Emerging models of de facto drug policy reforms in the United States.

BACKGROUND: Health and human rights organizations have endorsed drug decriminalization to promote public health-oriented approaches to substance use. In the US, policymakers have begun to pursue this via prosecutorial discretion-or the decision by a prosecutor to decline criminal charges for drug possession in their jurisdiction. This study characterizes drivers of adoption, policy design and implementation processes, and barriers to impact and sustainability of this approach to inform evolving policy efforts promoting the health of people who use drugs (PWUD). METHODS: We conducted n=22 key informant interviews with policymakers and national policy experts representing 13 jurisdictions implementing de facto drug policy reforms. Analyses were informed by the Exploration, Preparation, Implementation and Sustainment (EPIS) framework and analyzed using a hybrid inductive-deductive approach. RESULTS: Drivers of policy adoption included racial inequities, perceived failures of criminalization, and desires to prioritize violent crime given resource constraints. Three distinct policy typologies are described with varying conditions for eligibility, linkage to services, and policy transparency and dissemination. Public misinformation, police resistance and political opposition were seen as threats to sustainability. CONCLUSIONS: Given evidence that criminalization amplifies drug-related harms, many policymakers are adopting de facto drug policy reforms in the absence of formal legislation. This is the first study to systematically describe relevant implementation processes and emerging policy models. Findings have implications for designing rigorous evaluations on health outcomes and informing sustainable evidence-based policies to promote health and racial equity of PWUD in the US.

Exploring the impact of the COVID-19 pandemic on healthcare and substance use service access among women who inject drugs: a qualitative study.

BACKGROUND: The COVID-19 pandemic disrupted healthcare and substance use services engagement, including primary and mental health services as well as residential and outpatient drug treatment. Women who inject drugs (WWID) face known barriers to healthcare and substance use service engagement, which pre-date the COVID-19 pandemic. The impact of COVID-19 on WWID's engagement with healthcare and substance use services, however, remains understudied. METHODS: To explore the impact of the COVID-19 pandemic on service-seeking and utilization, we conducted in-depth interviews with 27 cisgender WWID in Baltimore, Maryland, in April-September 2021. Iterative, team-based thematic analysis of interview transcripts identified disruptions and adaptations to healthcare and substance use services during the COVID-19 pandemic. RESULTS: The COVID-19 pandemic disrupted service engagement for WWID through service closures, pandemic safety measures restricting in-person service provision, and concerns related to contracting COVID-19 at service sites. However, participants also described various service adaptations, including telehealth, multi-month prescriptions, and expanded service delivery modalities (e.g., mobile and home delivery of harm reduction services), which overwhelmingly increased service engagement. CONCLUSION: To build upon service adaptations occurring during the pandemic and maximize expanded access for WWID, it is vital for healthcare and substance use service providers to continue prioritizing expansion of service delivery modality options, like telehealth and the provision of existing harm reduction services through alternative platforms (e.g., mobile services), that facilitate care continuity and increase coverage.

A Novel Capacity-Strengthening Intervention for Frontline Harm Reduction Workers to Support Pre-exposure Prophylaxis Awareness-Building and Promotion Among People Who Use Drugs: Formative Research and Intervention Development.

BACKGROUND: HIV prevalence among people who use drugs (PWUD) in Baltimore, Maryland, is higher than among the general population. Pre-exposure prophylaxis (PrEP) is a widely available medication that prevents HIV transmission, yet its usefulness is low among PWUD in Baltimore City and the United States. Community-level interventions to promote PrEP uptake and adherence among PWUD are limited. OBJECTIVE: We describe the development of a capacity-strengthening intervention designed for frontline harm reduction workers (FHRWs) to support PrEP awareness-building and promotion among PWUD. METHODS: Our study was implemented in 2 phases in Baltimore City, Maryland. The formative phase focused on a qualitative exploration of the PrEP implementation environment, as well as facilitators and barriers to PrEP willingness and uptake, among cisgender women who use drugs. This work, as well as the existing literature, theory, and feedback from our community partners, informed the intervention development phase, which used an academic-community partnership model. The intervention involved a 1-time, 2-hour training with FHRWs aimed at increasing general PrEP knowledge and developing self-efficacy promoting PrEP in practice (eg, facilitating PrEP dialogues with clients, supporting client advancement along a model of PrEP readiness, and referring clients to PrEP services). In a separate paper, we describe the conduct and results of a mixed methods evaluation to assess changes in PrEP-related knowledge, attitudes, self-efficacy, and promotion practices among FHRWs participating in the training. RESULTS: The pilot was developed from October to December 2021 and implemented from December 2021 through April 2022. We leveraged existing relationships with community-based harm reduction organizations to recruit FHRWs into the intervention. A total of 39 FHRWs from 4 community-based organizations participated in the training across 4 sessions (1 in-person, 2 online synchronous, and 1 online asynchronous). FHRW training attendees represented a diverse range of work cadres, including peer workers, case managers, and organizational administrators. CONCLUSIONS: This intervention could prevent the HIV burden among PWUD by leveraging the relationships that FHRWs have with PWUD and by supporting advancement along the PrEP continuum. Given suboptimal PrEP uptake among PWUD and the limited number of interventions designed to address this gap, our intervention offers an innovative approach to a burgeoning public health problem. If effective, our intervention has the potential to be further developed and scaled up to increase PrEP awareness and uptake among PWUD worldwide.

Mycobacterium tuberculosis Requires the Outer Membrane Lipid Phthiocerol Dimycocerosate for Starvation-Induced Antibiotic Tolerance.

Tolerance of Mycobacterium tuberculosis to antibiotics contributes to the long duration of tuberculosis (TB) treatment and the emergence of drug-resistant strains. M. tuberculosis drug tolerance is induced by nutrient restriction, but the genetic determinants that promote antibiotic tolerance triggered by nutrient limitation have not been comprehensively identified. Here, we show that M. tuberculosis requires production of the outer membrane lipid phthiocerol dimycocerosate (PDIM) to tolerate antibiotics under nutrient-limited conditions. We developed an arrayed transposon (Tn) mutant library in M. tuberculosis Erdman and used orthogonal pooling and transposon sequencing (Tn-seq) to map the locations of individual mutants in the library. We screened a subset of the library (~1,000 mutants) by Tn-seq and identified 32 and 102 Tn mutants with altered tolerance to antibiotics under stationary-phase and phosphate-starved conditions, respectively. Two mutants recovered from the arrayed library, ppgK::Tn and clpS::Tn, showed increased susceptibility to two different drug combinations under both nutrient-limited conditions, but their phenotypes were not complemented by the Tn-disrupted gene. Whole-genome sequencing revealed single nucleotide polymorphisms in both the ppgK::Tn and clpS::Tn mutants that prevented PDIM production. Complementation of the clpS::Tn ppsD Q291* mutant with ppsD restored PDIM production and antibiotic tolerance, demonstrating that loss of PDIM sensitized M. tuberculosis to antibiotics. Our data suggest that drugs targeting production of PDIM, a critical M. tuberculosis virulence determinant, have the potential to enhance the efficacy of existing antibiotics, thereby shortening TB treatment and limiting development of drug resistance. IMPORTANCE Mycobacterium tuberculosis causes 10 million cases of active TB disease and over 1 million deaths worldwide each year. TB treatment is complex, requiring at least 6 months of therapy with a combination of antibiotics. One factor that contributes to the length of TB treatment is M. tuberculosis phenotypic antibiotic tolerance, which allows the bacteria to survive prolonged drug exposure even in the absence of genetic mutations causing drug resistance. Here, we report a genetic screen to identify M. tuberculosis genes that promote drug tolerance during nutrient starvation. Our study revealed the outer membrane lipid phthiocerol dimycocerosate (PDIM) as a key determinant of M. tuberculosis antibiotic tolerance triggered by nutrient starvation. Our study implicates PDIM synthesis as a potential target for development of new TB drugs that would sensitize M. tuberculosis to existing antibiotics to shorten TB treatment.

A Capacity-Strengthening Intervention to Support HIV Pre-exposure Prophylaxis (PrEP) Awareness-Building and Promotion by Frontline Harm Reduction Workers in Baltimore, Maryland: A Mixed Methods Evaluation.

Pre-exposure prophylaxis (PrEP) is a promising but underutilized HIV prevention tool among people who inject drugs (PWID). We developed and piloted an intervention to bolster PrEP promotion competencies among frontline harm reduction workers (FHRW) serving PWID clients in Baltimore, Maryland. Between December 2021 and February 2022, we developed and facilitated four trainings, which included didactic and practice-based/role-playing components, with 37 FHRW from four organizations. FHRW completed three structured surveys (pretest, posttest, 6-week posttest) and in-depth interviews (n = 14) to measure changes in PrEP promotion competencies attributable to training participation. PrEP knowledge and self-efficacy increased significantly (p < 0.001) from pretest to posttest, sustained through 6-week posttest. The proportion of FHRW discussing PrEP with clients doubled during the evaluation period (30-67%, p = 0.006). Feeling empowered to discuss PrEP and provision of population-tailored PrEP information were facilitators of PrEP promotion, while limited client interaction frequency/duration, privacy/confidentiality concerns, and anticipated PrEP stigma by clients inhibited PrEP promotion. Our capacity-strengthening intervention successfully increased PrEP knowledge, self-efficacy, and promotion among FHRW, affirming the adaptability and feasibility of integrating our training toolkit into FHRW practice across implementation settings.

Safety in solitude? Competing risks and drivers of solitary drug use among women who inject drugs and implications for overdose detection.

BACKGROUND AND AIMS: Solitary drug use (SDU) can amplify risks of fatal overdose. We examined competing risks and drivers of SDU, as well as harm reduction strategies implemented during SDU episodes, among women who inject drugs (WWID). DESIGN: A cross-sectional qualitative study, including telephone and face-to-face in-depth interviews. SETTING: Baltimore City, MD, USA. PARTICIPANTS: Twenty-seven WWID (mean age = 39 years, 67% white, 74% injected drugs daily) recruited via outreach and street intercept (April-September 2021). MEASUREMENTS: Interviews explored the physical (i.e. indoor/private, outdoor/public) and social (i.e. alone, accompanied) risk environments in which drug use occurred. Guided by the principles of emergent design, we used thematic analysis to interrogate textual data, illuminating women's preferences/motivations for SDU and strategies for minimizing overdose risks when using alone. FINDINGS: Many participants reported experiences with SDU, despite expressed preferences for accompanied drug use. SDU motivations clustered around three primary drivers: (1) avoiding opioid withdrawal, (2) preferences for privacy when using drugs and (3) safety concerns, including threats of violence. Participants nevertheless acknowledged the dangers of SDU and, at times, took steps to mitigate overdose risk, including naloxone possession, communicating to peers when using alone ('spotting') and using drugs in public spaces. CONCLUSIONS: WWID appear to engage frequently in SDU due to constraints of the physical and social environments in which they use drugs. They express a preference for accompanied drug use in most cases and report implementing strategies to mitigate their overdose risk, especially when using drugs alone.

Provider Perspectives on HIV Pre-Exposure Prophylaxis Service Disruptions and Adaptations During the COVID-19 Pandemic in Baltimore, Maryland: A Qualitative Study.

The COVID-19 pandemic continues driving unprecedented disruptions to health care provision, including HIV pre-exposure prophylaxis (PrEP) services. We explored service provider experiences promoting and prescribing PrEP to marginalized populations during the COVID-19 pandemic in Baltimore, Maryland. In February to April 2021, we facilitated four virtual focus group discussions with 20 PrEP providers, representing various professional cadres and practice settings. Employing an iterative, team-based thematic analysis, we identified salient enablers and constraints to PrEP promotion, initiation, and maintenance in the COVID-19 era, along with innovative adaptations to PrEP service delivery. Discussants described attenuated demands for PrEP early in the pandemic, exemplified by high PrEP discontinuation rates. This was attributed to changes in clients' sexual behaviors and shifting priorities, including caregiving responsibilities, during the pandemic. Substantial systems-level disruptions impacting PrEP provision were identified, including outreach service suspension, personnel shortages, and facility restrictions on face-to-face visits. Providers emphasized that these disruptions, though occurring early in the pandemic, had protracted impacts on PrEP accessibility. The transition to telemedicine rendered health care services, including PrEP, more accessible/convenient to some clients and expeditious to providers. However, structural barriers to telehealth engagement (telephone/internet access), coupled with limitations of the virtual care environment (difficulty establishing rapport), impeded efforts to equitably promote and prescribe PrEP. Expanding the PrEP outreach workforce and availing alternatives to telemedicine (e.g., community-based PrEP provision, specimen self-collection) could facilitate PrEP care continuity, especially as COVID-19 transitions from an acute to a protracted health crisis.

Structural, everyday, and symbolic violence and the heightened vulnerability to HIV of women who use drugs in Tanzania.

Women who use drugs shoulder a disproportionate burden of the HIV epidemic in Tanzania. The mechanisms through which violence contributes to their excessively high rates of HIV have not been explored. In this paper, we use concepts of everyday, symbolic, and structural violence to critically examine the relationship between violence and heightened HIV vulnerability of women who use drugs in Dar es Salaam, Tanzania. We conducted cross-sectional surveys with 200 women who use drugs and follow-up, in-depth interviews with 30 survey participants who identified as living with HIV between November 2018 and March 2019. We drew from grounded theory methods to analyze qualitative data and complemented qualitative findings with survey results. Structural violence perpetuated constraints on women's economic opportunities and reduced their agency in sexual encounters manifesting in their disproportionately high rates of HIV. Nearly all women in our study engaged in sex work to meet basic needs and to support their drug use. Their involvement in overlapping drug use and sex work scenes exposed them to physical and sexual violence. Despite the pervasiveness of structural and everyday violence, some women reenacted agency by adopting strategies to maintain control and safety, and to exercise harm reduction. A multi-pronged, structural harm reduction strategy is critical to reducing violence experienced by women who use drugs and their ability to protect themselves from HIV.

Correlates of Non-fatal, Opioid Overdose among Women Who Use Opioids in Dar es Salaam, Tanzania.

BACKGROUND: As opioid overdoses and deaths increase globally, little is known about these dimensions in Sub-Saharan Africa. In this paper, we explore factors associated with opioid overdose experiences among a sample of women who use opioids in Dar es Salaam, Tanzania. METHODS: We conducted a cross-sectional survey with 200 women who use opioids in Dar es Salaam, Tanzania, recruited via respondent-driven sampling. We fitted unadjusted and adjusted log-binomial regression models with robust standard errors to examine associations between participant characteristics and reporting ever had an opioid overdose in terms of prevalence ratios. RESULTS: Thirty-four percent (n = 68) of participants reported having ever had an opioid overdose. In the final adjusted model, having ever attempted to stop using heroin (adj. PR = 1.46, 95% CI: 1.01-2.12), sleeping outside in the past 6 months (adj. PR = 1.93, 95% CI: 1.29-2.91), injecting drugs (adj. PR = 1.78, 95% CI: 1.19-2.66), alcohol use (adj. PR = 1.56, 95% CI: 1.09-2.23), and having moderately severe to severe depression (adj. PR = 3.10, 95% CI: 1.07-8.97) were all found to be significantly associated with having ever had an opioid overdose. CONCLUSIONS: We demonstrate factors associated with opioid overdose among women who use drugs in Tanzania that may not be addressed with injection-focused harm reduction efforts. Our findings suggest the need for overdose surveillance efforts and further work to characterize overdose risks in this context in order to design relevant, targeted interventions to prevent opioid overdose in sub-Saharan Africa.

Distinct domains of human CDC5 direct its nuclear import and association with the spliceosome.

Genetic studies have shown that CDC5 proteins are essential for G2 progression and mitotic entry. CDC5 homologs in yeast and mammals are essential for pre-messenger ribonucleic acid (mRNA) processing. Other gene products also have been shown to play roles in both pre-mRNA splicing and cell cycle regulation, prompting the description of several models to explain the mechanism(s) linking these two processes. In this study, we demonstrate that the amino-terminus of human CDC5 directs nuclear import independent of consensus nuclear localization signals or phosphorylation, and that the carboxyl-terminus of human CDC5 preferentially associates with spliceosomal complexes in proximity of RNA transcription during interphase. hCDC5 colocalizes with Sm proteins in a cell cycle- and domain-dependent manner, and several proteins in the human CDC5-associated complex are identified that suggest potential roles for the complex in coupling pre-mRNA splicing to transcriptional activation and protein translation. These results indicate that human CDC5 may function in pre-mRNA processing and cell cycle progression through more than one mechanism.

Genome-wide examination of myoblast cell cycle withdrawal during differentiation.

Skeletal and cardiac myocytes cease division within weeks of birth. Although skeletal muscle retains limited capacity for regeneration through recruitment of satellite cells, resident populations of adult myocardial stem cells have not been identified. Because cell cycle withdrawal accompanies myocyte differentiation, we hypothesized that C2C12 cells, a mouse myoblast cell line previously used to characterize myocyte differentiation, also would provide a model for studying cell cycle withdrawal during differentiation. C2C12 cells were differentiated in culture medium containing horse serum and harvested at various time points to characterize the expression profiles of known cell cycle and myogenic regulatory factors by immunoblot analysis. BrdU incorporation decreased dramatically in confluent cultures 48 hr after addition of horse serum, as cells started to form myotubes. This finding was preceded by up-regulation of MyoD, followed by myogenin, and activation of Bcl-2. Cyclin D1 was expressed in proliferating cultures and became undetectable in cultures containing 40% fused myotubes, as levels of p21(WAF1/Cip1) increased and alpha-actin became detectable. Because C2C12 myoblasts withdraw from the cell cycle during myocyte differentiation following a course that recapitulates this process in vivo, we performed a genome-wide screen to identify other gene products involved in this process. Using microarrays containing approximately 10,000 minimally redundant mouse sequences that map to the UniGene database of the National Center for Biotechnology Information, we compared gene expression profiles between proliferating, differentiating, and differentiated C2C12 cells and verified candidate genes demonstrating differential expression by RT-PCR. Cluster analysis of differentially expressed genes revealed groups of gene products involved in cell cycle withdrawal, muscle differentiation, and apoptosis. In addition, we identified several genes, including DDAH2 and Ly-6A, whose expression specifically was up-regulated during cell cycle withdrawal coincident with early myoblast differentiation.