SIRT5 Regulates Ferroptosis through the Nrf2/HO-1 Signaling Axis to Participate in Ischemia-Reperfusion Injury in Ischemic Stroke.

This work aimed to study the role and mechanism of SIRT5 regulation of ferroptosis in cerebral ischemia-reperfusion (I/R) injury. A model of middle cerebral artery occlusion in rats was prepared using the method of thread occlusion. The ferroptosis inhibitor was injected intraperitoneally while the SIRT5 interfering lentivirus were injected into the brain, and neurological disorders were scored in the rats. TTC staining was used to detect infarct volume, and immunohistochemistry was used to detect the expression of SIRT5 in tissues. Rat hippocampal neuronal cells H19-7 were transduced with SIRT5 interfering lentivirus and ferroptosis was induced using erastin. The CCK8 detection kit was used to detect cell viability. Commercial kits were used to detect levels of iron ions, ROS, MDA, SOD, and inflammatory factor (TNF-α and IL-6) in brain tissue or cell supernatant. Western blot was used to detect the expression changes of ferroptosis related proteins GPX4, Nrf2, and HO-1 in tissues or cells. Compared with the sham group, the MCAO model group showed higher levels of neurological impairment score, increased cerebral infarction volume, iron ions, inflammatory factors, and oxidative stress levels in rats. Compared with the MCAO group, the MCAO + fer-1 group exhibited lower levels of neurological impairment scores, cerebral infarction volume, decreased iron ions, inflammatory factors, and oxidative stress levels in rats. Meanwhile, compared with the MCAO + DMSO/LV-shRNA group, the MCAO + fer-1/LV-shSIRT5 group showed a significant decrease in neurological impairment scores, cerebral infarction volume, iron ions, inflammatory factors, and oxidative stress levels in rats. In vitro experiments have found that LV-shSIRT5 can prevent erastin-induced cell ferroptosis. In summary, SIRT5 regulates ferroptosis through the Nrf2/HO-1 signaling axis to participate in ischemia-reperfusion injury in ischemic stroke.

Association Between Diverse Cell Death Patterns Related Gene Signature and Prognosis, Drug Sensitivity, and Immune Microenvironment in Glioblastoma.

Glioblastoma (GBM) is the most invasive type of glioma and is difficult to treat. Diverse programmed cell death (PCD) patterns have a significant association with tumor initiation and progression. A novel prognostic model based on PCD genes may serve as an effective tool to predict the prognosis of GBM. The study incorporated 11 PCD patterns, namely apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, and oxeiptosis, to develop the model. To construct and validate the model, both bulk and single-cell transcriptome data, along with corresponding clinical data from GBM cases, were obtained from the TCGA-GBM, REMBRANDT, CGGA, and GSE162631 datasets. A cell death-related signature containing 14 genes was constructed with the TCGA-GBM cohort and validated in the REMBRANDT and CGGA datasets. GBM patients with a higher cell death index (CDI) were significantly associated with poorer survival outcomes. Two separate clusters associated with clinical outcomes emerged from unsupervised analysis. A multivariate Cox regression analysis was conducted to examine the association of CDI with clinical characteristics, and a prognostic nomogram was developed. Drug sensitivity analysis revealed high-CDI GBM patients might be resistant to carmustine while sensitive to 5-fluorouracil. Less abundance of natural killer cells was found in GBM cases with high CDI and bulk transcriptome data. A cell death-related prognostic model that could predict the prognosis of GBM patients with good performance was established, which could discriminate between the prognosis and drug sensitivity of GBM.

A Prediction Model for Deciphering Intratumoral Heterogeneity Derived from the Microglia/Macrophages of Glioma Using Non-Invasive Radiogenomics.

Microglia and macrophages play a major role in glioma immune responses within the glioma microenvironment. We aimed to construct a prognostic prediction model for glioma based on microglia/macrophage-correlated genes. Additionally, we sought to develop a non-invasive radiogenomics approach for risk stratification evaluation. Microglia/macrophage-correlated genes were identified from four single-cell datasets. Hub genes were selected via lasso-Cox regression, and risk scores were calculated. The immunological characteristics of different risk stratifications were assessed, and radiomics models were constructed using corresponding MRI imaging to predict risk stratification. We identified eight hub genes and developed a relevant risk score formula. The risk score emerged as a significant prognostic predictor correlated with immune checkpoints, and a relevant nomogram was drawn. High-risk groups displayed an active microenvironment associated with microglia/macrophages. Furthermore, differences in somatic mutation rates, such as IDH1 missense variant and TP53 missense variant, were observed between high- and low-risk groups. Lastly, a radiogenomics model utilizing five features from magnetic resonance imaging (MRI) T2 fluid-attenuated inversion recovery (Flair) effectively predicted the risk groups under a random forest model. Our findings demonstrate that risk stratification based on microglia/macrophages can effectively predict prognosis and immune functions in glioma. Moreover, we have shown that risk stratification can be non-invasively predicted using an MRI-T2 Flair-based radiogenomics model.

Comparative effectiveness of different treatments for post-stroke insomnia: A network meta-analysis.

Background: ：Post-stroke insomnia（PSI）is one of the common complications after stroke and it is a chronic problem and hampers the patient's recovery. Some treatments have been shown to be effective in treating post-stroke insomnia. However, it is not clear which treatment is more effective. Methods: In this study, we searched CNKI, PubMed, and Cochrane Library for appropriate keywords with a deadline of October 2022 to select 23 randomized controlled trials（RCTs）. The mean difference between different treatments was assessed and summarized as mean and 95 % confidence interval (CI), resulting in a Bayesian network meta-analysis. Results: By meta-analysis of Bayesian networks, we found acupuncture(MD, -2.49; 95 % CI, [-3.63, -1.31]) and herbal (MD, -2.79; 95 % CI, [-4.9, -0.69]) were significantly better than estazolam in terms of PSQI score change, and the difference was statistically significant. Dexzopiclone, electrics stimulation, rTMS and zopiclone were not statistically significant with other treatments. Conclusion: Herbal, zopiclone, and acupuncture were more effective in improving PSQI scores in patients with post-stroke insomnia, followed by rTMS and dexzopiclone. However, the effectiveness between herbal, zopiclone and acupuncture was not statistically significant. Acupuncture and herbal are promising for the treatment of PSI, and more research remains to be invested.

Efficacy and safety of levetiracetam versus valproate in patients with established status epilepticus: A systematic review and meta-analysis.

Objective: Status epilepticus (SE) is a common neurological emergency that is defined as a prolonged seizure or a series of seizures which often leads to irreversible damage. Levetiracetam (LEV) and valproate (VPA) are second-line anti-seizure drugs that are frequently used in patients with established SE (ESE). This meta-analysis compared the efficacy and safety of LEV and VPA for the treatment of ESE. Method: MEDLINE, EMBASE, Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov were searched by two authors, which identified six randomized controlled trials (RCTs) that compared LEV and VPA for ESE. Results: The six RCTs included 1213 patients (LEV group, n = 593; VPA group, n = 620). Integrated patient data information display LEV was not superior to VPA in terms of clinical seizure termination (63.55% vs. 64.08%, respectively; relative risk [RR] = 1.03, 95% confidence interval [CI] = 0.94-1.11, p = 0.55), with no significant differences between LEV and VPA in terms of good functional outcome at discharge (Glasgow Outcome Scale [GOS] = 4 or 5), intensive care unit (ICU) admission, adverse events, and mortality. There was no statistically significant difference between the two drugs in different age groups. Previous multicenter studies have demonstrated that VPA was slightly more effective than LEV, whereas single-center studies showed the opposite results. In addition, LEV and VPA had similar rates of clinical seizure termination, ICU admission, and adverse events between the age subgroups (ages <18 and >18 years). Conclusions: Levetiracetam (LEV) was not superior to valproate (VPA) in terms of efficacy or safety outcomes. In addition, children (<18 years) and adults (>18 years) might have similar responses to LEV and VPA. Additional RCTs are required to verify our results.

Efficacy and Safety of Different Bioactive Coils in Intracranial Aneurysm Interventional Treatment, a Systematic Review and Bayesian Network Meta-Analysis.

BACKGROUND: Bioactive coils have been used for nearly 20 years to improve aneurysm treatments. Previous studies are inadequate for comparing the efficacy and safety between different coils. The aim of this study was to investigate the safety and efficacy of different coils by comparing the percentage of people with different modified Raymond scale grades, re-rupture rates, and mortality in patients with intracranial aneurysms embolized with different coils. METHOD: Randomized controlled trials (RCTs) containing coils for aneurysm interventional treatment were collected from Web of Science, PubMed, and the Cochrane Library up to December 2021. Bayesian network meta-analysis with a randomized or fixed model was performed to compare the efficacy and safety among different bioactive coils and bare platinum coils. RESULTS: We pooled 3362 patients from eight RCTs. No significant differences were found between coils in the proportion of patients with a three-grade classification assessed with the modified Raymond scale immediately after surgery. Hydrogel coils did not show a significant difference in the percentage of patients with a modified Raymond scale grade I postoperatively compared with bare platinum coils (OR, -0.1080; 95% CI, -0.4201-0.2423), but at follow-up, the percentage of patients with modified Raymond scale grade I was significantly higher with hydrogel coils than with bare platinum coils (OR, 0.4957; 95% CI, 0.0060-0.9442). There were no statistical differences between these four coils in terms of aneurysm rupture or re-rupture rate and mortality. CONCLUSION: Though there was no significant difference in the embolization effect between the several coils in the postoperative period, complete embolization was more likely to be achieved with hydrogel coils compared to bare platinum coils at follow-up. There were no significant differences in safety between the several coil materials.

Identification of Immunological Characteristics and Immune Subtypes Based on Single-Sample Gene Set Enrichment Analysis Algorithm in Lower-Grade Glioma.

Few breakthroughs have been achieved in the treatment of lower-grade glioma (LGG) in recent decades. Apart from the conventional pathological and histological classifications, subtypes based on immunogenomics would provide reference for individualized treatment and prognosis prediction. Our study identified four immunotypes of lower-grade glioma (clusters A, B, C, and D) by bioinformatics methods in TCGA-LGG and two CGGA datasets. Cluster A was an "immune-cold" phenotype with the lowest immune infiltration and longest survival expectation, whereas cluster D was an "immune-rich" subtype with the highest immune infiltration and poor survival expectation. The expression of immune checkpoints increased along with immune infiltration degrees among the clusters. It was notable that immune clusters correlated with a variety of clinical and immunogenomic factors such as age, WHO grades, IDH1/2 mutation, PTEN, EGFR, ATRX, and TP53 status. In addition, LGGs in cluster D were sensitive to cisplatin, gemcitabine, and immune checkpoint PD-1 inhibitors. RTK-RAS and TP53 pathways were affected in cluster D. Functional pathways such as cytokine-cytokine receptor interaction, antigen processing and presentation, cell adhesion molecules (CAMs), and ECM-receptor interaction were also enriched in cluster D. Hub genes were selected by the Matthews correlation coefficient (MCC) algorithm in the blue module of a gene co-expression network. Our studies might provide an immunogenomics subtyping reference for immunotherapy in LGG.

Protective Prognostic Biomarkers Negatively Correlated with Macrophage M2 Infiltration in Low-Grade Glioma.

Tumor-associated Macrophages (TAMs) play a vital role in the progression of glioma. Macrophage M2 has been confirmed to promote immunosuppression and proliferation of low-grade glioma (LGG). Here, we searched for genes negatively correlated with Macrophages M2 by bioinformatical methods and investigated their protective ability for prognosis. LGG and adjacent normal samples were screened out in TCGA and three GEO datasets. 326 overlapped differentially expressed genes were calculated, and their biological functions were investigated by Go and KEGG analyses. Macrophage M2 accounted for the highest proportion among all 22 immune cells by CIBERSORT deconvolution algorithm. The proportion of Macrophage M2 in LGG was also higher than that in normal tissue according to several deconvolution algorithms. 43 genes in the blue module negatively correlated with Macrophage M2 infiltration were identified by weighted gene coexpression network analysis (WGCNA). Through immune infiltration and correlation analysis, FGFBP3, VAX2, and SHD were selected and they were enriched in G protein-coupled receptors' signaling regulation and cytokine receptor interaction. They could prolong the overall and disease-free survival time. Univariate and multivariate Cox regression analyses were applied to evaluate prognosis prediction ability. Interestingly, FGFBP3 and AHD were independent prognostic predictors. A nomogram was drawn, and its 1-year, 3-year, and 5-year survival prognostic value was verified by ROC curves and calibration plots. In conclusion, FGFBP3, VAX2, and SHD were protective prognostic biomarkers against Macrophage M2 infiltration in low-grade glioma. The FGFBP3 and SHD were independent factors to effectively predict long-term survival probability.

The efficacy and safety of insertable cardiac monitor on atrial fibrillation detection in patients with ischemic stroke: a systematic review and meta-analysis.

Atrial fibrillation (AF) leads to a high risk of recurrent stroke, and the insertable cardiac monitor (ICM), as a new kind of electrocardiographic monitoring device, has been proven to enhance the recognition rate of AF. The aim of this systematic review was to evaluate the efficacy and safety of the ICM use in AF detection of patients with stroke. We pooled 1233 patients from three randomized controlled trials (RCTs). The detection rate of AF was superior in the ICM group to that in the control group at 6 months (risk ratio [RR], 4.63; P < 0.0001; 95% confidence interval [CI], 2.17-9.90) and 12 months (RR, 5.04; P < 0.00001; 95% CI, 2.93 to 8.68). Patients in the ICM group had a higher rate of oral anticoagulant usage (RR, 2.76; P < 0.00001; 95% CI, 1.89-4.02). However, there was no difference in the time to first detection of AF within 12 months (mean difference, - 8.28; P = 0.82; 95% CI, - 77.84-61.28) or the rate of recurrent ischemic stroke or transient ischemic attack (RR, 0.88; P = 0.51; 95% CI, 0.60-1.28) between the ICM and control groups. In addition, the ICM group experienced more adverse events than the control group within 12 months (RR, 4.42; P = 0.002; 95% CI, 1.69-11.55). To conclude, the sensitivity of ICM is superior to that of conventional external cardiac monitoring. Reducing adverse reactions will be a new development direction of ICM.

The efficacy and safety of dual orexin receptor antagonists in primary insomnia: A systematic review and network meta-analysis.

The efficacy and safety of dual orexin receptor antagonists (DORAs) for primary insomnia have been well verified in several large randomized controlled trials (RCTs) over the past several decades. However, there have been few systematic comparisons of different DORAs, and the best DORA for insomniacs has remained unclear. Here, Medline, Embase, Cochrane library, and clinicaltrials.gov were searched for RCTs (through December 31, 2020) to evaluate different DORAs versus a placebo. We pooled data from 13 RCTs. DORAs were superior to the placebo in all efficacy outcomes except the subjective number of awakenings (P = 0.90), but also showed higher risks of somnolence, abnormal dreams, fatigue, and dry mouth (somnolence: P < 0.00001; abnormal dreams: P = 0.03; fatigue: P = 0.001; dry mouth: P = 0.007). No statistical differences were found between any two of the DORAs in terms of primary efficacy outcomes. However, lemborexant yielded the three-highest surfaces under the curve ranking area (SUCRA) values (78.25%, 96.25% and 89.13%). Taken together, we conclude that DORAs are superior to the placebo in terms of efficacy and safety measures.

Treatments to post-stroke depression, which is more effective to HAMD improvement? A network meta-analysis.

Introduction: Post-stroke depression (PSD) is a common mental health problem after cerebrovascular accidents. There are several treatments that have been shown to be effective in treating post-stroke depression. However, it is not clear which treatment is more effective. Methods: In this meta-analysis, an appropriate search strategy was used to search eligible randomized controlled trials (RCTs) on different treatments to treat patients with Post-stroke depression published up to December 2021 from the CNKI, PubMed, and Cochrane Library. We assessed the mean difference or odds ratio between each treatment and placebo and summarized them as the average and 95% confidence interval (CI) by conducting Bayesian network meta-analyses. Results: By constructing a Bayesian network meta-analysis, we found that acupuncture combined with fluoxetine (vs placebo MD, -8.9; 95% CI, [-15, -2.9]) or paroxetine (vs placebo MD,-8.5; 95% CI, [-15, -2.5]) was the most effective for change in Hamilton depression scale (HAMD) at the end of the 4th week. For change in Hamilton depression scale at the end of the 8th week, rTMS combined with paroxetine (vs placebo MD, -13; 95% CI, [-17, -7.9]) had the greatest amount of change. The efficacy of medication combined with adjuvant therapy was also superior for the percentage of patients with Hamilton depression scale change over 50%. Discussion: The combination of antidepressants with adjuvant therapy may enhance the efficacy of antidepressants and achieve better results than antidepressant monotherapy in both Hamilton depression scale changes at the end of week 4 or 8 and 50% Hamilton depression scale improvement rate. Acupuncture combined with fluoxetine treatment was more effective in the treatment of post-stroke depression at week 4, while rTMS combined with paroxetine was more effective at week 8. Further research is needed to determine whether acupuncture combined with fluoxetine is better than rTMS combined with paroxetine for post-stroke depression at week 8.

Different Catechol-O-Methyl Transferase Inhibitors in Parkinson's Disease: A Bayesian Network Meta-Analysis.

Parkinson's disease (PD) is a common, chronic, progressive, debilitating neurodegenerative disease. The current levodopa treatment requires the addition of other drugs, such as catechol-O-methyl transferase (COMT) inhibitors, to alleviate motor fluctuations in advanced PD. Therefore, a theoretical reference for treatment is urgently needed. In this study, an appropriate search strategy was used to screen eligible studies on different drugs to treat patients with PD from the Embase, PubMed, and Cochrane Library. The publication dates were from January 1990 to June 2021. We integrated eligible randomized controlled trials, and statistical analysis was performed on three kinds of effectiveness outcomes and two types of safety outcomes. We assessed the average difference or odds ratio between each drug and placebo and summarized them as the average and 95% confidence interval (CI), respectively. In terms of efficacy, entacapone (mean difference [MD], 0.64 h; 95% CI, 0.29-1.0), opicapone (MD, 0.92 h; 95% CI, 0.35-1.5), and tolcapone (MD, 3.2 h; 95% CI, 2.1-4.2) increased patients' total ON-time compared to placebo. Tolcapone (MD, -100 mg; 95% CI -160 to -45) reduced the total daily dose of levodopa therapy. None of these three drugs was found to have statistical significance in mean change from baseline in UPDRS part III scores when compared with others. In terms of safety, tolcapone (MD, 3.8; 95% CI, 2.1-6.8), opicapone (MD, 3.7; 95% CI, 2-7.2), and entacapone (MD, 2.2; 95% CI, 1.5-3.3) increased the number of cases of dyskinesia compared to placebo. Entacapone (MD, 1.7; 95% CI, 1.3-2.2) and tolcapone (MD, 4.3; 95% CI, 1.3-15) were more likely to cause adverse events than placebo. In conclusion, opicapone showed higher efficiency and fewer safety problems in five indicators we selected when compared with the other two drugs.

The Function of Tranexamic Acid to Prevent Hematoma Expansion After Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis From Randomized Controlled Trials.

Objectives: The clinical results caused by spontaneous intracerebral hemorrhage (ICH) are disastrous to most patient. As tranexamic acid (TXA) has been proved to decrease the influence of ICH, we conducted this research to explore the function of TXA for the prognosis of ICH compared with placebo. Methods: We searched MEDLINE, Embase, Cochrane Library, and Clinicaltrials.gov for randomized controlled trials (RCTs) that were performed to evaluate TXA vs. placebo for ICH up to February 2021. The data were assessed by Review Manager 5.3 software. The risk ratio (RR) and mean difference were analyzed using dichotomous outcomes and continuous outcomes, respectively, with a fixed effect model. Results: We collected 2,479 patients from four RCTs. Then, we took the change of hematoma volume, modified Rankin Scale (mRS), and adverse events as evaluation standard of the treatment for ICH. Through statistical analysis, we found that there is no obvious hematoma expansion effect after the application of TXA (RR = 1.05), and we proceeded the quantitative analysis of percentage change in hematoma volume from baseline, indicating that TXA could inhibit the expansion of hematoma volume (RR = -2.02) compared with placebo. However, according to the outcomes of mRS (0-1, RR = 1.04; 0-2, RR = 0.96), TXA cannot improve neurological functional prognosis. As for the security outcomes-mortality (RR = 1.02), thromboembolic events (RR = 0.99), neurological deterioration (RR = 0.92), infection (RR = 0.86), and craniotomy (RR = 0.41), there seems exist no statistical difference between TXA and placebo. Conclusions: TXA has an advantage in the aspect of preventing hematoma expansion compared with placebo for ICH, but cannot illustrate the efficacy of TXA in improving neurological functional prognosis, which still needs more researches with large sample sizes. Moreover, for safety, we did not find obvious statistical difference between TXA and placebo.

Different Monoclonal Antibodies in Myasthenia Gravis: A Bayesian Network Meta-Analysis.

Background: Myasthenia gravis (MG) is a common autoimmune disease with acquired neuromuscular transmission disorders. Recently, monoclonal antibodies have been shown to successfully treat a variety of diseases. Methods: In this meta-analysis, an appropriate search strategy was used to search eligible randomized controlled trials (RCTs) on different monoclonal antibodies to treat patients with MG published up to September 2021 from the embase, PubMed, and Cochrane Library. We assessed the average difference or odds ratio between each drug and placebo and summarized them as the average and 95% confidence interval (CI), respectively. Results: In indicators of efficacy, patients receiving eculizumab (MD, -1.9; 95% CI, -3.2-0.76) had decreases in MG-ADL scores compared to placebo. In addition, only eculizumab (MD, -3.1; 95% CI, -4.7-1.5) and efgartigimod (MD, -1.4; 95% CI, -2.1-0.68) showed a significant difference from placebo in the amount of reduction in QMG scores, while neither of the other two monoclonal antibodies was statistically significant. With regard to the safety of monoclonal antibody therapy, there was no significant difference in the probability of AE in subjects treated with any of the four monoclonal antibodies compared to placebo. Conclusions: eculizumab was effective in reducing MG-ADL scores and QMG scores in myasthenia gravis. Meanwhile, eculizumab also caused fewer AE. As an emerging therapy, monoclonal antibodies are prospective in the treatment of MG. However, more researches are required to be invested in the future as the results obtained from small sample sizes are not reliable enough.