Predicting long-term outcomes in patients with classical trigeminal neuralgia following microvascular decompression with an MRI-based radiomics nomogram: a multicentre study.

OBJECTIVES: This study aimed to develop a clinical-radiomics nomogram to predict the long-term outcomes of patients with classical trigeminal neuralgia (CTN) following microvascular decompression (MVD). MATERIALS AND METHODS: This retrospective study included 455 patients with CTN who underwent MVD from three independent institutions A total of 2030 radiomics features from the cistern segment of the trigeminal nerve were extracted computationally from the three-dimensional steady-state free precession and three-dimensional time-of-flight magnetic resonance angiography sequences. Using the least absolute shrinkage and selection operator regression, 16 features were chosen to develop radiomics signatures. A clinical-radiomics nomogram was subsequently developed in the development cohort of 279 patients via multivariate Cox regression. The predictive performance and clinical application of the nomogram were assessed in an external cohort consisting of 176 patients. RESULTS: Sixteen highly outcome-related radiomics features extracted from multisequence images were used to construct the radiomics model, with concordance indices (C-index) of 0.804 and 0.796 in the development and test cohorts, respectively. Additionally, a clinical-radiomics nomogram was developed by incorporating both radiomics features and clinical characteristics (i.e., pain type and degree of neurovascular compression) and yielded higher C-indices of 0.865 and 0.834 in the development and test cohorts, respectively. K‒M survival analysis indicated that the nomogram successfully stratified patients with CTN into high-risk and low-risk groups for poor outcomes (hazard ratio: 37.18, p < 0.001). CONCLUSION: Our study findings indicated that the clinical-radiomics nomogram exhibited promising performance in accurately predicting long-term pain outcomes following MVD. CLINICAL RELEVANCE STATEMENT: This model had the potential to aid clinicians in making well-informed decisions regarding the treatment of patients with CTN. KEY POINTS: Trigeminal neuralgia recurs in about one-third of patients after undergoing MVD. The clinical-radiomics nomogram stratified patients into high- and low-risk groups for poor surgical outcomes. Using this nomogram could better inform patients of recurrence risk and allow for discussion of alternative treatments.

Efficacy and Complications of Percutaneous Balloon Compression for Patients With Trigeminal Neuralgia With and Without Concomitant Continuous Pain.

BACKGROUND: Percutaneous balloon compression (PBC) has become one of the most common and effective minimally invasive treatments for trigeminal neuralgia (TN). However, the initial and long-term pain outcomes, as well as the complication rates of PBC for patients with TN with concomitant continuous pain (CCP) have yet to be specifically documented. OBJECTIVE: In this clinical study, we aimed to evaluate and compare the results of PBC in treating TN with and without CCP. STUDY DESIGN: Retrospective study. METHODS: This research retrospectively analyzed the pain outcomes and complications of 57 patients with TN with CCP and 118 patients with TN without CCP who had undergone PBC at our institution from January 2019 through June 2022. Procedures were performed by one senior neurosurgeon in a single center. The postdischarge follow-up and the collection of clinical data, including immediate and long-term pain relief, time to recurrence, and complications, were completed through phone contact by an independent neurosurgeon blind to the patients' information. Then, the results of the 2 groups were compared; demographic and clinical data were evaluated for possible predictive factors for poor pain outcomes. RESULTS: In this study, PBC immediately resulted in complete pain relief in 70.2% of patients with CCP and significant pain relief in 84.2% of patients with CCP. For patients without CCP, the rates were 73.7% for complete pain relief and 85.6% for significant pain relief. After a minimum 6-month follow-up period, the rates decreased to 52.6% for complete pain relief and 73.7% for significant pain relief in patients with CCP, compared to 54.2% and 75.4% in those without CCP. The initial and long-term pain control rates in patients without CCP were slightly higher than those with CCP, but the differences were not statistically significant (P = 0.878, P = 0.968, respectively). The incidences of postoperative complications were similar between patients with and without CCP (21.1% vs 22.0%, P = 0.883), whereas the remission rate of complications in patients with CCP was significantly lower than that in patients without CCP (25.0% vs 69.2%, P = 0.011). A longer symptoms duration and having a history of neurodestructive procedures were predictive factors for poor outcomes following PBC. LIMITATIONS: The study was performed in a single-center. The nature of this research is retrospective instead of prospective and randomized, with the inability to control completely for variables. Additionally, the follow-up duration was not long enough to observe recurrence in some patients. CONCLUSIONS: This is the first specifically reported experience treating TN with CCP with PBC. PBC can result in significant relief of both episodic and constant pain from TN with CCP. Patients with a longer duration of pain and prior neurodestructive procedures have a higher risk of poor outcomes. The presence of CCP is not associated with pain outcomes and should not be considered a contraindication to PBC.

Proximal trigeminal nerve atrophy is associated with favourable outcomes and persistent facial numbness following percutaneous balloon compression for primary trigeminal neuralgia.

OBJECTIVE: Whether nerve atrophy can affect the prognosis of primary trigeminal neuralgia (PTN) patients undergoing percutaneous balloon compression (PBC) remains unclear. This study aimed to determine the association between nerve characteristics observed on preoperative magnetic resonance imaging (MRI) and PBC outcomes. METHODS: Between January 2019 and December 2022, a cohort of 58 patients with unilateral PTN treated with PBC were analysed retrospectively and included in this study. The relationship between MRI findings, including the proximal and distal nerve cross-sectional areas (CSAs), and favourable pain outcomes (BNI Grades I-III) was analysed through Kaplan‒Meier analysis. RESULTS: After a mean follow-up period of 23.8 ± 13.0 months (range, 6-50 months), 48 (82.8%) patients with PTN were pain free with or without medication. A smaller proximal CSA ratio (proximal CSA of the affected nerve/proximal CSA of the unaffected nerve) was significantly associated with favourable outcomes. The Kaplan-Meier survival analysis showed that patients with proximal nerve atrophy (proximal CSA ratio ≤ 87% after receiver operating characteristic curve analysis) had a higher estimated 4-year probability of maintaining a favourable outcome than those without nerve atrophy (94.4% vs. 30.8%, p = 0.005). In addition, patients with proximal nerve atrophy were more likely to suffer from postoperative persistent facial numbness. CONCLUSIONS: Proximal nerve atrophy is correlated with both favourable outcomes and persistent facial numbness following PBC. Prospective studies are required to determine the optimal duration and pressure of balloon compression in relation to the proximal CSA ratio to achieve better pain outcomes and less facial numbness.

Association of concomitant continuous pain in trigeminal neuralgia with a narrow foramen ovale.

Background: The pathogenesis of concomitant continuous pain remains unclear and is worthy of further study. In this clinical study, we aimed to explore the potential role of a narrow foramen ovale in the development of concomitant continuous pain. Methods: A total of 108 patients with classical trigeminal neuralgia affecting the third branch of the trigeminal nerve and 46 healthy individuals were enrolled in this study. Three-dimensional reconstructed computerized tomography images of all participants were collected, and the morphometric features of the foramen ovale were examined by two investigators who were blinded to the clinical data of the patients. Results: In this cohort, patients with concomitant continuous pain suffered from more sensory abnormalities (18.4% vs. 2.9%, p = 0.015) and responded more poorly to medication (74.3% vs. 91.9%, p = 0.018) than patients without concomitant continuous pain. While no significant differences regarding the mean length (5.02 mm vs. 5.36 mm, p > 0.05) and area (22.14 mm2 vs. 23.80 mm2, p > 0.05) were observed between patients with and without concomitant continuous pain, the mean width of the foramen ovale on the affected side in patients with concomitant continuous pain was significantly narrower than that in patients without concomitant continuous pain (2.01 mm vs. 2.48 mm, p = 0.003). Conclusion: This neuroimaging and clinical study demonstrated that the development of concomitant continuous pain was caused by the compression of the trigeminal nerve owing to a narrow foramen ovale rather than responsible vessels in classical trigeminal neuralgia.

Therapeutic potential of single-nucleotide polymorphism-mediated interleukin-6 receptor blockade in cancer treatment: A Mendelian randomization study.

Background: Interleukin-6 (IL-6) is a crucial member of the cytokine network and plays a pivotal role in the pathogenesis of various diseases, including cancer. IL-6 receptor (IL-6R) blockade is widely employed as a therapeutic strategy; however, its efficacy in anticancer therapy remains ambiguous. Methods: An inverse variance-weighted Mendelian randomization (MR) analysis was conducted to assess the causal effects exerted by IL-6R blockade in remediating cancer. Drug-targeted single-nucleotide polymorphisms (SNPs) were introduced within 300 kb of the IL-6R gene. An instrumental variable comprising 26 SNPs represented IL-6 signaling downregulation and C-reactive protein level reduction. Datasets pertaining to the 33 types of cancer investigated in this study were acquired from the FinnGen genome-wide association study. Results: The selected instrumental variable lowered fibrinogen levels, confirming its ability to mimic IL-6R blockade. IL-6R blockade exhibited therapeutic effects on five different cancer types documented in the FinnGen database (N = 334,364, including 76,781 cancer patients): bladder (odds ratios (OR) = 0.563), laryngeal (OR = 0.293), eye (OR = 0.098), gallbladder (OR = 0.059), and myeloid leukemia (OR = 0.442); however, it simultaneously elevated the risk of developing basal cell carcinoma (OR = 1.312) and melanoma (OR = 1.311). Sensitivity analyses did not alter the primary results. Conclusion: Therefore, this study aimed to evaluate the potential and efficacy of SNP-based IL-6R blockade in treating cancer.

Mendelian randomization analysis revealed a gut microbiota-mammary axis in breast cancer.

Background: Observational epidemiological studies suggested an association between the gut microbiota and breast cancer, but it remains unclear whether the gut microbiota causally influences the risk of breast cancer. We employed two-sample Mendelian randomization (MR) analysis to investigate this association. Methods: We used summary statistics of the gut microbiome from a genome-wide association study (GWAS) of 18,340 individuals in the MiBioGen study. GWAS summary statistics for overall breast cancer risk and hormone receptor subtype-specific analyses were obtained from the UK Biobank and FinnGen databases, totaling 400,000 individuals. The inverse variance-weighted (IVW) MR method was used to examine the causal relationship between the gut microbiome and breast cancer and its subtypes. Sensitivity analyses were conducted using maximum likelihood, MR-Egger, and MR pleiotropic residual sums and outliers methods. Results: The IVW estimates indicated that an increased abundance of Genus_Sellimonas is causally associated with an increased risk of ER+ breast cancer [odds ratio (OR) = 1.09, p = 1.72E-04, false discovery rate (FDR) = 0.02], whereas an increased abundance of Genus_Adlercreutzia was protective against ER+ breast cancer (OR = 0.88, p = 6.62E-04, FDR = 0.04). For Her2+ breast cancer, an increased abundance of Genus_Ruminococcus2 was associated with a decreased risk (OR = 0.77, p = 4.91E-04, FDR = 0.04), whereas an increased abundance of Genus_Erysipelatoclostridium was associated with an increased risk (OR = 1.25, p = 6.58E-04, FDR = 0.04). No evidence of heterogeneity or horizontal pleiotropy was found. Conclusion: Our study revealed a gut microbiota-mammary axis, providing important data supporting the potential use of the gut microbiome as a candidate target for breast cancer prevention, diagnosis, and treatment.

Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype.

Introduction: The current approaches that are used to treat ischemic stroke suffer from poor targeting, lack of effectiveness, and potential off-target effects, necessitating the development of new therapeutic strategies to enhance neuronal cell survival and regeneration. This study aimed to investigate the role of microglial Netrin-1 in ischemic stroke, a topic that has not been fully understood. Methods: Netrin-1 levels and its primary receptor expressions were investigated in cerebral microglia from acute ischemic stroke patients and age-matched control subjects. A public database (GEO148350), which supplied RNAseq results for rat cerebral microglia in a middle cerebral artery occlusion (MCAO) model, was analyzed to assess the expression of Netrin-1, its major receptors, and genes related to macrophage function. A microglia-specific gene targeting approach and a delivery system allowing for crossing the blood-brain barrier were applied in a mouse model for ischemic stroke to investigate the role of microglial Netrin-1. Netrin-1 receptor signaling in microglia was observed and the effects on microglial phenotype, apoptosis, and migration were analyzed. Results: Across human patients, rat and mouse models, activation of Netrin-1 receptor signaling was mainly conducted via its receptor UNC5a in microglia, which resulted in a shift in microglial phenotype towards an anti-inflammatory or M2-like state, leading to a reduction in apoptosis and migration of microglia. Netrin-1-induced phenotypic change in microglia exerted protective effects on neuronal cells in vivo during ischemic stroke. Conclusion: Our study highlights the potential of targeting Netrin-1 and its receptors as a promising therapeutic strategy for promoting post-ischemic survival and functional recovery.

Presence of PD-1 similarity genes in monocytes may promote the development of type 1 diabetes mellitus and poor prognosis of pancreatic cancer.

INTRODUCTION: To identify proteins and corresponding genes that share sequential and structural similarity with programmed cell death protein-1 (PD-1) in patients with type 1 diabetes mellitus (T1DM) via bioinformatics analysis. RESEARCH DESIGN AND METHODS: All proteins with immunoglobulin V-set domain were screened in the human protein sequence database, and the corresponding genes were obtained in the gene sequence database. GSE154609 was downloaded from the GEO database, which contained peripheral blood CD14+ monocyte samples from patients with T1DM and healthy controls. The difference result and the similar genes were intersected. Analysis of gene ontology and Kyoto encyclopedia of genes and genomes pathways was used to predict potential functions using the R package 'cluster profiler'. The expression differences of intersected genes were analyzed in The Cancer Genome Atlas pancreatic cancer dataset and GTEx database using t-test. The correlation between the overall survival and disease-free progression of patients with pancreatic cancer was analyzed using Kaplan-Meier survival analysis. RESULTS: 2068 proteins with immunoglobulin V-set domain similar to PD-1 and 307 corresponding genes were found. 1705 upregulated differentially expressed genes (DEGs) and 1335 downregulated DEGs in patients with T1DM compared with healthy controls were identified. A total of 21 genes were overlapped with the 307 PD-1 similarity genes, including 7 upregulated and 14 downregulated. Of these, mRNA levels of 13 genes were significantly increased in patients with pancreatic cancer. High expression of MYOM3 and HHLA2 was significantly correlated with shorter overall survival of patients with pancreatic cancer, while high expression of FGFRL1, CD274, and SPEG was significantly correlated with shorter disease-free survival of patients with pancreatic cancer. CONCLUSIONS: Genes encoding immunoglobulin V-set domain similar to PD-1 may contribute to the occurrence of T1DM. Of these genes, MYOM3 and SPEG may serve as potential biomarkers for the prognosis of pancreatic cancer.

Improving Effects of Peripheral Nerve Decompression Microsurgery of Lower Limbs in Patients with Diabetic Peripheral Neuropathy.

BACKGROUND: Peripheral nerve decompression microsurgery can relieve nerve entrapment and improve the symptoms of DPN. However, postoperative tissue adhesion will produce new pressure on the nerves, affecting the surgical efficacy. In this study, a nerve conduit was used in the peripheral nerve decompression microsurgery to prevent postoperative adhesions, and the role of the nerve conduit in surgical nerve decompression was explored. METHODS: A total of 69 patients with DPN were recruited and randomly divided into three groups: the nerve conduit group, conventional surgery group, and control group. Two weeks before surgery and 6 months after surgery, patients in each group were clinically tested using the visual analog scale (VAS) score, neurophysiological test, Toronto clinical scoring system (TCSS) score, and two-point discrimination (2-PD) test. RESULTS: The patients' symptoms in the nerve conduit group were relieved to varying degrees, and the relief rate reached 90.9%; the treatment efficacy was higher than that in the other groups. The postoperative nerve conduction velocity (NCV) in the two surgical groups was significantly higher than that before the surgery, and the difference between the nerve conduit group and the conventional surgery group was statistically significant (p < 0.05). For the 2-PD test, there was a statistically significant difference between the two surgical groups (p < 0.05). The TCSS score in the two surgical groups was significantly higher than that in the control group (p < 0.01). There was a significant difference in the TCSS scores between the nerve conduit group and the conventional surgery group (p < 0.05). CONCLUSIONS: The nerve conduit could further improve the efficacy of peripheral nerve decompression microsurgery in the treatment of DPN.

Multi-omics analysis revealed the role of CYP1A2 in the induction of mechanical allodynia in type 1 diabetes.

Background: Mechanical allodynia (MA) is one of the leading clinical symptoms of painful diabetic peripheral neuropathy (PDPN), which is a primary reason for non-traumatic amputations, foot ulceration, and gait abnormalities in patients with diabetes. However, the pathogenic mechanisms of MA have not yet been fully elucidated, and there is no effective treatment. This study aims to study the potential pathogenetic mechanisms of MA and to provide targets for the therapy of MA. Methods: A single intraperitoneal injection of streptozotocin induced type 1 diabetes in rat models. Subsequently, rats were divided into the control group, the diabetic group without MA, and the diabetic group with MA based on weekly behavioral assays. The differentially expressed lipids in the sciatic nerve of each group were detected using untargeted lipidomics, and the differentially expressed genes in the sciatic nerve of each group were detected by transcriptomics. The pathogenesis of MA was predicted using integrated analysis and validated by immunofluorescence staining and transmission electron microscopy. Results: Untargeted lipidomics revealed the accumulation of a more severe lipid in MA rats. Transcriptomics results suggested that differentially expressed genes in MA rats were primarily related to lipid droplets and myelin sheath. Integrated analysis results indicated that the downregulation of Cytochrome P450 1A2 (CYP1A2) expression was closely linked to lipid metabolism disorders. Immunofluorescence staining demonstrated that down-regulation of CYP1A2 expression occurred in MA rats. Transmission electron microscopy results showed that more severe lipid droplet accumulation and myelin sheath degeneration occurred in MA rats. Conclusion: Our findings imply that the downregulation of CYP1A2 expression leads to disorders of lipid metabolism and further leads to lipid droplet accumulation and myelin sheath degeneration, which might ultimately lead to the development of MA. Therefore, our study contributes to promoting the understanding of the molecular mechanisms of MA and providing potential targets for the clinical treatment of MA.

Netrin-1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m-AAA protease AFG3L2.

Cerebral ischemia-reperfusion (I/R) injury as the consequence of revascularization after ischemic stroke is associated with mitochondrial dysfunction, oxidative stress, and neuron loss. In this study, we used a deprivation/reoxygenation (OGD/R) model to determine whether interactions between Netrin-1, AKT, and the mitochondrial AAA protease AFG3L2 could influence mitochondrial function in neurons after I/R. We found that Netrin-1 protects primary cortical neurons from OGD/R-induced cell death and regulates mitochondrial reactive oxygen species (ROS) and Ca2+ levels. The accumulation of mitochondrial calcium uniporter (MCU) subunits was monitored in cells by immunoblot analysis. Although the regulatory subunits MICU1 and MICU2 were relatively unaffected, the accumulation of the essential MCU regulator (EMRE) subunit was impaired. In OGD/R-induced cells, the 7 kDa form of EMRE was significantly reduced. Netrin-1 inhibited the accumulation of EMRE and mitochondrial Ca2+ levels by upregulating AFG3L2 and AKT activation. Loss of AFG3L2 or inhibition of AKT increased levels of 7 kDa EMRE. Moreover, overexpression of AKT increased the expression of AFG3L2 in Netrin-1-knockdown neurons after OGD/R. Our results demonstrate that Netrin-1 enhanced AFG3L2 protein expression via activation of AKT. We also observed that overexpression of Netrin-1 significantly reduced infarction size in an I/R-induced brain injury model in rats but not when AKT was inhibited. Our data suggest that AFG3L2 is a protein substrate of AKT and indicate that Netrin-1 attenuates cerebral I/R injury by limiting mitochondrial ROS and Ca2+ levels through activating AKT phosphorylation and AFG3L2.

Lipoblastoma in one adult and 35 pediatric patients: Retrospective analysis of 36 cases.

Lipoblastoma is a rare benign mesenchymal neoplasm that typically occurs at various sites in infants and children but may also occur in adults. Thus, differential diagnoses are often performed. To understand this tumor type, the present study described clinicopathological features, diagnosis and differential diagnosis of different morphological lipoblastomas. A single-institution retrospective review of 36 lipoblastoma cases diagnosed between 2015 and 2021 was performed. Formalin-fixed paraffin-embedded tissue was used for S-100, CD34, P16 and desmin immunohistochemistry analysis, along with rapid fluorescence in situ hybridization (FISH) detection with pleiomorphic adenoma gene 1 (PLAG1). The 36 cases included 14 females and 22 males [age range, 7 days to 33 years (median, 16.5 years); 28 patients were aged ≤3 years] and the tumors were located in the trunk (n=16), limbs (n=12), head and neck (n=6), and perineum (n=2). Histologically, lipoblastomas were divided into classic (n=15), lipoma-like (n=13) and myxoid (n=8) subtypes. They comprised lobules of mature adipose tissue of varying size and a fine capillary network surrounded by mucinous stroma. Single- or multivesicular lipoblasts positive for S-100 (29/36, 81%) were observed, with occasional mature adipocytes. Peripheral vessels and cytoplasm of primitive mesenchymal cells were diffusely positive for CD34 (36/36, 100%), whereas primitive mesenchymal cells and striated muscle tissue were positive for desmin (26/36, 72%). Most tumor cells were negative while only few were positive for P16 (8/36, 22%). FISH revealed PLAG1 breakage and rearrangement in 24/32 (75%) patients. In total, 28 patients were followed up post-operatively (range, 2-84 months; median, 41 months; 3 patients relapsed and 8 were lost to follow-up). In conclusion, diagnosis of a typical lipoblastoma is not difficult and PLAG1 breakage detection is key for the diagnosis.

Impact of ferroptosis-related risk genes on macrophage M1/M2 polarization and prognosis in glioblastoma.

Objective: To explore the effect impact of ferroptosis on macrophage polarization and patient prognosis in glioblastoma. Methods: We screened ferroptosis-related risk from the public datasets of primary and recurrent glioblastoma, combined with reported ferroptosis genes, calculated the risk genes among the ferroptosis-related genes using the LASSO Cox regression model, and investigated the relationship between these ferroptosis-related risk genes in the tumor and the spectrum of infiltrating M1/M2 macrophages. Macrophages were analyzed using the CIBERSORTx deconvolution algorithm. Samples from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and a single-cell RNA sequencing dataset (GSE84465) were included. The expression levels of ferroptosis-related risk genes and molecular markers of M1 and M2 macrophages were detected by qPCR and western blot. Results: A total of fourteen ferroptosis-related risk genes were obtained and the patients' risk scores were calculated. Compared with patients in the low-risk group, patients in the high-risk group had worse prognosis. The M1/M2 macrophage ratio and risk score were negatively correlated, indicating that the tumor microenvironment of glioblastoma in the high-risk group contained more M2 than M1 macrophages. In the single-cell RNA sequencing dataset, the risk score of ferroptosis-related genes in tumor cells was positively correlated with the proportion of high M2 macrophages. The expression of eight ferroptosis-related risk genes was increased in glioblastoma cell, which promoted the polarization of M1 macrophages to M2. Conclusion: We investigated the fourteen ferroptosis-related risk genes in glioblastoma for the first time, and clarified the impact of ferroptosis-related risk genes on M1/M2 macrophage polarization and patient prognosis.

Causal relationship between gut microbes and cardiovascular protein expression.

Evidence supports associations between gut microbiota and cardiovascular protein levels in plasma. However, it is unclear whether these associations reflect a causal relationship. To reveal the causal relationship between gut microbiota and cardiovascular protein levels in plasma, we estimated their causal effects using two-sample Mendelian randomization (MR) analysis. Sensitivity analysis was also performed to assess the robustness of our results. Genome-wide association study (GWAS) of microbiomes in the MiBioGen study included 211 bacterial taxa (18,473 individuals), and GWAS of 90 cardiovascular proteins included 30,931 individuals. There were 196 bacterial taxa from five levels available for analysis. The following 14 causal relationships were identified: phylum Euryarchaeota and carbohydrate antigen 125 (ß = 0.289), order Bacillales and CSF-1 (ß = -0.211), genus Dorea and HSP-27 (ß = 0.465), phylum Actinobacteria and IL-8 (ß = 0.274), order Enterobacteriales and KIM-1 (ß = -0.499), class Actinobacteria, genus Bifidobacterium, phylum Actinobacteria and LEP (ß = -0.219, ß = -0.201, and ß = -0.221), genus Methanobrevibacter and NT-proBNP (ß = 0.371), family Peptostreptococcaceae and SRC (ß = 0.191), order Verrucomicrobiales, phylum Verrucomicrobia and TNF-R2 (ß = 0.251 and ß = 0.233), family Veillonellaceae and t-PA (ß = 0.271), and class Erysipelotrichia and VEGF-D (ß = 0.390). Sensitivity analysis showed no evidence of pleiotropy or heterogeneity. The results of the reverse MR analysis showed no reverse causality for any of the 13 gut microbes and 11 cardiovascular proteins. Mendelian randomization estimates provide strong evidence for a causal effect of gut microbiota-mediated alterations on cardiovascular protein expression.

DUSP8/TAK1 signaling mediates neuropathic pain through regulating neuroinflammation and neuron death in a spinal nerve ligation (SNL) rat model.

Nerve injury-induced neuropathic pain is a type of chronic pain associated with neuroinflammatory response and neuronal death; however the underlying molecular mechanisms are still unclear. Dual-specificity phosphatase 8 (DUSP8) can mediate numerous cellular events, but whether it's involved in neuropathic pain is unknown. In the study, we found that spinal nerve ligation (SNL) operation on rats significantly decreased DUSP8 expression levels in ipsilateral spinal cord (ISC) tissues. Consistently, lipopolysaccharide (LPS) exposure also reduced DUSP8 in murine microglial cells. Adeno-associated virus (AAV)-mediated DUSP8 over-expression was found to considerably ameliorate SNL-induced neuropathic pain in rats. Additionally, neuronal death in the ISC tissues was also attenuated by AAV-DUSP8 following SNL surgery. Moreover, SNL-triggered neuroinflammation and microglial activation were also mitigated upon DUSP8 over-expression by suppressing nuclear factor κB (NF-κB) signaling, which were validated in LPS-exposed microglial cells. Importantly, our in vitro experiments indicated that inflammatory response in microglial cells contributed to neuron death, and such effect could also be ameliorated by DUSP8 over-expression. Notably, we found that DUSP8 directly interacted with transforming growth factor ß activated kinase-1 (TAK1) in microglial cells. Both SNL and LPS led to the activation of TAK1/p38/JNK1/2 signaling, whereas being strongly abolished by DUSP8. Intriguingly, TAK1 blockage significantly diminished LPS-induced inflammation and neuron death, whereas being accelerated by DUSP8 knockdown, further indicating that DUSP8-ameliorated neuropathic pain was largely TAK1-dependent. Together, all our findings revealed that DUSP8/TAK1 signaling may be a potential target for neuropathic pain alleviation.

Narrow ovale foramina may be involved in the development of primary trigeminal neuralgia.

Background: The etiology of primary trigeminal neuralgia remains unclear and is worthy of further study; In this study, the morphometric characteristics of ovale foramina between various groups were compared and analyzed to explore the novel cause of primary trigeminal neuralgia. Methods: High-resolution three-dimensional reconstruction images from head computed tomography of 109 patients with primary trigeminal neuralgia affecting the third branch of the trigeminal nerve and 46 healthy controls were retrospectively reviewed. Among the 109 primary trigeminal neuralgia patients, 79 patients with apparent neurovascular compression (not simply contact) demonstrated on MRI or during surgery were divided into the classical trigeminal neuralgia group and 30 patients with MRI showing no significant abnormalities were divided into idiopathic trigeminal neuralgia group. The morphometric parameters including the area, width and length of ovale foramina were examined through the use of radiologic methods. Results: In this study, the average minimum area, width and length of 79 ovale foramina on the affected and unaffected sides in the classical trigeminal neuralgia group were 21.83 ± 8.45, 21.94 ± 7.93 mm2, 2.32 ± 0.91, 2.58 ± 0.81, 5.32 ± 1.29, and 5.26 ± 1.21 mm, respectively. No significant difference in these parameters was observed (p > 0.05). However, in the idiopathic trigeminal neuralgia group, the average minimum area, width and length of 30 ovale foramina were 21.33 ± 8.21, 22.85 ± 8.36 mm2, 2.25 ± 0.90, 2.79 ± 0.96, 5.20 ± 1.27, and 5.28 ± 1.19 mm, respectively. The width on the symptomatic side was significantly smaller (p = 0.03) than that on the asymptomatic side. No significant difference in area (p = 0.48) or length (p = 0.79) was observed. In addition, when compared with the healthy control group, the area and width of ovale foramina on the symptomatic side in both groups were significantly smaller. No significant difference in length was observed. Conclusions: By comparing and analyzing the statistical data, it can be inferred that a narrow foramen ovale is associated with primary trigeminal neuralgia, as well as its recurrence after microvascular decompression.

The efficacy of paxlovid in elderly patients infected with SARS-CoV-2 omicron variants: Results of a non-randomized clinical trial.

Objective: To evaluate the efficacy of Paxlovid in treating Chinese elder patients infected with SARS-CoV-2 omicron variants. Materials and methods: We performed a non-randomized, controlled trial in Shanghai, China. Participants infected with SARS-CoV-2 omicron variants were enrolled. All patients were divided into the Paxlovid group or the control group according to the Chinese guideline (version 9). The nucleic acid shedding time was the primary endpoint. Results: According to the inclusion criteria, 142 patients infected with omicron variants were enrolled, 36 patients who did not receive paxlovid were assigned to the control group, and 106 were in the Paxlovid group. The baseline characteristics were similar in either group. No significant difference in BMI, age, time from onset to patient enrollment, the severity on first admission, vaccination status, comorbidity, first symptoms, and laboratory results were recorded. Compared to the control group, participants in the Paxlovid group had a shorter viral shedding time [11.11 (2.67) vs. 9.32 (2.78), P = 0.001]. Conclusion: In Chinese elder patients infected with the variant of SARS-CoV-2 omicron, our data suggest that Paxlovid can significantly reduce the nucleic acid shedding time.