In situ production and secretion of proteins endow therapeutic benefit against psoriasiform dermatitis and melanoma.

Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over extracellular localization of therapeutic proteins. A critical gap therefore remains the need to develop and incorporate methodologies that allow for posttranslational control over expression dynamics, localization, and stability of nucleic acid-generated protein therapeutics. To address this, we explored how the body's endogenous machinery controls protein localization through signal peptides (SPs), including how these motifs could be incorporated modularly into therapeutics. SPs serve as a virtual zip code for mRNA transcripts that direct the cell where to send completed proteins within the cell and the body. Utilizing this signaling biology, we incorporated secretory SP sequences upstream of mRNA transcripts coding for reporter, natural, and therapeutic proteins to induce secretion of the proteins into systemic circulation. SP sequences generated secretion of various engineered proteins into the bloodstream following intravenous, intramuscular, and subcutaneous SP mRNA delivery by lipid, polymer, and ionizable phospholipid delivery carriers. SP-engineered etanercept/TNF-α inhibitor proteins demonstrated therapeutic efficacy in an imiquimod-induced psoriasis model by reducing hyperkeratosis and inflammation. An SP-engineered anti-PD-L1 construct mediated mRNA encoded proteins with longer serum half-lives that reduced tumor burden and extended survival in MC38 and B16F10 cancer models. The modular nature of SP platform should enable intracellular and extracellular localization control of various functional proteins for diverse therapeutic applications.

Understanding the role of financial capacity in the delivery of opioid use disorder treatment.

Opioid treatment programs must have adequate financial capacity to sustain operations and deliver a high standard of care for individuals suffering from opioid use disorder. However, there is limited consistency in the health services literature about the concept and relationship of organizational financial capacity and key outcome measures (wait time and retention). In this study, we explored five common measures of financial capacity that can be applied to opioid treatment programs: (a) reserve ratio, (b) equity ratio, (c) markup, (d) revenue growth, and (e) earned revenue. We used these measures to compare financial capacity among 135 opioid treatment programs across four data collection points: 2011 (66 programs), 2013 (77 programs), 2015 (75 programs), and 2017 (69 programs). We examined the relationship between financial capacity and wait time and retention. Findings from the literature review show inconsistencies in the definition and application of concepts associated with financial capacity across business and social service delivery fields. The analysis shows significant differences in components of financial capacity across years. We observed an increase in average earned revenue and markup in 2017 compared to prior years. The interaction between minorities and markup was significantly associated with higher likelihood of waiting (IRR = 1.077, p < .05). Earned revenue (IRR = 0.225, p < .05) was related to shorter wait time in treatment. The interaction between minorities and equity ratio is also significantly associated with retention (IRR = 0.796, p < .05). Our study offers a baseline view of the role of financial capacity in opioid treatment and suggests a framework to determine its effect on client-centered outcomes.

Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma.

Chimeric Antigen Receptor (CAR) T cell immunotherapy is revolutionizing treatment for patients suffering from B-cell lymphoma (BL). However, the current method of CAR T cell production is complicated and expensive, requiring collection of patient blood to enrich the T cell population, ex vivo engineering/activation, and quality assessment before the patient can receive the treatment. Herein we leverage Spleen Selective ORgan Targeted (SORT) Lipid Nanoparticles (LNPs) to produce CAR T cells in situ and bypass the extensive and laborious process currently used. Optimized Spleen SORT LNPs containing 10 % 18 : 1 PA transfected CD3+, CD8+, and CD4+ T cells in wild-type mice. Spleen SORT LNPs delivered Cre recombinase mRNA and CAR encoding mRNA to T cells in reporter mice and in a lymphoreplete B cell lymphoma model (respectively) after intravenous injection without the need for active targeting ligands. Moreover, in situ CAR T cells increased the overall survival of mice with a less aggressive form of B cell lymphoma. In addition, in situ transfected CAR T cells reduced tumor metastasis to the liver by increasing tumor infiltrating lymphocytes. Overall, these results offer a promising alternative method for CAR T cell production with pre-clinical potential to treat hematological malignancies.

Disparities in expected driving time to opioid treatment and treatment completion: findings from an exploratory study.

BACKGROUND: Commuting time to treatment has been shown to affect healthcare outcomes such as engagement and initiation. The purpose of this study is to extend this line of research to investigate the effects of driving time to opioid programs on treatment outcomes. METHODS: We analyzed discharge survey data from 22,587 outpatient opioid use disorder treatment episodes (mainly methadone) in Los Angeles County and estimated the associated driving time to each episode using Google Maps. We used multivariable logistic regressions to examine the association between estimated driving time and odds of treatment completion after adjusting for possible confounders. RESULTS: Findings show an average driving time of 11.32 min and an average distance of 11.18 km. We observed differences in estimated driving time across age, gender, and socioeconomic status. Young, male, less formally educated, and Medi-Cal-ineligible clients drove longer to treatment. A 10-min drive was associated with a 33% reduction in the completion of methadone treatment plans (p < .01). CONCLUSION: This systemwide analysis provides novel time estimates of driving-based experiences and a strong relationship with completion rates in methadone treatment. Specifically, the result showing reduced treatment completion rates for drive times longer than 10 min may inform policies regarding the ideal geographic placement of methadone-based treatment programs and service expansion initiatives.

Electronic Cigarette Use and Associated Risk Factors in U.S.-Dwelling Pacific Islander Young Adults.

Background: E-cigarette use is rapidly increasing among US young adults, heightening their risk for vaping-related illnesses. Yet, little is known about e-cigarette use among young adult Native Hawaiians and Pacific Islanders (NHPI): an indigenous-colonized US racial group rarely described in research literature. This exploratory study provides the first known data on e-cigarette use and potential risk factors in NHPI young adults. Method: Self-report data were collected from 143 NHPI young adults (age 18-30 years) living in two large NHPI communities: Samoans in urban Los Angeles County and Marshallese in rural Arkansas. We assessed rates of e-cigarette, cigarette, alcohol, and marijuana use, and positive and negative outcome expectancies from e-cigarettes, that is expected outcomes from e-cigarette use. To identify potential risk factors for NHPI e-cigarette use, regressions explored associations between participants' current e-cigarette use with current cigarette, alcohol, and marijuana use, and e-cigarette outcome expectancies. Results: Among NHPI young adults, lifetime e-cigarette use rate was 53% and current use rate was 39%. Current rate of dual e-cigarette/cigarette, e-cigarette/alcohol, and e-cigarette/marijuana use was 38%, 35%, and 25%, respectively. In our regression models, current marijuana use and positive e-cigarette outcome expectancies were significantly associated with current e-cigarette use. Conclusions: E-cigarette use is common among NHPI young adults, exceeding rates for other at-risk racial groups. Marijuana use and positive expectations about e-cigarette use may represent potential e-cigarette use risk factors. Collectively, findings underscore the need for additional research to further explore the scope of, and risk and protective factors for, e-cigarette use in this understudied high-risk population.

Advancing theory on the multilevel role of leadership in the implementation of evidence-based health care practices.

BACKGROUND: Top managers' transformational leadership is associated with significant influence on subordinates. Yet little is known about the extent to which top managers' transformational leadership influences middle managers' implementation leadership and, ultimately, frontline staff delivery of evidence-based health care practices. PURPOSE: To test a multilevel leadership model examining the extent to which top managers' transformational leadership, as mediated by implementation leadership of middle managers (i.e., those who supervise direct clinical services), affects staff attitudes toward evidence-based practices (EBPs) and their implementation. METHODOLOGY/APPROACH: We used data collected in 2013 from 427 employees in 112 addiction health services programs in Los Angeles County, California. We relied on hierarchical linear models with robust standard errors to analyze multilevel data, individuals nested in programs. We conducted two path models to estimate multilevel relationships with two EBPs: contingency management and medication-assisted treatment. RESULTS: Findings partially supported our theory-driven multilevel leadership model. Specifically, results demonstrated that middle managers' implementation leadership mediated the relationship between top managers' transformational leadership and attitudes toward EBPs. At the same time, they showed the mediated relationship for delivery of contingency management treatment was only marginally significant (standardized indirect effect = .006, bootstrap p = .091). We did not find a mediation effect for medication-assisted treatment. DISCUSSION: Findings advance leadership theory in health care, highlighting the importance of middle managers' implementation leadership in transmitting the influence of top managers' transformational leadership on staff attitudes toward EBPs. The full path model shows the extent to which transformational leadership may influence staff implementation of innovative practices as mediated through staff attitudes toward EBPs and middle managers' implementation leadership. PRACTICE IMPLICATIONS: Our findings have implications for developing a multilevel leadership approach to implementation in health care. Leadership development should build on different competencies based on managers' level but align managers' priorities on the same implementation goals.

Program Capacity to Deliver Prevention Services to Children of Adult Clients Receiving Substance Use Disorder Treatment.

Children whose parents have a history of substance use are at elevated risk of developing substance use disorders (SUDs) and related debilitating behaviors. Although specialty treatment programs are uniquely positioned to deliver prevention care to children of adult clients, these programs may have limited capacity to implement prevention and early intervention care services, particularly in racial and ethnic minority communities. We merged data from program surveys and client records collected in 2015 to examine the extent to which program capacity factors are associated with the odds of delivering prevention and early intervention services for children of adult clients attending outpatient SUD treatment in low-income minority communities in Los Angeles County, California. Our analytic sample consisted of 16,712 clients embedded in 82 programs. Our results show that 85% of these programs reported delivering prevention care services, while 71% of programs delivered early intervention services. Programs with organizational climates supporting change and those that served a high number of clients annually were more likely to implement both prevention and early intervention practices. Programs accepting Medicaid payments and serving clients whose primary drug was marijuana were more than three times as likely to implement prevention services. Overall, our findings suggest both program- and client-level characteristics are associated with delivering preventive care offered to children of adult clients receiving SUD treatment in communities of color. As Medicaid has become a major payor of SUD treatment services and marijuana use has been legalized in California, findings identify capacity factors to deliver public health prevention interventions in one of the nation's largest public SUD treatment systems.

Expected Impact of Health Care Reform on the Organization and Service Delivery of Publicly Funded Addiction Health Services.

Little is known about how the Affordable Care Act (ACA) will be implemented in publicly funded addiction health services (AHS) organizations. Guided by a conceptual model of implementation of new practices in health care systems, this study relied on qualitative data collected in 2013 from 30 AHS clinical supervisors in Los Angeles County, California. Interviews were transcribed, coded, and analyzed using a constructivist grounded theory approach with ATLAS.ti software. Supervisors expected several potential effects of ACA implementation, including increased use of AHS services, shifts in the duration and intensity of AHS services, and workforce professionalization. However, supervisors were not prepared for actions to align their programs' strategic change plans with policy expectations. Findings point to the need for health care policy interventions to help treatment providers effectively respond to ACA principles of improving standards of care and reducing disparities.

Relationship Satisfaction and Communication Among Urban Minority HIV-Positive and HIV-Negative Mothers: The Influence on Daughter's Alcohol Use.

Family relationships influence children's beliefs and behaviors. This work examined qualities associated with communication about alcohol among 176 mothers and the influence of this communication on daughters' alcohol use. Path analyses by maternal HIV status indicated significant differences. Relationship satisfaction was associated with self-efficacy for both HIV-positive (ß = 0.545, p < .001) and HIV-negative (ß = 0.557, p < .001) mothers. Maternal self-efficacy was associated with communication for both HIV-positive (ß = 0.364, p < .01) and HIV-negative (ß = 0.310, p < .05) mothers; maternal attitudes toward alcohol use were associated with communication among HIV-negative mothers (ß = 0.20, p < .05). Relationship satisfaction was indirectly related to daughter's alcohol use in HIV-positive dyads (ß = 0.153, p < .05). In families with interfamilial and environmental stressors, investing in the mother-daughter relationship, in part by discussing issues related to alcohol use, is protective in nature.

Program Capacity to Eliminate Outcome Disparities in Addiction Health Services.

We evaluated program capacity factors associated with client outcomes in publicly funded substance abuse treatment organizations in one of the most populous and diverse regions of the United States. Using multilevel cross-sectional analyses of program data (n = 97) merged with client data from 2010 to 2011 for adults (n = 8,599), we examined the relationships between program capacity (leadership, readiness for change, and Medi-Cal payment acceptance) and client wait time and treatment duration. Acceptance of Medi-Cal was associated with shorter wait times, whereas organizational readiness for change was positively related to treatment duration. Staff attributes were negatively related to treatment duration. Overall, compared to low program capacity, high program capacity was negatively associated with wait time and positively related to treatment duration. In conclusion, program capacity, an organizational indicator of performance, plays a significant role in access to and duration of treatment. Implications for health care reform implementation in relation to expansion of public health insurance and capacity building to promote health equities are discussed.

The Medicaid expansion gap and racial and ethnic minorities with substance use disorders.

We compared the race and ethnicity of individuals residing in states that did and did not expand Medicaid in 2014. Findings indicated that African Americans and Native Americans with substance use disorders who met new federal eligibility criteria for Medicaid were less likely than those of other racial and ethnic groups to live in states that expanded Medicaid. These findings suggest that the uneven expansion of Medicaid may exacerbate racial and ethnic disparities in insurance coverage for substance use disorder treatment.

Leadership and Licensure for Drug Treatment and the Implementation of Co-Occurring Disorder Treatment in Community Mental Health Centers.

Using a random sample of 48 outpatient mental health programs in low-income and racial and ethnic minority communities, this study examined directorial leadership, drug treatment licensure, and implementation of evidence-based protocols and practices to address co-occurring mental health and substance abuse disorders (COD). Understanding of findings was enhanced with focus groups at six clinics. Most programs (81 %) offered COD treatment. Directorial leadership was positively associated with COD treatment (ß = 0.253, p = 0.047, 95 % CI 0.003, 0.502) and COD supervision and training (ß = 0.358, p = 0.002, 95 % CI 0.142, 0.575). Licensure was negatively associated with COD treatment (ß = -0.235, p = 0.041, 95 % CI -0.460, -0.010) and COD supervision and training (ß = -0.195, p = 0.049, 95 % CI -0.389, -0.001). Although lack of financial integration may limit the effect of licensing on COD treatment implementation, the response of leaders to regulation, funding, and human resources issues may encourage COD treatment practices. Implications for leadership interventions and policy are discussed in the context of health care reform.

Organizational correlates of implementation of colocation of mental health and primary care in the Veterans Health Administration.

This study explored the role of organizational factors in the ability of Veterans Health Administration (VHA) clinics to implement colocated mental health care in primary care settings (PC-MH). The study used data from the VHA Clinical Practice Organizational Survey collected in 2007 from 225 clinic administrators across the United States. Clinic degree of implementation of PC-MH was the dependent variable, whereas independent variables included policies and procedures, organizational context, and leaders' perceptions of barriers to change. Pearson bivariate correlations and multivariable linear regression were used to test hypotheses. Results show that depression care training for primary care providers and clinics' flexibility and participation were both positively correlated with implementation of PC-MH. However, after accounting for other factors, regressions show that only training primary care providers in depression care was marginally associated with degree of implementation of PC-MH (p = 0.051). Given the importance of this topic for implementing integrated care as part of health care reform, these null findings underscore the need to improve theory and testing of more proximal measures of colocation in future work.

Organizational capacity for service integration in community-based addiction health services.

OBJECTIVES: We examined factors associated with readiness to coordinate mental health, public health, and HIV testing among community-based addiction health services programs. METHODS: We analyzed client and program data collected in 2011 from publicly funded addiction health services treatment programs in Los Angeles County, California. We analyzed a sample of 14 379 clients nested in 104 programs by using logistic regressions examining odds of service coordination with mental health and public health providers. We conducted a separate analysis to examine the percentage of clients receiving HIV testing in each program. RESULTS: Motivational readiness and organizational climate for change were associated with higher odds of coordination with mental health and public health services. Programs with professional accreditation had higher odds of coordinating with mental health services, whereas programs receiving public funding and methadone and residential programs (compared with outpatient) had a higher percentage of clients receiving coordinated HIV testing. CONCLUSIONS: These findings provide an evidentiary base for the role of motivational readiness, organizational climate, and external regulation and funding in improving the capacity of addiction health services programs to develop integrated care.

Organizational implementation of evidence-based substance abuse treatment in racial and ethnic minority communities.

We evaluated organizational factors associated with the implementation of contingency management treatment (CMT) and medication-assisted treatment (MAT) in substance abuse treatment (SAT) programs serving racial and ethnic minority communities. Analysis of cross-sectional data collected in 2010-2011 from a random sample of 148 publicly funded SAT programs showed that accepting private insurance was positively associated with CMT and MAT implementation, whereas larger programs were associated with greater implementation of MAT. Supervisorial openness to and expectations about implementing evidence-based practices (EBPs) and attributes for change were strongly associated with CMT, whereas the interactions between openness to EBPs and programs that accept private insurance and that are governed by parent organizations were positively associated with MAT. These external expectations and managerial attitudes supported the implementation of psychosocial and pharmacotherapy treatments in SAT. Implications for improving standards of care in minority communities are discussed.

Expert providers implement integrated and coordinated care in opioid use disorder treatment.

BACKGROUND: Enhancing care integration and coordination to improve patient outcomes in opioid use disorder treatment is a growing focus in the field. Understanding of how the treatment system implements coordination and integration, particularly in the aftermath of the COVID-19 pandemic, remains limited. In this study, we explored the implementation of medications for opioid use disorder (MOUD) and the evolution of service delivery toward a more comprehensive approach. We examined providers' perspectives from high-achieving programs in Los Angeles County, the largest and most diverse U.S. county, including barriers to integrating and coordinating care and strategies for integrating MOUD service delivery. METHODS: We gathered qualitative interview data from 30 high-performing programs in Los Angeles County, each represented by a manager or supervisor. High performance was defined by empirical indicators of access, retention, and program completion. Our data collection and analysis followed the constructivist grounded theory approach, explicating the social processes used by participating managers during the pandemic and subsequent organizational shifts. This approach yielded 14 major and six minor codes. Interrater reliability tests yielded a pooled Cohen's kappa statistic of 93%. RESULTS: Expert providers exhibited a strong commitment to destigmatizing MOUD and worked to overcome obstacles in delivering care to clients by advocating its efficacy to fellow health care providers. Along with their endorsement of MOUD, they identified challenges in integrating and coordinating MOUD care. Barriers included stigma at both patient and provider levels, inadequate education about MOUD, limited access to MOUD, and the complexities of operating in a fragmented health care framework. Despite these challenges, high-performing providers used strategies to harmonize and align MOUD service delivery with health and social services. These included establishing service colocation, adopting a multidisciplinary team-based approach, forming partnerships with the community, offering telehealth services, integrating and sharing data, and embracing a harm reduction philosophy. DISCUSSION: Through the adoption of these strategies, providers enhanced care accessibility, boosted patient engagement, sustained retention in treatment, and enhanced treatment outcomes. Even among highly skilled treatment providers in Los Angeles County, barriers to integrating and coordinating care using MOUD remain intricate and multifaceted. Addressing these challenges necessitates a comprehensive strategy involving provider education and training, increased availability of MOUD, enhanced coordination and communication among health care providers, resolution of regulatory hurdles, and addressing patient hesitancy toward MOUD.

Identifying the Heterogeneity in the Association between Workforce Diversity and Retention in Opioid Treatment among Black clients.

Background: This study investigates the impact of workforce diversity, specifically staff identified as Black/African American, on retention in opioid use disorder (OUD) treatment, aiming to enhance patient outcomes. Employing a novel machine learning technique known as 'causal forest,' we explore heterogeneous treatment effects on retention. Methods: We relied on four waves of the National Drug Abuse Treatment System Survey (NDATSS), a nationally representative longitudinal dataset of treatment programs. We analyzed OUD program data from the years 2000, 2005, 2014 and 2017 (n = 627). Employing the 'causal forest' method, we analyzed the heterogeneity in the relationship between workforce diversity and retention in OUD treatment. Interviews with program directors and clinical supervisors provided the data for this study. Results: The results reveal diversity-related variations in the association with retention across 61 out of 627 OUD treatment programs (less than 10%). These programs, associated with positive impacts of workforce diversity, were more likely private-for-profit, newer, had lower percentages of Black and Latino clients, lower staff-to-client ratios, higher proportions of staff with graduate degrees, and lower percentages of unemployed clients. Conclusions: While workforce diversity is crucial, our findings underscore that it alone is insufficient for improving retention in addiction health services research. Programs with characteristics typically linked to positive outcomes are better positioned to maximize the benefits of a diverse workforce in client retention. This research has implications for policy and program design, guiding decisions on resource allocation and workforce diversity to enhance retention rates among Black clients with OUDs.

Expanding RNAi to Kidneys, Lungs, and Spleen via Selective ORgan Targeting (SORT) siRNA Lipid Nanoparticles.

Inhibition of disease-causing mutations using RNA interference (RNAi) has resulted in clinically approved medicines with additional candidates in late stage trials. However, targetable tissues currently in preclinical development are limited to liver following systemic intravenous (IV) administration because predictable delivery of siRNA to non-liver tissues remains an unsolved challenge. Here, evidence of durable extrahepatic gene silencing enabled by siRNA Selective ORgan Targeting lipid nanoparticles (siRNA SORT LNPs) to the kidneys, lungs, and spleen is provided. LNPs excel at dose-dependent silencing of tissue-enriched endogenous targets resulting in 60%-80% maximal knockdown after a single IV injection and up to 88% downregulation of protein expression in mouse lungs after two doses. To examine knockdown potency and unbiased organ targeting, B6.129TdTom/EGFP mice that constitutively express the TdTomato transgene across all cell types are utilized to demonstrate 58%, 45%, and 15% reduction in TdTomato fluorescence in lungs, spleen, and kidneys, respectively. Finally, physiological relevance of siRNA SORT LNP-mediated gene silencing is established via acute suppression of endogenous Tie2 which induces lung-specific phenotypic alteration of vascular endothelial barrier. Due to plethora of extrahepatic diseases that may benefit from RNAi interventions, it is anticipated that the findings will expand preclinical landscape of therapeutic targets beyond the liver.

Explaining differences in hepatitis C between U.S. veterans and nonveterans in treatment for substance abuse: results from a regression decomposition.

Hepatitis C virus (HCV) infection is common among people with substance abuse histories and a burden for U.S. veterans in particular. This study compares self-reported HCV between 1,652 veterans and 48,013 nonveterans who received public-sector substance abuse treatment in Los Angeles between 2006 and 2010. A higher percentage of veterans than nonveterans reported HCV (6.5% vs. 3.8%, p < .0001). Homelessness and mental illness explained, respectively, 8.6% and 7.1% of the difference in HCV between the two groups, adjusting for other variables. Reducing homelessness and mental illness among veterans may also help reduce the excess burden of HCV in this population.