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We argue that the study of single-cell subcellular organelle omics is needed to understand and regulate cell function. This requires and is being enabled by new technology development.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

Objective: To determine in-hospital costs associated with performing an EEA to anterior skull base pathology and to identify drivers of cost variability for patients undergoing endoscopic anterior skull base surgery. Methods: All endoscopic anterior skull base surgeries performed over a period from January 1st, 2015 to October 24th, 2017 were evaluated. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables associated with each hospital stay and univariate analysis was performed using Stata software. Results: An EEA was associated with an average total in-hospital cost of $44 545. Compared to patients undergoing a transsphenoidal approach to pituitary tumor resection, EEA patients incurred higher in-hospital costs across all variables including a total cost increase of $15 921 (95% confidence interval $5720-26 122, P = .002). Univariate analysis of all endoscopic anterior skull base surgery patients showed a cost increase of $30 616 associated with post-operative cerebrospinal fluid (CSF) leak ($10 420-50 811, P = .004), $14 610 with post-operative diabetes insipidus (DI) ($4610-24 609, P = .004), and $11 522 with African-American patients relative to Caucasian patients ($3049-19 995, P = .008). Conclusions: Patients who undergo endoscopic EEA for resection of anterior skull base tumors typically incur greater in-hospital costs than patients undergoing a standard TSA. Post-operative complications such as CSF leak and DI, as well as ethnicity, are significant drivers of cost-variability.

Objective To determine the in-hospital cost implications of an endoscopic expanded endonasal approach (EEEA) for meningioma resection relative to the open transcranial approach. Methods All anterior skull base meningioma surgeries performed over a period from January 1st, 2015 to October 31th, 2017 were evaluated. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables associated with each hospital stay and univariate analysis was performed using R software. All cost data were converted into August 2021-equivalent dollar amounts using the United States Bureau of Labor Statistics consumer price index. Results Thirty-five patients met study criteria, including 27 patients undergoing an open transcranial approach and 8 undergoing an EEEA. Average length of stay for patients undergoing an open approach was 9.3 days compared to 5.6 within the EEEA group ( P = .126). The average total in-hospital cost of patient undergoing an EEEA was $35417.1 compared to $46406.9 among patients undergoing an open transcranial approach ( P = .168). On univariate analysis, the cost of an open transcranial approach relative to the EEEA was $10989.8 ( P = .411). Conclusions The open transcranial approach remained the dominant surgical approach to anterior skull base meningiomas over our study time period. However, despite limited patient numbers the EEEA was associated with decreased total in-hospital costs.

Surgeon providers and billing professionals use Current Procedural Terminology (CPT) codes to specify patient treatment and associated charges. In the present study, coding discrepancies between surgeons' first pass coding and employed coders' final codes were investigated. A total of 500 patients over 3 months were retrospectively analyzed for coding discrepancies. To quantify the impact of change, codes with the most accumulated discrepancies were studied and change to annual relative value unit (RVU) was determined. Final submission of codes to billing demonstrated a 161% increase in total codes by the professional coders, versus original surgeon-derived codes (1594 vs 987 CPT codes). The most common source of change between the surgeon and coder was the addition of distinct codes by the billing professional (270 patients, 54.51%). These results demonstrate the existence of coding discrepancies. Future investigation will evaluate the communication between surgeons and billing professionals.

Rathke cleft cysts (RCCs) arise from the development of the Rathke pouch. Recurrence is common after either drainage or cyst removal. The endoscopic endonasal approach (EEA) is increasingly utilized for the management of RCC. Various techniques have been described to try to reduce the rates of recurrence. We studied the effect of fenestration with a nasoseptal flap (NSF) on recurrence rates by comparing a cohort of patients undergoing this technique to a cohort of patients undergoing conventional drainage.Patients who underwent EEA for RCC between 2011 and 2020 were identified and divided into 2 cohorts: conventional fenestration versus fenestration with NSF. Surgical approach, reconstructive method, and recurrences were recorded. Primary end point was symptomatic or radiographic recurrence.21 patients were identified undergoing EEA. An NSF was used to line the cyst cavity in 11 cases. Conventional fenestration without mucosal reconstruction was performed in the remaining 10 cases. In the cases without NSF, 5 (50%) developed recurrence requiring revision surgery, while there was only one recurrence in the NSF group (P0.05). In patients requiring revision, all had an NSF placed and none had a second recurrence of their RCC.NSF placement into a fenestrated RCC is useful to prevent cyst reaccumulation and reoperation. Typical fenestration carries an unacceptably high rate of recurrence.

To determine the in-hospital cost implications of an expanded endoscopic endonasal approach (EEEA) for craniopharyngioma resection relative to the traditional open transcranial approach.All craniopharyngioma surgeries performed at a single institution over a period from January 1st 2001 to October 31th 2017 were evaluated. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables associated with each hospital stay and univariate regression analysis was performed using R software.Thirty-six patients met study criteria, including 22 undergoing an open approach and 14 undergoing an EEEA. There was a significantly longer average length of stay among patients undergoing open resection (21.5 vs. 10.6 days, p = 0.024). The average total in-hospital cost of a patient undergoing an EEEA was $58979.3 compared to $89142.3 for an open approach (p = 0.127). On univariate regression analysis, the total in-hospital cost for a patient undergoing an open approach relative to an EEEA was $30163.0 (p = 0.127). The open approach was exclusively performed from study onset until April 2010 (16 patients). From April 2010 to August 2013, 6 open approaches and 5 EEEA were performed. The EEEA has been exclusively performed from August 2013 until the conclusion of our study period (9 patients).There has been a shift toward surgical resection of craniopharyngioma via an EEEA approach for amenable tumors. Our study demonstrates that the EEEA has become the preferred surgical approach at our institution, and shows that the EEEA is associated with shorter postoperative length of stay and lower total in-hospital cost. Laryngoscope, 133:83-87, 2023.

Breast cancer treatment includes increasingly complex and expensive treatments. Accordingly, the current estimates of the cost of breast cancer treatment are out of date. The SEER-Medicare Data Link provided 142,837,978 paid Medicare claims from 398,148 female beneficiaries between the ages of 22 and 110 diagnosed with breast cancer between 2007 and 2016. These claims were compared with 153,071,044 claims from 443,952 Medicare beneficiaries without a cancer diagnosis. The total, fully adjudicated, amounts for each claim were summed to determine total treatment cost for each beneficiary. These costs were then aggregated by year after diagnosis and stage at diagnosis. The actuarial survival of beneficiaries with cancer was calculated using the Kaplan–Meier method. Mean costs for the control group were $8,019 per year. The 10-year cost of cancer treatment in Medicare beneficiaries was directly related to stage at diagnosis and ranged from $103,573 for stage 0 cancers to $376,573 for stage 4 cancers. The highest cost occurred during the first 2 years after diagnosis, the time of the beneficiary’s initial treatment. Following the first 2 years, healthcare costs remained elevated for at least 10 years after diagnosis. The 10-year treatment cost of female Medicare beneficiaries with breast cancer increases with increasing stage at diagnosis. Any effective screening technology that reduces stage at diagnosis will result in significant treatment cost savings to the Medicare program.

OBJECTIVE To characterize the patient and clinical factors that determine variability in hospital costs following endoscopic transphenoidal pituitary surgery. METHODS All endoscopic transphenoidal pituitary surgeries performed from January 1, 2015, to October 24, 2017, with complete data were evaluated in this retrospective single-institution study. The electronic medical record was reviewed for patient factors, tumor characteristics, and cost variables during each hospital stay. Multivariate linear regression was performed using Stata software. RESULTS The analysis included 190 patients and average length of stay was 4.71 days. Average total in-hospital cost was $28,624 (95% confidence interval $25,094-$32,155) with average total direct cost of $19,444 ($17,136-$21,752) and total indirect cost of $9181 ($7592-$10,409). On multivariate regression, post-operative cerebrospinal fluid (CSF) leak was associated with a significant increase in all cost variables, including a total cost increase of $40,981 ($15,474-$66,489, P = .002). Current smoking status was associated with an increased total cost of $20,189 ($6,638-$33,740, P = .004). Self-reported Caucasian ethnicity was associated with a significant decrease in total cost of $6646 (-$12,760 to -$532, P = .033). Post-operative DI was associated with increased costs across all variables that were not statistically significant. CONCLUSIONS Post-operative CSF leak, current smoking status, and non-Caucasian ethnicity were associated with significantly increased costs. Understanding of cost drivers of endoscopic transphenoidal pituitary surgery is critical for future cost control and value creation initiatives. LEVEL OF EVIDENCE 3 Laryngoscope, 131:760-764, 2021.

OBJECTIVEMultidisciplinary treatment including medical oncology, radiation oncology, and surgical consultation is necessary to provide comprehensive therapy for patients with spinal metastases. The goal of this study was to review the use of radiation therapy and/or surgical intervention and their impact on patient outcomes.METHODSIn this retrospective series, the authors identified at their institution those patients with spinal metastases who had received radiation therapy alone or had undergone surgery with or without radiation therapy within a 6-year period. Data on patient age, chemotherapy, surgical procedure, radiation therapy, Karnofsky Performance Status (KPS), primary tumor pathology, Spinal Instability Neoplastic Score (SINS), and survival after treatment were collected from the patient electronic medical records. N − 1 chi-square testing was used for comparisons of proportions. The Student t-test was used for comparisons of means. A p value < 0.05 was considered statistically significant. A survival analysis was completed using a multivariate Cox proportional hazards model.RESULTSTwo hundred thirty patients with spinal metastases were identified, 109 of whom had undergone surgery with or without radiation therapy. Among the 104 patients for whom the surgical details were reviewed, 34 (33%) had a history of preoperative radiation to the surgical site but ultimately required surgical intervention. In this surgical group, a significantly increased frequency of death within 30 days was noted for the SINS unstable patients (23.5%) as compared to that for the SINS stable patients (2.3%; p < 0.001). The SINS was a significant predictor of time to death among surgical patients (HR 1.11, p = 0.037). Preoperative KPS was not independently associated with decreased survival (p > 0.5) on univariate analysis. One hundred twenty-six patients met the criteria for inclusion in the radiation-only analysis. Ninety-eight of these patients (78%) met the criteria for potential instability (PI) at the time of treatment, according to the SINS system. Five patients (5%) with PI in the radiation therapy group had a documented neurosurgical or orthopedic surgery consultation prior to radiation therapy.CONCLUSIONSAt the authors’ institution, patients with gross mechanical instability per the SINS system had an increased rate of 30-day postoperative mortality, which remained significant when controlling for other factors. Surgical consultation for metastatic spine patients receiving radiation oncology consultation with PI is low. The authors describe an institutional pathway to encourage multidisciplinary treatment from the initial encounter in the emergency department to expedite surgical evaluation and collaboration.

OBJECTIVEAlthough it is known that intersurgeon variability in offering elective surgery can have major consequences for patient morbidity and healthcare spending, data addressing variability within neurosurgery are scarce. The authors performed a prospective peer review study of randomly selected neurosurgery cases in order to assess the extent of consensus regarding the decision to offer elective surgery among attending neurosurgeons across one large academic institution.METHODSAll consecutive patients who had undergone standard inpatient surgical interventions of 1 of 4 types (craniotomy for tumor [CFT], nonacute redo CFT, first-time spine surgery with/without instrumentation, and nonacute redo spine surgery with/without instrumentation) during the period 2015–2017 were retrospectively enrolled (n = 9156 patient surgeries, n = 80 randomly selected individual cases, n = 20 index cases of each type randomly selected for review). The selected cases were scored by attending neurosurgeons using a need for surgery (NFS) score based on clinical data (patient demographics, preoperative notes, radiology reports, and operative notes; n = 616 independent case reviews). Attending neurosurgeon reviewers were blinded as to performing provider and surgical outcome. Aggregate NFS scores across various categories were measured. The authors employed a repeated-measures mixed ANOVA model with autoregressive variance structure to compute omnibus statistical tests across the various surgery types. Interrater reliability (IRR) was measured using Cohen’s kappa based on binary NFS scores.RESULTSOverall, the authors found that most of the neurosurgical procedures studied were rated as “indicated” by blinded attending neurosurgeons (mean NFS = 88.3, all p values < 0.001) with greater agreement among neurosurgeon raters than expected by chance (IRR = 81.78%, p = 0.016). Redo surgery had lower NFS scores and IRR scores than first-time surgery, both for craniotomy and spine surgery (ANOVA, all p values < 0.01). Spine surgeries with fusion had lower NFS scores than spine surgeries without fusion procedures (p < 0.01).CONCLUSIONSThere was general agreement among neurosurgeons in terms of indication for surgery; however, revision surgery of all types and spine surgery with fusion procedures had the lowest amount of decision consensus. These results should guide efforts aimed at reducing unnecessary variability in surgical practice with the goal of effective allocation of healthcare resources to advance the value paradigm in neurosurgery.

OBJECTIVEIntraoperative molecular imaging with tumor-targeted fluorescent dyes can enhance resection rates. In contrast to visible-light fluorophores (e.g., 5-aminolevulinic-acid), near-infrared (NIR) fluorophores have increased photon tissue penetration and less contamination from tissue autofluorescence. The second-window ICG (SWIG) technique relies on passive accumulation of indocyanine green (ICG) in neoplastic tissues. OTL38, conversely, targets folate receptor overexpression in nonfunctioning pituitary adenomas. In this study, we compare the properties of these 2 modalities for NIR imaging of pituitary adenomas to better understand the potential for NIR imaging in neurosurgery.METHODSA total of 39 patients with pituitary adenomas were enrolled between June 2015 and January 2018 in 2, sequential, IRB-approved studies. Sixteen patients received systemic ICG infusions 24 hours prior to surgery, and another 23 patients received OTL38 infusions 2–3 hours prior to surgery. NIR fluorescence signal-to-background ratio (SBR) was recorded during and after resection. Immunohistochemistry was performed on the 23 adenomas resected from patients who received OTL38 to assess expression of folate receptor–alpha (FRα).RESULTSAll 16 adenomas operated on after ICG administration demonstrated strong NIR fluorescence (mean SBR 4.1 ± 0.69 [SD]). There was no statistically significant difference between the 9 functioning and 7 nonfunctioning adenomas (p = 0.9). After administration of OTL38, the mean SBR was 1.7 ± 0.47 for functioning adenomas, 2.6 ± 0.91 for all nonfunctioning adenomas, and 3.2 ± 0.53 for the subset of FRα-overexpressing adenomas. Tissue identification with white light alone for all adenomas demonstrated 88% sensitivity and 90% specificity. SWIG demonstrated 100% sensitivity but only 29% specificity for both functioning and nonfunctioning adenomas. OTL38 was 75% sensitive and 100% specific for all nonfunctioning adenomas, but when assessment was limited to the 9 FRα-overexpressing adenomas, the sensitivity and specificity of OTL38 were both 100%.CONCLUSIONSIntraoperative imaging with NIR fluorophores demonstrates highly sensitive detection of pituitary adenomas. OTL38, a folate-receptor–targeted fluorophore, is highly specific for nonfunctioning adenomas but has no utility in functioning adenomas. SWIG, which relies on passive diffusion into neoplastic tissue, is applicable to both functioning and nonfunctioning pituitary adenomas, but it is less specific than targeted fluorophores. Thus, targeted and nontargeted NIR fluorophores play important, yet distinct, roles in intraoperative imaging. Selectively and intelligently using either agent has the potential to greatly improve resection rates and outcomes for patients with intracranial tumors.

Introduction Vancomycin may be used as an alternative perioperative antibiotic for penicillin-allergic patients but follows a different infusion timing. At the institution presented herein, noncompliance with recommended vancomycin infusion timing has been hypothesized to contribute toward increased risk of surgical site infections and avoidable expenditures. The objective of this project was to utilize the Performance Improvement In Action methodology to identify, address, and solve the problem of vancomycin administration timing. Methodology This study took place at a multi-hospital, urban academic medical center. The protocol was developed by neurosurgery and anesthesia faculty, advanced practice providers, nursing, and pharmacy. Timing of the following points was recorded: initial order, order release, pharmacy verification, vancomycin infusion, and surgical incision. Fifty consecutive penicillin-allergic patients undergoing neurosurgical intervention were prospectively enrolled. Data comparison was made between the pilot and retrospective review cohorts. Results The pilot cohort achieved correct administration of vancomycin in 100% of cases. Average infusion start time prior to incision increased by 257% (p

Background: Early, high-quality advance care planning discussions are essential for supporting goal-concordant care among glioblastoma (GBM) patients. Objective: Using mixed methods, we sought to characterize current serious illness (SI) communication practices at our institution. Methods: The electronic medical records of 240 deceased GBM patients cared for at the Abramson Cancer Center in Philadelphia, PA between 2017 and 2019 were systematically reviewed for documented SI conversations about four domains: prognosis, goals, end-of-life planning, and code status. Patient outcomes and SI conversation characteristics were analyzed using descriptive statistics. Standardized interviews about GBM care were held with five clinicians. Interview transcripts were analyzed using grounded-theory coding to identify emergent themes. Results: Nearly all patients (96%) had at least one documented SI conversation (median: 4, interquartile range [IQR] 2-7), mostly outpatient with medical oncology physicians. Median timing of first SI conversation was 360 days before death. SI conversations were not significantly associated with patient outcomes, including inpatient death and hospice enrollment. Seven themes emerged from clinician interviews: balancing hope and reality, anticipatory guidance, neglect of the "big picture," need for earlier conversations, care coordination, the role of clinical expertise, and communication training. Conclusion: SI conversations were documented early and often in our sample, but their quality was difficult to assess. Contrary to our quantitative findings, interviewees reported that SI conversations were late, infrequent, inadequate, and fragmented across specialties, failing to explore critical issues such as prognosis and functional decline.

Objective Chronic rhinosinusitis (CRS) is a proposed risk factor for meningitis and other intracranial complications following the endoscopic endonasal transsphenoidal approach (TSA). Some have recommended staging TSA following surgery for CRS; however, delaying TSA has important ramifications. The objective of this study is to determine whether asymptomatic sinonasal inflammation (RSNI) on preoperative computed tomography scans, without clinical CRS, is associated with postoperative complications following TSA. Methods All consecutive TSA cases performed at a single tertiary care institution from January 1, 2009, to December 31, 2017, were reviewed for patient demographics, prior surgery, presence of RSNI on preoperative computed tomography scan based on Lund-Mackay (LM) score, intraoperative cerebrospinal fluid (CSF) leak, and postoperative complications (postoperative CSF leak, bleeding, infection). The association between preoperative RSNI and postoperative complications was analyzed via multivariate logistic regression. Results One hundred seventy-one cases of TSA were included with mean patient age of 52.6 years, 42.7% males, 18.1% revision cases, and mean LM score of 1.9 ± 2.7. Complications were identified in 9.9% of patients at the following rates: 5.3% postoperative CSF leak, 2.9% bleeding, and 1.8% infection (all sinusitis, no episodes of meningitis). Neither total LM score nor LM score > 5 (representative of clinically significant radiographic CRS) were predictors of any postoperative complication (both P > 0.05). Age, sex, revision status, intraoperative CSF leak, and total LM score were not independent predictors of any postoperative complication on multivariate analysis (all P > 0.05). Conclusion In asymptomatic patients, radiographic evidence of sinonasal inflammation is not associated with increased risk of complications following TSA. Level of evidence 4 Laryngoscope, 129:1545-1548, 2019.

Supplemental material, Malhotra_et_al_CPT_Discrepancy_Supplemental_Appendix_A_FINAL for Surgical CPT Coding Discrepancies: Analysis of Surgeons and Employed Coders by Gregory Glauser, Nikhil Sharma, Nathan Beatson, Ryan Dimentberg, Frank Savarese, Michael Gagliardi, M. Sean Grady and Neil R. Malhotra in American Journal of Medical Quality

OBJECTIVEWith nearly half of graduating US medical students being female, it is imperative to understand why females typically make up less than 20% of the neurosurgery applicant pool, a number that has changed very slowly over the past several decades. Organized neurosurgery has strongly indicated the desire to overcome the underrepresentation of women, and it is critical to explore whether females are at a disadvantage during the residency application process, one of the first steps in a neurosurgical career. To date, there are no published studies on specific applicant characteristics, including gender, that are associated with match outcome among neurosurgery resident applicants. The purpose of this study is to determine which characteristics of neurosurgery residency applicants, including gender, are associated with a successful match outcome.METHODSDe-identified neurosurgical resident applicant data obtained from the San Francisco Fellowship and Residency Matching Service for the years 1990–2007 were analyzed. Applicant characteristics including gender, medical school attended, year of application, United States Medical Licensing Exam (USMLE) Step 1 score, Alpha Omega Alpha (AOA) status, and match outcome were available for study.RESULTSOf the total 3426 applicants studied, 473 (13.8%) applicants were female and 2953 (86.2%) were male. Two thousand four hundred forty-eight (71.5%) applicants successfully matched. USMLE Step 1 score was the strongest predictor of match outcome with scores > 245 having an OR of 20.84 (95% CI 10.31–42.12) compared with those scoring < 215. The mean USMLE Step 1 score for applicants who successfully matched was 233.2 and was 210.8 for those applicants who did not match (p < 0.001). Medical school rank was also associated with match outcome (p < 0.001). AOA status was not significantly associated with match outcome. Female gender was associated with significantly lower odds of matching in both simple (OR 0.59, 95% CI 0.48–0.72) and multivariate analyses (OR 0.57, 95% CI 0.34–0.94 CI). USMLE Step 1 scores were significantly lower for females compared to males with a mean score of 230.1 for males and 221.5 for females (p < 0.001). There was no significant difference in medical school ranking or AOA status when stratified by applicant gender.CONCLUSIONSThe limited historical applicant data from 1990–2007 suggests that USMLE Step 1 score is the best predictor of match outcome, although applicant gender may also play a role.

BACKGROUND Bundled care payments are increasingly being explored for neurosurgical interventions. In this setting, skilled nursing facility (SNF) is less desirable from a cost perspective than discharge to home, underscoring the need for better preoperative prediction of postoperative disposition. OBJECTIVE To assess the capability of the Risk Assessment and Prediction Tool (RAPT) and other preoperative variables to determine expected disposition prior to surgery in a heterogeneous neurosurgical cohort, through observational study. METHODS Patients aged 50 yr or more undergoing elective neurosurgery were enrolled from June 2016 to February 2017 (n = 623). Logistic regression was used to identify preoperative characteristics predictive of discharge disposition. Results from multivariate analysis were used to create novel grading scales for the prediction of discharge disposition that were subsequently compared to the RAPT Score using Receiver Operating Characteristic analysis. RESULTS Higher RAPT Score significantly predicted home disposition (P

BACKGROUND: Surgical resection is the primary treatment for nonfunctional (NF) pituitary adenomas, but gross-total resection is difficult to achieve in all cases. NF adenomas overexpress folate receptor alpha (FRα). OBJECTIVE: To test the hypothesis that we could target FRα for highly sensitive and specific intraoperative detection of NF adenomas using near-infrared (NIR) imaging. METHODS: Fourteen patients with NF pituitary adenoma were infused with the folate analog NIR dye OTL38 preoperatively. NIR fluorescence signal-to-background ratio (SBR) was recorded for each tumor during resection of the adenomas. Extent of surgery was not modified based on the presence or absence of fluorescence. Immunohistochemistry was performed to assess FRα expression in all specimens. Magnetic resonance imaging (MRI) was performed postoperatively to assess residual neoplasm. RESULTS: Nine adenomas overexpressed FRα and fluoresced with a NIR SBR of 3.2 ± 0.52, whereas the 5 non-FRα-overexpressing adenomas fluoresced with an SBR of 1.5 ± 0.21. Linear regression demonstrated a significant correlation between intraoperative SBR and the FRα expression (P-value

Summary: A number of mitochondrial diseases arise from single-nucleotide variant (SNV) accumulation in multiple mitochondria. Here, we present a method for identification of variants present at the single-mitochondrion level in individual mouse and human neuronal cells, allowing for extremely high-resolution study of mitochondrial mutation dynamics. We identified extensive heteroplasmy between individual mitochondrion, along with three high-confidence variants in mouse and one in human that were present in multiple mitochondria across cells. The pattern of variation revealed by single-mitochondrion data shows surprisingly pervasive levels of heteroplasmy in inbred mice. Distribution of SNV loci suggests inheritance of variants across generations, resulting in Poisson jackpot lines with large SNV load. Comparison of human and mouse variants suggests that the two species might employ distinct modes of somatic segregation. Single-mitochondrion resolution revealed mitochondria mutational dynamics that we hypothesize to affect risk probabilities for mutations reaching disease thresholds. : Morris et al. use independent sequencing of multiple individual mitochondria from mouse and human brain cells to show high pervasiveness of mutations. The mutations are heteroplasmic within single mitochondria and within and between cells. These findings suggest mechanisms by which mutations accumulate over time, resulting in mitochondrial dysfunction and disease. Keywords: single mitochondrion, single cell, human neuron, mouse neuron, single-nucleotide variation

Objective The goal of this study is to provide a clinical pathway for shunt valve adjustment in the treatment of normal pressure hydrocephalus (NPH) patients. Patient and methods The authors conducted a single-center retrospective study of 102 patients (mean age 74 years, 66 men, 36 women) diagnosed with NPH. In all cases, a Medtronic Strata Adjustable Pressure valve set initially at 1.5 was implanted. Outcome was based on the clinical status of the patient at the last contact point with the senior author. Patients were adjusted with reductions or increases of 0.5 per follow-up visit to achieve the best clinical outcome and avoid complications. Complications were categorized as infection, shunt malfunction, subdural hygroma/hematoma, or any adverse event able to be attributed to a change in shunt setting or surgical procedure. Results Of the 102 patients, 60% had the triad of clinical symptoms, 5% had gait dysfunction only, 2% had dementia only, 4% had urine incontinence and gait dysfunction, 1% had urine incontinence and dementia, and 28% had gait dysfunction and dementia. Over a mean clinical follow-up of 19 months, 71 patients had improvement or resolution of NPH symptoms at the last point of contact with the senior author. Of the 71 patients, 24% improved in all 3 symptoms, 8% improved in urine incontinence only, 17% improved in gait dysfunction only, 15% improved in dementia only, 15% improved in urine incontinence and gait dysfunction only, 4% improved in urine incontinence and dementia only, and 15% improved in gait dysfunction and dementia only. Valve pressure adjustment was required at least once in 85 patients (mean number of 1.68 adjustments, 7 maximum); 10% had 0.5 as the final setting, 47% had 1.0 as the final setting, 36% had 1.5 as the final setting, 7% had 2.0 as the final setting, and 0% had 2.5 as the final setting. There were 41 (40%) complications overall: 28 subdural hygromas/hematomas, of which 5 required surgical evacuation; 9 distal obstructions requiring surgical revision; 4 seizures; 2 infections; 1 exposed shunt tubing; 1 intraparenchymal hematoma of unknown etiology. Conclusion Standardization of post-operative care for patients with NPH is possible. The present manuscript offers a safe and effective pathway for treatment of NPH patients with the Strata Adjustable Pressure Valve.

BACKGROUND Patients with an external ventricular drain (EVD) may not be readily mobilized because of concerns of catheter dislodgment and/or inappropriate cerebrospinal fluid drainage. Delayed mobilization may result in longer hospital stays and an increased risk for complications related to immobility. We aimed to determine the safety, feasibility, and outcome of an EVD mobilization protocol in patients with subarachnoid hemorrhage (SAH). METHODS A multidisciplinary group developed a formal algorithm for the mobilization of patients with SAH with EVDs. Outcome measures included intensive care unit (ICU) length of stay (LOS), day to first mobilization, and discharge disposition. Patients were prospectively enrolled during a 12-month period and compared with a historical control group of patients with SAH for the preceding 12-month period. RESULTS Thirty-nine of 45 (86.7%) patients were women. Mean age did not differ significantly between the preintervention (n = 19) and postintervention (n = 26) groups (59.6 vs 55.7). Number of EVD device days did not differ significantly between groups (16.3 vs 15, P = .422]. Of 101 attempted postintervention mobilization sessions, six were aborted for increased lethargy (1), pain (1), elevated intracranial pressure (1), drain malfunction (1), and hypotension (2). Twenty-four sessions were attempted but never initiated because of worsening neurologic examination (10), pulmonary instability (2), hemodynamic instability (2), medical instability (3), and provider request (1). No patient experienced catheter dislodgment. Mean ICU LOS was not different between groups (20.7 vs 18.2, P = .262). The day of first mobilization was significantly earlier in the postintervention group (18.7 vs 6.5, P < .0001). The percentage of patients discharged home or to acute rehabilitation was higher in the postintervention group (63.2% vs 88.5%, P = .018], when accounting for Hunt and Hess grade. CONCLUSIONS The mobilization of patients with EVDs is safe and feasible; it may be associated with earlier mobilization, reduced ICU LOS, and better discharge disposition. No major complications were attributable to early mobilization.

Investigation of human CNS disease and drug effects has been hampered by the lack of a system that enables single-cell analysis of live adult patient brain cells. We developed a culturing system, based on a papain-aided procedure, for resected adult human brain tissue removed during neurosurgery. We performed single-cell transcriptomics on over 300 cells, permitting identification of oligodendrocytes, microglia, neurons, endothelial cells, and astrocytes after 3 weeks in culture. Using deep sequencing, we detected over 12,000 expressed genes, including hundreds of cell-type-enriched mRNAs, lncRNAs and pri-miRNAs. We describe cell-type- and patient-specific transcriptional hierarchies. Single-cell transcriptomics on cultured live adult patient derived cells is a prime example of the promise of personalized precision medicine. Because these cells derive from subjects ranging in age into their sixties, this system permits human aging studies previously possible only in rodent systems.

Assays examining the open-chromatin landscape in single cells require isolation of the nucleus, resulting in the loss of spatial/microenvironment information. Here we describe CHEX-seq (CHromatin EXposed) for identifying single-stranded open-chromatin DNA regions in paraformaldehyde-fixed single cells. CHEX-seq uses light-activated DNA probes that binds to single-stranded DNA in open chromatin. In situ laser activation of the annealed probes’ 3’-Lightning Terminator™ in selected cells permits the probe to act as a primer for in situ enzymatic copying of single-stranded DNA that is then sequenced. CHEX-seq is benchmarked with human K562 cells and its utility is demonstrated in dispersed primary mouse and human brain cells, and immunostained cells in mouse brain sections. Further, CHEX-seq queries the openness of mitochondrial DNA in single cells. Evaluation of an individual cell’s chromatin landscape in its tissue context enables “spatial chromatin analysis”.One Sentence SummaryA new method, CHEX-seq (CHromatin eXposed), identifies the open-chromatin landscape in single fixed cells thereby allowing spatial chromatin analysis of selected cells in complex cellular environments.

IMPORTANCE: United States government personnel experienced potential exposures to uncharacterized directional phenomena while serving in Havana, Cuba, from late 2016 through May 2018. The underlying neuroanatomical findings have not been described. OBJECTIVE: To examine potential differences in brain tissue volume, microstructure, and functional connectivity in government personnel compared with individuals not exposed to directional phenomena. DESIGN, SETTING, AND PARTICIPANTS: Forty government personnel (patients) who were potentially exposed and experienced neurological symptoms underwent evaluation at a US academic medical center from August 21, 2017, to June 8, 2018, including advanced structural and functional magnetic resonance imaging analytics. Findings were compared with imaging findings of 48 demographically similar healthy controls. EXPOSURES: Potential exposure to uncharacterized directional phenomena of unknown etiology, manifesting as pressure, vibration, or sound. MAIN OUTCOMES AND MEASURES: Potential imaging-based differences between patients and controls with regard to (1) white matter and gray matter total and regional brain volumes, (2) cerebellar tissue microstructure metrics (eg, mean diffusivity), and (3) functional connectivity in the visuospatial, auditory, and executive control subnetworks. RESULTS: Imaging studies were completed for 40 patients (mean age, 40.4 years; 23 [57.5%] men; imaging performed a median of 188 [range, 4-403] days after initial exposure) and 48 controls (mean age, 37.6 years; 33 [68.8%] men). Mean whole brain white matter volume was significantly smaller in patients compared with controls (patients: 542.22 cm(3); controls: 569.61 cm(3); difference, −27.39 [95% CI, −37.93 to −16.84] cm(3); P

Objective Surgical resection is widely accepted as a critical component for definitive treatment of sinonasal mucosal melanoma. Systemic immunotherapy, including multiple newer agents, has been used to treat metastatic or unresectable disease. In this study, we examine its efficacy in locoregional control when used in conjunction with surgical resection for primary mucosal lesions. Design Present study is a retrospective review of all patients at a tertiary academic medical center with primary sinonasal mucosal melanoma and distant metastatic disease. Results A total of four patients were identified. In all cases, patients were treated with a combination of surgical resection of the primary tumor and systemic immunotherapy. Three patients were initially treated with surgery at the primary site followed by immunotherapy for distant metastases. Response to immunotherapy at the sites of primary and metastatic disease was seen in two patients. All four patients developed progression or recurrence at the primary site following initiation of immunotherapy for which they underwent surgical resection. One patient remains in follow-up without evidence of disease 20 months after initial treatment; three succumbed to the disease at 135, 37, and 16 months after initial treatment. Conclusion Surgical resection for local control plays a critically important role in the treatment of sinonasal mucosal melanoma regardless of the presence of metastases and whether immunotherapy will be given. This case series suggests that, though immunotherapy may demonstrate efficacy in managing distant disease, surgery should remain the first-line treatment for the primary site.

Objective Radiation therapy represents an uncommon but important component of treatment plans for some pituitary adenomas (PAs). Although radiation therapy has been used to treat pituitary adenomas for over a century, general trends in the usage of radiation therapy for this purpose have not been reviewed. Additionally, there are few large studies evaluating how radiation therapy is used for the treatment of these benign tumors. Investigating these trends and identifying any variations in radiation therapy utilization would help to better inform treatment decisions and improve patient outcomes. Design Present study is a retrospective analysis of cases using the National Cancer Database. Setting The research was organized at a tertiary academic medical center. Participants Patients were diagnosed with pituitary adenoma between 2004 and 2014 within the National Cancer Database (NCDB). Methods Temporal trends in the usage of radiation therapy to treat pituitary adenoma were analyzed through a retrospective analysis of 77,142 pituitary adenoma cases from the NCDB between 2004 and 2014. Univariate and multivariate analyses were to examine the relationship between patient, tumor, and treatment factors, and the incorporation of radiation therapy into the treatment of pituitary adenomas. We adjusted for potential confounders such as age, sex, race, comorbidity score, facility type, and year of diagnosis. Results A total of 77,142 patients met inclusion criteria. Inclusion of radiation therapy in pituitary adenoma treatment was 8.0% in 2004 and steadily declined to a low of 3.1% in 2014. Overall, patients were less likely to receive radiation for their pituitary adenoma over time (p Conclusion In this sample of pituitary adenoma patients treated at NCDB institutions between 2004 and 2014, we found a steady decline in the incorporation of radiation therapy in treatment, as well as in the use of any type of intervention for PA treatment, suggesting a rise in noninterventional observation of PA.

Meningiomas are the most common primary brain tumor of adults. The majority are benign (WHO grade I), with a mostly indolent course; 20% of them (WHO grade II and III) are, however, considered aggressive and require a more complex management. WHO grade II and III tumors are heterogeneous and, in some cases, can develop from a prior lower grade meningioma, although most arise de novo. Mechanisms leading to progression or implicated in de novo grade II and III tumorigenesis are poorly understood. RNA-seq was used to profile the transcriptome of grade I, II, and III meningiomas and to identify genes that may be involved in progression. Bioinformatic analyses showed that grade I meningiomas that progress to a higher grade are molecularly different from those that do not. As such, we identify GREM2, a regulator of the BMP pathway, and the snoRNAs SNORA46 and SNORA48, as being significantly reduced in meningioma progression. Additionally, our study has identified several novel fusion transcripts that are differentially present in meningiomas, with grade I tumors that did not progress presenting more fusion transcripts than all other tumors. Interestingly, our study also points to a difference in the tumor immune microenvironment that correlates with histopathological grade. Electronic supplementary material The online version of this article (10.1186/s40478-019-0690-x) contains supplementary material, which is available to authorized users.

No abstract available.

Chronic rhinosinusitis (CRS) is a proposed risk factor for meningitis and other intracranial complications following the endoscopic endonasal transsphenoidal approach (TSA). Some have recommended staging TSA following surgery for CRS; however, delaying TSA has important ramifications. The objective of this study is to determine whether asymptomatic sinonasal inflammation (RSNI) on preoperative computed tomography scans, without clinical CRS, is associated with postoperative complications following TSA.All consecutive TSA cases performed at a single tertiary care institution from January 1, 2009, to December 31, 2017, were reviewed for patient demographics, prior surgery, presence of RSNI on preoperative computed tomography scan based on Lund-Mackay (LM) score, intraoperative cerebrospinal fluid (CSF) leak, and postoperative complications (postoperative CSF leak, bleeding, infection). The association between preoperative RSNI and postoperative complications was analyzed via multivariate logistic regression.One hundred seventy-one cases of TSA were included with mean patient age of 52.6 years, 42.7% males, 18.1% revision cases, and mean LM score of 1.9 ± 2.7. Complications were identified in 9.9% of patients at the following rates: 5.3% postoperative CSF leak, 2.9% bleeding, and 1.8% infection (all sinusitis, no episodes of meningitis). Neither total LM score nor LM score 5 (representative of clinically significant radiographic CRS) were predictors of any postoperative complication (both P 0.05). Age, sex, revision status, intraoperative CSF leak, and total LM score were not independent predictors of any postoperative complication on multivariate analysis (all P 0.05).In asymptomatic patients, radiographic evidence of sinonasal inflammation is not associated with increased risk of complications following TSA.4 Laryngoscope, 129:1545-1548, 2019.

This cross-sectional analysis of nationally representative hospitalizations uses data from the National Inpatient Sample and 3 national surveys of ambulatory surgery to compare the frequency of use of optic nerve sheath fenestration vs cerebrospinal fluid shunt placement for the treatment of pseudotumor cerebri syndrome., Key Points Question How often is optic nerve sheath fenestration (ONSF) used relative to cerebrospinal fluid shunting procedures to treat pseudotumor cerebri syndrome (PTCS) in the United States? Findings In a cross-sectional analysis of nationally representative hospitalization data on 10 720 surgical procedures from the National Inpatient Sample, shunting was more than 10 times more common than ONSF, and this gap has widened as shunting for PTCS increased from 2002 to 2016. However, because the overall rate of PTCS-related hospitalization has increased even more rapidly, the percentage of inpatients with PTCS undergoing surgery has decreased. Meaning This study’s findings suggest that ONSF is used less frequently than shunting for PTCS, which may reflect underlying trends in medical treatment practices and outcomes or growing limitations in access to ophthalmic surgical expertise., Importance Optic nerve sheath fenestration (ONSF) and cerebrospinal fluid shunting are sometimes used to treat pseudotumor cerebri syndrome (PTCS), but their use patterns are unknown. Objectives To investigate the frequency of surgical PTCS treatment in the United States and to compare patients undergoing ONSF with those treated with shunting. Design, Setting, and Participants This was a retrospective longitudinal cross-sectional study. Inpatient data were obtained from the National Inpatient Sample (NIS), and outpatient surgical center data were obtained from the National Survey of Ambulatory Surgery (NSAS) and National Hospital Ambulatory Medical Care Survey (NHAMCS). Included in the analysis were 10 720 patients aged 18 to 65 years with a diagnosis code for PTCS, excluding venous thrombosis and other causes of intracranial hypertension. Time trends were explored and logistic regression was used to measure differences according to age, race/ethnicity, sex, Elixhauser comorbidity index, and other patient and hospital characteristics. Data analysis was performed from March 31 to October 7, 2020. Exposure Treatment for PTCS, excluding venous thrombosis and other causes of intracranial hypertension. Main Outcomes and Measures Annual number of PTCS-related admissions, ONSFs, and shunt procedures from 2002-2016. Patient and hospital-level characteristics of patients with PTCS undergoing ONSF or shunting were compared. Results Between 2010 and 2016, 297 ONSFs were performed and 10 423 shunts were placed as treatment for PTCS. The procedures were most commonly performed in individuals aged 26 to 35 years (39.4%), and 9920 (92.4%) of the surgically treated patients were women. ONSF was more common among younger patients (eg, adjusted odds ratio [AOR] for patients ≥46 years vs those 18-25 years, 0.22; 95% CI, 0.08-0.61) and in Black, Hispanic, or other minority populations (AOR, 2.37; 95% CI, 1.31-4.30) and less common in the South (AOR, 0.34; 95% CI, 0.13-0.88) and West (AOR, 0.15; 95% CI, 0.04-0.58) compared with the Northeast. Total PTCS-related hospitalizations increased from 6081 (95% CI, 5137-7025) in 2002 to 18 020 (95% CI, 16 607-19 433) in 2016. Shunting increased from 2002 to 2011 and subsequently plateaued and declined. ONSF was used much less frequently, and use has not increased. No instances of outpatient ONSF or shunting for PTCS were recorded in the NSAS or NHAMCS databases. Conclusions and Relevance This study’s findings suggest that shunting is more common than ONSF and that the use gap has widened as shunting has increased. However, because overall PTCS-related hospitalizations have increased even more rapidly, the percentage of inpatients with PTCS undergoing surgery has decreased. These trends may reflect changes in medical treatment practices and outcomes or growing limitations in access to ophthalmic surgical expertise.