Transradial approach for middle meningeal artery embolization is a safe alternative to transfemoral approach in patients with chronic subdural hematoma: A single-center retrospective comparative study.

BACKGROUND: Transradial approach (TRA) has been increasingly utilized in various neuroendovascular interventions as a safe alternative to the transfemoral approach (TFA). As middle meningeal artery (MMA) embolization emerges as an effective therapy for treating chronic subdural hematomas (cSDH), some studies have explored using TRA. In this study, we compared procedural times and post-operative outcomes between those with TRA and TFA. METHODS: This is a single-institution retrospective study of patients undergoing MMA embolization for cSDH. The cohort was divided into the TRA and TFA subgroups. Baseline characteristics, procedural times, and immediate outcomes were compared. Univariate analysis was performed. RESULTS: We performed 62 MMA embolizations for treatment of cSDH, of which 37 (59.7 %) were performed transradial and 25 (40.3 %) were performed transfemoral. Those who underwent TRA were significantly younger than those who had TFA (p = 0.02). For patients who underwent unilateral MMA embolization, those with TRA had significantly shorter duration of procedure compared to the TRF group (p = 0.01). This difference was not observed in the bilateral MMA embolization subgroup. Only three patients had access site complications, and all were in the TFA group. There was no significant difference in length of hospital stay. CONCLUSION: As MMA embolization for cSDH becomes more prevalent, efforts to optimize the safety and efficacy of the technical aspects become critical. In this study we demonstrate that TRA is a safe and efficient alternative to traditional TFA in those undergoing unilateral MMA embolization.

The functional antagonist of sphingosine-1-phosphate, FTY720, impairs gut barrier function.

FTY720 or fingolimod is a known functional antagonist of sphingosine-1-phosphate (S1P), and it is effective in treating multiple sclerosis and preventing inflammatory bowel disease (IBD). Evidence shows that its use in mice can increase the susceptibility to mucosal infections. Despite the significant contribution of S1P to barrier function, the effect of the administration of FTY720 on the mucosal barrier has never been investigated. In this study, we looked into how FTY720 therapy affected the function of the gut barrier susceptibility. Administration of FTY720 to C57BL/6 mice enhances the claudin-2 expression and reduces the expression of claudin-4 and occludin, as studied by qPCR, Western blot, and immunofluorescence. FTY720 inhibits the Akt-mTOR pathway to decrease occludin and claudin-4 expression and increase claudin-2 expression. FTY720 treatment induced increased colonic inflammation, with notably greater immune cell infiltration, colon histopathology, and increased production of TNF-α, IFN-γ, CXCL-1, and CXCL-2 than that in control mice. Taking into account the close association of "the leaky gut" and gut dysbiosis among the major diseases, we therefore can infer that the vigilance of gut pathology should be maintained, where FTY720 is used as a treatment option.

Cost Savings on Inpatient Hospitalization for Middle Meningeal Artery Embolization in the Setting of Increased Case Volume and Low Complications Rate.

BACKGROUND: Middle meningeal artery (MMA) embolization for the treatment of chronic subdural hematomas (cSDHs) is becoming increasingly prevalent. It is essential to optimize the safety and cost effectiveness of the postprocedural management. In this study, we examined our cases over time to determine the most appropriate postprocedural destination. METHODS: This is a retrospective study of patients who underwent MMA embolization for cSDH at our institution. The study cohort was divided into 2 groups based on the year of embolization. Baseline characteristics, postprocedural complications, and length of stay were compared. Patients with shorter intensive care unit (ICU) stay were also compared to those with longer stay. Univariate statistical analysis was performed. RESULTS: 92 MMA embolizations for cSDH have been performed at our institution, of which 36 (39.1%) were done between 2019 and 2022 and 56 (60.9%) after 2023. No patients experienced stroke, cranial nerve palsy, or intraparenchymal hemorrhage after embolization. All but 5 patients were admitted to the ICU postembolization, of which 59 (64.1%) were downgraded after one day. Factors associated with a longer ICU stay included preoperative location (P = 0.002) and need for surgery (P = 0.02). Of those who came from home or nonmonitored bed, 82% were downgraded from the ICU in less than 2 days. The average cost of one night in the ICU, intermediate care, and nonmonitored unit was $3671.75, $2605.22, and $2303.81 respectively. CONCLUSIONS: MMA embolization for cSDH is a safe procedure with low rate of procedure-related complications. In carefully selected patients, the necessity ICU admission postoperatively should be weighed against better hospital resource utilization.

Machine Learning Identifies Variation in Timing of Palliative Care Consultations Among Traumatic Brain Injury Patients.

Background and Objective Timely palliative care involvement offers demonstrable benefits for traumatic brain injury (TBI) patients; however, palliative care consultations (PCCs) are used inconsistently during TBI management. This study aimed to employ advanced machine learning techniques to elucidate the primary drivers of PCC timing variability for TBI patients. Methods Data on admission, hospital course, and outcomes were collected for a cohort of 232 TBI patients who received both PCCs and neurosurgical consultations during the same hospitalization. Principal Component Analysis (PCA) and K-means clustering were used to identify patient phenotypes, which were then compared using Kaplan-Meier analysis. An extreme gradient boosting model (XGBoost) was employed to determine drivers of PCC timing, with model interpretation performed using SHapley Additive exPlanations (SHAP). Results Cluster A (n = 86) consisted mainly of older (median [IQR] = 87 [78, 94] years), White females with mild TBIs and demonstrated the shortest time-to-PCC (2.5 [1.0, 7.0] days). Cluster B (n = 108) also sustained mild TBIs but comprised moderately younger (81 [75, 86] years) married White males with later PCC (5.0 [3.0, 10.8] days). Cluster C (n = 38) represented much younger (46.5 [29.5, 59.8] years), more severely injured, non-White patients with the latest PCC initiation (9.0 [4.2, 17.0] days). The clusters did not differ by discharge disposition (p = 0.4) or frequency inpatient mortality (p > 0.9); however, Kaplan-Meier analysis revealed a significant difference in the time from admission to PCC (p < 0.001), despite no differences in time from admission to mortality (p = 0.18). SHAP analysis of the XGBoost model identified age, sex, and race as the most influential drivers of PCC timing. Conclusions This study highlights crucial disparities in PCC timing for TBI patients and underscores the need for targeted strategies to ensure timely and equitable palliative care integration for this vulnerable population.

Nerve-Targeted Surgical Treatments for Spasticity: A Narrative Review.

Spasticity is a potentially debilitating symptom of various acquired and congenital neurologic pathologies that, without adequate treatment, may lead to long-term disability, compromise functional independence, and negatively impact mental health. Several conservative as well as non-nerve targeted surgical strategies have been developed for the treatment of spasticity, but these may be associated with significant drawbacks, such as adverse side effects to medication, device dependence on intrathecal baclofen pumps, and inadequate relief with tendon-based procedures. In these circumstances, patients may benefit from nerve-targeted surgical interventions such as (i) selective dorsal rhizotomy, (ii) hyperselective neurectomy, and (iii) nerve transfer. When selecting the appropriate surgical approach, preoperative patient characteristics, as well as the risks and benefits of nerve-targeted surgical intervention, must be carefully evaluated. Here, we review the current evidence on the efficacy of these nerve-targeted surgical approaches for treating spasticity across various congenital and acquired neurologic pathologies.

PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma.

Glioblastoma (GBM) is an immunologically "cold" tumor that does not respond to current immunotherapy. Here, we demonstrate a fundamental role for the α-isoform of the catalytic subunit of protein phosphatase-2A (PP2Ac) in regulating glioma immunogenicity. Genetic ablation of PP2Ac in glioma cells enhanced double-stranded DNA (dsDNA) production and cGAS-type I IFN signaling, MHC-I expression, and tumor mutational burden. In coculture experiments, PP2Ac deficiency in glioma cells promoted dendritic cell (DC) cross-presentation and clonal expansion of CD8+ T cells. In vivo, PP2Ac depletion sensitized tumors to immune-checkpoint blockade and radiotherapy treatment. Single-cell analysis demonstrated that PP2Ac deficiency increased CD8+ T-cell, natural killer cell, and DC accumulation and reduced immunosuppressive tumor-associated macrophages. Furthermore, loss of PP2Ac increased IFN signaling in myeloid and tumor cells and reduced expression of a tumor gene signature associated with worse patient survival in The Cancer Genome Atlas. Collectively, this study establishes a novel role for PP2Ac in inhibiting dsDNA-cGAS-STING signaling to suppress antitumor immunity in glioma. SIGNIFICANCE: PP2Ac deficiency promotes cGAS-STING signaling in glioma to induce a tumor-suppressive immune microenvironment, highlighting PP2Ac as a potential therapeutic target to enhance tumor immunogenicity and improve response to immunotherapy.

Butyrate driven raft disruption trots off enteric pathogen invasion: possible mechanism of colonization resistance.

The gut microbiome derived short chain fatty acids perform multitude of functions to maintain gut homeostasis. Here we studied how butyrate stymie enteric bacterial invasion in cell using a simplistic binary model. The surface of the mammalian cells is enriched with microdomains rich in cholesterol that are known as rafts and act as entry points for pathogens. We showed that sodium butyrate treated RAW264.7 cells displayed reduced membrane cholesterol and less cholera-toxin B binding coupled with increased membrane fluidity compared to untreated cells indicating that reduced membrane cholesterol caused disruption of lipid rafts. The implication of such cellular biophysical changes on the invasion of enteric pathogenic bacteria was assessed. Our study showed, in comparison to untreated cells, butyrate-treated cells significantly reduced the invasion of Shigella and Salmonella, and these effects were found to be reversed by liposomal cholesterol treatment, increasing the likelihood that the rafts' function against bacterial invasion. The credence of ex vivo studies found to be in concordance in butyrate fed mouse model as evident from the significant drift towards a protective phenotype against virulent enteric pathogen invasion as compared to untreated mice. To produce a cytokine balance towards anti-inflammation, butyrate-treated mice produced more of the gut tissue anti-inflammatory cytokine IL-10 and less of the pro-inflammatory cytokines TNF-α, IL-6, and IFN-γ. In histological studies of Shigella infected gut revealed a startling observation where number of neutrophils infiltration was noted which was correlated with the pathology and was essentially reversed by butyrate treatment. Our results ratchet up a new dimension of our understanding how butyrate imparts resistance to pathogen invasion in the gut.

PP2Ac/STRN4 negatively regulates STING-type I IFN signaling in tumor-associated macrophages.

Stimulator of IFN genes type I (STING-Type I) IFN signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonists as monotherapy have shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in macrophages. Mice with macrophage PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that Hippo kinase MST1/2 was required for STING activation. STING agonists induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of Hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human patients with glioblastoma (GBM), YAP/TAZ was highly expressed in tumor-associated macrophages but not in nontumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor-conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ has, in our opinion, been an unappreciated mechanism that mediates immunosuppression in tumor-associated macrophages, and targeting the PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.

Prenatal arsenic exposure stymies gut butyrate production and enhances gut permeability in post natal life even in absence of arsenic deftly through miR122-Occludin pathway.

This discourse attempts to capture a few important dimensions of gut physiology like microbial homeostasis, short chain fatty acid (SCFA) production, occludin expression, and gut permeability in post-natal life of mice those received arsenic only during pre-natal life. Adult Balb/c mice were fed with 4 ppm arsenic trioxide in drinking water during breeding and gestation. After the birth of the pups, the arsenic water was withdrawn and replaced with clean drinking water. The pups were allowed to grow for 28 days (pAs-mice) and age matched Balb/c mice which were never exposed to arsenic served as control The pAs-mice showed a striking reduction in Firmicutes to Bacteroidetes (F/B) ratio coupled with a decrease in tight junction protein, occludin resulting in an increase in gut permeability, increased infiltration of inflammatory cells in the colon and decrease in common SCFAs in which butyrate reduction was quite prominent in fecal samples as compared to normal control. The above phenotypes of pAs-mice were mostly reversed by supplementing 5% sodium butyrate (w/w) with food from 21st to 28th day. The ability of butyrate in enhancing occludin expression, in particular, was dissected further. As miR122 causes degradation of Occludin mRNA, we transiently overexpressed miR122 by injecting appropriate plasmids and showed reversal of butyrate effects in pAs-mice. Thus, pre-natal arsenic exposure orchestrates variety of effects by decreasing butyrate in pAs-mice leading to increased permeability due to reduced occludin expression. Our research adds a new dimension to our understanding that pre-natal arsenic exposure imprints in post-natal life while there was no further arsenic exposure.

AUF-1 knockdown in mice undermines gut microbial butyrate-driven hypocholesterolemia through AUF-1-Dicer-1-mir-122 hierarchy.

Introduction and objective: Cholesterol homeostasis is a culmination of cellular synthesis, efflux, and catabolism to important physiological entities where short chain fatty acid, butyrate embodied as a key player. This discourse probes the mechanistic molecular details of butyrate action in maintaining host-cholesterol balance. Methods: Hepatic mir-122 being the most indispensable regulator of cholesterol metabolic enzymes, we studied upstream players of mir-122 biogenesis in the presence and absence of butyrate in Huh7 cells and mice model. We synthesized unique self-transfecting GMO (guanidinium-morpholino-oligo) linked PMO (Phosphorodiamidate-Morpholino Oligo)-based antisense cell-penetrating reagent to selectively knock down the key player in butyrate mediated cholesterol regulation. Results: We showed that butyrate treatment caused upregulation of RNA-binding protein, AUF1 resulting in RNase-III nuclease, Dicer1 instability, and significant diminution of mir-122. We proved the importance of AUF1 and sequential downstream players in AUF1-knock-down mice. Injection of GMO-PMO of AUF1 in mouse caused near absence of AUF1 coupled with increased Dicer1 and mir-122, and reduced serum cholesterol regardless of butyrate treatment indicating that butyrate acts through AUF1. Conclusion: The roster of intracellular players was as follows: AUF1-Dicer1-mir-122 for triggering butyrate driven hypocholesterolemia. To our knowledge this is the first report linking AUF-1 with cholesterol biogenesis.