Characteristics of Students Participating in Collegiate Recovery Programs and the Impact of COVID-19: An Updated National Longitudinal Study.

The goals of the present study were to describe the development of the first national longitudinal study of collegiate recovery programs (CRP) students; provide an updated characterization of CRP students' demographics, past problem severity, and current recovery-related functioning; and examine the perceived impact of COVID-19 on CRP students' recovery. Universities and community colleges with CRPs across the United States and Ontario, Canada, were invited to partner on this project. Launched in fall 2020, three cohorts of participants were recruited. All participants who completed the baseline survey (N = 334 from 43 CRPs) were invited to complete follow-up surveys. The sample was composed of mostly undergraduate, White, cisgender women averaging 29 years old at baseline. They reported challenging backgrounds, including high levels of polysubstance use, alcohol/substance problem severity, mental health challenges, and involvement with the criminal legal system. Despite such adversity, they evidenced high levels of recovery-related functioning. Recovery capital and quality of life were high. Students reported an average of nearly four years in recovery, with most having between two and four years of abstinence from their primary substance of choice. COVID-19 represented a substantial source of stress for many, impacting some students' abstinence and recovery-related functioning. Results generally parallel findings from the only other national study of CRP students conducted a decade ago, providing a much-needed update and novel insights into CRP students. Findings can inform our understanding of the CRP student population and can be used to tailor CRP design and service offerings to students' backgrounds and needs.

Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes.

Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1α, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8+ T cells. Notably, the metabolic control of CD8+ T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8+ T cells, and this phenotype can be exploited by treatment with drugs.

Characterizing Participation and Perceived Engagement Benefits in an Integrated Digital Behavioral Health Recovery Community for Women: A Cross-Sectional Survey.

BACKGROUND: Research suggests that digital recovery support services (D-RSSs) may help support individual recovery and augment the availability of in-person supports. Previous studies highlight the use of D-RSSs in supporting individuals in recovery from substance use but have yet to examine the use of D-RSSs in supporting a combination of behavioral health disorders, including substance use, mental health, and trauma. Similarly, few studies on D-RSSs have evaluated gender-specific supports or integrated communities, which may be helpful to women and individuals recovering from behavioral health disorders. OBJECTIVE: The goal of this study was to evaluate the SHE RECOVERS (SR) recovery community, with the following 3 aims: (1) to characterize the women who engage in SR (including demographics and recovery-related characteristics), (2) describe the ways and frequency in which participants engage with SR, and (3) examine the perception of benefit derived from engagement with SR. METHODS: This study used a cross-sectional survey to examine the characteristics of SR participants. Analysis of variance and chi-square tests, as well as univariate logistic regressions, were used to explore each aim. RESULTS: Participants (N=729, mean age 46.83 years; 685/729, 94% Caucasian) reported being in recovery from a variety of conditions, although the most frequent nonexclusive disorder was substance use (86.40%, n=630). Participants had an average length in recovery (LIR) of 6.14 years (SD 7.87), with most having between 1 and 5 years (n=300). The most frequently reported recovery pathway was abstinence-based 12-step mutual aid (38.40%). Participants reported positive perceptions of benefit from SR participation, which did not vary by LIR or recovery pathway. Participants also had high rates of agreement, with SR having a positive impact on their lives, although this too did vary by recovery length and recovery pathway. Participants with 1 to 5 years of recovery used SR to connect with other women in recovery at higher rates, whereas those with less than 1 year used SR to ask for resources at higher rates, and those with 5 or more years used SR to provide support at higher rates. Lifetime engagement with specific supports of SR was also associated with LIR and recovery pathway. CONCLUSIONS: Gender-specific and integrated D-RSSs are feasible and beneficial from the perspective of participants. D-RSSs also appear to provide support to a range of recovery typologies and pathways in an effective manner and may be a vital tool for expanding recovery supports for those lacking in access and availability because of geography, social determinants, or other barriers.

Reducing harm and promoting recovery through community-based mutual aid: Characterizing those who engage in a hybrid peer recovery community organization.

BACKGROUND: Peer-based support services are often used within harm reduction organizations, and more recently within recovery community organizations (RCO). Identifying the characteristics of individuals who engage with these novel RCOs is needed. Additionally, conducting collaborative research with communities of people who use drugs (PWUD) or are in recovery is an effective and rewarding approach that allows individuals to take ownership and play a critical role in the study. METHODS: This exploratory study employs a community-based participatory research (CBPR) framework in partnership with a peer-led hybrid recovery community organization, Rebel Recovery, in Florida. Peer staff participated in all phases of the study, helping to inform the study protocol, data collection, analysis, interpretation, and results write-up. A cross-sectional survey instrument was used to collect consumer intake data. Pearson Chi-square tests and multivariate binomial logistic regressions were used to examine relationships between consumer characteristics and service utilization. RESULTS: Consumers (n = 396) of Rebel Recovery peer support services had a mean age of 35.60 years (SD = 9.74). Many were experiencing homelessness (35.4%), unemployed (69.7%), high school graduates or GED holders (68.2%) and had a last year income of less than $10,000 (58.3%). The majority were users of heroin primarily (70.7%), with intravenous use being the preferred route of administration (63.9%). Exploratory analysis found that gender, marital status, and involvement in the child welfare system were significantly related to primary substance of use. Past 30-day engagement in recovery meetings had several statistically significant predictors including primary substance of use, age, housing status, annual income level, past-30-day arrests, tobacco use, and alcohol harm perception. Process findings from the CBPR methods used reconfirm the value of including peers in research involving PWUD and individuals in recovery. CONCLUSIONS: Results suggest that peer-based support services at a hybrid recovery community organization can successfully engage populations that are often underserved (i.e., experiencing homelessness, involved in drug court, intravenous users, etc.). Significant relationships identified in the exploratory analysis suggest that additional education concerning overdose and the potential benefits of recovery meetings may be useful for specific consumers. Additionally, several recommendations and benefits of engaging in community-based participatory research with peer-led organizations are made for future research.

Responding to the opioid and overdose crisis with innovative services: The recovery community center office-based opioid treatment (RCC-OBOT) model.

Opioid use disorder (OUD) and opioid-related overdose mortality are major public health concerns in the United States. Recently, several community-based and professional innovations - including hybrid recovery community organizations, peer-based emergency department warm handoff programs, emergency department buprenorphine induction, and low-threshold OUD treatment programs - have emerged or expanded in an effort to address significant obstacles to providing patients the care needed for OUD and to reduce the risk of overdose. Additional innovations are needed to address the crisis. Building upon the foundational frameworks of each of these recent innovations, a new model of OUD pharmacotherapy is proposed and discussed: the Recovery Community Center Office-Based Opioid Treatment model. Additionally, two potential implementation scenarios, the overdose and non-overdose event protocols, are detailed for communities, peers, and practitioners interested in implementing the model. Potential barriers to implementation of the model include service reimbursement, licensing regulations, and organizational concerns. Future research should seek to validate the model and to identify actual implementation and sustainability barriers and best practices.

Biased labels: An experimental study of language and stigma among individuals in recovery and health professionals.

BACKGROUND: Labels such as "addict" and "substance abuser" have been found to elicit implicit and explicit stigma among the general public previously. The difference in the levels of this bias among individuals in recovery and those employed in the health profession has not yet been identified, however. The current study seeks to answer this question using measures of implicit bias. METHODS: A subset sample (n = 299) from a previously completed study (n = 1288) was selected for analysis. Mixed-model ANOVA tests were completed to identify variance between d-prime automatic association scores with the terms "addict" and "substance abuser" among individuals in recovery and those identified as working in the health professions. RESULTS: Individuals in recovery did not have lower negative associations with either term, whereas individuals employed as health professionals had greater negative associations with the term "substance abuser" but did not have greater negative associations with the term "addict." CONCLUSIONS: Results provide further evidence that previously identified stigmatizing labels have the potential to influence medical care and medical practitioner perceptions of individuals with substance use disorders and should be avoided. Further exploration into the role negative associations derived from commonly used labels have in the individual recovery process is needed to draw appropriate recommendations.

Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon.

Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteosomal destruction by engaging the DDB1-CUL4A-Roc1-RBX1 E3 ubiquitin ligase in human cells but not in mouse cells, suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers have the potential for broad applications in cancer and immune therapy by specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine the effects of defined sequence changes on CRBN's activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBN's nonprimate sequence variations. With a series of recombinant thalidomide-binding domain (TBD) proteins, we show that CRBN sequence variants retain their drug-binding properties to both classical immunomodulatory drugs and dBET1, a chemical compound and targeting ligand designed to degrade bromodomain-containing 4 (BRD4) via a CRBN-dependent mechanism. We further show that dBET1 stimulates CRBN's E3 ubiquitin-conjugating function and degrades BRD4 in both mouse and human cells. This insight paves the way for studies of CRBN-dependent proteasome-targeting molecules in nonprimate models and provides a new understanding of CRBN's substrate-recruiting function.

Photoexcited quantum dots for killing multidrug-resistant bacteria.

Multidrug-resistant bacterial infections are an ever-growing threat because of the shrinking arsenal of efficacious antibiotics. Metal nanoparticles can induce cell death, yet the toxicity effect is typically nonspecific. Here, we show that photoexcited quantum dots (QDs) can kill a wide range of multidrug-resistant bacterial clinical isolates, including methicillin-resistant Staphylococcus aureus, carbapenem-resistant Escherichia coli, and extended-spectrum ß-lactamase-producing Klebsiella pneumoniae and Salmonella typhimurium. The killing effect is independent of material and controlled by the redox potentials of the photogenerated charge carriers, which selectively alter the cellular redox state. We also show that the QDs can be tailored to kill 92% of bacterial cells in a monoculture, and in a co-culture of E. coli and HEK 293T cells, while leaving the mammalian cells intact, or to increase bacterial proliferation. Photoexcited QDs could be used in the study of the effect of redox states on living systems, and lead to clinical phototherapy for the treatment of infections.

GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia.

Granulocyte-macrophage-colony-stimulating factor (GM-CSF) hypersensitivity is a hallmark of juvenile myelomonocytic leukemia (JMML) but has not been systematically shown in the related human disease chronic myelomonocytic leukemia (CMML). We find that primary CMML samples demonstrate GM-CSF-dependent hypersensitivity by hematopoietic colony formation assays and phospho-STAT5 (pSTAT5) flow cytometry compared with healthy donors. Among CMML patients, the pSTAT5 hypersensitive response positively correlated with high-risk disease, peripheral leukocytes, monocytes, and signaling-associated mutations. When compared with IL-3 and G-CSF, GM-CSF hypersensitivity was cytokine specific and thus a possible target for intervention in CMML. To explore this possibility, we treated primary CMML cells with KB003, a novel monoclonal anti-GM-CSF antibody, and JAK2 inhibitors. We found that an elevated proportion of immature GM-CSF receptor-α(R) subunit-expressing cells were present in the bone marrow myeloid compartment of CMML. In survival assays, we found that myeloid and monocytic progenitors were sensitive to GM-CSF signal inhibition. Our data indicate that a committed myeloid precursor expressing CD38 may represent the progenitor population with enhanced GM-CSF dependence in CMML, consistent with results in JMML. These preclinical data indicate that GM-CSF signaling inhibitors merit further investigation in CMML and that GM-CSFR expression on myeloid progenitors may be a biomarker for this therapy.

Emerging immunosuppressive drugs in myelodysplastic syndromes.

INTRODUCTION: Myelodysplastic syndromes (MDS) are characterized by dysplastic morphologic features and ineffective hematopoiesis. Pathophysiological characteristics change over time making therapeutic development a major challenge. In early MDS, cytopenias arise or are exacerbated by humoral and cellular immune-mediators that suppress hematopoietic progenitor survival and alter the bone marrow microenvironment. AREAS COVERED: In this review, current immunosuppressive regimens are described. To identify new therapies that may enhance immunosuppressive therapy (IST) response and identify pharmacodynamic biomarkers for patient selection, the inflammasome, cytokines, metabolic pathways and signaling events are described. EXPERT OPINION: Agents with the potential to induce early, durable hematologic remissions are needed and many new immunosuppressive agents are available for investigation. An immune-mediated mechanism is likely to contribute to MDS early after diagnosis. New approaches that interfere with inflammatory pathways in the bone marrow microenvironment may move closer toward sustained disease control in MDS.

Molecular action of lenalidomide in lymphocytes and hematologic malignancies.

The immunomodulatory agent, lenalidomide, is a structural analogue of thalidomide approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome (MDS) and multiple myeloma (MM). This agent is also currently under active investigation for the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), as well as in drug combinations for some solid tumors and mantle cell lymphoma (MCL). Although treatment with lenalidomide has translated into a significant extension in overall survival in MM and MDS and has superior safety and efficacy relative to thalidomide, the mechanism of action as it relates to immune modulation remains elusive. Based on preclinical models and clinical trials, lenalidomide, as well as other structural thalidomide derivatives, enhances the proliferative and functional capacity of T-lymphocytes and amplifies costimulatory signaling pathways that activate effector responses and suppress inflammation. This paper summarizes our current understanding of T- and natural killer (NK) cell pathways that are modified by lenalidomide in hematopoietic neoplasms to inform future decisions about potential combination therapies.