Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression. See related article by Belle et al., p. 1324.

Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy. See related article by Ye et al., p. 1302.

Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC.

Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.

Tumor-associated fibrosis impairs immune surveillance and response to immune checkpoint blockade in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Immune checkpoint blockade has improved survival for many patients with NSCLC, but most fail to obtain long-term benefit. Understanding the factors leading to reduced immune surveillance in NSCLC is critical in improving patient outcomes. Here, we show that human NSCLC harbors large amounts of fibrosis that correlates with reduced T cell infiltration. In murine NSCLC models, the induction of fibrosis led to increased lung cancer progression, impaired T cell immune surveillance, and failure of immune checkpoint blockade efficacy. Associated with these changes, we observed that fibrosis leads to numerically and functionally impaired dendritic cells and altered macrophage phenotypes that likely contribute to immunosuppression. Within cancer-associated fibroblasts, distinct changes within the Col13a1-expressing population suggest that these cells produce chemokines to recruit macrophages and regulatory T cells while limiting recruitment of dendritic cells and T cells. Targeting fibrosis through transforming growth factor-ß receptor signaling overcame the effects of fibrosis to enhance T cell responses and improved the efficacy of immune checkpoint blockade but only in the context of chemotherapy. Together, these data suggest that fibrosis in NSCLC leads to reduced immune surveillance and poor responsiveness to checkpoint blockade and highlight antifibrotic therapies as a candidate strategy to overcome immunotherapeutic resistance.

Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer.

Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)-mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDAC) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 cDC2 development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from patients with PDAC for changes in cDCs. We found that circulating cDC2s and their progenitors were significantly decreased in the blood of patients with PDAC, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in patients with PDAC and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of patients with PDAC showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity.

Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity.

Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.

Induction of cancer neoantigens facilitates development of clinically relevant models for the study of pancreatic cancer immunobiology.

Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC. KP2 was treated with oxaliplatin and olaparib (OXPARPi), and a resistant cell line was subsequently cloned to generate multiple genetically distinct cell lines (KP2-OXPARPi clones). Clones A and E are sensitive to immune checkpoint inhibition (ICI), exhibit relatively high T cell infiltration, and have significant upregulation of genes involved in antigen presentation, T cell differentiation, and chemokine signaling pathways. Clone B is resistant to ICI and is similar to the parental KP2 cell line in terms of relatively low T cell infiltration and no upregulation of genes involved in the pathways noted above. Tumor/normal exome sequencing and in silico neoantigen prediction confirms successful generation of cancer neoantigens in the KP2-OXPARPi clones and the relative lack of cancer neoantigens in the parental KP2 cell line. Neoantigen vaccine experiments demonstrate that a subset of candidate neoantigens are immunogenic and neoantigen synthetic long peptide vaccines can restrain Clone E tumor growth. Compared to existing models, the KP2-OXPARPi clones better capture the diverse immunobiology of human PDAC and may serve as models for future investigations in cancer immunotherapies and strategies targeting cancer neoantigens in PDAC.

Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy.

Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that in PDAC, proliferation of TAMs could be driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression also drove response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.

A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages.

Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages.

U.S. veterans' experiences and factors associated with use of a smartphone application to self-manage unhealthy alcohol use.

Unhealthy alcohol use is common among Operations Enduring and Iraqi Freedom (OEF/OIF) veterans, yet barriers discourage treatment-seeking. Mobile applications (apps) that deliver alcohol interventions have potential to address these barriers and increase treatment receipt. Few studies have qualitatively assessed users' experiences with apps to manage alcohol use. We assessed OEF/OIF veterans' experiences with Step Away, an app to reduce alcohol-related risks, to identify factors that may influence engagement. This single-arm pilot study recruited OEF/OIF veterans with positive alcohol screens nationwide using mail/telephone. Veterans aged 18-55 who exceeded drinking guidelines and owned an iPhone were eligible. Twenty-one (16 men, 5 women) of 55 participants completed interviews. Interviews were analyzed using thematic analysis. Participants found Step Away easy to use, although setup was time consuming. Participants reported increased awareness of alcohol use, highlighting daily assessment, weekly feedback, goal setting, and high-risk notification features as helpful and associated awareness with an intent to decrease use. Participants described Step Away as informative, with over half reporting they would use it outside of the study and most recommending it. Suggestions for improvement included greater personalization and control over features. Step Away features appear to influence engagement and increase users' awareness about alcohol consumed and factors associated with drinking, as well as intent to change. Assessment, feedback, and customization features of apps may facilitate app engagement. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade.

The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor-stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival. SIGNIFICANCE: Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy. This article is highlighted in the In This Issue feature, p. 2711.

Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

A randomized clinical trial evaluating the impact of counselor training and patient feedback on substance use disorder patients' sexual risk behavior.

INTRODUCTION: High risk sex-such as sex with multiple partners, condomless sex, or transactional or commercial sex-is a risk factor in individuals with substance use disorders (SUDs). SUD treatment can reduce sexual risk behavior, but interventions to reduce such behavior in this context have not been consistently effective. This study sought to determine if the impact of treatment on sexual risk behavior can be increased. METHODS: In a nested 2 × 2 factorial repeated measures design, we examined outcomes of two interventions: training for counselors in talking to patients about sexual risk; and availability to both counselors and patients of a personalized feedback report based on patient self-report of sexual behavior. Counselors received either a brief, information-based, Basic Training, or a multi-session, skills-based Enhanced Training. Their patients completed an audio-assisted computerized assessment of sexual behavior and received either No Feedback or a Personalized Feedback Report (PFR). Four hundred seventy six patients participated. Patient follow-up occurred 3- and 6-months postbaseline. Primary patient outcome measures were Number of Unsafe Sex Occasions (USO) and whether patients reported talking about sex in counseling sessions (Discussed Sex), both in the past 90 days. Secondary outcomes included Number of Sexual Partners, Sex Under the Influence of Substances, and Perceived Condom Barriers. RESULTS: Patients of Enhanced-condition counselors compared to those of Basic-condition counselors were more likely to report talking about sex with their counselor at 6-month follow-up. Personalized feedback also increased the likelihood of reporting counselor discussions at 6-month follow-up. Neither the training nor the feedback condition affected USO, Number of Partners, or Sex Under the Influence. DISCUSSION: We discuss why these two interventions apparently altered counselor-patient communication about sexual risk behavior without affecting the behavior itself.

Usability and Acceptability of a Mobile App for the Self-Management of Alcohol Misuse Among Veterans (Step Away): Pilot Cohort Study.

BACKGROUND: Alcohol misuse is common among Operation Enduring Freedom and Operation Iraqi Freedom veterans, yet barriers limit treatment participation. Mobile apps hold promise as means to deliver alcohol interventions to veterans who prefer to remain anonymous, have little time for conventional treatments, or live too far away to attend treatment in person. OBJECTIVE: This pilot study evaluated the usability and acceptability of Step Away, a mobile app designed to reduce alcohol-related risks, and explored pre-post changes on alcohol use, psychological distress, and quality of life. METHODS: This single-arm pilot study recruited Operation Enduring Freedom and Operation Iraqi Freedom veterans aged 18 to 55 years who exceeded National Institute on Alcohol Abuse and Alcoholism drinking guidelines and owned an iPhone. Enrolled veterans (N=55) completed baseline and 1-, 3-, and 6-month assessments. The System Usability Scale (scaled 1-100, ≥70 indicating acceptable usability) assessed the effectiveness, efficiency, and satisfaction dimensions of usability, while a single item (scaled 1-9) measured the attractiveness of 10 screenshots. Learnability was assessed by app use during week 1. App engagement (proportion of participants using Step Away, episodes of use, and minutes per episode per week) over 6 months measured acceptability. Secondary outcomes included pre-post change on heavy drinking days (men: ≥5 drinks per day; women: ≥4 drinks per day) and Short Inventory of Problems-Revised, Kessler-10, and brief World Health Organization Quality of Life Questionnaire scores. RESULTS: Among the 55 veterans enrolled in the study, the mean age was 37.4 (SD 7.6), 16% (9/55) were women, 82% (45/55) were White, and 82% (45/55) had an alcohol use disorder. Step Away was used by 96% (53/55) of participants in week 1, 55% (30/55) in week 4, and 36% (20/55) in week 24. Step Away use averaged 55.1 minutes (SD 57.6) in week 1 and <15 minutes per week in weeks 2 through 24. Mean System Usability Scale scores were 69.3 (SD 19.7) and 71.9 (SD 15.8) at 1 and 3 months, respectively. Median attractiveness scores ranged from 5 to 8, with lower ratings for text-laden screens. Heavy drinking days decreased from 29.4% (95% CI 23.4%-35.4%) at baseline to 16.2% (95% CI 9.9%-22.4%) at 6 months (P<.001). Likewise, over 6 months, Short Inventory of Problems-Revised scores decreased from 6.3 (95% CI 5.1-7.5) to 3.6 (95% CI 2.4-4.9) (P<.001) and Kessler-10 scores decreased from 18.8 (95% CI 17.4-20.1) to 17.3 (95% CI 15.8-18.7) (P=.046). Changes were not detected on quality of life scores. CONCLUSIONS: Operation Enduring Freedom and Operation Iraqi Freedom veterans found the usability of Step Away to be acceptable and engaged in the app over the 6-month study. Reductions were seen in heavy drinking days, alcohol-related problems, and Kessler-10 scores. A larger randomized trial is warranted to confirm our findings.

Virtual Standardized Patients vs Academic Training for Learning Motivational Interviewing Skills in the US Department of Veterans Affairs and the US Military: A Randomized Trial.

Importance: Despite the need for effective and scalable training in motivational interviewing (MI) that includes posttraining coaching and feedback, limited evidence exists regarding the effectiveness of using virtual (computerized) standardized patients (VSPs) in such training. Objective: To evaluate the efficacy of training with a VSP on the acquisition and maintenance of MI skills compared with traditional academic study. Design, Setting, and Participants: This study was a 2-group, parallel-training randomized trial of 120 volunteer health care professionals recruited from a Department of Veterans Affairs and Department of Defense medical facility. Motivational interviewing skill was coded by external experts blinded to training group and skill assessment time points. Data were collected from October 17, 2016, to August 12, 2019. Interventions: After a computer course on MI, participants trained during two 45-minute sessions separated by 3 months. The 2 randomized training conditions included a branching storyline VSP, which provided MI skill rehearsal with immediate and summative feedback, and a control condition, which included academic study of content from the computerized MI course. Main Outcomes and Measures: Measurement of MI skill was based on recorded conversations with human standardized patients, assessed using the Motivational Interviewing Treatment Integrity 4.2.1 coding system, measured at baseline, after training, and after additional training in the randomized condition 3 months later. Results: A total of 120 volunteers (83 [69%] women), with a mean (SD) of 13.6 (10.3) years of health care experience, participated in the study; 61 were randomized to receive the intervention, and 59 were randomized to the control group. Those assigned to VSP training had significantly greater posttraining improvement in technical global scores (0.23; 95% CI, 0.03-0.44; P = .02), relational global scores (0.57; 95% CI, 0.33-0.81; P = .001), and the reflection-to-question ratio (0.23; 95% CI, 0.15-0.31; P = .001). Differences were maintained after the 3-month additional training session, with more improvements achieved after the 3-month training for the VSP trainees on the reflection-to- question ratio (0.15; 95% CI, 0.07-0.24; P = .001). Conclusions and Relevance: This randomized trial demonstrated a successful transfer of training from a VSP to human standardized patients. The VSP MI skill outcomes were better than those achieved with academic study and were maintained over time. Virtual standardized patients have the potential to facilitate dissemination of MI and may be useful for training in other evidence-based skills and treatments. Trial Registration: ClinicalTrials.gov Identifier: NCT04558060.

Dendritic Cell Paucity Leads to Dysfunctional Immune Surveillance in Pancreatic Cancer.

Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.

Hypermorphic SERK1 Mutations Function via a SOBIR1 Pathway to Activate Floral Abscission Signaling.

In Arabidopsis (Arabidopsis thaliana), the abscission of floral organs is regulated by two related receptor-like protein kinases, HAESA (HAE) and HAESA-LIKE2 (HSL2). In complex with members of the SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) family of coreceptor protein kinases, HAE and HSL2 are activated when bound by INFLORESCENCE DEFICIENT IN ABSICSSION, a proteolytically processed peptide ligand, activating the expression of genes encoding secreted cell wall remodeling and hydrolase enzymes. hae hsl2 mutants fail to induce expression of these genes and retain floral organs indefinitely. Here, we report identification of an allelic series of hae hsl2 suppressor mutations in the SERK1 coreceptor protein kinase gene. Genetic and transcriptomic evidence indicates that these alleles represent a novel class of gain-of-function mutations that activate signaling independently of HAE/HSL2. We show that, surprisingly, the suppression effect does not rely on the protein kinase activity of SERK1 and that activation of signaling relies on the receptor-like kinase gene SUPPRESSOR OF BIR1 (SOBIR1). The effect of these mutations can be mimicked by loss of function of BAK1-INTERACTING RECEPTOR-LIKE KINASE1 (BIR1), a known negative regulator of SERK-SOBIR1 signaling. These results suggest that BIR1 negatively regulates SERK-SOBIR1 signaling during abscission and that the identified SERK1 mutations likely interfere with this negative regulation.

Increasing substance use disorder counselors' self-efficacy and skills in talking to patients about sex and HIV risk: A randomized training trial.

BACKGROUND: People with substance use disorder (SUD) experience increased risk for HIV, Hepatitis C, and sexually transmitted illnesses via risky sex. This high-risk population would benefit from sexual risk reduction interventions integrated into SUD treatment. However, many SUD counselors report lack of skill or confidence in addressing sexual risk with patients. METHODS: This study was part of a larger nested 2 × 2 factorial repeated measures design, which compared two levels of counselor training (Basic-2 h versus Enhanced-10 h plus ongoing coaching). We determined whether counselors receiving Enhanced training addressing their motivation, confidence and skills (a) increased knowledge about sexual issues; (b) increased self-efficacy to discuss sex with patients; and (c) improved skills in discussing sex as part of SUD treatment, compared with those receiving shorter information-based training. Counselors providing individual therapy at two opioid treatment programs (OTP) and two psychosocial outpatient programs in the United States were eligible. Randomization occurred after Basic training. Measures included self-report (self-efficacy and knowledge) and blinded coding of standardized patient interviews (skill). RESULTS: Counselors receiving Enhanced training (n = 28) showed significant improvements compared to their Basic training counterparts (n = 32) in self-efficacy, use of reflections, and use of decision-making and communication strategies with standardized patients. These improvements were maintained from post-training to 3-month follow-up. No adverse effects of study participation were reported. CONCLUSIONS: Results suggest that counselors can improve their knowledge, self-efficacy and skill related to sexual risk conversations with patients based on modest skills-based training.

Counselor turnover in substance use disorder treatment research: Observations from one multisite trial.

Background: Counselor workforce turnover is a critical area of concern for substance use disorder (SUD) treatment providers and researchers. To facilitate the adoption and implementation of innovative treatments, attention must be paid to how SUD treatment workforce issues affect the implementation of clinical effectiveness research. Multiple variables have been shown to relate to turnover, yet reasons that are specific to conducting research have not been systematically assessed. Methods: In a randomized clinical trial testing a sexual risk reduction counselor training intervention, 69 counselors at 4 outpatient SUD treatment sites (2 opioid treatment programs [OTPs], 2 psychosocial) were enrolled and randomized to 1 of 2 training conditions (Standard vs. Enhanced). Study counselor and agency turnover rates were calculated. Agency context and policies that impacted research participation were examined. Results: Study turnover rates for enrolled counselors were substantial, ranging from 33% to 74% over approximately a 2-year active study period. Study counselor turnover was significantly greater at outpatient psychosocial programs versus OTPs. Counselor turnover did not differ due to demographic or training condition assignment. Leaving agency employment was the most typical reason for study counselor turnover. Conclusions: This secondary analysis used data from a multisite study with frontline counselors to provide a qualitative description of challenges faced when conducting effectiveness research in SUD treatment settings. That counselors may be both subjects and deliverers of the interventions studied in clinical trials, with implications for differential impact on study implementation, is highlighted. We offer suggestions for researchers seeking to implement effectiveness research in SUD clinical service settings.

Successful Development and Implementation of a Surgical Response Team for Emergent Surgical Cases.

: At our institution, we recognized a need for a standardized, efficient approach to safely evaluate, prepare, and transport patients in need of emergent surgery. With the establishment of an Emergency Surgery Transport and Assessment Team, we were able to substantially reduce our median transport time to the OR. We believe other institutions can establish an efficient team using existing resources to expedite care of the emergent surgical patient.