Self-reported concussions in Canada: A cross-sectional study.

Background: Traumatic brain injuries (TBIs) are a major public health concern impacting the lives of many Canadians. Among all TBIs, concussions are the most common. However, to date, the incidence of concussions among the Canadian population, has remained unknown. To address this data surveillance gap, this study presents national estimates on the percentage of Canadians aged 12 years or older (excluding those living in the territories) who sustained one or more concussions in 2019. Data and methods: This study used data collected from the Traumatic Brain Injury Rapid Response (TBIRR) module of the 2020 Canadian Community Health Survey, a cross-sectional health survey. Descriptive statistics and logistic regressions were conducted to summarize the information in the TBIRR module. Results: This study found that approximately 1.6% of Canadians aged 12 years or older reported sustaining one or more concussions in 2019. Age was significantly associated with concussion incidence after controlling for sex and annual household income, and the locations and activities surrounding respondents' most serious concussions varied by age group. Over one-third of respondents sustained multiple concussions. Interpretation: The results suggest that certain populations, particularly younger individuals, may be more affected by concussions. While circumstances surrounding concussions vary by age group, the most important contributing factors were sports or physical activities among youth and falls among the adult population. Monitoring concussions among the national population is an important activity in injury surveillance, as it can help evaluate the efficacy of injury prevention intervention and better understand knowledge gaps and the burden of this injury.

Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist.

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions.