Individuals Reporting Past 3-month Smoked Stimulant Use Are Placed at Risk for Infection and Injury Amid COVID-19.

OBJECTIVES: Smoking stimulants, such as methamphetamine and "crack" cocaine, can spread infections, including hepatitis C and COVID-19, and lead to injuries, particularly when individuals share or use makeshift pipes. The purpose of the study was to assess the practices of people who inhale ("smoke") stimulants to guide future clinical harm reduction efforts. METHODS: Anonymous surveys were administered to participants reporting inhalation of crack cocaine and/or methamphetamine in the past 3 months. Participants were eligible if they sought services from an outreach team staffed by a municipal syringe service program (SSP) or if they were patients at a low-threshold substance use disorder treatment program, the Massachusetts General Hospital Bridge Clinic. RESULTS: The survey was administered to 68 total participants, 30% of whom were recruited in the Massachusetts General Hospital Bridge Clinic and 70% through SSP outreach. Unsafe smoking practices were reported by 93% of participants. Among the 46% of participants surveyed who both smoked and injected stimulants, 61% of those participants stated that they injected instead of smoked stimulants because of lack of access to pipes. Amid COVID-19, 35% of participants adopted safer smoking practices. Most participants reported that they would be more likely to attend an SSP or health center if pipes were provided. CONCLUSIONS: Inhalational practices that place participants at risk of injury and illness are common. Providing safer smoking equipment may promote health and engage individuals in care.

"We were building the plane as we were flying it, and we somehow made it to the other end": syringe service program staff experiences and well-being during the COVID-19 pandemic.

BACKGROUND: Syringe service programs (SSPs) provide essential harm reduction and prevention services for people who inject drugs in the USA, where SSP coverage is expanding. During the COVID-19 pandemic, US SSPs underwent unprecedented shifts in operational procedures (e.g., closures of physical sites, staff redeployment into pandemic response efforts). Given the critical role of US SSP workers in the pandemic, we sought to explore the occupational experiences and well-being of SSP staff to inform future emergency response efforts. METHODS: From July-October 2020, we conducted semi-structured interviews with staff members of four SSPs in diverse regions of Massachusetts. Trained interviewers administered qualitative interviews virtually. Interviews were coded in NVivo v12 and thematic analysis identified common occupational experiences and related impacts on staff well-being in the context of the COVID-19 pandemic. RESULTS: Among 18 participants, 12 (67%) had client-facing roles such as harm reduction specialists and six (33%) worked in program management or leadership. We found that staff were frequently anxious about SARS-CoV-2 transmission, which contributed to staff turnover. SSPs rapidly adapted and expanded their services to meet increasing client needs during the pandemic (e.g., food distribution, COVID-19 testing), leading to staff overexertion. Simultaneously, public health measures such as physical distancing led to staff concerns about reduced social connections with clients and coworkers. Through these challenges, SSPs worked to protect staff well-being by implementing flexible and tangible COVID-19-related policies (e.g., paid sick leave), mental health resources, and frequent communication regarding pandemic-related operational changes. CONCLUSION: SSPs in the USA adapted to the COVID-19 pandemic out of necessity, resulting in operational changes that threatened staff well-being. Despite the protective factors revealed in some narratives, our findings suggest that during prolonged, complex public health emergencies, SSPs may benefit from enhanced occupational supports to prevent burnout and promote wellness for this essential public health workforce.

The Bronze Age of drug checking: barriers and facilitators to implementing advanced drug checking amidst police violence and COVID-19.

OBJECTIVES: Unpredictable fluctuations in the illicit drug market increase overdose risk. Drug checking, or the use of technology to provide insight into the contents of illicit drug products, is an overdose prevention strategy with an emerging evidence base. The use of portable spectrometry devices to provide point-of-service analysis of the contents of illicit drugs been adopted by harm reduction organizations internationally but is only emerging in the United States. This study aimed to identify barriers and facilitators of implementing drug checking services with spectrometry devices in an urban harm reduction organization and syringe service program serving economically marginalized people who use drugs in Boston, Massachusetts (USA). METHODS: In-vivo observations and semi-structured interviews with harm reduction staff and participants were conducted between March 2019 and December 2020. We used the consolidated framework for implementation research to identify implementation barriers and facilitators. RESULTS: This implementation effort was facilitated by the organization's shared culture of harm reduction-which fostered shared implementation goals and beliefs about the intervention among staff persons-its horizontal organizational structure, strong identification with the organization among staff, and strong relationships with external funders. Barriers to implementation included the technological complexity of the advanced spectroscopy devices utilized for drug checking. Program staff indicated that commercially available spectroscopy devices are powerful but not always well-suited for drug checking efforts, describing their technological capacities as "the Bronze Age of Drug Checking." Other significant barriers include the legal ambiguity of drug checking services, disruptive and oppositional police activity, and the responses and programmatic changes demanded by the COVID-19 pandemic. CONCLUSIONS: For harm reduction organizations to be successful in efforts to implement and scale drug checking services, these critical barriers-especially regressive policing policies and prohibitive costs-need to be addressed. Future research on the impact of policy changes to reduce the criminalization of substance use or to provide explicit legal frameworks for the provision of this and other harm reduction services may be merited.

Experience with a Mobile Addiction Program among People Experiencing Homelessness.

A mobile addiction-focused outreach program designed to improve access to care for people experiencing homelessness was implemented in response to the opioid overdose crisis. This innovative program was readily accepted among participants and can inform the development of similar programs delivering addiction-focused care to people experiencing homelessness elsewhere.

Community Care in Reach: Mobilizing Harm Reduction and Addiction Treatment Services for Vulnerable Populations.

Opioid overdoses killed 47,600 people in the United States in 2017. Despite increasing availability of office-based addiction treatment programs, the prevalence of opioid overdose is historically high and disproportionately affects vulnerable populations, including people experiencing homelessness. Despite availability of effective treatment, many at greatest risk of death from overdose experience myriad barriers to care. Launched in 2018, the Community Care in Reach mobile health initiative uses a data-driven approach to bring harm reduction and medication for opioid use disorder directly to those at highest risk of near-term death. Proof-of-concept results suggest that mobile addiction services may serve as a model for expanding access to addiction care for the most vulnerable.

Low Barrier Tele-Buprenorphine in the Time of COVID-19: A Case Report.

BACKGROUND: To reduce the spread of coronavirus disease 2019 (COVID-19), many substance use disorder treatment programs have transitioned to telemedicine. Emergency regulatory changes allow buprenorphine initiation without an in-person visit. We describe the use of videoconferencing for buprenorphine initiation combined with street outreach to engage 2 patients experiencing homelessness with severe opioid use disorder (OUD). CASE PRESENTATION: Patient 1 was a 30-year-old man with severe OUD who had relapsed to injection heroin/fentanyl after incarceration. A community drop-in center outreach harm reduction specialist facilitated a videoconference with an addiction specialist at an OUD bridge clinic. The patient completed a community buprenorphine/naloxone initiation and self-titrated to his prior dose, 8/2 mg twice daily. One week later, he reconnected with the outreach team for a follow-up videoconference visit. Patient 2, a 36-year-old man with severe OUD, connected to the addiction specialist via a syringe service program harm reduction specialist. He had been trying to connect to a community buprenorphine/naloxone provider, but access was limited due to COVID-19, so he was using diverted buprenorphine/naloxone to reduce opioid use. He was restarted on his previous dose of 12/3 mg daily which was continued via phone follow-up 16 days later. CONCLUSIONS: COVID-19-related regulatory changes allow buprenorphine initiation via telemedicine. We describe 2 cases where telemedicine was combined with street outreach to connect patients experiencing homelessness with OUD to treatment. These cases highlight an important opportunity to provide access to life-saving OUD treatment for vulnerable patients in the setting of a pandemic that mandates reduced face-to-face clinical interactions.

Use of promethazine, gabapentin and clonidine in combination with opioids or opioid agonist therapies among individuals attending a syringe service program.

BACKGROUND: Clonidine, gabapentin, and promethazine are commonly used by people who use opioids, including heroin, raising concern for increased morbidity and mortality in a vulnerable population. We aimed to characterize how and why individuals use opioids in combination with these three psychoactive medications (PAMs). METHODS: Participants (n = 103) were a convenience sample of adults attending a syringe service program who reported using a PAM in addition to opioids or opioid agonist therapies (buprenorphine or methadone). Face-to-face structured interviews consisted of closed and open-ended questions. RESULTS: Patterns of PAM use varied. Risky use, including use of high doses and with other sedating medications, was common. Most individuals reported multiple medical reasons for use, even while reporting the PAM had mind-altering effects. Use of high doses of PAMs was associated with a history of overdose. Among those with a history of overdose, 32% reported that a PAM was involved. CONCLUSION: The use of clonidine, gabapentin and promethazine among individuals who use opioids is complex. Providers should take individualized approaches to PAM prescribing, recognizing both the risks of PAMs and the potential unintended consequences of supply-side interventions in the era of the overdose crisis. Harm reduction interventions are needed to prevent PAM-involved overdoses.

Comparison of DNMT1 inhibitors by methylome profiling identifies unique signature of 5-aza-2'deoxycytidine.

AIM: 5-aza-2'deoxycytidine (Aza) is used to treat myelodysplastic syndrome and is in trials for other cancers. It acts chiefly as a hypomethylating agent inhibiting DNMT1. A lack of understanding of off-target effects in normal cells hinders wider usage. MATERIALS & METHODS: We compared treatment of the same normosomic, nontransformed fibroblast cell line with Aza and SMARTpool siRNA against DNMT1. Methylation and transcription were assayed using Illumina 450k and HT12 arrays. RESULTS: Both Aza and DNMT1 siRNA caused overall hypomethylation, with siRNA more efficient at demethylating gene bodies. Hypomethylation at the promoters of many histones, and hypermethylation at multiple sites genome wide, were unique to Aza treatment. CONCLUSION: Aza had important unique effects and targets compared with DNMT1 inhibition via siRNA.

Imprint stability and plasticity during development.

There have been a number of recent insights in the area of genomic imprinting, the phenomenon whereby one of two autosomal alleles is selected for expression based on the parent of origin. This is due in part to a proliferation of new techniques for interrogating the genome that are leading researchers working on organisms other than mouse and human, where imprinting has been most studied, to become interested in looking for potential imprinting effects. Here, we recap what is known about the importance of imprints for growth and body size, as well as the main types of locus control. Interestingly, work from a number of labs has now shown that maintenance of the imprint post implantation appears to be a more crucial step than previously appreciated. We ask whether imprints can be reprogrammed somatically, how many loci there are and how conserved imprinted regions are in other species. Finally, we survey some of the methods available for examining DNA methylation genome-wide and look to the future of this burgeoning field.

Depletion of DNMT1 in differentiated human cells highlights key classes of sensitive genes and an interplay with polycomb repression.

BACKGROUND: DNA methylation plays a vital role in the cell, but loss-of-function mutations of the maintenance methyltransferase DNMT1 in normal human cells are lethal, precluding target identification, and existing hypomorphic lines are tumour cells. We generated instead a hypomorphic series in normal hTERT-immortalised fibroblasts using stably integrated short hairpin RNA. RESULTS: Approximately two-thirds of sites showed demethylation as expected, with one-third showing hypermethylation, and targets were shared between the three independently derived lines. Enrichment analysis indicated significant losses at promoters and gene bodies with four gene classes most affected: (1) protocadherins, which are key to neural cell identity; (2) genes involved in fat homoeostasis/body mass determination; (3) olfactory receptors and (4) cancer/testis antigen (CTA) genes. Overall effects on transcription were relatively small in these fibroblasts, but CTA genes showed robust derepression. Comparison with siRNA-treated cells indicated that shRNA lines show substantial remethylation over time. Regions showing persistent hypomethylation in the shRNA lines were associated with polycomb repression and were derepressed on addition of an EZH2 inhibitor. Persistent hypermethylation in shRNA lines was, in contrast, associated with poised promoters. CONCLUSIONS: We have assessed for the first time the effects of chronic depletion of DNMT1 in an untransformed, differentiated human cell type. Our results suggest polycomb marking blocks remethylation and indicate the sensitivity of key neural, adipose and cancer-associated genes to loss of maintenance methylation activity.

Changes in public order after the opening of an overdose monitoring facility for people who inject drugs.

BACKGROUND: In the face of an increasingly fatal opioid crisis, Boston Health Care for the Homeless Program (BHCHP) opened the Supportive Place for Observation and Treatment (SPOT), a unique low-threshold harm reduction program for monitoring people who have injected drugs and are at imminent risk of overdose. This study examines the impact of the opening of the SPOT program on measures of injection drug-related public order in the neighborhood surrounding the facility. METHODS: Data was collected at 10 weeks prior and 12 weeks post SPOT implementation on: number of over-sedated individuals in public, publicly discarded syringes, publicly discarded injection-related litter, and instances of active injection drug use or exchange of drugs. Changes were evaluated using Poisson log-linear regression models. Potential confounders such as weather and police presence were measured and controlled for. RESULTS: The average number of over-sedated individuals observed in public significantly decreased by 28% (4.3 [95% Confidence Interval (CI) 2.7-6.9] v 3.1 [CI 1.4-6.8]) after SPOT opened. The opening of SPOT did not have a significant effect on the other measures of public order. The daily average number of publicly discarded syringes (28.5 [CI 24.5-33.1] v 28.4 [CI 22.0-36.5]), pieces of publicly discarded injection-related litter (376.3 [CI 358.6-394.8] v 375.0 [CI 345.8-406.6]), and observed instances of active use or exchange of drugs (0.2 [CI 0.1-0.9] v 0.1 [CI 0.0-0.1]) were not statistically significantly different after the opening of SPOT. CONCLUSIONS: The opening of SPOT was associated with a significant decrease in observed over-sedated individuals. Other measures of injection-drug related public order did not improve or worsen with the opening of SPOT, however, they have been shown to improve with the implementation of a supervised injection facility.

The willingness of people who inject drugs in Boston to use a supervised injection facility.

BACKGROUND: In Massachusetts, the number of opioid-related deaths has increased 350% since 2000. In the setting of increasing overdose deaths, one potential intervention is supervised injection facilities (SIFs). This study explores willingness of people who inject drugs in Boston to use a SIF and examines factors associated with willingness. METHODS: A cross-sectional survey of a convenience sample of 237 people who inject drugs and utilize Boston's needle exchange program (NEP). The drop-in NEP provides myriad harm reduction services and referrals to addiction treatment. The survey was mostly self-administered (92%). RESULTS: Results showed positive willingness to use a SIF was independently associated with use of heroin as main substance (odds ratio [OR]: 5.47; 95% confidence interval [CI]: 1.9-15.4; P = .0004), public injection (OR: 5.09; 95% CI: 1.8-14.3; P = .002), history of seeking substance use disorder (SUD) treatment (OR: 4.99; 95% CI: 1.2-21.1; P = .05), having heard of SIF (OR: 4.80; 95% CI: 1.6-14.8; P = .004), Hispanic ethnicity (OR: 4.22; 95% CI: 0.9-18.8; P = .04), frequent NEP use (OR: 4.18; 95% CI: 1.2-14.7; P = .02), current desire for SUD treatment (OR: 4.15; 95% CI: 1.2-14.7; P = .03), hepatitis C diagnosis (OR: 3.68; 95% CI: 1.2-10.1; P = .02), posttraumatic stress disorder (PTSD) diagnosis (OR: 3.27; 95% CI: 1.3-8.4; P = .01), report of at least 1 chronic medical diagnosis (hepatitis C, human immunodeficiency virus [HIV], hypertension, or diabetes) (OR: 3.27; 95% CI: 1.2-8.9; P = .02), and comorbid medical and mental health diagnoses (OR: 2.93; 95% CI: 1.2-7.4; P = .02). CONCLUSIONS: Most respondents (91.4%) reported willingness to use a SIF. Respondents with substance use behavior reflecting high risk for overdose were significantly more likely to be willing to use a SIF. Respondents with behaviors that contribute to public health burden of injection drug use were also significantly more likely to be willing to use a SIF. Results indicate that this intervention would be well utilized by individuals who could most benefit from the model. As part of a broader public health approach, SIFs should be considered to reduce opioid overdose mortality, decrease public health burden of the opioid crisis, and promote access to addiction treatment and medical care.

Widespread recovery of methylation at gametic imprints in hypomethylated mouse stem cells following rescue with DNMT3A2.

BACKGROUND: Imprinted loci are paradigms of epigenetic regulation and are associated with a number of genetic disorders in human. A key characteristic of imprints is the presence of a gametic differentially methylated region (gDMR). Previous studies have indicated that DNA methylation lost from gDMRs could not be restored by DNMT1, or the de novo enzymes DNMT3A or 3B in stem cells, indicating that imprinted regions must instead undergo passage through the germline for reprogramming. However, previous studies were non-quantitative, were unclear on the requirement for DNMT3A/B and showed some inconsistencies. In addition, new putative gDMR has recently been described, along with an improved delineation of the existing gDMR locations. We therefore aimed to re-examine the dependence of methylation at gDMRs on the activities of the methyltransferases in mouse embryonic stem cells (ESCs). RESULTS: We examined the most complete current set of imprinted gDMRs that could be assessed using quantitative pyrosequencing assays in two types of ESCs: those lacking DNMT1 (1KO) and cells lacking a combination of DNMT3A and DNMT3B (3abKO). We further verified results using clonal analysis and combined bisulfite and restriction analysis. Our results showed that loss of methylation was approximately equivalent in both cell types. 1KO cells rescued with a cDNA-expressing DNMT1 could not restore methylation at the imprinted gDMRs, confirming some previous observations. However, nearly all gDMRs were remethylated in 3abKO cells rescued with a DNMT3A2 expression construct (3abKO + 3a2). Transcriptional activity at the H19/Igf2 locus also tracked with the methylation pattern, confirming functional reprogramming in the latter. CONCLUSIONS: These results suggested (1) a vital role for DNMT3A/B in methylation maintenance at imprints, (2) that loss of DNMT1 and DNMT3A/B had equivalent effects, (3) that rescue with DNMT3A2 can restore imprints in these cells. This may provide a useful system in which to explore factors influencing imprint reprogramming.