Repression of pervasive antisense transcription is the primary role of fission yeast RNA polymerase II CTD serine 2 phosphorylation.

The RNA polymerase II carboxy-terminal domain (CTD) consists of conserved heptapeptide repeats that can be phosphorylated to influence distinct stages of the transcription cycle, including RNA processing. Although CTD-associated proteins have been identified, phospho-dependent CTD interactions have remained elusive. Proximity-dependent biotinylation (PDB) has recently emerged as an alternative approach to identify protein-protein associations in the native cellular environment. In this study, we present a PDB-based map of the fission yeast RNAPII CTD interactome in living cells and identify phospho-dependent CTD interactions by using a mutant in which Ser2 was replaced by alanine in every repeat of the fission yeast CTD. This approach revealed that CTD Ser2 phosphorylation is critical for the association between RNAPII and the histone methyltransferase Set2 during transcription elongation, but is not required for 3' end processing and transcription termination. Accordingly, loss of CTD Ser2 phosphorylation causes a global increase in antisense transcription, correlating with elevated histone acetylation in gene bodies. Our findings reveal that the fundamental role of CTD Ser2 phosphorylation is to establish a chromatin-based repressive state that prevents cryptic intragenic transcription initiation.

Characterizing the Association Between Traumatic Brain Injury and Discontinuation of Medications for Opioid Use Disorder in a Commercially Insured Adult Population.

OBJECTIVE: Extending prior research that has found that people with traumatic brain injury (TBI) experience worse substance use treatment outcomes, we examined whether history of TBI was associated with discontinuation of medication to treat opioid use disorder (MOUD), an indicator of receiving evidence-based treatment. SETTING: We used MarketScan claims data to capture inpatient, outpatient, and retail pharmacy utilization from large employers in all 50 states from 2016 to 2019. PARTICIPANTS: We identified adults aged 18 to 64 initiating non-methadone MOUD (ie, buprenorphine, injectable naltrexone, and oral naltrexone) in 2016-2019. The exposure was whether an individual had a TBI diagnosis in the 2 years before initiating MOUD. During this period, there were 709 individuals with TBI who were then matched with 709 individuals without TBI. DESIGN: We created a retrospective cohort of matched individuals with and without TBI and used quasi-experimental methods to identify the association between TBI status and MOUD use. We estimated propensity scores by TBI status and created a 1:1 matched cohort of people with and without TBI who initiated MOUD. We used a Cox proportional hazards model to identify the association between TBI and MOUD discontinuation. MAIN MEASURE: The outcome was discontinuation of MOUD (ie, a gap of 14 days or more of MOUD). RESULTS: Among those initiating MOUD, the majority were under 26 years of age, male, and living in an urban setting. Nearly 60% of individuals discontinued medication by 6 months. Adults with TBI had an elevated risk of MOUD discontinuation (hazard ratio [HR] 1.13; 95% confidence interval [CI], 1.01-1.27) compared to those without TBI. Additionally, initiating oral naltrexone was associated with a higher risk of discontinuation (HR 1.63; 95% CI, 1.40-1.90). CONCLUSION: We found evidence of reduced MOUD retention among people with TBI. Differences in MOUD retention may reflect health care inequities, as there are no medical contraindications to using MOUD for people with TBI or other disabilities.

Out-of-pocket spending and health care utilization associated with initiation of different medications for opioid use disorder: Findings from a national commercially insured cohort.

INTRODUCTION: Buprenorphine and naltrexone are effective medications for opioid use disorder (MOUD). Naltrexone requires complete detoxification from opioids before initiation while buprenorphine does not, which leads to a differential clinical induction challenge. Few studies have evaluated economic costs associated with MOUD initiation. METHODS: We conducted a retrospective cohort analysis using the 2014-2019 Merative MarketScan database. We included individuals diagnosed with opioid use, abuse, or dependence from 2014 to 2019 who initiated one of three MOUD types: 1) buprenorphine, 2) extended-release naltrexone, or 3) oral naltrexone. We calculated total and monthly out-of-pocket spending, for overall and MOUD-specific claims, for the three months prior through three months after MOUD initiation. We also calculated utilization of detoxification, inpatient, and outpatient services monthly over this period. RESULTS: Our cohort included 27,133 individuals; 19,536, 1886, and 5711 initiated buprenorphine, extended-release naltrexone, and oral naltrexone, respectively. Individuals who initiated naltrexone had the highest out-of-pocket spending over the study period. MOUD-specific spending did not contribute substantially to total out-of-pocket spending. Difference in overall spending by MOUD type was driven by a subset of individuals who initiated naltrexone and had very high out-of-pocket spending in the month prior to MOUD initiation. In this month, mean monthly out-of-pocket spending for high-spenders (above 90th percentile within MOUD type category) was $5734 (95 % confidence interval [CI]: $5181-$6286) and $4622 (95 % CI: $4161-$5082) for those who initiated oral and extended-release naltrexone, respectively, compared with $1852 (95 % CI: $1754-$1950) for those who initiated buprenorphine. In the month prior to MOUD initiation, those who initiated naltrexone also had higher detoxification, inpatient, and outpatient episode/visit frequency. In the month prior to initiation, 28.8 % (95 % CI: 27.7 %-30.0 %) and 25.5 % (95 % CI: 23.6 %-27.5 %) of individuals who initiated oral and extended-release naltrexone had detoxification episodes, compared with 9.7 % (95 % CI: 9.3 %-10.1 %) of those who initiated buprenorphine. CONCLUSION: Findings suggest that individuals who initiated naltrexone utilized more intensive health services, including detoxification, in the period prior to MOUD initiation, resulting in significantly higher out-of-pocket spending. Out-of-pocket spending is a patient-centered outcome reflecting potential patient burden. Our results should be considered as part of the shared decision-making process between patients and providers when choosing treatment for OUD.

Medication and procedural abortion uptake during a period of increasing abortion hostility.

Hundreds of state-level abortion restrictions were implemented in the US between 2010 and 2020. Medication abortion was being widely adopted during this same period. Understanding the impact of health policies and political climate will improve the delivery of and access to reproductive healthcare in a period of rapid change. To measure the association between state abortion hostility and mifepristone and procedural abortion rates, we conducted a state-level repeated cross-sectional study using 2010-2020 employer-sponsored insurance claims data from Merative MarketScan. The exposure of interest was a 13-point state-level abortion hostility score based on the presence of policies which either reduce or protect access to abortion. Outcomes of interest were annual mifepristone and procedural abortion claims per 100,000 enrollees. We used a linear mixed model adjusting for urbanicity, age group, and year. We assessed whether temporal trends in abortion claims were modified by state abortion hostility by interacting year with two measurements of abortion hostility: baseline score in 2010 and change from baseline score. We found that median state-level mifepristone claims increased from 20 to 37 per 100,000 included enrollees; meanwhile, median procedural abortions claims decreased from 69 to 20 per 100. For mifepristone, every unit increase in a state's baseline abortion hostility score was associated with 7.5 (CI, -12 to -3.6) fewer mifepristone claims per 100,000 in 2010. For states with baseline hostility and change scores of zero, we did not observe a significant time trend over the 11 year study period. For every unit increase in baseline hostility, the time trend changed by 0.5 fewer claims (CI, -0.8 to -0.2) per 100,000 per year. States with higher baseline abortion hostility had fewer overall abortions, less uptake of mifepristone abortions, and slower decline in procedural abortions between 2010 and 2020. Changes in hostility from new restrictions during this time period did not significantly impact claims. Advocates for abortion access must simultaneously attend to individual abortion policies and the overall political climate. Updated research on the relationship between political climate and the evolving clinical landscape of abortion care is needed to inform this work.

Prison Buprenorphine Implementation and Postrelease Opioid Use Disorder Outcomes.

Importance: Agonist medications for opioid use disorder (MOUD), buprenorphine and methadone, in carceral settings might reduce the risk of postrelease opioid overdose but are uncommonly offered. In April 2019, the Massachusetts Department of Correction (MADOC), the state prison system, provided buprenorphine for incarcerated individuals in addition to previously offered injectable naltrexone. Objective: To evaluate postrelease outcomes after buprenorphine implementation. Design, Setting, and Participants: This cohort study with interrupted time-series analysis used linked data across multiple statewide data sets in the Massachusetts Public Health Data Warehouse stratified by sex due to differences in carceral systems. Eligible participants were individuals sentenced and released from a MADOC facility to the community. The study period for the male sample was January 2014 to November 2020; for the female sample, January 2015 to October 2019. Data were analyzed between February 2022 and January 2024. Exposure: April 2019 implementation of buprenorphine during incarceration. Main Outcomes and Measures: Receipt of MOUD within 4 weeks after release, opioid overdose, and all-cause mortality within 8 weeks after release, each measured as a percentage of monthly releases who experienced the outcome. Segmented linear regression analyzed changes in outcome rates after implementation. Results: A total of 15 225 individuals were included. In the male sample there were 14 582 releases among 12 688 individuals (mean [SD] age, 35.0 [10.8] years; 133 Asian and Pacific Islander [0.9%], 4079 Black [28.0%], 4208 Hispanic [28.9%], 6117 White [41.9%]), a rate of 175.7 releases per month; the female sample included 3269 releases among 2537 individuals (mean [SD] age, 34.9 [9.8] years; 328 Black [10.0%], 225 Hispanic [6.9%], 2545 White [77.9%]), a rate of 56.4 releases per month. Among male participants at 20 months postimplementation, the monthly rate of postrelease buprenorphine receipt was higher than would have been expected under baseline trends (21.2% vs 10.6% of monthly releases; 18.6 additional releases per month). Naltrexone receipt was lower than expected (1.0% vs 6.0%; 8.8 fewer releases per month). Monthly rates of methadone receipt (1.4%) and opioid overdose (1.8%) were not significantly different than expected. All-cause mortality was lower than expected (1.9% vs 2.8%; 1.5 fewer deaths per month). Among female participants at 7 months postimplementation, buprenorphine receipt was higher than expected (31.6% vs 9.5%; 12.4 additional releases per month). Naltrexone receipt was lower than expected (3.4% vs 7.2%) but not statistically significantly different. Monthly rates of methadone receipt (1.1%), opioid overdose (4.8%), and all-cause mortality (1.6%) were not significantly different than expected. Conclusions and Relevance: In this cohort study of state prison releases, postrelease buprenorphine receipt increased and naltrexone receipt decreased after buprenorphine became available during incarceration.

Receipt of medications for opioid use disorder before and after incarceration in Massachusetts State prisons, 2014-2019.

BACKGROUND: Little is known about how use patterns of medications for opioid use disorder (MOUDs) evolve from pre-incarceration to post-incarceration among incarcerated individuals with opioid use disorder. This article describes pre- and post-incarceration MOUD receipt during a period when naltrexone was the only type of MOUD offered in a state prison system, the Massachusetts Department of Correction (MADOC). METHODS: A retrospective cohort study of individuals with opioid use disorder who had an incarceration episode in MADOC during January 2015 to March 2019. The data source was the Massachusetts Public Health Data Warehouse, a multi-sector data platform that links individual-level data from multiple statewide datasets. We described patterns of MOUD receipt during the four weeks prior to and after an incarceration episode. Multivariable logistic regression models characterized predictors of post-incarceration MOUD receipt. RESULTS: In the male sample (n=691 incarcerations), from the pre- to post-incarceration periods, receipt of buprenorphine increased (14.3 % to 18.3 %), naltrexone increased (5.0 % to 10.5 %), and methadone decreased (4.7 % to 1.7 %). Similarly, in the female sample (n=892 incarcerations), from the pre- to post-incarceration periods, receipt of buprenorphine increased (10.3 % to 12.3 %, naltrexone increased (4.5 % to 9.3 %), and methadone decreased (5.0 % to 2.9 %). Much of the post-release naltrexone receipt occurred among participants in MADOC's pre-release naltrexone program. CONCLUSIONS: MOUD receipt was low but increased slightly in the post-incarceration period. This change was driven by increases in buprenorphine and naltrexone and despite decreases in methadone.

Insurance Instability for Patients With Opioid Use Disorder in the Year After Diagnosis.

Importance: Transitions in insurance coverage may be associated with worse health care outcomes. Little is known about insurance stability for individuals with opioid use disorder (OUD). Objective: To examine insurance transitions among adults with newly diagnosed OUD in the 12 months after diagnosis. Design, Setting, and Participants: Longitudinal cohort study using data from the Massachusetts Public Health Data Warehouse. The cohort includes adults aged 18 to 63 years diagnosed with incident OUD between July 1, 2014, and December 31, 2014, who were enrolled in commercial insurance or Medicaid at diagnosis; individuals diagnosed after 2014 were excluded from the main analyses due to changes in the reporting of insurance claims. Data were analyzed from November 10, 2022, to May 6, 2024. Exposure: Insurance type at time of diagnosis (commercial and Medicaid). Main Outcomes and Measures: The primary outcome was the cumulative incidence of insurance transitions in the 12 months after diagnosis. Logistic regression models were used to generate estimated probabilities of insurance transitions by insurance type and diagnosis for several characteristics including age, race and ethnicity, and whether an individual started medication for OUD (MOUD) within 30 days after diagnosis. Results: There were 20 768 individuals with newly diagnosed OUD between July 1, 2014, and December 31, 2014. Most individuals with newly diagnosed OUD were covered by Medicaid (75.4%). Those with newly diagnosed OUD were primarily male (67% in commercial insurance, 61.8% in Medicaid). In the 12 months following OUD diagnosis, 30.4% of individuals experienced an insurance transition, with adjusted models demonstrating higher transition rates among those starting with Medicaid (31.3%; 95% CI, 30.5%-32.0%) compared with commercial insurance (27.9%; 95% CI, 26.6%-29.1%). The probability of insurance transitions was generally higher for younger individuals than older individuals irrespective of insurance type, although there were notable differences by race and ethnicity. Conclusions and Relevance: This study found that nearly 1 in 3 individuals experience insurance transitions in the 12 months after OUD diagnosis. Insurance transitions may represent an important yet underrecognized factor in OUD treatment outcomes.

Target trial emulation for comparative effectiveness research with observational data: Promise and challenges for studying medications for opioid use disorder.

Medications for opioid use disorder (MOUD) increase retention in care and decrease mortality during active treatment; however, information about the comparative effectiveness of different forms of MOUD is sparse. Observational comparative effectiveness studies are subject to many types of bias; a robust framework to minimize bias would improve the quality of comparative effectiveness evidence. This paper discusses the use of target trial emulation as a framework to conduct comparative effectiveness studies of MOUD with administrative data. Using examples from our planned research project comparing buprenorphine-naloxone and extended-release naltrexone with respect to the rates of MOUD discontinuation, we provide a primer on the challenges and approaches to employing target trial emulation in the study of MOUD.

Trends in Fatal Opioid-Related Overdose in American Indian and Alaska Native Communities, 1999-2021.

INTRODUCTION: Opioid-related overdose mortality rates have increased sharply in the U.S. over the past two decades, and inequities across racial and ethnic groups have been documented. Opioid-related overdose trends among American Indian and Alaska Natives require further quantification and assessment. METHODS: Observational, U.S. population-based registry data on opioid-related overdose mortality between 1999 and 2021 were extracted in 2023 using ICD-10 codes from the U.S. Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research multiple cause of death file by race, Hispanic ethnicity, sex, and age. Segmented time series analyses were conducted to estimate opioid-related overdose mortality growth rates among the American Indian and Alaska Native population between 1999 and 2021. Analyses were performed in 2023. RESULTS: Two distinct time segments revealed significantly different opioid-related overdose mortality growth rates within the overall American Indian and Alaska Native population, from 0.36 per 100,000 (95% CI=0.32, 0.41) between 1999 and 2019 to 6.5 (95% CI=5.7, 7.31) between 2019 and 2021, with the most pronounced increase among those aged 24-44 years. Similar patterns were observed within the American Indian and Alaska Native population with Hispanic ethnicity, but the estimated growth rates were generally steeper across most age groups than across the overall American Indian and Alaska Native population. Patterns of opioid-related overdose mortality growth rates were similar between American Indian and Alaska Native females and males between 2019 and 2021. CONCLUSIONS: Sharp increases in opioid-related overdose mortality rates among American Indian and Alaska Native communities are evident by age and Hispanic ethnicity, highlighting the need for culturally sensitive fatal opioid-related overdose prevention, opioid use disorder treatment, and harm-reduction efforts. Future research should aim to understand the underlying factors contributing to these high mortality rates and employ interventions that leverage the strengths of American Indian and Alaska Native culture, including the strong sense of community.

Medication for Opioid Use Disorder After Serious Injection-Related Infections in Massachusetts.

Importance: Serious injection-related infections (SIRIs) cause significant morbidity and mortality. Medication for opioid use disorder (MOUD) improves outcomes but is underused. Understanding MOUD treatment after SIRIs could inform interventions to close this gap. Objectives: To examine rehospitalization, death rates, and MOUD receipt for individuals with SIRIs and to assess characteristics associated with MOUD receipt. Design, Setting, and Participants: This retrospective cohort study used the Massachusetts Public Health Data Warehouse, which included all individuals with a claim in the All-Payer Claims Database and is linked to individual-level data from multiple government agencies, to assess individuals aged 18 to 64 years with opioid use disorder and hospitalization for endocarditis, osteomyelitis, epidural abscess, septic arthritis, or bloodstream infection (ie, SIRI) between July 1, 2014, and December 31, 2019. Data analysis was performed from November 2021 to May 2023. Exposure: Demographic and clinical factors potentially associated with posthospitalization MOUD receipt. Main Outcomes and Measures: The main outcome was MOUD receipt measured weekly in the 12 months after hospitalization. We used zero-inflated negative binomial regression to examine characteristics associated with any MOUD receipt and rates of treatment in the 12 months after hospitalization. Secondary outcomes were receipt of any buprenorphine formulation, methadone, and extended-release naltrexone examined individually. Results: Among 8769 individuals (mean [SD] age, 43.2 [12.0] years; 5066 [57.8%] male) who survived a SIRI hospitalization, 4305 (49.1%) received MOUD, 5919 (67.5%) were rehospitalized, and 973 (11.1%) died within 12 months. Of those treated with MOUD in the 12 months after hospitalization, the mean (SD) number of MOUD initiations during follow-up was 3.0 (1.7), with 956 of 4305 individuals (22.2%) receiving treatment at least 80% of the time. MOUD treatment after SIRI hospitalization was significantly associated with MOUD in the prior 6 months (buprenorphine: adjusted odds ratio [AOR], 16.51; 95% CI, 13.81-19.74; methadone: AOR, 28.46; 95% CI, 22.41-36.14; or naltrexone: AOR, 2.05; 95% CI, 1.56-2.69). Prior buprenorphine (incident rate ratio [IRR], 1.17; 95% CI, 1.11-1.24) or methadone (IRR, 1.89; 95% CI, 1.79-2.01) use was associated with higher treatment rates after hospitalization, and prior naltrexone use (IRR, 0.86; 95% CI, 0.77-0.95) was associated with lower rates. Conclusions and Relevance: This study found that in the year after a SIRI hospitalization in Massachusetts, mortality and rehospitalization were common, and only half of patients received MOUD. Treatment with MOUD before a SIRI was associated with posthospitalization MOUD initiation and time receiving MOUD. Efforts are needed to initiate MOUD treatment during SIRI hospitalizations and subsequently retain patients in treatment.

Buprenorphine Prescribing Characteristics Following Relaxation of X-Waiver Training Requirements.

Importance: Local-level data are needed to understand whether the relaxation of X-waiver training requirements for prescribing buprenorphine in April 2021 translated to increased buprenorphine treatment. Objective: To assess whether relaxation of X-waiver training requirements was associated with changes in the number of clinicians waivered to and who prescribe buprenorphine for opioid use disorder and the number of patients receiving treatment. Design, Setting, and Participants: This serial cross-sectional study uses an interrupted time series analysis of 2020-2022 data from the HEALing Communities Study (HCS), a cluster-randomized, wait-list-controlled trial. Urban and rural communities in 4 states (Kentucky, Massachusetts, New York, and Ohio) with a high burden of opioid overdoses that had not yet received the HCS intervention were included. Exposure: Relaxation of X-waiver training requirements (ie, allowing training-exempt X-waivers) on April 28, 2021. Main Outcomes and Measures: The monthly number of X-waivered clinicians, X-waivered buprenorphine prescribers, and patients receiving buprenorphine were each summed across communities within a state. Segmented linear regression models to estimate pre- and post-policy change by state were used. Results: The number of individuals in 33 participating HCS communities included 347 863 in Massachusetts, 815 794 in Kentucky, 971 490 in New York, and 1 623 958 in Ohio. The distribution of age (18-35 years: range, 29.4%-32.4%; 35-54 years: range, 29.9%-32.5%; ≥55 years: range, 35.7%-39.3%) and sex (female: range, 51.1%-52.6%) was similar across communities. There was a temporal increase in the number of X-waivered clinicians in the pre-policy change period in all states, which further increased in the post-policy change period in each state except Ohio, ranging from 5.2% (95% CI, 3.1%-7.3%) in Massachusetts communities to 8.4% (95% CI, 6.5%-10.3%) in Kentucky communities. Only communities in Kentucky showed an increase in the number of X-waivered clinicians prescribing buprenorphine associated with the policy change (relative increase, 3.2%; 95% CI, 1.5%-4.9%), while communities in other states showed no change or a decrease. Similarly, only communities in Massachusetts experienced an increase in patients receiving buprenorphine associated with the policy change (relative increase, 1.7%; 95% CI, 0.8%-2.6%), while communities in other states showed no change. Conclusions and Relevance: In this serial cross-sectional study, relaxation of X-waiver training requirements was associated with an increase in the number of X-waivered clinicians but was not consistently associated with an increase in the number of buprenorphine prescribers or patients receiving buprenorphine. These findings suggest that training requirements may not be the primary barrier to expanding buprenorphine treatment.