"I wanted to close the chapter completely and I feel like that [carrying naloxone] would keep it open a little bit": Refusal to carry naloxone among newly-abstinent opioid users and 12-step identity.

BACKGROUND: 12-step programs aim to address drug-related harms, like opioid overdose, via abstinence. However, abstaining from opioids can diminish tolerance, which increases risk for overdose death upon resumption. A recent study found that desire to abstain from drugs inhibited willingness to participate in take-home naloxone programming, which was linked to perceptions of harm reduction strategies being tied to drug use. In the present study, we uncovered a similar phenomenon occurring among newly-abstinent participants who were refusing to carry naloxone. METHODS: This study is an analysis of broader qualitative data collected throughout Southern California among persons who use opioids, including those recently abstinent. Preliminary analysis revealed that those newly abstinent refused to accept naloxone at the end of interviews, and so we began probing about this (N=44). We used thematic analysis and author positionality to explicate the emergent phenomenon and applied social identity theory to conceptualize findings. RESULTS: Mechanisms underlying naloxone refusal included its tie to a drug-using identity that newly-abstinent participants were attempting to retire. Carrying naloxone was also viewed as pointless due to doubt of witnessing an overdose again. Furthermore, the thought of being equipped with naloxone was not believed to be congruent with an abstinent identity, e.g. "me carrying it [naloxone] is making me feel like I'm going to be hanging out with people that are doing it [using drugs]." CONCLUSION: Recent detoxification heightens vulnerability to overdose, which other newly-abstinent peers might be positioned to respond to as bonds are formed through 12-step identity formation. However, naloxone is often refused by this group due to perceived 12-step identity clash. While some treatment spaces distribute naloxone, 12-step identity associated behavioral expectations appear to conflict with this strategy. Reframing these disconnects is essential for expanding the lifesaving naloxone community safety net.

Cytokine-dependent and cytokine-independent roles for Mcl-1: genetic evidence for multiple mechanisms by which Mcl-1 promotes survival in primary T lymphocytes.

Myeloid cell leukemia sequence-1 (Mcl-1) is a critical anti-apoptotic factor in T lymphocytes. However, in spite of the many pro-apoptotic proteins with proposed binding to Mcl-1, the specific interactions by which Mcl-1 regulates primary T-cell survival under different conditions have not been fully explored. Further, how different trophic cytokines modulate the specific role(s) of Mcl-1 is unknown. Here, we use genetic mouse models to dissect the roles of Mcl-1 in primary T lymphocytes. Using the inducible Mcl-1-floxed estrogen receptor-Cre fusion protein (Mcl-1(f/f)ERCre) deletion system in combination with genetic modification of other B-cell lymphoma 2 (Bcl-2) family members, we show that loss of pro-apoptotic Bcl-2 homologous antagonist/killer (Bak) rescues the survival of Mcl-1-deficient T cells in the presence of IL-7. Without IL-7, the survival of Mcl-1-deficient cells cannot be rescued by loss of Bak, but is partially rescued by overexpression of Bcl-2 or loss of Bcl-2-interacting mediator of cell death (Bim). Thus, Mcl-1 and Bcl-2 have a shared role, the inhibition of Bim, in promoting T-cell survival during cytokine withdrawal. Finally, we show that other common gamma-chain (γc) cytokines differentially modulate the roles of Mcl-1. IL-15 has effects similar to those of IL-7 in memory T cells and naïve CD8(+) cells, but not naïve CD4(+) cells. However, IL-4 maintains Mcl-1 and Bcl-2 but also upregulates Bim and Bcl-2-associated X protein (Bax), thus altering the cell's dependence on Mcl-1.

Mcl-1 promotes survival of thymocytes by inhibition of Bak in a pathway separate from Bcl-2.

The antiapoptotic proteins Mcl-1 and Bcl-2 have been shown to be critical in T-cell development and homeostasis, but the precise mechanism by which these proteins function in T cells and other cells of the body is unclear. Potential mechanisms have allowed both for overlapping and unique roles for these proteins because of their abilities to bind different proapoptotic Bcl-2 family members, but it is unclear which of these mechanisms are important in an in vivo context. By generation of various genetic mouse models, we found that Mcl-1-deficient thymocytes die largely by a Bak-specific mechanism. In vivo deletion of Bak rescued the survival and developmental blocks of Mcl-1-deficient thymocytes at the double-negative and single-positive stages. Transgenic overexpression of Bcl-2 and in vivo deletion of Bax or Bim were unable to rescue Mcl-1-deficient thymocytes. Thus, Mcl-1 functions in a unique pathway from Bcl-2 in T lymphocytes, likely because of its specific ability to bind and sequester proapoptotic Bak. Together, these data provide an in vivo model for Mcl-1 activity and present us with a greater understanding of the pathways that promote thymocyte survival.