Comparative Analysis of Clinical Severity and Outcomes in Penetrating Versus Blunt Traumatic Brain Injury Propensity Matched Cohorts.

Traumatic brain injury (TBI) is a global health challenge; however, penetrating brain injury (PBI) remains under-represented in evidence-based knowledge and research efforts. This study utilized data from the Trauma Quality Improvement Program (TQIP) of the National Trauma Data Bank (NTDB) to investigate outcomes of PBI as compared with clinical-severity-matched non-penetrating or blunt TBI. A total of 1765 patients with PBI were 1:1 propensity score-matched for clinical severity with blunt TBI patients. The intent of PBI was self-inflicted in 34.1% of the cases, and the mechanism was firearm-inflicted in 89.1%. Mortality was found to be significantly more common in PBI than in the severity- matched TBI cohort (33.9% vs. 14.3 %, p < 0.001) as was unfavorable outcome. Mortality was mediated by withdrawal of life-sustaining therapies (WOLST) 30% of the time, and WOLST occurred earlier (median 3 days vs. 6 days, p < 0.001) in PBI. Increased rate of mortality was observed with a Glasgow Coma Scale (GCS) of <11 in PBI as compared with <7 in blunt TBI. In conclusion, PBI patients exhibited higher mortality rates and unfavorable outcomes; one third of excess mortality was mediated by WOLST. The study also brings into question the applicability of the conventional TBI classification, based on GCS, in PBI. We emphasize the need to address the observed disparities and better understand the distinctive characteristics and mechanisms underlying PBI outcomes to improve patient care and reduce mortality.

Comparative Effectiveness of Early Neurosurgical Intervention in Civilian Penetrating Brain Injury Management.

BACKGROUND AND OBJECTIVES: To compare the outcomes of early vs no-neurosurgical intervention in civilians with penetrating brain injury (PBI). METHODS: We collected data from the National Trauma Data Bank for PBI between 2017 and 2019. A total of 10 607 cases were identified; 1276 cases met the following criteria: age 16-60 years, an intensive care unit (ICU) length of stay (LOS) of >2 days, a Glasgow Coma Scale of 3-12, and at least one reactive pupil on presentation. Patients with withdrawal of life-sustaining treatments within 72 hours were excluded, leaving 1231 patients for analysis. Neurosurgical intervention was defined as an open-approach cranial procedure involving release, drainage, or extirpation of brain matter performed within 24 hours. Outcomes of interest were mortality, withdrawal of life-sustaining treatments, ICU LOS, and dispositional outcome. RESULTS: The target population was 1231 patients (84.4% male; median [IQR] age, 29 [18] years); 267 (21.7%) died, and 364 (29.6%) had a neurosurgical intervention within the first 24 hours. 1:1 matching yielded 704 patients (352 in each arm). In the matched cohort (mortality 22.6%), 64 patients who received surgery (18.2%) died compared with 95 (27%) in the nonsurgical group. Survival was more likely in the surgical group (odds ratio [OR] 1.66, CI 1.16-2.38, P < .01; number needed to treat 11). Dispositional outcome was not different. Overlap propensity score-weighted analysis (1231 patients) resulted in higher odds of survival in the surgical group (OR 1.8, CI 1.16-2.80, P < .01). The E-value for the OR calculated from the matched data set was 2.83. Early neurosurgical intervention was associated with longer ICU LOS (median 12 days [7.0, 19.0 IQR] vs 8 days [4.0, 15.0 IQR], P < .05). CONCLUSION: Management including early neurosurgical intervention is associated with decreased mortality and increased ICU LOS in matched cohorts of PBI.

Comparative Effectiveness of Intracranial Pressure Monitoring vs No Monitoring in Severe Penetrating Brain Injury Management.

Importance: Civilian penetrating brain injury (PBI) is associated with high mortality. However, scant literature is available to guide neurocritical care monitoring and management of PBI. Objective: To examine the association of intracranial pressure (ICP) monitoring with mortality, intensive care unit (ICU) length of stay (LOS), and dispositional outcomes in patients with severe PBI. Design, Setting, and Participants: This comparative effectiveness research study analyzed data from the Trauma Quality Improvement Program of the National Trauma Data Bank in the US from January 1, 2017, to December 31, 2019. Patients with PBI were identified, and those aged 16 and 60 years who met these inclusion criteria were included: ICU LOS of more than 2 days, Glasgow Coma Scale (GCS) score lower than 9 on arrival and at 24 hours, and Abbreviated Injury Scale score of 3 to 5 for the head region and lower than 3 for other body regions. Patients with bilaterally fixed pupils or incomplete data were excluded. A 1:1 propensity score (PS) matching was used to create a subgroup of patients. Patients were divided into 2 groups: with vs without ICP monitoring. Data analysis was conducted between September and December 2022. Exposures: Intracranial pressure monitoring vs no monitoring. Main Outcomes and Measures: Outcomes were mortality, rate of withdrawal, ICU LOS, and dispositional outcome. Measures were age, initial systolic blood pressure, initial oxygen saturation level on a pulse oximeter, first-recorded GCS score, GCS score at 24 hours, Abbreviated Injury Scale score, midline shift, and pupillary reactivity. Results: A total of 596 patients (505 males [84.7%]; mean [SD] age, 32.2 [12.3] years) were included, among whom 220 (36.9%) died and 288 (48.3%) had ICP monitoring. The PS matching yielded 466 patients (233 in each group with vs without ICP monitoring). Overall mortality was 35.8%; 72 patients with ICP monitoring (30.9%) died compared with 95 patients (40.8%) without ICP monitoring . Patients with ICP monitoring were more likely to survive (odds ratio [OR], 1.54; 95% CI, 1.05-2.25; P = .03; number needed to treat, 10). No difference in favorable discharge disposition was observed. The PS-weighted analysis included all 596 patients and found that patients with ICP monitoring were more likely to survive than those without (OR, 1.40; 95% CI, 1.10-1.78; P = .005). The E-value for the OR calculated from the PS-matched data set was 1.79. In addition, ICP monitoring vs no monitoring was associated with an increase in median (IQR) ICU LOS (15.0 [8.0-21.0] days vs 7.0 [4.0-12.0] days; P < .001). Conclusions and Relevance: In this comparative effectiveness research study, PBI management guided by ICP monitoring was associated with decreased mortality and increased ICU LOS, challenging the notion of universally poor outcomes after civilian PBI. Randomized clinical trials that evaluate the efficacy of ICP monitoring in PBI are warranted.

Novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation of Hoxa cluster genes and promotion of neuronal lineage.

Background: Pediatric high-grade gliomas (pHGGs) are aggressive pediatric CNS tumors and an important subset are characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). Substitution of Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described and characterized in a large cohort of pHGG samples as occurring in 5-20% of pHGGs. Attempts to study the mechanism of H3.3G34R have proven difficult due to the lack of knowledge regarding the cell-of-origin and the requirement for co-occurring mutations for model development. We sought to develop a biologically relevant animal model of pHGG to probe the downstream effects of the H3.3G34R mutation in the context of vital co-occurring mutations. Methods: We developed a genetically engineered mouse model (GEMM) that incorporates PDGF-A activation, TP53 loss and the H3.3G34R mutation both in the presence and loss of Alpha thalassemia/mental retardation syndrome X-linked (ATRX), which is commonly mutated in H3.3G34 mutant pHGGs. Results: We demonstrated that ATRX loss significantly increases tumor latency in the absence of H3.3G34R and inhibits ependymal differentiation in the presence of H3.3G34R. Transcriptomic analysis revealed that ATRX loss in the context of H3.3G34R upregulates Hoxa cluster genes. We also found that the H3.3G34R overexpression leads to enrichment of neuronal markers but only in the context of ATRX loss. Conclusions: This study proposes a mechanism in which ATRX loss is the major contributor to many key transcriptomic changes in H3.3G34R pHGGs. Accession number: GSE197988.