Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We and others had shown that a subset of glioblastomas (GBM), the most malignant of all primary brain tumors in adults, are responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 led to resistance to etoposide and doxorubicin and impaired the induction of pro-apoptotic gene APAF1 following treatment. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from gliomas and multiple other cancers.

Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We show that glioblastoma (GBM), the most malignant of all primary brain tumors in adults is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 impaired the induction of pro-apoptotic gene APAF1 following etoposide treatment, and led to resistance to this drug and doxorubicin. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from multiple cancers. KeywordsCRISPR, Glioblastoma (GBM), Topoisomerase II poisons (TOP2: etoposide, doxorubicin), DNA damage and repair response, H2AX (gamma H2AX phosphorylation) FANCB, Protein Synthesis, Ribosomal proteins subunits: (RPS11, 16, and 18), APAF1, Pro-(BID, CASPASE3/7) and anti-apoptotic effectors (BCL2).

<b><i>Background:</i></b> Previous literature has identified a survival advantage in acute ischemic stroke (AIS) patients with elevated body mass indices (BMIs), a phenomenon termed the “obesity paradox.” <b><i>Objective:</i></b> The aim of this study was to evaluate the independent association between obesity and clinical outcomes following AIS. <b><i>Methods:</i></b> Weighted discharge data from the National Inpatient Sample were queried to identify AIS patients from 2015 to 2018. Multivariable logistic regression and Cox proportional hazards modeling were performed to evaluate associations between obesity (BMI ≥ 30) and clinical endpoints following adjustment for acute stroke severity and comorbidity burden. <b><i>Results:</i></b> Among 1,687,805 AIS patients, 216,775 (12.8%) were obese. Compared to nonobese individuals, these patients were younger (64 vs. 72 mean years), had lower baseline NIHSS scores (6.9 vs. 7.9 mean score), and a higher comorbidity burden. Multivariable analysis demonstrated independent associations between obesity and lower likelihood of mortality (adjusted odds ratio [aOR] 0.76, 95% confidence interval [CI]: 0.71, 0.82, <i>p</i> &#x3c; 0.001; hazard ratio 0.84, 95% CI: 0.73, 0.97, <i>p</i> = 0.015), intracranial hemorrhage (aOR 0.87, 95% CI: 0.82, 0.93, <i>p</i> &#x3c; 0.001), and routine discharge to home (aOR 0.97, 95% CI: 0.95, 0.99; <i>p</i> = 0.015). Mortality rates between obese and nonobese patients were significantly lower across stroke severity thresholds, but this difference was attenuated among high severity (NIHSS &#x3e; 20) strokes (21.6% vs. 23.2%, <i>p</i> = 0.358). Further stratification of the cohort into BMI categories demonstrated a “U-shaped” association with mortality (underweight aOR 1.58, 95% CI: 1.39, 1.79; <i>p</i> &#x3c; 0.001, overweight aOR 0.64, 95% CI: 0.42, 0.99; <i>p</i> = 0.046, obese aOR 0.77, 95% CI: 0.71, 0.83; <i>p</i> &#x3c; 0.001, severely obese aOR 1.18, 95% CI: 0.74, 1.87; <i>p</i> = 0.485). Sub-cohort assessment of thrombectomy-treated patients demonstrated an independent association of obesity (BMI 30–40) with lower mortality (aOR 0.79, 95% CI: 0.65, 0.96; <i>p</i> = 0.015), but not with routine discharge. <b><i>Conclusion:</i></b> This cross-sectional analysis demonstrates a lower likelihood of discharge to home as well as in-hospital mortality in obese patients following AIS, suggestive of a protective effect of obesity against mortality but not against all poststroke neurological deficits in the short term which would necessitate placement in acute rehabilitation and long-term care facilities.

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Delayed cerebral ischemia (DCI) secondary to vasospasm is a determinate of outcomes following non-traumatic subarachnoid hemorrhage (SAH). SAH patients are monitored using transcranial doppler (TCD) to measure cerebral blood flow velocities (CBFv). However, the accuracy and precision of manually acquired TCD can be operator dependent. The NovaGuide robotic TCD system attempts to standardize acquisition. This investigation evaluated the safety and efficacy of the NovaGuide system in SAH patients in a Neuro ICU. We retrospectively identified 48 NovaGuide scans conducted on SAH patients. Mean and maximum middle cerebral artery (MCA) CBFv were obtained from the NovaGuide and the level of agreement between CBFv and computed tomography angiography (CTA) for vasospasm was determined. Safety of NovaGuide acquisition of CBFv was evaluated based on number of complications with central venous lines (CVL) and external ventricular drains (EVD). There was significant agreement between the NovaGuide and CTA (Cohen’s Kappa = 0.74) when maximum MCA CBFv ≥ 120 cm/s was the threshold for vasospasm. 27/48 scans were carried out with CVLs and EVDs present without negative outcomes. The lack of adverse events associated with EVDs/CVLs and the strong congruence between maximal MCA CBFv and CTA illustrates the diagnostic utility of the NovaGuide.

BACKGROUND After MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) demonstrated that endovascular therapy improved outcomes in patients with stroke, the number of endovascular procedures has risen sharply. We describe acute transient contrast‐induced neurological deficit (ATCIND), a group of neurological syndromes associated with arterial contrast administration during angiography. Our goal is to elucidate the incidence, risk factors, outcomes, pathogenesis, and diagnostic characteristics of ATCIND. Our primary objective is to elucidate the incidence of ATCIND in the setting of coronary or cerebral angiography. Secondary outcomes include potential risk factors, demographics, treatment modalities, and patient recovery. METHODS The data that support the findings of this study are available from the corresponding author on reasonable request. The databases of the Cochrane Library, MEDLINE, Web of Science, and Embase were queried, yielding studies from 1974 to 2021. Inclusion criteria for articles were the following: (1) contrast‐induced encephalopathy, contrast‐induced neurotoxicity, or cortical blindness after contrast administration during angiography were the focus of the article; (2) incidence was reported; (3) studies included ≥3 cases; and (4) follow‐up tests were described to rule out other causes. Exclusion criteria included the following: (1) incidence was not reported; (2) unavailable in the English language; (3) abstracts and unpublished studies; and (4) did not exclude other possible causes, or findings suggested other possible causes, such as worsening ischemic injury. Of 627 articles, 7 were retained. This systematic review with meta‐analysis was performed in accordance with guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) and the Meta‐Analysis of Observational Studies in Epidemiology (MOOSE) checklists. Independent extraction by multiple reviewers was performed. Data were pooled using a random‐effects model. RESULTS The primary study outcome was incidence of ATCIND, which was formulated before data collection began. We hypothesized that the pooled incidence of ATCIND would be similar to that of individual studies. A total of 70 of 21007 patients had the diagnosis of contrast‐induced encephalopathy, contrast‐induced neurotoxicity or angiography‐associated cortical blindness, and ATCIND. The incidence rate of ATCIND is estimated to be 0.51% (CI, 0.3%–1.0%; P <0.001 [ I 2 =29.3]), or 51 per 10 000 patients. Pooled data for risk factors for contrast‐induced encephalopathy were higher contrast dose (odds ratio [OR], 1.072; 95% CI, 0.952–1.192 [ P <0.001]; I 2 =0), and prior stroke (OR, 5.153; CI 1.726–8.581 [ P =0.003]; I 2 =0). Contrast dose >150 mL was a positive, significant predictor of visual disturbance (OR, 7.083; CI, 1.1742–42.793 [ P =0.033]). Full recovery is estimated at 89.5% (95% CI, 76.9%–95.6%; P <0.001 [ I 2 =0]). CONCLUSIONS This study confirms the rare incidence of ATCIND, although it shows moderate heterogeneity, likely reflecting the type of angiography performed. Risk factors include larger contrast dose and prior stroke. Full recovery occurs in the majority of patients. It should remain in the differential diagnosis in patients with certain risk factors for blood–brain barrier compromise.

OBJECTIVE Limited evidence exists characterizing the incidence, risk factors, and clinical associations of cerebral vasospasm following traumatic intracranial hemorrhage (tICH) on a large scale. Therefore, the authors sought to use data from a national inpatient registry to investigate these aspects of posttraumatic vasospasm (PTV) to further elucidate potential causes of neurological morbidity and mortality subsequent to the initial insult. METHODS Weighted discharge data from the National (Nationwide) Inpatient Sample from 2015 to 2018 were queried to identify patients with tICH who underwent diagnostic angiography in the same admission and, subsequently, those who developed angiographically confirmed cerebral vasospasm. Multivariable logistic regression analysis was performed to identify significant associations between clinical covariates and the development of vasospasm, and a tICH vasospasm predictive model (tICH-VPM) was generated based on the effect sizes of these parameters. RESULTS Among 5880 identified patients with tICH, 375 developed PTV corresponding to an incidence of 6.4%. Multivariable adjusted modeling determined that the following clinical covariates were independently associated with the development of PTV, among others: age (adjusted odds ratio [aOR] 0.98, 95% CI 0.97–0.99; p < 0.001), admission Glasgow Coma Scale score < 9 (aOR 1.80, 95% CI 1.12–2.90; p = 0.015), intraventricular hemorrhage (aOR 6.27, 95% CI 3.49–11.26; p < 0.001), tobacco smoking (aOR 1.36, 95% CI 1.02–1.80; p = 0.035), cocaine use (aOR 3.62, 95% CI 1.97–6.63; p < 0.001), fever (aOR 2.09, 95% CI 1.34–3.27; p = 0.001), and hypokalemia (aOR 1.62, 95% CI 1.26–2.08; p < 0.001). The tICH-VPM achieved moderately high discrimination, with an area under the curve of 0.75 (sensitivity = 0.61 and specificity = 0.81). Development of vasospasm was independently associated with a lower likelihood of routine discharge (aOR 0.60, 95% CI 0.45–0.78; p < 0.001) and an extended hospital length of stay (aOR 3.53, 95% CI 2.78–4.48; p < 0.001), but not with mortality. CONCLUSIONS This population-based analysis of vasospasm in tICH has identified common clinical risk factors for its development, and has established an independent association between the development of vasospasm and poorer neurological outcomes.

The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors.Experimental Design: To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes.Results: We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA.Conclusions: Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.