An In-Vitro Comparison of Mixed Reality Navigation to Traditional Freehand and Patient Specific Instrumentation Techniques for Glenoid Guide Pin Insertion during Shoulder Arthroplasty.

BACKGROUND: Accurate insertion of the glenoid guide pin in shoulder arthroplasty (RSA) is important for obtaining optimized glenoid component position and orientation. The objective of this study was to evaluate and compare the accuracy of three glenoid guide pin insertion techniques: 1) traditional software planning using freehand guide pin insertion (freehand), 2) guide pin insertion utilizing patient-specific instrumentation (PSI), and 3) using a mixed reality navigation (MR-NAV) system. METHODS: Twenty (20) computer tomography (CT) scans were obtained from patients exhibiting glenoid erosion patterns according to the Walch and Favard classifications. Cases were planned using validated three-dimensional (3D) preoperative planning software. The CT data was then used to 3D print triplicate plastic models of each glenoid to evaluate the three guide pin insertion techniques. The first technique employed traditional software planning with freehand guide pin insertion. The second method used preoperatively planned PSI guides, while the third utilized a MR-NAV system, which provided real-time holographic guidance during guide pin insertion. Once all guide pins had been inserted into the models, an independent optical tracking system and custom digitization device was used to quantify the position and orientation of each guide pin relative to the glenoid. The outcomes for this study included the absolute mean error in guide pin inclination, version, and entry point relative to the preoperative plan. The absolute Total Global Error was also assessed, which was defined as the sum of the absolute guide pin orientation and position error relative to the preoperative plan. RESULTS: No statistically significant differences between MR-NAV and PSI were found for the inclination error (2±1° versus 2±1°; P=0.056), version error (1±1° versus 1±1°; P=1.000), and Total Global Error (5±1 [mm+deg] versus 5±1 [mm+deg], P=1.000), respectively. The freehand technique produced significantly greater error than MR-NAV and PSI for inclination (5±3°, P≤0.017), version (4±3°, P≤0.032) and Total Global Error (8±3 [mm+deg], P<0.001). No statistically significant differences in the entry point error were observed between all guide pin insertion methods (P≥0.058). DISCUSSION: These results demonstrate that the precision and accuracy of MR-NAV is comparable to PSI and superior to a freehand technique for glenoid guide pin insertion in-vitro. Further study is needed to compare the accuracy of these techniques intra-operatively, in addition to assessing a potential learning curve between surgeons of varying experience with the MR-NAV system.

Practical Answers to Frequently Asked Questions in Anterior Cervical Spine Surgery for Degenerative Conditions.

INTRODUCTION: Surgical counseling enables shared decision making and optimal outcomes by improving patients' understanding about their pathologies, surgical options, and expected outcomes. Here, we aimed to provide practical answers to frequently asked questions (FAQs) from patients undergoing an anterior cervical diskectomy and fusion (ACDF) or cervical disk replacement (CDR) for the treatment of degenerative conditions. METHODS: Patients who underwent primary one-level or two-level ACDF or CDR for the treatment of degenerative conditions with a minimum of 1-year follow-up were included. Data were used to answer 10 FAQs that were generated from author's experience of commonly asked questions in clinic before ACDF or CDR. RESULTS: A total of 395 patients (181 ACDF, 214 CDR) were included. (1, 2, and 3) Will my neck/arm pain and physical function improve? Patients report notable improvement in all patient-reported outcome measures. (4) Is there a chance I will get worse? 13% (ACDF) and 5% (CDR) reported worsening. (5) Will I receive a significant amount of radiation? Patients on average received a 3.7 (ACDF) and 5.5 mGy (CDR) dose during. (6) How long will I stay in the hospital? Most patients get discharged on postoperative day one. (7) What is the likelihood that I will have a complication? 13% (8% minor and 5% major) experienced in-hospital complications (ACDF) and 5% (all minor) did (CDR). (8) Will I need another surgery? 2.2% (ACDF) and 2.3% (CDR) of patients required a revision surgery. (9 & 10) When will I be able to return to work/driving? Most patients return to working (median of 16 [ACDF] and 14 days [CDR]) and driving (median of 16 [ACDF] and 12 days [CDR]). CONCLUSIONS: The answers to the FAQs can assist surgeons in evidence-based patient counseling.

A Scapular Statistical Shape Model can Reliably Predict Premorbid Glenoid Morphology in Conditions of Severe Glenoid Bone Loss.

BACKGROUND: Knowledge of premorbid glenoid parameters at the time of shoulder arthroplasty, such as inclination, version, joint line position, height, and width, can assist with implant selection, implant positioning, metal augment sizing and/or bone graft dimensions. The objective of this study was to validate a scapular statistical shape model (SSM) in predicting patient-specific glenoid morphology in scapulae with clinically relevant glenoid erosion patterns. METHODS: Computer tomography scans of 30 healthy scapulae were obtained and used as the control group. Each scapula was then virtually eroded to create seven erosion patterns (Walch A1, A2, B2, B3, D, Favard E2, and E3). This resulted in 210 uniquely eroded glenoid models, forming the eroded glenoid group. A scapular SSM, created from a different database of 85 healthy scapulae, was then applied to each eroded scapula to predict the premorbid glenoid morphology. The premorbid glenoid inclination, version, height, width, radius of best fit sphere, and glenoid joint line position were automatically calculated for each of the 210 eroded glenoids. The mean values for all outcome variables were compared across all erosion types between the healthy, eroded, and SSM predicted groups using a two-way repeated-measures analysis of variance. RESULTS: The SSM was able to predict the mean premorbid glenoid parameters of the eroded glenoids with a mean absolute difference of 3±2° for inclination, 3±2° for version, 2±1mm for glenoid height, 2±1mm for glenoid width, 5±4mm for radius of best fit sphere, and 1±1mm for glenoid joint line. The mean SSM predicted values for inclination, version, height, width, and radius were not significantly different than the control group (P>0.05). DISCUSSION: A statistical shape model has been developed that can reliably predict premorbid glenoid morphology and glenoid indices in patients with common glenoid erosion patterns. This technology can serve as a useful template to visually represent the premorbid healthy glenoid in patients with severe glenoid bony erosions. Knowledge of the premorbid glenoid preoperatively can assist with implant selection, positioning, and sizing.

The Kouvalchouk Procedure versus Distal Tibial Allograft for Treatment of Posterior Shoulder Instability: The Deltoid "Hammock" Effect Exists.

BACKGROUND: In 1993, Kouvalchouk described an acromial bone block with a pedicled deltoid flap for the treatment of posterior shoulder instability. This procedure provides a "double blocking" effect in that the acromial autograft restores posterior glenoid bone loss and the deltoid flap functions as a muscular "hammock" resembling the sling effect of the conjoint in the Latarjet procedure. The primary aim of this study was to compare the Kouvalchouk procedure to distal tibial allograft (DTA) reconstruction for the management of posterior shoulder instability with associated bone loss, while the secondary aim was to evaluate the deltoid hammock effect. s METHODS: Ten upper extremity cadavers were evaluated using a validated shoulder testing apparatus in 0° and 60° of glenohumeral abduction in the scapular plane. Testing was first performed on the normal shoulder state and was followed by the creation of a 20% posterior glenoid defect. Subsequently, the Kouvalchouk and DTA procedures were conducted. Forces of 0N, 5N, 10N and 15N were applied to the posterior deltoid tendinous insertion on the Kouvalchouk graft along the physiological muscle line-of-action to evaluate the 'hammock" effect of this procedure. Testing was additionally performed on the Kouvalchouk bone graft with the deltoid muscle sectioned from its bony attachment. For all test states, a posteriorly directed force was applied to the humeral head perpendicular to the direction of the glenoid bone defect, with the associated translation quantified using an optical tracking system. The outcome variable was posterior translation of the humeral head at an applied force magnitude of 30N. RESULTS: The Kouvalchouk procedure with the loaded deltoid flap (10N: P=0.039 and 15N: P<0.001) was significantly better at reducing posterior humeral head translation than the DTA. Overall, increased glenohumeral stability was observed with increased force applied to the posterior deltoid flap in the Kouvalchouk procedure. The 15N Kouvalchouk was most effective at preventing posterior humeral translation, and the difference was statistically significant compared with the 20% glenoid defect (P=0.003), detached Kouvalchouk (P<0.001), and 0N Kouvalchouk (P<0.001). The 15N Kouvalchouk procedure restored posterior shoulder joint stability to near normal levels, such that it was not significantly different from the intact state (P=0.203). CONCLUSIONS: The Kouvalchouk procedure with load applied to the deltoid was found to be biomechanically superior to the DTA for the management of posterior shoulder instability with associated bone loss. Additionally, the results confirmed the presence and effectiveness of the deltoid "hammock" effect.

Updates of the role of B-cells in ischemic stroke.

Ischemic stroke is a major disease causing death and disability in the elderly and is one of the major diseases that seriously threaten human health and cause a great economic burden. In the early stage of ischemic stroke, neuronal structure is destroyed, resulting in death or damage, and the release of a variety of damage-associated pattern molecules induces an increase in neuroglial activation, peripheral immune response, and secretion of inflammatory mediators, which further exacerbates the damage to the blood-brain barrier, exacerbates cerebral edema, and microcirculatory impairment, triggering secondary brain injuries. After the acute phase of stroke, various immune cells initiate a protective effect, which is released step by step and contributes to the repair of neuronal cells through phenotypic changes. In addition, ischemic stroke induces Central Nervous System (CNS) immunosuppression, and the interaction between the two influences the outcome of stroke. Therefore, modulating the immune response of the CNS to reduce the inflammatory response and immune damage during stroke is important for the protection of brain function and long-term recovery after stroke, and modulating the immune function of the CNS is expected to be a novel therapeutic strategy. However, there are fewer studies on B-cells in brain function protection, which may play a dual role in the stroke process, and the understanding of this cell is still incomplete. We review the existing studies on the mechanisms of the role of B-cells, inflammatory response, and immune response in the development of ischemic stroke and provide a reference for the development of adjuvant therapeutic drugs for ischemic stroke targeting inflammatory injury.

Role of microRNA-34a in blood-brain barrier permeability and mitochondrial function in ischemic stroke.

Over the past decade, there has been an uptick in the number of studies conducting research on the role of microRNA (miRNA) molecules in stroke. Among these molecules, miR-34a has emerged as a significant player, as its levels have been observed to exhibit a substantial rise following ischemic events. Elevated levels of miR-34a have been found to have multiple effects, including the modulation of inflammatory molecules involved in the post-stroke recovery process, as well as negative effects on the blood-brain barrier (BBB) permeability. Interestingly, the increase of miR-34a appears to increase BBB permeability post stroke, through the negative effect on mitochondrial function. The strength of mitochondrial function is crucial for limiting para-cellular permeability and maintaining the structural integrity of the BBB. Furthermore, the activation of ischemic repair mechanisms and the reduction of ischemic event damage depend on healthy mitochondrial activity. This review aims to emphasize the involvement of miR-34a in ischemic stroke, specifically its interaction with mitochondrial genes in cerebrovascular endothelial cells, the effect on mitochondrial function, and lastly its regulatory role in BBB permeability. A comprehensive understanding of the role of miR-34a in maintaining BBB integrity and its contribution to the pathogenesis of stroke holds significant value in establishing a foundation for the development of future therapeutics and diagnostic markers.

Adapting antibacterial display to identify serum-active macrocyclic peptide antibiotics.

The lack of available treatments for many antimicrobial-resistant infections highlights the critical need for antibiotic discovery innovation. Peptides are an underappreciated antibiotic scaffold because they often suffer from proteolytic instability and toxicity toward human cells, making in vivo use challenging. To investigate sequence factors related to serum activity, we adapt an antibacterial display technology to screen a library of peptide macrocycles for antibacterial potential directly in human serum. We identify dozens of new macrocyclic peptide antibiotic sequences and find that serum activity within our library is influenced by peptide length, cationic charge, and the number of disulfide bonds present. Interestingly, an optimized version of our most active lead peptide permeates the outer membrane of Gram-negative bacteria without strong inner-membrane disruption and kills bacteria slowly while causing cell elongation. This contrasts with traditional cationic antimicrobial peptides, which kill rapidly via lysis of both bacterial membranes. Notably, this optimized variant is not toxic to mammalian cells and retains its function in vivo, suggesting therapeutic promise. Our results support the use of more physiologically relevant conditions when screening peptides for antimicrobial activity which retain in vivo functionality.

Two sequence- and two structure-based ML models have learned different aspects of protein biochemistry.

Deep learning models are seeing increased use as methods to predict mutational effects or allowed mutations in proteins. The models commonly used for these purposes include large language models (LLMs) and 3D Convolutional Neural Networks (CNNs). These two model types have very different architectures and are commonly trained on different representations of proteins. LLMs make use of the transformer architecture and are trained purely on protein sequences whereas 3D CNNs are trained on voxelized representations of local protein structure. While comparable overall prediction accuracies have been reported for both types of models, it is not known to what extent these models make comparable specific predictions and/or generalize protein biochemistry in similar ways. Here, we perform a systematic comparison of two LLMs and two structure-based models (CNNs) and show that the different model types have distinct strengths and weaknesses. The overall prediction accuracies are largely uncorrelated between the sequence- and structure-based models. Overall, the two structure-based models are better at predicting buried aliphatic and hydrophobic residues whereas the two LLMs are better at predicting solvent-exposed polar and charged amino acids. Finally, we find that a combined model that takes the individual model predictions as input can leverage these individual model strengths and results in significantly improved overall prediction accuracy.

Adapting antibacterial display to identify serum active macrocyclic peptide antibiotics.

The lack of available treatments for many antimicrobial resistant infections highlights the critical need for antibiotic discovery innovation. Peptides are an underappreciated antibiotic scaffold because they often suffer from proteolytic instability and toxicity towards human cells, making in vivo use challenging. To investigate sequence factors related to serum activity, we adapt an antibacterial display technology to screen a library of peptide macrocycles for antibacterial potential directly in human serum. We identify dozens of new macrocyclic peptide antibiotic sequences and find that serum activity within our library is influenced by peptide length, cationic charge, and the number of disulfide bonds present. Interestingly, an optimized version of our most active lead peptide permeates the outer membrane of gram-negative bacteria without strong inner membrane disruption and kills bacteria slowly while causing cell elongation. This contrasts with traditional cationic antimicrobial peptides, which kill rapidly via lysis of both bacterial membranes. Notably, this optimized variant is not toxic to mammalian cells and retains its function in vivo , suggesting therapeutic promise. Our results support the use of more physiologically relevant conditions when screening peptides for antimicrobial activity which retain in vivo functionality. Significance: Traditional methods of natural antibiotic discovery are low throughput and cannot keep pace with the development of antimicrobial resistance. Synthetic peptide display technologies offer a high-throughput means of screening drug candidates, but rarely consider functionality beyond simple target binding and do not consider retention of function in vivo . Here, we adapt a function-based, antibacterial display technology to screen a large library of peptide macrocycles directly for bacterial growth inhibition in human serum. This screen identifies an optimized non-toxic macrocyclic peptide antibiotic retaining in vivo function, suggesting this advancement could increase clinical antibiotic discovery efficiency.

Endovascular Treatment of Cerebrovascular Lesions Using Nickel- or Nitinol-Containing Devices in Patients with Nickel Allergies.

Nickel is used in many cerebral endovascular treatment devices. However, nickel hypersensitivity is the most common metal allergy, and the relative risk of treatment in these patients is unknown. This retrospective analysis identified patients with nickel or metal allergies who underwent cerebral endovascular treatment with nickel-containing devices. Seven patients with nickel and/or other metal allergies underwent treatment with 9 nickel-containing devices. None experienced periprocedural complications. No patient received treatment with corticosteroids or antihistamines. At a mean clinical follow-up for all patients of 22.8 months (range, 10.5-38.0 months), no patients had symptoms attributable to nickel allergic reactions. The mean radiographic follow-up for all patients at 18.4 months (range, 2.5-37.5 months) showed successful treatment of the targeted vascular pathologies, with no evidence of in-stent stenosis or other allergic or hypersensitivity sequelae. The treatment of cerebrovascular lesions with a nickel-containing device resulted in no adverse outcomes among these patients and was safe and effective.

ExoDx prostate test as a predictor of outcomes of high-grade prostate cancer - an interim analysis.

BACKGROUND: Patient outcomes were assessed based on a pre-biopsy ExoDx Prostate (EPI) score at 2.5 years of the 5-year follow-up of ongoing prostate biopsy Decision Impact Trial of the ExoDx Prostate (IntelliScore). METHODS: Prospective, blinded, randomized, multisite clinical utility study was conducted from June 2017 to May 2018 (NCT03235687). Urine samples were collected from 1049 men (≥50 years old) with a PSA 2-10 ng/mL being considered for a prostate biopsy. Patients were randomized to EPI vs. standard of care (SOC). All had an EPI test, but only EPI arm received results during biopsy decision process. Clinical outcomes, time to biopsy and pathology were assessed among low (<15.6) or high (≥15.6) EPI scores. RESULTS: At 2.5 years, 833 patients had follow-up data. In the EPI arm, biopsy rates remained lower for low-risk EPI scores than high-risk EPI scores (44.6% vs 79.0%, p < 0.001), whereas biopsy rates were identical in SOC arm regardless of EPI score (59.6% vs 58.8%, p = 0.99). Also in the EPI arm, the average time from EPI testing to first biopsy was longer for low-risk EPI scores compared to high-risk EPI scores (216 vs. 69 days; p < 0.001). Similarly, the time to first biopsy was longer with EPI low-risk scores in EPI arm compared to EPI low-risk scores in SOC arm (216 vs 80 days; p < 0.001). At 2.5 years, patients with low-risk EPI scores from both arms had less HGPC than high-risk EPI score patients (7.9% vs 26.8%, p < 0.001) and the EPI arm found 21.8% more HGPC than the SOC arm. CONCLUSIONS: This follow-up analysis captures subsequent biopsy outcomes and demonstrates that men receiving EPI low-risk scores (<15.6) significantly defer the time to first biopsy and remain at a very low pathologic risk by 2.5-years after the initial study. The EPI test risk stratification identified low-risk patients that were not found with the SOC.

Two sequence- and two structure-based ML models have learned different aspects of protein biochemistry.

Deep learning models are seeing increased use as methods to predict mutational effects or allowed mutations in proteins. The models commonly used for these purposes include large language models (LLMs) and 3D Convolutional Neural Networks (CNNs). These two model types have very different architectures and are commonly trained on different representations of proteins. LLMs make use of the transformer architecture and are trained purely on protein sequences whereas 3D CNNs are trained on voxelized representations of local protein structure. While comparable overall prediction accuracies have been reported for both types of models, it is not known to what extent these models make comparable specific predictions and/or generalize protein biochemistry in similar ways. Here, we perform a systematic comparison of two LLMs and two structure-based models (CNNs) and show that the different model types have distinct strengths and weaknesses. The overall prediction accuracies are largely uncorrelated between the sequence- and structure-based models. Overall, the two structure-based models are better at predicting buried aliphatic and hydrophobic residues whereas the two LLMs are better at predicting solvent-exposed polar and charged amino acids. Finally, we find that a combined model that takes the individual model predictions as input can leverage these individual model strengths and results in significantly improved overall prediction accuracy.

Killer Knots: Molecular Evolution of Inhibitor Cystine Knot Toxins in Wandering Spiders (Araneae: Ctenidae).

Venom expressed by the nearly 50,000 species of spiders on Earth largely remains an untapped reservoir of a diverse array of biomolecules with potential for pharmacological and agricultural applications. A large fraction of the noxious components of spider venoms are a functionally diverse family of structurally related polypeptides with an inhibitor cystine knot (ICK) motif. The cysteine-rich nature of these toxins makes structural elucidation difficult, and most studies have focused on venom components from the small handful of medically relevant spider species such as the highly aggressive Brazilian wandering spider Phoneutria nigriventer. To alleviate difficulties associated with the study of ICK toxins in spiders, we devised a comprehensive approach to explore the evolutionary patterns that have shaped ICK functional diversification using venom gland transcriptomes and proteomes from phylogenetically distinct lineages of wandering spiders and their close relatives. We identified 626 unique ICK toxins belonging to seven topological elaborations. Phylogenetic tests of episodic diversification revealed distinct regions between cysteine residues that demonstrated differential evidence of positive or negative selection, which may have structural implications towards the specificity and efficacy of these toxins. Increased taxon sampling and whole genome sequencing will provide invaluable insights to further understand the evolutionary processes that have given rise to this diverse class of toxins.

Visible light induced formation of a tungsten hydride complex.

When irradiated with blue light in the presence of a Lewis base (L), [CpW(CO)3]2 undergoes metal-metal bond cleavage followed by a disproportionation reaction to form [CpW(CO)3L]+ and [CpW(CO)3]-. Here, we show that in the presence of pyridinium tetrafluoroborate, [CpW(CO)3]- reacts further to form a metal hydride complex CpW(CO)3H. The rection was monitored through in situ photo 1H NMR spectroscopy experiments and the mechanism of light-driven hydride formation was investigated by determining quantum yields of formation. Quantum yields of formation of CpW(CO)3H correlate with I-1/2 (I = photon flux on our sample tube), indicating that the net disproportionation of [CpW(CO)3]2 to form the hydride precursor [CpW(CO)3]- occurs primarily through a radical chain mechanism.

Designing and identifying ß-hairpin peptide macrocycles with antibiotic potential.

Peptide macrocycles are a rapidly emerging class of therapeutic, yet the design of their structure and activity remains challenging. This is especially true for those with ß-hairpin structure due to weak folding properties and a propensity for aggregation. Here, we use proteomic analysis and common antimicrobial features to design a large peptide library with macrocyclic ß-hairpin structure. Using an activity-driven high-throughput screen, we identify dozens of peptides killing bacteria through selective membrane disruption and analyze their biochemical features via machine learning. Active peptides contain a unique constrained structure and are highly enriched for cationic charge with arginine in their turn region. Our results provide a synthetic strategy for structured macrocyclic peptide design and discovery while also elucidating characteristics important for ß-hairpin antimicrobial peptide activity.

Evidence for Widespread Class II Microcins in Enterobacterales Genomes.

Microcins are a class of antimicrobial peptides produced by certain Gram-negative bacterial species to kill or inhibit the growth of competing bacteria. Only 10 unique, experimentally validated class II microcins have been identified, and the majority of these come from Escherichia coli. Although the current representation of microcins is sparse, they exhibit a diverse array of molecular functionalities, uptake mechanisms, and target specificities. This broad diversity from such a small representation suggests that microcins may have untapped potential for bioprospecting peptide antibiotics from genomic data sets. We used a systematic bioinformatics approach to search for verified and novel class II microcins in E. coli and other species within its family, Enterobacteriaceae. Nearly one-quarter of the E. coli genome assemblies contained one or more microcins, where the prevalence of hits to specific microcins varied by isolate phylogroup. E. coli isolates from human extraintestinal and poultry meat sources were enriched for microcins, while those from freshwater were depleted. Putative microcins were found in various abundances across all five distinct phylogenetic lineages of Enterobacteriaceae, with a particularly high prevalence in the "Klebsiella" clade. Representative genome assemblies from species across the Enterobacterales order, as well as a few outgroup species, also contained putative microcin sequences. This study suggests that microcins have a complicated evolutionary history, spanning far beyond our limited knowledge of the currently validated microcins. Efforts to functionally characterize these newly identified microcins have great potential to open a new field of peptide antibiotics and microbiome modulators and elucidate the ways in which bacteria compete with each other. IMPORTANCE Class II microcins are small bacteriocins produced by strains of Gram-negative bacteria in the Enterobacteriaceae. They are generally understood to play a role in interbacterial competition, although direct evidence of this is limited, and they could prove informative in developing new peptide antibiotics. However, few examples of verified class II microcins exist, and novel microcins are difficult to identify due to their sequence diversity, making it complicated to study them as a group. Here, we overcome this limitation by developing a bioinformatics pipeline to detect microcins in silico. Using this pipeline, we demonstrate that both verified and novel class II microcins are widespread within and outside the Enterobacteriaceae, which has not been systematically shown previously. The observed prevalence of class II microcins suggests that they are ecologically important, and the elucidation of novel microcins provides a resource that can be used to expand our knowledge of the structure and function of microcins as antibacterials.

Targeting protein arginine methyltransferase 5 sensitizes glioblastoma to trametinib.

Background: The prognosis of glioblastoma (GBM) remains dismal because therapeutic approaches have limited effectiveness. A new targeted treatment using MEK inhibitors, including trametinib, has been proposed to improve GBM therapy. Trametinib had a promising preclinical effect against several cancers, but its adaptive treatment resistance precluded its clinical translation in GBM. Previously, we have demonstrated that protein arginine methyltransferase 5 (PRMT5) is upregulated in GBM and its inhibition promotes apoptosis and senescence in differentiated and stem-like tumor cells, respectively. We tested whether inhibition of PRMT5 can enhance the efficacy of trametinib against GBM. Methods: Patient-derived primary GBM neurospheres (GBMNS) with transient PRMT5 knockdown were treated with trametinib and cell viability, proliferation, cell cycle progression, ELISA, and western blot were analyzed. In vivo, NSG mice were intracranially implanted with PRMT5-intact and -depleted GBMNS, treated with trametinib by daily oral gavage, and observed for tumor progression and mice survival rate. Results: PRMT5 depletion enhanced trametinib-induced cytotoxicity in GBMNS. PRMT5 knockdown significantly decreased trametinib-induced AKT and ERBB3 escape pathways. However, ERBB3 inhibition alone failed to block trametinib-induced AKT activity suggesting that the enhanced antitumor effect imparted by PRMT5 knockdown in trametinib-treated GBMNS resulted from AKT inhibition and not ERBB3 inhibition. In orthotopic murine xenograft models, PRMT5-depletion extended the survival of tumor-bearing mice, and combination with trametinib further increased survival. Conclusion: Combined PRMT5/MEK inhibition synergistically inhibited GBM in animal models and is a promising strategy for GBM therapy.

Emergency Department Visits for Chronic Subdural Hematomas within 30 Days after Surgical Evacuation with and without Middle Meningeal Artery Embolization.

BACKGROUND AND PURPOSE: Middle meningeal artery embolization after surgical evacuation of a chronic subdural hematomas is associated with fewer treatment failures than surgical evacuation. We compared emergency department visits within 30 days for patients with chronic subdural hematomas with and without adjunctive middle meningeal artery embolization. MATERIALS AND METHODS: All cases of chronic subdural hematoma treated from January 1, 2018, through December 31, 2020, were retrospectively reviewed. Treatment was classified as surgery only or surgery combined with middle meningeal artery embolization. The primary outcome was 30-day emergency department presentation and readmission. RESULTS: Of 137 patients who met the study criteria, 28 (20%) underwent surgery combined with middle meningeal artery embolization. Of these 28 patients, 15 (54%) underwent planned middle meningeal artery embolization and 13 (46%) underwent embolization after surgical failure. The mean chronic subdural hematoma size at presentation in the group with surgery only (n = 109, 20.5 [SD, 6.9] mm) was comparable with that in the combined group (n = 28, 18.7 [SD, 4.5] mm; P = .16). A significantly higher percentage of the surgery-only group presented to the emergency department within 30 days compared with the combined group (32 of 109 [29%] versus 2 of 28 [7%] patients; P = .02). No significant difference was found with respect to readmission (16 [15%] versus 1 [4%] patient; P = .11). Nine patients (8%) in the surgery-only group were readmitted for significant reaccumulation or residual subdural hematoma compared with only 1 patient (4%) in the combined group (P = .40). CONCLUSIONS: Surgical evacuation combined with middle meningeal artery embolization in patients with chronic subdural hematoma is associated with fewer 30-day emergency department visits compared with surgery alone.