HEPATITIS C: NATURAL HISTORY, PATHOGENESIS, THERAPY AND PREVENTION Release Date: June 30, 1998 RFA: DK-98-017 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Cancer Institute National Institute of Allergy and Infectious Diseases National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse Office of AIDS Research Office of Research on Minority Health American Digestive Health Foundation Letter of Intent Receipt Date: October 13, 1998 Application Receipt Date: November 13, 1998 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Cancer Institute (NCI), National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Drug Abuse (NIDA), Office of AIDS Research (OAR), and the Office of Research on Minority Health (ORMH) in partnership with the American Digestive Health Foundation invite grant applications for both basic and clinical research in the areas of pathogenesis, natural history, therapy and prevention of hepatitis C. The hepatitis C virus is a major cause of acute and chronic liver disease in the United States and now ranks second only to alcoholism as the cause of cirrhosis and end-stage liver disease. Acute hepatitis C leads to chronic infection in approximately 75% of cases. Chronic hepatitis C is often asymptomatic and can be mild, but in a proportion of patients, the chronic infection leads to progressive liver disease and ultimately cirrhosis and end stage-liver disease, including cancer. The determinants of outcome and progression of liver disease in hepatitis C are unknown but may be related either to viral, behavioral, environmental or genetic factors of the infected host. Alcohol use, other medical conditions, and co-infection with other viruses may also affect the disease outcome of hepatitis C infection. At present the therapy of hepatitis C is unsatisfactory. Only 20-25 percent of patients respond to currently available therapies with long term remission of liver disease. The mechanism(s) by which alpha interferon and other anti-viral agents induce clearance of virus and improvement of liver disease in only a subpopulation of patients is not known. In addition, its lack of response in a high proportion of patients with hepatitis C is also unexplained. Thus, the elucidation of the mechanism(s) by which hepatitis C leads to liver injury and the factors determining the course and outcome of chronic infection with and without therapy are the focus of this RFA. Noting that the most effective way to prevent the liver disease of hepatitis C is through the generation of a preventative vaccine, this RFA also supports the submission of applications with the aim of generating a vaccine for hepatitis C. In recognition of the importance of this research, the American Digestive Health Foundation (a cooperative effort of the American Gastroenterological Association, the American Society of Gastrointestinal Endoscopy, and the American Association for the Study of Liver Disease) will be providing partial funding through the NIH for direct costs of the portfolio of grants that receive support under this initiative. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Hepatitis C: Natural History, Pathogenesis, Therapy, and Prevention, is related to the priority area of chronic disabling diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017- 001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Support of this program will be through the NIH grant-in-aid research project grant (R01) award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The total requested project period for an application submitted in response to this RFA may not exceed five years. A maximum of five years can be requested for foreign awards. The anticipated award date is July 1, 1999. Applications comprising multicenter clinical trials for the treatment of hepatitis C will not be considered responsive to this RFA. Such applications can respond to the Program Announcement PAR-98-071 entitled "Small Grants in Digestive and Nutritional Disorders". FUNDS AVAILABLE For FY 1999, $5.15 million will be committed to fund applications submitted in response to this RFA. It is anticipated that 17 to 22 awards will be made, however, this funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. The American Digestive Health Foundation will provide additional funds for across the board support this initiative, but funding decisions will be the sole prerogative of the NIH. Although this program is provided for in the financial plans of the NIDDK, NCI, NIDA, NIAAA, NIAID, ORMH, OAR, and the American Digestive Health Foundation, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background The hepatitis C virus (HCV) is a major cause of acute and chronic liver disease. In the United States, hepatitis C accounts for approximately 20 percent of acute viral hepatitis and 60-70 percent of chronic viral hepatitis. In 1995, chronic hepatitis C infection accounted for 30 percent of all transplants making it the single major indication for liver transplantation in adults. Approximately 75 percent of persons infected with this virus develop chronic infection. Chronic hepatitis C is typically insidious and asymptomatic, but leads to cirrhosis and end-stage liver disease in 20-30 percent of persons, usually over the course of 2 to 3 decades. Nearly 4 million Americans are infected with hepatitis C and the infection is more common in minority populations than in non-Hispanic whites. Chronic hepatitis C is responsible for an estimated 8,000 to 10,000 deaths annually. At present there are no means of prevention of hepatitis C, and treatments are unsatisfactory. A recent NIH Consensus Development Conference summarized the current knowledge about hepatitis C and made recommendations regarding management and therapy. The Conference also provided key recommendations of areas for future research studies. Those areas related to this RFA were: o Monitoring of the epidemiology of acute and chronic hepatitis C with additional focus on the specific mode of transmission in minority groups, institutionalized individuals, and injection and intranasal drug users as well as studies on sexual, household, occupational, nosocomial and perinatal transmission, o Long term studies defining the natural history of hepatitis C in all infected persons, as well as among specific cohorts such as minorities, children, the aged, persons with hemophilia, and individuals co-infected with HIV, with an emphasis on identifying factors associated with disease progression to cirrhosis as well as studies on establishing the best means of monitoring for the early detection of hepatocellular carcinoma using alpha fetoprotein testing and ultrasonography and other detection modalities still to be established, o Studies on the pathogenesis and mechanisms of liver cell injury by HCV, elucidation of cytopathic effects of the virus, mechanism(s) of liver fibrosis and liver cell necrosis particularly through the generation of new animal and cell culture models. One of the significant impediments to progress against hepatitis C is the absence of suitable animal and cell culture models. This issue was described by the consensus conference as "a major bottleneck" and the development of such model systems as a "high priority. Also, studies to define the bases for persistence of or recovery from viral hepatitis and on detailing the mechanism(s) of development of hepatocellular carcinoma in patients with hepatitis. o The generation of effective new anti-viral therapies that inhibit virus replication and prevent or delay the progression of liver disease concomitant with a full understanding of the molecular virology of the virus, o Studies of alcohol ingestion and the course of disease as well as the interaction between HCV and diabetes mellitus, obesity, iron metabolism and medications, o Development of a safe and effective vaccine Research Areas of Focus for this RFA The current RFA addresses the areas of research recommended by the NIH Consensus Development Conference through the specific request for basic and clinical research grant applications related to Transmission, Clinical Manifestations, Natural History of Acute and Chronic Hepatitis C, Transfusion-related Hepatitis C, Liver Cell Injury, Fibrosis and Cirrhosis, Hepatocellular Carcinoma, Treatment of Hepatitis C and Vaccine Development. o Transmission. Studies are requested to elucidate the modes of non-parenteral transmission of hepatitis C, particularly within specific cohorts such as minority populations, lower socioeconomic groups, alcohol users, immunosuppressed persons, the young and the aged. Investigations of nonspecific means of decreasing transmission in high risk groups such as substance abusers, medical care personnel, dialysis and transplant patients are also sought. Mechanisms of enhanced transmission possibly associated with host genetic susceptibility or viral types are also of interest. o Clinical manifestations. Elucidation of the basis for differing clinical presentations-icteric hepatitis, anicteric hepatitis, cholestatic hepatitis, fulminant hepatitis and determination of the basis for such clinical symptoms as fatigue, myalgia, arthritis and pruritus is needed. The determination of the biological mechanisms and clinical implications of extrahepatic HCV-related manifestations such as cryoglobulinemia, glomerulonephritis, arthritis, porphyria cutanea tarda and neuropathies is also needed, as well as the investigation of the association and etiology of HCV-related B cell lymphomas. o Natural history of acute and chronic hepatitis C infection and disease outcome. Studies are needed to elucidate the immunological and virologic basis of recovery from acute hepatitis C as opposed to persistence of viral infection after acute infection. The role of host genetic background in outcome of infection should be explored. In addition, investigations are needed of viral and host factors responsible for and mechanisms of continued persistence of infection with and without hepatocellular injury in chronic hepatitis C as well as the determination of factors responsible for disease progression including: alcohol and smoking, diet and nutrition, environmental factors, geographic location, the role of concomitantly administered medications and nutritional supplements and other viral co-infections. Also, studies on alcohol"s effects on levels of viremia in HCV-infected individuals, and whether alcohol enhances expression of HCV proteins in the liver or skews the cellular immune response to HCV (e.g., by preferentially affecting specific cell types such as TH1 vs. TH2) are sought. o Transfusion-related hepatitis C. Long term studies should define the natural history of hepatitis C infection in specific populations that have received and continue to receive frequent transfusions of blood components and pooled plasma derivatives. Persons with hematologic disorders, such as hemophilia, thalassemia, sickle cell disease, and persons that have been and may be further exposed to different genotypes of HCV should be included. Genetic interactions could facilitate escape from initially established immune mechanisms. Studies should focus on the long-term morbidity and mortality of chronically infected individuals, including factors contributing to cirrhosis and hepatocellular carcinoma and to amelioration by therapies directed against HCV itself. Factors to be considered are viral characteristics (genotypic variations, viral load), host characteristics (gender, age, genetic susceptibility, and contributions of the underlying disease), antecedent and superimposed co-infections (HBV, HIV and other agents affecting hepatic and immunologic functions), and allogeneic exposure to variant proteins in infused materials. Potential contributing factors to variations in the course of HCV infection include geographic location, diet, alcohol, smoking, environmental contaminants and medications. o Liver cell injury. Basic research studies are sought to define the biologic mechanisms by which hepatitis C virus induces cell injury, be it directly or indirectly, including interaction of apoptotic cell pathways, intracellular signaling pathways and possible contributions of oxidants and oxidant factors, iron and cytoprotection factors. Applications are also sought that develop in vitro viral propagation for the study of mechanisms of liver cell infectivity and cellular injury. The goal of this research could also be the development of a readily available cell culture system that is fully permissive for viral replication thus promoting the identification of infectious molecular clones, pathways of infection and liver cell injury. o Model Systems. Applications are sought that develop in vitro viral propagation for the study of mechanisms of cell infectivity. A goal of this research might be to identify antiviral strategies and neutralizing antibodies and epitopes. Another goal could be the development of a readily available cell culture system that is fully permissive for viral replication thus promoting the identification of infectious molecular clones in the support of the analysis of the viral structure. Studies are also requested that develop small animal models of acute and chronic infection for the characterization of replicative cycle of the virus, the hosts" immune response to the virus, mechanisms of recovery and persistence, and viral mechanisms of liver pathogenesis including oncogenesis. o Fibrosis and cirrhosis. Studies are needed to investigate mechanisms of augmented liver matrix formation and hepatic fibrosis formation induced by hepatitis C. Studies are also needed to better define means of staging of fibrosis in chronic hepatitis C using liver biopsy tissue as well as noninvasive means such blood tests or imaging procedures. Studies are also requested that develop small animal models of acute and chronic infection for the characterization of viral mechanisms of liver pathogenesis including oncogenesis. Also studies are needed to determine the mechanism(s) by which alcohol enhances virus-induced cytopathology in hepatocytes, and whether chronic alcohol consumption sensitizes hepatocytes to the fibrogenic effects of cytokines, especially in the presence of HCV infection. Also, alcohol"s effects on hepatocellular pathology need to be investigated in transgenic animals that express HCV structural and non-structural proteins. o Hepatocellular carcinoma (HCC). Studies are needed to elucidate the mechanism(s) of development of hepatocellular carcinomas in HCV-infected patients. Epidemiologic studies are needed to determine the contribution of HCV to the development of HCC, with an emphasis on studies of etiologic co-factors that might interact with HCV to promote the development of liver cancer. Examples of such co-factors include concurrent infection with other tumor viruses such as hepatitis B and the human immunodeficiency virus (HIV), aflatoxin, iron stores, hormones/growth factors and cirrhotic changes. Also, studies are needed to elucidate why alcohol increases the progression rate of HCC in HCV infection. Studies are sought to investigate the role of genetic susceptibility to HCV- related HCC, as well as the relationship of HCC to specific HCV genotypes. Of particular importance are studies to develop techniques for the early detection of HCC, such as inexpensive and specific blood tests and/or new imaging techniques. o Treatment. Research applications designed to identify and develop new therapeutic modalities based upon HCV"s replication cycle and protein structures/activities as well as the host response to the virus are encouraged. Liver cancer therapies are needed. Model system development as outlined above would help in these research efforts. In addition, studies are needed to improve current treatment modalities of HCV-related liver disease. These include studies to better define the determinants of response to therapy, the mechanisms by which alpha interferon treatment leads to decreases in viral load and virus eradication as well as the mechanisms of resistance to interferon treatment whether viral or host, immunological or related to intracellular signaling pathways of alpha interferon effects. Application are sought to develop better and practical means of predicting a response to alpha interferon and other treatments including mathematical models using predictive factors, develop means of defining whether and when viral eradication versus viral suppression has occurred during therapy, and elucidate the mechanisms of toxicities and side effects of interferon treatment and means of their management and amelioration especially in regard to the use of long term therapy. Studies on why alcoholics are resistant to interferon treatment are needed to develop the optimum treatment for this large sub-group of patients o Vaccine Development. Applications are sought to: 1) develop fully permissive tissue culture systems that support viral replication, since no in vitro systems currently exist, either to serve as a source of virus or as a method of screening possible anti-viral strategies, including vaccines, 2) develop well characterized, representative small animal models to determine immune response to HCV-induced disease and malignant sequelae and to test the safety and efficacy of proposed vaccines, 3) emphasize basic and applied studies on the identification of HCV viral or viral-induced antigens that elicit protective immunity and that form the basis for vaccine preparation, 4) elucidate the mechanism(s) of development of hepatocellular carcinomas in HCV-infected patients, 5) enhance understanding of the molecular determinants of both cellular and humoral immunity to HCV, the nature of antigenic variation as related to quasi-species diversity, and the mechanism(s) by which HCV regularly eludes the host immune system and established persistent infections INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide For Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit, by October 13, 1998, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 NIDDK staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, Email GrantsInfo@nih.gov. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. 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. Submit a signed, typewritten original of the application, including the Checklist, plus three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-37F, MSC 6600 Bethesda, MD 20892-6600 Applications must be received by November 13, 1998. 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 previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group(s) convened by the NIDDK in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council or other Institute Advisory Council as assigned. 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 review, comments on the following aspects of the application will be made in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assignment of the overall score. o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the 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? o Appropriateness of the proposed budget and duration in relation to the proposed research. o Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries that are not readily available in the United States or that provide augmentation of existing U.S. resources. AWARD CRITERIA The anticipated date of award is July 1, 1999. Award criteria are: scientific merit as determined by peer review, availability of funds, and programmatic priorities of participating Institutes. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Thomas F. Kresina, Ph.D. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8871 FAX: (301) 480-8300 Email: tk13v@nih.gov John S. Cole, III, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Room 540, MSC 7398 Bethesda, MD 20891-7398 Telephone: (301) 496-1718 FAX: (301) 496-2025 Email: jcole3@helix.nih.gov Sandra L. Melnick, Dr.P.H. Division of Cancer Control and Population Sciences National Cancer Institute 6130 Executive Boulevard, Room 535, MSC 7395 Bethesda, MD 20891-7395 Telephone: (301) 435-4914 FAX: (301) 402-4279 Email: sm33k@nih.gov Dr. Sam Zakhari Biomedical Research Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 402 Bethesda, MD 20892-7003 Telephone: (301) 443-0799 FAX: (301) 594-0673 Email: sz14w@nih.gov Leslye D. Johnson, Ph.D. Chief, Enteric and Hepatic Diseases Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 3A22 Bethesda, MD 20892 Telephone: (301) 496-7051 FAX: (301) 402-1456 Email: Lj7m@nih.gov Direct inquiries regarding fiscal and administrative matters to: Ms. Donna Huggins Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8848 Email: HugginsD@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices



NIH Office of Extramural Research Logo
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®



Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.