Steven L. Bernstein - US grants

DESCRIPTION (provided by applicant): Isolated axonal strokes comprise more than 3/4ths of the 166,000 strokes that occur in the US every year, but until now there has been no in-vivo model to analyze this stroke form. We have developed a new rodent anterior ischemic optic neuropathy (rAION) model of CNS axonal stroke that directly correlates with human AION. We have characterized the response of the neurons and optic nerve following axonal stroke. We have determined that rAlON results in optic nerve demyelination and loss of function. We have also found that estrogen significantly reduces the loss of neurons following rAION. We hypothesize that: 1) axon ischemia-associated demyelination blocks optic nerve repair. 2) Estrogen enhances post-stroke optic nerve recovery. Our proposal is designed to answer three related questions: 1) What RGC axonal transport and glial changes occur in-vivo following rAION, contributing to permanent optic nerve damage? To answer this question, we will use the rAION model to define early retina and optic nerve stress-related cellular events, and identify the time course of optic nerve demyelination and remodeling resulting from optic nerve stroke. This work will be performed using histological, electrophysiological, and molecular methods. 2) Can reducing post-stroke demyelination increase post-stroke function? With the rAION model, we will use anti-demyelinating drugs, to determine whether reducing post-stroke demyelination decreases permanent optic nerve damage and increases function. This work will be performed using electrophysiological, stereotactic retrograde tracing, molecular, and histological methods. 3) Does estrogen also exert neuroprotective effects when administered after optic nerve insult? With the rAION model, estrogen and estrogen inhibitors, electrophysiological, histological, stereotactic, and molecular methods, we will determine the effect of differences in dose, timing, sex, and blockade of endogenous estrogen. Our experimental results obtained with this model will enable rational design of clinically effective, neuroprotective strategies that can minimize ischemic axonal stroke damage.

DESCRIPTION (provided by applicant): In urban communities, the prevalence of tobacco use among adults visiting a hospital emergency room (ER) nears 40%, well in excess of the 25% smoking prevalence rate of the general population. Many of these patients lack easy access to primary care, suggesting the ER may be an attractive locus to initiate tobacco cessation efforts. With over 100 million annual visits to U.S. ERs, it may be possible to engage millions of smokers in tobacco cessation efforts. The major purpose of this study is to examine whether a multicomponent intervention delivered in the ER by a Lay Educator to adult smokers interested in quitting is more likely to result in cessation than usual care. A secondary goal is to test whether patients who present to the ER with a tobacco-related illness (as indicated by ICD9 code) are more likely to quit than ER smokers with a non-tobacco-related condition. This will allow us to test the validity of the "teachable moment" as an opportune time to engage patients in considering a behavioral change. The proposed study is a randomized trial of a motivational interview, provision of literature, and post-visit follow-up (Enhanced Care) vs. referral to a cessation clinic (Minimal Care) for ER patients who smoke. Eligibility criteria: age >= 21 years, contemplation or preparation stage of change, not admitted to hospital. All patients will undergo a standardized stage of change assessment, and measurements of nicotine dependence and exhaled carbon monoxide. All will receive a cessation fact sheet and referral card to the smoking cessation clinic; the cards of those in the Enhanced Care group will have a specific appointment date and time. The Enhanced Care group will receive a language-appropriate pamphlet discussing smoking cessation. We will record the ICD9 codes associated with each visit. Major outcome measure: cessation within 3 months of the ER visit, stratified by treatment group. Secondary outcome measure: cessation within 3 months of the ER visit, stratified by whether the visit was smoking-related. If smokers receiving Enhanced Care are more likely to quit, then the ER could be considered a new, effective locus for tobacco control, potentially reaching several million smokers. If patients with a smoking-related diagnosis for the ER visit are more likely to quit than those with nonsmoking-related ICD9, then this supports the construct of the teachable moment.

DESCRIPTION (provided by applicant): Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) infarct, and the most common cause of sudden optic nerve (ON) related vision loss, NAION affects ~15,000 individuals/year and has no effective treatments. Little is known about the mechanisms in NAION pathophysiology. Our lab developed the first rodent and primate NAION models that have been validated for nearly every finding found in NAION, and us to critically dissect NAIONs likely processes. We have determined that early and late inflammatory changes play a key role in NAION model development and damage. Soon after NAION model induction, ON head edema and a compartment syndrome occur along with soluble inflammatory cytokine expression and progressive ischemia. Later (>3d) changes include significant cellular inflammatory infiltration, with increased M1 (degenerative macrophage response) and decreased M2 (regenerative macrophage response) activities, and progressive axon- and oligodendrocyte damage. These responses ultimately result in retinal ganglion cell (RGC) and oligodendrocyte death. We identified prostaglandin J2 (PGJ2) as the first agent that can potentially treat early stage disease. In aim 1, we will separately evaluate PGJ2's neuroprotective mechanisms, confirming their individual identities and their maximal effects. We will then determine whether these mechanisms act synergistically, to maximize neuroprotection. In aim 2, we will determine whether selectively immunomodulating the neuroprotective M2 macrophage inflammatory response will reduce RGC and myelin dysfunction and cellular death, and improve post-infarct recovery. Results of these interventions will be evaluated using a variety of techniques, to quantify effects at the gene expression level, histochemically and functionally. This combination early and later approaches is designed to maximize development of clinically effective treatments for NAION and related diseases, and greatly improve post- NAION recovery.

DESCRIPTION (provided by applicant): Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) stroke and the most common cause of sudden optic nerve-related vision loss. NAION affects more than 6000 Americans every year, often bilaterally, with no currently effective treatments. Every NAION clinical treatment trial has failed. A major reason for these failures is the lack of appropriate animal models closely resembling NAION physiologically and pathologically, and that would allow testing of relevant treatments for translation to the human condition.I have now generated an old-world primate model of non-arteritic anterior ischemic optic neuropathy (pNAION). My preliminary data reveal a high degree of similarity between pNAION and human NAION. A great advantage of the current proposal is my ability to test potential optic nerve stroke treatments, using well- defined model systems, from rodents through old-world primates. This will yield improved potential for clinical success. I have assembled an incredibly capable, highly focused, integrated and dedicated team for the proposal. My preliminary data reveal that activating the Nonarteritic anterior ischemic optic neuropathy (NAION) (PGD2) metabolic pathway after rodent ON infarct reduces ON edema and improves long-term retinal ganglion cell (RGC) survival. This pathway is highly conserved from rodents to humans. Recent anecdotal studies also report improved clinical function in NAION patients following treatment with other agents that reduce tissue edema. I hypothesize that, by reducing early ON edema in pNAION, I can improve post-infarct RGC survival and optic nerve function. This translational study will determine whether PGD2 activation and ON edema reduction are likely to be effective neuroprotective treatments in NAION. There are three subaims: a. Characterize early changes in retinal and optic nerve function with ultimate neuronal loss, and tissue remodeling, to determine the appropriate intervals for early intervention and maximum recovery. b. Determine if early edema reduction improves post-stroke optic nerve function. I will activate the PGD2 pathway to reduce pNAION-induced ON edema and evaluate ON function using high-resolution optical coherence tomography (OCT), electrophysiological techniques, and magnetic resonance (MR) imaging. In vivo results will be correlated with histopathologic and immunochemical findings. c. Compare PGD2 activation with currently available VEGF-blocking drugs used to reduce clinical NAION- induced ON edema, to confirm the potential clinical effectiveness of the edema-reduction approach. PUBLIC HEALTH RELEVANCE: Nonarteritic optic nerve (ON) stroke (NAION) currently affects over 6000 Americans each year. There are no effective treatments, partly because no model of the disease in a closely-related species was available for evaluating approaches that can be translated into clinical therapy. I have developed the first relevant non-human primate model of NAION, and have identified a conserved pathway effective in treating rodent ON stroke. This proposal will determine whether by activating this pathway, and additionally by reducing post-stroke ON swelling using a commercially available drug, we can improve post-ON stroke function and speed recovery after infarct.

DESCRIPTION (provided by applicant): Of the nation's 45 million adult smokers, nearly 20 million visit hospital emergency departments (EDs) each year. ED patients, particularly smokers, are disproportionately low-income, with limited access to traditional primary care settings. Patients presenting to the ED with a tobacco-related trigger event, like an asthma attack, may be experiencing a teachable moment. Thus, the ED may be an ideal location in which to identify smokers and initiate treatment for tobacco dependence. Initial pilot research by our group has demonstrated the feasibility of ED-based brief interventions for smokers. Based on our feasibility studies, the Institute of Medicine 2006 report on tobacco and the 2008 US Public Health Service guidelines now list EDs as appropriate loci for tobacco control efforts. This study aims to test the efficacy of an ED-initiated tobacco intervention which includes counseling and medication. The intervention-Screening, Brief Intervention, and Referral to Treatment (SBIRT)-uses a form of motivational interviewing known as the Brief Negotiation Interview (BNI). Our proposed intervention combines a BNI with initiation of nicotine replacement therapy (NRT) and a fax referral to the state Smokers' Quitline during the ED visit. A 6-week starter kit of NRT (patch and/or gum, tailored to level of addiction and patient preference) will be provided with written materials. The initial dose of NRT will be given in the ED. A trained nurse will administer the booster intervention via telephone 3 days post-visit. The SBIRT+NRT arm will be compared to standard care (SC), which consists of written materials only, in a controlled trial of 778 smokers age 18 years or older randomized in a 1:1 fashion. The primary hypothesis is that SBIRT+NRT will be superior to SC in reducing self-reported and biochemically verified 7-day tobacco abstinence at 3 months. Secondary hypotheses include: (1) Patients with a tobacco- related diagnosis for the ED visit will have a higher cessation rate than patients without a tobacco-related diagnosis, and (2) Patients who believe their ED visit is smoking-related will have a higher quit rate than others. We will conduct a cost benefit analysis of the interventions. Follow-up assessments at 1, 3 and 12 months will combine self-report with in-person salivary cotinine testing at 3 months for smokers who assert abstinence via phone. Expansions of the proposed project as compared to earlier studies include: 1) initiation of NRT during the ED visit; 2) provision of multiple forms of NRT; 3) a proactive referral made to the Quitline; 4) a credible control condition with minimal baseline assessment, to avoid the assessment reactivity seen in similar ED studies; and 5) an economic analysis of the tested interventions.

DESCRIPTION (provided by applicant): Forty-six million US smokers account for 6-12 million hospitalizations each year. These admissions provide a teachable moment for tobacco control. Advances in health information technology (HIT), like electronic medical records (EMR), provide an opportunity to implement evidence-based, cost-effective, sustainable programs in tobacco treatment for hospitalized smokers. The overall goal of this proposal is to study the effectiveness of a novel Integrated Tobacco Order Set (ITOS), embedded within an EMR, in promoting sustained smoking abstinence in a cohort of adult inpatients. We propose a 2-arm trial, randomized by provider, of ITOS + Academic Detailing (AD) at Yale-New Haven Hospital (YNHH) compared to AD alone. Subjects admitted to physicians in the AD arm may receive a smoking cessation brochure and medications ordered electronically, our standard of care. Providers in the ITOS arm will access an electronic order set that includes: (1) medication orders for varenicline, bupropion and nicotine replacement therapy; (2) a fax automatically sent to the patient's primary care provider, informing him/her of the initiation of tobacco treatment (3 an electronic fax sent to the state smokers' quitline (QL) for post-discharge treatment (4) a prompt at discharge encouraging prescription of outpatient pharmacotherapy, and (5) a set of 5 or more QL-initiated counseling calls to subjects for 2 months post-discharge. Prior to study initiation, internal medicine and emergency medicine housestaff and hospitalists will be trained in tobacco treatment. ITOS will be activated, and will cover all inpatient units. Outcome measures include biochemically confirmed tobacco abstinence and an economic analysis. Follow-up will be done at 1, 6, and 12 months. The primary aim of this project is to determine whether ITOS+AD compared to AD improves 12-month smoking cessation in 960 smokers age > 18 years admitted to YNHH. Secondary aims are to 1) evaluate ITOS's ability to encourage smokers to engage in treatment; 2) assess ITOS's ability to enhance inpatient treatment of smoking; and 3) conduct an economic analysis of the intervention. Study findings and a toolkit will be disseminated through various professional societies and organizations. The study team consists of an outstanding group of investigators with rich experience in tobacco treatment, provider training, implementation science, and HIT.

DESCRIPTION (provided by applicant): Health behavior is the single greatest determinant of health. We want people to take their medication as prescribed, follow healthful diets, get adequate sleep, and avoid harmful substances and addictions. These actions may be thought of as binary behaviors-adherence and abstinence-that individuals may engage in-or not-on a daily basis. Yet, clinical trials of substance use treatment or abstinence use widely disparate measures of effect. There is no obvious biological or behavioral explanation for these disparate measurements. Further, measures of adherence and abstinence often fail to account for the rich variation in the pattern of the health behavior. These patterns of adherence or abstinence may further contribute to the individual's prognosis. This proposal offers a novel method to measure adherence and abstinence, using concepts adapted from network analysis. The gamma index, which measures the connectedness of doses taken (or substances not taken), accounts for the pattern of an individual's adherence, or abstinence, in an innovative algebraic model. This index can be used to model adherence and abstinence to examine their effect on clinically relevant biologic outcomes. Gamma is bounded at a value of 0 for perfect non-adherence (or non-abstinence), and 1 for perfect adherence (or perfect abstinence). We propose to analyze a series of datasets from completed clinical trials in four domains (1) adherence to Highly Active Antiretroviral Therapy (HAART) in subjects with HIV/AIDS; (2) adherence to buprenorphine treatment in subjects with opioid dependence; (3) abstinence from tobacco in trials of smoking cessation; and (4) abstinence or reduction in drinking in trials of subjects with alcohol use disorders. In trials of antiviral adherence, we will examine associations between the index and changes in viral load. In trials of tobacco, alcohol and drug treatment, we will examine associations between the index and long-term abstinence rates. The Specific Aims of this project are to (1) Assess the ability of the gamma index to improve the explanatory power of adherence on changes in viral load in trials of antiviral therapy in individuals infected with HIV, and (2) Assess the ability of the gamma index to explain differences in cessation endpoints in trials of subjects with substance use disorders, such as alcohol abuse, drug use, and smoking. Daily records of adherence (or substance use) are needed for this modeling, which makes these studies, which employ ecological momentary assessment (EMA) methods, timeline follow-back techniques, or electronic pill cap data, ideal. The outstanding interdisciplinary team for this project includes renowned experts in adherence, graph theory and network analysis, the treatment of HIV, and use of licit and illicit substances. The gamma index offers to provide new insights into underlying patterns of health behavior, their relationship to clinical outcomes, a means of quantifying these patterns, and the possibility of novel real-time interventions to promote healthy behaviors.

Abstract Tobacco use remains the leading cause of preventable death in the United States. Smoking is increasingly a disease of medically underserved populations, including individuals of lower socioeconomic status and those with behavioral or substance use disorders. Emergency departments (EDs), to which Americans paid 130 million visits in 2013, are excellent clinical settings in which to identify smokers, initiate treatment, and refer for aftercare. Our previous work has demonstrated the efficacy of a multicomponent intervention in promoting tobacco abstinence at 3 months. The intervention included a full package of evidence-based treatments, including initiation of nicotine replacement therapy in the ED, provision of 6 weeks of patches and gum, a brief motivational interview, active referral to a state smokers' quitline, and a brochure with information on the health risks of smoking. A subsequent pilot study demonstrated the feasibility and potential efficacy of an intervention that included short-message-service (SMS) texting to subject cellphones to promote tobacco abstinence. While efficacious, it is not clear which components of the intervention had the greatest impact, which combinations of therapy might work best, or which are generalizable to all EDs. In order to design an intervention that is clinically effective, cost-effective, and practicable, we propose to disentangle the effects of these components and assemble an intervention that maximizes clinical efficacy, feasibility, and acceptability, given a cost- effectiveness constraint and findings from qualitative analysis. The methodology we propose using is the Multiple Optimization Strategy (MOST), a clinical trials design that uses principles adapted from industrial engineering. We propose an innovative 16-arm full-factorial design in a cohort of 1056 adult smokers in an urban ED, to test the efficacy of four key components: motivational interviewing, initiation of nicotine replacement medication, quitline referral, and texting. All subjects will receive a smoking cessation brochure. At the trial's completion, we will use a novel mixed-methods approach to identify components that were efficacious within the proposed cost constraint, along with feasibility and acceptability to subjects. We will assemble components found to be clinically efficacious, cost-effective, and feasible/acceptable into a multicomponent package for testing in a future randomized clinical trial. Study Aim (1) is to conduct the factorial experiment; Aim (2) is to analyze trial results to identify the effective components, and Aim (3) is to lay the groundwork for the subsequent clinical trial testing this multicomponent intervention, versus a control condition. The multicomponent intervention, once disseminated and implemented, can transform the care of the tens of millions of smokers who visit U.S. EDs. Our team includes an outstanding array of experts with deep experience in trial design, including the developer of MOST, emergency department-based investigation, tobacco dependence treatment, texting, health economics, and qualitative methods.  

Yale Scholars in Implementation Science Abstract The proposed program aims to improve health and health care in the United States by developing the next generation of implementation scientists skilled in research, knowledge translation, and leadership. Reducing the lag between the generation and the adoption of evidence to support clinical, organizational and policy decisions was identified as a national priority by the National Academy of Medicine in 2010. Far too few investigators are trained in dissemination and implementation science, with the skills to engage a broad range of stakeholders as partners and to translate research into action. The proposed program will: [Aim 1] Develop scientists with the knowledge, skills, and ability to become independent investigators in implementation science; [Aim 2] Build a cadre of knowledge translators who collaborate successfully with stakeholders, including community partners, to identify and address barriers to implementing evidence in practice and policy. [Aim 3] Enhance their capacity to serve effectively in leadership roles on broadly inclusive multidisciplinary research teams. This proposal has three distinguishing characteristics: (1) Faculty mentors representing an extraordinary breadth of disciplines from a wide array of schools within Yale, including Medicine, Nursing, Public Health, and Management, and areas within medicine, including internal medicine, pediatrics, emergency medicine, critical care medicine, obstetrics and gynecology, and psychiatry; (2) Intense engagement with the broader New Haven community, with key partners and mentors including the local Department of Health, a federally qualified health center, and several local nonprofit organizations serving the homeless, recent immigrants, and medically underserved communities, and (3) Novel use of social network modeling to assess the professional development and progress of YSIS Scholars. The curriculum includes coursework developed especially for this program, along with longstanding courses that have trained a generation of scholars in Yale's Robert Wood Johnson Clinical Scholars Program, the Investigative Medicine Program, and Schools of Public Health and Management. Scholars will also develop and conduct at least one major research project with close mentorship from national and international experts in heart, lung, blood, and sleep medicine. Eligible Scholars will receive a Masters in Health Services degree. Training duration will be three years, with coursework based upon Scholars' needs and prior training. We anticipate recruiting three Scholars in Year Two, and two Scholars in Year Three. Candidates must: a) have a Doctoral Degree (MD, DO, PhD, or equivalent) from an accredited program and b) be a United States citizen or non-citizen national, or be lawfully admitted for permanent residence. In addition, the following qualifications are essential: a) evidence of a strong commitment to implementation science; b) a solid record of academic excellence in fields of previous academic or clinical training; c) dedication to work with stakeholders as partners and to focus on dissemination and implementation of evidence-based practice.

ABSTRACT Smoking is the leading threat to health of patients living with HIV (PLWH). Unfortunately, the evidence-base for tobacco use disorder treatment in PLWH lags behind that of HIV itself. A 2016 Cochrane meta-analysis of data from 12 clinical trials involving 2,087 participants receiving both medications and behavioral support found modest evidence of improved abstinence in the short term (<6 months), but not long-term. A short-coming of these studies is that treatment algorithms did not include plans for non-response, or relapse to smoking. A newer clinical trial design, the Sequential Multiple Assignment Randomized Trial (SMART), includes a dynamic treatment strategy in which pre- specified decision rules guide the ongoing treatment of both responders and non-responders. This approach allows SMART designs to better mirror the management of chronic relapsing conditions, such as tobacco use disorder. We, therefore, propose a two-arm, two-stage randomized trial of 622 adult PLWH who smoke cigarettes and receive care in one of three health systems. At inception, participants will be randomized to either combination nicotine replacement therapy (NRT) (patch and gum or lozenge) or combination NRT+contingency management (CM). At 12 weeks, responders (non-smoking participants confirmed by exhaled carbon monoxide [eCO]) in both arms will receive 12 more weeks of the same treatment. Non-responders (participants with continued smoking by self-report and/or eCO) in both the NRT and NRT+CM arms will be re-randomized to 12 weeks of treatment, either with varenicline (VAR) or varenicline+CM (VAR+CM). The intervention will be delivered by trained clinical pharmacists. The primary outcome will be eCO-confirmed abstinence at 24 weeks post-enrollment. The specific aims of the proposed study are to: (1) study the effectiveness of a dynamic treatment approach to reduce the prevalence of smoking in a cohort of PLWH, and to identify the optimal approach; (2), study the effectiveness of various dynamic regimens on CD4 count, HIV viral suppression, and VACS index (validated measure of morbidity and mortality risk); and (3) grounded in implementation science and using a Hybrid Effectiveness-Implementation Type I design, identify barriers and facilitators to delivering our intervention to inform future implementation. The study team includes individuals with expertise in tobacco use disorder treatment, HIV and addiction in PLWH, clinical trials, CM, implementation science, and SMART designs. Study components are readily scalable and all interventions are richly evidence-based. This proposal offers innovation as the first use of the following in a smoking intervention targeting PLWH: (1) a SMART design with first-line tobacco treatment medications; (2) clinical pharmacists as key interventionists; (3) VACS Index 2.0 as an outcome among a general sample of PLWH who smoke; and (4) implementation-focused process evaluation of tobacco intervention including pharmacists and CM in HIV clinics. This study holds exceptional promise to transform tobacco use disorder treatment in HIV treatment settings nationally.

Abstract Implementation science is the domain of scholarship that studies methods to facilitate the spread and adoption of evidence-based practices into real-world settings. The field has seen tremendous growth in the last decade. Yet, a critical gap impeding further growth is the lack of rigorous training opportunities for young investigators. Hence the objective of this proposed program is to launch the first T32 program dedicated to implementation science training to improve heart, lung, blood, and sleep (HLBS) health promotion and clinical practice. We seek applications from MDs, PhDs, and predoctoral candidates, from a wide range of clinical and scientific disciplines, and diverse personal backgrounds. The proposed program will take full advantage of the stellar resources of two new centers at Yale: the Yale Center for Implementation Science (YCIS), based at the School of Medicine, and the Center for Methods in Implementation and Prevention Science (CMIPS), based at the School of Public Health. The program?s aims are to: [1] Develop scientists with the knowledge, skills, and ability to become independent investigators who will continue to expand the field; [2] build a cadre of investigators/leaders who collaborate with stakeholders, including patients, caregivers, and public health professionals, from inception through dissemination of research results, with the goal of promoting the uptake of findings in practice and policy. [3] Enhance the diversity of the implementation science workforce. This proposal has 4 distinguishing characteristics: (1) Integration with an NHLBI-supported K12 program that serves as the training core of YCIS; (2) Mentors and resources representing an extraordinary breadth of disciplines from a wide array of schools at Yale, including Medicine, Public Health, Nursing, and Management, with expertise in implementation science, organizational behavior, study design, and (HLBS) health promotion and medical care; (3) Intense engagement with the broader New Haven community, including the Department of Health, federally qualified health centers, and local nonprofit groups, and (4) A novel use of social network modeling to assess the professional development and progress of T32 trainees. Our initial cohort of K12 scholars have secured NIH, foundation, and industry grants, and averaged 4 papers/year each, attesting to the rigor of our training. Didactic components leverage coursework developed by YCIS and CMIPS, and additional Yale programs that have trained generations of scientists in clinical investigation and public health research methods. A research practicum will offer close mentorship from national and international experts in HLBS medicine. Eligible trainees will receive a PhD or Masters in Health Science degree, depending on professional needs. Training duration will be 2-3 years, based on needs. We will have 3-7 slots per year. Successful candidates must show evidence of a strong commitment to implementation science, academic excellence in fields of previous academic training, and a commitment to work with stakeholders as partners. Trainee progress will be monitored and evaluated by the Program Directors, mentors, and an Advisory Committee.