Implementation of pharmaceutical alternatives to a toxic drug supply in British Columbia: A mixed methods study.

BACKGROUND: North America has been in an unrelenting overdose crisis for almost a decade. British Columbia (BC), Canada declared a public health emergency due to overdoses in 2016. Risk Mitigation Guidance (RMG) for prescribing pharmaceutical opioids, stimulants and benzodiazepine alternatives to the toxic drug supply ("safer supply") was implemented in March 2020 in an attempt to reduce harms of COVID-19 and overdose deaths in BC during dual declared public health emergencies. Our objective was to describe early implementation of RMG among prescribers in BC. METHODS: We conducted a convergent mixed methods study drawing population-level linked administrative health data and qualitative interviews with 17 prescribers. The Consolidated Framework for Implementation Research (CFIR) informs our work. The study utilized seven linked databases, capturing the characteristics of prescribers for people with substance use disorder to describe the characteristics of those prescribing under the RMG using univariate summary statistics and logistic regression analysis. For the qualitative analysis, we drew on interpretative descriptive methodology to identify barriers and facilitators to implementation. RESULTS: Analysis of administrative databases demonstrated limited uptake of the intervention outside large urban centres and a highly specific profile of urban prescribers, with larger and more complex caseloads associated with RMG prescribing. Nurse practitioners were three times more likely to prescribe than general practitioners. Qualitatively, the study identified five themes related to the five CFIR domains: 1) RMG is helpful but controversial; 2) Motivations and challenges to prescribing; 3) New options and opportunities for care but not enough to 'win the arms race'; 4) Lack of implementation support and resources; 5) Limited infrastructure. CONCLUSIONS: BC's implementation of RMG was limited in scope, prescriber uptake and geographic scale up. Systemic, organizational and individual barriers and facilitators point to the importance of engaging professional regulatory colleges, implementation planning and organizational infrastructure to ensure effective implementation and adaptation to context.

The human tubal lavage proteome reveals biological processes that may govern the pathology of hydrosalpinx.

Hydrosalpinx, the blockage of fallopian tubes, can result from pelvic inflammatory disease. Hydrosalpinx is a cause of infertility and negatively impacts in vitro fertilization. To better understand the pathobiology of hydrosalpinx, we compared the proteome of lavages from disease vs. healthy fallopian tubes. Results indicate a disruption of redox homeostasis and activation of the complement system, immune cell infiltration, and phagocytosis; pathways that may drive tubal injury. To our surprise among the most prominent proteins with hydrosalpinx was mesothelin (MSLN), which until now has only been associated with epithelial malignancies. Analogous to mesothelioma and ovarian carcinoma, a significant increase of MSLN was detected in plasma from patients with hydrosalpinx. This finding suggests MSLN may provide clinical diagnosis in lieu of the current approaches that require invasive imaging. Importantly, these findings implicate MSLN in a benign disease, indicating that the activation and role of MSLN is not restricted to cancer.

Fast Generation of Functional Subtype Astrocytes from Human Pluripotent Stem Cells.

Differentiation of astrocytes from human pluripotent stem cells (hPSCs) is a tedious and variable process. This hampers the study of hPSC-generated astrocytes in disease processes and drug development. By using CRISPR/Cas9-mediated inducible expression of NFIA or NFIA plus SOX9 in hPSCs, we developed a method to efficiently generate astrocytes in 4-7 weeks. The astrocytic identity of the induced cells was verified by their characteristic molecular and functional properties as well as after transplantation. Furthermore, we developed a strategy to generate region-specific astrocyte subtypes by combining differentiation of regional progenitors and transgenic induction of astrocytes. This simple and efficient method offers a new opportunity to study the fundamental biology of human astrocytes and their roles in disease processes.