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Background In response to the devastating drug toxicity crisis in Canada driven by an unregulated opioid supply predominantly composed of fentanyl and analogues, safer supply programs have been introduced. These programs provide people using street-acquired opioids with prescribed, pharmaceutical opioids. We use six core components of safer supply programs identified by people who use drugs to explore participant perspectives on the first year of operations of a safer supply program in Victoria, BC, during the dual public health emergencies of COVID-19 and the drug toxicity crisis to examine whether the program met drug-user defined elements of an effective safer supply model. Methods This study used a community-based participatory research approach to ensure that the research was reflective of community concerns and priorities, rather than being extractive. We interviewed 16 safer supply program participants between December 2020 and June 2021. Analysis was structured using the six core components of effective safer supply from the perspective of people who use drugs, generated through a prior study. Results Ensuring access to the ‘right dose and right drugs’ of medications was crucial, with many participants reporting success with the available pharmaceutical options. However, others highlighted issues with the strength of the available medications and the lack of options for smokeable medications. Accessing the safer supply program allowed participants to reduce their use of drugs from unregulated markets and manage withdrawal, pain and cravings. On components related to program operations, participants reported receiving compassionate care, and that accessing the safer supply program was a non-stigmatizing experience. They also reported receiving support to find housing, access food, obtain ID, and other needs. However, participants worried about long term program sustainability. Conclusions Participants in the safer supply program overwhelmingly appreciated it and felt it was lifesaving, and unlike other healthcare or treatment services they had previously accessed. Participants raised concerns that unless a wider variety of medications and ability to consume them by multiple routes of administration became available, safer supply programs would remain unable to completely replace substances from unregulated markets.

People who are incarcerated experience a high rate of hepatitis C (HCV) worldwide, and HCV micro-elimination in prisons is an effective strategy to support treatment. In Victoria, British Columbia, administrative barriers limited HCV testing and treatment at Vancouver Island Correctional Centre (VIRCC), and people who were HCV RNA+ were lost to follow up. Cool Aid Community Health Centre (CACHC) is an inner-city, primary care clinic that serves a marginalized population. The CACHC HCV nurse coordinator with the VIRCC nurse held HCV testing 'blitzes' at VIRCC and offered phlebotomy for screening and pre-treatment bloodwork. Clients who tested HCV RNA+ were started on HCV treatment and if discharged before completion, CACHC followed them in the community. A retrospective chart review was conducted to identify all clients who accessed HCV testing and treatment through the VIRCC partnership. To date, 230 clients were tested: 49 tested HCV antibody+, 11 tested HCV RNA+, and 10 started on treatment (6 SVR). Case management and consultation with the nurse coordinator and VIRCC nurse supported treatment starts for an additional 18 clients (14 SVR). This pragmatic and innovative approach to HCV care with people who are incarcerated demonstrated effective HCV testing and treatment. CACHC and VIRCC have established closer relationships and reduced barriers to reach and maintain continuity with this target population.

Background Blood and oral fluid-based HIV self-tests are important for reaching the undiagnosed living with HIV. The study objectives were to evaluate the oral fluid-based OraQuick® HIV Self-Test (HIV-ST) performance in comparison to laboratory reference testing; determine if laypersons can correctly perform the HIV-ST; document if intended users can successfully interpret pre-made contrived positive, negative, and invalid results; and document if intended users can understand the key messages in the product labeling. Methods This prospective study enrolled consenting adult intended users of HIV self-testing from six community health centres in four Canadian provinces between June 2022 and January 2024. Positive and negative agreement was determined by comparing the results of the HIV self-tests with the results of the laboratory-based “gold standard” Abbott Alinity HIV Antigen/Antibody Combo test. Descriptive statistics were used to summarize usability self-test procedure steps. Results Overall, 951 participants were recruited and consented with 911 available for all analyses. With respect to sociodemographics: 84% of participants were between 18–45 years of age, 73% had at least a college education, 48% were Cis-male, 45% were employed; and 26% identified as White, 23% as African, Caribbean or Black, 5% as Indigenous [First Nations, Métis or Inuit], 33% as Asian, and 6% as LatinX. Primary efficacy analysis on the 911 who completed HIV-ST revealed a single confirmed positive participant and a negative percent agreement of 100% (880/880, 95% CI: 99.9–100%) with the comparator method. For usability determination, the average success rate for “critical” steps for completing the test was 94.1%. Approximately 97% of participants found the instructions easy to follow and 98% of participants reported they would use the test again. Of the 465 participants who interpreted the strong positive, weak positive, negative, and invalid pre-made contrived results, the average of correct interpretations ranged from 59–97% Conclusions A licensed oral fluid-based HIV self-test in Canada can present an accurate, easy-to-use, and less invasive alternative to blood-based HIV testing. The addition of an oral-fluid self-test along with the current licensed blood-based HIV self-test could help reach the undiagnosed with HIV in Canada and positively impact HIV testing rates overall by offering individuals a choice of self-testing devices.

Background In March 2020, British Columbia, Canada, introduced prescribed safer supply involving the distribution of pharmaceutical grade alternatives to the unregulated toxic drug supply. Prior research has demonstrated positive impacts on overdose mortality, but with limited reach to people who use substances. Objectives of this study were to (1) identify barriers to accessing safer supply prescribing among people who use substances; and (2) determine whether and how barriers differed between people with and without prescriptions, and between urban and rural settings. Methods We conducted a participatory mixed-methods study guided by the Consolidated Framework for Implementation Research. Participants (≥ 19 years old) had received a safer supply prescription or were seeking one (survey n  = 353; interviews n  = 54). Results Participants who had a prescription were more likely to be living in a large urban centre, compared to medium/smaller centres and rural areas (78.5% vs. 65.8%, standardized mean difference = 0.286). Participants who did not have a prescription were more likely to report an array of structural, interpersonal, and health-related barriers (compared to those who had a prescription). In interviews, participants linked experiences of barriers to stigma and criminalization, low availability of services, lack of information and prescribers, not being able to get what they need, and anxieties, worries and doubts stemming from personal circumstances. There were no notable differences between large urban centres and medium/smaller centres and rural areas in the presence of specific types of barriers. Conclusions Findings demonstrate restricted access to safer supply prescribing outside of large urban centres and provide future targets for enhancing implementation. Attention is needed to promote equity and counter systemic barriers in the implementation of responses to the ongoing toxic drug emergency.

Nancy Lesko

Nancy Lesko

The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α- (but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response.

Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.