Michael Fleming - US grants

The goal of this trial is to test the effect of brief physician advice on alcohol-related behaviors and health status of problem drinkers. Subjects will be selected from the practices of 60 primary care physicians located in southern Wisconsin. Approximately 320 patients from each practice with regularly scheduled appointments will complete an imbedded alcohol screening instrument which contains questions on smoking, weight loss, exercise, and alcohol use. The trial is focused on the treatment of adult male problem drinkers, defined as subjects who drink more than 20 drinks per week. Following a face-to-face interview of those subjects who score positive on the alcohol screening instrument, subjects will be randomly assigned to an experimental or a control group. The experimental group will be exposed to a standardized intervention protocol administered by their physician. A sample of 540 subjects is needed in each group to achieve an 80% chance of detecting a 10% difference in alcohol use. The protocol includes a diagnostic interview, a brief intensive counseling session, a self-help manual, a prescription to change their drinking habits and two follow-up visits. Fourteen outcome variables were selected based on the findings of completed clinical trials. These variables include: 1) number of weeks of sobriety; 2) number of episodes of binge drinking; 3) alcohol use in 7 days prior to six- and twelve-month follow-up telephone interviews; 4) days of hospitalization; 5) sick days; 6) injuries and accidents; 7) emergency room visits; 8) legal events; 9) global perception of health; 10) number of outpatient visits; 11) number of prescriptions; 12)self-reported health status; 13) family relationships; 14) number of chronic illness visits. The outcome variables will be assessed by a self-report telephone interview at six and twelve months, a telephone interview with a family member as twelve months, a review of medical records and a review of county and state legal records. Laboratory measures were not included for the following reasons: 1) poor psychometric properties of currently available tests in primary care populations of problem drinkers; 2) practical issues of recruiting subjects in a primary care setting; and 3) resource limitations. The analysis will be based on the development of a performance model of the outcome variables of interest. The proposed trial would be the first large scale randomized clinical trial conducted in the United States to test the effect of brief physician advice with problem dhnkers in a non-academic primary care setting.

The goal of this research is to test the efficacy of brief physician advice in reducing alcohol use, health care utilization, and in improving health status in problem drinkers in Polish primary care clinics. Although evidence exists - both internationally and in the United States - to support the conclusion that brief physician advice can decrease alcohol use, additional research is needed to support implementation of brief intervention treatment in the new health care system of Poland and eastern Europe. Alcohol use is an enormous health and social problem in Poland. Rates of alcohol-related problems such as cirrhosis, stroke, and accidents,are among the highest in the world. Primary care physicians, a new and essential component of the completely re-focused Polish health care system, are in an opportune situation to identify and treat the majority of people adversely affected by alcohol. The proposed trial is a joint project between the University of Wisconsin Center for Addiction Research and Education (CARE) and the Policy Institute of Psychiatry and Neurology. The trial is designed to replicate a successful brief intervention trial (Project TrEAT) conducted in the U.S. health care system. Project TrEAT, an NIAAA-funded R-01 trial, was conducted by the Principal Investigator in the offices of 64 primary care physicians in southern Wisconsin. For the past 15 months, the PI has been working with Poland to develop a nationwide faculty development program focused on the prevention and treatment of alcohol use disorders. The proposed trial defines problem drinkers as men who consume 3 or more drinks/day or 21 drinks/week, or women who drink 2 or more drinks/day or 14 or more drinks/week in the 7 days prior to the research interview. These subjects will be recruited from the practices of 20 primary care physicians in Lodz, Katowice, and Warzsawa, Poland. The intervention will consist of a structured brief advice protocol administered by the subject's primary care physician. The 20 physician interventionists will participate in a skills training workshop and periodic booster sessions to standardize the intervention. The effect of the intervention will be assessed by examining changes in alcohol-related behaviors and health status over a six month period. Changes will be assessed utilizing patient self-report, family member interview, and medical record review. This project will be the first large-scale randomized clinical trial conducted in Poland to test the effect of brief physician advice with problem drinkers. The study uniquely addresses the important research area of alcohol abuse and would significantly add to our understanding of the efficacy of physician intervention in the secondary prevention of alcohol problems in Poland and Eastern Europe.

APPLICANT'S ABSTRACT: The primary goal of this project is to develop an interdisciplinary faculty of development model designed to enhance the research, teaching, and clinical skills of university faculty in the prevention and treatment of alcohol use disorders. A second goal is to provide faculty participants with an up-to-date review of recent scientific findings in the alcohol area including fetal alcohol effects. The model to be tested is based on skills-based courses previously developed by the P.I. for full-time clinic/teaching family medicine faculty who have limited time and resources. Schools of interest for this project include medicine, nursing, pharmacy, dentistry, allied health, social work, psychology, public health. Over the three years of the project, two courses will be held at each of six U.S. university sites. These include the University of Nebraska, Howard University, University of Arizona, University of Louisville, University of Hawaii, and the University of Texas at Houston. The project curriculum is based on the NIAAA International Medical Education Project. We expect to offer a menu of 20 skills-based workshops. Topics include fetal alcohol exposure, care of special populations such as women and the elderly, brief intervention treatment, specialized treatment, prevention, teaching skills, clinical research design, methods to interpret the alcohol literature, scientific writing, educational evaluation, and grant preparation. Two courses will be offered at each site, three months apart. The courses will be taught by members of the UW Center for Addiction Research and Education (CARE) and local clinicians and researchers. Project Evaluation will focus on changes in skills and activities. A pre-post quasi- experimental design with six-months follow-up will be used to assess the variables of interest. These variables include completion of take-home assignments, implementation of teaching programs, increase in clinical skills, and development of collaborative projects. A CARE researcher will conduct on-site face-to-face interviews with course participants and academic deans. Changes in participants' clinical skills will be assessed using a standardized patient protocol. This low-cost, low intervention project has the potential to serve as a national model that could be applied to most universities.

Background: The prevention of Fetal Alcohol Syndrome and fetal alcohol exposure is an important national priority. A 1995 national survey conducted by the Centers for Disease Control estimates that as many as 140,000 children born in the US are exposed to. potentially harmful effects of alcohol. during fetal development (3.5% of 4 million live births). One prevention strategy is to establish screening and intervention procedures that can be administered in primary care settings to women who are drinking above recommended limits. Goal: This study is designed to test the efficacy of a primary care-based brief intervention for women who resume heavy drinking during the post partum period and who used alcohol during their last pregnancy. The ultimate goal is to reduce alcohol use, alcohol-related harm, and fetal alcohol exposure in subsequent pregnancies. Method: The trial will utilize methods successfully employed by the PI in three brief intervention trials (Project TrEAT, Project GOAL, and an ongoing trial in Poland). Women will be asked to complete an embedded alcohol questionnaire (Health Screening Survey) while seeing their obstetrician for a routine post partum visit. Women who screen positive for heavy drinking (>7 drinks/week in the past month, 4 or more drinks/occasion, or two or more positive responses on the T-ACE) will be invited by a researcher to participate in a health interview. Women who meet eligibility criteria for the trial will be randomized to a usual care control group or a physician/nurse brief intervention group. The intervention will consist of two 10-15 minute physician/nurse visits and two 2- minute follow-up phone calls. All subjects will be contacted at 6, 12, 18 and 24 months by telephone to assess outcomes of interest which include alcohol use, quality of life, mental health problems, accidents, and health care utilization. Power analysis suggests that 250 women in each arm of the trial will have sufficient power to detect a difference for the main outcome variables of interest. Significance: The proposed study would significantly increase our understanding of how to reduce alcohol use in post partum patients and how to limit FAS and fetal alcohol exposure.

DESCRIPTION (provided by applicant): HIV infection, tuberculosis, and hazardous drinking are of increasing concern in Russia. While the number of officially registered cases of HIV infection as of October 31, 2000 was 69,120, experts expect an exponential increase in the number of Russian people infected with the human immunodeficiency virus in the next 10 years. Incident cases of TB and multi drug resistant tuberculosis in Russia are among the highest in the world. Mortality rates exceed 10% with over 125,000 persons receiving medical treatment for active TB in 1999. Hazardous drinking is common and a major source of morbidity and mortality in Russia. Alcohol use also complicates prevention and treatment programs for HIV infection and TB. Russia shares borders with 13 countries. The global health implications of a large reservoir of HIV infection and tuberculosis in a country that crosses 8 time zones is enormous. Now is the time to prevent the spread of HIV infection and tuberculosis in Russia and neighboring countries. Potential strategies include testing of HIV prevention programs (i.e., Project RESPECT) and treatment programs to reduce rates of hazardous drinking. This proposal is designed to increase our understanding of HIV risk factors, and to increase the role and treatment of alcohol use disorders in the prevention of HIV infection in the context of a TB treatment population. This proposal will conduct the following 3 studies in St. Petersburg and Ivanovo, Russia: a) a prevalence study designed to assess the frequency of HIV risk factors and alcohol use in a patient population being treated for tuberculosis (n=600); b) a naturalistic study designed to assess the effects of alcohol use on HIV risk behaviors and TB treatment outcomes (n=200); c) a combined day-treatment program for HIV risk reduction and alcohol treatment (n=80). The data from these studies will provide new information. The findings are expected to facilitate the development, testing and implementation of HIV prevention and alcohol treatment programs. It is hoped that these programs can reduce the spread of HIV infection and TB in Russia and neighboring countries.

DESCRIPTION (provided by applicant): Background: Non-malignant chronic pain is an increasingly common and complex clinical problem. Primary care physicians are being encouraged by patients, pain specialists, and policy makers to increase the use of chronic opiold therapy as a primary treatment for chronic pain. Some of the major concerns of both physicians and leaders of health care systems are the development of addiction, drug-seeking behavior, and diversion in patients receiving chronic opioid therapy. Specific aims: The proposed study is designed to estimate the current and lifetime prevalence of drug use and dependence in patients receiving chronic narcotics from their primary care physicians. Drugs of interest include licit opioids, illicit opiolds, sedatives, cocaine, stimulants, cannabis, and alcohol. Secondary questions of interest involve levels of pain control on narcotics, co-morbidity issues, health status, and quality of life issues. Methods: A prevalence study will be conducted in six health care systems in Dane and Milwaukee counties in Wisconsin. A sample of 1,000 patients will be recruited from the practices of approximately 200 primary care physicians who work in the six health care systems. Inclusion criteria include taking prescription opioids for at least the past 30 days, age between 18 and 70, a diagnosis of chronic non-malignant pain, and narcotics prescribed by a primary care clinician. Face-to-face interviews will be conducted utilizing the SDSS and PRISM to assess current and lifetime drug addiction. Patients will also complete questionnaires to assess the secondary questions of interest. The physicians will participate in a short interview to assess their current approach to the use of narcotics for chronic pain. Summary: This would be the first large prevalence survey conducted in the US health care system to assess rates of addiction in a primary care chronic pain population.

DESCRIPTION (provided by applicant): Background: Non-malignant chronic pain is an increasingly common and complex clinical problem. Primary care physicians are being encouraged by patients, pain specialists, and policy makers to increase the use of chronic opiold therapy as a primary treatment for chronic pain. Some of the major concerns of both physicians and leaders of health care systems are the development of addiction, drug-seeking behavior, and diversion in patients receiving chronic opioid therapy. Specific aims: The proposed study is designed to estimate the current and lifetime prevalence of drug use and dependence in patients receiving chronic narcotics from their primary care physicians. Drugs of interest include licit opioids, illicit opiolds, sedatives, cocaine, stimulants, cannabis, and alcohol. Secondary questions of interest involve levels of pain control on narcotics, co-morbidity issues, health status, and quality of life issues. Methods: A prevalence study will be conducted in six health care systems in Dane and Milwaukee counties in Wisconsin. A sample of 1,000 patients will be recruited from the practices of approximately 200 primary care physicians who work in the six health care systems. Inclusion criteria include taking prescription opioids for at least the past 30 days, age between 18 and 70, a diagnosis of chronic non-malignant pain, and narcotics prescribed by a primary care clinician. Face-to-face interviews will be conducted utilizing the SDSS and PRISM to assess current and lifetime drug addiction. Patients will also complete questionnaires to assess the secondary questions of interest. The physicians will participate in a short interview to assess their current approach to the use of narcotics for chronic pain. Summary: This would be the first large prevalence survey conducted in the US health care system to assess rates of addiction in a primary care chronic pain population.

[unreadable] DESCRIPTION (provided by applicant): Goal: The primary goals of the proposed University of Wisconsin NIAAA T32 post doctoral fellowship is to train family physicians, pediatricians, internists, obstetricians, surgeons and emergency medicine physicians to: a) successfully compete for NIH research grants; b) become NIH level scientists; and c) conduct alcohol research in general medical and surgical care sites. [unreadable] [unreadable] Rationale: There are currently less than a dozen practicing physicians in the specialties cited above who have current NIH funding from the NIAAA. With the development of new therapies for the prevention and treatment of alcohol problems, there is a critical need to expand the number of physician scientists working in the alcohol area. [unreadable] [unreadable] Environment: The fellowship will be based in the Department of Family Medicine. The University of Wisconsin Madison is an ideal place to train physician scientists. There are over 20 physicians and scientists in the Schools of Medicine, Letters and Science and College of Agriculture and Life Science who work in the alcohol area. In addition there are a number of federally funded training programs (T32, K30, K12) that provide training and research opportunities for physicians. Training Program: The training program would include weekly post doc seminars, course work in clinical research methodology, seminars on medical ethics, grant writing, and preparation of research publications. [unreadable] [unreadable] Each fellow would have two or three mentors to help them develop their research program. As described in the application, the associate directors for the program include faculty from the departments of Population Health, Pediatrics, Human Development & Family Studies, Family Medicine, Medicine, and Psychiatry. [unreadable] [unreadable] Significance: This would be the first NIAAA T32 focused on training physician scientists to conduct clinical and behavioral science research general medical and surgical care settings. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Goal: Test the efficacy of a primary care-based brief intervention protocol in a sample of college students. Outcomes of interest include reductions in a) high-risk drinking; b) injuries, accidents and other health effects; c) high-risk sexual activity; d) unwanted sexual experiences; e) violence; f) contacts with dean of students office, university police and other legal agencies; and g) health care utilization events; as well as improved academic performance. Background: A 2001 national survey of colleges conducted by the Center for Alcohol Studies at the Harvard School of Public Health (Weschler, 2002) found that 44% of college students reported consuming five or more alcoholic drinks in a row at least once in the previous two weeks. Parents, college alumni, university leaders and others are increasingly concerned about the safety of young people on college campuses and the adverse effects of alcohol on the academic environment. While brief intervention studies have been conducted in many populations and settings, this method has not been tested in primary care college health centers. Method: Students will be asked to complete an embedded alcohol questionnaire at routine visits to a primary care provider at five student health centers in Wisconsin. Men and women who are enrolled as full time students who screen positive for high-risk drinking will be invited to participate in a health interview by a researcher. Students who meet eligibility criteria will be randomized to a "usual care" control group or a "brief intervention group". An intervention will be conducted by a primary care provider and utilizing a scripted workbook. Intervention will consist of two 15-20 minute provider visits and two 5-10 minute follow up phone calls. All subjects will be contacted at 6, 12, 18 and 24 months by telephone to assess changes in outcomes of interest. Additional sources of data include corroborative interview with a friend, university records, local hospital records and state legal records. Power analysis suggests 500 students in each arm of the trial will have sufficient power to detect a difference between groups. Significance: The proposed trial will significantly increase our understanding of how to reduce alcohol use and alcohol-related harm among college students. A positive trial would have important implications for the 4000 colleges and universities in the United States.

DESCRIPTION (provided by applicant): Background: Dr. Fleming has spent the majority of the last 15 years conducting alcohol research, mentoring alcohol researchers, caring for patients and providing consultation to physicians and health care leaders. The PI is committed to continuing his work in the area of patient-oriented research, mentoring, leadership and patient care for the remainder of his academic career. Dr. Fleming is committed to addressing the critical shortage of physician scientists conducting research in the alcohol area. Goal of K24 application: The goal of this application is to provide the PI with 25% time to mentor junior patient oriented investigators and develop new graduate school courses in clinical research as well as an additional 25% time to expand his research program into the areas of alcohol biomarkers, alcohol-related trauma and medication treatment of children with ADHD and fetal alcohol spectrum disorder. If the K24 is awarded in July 2005, he would be funded 40% time on two NIAAA funded R01 grants (R01AA012522-03 and R01AA014685-01), 10% time by his department for his clinical work and 50% time by the proposed K24 grant. Dr. Fleming is completing follow up work on three NIH grants that were completed in the fall of 2004 (R21AA013368-02, R01DA013686-02 and R01AA12664-01A2). Proposed mentoring activities: The K24 award will allow him to expand his research mentoring activities in the alcohol area to include new research fellows and graduate students. It would allow him to spend more time on his recently awarded new NIAAA T32 grant which will fund three physician scientists per year. This training program will focus on increasing the number of physicians who conduct NIAAA funded research. He plans to develop 1-2 new graduate school courses on how to conduct alcohol research with a focus on research methodology and analysis strategies. Significance: The proposed K24 complements the current NIH Roadmap Initiatives. The grant will facilitate Dr. Fleming's ability to train new physician scientists, develop graduate-level courses for masters and PhD students interested in clinical research as well as increasing his capacity to conduct translational research.

DESCRIPTION (provided by applicant): Neuron-Schwann cell interactions are important for the development, function, and regeneration of the peripheral nervous system (PNS). Perturbations in this crosstalk can cause debilitating diseases, such as Charcot- Marie-Tooth disease and other peripheral neuropathies. However, the molecular nature of the interactions between axons and different classes of Schwann cells and the regulation of these interactions are not fully understood. In this proposal, I will determine how the transcription factor Er81 controls development of Pacinian corpuscles, which are specialized sensory end organs composed of a single myelinated sensory axon and non-myelinating corpuscle-forming Schwann cells. Er81 mutant mice have no Pacinian corpuscles, and my preliminary data suggest that the primary deficit comes from disrupted axon-Schwann cell interactions. Since Er81 is a transcription factor, this effect must be executed by other downstream effectors. Neuregulin-1 (Nrg1) is a key mediator of axon-Schwann cell interactions. The expression level of an isoform of Nrg1 with cysteine rich extracellular domain (Nrg1-CRD) determines the thickness of myelination of peripheral axons. In addition, the development of muscle spindles, which contain sensory axons, muscle fibers, and non-myelinating Schwann cells, requires other Nrg1 isoforms, most likely those with an Ig-like extracellular domain (Nrg1-Ig). Despite the important functions of Nrg1, how Nrg1 is regulated to acquire an appropriate expression level is completely unknown. Interestingly, I found that Er81 mutant mice display decreased expression of both isoforms of Nrg1 in somatosensory neurons and reduced myelination thickness of peripheral axons. Therefore, I hypothesize that Er81 regulates the expression of multiple isoforms of Nrg1 to control axonal interactions with both myelinating and non-myelinating Schwann cells. In Aim 1, I will determine that Er81 is required in neurons to maintain a high level of myelination of large-diameter somatosensory axons. I will quantify the extent of the downregulation of Nrg1-CRD and Nrg1-Ig in Er81 mutant somatosensory neurons, and demonstrate that Er81 regulates Nrg1 expression by direct binding to the Nrg1 promoter. To place Nrg1 downstream of Er81 in Pacinian corpuscle development, I will rescue Pacinian corpuscles in Er81 mutant mice by ectopically supplying Nrg1. In Aim 2, I will determine the role of Nrg1 in Pacinian corpuscle formation by ablating all isoforms of Nrg1 from somatosensory neurons. I will also determine which isoforms of Nrg1 are required for corpuscle formation through rescue experiments and analyzing isoform specific mutant mice. Lastly, I will examine if a high level of Nrg1 is sufficient to induce the formation of Pacinian corpuscles in an ectopic location, the mouse foot pad. Collectively, anticipated results from my work will identify the firs transcriptional mechanism that controls the extent of myelination of PNS axons via the regulation of Nrg1, and elucidate molecular mechanisms of neuronal interaction with non-myelinating Schwann cells.