Predictors of opioid overdose during the COVID-19 pandemic: The role of relapse, treatment access and nonprescribed buprenorphine/naloxone.

INTRODUCTION: Emerging data indicate a disproportionate increase in overdose deaths since the onset of COVID-19. Speculation about causes for the increase center on rising drug use, illicit drug supply changes, and reduced treatment access. Possible overdose mitigation factors include reduced federal MOUD prescribing restrictions, naloxone distribution programs, and increased use of telehealth. Similarly, nonprescribed buprenorphine (NPB) use, increasingly described as a harm reduction strategy in the absence of treatment, may have moderated overdose risk. This study explored factors associated with pandemic-related overdose in people who use opioids (PWUO) in New Jersey. METHODS: We surveyed 342 PWUO from March to May 2021. Approximately 50 % of our sample was treated at some time since the COVID-19 emergency declaration in March 2020. The risk and protective factors associated with overdose were identified using Pearson's chi square test and ANOVA and tested in a series of multivariable logistic regression models for the full sample and the subsample of PWUO treated during the pandemic. RESULTS: Forty-eight percent of respondents increased their drug use during the pandemic, including 32 % who relapsed after previous abstinence. Fifteen percent overdosed at least once since March 2020. In the full sample, overdose was associated with Hispanic ethnicity (AOR = 3.51; 95 % CI = 1.22-10.11), pre-pandemic overdose (AOR = 6.75; 95 % CI = 3.03-15.02), lack/loss of medical insurance (AOR = 3.02; 95 % CI = 1.01-9.02), relapse (AOR = 2.94; 95 % CI = 1.36-6.36), and nonprescribed use of buprenorphine/naloxone (AOR = 3.16; 95 % CI = 1.49-6.70). The study found similar trends in the treatment sample, with the exceptions that heroin/fentanyl use also predicted overdose (AOR = 3.43; 95 % CI = 1.20-9.78) and the association of overdose with nonprescribed buprenorphine/naloxone was stronger (AOR = 4.91; 95 % CI = 2.01-12.03). Potential mitigating factors, such as take-home methadone and telehealth, were not significant. CONCLUSIONS: Relapse during the pandemic was widespread and a significant contributor to overdose. Lack/loss of medical insurance further exacerbated the risk. Despite the growing literature reporting "therapeutic" use of NPB, people using nonprescribed buprenorphine/naloxone in the current study experienced up to five times the risk of overdose as nonusers. This finding suggests that, despite therapeutic intent, PWUO may be using NPB in ways that are ineffectual for addiction management, especially in the context of changing buprenorphine induction protocols in the context of fentanyl.

Educating the community about the opioid epidemic and medications for opioid use disorder.

BACKGROUND AND OBJECTIVES: Despite overwhelming evidence of benefit, medications for opioid use disorder (MOUD) remain stigmatizing and more efforts are needed to educate health care professionals and the general public. METHODS: We developed and evaluated an educational program for graduate students studying health sciences, teaching them to deliver 1 h presentations to the community on the opioid crisis and the usefulness of MOUD. RESULTS: To date, 120 graduate students have participated in this training experience on substance use disorders and delivered 59 presentations to more than 1065 community members. We found a significant increase in knowledge among students following the training. In addition, although attitudes and beliefs were generally positive at baseline, we also found significant increases in positives attitudes about the treatment of addiction and working with patients with addictions. Almost all students believed the course enhanced their professional expertise and would recommend it to others. We compared our students' baseline knowledge and attitudes to a large sample of other graduate students and did not find significant differences indicating good external validity of our results. Finally, we evaluated change in community members' knowledge and attitudes (N = 315) following student presentations and found significant increases in knowledge and positive attitude change toward MOUD. DISCUSSION AND CONCLUSIONS: Overall our program was feasible, enjoyable, and effective in meeting its goals of increasing knowledge acquisition and improving attitudes among students and the greater community. SCIENTIFIC SIGNIFICANCE: Graduate students in health sciences can be trained to successfully teach the public about the opioid crisis and the usefulness of MOUD.

Practice Change After Training Psychiatry Residents in Tobacco Use Disorder.

The goal of this study was to evaluate treatment practices among psychiatry residents before and 3 months after a course on tobacco use disorder. After completing the course, residents (N=89) reported a significant increase in the frequency in nine of the 12 tobacco use disorder treatment practices studied. Participants reported being more likely to assess patient willingness to quit smoking, advise patients to stop smoking, prescribe treatment medications, and provide cessation treatment. Being a junior vs. senior resident was a significant predictor of increased practices. Completing online training was associated with significant increases in the use of specific tobacco treatments.

Evaluation of an Online Residency Training in Tobacco Use Disorder.

BACKGROUND AND OBJECTIVES: Despite the overwhelming need for tobacco use disorder (TUD) treatment in behavioral health settings, few models have emerged for training psychiatry residents. One barrier may be a lack of curricula or faculty expertize in this area. The goal of this project was to develop and evaluate a 3 hour online webinar-based course for teaching psychiatry residents about TUD. METHODS: Residents from 42 participating general psychiatry residency programs were emailed a unique link to course materials. Participation was voluntary. RESULTS: Two-hundred and seven residents completed the pretest measuring baseline knowledge and 199 completed the survey measuring attitudes toward treatment of tobacco use. Mean pretest scores were 53.0% correct (SD 19.6), showing low levels of baseline knowledge. Pretest knowledge scores differed by residency year, suggesting no gain in knowledge during residency training. About 80% of participants completed the entire course and posttest evaluations. Paired t tests for 150 individuals who completed both a pretest and posttest indicated a significant increase in knowledge, with a mean gain in score of 35 points. DISCUSSION AND CONCLUSIONS: Many residents reported feeling not well prepared to treat TUD from prior education. The vast majority (98%) felt the program enhanced their professional experience somewhat or substantially or would recommend the program to others (82%). SCIENTIFIC SIGNIFICANCE: Online training for residents is a viable option to address knowledge deficits in TUD. (Am J Addict 2019;28:277-284).

BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation.

Expression of functional breast cancer susceptibility gene 1 (BRCA1) in human breast and ovarian cancers is associated with resistance to platinum-based chemotherapeutics and poly(ADP ribose) polymerase (PARP) inhibitors. BRCA1 is a nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR). In vitro, animal and human clinical data have demonstrated that BRCA1-deficient cancers are highly sensitive to ICL-inducing chemotherapeutic agents, are amenable to synthetic lethal approaches that exploit defects in DSB/ICL repair, and may be associated with improved survival. Conversely, high or restored expression of BRCA1 in breast and ovarian cancer is associated with therapeutic resistance and poor prognosis. There has been much interest in identifying agents that interfere with BRCA1-dependent DSB/ICL repair to restore or enhance sensitivity to cancer therapeutics. We demonstrate that the heat-shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin [17-AAG (Tanespimycin)], currently in Phase II/III clinical evaluation for several cancers, induces BRCA1 ubiquitination and proteasomal degradation, resulting in compromised repair of ionizing radiation- and platinum-induced DNA damage. We show that loss of HSP90 function abolishes BRCA1-dependent DSB repair and that BRCA1-deficient cells are hypersensitive to 17-AAG due to impaired Gap 2/Mitosis (G2/M) checkpoint activation and resultant mitotic catastrophe. In summary, we document an upstream HSP90-dependent regulatory point in the Fanconi anemia/BRCA DSB/ICL repair pathway, illuminate the role of BRCA1 in regulating damage-associated checkpoint and repair responses to HSP90 inhibitors, and identify BRCA1 as a clinically relevant target for enhancing sensitivity in refractory and/or resistant malignancies.

Natural withanolide withaferin A induces apoptosis in uveal melanoma cells by suppression of Akt and c-MET activation.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. While effective therapy exists for the primary tumor, there is a lack of effective treatment for metastatic disease currently. Natural withanolide withaferin A (WA) has shown efficacy in cancers demonstrating upregulation of pro-survival pathways. The purpose of the present study is to investigate the effect of WA as a potential therapeutic agent for UM in vitro as well as in vivo. UM cells were treated with WA and several cell-based assays, such as MTS, trypan blue exclusion assay, clonogenic, wound healing, cell cycle shift, annexin V/propidium iodide, and Western blot, were performed. In vivo experiments utilized the 92.1 cells in a xenograft murine model. WA inhibits cell proliferation of uveal melanoma cells with an IC50 of 0.90, 1.66, and 2.42 µM for OMM2.3, 92.1, and MEL290 cells, respectively. Flow cytometry analysis demonstrates G2/M cell cycle arrest and apoptosis at 1 µM WA in treated cells. WA induced apoptosis partly through the suppression of c-Met, Akt, and Raf-1 signaling activation. In vivo studies using WA reduced tumor growth in 100% of animals (p = 0.015). Our observation indicates that WA is a potent drug that inhibits cell proliferation, shifts cell cycle arrest, and induces apoptosis in multiple UM cell lines in vitro. WA-mediated apoptosis in UM cells is partly mediated though the suppression of c-Met and Akt activation. WA significantly decreases UM tumor growth in vivo and justifies further evaluation of this drug for the treatment of metastatic uveal melanoma.

Characterization of a novel novobiocin analogue as a putative C-terminal inhibitor of heat shock protein 90 in prostate cancer cells.

PURPOSE: Hsp90 is important in the folding, maturation and stabilization of pro-tumorigenic client proteins and represents a viable drug target for the design of chemotherapies. Previously, we reported the development of novobiocin analogues designed to inhibit the C-terminal portion of Hsp90, which demonstrated the ability to decrease client protein expression. We now report the characterization of the novel novobiocin analogue, F-4, which demonstrates improved cytotoxicity in prostate cancer cell lines compared to the N-terminal inhibitor, 17-AAG. MATERIALS AND METHODS: LNCaP and PC-3 cells were treated with 17-AAG or F-4 in anti-proliferative, apoptosis, cell cycle and cytotoxicity assays. Western blot and prostate specific antigen (PSA) ELISAs were used to determine client protein degradation, induction of Hsp90 and to assess the functional status of the androgen receptor (AR) in response to F-4 treatment. Surface plasmon resonance (SPR) was also used to determine the binding properties of F-4 to Hsp90. RESULTS: F-4 demonstrated improved potency and efficacy compared to novobiocin in anti-proliferative assays and decreased expression of client proteins. PSA secretion was inhibited in a dose-dependent manner that paralleled a decrease in AR expression. The binding of F-4 to Hsp90 was determined to be saturable with a binding affinity (K(d)) of 100 microM. In addition, superior efficacy was demonstrated by F-4 compared to 17-AAG in experiments measuring cytotoxicity and apoptosis. CONCLUSIONS: These data reveal distinct modes of action for N-terminal and C-terminal Hsp90 inhibitors, which may offer unique therapeutic benefits for the treatment of prostate cancer.