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.

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.

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.

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.

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.

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.

Utilizing transesophageal echocardiography for placement of pulmonary artery catheters.

OBJECTIVE: Pulmonary artery catheters (PACs) have routinely been positioned by wedging into the pulmonary artery before pulling back 1-2 centimeters or advancing the PAC several centimeters after achieving a pulmonary artery waveform. A rare, major complication is pulmonary artery rupture. This study presents transesophageal echocardiography (TEE) for PAC placement by leaving the catheter tip at the one o'clock position, upper window short-axis view of the ascending aorta at the bifurcation of the pulmonary artery (TEE distance). DESIGN: Prospective observational cohort study. SETTING: Large urban academic medical center. PARTICIPANTS: 30 males and 30 females undergoing cardiac surgery requiring cardiopulmonary bypass. INTERVENTION: TEE was utilized to obtain an upper esophageal short-axis view of the aorta with long-axis view of the main and right pulmonary arteries. MEASUREMENTS AND RESULTS: The distance between TEE position and wedge position was recorded along with patients' gender, height, and weight. A correlation was found between TEE and wedge distances (P < .0001). There were significant gender differences in TEE distance, with a mean of 43.6 cm in females and 46.5 cm in males (P = .0004). The mean wedge distance was 47.5 cm in females and 51.9 cm in males (P < .0001). The differences between distances of wedge and TEE positions (5.39 cm, males; 3.93 cm, females) were also significant (P < .0001). CONCLUSIONS: By securing the PAC at the one o'clock TEE position, physicians are assured of a safety margin of several centimeters. This direct visualization method for PAC placement may decrease the risk for accidental wedging intraoperatively.

High inpatient utilization among Veterans Health Administration patients with substance-use disorders and co-occurring mental health conditions.

BACKGROUND: Substance-use disorders (SUDs) are common and costly conditions. Understanding high inpatient utilization (HIU) among patients with SUD can inform the development of treatment approaches designed to reduce healthcare expenditures and improve service quality. OBJECTIVES: To examine the prevalence, type, and predictors of HIU among patients with SUD and co-occurring mental health conditions. METHODS: Service utilization and demographic and clinical variables were extracted from a national sample of Veterans Health Administration (VA) patients with SUD-only [n = 148,960 (98.3% male)], SUD plus serious mental illness ([i.e. schizophrenia- and/or bipolar-spectrum disorders; SUD/SMI; n = 75,913 (91.6% male)], and SUD plus other mental illness [SUD/MI; n = 245,675 (94.6% male)]. Regression models were used to examine HIU during a follow-up year. RESULTS: Prevalence of HIU among the SUD-only group was 6.2% (95% confidence interval (CI): 6.1%-6.3%) compared with 22.7% (95% CI: 22.4%-23.0%) and 9.7% (95% CI: 9.6%-9.8%) among the SUD/SMI and SUD/MI groups, respectively. Patients with SUD/MI represented nearly half of the HIU sample. Primary type of inpatient service use varied by comorbidity: SUD-only = medicine; SUD/SMI = psychiatric; SUD/MI similar use of psychiatric, SUD-related, and medicine. Predictors of HIU were generally similar across groups: older age, unmarried, homelessness, suicide risk, pain diagnosis, alcohol/opioid/sedative-use disorders, and prior-year emergency department/inpatient utilization. CONCLUSIONS: Substantial reductions in HIU among an SUD population will likely require treatment approaches that target patients with less-severe mental health conditions in addition to SMI. Cross-service collaborations (e.g., integration of medical providers in SUD care) and interventions designed to target issues and/or conditions that lead to HIU (e.g., homeless care services) may be critical to reducing HIU in this population.

Disrupting ER-associated protein degradation suppresses the abscission defect of a weak hae hsl2 mutant in Arabidopsis.

In Arabidopsis thaliana, the process of abscission, or the shedding of unwanted organs, is mediated by two genes, HAESA (HAE) and HAESA-LIKE 2 (HSL2), encoding receptor-like protein kinases (RLKs). The double loss-of-function mutant hae-3 hsl2-3 is completely deficient in floral abscission, but, interestingly, the hae-3 hsl2-9 mutant displays a less severe defect. This mutant was chosen for an ethyl methanesulfonate (EMS) screen to isolate enhancer and suppressor mutants, and two such suppressors are the focus of this study. Pooled DNA from the F2 generation of a parental backcross was analyzed by genome sequencing to reveal candidate genes, two of which complement the suppressor phenotype. These genes, EMS-MUTAGENIZED BRI1 SUPPRESSOR 3 (EBS3) and EBS4, both encode mannosyltransferases involved in endoplasmic reticulum (ER)-associated degradation (ERAD) of proteins. Further analysis of these suppressor lines revealed that suppressor mutations are acting solely on the partially functional hsl2-9 mutant receptor to modify the abscission phenotype. Expressing a hsl2-9-yellow fluorescent protein (YFP) transgene in ebs3 mutants yields a higher fluorescent signal than in EBS3/ebs3, suggesting that these mutants restore abscission by disrupting ERAD to allow accumulation of the hsl2-9 receptor, which probably escapes degradation to be trafficked to the plasma membrane to regain signaling.

Creativity Doesn't Develop in a Vacuum.

The skills, knowledge, attitudes, motivations, and personality traits that lead to creative thinking and creative behavior do not exist-and do not develop-in a vacuum. They are inextricably tied to content, to domains, in particular, and they therefore vary by domains. The more we learn about creativity, the more we discover how domain specific creativity is. This means we cannot nurture creativity, or any of the skills or attributes that contribute to creativity, without thinking about content. One cannot become physically fit by doing just one kind of exercise that trains a single set of muscles; all-around fitness requires diverse exercises that use and train many different sets of muscles. So it is with creativity. Different domains require different creativity-relevant skills, knowledge, attitudes, motivations, and personality traits. If we want to help children and adolescents become more creative, then we need to attend to the domains we use in the development of creativity.

The association of therapist empathy and synchrony in vocally encoded arousal.

Empathy is a critical ingredient in motivational interviewing (MI) and in psychotherapy generally. It is typically defined as the ability to experience and understand the feelings of another. Basic science indicates that empathy is related to the development of synchrony in dyads. However, in clinical research, empathy has proved difficult to operationalize and measure, and has mostly relied on the felt sense of observers, clients, or therapists. We extracted estimates of therapist and standardized patient (SP) vocally encoded arousal (mean fundamental frequency; mean f0) in 89 MI sessions with high and low empathy ratings from independent observers. We hypothesized (a) therapist and SP mean f0 would be correlated and (b) the correlation of therapist and SP mean f0 would be greater in sessions with high empathy as compared with low. On the basis of a multivariate mixed model, the correlation between therapist and SP mean f0 was large (r = .71) and close to 0 in randomly assigned therapist-SP dyads (r = -.08). The association was higher in sessions with high empathy ratings (r = .80) than in sessions with low ratings (r = .36). There was strong evidence for vocal synchrony in clinical dyads as well as for the association of synchrony with empathy ratings, illustrating the relevance of basic psychological processes to clinical interactions. These findings provide initial evidence for an objective and nonobtrusive method for assessing therapist performance. Novel indicators of therapist empathy may have implications for the study of MI process as well as the training of therapists generally. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

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.

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.

Callous-unemotional traits and conduct disorder symptoms as prospective risk factors for adolescent sexual activity.

Conduct disorder (CD) has been shown to increase risk for adolescent sexual activity and pregnancy. Despite increasing evidence underscoring callous-unemotional (CU) traits as a marker for youth with CD prone to especially poor outcomes, researchers have yet to explore whether CU traits confer additional risk of early sexual intercourse, unprotected sex, and pregnancy. The Developmental Pathways Project sample, including 471 ethnically diverse 6th-grade boys and girls followed into 12th grade, was used to examine whether CU traits and CD symptoms in 6th grade uniquely and/or synergistically predicted having sexual intercourse by age 13 as well as unprotected sex and pregnancy by 12th grade. Parent-rated CU traits and CD symptoms interacted to predict young adolescents having sexual intercourse, such that youth with elevated CU traits and CD symptoms in 6th grade were more likely to reporting having sex by age 13 than those with low CU traits and/or low CD symptoms. Elevated CD symptoms, but not CU traits, uniquely increased risk of pregnancy by 12th grade. Neither CU traits nor CD symptoms predicted engagement in unprotected sex in 12th grade. Our findings indicate that adolescents with conduct problems and CU traits are especially at risk for early sexual intercourse. Conversely, elevated CU traits do not appear to increase risk of unprotected sex or pregnancy among young adolescents with conduct problems. Research is needed to replicate these findings and to explore mechanisms underlying the association between CU traits, CD symptoms, and early adolescent sexual activity.

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).

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.

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 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.