Full Text HL-94-012 SPECIALIZED CENTERS OF RESEARCH: TRANSFUSION BIOLOGY AND MEDICINE NIH GUIDE, Volume 23, Number 13, April 1, 1994 RFA: HL-94-012 P.T. Keywords: National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: May 31, 1994 Application Receipt Date: September 15, 1994 PURPOSE The objectives of the Specialized Centers of Research (SCOR) program in Transfusion Biology and Medicine are to improve the safety and efficacy of blood and blood components, define the indications for their use, evaluate and possibly modify immunological responsiveness following their administration, and develop and evaluate alternative treatment strategies that substitute for certain of their functions or stimulate their endogenous production so as to reduce transfusion needs. This initiative also encourages the use of new and innovative technologies to pursue fundamental research studies in transfusion biology and clinical investigations in transfusion medicine. The goals of this program are to understand better the basic biology of transfusion; make optimal use of blood, blood components, and plasma protein derivatives in specific replacement therapy; improve transfusion practice; and perform basic and applied research on blood substitutes. 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 Request for Applications (RFA), Specialized Centers of Research in Transfusion Biology and Medicine, is related to the priority area of maternal and infant health. 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 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit and non-profit domestic institutions, public and private, such as universities, colleges, hospitals, and laboratories. This RFA is intended to support SCOR grants for basic and clinical investigations. Therefore, applications that include only basic or only clinical research will not be responsive to this RFA. In addition, clinical research projects focused on large epidemiologic studies or large clinical trials will be considered unresponsive to this RFA. Awards will not be made to foreign institutions. However, under exceptional circumstances, a foreign component critical to a project may be included as a part of that project. Women and minority investigators are encouraged to apply. MECHANISM OF SUPPORT This RFA will use the National Heart, Lung, and Blood Institute (NHLBI) SCOR (P50) grant to support this research program. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Basic and Clinical Research The overall concept of a SCOR program focuses on scientific issues related to diseases and therapies relevant to the mission of the NHLBI. It is essential, therefore, that all applications include both basic and clinical research. Interactions between basic and clinical scientists are expected to strengthen the research, enhance transfer of fundamental research findings to the clinical setting, and identify new research directions. Plans for transfer of findings from basic to clinical studies should be described. Each SCOR grant application and award must include research involving human patients/subjects. Support may be provided for human biomedical and behavioral studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders, or conditions. Small population-based studies, where the research can be completed within five years, may also be proposed. In addition, basic research projects must be included that relate to the clinical focus. A SCOR may also contain one or more core units that support the research projects. The Principal Investigator should be an established research scientist with the ability to ensure quality control and the experience to administer effectively and integrate all components of the program. A minimum time commitment of 25 percent is expected for this individual. The Principal Investigator must also be the project leader of one of the component research projects. Project leaders must agree to commit at least 20 percent effort to each project for which they are responsible. Applications 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 the GCRC program director/principal investigator could be included with the application. Length of SCOR Programs Each NHLBI SCOR program is limited to 10 years of support. Exceptions to this policy will be made only if a thorough evaluation of needs and opportunities, conducted by a committee composed of non-federal experts, determines that there are extraordinarily important reasons to continue a specific SCOR program. Thus, under this policy, a given SCOR grant is awarded for a five-year project period following an open competition. If the one five-year competing renewal that is permitted is awarded, a total of no more than 10 years of support is possible, unless the SCOR program is recommended for extension. The NHLBI comprehensive evaluation of the Transfusion Biology and Medicine SCOR program will be conducted during the second project period according to the following timetable: Program Announced: FY 1994 Project Period (First Competition): FY 1996 to FY FY 2000 Program Reannounced: FY 1999 Project Period: FY 2001 to FY 2005 (Second Competition) Letter to SCOR Directors Regarding SCOR Evaluation: FY 2002 (midway in year 02 of 2nd project period) SCOR Evaluation Meeting: FY 2003 (late in year 02 of 2nd project period) Notification of SCOR Directors Regarding NHLBI Decision: FY 2003 (midway in year 03 of 2nd project period) Number of Applications The NHLBI does not limit the number of SCOR applications in a given SCOR program from one institution provided there is a different SCOR Principal Investigator for each application and each application is self-contained and independent of the other(s). This arrangement does not preclude cooperation planned or possible among participants of SCORs after awards are made. Scientific overlap among applications will not be accepted. If more than one application is envisioned from an institution, the institution is encouraged to discuss its plans in advance with the NHLBI SCOR program administrator. FUNDS AVAILABLE Applicants may request up to $1,125,000 in direct costs, not including indirect costs for collaborating institutions, in the first year with a maximum increase of no more than four percent in each additional year requested in the application. Award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that at least two SCOR grants will be funded. NHLBI's FY 1996 plans for this initiative include a maximum of $4.4 million. The specific amount to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Equipment is included in the budget limitation. However, requests for expensive special equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires in-depth justification. Final decisions will depend on the nature of the justification and the fiscal situation of the NHLBI. Consortium Arrangements If a grant application includes research activities that involve institutions other than the grantee institution, the program is considered a consortium effort. Such activities may be included in a SCOR grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are fully explained. The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in-aid. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, contact Ms. Jane Davis, Grants Operations Branch, NHLBI, 301-594-7436. Applicants of SCOR grants should exercise great diligence in preserving the interactions of the participants and the integration of the consortium project(s) with those of the parent institution, because synergism and cohesiveness can be diminished when projects are located outside of the group at the parent institution. Indirect costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. RESEARCH OBJECTIVES Background During the past decade, significant scientific advances have been made in Transfusion Medicine that have improved the safety and quality of blood, blood components, and plasma derivatives and changed transfusion practices. Advances have been made in detecting evidence for viral pathogens such as HIV-1, HIV-2, HTLV-I/HTLV-II and hepatitis C in donated blood, thus preventing such agents from entering the blood supply. Moreover, procedures have been developed to inactivate viruses in plasma derivatives and soon in plasma itself. Improved apheresis technologies have been developed that permit more efficient collection and manipulation of blood components and bone marrow. Investigators have described properties of newly developed plasma derivatives. Techniques have been developed that may lead to the use of stem cells from umbilical cord blood for bone marrow transplantation. As a result, the importance of blood transfusion has been greatly expanded through the use of components and derivatives in increasingly specialized and effective forms of therapy. The use of blood and blood components continues to increase. Improved patient care, including aggressive cancer chemotherapy programs, bone marrow transplantation, and sophisticated cardiac surgery procedures have contributed heavily to this growth, which is expected to continue into the future. Consequently, the implementation of research programs to determine the optimal use of this valuable resource is important and timely. Blood centers, as well as medical centers with large transfusion services, provide an important environment for research in transfusion medicine. These centers also provide a variety of educational opportunities aimed at several groups, both within and outside the special blood bank community, including laboratory technicians, undergraduate and graduate students, and practicing physicians. The SCOR mechanism is a very important and vital approach to address issues and problems confronting transfusion medicine today. Some of the advantages of this mechanism are: o A SCOR brings together multidisciplinary groups of investigators with valuable expertise to transfusion medicine. o With its multidisciplinary mix of basic, applied, and clinical research, a SCOR offers investigators invaluable resources for research through coordinated interactions. o The information that emerges from the research program of a SCOR may be useful in addressing important national policy issues in transfusion medicine. In the past, the SCOR program made important contributions to the NHLBI and other federal agencies. This involvement was particularly important during the turbulent times brought about by the AIDS epidemic. o A SCOR also addresses difficult clinical questions and provides the research needed to address related policy questions. The Transfusion Medicine SCOR program, like the subspecialty that it serves, is in an early, but continually evolving, state of development. Nevertheless, in the brief history of the program there have been major accomplishments in basic and clinical research that include: o Discovery of gp120 in the envelope of HIV-1 and recognition of its importance for use as an antigen to detect HIV-1 antibody in blood. o Discovery of HIV-1 and HIV-2 specific regulatory proteins and demonstration that they provide a means of distinguishing between the two viruses. o Initial development of assays to detect HIV-2 by serological means. o Recognition of the importance of the Tax gene product of HTLV-I/HTLV-II for screening blood. o Discovery of a pronounced downturn in national rates of blood collection and transfusion of red blood cells following proof that HIV is transmissible by transfusion. o Discovery of significant differences across hospitals in transfusion practice in patients undergoing the same surgical procedures. o Recognition of the importance of type specific screening of HTLV-II for the blood supply. o Use of soluble HLA Class I antigens to induce tolerance. o Performance of some feasibility studies in unrelated bone marrow transplantation. o Characterization of transfusion-related tolerance induction for solid organ transplantation. o Development of practical management strategies for platelet transfusion therapy. Since inception of the Transfusion Medicine SCOR program eight years ago, a large proportion of studies in this program have dealt with transfusion-transmitted infectious diseases, particularly AIDS. This focus on infectious disease was in part a response to the recognition that HIV-1 could be transmitted by blood transfusion. The multidisciplinary configuration of the SCOR program was ideally suited to meet the challenge of transfusion-associated AIDS. As a consequence, significant contributions were made in the understanding of HIV-1, HIV-2 and other human retroviruses. The knowledge gained from the Transfusion Medicine SCOR program contributed significantly, for example, in the selection, design and development of specific assays to detect the presence of human retroviruses in blood donors. With implementation of donor screening procedures that virtually eliminate HIV-1 and significantly reduce the likelihood of other transfusion-transmitted viruses from entering the blood supply, the NHLBI is now redirecting its SCOR program to address other important areas of scientific need and opportunity in Transfusion Biology and Medicine. Proposed Research Five areas of special emphasis have been identified that are essential for the optimal use and improvement of transfusion therapy. Recent progress in the understanding in such areas as immune regulation and hematopoiesis make this an opportune time to encourage research in the following areas of emphasis. Immunomodulatory Aspects of Transfusion The immune system occupies a central role in the safety and efficacy of transfusion therapy. One of the major problems in transfusion therapy is alloimmunization. In some situations, the occurrence may be of little consequence, but as a general problem, alloimmunization is of great importance as it limits the effectiveness of transfusions and in some cases results in death of the patient. Investigators in this SCOR program are encouraged to pursue studies that focus on the mechanisms, prevention, and management of alloimmunization to transfused blood and blood components. One approach could include strategies for rendering transfused products such as platelets nonimmunogenic by removing, altering, or masking surface antigens or interfering with immune "trigger cells." More information is needed about factors that determine immune responses in different individuals and the ways of predicting patients' potential responses. It is also important to improve our understanding of possible deleterious immunologic effects of transfusions such as enhancement of tumor growth and tumor recurrence as well as increasing susceptibility to infections. Studies on potential therapeutic applications of immune modulation might be pursued such as the use of intravenous immune globulins, staph protein A columns, photopheresis, and soluble class I and class II HLA antigens. Development of Novel Cell Therapies and Cytokine Therapies Recent developments in the understanding of hematopoiesis and stem cell biology, the identification of hematopoietic growth factors and cytokines, and cell culture technology hold promise for the creation of novel cellular components and transfusion therapies. Studies are needed on the identification, collection, purification, and preservation of hematopoietic stem cells for use in transplantation. Studies on the in vitro expansion of hematopoietic stem cells for later use in vivo are also encouraged. Significant advances have been made that create realistic prospects for the establishment of in vitro culture systems for production of stem cells for transplantation and for the production of specific cell populations for transfusion therapy. Studies are encouraged to further the understanding of the in vitro requirements for such culture systems including the use of cytokines. In addition to the use of cytokines to support the in vitro expansion of cells, studies are also needed to determine the optimal use of cytokines in vivo to reduce transfusion needs. Studies might address the identification of those disease states where cytokine therapy might be of use. Studies are needed on the dose and timing of cytokine therapy. Research studies on the regulation of endogenous cytokine production are important and could eventually lead to clinical therapies. Structure/Function Relationships of Human Blood Cell Surface Antigens Studies are needed to better understand the relation of structure to function in human blood cells, particularly red blood cells and platelets. There is a need for studies on the characterization and biological significance of blood cell surface antigens, particularly as they relate to the structural integrity of the cells, to specific cell functions, and to specific disease processes. Until recently, the major reasons for identifying blood group antigens and antibodies has been their importance in assuring safe and effective blood transfusions. In recent years, however, clinical information regarding the relation of blood cell antigens to disease has accumulated, as has knowledge of blood cell membrane structure and function. Platelet antigens are known to be associated with functional glycoproteins on platelet membranes and platelet antibodies have been shown to affect platelet function. Similar studies are needed to determine what role antibodies may play in altering red blood cell function. Basic research studies might also be pursued into understanding membrane biology and signaling in blood cells. In the area of applied research, more studies are needed on the improvement in the quality of cellular products used in transfusion therapy. With the recent emergence of new technologies to study cellular membranes and other cellular elements, this is an opportune time to pursue studies to improve the quality of platelet concentrates used for transfusion. Blood Substitutes Research on oxygen-carrying red cell substitutes could lead to the development of products that provide short or even possibly long term support for anemic patients with the advantages of being universally compatible, pathogen free, and without the requirement for cross-matching. They would ideally have a long shelf-life and offer convenient storage. There are currently several Phase I human safety trials of artificial oxygen carriers in various stages of study. The results reported thus far, have been disappointing as unexpected toxicities have been observed. Studies are needed to understand the mechanisms of toxicity of hemoglobin-based oxygen carriers. Projects might address the apparent vasoactivity of these preparations. Animal models or in need to be delineated. Studies on the efficacy of artificial oxygen carriers also need to be conducted under the experimental conditions that reflect the intended clinical use. Of particular importance are the function of artificial oxygen carriers in the presence of red cells; the measurement of tissue and organ function as an indication of efficacy; and the comparison of the efficacy of artificial oxygen carriers with that of red cells. Indications for Red Blood Cell or Platelet Transfusion Despite the obvious advantages of blood transfusion, there is concern that blood components such as red blood cells and platelets are at times given to patients who do not really need them, are given too frequently to patients who do need them, and occasionally, either are not given or are given in insufficient quantities when treatment is urgently required. Clinical decisions regarding red blood cell and platelet transfusions are hampered by a general lack of well designed clinical studies, by imprecise methods of evaluating clinical need and by uncertain methods for measuring effects. The time-honored and useful measurements of hemoglobin concentration and hematocrit are clearly not sufficient, by themselves, for many patients much of the time. Research studies are clearly needed to improve knowledge in these areas. Studies might focus on the detection or development of predictors that better define the need for red blood cell transfusion. The identification of organs that are specifically at risk during acute anemia and the development of clinical monitors that measure the state of perfusion and the presence of cellular hypoxia in those organs that are specifically sensitive to low hemoglobin values or a combination of low Hb and low perfusion are promising approaches that could be pursued. Studies are also needed to determine the appropriate indications for platelet transfusions. The platelet levels that predispose thrombocytopenic patients to hemorrhage and the efficacy of therapeutic modalities other than transfusion are not well understood and require investigation. The development of a practical test that predicts the likelihood of clinically significant platelet-related bleeding would be extremely useful. An area of special interest to the NHLBI is neonatal transfusion therapy. Dramatic advances in the care of infants of low to extremely low birth weight have resulted in survival beyond the immediate intrapartum period. Current practice often includes transfusions with red blood cells as part of the therapy for most of these infants. However, adequacy of red blood cell transfusion in the premature infant is most often assessed by measuring hemoglobin and hematocrit, two parameters that, as in adults, have limited correlation with both the need to transfuse as well as transfusion outcome. Research is needed to establish quantitative, clinically useful criteria to be used in addition to or instead of hemoglobin and hematocrit measurements in determining when to begin and end blood transfusions in newborns. There is a need for new, innovative methods to assess oxygen delivery in the newborn. Furthermore, studies to determine transfusion outcomes in this population are also needed. The different research topics and approaches described in the five areas of emphasis are intended to provide potential applicants with examples of the types of topics that are of interest to the NHLBI and worthy of pursuit. These examples, however, are not meant to be all inclusive. Investigators are encouraged to consider pursuing other important and innovative scientific topics as well. It should be emphasized, however, that the topics chosen must relate directly to the five areas of emphasis identified in this initiative. Furthermore, the topics may address one or more than one area of emphasis. For example, it would be appropriate for a SCOR applicant to propose projects that address research issues pertaining to one area of interest such as structure/function relationships of human blood cell surface antigens or a combination such as structure/function relationships of human blood cell surface antigens and immunomodulatory aspects of transfusion. Applicants should also note that a SCOR program must meet the following criteria: (1) address areas of significant national need and clinical importance; (2) attract talented investigators who foster the development of a multidisciplinary and collaborative synergistic approach; (3) include both basic and clinical components; and, most importantly; (4) have the potential to accelerate the transfer of basic research to clinical application. Applicants are requested to contact the project officer of this initiative prior to preparing a SCOR application to make certain that their proposed program is compatible with the objectives of this solicitation. The major emphasis of this SCOR program is on basic, applied and clinical research in transfusion biology and medicine, the nature of which will depend upon the interests and areas of expertise of its investigators, as well as on the physical resources and population available. However, each institution requesting SCOR support should have a basic range of competence and potential that will enable it to develop a program addressing the objectives and goals of this initiative. SCORs should also provide a challenging environment for attracting talented young scientists into biomedical research and offering opportunities for career development. STUDY POPULATIONS 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 subpopulations 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 9, 1994 (FR 59 11146-11151) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. (NOTE: When the proposed study or studies in the RFA or PA involves a gender specific study or a single or limited number of minority population groups, this should also be stated to inform potential applicants and reviewers.) LETTER OF INTENT Prospective applicants are asked to submit, by May 31, 1994, 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 subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 557A Bethesda, MD 20892 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267. The RFA label available in the PHS 398 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, to identify the application as a response to this RFA, check "YES", enter the title "Specialized Centers of Research in Transfusion Biology and Medicine", and the RFA number HL-94-012 on line 2a of the face page of the application. Send or deliver a signed, typewritten original of the application, including the checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to the Chief, Review Branch at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants (DRG), otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by September 15, 1994. If an application is received after that date, it will be returned to the applicant. DRG 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. DRG 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by National Institutes of Health (NIH) staff for completeness and responsiveness. Incomplete applications or applications deemed not responsive to the RFA will be returned to the applicant without further consideration. Those applications that are complete and responsive will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI. Crucial to the initial scientific review will be a triage process that will eliminate all applications that are deemed not scientifically competitive within the goals and criteria of the RFA. The second level of review will be provided by the National Heart, Lung, and Blood Advisory Council. If, through peer review, this project is not recommended for further consideration, the overall SCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, it will markedly reduce the overall scientific merit ranking assigned to the entire application by the review committee. Factors to be considered in the evaluation of each application will be similar to those used in review of traditional research grant applications and, in addition, will include overall proposed interactions among basic and clinical research projects. Major factors to be considered in the evaluation of applications include: o Scientific merit of the proposed basic and clinical research projects including significance, importance, and appropriateness of the theme; innovation, originality, and feasibility of the approach; and adequacy of the experimental design. o Leadership, scientific stature, and commitment of the program director; competence of the investigators to accomplish the proposed research goals and their time commitment to the program; and the feasibility and strength of consortium arrangements. o Collaborative interaction among basic and clinical research components, the balance between them, and plans for transfer of potential findings from basic to clinical studies. o Adequacy of the environment for performance of the proposed research including clinical populations and/or specimens; laboratory facilities; proposed instrumentation; quality controls; administrative structure; institutional commitment; and, when needed, data management systems. o Appropriateness of the budget for the proposed program. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific issues to: George J. Nemo, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Federal Building, Room 504 Bethesda, MD 20892 Telephone: (301) 496-1537 FAX: (301) 402-4843 Direct inquiries regarding fiscal and administrative matters to: Ms. Jane Davis Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A15C Bethesda, MD 20892 Telephone: (301) 594-7436 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS The programs of the Division of Blood Diseases and Resources, NHLBI are described in the Catalog of Federal Domestic Assistance No. 93.839. Awards will be made under the 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 requirement of Executive Order 12372 or Health Systems Agency review. .
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