ROLE OF INFECTIOUS AGENTS IN VASCULAR DISEASES

Release Date:  September 10, 2001

RFA:  RFA-HL-02-002

National Heart, Lung, and Blood Institute
 (http://www.nhlbi.nih.gov)

Letter of Intent Receipt Date:  January 7, 2002
Application Receipt Date:       February 12, 2002

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN 
$250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN 
SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites research grant 
applications to conduct studies on the role of infectious agents in the 
development of vascular disease.  A potentially important role of infectious 
agents in the development of vascular disease is suggested by studies showing 
an association between vascular diseases and certain bacterial and viral 
infections.  The objective of this program is to encourage in vitro and in 
vivo research on the specific cellular and molecular mechanisms by which 
infectious agents contribute to atherogenesis.  The secondary objective is to 
encourage the development of the biological basis for therapeutic 
interventions that target these molecular mechanisms.

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 Request for Applications (RFA), 
"Role of Infectious Agents in Vascular Diseases" 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/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit 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

This RFA will use the National Institutes of Health (NIH) investigator-
initiated grant award (R01) mechanism.  Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 
applicant.  The total project period for an application submitted in response 
to this RFA may not exceed four years.  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 anticipated award date is September 30, 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH.  Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

The NHLBI intends to commit approximately $3 million in FY 2002 to fund up to 
eight new grants in response to this RFA.  An applicant may request a project 
period of up to four years and a budget for direct costs not to exceed 
$250,000 per year, or ten modules of $25,000 per year.  Because the nature and 
scope of the research proposed may vary, it is anticipated that the size of 
each award will also vary.  Although the financial plans of the NHLBI 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.  

RESEARCH OBJECTIVES

Background

Established cardiovascular risk factors such as hypercholesterolemia, smoking, 
diabetes, and hypertension do not fully explain the etiology or incidence of 
coronary heart disease.  Such findings suggest that additional, less 
substantiated risk factors may contribute significantly to vascular 
pathogenesis.  For a number of years, observational studies in humans have 
provided intriguing hints linking certain viral and bacterial infections to 
atherosclerosis, coronary events, or restenosis after arterial intervention.

The in vivo documentation of the involvement of members of the herpes virus 
family in atherosclerotic processes ranges from solid evidence of causality in 
chickens to observational and associative studies in humans.  More recently, a 
growing body of in vitro work has suggested possible pathophysiological 
mechanisms by which herpes viruses, most notably cytomegalovirus (CMV), might 
contribute to vascular disease.  Regarding bacterial agents, the association 
of Chlamydia pneumoniae and atherosclerosis has been demonstrated indirectly 
by seroepidemiology, and this obligate intracellular prokaryote has been 
detected in atherosclerotic plaques.  In studies performed in vitro, 
atherogenic changes in vascular cells following infection by Chlamydia have 
been described.  Recent studies combining animal models of atherosclerosis 
with animal models of infectious disease have produced results consistent with 
a vasculopathic role for infectious agents in mammals.

Both Chlamydia and CMV are ubiquitous pathogens found in 50 to 70% of most 
populations where they can reside intracellularly in a chronic, persistent or 
latent state.  Whether periods of reactivation and productive infection are 
required for pathogenesis is unknown.  Although Chlamydia and CMV have been 
found in vascular lesions, the primary cell types in which these agents act is 
still unclear.  Macrophages are thought to be one of the primary sites of CMV 
latency, and macrophage infiltration of injured vascular wall endothelium may 
be the method by which CMV is deposited in plaques.  However, the conditions 
and specific factors controlling macrophage permissiveness for CMV, 
establishment of CMV latency, and reactivation of productive infection are not 
well understood.  Similarly, the local factors and conditions that mediate the 
ability of CMV to infect vascular endothelium or smooth muscle cells are 
largely unknown.  It has been hypothesized that Chlamydia antigens found in 
plaques may have been deposited by circulating macrophages carrying 
phagocytized or parasitic Chlamydia from the lung.

A number of in vitro studies in macrophages, endothelial cells, and smooth 
muscle cells have identified mechanisms by which Chlamydia, CMV or other 
herpes viruses might potentiate atherogenesis.  Such mechanisms include 
increases in proliferation, procoagulant proteins, leukocyte adhesion, and 
cytokine production, as well as augmented cholesterol uptake and 
esterification.  CMV immediate-early gene products inhibit the tumor 
suppressor p53, which may mediate the accumulation of smooth muscle cells seen 
in atherosclerotic plaques.  DNA fragments from herpes simplex virus (HSV), 
and CMV have been shown to immortalize aortic smooth muscle cells.  Chlamydia 
and herpes virus infection of endothelium each result in increased expression 
of growth factors, cytokines, and cell adhesion molecules, which promotes 
binding of inflammatory cells--a cascade that may be accompanied by 
endothelial dysfunction.  Chlamydia, HSV or CMV infection of endothelial cells 
also increases acute phase reactants, and each of these pathogens alters 
cholesterol metabolism in infected cells.  For many of these infection-related 
cellular changes, a cause-and-effect relationship remains to be proven 
definitively by the identification of the specific molecular interactions that 
trigger these events. 

Mechanistic studies suggest that gene products of infectious agents can act 
directly on vascular cells.  Nevertheless, an important question is whether 
infectious agents--only sometimes found in atheroma--can exert vasculopathic 
effects without infecting vascular cells.  For example, the atherogenic 
changes seen in infected endothelial and smooth muscle cells can be caused by 
systemic inflammation due to chronic infection and activation of circulating 
inflammatory cells.  In addition, another important mechanism by which 
infectious agents might increase vascular disease without directly infecting 
vascular cells is through exacerbation or augmentation of well known risk 
factors such as hypercholesterolemia.

Several animal models have been developed for vascular diseases, including 
atherosclerosis, in non-human primates, rabbits and mice.  CMV infection has 
been studied in numerous animals including rats, mice and guinea pigs, and 
Chlamydia infection has been studied in rabbits and mice.  More recent studies 
combining infectious-agent and atherosclerotic animal models have shown 
increases in various measures of vascular disease such as prevalence of 
arterial inflammatory cell infiltrates or accelerated arterial intimal 
thickening.  While the development of these models is essential, it is 
critical that animal models be established that mimic the subclinical status 
of these pathogens in man.   

The establishment of infectious disease/vascular disease animal models opens 
the opportunity to test specific inhibitors of the disease process, which can 
provide solid evidence of causality.  Also, these models allow rational 
development of antiviral and antibacterial therapies including drugs, 
vaccines, and other novel approaches that target specific pathogenic 
mechanisms.  A preventive CMV vaccine has been available for a number of years 
but it has limited efficacy and is unlikely to affect latent CMV. A Chlamydia 
vaccine is not yet available.  While traditional vaccines may be beneficial 
for uninfected individuals, they may be ineffective against existing 
intracellular latent and chronic pathogens.  Therefore, the testing of a 
variety of therapeutic possibilities that target direct, indirect, or systemic 
atherogenic mechanisms of infectious agents seems warranted.

It is possible that infectious agents currently showing weak associations with 
vascular disease, as well as infectious agents not previously associated with 
atherogenesis, may contribute to vascular pathogenesis.  Indeed, the presence 
of such unrecognized agents could be a confounding factor in studies of 
infectious agents that are associated with increased vascular disease. 
Therefore, studies of new agents and those that have been shown to have 
marginal association to vascular disease will continue to be important.

Research Areas

Areas of research that would be considered responsive to the RFA are listed 
below.  These areas are not inclusive, however, and investigators are strongly 
encouraged to discuss proposed submissions with the appropriate staff at the 
NHLBI.

o  Biology of Latency and Infection: 
Identification and study of in vivo sites of latency at the organ, tissue, and 
cellular levels, characterization of conditions/factors controlling 
permissiveness for infection, establishment of latency, and reactivation of 
productive infection in macrophages, endothelium, smooth muscle cells, and 
other relevant cell types.
 
o  Molecular Mechanisms of Pathogenesis: 
Characterization of direct, specific molecular interactions between 
genomes/gene products of infectious agents and infected cells, and the 
resulting atherogenic potential of altered cell characteristics and functions, 
 study of indirect or systemic effects of infectious agents harbored in both 
vascular and non-vascular-wall cells, such as macrophages, and other cell 
types, studies of specific mechanisms by which infectious agents might augment 
or exacerbate traditional risk factor such as hypercholesterolemia, 
hypertension and others.

o  Animal Models:
Development and characterization of models of atherosclerosis in which the 
infectious agent is the primary cause of atherosclerosis.  Specific aims 
should include studies elucidating the underlying mechanisms.  In addition, 
plans to disseminate the animal models and willingness to share these models 
and tissue from the models with the scientific community are expected to be 
part of these proposals.

o  Animal Studies: 
Studies in animal models of infection and atherosclerosis that define the 
status of the infectious agent including pathogen load, temporal and spatial 
distribution, and state of latency/activation with the aim of precisely 
determining and substantiating in vivo pathobiologic mechanisms of 
atherogenesis.  These studies may be done either in existing models or in 
models developed specifically for this purpose.
 
o  Molecular Interventions:
Development of specific interventions in both in vitro and in vivo systems 
that target the molecular mechanisms of atherogenesis induced by infectious 
agents in order to establish causality, and determine possible therapeutic 
approaches.

o  Other Pathogens: 
Study of vasculopathic effects of agents with potential association with 
atherogenesis. 

EXCLUSIONS

Applications focusing on the following areas will be considered nonresponsive 
to the objectives of this initiative: 

o  Applications that propose development of animal models without plans to 
study the underlying molecular mechanisms, and prevention or treatment 
modalities.

o  Applications that propose to study the biology of latency of infection not 
related to atherogenesis.

o  Applications that propose to study the role of HIV in atherogenesis.

o  Applications that propose large clinical or epidemiological studies.

SPECIAL REQUIREMENTS

Upon initiation of the program, NHLBI will sponsor periodic meetings to 
encourage exchange of information and collaborations among investigators who 
participate in this program.  Applicants should request travel funds for the 
Principal Investigator and key personnel for two 2-day meetings, to be held 
the first and the third year of the program, most likely in Bethesda, 
Maryland.  Applicants should include a statement in their applications 
indicating their willingness to participate in these meetings, and to interact 
openly and to share animal models, tissues and special reagents with other 
study participants  to provide the greatest promise for scientific advances 
from the approved research scope of the awards.

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 are 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), 
a complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

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

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

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.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

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 RFA 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.

LETTER OF INTENT

Prospective applicants are asked to submit 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 NHLBI staff 
to estimate the potential review workload and plan the review.

The letter of intent is to be sent to Dr. Deborah Beebe at the address listed 
under INQUIRIES by January 7, 2002.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants.  This version of the PHS 398 is available in an 
interactive, searchable PDF format.  Beginning January 10, 2002, the NIH will 
return applications that are not submitted on the 5/2001 version.  For further 
assistance contact GrantsInfo, Telephone 301/710-0267, Email: 
[email protected]. 

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS  

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and NIH staff. 
 The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions beginning on page 
13 of the application instructions.

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.

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
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 as well as 
all five collated sets of Appendix material must be sent to Dr. Deborah Beebe 
at the address listed under Inquiries.  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.

Principal investigators should not sent supplementary material without first 
contacting the Scientific Review Administrator (SRA).  The SRA will be 
identified in the letter sent to you indicating that your application has been 
received.  If you have not yet received such a letter within three weeks after 
submitting the application, contact Dr. Deborah Beebe at the address listed 
under Inquiries.
  
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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI.  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 
the NHLBI in accordance with the review criteria stated below.  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, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the National Heart, Lung and, Blood Advisory Council.

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 the application 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 assigning the overall score, 
weighting them as appropriate for each application.  Note that the 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, an 
investigator 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 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?

(2) 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?

(3) 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?

(4) 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)?

(5) 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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The 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.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  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  The adequacy of the proposed plan to share and disseminate data, animal 
models (newly developed and existing), tissues and special reagents.

Schedule

Letter of Intent Receipt Date:    January 7, 2002
Application Receipt Date:         February 12, 2002
Peer Review Date:                 May-June, 2002
Council Review:                   September 5-6, 2002
Earliest Anticipated Start Date:  September 30, 2002

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.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Eser Tolunay, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 10-186, MSC 7956
Bethesda, MD  20892
Telephone:  (301) 435-0550
FAX:  (301) 480-2858
Email:  [email protected]

Send letter of intent and 2 copies of the application, and direct inquiries 
regarding review matters to:

Deborah P. Beebe, Ph. D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7178, MSC 7924
Bethesda, MD  20892-7924					
Telephone:  (301) 435-0270
Fax:  (301) 480-3541
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Owen Bobbitt
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7134, MSC 7926
Bethesda, MD  20892
Telephone:  (301) 435-0177						
FAX:  (301) 480-0422
Email:  [email protected]  

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.837.  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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  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 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.

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