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Microglia are immune system cells that function in protecting and maintaining the brain. Gosselin et al. examined the epigenetics and RNA transcripts from single microglial cells and observed consistent profiles among samples despite differences in age, sex, and diagnosis. Mouse and human microglia demonstrated similar microglia-specific gene expression profiles, as well as a shared environmental response among microglia collected either immediately after surgery (ex vivo) or after culturing (in vitro). Interestingly, those genes exhibiting differences in expression between humans and mice or after culturing were often implicated in neurodegenerative diseases. Science , this issue p. eaal3222 Single-cell sequencing of brain microglia reveals ex vivo and in vitro differences in transcription. Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and after transition to an in vitro environment. Transfer to a tissue culture environment resulted in rapid and extensive down-regulation of microglia-specific genes that were induced in primitive mouse macrophages after migration into the fetal brain. Substantial subsets of these genes exhibited altered expression in neurodegenerative and behavioral diseases and were associated with noncoding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human brain diseases.

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type–specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

Purpose Understanding the complication profile of craniosynostosis surgery is important, yet little is known about complication co-occurrence in syndromic children after multi-suture craniosynostosis surgery. We examined concurrent perioperative complications and predictive factors in this population. Methods In this retrospective cohort study, children with syndromic diagnoses and multi-suture involvement who underwent craniosynostosis surgery in 2012–2020 were identified from the National Surgical Quality Improvement Program-Pediatric database. The primary outcome was concurrent complications; factors associated with concurrent complications were identified. Correlations between complications and patient outcomes were assessed. Results Among 5,848 children identified, 161 children (2.75%) had concurrent complications: 129 (2.21%) experienced two complications and 32 (0.55%) experienced ≥ 3. The most frequent complication was bleeding/transfusion (69.53%). The most common concurrent complications were transfusion/superficial infection (27.95%) and transfusion/deep incisional infection (13.04%) or transfusion/sepsis (13.04%). Two cardiac factors (major cardiac risk factors (odds ratio (OR) 3.50 [1.92–6.38]) and previous cardiac surgery (OR 4.87 [2.36–10.04])), two pulmonary factors (preoperative ventilator dependence (OR 3.27 [1.16–9.21]) and structural pulmonary/airway abnormalities (OR 2.89 [2.05–4.08])), and preoperative nutritional support (OR 4.05 [2.34–7.01]) were independently associated with concurrent complications. Children who received blood transfusion had higher odds of deep surgical site infection (OR 4.62 [1.08–19.73]; p = 0.04). Conclusions Our results indicate that several cardiac and pulmonary risk factors, along with preoperative nutritional support, were independently associated with concurrent complications but procedural factors were not. This information can help inform presurgical counseling and preoperative risk stratification in this population.

In analyzing the neural correlates of naturalistic and unstructured behaviors, features of neural activity that are ignored in a trial-based experimental paradigm can be more fully studied and investigated. Here, we analyze neural activity from two patients using electrocorticography (ECoG) and stereo-electroencephalography (sEEG) recordings, and reveal that multiple neural signal characteristics exist that discriminate between unstructured and naturalistic behavioral states such as “engaging in dialogue” and “using electronics”. Using the high gamma amplitude as an estimate of neuronal firing rate, we demonstrate that behavioral states in a naturalistic setting are discriminable based on long-term mean shifts, variance shifts, and differences in the specific neural activity’s covariance structure. Both the rapid and slow changes in high gamma band activity separate unstructured behavioral states. We also use Gaussian process factor analysis (GPFA) to show the existence of salient spatiotemporal features with variable smoothness in time. Further, we demonstrate that both temporally smooth and stochastic spatiotemporal activity can be used to differentiate unstructured behavioral states. This is the first attempt to elucidate how different neural signal features contain information about behavioral states collected outside the conventional experimental paradigm.

The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog ( MYC ) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development. Glioblastoma is the most common type of adult brain cancer, with near-uniform fatality within 2 y of diagnosis. Therapeutic failure is thought to be related to small subpopulations of cells that exhibit tumorigenicity, the cellular capacity to reconstitute the entire tumor mass. One fundamental issue is whether tumorigenicity exists within a static subpopulation of cells or whether the capacity is stochastically acquired. We provide evidence that tumorigenicity is a cellular property that is durable yet undergoes low-frequency stochastic changes. We showed that these changes are driven by lysine-specific demethylase 1 (LSD1)-mediated epigenetic (heritable non-DNA sequence-altering) modifications that impact expression of key transcription factors, which in turn govern transitions between tumorigenic states. These findings harbor implications for glioblastoma therapeutic development.

(B) MSH2 immunohistochemical stain shows loss of expression of mismatch repair protein in the vast majority of the tumour cells (MSH2 immunohistochemical stain, 400× original magnification). Microarray analysis revealed a complex karyotype with masked hypodiploid genome and copy-neutral loss of heterozygosity or copy gain of numerous chromosomes, a pattern commonly seen with DNA repair defects. Non-glial extra-axial supratentorial neoplasms occur much less commonly in children than in adults.6 7 LS is an autosomal dominant disorder caused by heterozygous germline mutations in 4 DNA mismatch repair (MMR) genes which leads to increased risk for gastrointestinal, gynaecological, urothelial and biliary malignancies usually in adulthood.8 LS does not typically cause increased childhood malignancies, and associated brain tumours are rare. [...]if pathogenic germline mutations in both alleles of an MMR gene are inherited, constitutional mismatch repair deficiency syndrome (CMMRD), an even more severe autosomal recessive cancer predisposition syndrome, occurs with patients developing brain and/or haematological malignancies in the first decade of life.

Abstract BACKGROUND: Management of patients afflicted with brain metastasis requires tailoring of therapeutic strategies based on survival expectations. Therefore, the development of prognostic indices is of critical importance in this patient population. OBJECTIVE: To determine whether the cumulative intracranial tumor volume (CITV) of brain metastasis augments the prognostic value of the lung-specific Graded Prognostic Assessment (GPA) index. METHODS: Patient data were derived from 365 lung cancer patients with brain metastasis who were consecutively treated with stereotactic radiosurgery at the University of California, San Diego/San Diego Gamma Knife Center. CITV was analyzed to determine the volume cutoff that maximized sensitivity and specificity for 1-year survival. Multivariate Cox proportional hazard modeling was performed, and overall survival was estimated by the Kaplan-Meier method risk stratifying with or without this optimal CITV. The prognostic value of these models (lung-specific GPA ± CITV) was quantitatively compared with the use of net reclassification improvement (>0) and integrated discrimination improvement. RESULTS: For the University of California, San Diego/San Diego Gamma Knife Center cohort, the CITV cutoff that had the greatest survival discrimination at 1 year was 4 cm3. The addition of CITV to the lung-specific GPA indexes significantly improved the prognostic value of lung-specific GPA, with net reclassification improvement >0 of 0.430 (95% confidence interval, 0.228-0.629) and integrated discrimination improvement of 0.029 (95% confidence interval, 0.004-0.073). These findings were validated in an independent cohort of 1638 lung cancer patients with brain metastasis who were treated with stereotactic radiosurgery at the Katsuta Hospital Mito Gamma House in Japan. CONCLUSION: In independent cohorts, the addition of CITV to the lung-specific GPA index significantly improved the prognostic value of this index. ABBREVIATIONS: AUC area under the receiveroperating characteristic curve BM brain metastasis CITV cumulative intracranial tumor volume ds-GPA disease-specific Graded Prognostic Assessment GPA Graded Prognostic Assessment IDI integrated discrimination improvement KHMGH Katsuta Hospital Mito Gamma House KPS Karnofsky Performance Status NRI net reclassification improvement ROC receiver-operating characteristic curve SRS stereotactic radiosurgery UCSD/SDGKC University of California, San Diego/San Diego Gamma Knife Center Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.neurosurgery-online.com).

Study Design Retrospective cohort study. Objectives Preoperative risk stratification using frailty is common for adults but difficult to apply to pediatric populations. We aimed to identify risk factors indicating physiologic vulnerability and predict perioperative complications in children with neuromuscular scoliosis (NMS) and to create a prediction model for physiological vulnerability (PV-5). Methods Patients with NMS were identified from the American College of Surgeons National Surgical Quality Improvement Program Pediatric database. The 9442 patients identified were randomly divided into training and testing cohorts. Univariate and multivariable logistic regression were performed; variables significantly associated with complications were evaluated using the Akaike information criterion and area under the curve. Significant variables received weighted scores, and a patient-specific prediction model was generated and evaluated using the Brier score. Results Patients with central nervous system abnormality (OR 1.32 [95%CI 1.13-1.53]), hematologic disorder (OR 1.40 [1.06-1.85]), congenital malformation (OR 1.30 [1.1-1.54]), nutritional support (OR 2.21 [1.91-2.57]), and preoperative wound infection (OR 2.3 [1.4-3.76]) were more likely to develop complications after spinal fusion surgery. PV-5 scores were calculated from these risk factors to generate a prediction model. PV-5 scores of 1 (OR: 2.0 [1.27-3.43], P < 0.004), 2 (OR: 2.75 [1.63-4.64], P < 0.001), 3 (OR: 3.67 [2.18-6.19], P < 0.001), 4 (OR: 4.09 [2.39-6.99], P < 0.001), and 5+ (OR: 3.58 [1.35-9.47], P = 0.01) predicted greater complication risk than PV-5 of zero (accuracy = 89.65%, Brier score = 0.09). Conclusions Using factors associated with complications in children with NMS undergoing spinal fusion surgery, we created a prediction model to illustrate physiologic vulnerability and morbidity. Our model serves as a foundation for further body system-specific investigation.

Key Clinical Message Giant occipital encephalocele is a rare form of congenital anomaly that involves protrusion of brain tissue (greater in size than the patient's cranial cavity) from a defect in the skull. This case reports illustrates repair of a giant encephalocele and emphasizes important methods to reduce risk for blood loss and other complications. A rare form of congenital anomaly, giant occipital encephalocele involves protrusion of brain tissue from a defect in the skull (in this case from the occiput). While encephalocele itself is a fairly rare entity, those qualifying as “giant”—defined by size of the deformity exceeding that of the skull itself – require very technically challenging surgery.