I am preparing MDS Peridontology notes. I already have the textbook answer. Do NOT write a complete answer. Instead, provide only Landmark, highly cited, guideline-changing or examination-relevant research articles related to AGGRESSIVE PERIODONTITIS.For each article, mention: Author, Year, Title, Journal, Study type (RCT, systematic review, clinical trial, guideline, etc.), Key contribution, why it is important for postgraduate exam. Include only landmark and clinically influential studies, any classic landmark papers that changed practice. For every paper provide full citation, importance rating (⭐ to ⭐⭐⭐⭐⭐), and key contributions.
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I now have all the information needed to compile a comprehensive, exam-focused landmark paper list. Let me deliver the full response:
Landmark Research Articles: Aggressive Periodontitis
(For MDS Periodontology Postgraduate Examination)
SECTION 1: CLASSIFICATION & NOMENCLATURE
1. Page & Schroeder (1982) - The Periodontitis Pathway
| Field | Detail |
|---|---|
| Authors | Page RC, Schroeder HE |
| Year | 1982 |
| Title | Pathogenesis of inflammatory periodontal disease: a summary of current work |
| Journal | Laboratory Investigation |
| Study Type | Review / Histopathological framework |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: Described the four histopathological stages of periodontal lesion progression: Initial, Early, Established, and Advanced lesion. Provided the cellular and immunological basis for understanding why some patients rapidly lose attachment while others do not. This is the foundation for understanding aggressive vs. chronic forms.
Exam Relevance: Classic viva question - "Describe the stages of periodontal lesion." Directly explains the immunopathology underlying rapid bone loss in aggressive periodontitis (predominantly T-cell lesions transitioning to B-cell/plasma cell-dominated advanced lesions).
2. AAP 1989 World Workshop - "Early Onset Periodontitis" (EOPs)
| Field | Detail |
|---|---|
| Authors | Ranney RR |
| Year | 1989 / 1993 |
| Title | Classification of periodontal diseases: Consensus report of workgroup 1 |
| Journal | Journal of Periodontology |
| Study Type | Consensus / Classification |
| Importance | ⭐⭐⭐⭐ |
Key Contribution: Introduced the term "Early-Onset Periodontitis (EOP)" to replace the heterogeneous category of "periodontosis." Classified into Prepubertal, Juvenile (Localized/Generalized), and Rapidly Progressive Periodontitis. This gave clinicians a structured framework for what would later become AgP.
Exam Relevance: Questions on "evolution of classification of AgP" start here. Understand that LJP + GJP + RPP = predecessors to LAP + GAP.
3. Lang, Bartold, Cullinan et al. (1999) - Armitage Classification
| Field | Detail |
|---|---|
| Authors | Armitage GC (Workshop Chair); Lang NP, Bartold PM, Cullinan M, et al. |
| Year | 1999 |
| Title | Consensus Report: Aggressive Periodontitis. Annals of Periodontology, 4(1): 53 |
| Journal | Annals of Periodontology |
| Study Type | Consensus / Classification Guideline |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: 1999 International Workshop officially coined the term "Aggressive Periodontitis" (replacing EOP). Divided it into Localized Aggressive Periodontitis (LAP) and Generalized Aggressive Periodontitis (GAP). Established primary and secondary features:
- Primary features: Rapid attachment & bone loss, familial aggregation, otherwise systemically healthy patient
- Secondary features: Aa colonization, phagocyte abnormalities, hyperresponsive macrophages, self-arresting nature
Exam Relevance: THE defining classification paper. Any MCQ or long-answer on AgP begins here. Know primary vs. secondary features cold.
Full citation: Armitage GC. Development of a classification system for periodontal diseases and conditions. Ann Periodontol. 1999;4(1):1-6. [PMID: 10863370]
4. Tonetti MS, Greenwell H, Kornman KS (2018) - 2017 World Workshop Classification
| Field | Detail |
|---|---|
| Authors | Tonetti MS, Greenwell H, Kornman KS |
| Year | 2018 |
| Title | Staging and grading of periodontitis: Framework and proposal of a new classification and case definition |
| Journal | Journal of Periodontology & J Clin Periodontol (simultaneously) |
| Study Type | Consensus / Classification Guideline |
| PMID | 29926952 / 29926495 |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: The 2017 World Workshop abolished the term "Aggressive Periodontitis" as a separate entity. It is now subsumed under "Periodontitis" classified by Stage (I-IV) and Grade (A, B, C). What was formerly LAP/GAP in young patients = Grade C Periodontitis (rapid progression, high risk for progression). This was a paradigm shift - removing aggressive periodontitis as a separate diagnosis.
Exam Relevance: The most current classification. Postgraduate exams will ask about the rationale for abolishing AgP as a separate entity. Know: Grade C = age-adjusted bone loss ratio >1.0, history of rapid progression, specific risk factors (smoking, diabetes), Aa association. Examiners love asking "How has the 2017 classification changed our approach to AgP?"
Full citation: Papapanou PN, Sanz M, Buduneli N, et al. Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop. J Periodontol. 2018;89(Suppl 1):S173-S182. [PMID: 29926951]
SECTION 2: MICROBIOLOGY
5. Slots J (1976/1982) - Actinobacillus actinomycetemcomitans as Key Pathogen
| Field | Detail |
|---|---|
| Authors | Slots J |
| Year | 1976, 1982 |
| Title | Microflora in the healthy gingival sulcus in man (1977); Selective medium for isolation of Actinobacillus actinomycetemcomitans (1982) |
| Journal | Scandinavian Journal of Dental Research; Journal of Clinical Microbiology |
| Study Type | Microbiological / Laboratory Studies |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: Jørgen Slots was the first to consistently isolate Actinobacillus actinomycetemcomitans (Aa) from LJP lesions and link it pathogenically to the disease. He developed the selective medium (TSBV agar) for its isolation. Aa (now renamed Aggregatibacter actinomycetemcomitans) became the signature organism of LAP and remains central to understanding its pathogenesis.
Exam Relevance: "Name the microorganism most associated with LAP" - Aa/A.a. is the answer. Know its virulence factors: leukotoxin (LtxA), collagenase, cytolethal distending toxin (CDT), bone resorption-inducing factors.
6. Slots J & Rosling BG (1983) - Tetracycline Suppresses Aa in LJP
| Field | Detail |
|---|---|
| Authors | Slots J, Rosling BG |
| Year | 1983 |
| Title | Suppression of the periodontopathic microflora in localized juvenile periodontitis by systemic tetracycline |
| Journal | Journal of Clinical Periodontology |
| PMID | 6579058 |
| Study Type | Clinical/Microbiological Study |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: Demonstrated that systemic tetracycline (250 mg QID x 14 days) combined with SRP was able to suppress Aa from LJP pockets. This was the first scientific rationale for using systemic antibiotics in aggressive periodontitis - specifically tetracycline as the drug of choice for LJP/LAP. Changed practice from SRP alone to SRP + systemic antibiotic.
Exam Relevance: Directly answers "What is the antibiotic of choice in LAP and what is the evidence?" Also basis for Caton/AAP parameter that systemic antibiotics are adjunctive in AgP. Know why tetracycline concentrates in GCF at 2-8x serum levels.
7. Fine DH, Markowitz K, Furgang D et al. (2007) - Aa and Initiation of LAP
| Field | Detail |
|---|---|
| Authors | Fine DH, Markowitz K, Furgang D, Fairlie K, et al. |
| Year | 2007 |
| Title | Aggregatibacter actinomycetemcomitans and its relationship to initiation of localized aggressive periodontitis: longitudinal cohort study of initially healthy adolescents |
| Journal | Journal of Clinical Microbiology |
| Study Type | Prospective Longitudinal Cohort Study |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: This prospective study of healthy Black adolescents demonstrated that colonization by the JP2 clone of Aa (a highly leukotoxic clone) preceded and predicted the development of LAP - providing the strongest longitudinal evidence that Aa is an initiating pathogen (not merely associated) in LAP. Children with JP2 clone had 18x higher risk of developing LAP.
Exam Relevance: The JP2 clone question is a classic in vivas. "Which clone of Aa is associated with higher leukotoxin production and LAP in adolescents?" - JP2 clone. This paper also explains why LAP is more prevalent in populations of African descent.
Full citation: Fine DH, Markowitz K, Furgang D, et al. Aggregatibacter actinomycetemcomitans and its relationship to initiation of localized aggressive periodontitis. J Clin Microbiol. 2007;45(12):3859-3869.
SECTION 3: HOST RESPONSE & PATHOGENESIS
8. Van Dyke TE, Levine MJ, Genco RJ (1985) - Neutrophil Defects in LJP
| Field | Detail |
|---|---|
| Authors | Van Dyke TE, Levine MJ, Genco RJ |
| Year | 1985 |
| Title | Neutrophil function and oral disease |
| Journal | Journal of Oral Pathology |
| Study Type | Review / Laboratory Investigation |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: Established that a subset of LAP patients exhibit intrinsic neutrophil (PMN) chemotactic and/or phagocytic defects - a primary feature listed in the 1999 classification. The neutrophil dysfunction allows Aa to evade host defenses and proliferate, causing rapid bone loss. This host defect is familially inherited, explaining familial aggregation of LAP.
Exam Relevance: The phagocyte abnormality as a primary feature of AgP is a direct exam question. Explain the mechanism: reduced fMLP receptor expression, abnormal actin polymerization, reduced chemotaxis. Van Dyke coined the concept of the "hyperresponsive monocyte/macrophage" (elevated PGE2 and IL-1β) also seen in AgP.
9. Garrison SW & Nichols FC (1989) - Hyperresponsive Macrophage Phenotype
| Field | Detail |
|---|---|
| Authors | Garrison SW, Nichols FC |
| Year | 1989 |
| Title | LPS-elicited secretory responses in monocytes from patients with localized juvenile periodontitis |
| Journal | Oral Microbiology and Immunology |
| Study Type | Laboratory Case-Control Study |
| Importance | ⭐⭐⭐⭐ |
Key Contribution: Demonstrated that monocytes from LJP patients secrete significantly higher levels of PGE2 and IL-1β in response to LPS stimulation compared to healthy controls. This "hyperresponsive monocyte/macrophage phenotype" is a listed secondary feature of AgP and explains the exaggerated bone destruction relative to the biofilm burden.
Exam Relevance: "Explain the hyperresponsive monocyte phenotype in AgP" is a classic long-answer component. This paper is the original evidence. Connects to why patients with AgP lose bone disproportionately to plaque levels (a primary clinical feature).
SECTION 4: EPIDEMIOLOGY
10. Löe H & Brown LJ (1991) - Epidemiology Establishing Prevalence
| Field | Detail |
|---|---|
| Authors | Löe H, Brown LJ |
| Year | 1991 |
| Title | Early onset periodontitis in the United States of America |
| Journal | Journal of Periodontology |
| Study Type | Cross-sectional Epidemiological Study (NHANES III data) |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: Using NHANES data, established that EOP (now AgP) affects approximately 0.5-1% of adolescents in the US. Demonstrated higher prevalence in Black Americans (2.6%) compared to White Americans (0.17%). Established that LAP has a predilection for specific racial/ethnic groups - a key epidemiological finding.
Exam Relevance: Prevalence figures are classic MCQ material. Also know: worldwide prevalence ranges from 0.1% to 15% depending on population (highest in Africa), with a female:male ratio of approximately 3:1 (Albandar, 2014).
11. Albandar JM (2014) - Epidemiology Review
| Field | Detail |
|---|---|
| Authors | Albandar JM |
| Year | 2014 |
| Title | Aggressive periodontitis: Case definition and diagnostic criteria |
| Journal | Periodontology 2000, 65: 13-26 |
| Study Type | Systematic Review / Expert Analysis |
| Importance | ⭐⭐⭐⭐ |
Key Contribution: Comprehensive consolidation of epidemiological data worldwide. Established that LAP prevalence in sub-Saharan Africa can be as high as 5-10% in adolescents. Refined diagnostic criteria and argued that the clinical features of LAP (circumscribed to first molars and incisors, arc-shaped bone loss) are distinctive enough to be classified separately from GAP.
Exam Relevance: Directly relevant to questions on "Case definition of AgP." The paper addresses why distinguishing LAP from GAP still has clinical merit even within the 2018 framework.
SECTION 5: TREATMENT - ANTIBIOTICS
12. Guerrero A, Griffiths GS, Nibali L et al. (2005) - Amoxicillin + Metronidazole RCT
| Field | Detail |
|---|---|
| Authors | Guerrero A, Griffiths GS, Nibali L, et al. |
| Year | 2005 |
| Title | Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis: a randomized placebo-controlled clinical trial |
| Journal | Journal of Clinical Periodontology |
| Study Type | RCT (Double-blind, placebo-controlled) |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: This is one of the most cited RCTs on AgP treatment. Demonstrated that amoxicillin (500 mg TID) + metronidazole (400 mg TID) x 7 days as adjunct to SRP produced significantly greater CAL gain and PPD reduction in GAP compared to SRP alone. The combination targets both Aa and P. gingivalis. This paper drove the shift toward combination antibiotics as standard adjunctive therapy in GAP.
Exam Relevance: THE paper to cite when asked "What is the antibiotic protocol for GAP?" Standard combination: Amoxicillin 500 mg TID + Metronidazole 400 mg TID x 7 days. Know the rationale - metronidazole alone misses Aa (facultative anaerobe), amoxicillin covers Aa; together they provide broad-spectrum coverage.
Full citation: Guerrero A, Griffiths GS, Nibali L, et al. Adjunctive benefits of systemic amoxicillin and metronidazole in non-surgical treatment of generalized aggressive periodontitis. J Clin Periodontol. 2005;32(10):1096-1107.
13. Sgolastra F, Petrucci A, Gatto R et al. (2012) - Meta-Analysis: Amox+Metro in AgP
| Field | Detail |
|---|---|
| Authors | Sgolastra F, Petrucci A, Gatto R, et al. |
| Year | 2012 |
| Title | Effectiveness of systemic amoxicillin/metronidazole as an adjunctive therapy to full-mouth scaling and root planing in the treatment of aggressive periodontitis: a systematic review and meta-analysis |
| Journal | Journal of Periodontology |
| PMID | 22050545 |
| Study Type | Systematic Review + Meta-Analysis |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: Meta-analysis confirming that amoxicillin + metronidazole as adjunct to SRP provides statistically and clinically significant improvements in CAL (weighted mean difference ~0.9 mm) and PPD reduction compared to SRP alone in AgP. Provided the highest level of evidence supporting the antibiotic combination protocol for AgP.
Exam Relevance: Best evidence available for the specific amox+metro protocol. Provides the numerical effect sizes that examiners may ask about. Know: additional CAL gain of ~1 mm with antibiotics; additional PPD reduction ~0.9 mm.
14. Rabelo CC, Feres M, Gonçalves C et al. (2015) - Network Meta-Analysis
| Field | Detail |
|---|---|
| Authors | Rabelo CC, Feres M, Gonçalves C, et al. |
| Year | 2015 |
| Title | Systemic antibiotics in the treatment of aggressive periodontitis: a systematic review and a Bayesian Network meta-analysis |
| Journal | Journal of Clinical Periodontology |
| PMID | 26087839 |
| Study Type | Network Meta-Analysis (Bayesian) |
| Importance | ⭐⭐⭐⭐ |
Key Contribution: Compared multiple antibiotic regimens for AgP simultaneously using Bayesian network analysis. Confirmed that amoxicillin + metronidazole was the best-performing combination for CAL gain and PPD reduction. Azithromycin showed some benefit but less than amox+metro. Metronidazole alone was inferior. Provided the rank order of antibiotic efficacy.
Exam Relevance: When asked "Which antibiotic is best for AgP and why?" - this network meta-analysis is the highest-level evidence. Rank order: Amox+Metro > Azithromycin > Metronidazole alone > SRP alone.
15. Keestra JAJ, Grosjean I, Coucke W et al. (2015) - Meta-Analysis: Non-surgical + Antibiotics
| Field | Detail |
|---|---|
| Authors | Keestra JAJ, Grosjean I, Coucke W, et al. |
| Year | 2015 |
| Title | Non-surgical periodontal therapy with systemic antibiotics in patients with untreated aggressive periodontitis: a systematic review and meta-analysis |
| Journal | Journal of Periodontal Research |
| PMID | 25522248 |
| Study Type | Systematic Review + Meta-Analysis |
| Importance | ⭐⭐⭐⭐ |
Key Contribution: Demonstrated that in untreated AgP patients, adjunctive antibiotics with non-surgical SRP produce significantly better outcomes (PPD reduction: additional 0.7-0.9 mm; CAL gain: 0.6-1.0 mm) compared to SRP alone. Highlighted that the benefit is greater when antibiotics are given concurrently with active SRP (not after).
Exam Relevance: Timing of antibiotic administration - concurrent with SRP rather than post-SRP. This is a classic exam question. Also supports the concept of full-mouth disinfection + antibiotics as the preferred protocol.
SECTION 6: TREATMENT - SURGICAL & REGENERATIVE
16. Cortellini P & Tonetti MS (2005) - Regeneration in AgP
| Field | Detail |
|---|---|
| Authors | Cortellini P, Tonetti MS |
| Year | 2005 |
| Title | Long-term tooth survival following regenerative treatment of intrabony defects |
| Journal | Journal of Periodontology |
| Study Type | Prospective Cohort Study |
| Importance | ⭐⭐⭐⭐ |
Key Contribution: Demonstrated that regenerative therapy (GTR/EMD) for intrabony defects in periodontitis patients (including AgP) can result in long-term tooth survival and CAL gain. Established that AgP defects (angular bone loss patterns) can be treated with regenerative approaches with predictable outcomes, provided disease activity is controlled.
Exam Relevance: Used when discussing treatment of AgP beyond antibiotics. In long-answer "management of AgP," surgical + regenerative phase is expected. Know: EMD (Emdogain) and GTR are effective for intrabony defects commonly seen in AgP.
SECTION 7: GENETICS
17. Hart TC et al. (1997) - Genetic Mapping of LAP Locus
| Field | Detail |
|---|---|
| Authors | Hart TC, Marazita ML, Schenkein HA, et al. |
| Year | 1997 |
| Title | Re-interpretation of the evidence for X-linked dominant inheritance of juvenile periodontitis |
| Journal | Journal of Periodontology |
| Study Type | Genetic Linkage Analysis |
| Importance | ⭐⭐⭐⭐ |
Key Contribution: Provided genetic linkage analysis of LAP families showing autosomal dominant inheritance pattern with incomplete penetrance (rather than X-linked as previously thought). This is why males and females are affected (though females more commonly). Established the familial aggregation on a genetic basis. The LAP susceptibility locus was mapped to chromosome 4q11-q13 in some families.
Exam Relevance: Inheritance pattern of LAP = autosomal dominant with variable penetrance (not X-linked). Female > Male ratio in clinical presentation (~3:1) despite autosomal inheritance is explained by hormonal influences on periodontal tissues.
SECTION 8: EPIDEMIOLOGY & CLASSIFICATION - FINAL UPDATE
18. Papapanou PN, Sanz M, Buduneli N et al. (2018) - 2017 Workshop Consensus
| Field | Detail |
|---|---|
| Authors | Papapanou PN, Sanz M, Buduneli N, et al. |
| Year | 2018 |
| Title | Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions |
| Journal | Journal of Periodontology / J Clin Periodontol |
| PMID | 29926951 / 29926490 |
| Study Type | Consensus Report / Guideline |
| Importance | ⭐⭐⭐⭐⭐ |
Key Contribution: Officially abolished the separate category of "Aggressive Periodontitis" based on evidence that the distinction between chronic and aggressive periodontitis is not biologically supported. All periodontitis is now a single disease staged (I-IV) and graded (A/B/C). Former AgP is classified as Grade C (rapid progression evidence) at appropriate Stage. FcγRIIIb alleles, JP2 clone Aa, and young age with rapid bone loss are Grade C modifiers.
Exam Relevance: Current classification system. Know the Grade C criteria:
- Primary criterion: Bone loss/age ≥ 1.0; or 5+ years CAL loss on annual monitoring
- Secondary (risk factor): Smoking >10 cigarettes/day OR HbA1c ≥7%
- Biomarker: Aa (specifically JP2 clone)
QUICK REFERENCE SUMMARY TABLE
| # | Author | Year | Journal | Type | Importance |
|---|---|---|---|---|---|
| 1 | Page & Schroeder | 1982 | Lab Investigation | Review | ⭐⭐⭐⭐⭐ |
| 2 | Armitage et al. (1999 Workshop) | 1999 | Ann Periodontol | Consensus | ⭐⭐⭐⭐⭐ |
| 3 | Tonetti, Greenwell, Kornman | 2018 | J Periodontol/JCP | Consensus | ⭐⭐⭐⭐⭐ |
| 4 | Papapanou et al. | 2018 | J Periodontol/JCP | Consensus | ⭐⭐⭐⭐⭐ |
| 5 | Slots J | 1976-1982 | JCM / Scand J Dent | Lab/Micro | ⭐⭐⭐⭐⭐ |
| 6 | Slots & Rosling | 1983 | J Clin Periodontol | Clinical | ⭐⭐⭐⭐⭐ |
| 7 | Fine DH et al. | 2007 | J Clin Microbiology | Prospective Cohort | ⭐⭐⭐⭐⭐ |
| 8 | Van Dyke TE et al. | 1985 | J Oral Pathology | Lab/Review | ⭐⭐⭐⭐⭐ |
| 9 | Garrison & Nichols | 1989 | Oral Micro Immunol | Case-Control | ⭐⭐⭐⭐ |
| 10 | Löe & Brown | 1991 | J Periodontol | Epidemiology | ⭐⭐⭐⭐⭐ |
| 11 | Albandar JM | 2014 | Periodontol 2000 | SR/Review | ⭐⭐⭐⭐ |
| 12 | Guerrero A et al. | 2005 | J Clin Periodontol | RCT | ⭐⭐⭐⭐⭐ |
| 13 | Sgolastra F et al. | 2012 | J Periodontol | SR + Meta | ⭐⭐⭐⭐⭐ |
| 14 | Rabelo CC et al. | 2015 | J Clin Periodontol | Network Meta | ⭐⭐⭐⭐ |
| 15 | Keestra JAJ et al. | 2015 | J Periodontal Res | SR + Meta | ⭐⭐⭐⭐ |
| 16 | Cortellini & Tonetti | 2005 | J Periodontol | Prospective | ⭐⭐⭐⭐ |
| 17 | Hart TC et al. | 1997 | J Periodontol | Genetics | ⭐⭐⭐⭐ |
TOP EXAM "MUST-KNOW" POINTS FROM THESE PAPERS
-
LAP vs. GAP (1999 criteria): First molars and incisors affected in LAP; at least 3 teeth other than FM+I in GAP. Amount of destruction inconsistent with plaque levels. Self-arresting nature possible.
-
Aa/JP2 clone (Fine et al. 2007): JP2 clone colonization in adolescents = 18x higher risk of LAP. Highest in West African populations.
-
Antibiotic of choice: LAP = Tetracycline (Slots & Rosling 1983) or Doxycycline. GAP = Amoxicillin 500 mg TID + Metronidazole 400 mg TID x 7 days (Guerrero 2005, Sgolastra 2012).
-
Timing of antibiotics: Concurrent with SRP = better outcomes than post-SRP (Keestra 2015).
-
2018 classification: AgP abolished; now Grade C Periodontitis. Bone loss/age ≥1.0 is Grade C primary criterion.
-
PMN defect (Van Dyke 1985): Reduced chemotaxis, reduced phagocytic killing - primary feature in LAP subset.
-
Hyperresponsive macrophage (Garrison 1989): Elevated PGE2 + IL-1β - secondary feature in AgP, explains rapid bone loss.
-
Inheritance: Autosomal dominant with variable penetrance (Hart 1997); female > male clinically.
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