Minutes of the 157th Meeting of the NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
157th Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
May 11, 2021
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 157th meeting at 12:16 p.m. on Tuesday, May 11, 2021, via Zoom videoconference and NIH Webcast. The Council met in closed session from 11:00 a.m. to 11:45 a.m. to review grant applications and cooperative agreements. Dr. Abraham Bautista, Director, Office of Extramural Activities, presided over the Council’s review session, which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C., and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. The closed session recessed at 11:45 a.m.
Council Members Present:
Jill B. Becker, Ph.D.
Christopher S. Carpenter, Ph.D.
Constance M. Horgan, Sc.D.
Beth Kane-Davidson, LCADC, LCPC
Charles H. Lang, Ph.D.
Mary E. Larimer, Ph.D.
Laura E. Nagy, Ph.D.
Laura Elena O’Dell, Ph.D.
Scott J. Russo, Ph.D.
Edith Vioni Sullivan, Ph.D.
Col. Charles S. Milliken, M.D.
NIAAA Director and Chair: George F. Koob, Ph.D.
NIAAA Deputy Director: Patricia Powell, Ph.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Senior Staff: Vicki Buckley, M.B.A.; David Goldman, M.D.; Ralph Hingson, Sc.D.; M. Katherine Jung, Ph.D.; George Kunos, M.D., Ph.D.; Raye Litten, Ph.D.; Antonio Noronha, Ph.D.; Aaron White, Ph.D., and Bridget Williams-Simmons, Ph.D.
Other Attendees at the Open Session
Approximately 75 people viewed the NIH live webcast, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order
NIAAA Director George F. Koob, Ph.D., called the open session of the Council meeting to order at 12:16 p.m. on Tuesday, May 11, 2021. Council members and senior staff introduced themselves.
Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report, which was distributed to Council members.
In Memoriam: Dr. Koob acknowledged the passing of two eminent members of the research community, recognized their contributions, and expressed condolences on behalf of NIAAA. Mary Jeanne Kreek, M.D. was a Physician-Scientist and the Patrick E & Beatrice M. Haggerty Professor at The Rockefeller University. Dr. Kreek helped develop methadone and contributed significantly to the field’s basic understanding of the neurobiology of addiction. Emmanuel (Manny) Rubin, M.D. was the Gonzalo E. Aponte Distinguished Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University. Dr. Rubin provided definitive evidence that alcohol toxicity, rather than poor nutrition, was responsible for organ damage related to alcohol misuse. He also identified mitochondrial dysfunction in the heart and liver as the target of alcohol toxicity.
Staff Transitions: Dr. Koob welcomed Shera Smith, Extramural Support Assistant in the Office of Extramural Activities, and the following Visiting Postdoctoral Fellows in the Division of Intramural Clinical and Biological Research (DICBR): Khushbu Agarwal, Ph.D.; Abhishek Basu, Ph.D.; Yukum Guan, Ph.D.; and Markos Woldeyohannes, M.D., Ph.D. He also noted the transitions of Resat Cinar, Ph.D., to Tenure Track Investigator and Acting Chief for the Section on Fibrotic Disorders, DICBR; Malliga Iyer, Ph.D., to Tenure Track Investigator and Acting Chief for the Section on Medicinal Chemistry, DICBR; and Janos Paloczi, Ph.D., to Research Fellow in the Laboratory on Cardiovascular Physiology Tissue Injury, DICBR. Dr. Koob also announced the departures of Administrative Officers Emily Buzgierski and Carlos Gomez.
FY2021 Budget: NIH received a total of $42.9 billion for FY 2021, including general increases to NIH Institutes and Centers (ICs); coronavirus supplemental appropriations; allocations for the Helping to End Addiction Long-term (HEAL) Initiative, the 21st Century Cures Act, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, and research on influenza; and continued support for the Gabriella Miller Kids First Act pediatric research initiative. NIAAA received a total of $554.9 million for 2021. Preparation of the FY 2022 President’s Budget is underway.
NIAAA Funding Opportunities: Dr. Koob announced the following NIAAA-issued New Notice of Funding Opportunities (NOFOs) and Notices of Special Interest (NOSIs):
- SARS-CoV-2, COVID-19, and Consequences of Alcohol Use, RFA-AA-21-002; RFA-AA-21-003; RFA-AA-21-004;
- Specialized Alcohol Research Centers, RFA-AA-21-005; and
- Comprehensive Alcohol Research Centers, RFA-AA-21-006.
Dr. Koob also presented examples of NIH-wide NOFOs and NOSIs with NIAAA participation as follows:
- BRAIN Initiative: Development and Validation of Novel Tools to Probe Cell-Specific and Circuit-Specific Processes in the Brain, RFA-MH-21-175;
- Emergency Award: RADx-UP - Social, Ethical, and Behavioral Implications (SEBI) Research on Disparities in COVID-19 Testing among Underserved and Vulnerable Populations, RFA-OD-21-009; and
- NIH Blueprint and BRAIN Initiative Diversity Specialized Predoctoral to Postdoctoral Advancement in Neuroscience (D-SPAN) Award, RFA-NS-21-012.
Dr. Koob also made note of these special notices for early career investigators:
- Notice of Special Interest: Availability of Administrative Supplements for Childcare Costs for Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellows, NOT-OD-21-070, NOT-OD-21-074, NOT-OD-21-075;
- Reminder Requesting Extensions for Early Career Scientists Whose Career Trajectories Have Been Significantly Impacted by COVID-19, NOT-OD-21-052; and
- Notice of Continuation of Temporary Extension of Eligibility for the NIH K99/R00 Pathway to Independence Award During the COVID-19 Pandemic NOT-OD-21-106
A full list of NOFOs and NOSIs may be found in the NIAAA Director’s Report.
NIAAA Priorities: Dr. Koob shared the following NIAAA priorities with Council:
Addressing Diversity and Health Disparities in the Alcohol Field. NIAAA fully supports and is committed to the NIH UNITE initiative, a coordinated effort to address structural racism and promote racial equity and inclusion at NIH and within the larger biomedical research enterprise. To advance equity, diversity, and inclusion in the alcohol research enterprise, NIAAA is focusing on three primary areas: improving the NIAAA intramural and extramural workplace and culture; increasing diversity and equity in the scientific and administrative alcohol research workforce; and enhancing the NIAAA intramural and extramural scientific research portfolio. Dr. Koob described the following NOFOs to support this effort:
- Improving Health Disparities in Alcohol Health Services, RFA-AA-21-001
- Health disparate and vulnerable populations face unique and intersecting barriers to treatment, including but not limited to stigma, mistrust, bias, and structural racism. This new funding opportunity seeks to expand alcohol health services research on health disparities as well as encourage new studies on the accessibility, appeal, costs, dissemination, and implementation of alcohol use disorder (AUD) treatment.
- Understanding and Addressing the Impact of Structural Racism and Discrimination on Minority Health and Health Disparities, RFA-MD-21-004
- Despite increased awareness of the contribution of racism and discrimination to poorer health outcomes, these issues are not routinely included as determinants of health in biomedical research. The goal of this initiative is to support observational or intervention research to understand and address the impact of structural racism and discrimination on minority health and health disparities.
Training Opportunities to Support a Diverse Workforce: Dr. Koob also noted the following training opportunities:
- NIH Ruth L. Kirschstein NRSA for Individual Predoctoral Fellowships to Promote Diversity in Health-Related Research (F31), PA-20-251;
- NIH Blueprint Diversity Specialized Predoctoral to Postdoctoral Advancement in Neuroscience (D-SPAN) Award (F99/K00), RFA-NS-21-012;
- BRAIN Initiative Advanced Postdoctoral Career Transition Award to Promote Diversity (K99/R00); RFA-NS-19-043, RFA-NS-19-044;
- Maximizing Opportunities for Scientific and Academic Independent Careers (MOSAIC) Postdoctoral Career Transition Award to Promote Diversity (K99/R00), PAR-19-343; and
- Diversity supplements (PA-21-071) provide supplements to existing NIH-funded active grants to increase the diversity of the research workforce by supporting and recruiting students, and postdoctoral and other new investigators from groups that are underrepresented. More details about diversity supplements are available on the NIAAA website at https://go.usa.gov/xHf2j.
Supporting the Next Generation of Alcohol Researchers: Since 2014, NIAAA has steadily increased its number of training positions (F and T) and Career Development (K) awards.
Envisioning the Role of Telehealth in Addressing AUD in the Post-Pandemic Era: The COVID-19 pandemic caused a rapid expansion in the use of telehealth. Evidence suggests telehealth can be effective for addressing alcohol misuse and can reach people who might not otherwise get support.
NIAAA supports a variety of telehealth projects (pre-pandemic and pandemic-related), including Screening, Brief Intervention, and Referral to Treatment (SBIRT) with clinicians by phone or video chat; cognitive behavioral therapy (CBT) with a clinician or self-guided (Computer Based Training for Cognitive Behavioral Therapy [CBT4CBT]); telehealth to address post-traumatic stress disorder (PTSD) and alcohol use following sexual assault; and video-conferencing based motivational interviewing (MI) for alcohol misuse and medication adherence in patients living with HIV. The NIAAA Treatment Navigator links to effective options. NIAAA anticipates a larger role for telehealth for alcohol prevention, treatment, and recovery going forward.
Expanding Uptake of SBI/SBIRT: The U.S. Preventive Services Task Force recommends alcohol screening and brief intervention (alcohol SBI) or counseling in primary care settings for adults ages 18 and older. However, evidence highlights missed opportunities for healthcare providers to intervene with patients who report binge drinking. For example, among patients 18+ who saw a healthcare provider in the past 2 years, 81 percent were asked at least one question about their alcohol use, but only 38 percent were asked whether they binged in the past month. Among those who reported binge drinking, about 1 in 5 were given advice to cut down. Women were less likely than men to be advised about the risks of binge drinking (33 percent vs. 47 percent). Women who reported binge drinking were less likely to be advised to cut down than men who reported binge drinking (14 percent vs. 25 percent). Older drinkers (65+) were less likely to be screened or advised to cut down. According to the 2018-2019 National Survey on Drug Use and Health (NSDUH), very few people who report drinking to a healthcare provider are asked if they have any problems related to their drinking (~7 percent) and even fewer (<5 percent) are offered additional information about alcohol or advised to cut down. This is concerning because many patients are prescribed medications that could interact negatively with alcohol. Further, alcohol misuse is increasing among women and older drinkers, two groups that are less likely to be given advice or offered more information about alcohol. Alcohol screening has other implications for health, i.e., questions about alcohol misuse can provide clues about other important aspects of health (e.g., binge drinkers are more likely to have serious thoughts of suicide and to misuse prescription opioids or sedatives). NIAAA’s core resource for healthcare providers, available later this year, aims to provide physicians the information they need to become more comfortable discussing alcohol misuse with patients. Healthy People 2030 is a U.S. Department of Health and Human Services (HHS) initiative that has outlined a goal of increasing the percentage of people with substance use disorders (SUDs) receiving specialty treatment from 11 percent to 14 percent. SBIRT offers a route for achieving this goal.
Alcohol and Cancer: The American Cancer Society estimates that about 41 percent of men and 39 percent of women will eventually develop cancer; about 5.6 percent of newly diagnosed cases are alcohol-attributable. A recent study estimated that 75,000 new cancer cases and 19,000 cancer deaths per year are attributed to alcohol consumption in America. These cancers include those of the mouth, larynx, throat, esophagus, breast, liver, colon, and rectum. Yet there is a common lack of awareness: A 2017 survey from the American Society for Clinical Oncology found that fewer than one-third of respondents recognized that alcohol could cause cancer. Similarly, a 2019 survey from the American Institute for Cancer Research found that fewer than 50 percent of respondents recognized the cancer risks posed by alcohol. NIAAA and the National Cancer Institute (NCI) have partnered on a NOSI on Alcohol and Cancer Control, NOT-CA-20-034.
NESARC-III Genetic Data Now Available to Researchers: The NESARC-III is a large, nationally representative epidemiologic survey of substance use and mental health in adults in the United States. More than 36,000 people aged 18 and older were interviewed in 2012-2013. Among them, roughly 23,000 also provided samples of their DNA. This genetic data is now available to the research community. The combination of genotypic and phenotypic data about substance use and mental health makes NESARC-III unique. Exploration of the new genetic dataset with its rich phenotypic and family background variables could yield important insight into the relationships between genes and observable behaviors, including AUD and other substance use disorders, depression, post-traumatic stress disorder and other conditions, all diagnosed using criteria from the DSM-5. Thus, the NESARC-III genetic dataset will be a critical resource for helping scientists to better understand these disorders and develop novel diagnostic methods and treatments.
A New Strategic Plan for NIAAA: Work is in progress on NIAAA’s strategic plan for 2022-2026. A Request for Information (RFI) seeking input on the Institute’s priorities and objectives will be published soon.
Research Highlights: Dr. Koob presented highlights of NIAAA-funded studies focused on the negative effects of alcohol and the effects of alcohol on the immune system:
“Brain Ethanol Metabolism by Astrocytic ALDH2 Drives the Behavioral Effects of Ethanol Intoxication” was published in Nature Metabolism (2021 Mar;3(3):337-351) by S Jin, Q Cao, F Yang, H Zhu, S Xu, Q Chen, Z Wang, Y Lin, R Cinar, RJ Pawlosky, Y Zhang, W Xiong, B Gao, GF Koob, DM Lovinger, and L Zhang. Ethanol metabolites such as acetate, thought to be primarily the result of ethanol breakdown by hepatic aldehyde dehydrogenase 2 (ALDH2), contribute to behavioral effects of alcohol. The possibility that ethanol is metabolized inside the brain has been a long-standing topic of controversy in alcohol research. Researchers first examined ALDH2 expression in multiple brain regions. Because ALDH2 was most abundant in the cerebellum, they next explored the cell-type-specific distribution of ALDH2 in this brain region. Investigators identified the presence of ALDH2 in the brains of both humans and mice in cerebellar astrocytes. Astrocytic ALDH2 was found to mediate both ethanol- and acetate-induced cellular and behavioral effects, including impairment of balance and coordination skills, via GABAergic signaling. The findings indicate astrocytic ALDH2 as a potential target for the pathophysiology of alcohol use disorder.
“TRAIL Mediates Neuronal Death in AUD: A Link between Neuroinflammation and Neurodegeneration” was published in International Journal of Molecular Sciences (2021 Mar 4;22(5):2547) by L Qin, J Zou, A Barnett, RP Vetreno, FT Crews, and LG Coleman Jr. Analysis of postmortem human cortex of individuals diagnosed with alcohol use disorder (AUD) implicated the induction of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) apoptotic death receptors as a mediator of neuronal death. TRAIL acts via the Toll-like receptor 7 (TLR7) neuroimmune signaling pathway and its endogenous ligand, microRNA let-7b. Chronic binge levels of ethanol exposure in mice increased let-7b/TLR7 signaling and enhanced TLR7-mediated cell death responses through TRAIL, mimicking the increased TLR-7 induction and neurodegeneration observed in human cortex in AUD. Additionally, inhibition of TLR7 and let-7b blocked ethanol-induced neuronal death. Together, these findings suggest that TRAIL is a mediator of neuronal death involving TLR7 activation in AUD.
“Diagnostic and Prognostic Significance of Complement in Patients with Alcohol-Associated Hepatitis (AH)” was published in Hepatology (2021 Mar;73(3):983-997) by X Fan, RL McCullough, E Huang, A Bellar, A Kim, KL Poulsen, CJ McClain, M Mitchell, AJ McCullough, S Radaeva, B Barton, G Szabo, S Dasarathy, DM Rotroff, and LE Nagy. Researchers compared plasma samples of participants with moderate or severe AH to healthy controls to assess whether complement proteins, which have a critical role in the innate immune system, correlated with AH disease status and progression. Complement factor I (CFI) and soluble complement 5b‐9 (sC5b9) were decreased in non-survivor AH participants and predicted 90‐day mortality. Integration of CFI and sC5b9 with current models for predicting 90-day mortality, including MELD (Model for End-Stage Liver Disease) and mDF (Maddrey’s discriminant function), improved predictions compared to current models alone. Results suggest that complement factors are valuable diagnostic and prognostic biomarkers in patients with AH.
“Evaluation of the Addictions Neuroclinical Assessment (ANA) Framework through Deep Phenotyping of Problem Drinkers” was published in Drug and Alcohol Dependence (2021 Apr 1;221:108603) by SJ Nieto, EN Grodin, R Green, and LA Ray. ANA is a neuroscience-informed framework for addictive disorders that captures three functional domains: incentive salience, negative emotionality, and executive function. Investigators conducted an independent test of the ANA framework using a large clinical sample of participants across a range of alcohol misuse phenotypes. Participants completed a battery of scales and behavioral tasks of alcohol use and misuse, mood, attention, and impulsivity, which were analyzed to derive a factor solution that explained biobehavioral variation in the sample. Results implicated four functional domains that complemented and extended the ANA domains: negative alcohol-related consequences, incentive salience, negative emotionality, and executive function. Of note, ANA domains were distinct from latent factors that reflect AUD phenomenology (i.e., alcohol-related consequences). This study largely supports and extends the ANA framework for understanding the heterogeneity in AUD.
“Changes in Young Adults’ Alcohol and Marijuana Use, Norms, and Motives from Before to During the COVID-19 Pandemic” was published in Journal of Adolescent Health (2021 Apr;68(4):658-665) by S Graupensperger, CB Fleming, AE Jaffe, IC Rhew, ME Patrick, and CM Lee. Individual changes in alcohol and marijuana use, norms, and motives during the COVID-19 pandemic were estimated in a community sample of young adults (median age 25) from Washington state. Using a repeated measures design, data were collected prior to the pandemic (January 2020) and again following the implementation of major physical/social distancing restrictions (April/May 2020). The results indicated an increase in the frequency of alcohol consumption with no significant change in the total amount of alcohol consumed on average. No variation in marijuana use was identified. Young adults overestimated peer alcohol/marijuana use compared to actual rates, but correctly perceived an increase in alcohol use frequency. Motives for alcohol and marijuana use also changed during the pandemic.
“Network Meta-Analysis on the Mechanisms Underlying Alcohol Augmentation of COVID-19 Pathologies” was published in Alcoholism: Clinical and Experimental Research (2021 Feb 13;10.1111/acer.14573) by W Huang, H Zhou, C Hodgkinson, A Montero, D Goldman, and SL Chang. Investigators examined the possible relationships between alcohol exposure and COVID-19 pathologies by performing a network meta-analysis of gene expression changes reported in patients with COVID-19 derived from literature searches, the Gene Expression Omnibus database (RNA-sequencing data from autopsied lungs of COVID-19 patients), and Qiagen Coronavirus Network Explorer (QCNE). Analysis indicated that alcohol augmented effects of SARS-CoV-2 on the hepatic fibrosis signaling pathway, cellular metabolism and homeostasis, inflammation, and neuroinflammation and inhibited effects of SARS-CoV-2 on anti-inflammatory mediators such as the glucocorticoid receptor. These findings suggest that alcohol consumption may augment SARS-CoV-2-induced inflammation by altering the activity of key inflammatory mediators, potentially leading to poorer clinical outcomes.
Council Discussion: Edith Sullivan, Ph.D. commented favorably on two aspects of Dr. Koob’s report: 1) the attention to the cerebellum, which is probably fundamental to alcohol use disorder and recovery, among the research highlights, and 2) the attention paid to older drinkers in NIAAA’s priority areas. Alcohol is a preventable risk factor for falling and, possibly, dementia. The gap in alcohol consumption between men and women is narrowing among older drinkers. Beth Kane-Davidson offered kudos from the treatment community for NIAAA’s telehealth priority; good progress has been made in working with patients via telehealth during the pandemic. Regarding SBIRT, she noted that clinicians need to become comfortable asking patients about their alcohol use and counseling them about the consequences of misuse. Dr. Koob responded that other governmental agencies, such as the Substance Abuse and Mental Health Services Administration (SAMHSA) and Office of National Drug Control Policy (ONDCP) are also very interested in telehealth. Laura O’Dell, Ph.D., inquired about what the new ANA domains imply for animal researchers trying to model AUD, e.g., are there new domains to model? Dr. Koob responded that the same domains remain; what is important is that the domains have now been validated in human populations. Dr. O’Dell wondered specifically about domains that may have been missed in animal studies, such as negative emotions. Dr. Koob responded that there is a need for more clinical and pre-clinical research on negative emotions, noting challenges such as how to measure negative emotionality and select appropriate samples. Jill Becker, Ph.D., commented that she was pleased to see diversifying the workforce as an NIAAA priority. Col. Charles Milliken, M.D., commented that It would be helpful if the hepatitis biomarkers mentioned in the research highlights can be further refined so they can be used to identify those at higher risk for alcoholic hepatitis before its onset. Kathy Jung, Ph.D., replied that the search for biomarkers of alcohol-related disease is an active research area; Laura Nagy, Ph.D., noted that the Alcoholic Hepatitis Network (AlcHepNet) is examining biomarkers it had identified in a previous study in a current one of healthy controls, heavy drinkers, and those with alcoholic liver disease. Scott Russo, Ph.D., commented that he was happy to see the emphasis on brain-body interactions among the research highlights in Dr. Koob’s report. Noting that NIAAA is positioned to take the lead on research in this area, he asked if there have been any discussions about doing so. Antonio Noronha, Ph.D., reported that NIAAA has issued two NOFOs on this topic, and funded five applications. There will also be additional opportunities under the BRAIN and NIH Blueprint for Neuroscience Research initiatives in the coming fiscal year. Dr. Koob recommended that Dr. Russo’s conceptual point be noted for development of the NIAAA strategic plan. Changhai Cui, Ph.D., noted that NIAAA contributed to an issue about interoception in Trends in Neuroscience, and that a Blueprint RFA on this topic has been issued; NIAAA will be able to support seven grants under it. Constance Horgan, Sc.D., asked for further comment about the emphasis on workplace and culture under the NIAAA priority to increase diversity. Patricia Powell, Ph.D., commented that NIAAA is aware of the structural hierarchy of NIH, and considering ways to address this issue. This work is still early-stage and involves examining staff perceptions and experiences in both the scientific and administrative areas. Bridget Simmons-Williams, Ph.D., agreed that the work is at an early stage at NIAAA and the goal is to reinforce NIAAA’s inclusive values. Dr. Koob read a comment from Sulie Chang, Ph.D., Seton Hall University, thanking him for sharing the study on alcohol augmentation of COVID-19 pathologies in his discussion of research highlights. She noted that this study has convinced its authors that integration of in silico studies with both in vitro and in vivo ones will be very powerful.
Council Member Presentation: Innate Immune Sensitivity in Alcohol-Related Liver Disease
Dr. Koob introduced Council member Laura Nagy, Ph.D., Professor at the Cleveland Clinic, who shared her research on the interaction between the body’s innate immune system and the development of alcohol-related liver disease (ALD). ALD is a progressive disease. Most individuals who develop ALD develop steatosis in the liver, followed by a slower progression to fibrosis, cirrhosis, and for some, hepatocellular carcinoma. Yet not all individuals who regularly consume excessive amounts of alcohol develop ALD. However, at any stage in the disease progression, patients can develop alcohol associated hepatitis (AH) which is characterized by profound inflammation and has a very mortality rate high (20 to 50 percent). There are currently no practical treatments for AH.
The liver is a complex organ made up of hepatocytes that do the bulk of the liver metabolism tasks. Within the liver there are other cells that contribute to homeostasis in health as well as disease. These include innate immune cells that reside in the liver at all times, such as the resident macrophage Kupffer cell. One of the early effects of alcohol on the innate immune system is to activate the complement system. Complement activation products can then interact with receptors on the cell surface of the macrophages and monocytes to generate inflammatory cytokines which, in turn, injure the liver and mediate cell death, either by apoptosis, necrosis, or pyroptosis, further accelerating injury. Alcohol also impairs the barrier function of the intestine, allowing for the leakage of bacterial and viral products into the portal circulation. These in turn interact with pattern recognition receptors (PRRs) such as the toll-like receptor family or the C-type lectin family.
When Dr. Nagy began her research, it was known that alcohol increased the exposure of macrophages to bacterial lipopolysaccharide (LPS). She hypothesized that exposure to alcohol would also change the signaling or sensitivity of the macrophage to LPS. Over the next 20 years, using primary cultures of Kupffer cells from rodent animals of alcohol exposure, her laboratory demonstrated that alcohol exposure did indeed increase the sensitivity to simulation by LPS. More recently, she and her colleagues have begun using human tissue from clinical samples to compare the LPS-stimulated signal transduction in peripheral blood monocytic cells (PBMCs) in healthy controls and patients with AH, and to expand their focus beyond LPS to other microbial products, such as viruses, bacteria, fungi, and other parasites.
Human Tissue Studies. Adam Kim, Ph.D., a post-doctoral fellow in Dr. Nagy’s laboratory, used single cell RNA sequencing to reveal differences in immune cell function in 4 patients with AH and 4 healthy controls following 24-hour exposure to a physiologically-appropriate low dose of LPS, to address these questions: 1) Do cell populations differ between AH and healthy controls? 2) Is baseline and/or LPS stimulated gene expression different? He learned that the circulating cells include a number of different T cells, including CD4 T cells and cytotoxic T cells as well as monocytes. The investigators were able to distinguish 4 distinct populations of monocytes that showed the biggest change between the AH patients and the healthy controls. Overall, there were many more CD 14 and CD 16 positive monocytes in AH compared to controls. In the CD 14 Cluster 1, there was very little expression of IL-1β which is an important inflammatory mediator or of the chemokine CCL2 (C-C motif chemokine ligand 2), in the healthy controls at baseline and following exposure to LPS. In the AH patients, however, CCL2 was expressed at baseline and showed a very robust response to LPS. In Cluster 2, there was an LPS response both in the healthy controls and AH, but the AH Cluster 2 had higher levels of expression of these mediators. Clusters 3 and 4 each had a different pattern of expression, with Cluster 3 having mostly IL-1β and not the chemokine, and Cluster 4 showing high levels of CCL2 post-LPS exposure. Thus, individual clusters displayed different phenotypes at baseline and in response to LPS in AH patients compared to controls. In subsequent studies, Dr. Kim examined other pro-inflammatory mediators. He found, for example, that monocyte Cluster 1 in healthy controls produced anti-viral genes and anti-inflammatory genes in response to LPS, whereas the AH cells produced more of a pro-inflammatory mediator, S100A9, with extensive chemokine and cytokine expression. Thus, there was an accumulation of more pro-inflammatory cells in the PBMCs in AH patients compared to healthy controls.
Beyond LPS. Dr. Nagy’s laboratory also examined how the innate immune system deals with gut-derived microbial products, other than LPS. Dr. Kim focused his research on C-type leptin receptors which are another family of pattern recognition receptors that respond to a variety of microbial products. These receptors include DCIR (dendritic cell immunoreceptors), Dectin 1, Dectin 2, Dectin 3, MINCLE (macrophage inducible Ca2+ dependent lectin), and MDL (myeloid DAP12-associating lectin). They are closely clustered together on chromosome 12 in humans in the NKC (natural killer cells) cassette. When genes are clustered together like this in cassettes, they are often coordinately regulated. Based on parallel studies, in collaboration with Dr. Xiaoxia Li at the Cleveland Clinic, Dr. Kim chose to focus on MINCLE. He hypothesized that low dose LPS might upregulate MINCLE as a way of sensing other bacterial products coming in from the gut. After stimulating PBMCs in healthy controls and AH patients with LPS and conducting a single cell analysis, he found that healthy controls showed some upregulation of MINCLE in response to the low dose LPS, but that response was much higher in patients with AH. That higher expression of MINCLE sensitizes the PBMCs to MINCLE ligands (TDB and Sap130) that can come from hepatocytes. There was much greater expression of IL-6 in the cells that were treated with LPS and then challenged with a MINCLE agonist; the same pattern was observed with IL 1-β. Thus, the investigators concluded that LPS induction of MINCLE sensitizes the cells to alternative microbial products. These data are consistent with previous studies by Dr. Nagy and Dr. Li that demonstrate, using the MINCLE-deficient mice that MINCLE contributes to ethanol-induced liver injury in mice. Studies from Dr. Bernd Schnabl’s group also showed that Dectin 1-deficient mice were protected from ethanol-induced liver injury. Collectively, these data suggest that C-type leptin receptors are probably important collectively in the development of ALD.
Dr. Kim remained interested in determining whether these C-type leptin receptors were upregulated in a coordinate fashion. He found that DCIR and Dectins 1, 2, and 3 were more greatly enhanced by LPS in AH patients; Dectin 1 was higher at baseline for those with AH. Additional studies comparing healthy liver tissue with that from patients with severe AH revealed that, similar to the PBMCs, many of the C-type leptin receptors showed increased in expression in patients with AH.
Using a bulk RNAseq dataset composed of liver samples from patients with different types of liver disease, the investigators found that expression of the C-type leptin receptors differs across different etiologies of liver disease. In some cases, (e.g., in Dectin 2, Dectin 3, and MINCLE), the AH sample was very much higher than other forms of disease, suggesting that there might be some specificity to AH in terms of C-Type leptin receptor expression. In subsequent studies using single cell analysis looking for gene expression across the entire NKC cassette, Dr. Kim found that the level of correlated expression, both at baseline and after LPS exposure, was greater for AH patients than for healthy controls. Thus, it is fair to conclude from the research described here that LPS drives a coordinated expression of multiple immune response genes.
In summary, patients with AH have increased proportions of peripheral monocytes with heightened pro-inflammatory gene expression combined with loss of anti-viral and anti-inflammatory functions. In response to LPS, monocytes from patients with AH increase expression of CTRs, thus enabling the cells to sense a greater variety of microbial byproducts. These findings have multiple implications. For example, in terms of COVID infection, the loss of the anti-viral and anti-inflammatory functions of peripheral monocytes due to LPS exposure may impact susceptibility to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Further, the loss of anti-inflammatory functions also contributes to the inability of patients with AH to resolve their inflammation. Beyond LPS, if the monocytes are sensing a low level of bacteria, it suggests that other microbial products will also come through and need to be considered. Finally, it will be important to think about how it is that alcohol sensitizes monocytes such as MINCLE and other microbial ligands within this family.
Discussion: Dr. Becker inquired about the extent of sex differences in the research presented, in light of known sex differences in the immune system and inflammatory response. Dr. Nagy responded that her laboratory is just beginning to look at sex differences; to date, they have found that obesity appears to have a great effect than sex. Dr. Koob asked how early in the progression of ALD researchers can identify changes described in the presentation. Dr. Nagy responded that it takes a couple of weeks in animals administered heavy doses of ethanol; better answers should be forthcoming in the future from the current AlcHepNet study of heavy drinkers. Dr. Koob also inquired if LPS could be driving the malaise experienced by COVID “long haulers.” Dr. Nagy replied that while It does make sense that there is some innate immune component that is going to be altered and stay altered in such patients, it’s always difficult to know if it’s some kind of tissue residence response or something that can be detected in circulation. She noted the need to establish bio-repositories so that this question can be addressed in the future. Dr. Russo asked if any researchers had looked at communication of bone-marrow derived monocytes with brain tissues, e.g., are they breaching the blood brain barrier (BBB)? Dr. Nagy responded that it’s not the cells themselves that get across the BBB but most likely the mediators. The data suggest that some of these same pattern recognition receptors are driving acceleration of drinking, as well as tissue injury effects. Dr. Russo asked about the use of monoclonals to treat liver disease and address behavior. Dr. Nagy explained that CD14 is extensively distributed across many monocyte populations, three-quarters of which have CD14 on them. Therefore, it will be important to determine the anchor genes that distinguish monocyte cluster-1. To find an appropriate treatment, looking more closely at epigenetic changes that might lead to long term changes in the phenotype of peripheral monocytes in patients with ALD. Dr. Nagy would like to sort those cells by flow cytometry and look more closely at epigenetic changes that might lead to long term changes in the phenotype of peripheral monocytes in patients with ALD.
Council Member Presentation: Mechanisms Underlying Alcohol-Induced Myopathy
Dr. Koob introduced Council member Charles Lang, Ph.D., Distinguished University Professor and Associate Dean at Penn State College of Medicine, who provided a high-level overview of alcohol-induced myopathy (skeleton muscle wasting). Myopathy has a high prevalence (50-70 percent) in individuals with sustained excessive alcohol intake. It is one of the most prevalent muscle diseases, characterized by decreased size of fast-twitch fibers with little evidence of necrosis or fibrosis. Myopathy is associated with profound muscle weakness and decreased quality of life. The etiology of this pathology has been particularly difficult to pinpoint in studies on humans, because of the large number of interacting and poorly controlled variables.
Dr. Lang’s laboratory has studied the mechanisms underlying this loss of lean body mass (LBM) and muscle mass in animal models, keeping the animals on an alcohol diet for 12-24 weeks. Using NMR spectroscopy, the investigators recorded decreases in LBM and muscle mass, particularly in the gastrocnemius and psoas muscles which have a relatively high percentage of fast-twitch fibers compared to the slow-twitch soleus muscle where there was little or no change in mass.
In the muscle, as in all tissues, the protein content of that tissue represents a balance between the synthesis and degradation of protein. Dr. Lang and his colleagues examined the in vivo synthesis of protein muscle by incorporating radioactive phenylalanine (Phe) into muscle proteins. They observed
a proportional alcohol-induced decrease in muscle protein synthesis, specifically in muscles that have a high proportion of fast twitch fibers, i.e., the gastrocnemius as opposed to the soleus muscle which did not show a drop in muscle mass and correspondingly had no change in the amount of protein synthesis. The investigators further examined the myofibrillar and sarcoplasmic protein pools in the gastrocnemius muscle and found that alcohol reduces protein synthesis in both. The ribosome number in the gastrocnemius, however, did not change with alcohol consumption, suggesting that the translational machinery is intact, but suppressed.
The researchers also examined muscle contractibility or muscle function under in vitro situations, learning that the force frequency relationship in alcohol-fed animals is reduced. Further, the muscles from alcohol consuming animals fatigue more rapidly.
Dr. Lang’s laboratory also investigated the role of pro-inflammatory cytokines, particularly IL-1, TNFα, and IL-6. These levels in plasma or sometimes in skeletal muscle are often increased in animals following chronic alcohol consumption. Previously, the investigators had successfully ameliorated cancer-or sepsis related cachexia in animals by blocking one or more of these pro-inflammatory cytokines. They anticipated that by blocking one or more of these cytokines and inhibiting the catabolic response, they would find a corresponding increasing muscle protein synthesis. In one study, they compared pair-fed and alcohol-fed animals that received a continuous infusion of IL-1 receptor antagonist (IL-1Ra) from 2-6 weeks during their alcohol feeding. Inhibiting the IL-1 receptor in vivo was sufficient to ameliorate some of the hepatic injury as evidenced by a reduction in ALT concentration in the blood. However, there was no inhibition in alcohol-related muscle protein synthesis. The investigators subsequently conducted a number of experiments with TNFα and IL-6 using receptor antagonists, binding proteins, and knockout animals, but none of these reversed or prevented the alcohol-induced decrease in muscle protein synthesis.
Therefore, the investigators changed focus to examine growth factors and nutrients that might impact the animals’ anabolic response, particularly circulating growth factor 1 (IGF-1), which had been shown to substantially decrease in alcohol-fed animals and in people with sustained alcohol consumption. The hypothesis was that increasing IGF-1 levels over time would ameliorate the reduction in protein synthesis and restore muscle mass in alcohol-fed animals. The investigators administered a binary complex of IGF-1 with one of its natural binding protein IGF-BP3 that slows the removal of the peptide hormone from the circulation and extends its biological half-life. This resulted in a robust increase in muscle protein synthesis in the control animals. In the alcohol-fed animals, in contrast, muscle protein synthesis increased to the control levels but not to the stimulated levels. This finding suggested that alcohol feeding leads to IGF-1 resistance in skeletal muscle, equivalent to the insulin resistance one sees in diabetes. Further investigation revealed that alcohol resistance to many types of anabolic agents other than IGF-1 is non-specific or generalized. For example, the investigators examined the impact of an acute administration of the branched-chain amino acid leucine, the primary amino acid in a high protein meal that would lead to an increase in protein synthesis. However, there was a complete blunting of the ability of this amino acid to increase protein synthesis in the alcohol-fed animals. The researchers then sought to circumvent areas or potential blockages in metabolic pathways that were inhibited by alcohol by employing different types of stimuli, e.g., electrically stimulating muscle directly. However, the alcohol-fed animals also failed to produce increased protein synthesis in response to a contractile activity.
Dr. Lang and his colleagues then switched their paradigm from using chronically alcohol-fed animals to intervening with them prior to the administration of alcohol. For example, in one study, animals fasted overnight and were then administered a gavage of alcohol for one hour. Their muscle protein synthesis lowered acutely. If allowed to refeed for about an hour, non-alcohol treated control animals increased their protein synthesis by about 50 percent. But if the animals were refed and are then administered alcohol, there was no increase in muscle protein synthesis.
These experiments demonstrated that alcohol decreases muscle protein synthesis or causes resistance. At the same time, alcohol exacerbates catabolic stresses. Dr. Lang shared findings from three experiments at his laboratory that examined the impact of stressors that cause muscle wasting, including chronic dexamethasone administration, muscle immobilization via hindlimb casting, and aging. In each case, these catabolic stresses on animals that have been alcohol fed resulted in a decrease in muscle protein synthesis greater than what would normally be observed, either with the catabolic stress alone or with the alcohol consumption alone.
Dr. Lang’s laboratory also examined mammalian target of rapamycin complex 1 (mTORC1) signaling, a protein kinase that integrates signaling pathways from growth factors, amino acids, and energy status, and stimulates protein translation. In alcohol-fed animals, the in vitro activity kinase activity related to mTORC1 was markedly reduced.
mTORC1 is a multi-protein complex that is a primary driver of protein synthesis in tissues. It is composed of core proteins and a variety of associated proteins. Alcohol consumption does not change the overall abundance of any particular protein within muscle, but it does change the association of these proteins with mTORC1 or with Raptor, a scaffolding protein that is bound to mTORC1. One of the very dramatic effects that alcohol feeding has on muscle is that it increases the association of the protein Deptor with Raptor and the mTORC1 complex. Previous studies have shown that Deptor is a negative regulator of muscle protein synthesis. Thus, the more Deptor is bound to the mTORC1 complex, the lower the rate of protein synthesis.
Dr. Lang and colleagues hoped that they would be able to reduce or prevent alcohol-induced reduction in muscle protein synthesis by reducing the levels of Deptor both in vitro and in vivo. Beginning in vitro, they injected shRNA into C2C12 myocytes to reduce the Deptor abundance within these cells; it had a dramatic effect in non-alcohol-treated cells, increasing protein synthesis by 50 percent. The alcohol-treated cells increased in the absence of Deptor, but not to control levels. They next did in vivo electroporation of muscle in which they injected shRNA into the gastrocnemius muscle. The impact was not as great as in the in vitro experiment. It was, however, sufficient to bring the protein synthetic rate back to normal in the alcohol-fed animals. One caveat, however, is that the shRNA knock down was only effective for 4-5 days before the internal machinery of the muscle degrades it and protein levels come back to normal. Therefore, it is not possible to determine whether this increase in protein synthesis over a long period of time would actually result in prevention of muscle loss.
In summary, Dr. Lang’s laboratory studies have shown that there is a decrease in mTORC1 activity within skeletal muscle, and this is primarily due not only to changes in Deptor but also the selective binding of associated proteins in the mTORC1 complex that alcohol affects. In doing so, alcohol decreases the rate of anabolic effects, such as hormones like IGF-1, nutrients such as refeeding and branched-chain amino acids, and other stimuli such as contraction. Under fasting conditions and under catabolic conditions, alcohol seems to increase the sensitivity of muscle and result in larger decreases in muscle protein synthesis. Thus, collectively and over a long period of sustained alcohol consumption, alcohol is linked to an increase in nitrogen balance and an increase in muscle wasting. A major research gap in the field is the current inability to translate these findings back into the clinic.
Discussion: Dr. Koob asked if the same patterns of wasting and reduced muscle protein synthesis that occurs in animals also occurs in humans. Dr. Lang responded affirmatively, noting that there’s a single human study among individuals entering rehabilitation in which muscle protein synthesis has been measured and shown to be decreased. There are many studies in humans showing that body muscle mass has decreased. What remains unclear, however, is the molecular mechanisms in humans. This is a major gap in knowledge. Dr. Koob commented that the literature on the central nervous system suggests mTOR is activated by alcohol and contributes to the pathophysiology in the brain. He asked if mTOR were blocked in the brain, would that cause an exacerbation of the impact of alcohol on the muscle? Dr. Lang commented that any attempts to inhibit mTOR centrally, unless it’s centrally specific, is going to lead to generalized immune suppression making this a potentially dangerous strategy. There are other tissues that respond to alcohol with an increase in mTOR activity, but the heart and skeletal muscle do not. Dr. Koob suggested there could be muscle wasting from some of those types of treatments; Dr. Lang agreed. Dr. O’Dell inquired about the impact of alcohol’s interactions with other drugs, such as nicotine. Dr. Lang responded that he has little data on alcohol and nicotine interaction as a previous study showed little effect and the line of inquiry was not pursued. In work with behavioral scientists about cocaine, they were unable to identify any additive effect on muscle wasting. Dr. Becker noted that Dr. Lang’s studies did not see a sex difference in muscle protein synthesis, yet it’s known that testosterone and estradiol impact muscle function and mass. She asked if they were working on completely different pathways or if there were alternative explanations. Dr. Lang responded that it’s clear that when ovaries are removed from a female mouse or rat, the animal’s protein synthesis declines. If testosterone is administered, protein synthesis can increase. He does not know, however, if the observed lack of sex differences in animals are due to the inability of alcohol to modulate sex hormone production differentially in rodents compared to humans. The data in the literature demonstrate that women are more sensitive to the effects of alcohol than men, especially for cardiomyopathy, but it’s hard to reproduce in animals. It’s unknown if that’s because researchers are unable to control for confounding variables that may affect humans or if animals simply behave differently. Col. Milliken commented that the fact that chronic alcohol use suppresses testosterone has been a great motivator in the young male active-duty population; he suggested the findings that alcohol also reduces muscle mass would be a great addition to SBIRT/alcohol screening in the military. Dr. Lang noted that the lay press was very interested in these findings because they informed athletes that post-exercise alcohol consumption could negate the effects of their workouts. D. Koob inquired if alcohol-related muscle wasting contributes to the risks of falling among the aging population. Dr. Lang replied that in the study he shared about the impact of aging on muscle protein synthesis, the aged animals did not show signs of muscle wasting prior to consumption of alcohol. Afterward, however, they experienced rapid muscle loss and decreased protein synthesis. Another part of the protein balance equation not discussed here is protein degradation. It is much higher in aged animals, especially those who have consumed alcohol, so they suffer from both reduced protein synthesis and increased protein degradation. Dr. Sullivan thanked Dr. Lang for his presentation which parallels many of the issues she is studying in aging humans.
Concept Clearance: Reissue of R28 Clinical Resource PAR (Clinical Trial Not Allowed)
Hemin Chin, Ph.D., presented a concept clearance to issue and establish a Brain Tissue Resource Center for Alcohol Research (BTRC). The primary goal of BTRC is to support a brain tissue center that provides unique and well-characterized post-mortem brain tissue from human subjects with AUD without comorbidities. The BTRC is expected to develop a “bank” of brain tissues (fresh-frozen and formalin-fixed) from human subjects with AUD and control cases with confirmed clinical and pathological diagnoses; develop and promote a prospective brain donor program to enhance the “brain bank”; establish an associated DNA (blood) bank from the brain donor group; and provide these brain tissue samples to research groups with an interest in AUD-related brain damage. Although there are many human brain banks providing access for use in research into neurological and psychiatric disease, there exists a critical need for a unique resource for brain tissues that are obtained from people with AUD and documented not to have misused other drugs (besides nicotine). Further, post-mortem brain tissues from cohorts of carefully selected brains for “pure” AUD in the absence of other potentially confounding disorders are useful and unique research resources for both basic and clinical neuroscience investigators, allowing for solid conclusions to be drawn about the effects of alcohol on the brain versus other drugs of misuse.
The brain bank established under this NOFO will facilitate research into AUD and alcohol-related brain damage (ARBD), by providing human post-mortem brain tissue, and associated clinical information to researchers in the US and around the world. Human post-mortem brain tissue with well characterized, high quality tissues and associated clinical and lifestyle information is an essential resource to study the molecular and cellular basis of AUD and ARBD. Tissue based studies augment clinical and preclinical studies and facilitate translation of research findings into better diagnosis and treatment of patients.
Action: Dr. Russo, endorsed the concept, noting the strong need for such a brain bank.
Concept Clearance: Reissue of Wearable Biosensors
Kathy Jung, Ph.D., Division of Metabolism and Health Effects, presented a concept clearance for reissuance of an NOFO for development of wearable biosensors to detect the amount of alcohol consumed. Prior to 2015, the primary means to collect such data was surveys and self-reports, which may be unreliable and provide only a snapshot in time. Continuous alcohol monitoring was possible through the SCRAM anklet and WrisTAS device, used mainly by law enforcement, which measure the amount of alcohol in sweat. However, they are stigmatizing, provide only qualitative output, and are subject to biological delay.
NIAAA efforts to stimulate improved biosensor development began in 2015 with a Challenge Prize competition that resulted in the Milo and BACTrack prototypes, which were sleeker and more wearable. Both measure the amount of alcohol in sweat; results can be sent to wearers’ smartphone so they can see the data, but to date these devices cannot provide an actual blood alcohol level (BAL) and there is a significant time delay in the readings. In addition, between 2015 to the present, NIAAA solicited additional ideas through the Small Business Innovation Research (SBIR)/Small Business Technology Transfer (STTR) program, resulting in 24 awards.
The goal is to develop a non-invasive sensor. There are other technological approaches beyond sweat-based biosensing that could be developed, e.g., infrared and micro-needle approaches, Based on input from the alcohol research community, the ideal wearable alcohol biosensor will detect and record BAL in real time and provide meaningful output; collect and interpret data, eliminating as much of the biological and device-related delays as possible; store or transmit data to a smartphone or other device by wireless transmission; provide data storage and transmission that is completely secure, protecting the privacy of the individual; verify standardization at regular intervals and indicate loss of functionality; operate from a dependable and rechargeable power source; and feature a non-invasive or minimally invasive form factor, acceptable to wearers.
To that end, NIAAA seeks to reissue an NOFO for the development of a wearable alcohol biosensor. The availability of a functional, reliable wearable alcohol biosensor will advance NIAAA’s mission in multiple arenas, including treatment for alcohol use disorder; medications development; addiction research; research on adverse health effects of alcohol misuse, including alcohol-related organ damage; and consumer education on individual consumption.
Discussion: Ms. Kane-Davidson commented that wearable biosensors are much needed in helping patients with compliance in telehealth treatment. Col. Milliken inquired if there are efforts to bundle alcohol monitoring with other monitoring devices, such as those for exercise or sleep, which could increase consumer penetration. Dr. Cui noted that some of RADx-rad technologies may be used in alcohol sensors.
Action: Dr. O’Dell endorsed the concept to reissue on NOFO for a wearable biosensor.
Concept Clearance: HIV Prevention and Alcohol
Kendall Bryant, Ph.D., Director, HIV/AIDS Research at NIAAA, presented a concept clearance on HIV prevention and alcohol. The purpose of this FY2022 NOFO is to develop new interventions and implement existing integrative preventive activities in diverse settings and populations. It seeks to expand the HIV/AIDS prevention toolkit for alcohol-impacted populations who are at behavioral and biological risk for HIV acquisition.
NIAAA HIV/AIDS research activities have been supported by NIH/Office of the Director (OD) Office of AIDS Research, in accordance with the NIH Strategic Plan for HIV and HIV-Related Research FY2021-2025. This NOFO will balance NIAAA’s portfolio and complement other ongoing activities focused on the treatment of People Living with HIV/AIDS (PLWH) who may have additional comorbidities, coinfections, and complications. In addition, this NOFO is responsive to the overall goal of the Office of Infectious Disease and HIV/AIDS Policy to reduce the incidence of new infections by 90 percent by 2030 in the U.S.
The proposed NOFO addresses NIH priorities to reduce the incidence of HIV/AIDS and to address cross-cutting areas, such as health disparities. Multiple areas for potential research collaboration and integration of the HIV prevention care continuum include (but are not limited to) both ongoing and expanding activities related to the impact of alcohol. Ongoing activities include pre-exposure prophylaxis (PrEP); treatment as prevention (TasP); and combination and adaptive Interventions. Expanded activities address cross-cutting and translational pre-interventions; syndemic and health disparities outcomes; and implementation and operations.
In summary, this NOFO is intended to develop, test, and combine interventions to achieve NIH-CDC 2030 Ending the Epidemic targets; improve identification of “at-risk” individuals with measurable complex patterns of drinking in the context of comorbidities, situations, and settings; integrate alcohol and alcohol-related measurement into targeted cohorts, consortia, and community settings (at multiple levels) and improvement of analytic strategies; and focus on ending the epidemic and bridging research and implementation gaps through dissemination of information and training of a new generation of researchers.
Discussion: Christopher Carpenter, Ph.D., encouraged NIAAA to include public policy activities in this NOFO. Dr. Bryant noted that policies that impact distribution of PReP would be important in LGBTQ populations that are at high risk.
Action: Dr. Carpenter endorsed the HIV and Alcohol concept.
Concept Clearance: Patient Registry
Raye Litten, Ph.D., Acting Director, Division of Treatment and Recovery (DTR), reported on the Kaiser Permanent Northern California (KPNC) Alcohol Registry Contract concept clearance. NIAAA is proposing a single source acquisition per Federal Acquisition Regulations (FAR) to KPNC to support the creation of a patient registry for the purpose of NIAAA -directed analysis and studies pertaining to the health-effects of alcohol misuse and to better understand recovery from AUD.
On January 5, 2021, DTR issued a Notice of Special Interest (NOT-AA-20-22) to advance research on various topics, including a focus on recovery from AUD (endorsed by Council in September 2020). The priority aim under this focus is to increase understanding of recovery from AUD, including factors that affect the likelihood of recovery success, such as quantity of alcohol consumed and the involvement of health and substance abuse comorbidities. This priority coincides with NIAAA’s new Research Definition of Recovery from AUD (endorsed May 2020 by Council).
KPNC is an integrated health care system that provides primary and specialty care (including addiction medicine and psychiatry). KPNC has a mature, fully-developed electronic health record (EHR) system that stores data collected throughout the full course of patient care. Since 2005, KPNC has been collecting data on patients with an AUD diagnosis, including patient alcohol consumption and related health outcomes. Over the past seven years, over 823,000 patients were screened and identified for AUD/unhealthy drinking and assessed regularly via long-term healthcare follow-ups. Under the scope of this contract, KPNC will curate a patient registry of those Kaiser patients diagnosed with AUD or have reported alcohol misuse from their vast EHR and continually add to the registry over time (estimated to be 87,000 new patients per year). NIAAA will direct the analyses and studies pertaining to recovery from AUD, treatment services utilization and the confluence of health effects from AUD and alcohol misuse. Additionally, various groups will be analyzed, including health disparities, women, age, and comorbidities. The longitudinal, multi-dimensional patient-level data that can be obtained from KPNC’s EHR system (including health service utilization, diagnoses, medications, laboratory tests, and health questionnaires), provides a unique opportunity to study the onset and progression of alcohol problems, care provided during all phases (i.e., follow-up, management, continuity of care), and long-term recovery outcomes.
During a review of the concept, one Council member inquired if the database would be available to commercial and/or corporate entities that might be searching for background information on AUD history, expressing a concern for patient protection. Dr. Litten responded that no entity (commercial or otherwise), other than Kaiser, will have access to this registry. NIAAA will not be receiving or have direct access to any patient-level registry data. Kaiser will create the registry that will remain in Kaiser’s control and perform NIAAA-directed analyses. Kaiser will provide NIAAA only with summary data resulting from these analyses.
Action: Council voted unanimously for KPNC to submit a proposal in response to the future announcement.
Dr. Koob encouraged Council members to share their ideas about how NIAAA can increase diversity and to suggest other Institutes to which NIAAA should reach out for collaborative efforts. He also noted that NIAAA is hoping that SAMHSA and ONDCP will continue to disseminate information about alcohol and its effects to the public. Dr. Powell encouraged Council members to share information with colleagues, especially those in the clinical world, about the impact of alcohol on health. Col. Milliken suggested that NIAAA provide an hour of Continuing Medical Education (CME) training per month for clinicians as one way to accomplish that goal. Dr. Koob asked Bridget Williams-Simmons, Ph.D., to note that suggestion.
Consideration of Council February 4, 2021 Minutes/Future Meeting Dates
Council members voted unanimously to approve the minutes of the NIAAA Advisory Council meeting held on February 4, 2021.
Dr. Bautista announced upcoming meeting dates for 2021-2024. In 2021, the Council will meet on September 9; the CRAN Council will meet on May 12, 2021. In 2022, Council will meet on February 10, May 10 and September 8; the CRAN meeting will be on May 11. In 2023, Council will meet on February 9, May 9, and September 7; the CRAN Council will meet on May 10. In 2024, Council will meet on February 8, May 14, and September 12; the CRAN Council meeting will meet on May 15.
Dr. Koob adjourned the meeting at 4:26 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
George F. Koob, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
National Advisory Council on Alcohol Abuse and Alcoholism s/s
Abraham P. Bautista, Ph.D.
Office of Extramural Activities
National Advisory Council on Alcohol Abuse and Alcoholism