nutritional armor: omega-3 for the warfighter
TRANSCRIPT
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Guest Editors Wayne B. Jonas, M.D. and Scott J. Montain, Ph.D.
NUTRITIONAL ARMOR:NUTRITIONAL ARMOR:Omega-3 for the WarfighterOmega-3 for the Warfighter
Special Issue | Supplement to Military Medicine, Volume 179, Number 11 l November 2014
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Military MedicineInternational Journal of AMSUS1891-2014 ISSN 0026-4075
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NUTRITIONAL ARMOR: Omega-3 for the Warfighter
Nutritional Armor: Omega-3 for the Warfighter 1Scott Montain, Wayne B. Jonas
The Effect of Omega-3 Fatty Acids on Biomarkers of Inflammation: A Rapid Evidence Assessment of the Literature 2Raheleh Khorsan, Cindy Crawford, John A. Ives, Avi R. Walter, Wayne B. Jonas
Nutritional Armor in Evolution: Docosahexaenoic Acid as a Determinant of Neural, Evolution and Hominid Brain Development 61
Michael A. Crawford, C. Leigh Broadhurst, Stephen Cunnane, David E. Marsh, Walter F. Schmidt, Annette Brand, Kebreab GhebremeskelDietary Omega-3 and Omega-6 Fatty Acids Compete in Producing Tissue Compositions and Tissue Responses 76
Bill LandsOmega-3 Fatty Acid Biochemistry: Perspectives From Human Nutrition 82
Sheila M. InnisNutritional Armor for the Injured Warfighter: Omega-3 Fatty Acids in Surgery, Trauma, and Intensive Care 88
Mary S. McCarthy, Brian B. Morgan, John T. Heineman, Robert G. MartindaleLong-Chain Omega-3 Fatty Acids and Optimization of Cognitive Performance 95
Matthew F. Muldoon, Christopher M. Ryan, Jeffrey K. Yao, Sarah M. Conklin, Stephen B. ManuckNeuroprotection by Docosahexaenoic Acid in Brain Injury 106
Hee-Yong KimThe Potential for DHA to Mitigate Mild Traumatic Brain Injury 112
Julian E. Bailes, Vimal PatelThe Potential for Military Diets to Reduce Depression, Suicide, and Impulsive Aggression: A Review of Current Evidence for Omega-3 and Omega-6 Fatty Acids 117
Joseph R. Hibbeln, Rachel V. GowOmega-3 Fatty Acids and Stress-Induced Immune Dysregulation: Implications for Wound Healing 129
Janice K. Kiecolt-Glaser, Ronald Glaser, Lisa M. ChristianThe Safety of Fish Oils for Those Whose Risk of Injury is High 134
Tomohito Hamazaki, Heather Colleran, Kei Hamazaki, Yutaka Matsuoka, Miho Itomura, Joseph HibbelnMetabolic Health Benefits of Long-Chain Omega-3 Polyunsaturated Fatty Acids 138
Peter Howe, Jon BuckleyOmega-3 Polyunsaturated Fatty Acids in the Optimization of Physical Performance 144
Ren-Jay Shei, Martin R. Lindley, Timothy D. MickleboroughConsiderations for Incorporating Eicosapentaenoic and Docosahexaenoic Omega-3 Fatty Acids into the Military Food Supply Chain 157
Adam Ismail, Harry B. RiceThe Challenges of Incorporation of Omega-3 Fatty Acids into Ration Components and Their Prevalence in Garrison Feeding 162
Betty A. Davis, Brian C. PrallUnderstanding Diet and Modeling Changes in the Omega-3 and Omega-6 Fatty Acid Composition of U.S. Garrison Foods for Active Duty Personnel 168
Bernadette P. Marriott, Karina Yu, Sharon Majchrzak-Hong, Jeremiah Johnson, Joseph R. HibbelnOmega-3 Fatty Acids: Nutritional Armor for the Warfighter and Historical Trends Behind Optimal Warrior Performance 176
Richard H. CarmonaSummary Comments From Workshop Day 1: Nutritional Armor for the WarfighterCan Omega-3 Fatty Acids Enhance Stress Resilience, Wellness, and Military Performance? 181
Rhonda L. CornumNutritional Armor for the Warfighter: Can Omega-3 Fatty Acids Enhance Stress Resilience, Wellness, and Military Performance? 185
Patricia DeusterThe Response of an Expert Panel to Nutritional Armor for the Warfighter: Can Omega-3 Fatty Acids Enhance Stress Resilience, Wellness, and Military Performance? 192
Ian D. Coulter
VOLUME 179 NOVEMBER 2014 SUPPLEMENT
MILITARY MEDICINE
The Association of Military Surgeons of the United States (AMSUS) should not be held responsible for statements made in its publication by contributors or advertisers. Therefore the articles reported in this supplement to MILITARY MEDICINE do not necessarily refl ect the endorsement, offi cial attitude, or position of AMSUS or the Editorial Board.
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MILITARY MEDICINE, 179, 11:1, 2014
Nutritional Armor: Omega-3 for the Warfighter
Scott Montain, PhD*; Wayne B. Jonas, MD
Nutritional Armor: Omega-3 for the Warfighter is a
special issue of Military Medicine containing peer-reviewedarticles, panel summaries, and expert commentaries about
omega-3 and omega-6 essential fatty acids, in dietary and
supplement protocols, and their relationship to health, brain
function, response to injury and trauma, and the enhancement
of performance. Much of this research was originally pre-
sented in 2009 at the Nutritional Armor for the Warfighter
Conference, jointly hosted by the Samueli Institute through
its Metabolic Defense Program and National Institute on
Alcohol Abuse and Alcoholism. At the conference, experts
in nutritional science, biochemistry, physiology and clinical
applications, as well as doctors and high-ranking military
personnel presented the latest research on essential fatty
acids. Subsequently, participants prepared manuscripts sum-
marizing their research and presented material. Updates on
these articles were obtained over the last year and peer
reviewed. Of particular interest was gathering evidence to
determine whether omega-3 and omega-6 intake should be
changed in the military and, if so, in what populations, pro-
portions, and through which methods.
Manuscripts in this special issue include information from
the following categories: (1) cellular and whole-body func-
tions of omega-3 and omega-6 and their potential to modulate
health; (2) nutritional sources, requirements, and conse-
quences of fatty acid balance, including nutritional modeling
of garrison feeding programs; and (3) how service members
and veterans can optimize health, fitness, and recovery
through nutritional protocols that incorporate omega-3-rich
foods or supplements into daily intake.
Although no final recommendations were sought, nor can
be made from the research presented in this issue, the articles
demonstrate an urgent need to examine the ratio of fatty
acid intake. Increasing evidence demonstrates a balance of
omega-3 and omega-6 is critical to mental and physical
health. Research reveals the possibility that modern western-
ized diets poor in omega-3 and rich in omega-6 fatty acids
may increase chronic diseases and diminish optimal function-
ing. These diets contain 80+% of their polyunsaturated fattyacids (PUFA) as omega-6 linoleic acid (LA) and are low in
omega-3 fatty acids compared to Paleolithic and more bal-
anced diets with similar proportions of LA to a-linoleic acid(ALA), and eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA). Studies document that excessive consumption
and tissue levels of omega-6 compared to omega-3 may
adversely affect health in areas such as cardiovascular disease,
metabolic syndrome, depression, increased suicidal risk, sur-
gical recovery, immune function, wound healing, proper
inflammatory response, and other conditions. In addition,
adding omega-3 supplements under certain conditions can
enhance recovery.
It is our hope that the content in this special issue ele-
vates awareness about essential fatty acids and the potential
they offer in terms of providing nutritional armor for the
warfighter and veteran to promote health and well-being.
We urge scientists, clinicians, and military and veteran
leaders to increase their focus on improving our knowledge
about the optimal omega-3 and omega-6 intake and use. Our
country needs it and our service members and veterans
deserve it.
The Samueli Institute would like to thank the following
individuals for their role as Conference Organizers: CAPT
Joeseph R. Hibbeln, MDActing Chief, Section on Nutri-
tional Neurosciences LMBB, NIAAA, NIH. Dr. Bernadette
P. MarriottProfessor, Division of Gastroenterology and
Hepatology, Department of Medicine, and Military Division,
Department of Psychiatry and Behavioral Sciences, Medical
University of South Carolina.
*Military Nutrition Division, U.S. Army Research Institute of Environ-
mental Medicine, Building 42, Kansas Street, Natick, MA 01760-5007.
Samueli Institute, 1737 King Street, Suite 600, Alexandria, VA 22314.
doi: 10.7205/MILMED-D-14-00452
MILITARY MEDICINE, Vol. 179, November Supplement 2014 1
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MILITARY MEDICINE, 179, 11:2, 2014
The Effect of Omega-3 Fatty Acids on Biomarkers of Inflammation:A Rapid Evidence Assessment of the Literature
Raheleh Khorsan, PhDc*; Cindy Crawford, BA; John A. Ives, PhD;Avi R. Walter, MSc; Wayne B. Jonas, MD
ABSTRACT Introduction: Previous studies of omega-3 fatty acids report improved outcomes where inflammation isa key factor. The objective of this systematic review is to evaluate effects of omega-3s on inflammatory biomarkers.Methods: Randomized clinical studies that measured the influence of omega-3 fatty acids on inflammatory biomarkerswere identified using a comprehensive search. Eligible studies were rated with the American Dietetic AssociationEvidence Analysis Manual and Grading of Recommendations, Assessment, Development and Evaluation (GRADE)process to examine study quality and risk/benefit. Results: 112 studies were included. Over 65% reported statisticallysignificant effects. The majority were scored as low risk of bias (high quality) and scored strong (cardiac populationsand critically ill) to weak (Alzheimers Disease, hypertriglyceridemia/diabetes, and obesity) on the risk/benefit ratioevidence for modulation of inflammatory biomarkers. There was inadequate data to determine a GRADE for inflamma-tory biomarker studies for some conditions (healthy individuals, rheumatoid arthritis, metabolic syndrome, renaldisease, pregnancy, or children). Conclusion: Clinical literature on the effects of omega-3 fatty acids on inflammatorybiomarkers contains mostly small sample sizes, is neutral to high quality, and report mixed effects. Larger studiesexamining dose and delivery are needed.
INTRODUCTION
Omega-3 Fatty Acids
In 1946, the first major study of essential fatty acids (EFA)
identified vitamin-like properties of linoleic acid (18:2n-6)
(omega-6) and linolenic acid (18:3n-3) (omega-3) in human
infants.1 Today, there is much debate over assisting the
public in identifying and preventing the current imbalanced
intakes of omega-3 and omega-6 nutrients that cause pre-
ventable clinical disorders and continue escalating healthcare
costs.2 Indeed, studies continue to assess the importance
of the omega-6/omega-3 fatty acid ratio in cardiovascular
disease and other chronic diseases.3 Current studies advo-
cate lower intake of omega-6 compared to greater intake
of omega-3 fatty acids in reducing the risk of some of
the chronic diseases of high prevalence that are associated
with inflammation.1,3
Omega-3 fatty acids (also known as n-3 or w-3) includea-linolenic acid (ALA), eicosapentaenoic acid (EPA), doco-sahexaenoic acid (DHA), and docosapentaenoic acid (DPA).
Among fatty acids (FAs), long-chain omega-3 polyunsatu-
rated FAs (PUFAs) possess the most potent immunomodu-
latory activity,4 and among the omega-3 PUFAs, those from
fish oil (FO) are rich sources of the bioactive long-chain n-3
including EPA and DHA. The majority of DHA and EPA
are found in diets containing cold-water fatty fish, FOs, flax,
range-fed poultry, eggs and farm animals, and in supple-
ments and prescription formulations. Other less biologically
potent FAs include plant-based ALA with n-3 PUFA.4 The
major plant omega-3 ALA is found in walnuts, soybean,
canola oil, and flaxseed.
Epidemiological and experimental studies on the benefits
of FOs and omega-3 FA consumption has increased over
the past few decades.5 Diets enriched with high amounts of
both plant- and marine-derived omega-3 PUFAs seem to
be associated with a lower incidence of coronary heart dis-
ease (CHD)6,7 and a reduction in cardiovascular events.8
In addition, both animal and clinical studies support the use
of omega-3 FAs for inflammatory9 and autoimmune disease
management.10 There have been a number of clinical trials
assessing the benefits of dietary supplementation with FOs
in treating several inflammatory and autoimmune diseases
among humans,4 including rheumatoid arthritis (RA),11,12
Crohns disease,13,14 inflammatory bowel disease,13,1517 as
well as other inflammatory conditions.18,19 Many of the
placebo-controlled trials of FO with chronic inflammatory dis-
eases report significant benefit, including decreased disease
activity and a lowered use of anti-inflammatory drugs.4,20
In 2012, a systematic review (SR) of randomized con-
trolled trials (RCTs) on omega-3 FAs and inflammatory bio-
markers in healthy and clinical populations was conducted
utilizing PubMed and LILACS databases.21 This study
selected 26 RCTs published over the preceding 10 years
and written in the English language that evaluated omega-3
diet supplementation or dietary manipulation. Studies were
excluded if a supplement was administered that could poten-
tially confound the effects of omega-3 FAs or if there was
*Samueli Institute, 2101 East Coast Highway, Suite 300, Corona del
Mar, CA 92625.
Department of Planning, Policy and Design, School of Social Ecology,
University of California Irvine, Irvine, CA 92697.
Samueli Institute, 1737 King Street, Suite 600, Alexandria, VA 22314.
The views opinions and/or findings contained in this work are those of the
author(s) and should not be construed as an official Department of the Army
position, policy, or decision unless so designated by other documentation.
doi: 10.7205/MILMED-D-14-00339
MILITARY MEDICINE, Vol. 179, November Supplement 20142
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no ethical approval. Specifically, they excluded five studies
in which arginine and omega-3 FA were used together as
supplement sources. Twenty-six articles2246 met their inclu-
sion criteria. The quality of each publication was determined
by using the JADAD scale and the CONSORT checklist, and
combining the results to come up with an aggregate total
score. The outcome of the SR was that omega-3 supplemen-
tation may be beneficial for lowering levels of inflammation
and endothelial activation in cardiovascular disease and other
chronic and acute diseases, including chronic renal disease,
sepsis, and acute pancreatitis.21 However, numerous studies
evaluating the effects of omega-3 in which inflammatory bio-
markers were considered as outcomes were omitted from their
review. Moreover, in the interim, there have been additional
clinical studies published.
The SR reported here builds on the Rangel-Huerta et al
SR21 and reviews the potential of omega-3 FAs to amelio-
rate inflammatory conditions, especially those of military rele-
vance. In support of a conference in 2009, titled Nutritional
Armor for the Warfighter Workshop,47 speakers noted that
omega-3 FAs have the potential to ameliorate inflammatory
conditions in warfighters. As a consequence of a conference
where speakers discussed the pros and cons for omega supple-
mentation in warfighters, the authors were asked to evaluate
the effects of omega-3 FAs on biomarkers of inflammation
in clinical studies. The purpose of this report is to provide
an updated and more extensive analysis of the available
evidence on markers of inflammation, clinical efficacy, and
safety of n-3 PUFA in healthy and clinically ill humans, as
compared to standard (non n-3 enriched) care.
Objective
The purpose of this review is to examine the quality and quan-
tity of clinical research using the REAL SR approach4851
and to assess the evidence for the effects of omega-3
FA interventions on inflammatory biomarkers for clinical
conditions associated with inflammation and in studies of
healthy humans.
The specific objectives of this review were to (1) survey
the available literature on omega-3 FAs for conditions related
to inflammation in the human population using a REAL;(2) assess the literature for quantity, quality, and effective-
ness of omega-3 FAs on inflammatory biomarkers that used
RCTs study design; and (3) identify gap areas and suggest
next steps for the research field.
METHODSThe following databases were searched from inception
through February 2014: Pubmed, CINAHL, PsycINFO, all
of Cochrane EBM Databases, and the National Agricultural
Library Online. The initial search terms were EPA, DHA,
omega-3 PUFA, or Omega, coupled with inflammation terms
or those conditions known as inflammatory conditions (i.e.,
RA, etc.). Medical subject headings vocabulary was uti-
lized in relevant databases where applicable. The search
was restricted to only English language, peer-reviewed
published literature, and experiments involving human sub-
jects. Reference lists were pearled of all relevant studies to
capture additional reports not found through traditional
searching of databases, as well as conversing with subject
matter experts (SMEs).
Eligibility Criteria
Articles were included in this REAL if they met thefollowing criteria: (1) an inflammatory condition and/or
inflammation itself was being assessed; (2) the interven-
tion involved omega-3 FA supplementation; (3) a control/
comparator intervention was assessed at same time; and
(4) the outcome assessed inflammatory biomarkers as pri-
mary or secondary outcomes, and the study design was a
RCT or SR published in the English language.
Articles were excluded if the report was on a combina-
tion treatment, such as omega-3 FAs plus Vitamin E or the
nutritional package included omega-3 FAs as one of the
components where the effect of omega-3 FAs alone could
not be directly assessed, or if the study was unable to
control for confounding effects of the add-on therapy; how-
ever, studies that administered combination treatments of
FAs only, such as omega-3 FAs and omega-6 FAs or if the
effect of omega-3 FAs alone could be directly assessed
were included. Any study not assessing inflammatory bio-
markers was excluded.
Three investigators (CC, ARW, and RK) independently
screened titles and abstracts for relevance based on the
inclusion criteria. Any disagreements about including a study
were resolved through discussion and consensus with the
review team, or by SMEs (JAI and WBJ).
Quality Assessment and Data Extraction
Methodological quality of the included studies was assessed
independently by three reviewers (CC, RK, and AW). The
individual studies were all RCTs and were evaluated for
study quality and bias using Section 1 and 2 of the American
Dietetic Association (ADA) Evidence Analysis Manual
Quality Criteria Checklist for Primary Research.52 This
checklist was developed to conduct evidence analysis on
nutrition and dietary supplement topics of research and is
well-accepted in the field.53 Each study, once assessed,
received a score of positive/high (+), neutral (0), or negative/low () according to the quality criteria for ADA. Data
extraction was conducted to describe each study included
by population, whether a power calculation was conducted
and achieved, the intervention (diet, supplement, etc.), dose
of the omega-3 FA product, nature of controls, dropout rates
among groups, relevant outcomes and results for the inflam-
matory biomarkers assessed, authors main conclusions, and
any related adverse events reported. Once the quality assess-
ment of the individual studies was completed, the SMEs with
the reviewers conducted a quality assessment of the overall
MILITARY MEDICINE, Vol. 179, November Supplement 2014 3
Omega-3 and Inflammatory Biomarkers REAL
-
literature pool for each condition using a modification of
the international standard for Grading of Recommenda-
tions Assessment, Development and Evaluation (GRADE)
approach.54 The modified GRADE evaluates (1) the confi-
dence in the estimate of the effect; (2) the magnitude of
the effect size; and (3) safety; to be able to assess an
overall recommendation for the intervention. All screeners,
reviewers, as well as SMEs were fully trained in the meth-
odologies employed and were able to attain a consistent
Kappa above 90%.
Study Selection
Conditions and Populations
Eligible studies included participants of all ages, either
healthy or with acute or chronic disease. There was no restric-
tion on the basis of gender, ethnicity, study setting, or other
clinical characteristics. This SR grouped the studies included
in the analysis into the following categories that emerged
from the literature: (1) healthy populations; (2) cardiac
patients; (3) RA patients; (4) functional conditions, which
includes populations with an active inflammatory process
that impacts ongoing function including asthma, bone
marrow transplant patients, Crohns disease, metabolic syn-
drome (MetS), periodontitis, and ulcerative colitis patients;
(5) long-term organic conditions, which captures those
populations with AD, hypertriglyceridemia and diabetes, obe-
sity, peripheral arterial occlusive disease, and renal disease;
(6) emulsion, which mainly included critically ill patients,
primarily those with septic shock patients; (7) children; and
(8) pregnant women.
Proinflammatory vs. Anti-Inflammatory Markersas Outcomes
Inflammation is characterized by interplay between pro- and
anti-inflammatory cytokines. Major anti-inflammatory cyto-
kines include interleukin (IL)-1 receptor antagonist, IL-4,
IL-6, IL-10, IL-11, IL-13, and alpha-interferon (IFN-a).Tumor necrosis factor-alpha (TNF-a), gamma-interferon(IFN-g), IL-12, IL-18, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are well characterized as pro-
inflammatory cytokines.55,56 Also, a number of biomarkers
can be either pro- or anti-inflammatory depending on their
dose, location of action, and the conditions of the system.
For example, endothelial nitric oxide synthase plays a
role in inflammation and can regulate the expression of
the proinflammatory molecules factor- kB (NF-kB) andcyclooxygenase-2.57 Alternatively, proinflammatory cyto-
kines can modulate the expression of endothelial nitric
oxide synthase.
Molecules of this sort can be classified as inflammation
modulators. Any and all pro- or anti-inflammatory biomarkers
were of interest to this SR and included for analysis. The
majority of inflammatory biomarkers included in this SR
review were (1) the cytokines including chemokines (CCL2,
CCL3, CCL5, CCL11), interferons (IFN-a and IFN-b), ILs(IL-1a, IL-1b, IL-8, IL-10, IL-12, IL-13), lymphokines(IL-2, IL-3, IL-4, IL-5, IL-6, GM-CSF, IFN-g), tumornecrosis factor (TNF-a, TNF-b), transforming growthfactor; (2) acute phase reactant proteins; (3) eicosanoids
(PGE1, PGE2, LTB4, F2-isoprostanes); (4) adhesion mole-
cules (sVCAM-1, sICAM-1, sE-selectin, sP-selectin); and
(5) related biofactors (sIL-1RII; sIL-6R, sTNF-Rs 1 and 2,
CD11b, CD18, CD49, CCR2 and CCR5, MMP-7, MMP-9,
MMP-12, TIMP-2, a1-ntichymotrypsin, fibrinogen, PAI-1,
orosomucoid AGP).21
RESULTS
Included Studies
From the total of 355 articles screened according to eligi-
bility criteria, a total of 112 articles2238,4042,4446,58146
were included in the present analysis. These included arti-
cles were cross-checked against the previous 2012 SR
discussed above.21 Two articles,39,43 which were included
and scored for bias in the Rangel-Huerta et al21 SR were
excluded from this review as we were unable to (1) locate
an inflammatory biomarker in the Engler et al39 study or
(2) confirm the Perunicic-Pekovic et al43 was a RCT design
(Fig. 1).
Healthy Populations
Twenty-one studies2228,38,45,5869 included in the REALSR analysis were on healthy populations where omega-3
FAs were introduced and inflammatory biomarkers were
assessed (Table I). Most of the subjects were given capsules
containing omega-3 FAs, but in some studies, they were
provided as part of their diets.58,61 Two studies tested
omega-3 fortified drink while continuing to consume their
usual diet.25,68 Three studies were emulsion studies admin-
istering omega-3 via infusion (intravenously) to healthy
FIGURE 1. Flow chart.
MILITARY MEDICINE, Vol. 179, November Supplement 20144
Omega-3 and Inflammatory Biomarkers REAL
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participants and are presented in the emulsion section
(Table II).36,126,127
Of the twenty-one studies included, fourteen were scored
as high quality (+) with primarily mixed results or no effect.Six studies scored a neutral quality, of which two showed
statistically significant results.22,67 The remaining study scored
low quality (), which showed an effect in favor of
omega-3.61 The doses provided, the duration of adminis-
tration, and age range of participants varied widely across
studies (Table I). In addition, most studies had more male
participants (about 71% male participants completed) com-
pared to female participants. In fact, eight studies included
only male participants.12,22,24,60,61,6769
Cardiac Patients
Twelve studies24,30,32,41,7077 examined cardiac populations
of which eight were scored as high quality (+), six ofwhich (75%) were statistically significant in favor of
omega-3 in reducing inflammation across all biomarkers
assessed such as ICAM, sV-CAM-1, CRP, TNF, IL-6, or
IL-18,30,41,71,74,76,77 with the remaining having at least
one biomarker showing favorable reduction in inflamma-
tion. Four studies scored as neutral quality (0), with pri-
marily conflicting results across these studies (Table III).
There were no poor quality studies in this category. Simi-
lar to healthy subjects, most of the cardiac study subjects
were given capsules containing omega-3 FAs, but in some
studies, diet was manipulated.71,76 Dose for omega-3, EPA,
and DHA varied across studies. Also like in the healthy
subject studies, the majority of cardiac studies reported out-
comes based on male subjects. In total, cardiac studies had
about 78% of male participants complete the intervention.
Three studies did not report gender as a demographic.32,71,72
Rheumatoid Arthritis (RA) Patients
Eleven studies7888 examined RA patients. Four scored
high quality (+) with primarily conflicting results acrossstudies.7981,83 The other two studies showed nonsignifi-
cant effects on C-reactive protein (CRP) when given
FO supplements.79,83 There were five neutral quality (0)
studies,78,84,8688 with one showing positive effects across
biomarkers,84 three with at least one biomarker with an
effect in favor of omega-3,78,86,87 and one showing no effect
across any biomarkers assessed.88 In addition, there were
two low quality () studies showing a reduction across
at least one of the several proinflammatory biomarkers
assessed82,84 (Table IV). Again, like most of the cardiac
study subjects, RA patients were given capsules con-
taining omega-3 FAs rather than a fatty fish diet. In
one study, patients received FO as part of their diets
intravenously.79 This single study is discussed both in
this section of the review as well as the emulsion sec-
tion (Table II). Unlike the healthy participants and car-
diac patient omega-3 studies, RA patients were primarily
female (about 78% females completed interventions). Two
studies did not describe gender.82,86
Functional and Other Conditions
Eleven studies42,59,8997 of varying conditions (asthma, Crohns
disease, MetS, periodontitis, ulcerative colitis) were included
in our functional category (Table V). Seven studies (64%)
scored high quality (+) and four studies (36%) scored neutralin quality (0) according to ADA criteria. Forty-two percent
(42%) of the completed participants in the functional con-
dition group were male. A few studies involved dietary
interventions of omega-392,94 compared to omega-3 sup-
plement capsules. Two studies administered omega-3 via
powder drinks.91,92
Asthma
Two studies89,90 involving asthmatic patients with statisti-
cally significant results scored as high quality (+). Thefirst study involved 60 patients with atopic asthma who
received lipid extract of New Zealand green-lipped mussel
or a matching placebo for a period of 8 weeks and reported
a significant decrease in daytime wheeze and the con-
centration of exhaled H2O2.89 The second study involved
23 dust mite allergic asthmatics receiving PUFA-enriched
fat blend or placebo for 5 weeks and reported significantly
lower exhaled NO (eNO) levels in the omega3 PUFA-
supplemented group.90 These two studies measured what
we are terming modulators and not necessarily pro or
anti-inflammatory biomarkers.
Crohns Disease
Two studies91,92 examined Crohns disease, one scoring
high quality (+) and the other neutral (0). One of thesestudies involved 31 patients who received either omega-3
or omega-6 Impact Powder (IP) and showed a significant
difference in concentration of IL-1b and in concentration
of monocyte chemoattractant protein (MCP-1) in week 9
for omega-3 supplementation.92 The second study was
neutral in quality (0) and had nonstatistically significant
results. These patients were provided with omega-3 or
omega-6 IP and both groups showed a decrease in CRP;
however, there was no statistically significant difference
between the two groups.91
Metabolic Syndrome
Four studies42,9395 included patients with MetS, two of
which scored high quality94,95 and two scored neutral in
quality (0).42,93 Of those studies that were high quality (+),one study94 examined the effect of four different diets
(including omega-3) on inflammation, reporting no statis-
tically significant dietary effects between the pre and post-
intervention on inflammatory status in fasting MCP-1, IL-6,
or IL-1b. The other high-quality score study,95 a four-armresearch design, found statistically significant decreases
MILITARY MEDICINE, Vol. 179, November Supplement 2014 5
Omega-3 and Inflammatory Biomarkers REAL
-
between treatment groups ( p < 0.05) in DBP in the kinakogroup after 90 days when compared to the results obtained
from the FO and kinako groups. Both studies, which scored
neutral in quality (0), did not find significant differences
between groups.42,93
Periodontitis
Two studies59,96 on periodontitis populations assessed modu-
lators as their inflammatory biomarkers instead of pro- or
anti-inflammatory biomarkers. One study involved partici-
pants who were asked to stop brushing their teeth for a
period of time and then provided with omega-3 PUFA or
olive oil (OO) for 8 days. This study scored high quality
according to ADA and showed a tendency toward improve-
ment in plaque and gingival index (GI), but no statistically
significant between-group differences were found.59 The other
study involved participants taking borage oil, EPA, or a com-
bination of both or a placebo oil where the use of borage oil
showed better results than EPA for plaque index (PI) and
GI,96 and received a neutral ADA score.
Ulcerative Colitis
The final study in this category included 18 patients with
ulcerative colitis who received FO capsules or a vegetable
oil placebo for 4 months. This study scored high quality (+)and reported statistically significant results for reductions in
rectal dialysate leukotriene B4 levels, improvements in his-
tologic findings, and weight gain for the FO group.97
Long-Term Organic Conditions
We categorized twenty-seven studies29,31,3335,46,98118 as
long-term organic conditions (Table VI). These conditions
included AD, hypertriglyceridemia and diabetes, overweight
and obesity, peripheral arterial occlusive disease, renal disease,
and cancer and bone marrow transplant. Nineteen studies
(70%) scored high quality (+) and eight studies (30%) scoredneutral in quality (0) according to ADA criteria. Fifty-four
percent (54%) of the participants in the long-term organic
conditions were male participants.
Alzheimers Disease
Three studies34,35,98 assessed AD patients, all of which scored
high quality (+). One of these studies showed statisticallysignificant results with DHA-rich omega-3 FAs supplementa-
tion, which increased plasma concentrations of DHA (and
EPA), and were associated with reduced release of IL-1, IL-6,
and granulocyte colony-stimulating factor (G-CSF) from
peripheral blood mononuclear cells (PBMCs) for patients
receiving omega-3 FAs vs. placebo oil capsules.35 This is one
of the few studies with a relatively large sample size (N = 361)and that measured blood levels of FA. In the other two studies,
patients received DHA and EPA or a placebo oil capsules
for 6 months, and showed no influence on inflammatory or
other measured biomarkers in CSF or plasma.34,98
Hypertriglyceridemia and Diabetes
There were eight studies on hypertriglyceridemia33,99102 or
diabetes.31,103,104 Most of the studies (75%)31,99,101104 in this
group scored high quality (+) according to ADA criteria. Ofthe six studies that scored high quality, most reported reduc-
tions in inflammatory markers.99101 Of the two studies33,100
that scored neutral (0) according to ADA criteria, one study
examined subjects with hypertriglyceridemia that were other-
wise healthy individuals and showed statistically significant
results with DHA supplementation in the absence of EPA,
which resulted in a reduction in the number of circulating
neutrophils and serum CRP and GM-CSF and an increase
in the concentration of matrix metalloproteinase (MMP-2)
according to ADA criteria.100 The other study compared two
different doses of DHA plus EPA and found that neither dose
statistically improved inflammatory markers (IL-1b, IL-6,TNF-a, and high-sensitivity CRP) or the expression of inflam-matory cytokine genes in isolated lymphocytes.33
There were three studies scoring high quality (+) involv-ing patients with type 2 diabetes with or without hypertension
consuming EPA, DHA, or placebo capsules.31,103,104 Although
the serum IL-2 and TNF-a levels were reduced in the treatmentgroup serum, CRP levels varied across these studies.31,103,104
Overweight and Obesity
There were ten studies29,105112,115 on overweight/obesity
patients, five scoring high quality (+) and five scoring neu-tral quality (0). For the five high-quality studies, four (80%)
reported nonsignificant statistical results for TNF, IL-6, and
CRP inflammatory biomarkers in patients receiving omega-3
or a placebo29,108110 (Table VI). For the neutral quality
studies, one showed statistically significant results across
various inflammatory biomarkers when patients consumed
flaxseed flour vs. a placebo.106 The other neutral quality studies
showed nonsignificant results for inflammatory biomarkers
when patients consumed omega-3 long-chain PUFA-enriched
versions of typical processed foods or placebo.105,111,112
Peripheral Arterial Occlusive Disease
One study addressed patients with peripheral arterial occlu-
sive disease where participants received canola oil or
sunflower oil, as placebo, added to their usual diets for
8 weeks. This study was scored as high quality and there
were no significant differences for either group for CRP
inflammatory biomarkers.116
Renal Disease
Three studies assessed omega-3 among patients with renal
disease.46,113,114 Two of the three studies (67%) scored high
quality (+) according to ADA criteria.46,113 For all threestudies, patients received pills of omega-3 FA or placebo
pills. The two high-quality studies concluded that consum-
ing omega-3 FA lowers CRP and IL-1b significantly morethan placebo.46,113
MILITARY MEDICINE, Vol. 179, November Supplement 20146
Omega-3 and Inflammatory Biomarkers REAL
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Cancer and Bone Marrow Transplant
Two studies reported on omega-3 interventions for cancer
and bone marrow transplant patients.117,118 Both studies
scored as high quality (+) according ADA criteria. The firststudy where 16 patients underwent allergic bone marrow
transplant received EPA orally and showed significantly
lower levels of TNF-a, IFN-g, and IL-10 compared withthe non-EPA group.117 The second study investigated the
effects of an oral nutritional supplement containing n-3
PUFAs on nutritional status and inflammatory markers
where the EPA plus DHA group had greater weight loss
and lower IL-6 production after 5 week, though not statisti-
cally significant (B = 227.9; p = 0.08).
Parenteral Omega-3 (Emulsion Studies)
Our SR retrieved twenty-seven studies36,37,40,44,79,119140 on
parenteral nutrition (PN) of omega-3 on participants to
reduce inflammation. Nineteen (68%) of these studies were
published since 2004. Twenty-three studies (85%) scored
high quality (+) and four studies (15%) scored neutral inquality (0) according to ADA criteria. Emulsion studies were
done for healthy participants, patients with RA, and critically
ill patients. Four studies were categorized as healthy partici-
pants and patients with RA. The three healthy participant
emulsion studies are referenced in Table II and of the single
RA emulsion study is referenced in Tables II and IV. The
majority of the studies (n = 23) were on critically ill patientsor surgical patients. In fact, 16 of the 27 studies (59%) were
surgery-related studies and six studies (22%) included patients
in intensive care units (ICUs).
Studies of Parenteral Omega-3 in Healthy and RA Patients
Four studies, all assessed as high quality (+),36,79,126,127
addressed inflammatory responses and the composition of
platelets in healthy subjects and patients with RA given FO
intravenously or with usual treatment (soybean oil lipid emul-
sion). These studies reported that the use of omega-3-enriched
emulsions increases the serum concentration of alpha-
tocopherol and the percentage content of EPA and DHA
from start of study to end of study. In addition, these studies
also reported that omega-3 emulsion resulted in a greater
reduction in IL-6 and TNF-a, though most of these findingwere not significant.
Studies of Parenteral Omega-3 in Critically Ill Patients
Twenty-three studies (85%) were included in our critical
illness population category receiving PN (Table II). Six
studies that met our inclusion criteria involved patients in
the ICU and three with systemic inflammatory response
syndrome (SIRS). Nineteen (83%) of these studies were
scored high quality (+) according to ADA criteria. Four(17%) scored natural (0) according to ADA criteria.
Of those that scored high quality (+), one high-qualitystudy demonstrated nonsignificant effects for the inflamma-
tory biomarker assessed (IL-6), showing that supplementa-
tion with FO did not affect this inflammatory biomarker.121
Two other high-quality studies on septic patients who were
given enteral nutrition received a standard soybean oil-based
emulsion or an emulsion containing FO (Omegaven) for540 or 10131 days. Within 2 days of FO infusion, free n-3
FAs increased, and the n-3/n-6 ratio was reversed and the
generation of proinflammatory cytokines by mononuclear
leukocytes was markedly elevated during n-6 and was sup-
pressed during n-3 lipid application.40 The authors reported
that both these studies establish that infusion of long-chain
n-3 PUFA for patients with sepsis can modulate inflam-
matory mediator production and related inflammatory pro-
cesses.147 Of the four studies that scored neutral in quality
(0) according to ADA criteria, two studies compared the
effects of a medium- and long-chain triglyceride fat infu-
sion on systemic inflammation and hepatic steatosis in ICU
patients. The first study44 found that plasma cytokine, PGE2,
LTB4, IL-1b, IL-6, IL-10, and TNF-a concentrationsdecreased over time in both groups ( p < 0.05). The secondstudy included sepsis and SIRS patients who received PN
employing the MCT/LCT fat infusion or the FO-based fat
infusion over 7 days in the ICU. Groups receiving the
MCT/LCT PN had higher proinflammatory cytokine (TNF-a,IL-1, and IL-6) values and lower anti-inflammatory cytokine
(IL-10) values than patients fed with FO, but statistical sig-
nificance was seen only at the middle and end of the study
periods in the septic groups. The results of this study may
support that FO could be more effective than MCT/LCT fat
emulsion, especially in patients with infectious conditions.136
Taken together, these studies indicate that inclusion of FO
in PN regimens for critically ill and surgical patients modu-
lates the generation of inflammatory eicosanoids and cytokines.
It seems there is a shift in the generation of leukotrienes
toward the leukotriene-5 series and an ameliorated LTB5:
LTB4 ratio, thereby reducing the incidence of systemic inflam-
matory response.148 Furthermore, the inclusion of FO in PN
regimens, may help to counter the surgery-induced decline in
antigen presenting cell activity139 and T-lymphocyte cytokine
production.135 Importantly, these studies do not reveal any
deleterious effects of FO infusion in these patients.147(p567)
Pediatric Populations
This review retrieved four studies128,141143 on the effect on
omega-3 FAs in children. Two scored high quality (+) andtwo studies scored neutral in quality (0) according to ADA
criteria. One study, neutral in quality, was unable to find
significant effect on biomarkers for inflammation for DHA
supplementation compared to corn and soy oil (control).141
The other remaining three studies reported mixed results.
A study on lipid omega-3 emulsion was administered
in infants for days 1 to 4 before open-heart surgery, and
10 days after surgery found that the plasma TNF-a con-centration was significantly lower ( p = 0.003) in the treat-ment compared to the control group. In infants without
MILITARY MEDICINE, Vol. 179, November Supplement 2014 7
Omega-3 and Inflammatory Biomarkers REAL
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sepsis, plasma TNF-a did not differ according to treat-ment; however, when sepsis developed, mean plasma TNF-awas significantly lower in treatment compared to control
( p = 0.0007).128 The two remaining studies in this groupof studies reported similar findings. In neonates that have
undergone surgery and are fed omega-3 FAs through a
nasogastric tube, it was found that although decreases of
cytokines during hospitalization were similar in both groups,
there was a greater decrease of IL-1b in the DHA group than in
the OO group after adjusting for confounders (p = 0.028)142
(Table VII).
Pregnant Women
The role of omega-3 on inflammation during pregnancy and
fetal development is not well studied. We retrieved three
studies on the effect of these EFAs on pregnancy inflam-
mation outcomes. During pregnancy, the immune tolerance
between the fetus and the mother is mediated by a number of
complex processes at the maternofetal interface.149 Omega-3
FAs may play a part in a number of these pathways. Two
studies scored high quality (+) and one scored neutral inquality (0) according to ADA criteria. Of the two high-
quality studies, one study145 on pregnant women (100). In total, there were twenty-one studies and 1,191 participants in this group. Therefore,
we believe that further research is very unlikely to change
our confidence in the estimate of effect. Thus, we are unable
to recommend omega-3 to reduce inflammation in healthy par-
ticipants. In contrast, most high-quality studies in patients with
established cardiovascular disease had improved inflammatory
status (lower proinflammatory and higher anti-inflammatory)
biomarkers compared to controls. Three studies in this group
had a large number of participants (>100). In total, there were12 studies and 1,121 participants in this group. This category
was dominated by one study with a large sample size and good
score.77 In this study, levels of IL-18 were decreased by diet
(10.5% vs. baseline, p = 0.012 compared with no diet) andby omega-3 PUFA supplementation (9.9% vs. baseline, p =0.008 compared with placebo). Levels of IL-18 were also
significantly reduced in each treatment group compared
with the control group ( p = 0.021 for both), with a poten-tially additive effect of the 2 intervention principles ( p > ]>> setdistillerparams> setpagedevice
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/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /FlateEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict > /GrayImageDict > /JPEG2000GrayACSImageDict > /JPEG2000GrayImageDict > /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1000 /MonoImageMinResolutionPolicy /Warning /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict > /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False
/CreateJDFFile false /Description > /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ > /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ]>> setdistillerparams> setpagedevice
/ColorImageDict > /JPEG2000ColorACSImageDict > /JPEG2000ColorImageDict > /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /Warning /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth 8