DDIT4L regulates mitochondrial and innate immune activities in early life.

Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Taken together, these data show that DDIT4L regulates mitochondrial activity and provide what we believe to be the first direct evidence for its potential role supressing innate immune activity in myeloid cells during development.

The Cost of Caring: Compassion Fatigue among Peer Overdose Response Workers in British Columbia.

Background: The drug toxicity crisis has had dramatic impacts on people who use drugs. Peer overdose response workers (peer responders), i.e., individuals with lived/living experience of drug use who work in overdose response settings, are particularly susceptible to negative physical and mental health impacts of the crisis. Despite that, the mental health impacts on peer responders have yet to be studied and measured. Methods: The Professional Quality of Life survey (Version 5) was completed by 47 peer responders at two organizations in British Columbia between September 2020 and March 2021 to assess compassion satisfaction and compassion fatigue. The Likert scale responses were converted into numerical values and scores were calculated for each sub-scale. The mean score was calculated for each sub-scale and categorized as low, medium, or high, based on the instructions for Version 5 of the instrument. Results: Our study uncovered a high mean score for compassion satisfaction, low mean score for burnout, and medium mean score for secondary traumatic stress among peer responders. These results may be due to the participants' strong feelings of pride and recognition from their work, as well as the low number of participants that felt they had too much to do at work. Conclusion: Although peer responders derive pleasure and fulfillment from their jobs, i.e., compassion satisfaction, they also sometimes face burnout and stress due to continuous exposure to the trauma of the people they support. These results shed light on the areas that need to be targeted when creating supports for peer responders.

"There are solutions and I think we're still working in the problem": The limitations of decriminalization under the good Samaritan drug overdose act and lessons from an evaluation in British Columbia, Canada.

BACKGROUND: Drug prohibition has been associated with increased risk of overdose. However, drug prohibition remains the dominant drug policy, including in Canada with the Controlled Drugs and Substances Act. In 2017, the Good Samaritan Drug Overdose Act (GSDOA) was enacted, to encourage people to contact emergency medical services by providing bystanders at the scene of an overdose with legal protection for simple possession and conditions related to simple possession. METHODS: We conducted an evaluation of the GSDOA in British Columbia, Canada that included one-on-one interviews with people who use illicit drugs (PWUD), to determine peoples' experiences and perceptions surrounding this form of decriminalization. We present findings from a thematic analysis of 37 interviews. RESULTS: We identified limitations of the GSDOA at overdose events; key themes and concerns causing PWUD to hesitate to or avoid contacting emergency medical services included drug confiscation, the thin line between simple possession and drug trafficking, and enforcement of other charges and court ordered conditions that are not legally protected by the GSDOA. Moreover, participants discussed the GSDOA as inequitable; benefiting some while excluding PWUD with intersecting marginalized identities. CONCLUSION: Our findings are pertinent in light of many jurisdictions across the world considering dejure decriminalization, including BC and Vancouver. The GSDOA and associated limitations that emerged in our evaluation can serve to guide jurisdictions implementing or amending dejure decriminalization policies.

Awareness and knowledge of the Good Samaritan Drug Overdose Act among people at risk of witnessing an overdose in British Columbia, Canada: a multi-methods cross sectional study.

INTRODUCTION: Bystanders to drug overdoses often avoid or delay calling 9-1-1 and cite fear of police involvement as a main reason. In 2017, the Good Samaritan Drug Overdose Act (GSDOA) was enacted by the Canadian government to provide people present at an overdose with legal protection from charges for simple drug possession, and conditions stemming from simple possession. Few studies have taken a multi-methods approach to evaluating the GSDOA. We used quantitative surveys and qualitative interviews to explore awareness, understanding, and perceptions of the GSDOA in people at risk of witnessing an overdose. METHODS: Quantitative cross-sectional surveys and qualitative telephone interviews were conducted with adults and youth at risk of witnessing an overdose across British Columbia. Cross-sectional survey participants were recruited at 19 Take Home Naloxone sites and online through Foundry. Multivariable logistic regression models were constructed hierarchically to determine factors associated with GSDOA awareness. Telephone interview participants were recruited by research assistants with lived/living experience of substance use. Deductive and inductive thematic analyses were conducted to identify major themes. RESULTS: Overall, 52.7% (n = 296) of the quantitative study sample (N = 453) reported being aware of the GSDOA. In multivariable analysis, cellphone possession (adjusted odds ratio [AOR] = 2.19; 95% confidence interval [CI] 1.36, 3.54) and having recently witnessed an opioid overdose (AOR = 2.34; 95% CI 1.45, 3.80) were positively associated with GSDOA awareness. Young adults (25 - 34 years) were more likely to be aware of the Act (AOR = 2.10; 95% CI 1.11, 3.98) compared to youth (16-24 years). Qualitative interviews (N = 42) revealed that many overestimated the protections offered by the GSDOA. To increase awareness and knowledge of the Act among youth, participants recommended adding the GSDOA to school curricula and using social media. Word of mouth was suggested to reach adults. CONCLUSION: Both awareness and knowledge of the GSDOA remain low in BC, with many overestimating the protections the Act offers. Dissemination efforts should be led by people with lived/living experience and should target those with limited awareness and understanding of the Act as misunderstandings can erode trust in law enforcement and harm reduction policy.