Aligning public health and public safety: Probation as a touchpoint to identify and link patients with opioid use disorder to opioid agonist treatment.

BACKGROUND: People in criminal justice settings (CJS) have high rates of opioid use disorder (OUD) and HIV. Probation is part of the CJS and congregates many individuals with high rates of mental health and substance use disorders relative to the general population; nevertheless, probation remains a major improvement to incarceration. As a steppingstone to full decarceration efforts, community supervision settings like probation can be leveraged as "touchpoints" to identify and link people with OUD (and other co-morbid conditions) to treatment and reduce criminal activity. METHODOLOGY: To determine the feasibility of a modified screening, brief intervention and referral to treatment (SBIRT) strategy to link probationers to opioid agonist therapies (OAT) in the newly created probation system in Ukraine, we conducted a single-arm SBIRT intervention in eight probation centers in four Ukrainian administrative regions. For those screening positive for OUD, interest in OAT was assessed before and after a brief intervention. Those interested in OAT were referred to community OAT services. Participants with OUD also underwent HIV testing. PRINCIPAL FINDINGS: Of the 1,298 consecutive individuals screened, 208 (16.0%) met criteria for opioid dependence. Of these, 122 (58.7%) enrolled in brief intervention, of which 54 (44.3%) had HIV and 14 (25.9%) of these were newly diagnosed. After the brief intervention, interest in starting OAT increased significantly from a median of 7.0 to 8.0 (P = <0.001) using a 10-point scale. Thirty (N = 30; 24.6%) of the enrolled participants initiated OAT and 21 of these (70%) were retained in treatment for 6 months. SIGNIFICANCE: The prevalence of OUD (and HIV) is high among people in probation in Ukraine. SBIRT can identify a large number of people eligible for OAT, many of whom were willing to initiate and remain on OAT. Integrating SBIRT into probation can potentially assist with OAT scale-up and help address HIV prevention efforts.

The Properties and Domain Requirements for Phase Separation of the Sup35 Prion Protein In Vivo.

The Sup35 prion protein of budding yeast has been reported to undergo phase separation to form liquid droplets both at low pH in vitro and when energy depletion decreases the intracellular pH in vivo. It also has been shown using purified proteins that this phase separation is driven by the prion domain of Sup35 and does not re-quire its C-terminal domain. In contrast, we now find that a Sup35 fragment consisting of only the N-terminal prion domain and the M-domain does not phase separate in vivo; this phase separation of Sup35 requires the C-terminal domain, which binds Sup45 to form the translation termination complex. The phase-separated Sup35 not only colocalizes with Sup45 but also with Pub1, a stress granule marker protein. In addition, like stress granules, phase separation of Sup35 appears to require mRNA since cycloheximide treatment, which inhibits mRNA release from ribosomes, prevents phase separation of Sup35. Finally, unlike Sup35 in vitro, Sup35 condensates do not disassemble in vivo when the intracellular pH is increased. These results suggest that, in energy-depleted cells, Sup35 forms supramolecular assemblies that differ from the Sup35 liquid droplets that form in vitro.

Interest without uptake: A mixed-methods analysis of methadone utilization in Kyrgyz prisons.

HIV incidence continues to increase in Eastern Europe and Central Asia (EECA), in large part due to non-sterile injection drug use, especially within prisons. Therefore, medication-assisted therapy with opioid agonists is an evidence-based HIV-prevention strategy. The Kyrgyz Republic offers methadone within its prison system, but uptake remains low. Screening, Brief Intervention, and Referral to Treatment (SBIRT) is a framework for identifying people who would potentially benefit from methadone, intervening to identify OUD as a problem and methadone as a potential solution, and providing referral to methadone treatment. Using an SBIRT framework, we screened for OUD in Kyrgyz prisons among people who were within six months of returning to the community (n = 1118). We enrolled 125 people with OUD in this study, 102 of whom were not already engaged in methadone treatment. We conducted a pre-release survey followed by a brief intervention (BI) to address barriers to methadone engagement. Follow-up surveys immediately after the intervention and at 1 month, 3 months, and 6 months after prison release assessed methadone attitudes and uptake. In-depth qualitative interviews with 12 participants explored factors influencing methadone utilization during and after incarceration. Nearly all participants indicated favorable attitudes toward methadone both before and after intervention in surveys; however, interest in initiating methadone treatment remained very low both before and after the BI. Qualitative findings identified five factors that negatively influence methadone uptake, despite expressed positive attitudes toward methadone: (1) interpersonal relationships, (2) interactions with the criminal justice system, (3) logistical concerns, (4) criminal subculture, and (5) health-related concerns.

Multi-level implementation factors that influence scale-up of methadone maintenance treatment in Moldovan prisons: A qualitative study.

INTRODUCTION: People who inject drugs (PWID) are overrepresented in prison populations, especially in the Eastern European and Central Asian region (EECA), where HIV incidence and mortality continue to rise. Modeling data suggest that methadone maintenance treatment (MMT) scale-up in prison with continuation after release could substantially reduce new HIV infections. Moldova, one of four countries in the EECA to have introduced MMT in prisons, has faced challenges with its scale-up. METHOD: To improve implementation of MMT in Moldovan prisoners, we analyzed the qualitative interviews of 44 recently released Moldovan prisoners with opioid use disorder who either accepted or rejected MMT while incarcerated; these 44 were among a subset of 56 participants in a quantitative survey who had complete interview data. After translating and back-translating interviews, we used content analysis to identify key barriers and facilitators to MMT uptake. RESULTS: Our qualitative analyses revealed that positive attitudes toward methadone facilitated treatment uptake, yet the study identified three thematic barriers as to why PWID do not accept MMT while in prison, including: 1) negative personal attitudes toward MMT; 2) stigmatization of MMT by informal hierarchies within prison; and 3) distrust of the formal prison hierarchy (i.e., administration), which provides MMT. CONCLUSION: Overall, the social forces of the two prisoner hierarchies and distrust between them appeared to outweigh the perceived benefits of MMT and impacted MMT uptake. Here we provide strategies to promote MMT more effectively in prison settings.

Decisional considerations for methadone uptake in Kyrgyz prisons: The importance of understanding context and providing accurate information.

BACKGROUND: The Kyrgyz Republic (Kyrgyzstan) is one of few countries in Eastern Europe and Central Asia to provide methadone within its prisons, but uptake of this program has been suboptimal, in part because methadone uptake may have personal or social risks and consequences. Decision aids are evidence-based strategies that are designed to inform the patient's choice by objectively providing information that incorporates patient preferences. METHODS: We conducted qualitative interviews in Kyrgyz and Russian with currently and formerly incarcerated people (n = 36) in Kyrgyzstan from October 2016 to September 2018. Interviews explored factors influencing methadone utilization in prisons. Transcripts were coded by five researchers using content analysis. A secondary thematic analysis was conducted to determine factors specific to initiation or continuation of methadone treatment in prisons. RESULTS: We identified six interrelated themes affecting an individual's decision to initiate or continue methadone treatment: 1) informal prison governance (incarcerated people governing themselves); 2) informal prison economy; 3) perceived and objective benefits of methadone treatment; 4) perceived and objective side effects of methadone treatment; 5) distrust of formal prison administration (medical and correctional staff); and 6) desire for a "cure" from addiction. CONCLUSION: Respondents' perceptions about benefits, side effects, and addiction as a curable disease are not consistent with the available evidence. An evidence-based, informed decision-making aid would need to address the six themes identified here, of which several are specific to the Kyrgyz prison context. Unlike decision aids elsewhere, the unique aspects of incarceration itself alongside the informal governance system strongly present within Kyrgyz prisons will need to be incorporated into decisional processes to promote HIV prevention and treatment in a region with high rates of HIV transmission and mortality.

Modeling Strengthens Molecular Link between Circadian Polymorphisms and Major Mood Disorders.

Anxiety and other mood disorders, such as major depressive disorder (MDD) and seasonal affective disorder (SAD), affect nearly one-fifth of the global population and disproportionately affect young adults. Individuals affected by mood disorders are frequently plagued by sleep and circadian problems, and recent genetic studies provide ample support for the association of circadian and sleep syndromes with depression and anxiety. Mathematical modeling has been crucial in understanding some of the essential features of the mammalian circadian clock and is now a vital tool for dissecting how circadian genes regulate the molecular mechanisms that influence mood. Here, we model the effect of five clock gene polymorphisms, previously linked to mood disorders, on circadian gene expression and, ultimately, on the period length and amplitude of the clock, two parameters that dictate the phase, or alignment, of the clock relative to the environment. We then test whether these gene variants are associated with circadian phenotypes (Horne-Ostberg Morningness-Eveningness scores) and well-established measures of depression (Beck Depression Inventory) and anxiety (State-Trait Anxiety Inventory) in a population of undergraduates ( n = 546). In this population, we find significant allelic and/or genotypic associations between CRY2 and two PER3 variants and diurnal preference. The PER3 length polymorphism (rs57875989) was significantly associated with depression in this sample, and individuals homozygous for the PER3 single nucleotide polymorphism (SNP) (rs228697) reported significantly higher anxiety. Our simple model satisfies available experimental knockdown conditions as well as existing data on clock polymorphisms associated with mood. In addition, our model enables us to predict circadian phenotypes (e.g., altered period length, amplitude) associated with mood disorders in order to identify critical effects of clock gene mutations on CRY/BMAL binding and to predict that the intronic SNPs studied represent gain-of-function mutations, causing increased transcription rate. Given the user-friendly structure of our model, we anticipate that it will be useful for further study of the relationships among clock polymorphisms, circadian misalignment, and mood disorders.

Circadian Clock Model Supports Molecular Link Between PER3 and Human Anxiety.

Generalized anxiety and major depression have become increasingly common in the United States, affecting 18.6 percent of the adult population. Mood disorders can be debilitating, and are often correlated with poor general health, life dissatisfaction, and the need for disability benefits due to inability to work. Recent evidence suggests that some mood disorders have a circadian component, and disruptions in circadian rhythms may even trigger the development of these disorders. However, the molecular mechanisms of this interaction are not well understood. Polymorphisms in a circadian clock-related gene, PER3, are associated with behavioral phenotypes (extreme diurnal preference in arousal and activity) and sleep/mood disorders, including seasonal affective disorder (SAD). Here we show that two PER3 mutations, a variable number tandem repeat (VNTR) allele and a single-nucleotide polymorphism (SNP), are associated with diurnal preference and higher Trait-Anxiety scores, supporting a role for PER3 in mood modulation. In addition, we explore a potential mechanism for how PER3 influences mood by utilizing a comprehensive circadian clock model that accurately predicts the changes in circadian period evident in knock-out phenotypes and individuals with PER3-related clock disorders.