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In genetic studies of cerebrovascular diseases, the optimal vessels to use as controls remain unclear. Our goal is to compare the transcriptomic profiles among 3 different types of control vessels: superficial temporal artery (STA), middle cerebral arteries (MCA), and arteries from the circle of Willis obtained from autopsies (AU). We examined the transcriptomic profiles of STA, MCA, and AU using RNAseq. We also investigated the effects of using these control groups on the results of the comparisons between aneurysms and the control arteries. Our study showed that when comparing pathological cerebral arteries to control groups, all control groups presented similar responses in the activation of immunological processes, the regulation of intracellular signaling pathways, and extracellular matrix productions, despite their intrinsic biological differences. When compared to STA, AU exhibited upregulation of stress and apoptosis genes, whereas MCA showed upregulation of genes associated with tRNA/rRNA processing. Moreover, our results suggest that the matched case-control study design, which involves control STA samples collected from the same subjects of matched aneurysm samples in our study, can improve the identification of non-inherited disease-associated genes. Given the challenges associated with obtaining fresh intracranial arteries from healthy individuals, our study suggests that using MCA, AU, or paired STA samples as controls are feasible strategies for future large-scale studies investigating cerebral vasculopathies. However, the intrinsic differences of each type of control should be taken into consideration when interpreting the results. With the limitations of each control type, it may be most optimal to use multiple tissues as controls.

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Background and Objectives: While somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms. Methods: We performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results. Results: Somatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway. Discussion: We propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.

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Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Designing effective individualized therapies for GBM requires quality fresh tissue specimens, and a comprehensive molecular profile of this highly heterogenous neoplasm. Novel neuro-surgical approaches, such as the automated resection NICO Myriad™ system, are increasingly used by neurosurgeons to better reach the invasive front of tumors. However, no information exists on how harvesting GBM tissue using this approach may impact the translational research value of the sample. Here, we set out to characterize matched specimens from 15 patients, where one tissue sample was obtained using traditional tumor de-bulking (herein referred to as "en bloc" sample), and the other sample was obtained using the MyriadTM System (herein referred to as "Myriad" sample). We investigated the fidelity of patient derived xenografts (PDXs) for each sample type to the corresponding human tissues and evaluated the added value of sequencing both samples for each patient. Matched en bloc and Myriad samples processed in parallel, were subjected to the following assays: cell viability, self-renewal, in vivo tumorigenicity using an orthotopic model of glioma, genomic sequencing, and pharmacological testing using PI3K-MTOR pathway inhibitors. Our results demonstrate that primary GBM cultures derived from matched specimens grew at similar rates (correlation coefficient R = 0.72), generated equivalent number of neurospheres, and had equivalent tumorigenic potential in vivo (mouse survival correlation coefficient R = 0.93). DNA Sequencing using the Illumina tumor panel amplicons revealed over 70% concordance in non-synonymous mutations between matched human GBM specimens. PDX genomic profiles were also highly concordant with the corresponding patient tissues (>70%). RNA sequencing of paired GBM samples revealed unique genomic variants and differential gene expression between the en bloc and Myriad specimens, with the former molecularly resembling the "tumor core" and the latter resembling the "invasive tumor front" signature. Functionally, we show that primary-derived GBM cells-obtained after fresh specimen's dissociation-are more effectively growth-inhibited by co-targeting non-overlapping mutations enriched in each sample type, suggesting that profiling both specimens more adequately capture the molecular heterogeneity of GBM and may enhance the design accuracy and efficacy of individualized therapies.

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BACKGROUND: Neurosurgical educators strive to identify the best applicants, yet formal study of resident selection has proved difficult. We conducted a systematic review to answer the following question: What objective and subjective preresidency factors predict resident success? METHODS: PubMed, ProQuest, Embase, and the CINAHL databases were queried from 1952 to 2015 for literature reporting the impact of preresidency factors (PRFs) on outcomes of residency success (RS), among neurosurgery and all surgical subspecialties. Due to heterogeneity of specialties and outcomes, a qualitative summary and heat map of significant findings were constructed. RESULTS: From 1489 studies, 21 articles met inclusion criteria, which evaluated 1276 resident applicants across five surgical subspecialties. No neurosurgical studies met the inclusion criteria. Common objective PRFs included standardized testing (76%), medical school performance (48%), and Alpha Omega Alpha (43%). Common subjective PRFs included aggregate rank scores (57%), letters of recommendation (38%), research (33%), interviews (19%), and athletic or musical talent (19%). Outcomes of RS included faculty evaluations, in-training/board exams, chief resident status, and research productivity. Among objective factors, standardized test scores correlated well with in-training/board examinations but poorly correlated with faculty evaluations. Among subjective factors, aggregate rank scores, letters of recommendation, and athletic or musical talent demonstrated moderate correlation with faculty evaluations. CONCLUSION: Standardized testing most strongly correlated with future examination performance but correlated poorly with faculty evaluations. Moderate predictors of faculty evaluations were aggregate rank scores, letters of recommendation, and athletic or musical talent. The ability to predict success of neurosurgical residents using an evidence-based approach is limited, and few factors have correlated with future resident performance. Given the importance of recruitment to the greater field of neurosurgery, these data provide support for a national, prospective effort to improve the study of neurosurgery resident selection.

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Neurosurgeons are highly specialized surgeons whose pride is mastery of the complexity of form and function that is the nervous system and then knowing when and how these require surgical intervention. Following years of arduous postgraduate education, neurosurgeons enter the world of practice that is not only daunting in its intricacies of regulations, mandates, and unknown business practices, but also changing at a meteoric pace. Overwhelmingly, graduating residents and fellows are choosing to practice as employed physicians, a trend that is new in its magnitude and also changed because of the rapid evolution of large health systems. Case studies of challenges other employed surgical specialists have faced can provide critical and important education for any neurosurgeon in this arena. As with the lessons of all case studies, the teachings are remarkably universal, but how those lessons apply to an individual's specific situation will require personalized adaptation.

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The Health Care Reform Act has fostered a shift toward capitation and shared risk among providers to improve quality and reduce the escalating costs of healthcare. Like all physicians, neurosurgeons are increasingly being incentivized to participate in efforts to streamline care through the use of surgical pathways to reduce hospital length of stay and prevent readmissions. These changes have expanded the role of the neurosurgeon along the continuum of care for the neurosurgery patient. This paper predicts and advocates for a further broadening of neurosurgery participation from programs that reward physicians for helping to prevent a high-risk patient's need for surgery to management of postacute rehabilitation. It also introduces the concept of risk reduction more generally at the community level through collaborative interventions that improve health through changes to the built environment, innovations in transportation, and improved access to healthy food and recreation opportunities.

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Healthcare delivery is evolving rapidly with an increasing emphasis on the concept of "value." At the same time, neurosurgeons are disproportionately working in employed positions where external definition of value becomes directly linked with compensation, work environment, and career satisfaction. Few neurosurgeons have an understanding of the various ways in which value is and can be defined and there are limited resources to assist in this realm. This paper covers the essential value concepts of National Standards, Pitfalls of National Standards, Call Coverage Compensation, Valuation Through Demand, Value Beyond Productivity, and Neurosurgical Value in the Accountable Care Organization Era. This framework should help neurosurgeons better understand critical trends impacting practice across the country.

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The 2010 Affordable Care Act's (ACA) aims of lowering costs and improving quality of care will renew focus on preventive health strategies. This coincides with a trend in medicine to reconsider population health approaches as part of the standard curriculum. This intersection of new policy and educational climates presents a unique opportunity to reconsider traditional healthcare structures. This paper introduces and advances an alignment that few have considered. We propose that accountable care organizations (ACOs), which are expected to proliferate under the ACA, present the best opportunity to establish partnerships between healthcare, public health, and community-based organizations to achieve the legislation's goals. One example is encouraging daily physical activity via built environment interventions and programs, which is recommended by numerous groups. We highlight how nonprofit organizations in Sacramento, California have been able to leverage influence, capital, and policy to encourage design for active living, and how their work is coordinating with public health and healthcare initiatives. In conclusion, we critically examine potential barriers to the success of partnerships between ACOs and community organizations and encourage further exploration and evaluation.

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In times of fiscal and political uncertainty, philanthropy has become an increasingly important mechanism for building, maintaining, and expanding neurosurgical research programs. Although philanthropy has historically helped launch many hospital systems, scientists and clinicians have generally relied on government grants and industry investment to support research and program infrastructure. However, competition for funds from all sources has increased at the same time as the pipelines for those funds have eroded. Philanthropy can provide salary support to allow neurosurgeons to pursue research and, ultimately, advance the field to improve outcomes for patients. Funds raised can fill financial gaps to recruit and pay for needed research staff, equipment, and facilities. To foster charitable giving, institutions can develop both a culture and processes to promote and support philanthropy. Furthermore, it is essential to ensure that donor relationships are properly nurtured with ongoing stewardship. In addition to cultivating grateful patients, there are numerous creative models of fundraising for research that can be explored, including venture philanthropy, in which voluntary health organizations or individuals partner with academia and industry to invest in early-stage drug development and other innovations. Other approaches include formation of nonprofit foundations and partnerships with other entities to work jointly on shared development goals.

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