B-cell-directed CAR-T cell therapy activates CD8+ cytotoxic CARneg bystander T-cells in non-human primates and patients.

CAR-T cells hold promise as a therapy for B-cell-derived malignancies, yet despite their impressive initial response rates, a significant proportion of patients ultimately experience relapse. While recent studies have explored the mechanisms of in vivo CAR-T cell function, little is understood about the activation of surrounding CARneg bystander T-cells and their potential to enhance tumor responses. We performed single-cell RNA-Seq (scRNA-Seq) on non-human primate (NHP) and patient-derived T-cells to identify the phenotypic and transcriptomic hallmarks of bystander activation of CARneg T-cells following B-cell targeted CAR-T cell therapy. Utilizing a highly translatable CD20 CAR NHP model, we observed a distinct population of activated CD8+ CARneg T-cells emerging during CAR-T cell expansion. These bystander CD8+ CARneg T-cells exhibited a unique transcriptional signature with upregulation of NK-cell markers (KIR3DL2, CD160, KLRD1), chemokines and chemokine receptors (CCL5, XCL1, CCR9), and downregulation of naive T-cell-associated genes (SELL, CD28). A transcriptionally similar population was identified in patients following Tisagenlecleucel infusion. Mechanistic studies revealed that IL-2 and IL-15 exposure induced bystander-like CD8+ T-cells in a dose dependent manner. In vitro activated and patient-derived T-cells with the bystander phenotype efficiently killed leukemic cells through a TCR-independent mechanism. Collectively, this dataset provides the first comprehensive identification and profiling of CARneg bystander CD8+ T-cells following B-cell targeting CAR-T cell therapy and suggests a novel mechanism through which CAR-T cell infusion might trigger enhanced anti-leukemic responses.

Addressing high flow overuse in bronchiolitis - Successes and future directions.

The use of high flow nasal cannula (HFNC) in the treatment of bronchiolitis has markedly increased in the last decade, yet randomized controlled trials have reported little clinical benefit with early, routine use. This article provides a concise overview of the current status of HFNC therapy, discusses successful de-implementation strategies to curtail HFNC overuse, and explores future bronchiolitis and HFNC quality improvement and research considerations.

Working Through Stigma: A Constructivist Grounded Theory of Delivering Health Services to Diverse 2SLGBTQ Populations.

Previous research inadequately explores processes and factors influencing the delivery of health services to sexual and gender minorities in ways that equitably attend to the infinite diversity held by these groups. This study employed Intersectionality and Critical Theories to inform Constructivist Grounded Theory methods and methodology; social categories of identity were strategically adopted to explore domains of power operating across multiple forms of oppression, think through subjective realities, and generate a nuanced rendering of power relations influencing health service delivery to diverse 2SLGBTQ populations in a Canadian province. Semi-structured interviews were conducted and the co-constructed theory of Working Through Stigma, with three interrelated concepts, depending on context, resolving histories, and surviving the situation, was generated. The theory depicts the concerns of participants and what they do about power relations influencing health service delivery and broader social contexts. While the negative impacts of stigma were widely and diversely experienced by patients and providers, ways of working within power relations emerged that would be impossible if stigma was not present, highlighting opportunities to positively impact those from stigmatized groups. As such, Working Through Stigma is a theory that flouts the tradition of stigma research; it offers theoretical knowledge that can be used to work within power relations upholding stigma in ways that increase access to quality health services for those whose historical underservicing can be attributed to stigma. In doing so, the stigma script is flipped and strategies for working against practices and behaviours that uphold cultural supremacies may be realized.

Creating psychological safety in interprofessional simulation for health professional learners: a scoping review of the barriers and enablers.

Interprofessional simulation-based education (IP-SBE) supports the acquisition of interprofessional collaborative competencies. Psychologically safe environments are necessary to address socio-historical hierarchies and coercive practices that may occur in IP-SBE, facilitating fuller student participation. A scoping review was conducted to understand the barriers and enablers of psychological safety within IP-SBE. Research papers were eligible if they included two or more undergraduate and/or post-graduate students in health/social care qualifications/degrees and discussed barriers and/or enablers of psychological safety within simulation-based education. Sources of evidence included experimental, quasi-experimental, analytical observational, descriptive observational, qualitative, and mixed-methodological peer-reviewed studies. English or English-translated articles, published after January 1, 1990, were included. Data were extracted by two members of the research team. Extraction conflicts were resolved by the principal investigators. In total, 1,653 studies were screened; 1,527 did not meet inclusion criteria. After a full-text review, 99 additional articles were excluded; 27 studies were analyzed. Psychological safety enablers include prebriefing-debriefing by trained facilitators, no-blame culture, and structured evidenced-based simulation designs. Hierarchy among/between professions, fear of making mistakes, and uncertainty were considered barriers. Recognition of barriers and enablers of psychological safety in IP-SBE is an important first step towards creating strategies that support the full participation of students in their acquisition of IPC competencies.

Characteristics and outcomes of 627 044 COVID-19 patients living with and without obesity in the United States, Spain, and the United Kingdom.

BACKGROUND: A detailed characterization of patients with COVID-19 living with obesity has not yet been undertaken. We aimed to describe and compare the demographics, medical conditions, and outcomes of COVID-19 patients living with obesity (PLWO) to those of patients living without obesity. METHODS: We conducted a cohort study based on outpatient/inpatient care and claims data from January to June 2020 from Spain, the UK, and the US. We used six databases standardized to the OMOP common data model. We defined two non-mutually exclusive cohorts of patients diagnosed and/or hospitalized with COVID-19; patients were followed from index date to 30 days or death. We report the frequency of demographics, prior medical conditions, and 30-days outcomes (hospitalization, events, and death) by obesity status. RESULTS: We included 627 044 (Spain: 122 058, UK: 2336, and US: 502 650) diagnosed and 160 013 (Spain: 18 197, US: 141 816) hospitalized patients with COVID-19. The prevalence of obesity was higher among patients hospitalized (39.9%, 95%CI: 39.8-40.0) than among those diagnosed with COVID-19 (33.1%; 95%CI: 33.0-33.2). In both cohorts, PLWO were more often female. Hospitalized PLWO were younger than patients without obesity. Overall, COVID-19 PLWO were more likely to have prior medical conditions, present with cardiovascular and respiratory events during hospitalization, or require intensive services compared to COVID-19 patients without obesity. CONCLUSION: We show that PLWO differ from patients without obesity in a wide range of medical conditions and present with more severe forms of COVID-19, with higher hospitalization rates and intensive services requirements. These findings can help guiding preventive strategies of COVID-19 infection and complications and generating hypotheses for causal inference studies.

Prognostic factors for finger interphalangeal joint osteoarthritis: a systematic review.

OBJECTIVE: Radiographic hand OA affects one in five adults. Symptomatic hand OA can result in functional impairment, pain and reduced quality of life. A prevalent form of hand OA is IP joint OA, however prognostic factors for IP joint OA remain poorly understood. This systematic review aimed to identify prognostic factors for IP joint OA, and to summarize the diagnostic criteria for IP joint OA in prognostic studies. METHODS: EMBASE, MEDLINE, Scopus and The Cochrane Library were searched from inception until 19 February 2020 (PROSPERO CRD42019116782). Eligible studies described diagnostic criteria defining IP joint OA, and assessed potential prognostic factors for IP joint OA. Risk of bias was assessed using a modified Quality in Prognosis Studies (QUIPS) tool and a best evidence synthesis was used. RESULTS: Eighteen studies were included (risk of bias: eight high, three moderate, seven low). All defined OA radiographically, and three studies incorporated clinical symptoms into their definition of OA. Forty-nine potential prognostic factors were assessed. Eight were prognostic: older age in women, female gender (both moderate evidence); family history of Heberden's nodes, Kashin-Beck disease, older age in men, dental occupation in men, finger fracture, parity (all limited evidence). Higher BMI in women (limited evidence) was prognostic for symptomatic radiographic OA. No prognostic factors for symptomatic OA were identified. CONCLUSION: IP joint OA is most commonly defined radiographically, yet criteria were heterogeneous. Eight prognostic factors for radiographic IP joint OA and one for symptomatic radiographic IP joint OA were identified, all with limited or moderate evidence. Further studies on causality and on prognostic pathways are needed.

Low rate of subsequent surgery and serious complications following intra-articular steroid injection for base of thumb osteoarthritis: national cohort analysis.

OBJECTIVES: Intra-articular steroid injection is commonly used to treat base of thumb osteoarthritis (BTOA), despite a lack of large-scale data on safety and effectiveness. We estimate the incidence of serious complications and further procedures following BTOA injection, including the risk of post-operative serious surgical site infection for subsequent operative intervention. METHODS: Hospital Episode Statistics data linked to mortality records from 1 April 1998 to 31 March 2017 were used to identify all BTOA injections undertaken in adults in the National Health Service secondary care in England. Patients were followed up longitudinally until death or 31 March 2017. A multivariable regression with a Fine and Gray model adjusting for the competing risk of mortality in addition to age, sex and socioeconomic deprivation was used to identify factors associated with progression to further procedure. Secondary outcomes included serious complications after injection and subsequent surgical site infection. RESULTS: A total of 19 120 primary injections were performed during the 19-year period in 18 356 patients. Of these 76.5% were female; mean age 62 years (s.d. 10.6); 50.48% underwent further procedure; 22.40% underwent surgery. Median time to further intervention was 412 days (IQR 110-1945). Female sex was associated with increased risk of proceeding to surgery. Serious complication rate following injection was 0.04% (0.01-0.08) within 90 days. Of those proceeding to surgery 0.16% (0.06-0.34) presented with a wound infection within 30 days and 90 days, compared with an overall post-operative wound infection rate of 0.03% (0.02-0.05). CONCLUSIONS: Very low rates of serious complications were identified following BTOA injections performed in secondary care; only one in five patients proceeded to subsequent surgery. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, https://www.clinicaltrials.gov, NCT03573765.

Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multinational network cohort study.

OBJECTIVES: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA. METHODS: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%. RESULTS: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis. CONCLUSION: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation. TRIAL REGISTRATION: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.

COVID-19 in patients with autoimmune diseases: characteristics and outcomes in a multinational network of cohorts across three countries.

OBJECTIVE: Patients with autoimmune diseases were advised to shield to avoid coronavirus disease 2019 (COVID-19), but information on their prognosis is lacking. We characterized 30-day outcomes and mortality after hospitalization with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza. METHODS: A multinational network cohort study was conducted using electronic health records data from Columbia University Irving Medical Center [USA, Optum (USA), Department of Veterans Affairs (USA), Information System for Research in Primary Care-Hospitalization Linked Data (Spain) and claims data from IQVIA Open Claims (USA) and Health Insurance and Review Assessment (South Korea). All patients with prevalent autoimmune diseases, diagnosed and/or hospitalized between January and June 2020 with COVID-19, and similar patients hospitalized with influenza in 2017-18 were included. Outcomes were death and complications within 30 days of hospitalization. RESULTS: We studied 133 589 patients diagnosed and 48 418 hospitalized with COVID-19 with prevalent autoimmune diseases. Most patients were female, aged ≥50 years with previous comorbidities. The prevalence of hypertension (45.5-93.2%), chronic kidney disease (14.0-52.7%) and heart disease (29.0-83.8%) was higher in hospitalized vs diagnosed patients with COVID-19. Compared with 70 660 hospitalized with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2-4.3% vs 6.32-24.6%). CONCLUSION: Compared with influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality.

Temporal Trends and Geographical Variation in Dupuytren Disease Surgery in England: A Population-Based Cohort Study.

BACKGROUND: Dupuytren disease (DD) is a common fibroproliferative disease of the palmar fascia. The mainstay of DD treatment in England is surgery with either percutaneous needle fasciotomy, limited fasciectomy, or dermofasciectomy. This study aimed to investigate the temporal trends and geographical variation of primary DD surgery in England. METHODS: A longitudinal population-based cohort study was perfomed using the Hospital Episode Statistics database from April 1, 2007, to March 31, 2017. Directly standarized rates were estimated over time (between financial years 2007-2008 and 2016-2017) and by geographic region (by clinical commissioning groups [CCGs]; financial years 2010-2011, 2013-2014, and 2016-2017). The Office for National Statistics midyear population estimates were used as the reference population. MAIN FINDINGS: Primary DD surgery was undertaken at a steadily increasing rate from financial year 2007 to 2008, to 2016 to 2017 in England. There was a striking 3.6-fold variation in the rates of primary DD surgery among National Health Service CCGs in England place of residence. CONCLUSIONS: This significant variation in DD surgical treatment in England suggests a need for the development of standardized surgical practice across all CCGs and National Health Service hospitals, promoting equality of access to cost-effective health care.

Risk factors for the progression of finger interphalangeal joint osteoarthritis: a systematic review.

Progressive hand interphalangeal joint (IPJ) osteoarthritis is associated with pain, reduced function and impaired quality of life. However, the evidence surrounding risk factors for IPJ osteoarthritis progression is unclear. Identifying risk factors for IPJ osteoarthritis progression may inform preventative strategies and early interventions to improve long-term outcomes for individuals at risk of IPJ osteoarthritis progression. The objectives of the study were to describe methods used to measure the progression of IPJ osteoarthritis and identify risk factors for IPJ osteoarthritis progression. MEDLINE, EMBASE, Scopus, and The Cochrane Library were searched from inception to 19th February 2020 (PROSPERO CRD42019121034). Eligible studies assessed potential risk factor/s associated with IPJ osteoarthritis progression. Risk of bias was assessed using a modified QUIPS Tool, and a best evidence synthesis was performed. Of eight eligible studies, all measured osteoarthritis progression radiographically, and none considered symptoms. Eighteen potential risk factors were assessed. Diabetes (adjusted mean difference between 2.06 and 7.78), and larger finger epiphyseal index in males (regression coefficient ß = 0.202) and females (ß = 0.325) were identified as risk factors (limited evidence). Older age in men and women showed mixed results; 13 variables were not risk factors (all limited evidence). Patients with diabetes and larger finger epiphyseal index might be at higher risk of radiographic IPJ osteoarthritis progression, though evidence is limited and studies are biased. Studies assessing symptomatic IPJ osteoarthritis progression are lacking.

Effect of Macrolide and Rifampin Resistance on Fitness of Rhodococcus equi during Intramacrophage Replication and In Vivo.

The soil-dwelling, saprophytic actinomycete Rhodococcus equi is a facultative intracellular pathogen of macrophages and causes severe bronchopneumonia when inhaled by susceptible foals. Standard treatment for R. equi disease is dual-antimicrobial therapy with a macrolide and rifampin. Thoracic ultrasonography and early treatment with antimicrobials prior to the development of clinical signs are used as means of controlling endemic R. equi infection on many farms. Concurrently with the increased use of macrolides and rifampin for chemoprophylaxis and the treatment of subclinically affected foals, a significant increase in the incidence of macrolide- and rifampin-resistant R. equi isolates has been documented. Previously, our laboratory demonstrated decreased fitness of R. equi strains that were resistant to macrolides, rifampin, or both, resulting in impaired in vitro growth in iron-restricted media and in soil. The objective of this study was to examine the effect of macrolide and/or rifampin resistance on intracellular replication of R. equi in equine pulmonary macrophages and in an in vivo mouse infection model in the presence and absence of antibiotics. In equine macrophages, the macrolide-resistant strain did not increase in bacterial numbers over time and the dual macrolide- and rifampin-resistant strain exhibited decreased proliferation compared to the susceptible isolate. In the mouse model, in the absence of antibiotics, the susceptible R. equi isolate outcompeted the macrolide- or rifampin-resistant strains.

Effect of Macrolide and Rifampin Resistance on the Fitness of Rhodococcus equi.

Rhodococcus equi is a leading cause of severe pneumonia in foals. Standard treatment is dual antimicrobial therapy with a macrolide and rifampin, but the emergence of macrolide- and rifampin-resistant R. equi isolates is an increasing problem. The objective of this study was to determine the effect of macrolide and/or rifampin resistance on fitness of R. equi Three unique isogenic sets were created, each consisting of four R. equi strains, as follows: a susceptible parent isolate, strains resistant to macrolides or rifampin, and a dual macrolide- and rifampin-resistant strain. Each isogenic set's bacterial growth curve was generated in enriched medium, minimal medium (MM), and minimal medium without iron (MM-I). Bacterial survival in soil was analyzed over 12 months at -20°C, 4°C, 25°C, and 37°C, and the ability of these strains to retain antimicrobial resistance during sequential subculturing was determined. Insertion of the mobile element conferring macrolide resistance had minimal effect on in vitro growth. However, two of three rpoB mutations conferring rifampin resistance resulted in a decreased growth rate in MM. In soil, macrolide- or rifampin-resistant R. equi strains exhibited limited growth compared to that of the susceptible R. equi isolate at all temperatures except -20°C. During subculturing, macrolide resistance was lost over time, and two of three rpoB mutations reverted to the wild-type form. The growth of rifampin-resistant R. equi colonies is delayed under nutrient restriction. In soil, possession of rifampin or macrolide resistance results in decreased fitness. Both macrolide and rifampin resistance can be lost after repeated subculturing.IMPORTANCE This work advances our understanding of the opportunistic environmental pathogen Rhodococcus equi, a disease agent affecting horses and immunocompromised people. R. equi is one of the most common causes of severe pneumonia in young horses. For decades, the standard treatment for R. equi pneumonia in horses has been dual antimicrobial therapy with a macrolide and rifampin; effective alternatives to this combination are lacking. The World Health Organization classifies these antimicrobial agents as critically important for human medicine. Widespread macrolide and rifampin resistance in R. equi isolates is a major emerging problem for the horse-breeding industry and might also adversely impact human health if resistant strains infect people or transfer resistance mechanisms to other pathogens. This study details the impact of antimicrobial resistance on R. equi fitness, a vital step for understanding the ecology and epidemiology of resistant R. equi isolates, and will support development of novel strategies to combat antimicrobial resistance.

The Adolescent Champion Model: Primary Care Becomes Adolescent-Centered via Targeted Quality Improvement.

OBJECTIVE: To evaluate the effects of implementing the Adolescent Champion model, a novel quality improvement program targeted at helping primary care sites become more adolescent-centered. STUDY DESIGN: Nine primary care sites from pediatrics, family medicine, and medicine-pediatrics implemented the Adolescent Champion model. Each site identified a multidisciplinary champion team to undergo training on adolescent-centered care, deliver prepackaged trainings to other staff and providers, make youth-friendly site changes, implement a standardized flow to confidentially screen for risky behaviors, and complete a quality improvement project regarding confidentiality practices. Adolescent patients, staff, and providers were surveyed at baseline, year-end, and 1-year follow-up to assess changes. RESULTS: Adolescent patients' experiences with both their provider and the site overall significantly improved (P values from <.0001 to .004, N = 474 baseline, 386 year-end). Staff perceived an improvement in clinic practices relating to adolescents and in their ability to make institutional and personal change (P < .0001, N = 121 baseline, 109 year-end). The majority of changes were sustained 1-year postintervention. Frequently noted site improvements included: (1) initiating a method to gather feedback from adolescent patients; (2) adding trainings on confidentiality, cultural humility, and using a nonjudgmental approach; (3) updating immunizations at every visit; and (4) training providers in long acting reversible contraception via implant training. CONCLUSIONS: Implementing the Adolescent Champion model successfully helped primary care sites become more adolescent-centered. Further studies are needed to evaluate the effects of this model on patient outcomes.

A new acute scaphoid fracture assessment method: a reliability study of the 'long axis' measurement.

BACKGROUND: The aim of this study was to assess the inter observer and intra observer reliability of acute scaphoid fracture classification methods including a novel 'long axis' measurement, a simple method which we have developed with the aim of improving agreement when describing acute fractures. METHODS: We identified sixty patients with acute scaphoid fractures at two centres who had been investigated with both plain radiographs and a CT (Computed Tomography) scan within 4 weeks of injury. The fractures were assessed by three observers at each centre using three commonly used classification systems and the 'long axis' method. RESULTS: Inter observer reliability: based on X-rays the 'long axis' measurement demonstrated substantial agreement (Intraclass Correlation Coefficient (ICC) =0.76) and was significantly more reliable than the Mayo (p < 0.01), the most reliable of the established classification systems with moderate levels of agreement (kappa = 0.56). Intra observer reliability: the long axis measurement demonstrated almost perfect agreement whether based on X-ray (ICC = 0.905) or CT (ICC = 0.900). CONCLUSIONS: This study describes a novel pragmatic 'long axis' method for the assessment of acute scaphoid fractures which demonstrates substantial inter and intra observer reliability. The 'long axis' measurement has clear potential benefits over traditional classification systems which should be explored in future clinical research.

Transmission of MDR MRSA between primates, their environment and personnel at a United States primate centre.

OBJECTIVES: MDR MRSA isolates cultured from primates, their facility and primate personnel from the Washington National Primate Research Center were characterized to determine whether they were epidemiologically related to each other and if they represented common local human-associated MRSA strains. METHODS: Human and primate nasal and composite environmental samples were collected, enriched and selected on medium supplemented with oxacillin and polymyxin B. Isolates were biochemically verified as Staphylococcus aureus and screened for the mecA gene. Selected isolates were characterized using SCCmec typing, MLST and WGS. RESULTS: Nasal cultures were performed on 596 primates and 105 (17.6%) were MRSA positive. Two of 79 (2.5%) personnel and two of 56 (3.6%) composite primate environmental facility samples were MRSA positive. Three MRSA isolates from primates, one MRSA from personnel, two environmental MRSA and one primate MSSA were ST188 and were the same strain type by conventional typing methods. ST188 isolates were related to a 2007 ST188 human isolate from Hong Kong. Both MRSA isolates from out-of-state primates had a novel MLST type, ST3268, and an unrelated group. All isolates carried ≥1 other antibiotic resistance gene(s), including tet(38), the only tet gene identified. CONCLUSIONS: ST188 is very rare in North America and has almost exclusively been identified in people from Pan-Asia, while ST3268 is a newly reported MRSA type. The data suggest that the primate MDR MRSA was unlikely to come from primate centre employees. Captive primates are likely to be an unappreciated source of MRSA.

Noradrenergic ß-receptor antagonism within the central nucleus of the amygdala or bed nucleus of the stria terminalis attenuates the negative/anxiogenic effects of cocaine.

Cocaine has been shown to produce both initial rewarding and delayed anxiogenic effects. Although the neurobiology of cocaine's rewarding effects has been well studied, the mechanisms underlying its anxiogenic effects remain unclear. We used two behavioral assays to study these opposing actions of cocaine: a runway self-administration test and a modified place conditioning test. In the runway, the positive and negative effects of cocaine are reflected in the frequency of approach-avoidance conflict that animals develop about entering a goal box associated with cocaine delivery. In the place conditioning test, animals develop preferences for environments paired with the immediate/rewarding effects of cocaine, but avoid environments paired with the drug's delayed/anxiogenic actions. In the present study, these two behavioral assays were used to examine the role of norepinephrine (NE) transmission within the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), each of which has been implicated in drug-withdrawal-induced anxiety and stress-induced response reinstatement. Rats experienced 15 single daily cocaine-reinforced (1.0 mg/kg, i.v.) runway trials 10 min after intracranial injection of the ß1 and ß2 NE receptor antagonists betaxolol and ICI 118551 or vehicle into the CeA or BNST. NE antagonism of either region dose dependently reduced approach-avoidance conflict behavior compared with that observed in vehicle-treated controls. In addition, NE antagonism selectively interfered with the expression of conditioned place aversions while leaving intact cocaine-induced place preferences. These data suggest a role for NE signaling within the BNST and the CeA in the anxiogenic actions of cocaine.