Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1).

Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.

Clear Cell Ovarian Carcinoma With C1 Lateral Mass Metastasis and Pathologic Fracture: A Case Report.

Osseous metastasis (OM) in ovarian cancer (OC) are rare, with an incidence ranging from 0.8% to 2.6%, and are associated with poor prognosis. The available literature on their management and associated complications is scarce. We report a case of International Federation of Gynecology and Obstetrics (FIGO) stage IVB clear cell epithelial OC (EOC) who presented with neck pain. Imaging revealed multiple cervical spine metastases with left vertebral artery encasement and concurrent C1 lateral mass compression fracture, without neurological deficit, requiring occiput to C2 posterior instrumentation and fusion. Early OM may be associated with shorter overall survival, and survival after OM diagnosis is on the order of months. Management of OM should include a multidisciplinary team and may require surgical stabilization in addition to systemic chemotherapy, local radiotherapy, and osteoclast inhibitors.

Biochemical and Structural Characterization of a Peptidic Inhibitor of the YAP:TEAD Interaction That Binds to the α-Helix Pocket on TEAD.

The TEAD transcription factors are the most distal elements of the Hippo pathway, and their transcriptional activity is regulated by several proteins, including YAP. In some cancers, the Hippo pathway is deregulated and inhibitors of the YAP:TEAD interaction are foreseen as new anticancer drugs. The binding of YAP to TEAD is driven by the interaction of an α-helix and an Ω-loop present in its TEAD-binding domain with two distinct pockets at the TEAD surface. Using the mRNA-based display technique to screen a library of in vitro-translated cyclic peptides, we identified a peptide that binds with a nanomolar affinity to TEAD. The X-ray structure of this peptide in complex with TEAD reveals that it interacts with the α-helix pocket. Under our experimental conditions, this peptide can form a ternary complex with TEAD and YAP. Furthermore, combining it with a peptide binding to the Ω-loop pocket gives an additive inhibitory effect on the YAP:TEAD interaction. Overall, our results show that it is possible to identify nanomolar inhibitors of the YAP:TEAD interaction that bind to the α-helix pocket, suggesting that developing such compounds might be a strategy to treat cancers where the Hippo pathway is deregulated.

Clinical Characteristics, Outcomes, and Pathology Analysis in Patients With Dorsal Arachnoid Web.

BACKGROUND: Dorsal arachnoid webs (DAWs) are rare pathological abnormalities of the arachnoid layer of the spinal cord that can result in pain and myelopathy. OBJECTIVE: To present clinical, imaging, and pathological characteristics of patients diagnosed with DAW, case illustrations, and a review of the literature. METHODS: Seventeen cases of DAW between 2015 and 2019 at a tertiary medical center were retrospectively identified through a case log search. Patient characteristics, preoperative imaging, operative notes, and pathology reports were collected. Our main outcome assessed was postoperative resolution of symptoms. Odds ratios were used to determine associations between preoperative signs and symptoms with postoperative symptom resolution. RESULTS: The mean age of the cohort was 50.5 years (IQR = 16) and presented primarily with back pain (64.7%). On imaging, all patients were found to have the "scalpel sign," and nearly half had a syrinx present (41.2%). All DAWs were located in the thoracic spine, with the most common location being the midthoracic (70.6%). The mean follow-up length for all patients was 4.3 months. There were no preoperative symptoms significantly associated with postoperative symptom resolution; however, a trend was noted with the presence of a preoperative syrinx. Pathology samples consistently demonstrated fibroconnective or collagenous tissue with no evidence of inflammation or neoplasm. CONCLUSION: DAW is a rare pathology that can result in myelopathy or inappropriate interventions if misdiagnosed. Surgical intervention using laminectomy with intradural exploration should be considered in symptomatic patients with DAW because it is curative with a strong chance of preoperative symptom resolution with relatively low complication rates.

Identification of a PCSK9-LDLR disruptor peptide with in vivo function.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 1013in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., 13PCSK9i). In mice, 13PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. 13PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.

Inhibition of Escherichia coli Lipoprotein Diacylglyceryl Transferase Is Insensitive to Resistance Caused by Deletion of Braun's Lipoprotein.

Lipoprotein diacylglyceryl transferase (Lgt) catalyzes the first step in the biogenesis of Gram-negative bacterial lipoproteins which play crucial roles in bacterial growth and pathogenesis. We demonstrate that Lgt depletion in a clinical uropathogenic Escherichia coli strain leads to permeabilization of the outer membrane and increased sensitivity to serum killing and antibiotics. Importantly, we identify G2824 as the first-described Lgt inhibitor that potently inhibits Lgt biochemical activity in vitro and is bactericidal against wild-type Acinetobacter baumannii and E. coli strains. While deletion of a gene encoding a major outer membrane lipoprotein, lpp, leads to rescue of bacterial growth after genetic depletion or pharmacologic inhibition of the downstream type II signal peptidase, LspA, no such rescue of growth is detected after Lgt depletion or treatment with G2824. Inhibition of Lgt does not lead to significant accumulation of peptidoglycan-linked Lpp in the inner membrane. Our data validate Lgt as a novel antibacterial target and suggest that, unlike downstream steps in lipoprotein biosynthesis and transport, inhibition of Lgt may not be sensitive to one of the most common resistance mechanisms that invalidate inhibitors of bacterial lipoprotein biosynthesis and transport. IMPORTANCE As the emerging threat of multidrug-resistant (MDR) bacteria continues to increase, no new classes of antibiotics have been discovered in the last 50 years. While previous attempts to inhibit the lipoprotein biosynthetic (LspA) or transport (LolCDE) pathways have been made, most efforts have been hindered by the emergence of a common mechanism leading to resistance, namely, the deletion of the gene encoding a major Gram-negative outer membrane lipoprotein lpp. Our unexpected finding that inhibition of Lgt is not susceptible to lpp deletion-mediated resistance uncovers the complexity of bacterial lipoprotein biogenesis and the corresponding enzymes involved in this essential outer membrane biogenesis pathway and potentially points to new antibacterial targets in this pathway.

Design of Thioether Cyclic Peptide Scaffolds with Passive Permeability and Oral Exposure.

Advances in the design of permeable peptides and in the synthesis of large arrays of macrocyclic peptides with diverse amino acids have evolved on parallel but independent tracks. Less precedent combines their respective attributes, thereby limiting the potential to identify permeable peptide ligands for key targets. Herein, we present novel 6-, 7-, and 8-mer cyclic peptides (MW 774-1076 g·mol-1) with passive permeability and oral exposure that feature the amino acids and thioether ring-closing common to large array formats, including DNA- and RNA-templated synthesis. Each oral peptide herein, selected from virtual libraries of partially N-methylated peptides using in silico methods, reflects the subset consistent with low energy conformations, low desolvation penalties, and passive permeability. We envision that, by retaining the backbone N-methylation pattern and consequent bias toward permeability, one can generate large peptide arrays with sufficient side chain diversity to identify permeability-biased ligands to a variety of protein targets.

Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors.

Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >1012 in vitro-translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects.

A new modular radiographic classification of adult idiopathic scoliosis as an extension of the Lenke classification of adolescent idiopathic scoliosis.

PURPOSE: To propose and test the reliability of a radiographic classification system for adult idiopathic scoliosis. METHODS: A three-component radiographic classification for adult idiopathic scoliosis consisting of curve type, a lumbosacral modifier, and a global alignment modifier is presented. Twelve spine surgeons graded 30 pre-marked cases twice, approximately 1 week apart. Case order was randomized between sessions. RESULTS: The interrater reliability (Fleiss' kappa coefficient) for curve type was 0.660 and 0.798, for the lumbosacral modifier 0.944 and 0.965, and for the global alignment modifier 0.922 and 0.916, for round 1 and 2 respectively. Mean intrarater reliability was 0.807. CONCLUSIONS: This new radiographic classification of adult idiopathic scoliosis maintains the curve types from the Lenke classification and introduces the lumbosacral and global alignment modifiers. The reliability of the lumbosacral modifier and global alignment modifier shows near perfect agreement, and sets the foundation for further studies to validate the reliability, utility, and applicability of this classification system.

3D printing of silk fibroin-based hybrid scaffold treated with platelet rich plasma for bone tissue engineering.

3D printing/bioprinting are promising techniques to fabricate scaffolds with well controlled and patient-specific structures and architectures for bone tissue engineering. In this study, we developed a composite bioink consisting of silk fibroin (SF), gelatin (GEL), hyaluronic acid (HA), and tricalcium phosphate (TCP) and 3D bioprinted the silk fibroin-based hybrid scaffolds. The 3D bioprinted scaffolds with dual crosslinking were further treated with human platelet-rich plasma (PRP) to generate PRP coated scaffolds. Live/Dead and MTT assays demonstrated that PRP treatment could obviously promote the cell growth and proliferation of human adipose derived mesenchymal stem cells (HADMSC). In addition, the treatment of PRP did not significantly affect alkaline phosphatase (ALP) activity and expression, but significantly upregulated the gene expression levels of late osteogenic markers. This study demonstrated that the 3D printing of silk fibroin-based hybrid scaffolds, in combination with PRP post-treatment, might be a more efficient strategy to promote osteogenic differentiation of adult stem cells and has significant potential to be used for bone tissue engineering.

State of the union: a review of lumbar fusion indications and techniques for degenerative spine disease.

Lumbar fusion is an accepted and effective technique for the treatment of lumbar degenerative disease. The practice has evolved continually since Albee and Hibbs independently reported the first cases in 1913, and advancements in both technique and patient selection continue through the present day. Clinical and radiological indications for surgery have been tested in trials, and other diagnostic modalities have developed and been studied. Fusion practices have also advanced; instrumentation, surgical approaches, biologics, and more recently, operative planning, have undergone stark changes at a seemingly increasing pace over the last decade. As the general population ages, treatment of degenerative lumbar disease will become a more prevalent-and costlier-issue for surgeons as well as the healthcare system overall. This review will cover the evolution of indications and techniques for fusion in degenerative lumbar disease, with emphasis on the evidence for current practices.

Utility of neuromonitoring during lumbar pedicle subtraction osteotomy for adult spinal deformity.

OBJECTIVE: The benefits and utility of routine neuromonitoring with motor and somatosensory evoked potentials during lumbar spine surgery remain unclear. This study assesses measures of performance and utility of transcranial motor evoked potentials (MEPs) during lumbar pedicle subtraction osteotomy (PSO). METHODS: This is a retrospective study of a single-surgeon cohort of consecutive adult spinal deformity (ASD) patients who underwent lumbar PSO from 2006 to 2016. A blinded neurophysiologist reviewed individual cases for MEP changes. Multivariate analysis was performed to determine whether changes correlated with neurological deficits. Measures of performance were calculated. RESULTS: A total of 242 lumbar PSO cases were included. MEP changes occurred in 38 (15.7%) cases; the changes were transient in 21 cases (55.3%) and permanent in 17 (44.7%). Of the patients with permanent changes, 9 (52.9%) had no recovery and 8 (47.1%) had partial recovery of MEP signals. Changes occurred at a mean time of 8.8 minutes following PSO closure (range: during closure to 55 minutes after closure). The mean percentage of MEP signal loss was 72.9%. The overall complication rate was 25.2%, and the incidence of new neurological deficits was 4.1%. On multivariate analysis, MEP signal loss of at least 50% was not associated with complication (p = 0.495) or able to predict postoperative neurological deficits (p = 0.429). Of the 38 cases in which MEP changes were observed, the observation represented a true-positive finding in only 3 cases. Postoperative neurological deficits without MEP changes occurred in 7 cases. Calculated measures of performance were as follows: sensitivity 30.0%, specificity 84.9%, positive predictive value 7.9%, and negative predictive value 96.6%. Regarding the specific characteristics of the MEP changes, only a signal loss of 80% or greater was significantly associated with a higher rate of neurological deficit (23.0% vs 0.0% for loss of less than 80%, p = 0.021); changes of less than 80% were not associated with postoperative deficits. CONCLUSIONS: Neuromonitoring has a low positive predictive value and low sensitivity for detecting new neurological deficits. Even when neuromonitoring is unchanged, patients can still have new neurological deficits. The utility of transcranial MEP monitoring for lumbar PSO remains unclear but there may be advantages to its use.

Effect of Bone Flap Surface Area on Outcomes in Decompressive Hemicraniectomy for Traumatic Brain Injury.

BACKGROUND: Decompressive hemicraniectomy to control medically refractory intracranial hypertension and cerebral edema and evacuate mass lesions in traumatic brain injury is a widely accepted treatment paradigm. However, the critical specifications of the bone flap size necessary to control the intracranial pressure (ICP) and provide improved patient outcomes is unknown. We assessed the effect of craniectomy size on the outcomes in surgical decompression for traumatic brain injury. METHODS: From 2003 to 2011, 58 cases of decompressive hemicraniectomy were performed for evacuation of hematoma and treatment of refractory ICP in adult patients with traumatic brain injury. The surface area of the decompressive bone flaps was calculated from the postoperative computed tomography scans and correlated with the ICP and Glasgow Coma Scale scores immediately postoperatively and during long-term follow-up. RESULTS: Decompressive craniectomy led to a statistically significant continued reduction in the preoperative ICP values (24.5 mm Hg; range, 5-30 mm Hg) compared with the postoperative ICP (16.7 mm Hg; range, 1-30; P = 0.006). However, no significant improvement in the preoperative Glasgow Coma Scale (7.47 mm Hg; range, 3-15; vs. 7.50 mm Hg; range, 3-15; P = 0.96) was observed with hemicraniectomy. CONCLUSION: For surface areas of 7000-16,000 mm2, size was an independent factor in ICP reduction but not for the overall neurologic outcome.

Evaluation of C2 pedicle screw placement via the freehand technique by neurosurgical trainees.

OBJECTIVE Freehand placement of C2 instrumentation is technically challenging and has a learning curve due the unique anatomy of the region. This study evaluated the accuracy of C2 pedicle screws placed via the freehand technique by neurosurgical resident trainees. METHODS The authors retrospectively reviewed all patients treated at the LAC+USC Medical Center undergoing C2 pedicle screw placement in which the freehand technique was used over a 1-year period, from June 2016 to June 2017; all procedures were performed by neurosurgical residents. Measurements of C2 were obtained from preoperative CT scans, and breach rates were determined from coronal reconstructions on postoperative scans. Severity of breaches reflected the percentage of screw diameter beyond the cortical edge (I = < 25%; II = 26%-50%; III = 51%-75%; IV = 76%-100%). RESULTS Neurosurgical residents placed 40 C2 pedicle screws in 24 consecutively treated patients. All screws were placed by or under the guidance of Pham, who is a postgraduate year 7 (PGY-7) neurosurgical resident with attending staff privileges, with a PGY-2 to PGY-4 resident assistant. The authors found an average axial pedicle diameter of 5.8 mm, axial angle of 43.1°, sagittal angle of 23.0°, spinal canal diameter of 25.1 mm, and axial transverse foramen diameter of 5.9 mm. There were 17 screws placed by PGY-2 residents, 7 screws placed by PGY-4 residents, and 16 screws placed by the PGY-7 resident. The average screw length was 26.0 mm, with a screw diameter of 3.5 mm or 4.0 mm. There were 7 total breaches (17.5%), of which 4 were superior (10.0%) and 3 were lateral (7.5%). There were no medial breaches. The breaches were classified as grade I in 3 cases (42.9%), II in 3 cases (42.9%), III in 1 case (14.3%), and IV in no cases. There were 3 breaches that occurred via placement by a PGY-2 resident, 3 breaches by a PGY-4 resident, and 1 breach by the PGY-7 resident. There were no clinical sequelae due to these breaches. CONCLUSIONS Freehand placement of C2 pedicle screws can be done safely by neurosurgical residents in early training. When breaches occurred, they tended to be superior in location and related to screw length choice, and no breaches were found to be clinically significant. Controlled exposure to this unique anatomy is especially pertinent in the era of work-hour restrictions.

Tumefactive Multiple Sclerosis Masquerading as High Grade Glioma.

Tumefactive multiple sclerosis is a demyelinating lesion that can radiographically mimic high-grade gliomas during acute episodes, thus affecting clinical decision making. A delay in appropriate diagnoses can result in unnecessary invasive resections. The following case is a patient with unilateral weakness and radiologic findings that were concerning for a high-grade glioma. Peripheral studies were equivocal. The decision was made to proceed with a stereotactic biopsy, yielding a definitive diagnosis of tumefactive demyelinating lesion (TDL). The patient responded robustly to medical management and made a full clinical recovery. While TDLs and gliomas may look radiologically identical during acute demyelinating episodes, unlike gliomas, TDLs will demonstrate evolvement over serial imaging and robust clinical response to high dose steroids. Clinicians should proceed with caution when considering invasive procedures with such lesions. Conservative medical management is often sufficient as seen in this patient. This case highlights the importance of timely diagnosis and management of TDLs.

Neurological complications in adult spinal deformity surgery.

The number of surgeries performed for adult spinal deformity (ASD) has been increasing due to an aging population, longer life expectancy, and studies supporting an improvement in health-related quality of life scores after operative intervention. However, medical and surgical complication rates remain high, and neurological complications such as spinal cord injury and motor deficits can be especially debilitating to patients. Several independent factors potentially influence the likelihood of neurological complications including surgical approach (anterior, lateral, or posterior), use of osteotomies, thoracic hyperkyphosis, spinal region, patient characteristics, and revision surgery status. The majority of ASD surgeries are performed by a posterior approach to the thoracic and/or lumbar spine, but anterior and lateral approaches are commonly performed and are associated with unique neural complications such as femoral nerve palsy and lumbar plexus injuries. Spinal morphology, such as that of hyperkyphosis, has been reported to be a risk factor for complications in addition to three-column osteotomies, which are often utilized to correct large deformities. Additionally, revision surgeries are common in ASD and these patients are at an increased risk of procedure-related complications and nervous system injury. Patient selection, surgical technique, and use of intraoperative neuromonitoring may reduce the incidence of complications and optimize outcomes.

Adeno associated viral-mediated intraosseous labeling of bone marrow derived cells for CNS tracking.

Inflammation, including microglial activation in the CNS, is an important hallmark in many neurodegenerative diseases. Microglial stimuli not only impact the brain microenvironment by production and release of cytokines and chemokines, but also influence the activity of bone marrow derived cells and blood born macrophage populations. In many diseases including brain disorders and spinal cord injury, researchers have tried to harbor the neuroprotective and repair properties of these subpopulations. Hematopoietic bone marrow derived cells (BMDCs) are of great interest, especially during gene therapy because certain hematopoietic cell subpopulations traffic to the sites of injury and inflammation. The aim of this study was to develop a method of labeling endogenous bone marrow derived cells through intraosseous impregnation of recombinant adeno-associated virus (rAAV) or lentivirus. We utilized rAAV serotype 9 (rAAV-9) or lentivirus for gene delivery of green florescence protein (GFP) to the mouse bone marrow cells. Flow cytometry showed that both viruses were able to efficiently transduce mouse bone marrow cells in vivo. However, the rAAV9-GFP viral construct transduced BMDCs more efficiently than the lentivirus (11.2% vs. 6.8%), as indicated by cellular GFP expression. We also demonstrate that GFP labeled cells correspond to bone marrow cells of myeloid origin using CD11b as a marker. Additionally, we characterized the ability of bone marrow derived, GFP labeled cells to extravasate into the brain parenchyma upon acute and subchronic neuroinflammatory stimuli in the mouse CNS. Viral mediated over expression of chemokine (C-C motif) ligand 2 (CCL2) or intracranial injection of lipopolysaccharide (LPS) recruited GFP labeled BMDCs from the periphery into the brain parenchyma compared to vehicle treated mice. Altogether our findings demonstrate a useful method of labeling endogenous BMDCs via viral transduction and the ability to track subpopulations throughout the body following insult or injury. Alternatively, this method might find utility in delivering therapeutic genes for neuroinflammatory conditions.

Combative Sports Injuries: An Edmonton Retrospective.

OBJECTIVE: Mixed martial arts (MMA) is an increasingly popular combative sport involving aggressive techniques that present substantial injury risk. We examined the incidence and types of injuries sustained in MMA fights and compared this with injuries sustained in boxing matches. DESIGN: Consecutive Case Series. SETTING: We used data from post-fight medical examinations on all bouts in Edmonton, Canada, between 2000 and 2013. PARTICIPANTS: The participants were 1181 MMA competitors and 550 boxers. MAIN OUTCOME MEASURES: The attending physician conducted a mandatory post-fight examination of all fighters and documented the nature of injuries sustained. RESULTS: Boxers were significantly more likely not to experience injury (49.8% vs 59.4%, P < 0.001), whereas MMA fighters were significantly more likely to experience 1 injury (typically contusion/bruising, P < 0.001). Boxers were more likely to experience loss of consciousness (7.1% vs 4.2%, P = 0.01) and serious eye injury (1.1% vs 0.3%, P = 0.02). CONCLUSIONS: The overall injury incidence in MMA competitors appears slightly higher than for boxers, but MMA fighters experience more minor contusion/bruising injuries. Boxers are more likely to experience serious injury such as concussion/head trauma involving loss of consciousness or eye injury such as retinal detachment.

Evaluation of time to aneurysm treatment following subarachnoid hemorrhage: comparison of patients treated with clipping versus coiling.

INTRODUCTION: Prior studies of aneurysmal subarachnoid hemorrhage (SAH) have shown that treatment at teaching institutions and decreased time to surgery are factors that correlate with improved patient outcome. We aimed to individually evaluate the effect of teaching institution treatment on rates of surgical clipping or endovascular coiling. METHODS: Patients with SAH treated by either aneurysm clipping or coiling between 2002 and 2010 in the Nationwide Inpatient Sample were analyzed. Time to aneurysm treatment was dichotomized to >3 days or ≤3 days and evaluated by multivariable logistic regression modeling, controlling for patient and hospital covariates. Identified predictors for prolonged time to procedure were compared between the clipping and coiling populations. RESULTS: Between 2002 and 2010 there were 90 684 SAH admissions with subsequent clipping and coiling procedures. Treatment at teaching hospitals was associated with faster time to clipping (OR 0.60, 95% CI 0.44 to 0.80, p=0.001) but not coiling procedures (p=0.66). Likewise, older age (≥80 years) was associated with delays to clipping (p<0.05) but not coiling procedures (p>0.05). Patients with delayed time to treatment were associated with increased rates of moderate to severe neurological disability. CONCLUSIONS: Older patients with SAH and those treated at non-teaching hospitals were more likely to have delays to aneurysm clipping procedures. These associations were unique to open surgery as age and hospital teaching status did not affect time to coiling procedures.