the COVID-19 pandemic, approximately 10%-35% of COVID-19 infected patients experience post-COVID sequela. Among these sequelae, pain symptoms should not be neglected. In addition, the sequelae of COVID-19 also decrease the quality of life of these populations. However, meta-analyses that systematically evaluated post-COVID pain are sparse. METHODS AND ANALYSIS: A comprehensive screening will be performed by searching MEDLINE and Embase without language restriction from inception to August 2021. Cohort studies, case-control studies, cross-sectional studies and case series will be included. Case report and interventional studies will be excluded. Studies with less than 20 participants will be also excluded. We aim to investigate the prevalence of pain-related symptoms in patients after the acute phase of COVID-19. The impact of COVID-19 on the quality of life and pain symptoms among these populations in the post-acute phase will also be evaluated. ROBINS-I tool will be used to assess the risk of bias of cohort studies. The risk of bias tool developed by Hoy et al will be used to assess the risk of bias of prevalence studies. Metaprop command in Stata will be used to estimate the pooled prevalence of pain symptoms. DerSimonian and Laird random-effects models will be used to calculate the pooled relative risks. All analyses will be calculated using Stata software (V.15.0; StataCorp) ETHICS AND DISSEMINATION: Ethics approval is not required. Results of our study will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42021272800.

Individualized positive end-expiratory pressure (PEEP) during one-lung ventilation for prevention of postoperative pulmonary complications in patients undergoing thoracic surgery: A meta-analysis.

BACKGROUND: Positive end-expiratory pressure (PEEP) is an important part of the lung protection strategies for one-lung ventilation (OLV). However, a fixed PEEP value is not suitable for all patients. Our objective was to determine the prevention of individualized PEEP on postoperative complications in patients undergoing one-lung ventilation. METHOD: We searched the PubMed, Embase, and Cochrane and performed a meta-analysis to compare the effect of individual PEEP vs fixed PEEP during single lung ventilation on postoperative pulmonary complications. Our primary outcome was the occurrence of postoperative pulmonary complications during follow-up. Secondary outcomes included the partial pressure of arterial oxygen and oxygenation index during one-lung ventilation. RESULT: Eight studies examining 849 patients were included in this review. The rate of postoperative pulmonary complications was reduced in the individualized PEEP group with a risk ratio of 0.52 (95% CI:0.37-0.73; P = .0001). The partial pressure of arterial oxygen during the OLV in the individualized PEEP group was higher with a mean difference 34.20 mm Hg (95% CI: 8.92-59.48; P = .0004). Similarly, the individualized PEEP group had a higher oxygenation index, MD: 49.07mmHg, (95% CI: 27.21-70.92; P < .0001). CONCLUSIONS: Individualized PEEP setting during one-lung ventilation in patients undergoing thoracic surgery was associated with fewer postoperative pulmonary complications and better perioperative oxygenation.