Surveillance of laboratory exposures to human pathogens and toxins, Canada, 2021.

Background: The Laboratory Incident Notification Canada surveillance system monitors laboratory incidents that are mandated to be reported under the Human Pathogens and Toxins Act and the Human Pathogens and Toxins Regulations. This article describes laboratory exposure incidents that occurred in Canada in 2021 and individuals affected in these incidents. Methods: We extracted all laboratory incidents occurring in licensed Canadian laboratories in 2021 from the Laboratory Incident Notification Canada system and analyzed them using the software R. We calculated the rate of exposure incidents and performed descriptive statistics by sector, root cause, activity, occurrence type and type of pathogen/toxin. Analysis of the education level, route of exposure, sector, role and laboratory experience of the affected persons was also conducted. We conducted seasonality analysis to compare the median monthly occurrence of exposure incidents between 2016 and 2020 to monthly incidents in 2021. Results: Forty-three exposure incidents involving 72 individuals were reported to Laboratory Incident Notification Canada in 2021. There were two confirmed laboratory-acquired infections and one suspected infection. The annual incident exposure rate was 4.2 incidents per 100 active licenses. Most exposure incidents involved non-Security Sensitive Biological Agents (n=38; 86.4%) and human risk group 2 (RG2) pathogens (n=27; 61.4%), with bacteria (n=20; 45.5%) and viruses (n=16; 36.4%) as the most implicated agent types. Microbiology was the most common activity associated with these incidents (n=18; 41.9%) and most incidents were reported by the academic sector (n=20; 46.5%). Sharps-related (n=12; 22.2%) incidents were the most common, while human interaction (e.g. workload constraints/pressures/demands, human error) (n=29, 28.2%) was the most common root cause. Most affected individuals were exposed through inhalation (n=38; 52.8%) and worked as technicians or technologists (n=51; 70.8%). Seasonality analyses revealed that the number of exposure incidents reported in 2021 were highest in September and May. Conclusion: The rate of laboratory incidents was slightly lower in 2021 than in 2020. The most common occurrence type was sharps-related while issues with human interaction was the most cited root cause.

Tamoxifen therapy in a murine model of myotubular myopathy.

Myotubular myopathy (MTM) is a severe X-linked disease without existing therapies. Here, we show that tamoxifen ameliorates MTM-related histopathological and functional abnormalities in mice, and nearly doubles survival. The beneficial effects of tamoxifen are mediated primarily via estrogen receptor signaling, as demonstrated through in vitro studies and in vivo phenotypic rescue with estradiol. RNA sequencing and protein expression analyses revealed that rescue is mediated in part through post-transcriptional reduction of dynamin-2, a known MTM modifier. These findings demonstrate an unexpected ability of tamoxifen to improve the murine MTM phenotype, providing preclinical evidence to support clinical translation.

PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models.

Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets.