The human craniospinal venous system and its influence on postural intracranial pressure: a review.

OBJECTIVE: The cerebral and spinal venous systems have similar functions but unique anatomical and physiological properties. CSF occupies space in the cranial and spinal vaults, is continuously produced, and has many roles, including maintaining a favorable environment for CNS structures. The influence of the cerebrospinal venous system on CSF dynamics has been theorized since the 1940s. Newer studies suggest venous outflow pattern alterations in response to changes in body position. However, the relationship of postural cerebrospinal venous outflow shifts with and their influence on CSF homeostasis is not well understood. METHODS: The authors searched the published literature related to the anatomy and function of vertebral venous plexus (VVP), CSF, and positional cerebral venous flow characteristics. A comprehensive collection of literature was compiled and reviewed, and the relationship between cerebrospinal and venous system changes and alterations in body positions, with an emphasis on the craniocervical system, is discussed. RESULTS: The VVP is a network of valveless veins extending from the sacrum to the cranium that are interconnected with the cranial dural sinuses. The internal VVP occupies space within the extradural spinal canal and functions to return spinal venous blood to the heart, but it has additional properties, including the capability of bidirectional venous flow, an intraspinal dilatory capacity, and a role in cerebral venous outflow. When one rises to the upright position, CSF shifts toward the spinal canal and force vectors change, leading to reduced intracranial CSF pressure; simultaneously, cerebral venous outflow shifts from the jugular vein to the VVP outflow pathway. The venous outflow shift mechanism and its purpose are poorly understood. The authors review the known physiology of the system, identify gaps in knowledge to direct future research, and propose an interpretation of these data, concluding that position-dependent CSF and cerebrospinal venous shifts are part of a complementary positional craniospinal pressure regulation system that must be kept in balance for optimal CNS function. CONCLUSIONS: Current knowledge of the cerebrospinal venous anatomy, dynamic flow characteristics in response to gravity, and the venous system's influence on CSF suggests that the VVP plays a role in influencing CSF pressure, and the authors hypothesize that it plays a role in supporting intracranial pressure in the upright body posture. Further research is needed to better characterize the functional relationship of the VVP to CSF dynamics as well as identify potentially related disease states.

Concurrent Middle Cerebral Artery and Basilar Artery Occlusions Treated With Mechanical Thrombectomy in a Patient With Active COVID-19 Infection.

We report a rare case of acute ischemic stroke from concurrent large vessel occlusions (LVOs) and subsequent successful mechanical thrombectomy revascularization in a patient with active coronavirus disease 2019 (COVID-19) pneumonia. A 59-year-old woman presented to the emergency department after one week of intermittent chest pain, dyspnea, and diarrhea found to have COVID-19 pneumonia. On hospital day three, the patient developed acute altered mental status and hemiparesis with a National Institutes of Health Stroke Scale (NIHSS) of 22. CT with angiography demonstrated concurrent occlusions of the basilar artery and the M1 segment of the right middle cerebral artery (MCA) without intracranial hemorrhage. The patient was taken for urgent mechanical thrombectomy of the basilar artery, followed by the MCA, both of which were successful (thrombolysis in cerebral infarction (TICI) 3 and 2B) and timely. Despite early revascularization, the patient did not improve clinically with absent brainstem reflexes and a full MCA territorial infarct on imaging. This case describes a rare stroke syndrome of concurrent LVOs with rapid infarct progression despite timely revascularization. This example illustrates a severe cerebrovascular complication of active COVID-19 infection and the importance of vigilance regarding stroke prevention and neurological examination monitoring.

The neurosurgery research & education foundation-young neurosurgeons committee webinar series: Providing education and inspiration during the COVID-19 pandemic.

OBJECTIVE: During the COVID-19 pandemic, the American Association of Neurological Surgeons (AANS) Young Neurosurgeons Committee (YNC) and Neurosurgery Research & Education Foundation (NREF) launched the YNC-NREF Webinar Series to provide young and aspiring neurosurgeons with timely information, education, and inspiration in the absence of in-person programming. DESIGN: Five 90-minute Zoom webinars were evaluated, each including 1-2 keynote speakers, a panel discussion, and an audience question-and-answer section. Topics included overviews of neurosurgery, the match, subspecialties, and inspirational career stories. Optional pre- and post-webinar surveys with 11-point Likert-type scores were distributed to attendees. We compared groups using chi-squared and Kruskal-Willis tests, and perceptions pre- and post-webinar using Mann-Whitney tests. SETTING: The webinars were live using Zoom, and the recordings were published on NREF's YouTube channel. PARTICIPANTS: The webinar series targeted young neurosurgeons. The first five episodes had a particular focus on medical students and undergraduates. RESULTS: A total of 673 unique participants attended the webinar series; 257 (38%) and 78 (11%) attendees completed the pre- and post-webinar survey, respectively. Respondents had high baseline interest in neurosurgery and were motivated to learn about the match and training in the US, understand neurosurgeons' day-to-day lives, and ask questions. There were significant differences in perceptions between USMSs, IMSs, and undergraduate students. The webinar improved attendees' knowledge about neurosurgical specialties, the match, and US neurosurgery training. CONCLUSIONS: The YNC and NREF effectively engaged a large, diverse audience through an online webinar series, building a foundation for future virtual programming by organized neurosurgery. ACGME competencies.

Development of a rabbit human glioblastoma model for testing of endovascular selective intra-arterial infusion (ESIA) of novel stem cell-based therapeutics.

BACKGROUND: Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24). METHODS: Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on magnetic resonance imaging, histologic, and immunohistochemistry analysis. Selective microcatheter infusion of MSC-D24 was performed via the ipsilateral internal carotid artery to assess model utility and the efficacy and safety of this approach. RESULTS: Twenty-five rabbits were implanted (18 with U87, 2 MDA-GSC-17, and 5 MDA-GSC-8-11). Tumors formed in 68% of rabbits (77.8% for U87, 50.0% for MDA-GSC-17, and 40.0% for MDA-GSC-8-11). On MRI, the tumors were hyperintense on T2-weighted image with variable enhancement (evidence of blood brain barrier breakdown). Histologically, tumors showed phenotypic traits of human GBM including varying levels of vascularity. ESIA infusion into the distal internal carotid artery of 2 ml of MSCs-D24 (107 cells) was safe in the model. Examination of post infusion specimens documented that MSCs-D24 homed to the implanted tumor at 24 hours. CONCLUSIONS: The intracranial immunosuppressed rabbit human GBM model allows testing of ESIA infusion of novel therapeutics (eg, MSC-D24) in a clinically relevant fashion.

Endoscope-Assisted Pedicled Maxillary Artery to Middle Cerebral Artery Bypass: An Anatomic Feasibility Study.

BACKGROUND: Extracranial to intracranial bypass is used to augment and/or replace the intracranial circulation for various pathologies. The superficial temporal artery is the mainstay donor for pedicled bypasses to the anterior circulation but can be limited by its variable size, low native flow rates, and potential scalp complications. Interposition grafts such as the radial artery or greater saphenous vein are alternatives but are sometimes limited by size mismatch, length needed to reach the extracranial circulation, and loss of inherent vascular elasticity. Interposition grafts between the maxillary artery (IMA) and middle cerebral artery (MCA) address these limitations. OBJECTIVE: To explore the feasibility of harvesting the IMA through an endoscopic transnasal, transmaxillary approach to perform a direct IMA to MCA bypass. METHODS: Combined transcranial and endoscopic endonasal dissections were performed in embalmed human cadavers to harvest the IMAs for intracranial transposition and direct anastomosis to the MCA. Donor and recipient vessel calibers were measured and recorded. RESULTS: A total of 8 procedures were performed using the largest and distal-most branches of the IMA (the sphenopalatine branch and the descending palatine branch) as pedicled conduits to second division of middle cerebral artery (M2) recipients. The mean diameter of the IMA donors was 1.89 mm (SD ± 0.42 mm), and the mean diameter of the recipient M2 vessels was 1.90 mm (SD ± 0.46 mm). CONCLUSION: Endoscopic harvest of the IMA using a transnasal, transmaxillary approach is a technically feasible option offering an excellent size match to the M2 divisions of the MCA and the advantages of a relatively short, pedicled donor vessel.

Assessing opportunities for formal exposure to clinical neurosurgery within United States allopathic medical education curricula.

OBJECTIVE: The objective of this study was to evaluate opportunities for early clinical exposure to neurosurgery at US allopathic medical schools and to assess associations between early exposure and recruitment into neurosurgery. METHODS: The authors conducted a standardized review of online curriculum documentation for all US allopathic medical schools, including descriptive review of opportunities for clinical neurosurgical training among medical students. Chi-square analysis was used to compare baseline characteristics of institutions. Logistic regression was performed to assess factors predictive of early exposure to clinical neurosurgery, defined as completion of a formal rotation at least 6 months prior to Electronic Residency Application Service submission. RESULTS: Among 155 allopathic US medical schools, 143 are fully accredited by the Liaison Committee on Medical Education. Eleven schools have no affiliated hospitals with a neurosurgery practice, and 26 do not have an American Association of Neurological Surgeons (AANS) medical student chapter. Overall, 94 (60.6%) have a traditional preclinical curriculum lasting 21-25 months, 50 (32.3%) offer an intermediate preclinical period of 15-20 months, and 11 (7.1%) report a short preclinical curriculum of 12-14 months. Early formal exposure to clinical neurosurgery was offered by 113 schools (72.9%). Early clinical exposure to neurosurgery was associated with a short (100%) or intermediate (76%) preclinical curriculum, as compared with a traditional curriculum (68.1%; p = 0.066). Early exposure was significantly associated with a shorter preclinical curriculum (OR 0.784, p = 0.005). AANS medical student chapters were present at a high majority of schools with early exposure (OR 4.114, p = 0.006). Medical schools with a higher percentage of graduating medical students matching into neurosurgery were associated with a shorter preclinical curriculum length (ß = -0.287, p < 0.001), were more commonly private medical schools (ß = 0.338, p < 0.001), and had early clinical exposure to neurosurgery (ß = 0.191, p = 0.032). CONCLUSIONS: Early exposure to clinical neurosurgery is available at most US allopathic medical schools and is associated with shorter preclinical curricula and institutions with AANS medical student chapters. Medical schools with a higher proportion of medical students entering neurosurgery had a shorter preclinical curriculum length and early clinical exposure to neurosurgery. Further study is recommended to characterize the impact of early exposure on long-term pedagogical outcomes.

A robust fluorescence-based assay for human erythrocyte Ca++ efflux suitable for high-throughput inhibitor screens.

Intracellular calcium is maintained at very low concentrations through the action of PMCA Ca++ extrusion pumps. Although much of our knowledge about these Ca++ extrusion pumps derives from studies with human erythrocytes, kinetic studies of Ca++ transport for these cells are limited to radioisotope flux measurements. Here, we developed a robust, microplate-based assay for erythrocyte Ca++ efflux using extracellular fluorescent Ca++ indicators. We optimized Ca++ loading with the A23187 ionophore, established conditions for removal of the ionophore, and adjusted fluorescent dye sensitivity by addition of extracellular EGTA to allow continuous tracking of Ca++ efflux. Efflux kinetics were accelerated by glucose and inhibited in a dose-dependent manner by the nonspecific inhibitor vanadate, revealing that Ca++ pump activity can be tracked in a 384-well microplate format. These studies enable radioisotope-free kinetic measurements of the Ca++ pump and should facilitate screens for specific inhibitors of this essential transport activity.

Impact of histological clot composition on preprocedure imaging and mechanical thrombectomy.

INTRODUCTION: We studied the relationship of acute ischemic stroke (AIS) large-vessel occlusion clot composition with vessel recanalization and preprocedure imaging. SUBJECTS AND METHODS: Individual clots from AIS patients who underwent mechanical thrombectomy (MT) between September 2016 and September 2018 were examined. Clot composition was analyzed histologically through a trichrome staining and image segmentation, and the area occupied by red blood cells (RBCs), fibrin, or mixed composition was quantified. RESULTS: Forty-three patients (65.4 ± 12.7 years, 39% of females) who underwent 92 retrieval passes (mean 2.14, range 1-6) were included in this study. Fibrin (44%) occupied the greatest area, followed by mixed composition (34%) and RBCs (22%). A stent retriever was deployed in 81% of cases, 20 patients (47%) achieved first-pass efficacy (FPE) (thrombolysis in cerebral infarction [TICI] 2b-3 after first pass), 41 (95%) achieved successful revascularization (TICI 2b-3), and 21 (49%) had good outcome (modified Rankin Scale [mRS] ≤2) at 90 days. Hyperdense artery sign (HAS) on initial computed tomography was correlated with mixed clot composition (P = 0.01) and lack of fibrin content (P = 0.03). In the univariate analysis, FPE was associated with RBC clot area, atrial fibrillation, and occlusion location but not with fibrin clot area, mixed clot area, stroke etiology, thrombectomy technique, distal emboli, or 90-day mRS. In the multivariate analysis, FPE was significantly correlated with low RBC clot area (odd ratio = 0.96, confidence interval [0.92.99], P = 0.034) but not with atrial fibrillation or location. CONCLUSION: Our results suggest that HAS is correlated with mixed clot composition and lower fibrin content and that lower RBC clot composition is associated with FPE in patients undergoing MT.

Evaluating Phenotypic and Transcriptomic Responses Induced by Low-Level VOCs in Zebrafish: Benzene as an Example.

Urban environments are plagued by complex mixtures of anthropogenic volatile organic compounds (VOCs), such as mixtures of benzene, toluene, ethylene, and xylene (BTEX). Sources of BTEX that drive human exposure include vehicle exhaust, industrial emissions, off-gassing of building material, as well as oil spillage and leakage. Among the BTEX mixture, benzene is the most volatile compound and has been linked to numerous adverse health outcomes. However, few studies have focused on the effects of low-level benzene on exposure during early development, which is a susceptible window when hematological, immune, metabolic, and detoxification systems are immature. In this study, we used zebrafish to conduct a VOC exposure model and evaluated phenotypic and transcriptomic responses following 0.1 and 1 ppm benzene exposure during the first five days of embryogenesis (n = 740 per treatment). The benzene body burden was 2 mg/kg in 1 ppm-exposed larval zebrafish pools and under the detection limit in 0.1 ppm-exposed fish. No observable phenotypic changes were found in both larvae except for significant skeletal deformities in 0.1 ppm-exposed fish (p = 0.01) compared with unexposed fish. Based on transcriptomic responses, 1 ppm benzene dysregulated genes that were implicated with the development of hematological system, and the regulation of oxidative stress response, fatty acid metabolism, immune system, and inflammatory response, including apob, nfkbiaa, serpinf1, foxa1, cyp2k6, and cyp2n13 from the cytochrome P450 gene family. Key genes including pik3c2b, pltp, and chia.2 were differentially expressed in both 1 and 0.1 ppm exposures. However, fewer transcriptomic changes were induced by 0.1 ppm compared with 1 ppm. Future studies are needed to determine if these transcriptomic responses during embryogenesis have long-term consequences at levels equal to or lower than 1 ppm.

Silk Vista Baby for the Treatment of Complex Posterior Inferior Cerebellar Artery Aneurysms.

BACKGROUND: Treatment of small-caliber vessel lesions using flow diverters remains challenging because of vasculature's narrow luminal diameter and tortuosity. This in turn makes navigation and delivery of conventional devices with standard microcatheters more difficult. The Silk Vista Baby (SVB, Balt) flow diversion device was designed for ease of use in vessels with a smaller diameter, distal lesions, and 0.017 ″ microcatheter delivery systems. OBJECTIVE: To report the outcomes of the SVB device on the treatment of posterior inferior cerebellar artery (PICA) aneurysms. METHODS: Databases from different centers were retrospectively reviewed for PICA aneurysms treated with SVB. Demographic information, clinical presentation, radiographic characteristics, procedural complications, and immediate postprocedure outcomes were obtained. RESULTS: Fourteen patients harboring 15 true PICA aneurysms were treated between January 2019 and June 2021. Nine were female (n = 9/14; 64.2%), and the mean age was 51 ± 14.9 years. Most patients had previously ruptured aneurysms, treated by another endovascular technique. Six aneurysms were located distally (n = 6/15; 40%). The mean neck size was 3 mm (SD 1.35, range 2.5-5 mm), whereas the mean PICA diameter was 1.6 mm (SD 0.26, range 1.5-1.7 mm). The mean length of follow-up was 6 months (SD 8.28, range 4.5-16 months). Treatment-related adverse events included 1 case of transient hypoesthesia. Two additional events were reported, but adjudicated as unrelated to the procedure. Complete occlusion, measured as Raymond-Roy class I, was achieved in all cases. CONCLUSION: The SVB device was safely and effectively used in the treatment of PICA aneurysms. The smaller delivery system profile reduces the risk of procedure complications and creates new treatment options for distal lesions.

The Perceived Utility of 3 Online Resources for Medical Student Neurosurgery Education.

OBJECTIVE: Neurosurgery has a high barrier of educational access for medical students. The Medical Student Neurosurgery Training Center (MSNTC) is a novel online learning platform that provides on-site and virtual training opportunities and resources that aim to increase student access to neurosurgical education. The objective of this article was to describe student-reported utility of Medical Student Neurosurgery Training Center educational resources. METHODS: A Qualtrics survey was sent to attendees after the 2020 Virtual Neurosurgery Training Camp. Ratings were quantified on modified 5-point Likert scales and compared using Wilcoxon rank sum tests, with a P value of 0.05. RESULTS: Response was obtained from 119 (25.2%) of 473 Virtual Neurosurgery Training Camp registrants. Of respondents, 65 (54.6%) reported prior use of Brain & Spine Report (BSR), 68 (57.14%) reported use of the Video Library (VL), and 78 (65.5%) reported use of the Global Events Calendar (GEC). Among respondents who previously used the BSR, VL, or GEC, mean ratings of usefulness were 3.94 ± 1.01, 4.06 ± 0.91, and 4.10 ± 0.99, respectively. Medical students with a neurosurgery interest group at their home institution reported greater utility of the BSR (P = 0.0008), VL (P = 0.0018), and GEC (P = 0.0250). Medical students with a home program reported greater utility of the BSR (P = 0.0079), and international students reported greater utility of the VL (P = 0.0447). CONCLUSIONS: Medical Student Neurosurgery Training Center resources appear to have promising preliminary benefits for students. Increasing medical student awareness, continued development of these resources, and objectively assessing outcomes in neurosurgery education are warranted.

Impact of lockdown and unlocking on symptomatology and emergency department visits during the first wave of the COVID-19 pandemic.

Background: The COVID-19 pandemic resulted in a complete nationwide lockdown on March 24, 2020. The months of April and May had stringent lockdown measures followed by a gradual loosening of restrictions in a graded manner. Methods: This observational study was performed in the emergency department (ED) of a tertiary hospital in south India triage Priority 1 and Priority 2 patients presented during the COVID-19 lockdown and unlock periods spanning from April 2020 to August 2020. The three different lockdown periods and the subsequent unlock periods were categorized as lockdown 1 (LD1), lockdown 2 (LD2), lockdown 3 (LD3), and unlock phase (UL), and a 7-day time period in each were taken for 7-day incidence analysis. Results: During the 5-month study period, a total of 1,954 patients were analyzed for the study that included 405, 440, 492, and 617 patients during the 7-day time periods in the LD1, LD2, LD3, and UL periods, respectively. The 7-day incidence of COVID-19 suspects increased significantly by 101.9% from LD1 to UL phases, whereas trauma cases increased by 52.9% in the same two time periods. Compared with LD1, in the UL phase, the 7-day ED admission and in-hospital mortality rates increased by 50.3% and 66.7%, respectively. Conclusion: The number of COVID-19 suspects saw a near-constant increase through the different phases of lockdown, culminating in the UL phase. The stringent lockdown measures resulted in a significant reduction in the incidence of trauma with a rebound increase in the UL phase.

A retrospective anatomical study of the cerebral dural venous sinus outflow pathways utilizing three-dimensional rotational venography.

OBJECTIVE: Proper blood flow is essential for the maintenance of homeostasis for the human cerebrum. The dural venous sinuses comprise the dominant cerebral venous outflow path. Understanding the spatial configuration of the dural venous sinuses can provide valuable insight into several pathological conditions. Previously, only two-dimensional or cadaveric data have been used to understand cerebral outflow. For the first time, we applied three-dimensional rotational venography (3D-RV) to study and provide detailed quantitative morphological measurements of the terminal cerebral venous sinus system in several pathological states. SUBJECTS AND METHODS: Patients who underwent a 3D-RV procedure were identified by reviewing our local institution's endovascular database. Patients with high-quality angiographic images were selected. Eighteen patients were included (37.1 ± 3.8 years). Sinuses were divided into four segments, starting at the torcula and ending at the internal jugular vein. Segment length, 3D displacement, and cross-sectional area were measured. RESULTS: The transverse sinus (60.2 mm) was the longest segment, followed by the sigmoid sinus (55.1 mm). Cross-sectional areas were smallest at the middle of the transverse sinus (21.3 mm2) but increased at the sigmoid sinus (33.5 mm2) and at the jugular bulb (49.7 mm2). The only variation in displacements of venous flow was at the sigmoid-jugular junction, where 55% of cases had lateral displacements versus 45% medial, and 78% superior versus 22% inferior. CONCLUSIONS: We describe the terminal venous sinus system of patients with a variety of diagnoses, detailing segment length, cross-sectional area, and 3D path.

Retreatment of Residual and Recurrent Aneurysms After Embolization With the Woven EndoBridge Device: Multicenter Case Series.

BACKGROUND: The Woven EndoBridge (WEB) device (Terumno Corp. [parent company of Microvention]) was approved by the U.S. Food and Drug Administration as the first intrasaccular device for intracranial aneurysm treatment in December 2018. Its use has become more common since then, but both trial results and postmarket experiences have raised questions about the efficacy in achieving complete aneurysm obliteration. Retreatment after WEB embolization has not been extensively discussed. OBJECTIVE: To discuss the incidence and retreatment of aneurysms after initial WEB embolization. METHODS: Retrospective review across 13 institutions identified all occurrences of WEB retreatment within neurovascular databases. Details regarding demographics, aneurysm characteristics, treatment considerations, clinical outcomes, and aneurysm occlusion were obtained and analyzed. RESULTS: Thirty aneurysms were retreated in 30 patients in a cohort of 342 WEB-treated aneurysms. The retreatment rate was 8.8%. Endovascular methods were used for 23 cases, and 7 were treated surgically. Two aneurysms presented with rehemorrhage after initial WEB embolization. Endovascular treatments included stent-assisted coiling (12), flow diversion (7), coiling (2), PulseRider (Johnson & Johnson)-assisted coiling (1), and additional WEB placement (1). Surgical treatments included primary clipping (6) and Hunterian ligation (1). There were no major complications within the study group. CONCLUSION: WEB retreatments were successfully performed by a variety of techniques, including stent-assisted coiling, clipping, and flow diversion as the most common. These procedures were performed safely with subsequent obliteration of most aneurysms. The potential need for retreatment of aneurysms should be considered during primary WEB treatments.

Developmental Phenotypic and Transcriptomic Effects of Exposure to Nanomolar Levels of 4-Nonylphenol, Triclosan, and Triclocarban in Zebrafish (Danio rerio).

Triclosan, triclocarban and 4-nonylphenol are all chemicals of emerging concern found in a wide variety of consumer products that have exhibited a wide range of endocrine-disrupting effects and are present in increasing amounts in groundwater worldwide. Results of the present study indicate that exposure to these chemicals at critical developmental periods, whether long-term or short-term in duration, leads to significant mortality, morphologic, behavioral and transcriptomic effects in zebrafish (Danio rerio). These effects range from total mortality with either long- or short-term exposure at 100 and 1000 nM of triclosan, to abnormalities in uninflated swim bladder seen with long-term exposure to triclocarban and short-term exposure to 4-nonylphenol, and cardiac edema seen with short-term 4-nonylphenol exposure. Additionally, a significant number of genes involved in neurological and cardiovascular development were differentially expressed after the exposures, as well as lipid metabolism genes and metabolic pathways after exposure to each chemical. Such changes in behavior, gene expression, and pathway abnormalities caused by these three known endocrine disruptors have the potential to impact not only the local ecosystem, but human health as well.

Optimizing the residency application process: insights from neurological surgery during the pandemic virtual application cycle.

OBJECTIVE: In this article, the authors describe the impact of the COVID-19 virtual match cycle and discuss approaches to optimize future cycles through applicant and neurosurgical education leadership insights. METHODS: Anonymous surveys of neurosurgery program leaders (program directors and program chairs), program administrators (PAs), and 2020-2021 neurosurgery residency match applicants were distributed by the SNS, in conjunction with the Association of Resident Administrators in Neurological Surgery and AANS Young Neurosurgeons Committee. RESULTS: Responses were received from 77 (67.0%) of 115 PAs, 119 (51.7%) of 230 program leaders, and 124 (44.3%) of 280 applicants representing geographically diverse regions. During the virtual application cycle relative to the previous year, programs received more Electronic Residency Application Service applications (mean 314.8 vs 285.3, p < 0.0001) and conducted more applicant interviews (mean 45.2 vs 39.9, p = 0.0003). More than 50% of applicants applied to > 80 programs; 60.3% received ≤ 20 interview invitations, and 9% received > 40 invitations. Overall, 65% of applicants completed ≤ 20 interviews, whereas 34.7% completed > 20 interviews. Program leaders described one 4-week home subinternship (93.3%) and two 4-week external subinternships (68.9%) as optimal neurosurgical exposure; 62.8% of program leaders found the standardized letter of recommendation template to be somewhat (47.5%) or significantly (15.3%) helpful. Applicants, PAs, and program leaders all strongly preferred a hybrid model of in-person and virtual interview options for future application cycles over all in-person or all virtual options. Ninety-three percent of applicants reported matching within their top 10-ranked programs, and 52.9% of programs matched residents within the same decile ranking as in previous years. CONCLUSIONS: Optimizing a national strategy for the neurosurgery application process that prioritizes equity and reduces costs, while ensuring adequate exposure for applicants to gain educational opportunities and evaluate programs, is critical to maintain a successful training system.

Global Regulatory Pathways Converge To Control Expression of Pseudomonas aeruginosa Type IV Pili.

The opportunistic pathogen Pseudomonas aeruginosa relies upon type IV pili (Tfp) for host colonization and virulence. Tfp are retractile surface appendages that promote adherence to host tissue and mediate twitching motility, a form of surface-associated translocation. Tfp are composed of a major structural pilin protein (PilA), several less abundant, fiber-associated pilin-like proteins (FimU, PilV, PilW, PilX, and PilE), and a pilus-associated tip adhesin and surface sensor (PilY1). Several proteins critical for Tfp biogenesis and surface sensing are encoded by the fimU-pilVWXY1Y2E operon. Tfp biogenesis is regulated by the global transcription factor Vfr and its allosteric effector, cyclic AMP (cAMP). Our investigation into the basis for reduced Tfp production in cAMP/vfr mutants revealed a defect in the expression of the fimU operon. We found that cAMP/Vfr activation of the fimU operon occurs via direct binding of Vfr to a specific fimU promoter sequence. We also refined the role of the AlgZ/AlgR two-component system in fimU regulation by demonstrating that phosphorylation of the response regulator AlgR is required for maximal binding to the fimU promoter region in vitro. Vfr also regulates expression of the algZR operon, revealing an indirect regulatory loop affecting fimU operon transcription. Overall, these results demonstrate that two linked but independent regulatory systems couple the expression of Tfp biogenesis and surface sensing genes and highlight the regulatory complexity governing expression of P. aeruginosa virulence factors. IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen responsible for a wide range of infections. An extensive repertoire of virulence factors aid in P. aeruginosa pathogenesis. Type IV pili (Tfp) play a critical role in host colonization and infection by promoting adherence to host tissue, facilitating twitching motility and mediating surface-associated behaviors. The fimU operon encodes several pilus-associated proteins that are essential for proper Tfp function and surface sensing. In this study, we report that linked but independent regulatory systems dictate Tfp biogenesis. We also demonstrated the importance of different phosphorylation states of the AlgZ/AlgR two-component system and its role in Tfp biogenesis. Overall, this study furthers our understanding of the complex regulatory mechanisms that govern the production of a critical and multifaceted virulence factor.

Middle meningeal artery embolization for chronic subdural hematoma in cancer patients with refractory thrombocytopenia.

OBJECTIVE: Surgical evacuation of chronic subdural hematoma (SDH) in cancer patients is often contraindicated owing to refractory thrombocytopenia. Middle meningeal artery embolization (MMAE) recently emerged as a potential alternative to surgical evacuation for patients with chronic SDH. The goal of this study was to evaluate the safety and efficacy of MMAE for chronic SDH in cancer patients with refractory thrombocytopenia. METHODS: A multiinstitutional registry was reviewed for clinical and radiographic outcomes of cancer patients with transfusion-refractory thrombocytopenia and baseline platelet count < 75 K/µl, who underwent MMAE for chronic SDH. RESULTS: MMAE was performed on a total of 31 SDHs in 22 patients, with a mean ± SD (range) platelet count of 42.1 ± 18.3 (9-74) K/µl. At the longest follow-up, 24 SDHs (77%) had reduced in size, with 15 (48%) showing > 50% reduction. Two patients required surgical evacuation after MMAE. There was only 1 procedural complication; however, 16 patients (73%) ultimately died of cancer-related complications. Median survival was significantly longer in the 16 patients with improved SDH than the 6 patients with worsened SDH after MMAE (185 vs 24 days, p = 0.029). Length of procedure, technical success rate, SDH size reduction, and complication rate were not significantly differ between patients who underwent transfemoral and transradial approaches. CONCLUSIONS: Transfemoral or transradial MMAE is a potential therapeutic option for thrombocytopenic cancer patients with SDH. However, treatment benefit may be marginal for patients with high disease burden and limited life expectancy. A prospective trial is warranted to address these questions.

The evolution of intracranial aneurysm treatment techniques and future directions.

Treatment techniques and management guidelines for intracranial aneurysms (IAs) have been continually developing and this rapid development has altered treatment decision-making for clinicians. IAs are treated in one of two ways: surgical treatments such as microsurgical clipping with or without bypass techniques, and endovascular methods such as coiling, balloon- or stent-assisted coiling, or intravascular flow diversion and intrasaccular flow disruption. In certain cases, a single approach may be inadequate in completely resolving the IA and successful treatment requires a combination of microsurgical and endovascular techniques, such as in complex aneurysms. The treatment option should be considered based on factors such as age; past medical history; comorbidities; patient preference; aneurysm characteristics such as location, morphology, and size; and finally the operator's experience. The purpose of this review is to provide practicing neurosurgeons with a summary of the techniques available, and to aid decision-making by highlighting ideal or less ideal cases for a given technique. Next, we illustrate the evolution of techniques to overcome the shortfalls of preceding techniques. At the outset, we emphasize that this decision-making process is dynamic and will be directed by current best scientific evidence, and future technological advances.

PmtA Regulates Pyocyanin Expression and Biofilm Formation in Pseudomonas aeruginosa.

The opportunistic pathogen Pseudomonas aeruginosa expresses a small molecular weight, cysteine-rich protein (PmtA), identified as a metallothionein (MT) protein family member. The MT family proteins have been well-characterized in eukaryotes as essential for zinc and copper homeostasis, protection against oxidative stress, and the ability to modify a variety of immune activities. Bacterial MTs share sequence homology, antioxidant chemistry, and heavy metal-binding capacity with eukaryotic MTs, however, the impact of bacterial MTs on virulence and infection have not been well-studied. In the present study, we investigated the role of PmtA in P. aeruginosa PAO1 using a PmtA-deficient strain (ΔpmtA). Here we demonstrated the virulence factor, pyocyanin, relies on the expression of PmtA. We showed that PmtA may be protective against oxidative stress, as an alternative antioxidant, glutathione, can rescue pyocyanin expression. Furthermore, the expression of phzM, which encodes a pyocyanin precursor enzyme, was decreased in the ΔpmtA mutant during early stationary phase. Upregulated pmtA expression was previously detected in confluent biofilms, which are essential for chronic infection, and we observed that the ΔpmtA mutant was disrupted for biofilm formation. As biofilms also modulate antibiotic susceptibility, we examined the ΔpmtA mutant susceptibility to antibiotics and found that the ΔpmtA mutant is more susceptible to cefepime and ciprofloxacin than the wild-type strain. Finally, we observed that the deletion of pmtA results in decreased virulence in a waxworm model. Taken together, our results support the conclusion that PmtA is necessary for the full virulence of P. aeruginosa and may represent a potential target for therapeutic intervention.