This document provides an overview of host modulation therapy for periodontal disease. It discusses the history and rationale for host modulation, targeting the host inflammatory response to reduce tissue destruction. Specific targets of host modulation therapy include inhibition of matrix metalloproteinases (MMPs), arachidonic acid metabolites, modulation of bone metabolism and the immune response. Common agents that act on these targets include nonsteroidal anti-inflammatory drugs (NSAIDs), omega-3 fatty acids, bisphosphonates, and tetracyclines. Host modulation therapy aims to modify the host response to shift the balance towards periodontal health and stability.

1. 1

2. HOST
MODULATION
SEMINAR
2

3. • INTRODUCTION
• HISTORY
• PATHOGENESIS OF PERIODONTAL DISEASE
• HOST MODULATION
• HOST MODULATION THERAPY & DEFINITION
• BENEFITS OF HMT
• RATIONALE OF HMT
• TYPES OF HMT AGENTS
3

4. • MODULATION OF ARACHIDONIC ACID METABOLITES
• MODULATION OF MMPs
• MODULATION OF HOST CELL RESPONSES
• MODIFICATION OF BONE METABOLISM
• MODULATION OF NITRIC OXIDE ACTIVITY
• DISRUPTION OF RANKL/RANK/OSTEOPROTEGERIN AXIS
• LOCAL HMT’s
• OTHER RECENT AGENTS
• CONCLUSION
4

5. 5

6. HISTORY
• Introduced by Williams (1990) & Golub et al.(1992) (Pioneers)
• Page et al. (1997) stated that periodontal destruction in periodontitis is the
result of connective tissue-degrading mediators such as matrix
metalloproteinases (MMPs) and inflammatory mediators (prostaglandins,
interleukins) that occur as a part of inflammatory response.
6

7. HOST
• Organism from which a parasite derive its nourishment
• The individual who receives the graft
• In relation with periodontal diseases, an individual who harbors
pathogens associated with periodontal diseases.
7

8. MODULATION
• The alteration of function or status of something in response to a stimulus
or an altered chemical or physical environment.
• In terms of Periodontal disease: Host Modulation means altering the host
/host periodontal tissue’s reaction to the bacterial challenge.
8

9. • The immune-inflammatory response against bacterial plaque can thus be viewed as
a double-edged sword.
• Excessive quantities of destructive enzymes and inflammatory mediators &
inflammatory response to bacterial challenge.
• Periodontal disease is characterized by high concentrations of MMPs, cytokines &
Prostanoids
9

10. MODELS OF PERIODONTAL
PATHOGENESIS
1. Linear Model (Mid 1960’s Loe et al.)
2. Basic Conceptual Model (CIRCA MODEL, 1981, IVANYI L., LEHNER).
3. Critical Pathway Model (OFFENBACHER, 1996)
4. Non-Linear Model (The 1997 revised model of basic conceptual model – R.C. PAGE, K.S. KORNMAN)
5. Multilevel Hierarchal Model
6. Biologic Systems Model
Models of periodontal pathogenesis – Pushpa Latha et al, IndianJournal of Dental advancements, Vol.08 (1).
10

11. 11

12. BIOLOGIC SYSTEMS MODEL BY
OFFENBACHER
12

13. • Kornman(1999) proposed a model of periodontal disease pathogenesis that
explains how the host-parasite interactions takes place & lead to the disease
progression
• Oral cavity – open cavity – clean tooth surface – soon inhabited by various
microorganisms
• Periodontal pathogens – create environment of DYSBIOSIS
13

14. 14

15. NEED TO MODULATE HOST
RESPONSE
Improve therapeutic outcomes
Slow the progression of diseases
Allow for more predictable management of
patients
15

16. DYNAMIC BALANCE
• The balance between inflammatory mediators & their counter-regulatory
molecules is crucial for determining outcome of immuno-inflammatory
pathology of periodontal diseases.
• Stable Gingivitis – pro & anti-inflammatory response – in balance
16

17. 17

18. TARGETS OF HOST MODULATION
• Matrix Metalloproteinases(MMPs)
• Cytokines (IL & TNF-)
• Prostanoids
• Osteoclasts
• Elevation of endogenous anti-inflammatory mediators
18

19. 19

20. HOST
RESPONSE
ROLE IN
PROTECTION
ROLE IN
DESTRUCTION
20

21. 21

22. Virulent Plaque
bacteria
Host response
Disease resistant
Primary defense:
Controls disease
SRP
Disease susceptible
Primary defense:
Does not control
disease & excessive
host response
ANTIMICROBIAL
& HMT
22

23. Host Modulatory Therapy (HMT)
It is a treatment concept that aims to reduce tissue
destruction & stabilize or even regenerate the
periodontium by modifying or downregulating
destructive aspects of the host response &
upregulating protective or regenerative responses
(Oringer, 2002)
23

24. HMT – treating the host side of the host-bacteria interaction
Host response
Tissue
breakdown
Clinical signs
of periodontitis
24

25. HMT
• Modulating/reducing this destruction by treating aspects of the chronic
inflammatory response
• Do not “switch off” normal defense mechanisms/inflammation
• They ameliorate excessive/pathologically elevated inflammatory processes
to enhance the opportunities for wound healing & periodontal stability.
25

26. RATIONALE OF HMT
• HMT is directed on the host side of the host-microbial interactions
• Host response is responsible for most of the tissue breakdown during
host-microbial interactions.
• Provides opportunity to modify host immune response in such a way that
tissue destruction is minimized.
• HMT – does not stop the normal defense mechanisms, it amends the
excessively elevated mediators to enhance healing.
26

27. reduce excessive
levels of enzymes,
cytokines &
Prostanoids
modulate
osteoclast &
osteoblast
function
increase the levels
of person’s own
anti-inflammatory
mediators
Tilting balance
toward Health
Improves
therapeutic
outcomes
Slowing
progression of
disease
27

28. 28

29. BASED ON TYPE OF HOST RESPONSE
BEING MODULATED
INHIBITION OF
MMPs
INHIBITION OF
ARACHIDONIC
ACID
MODIFICATION
OF BONE
METABOLISM
REGULATION OF
IMMUNE &
INFLAMMATORY
RESPONSE
29

30. INHIBITON OF MMPs
• Tetracycline
30

31. INHIBITOR OF ARACHIDONIC ACID
METABOLITES
• A) COX-1 Inhibitor: Flurbiprofen
• B)COX-2 Inhibitor: Nimesulide
• C)Lipoxygenase(LOX)Inhibitor: Meclofenamate sodium, Lipoxins
• D)COX & LOX Inhibitor: Triclosan, Ketoprofen
31

32. MODIFICATION OF BONE
METABOLISM
• Bisphosphonates: Aldendronate
• Hormone Replacement Therapy
• Calcium Supplementation
• Vitamin D supplementation
32

33. REGULATION OF IMMUNE &
INFLAMMATORY RESPONSE
• Suppressing proinflammatory cytokine: IL-1 & IL-6 receptor antagonist
• Nitric oxide inhibitor: Mecaptoetylguanidine (MEG)
• Generate protective antibodies: Vaccines
• Supplementation with anti-inflammatory cytokine
33

34. BASED ON THE MODE OF DELIVERY
• NSAIDs, Bisphosphonates, SDD
SYSTEMIC
• Ketorolac mouth rinse, triclosan,
enamel matrix protein(EMP), growth
factors, bone morphogenetic proteins
LOCAL
34

35. 35

36. 36

37. 37

38. • Prostaglandins were first discovered by VON EULER in 1939
• PGE2 has been extensively studied in periodontal disease and is considered as one
of the most potent prostaglandins that upregulates bone resorption by Osteoclast.
• PGE2 also inhibits fibroblast function and has inhibitory and modulatory effects on
the immune response.
38

39. Cyclooxygenase
COX-1
Antithrombogenic
& Cytoprotective
function
COX-2
Inhibition –
Reduction of
inflammation
Converts
Arachidonic acid
into
Prostaglandins
39

40. 40

41. • Endogenous anti-inflammatory mediator
• Reduce neutrophil infiltration, block
cytokines, prevents CT & Bone loss
LIPOXINS
• Endogenous chemical mediators
• Role similar to lipoxins
RESOLVINS,
PROTECTINS,
MARESINS
41

42. • The development of all periodontal diseases is a
consequence of the inflammatory & immunological
reaction of the host to bacterial plaque.
• Any drug that has anti-inflammatory properties,
therefore, should be capable of modifying the host’s
reactions to the bacterial insult & so have clinical effect
upon the progression of disease
42

43. Nonsteroidal Anti-inflammatory drugs
• Inhibit formation of prostaglandins + PGE ( produced by neutrophils,
macrophages, fibroblasts & gingival epithelial cells in response to the
presence of LPS)
• PGE - elevated in patients with periodontal disease compared with healthy
patients
• PGE – inhibits fibroblast function & has inhibitory & modulatory effects on
immune response
• NSAIDs – reduce tissue inflammation
43

44. Nonsteroidal Anti-inflammatory drugs
• Used to treat pain, acute inflammation & chronic inflammatory
conditions
• Include Salicylates ( eg., Aspirin), indomethacin & propionic acid
derivatives (eg., ibuprofen & naproxen)
• Studies- have shown indomethacin, flurbiprofen & naproxen
administered daily for up to 3 years significantly slowed the rate of
alveolar bone loss compared with placebo
44

45. TYPES OF NSAID
I. NON SELECTIVE COX INHIBITORS:- (i.e. Traditional NSAIDS) e.g.
Salicylates, Propionic acid derivatives, Indole derivatives, Oxicam derivatives etc.
II. PREFERENTIAL COX-2 INHIBITORS:- e.g. Nimesulide, Meloxicam,
Nabumetone etc.
III. SELECTIVE COX-2 INHIBITORS:- e.g. Colecoxib, Etoricoxib, Parecoxib
etc.
45

46. • Drugs like flurbiprofen (William RC et al. 1989)
indomethacin (William RC et al 1987), naproxen(Howell TH
et al, 1993), administered daily up to 3 years showed
significantly slowed rate of alveolar bone resorption as
compared to placebo.
46

47. Disadvantages of NSAIDs
• Gastrointestinal problems
• Hemorrhage (decreased platelet aggregation)
• Renal & Hepatic Impairment
• “REBOUND EFFECT” 47

48. • Selective COX-2 inhibitors slowed alveolar bone loss in animal models and
modified prostaglandin production in human periodontal tissues
• Selective COX-2 inhibitors were later identified to be associated with
significant and life threatening adverse effects
• NSAIDs - presently not indicated as HMT
48

49. Nonsteroidal Anti-Inflammatory Drug
(NSAID) (LOCALLY ADMINISTERED)
• Topical NSAIDs have shown benefit in the treatment of periodontitis.
• One study of 55 patients with chronic periodontitis who received topical ketorolac mouth
rinse reported that GCF levels of PGE2 were reduced by approximately half over 6
months and that bone loss was halted.
• Locally administered ketoprofen has been investigated.
• Topically administered NSAIDs have not been approved as local HMTs for the management of
periodontitis
49

50. OMEGA-3 FATTY ACID DERIVATIVES
• Inhibition of cyclooxygenase & lipoxygenase pathway
• Reduction of Prostanoids & leukotrienes
• Regulate inflammatory cytokine
50

51. • Omega -3 PUFAs are widely held to act via several possible mechanisms,
such as preventing conversion of arachidonate to proinflammatory
eicosanoids or serving as an alternative substrate producing less-potent
products (Serhan CN et al., 2004)
51

52. 52

53. MMPs
• MMPs are zinc dependent enzymes
• Capable of degrading extracellular matrix molecules including
collagen
• Rationale for the inhibition of MMPs is to control host response
related destruction in the periodontal tissues
53

54. TETRACYCLINE
 They are effective in treating periodontal diseases because their concentration in the gingival
crevice is 2-10 times that in serum.
 They bind to tooth surface and bone at low GCF concentration of 2-4 g/ml and are effective
against many periodontal pathogens.
 They are effective host modulators due to their ability to prevent connective tissue breakdown
(anticollagenase) and bone loss (osteoclast inhibiton) independent of their antibacterial property.
54

55. INHIBITION OF MMPs
• Chemically modified tetracyclines (CMTs)
MECHANISM OF ACTION:
• Inhibit/chelates the calcium atoms that MMP require for their action
• Inhibit already active MMPs
• Down-regulate MMPs expression
• Scavenges Reactive Oxygen species
• Modulates the osteoclast function
•
55

56. 56

57. SUBANTIMICROBIAL DOSE OF
DOXYXYLINE (SDD)
• Only FDA approved HMT
• The tetracyclines have been used locally and systemically as antimicrobial
agents and more recently, systemically as a host modulation agent (SDD).
Antibiotic
property
Downregulate
MMP’s
Reduction in
cytokine
levels
New bone
formation
57

58. PERIOSTAT
• Subantimicrobial-dose doxycycline (SDD) is a 20-mg dose of doxycycline
(Periostat)
• Taken twice daily for 3 months, up to a maximum of 9 months of
continuous dosing.
• 20-mg dose exerts its therapeutic effect by enzyme, cytokine, and
osteoclast inhibition rather than by any antibiotic effect.
• Only systemically administered HMT specifically indicated for the treatment
of chronic periodontitis
58

59. • Studies conducted by Preshaw et al, using this same modified-release SDD versus placebo
in 266 subjects with periodontitis as an adjunct to SRP resulted in significantly greater
clinical benefits than SRP alone.
• A modified-release SDD (i.e., Oracea) was approved by the FDA for the treatment of the
common skin disorder rosacea
• Preshaw and coworkers demonstrated that this modified-release SDD resulted in
significantly improved clinical benefits in the treatment of periodontitis.
59

60. 60

61. INDICATIONS OF SDD
1. Chronic and Aggressive Periodontitis
2. Refractory Periodontitis, especially in smokers
3. Periodontitis cases associated with risk factors like smoking and Diabetes
Mellitus.
61

62. 62

63. PRO-INFLAMMATORY CYTOKINE
INHIBITION
• Studies – Variety of cytokines (IL-1,IL-6 & TNF) – elevated in diseased
periodontal destruction
• Cytokines – synergistic effect (IL-1 + TNF- causes bone resorption)
• Pentoxifylline (PTX) – block synthesis of TNF-
63

64. ANTI-CYTOKINE DRUGS
• Cytokines are regulatory proteins that control different functions of cells and
also play an important role in immune response of periodontal diseases.
• Pro-inflammatory cytokines like IL- 1 Beta and TNF play an important
role in the initiation, regulation and perpetuation of innate response of
periodontal diseases.
• Cytokines functions as a network, share overlapping features- BIOLOGICAL
REDUNDANCY.
64

65. Commercially Available
Anti-cytokines
• TNF-: Certolizumab pegol, Adalimunab, Golimunab
• Il-6: Tocilizumab
• IL-15: AMG714
• IL-12 & IL-13: Ustekinumab
• IL-17:AIN457
65

66. 66

67. 67

68. • Bone seeking agents
• Inhibit bone resorption by disrupting osteoclast activity
• Interfere with osteoblast mechanism & secretion of lysosomal enzymes
• Osteoclast modulation – useful in treatment of periodontitis
• Some bisphosphonates - unwanted effects
• Inhibiting bone calcification & changes in WBC counts
68

69. BISPHOSPHONATES
1ST GENERATION
Alkyl side chains (e.g.
etidronate)
2ND GENERATION
Aminobiphosphonates
with an amino – terminal
group (e.g. alendronate
and pamidronate)
3RD GENERATION
have cyclic side chains
(e.g. risedronate)
69

70. MECHANISM OF ACTION
70

71. • Primarily associated with intravenous administration of
bisphosphonates rather than oral administration
• Has impeded the development of bisphosphonates as an HMT to
manage periodontitis.
71

72. DISRUPTION OF THE
RANKL/RANK/OSTEOPROTEGERIN
• The discovery of a novel receptor called ostoprotegerin(OPG) revealed a key
regulatory mechanism in osteoclast differentiation & activity.
• OPG & receptor activator of nuclear factor kappa  ligand (rankl) are two
molecules that regulate osteoclast formation & bone resorption
• RANKL induces osteoclast differentiation & activation, whereas OPG blocks this
process by acting as a decoy receptor for RANKL.
72

73. • The use of OPG as a therapeutic agent was 1st evaluated by Simonet et al. 1997.
• OPG mimetic drug – “DENOSUMAB” (effects osteoclasts by inhibiting their
formation & survival)
• Based on animal studies: OPG/RANKL/RANK – new target for the treatment of
destructive periodontal disease & other bone resorption-related diseases.
73

74. MODULATION OF NITRIC OXIDE
ACTIVITY
• Nitric oxide(NO) - Short lived molecule implicated in a wide range of
biological process.
• NO- highly reactive free radical reacting with metal & thiol residues leading
to lipid peroxidation, protein & DNA damages and stimulation of cytokine
release
74

75. INHIBITION OF NO
• Lohinai et al. (1998) demonstrated the protective effects of
mercaptoethylguanidine (MEG), which is a selective inhibitor of iNOS
against bone destruction in ligature induced periodontitis in the rat
• Ribeiro and Leitao et al(2005) found that nitric oxide synthase inhibition
prevents alveolar bone resorption in experimental periodontitis in rats.
75

76. 76

77. Enamel Matrix protein
Bone Morphogenetic
Protein (BMP)
Growth factors
77

78. Enamel matrix proteins, growth factors,
and bone morphogenetic proteins
FDA approved
: Emdogain
78

79. Administration of BMP’s
• Bone morphogenetic proteins are non-collagenous proteins found in bone &
are characterized by their ability to induce bone & cartilage formation
Non collagenous
Support
angiogenesis
Bioresorbable
Immunologically
inert
Osteoconductive
79

80. IN PERIODONTAL RGENERATION
• Bone morphogenetic protein Protein-2 (OP-2)
• BMP-3 (Osteogenin)
• BMP-7(OP-1)
• rhBMP-2 commercially supplied in USA as INFUSE bone graft
80

81. Administration of BMP’s
Osteolysis Seroma/hematoma
Infection, Arahnoiditis
Dysphagia, Increased
neurologic deficits & Cancer
Disadvantages
81

82. NEWER HOST MODULATION AGNETS
UNDER TRIAL
 Recombinant anti-inflammatory cytokine (Rh-IL-11)
 Omega-3 fatty Acid derivatives
 Anti-Integrins
 Mercaptoethylguanidine (MEG)
 Metformin
 Probiotics
 Aloe Vera
 Chemically Modified CURCUMIN
82

83. PROBIOTICS
• Teughels et al. 2011 explored the use of probiotics in influencing the
periodontal microbiota & periodontal health & concluded that probiotics
might offer opportunities to manipulate the oral microbiota & periodontal
health by either direct microbiological interactions or by immunomodulatory
interaction
83

84. PROBIOTICS
Influence periodontal microbiota
Modulate cytokine secretion profiles
Influence T lymphocyte populations
Protect against physiological stress
84

85. • George Hjishengallis et al (2009) reported that toll like receptors(TLRs) may offer
novel targets for host-modulation therapy in periodontitis since manipulation of TLR
signaling may contribute to control of infection or regulation of inflammation and,
moreover, synthetic or natural TLR agonists could serve as periodontal vaccine adjuvants
• Yokoyama et al. in 2007 also demonstrated that egg yolk antibody against P. gingivalis
proved to be an effective immunotherapeutic agents in the treatment of periodontitis.
• Choi et al. in 2001 reported that prior immunization of mice to Fusobacterium
nucleatum modulated the host immune response to P. Gingivalis at the humoral, cellular
and molecular level
85

86. Major extracellular
antioxidants(Vit-C/E,
caretnoids): Scavenge
Free radicals
Cranberry juice
contains molecules
that inhibit MMPs,
IL-6/8 & PGE
Reddy S, Kul s, Asutkar H, Bhowmik N, Amudha. Host modulation in periodontics. e-journal of dentistry 2011;1:51-62
86

87. • Subcutaneous recombinant human IL-11
• Slow progression of attachment loss &
radiographic alveolar bone loss in
experimental animals
Recombinant anti-
inflammatory cytokine
• Block initial osteoclast adhesion to the
matrix & thus prevent bone resorption
Anti-Integrins
• Selective inhibitor of iNOS (Nitric oxide
synthase): Prevents bone regenration
Mecaptoetylguanidine
87

88. HERBAL DRUGS
• More recently, herbal drugs have been found to be promising in managing
inflammatory disorders.
• Herbal immunomodulator drugs (HID), such as Balsamodendron mukul,
Maharasnadi quath, Trikuta, Tinospora cordifolia, Phyllanthus
emblica, Saussurea lappa, Rubia cordifolia, and Glycyrrhiza glabra,
have been reported to possess antibacterial, anti-inflammatory,
antiexudative, and immunomodulation properties
88

89. Shown some potency in
modulating immune functions in
animal models .
It includes various herbal
products, each with its own
unique immunomodulatory
effect
89

90. ALOE VERA
• Has been used as natural remedy for throat infections & painful teeth
eruptions
• A clinical study demonstrated improvement in clinical parameters
such as plaque index, probing pocket depth, and gain in clinical
attachment following an intra-pocket placement of aloe vera gel in
type 2 diabetes mellitus patients with chronic periodontitis
(Pradeep AR et al, 2015)
90

91. POMGRENATE EXTRACTS
• have found application as anticaries agents & also in management of denture
stomatitis
• A study demonstrated a trend toward decreasing plaque formation and
significant pocket depth reduction & attachment level gain at 3 months
study period as compared to placebo.
• There was significant decrease in IL-1 & IL-6 levels
(Satravaha G et al, 2005)
91

92. TURMERIC
• Has been used as a pit & fissure sealant & also as an ingredient in plaque detection
system
• An animal study was conducted to evaluate the effect of systemically
administered curcumin on periodontal disease.
• Curcumin effectively inhibited cytokine gene expression on both the
messenger RNA and the protein level.
Inhibits progression of inflammatory bone loss associated with periodontitis
& inhibits cytokines
(Guimares MR et al)
Shah, Rucha & G V, Gayathri & Mehta, DhoomSingh. Application of herbal products in management of
periodontal diseases: A mini rivew. International Journal of Oral Health Sciences.2015;1(2):22-38
92

93. HOST MODULATION FACTORS IN
SYSTEMIC DISORDERS
• Host modulators – used to manage periodontal disease, MMP, cytokine, &
Prostanoids inhibitors
• Systemic diseases- linked to periodontal disease such as CVD & diabetes
• CVD – periodontal disease patient- twice as likely to have fatal heart attack
& three times likely to have stroke
• MMP & cytokines – play major role in weakening plaques formed with CVD –
thrombosis & infarction
• HMT – aid in treatment & prevention of CVD & diabetic complications
93

94. Host modulation and comprehensive
periodontal management
• Management includes thorough medical and dental history and examination
• Assessment of risk factors,
• Diagnosis,
• Development of a treatment strategy, initial and definitive treatment planning,
• Review of treatment outcomes and reevaluation,
• Long-term supportive periodontal therapy (maintenance care), and assessment of
prognosis
94

95. 95

96. LIMITATIONS OF HMT
• Duration of treatment is not well established
• Associated Side effects
• Newer agents ( cytokine inhibitors, human recombinant anti-
inflammatory cytokines, docosa-hexaenoic acid metabolites) still
under development
• Not economical for clinical use
96

97. Host modulation therapy has become an important modality of
treatment for periodontal diseases.
However, this therapy is an adjunct to the conventional
periodontal treatment.
Furthermore, this therapy is not indicated in all the patients &
should be used after a thorough evaluation of the patient. 97

98. REFERENCES
• Carranza Clinical Periodontology 11th edition
• Davidw. Paquette & ray c.Williams; modulation of host inflammatory meditors as a
treatment strategy for periodontal diseases: periodontology 2000, vol.24,2000. 239-252
• Philip m. Pershaw; host response modulation in
periodontics:periodontology2000,vol.48,2008,92-110
• Antush mittal, v.Ranganath, ashish nichani;omega fatty acids and resolution of
inflammation: a new twist in an old tale: journal of Indian society of periodontology-vol.43,
2007, 294-315
98

99. REFERENCES
• MK Ah, GK Johnson, WB Kaldahl. et al: The effect of smoking on the response to periodontal therapy J Clin
Periodontol 1994;21:91-
• KF Al-Shammari, WV Giannobile, WA Aldredge. et al: Effect of non-surgical periodontal therapy on
Ctelopeptidepyridinoline cross-links (ICTP) and interleukin-1 levels J Periodontol 2001;72:1045-
• RA Ashley. Clinical trials of a matrix metalloproteinase inhibitor in human periodontal disease. SDD Clinical
Research Team Ann NY AcadSci 1999;878:335-
• JD Beck, S Offenbacher, R Williams. et al: Periodontitis: a risk factor for coronary heart disease Ann Periodontol
1998;3:127-
• H Birkedal-Hansen. Role of matrix metalloproteinases in human periodontal diseases J Periodontol 1993;64:474-
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