Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

Relapsing White Matter Disease and Subclinical Optic Neuropathy: From the National Multiple Sclerosis Society Case Conference Proceedings

A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.

Characterisation of a novel missense mutation in the ERCC5 gene leading to group G xeroderma pigmentosum/Cockayne syndrome overlap.

Xeroderma pigmentosum-Cockayne syndrome complex (XP-CS) is exceedingly rare, with 43 cases described over the past five decades; 21 of these cases exhibited mutations in the ERCC5 endonuclease associated with xeroderma pigmentosum, group G.We report the first known phenotypic characterisation of the homozygous chromosome 13 ERCC5, Exon 11, c.2413G>A (p.Gly805Arg) missense mutation in a female toddler presenting with findings of both XP and CS.Her severe presentation also questions previous hypotheses that only truncating mutations and early missense mutations of XPG are capable of producing the dire findings of XP-CS.

Direct, carryover, and maternal effects of ocean acidification on snow crab embryos and larvae.

Ocean acidification, a decrease in ocean pH with increasing anthropogenic CO2 concentrations, is expected to affect many marine animals. To examine the effects of decreased pH on snow crab (Chionoecetes opilio), a commercial species in Alaska, we reared ovigerous females in one of three treatments: Ambient pH (~8.1), pH 7.8, and pH 7.5, through two annual reproductive cycles. Morphometric changes during development and hatching success were measured for embryos both years and calcification was measured for the adult females at the end of the 2-year experiment. Embryos and larvae analyzed in year one were from oocytes developed, fertilized, and extruded in situ, whereas embryos and larvae in year two were from oocytes developed, fertilized, and extruded under acidified conditions in the laboratory. In both years, larvae were exposed to the same pH treatments in a fully crossed experimental design. Starvation-survival, morphology, condition, and calcium/magnesium content were assessed for larvae. Embryo morphology during development, hatching success, and fecundity were unaffected by pH during both years. Percent calcium in adult females' carapaces did not differ among treatments at the end of the experiment. In the first year, starvation-survival of larvae reared at Ambient pH but hatched from embryos reared at reduced pH was lowered; however, the negative effect was eliminated when the larvae were reared at reduced pH. In the second year, there was no direct effect of either embryo or larval pH treatment, but larvae reared as embryos at reduced pH survived longer if reared at reduced pH. Treatment either did not affect other measured larval parameters, or effect sizes were small. The results from this two-year study suggest that snow crabs are well adapted to projected ocean pH levels within the next two centuries, although other life-history stages still need to be examined for sensitivity and potential interactive effects with increasing temperatures should be investigated.

Chondroitin sulfate supplementation improves clinical outcomes in a murine model of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) continues to be a devastating disease in preterm neonates and has a paucity of medical management options. Chondroitin sulfate (CS) is a naturally occurring glycosaminoglycan (GAG) in human breast milk (HM) and has been shown to reduce inflammation. We hypothesized that supplementation with CS in an experimental NEC model would alter microbial diversity, favorably alter the cytokine profile, and (like other sulfur compounds) improve outcomes in experimental NEC via the eNOS pathway. NEC was induced in 5-day-old pups. Six groups were studied (n = 9-15/group): (1) WT breastfed and (2) Formula fed controls, (3) WT NEC, (4) WT NEC + CS, (5) eNOS KO (knockout) NEC, and (6) eNOS KO NEC + CS. Pups were monitored for clinical sickness score and weights. On postnatal day 9, the pups were killed. Stool was collected from rectum and microbiome analysis was done with 16 s rRNA sequencing. Intestinal segments were examined histologically using a well-established injury scoring system and segments were homogenized and analyzed for cytokine profile. Data were analyzed using GraphPad Prism with p < 0.05 considered significant. CS supplementation in formula improved experimental NEC outcomes when compared to NEC alone. CS supplementation resulted in similar improvement in NEC in both the WT and eNOS KO mice. CS supplementation did not result in microbial changes when compared to NEC alone. Our data suggest that although CS supplementation improved outcomes in NEC, this protection is not conferred via the eNOS pathway or alteration of microbial diversity. CS therapy in NEC does improve the intestinal cytokine profile and further experiments will explore the mechanistic role of CS in altering immune pathways in this disease.

Recurrent TRAK1::RAF1 Fusions in pediatric low-grade gliomas.

Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Promoting clinical reasoning with meta-memory techniques to teach broad differential diagnosis generation in a pediatric core clerkship.

OBJECTIVES: Clinical reasoning with generation and prioritization of differential diagnoses (DDx) is a key skill for medical students, but no consensus exists on the best method to teach these skills. Meta-memory techniques (MMTs) may be useful, but the efficacy of individual MMTs is unclear. METHODS: We designed a 3-part curriculum for pediatric clerkship students to teach one of 3 MMTs and provide practice in DDx generation through case-based sessions. Students submitted DDx lists during two sessions and completed pre- and post-curriculum surveys assessing self-reported confidence and perceived helpfulness of the curriculum. Results were analyzed using ANOVA with multiple linear regression. RESULTS: A total of 130 students participated in the curriculum, with 96 % (125/130) completing at least one DDx session, and 44 % (57/130) completing the post-curriculum survey. On average, 66 % of students rated all three sessions as "quite helpful" (4/5 on 5-point Likert scale) or "extremely helpful" (5/5) without difference between MMT groups. Students generated an average of 8.8, 7.1 and 6.4 diagnoses using the VINDICATES, Mental CT, and Constellations methods, respectively. When controlling for case, case order, and number of prior rotations, students using VINDICATES produced 2.8 more diagnoses than those using Constellations (95 % CI [1.1,4.5], p<0.001). There was no significant difference between VINDICATES and Mental CT (Δ=1.6, 95 % CI [-0.2,3.4], p=0.11) or Mental CT and Constellations (Δ=1.2, 95 % CI [-0.7,3.1], p=0.36). CONCLUSIONS: Medical education should include curricula focused on enhancing DDx development. Although VINDICATES helped students produce the most DDx, further research is needed to identify which MMT generates more accurate DDx.

Occipital Nocardia Abscess Presenting With Positive Visual Phenomenon and Quadrantanopsia.

ABSTRACT: A 74-year-old man with chronic obstructive pulmonary disease, glaucoma, and Stage IIIB squamous cell lung cancer experienced several minutes of flashing lights in his right visual hemifield, followed by onset of a right visual field defect. On examination, the patient had a right homonymous hemianopsia that was most dense inferiorly by confrontation testing. Emergent CT scan of the head revealed a 2.5 × 3 cm hypodensity in the left occipital lobe, which was interpreted as an acute stroke. Continuous EEG monitoring captured left posterior quadrant seizures that were temporally correlated to the positive visual phenomena. Subsequent MRI of the brain with and without contrast revealed a conglomerate of centrally necrotic and peripherally enhancing mass lesions. On biopsy, a thick purulent material was drained and Gram stain of the sample revealed gram-positive beaded rods, which speciated to Nocardia farcinica . The patient was treated with a six-week course of intravenous meropenem and a one-year course of oral trimethroprim-sulfamethoxazole. On follow-up, the patient experienced resolution of the right visual field deficit.

Clinical Validation of Stimulated Raman Histology for Rapid Intraoperative Diagnosis of Central Nervous System Tumors.

Stimulated Raman histology (SRH) is an ex vivo optical imaging method that enables microscopic examination of fresh tissue intraoperatively. The conventional intraoperative method uses frozen section analysis, which is labor and time intensive, introduces artifacts that limit diagnostic accuracy, and consumes tissue. SRH imaging allows rapid microscopic imaging of fresh tissue, avoids tissue loss, and enables remote telepathology review. This improves access to expert neuropathology consultation in both low- and high-resource practices. We clinically validated SRH by performing a blinded, retrospective two-arm telepathology study to clinically validate SRH for telepathology at our institution. Using surgical specimens from 47 subjects, we generated a data set composed of 47 SRH images and 47 matched whole slide images (WSIs) of formalin-fixed, paraffin-embedded tissue stained with hematoxylin and eosin, with associated intraoperative clinicoradiologic information and structured diagnostic questions. We compared diagnostic concordance between WSI and SRH-rendered diagnoses. Also, we compared the 1-year median turnaround time (TAT) of intraoperative conventional neuropathology frozen sections with prospectively rendered SRH-telepathology TAT. All SRH images were of sufficient quality for diagnostic review. A review of SRH images showed high accuracy in distinguishing glial from nonglial tumors (96.5% SRH vs 98% WSIs) and predicting final diagnosis (85.9% SRH vs 93.1% WSIs). SRH-based diagnosis and WSI-permanent section diagnosis had high concordance (κ = 0.76). The median TAT for prospectively SRH-rendered diagnosis was 3.7 minutes, approximately 10-fold shorter than the median frozen section TAT (31 minutes). The SRH-imaging procedure did not affect ancillary studies. SRH generates diagnostic virtual histologic images with accuracy comparable to conventional hematoxylin and eosin-based methods in a rapid manner. Our study represents the largest and most rigorous clinical validation of SRH to date. It supports the feasibility of implementing SRH as a rapid method for intraoperative diagnosis complementary to conventional pathology laboratory methods.

Health inequities and socioeconomic factors predicting the access to treatment for unruptured intracranial aneurysms in the USA in the last 20 years: interaction effect of race, gender, and insurance.

BACKGROUND: The literature suggests that minority racial and ethnic groups have lower treatment rates for unruptured intracranial aneurysms (UIA). It is uncertain how these disparities have changed over time. METHODS: A cross-sectional study using the National Inpatient Sample database covering 97% of the USA population was carried out. RESULTS: A total of 213 350 treated patients with UIA were included in the final analysis and compared with 173 375 treated patients with aneurysmal subarachnoid hemorrhage (aSAH) over the years 2000-2019. The mean (SD) age of the UIA and aSAH groups was 56.8 (12.6) years and 54.3 (14.1) years, respectively. In the UIA group, 60.7% were white patients, 10.2% were black patients, 8.6% were Hispanic, 2% were Asian or Pacific Islander, 0.5% were Native Americans, and 2.8% were others. The aSAH group comprised 48.5% white patients, 13.6% black patients, 11.2% Hispanics, 3.6% Asian or Pacific Islanders, 0.4% Native Americans, and 3.7% others. After adjusting for covariates, black patients (OR 0.637, 95% CI 0.625 to 0.648) and Hispanic patients (OR 0.654, 95% CI 0.641 to 0.667) had lower odds of treatment compared with white patients. Medicare patients had higher odds of treatment than private patients, while Medicaid and uninsured patients had lower odds. Interaction analysis showed that non-white/Hispanic patients with any insurance/no insurance had lower treatment odds than white patients. Multivariable regression analysis showed that the treatment odds of black patients has improved slightly over time, while the odds for Hispanic patients and other minorities have remained the same over time. CONCLUSION: This study from 2000 to 2019 shows that disparities in the treatment of UIA have persisted but have slightly improved over time for black patients while remaining constant for Hispanic patients and other minority groups.

Cervicothoracic junction instrumentation strategies following separation surgery for spinal metastases.

OBJECTIVE: The cervicothoracic junction (CTJ) is a challenging region to stabilize after tumor resection for metastatic spine disease. The objective of this study was to describe the outcomes of patients who underwent posterolateral decompression and instrumented fusion (i.e., separation surgery across the CTJ for instability due to metastatic disease). METHODS: The authors performed a single-institution retrospective study of a prospectively collected cohort of patients who underwent single-approach posterior decompression and instrumented fusion across the CTJ for metastatic spine disease between 2011 and 2018. Adult patients (≥ 18 years old) who presented with mechanical instability, myelopathy, and radiculopathy secondary to metastatic epidural spinal cord compression (MESCC) of the CTJ (C7-T1) from 2011 to 2018 were included. RESULTS: Seventy-nine patients were included, with a mean age of 62.1 years. The most common primary malignancies were non-small cell lung (n = 17), renal cell (11), and prostate (8) carcinoma. The median number of levels decompressed and construct length were 3 and 7, respectively. The average operative time, blood loss, and length of stay were 179.2 minutes, 600.5 ml, and 7.7 days, respectively. Overall, 58 patients received adjuvant radiation, and median dose, fractions, and time from surgery were 27 Gy, 3 fractions, and 20 days, respectively. All patients underwent lateral mass and pedicle screw instrumentation. Forty-nine patients had tapered rods (4.0/5.5 mm or 3.5/5.5 mm), 29 had fixed-diameter rods (3.5 mm or 4.0 mm), and 1 had both. Ten patients required anterior reconstruction with poly-methyl-methacrylate. The overall complication rate was 18.8% (6 patients with wound-related complications, 7 with hardware-related complications, 1 with both, and 1 with other). For the 8 patients (10%) with hardware failure, 7 had tapered rods, all 8 had cervical screw pullout, and 1 patient also experienced rod/screw fracture. The average time to hardware failure was 146.8 days. The 2-year cumulative incidence rate of hardware failure was 11.1% (95% CI 3.7%-18.5%). There were 55 deceased patients, and the median (95% CI) overall survival period was 7.97 (5.79-12.60) months. For survivors, the median (range) follow-up was 12.94 (1.94-71.80) months. CONCLUSIONS: Instrumented fusion across the CTJ demonstrated an 18.8% rate of postoperative complications and an 11% overall 2-year rate of hardware failure in patients who underwent metastatic epidural tumor decompression and stabilization.

Microsurgical clipping and endovascular management of unruptured anterior circulation aneurysms: how age, frailty, and comorbidity indexes influence outcomes.

OBJECTIVE: Frailty is one of the important factors in predicting the outcomes of surgery. Many surgical specialties have adopted a frailty assessment in the preoperative period for prognostication; however, there are limited data on the effects of frailty on the outcomes of cerebral aneurysms. The object of this study was to find the effect of frailty on the surgical outcomes of anterior circulation unruptured intracranial aneurysms (UIAs) and compare the frailty index with other comorbidity indexes. METHODS: A retrospective study was performed utilizing the National Inpatient Sample (NIS) database (2016-2018). The Hospital Frailty Risk Score (HFRS) was used to assess frailty. On the basis of the HFRS, the whole cohort was divided into low-risk (0-5), intermediate-risk (> 5 to 15), and high-risk (> 15) frailty groups. The analyzed outcomes were nonhome discharge, complication rate, extended length of stay, and in-hospital mortality. RESULTS: In total, 37,685 patients were included in the analysis, 5820 of whom had undergone open surgical clipping and 31,865 of whom had undergone endovascular management. Mean age was higher in the high-risk frailty group than in the low-risk group for both clipping (63 vs 55.4 years) and coiling (64.6 vs 57.9 years). The complication rate for open surgical clipping in the high-risk frailty group was 56.1% compared to 0.8% in the low-risk group. Similarly, for endovascular management, the complication rate was 60.6% in the high-risk group compared to 0.3% in the low-risk group. Nonhome discharges were more common in the high-risk group than in the low-risk group for both open clipping (87.8% vs 19.7%) and endovascular management (73.1% vs 4.4%). Mean hospital charges for clipping were $341,379 in the high-risk group compared to $116,892 in the low-risk group. Mean hospital charges for coiling were $392,861 in the high-risk frailty group and $125,336 in the low-risk group. Extended length of stay occurred more frequently in the high-risk frailty group than in the low-risk group for both clipping (82.9% vs 10.7%) and coiling (94.2% vs 12.7%). Frailty had higher area under the receiver operating characteristic curve values than those for other comorbidity indexes and age in predicting outcomes. CONCLUSIONS: Frailty affects surgical outcomes significantly and outperforms age and other comorbidity indexes in predicting outcome. It is imperative to include frailty assessment in preoperative planning.

The role of neoadjuvant denosumab in the treatment of aneurysmal bone cysts: a case series and review of the literature.

OBJECTIVE: Aneurysmal bone cysts (ABCs) are benign cystic lesions most commonly occurring in the long bones of pediatric patients. Spinal ABCs may be difficult to resect given their invasive, locally destructive nature, proximity to critical structures such as the spinal cord, and their intrinsic hypervascularity, for which complete embolization is often constrained by radiculomedullary segmental feeders. Denosumab, a monoclonal antibody that binds the receptor activator of nuclear factor kappa B (NF-κB) ligand, has been utilized in the treatment of ABCs most often as a rescue therapy for recurrent disease. Here, the authors present 3 cases of neoadjuvant denosumab use in surgically unresectable tumors to calcify and devascularize the lesions, allowing for safer, more complete resection. METHODS: This is a single-center, retrospective case series treated at a tertiary care cancer center. The authors present 3 cases of spinal ABC treated with neoadjuvant denosumab. RESULTS: All 3 patients experienced calcification, size reduction, and a significant decrease in the vascularity of their ABCs on denosumab therapy. None of the patients developed new neurological deficits while on denosumab. Subsequently, all underwent resection. One patient continued denosumab during the immediate postoperative period because a subtotal resection had been performed, with stabilization of the residual disease. No complications were associated with denosumab administration. CONCLUSIONS: The use of denosumab in unresectable ABCs can cause calcification and devascularization, making safe resection more likely.

Associations between drug and alcohol use, smoking, and frailty among people with HIV across the United States in the current era of antiretroviral treatment.

OBJECTIVE: To examine associations between frailty and drug, alcohol, and tobacco use among a large diverse cohort of people with HIV (PWH) in clinical care in the current era. METHODS: PWH at 7 sites across the United States completed clinical assessments of patient-reported measures and outcomes between 2016 and 2019 as part of routine care including drug and alcohol use, smoking, and other domains. Frailty was assessed using 4 of the 5 components of the Fried frailty phenotype and PWH were categorized as not frail, pre-frail, or frail. Associations of substance use with frailty were assessed with multivariate Poisson regression. RESULTS: Among 9336 PWH, 43% were not frail, 44% were prefrail, and 13% were frail. Frailty was more prevalent among women, older PWH, and those reporting current use of drugs or cigarettes. Current methamphetamine use (1.26: 95% CI 1.07-1.48), current (1.65: 95% CI 1.39-1.97) and former (1.21:95% CI 1.06-1.36) illicit opioid use, and former cocaine/crack use (1.17: 95% CI 1.01-1.35) were associated with greater risk of being frail in adjusted analyses. Current smoking was associated with a 61% higher risk of being frail vs. not frail (1.61: 95% CI 1.41-1.85) in adjusted analyses. CONCLUSIONS: We found a high prevalence of prefrailty and frailty among a nationally distributed cohort of PWH in care. This study identified distinct risk factors that may be associated with frailty among PWH, many of which, such as cigarette smoking and drug use, are potentially modifiable.

Drip and Ship versus Mothership Model in the Middle Cerebral Artery Stroke: A Propensity-Matched Real-World Analysis Through National Inpatient Sample Data.

BACKGROUND: The superiority of mechanical thrombectomy and intravenous thrombolysis versus intravenous thrombolysis alone for acute ischemic stroke caused by large vessel occlusions has been established. This treatment can be organized into 2 models: drip and ship (DS) versus mothership (MS). We analyzed the National Inpatient Sample (NIS) data to compare the outcomes between these models in real-world settings. METHODS: NIS data were queried for 2017-2018 and propensity matching was used to match the differences. Outcomes for each group (disability at discharge and procedural complications) were compared. RESULTS: A total of 1226 patients were included in analysis (DS, n = 540; MS, n = 686) and groups were matched with respect to age, gender, and comorbidities. A total of 930 patients were included in the final analysis after propensity matching (DS, n = 465, MS, n = 465). The mean age in the DS group was 68.9 years (standard deviation [SD], 14.7) and 69.4 years (SD, 14) in the MS group (P = 0.752). The mean National Institutes of Health Stroke Scale score was 16.75 (SD, 6.07) in the DS group and 16.54 (SD, 5.99) in the MS group (P = 0.478). At discharge, minimal disability was noted in 22.4% in the DS group versus 26.2% in the MS group (P = 0.293). In-hospital mortality was lower in the MS group (8.8% vs. 7.1%; P = 0.32). The intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) rates were higher in the DS group (ICH, 24.3% vs. 18.7%; IVH, 2.4% vs. 0.9%) (ICH, P = 0.038; IVH, P = 0.068). CONCLUSIONS: Analyzing the efficacy and safety profile of DS versus MS models with the NIS database showed a trend toward better discharge outcomes and lower mortality for the MS group, although it did not reach statistical significance.

Clinical, Pathological, and Molecular Characteristics of Diffuse Spinal Cord Gliomas.

Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood.

Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10-15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10-21, z = - 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10-6, z = 2.65) and CA1-3 (p = 4.7 × 10-6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10-5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10-3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10-5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10-3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.