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.

Committing to genomic answers for all kids: Evaluating inequity in genomic research enrollment.

PURPOSE: Persistent inequities in genomic medicine and research contribute to health disparities. This analysis uses a context-specific and equity-focused strategy to evaluate enrollment patterns for Genomic Answers for Kids (GA4K), a large, metropolitan-wide genomic study on children. METHODS: Electronic health records for 2247 GA4K study participants were used to evaluate the distribution of individuals by demographics (race, ethnicity, and payor type) and location (residential address). Addresses were geocoded to produce point density and 3-digit zip code maps showing local and regional enrollment patterns. Health system reports and census data were used to compare participant characteristics with reference populations at different spatial scales. RESULTS: Racial and ethnic minoritized and populations with low-income were underrepresented in the GA4K study cohort. Geographic variation demonstrates inequity in enrollment and participation among children from historically segregated and socially disadvantaged communities. CONCLUSION: Our findings illustrate inequity in enrollment related to both GA4K study design and structural inequalities, which we suspect may exist for similar US-based studies. Our methods provide a scalable framework for continually evaluating and improving study design to ensure equitable participation in and benefits from genomic research and medicine. The use of high-resolution, place-based data represents a novel and practical means of identifying and characterizing inequities and targeting community engagement.

Standardized Health data and Research Exchange (SHaRE): promoting a learning health system.

Aggregate de-identified data from electronic health records (EHRs) provide a valuable resource for research. The Standardized Health data and Research Exchange (SHaRE) is a diverse group of US healthcare organizations contributing to the Cerner Health Facts (HF) and Cerner Real-World Data (CRWD) initiatives. The 51 facilities at the 7 founding organizations have provided data about more than 4.8 million patients with 63 million encounters to HF and 7.4 million patients and 119 million encounters to CRWD. SHaRE organizations unmask their organization IDs and provide 3-digit zip code (zip3) data to support epidemiology and disparity research. SHaRE enables communication between members, facilitating data validation and collaboration as we demonstrate by comparing imputed EHR module usage to actual usage. Unlike other data sharing initiatives, no additional technology installation is required. SHaRE establishes a foundation for members to engage in discussions that bridge data science research and patient care, promoting the learning health system.

Revealing the racial and spatial disparity in pediatric asthma: A Kansas City case study.

Black and other socially disadvantaged children are disproportionately burdened by high rates of pediatric asthma. Intraurban variation in environmental risk factors and limited access to high-resolution health data make it difficult to identify vulnerable patients, communities, or the immediate exposures that may contribute to pediatric asthma exacerbation. This article presents a novel, interdisciplinary health disparities research and intervention strategy applied to the problem of pediatric asthma in Kansas City. First, address-level electronic health records from a major children's hospital in the Kansas City region are used to map the distribution of asthma encounters in 2012 at a high spatial resolution. Census tract Environmental Justice Screening Method (EJSM) indicators are then developed to scan for patterns in both the population health risks and vulnerabilities that may contribute to the burden of asthma in different communities. A Bayesian Profile Regression cluster analysis is used to systematically explore the complex relationships between census tract EJSM indicators and pediatric asthma incidence rates, helping to identify population characteristics and risk factors associated with both high and low rates of pediatric asthma throughout the region. The EJSM scanning exercise and BPR analysis demonstrate that each community faces a distinct set of risks and vulnerabilities that can contribute to the rate of acute pediatric asthma acute care encounters, providing targets for research and intervention. It is clear, however, that different forms of social disadvantage are driving high rates of pediatric asthma, which is closely tied to uneven development patterns and racial residential segregation. The results provide a starting point for designing place-based health disparities research and intervention strategies catered to the unique needs of vulnerable patients and communities; disparities-focused research and intervention strategies that leverage local knowledge and resources through community-based practices.