ZFP423 controls EBF2 coactivator recruitment and PPARγ occupancy to determine the thermogenic plasticity of adipocytes.

Energy-storing white adipocytes maintain their identity by suppressing the energy-burning thermogenic gene program of brown and beige adipocytes. Here, we reveal that the protein-protein interaction between the transcriptional coregulator ZFP423 and brown fat determination factor EBF2 is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423-EBF2 protein interaction through CRISPR-Cas9 gene editing triggers widespread "browning" of WAT in adult mice. Mechanistically, ZFP423 recruits the NuRD corepressor complex to EBF2-bound thermogenic gene enhancers. Loss of adipocyte Zfp423 induces an EBF2 NuRD-to-BAF coregulator switch and a shift in PPARγ occupancy to thermogenic genes. This shift in PPARγ occupancy increases the antidiabetic efficacy of the PPARγ agonist rosiglitazone in obesity while diminishing the unwanted weight-gaining effect of the drug. These data indicate that ZFP423 controls EBF2 coactivator recruitment and PPARγ occupancy to determine the thermogenic plasticity of adipocytes and highlight the potential of therapeutically targeting transcriptional brakes to induce beige adipocyte biogenesis in obesity.

A fixation method to preserve cultured cell cytonemes facilitates mechanistic interrogation of morphogen transport.

During development, extracellular cues guiding cell fate determination are provided by morphogens. One mechanism by which morphogens are proposed to traverse extracellular space is by traveling along specialized filopodia called cytonemes. These cellular highways extend between signal-producing and -receiving cells to enable direct morphogen delivery. Although genetic studies support cytoneme involvement in morphogen transport, mechanistic insight into how they are regulated is limited owing to technical challenges associated with performing cell biological analysis of the delicate filopodial structures. Here, we introduce a fixation method whereby cultured cell cytonemes can be preserved for imaging studies, allowing investigation of cytoneme regulation using standard cell biological techniques. Using this method, we examined Hedgehog-containing cytonemes and identified a role for the Hedgehog deployment protein Dispatched in cytoneme stabilization. We demonstrate that Hedgehog and Dispatched colocalize in cytonemes, and that cholesterol-modified Hedgehog acts through Dispatched to increase cytoneme occurrence. Live imaging suggests that this occurs through Dispatched-mediated slowing of cytoneme retraction rates. Dispatched-induced cytoneme modulation was recapitulated in wing imaginal discs of transgenic Drosophila, providing evidence that cultured cell cytoneme analysis is predictive of in vivo functionality.

Perceptions of Patient-Centered Care among First-Year Medical Students.

Phenomenon: Teaching patient-centered care (PCC) is a key component of undergraduate medical curricula. Prior frameworks of PCC describe multiple domains of patient-centeredness, ranging from interpersonal encounters to systems-level issues. Medical students' perceptions of PCC are thought to erode as they progress through school, but little is known about how students view PCC toward the beginning of training. This study explores the perceptions of PCC among 1st-year medical students to inform curricular development and evaluation. Approach: Medical students participated in semistructured, in-person interviews within 4 months of starting medical school as part of a longitudinal study. Transcripts were analyzed using a grounded theory approach and the constant comparative method to describe responses and characterize emergent themes. Transcripts were reviewed to compare codes and compile a final codebook. Findings: Thirty-eight students completed interviews. Students provided heterogeneous definitions of PCC, including perceptions that PCC is implicit and obvious. Many students were unable to provide a concrete definition of PCC, juxtaposing PCC with other priorities such as profit- or physician-centered care, whereas others thought the term was jargon. Some participants defined PCC as upholding patient values using hypothetical examples centered around physician behavior. Insights: Although students appeared to enter medical school with a range of perceptions about PCC, many of their descriptions were limited and only scratch the surface of existing frameworks. Rather than their perceptions of PCC eroding during medical school, students may never fully develop a foundational understanding of PCC. Our findings reinforce the need for authentic, clinically experiential learning opportunities that promote PCC from the earliest stages of medical education.

Functional Divergence in the Role of N-Linked Glycosylation in Smoothened Signaling.

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice.

The small GTPase Rap1 is a modulator of Hedgehog signaling.

During development, the evolutionarily conserved Hedgehog (Hh) morphogen provides instructional cues that influence cell fate, cell affinity and tissue morphogenesis. To do so, the Hh signaling cascade must coordinate its activity with other morphogenetic signals. This can occur through engagement of or response to effectors that do not typically function as core Hh pathway components. Given the ability of small G proteins of the Ras family to impact cell survival, differentiation, growth and adhesion, we wanted to determine whether Hh and Ras signaling might intersect during development. We performed genetic modifier tests in Drosophila to examine the ability of select Ras family members to influence Hh signal output, and identified Rap1 as a positive modulator of Hh pathway activity. Our results suggest that Rap1 is activated to its GTP-bound form in response to Hh ligand, and that the GTPase exchange factor C3G likely contributes to this activation. The Rap1 effector Canoe (Cno) also impacts Hh signal output, suggesting that a C3G-Rap1-Cno axis intersects the Hh pathway during tissue morphogenesis.

"I want to stay here": Patient and staff perspectives on transitioning from a low-threshold buprenorphine program to clinic-based care.

BACKGROUND: The Project Connections At Re-Entry (PCARE) Van is a low-threshold buprenorphine program operating outside the Baltimore City Detention Center. Like other low-threshold programs, PCARE seeks to engage a vulnerable population in care, stabilize patients, then transition patients to longer-term care; however, <10% of patients transition to clinic-based buprenorphine treatment. Our goal was to better understand these low transition rates and center patient perspectives in discussion of broader low-threshold program design. METHODS: From December 2022 to June 2023, semi-structured interviews were conducted with 20 former and current PCARE patients and 6 staff members. We used deductive and inductive coding followed by thematic content analysis to identify themes around treatment experiences and care preferences. RESULTS: There were strong preferences among current and former patients for continuing buprenorphine treatment at the PCARE Van. Several themes emerged from the data that explained patient preferences, including both advantages to continuing care at the van (preference for continuity, feeling respected by the program's structure and philosophy) and disadvantages to transitioning to a clinic (perceived harms associated with rigid or punitive care models). Staff noted limited program capacity, and patients expressed that if needed, they would transition to a clinic for altruistic reasons. Staff expressed varied perspectives on low-threshold care, emphasizing both larger systems factors, as well as beliefs about individual patient responsibility. CONCLUSIONS: While many low-threshold care settings are designed as transitional bridge models, this research highlights patient preference for long-term care at low-threshold programs and supports efforts to adapt low-threshold models to be sustainable as longitudinal care.

Abdominoplasty in the Presence of a Stoma for Functional and Aesthetic Indications.

Background: Abdominoplasty is widely available; however, patients with abdominal stomas appear to be relatively undertreated. Apprehension to offer abdominoplasty in the presence of a stoma may be secondary to the fear of surgical site infection and stoma compromise. Objectives: To demonstrate the feasibility and safety of abdominoplasty in the presence of an abdominal stoma for both functional and aesthetic indications and to define perioperative protocols to reduce the risk of surgical site infection in this patient population. Methods: The authors present 2 patients with stomas who underwent abdominoplasty. Patient 1 was a 62-year-old female with a history of urostomy formation and weight loss. She had a fold of skin overhanging her ostomy site, making it difficult to maintain a seal on her urostomy bag. She underwent fleur-de-lis abdominoplasty and urostomy revision. Patient 2 was a 43-year-old female with a history of end ileostomy formation, who requested cosmetic abdominoplasty to address postpartum abdominal changes; she had no functional stoma-related complaints. Abdominoplasty, flank liposuction, and ileostomy revision were performed. Results: Both patients were satisfied with their aesthetic and functional outcomes. There were no complications and no instances of stoma compromise. At follow-up, Patient 1 reported a complete amelioration of her urosotomy appliance issues. Conclusions: Abdominoplasty may confer both functional and aesthetic benefits to patients with abdominal stomas. The authors present peri- and intraoperative protocols, both to prevent stoma compromise and to reduce the risk of surgical site infection. The presence of a stoma does not appear to be an absolute contraindication to cosmetic abdominoplasty.

Higher buprenorphine dose associated with increased treatment retention at low threshold buprenorphine clinic: A retrospective cohort study.

INTRODUCTION: Controversy exists regarding effective sublingual buprenorphine dosing for treatment of opioid use disorder (OUD), leading to dose caps of 16 mg per day. The Project Connections at Re-Entry (PCARE) program is a low-threshold buprenorphine clinic that provides medication for OUD to vulnerable populations in Baltimore City. OBJECTIVES: To compare retention in care based on treatment dose of buprenorphine, and to examine associated population characteristics. METHODS: This analysis includes clinical patients who received buprenorphine treatment at PCARE between January and July 2021. The study categorized patients into two dosing groups (16 mg or >16 mg). We conducted chi-square tests of independence for categorical variables and independent sample t-tests for continuous variables to evaluate any significant differences in demographic and clinical characteristics by dosing category. To examine differences in 30- and 90-day retention, we conducted multivariable logistic regression analyses with the outcome variable defined as successful retention (at 30 and 90 days, respectively) controlling for demographic and clinical characteristics. RESULTS: In the study period, 566 patients received buprenorphine treatment at the PCARE van. Patients were primarily male (70.9 %), Black (89.4 %), had a mean age of 46.3 years (SD = 11.5), and a mean opioid use of 22.1 years (SD = 13.5). The majority had previous criminal justice involvement (73.9 %), Medicaid insurance coverage (75.4 %), and were unemployed (69.6 %). Nearly half of the sample had reported a previous overdose event (48.4 %). The study found no significant demographic differences between patients receiving 16 mg of buprenorphine per day compared to patients receiving >16 mg. Patients receiving >16 mg had significantly higher rates of treatment retention at 30 and 90 days: 95.4 % vs 86.7 % (p = 0.001), and 82.7 % vs. 67.6 % (p < 0.001) than those receiving 16 mg, respectively. In a multivariable logistic regression controlling for demographic and drug use characteristics, odds of 30-day (Adjusted Odds Ratio [AOR] = 3.98, 95 % Confidence Interval [CI] = 1.92, 8.74, p < 0.001) and 90-day retention (AOR = 2.56, 95 % CI = 1.55, 4.22, p < 0.001) were greater among patients receiving >16 mg daily compared to 16 mg. CONCLUSIONS: In this study examining patients with OUD in a low-threshold buprenorphine clinic, we observed higher rates of treatment retention with buprenorphine doses >16 mg.

Anticipated Barriers to Sustained Engagement in Treatment With Medications for Opioid Use Disorder After Release From Incarceration.

BACKGROUND: Although the burden of opioid use disorder is disproportionately high among persons who are incarcerated, medications for opioid use disorder are often unavailable in correctional settings. The Rhode Island Department of Corrections provides all 3 classes of medications for opioid use disorder to clinically eligible persons who are incarcerated. Despite a decrease in fatal overdoses among persons with recent criminal legal system involvement since the program's implementation, barriers to continued engagement in treatment after release from incarceration still exist. METHODS: We conducted 40 semistructured, qualitative interviews with people who were incarcerated and enrolled in the comprehensive medications for opioid use disorder program at the Rhode Island Department of Corrections. Analysis applied a general, inductive approach using NVivo 12. RESULTS: Participants discussed barriers to treatment engagement before incarceration, as well as anticipated barriers to medications to treat opioid use disorder continuation after release from incarceration. Structural factors including housing, health insurance, transportation, and the treatment program structure, as well as social factors such as social support networks were perceived to influence retention in medications to treat opioid use disorder post-release. CONCLUSION: Our findings suggest that people with opioid use disorder who are incarcerated encounter unique challenges upon community reentry. Addressing structural factors that pose barriers to post-release engagement is essential to sustaining retention. We recommend utilization of peer recovery specialists to alleviate some of the stress of navigating the structural barriers identified by participants.

Treatment preference for opioid use disorder among people who are incarcerated.

INTRODUCTION: The devastating overdose crisis remains a leading cause of death in the United States, especially among individuals involved in the criminal legal system. Currently, three classes (opioid agonist, partial agonist-antagonist, and antagonist) of FDA-approved medications for opioid use disorder (MOUD) exist, yet few correctional settings offer any medication treatment for people who are incarcerated. Facilities that do often provide only one medication. METHODS: We conducted 40 semi-structured qualitative interviews with individuals receiving MOUD incarcerated at the Rhode Island Department of Corrections. RESULTS: Results from this study indicate that people who are incarcerated have preferences for certain types of MOUD. Individuals' preferences were influenced by medication side effects, route of administration, delivery in the community, and stigma. CONCLUSION: MOUD programs in the community and in correctional settings should use a patient-centered approach that allows choice of medication by offering all FDA-approved MOUD treatment options.

Changes In Health Services Use After Receipt Of Medications For Opioid Use Disorder In A Statewide Correctional System.

To decrease opioid overdose mortality, prisons and jails in the US are increasingly offering medications for opioid use disorder (OUD) to incarcerated people. It is unknown how receipt of these medications in a correctional setting affects health services use after release. In this article we analyze changes in postrelease health care use after the implementation of a statewide medications for OUD program in the unified jail and prison system of the Rhode Island Department of Corrections. Using Medicaid claims data, we examined individual health care use in the community before and after receipt of medications for OUD while incarcerated. We found that inpatient admissions did not change, emergency department visits decreased, and both nonacute outpatient services and pharmacy claims increased after people received medications for OUD while incarcerated. There was no change in total health care costs paid by Medicaid. Our findings provide evidence that people's use of health care services paid for by Medicaid did not increase after they started medications for OUD in correctional settings. Given the frequent interaction of people with OUD with the criminal justice system, offering evidence-based treatment of OUD in correctional settings is an important opportunity to initiate addiction treatment.

Fentanyl-related overdose during incarceration: a comprehensive review.

BACKGROUND: Fentanyl and related compounds have recently saturated the illicit drug supply in the United States, leading to unprecedented rates of fatal overdose. Individuals who are incarcerated are particularly vulnerable, as the burden of opioid use disorder is disproportionately higher in this population, and tolerance generally decreases during incarceration. METHODS: We conduct a systematic search for publications about fentanyl overdoses during incarceration in PubMed and PsycINFO, as well as lay press articles in Google, from January 1, 2013 through March 30th, 2021. RESULTS: Not a single fentanyl overdose was identified in the medical literature, but 90 overdose events, comprising of 76 fatal and 103 nonfatal fentanyl overdoses, were identified in the lay press. Among the 179 overdoses, 138 occurred in jails and 41 occurred in prisons, across the country. CONCLUSIONS: Fentanyl-related overdoses are occurring in correctional facilities with unknown but likely increasing frequency. In addition to the need for improved detection and reporting, immediate efforts to 1) increase understanding of the risks of fentanyl and how to prevent and treat overdose among correctional staff and residents, 2) ensure widespread prompt availability of naloxone and 3) expand the availability of medications to treat opioid use disorder for people who are incarcerated will save lives.

Source specific PM2.5 associated with heart rate variability in the elderly with coronary heart disease: A community-based panel study.

There is increasingly concern that PM2.5 constituents play a significant role in PM2.5-related cardiovascular outcomes. However, little is known about the associations between specific constituents of PM2.5 and risk for cardiovascular health. To evaluate the exposure to specific chemicals of PM2.5 from various sources and their cardiac effects, a longitudinal investigation was conducted with four repeated measurements of elderly participants' HRV and PM2.5 species in urban Beijing. Multiple chemicals in PM2.5 (metals, ions and PAHs) were characterized for PM2.5 source apportionment and personalized exposure assessment. Five sources were finally identified with specific chemicals as the indicators: oil combustion (1.1%, V & PAHs), secondary particle (11.3%, SO42- & NO3-), vehicle emission (1.2%, Pd), construction dust (28.7%, Mg & Ca), and coal combustion (57.7%, Se & As). As observed, each IQR increase in exposure to oil combustion (V), vehicle emission (Pd), and coal combustion (Se) significantly decreased rMSSD by 13.1% (95% CI: -25.3%, -1.0%), 27.4% (95% CI: -42.9%, -7.6%) and 24.7% (95% CI: -39.2%, -6.9%), respectively, while those of PM2.5 mass with decreases of rMSSD by 11.1% (95% CI: -19.6%, -1.9%) at lag 0. Elevated exposures to specific sources/constituents of PM2.5 disrupt cardiac autonomic function in elderly and have more adverse effects than PM2.5 mass. In the stratified analysis, medication and gender modify the associations of specific chemicals from variable sources with HRV. The findings of this study provide evidence on the roles of influential constituents of ambient air PM2.5 and their sources in terms of their adverse cardiovascular health effects.

Pre-exposure prophylaxis awareness and interest among participants in a medications for addiction treatment program in a unified jail and prison setting in Rhode Island.

People who are incarcerated are at increased risk for HIV (human immunodeficiency virus) acquisition upon release, and one possible intervention for prevention is the use of pre-exposure prophylaxis (PrEP) upon release. The present study assessed HIV risk perceptions as well as PrEP awareness and interest among 39 people who were incarcerated and enrolled in a structured Medication for Addiction Treatment (MAT) program at the Rhode Island Department of Corrections using semi-structured, qualitative interviews. Analysis was conducted using a generalized, inductive method in NVivo 12. While PrEP awareness was low across the study sample, some participants were interested in PrEP uptake or learning more about PrEP after they were provided with an overview of it. PrEP interest strongly related to current perceived HIV risk. Potential barriers included side effects, adherence, and reluctance to take medications in general. MAT programs for people who are criminal justice (CJ) involved may serve as useful linkage spaces to PrEP information, access, and retention.

Brief video intervention to improve attitudes throughout medications for opioid use disorder in a correctional setting.

OBJECTIVES: Medications for opioid use disorder (MOUD) in the criminal justice setting is an effective way to address opioid use disorder and prevent associated deaths in the community. The Rhode Island Department of Corrections (RIDOC) is the first statewide correctional system in the United States to offer comprehensive MOUD services to incarcerated individuals.However, due to stigma, eligible individuals may be reluctant to engage with MOUD. This study aims to 1) evaluate the efficacy of an educational video intervention about MOUD and 2) characterize MOUD-related attitudes in a general incarcerated population. METHODS: Participants were recruited from eight elective classes offered to soon-to-be-released incarcerated individuals at RIDOC. Participants viewed an eight-minute video featuring incarcerated individuals speaking about their experiences using MOUD, designed to reduce MOUD-related stigma. Participants were administered surveys prior to and after watching the video to assess changes in MOUD knowledge (MOUD-K) and MOUD attitudes (MOUD-A). RESULTS: This evaluation of the intervention included 80 incarcerated participants (median age = 35, 93% male, 36% non-Hispanic White, and 26% non-Hispanic Black). Forty percent indicated non-medical opioid use within six months prior to incarceration; 13% had previously used MOUD. Significant improvements in MOUD-K scores (t(65) = -7.0, p < 0.0001) and MOUD-A scores (t(69) = -5.8, p < 0.0001) were detected after participants viewed the video. The intervention yielded greater ΔMOUD-A scores among those identifying as non-Hispanic Black, compared to non-Hispanic Whites (ß = 2.6, CI = 0.4, 4.8). CONCLUSION: The educational video improved both knowledge and positive attitudes towards MOUD, with changes in MOUD attitudes being influenced by race. These findings may inform future MOUD educational programs, thereby helping to reduce opioid use disorder-related morbidity and mortality.

"One guy goes to jail, two people are ready to take his spot": Perspectives on drug-induced homicide laws among incarcerated individuals.

BACKGROUND: As overdose deaths have increased in the United States, some lawmakers have explored punitive, "supply-side" interventions aimed at reducing the supply of fentanyl. While a rationale of seeking to protect people who use drugs is often given to justify harsh sentences for fentanyl distribution, there is no research to our knowledge on perceptions of the effect of drug-induced homicide laws among people who use drugs. METHODS: We conducted semi-structured, qualitative interviews with 40 people with opioid use disorder (OUD) who were enrolled in a medication for addiction treatment (MAT) program in a unified jail and prison system in Rhode Island on attitudes surrounding increased sentences for distribution of fentanyl, including recently enacted drug-induced homicide laws. Codes were developed using a generalized, inductive method and interviews analyzed in NVivo 12 after being coded by two coders. RESULTS: Most participants stated that drug-induced homicide laws would not be an effective strategy to stem the overdose crisis. We identified key themes, including discussions surrounding the autonomy of people who use drugs, widespread fentanyl prevalence as a barrier to implementation of drug-induced homicide laws, discussions of mass incarceration as ineffective for addressing substance use disorders, feelings that further criminalization could lead to violence, criminalization as a justification for interpersonal loss, and intention as meaningful to categorizing an act as homicide. CONCLUSIONS: Findings highlight the importance of centering the experiences of people with OUD in creating policies surrounding the overdose epidemic, potential unintended health consequences of drug-induced homicides laws such as deterrence from calling 911 and increased violence, and how drug-induced homicide laws may undermine advances made in expanding access to OUD treatment for people who are criminal justice-involved.

The long-term rapid increase in incidence of adenocarcinoma of the kidney in the USA, especially among younger ages.

BACKGROUND: We previously observed a rapid increase in the incidence of renal cell carcinoma (RCC) in men and women between 1935 and 1989 in the USA, using data from the Connecticut Tumor Registry. This increase appeared to be largely explained by a positive cohort effect, but no population-based study has been conducted to comprehensively examine age-period-cohort effects by histologic types for the past decade. METHODS: We calculated age-adjusted and age-specific incidence rates of the two major kidney-cancer subtypes RCC and renal urothelial carcinoma, and conducted an age-period-cohort analysis of 114 138 incident cases of kidney cancer reported between 1992 and 2014 to the Surveillance, Epidemiology, and End Results programme. RESULTS: The age-adjusted incidence rates of RCC have been increasing consistently in the USA among both men and women (from 12.18/100 000 in 1992-1994 to 18.35/100 000 in 2010-2014 among men; from 5.77/100 000 in 1992-1994 to 8.63/100 000 in 2010-2014 among women). Incidence rates generally increased in successive birth cohorts, with a continuing increase in rates among the younger age groups (ages 0-54 years) in both men and women and among both Whites and Blacks. These observations were confirmed by age-period-cohort modelling, which suggested an increasing birth-cohort trend for RCC beginning with 1955 birth cohorts, regardless of the assumed value for the period effect for both men and women and for Whites and Blacks. CONCLUSIONS: Known risk factors for kidney cancer may not fully account for the observed increasing rates or the birth-cohort pattern for RCC, prompting the need for additional etiologic hypotheses (such as environmental exposures) to investigate these descriptive patterns.

The benefits and implementation challenges of the first state-wide comprehensive medication for addictions program in a unified jail and prison setting.

The prevalence of opioid use disorders among people who are incarcerated is high. People who are released from incarceration are at increased risk for overdose. The current study details the first year of implementation of a state-wide medications for addiction treatment (MAT) program in a unified jail and prison setting at the Rhode Island Department of Corrections in Cranston, Rhode Island. We conducted 40 semi-structured, qualitative interviews with people who were incarcerated and concurrently enrolled in the MAT program. Analysis employed a general, inductive approach in NVivo 12. We found that a majority of participants discussed program benefits such as reduced withdrawal symptoms, decreased prevalence of illicit drug use in the facility, improved general environment at the RIDOC, and increased post-release intentions to continue MAT. Suggested areas of improvement include reducing delays to first dose, increasing access to other recovery services in combination with MAT, improving staff training on stigma, and earlier access to medical discharge planning information prior to release. Our findings suggest that correctional MAT programs are acceptable to targeted populations and are a feasible intervention that may be transferable to other states.

Cleavage activates dispatched for Sonic Hedgehog ligand release.

Hedgehog ligands activate an evolutionarily conserved signaling pathway that provides instructional cues during tissue morphogenesis, and when corrupted, contributes to developmental disorders and cancer. The transmembrane protein Dispatched is an essential component of the machinery that deploys Hedgehog family ligands from producing cells, and is absolutely required for signaling to long-range targets. Despite this crucial role, regulatory mechanisms controlling Dispatched activity remain largely undefined. Herein, we reveal vertebrate Dispatched is activated by proprotein convertase-mediated cleavage at a conserved processing site in its first extracellular loop. Dispatched processing occurs at the cell surface to instruct its membrane re-localization in polarized epithelial cells. Cleavage site mutation alters Dispatched membrane trafficking and reduces ligand release, leading to compromised pathway activity in vivo. As such, convertase-mediated cleavage is required for Dispatched maturation and functional competency in Hedgehog ligand-producing cells.