Suicide within 1 year of non-fatal overdose: Risk factors and risk reduction with medications for opioid use disorder.

OBJECTIVE: Individuals with substance use disorders and overdoses have high risk of suicide death, but evidence is limited on the relationship between interventions following the initial overdose and subsequent suicide death. METHODS: National Medicare data were used to identify Medicare disability beneficiaries (MDBs) with inpatient or emergency care for non-fatal opioid overdoses from 2008 to 2016. Data were linked with National Death Index (NDI) to obtain dates and causes of death for the sample. Cox proportional hazards models estimated the associations between exposure to interventions (mechanical ventilation, MOUD) and suicide death. RESULTS: The sample (n = 81,654) had a suicide rate in the year following a non-fatal overdose of 566 per 100,000 person-years. Post-overdose MOUD was associated with an adjusted hazard ratio of 0.20 (95%CI: 0.05,0.85). Risk of suicide was elevated for those whose initial overdoses required mechanical ventilation as part of the treatment (aHR: 1.86, 95%CI:[1.48,2.34]). CONCLUSIONS: The year following a non-fatal opioid overdose is a very high-risk period for suicide among MDBs. Those receiving MOUD had an 80% reduction in the hazards of suicide, while those whose overdose treatment involved mechanical ventilation had 86% higher hazards of death by suicide. Our findings highlight the importance of psychiatric intervention in this high-risk population. Efforts are needed to initiate and retain more patients in MOUD.

Inhibition of Aurora-A/N-Myc Protein-Protein Interaction Using Peptidomimetics: Understanding the Role of Peptide Cyclization.

Using N-Myc61-89 as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N-Myc/Aurora-A protein-protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these - N-Myc73-94-N85C/G89C-mal - is shown to favour a more Aurora-A compliant binding ensemble in comparison to the linear wild-type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora-A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora-A surface. Taken together this work unveils the first orthosteric N-Myc/Aurora-A inhibitor and provides useful insights on the biophysical properties and thus design of constrained peptides, an attractive therapeutic modality.

Racial And Ethnic Disparities In Buprenorphine Receipt Among Medicare Beneficiaries, 2015-19.

We examined Medicare Part D claims from the period 2015-19 to identify state and national racial and ethnic disparities in buprenorphine receipt among Medicare disability beneficiaries with diagnosed opioid use disorder or opioid overdose. Racial and ethnic disparities in buprenorphine use remained persistently high during the study period, especially for Black beneficiaries, suggesting the need for targeted interventions and policies.

Racial/ethnic disparities in timely receipt of buprenorphine among Medicare disability beneficiaries.

BACKGROUND: Medicare disability beneficiaries (MDBs) have disproportionately high risk of opioid use disorder (OUD) and related harms given high rates of comorbidities and high-dose opioid prescribing. Despite this increased risk, little is known about timely receipt of medication for opioid use disorder (MOUD), including potential disparities by patient race/ethnicity or moderation by county-level characteristics. METHODS: National Medicare claims for a sample of MDBs with incident OUD diagnosis between March 2016 and June 2019 were linked with county-level data. Multivariable mixed effects Cox proportional hazards models estimated time (in days) to buprenorphine receipt within 180 days of incident OUD diagnosis. Primary exposures included individual-level race/ethnicity and county-level buprenorphine prescriber availability, percent non-Hispanic white (NHW) residents, and Social Deprivation Index (SDI) score. RESULTS: The sample (n=233,079) was predominantly White (72.3%), ≥45 years old (76.3%), and male (54.8%). Black (adjusted hazard ratio [aHR]=0.50; 95% CI, 0.47-0.54), Asian/Pacific Islander (aHR=0.54; 95% CI, 0.41-0.72), Hispanic/Latinx (aHR=0.81; 95% CI, 0.76-0.87), and Other racial/ethnic groups (aHR=0.75; 95% CI, 0.58-0.97) had a lower likelihood of timely buprenorphine than non-Hispanic white beneficiaries after adjusting for individual and county-level confounders. Timely buprenorphine receipt was positively associated with county-level buprenorphine prescriber availability (aHR=1.05; 95% CI, 1.04-1.07), percent non-Hispanic white residents (aHR=1.01; 95% CI, 1.00-1.01), and SDI (aHR=1.06; 95% CI, 1.01-1.10). CONCLUSIONS: Racial/ethnic disparities highlight the need to improve access to care for underserved groups. Implementing equity-focused quality and performance measures and developing interventions to increase office-based buprenorphine prescribing in predominantly minority race/ethnicity counties may reduce disparities in timely access to medication for OUD.

Audiometric and Otologic Findings in Children and Young Adults with Neurofibromatosis Type 1 and Plexiform Neurofibromas.

OBJECTIVES: To characterize otologic and audiologic manifestations in our NF1 cohort and explore the relationship between otologic and audiologic findings in a subset of patients with ear-related plexiform neurofibromas (PNs). METHODS: Audiologic and otologic clinical evaluations were conducted on 102 patients with NF1 in a natural history study (5-45 years; M = 14.4 years; Mdn = 14). Testing included pure tone and speech audiometry, middle ear function, neurodiagnostic auditory brainstem response (ABR), auditory processing, and MRIs of the head and neck region. Patients referred to this study had an overall higher incidence and burden of PNs than the overall NF1 population. RESULTS: The majority of subjects in this cohort had normal hearing sensitivity (81%) and normal middle ear function (78%). Nineteen participants had hearing loss that ranged in degree from mild to profound, with the majority in the mild range. Hearing loss was twice as likely to be conductive than sensorineural. In patients with ear-related PNs (n = 12), hearing loss was predominantly conductive (60%). Seventy-five percent of ears with PNs had atypical tympanometric tracings that could not be characterized by the classic categories. In all 20 patients with a PN in the temporal bone, the ear canal was affected, and the PNs often extended to the surrounding soft tissue regions. CONCLUSIONS: People with NF1-related PNs in the temporal bone and adjacent skull base should have audiometric and otologic monitoring. Addressing hearing concerns should be part of routine clinical evaluations in patients with NF1. Magnetic resonance imaging (MRI) should be performed in patients with NF1 who have hearing loss. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2770-2778, 2023.

Pre and Post-Lockdown Cesarean Deliveries and Perinatal Quality Indicators During the COVID-19 Pandemic.

We examined statewide perinatal quality indicators: nulliparous singleton term vertex cesarean births (NTSV) or low risk cesarean births, and non-medically indicated early term delivery (NMETD) rates during COVID-19 pandemic pre-lockdown (1/1/2019 to 3/23/2020) and post-lockdown (after 3/23/2020). Interrupted time-series analyses were used to examine the effects of the COVID-19 pandemic on these indicators. We observed a statistically significant increase in NTSV cesarean rates, 4.4% (95%CI: 1.3,7.4) immediately after lockdown, and a decrease in NMETD rate, 1.6% (95%CI: -2.5,-0.7). We observed an increase (0.3%; 95%CI: 0.0,0.6) in the slope (i.e., trend change) of NTSV rates post-lockdown and a decrease (-0.2%; 95%CI: -0.3,-0.1) in the slope of NMETD rates. Results suggest that the COVID-19 pandemic had an immediate effect on perinatal quality indicators in Delaware, with gradual return to pre-pandemic rates as the pandemic continued. In addition to emergency preparedness planning, hospital monitoring of perinatal quality indicators might improve obstetrical care during public health emergencies.

Racial and Ethnic Disparities in Buprenorphine and Extended-Release Naltrexone Filled Prescriptions During the COVID-19 Pandemic.

Importance: COVID-19 disrupted delivery of buprenorphine and naltrexone treatment for opioid use disorder (OUD), and during the pandemic, members of racial and ethnic minority groups experienced increased COVID-19 and opioid overdose risks compared with White individuals. However, whether filled buprenorphine and naltrexone prescriptions varied across racial and ethnic groups during the COVID-19 pandemic remains unknown. Objective: To investigate whether disruptions in filled buprenorphine and naltrexone prescriptions differed by race and ethnicity and insurance status or payer type. Design, Setting, and Participants: This cross-sectional study used retail pharmacy claims from May 2019 to June 2021 from the Symphony Health database, which includes 92% of US retail pharmacy claims, with race and ethnicity data spanning all insurance status and payer categories. Interrupted time series were used to estimate levels and trends of dispensed buprenorphine and naltrexone prescriptions before and after pandemic onset. Included individuals were those who filled buprenorphine and extended-release naltrexone prescriptions. Data were analyzed from July 2021 through March 2022. Main Outcomes and Measures: Weekly rates of dispensed buprenorphine and extended-release naltrexone prescription fills per 1000 patients and proportion of longer (ie, ≥14 days' supply) buprenorphine prescription fills were calculated. Analyses were stratified by patient race and ethnicity and further by insurance status and payer type for White and Black patients. Results: A total of 1 556 860 individuals who filled buprenorphine prescriptions (4359 Asian [0.3%], 94 657 Black [6.1%], 55 369 Hispanic [3.6%], and 664 779 White [42.7%]) and 127 506 individuals who filled extended-release naltrexone prescriptions (344 Asian [0.3%], 8186 Black [6.4%], 5343 Hispanic [4.2%], and 53 068 White [41.6%]) from May 6, 2019, to June 5, 2021, were analyzed. Prepandemic increases in buprenorphine fill rate flattened for all groups after COVID-19 onset (30.5 percentage point difference in trend; P < .001) compared with prepandemic trends. Significant level decreases in buprenorphine fills (ranging from 2.5% for Black patients; P = .009 to 4.0% for Hispanic patients; P = .009) at pandemic onset were observed for members of racial and ethnic minority groups but not White patients. At pandemic onset, rate of buprenorphine fills decreased in level for Medicare and cash-paying patients but with greater decreases for Black patients (Medicare: 10.0%; P < .001; cash: 20.0%; P < .001) than White patients (Medicare: 3.5%; P = .004; cash: 15.0%; P < .001). No decreases were found among Medicaid patients. Unlike buprenorphine, extended-release naltrexone had uniform level (from 10.0% for White patients with private insurance; P < .001 to 23.3% for Black patients with Medicare; P < .001) and trend (from 15.5 percentage points for White patients with Medicaid; P = .001 to 52.0 percentage points for Black patients with private insurance; P < .001) decreases across groups. Conclusions and Relevance: This study found that the COVID-19 pandemic was associated with immediate decreases in filled buprenorphine prescriptions by members of racial and ethnic minority groups but not White individuals. These findings suggest that members of racial and ethnic minority groups had larger losses in buprenorphine access during the pandemic across payer types.

Acceptance of medications for opioid use disorder in recovery housing programs in Missouri.

BACKGROUND: Recovery housing plays an important role in supporting individuals in their recovery by building recovery capital and providing stable living environments; however, the extent to which medications for opioid use disorder (MOUD), the gold standard for OUD treatment, are accepted in recovery housing settings is unclear. The purpose of this study, as part of a larger statewide evaluation of Missouri recovery homes, was to identify the extent to which Missouri recovery houses were accepting of methadone, buprenorphine, and naltrexone as well as the extent to which the acceptance of each medication was linked to whether the recovery home encouraged tapering off MOUDs. METHODS: Sixty-four recovery housing managers and/or staff, out of 66 eligible recovery homes in Missouri completed the survey. RESULTS: Results indicated that methadone was the least accepted medication for long-term use followed by buprenorphine and then naltrexone. Recovery houses that had significantly lower overall acceptance of methadone encouraged tapering; however, the overall acceptance for buprenorphine and naltrexone was not significantly related to the encouragement of tapering off MOUDs. CONCLUSION: This work highlights the need to develop reliable instruments to measure and assess MOUD-capable recovery homes and to increase knowledge and acceptance of MOUD within recovery home settings.

Assessing Technical Assistance Needs among Recovery Residence Operators in the United States.

Recovery support services such as recovery housing assist individuals with increasing their access to social support, employment services, and systems of care. Lack of evidence-based practices and calls for increased oversight of these settings suggests a growing need for technical assistance and training for recovery residence owners and staff, yet little is known about their areas of greatest need for technical assistance. We developed and administered a survey to assess the technical assistance needs of recovery housing operators in the United States using a convenience sample of individuals who own or operate a recovery residence (N = 376). A total of 77 owners/operators completed the survey (20% response rate), representing urban, suburban, and rural communities. Differences were observed between number of owned residences: owners/operators of a single residence were interested in technical assistance on house-specific policies and linkage to established systems of care, whereas owners/operators of multiple residences were interested in technical assistance on building financial sustainability and incorporation of best practices into their recovery residences. As an increasing number of states move to implement voluntary certification or licensing for recovery residences, targeted training and technical assistance to owners/operators will facilitate the successful adoption of recovery residence best practices and quality standards.

Association of facility characteristics and substance use disorder outcomes at discharge from residential treatment.

INTRODUCTION: Individuals with substance use disorder (SUD) may benefit from services and supports delivered in residential settings. Prior research in this area has primarily focused on individual-level factors that affect outcomes, with little focus on the relationship between facility-level characteristics and treatment outcomes. METHODS: Administrative data from 2713 individuals with an index enrollment in publicly funded residential treatment in Massachusetts during 2015 were linked with facility-level survey data from 33 treatment providers. This study conducted multilevel linear and logisitc regression analysis, adjusting for resident demographic, socioeconomic, and substance use history and severity, to examine relationships between facility-level characteristics, treatment duration and completion, and housing and employment status at discharge. RESULTS: Residents stayed longer when they made and enforced rules (ß = 30.22, p = 0.006). Residents were less likely to complete treatment as the number of non-clinical services increased (aOR = 0.918, p = 0.029), or in facilities where residents ate together family style (aOR = 0.485, p = 0.039). Being employed at discharge was more likely when house meetings were held less than once per week (aOR = 3.37, p = 0.005) and less likely when held more than once per week (aOR = 0.385, p = 0.038). CONCLUSION: Overall, increased resident governance and fewer contingencies for successful treatment participation were associated with positive treatment outcomes. Future research should examine the internal processes of residential settings, including peer-to-peer interactions, to better understand how within-residence features affect outcomes.

The evolutionary origins of peroxynitrite signalling.

Peroxynitrite is a reactive intermediate formed in vivo through uncatalysed reaction of superoxide and nitric oxide radicals. Despite significant interest in detecting peroxynitrite in vivo and understanding its production, little attention has been given to the evolutionary origins of peroxynitrite signalling. Herein we focus on two enzymes that are key to the biosynthesis of superoxide and nitric oxide, NADPH oxidase 5 (NOX5) and endothelial nitric oxide synthase (eNOS), respectively. Multiple sequence alignments of both enzymes including homologues from all domains of life, coupled with a phylogenetic analysis of NOX5, suggest eNOS and NOX5 are present in animals as the result of horizontal gene transfer from ancestral cyanobacteria to ancestral eukaryotes. Therefore, biochemical studies from other laboratories on a NOX5 homologue in Cylindrospermum stagnale and an eNOS homologue in Synechococcus sp. PCC 7335 are likely to be of relevance to human NOX5 and eNOS and to the production of superoxide, nitric oxide and peroxynitrite in humans.

Selective Affimers Recognise the BCL-2 Family Proteins BCL-xL and MCL-1 through Noncanonical Structural Motifs*.

The BCL-2 family is a challenging group of proteins to target selectively due to sequence and structural homologies across the family. Selective ligands for the BCL-2 family regulators of apoptosis are useful as probes to understand cell biology and apoptotic signalling pathways, and as starting points for inhibitor design. We have used phage display to isolate Affimer reagents (non-antibody-binding proteins based on a conserved scaffold) to identify ligands for MCL-1, BCL-xL , BCL-2, BAK and BAX, then used multiple biophysical characterisation methods to probe the interactions. We established that purified Affimers elicit selective recognition of their target BCL-2 protein. For anti-apoptotic targets BCL-xL and MCL-1, competitive inhibition of their canonical protein-protein interactions is demonstrated. Co-crystal structures reveal an unprecedented mode of molecular recognition; where a BH3 helix is normally bound, flexible loops from the Affimer dock into the BH3 binding cleft. Moreover, the Affimers induce a change in the target proteins towards a desirable drug-bound-like conformation. These proof-of-concept studies indicate that Affimers could be used as alternative templates to inspire the design of selective BCL-2 family modulators and more generally other protein-protein interaction inhibitors.

A Case Study of Eukaryogenesis: The Evolution of Photoreception by Photolyase/Cryptochrome Proteins.

Eukaryogenesis, the origin of the eukaryotes, is still poorly understood. Herein, we show how a detailed all-kingdom phylogenetic analysis overlaid with a map of key biochemical features can provide valuable clues. The photolyase/cryptochrome family of proteins are well known to repair DNA in response to potentially harmful effects of sunlight and to entrain circadian rhythms. Phylogenetic analysis of photolyase/cryptochrome protein sequences from a wide range of prokaryotes and eukaryotes points to a number of horizontal gene transfer events between ancestral bacteria and ancestral eukaryotes. Previous experimental research has characterised patterns of tryptophan residues in these proteins that are important for photoreception, specifically a tryptophan dyad, a canonical tryptophan triad, an alternative tryptophan triad, a tryptophan tetrad and an alternative tetrad. Our results suggest that the spread of the different triad and tetrad motifs across the kingdoms of life accompanied the putative horizontal gene transfers and is consistent with multiple bacterial contributions to eukaryogenesis.

Supporting individuals using medications for opioid use disorder in recovery residences: challenges and opportunities for addressing the opioid epidemic.

Full and partial opioid agonists and opioid antagonist medications play an important role in containing the opioid epidemic. However, these medications have not been used to their full extent. Recovery support services, such as recovery residences (RRs), also play a key role. RRs may increase an individual's recovery capital, facilitate social support for abstinence, and foster a sense of community among residents. These processes may be critical for individuals with opioid use disorder (OUD). In combination these two recovery pathways have the potential to enhance one another and improve outcomes among residents with OUD. Barriers to doing so have resulted in a limited supply of residences that can support residents using opioid agonist and antagonist medications. This perspective describes key interpersonal and structural barriers to medication use among individuals with an OUD seeking support from a recovery residence and discusses measures for reducing these barriers. These measures include workforce development to address stigma and attitudinal barriers and enhancing residence capability to ensure resident safety and reduce potential diversion. The perspective also highlights the need for additional research to facilitate the identification of best practices to improve outcomes among residents treated with medications living in recovery residences.

Race/Ethnicity, Community of Residence, and DUI Arrest After Beginning Treatment for an Alcohol Use Disorder.

The purpose of this study was to examine whether racial/ethnic disparities in post-treatment arrests for driving under the influence (DUI) exist among clients receiving outpatient treatment for an alcohol use disorder (AUD) and to assess whether community characteristics were associated with this outcome. The sample included adults with an AUD entering publicly funded outpatient treatment in Washington State in 2012. Treatment data were linked with criminal justice and US Census data. Multilevel time-to-event analysis was employed to answer the research questions. Key independent variables included client race/ethnicity, community-level economic disadvantage, and racial/ethnic composition of the community. Latino clients and clients residing in communities with a higher proportion of Black residents had higher hazards of a DUI arrest post-treatment admission. Future research should examine whether disparities in DUI arrests are related to differences in treatment effectiveness or other factors (e.g., inequities in law enforcement) so that these disparities can be addressed.

Disparities in Criminal Justice Outcomes After Beginning Treatment for Substance Use Disorders: The Influence of Race/Ethnicity and Place.

OBJECTIVE: This study examined whether racial/ethnic disparities exist in posttreatment arrests and assessed the extent to which community characteristics account for such disparities. METHOD: Administrative data on clients (N = 10,529) receiving publicly funded services in Washington State were linked with criminal justice and census data. Multilevel survival models were used for two outcomes measuring time (in days) to any arrest and to any substance-related arrest. Community characteristics included a factor measuring community economic disadvantage and the proportions of residents in the client's residential census tract who were Black, Latino, or American Indian/Alaskan Native. RESULTS: When we controlled for age, sex, substance use, referral source, and prior criminal justice involvement, Black clients (hazard ratio [HR] = 1.47, p < .01) had a higher hazard of any arrest compared with White clients, and Black (HR = 1.27, p < .05) and Latino (HR = 1.20, p < .05) clients had a higher hazard of a substance-related arrest. Clients living in census tracts with a higher proportion of Black residents had a higher hazard of any arrest (HR = 1.25, p < .01) as well as substance-related arrests (HR = 1.39, p < .01). Community characteristics did not account for racial/ethnic disparities in arrests but provided an independent effect. CONCLUSIONS: Disparities in arrest outcomes are influenced by both individual- and community-level factors; therefore, strategies for reducing disparities in this treatment outcome should be implemented at both levels.

A catalytic protein-proteomimetic complex: using aromatic oligoamide foldamers as activators of RNase S.

Foldamers are abiotic molecules that mimic the ability of bio-macromolecules to adopt well-defined and organised secondary, tertiary or quaternary structure. Such templates have enabled the generation of defined architectures which present structurally defined surfaces that can achieve molecular recognition of diverse and complex targets. Far less explored is whether this mimicry of nature can extend to more advanced functions of biological macromolecules such as the generation and activation of catalytic function. In this work, we adopt a novel replacement strategy whereby a segment of protein structure (the S-peptide from RNase S) is replaced by a foldamer that mimics an α-helix. The resultant prosthetic replacement forms a non-covalent complex with the S-protein leading to restoration of catalytic function, despite the absence of a key catalytic residue. Thus this functional protein-proteomimetic complex provides proof that significant segments of protein can be replaced with non-natural building blocks that may, in turn, confer advantageous properties.

Changes in Residential Substance Use Treatment Service Access Resulting From Recent Medicaid Section 1115 Waivers.

Medicaid stands to play a significant role in addressing the needs of individuals with a substance use disorder; however, many state Medicaid programs do not cover a full continuum of care. A growing number of states are taking advantage of Section 1115 demonstration waivers to augment their covered benefits, including experimenting with financing residential treatment services that previously were not eligible for reimbursement. Concerns over potential overuse of these services or increased spending due to this service expansion may be tempered by complementary delivery system transformation focused on reining in costs and improving care quality.

Identification of a cyanobacterial aldehyde dehydrogenase that produces retinoic acid in vitro.

Retinoic acid signalling is generally considered to be of animal origin. Recently, retinoic acid has been identified in cyanobacteria, yet no mechanism for its production has been identified. Here, we characterise for the first time a cyanobacterial aldehyde dehydrogenase that produces retinoic acid in vitro. Our computational studies suggest that the cyanobacterial aldehyde dehydrogenase resembles an ancestor of both eukaryotic aldehyde dehydrogenase 1 and aldehyde dehydrogenase 2. The Chlorogloeopsis fritschii aldehyde dehydrogenase described here may find applications in synthetic production of retinoic acid as well as contributing to our understanding of retinoid synthesis in cyanobacteria.

Correction to: Disparities in the Treatment of Substance Use Disorders: Does Where You Live Matter?

The professional degree of co-author Kevin Campbell is incorrect. It should be "DrPH" and not "PhD".