The neutral CB1 antagonist AM6527 reduces ethanol seeking, binge-like consumption, reinforcing, and withdrawal effects in male and female mice.

RATIONALE: Alcohol use disorder (AUD) is a debilitating physiological and psychiatric disorder which affects individuals globally. The current pharmacological interventions to treat AUD are limited, and hence there is an urgent need for a novel pharmacological therapy which can be effective and safe across the population. OBJECTIVE: We aimed to investigate a novel neutral cannabinoid receptor-1 (CB1R) antagonist, AM6527, in several preclinical models of ethanol consumption using male and female C57BL6/J mice. METHODS: Independent groups of male and female mice were subjected to repeated cycles of drinking in the dark (DID), or intermittent access to alcohol (IAA) procedures. Twenty minutes prior to ethanol access in each procedure, animals were treated with intraperitoneal injections of either 1, 3, and 10 mg/kg of AM6527 or its respective vehicle. Acamprosate (100, 200, 300, and 400 mg/kg) or its respective vehicle was used as a positive control. Separate groups of male mice were subjected to a chain schedule of ethanol reinforcement to gain access to ethanol wherein completion of a fixed interval (FI; 5 min) schedule (link 1: "Seeking") was reinforced with continuous access to ethanol (fixed ratio; FR1) for up to 1.8 g/kg (link 2: "consumption"). All the animals were treated with 1, 3, and 10 mg/kg of AM6527 or its respective vehicle 20 mins prior to the start of the FI chain of the procedure. Separately, AM6527 was also evaluated in male and female mice undergoing acute ethanol withdrawal following 8 weeks of intermittent or continuous access to 20% ethanol drinking. RESULTS: In both DID and IAA procedures, AM6527 reduced ethanol consumption in a dose-related manner in both male and female mice. AM6527 produced no tolerance in the DID procedure; mice treated with 3 mg/kg of AM6527 for 3 weeks continuously drank significantly smaller amounts of ethanol as compared to vehicle-treated mice over a period of three DID cycles. Moreover, in the IAA procedure, AM6527 caused an increase in water intake over the 24-h period. Acamprosate transiently reduced ethanol intake in male mice in both the DID and the IAA procedures but failed to produce any significant effect in female mice. AM6527 also produced a decrease in the FI responding ("ethanol seeking") in animals trained to self-administer ethanol. Lastly, AM6527 mitigated neurological withdrawal signs, i.e., handling induced convulsions (HIC) in mice undergoing acute ethanol withdrawal. CONCLUSIONS: Current findings support previous studies with CB1R neutral antagonist in reducing voluntary ethanol intake and seeking behavior. Based on results shown in this work, AM6527 can be developed as a first in class CB1R neutral antagonist to treat AUD in both males and females.

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking.

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome, in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, male Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an fixed-ratio 1 schedule. However, microbiome-depleted rats exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence and altered transcriptional regulation in the nucleus accumbens. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

BACKGROUND: Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants. METHODS: Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed effects models adjusted for race/ethnicity, CD4, age, BMI and INSTI type assessed relationships between CYP2B6 genotype and estimated differences in weight change. RESULTS: A total of 159 eligible participants switched ART from 2007 to 2019, of whom 138 had plasma HIV-1 RNA < 200 copies/mL (65 CYP2B6 normal, 56 intermediate, 17 poor metabolizers). Among participants with switch HIV-1 RNA < 200 copies/mL, weight increased in all 3 CYP2B6 groups. The rate of weight gain was greater in CYP2B6 poor than in CYP2B6 normal metabolizers overall, and within 9 subgroups (male, female, White, Black, Hispanic, dolutegravir, elvitegravir, raltegravir, and TDF in the pre-switch regimen); only in Hispanic and elvitegravir subgroups were these associations statistically significant ( P  < 0.05). Compared to normal metabolizers, CYP2B6 intermediate status was not consistently associated with weight gain. CONCLUSION: CYP2B6 poor metabolizer genotype was associated with greater weight gain after switch from efavirenz- to INSTI-containing ART, but results were inconsistent. Weight gain in this setting is likely complex and multifactorial.

D1 and D2 medium spiny neurons in the nucleus accumbens core have distinct and valence-independent roles in learning.

At the core of value-based learning is the nucleus accumbens (NAc). D1- and D2-receptor-containing medium spiny neurons (MSNs) in the NAc core are hypothesized to have opposing valence-based roles in behavior. Using optical imaging and manipulation approaches in mice, we show that neither D1 nor D2 MSNs signal valence. D1 MSN responses were evoked by stimuli regardless of valence or contingency. D2 MSNs were evoked by both cues and outcomes, were dynamically changed with learning, and tracked valence-free prediction error at the population and individual neuron level. Finally, D2 MSN responses to cues were necessary for associative learning. Thus, D1 and D2 MSNs work in tandem, rather than in opposition, by signaling specific properties of stimuli to control learning.

A new look at an old well-being construct: evaluating the psychometric properties of 9, 5, and 1-item versions of emotional exhaustion metrics.

Objective: To compare the relative strengths (psychometric and convergent validity) of four emotional exhaustion (EE) measures: 9- and 5-item scales and two 1-item metrics. Patients and methods: This was a national cross-sectional survey study of 1409 US physicians in 2013. Psychometric properties were compared using Cronbach's alpha, Confirmatory Factor Analysis (CFA), Exploratory Factor Analysis (EFA), and Spearman's Correlations. Convergent validity with subjective happiness (SHS), depression (CES-D10), work-life integration (WLI), and intention to leave current position (ITL) was assessed using Spearman's Correlations and Fisher's R-to-Z. Results: The 5-item EE scale correlated highly with the 9-item scale (Spearman's rho = 0.828), demonstrated excellent internal reliability (alpha = 0.87), and relative to the 9-item, exhibited superior CFA model fit (RMSEA = 0.082, CFI = 0.986, TLI = 0.972). The 5-item EE scale correlated as highly as the 9-item scale with SHS, CES-D10, and WLI, and significantly stronger than the 9-item scale to ITL. Both 1-item EE metrics had significantly weaker correlation with SHS, CES-D10, WLI, and ITL (Fisher's R-to-Z; p < 0.05) than the 5- and 9-item EE scales. Conclusion: The 5-item EE scale was repeatedly found equivalent or superior to the 9-item version across analyses, particularly with respect to the CFA results. As there is no cost to using the briefer 5-item EE scale, the burden on respondents is smaller, and widespread access to administering and interpreting an excellent wellbeing metric is enhanced at a critical time in global wellbeing research. The single item EE metrics exhibited lower convergent validity than the 5- and 9-item scales, but are acceptable for detecting a signal of EE when using a validated EE scale is not feasible. Replication of psychometrics and open-access benchmarking results for use of the 5-tem EE scale further enhance access and utility of this metric.

Food Restriction Level and Reinforcement Schedule Differentially Influence Behavior during Acquisition and Devaluation Procedures in Mice.

Behavioral strategies are often classified based on whether reinforcer value controls reinforcement. Value-sensitive behaviors, in which animals update their actions when reinforcer value is changed, are classified as goal-directed; conversely, value-insensitive actions, where behavior remains consistent when the reinforcer is removed or devalued, are considered habitual. Basic reinforcement schedules can help to bias behavior toward either process: random ratio (RR) schedules are thought to promote the formation of goal-directed behaviors while random intervals (RIs) promote habitual control. However, how the schedule-specific features of these tasks interact with other factors that influence learning to control behavior has not been well characterized. Using male and female mice, we asked how distinct food restriction levels, a strategy often used to increase task engagement, interact with RR and RI schedules to control performance during task acquisition and devaluation procedures. We determined that food restriction level has a stronger effect on the behavior of mice following RR schedules compared with RI schedules, and that it promotes a decrease in response rate during devaluation procedures that is best explained by the effects of extinction rather than devaluation. Surprisingly, food restriction accelerated the decrease in response rates observed following devaluation across sequential extinction sessions, but not within a single session. Our results support the idea that the relationships between schedules and behavioral control strategies are not clear-cut and suggest that an animal's engagement in a task must be accounted for, together with the structure of reinforcement schedules, to appropriately interpret the cognitive underpinnings of behavior.

Efficacy of Alexa, Google Assistant, and Siri for Supporting Informed Prostate Cancer Screening Decisions for African-American Men.

Prostate cancer is the most prevalent non-skin cancer among all men, but African-Americans have morbidity and mortality at significantly higher rates than White men. To reduce this burden, authorities such as the American Cancer Society recommend that men make informed/shared screening decisions with a healthcare provider. Informed/shared screening decisions require that men have adequate prostate cancer knowledge. Virtual assistants are interactive communication technologies that have become popular for seeking health information, though information quality has been mixed. No prior research has investigated the quality of prostate cancer information disseminated by virtual assistants. The purpose of this study was to determine the response rates, accuracy, breadth, and credibility of three popular virtual assistants (Alexa, Google Assistant, and Siri) for supporting informed/shared prostate cancer screening decisions for African-American men. Each virtual assistant was evaluated on a tablet, cell phone, and smart speaker using 12 frequently asked screening questions. Responses were rated dichotomously (i.e., yes/no), and analyses were conducted using SPSS. Alexa on a phone or tablet and Google Assistant on a smart speaker had the best overall performance based on a combination of response, accuracy, and credibility scores. All other assistants scored below 75% in one or more areas. Additionally, all virtual assistants lacked the breadth to support an informed/shared prostate cancer screening decision. African-American men may be especially disadvantaged by using virtual assistants for prostate cancer information because of the lack of emphasis on their greater disease risk, higher mortality rates, and appropriate ages at which they should begin screening conversations.

Evaluation of a health system's implementation of a monkeypox care model under the RE-AIM framework.

Objective: Emerging infectious diseases challenge healthcare systems to implement new models of care. We aim to evaluate the rapid implementation of a new care model for monkeypox in our health system. Design: This is a retrospective case series evaluation under the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework of implementation of a testing and care model for monkeypox in a large, integrated health system. Methods: Atrium Health implemented education of providers, testing protocols, and management of potential monkeypox cases using electronic health record (EHR) data capabilities, telehealth, and collaboration between multiple disciplines. The first 4 weeks of care model implementation were evaluated under the RE-AIM framework. Results: One hundred fifty-three patients were tested for monkeypox by 117 unique providers at urgent care, emergency departments, and infectious disease clinics in our healthcare system between 18 July 2022 and 14 August 2022. Fifty-eight monkeypox cases were identified, compared with 198 cases in the state during the time period, a disproportionate number compared with the health system service area, and 52 patients were assessed for need for tecovirimat treatment. The number of tests performed and providers sending tests increased during the study period. Conclusion: Implementation of a dedicated care model leveraging EHR data support, telehealth, and cross-disciplinary collaboration led to more effective identification and management of emerging infectious diseases and is important for public health. Plain Language Summary: Impact of care model implementation on monkeypox New infectious diseases challenge health systems to implement new care practices. Our health system responded to this challenge by implementing a care model for education, testing, and clinical care of monkeypox patients. We analyzed results from implementing the model. We were able to identify a disproportionate number of monkeypox cases compared with the rest of our state by using our model to educate medical providers, encourage testing, and ensure patients had access to best disease care. Implementation of care models for testing and management of new diseases will improve patient care and public health.

Mpox (Monkeypox) Infection During Pregnancy.

BACKGROUND: An mpox (formerly "monkeypox") outbreak began in 2022, leading to infection in special populations, including pregnant individuals. CASE: We present a case of an individual who presented with a labial ulcer and subsequent papular rash at 31 weeks of gestation. She was diagnosed with mpox infection and was treated with tecovirimat. She had an uncomplicated induction of labor at 39 2/7 weeks of gestation and delivered a healthy neonate. The neonate had a positive immunoglobulin G test result for orthopoxvirus but did not have skin lesions or positive molecular test results suggestive of infection. CONCLUSION: Transplacental transmission of mpox is possible, but, in this case, the neonate did not have clinical findings suggestive of active or antenatal mpox infection. Treatment with tecovirimat in gestational cases of mpox may be beneficial.

Total Hip Arthroplasty in the Setting of Post-Traumatic Arthritis Following Acetabular Fracture: A Systematic Review.

Background: Acetabular fractures are frequently associated with post-traumatic arthritis (PTA), for which total hip arthroplasty (THA) has emerged as the established procedure. The purpose of this systematic review is to report the patient outcomes, complications, and implant survival of delayed THA for patients with PTA following acetabular fracture. Methods: A systematic review was performed in December 2021 as per Preferred Reporting Items for Systematic Review and Meta-Analysis Guidelines to identify all studies reporting outcomes of delayed THA performed for PTA with a history of acetabular fracture. From an initial screen of 893 studies, 29 studies which met defined inclusion criteria including minimum 12 months of follow-up and minimum 10 THA were included in the final review. Results: A total of 1220 THA were reported across 29 studies, with 1174 THA completing a minimum of 1-year follow-up at a mean of 86 months. All 29 studies reported upon complications, with a control included in 6 for comparison. Higher complication rates were observed both in patients who had prior open reduction internal fixation and conservative treatment, most notably infection which was observed following 3.6% THA. The total joint revision rate was 9.7%. An improvement was noted in all 25 studies which recorded patient-reported outcomes, with a mean rise in the Harris hip score from 45 to 86 across 18 studies. Conclusions: THA may reduce reported pain levels and improve functional outcomes in selected patients experiencing PTA following acetabular fractures. There is an increased risk of complications, necessitating careful consideration when planning the operation and open discussion with prospective patients and caregivers.

Leadership Behavior Associations with Domains of Safety Culture, Engagement, and Health Care Worker Well-Being.

BACKGROUND: Leadership is a key driver of health care worker well-being and engagement, and feedback is an essential leadership behavior. Methods for evaluating interaction norms of local leaders are not well developed. Moreover, associations between local leadership and related domains are poorly understood. This study sought to evaluate health care worker leadership behaviors in relation to burnout, safety culture, and engagement using the Local Leadership scale of the Safety, Communication, Operational Reliability, and Engagement (SCORE) survey. METHODS: The SCORE survey was administered to 31 Midwestern hospitals as part of a broad effort to measure care context, with domains including Local Leadership, Emotional Exhaustion/Burnout, Safety Climate, and Engagement. Mixed-effects hierarchical logistic regression was used to evaluate the relationships between local leadership scores and related domains, adjusted for role and work-setting characteristics. RESULTS: Of the 23,853 distributed surveys, 16,797 (70.4%) were returned. Local leadership scores averaged 68.8 ± 29.1, with 7,338 (44.2%) reporting emotional exhaustion, 9,147 (55.9%) reporting concerning safety climate, 10,974 (68.4%) reporting concerning teamwork climate, 7,857 (47.5%) reporting high workload, and 3,436 (20.7%) reporting intentions to leave. Each 10-point increase in local leadership score was associated with odds ratios of 0.72 (95% confidence interval [CI] 0.71-0.73) for burnout, 0.48 (95% CI 0.47-0.49) for concerning safety climate, 0.64 (95% CI 0.63-0.66) for concerning teamwork climate, 0.90 (95% CI 0.89-0.92) for high workload, and 0.80 (95% CI 0.78-0.81) for intentions to leave, after adjustment for unit and provider characteristics. CONCLUSION: Local leadership behaviors are readily measurable using a five-item scale and strongly associate with established domains of health care worker well-being, safety culture, and engagement.

Assessing Leadership Behavior in Health Care: Introducing the Local Leadership Scale of the SCORE Survey.

BACKGROUND: Engaged and accessible leadership is a key component of care excellence. However, the field lacks brief, reliable, and actionable measures of feedback and coaching-related behaviors of local leaders (for example, provides frequent feedback). The current study introduces a five-item Local Leadership (LL) scale by examining its psychometric properties, providing benchmarking across demographic factors and work settings, assessing its association with psychological safety, and testing whether LL predicts reports of restricted activities and absenteeism. METHODS: In this cross-sectional study, 23,853 questionnaires were distributed across 31 Midwestern US hospitals. The survey included the LL scale, as well as safety culture and well-being scales. Psychometric analyses (Cronbach's α, confirmatory factor analysis [CFA] fit: root square mean error of the approximation [RMSEA], comparative fit index [CFI], Tucker-Lewis index [TLI]), Spearman correlations, t-tests, and analyses of variance (ANOVAs) were used to test the properties of the LL scale and differences by health care worker and work setting characteristics. RESULTS: A total of 16,797 surveys were returned (70.4% response rate). The LL scale exhibited strong psychometric properties (Cronbach's α = 0.94; RMSEA = 0.079; CFI = 0.99; TLI = 0.98). LL scores differed by role, shift, shift length, and years in specialty. Of all roles, leaders (for example, managers) rated leaders most favorably. Nonclinical (vs. clinical) and nonsurgical (vs. surgical) work settings reported higher LL. LL scores correlated positively with psychological safety, absenteeism, and activities restricted due to illness. CONCLUSION: The LL scale exhibits strong psychometric properties, convergent validity with psychological safety, and variation by work setting, work setting type, role, shift, shift length, and specialty. The study indicates that assessing leadership behaviors with the LL scale is useful and offers actionable behaviors for leaders to improve safety culture within teams.

Task parameters influence operant response variability in mice.

RATIONALE: During operant conditioning, animals associate actions with outcomes. However, patterns and rates of operant responding change over learning, which makes it difficult to distinguish changes in learning from general changes in performance or movement. Thus, understanding how task parameters influence movement execution is essential. OBJECTIVES: To understand how specific operant task parameters influenced the repetition of future operant responses, we investigated the ability of operant conditioning schedules and contingencies to promote reproducible bouts of five lever presses in mice. METHODS: Mice were trained on one of the four operant tasks to test three distinct hypotheses: (1) whether a cue presented concurrently with sucrose delivery influenced the pattern of lever pressing; (2) whether requiring animals to collect earned sucrose promoted the organization of responses into bouts; and (3) whether only reinforcing bouts where interresponse time (IRT) variances were below a target promoted reproducible patterns of operant behavior. RESULTS: (1) Signaling reinforcer delivery with a cue increased learning rates but resulted in mice pressing the lever in fast succession until the cue turned on, rather than executing discrete bouts. (2) Requiring mice to collect the reinforcer between bouts had little effect on behavior. (3) A training strategy that directly reinforced bouts with low variance IRTs was not more effective than a traditional fixed ratio schedule at promoting reproducible action execution. CONCLUSIONS: Together, our findings provide insights into the parameters of behavioral training that promote reproducible actions and that should be carefully selected when designing operant conditioning experiments.

Primary Care Evaluation of a Hepatitis C Virus (HCV) Screening Education Intervention.

INTRODUCTION: Increased screening efforts and the development of effective antiviral treatments have led to marked improvement in Hepatitis C (HCV) patient outcomes. However, many people in the US are believed to have undiagnosed HCV. Successful screening strategies and access to a coordinated system of care are critical for HCV affected adults. The objective of this study was to evaluate a primary care HCV screening education intervention that took place 2018 to 2019 to improve primary care training and management of patients after the implementation of the electronic medical record (EMR) screening alert. METHODS: Using 15 primary care practices located in vicinity of neighborhoods at-risk for higher rates of HCV infections, a stepped wedge randomized control study design was utilized to deliver an educational screening intervention. The education intervention was implemented sequentially with 5 practices being presented to every 3 months. Number of patients within the Baby Boomer cohort (birth years 1945-1965) were collected 3 months before the first practice receiving the intervention to 3 months after the last practice receiving the education intervention. The main outcome collected was the HCV screening. Generalized linear mixed models were used to test the hypothesis of improved screening rates after intervention implementation. RESULTS: There were a total of 85,697 patients within the Baby Boomer cohort seen at the 15 practices. Practices receiving the intervention had patients who were more likely to be screened for HCV (ß = 0.259, P < .001; Odds Ratio [OR] [95%CI] 1.296 [1.098-1.529]).In terms of demographics, results showed that females are less likely to be screened than males (ß = -0.141, P < .001; OR [95%CI] 0.868[0.813 to 0.927]), Baby Boomer patients aged less than 65 were more likely to be screened than Baby Boomer patients aged 65 and older (ß = 0.293, P < .001; OR [95%CI] 1.340[1.251 to 1.436]). DISCUSSION: This study looked at screening rates before and after an educational intervention which happened subsequent to the activation of an EMR alert. Whereas HCV EMR alerts showed an increase in HCV screenings before the education intervention, the addition of the education showed a modest increase in HCV screening rates for Baby Boomer patients.

Outcomes and antibiotic use in patients with coronavirus disease 2019 (COVID-19) admitted to an intensive care unit.

Antibiotic overuse is high in patients hospitalized with coronavirus disease 2019 (COVID-19) despite a low documented prevalence of bacterial infections in many studies. In this study evaluating 65 COVID-19 patients in the intensive care unit, empiric broad-spectrum antibiotics were often overutilized with an inertia to de-escalate despite negative culture results.