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Introduction: Gray-white matter ratio (GWR) on non-contrast head computed tomography (HCT) is a helpful tool in neuro-prognostication in post-cardiac arrest patients. Its usage is unclear for those with angiography due to residual contrast. Hypothesis: GWR remains valid for neuro-prognostication in comatose patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) followed by coronary angiography (CAG) after out-hospital cardiac arrest (OHCA). Methods: We performed a retrospective study of comatose OHCA adults post ECPR and CAG at University of Minnesota from January to June 2022 with dual energy HCT within 12 hours. GWR was measured at basal ganglia, centrum semiovale, and high convexity levels. Gray matter areas of interest included caudate nucleus, putamen, thalamus, and medial cortex. The white matter areas of interest included the genu of the corpus callosum, posterior limb of the internal capsule, and medial white matter. Circular regions of interest (ROI, 10-15 mm 2 ) were placed bilaterally in corresponding areas to record the average attenuation in Hounsfield unit (HU). The basal ganglia, cerebrum, and overall GWRs were calculated as the ratio of average HU between the gray and white matter ROIs within the area. Primary outcome was inpatient death, further categorized by the primary cause being neurological or not. Logistic regression followed by receiver operating characteristic (ROC) curves was used to validate GWR in predicting death. All data analysis was performed by StataCorp Software (STATA 14). Result: 25 patients were included in the study. 18 (72%) were male with a median age of 60 (interquartile range (IQR): 45-67). The initial HCT was obtained at 2.08 hours (median, IQR: 1.37–2.43) post ECPR cannulation. 7 (28%) patients died from brain death or herniation and 15 (60%) died from non-neurological causes. None had intracranial bleeding. 1 patient had unilateral hypodensity on initial HCT, suggesting an acute embolic infarct. Patients who died had lower GWRs on initial HCT (Figure 1). ROC regression showed all GWRs demonstrated good prognostic performance on inpatient death with area under the curve (AUC) of 0.6970 (basal ganglia), 0.8485 (cerebrum), and 0.7576 (overall) (Figure 2). Conclusions: GWR in early HCT has prognostic value in predicting neurological outcomes despite residual contrast. It may be used as a risk stratification tool for comatose OHCA patients undergoing ECPR and angiography.

Abstract Improved response assessment methods are needed for patients with gliomas. Intracranial cerebrospinal fluid (CSF) is longitudinally accessible and provides an abundance source of candidate biomarkers, such as cell-free DNA (cfDNA), for disease monitoring. To evaluate the clinical feasibility of molecular profiling from longitudinal intracranial CSF, CSF was acquired from patients with CSF access devices, including Ommaya reservoirs and ventriculoperitoneal shunts. cfDNA was extracted and analyzed via PredicineCARE (Next Generation sequencing) or PredicineSCORE (low pass whole genome sequencing). Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or VP shunt (n=1). In total, forty-eight CSF samples were obtained (median volume: 4.00 mL; 0.5-5 mL), with 39 samples (81.3%) yielding sufficient cfDNA for variant profiling. Our initial findings suggest that tumor fraction increased by 6.28x, 2.87x, and 8.31x with radiographic progression in three patients. Tumor fraction decreased by 0.08x and 0.04x in two patients with paired immediate pre-versus-post chemoradiation samples. Despite ongoing pseudoprogression in one patient, tumor fraction decreased to unmeasurable levels from a post-resection baseline of 0.26. Patient-specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, TERT, and CDKN2A/B, decreased within individual patients after resection and chemoradiation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection and chemoradiation correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both CSF IDH1 VAF and CSF D-2-HG increased a patient who had radiographic progression (2.56x and 9.21x, respectively). Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression. In conclusion, longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course toward evaluating candidate monitoring biomarkers.

OBJECTIVE The purpose of this study was to determine the effect of osteoporosis medications on opportunistic CT-based Hounsfield units (HU). METHODS Spine and nonspine surgery patients were retrospectively identified who had been treated with romosozumab for 3 to 12 months, teriparatide for 3 to 12 months, teriparatide for > 12 months, denosumab for > 12 months, or alendronate for > 12 months. HU were measured in the L1–4 vertebral bodies. One-way ANOVA was used to compare the mean change in HU among the five treatment regimens. RESULTS In total, 318 patients (70% women) were included, with a mean age of 69 years and mean BMI of 27 kg/m 2 . There was a significant difference in mean HU improvement (p < 0.001) following treatment with romosozumab for 3 to 12 months (n = 32), teriparatide for 3 to 12 months (n = 30), teriparatide for > 12 months (n = 44), denosumab for > 12 months (n = 123), and alendronate for > 12 months (n = 100). Treatment with romosozumab for a mean of 10.5 months significantly increased the mean HU by 26%, from a baseline of 85 to 107 (p = 0.012). Patients treated with teriparatide for > 12 months (mean 23 months) experienced a mean HU improvement of 25%, from 106 to 132 (p = 0.039). Compared with the mean baseline HU, there was no significant difference after treatment with teriparatide for 3 to 12 months (110 to 119, p = 0.48), denosumab for > 12 months (105 to 107, p = 0.68), or alendronate for > 12 months (111 to 113, p = 0.80). CONCLUSIONS Patients treated with romosozumab for a mean of 10.5 months and teriparatide for a mean of 23 months experienced improved spinal bone mineral density as estimated by CT-based opportunistic HU. Given the shorter duration of effective treatment, romosozumab may be the preferred medication for optimization of osteoporotic patients in preparation for elective spine fusion surgery.

Abstract BACKGROUND Medulloblastoma (MB) is a highly malignant childhood cerebellar tumor comprising a collection of molecularly and clinically distinct entities. Group 3 and Group 4-MB subgroups originate from overlapping progenitor pools of the developing rhombic lip when neuronal differentiation hierarchies are subverted through somatic alterations. Mutations suspected to deregulate the activity of chromatin-modifying genes are pervasive in Group 3 and Group 4-MB. However, the molecular consequences of these alterations remain largely undefined. METHODS We characterized the chromatin landscape of fifty-two primary MBs using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for six histone modifications and performed multi-modal integration with sample-matched somatic lesions, genome-wide DNA methylation, and transcriptomic profiles. RESULTS Analysis of differential chromatin states across MB subgroups using a Hidden Markov Model revealed a significant enrichment of the bivalent enhancer state (EnhBiv; marked by coincident H3K4me1 and H3K27me3) in Group 4-MB which localized to promoters of neurodevelopmental genes and transcription factors. To functionally dissect the pathogenetic significance of the enriched EnhBiv state in Group 4-MB, we sought to identify key regulators that confer this state. Integrative bioinformatics coupled with CUT&RUN analysis revealed significant enrichment of KDM2B, a histone lysine demethylase overexpressed in Group 4-MB, in gene promoters marked by the EnhBiv state. CRISPR gene targeting or targeted protein degradation of KDM2B selectively suppressed growth of Group 3 and Group 4-MB models in vitro and in vivo. Mechanistically, inhibition of KDM2B disrupted chromatin bivalency by blocking PRC2 complex recruitment and reducing H3K27me3 deposition, profoundly derepressing PRC2 targets involved in neuronal differentiation. CONCLUSIONS Our comprehensive characterization of the MB chromatin landscape in a large cohort of primary tumors provides unprecedented insights into the epigenetic basis of MB subgroups, implicating novel mechanisms of tumorigenesis, and nominating KDM2B as a selective dependency in Group 3/4-MB that should be prioritized as an attractive therapeutic target.

Introduction: The incidence and pattern of neurological complications after congenital cardiac surgery have been changing over the years due to improvement in surgical technique and perioperative management. The aim of this study was to evaluate the incidence and pattern of neurological injury in our institute. Materials and Methods: We retrospectively reviewed all pediatric patients who underwent noncontrast computed tomography of the brain for suspected postoperative neurological injury occurring during the 1 st week after pediatric cardiac surgery between April 2016 and February 2020. We identified neurological injury as patients having ischemic infarct and intracranial hemorrhage. Results: A total of 2971 pediatric cardiac surgeries were performed at our institute. Sixty-seven patients (2.25%) developed neurological injury. Fifty-five patients (82%) developed ischemic infarct while 12 patients (18%) had intracranial hemorrhagic. Pattern of ischemic infarct included global hypoxic injury in 30 patients (54.5%), posterior cerebral artery territory in 9 patients (16.3%), middle cerebral artery territory in 8 patients (14.5%), multiterritory involvement in 5 patients (9.0%), and anterior cerebral artery territory in 3 patients (5.4%). In patients with intracranial hemorrhage, 5 patients (7.4%) developed subarachnoid hemorrhage (SAH), 4 patients (5.9%) developed subdural hemorrhage, and 3 patients (4.4%) developed intraparenchymal hemorrhage. Conclusions: Neurological complication accounts for significant morbidity and mortality after congenital cardiac surgery. In our study, ischemic infarct accounted for 82% cases. In ischemic infarct, global ischemia was the most common type and carried high risk of mortality. In hemorrhage group, SAH was the most common finding. Nevertheless, the aim of this study was to characterize the current incidence of acute clinically evident neurologic complications in children undergoing congenital cardiac surgery in a tertiary hospital, although acute neurologic morbidity appears to be appreciably lower than in the past at our institution.

Background: Neurological complications (NCs) (stroke) remain a devastating complication after cardiovascular surgical procedures despite advances in perioperative monitoring and management. The incidence of NC related to cardiovascular surgeries (CS) is comparatively very high and associated with high morbidity and mortality. The aim of this study is to evaluate the overall incidence of neurological complications in adult as well as pediatric patients and various pattern of neurological injury on noncontrast computed tomography head (NCCT) associated with various types of CS. Materials and Methods: We retrospectively analyzed all the NCCT heads of the postoperative cardiovascular surgery patients done in the immediate and early postoperative period (<7 days) who developed postoperative neurological deficits between April 2016 and February 2020. The medical records of all these cardiac surgery patients were analyzed for various variants such as the total number of patients who underwent CS, various types of cardiac surgery done during the study period, demographic information, associated comorbidities, various types of NC, postoperative data and various spectrum of computed tomography (CT) findings in the brain. Results: A total of 12,896 adult and pediatric cardiac surgeries were performed at our institute. Out of these, 1115 patients (8.6%) underwent CT brain for suspected neurological injury. A total of 215 patients (1.6%) had a positive finding on their NCCT head. Out of 215 patients, 148 (68.9%) were adult patients, whereas 67 (31.1%) were pediatric patients. A total of 156 (72.5%) patients had ischemic infarction (stroke), whereas hemorrhagic lesions were present in 59 patients (27.4%). The various types of positive CT scan findings were-156 ischemic infarcts (72.5%), 20 intraparenchymal hemorrhages (9.3%), 16 subdural hemorrhage (7.4%), 15 subarachnoid hemorrhage (6.9%), 01 cerebrovascular thrombosis (0.4%), and 07 intraventricular hemorrhage (3.2%). In an adult patient, pattern of ischemic infarct comprised middle cerebral artery (MCA) territory in 42 patients (41.5%), posterior territory in 34 patients (33.6%), anterior cerebral territory in seven patients (7.0%), multi-territory infracts in 11 patients (11.0%) and global ischemia in six patients (6.0%). Intraparenchymal hemorrhage was present in 17 patients (11.4%). In a pediatric subset of patient, the pattern of ischemic infarct included global hypoxic injury (GHI) in 30 patients (54.5%), posterior cerebral artery territory in nine patients (16.3%), MCA territory in eight patients (14.5%), multi-territory involvement in five patients (9.0%), and anterior cerebral artery territory in three patients (5.4%). In the hemorrhage group, five patients (7.4%) developed subarachnoid hemorrhage (SAH). Conclusion: In an adult patient, subset MCA territory infarcts were common in the infract group, whereas intra parenchymal haemorrhage (IPH) in the hemorrhage group. In the pediatric patient subset, GHI was common in infract group and SAH in hemorrhage group. Moreover, NCCT of the head is very useful in diagnosing early postoperative neurological complications in cardiovascular surgeries and managing the complications accordingly.

Abstract Medulloblastoma (MB) is a highly malignant childhood brain tumor comprising a collection of molecularly and clinically distinct entities. Mutations in chromatin-modifying genes distribute across subgroups and account for nearly half of all MBs. However, the molecular consequences of chromatin modifier alterations remain poorly understood. Herein, we characterize the chromatin landscape of fifty-two primary MBs representing each MB subgroup using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for six histone marks and perform multi-layered integration with somatic genetics, genome-wide DNA methylation, and transcriptomic datasets extracted from the same tumors. Analysis of differential chromatin states across MB subgroups identified significant enrichment of a bivalent enhancer state (EnhBiv) in Group 4 MB. Group 4-specific EnhBivs mapped to promoters of key neurodevelopmental genes and transcription factors and was associated with increased DNA methylation and reduced expression. In accordance with higher EnhBivs coverage in Group 4 MB, we found that KDM2B, a H3K4me3 and H3K36me2 demethylase, is highly expressed in Group 4 MBs and patient-derived xenografts (PDXs). KDM2B knockout mediated by CRISPR targeting suppressed growth of both Group 3 MB cell lines in vitro and Group 4 MB PDXs in vivo but had no effect on control SHH-MB cells, suggesting that KDM2B is a novel selective dependency in MB. Knockout of KDM2B in MB cells induced profound upregulation of PRC2 targets, genes regulated by bivalent histone marks, as well as genes involved in neuronal differentiation. Further biochemical and molecular studies demonstrated that KDM2B interacts with PRC2 complex subunits and occupies gene promoters associated with Group 4-specific EnhBiv chromatin. In summary, our comprehensive characterization of the MB chromatin landscape in a large cohort of primary tumors provides novel insights into the epigenetic basis of MB and implicates KDM2B as a novel Group 4 MB dependency that should be prioritized as a therapeutic target in this subgroup.

Introduction D-dimer levels, which originate from the lysis of cross-linked fibrin, are serially measured during coronavirus disease 2019 illness to rule out hypercoagulability as well as a septic marker. Methods This multicenter retrospective study was carried out in two tertiary care hospitals in Karachi, Pakistan. The study included adult patients admitted with a laboratory-confirmed coronavirus disease 2019 infection, with at least one measured d-dimer within 24 h following admission. Discharged patients were compared with the mortality group for survival analysis. Results The study population of 813 patients had 68.5% males, with a median age of 57.0 years and 14.0 days of illness. The largest d-dimer elevation was between 0.51–2.00 mcg/ml (tertile 2) observed in 332 patients (40.8%), followed by 236 patients (29.2%) having values greater than 5.00 mcg/ml (tertile 4). Within 45 days of hospital stay, 230 patients (28.3%) died, with the majority in the ICU (53.9%). On multivariable logistic regression between d-dimer and mortality, the unadjusted (Model 1) had a higher d-dimer category (tertile 3 and tertile 4) associated with a higher risk of death (OR: 2.15; 95% CI: 1.02–4.54, P=0.044) and (OR: 4.74; 95% CI: 2.38–9.46, P<0.001). Adjustment for age, sex, and BMI (Model 2) yields only tertile 4 being significant (OR: 4.27; 95% CI: 2.06–8.86, P<0.001). Conclusion: Higher d-dimer levels were independently associated with a high risk of mortality. The added value of d-dimer in risk stratifying patients for mortality was not affected by invasive ventilation, ICU stays, length of hospital stays, or comorbidities.