TRANSLATING TOBACCO ADDICTION RESEARCH TO TREATMENT RELEASE DATE: December 10, 2002 RFA: DA-03-010 National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) LETTER OF INTENT RECEIPT DATE: March 24, 2003 APPLICATION RECEIPT DATE: April 23, 2003 THIS REQUEST FOR APPLICAIONS (RFA) CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute on Drug Abuse (NIDA) is committed to the translation of research findings into practice. The purpose of this initiative is to support research designed to translate existing knowledge about the targets, mechanisms and processes of nicotine addiction into treatments immediately applicable or demonstrably exportable to the treatment of tobacco addiction in humans. It is envisioned that the research will be conducted using laboratory studies with human volunteers, or Stage I style clinical studies. However, it is possible that basic research studies may be relevant to the objective of this RFA and, as such, may be one logical component of the work plan of an application. For example, studies with animal models might be relevant to the discovery of more details regarding the mode of action of a clinically used medication, knowledge that, in turn, would allow development of more specific medications. For such applications the applicant will need to provide a compelling rational that the basic research, if successful will, in fact, have direct impact on clinical research, with direct application to treatment interventions. Notwithstanding the importance of the further discovery of the targets, mechanisms and processes of drug addiction, such research itself is not the focus of this RFA. The purpose of this announcement is to foster research that translates existing knowledge into treatment and treatment practice, or research that, in and of itself, will readily translate to clinical research or practice. RESEARCH OBJECTIVES Background and Rationale Significant progress has been made in the treatment of tobacco addiction, and as a result, there are several medications available as the first line treatments of choice. Similarly, behavioral approaches have been shown to produce a treatment response. However, a significant number of tobacco users remain addicted, many of whom are unable to quit their use of tobacco products even when assisted by current treatment approaches. There are at present real opportunities to develop new treatment approaches by building on contemporary advances in our understanding of the biological substrates and behavioral mechanisms of nicotine and tobacco addiction. For example, contemporary discoveries from the field of neuroscience have challenged concepts of the neurochemical substrates that might underlie general addictive processes, and have provided a broad range of alternative candidate systems for exploration as treatment targets for drugs including nicotine, and in some cases, for nicotine specifically. Behavioral research has demonstrated the profound role that conditioned cues play in drug addiction, and has shown that drug-taking behavior is modified by environmental and situational factors. The neurochemical systems mediating some of these effects have been identified. As another example, cognitive science suggests an influence of higher-order mental processes in decision- making expectancies and memories of drug use. Epidemiological studies of the onset of tobacco dependence show clearly that treatment interventions targeting adolescents and young adults are needed; understanding decision- making and information processing in this population may contribute to the development of successful interventions in this case. Outcomes of current treatments and basic research suggest that gender-based approaches are also required, and existing science provides some clues with which to develop them. Nicotine and tobacco addiction offer unique opportunities to the translational scientist to advance treatment approaches. This RFA invites researchers from diverse disciplines to synthesize knowledge from basic research findings into a cogent plan for study that will produce findings directly applicable to the creation of new treatments for tobacco dependence. Areas of Interest This announcement focuses exclusively on the support of translational studies that are based solidly on existing knowledge of the mechanisms and processes of tobacco and nicotine addiction or related areas. The applicant will need to clearly present the existing evidence and appropriate background that justifies building on, translating and applying this body of work to the proposed translational studies. It is expected that studies will primarily involve volunteers in laboratory-based or Stage I style experiments. (For greater detail about Stage I behavioral treatment research, please see the Behavioral Therapies Development Program Announcement at http://grants.nih.gov/grants/guide/pa-files/PA-99-107.html.) However, as noted above, experiments with cells, tissues or animals may be required to clarify mechanisms of existing medications/treatments in ways that directly contribute to making improvements in them. This initiative does not support research to expand the basic science base of nicotine and tobacco addiction per se. Researchers interested in conducting studies of this kind are encouraged to contact NIDA staff to discuss other support and opportunities for them at NIH. Illustrative examples of research described below serve as a guide and are not meant to subsume all research topics that would be appropriate under this announcement. o Testing pharmacological interventions that are logically based on targets that have been identified in basic research studies. These interventions could have utility in reducing use, ameliorating withdrawal symptoms or attenuating cravings in tobacco users. For example, several neurochemical systems (including glutamatergic, noradrenergic and GABAergic) have been identified as playing a role in the reinforcement of nicotine self- administration in animals and/or in neuronal and synaptic processes associated with nicotine addiction. Studies might examine the efficacy of agents that target these neurochemical systems in smokers or other tobacco users; o Similarly, developing and testing new behavioral approaches to treatment. For example, conditioning factors play a prominent role in tobacco addiction as they do for other drug use, and their role in treatment has been examined in some contexts and with certain drugs. However, it may be possible to develop effective ways to extinguish conditioned stimuli associated with tobacco use, and thereby reduce relapse. Indeed, treatment studies are needed that will explore ways to extinguish the multiplicity of cues associated with tobacco use as well as with the context specificity of extinction. In addition, the nature of tobacco use and nicotine addiction, and the availability of nicotine replacement therapies may contribute to success in this area; o Development and validation of treatments applicable to particular population groups. There is a considerable body of research showing gender differences relevant to the treatment of nicotine dependence, including differences in the control of smoking by non-nicotine factors, differences in the effectiveness of nicotine replacement therapies and other pharmacotherapies, differences in cessation rates and relapse rates, and issues specific to females such as menstrual cycle and weight control concerns. Such research points to the need for new gender-sensitive and gender-specific treatment research and approaches. A second example centers on the treatment of smokers with co-occurring mental illness that predispose them to engage in sustained, heavy use of tobacco products. For example, research has shown that tobacco use is prevalent in individuals with depression and schizophrenia. New approaches with medications and new behavioral strategies may improve the effectiveness of treatment in such populations. o Approaches based on employing existing nicotine replacement therapies in new ways to affect sustained reduction of smoking behavior or a sustained attenuation of relapse; o Applying the knowledge of cognitive neuroscience to relapse prevention. Examples in this area include developing methods to improve the decision- making skills of nicotine-dependent individuals, applying knowledge about cognitive development to processes such as attitude formation that may influence relapse and its prevention, and applying knowledge of the role of context in accessing knowledge; o Certain clinical observations may require greater exploration with basic research studies to improve efficacy, or to discover mechanisms of action that would be valuable to the further development of treatments. For example, discovery of the pharmacological profile of bupropion might identify elements that would support the development of new medications; o Applying new technologies to tobacco cessation, withdrawal management, and relapse prevention, where the use of such technologies is justified by our understanding of tobacco addiction. For example, a new nicotine delivery system might be more useful as a cigarette substitute, or the application of virtual reality approaches might facilitate the extinction of tobacco-related cues; o Assess the effectiveness and utility of using established basic behavioral and cognitive assessment paradigms (e.g., measures of implicit cognition, inter-temporal choice, semantic networks) in treatment intervention and in predicting treatment outcomes and relapse. MECHANISMS OF SUPPORT This RFA will use NIH research project grant (R01), the small grant (R03), and the exploratory/developmental grant (R21) award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. FUNDS AVAILABLE NIDA intends to commit approximately $2,000,000 in FY 2003 to fund 7 to 10 new grants in response to this RFA. An applicant may request a project period of up to five years for the R01 and a budget for direct costs of up to $250,000 per year. For R03 applications, the project period cannot exceed 2 years and $50,000 in direct costs in each of those years, and the application research plan (items a-d) cannot exceed 10 pages. Foreign applicants are not eligible for the R03 mechanism. For 21 applications, the project period cannot exceed 3 years and $100,000 in direct costs in each of those years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of NIDA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: William A. Corrigall, Ph.D. Division of Neuroscience and Behavioral Research National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 435-1324 Fax: (301) 594-6043 Email: wcorriga@nida.nih.gov Lisa Onken, Ph.D. Division of Treatment Research and Development National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 4241, MSC 9551 Bethesda, MD 20892-9551 Telephone: (301) 443-2235 Fax: (301) 443-6814 Email: lonken@nida.nih.gov o Direct your questions about peer review matters to: Teresa Levitin, Ph.D. Office of Extramural Affairs National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Telephone: (301) 443-2755 Email: tlevitin@mail.nih.gov o Direct your questions about financial or grants management matters to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3131 MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 E-mail: gfleming@mail.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDA staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Director Office of Extramural Affairs National Institute on Drug Abuse/NIH/DHHS 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-2755 Fax: (301) 443-0538 Email: tlevitin@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health/DHHS 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Director Office of Extramural Affairs National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD (for express/courier service) Telephone: (301) 443-2755 Fax: (301) 443-0538 APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIDA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIDA in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory Council on Drug Abuse REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? (6) RELEVANCE: The relevance of the proposed work to the purpose of the RFA. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: March 24, 2003 Application Receipt Date: April 23, 2003 Peer Review Date: June/July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phases I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. HIV/AIDS COUNSELING AND TESTING POLICY FOR THE NATIONAL INSTITUTE ON DRUG ABUSE: Researchers funded by NIDA who are conducting research in community outreach settings, clinical, hospital settings, or clinical laboratories and have ongoing contact with clients at risk for HIV infection, are strongly encouraged to provide HIV risk reduction education and counseling. HIV counseling should include offering HIV testing available on-site or by referral to other HIV testing service for persons at risk for HIV infection including injecting drug users, crack cocaine users, and sexually active drug users and their sexual partners. For more information see http://grants.nih.gov/grants/guide/notice-files/NOT-DA-01-001.html NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS: The National Advisory Council on Drug Abuse recognizes the importance of research involving the administration of drugs to human subjects and has developed guidelines relevant to such research. Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Home Page at www.nida.nih.gov under the Funding, or may be obtained by calling (301) 443-2755. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.279, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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