Examining inequities in access to opioid agonist treatment (OAT) take-home doses (THD): A Canadian OAT guideline synthesis and systematic review.

BACKGROUND: Daily supervised Opioid Agonist Treatment (OAT) medication has been identified as a barrier to treatment retention. Canadian OAT guidelines outline take-home dose (THD) criteria, yet, OAT prescribers use their clinical judgement to decide whether an individual is 'clinically stable' to receive THD. There is limited information regarding whether these decisions may result in inequitable access to THD, including in the context of updated COVID-19 guidance. The current Canadian OAT THD guideline synthesis and systematic review aimed to address this knowledge gap. METHODS: This systematic review included a two-pronged approach. First, we searched available academic literature in Embase, Medline, and PsychINFO up until October 12th, 2022, to identify studies that compared characteristics of individuals on OAT who had and had not been granted access to THD to explore potential inequities in access. Next, we identified all Canadian national and provincial OAT guidelines through a semi-structured grey literature search (conducted between September-October 2022) and extracted all THD 'stability' and allowances/timeline criteria to compare against characteristics identified in the literature search. Data from both review arms were synthesized and narratively presented. RESULTS: A total of n = 56 guidelines and n = 7 academic studies were included. The systematic review identified a number of patient characteristics such as age, sex, race/ethnicity, marital status, housing, employment, neighborhood income, drug use, mental health, health service utilization, as well as treatment duration that were associated with differential access to THD. The Canadian OAT THD guideline synthesis identified many of these same characteristics as 'stability' criteria, underscoring the potential for Canadian OAT guidelines to result in inequitable access to THD. CONCLUSIONS: This two-pronged literature review demonstrated that current guidelines likely contribute to inequitable OAT THD access due primarily to inconsistent 'stability' criteria across guidelines. More research is needed to understand differential OAT THD access with a focus on prescriber decision-making and evaluating associated treatment and safety outcomes. The development of a client-centered, equity-focused, and evidence-informed decision making framework that incorporates more clear definitions of 'stability' criteria and indications for prescriber discretion is warranted.

Exploring the Impact of ECHO Ontario Integrated Mental and Physical Health on Participants' Approach and Attitude Toward the Care of Patients With Complex Needs.

OBJECTIVE: To examine how project Extension for Community Healthcare Outcomes-Integrated Mental and Physical Health (ECHO-IMPH) influences the attitudes and approaches of primary care providers and other participants towards patients. METHODS: An exploratory qualitative approach was undertaken using semistructured interviews conducted between August 2020 and March 2021. One hundred and sixty-four individuals from two cycles of ECHO-IMPH were invited to participate, and 22 (n = 22) agreed to participate. Data were analyzed using the Braun and Clarke method for thematic analysis. RESULTS: Three major themes were identified: 1) enhanced knowledge and skills; 2) changes in attitude and approach; 3) space for reflection and exploration. When participants were asked about areas for improvement, suggestions were focused on the structure of the sessions. Participants identified that ECHO-IMPH helped them to view patients more holistically, which led to greater patient-centered care in their practice. Additionally, skills gained in ECHO-IMPH gave participants the concrete tools needed to have more empathetic interactions with patients with complex needs. CONCLUSIONS: ECHO-IMPH created a safe space for participants to reflect on their practice with patients with complex needs. Participants applied newly acquired knowledge and skills to provide more empathetic and patient-centered care for patients with complex needs. Based on the shift in perspectives described by participants, transformative learning theory was proposed as a model for how ECHO-IMPH created change in participants' practice.

The Role of the Pharmacist in the Care of Patients with Chronic Pain.

Pharmacists across the healthcare continuum are well positioned to collaborate with patients to effectively manage their chronic pain. Evidence supports positive outcomes when pharmacists undertake these roles; however, there are barriers preventing uptake across the profession. This paper aims to expand awareness of the breadth of these roles, including pharmaceutical care provision, interprofessional collaboration, pain and medication education, support for patients in self-management and acceptance of responsibility to be culturally responsive and decrease stigma. Pharmacists are accessible healthcare professionals and can improve the care of patients with chronic pain.

Exploring the use of extended release opioids at shortened dosing intervals in people with chronic pain and high risk medication or substance use.

Background Critical attention to rational opioid prescribing has emerged from the opioid epidemic in North America. Individuals with chronic pain are prescribed extended release opioids in an effort to maintain stable drug levels and for more convenient dosing, though evidence to support improvements in pain or function is lacking. It has been observed that extended release opioid products are used at intervals shorter than recommended by product monographs. The need for shortened intervals has been linked with potential inter-patient variability in pharmacokinetics, among other rationale. Implications of shortened dosing intervals for extended release opioids have not been systematically studied. Objective The aim of this study was to characterize the use of extended release opioid formulations at shortened dosing intervals in a population of patients with chronic pain and high risk for opioid-related harms. Setting This study took place in the Interprofessional Pain and Addiction Recovery Clinic, a specialty ambulatory clinic at the Centre for Addiction and Mental Health in Toronto, Canada for adults with chronic pain and a diagnosis or suspicion of substance use disorder. Method This was a retrospective cross-sectional study. Data were collected from records of patients with assessments completed in the years 2012-2017 (n = 210). Main outcome measure Proportion of patients using extended release opioids at shortened intervals. Results Sixty-one percent of individuals using extended release opioids (n = 78) were using them at shortened intervals. This use was associated with a higher daily morphine equivalent dose (533 mg vs 236 mg, p < 0.01), use of oxycodone extended release products (50% vs. 27%, p < 0.01), a longer duration of opioid therapy (8.9 vs. 6.8 years, p = 0.03) and a diagnosis of chronic neuropathic pain (63% vs. 39%, p < 0.01), with no differences in reported pain intensities, compared with use at standard intervals. Conclusion The use of extended release opioids at shortened intervals was associated with increased daily morphine equivalent doses, thus an increased risk of opioid-related mortality. It is unlikely that of those using extended release opioids, the high proportion of use at shortened intervals is the result of inter-patient differences in metabolism alone. Further study is warranted to explore the underlying drivers and implications for people with chronic pain.

Evaluation of Homology-Independent CRISPR-Cas9 Off-Target Assessment Methods.

The ability to alter genomes specifically by CRISPR-Cas gene editing has revolutionized biological research, biotechnology, and medicine. Broad therapeutic application of this technology, however, will require thorough preclinical assessment of off-target editing by homology-based prediction coupled with reliable methods for detecting off-target editing. Several off-target site nomination assays exist, but careful comparison is needed to ascertain their relative strengths and weaknesses. In this study, HEK293T cells were treated with Streptococcus pyogenes Cas9 and eight guide RNAs with varying levels of predicted promiscuity in order to compare the performance of three homology-independent off-target nomination methods: the cell-based assay, GUIDE-seq, and the biochemical assays CIRCLE-seq and SITE-seq. The three methods were benchmarked by sequencing 75,000 homology-nominated sites using hybrid capture followed by high-throughput sequencing, providing the most comprehensive assessment of such methods to date. The three methods performed similarly in nominating sequence-confirmed off-target sites, but with large differences in the total number of sites nominated. When combined with homology-dependent nomination methods and confirmation by sequencing, all three off-target nomination methods provide a comprehensive assessment of off-target activity. GUIDE-seq's low false-positive rate and the high correlation of its signal with observed editing highlight its suitability for nominating off-target sites for ex vivo CRISPR-Cas therapies.

Sel1L-Hrd1 ER-associated degradation maintains ß cell identity via TGF-ß signaling.

ß Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying ß cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying ß cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for ß cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of ß cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with ß cell loss, but rather loss of ß cell identity. Sel1L-Hrd1 ERAD controlled ß cell identity via TGF-ß signaling, in part by mediating the degradation of TGF-ß receptor 1. Inhibition of TGF-ß signaling in Sel1L-deficient ß cells augmented the expression of ß cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in ß cells, providing a framework for therapies targeting distinct mechanisms of protein quality control.