Publications by authors named "Kristopher T Kahle"

197 Publications

Genomics of human congenital hydrocephalus.

Childs Nerv Syst 2021 Jul 7. Epub 2021 Jul 7.

Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of pathological cerebrospinal fluid (CSF) accumulation and, therefore, treated largely by neurosurgical CSF diversion. The persistence of ventriculomegaly and poor neurodevelopmental outcomes in some post-surgical patients highlights our limited knowledge of disease mechanisms. Recent whole-exome sequencing (WES) studies have shown that rare, damaging de novo and inherited mutations with large effect contribute to ~ 25% of sporadic CH. Interestingly, multiple CH genes are key regulators of neural stem cell growth and differentiation and converge in human transcriptional networks and cell types pertinent to fetal neurogliogenesis. These data implicate genetic disruption of early brain development as the primary pathomechanism in a substantial minority of patients with sporadic CH, shedding new light on human brain development and the pathogenesis of hydrocephalus. These data further suggest WES as a clinical tool with potential to re-classify CH according to a molecular nomenclature of increased precision and utility for genetic counseling, outcome prognostication, and treatment stratification.
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http://dx.doi.org/10.1007/s00381-021-05230-8DOI Listing
July 2021

Molecular Genetics and Complex Inheritance of Congenital Heart Disease.

Genes (Basel) 2021 Jun 30;12(7). Epub 2021 Jun 30.

Department of Genetics, School of Medicine, Washington University, St. Louis, MO 63110, USA.

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.
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http://dx.doi.org/10.3390/genes12071020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307500PMC
June 2021

Inflammatory hydrocephalus.

Childs Nerv Syst 2021 Jun 23. Epub 2021 Jun 23.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT, 06510, USA.

Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells, and physical irritants. However, inappropriately triggered or sustained inflammation can respectively initiate, propagate, or prolong disease. Post-hemorrhagic (PHH) and post-infectious hydrocephalus (PIH) are the most common forms of hydrocephalus worldwide. They are treated using neurosurgical cerebrospinal fluid (CSF) diversion techniques with high complication and failure rates. Despite their distinct etiologies, clinical studies in human patients have shown PHH and PIH share similar CSF cytokine and immune cell profiles. Here, in light of recent work in model systems, we discuss the concept of "inflammatory hydrocephalus" to emphasize potential shared mechanisms and potential therapeutic vulnerabilities of these disorders. We propose that this change of emphasis could shift our thinking of PHH and PIH from a framework of life-long neurosurgical disorders to that of preventable conditions amenable to immunomodulation.
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http://dx.doi.org/10.1007/s00381-021-05255-zDOI Listing
June 2021

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Aug;78(8):993-1003

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
August 2021

Intraventricular CSF Turbulence in Pediatric Communicating Hydrocephalus.

Neurology 2021 08 24;97(5):246-247. Epub 2021 May 24.

From the Department of Neurosurgery, Yale School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1212/WNL.0000000000012237DOI Listing
August 2021

Impact of race on outcomes and healthcare utilization following spinal fusion for adolescent idiopathic scoliosis.

Clin Neurol Neurosurg 2021 Jul 4;206:106634. Epub 2021 May 4.

Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Objectives: Racial disparities in spine surgery have been shown to impact surgical management and postoperative complications. However, for adolescent patients with idiopathic scoliosis (AIS) treated by posterior spinal fusion (PSF), the influence of race on postoperative outcomes remains unclear. The aim of the study was to investigate the differences in baseline patient demographics, inpatient management, and postoperative complications for adolescents with AIS undergoing elective, posterior spinal surgery (≥ 4 levels).

Patients And Methods: The Kids' Inpatient Database year 2012 was queried. Adolescent patients (age 10-17 years old) with AIS undergoing elective, PSF (≥ 4 levels) were selected using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. Patients were divided into 4 cohorts: Black, White, Hispanic, and Other. Patient demographics, comorbidities, complications, length of hospital stay (LOS), discharge disposition and total cost were recorded. The primary outcome was the rate of intraoperative and postoperative complications and resource utilization after elective PSF intervention.

Results: Patient demographics significantly differed between the four cohorts. While age was similar (p = 0.288), the White cohort had a greater proportion of female patients (White: 79.0%; Black: 72.1%; Hispanic: 78.2%; Other: 75.9%, p = 0.006), and the Black cohort had the largest proportion of patients in the 0-25th income quartile (White: 16.1%; Black: 43.3%; Hispanic: 28.0%; Other: 15.3%, p < 0.001). There were significant differences in hospital region (p < 0.001) and bed size (p < 0.001) between the cohorts, with more Hispanic adolescents being treated in the West (White: 21.9%; Black: 8.9%; Hispanic: 40.3%; Other: 29.3%) at small hospitals (White: 14.0%; Black: 13.9%; Hispanic: 16.2%; Other: 7.1%). Baseline comorbidities were similar between the cohorts. The use of blood transfusions was significantly greater in the Black cohort compared to the other racial groups (White: 16.7%; Black: 25.0%; Hispanic: 24.5%; Other: 22.7%, p < 0.001). The number of vertebral levels involved differed significantly between the cohorts (p < 0.001), with the majority of patients having 9-levels or greater involved (White: 80.9%; Black: 81.7%; Hispanic: 84.3%; Other: 67.3%). The rate of complications encountered during admission was greatest in the Other cohort (White: 21.9%; Black: 23.6%; Hispanic: 22.2%; Other: 34.9%, p < 0.001). While LOS was similar between the cohorts (p = 0.702), median total cost of admission was highest for Hispanic patients (White: $49,340 [37,908-65,078]; Black: $47,787 [37,718-64,670]; Hispanic: $54,718 [40,689-69,266]; Other: $54,110 [41,292-71,540], p < 0.001).

Conclusions: Our study suggests that race may not have a significant impact on surgical outcomes after elective posterior spine surgery for adolescent idiopathic scoliosis. Further studies are necessary to corroborate our findings.
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http://dx.doi.org/10.1016/j.clineuro.2021.106634DOI Listing
July 2021

Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination.

Clin Genet 2021 08 2;100(2):176-186. Epub 2021 Jun 2.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. The lethality of the homozygote mouse prevented us from performing an assessment of locomotor behavior. The mutant heterozygote mouse; however, exhibited a significant increase in kainate-induced seizure activity over wild-type mice, supporting the hypothesis that the PKD1 variant is a candidate for the cause of the patient epilepsy. Because PKD1 was previously identified in a kinomic screen as an interacting partner of the K-Cl cotransporter 3 (KCC3), and since KCC3 is involved in peripheral nerve disease and brain hyperexcitability, one possible mechanism of action of PKD1 in disease is through KCC3. We show that catalytically inactive PKD1 stimulates KCC3 activity, consistent with tonic relief of inhibitory phosphorylation. Our findings implicate a novel role for PKD1 in the human nervous system, and uncover a mechanism that could serve as a potential target to promote nervous system myelination.
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http://dx.doi.org/10.1111/cge.13973DOI Listing
August 2021

Unique Actions of GABA Arising from Cytoplasmic Chloride Microdomains.

J Neurosci 2021 Jun 26;41(23):4957-4975. Epub 2021 Apr 26.

Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114

Developmental, cellular, and subcellular variations in the direction of neuronal Cl currents elicited by GABA receptor activation have been frequently reported. We found a corresponding variance in the GABA receptor reversal potential (E) for synapses originating from individual interneurons onto a single pyramidal cell. These findings suggest a similar heterogeneity in the cytoplasmic intracellular concentration of chloride ([Cl]) in individual dendrites. We determined [Cl] in the murine hippocampus and cerebral cortex of both sexes by (1) two-photon imaging of the Cl-sensitive, ratiometric fluorescent protein SuperClomeleon; (2) Fluorescence Lifetime IMaging (FLIM) of the Cl-sensitive fluorophore MEQ (6-methoxy--ethylquinolinium); and (3) electrophysiological measurements of E by pressure application of GABA and RuBi-GABA uncaging. Fluorometric and electrophysiological estimates of local [Cl] were highly correlated. [Cl] microdomains persisted after pharmacological inhibition of cation-chloride cotransporters, but were progressively modified after inhibiting the polymerization of the anionic biopolymer actin. These methods collectively demonstrated stable [Cl] microdomains in individual neurons and and the role of immobile anions in its stability. Our results highlight the existence of functionally significant neuronal Cl microdomains that modify the impact of GABAergic inputs. Microdomains of varying chloride concentrations in the neuronal cytoplasm are a predictable consequence of the inhomogeneous distribution of anionic polymers such as actin, tubulin, and nucleic acids. Here, we demonstrate the existence and stability of these microdomains, as well as the consequence for GABAergic synaptic signaling: each interneuron produces a postsynaptic GABA response with a unique reversal potential. In individual hippocampal pyramidal cells, the range of GABA reversal potentials evoked by stimulating different interneurons was >20 mV. Some interneurons generated postsynaptic responses in pyramidal cells that reversed at potentials beyond what would be considered purely inhibitory. Cytoplasmic chloride microdomains enable each pyramidal cell to maintain a compendium of unique postsynaptic responses to the activity of individual interneurons.
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http://dx.doi.org/10.1523/JNEUROSCI.3175-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197632PMC
June 2021

Patient Risk Factors Associated With 30- and 90-Day Readmission After Ventriculoperitoneal Shunt Placement for Idiopathic Normal Pressure Hydrocephalus in Elderly Patients: A Nationwide Readmission Study.

World Neurosurg 2021 Aug 20;152:e23-e31. Epub 2021 Apr 20.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Radiology & Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Objective: For idiopathic normal pressure hydrocephalus (iNPH), risk stratifying patients and identifying those who are likely to fare well after ventriculoperitoneal shunt (VP) surgery may help improve quality of care and reduce unplanned readmissions. The aim of this study was to investigate the drivers of 30- and 90-day readmissions after VP shunt surgery for iNPH in elderly patients.

Methods: The Nationwide Readmission Database, years 2013 to 2015, was queried. Elderly patients (≥65 years old) undergoing VP shunt surgery were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. Unique patient linkage numbers were used to follow patients and identify 30- and 31- to 90-day readmission rates. Patients were grouped by no readmission (Non-R), readmission within 30 days (30-R), and readmission within 31 to 90 days (90-R).

Results: We identified 7199 elderly patients undergoing VP shunt surgery for iNPH. A total of 1413 (19.6%) patients were readmitted (30-R: n = 812 [11.3%] vs. 90-R: n = 601 [8.3%] vs. Non-R: n = 5786). The most prevalent 30- and 90-day complications seen among the readmitted cohort were mechanical complication of nervous system device implant (30-R: 16.1%, 90-R: 12.4%), extracranial postoperative infection (30-R: 10.4%, 90-R: 7.0%), and subdural hemorrhage (30-R: 6.0%, 90-R: 16.4%). On multivariate regression analysis, age, diabetes, and renal failure were independently associated with 30-day readmission; female sex, and 26th to 50th household income percentile were independently associated with reduced likelihood of 90-day readmission. Having any complication during the index admission independently associated with both 30- and 90-day readmission.

Conclusions: In this study, we identify the most common drivers for readmission for elderly patients with iNPH undergoing VP shunt surgery.
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http://dx.doi.org/10.1016/j.wneu.2021.04.010DOI Listing
August 2021

Analysis workflow to assess genetic variants from human whole-exome sequencing.

STAR Protoc 2021 Mar 10;2(1):100383. Epub 2021 Mar 10.

Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.

Here, we present a protocol to analyze genetic variants derived from the whole-exome sequencing (WES) of proband-parent trios. We provide stepwise instructions for using existing pipelines to call mutations (DNMs) and determine whether the observed number of such mutations is enriched relative to the expected number. This protocol may be extended to any human disease trio-based cohort. Cohort size is a limiting determinant to the discovery of high-confidence pathogenic DNMs. For complete details on the use and execution of this protocol, please refer to Dong et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960548PMC
March 2021

Post-traumatic seizures following pediatric traumatic brain injury.

Clin Neurol Neurosurg 2021 Apr 10;203:106556. Epub 2021 Feb 10.

Department of Neurosurgery, Yale University School of Medicine, New Haven, 06520, CT, United States. Electronic address:

Objectives: The aim of this study was to investigate the national impact of demographic, hospital, and inpatient risk factors on post-traumatic seizure (PTS) development in pediatric patients who presented to the ED following a traumatic brain injury (TBI).

Patients And Methods: The Nationwide Emergency Department Sample database years 2010-2014 was queried. Patients (<21 years old) with a primary diagnosis of TBI and subsequent secondary diagnosis of PTS were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. We identified demographic variables, hospital characteristics, pre-existing medical comorbidities, etiology of injuries, and type of injury. Univariate and multivariate logistic regression analyses were performed to identify the factors associated with post-traumatic seizures.

Results: We identified 1,244,087 patients who sustained TBI, of which 10,340 (0.83%) developed PTS. Of the patients who had seizures, the youngest cohort aged 0-5 years had the greatest proportion of seizure development (p < 0.001). Compared to those TBI patients with loss of consciousness (LOC), patients encountering no LOC after TBI had the smallest proportion of seizures while Prolonged LOC with baseline return had the greatest proportion. On univariate analysis of the effect of in-hospital complication on rate of seizures, respiratory, renal and urinary, hematoma, septicemia, and other neurological complications were all significantly associated with seizure development. On multivariate regression, age 6-10 years (OR: 0.48, p < 0.001) 11-15 years (OR: 0.41, p < 0.001), and 16-20 years (OR: 0.51, p < 0.001) were independently associated with decreased risk of developing seizures. Extended LOC with baseline return (OR: 6.33, p < 0.001), extended LOC without baseline return (OR: 1.95, p = 0.009), and Other LOC (OR: 3.02, p < 0.001) were independently associated with increased risk of developing seizures. Subarachnoid hemorrhage (OR: 4.14, p < 0.001), subdural hemorrhage [OR: 7.72, p < 0.001), and extradural hemorrhage (OR: 3.13, p < 0.001) were all independently associated with increased risk of developing seizures.

Conclusion: Out study demonstrates that various demographic, hospital, and clinical risk factors are associated with the development of seizures following traumatic brain injury. Enhancing awareness of these drivers may help provide greater awareness of patients likely to develop post-traumatic seizures such that this complication can be decreased in incidence so as to improve quality of care and decrease healthcare costs.
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http://dx.doi.org/10.1016/j.clineuro.2021.106556DOI Listing
April 2021

The Effects of Pulmonary Risk Factors on Hospital Resource Use After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis Correction.

World Neurosurg 2021 05 3;149:e737-e747. Epub 2021 Feb 3.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Objective: The aim of this study was to determine the impact of preoperative pulmonary risk factors (PRFS) on surgical outcomes after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS).

Methods: A retrospective cohort study was performed using the American College of Surgeons National Surgical Quality Improvement Program-Pediatric database from 2016 to 2018. All pediatric patients with AIS undergoing PSF were identified. Patients were then categorized by whether they had recorded baseline PRF or no-PRF. Patient demographics, comorbidities, intraoperative variables, complications, length of stay, discharge disposition, and readmission rate were assessed.

Results: A total of 4929 patients were identified, of whom 280 (5.7%) had baseline PRF. Compared with the no-PRF cohort, the PRF cohort had higher rates of complications (PRF, 4.3% vs. no-PRF, 2.2%; P = 0.03) and longer hospital stays (PRF, 4.6 ± 4.3 days vs. no-PRF, 3.8 ± 2.3 days; P < 0.001), yet, discharge disposition was similar between cohorts (P = 0.70). Rates of 30-day unplanned readmission were significantly higher in the PRF cohort (PRF, 6.3% vs. no-PRF, 2.7%; P = 0.009), yet, days to readmission (P = 0.76) and rates of 30-day reoperation (P = 0.16) were similar between cohorts. On multivariate analysis, PRF was found to be a significant independent risk factor for longer hospital stays (risk ratio, 0.74; 95% confidence interval, 0.44-1.04; P < 0.001) but not postoperative complication or 30-day unplanned readmission.

Conclusions: Our study showed that PRF may be a risk factor for slightly longer hospital stays without higher rates of complication or unplanned readmission for patients with AIS undergoing PSF and thus should not preclude surgical management.
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http://dx.doi.org/10.1016/j.wneu.2021.01.109DOI Listing
May 2021

Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma.

Mol Genet Genomic Med 2021 02 14;9(2):e1597. Epub 2021 Jan 14.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.

Background: Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic region, affecting diencephalic structures, and characterized by shorter survival and high recurrence rates. Pilomyxoid astrocytoma management remains controversial, with pathologic tissue diagnosis and relief of mass effect being the main goals of surgery while avoiding treatment-related morbidity, including vision loss, panhypopituitarism, and hypothalamic dysfunction. Chemotherapy (typically vincristine and carboplatin) in all pediatric patients and radiation therapy in pediatric patients over 5 years of age are used for treatment.

Methods: We report clinical presentation, surgical management, and whole exome sequencing results in a pediatric patient with the subtotally resected pilomyxoid astrocytoma.

Results: We identified two somatic activating missense mutations affecting FGFR1, including FGFR1 p.K656E and FGFR1 p.V561M. While the former is a known hotspot mutation that is both activating and transforming, the latter has been described as a gatekeeper mutation imparting resistance to FGFR inhibitors. Interestingly, both mutations were present with similar variant allele frequency within the tumor.

Conclusion: Similar variant allele frequencies of FGFR1 p.K656E and FGFR1 p.V561M mutations in our patient's tumor suggest that these mutations may have occurred at similar time points. Use of FGFR inhibitors in addition to STAT3 or PI3K/mTOR inhibition may prove a useful strategy in targeting our patient's pilomyxoid astrocytoma.
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http://dx.doi.org/10.1002/mgg3.1597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077124PMC
February 2021

Impact of Preoperative Anemia on Outcomes After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis.

World Neurosurg 2021 02 19;146:e214-e224. Epub 2020 Oct 19.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Objective: The aim of this study was to investigate the relationship of preoperative anemia and outcomes after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS).

Methods: A retrospective cohort study was performed using the American College of Surgeons National Surgical Quality Improvement Program-Pediatric database from 2016 to 2018. All pediatric patients (age 10-18 years) with AIS undergoing PSF were identified. Two cohorts were categorized into anemic and nonanemic cohorts based on age-based and sex-based criteria for anemia. Thirty-day outcomes and readmission rates were evaluated.

Results: A total of 4929 patients were identified, of whom 592 (12.0%) were found to have preoperative anemia. The anemic cohort had a greater prevalence of comorbidities and longer operative times. Compared with the nonanemic cohort, the anemic cohort experienced significantly higher rates of perioperative bleed/transfusion (nonanemic, 67.4% vs. anemic, 73.5%; P = 0.004) and required a greater total amount of blood transfused (nonanemic, 283.2 ± 265.5 mL vs. anemic, 386.7 ± 342.6 mL; P < 0.001). The anemic cohort experienced significantly longer hospital stays (nonanemic, 3.8 ± 2.2 days vs. anemic, 4.2 ± 3.9 days; P = 0.001), yet discharge disposition (P = 0.58), 30-day complication rates (P = 0.79) and unplanned reoperation rates (P = 0.90) were similar between cohorts. On multivariate analysis, anemia was found to be an independent predictor of perioperative bleed/transfusion (odds ratio, 1.36; 95% confidence interval, 1.12-1.66; P = 0.002) as well as a longer length of hospital stay (relative risk, 0.46; 95% confidence interval, 0.25-0.67; P < 0.001) but was not an independent predictor for postoperative complications (P = 0.85).

Conclusions: Our study suggests that preoperative anemia may be a risk factor for a greater perioperative bleed/transfusion event and slightly longer length of stay; however, it was not associated with greater 30-day complication and readmission rates in patients with AIS undergoing PSF.
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http://dx.doi.org/10.1016/j.wneu.2020.10.074DOI Listing
February 2021

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.

iScience 2020 Oct 11;23(10):101552. Epub 2020 Sep 11.

Yale Center for Genome Analysis, West Haven, CT, USA.

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated mutation (p.Cys188Trp) in the GABA receptor Cl channel γ-1 subunit () exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na and Ca channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca channel Ca3.2 (). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.
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http://dx.doi.org/10.1016/j.isci.2020.101552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554653PMC
October 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

New drugs on the horizon for cerebral edema: what's in the clinical development pipeline?

Expert Opin Investig Drugs 2020 Oct 20;29(10):1099-1105. Epub 2020 Sep 20.

Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology and Yale-Rockefeller NIH Centers for Mendelian Genomics, Yale School of Medicine , New Haven, CT, USA.

Introduction: Research has advanced our understanding of the molecular and cellular mechanisms of cerebral edema and has propelled the development of novel antiedema therapeutics. Current evidence supports aberrant neuro-glial ion transport as a central mechanism that underlies pathological fluid accumulation after central nervous system injury.

Areas Covered: Novel agents in clinical development show potential in altering the natural history and treatment of cerebral edema. Using the PubMed and Google Scholar databases, we review recent advances in our understanding of cerebral edema and describe agents under active investigation, their mechanism, and their application in recent and ongoing clinical trials.

Expert Opinion: Pharmacotherapies that target molecular mechanisms underlying the compensatory post-injury response of ion channels and transporters that lead to pathological alteration of osmotic gradients are the most promising therapeutic strategies. Repurposing of drugs such as glyburide that inhibit the aberrant upregulation of ion channels such as SUR1-TRPM4, and novel agents, such as ZT-1a, which reestablish physiological regulation of ion channels such as NKCC1/KCC, could be useful adjuvants to prevent and even reverse fluid accumulation in the brain parenchyma.
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http://dx.doi.org/10.1080/13543784.2020.1813715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104020PMC
October 2020

Comparison of epidemiology, treatments, and outcomes in pediatric versus adult ependymoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa019. Epub 2020 Feb 21.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: Mounting evidence supports the presence of heterogeneity in the presentation of ependymoma patients with respect to location, histopathology, and behavior between pediatric and adult patients. However, the influence of age on treatment outcomes in ependymoma remains obscure.

Methods: The SEER database years 1975-2016 were queried. Patients with a diagnosis of ependymoma were identified using the International Classification of Diseases for Oncology, Third Edition, coding system. Patients were classified into one of 4 age groups: children (age 0-12 years), adolescents (age 13-21 years), young adults (age 22-45 years), and older adults (age >45 years). The weighed multivariate analysis assessed the impact of age on survival outcomes following surgical treatment.

Results: There were a total of 6076 patients identified with ependymoma, of which 1111 (18%) were children, 529 (9%) were adolescents, 2039 (34%) were young adults, and 2397 (40%) were older adults. There were statistically significant differences between cohorts with respect to race ( < .001), anatomical location ( < .001), extent of resection ( < .001), radiation use ( < .001), tumor grade ( < .001), histological classification ( < .001), and all-cause mortality ( < .001). There was no significant difference between cohorts with respect to gender ( = .103). On multivariate logistic regression, factors associated with all-cause mortality rates included males (vs females), supratentorial location (vs spinal cord tumors), and radiation treatment (vs no radiation).

Conclusions: Our study using the SEER database demonstrates the various demographic and treatment risk factors that are associated with increased rates of all-cause mortality between the pediatric and adult populations following a diagnosis of ependymoma.
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http://dx.doi.org/10.1093/noajnl/vdaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212900PMC
February 2020

Persistent mutation despite multimodal therapy in recurrent pediatric glioblastoma.

NPJ Genom Med 2020 1;5:23. Epub 2020 Jun 1.

Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06511 USA.

Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from whole-exome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleterious mutation, whose deficiency in preclinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of an mutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistently mutated clone, with rare mutations in and , the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlying deficiency. As such, this case represents a novel report following the clinical and genetic progression of a mutated glioblastoma, including treatment with a novel and emerging immunotherapy. Although deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing preclinical data supporting a role for mutations in gliomagenesis and resistance to standard therapies.
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http://dx.doi.org/10.1038/s41525-020-0130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264170PMC
June 2020

Pre-operative headaches and obstructive hydrocephalus predict an extended length of stay following suboccipital decompression for pediatric Chiari I malformation.

Childs Nerv Syst 2021 01 9;37(1):91-99. Epub 2020 Jun 9.

Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.

Purpose: For young children and adolescents with Chiari malformation type I (CM-I), the determinants of extended length of hospital stay (LOS) after neurosurgical suboccipital decompression are obscure. Here, we investigate the impact of patient- and hospital-level risk factors on extended LOS following surgical decompression for CM-I in young children to adolescents.

Methods: The Kids' Inpatient Database year 2012 was queried. Pediatric CM-I patients (6-18 years) undergoing surgical decompression were identified. Weighted patient demographics, comorbidities, complications, LOS, disposition, and total cost were recorded. A multivariate logistic regression was used to determine the odds ratio for risk-adjusted LOS. The primary outcome was the degree patient comorbidities or post-operative complications correlated with extended LOS.

Results: A total of 1592 pediatric CM-I patients were identified for which 328 (20.6%) patients had extended LOS (normal LOS, 1264; extended LOS, 328). Age, gender, race, median household income quartile, and healthcare coverage distributions were similar between the two cohorts. Patients with extended LOS had significantly greater admission comorbidities including headache symptoms, nausea and vomiting, obstructive hydrocephalus, lack of coordination, deficiency anemias, and fluid and electrolyte disorders. On multivariate logistic regression, several risk factors were associated with extended LOS, including headache symptoms, obstructive hydrocephalus, and fluid and electrolyte disorders.

Conclusions: Our study using the Kids' Inpatient Database demonstrates that presenting symptoms and signs, including headaches and obstructive hydrocephalus, respectively, are significantly associated with extended LOS following decompression for pediatric CM-I.
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http://dx.doi.org/10.1007/s00381-020-04688-2DOI Listing
January 2021

Risk Factors for the Development of Post-Traumatic Hydrocephalus in Children.

World Neurosurg 2020 09 7;141:e105-e111. Epub 2020 May 7.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Objective: The aim of this study was to investigate the national impact of demographic, hospital, and inpatient risk factors on posttraumatic hydrocephalus (PTH) development in pediatric patients who presented to the emergency department after a traumatic brain injury (TBI).

Methods: The Nationwide Emergency Department Sample database 2010-2014 was queried. Patients (<21 years old) with a primary diagnosis of TBI and subsequent secondary diagnosis of PTH were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system.

Results: We identified 1,244,087 patients who sustained TBI, of whom 930 (0.07%) developed PTH. The rates of subdural hemorrhage and subarachnoid hemorrhage were both significantly higher for the PTH cohort. On multivariate regression, age 6-10 years (odds ratio [OR], 0.6; 95% confidence interval [CI], 0.38-0.93; P = 0.022), 11-15 years (OR, 0.32; 95% CI, 0.21-0.48; P < 0.0001), and 16-20 years (OR, 0.24; 95% CI, 0.15-0.37; P < 0.0001) were independently associated with decreased risk of developing hydrocephalus, compared with ages 0-5 years. Extended loss of consciousness with baseline return and extended loss of consciousness without baseline return were independently associated with increased risk of developing hydrocephalus. Respiratory complication (OR, 28.35; 95% CI, 15.75-51.05; P < 0.0001), hemorrhage (OR, 37.12; 95% CI, 4.79-287.58; P = 0.0001), thromboembolic (OR, 8.57; 95% CI, 1.31-56.19; P = 0.025), and neurologic complication (OR, 64.64; 95% CI, 1.39-3010.2; P = 0.033) were all independently associated with increased risk of developing hydrocephalus.

Conclusions: Our study using the Nationwide Emergency Department Sample database shows that various demographic, hospital, and clinical risk factors are associated with the development of hydrocephalus after traumatic brain injury.
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http://dx.doi.org/10.1016/j.wneu.2020.04.216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484270PMC
September 2020

Preclinical insights into therapeutic targeting of KCC2 for disorders of neuronal hyperexcitability.

Expert Opin Ther Targets 2020 07 5;24(7):629-637. Epub 2020 May 5.

Department of Neurosurgery, Yale University School of Medicine , New Haven, CT, USA.

Introduction: Epilepsy is a common neurological disorder of neuronal hyperexcitability that begets recurrent and unprovoked seizures. The lack of a truly satisfactory pharmacotherapy for epilepsy highlights the clinical urgency for the discovery of new drug targets. To that end, targeting the electroneutral K/Cl cotransporter KCC2 has emerged as a novel therapeutic strategy for the treatment of epilepsy.

Areas Covered: We summarize the roles of KCC2 in the maintenance of synaptic inhibition and the evidence linking KCC2 dysfunction to epileptogenesis. We also discuss preclinical proof-of-principle studies that demonstrate that augmentation of KCC2 function can reduce seizure activity. Moreover, potential strategies to modulate KCC2 activity for therapeutic benefit are highlighted.

Expert Opinion: Although KCC2 is a promising drug target, questions remain before clinical translation. It is unclear whether increasing KCC2 activity can reverse epileptogenesis, the ultimate curative goal for epilepsy therapy that extends beyond seizure reduction. Furthermore, the potential adverse effects associated with increased KCC2 function have not been studied. Continued investigations into the neurobiology of KCC2 will help to translate promising preclinical insights into viable therapeutic avenues that leverage fundamental properties of KCC2 to treat medically intractable epilepsy and other disorders of failed synaptic inhibition with attendant neuronal hyperexcitability.
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http://dx.doi.org/10.1080/14728222.2020.1762174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104019PMC
July 2020

Targeting TLR4-dependent inflammation in post-hemorrhagic brain injury.

Expert Opin Ther Targets 2020 06 17;24(6):525-533. Epub 2020 Apr 17.

Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.

Recent data have implicated inflammation of the cerebrospinal fluid spaces after subarachnoid, intraventricular, and intracerebral hemorrhage to be a critical driver of multiple secondary brain injuries such as hydrocephalus, cerebral edema, and vasospasm. While TLR4-dependent reparative inflammation is an important protective response that can eliminate physical irritants and damaged cells, sustained or inappropriately triggered inflammation can initiate or propagate disease.: We review recent advances in our understanding of how TLR4, including its upstream damage-associated molecular patterns and its downstream MyD88-dependent and independent signaling pathways, contributes to hemorrhage-induced inflammation in numerous brain diseases. We discuss prospects for the pharmacotherapeutic targeting of TLR4 in these disorders, including the use of repurposed FDA-approved agents.: TLR4 inhibitors with good blood-brain-barrier (BBB) penetration could be useful adjuncts in post-hemorrhagic hydrocephalus and multiple other diseases associated with brain hemorrhage and inflammation.
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http://dx.doi.org/10.1080/14728222.2020.1752182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104018PMC
June 2020

Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets.

Nat Rev Neurol 2020 May 9;16(5):285-296. Epub 2020 Mar 9.

Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology and Yale-Rockefeller NIH Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, USA.

Hydrocephalus is the most common neurosurgical disorder worldwide and is characterized by enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles resulting from failed CSF homeostasis. Since the 1840s, physicians have observed inflammation in the brain and the CSF spaces in both posthaemorrhagic hydrocephalus (PHH) and postinfectious hydrocephalus (PIH). Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells and physical irritants; however, inappropriately triggered or sustained inflammation can respectively initiate or propagate disease. Recent data have begun to uncover the molecular mechanisms by which inflammation - driven by Toll-like receptor 4-regulated cytokines, immune cells and signalling pathways - contributes to the pathogenesis of hydrocephalus. We propose that therapeutic approaches that target inflammatory mediators in both PHH and PIH could address the multiple drivers of disease, including choroid plexus CSF hypersecretion, ependymal denudation, and damage and scarring of intraventricular and parenchymal (glia-lymphatic) CSF pathways. Here, we review the evidence for a prominent role of inflammation in the pathogenic mechanism of PHH and PIH and highlight promising targets for therapeutic intervention. Focusing research efforts on inflammation could shift our view of hydrocephalus from that of a lifelong neurosurgical disorder to that of a preventable neuroinflammatory condition.
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http://dx.doi.org/10.1038/s41582-020-0321-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375440PMC
May 2020

Risk Factors Portending Extended Length of Stay After Suboccipital Decompression for Adult Chiari I Malformation.

World Neurosurg 2020 06 5;138:e515-e522. Epub 2020 Mar 5.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Objective: For adult patients undergoing surgical decompression for Chiari malformation type I (CM-I), the patient-level factors that influence extended length of stay (LOS) are relatively unknown. The aim of this study was to investigate the impact of patient-baseline comorbidities, demographics, and postoperative complications on extended LOS after intervention after adult CM-I decompression surgery.

Methods: A retrospective cohort study using the National Inpatient Sample years 2010-2014 was performed. Adults (≥18 years) with a primary diagnosis of CM-I undergoing surgical decompression were identified. Weighted patient demographics, comorbidities, complications, LOS, disposition, and total cost were recorded. A multivariate logistic regression was used to determine the odds ratio for risk-adjusted LOS.

Results: A total of 29,961 patients were identified, 6802 of whom (22.7%) had extended LOS. The extended LOS cohort had a significantly greater overall complication rate (normal LOS, 10.6% vs. extended LOS, 29.1%; P < 0.001) and total cost (normal LOS, $14,959 ± $6037 vs. extended LOS, $25,324 ± $21,629; P < 0.001) compared with the normal LOS cohort. On multivariate logistic regression, black race, income quartiles, private insurance, obstructive hydrocephalus, lack of coordination, fluid and electrolyte disorders, and paralysis were all independently associated with extended LOS. Additional duraplasty (P = 0.132) was not significantly associated with extended LOS after adjusting for other variables. The odds ratio for extended LOS was 2.07 (95% confidence interval, 1.59-2.71) for patients with 1 complication and 9.47 (95% confidence interval, 5.86-15.30) for patients with >1 complication.

Conclusions: Our study shows that extended LOS after adult CM-I decompression surgery may be influenced by multiple patient-level factors.
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http://dx.doi.org/10.1016/j.wneu.2020.02.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379177PMC
June 2020

Author Correction: Visualizing flow in an intact CSF network using optical coherence tomography: implications for human congenital hydrocephalus.

Sci Rep 2020 Feb 12;10(1):2791. Epub 2020 Feb 12.

Pediatric Genomics Discovery Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-59301-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012820PMC
February 2020

Glymphatic System Impairment in Alzheimer's Disease and Idiopathic Normal Pressure Hydrocephalus.

Trends Mol Med 2020 03 18;26(3):285-295. Epub 2020 Jan 18.

Departments of Neurosurgery, Pediatrics, and Cellular and Molecular Physiology; and Yale-Rockefeller National Institutes of Health (NIH) Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address:

Approximately 10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer's disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and amyloid-β (Aβ) plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte aquaporin-4 (AQP4). The glia-lymphatic (glymphatic) system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics.
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http://dx.doi.org/10.1016/j.molmed.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489754PMC
March 2020

Novel EWSR1-VGLL1 fusion in a pediatric neuroepithelial neoplasm.

Clin Genet 2020 05 16;97(5):791-792. Epub 2020 Jan 16.

Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1111/cge.13703DOI Listing
May 2020

Geographic Variation in Outcomes and Costs After Spinal Fusion for Adolescent Idiopathic Scoliosis.

World Neurosurg 2020 Apr 7;136:e347-e354. Epub 2020 Jan 7.

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Objective: The aim of this study was to evaluate regional variations in the management, complications, and total cost of admission for adolescent idiopathic scoliosis (AIS) treated by elective posterior spinal surgery (PSF, ≥4 levels).

Methods: The Kids' Inpatient Database year 2012 was queried and adolescent patients (age 10-17 years old) with AIS undergoing elective PSF (≥4 levels) were selected. The primary outcome was regional variations for intraoperative and postoperative complications, length of surgery, and total cost of admission after elective PSF intervention.

Results: In our cohort of 3759 adolescent patients identified, 704 (18.7%) patients were treated in the Northeast, 917 (24.4%) in the Midwest, 1329 (35.4%) in the South, and 809 (21.5%) in the West (Northeast: n = 704; Midwest: n = 917; South: n = 1329; West: n = 809). The Northeast had the greatest complication rate, followed by the Midwest, South, and West region cohorts (Northeast: 27.7% vs. Midwest: 24.5% vs. South: 23.0% vs. West: 17.2%, P < 0.001). On average, length of surgery was shortest in the South (Northeast: 5.3 ± 2.7 days vs. Midwest: 5.3 ± 3.1 days vs. South: 4.9 ± 3.1 days vs. West: 5.3 ± 2.1 days, P < 0.001), while the total cost of admission was greatest in the West (Northeast: $51,760 ± $25,177 vs. Midwest: $55,201 ± $23,750 vs. South: $58,847 ± $28,227 vs. West: $60,636 ± $29,372, P < 0.001).

Conclusions: Our study suggests that there may be regional variations in health care resource utilization in AIS patients undergoing multilevel posterior spinal fusions. Further study is warranted to determine the specific factors contributing to disparities in regional outcomes.
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http://dx.doi.org/10.1016/j.wneu.2019.12.175DOI Listing
April 2020
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