INTO-HLH Registry Overview

The INTO-HLH Registry is designed to create a detailed dataset of HLH patient treatment and outcomes across three domains:

  1. HLH diversity and disease course
  2. Treatment patterns, responses, complications, and outcomes
  3. Patients' quality of life

It is focused on all forms of HLH and aims to obtain comprehensive and unbiased information to improve the understanding of the condition and its treatments.  

STUDY DESIGN

Observational (i.e., non-interventional) natural history study

STUDY DURATION

Up to 5 years follow up for each patient

SAMPLE SIZE

≥200 patients with different variants of HLH

ELIGIBILITY CRITERIA

  • Pediatric and adult patients of all ages
  • Clinically suspected or confirmed diagnosis of HLH or related disorders (e.g., MAS, CRS)
  • The ability of patients, family members, and/or legal guardian to provide informed consent/assent (deceased patients are also eligible)
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This Registry will allow the research community to gain a deeper understanding of the natural history of HLH and its complications
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The insights gathered could potentially help to improve treatment outcomes for future patients

Why encourage your patients to participate in the INTO-HLH Registry?

  • This Registry will allow the research community to gain a deeper understanding of the natural history of HLH and its complications
  • The insights gathered could potentially help to improve treatment outcomes for future patients
  • Both physicians and patients can be a part of a community that improves research and care of HLH, a small effort that will contribute to the advancement of knowledge about HLH

INTO-HLH Registry Structure

This Registry is modeled after the ACCELERATE registry (see PMID: 33377129).

The INTO-HLH Registry will recruit patients through two arms:

THE PATIENT POWERED ARM

Individuals (or their guardians) will volunteer to join the Registry directly through this website and correspond with the IHRT after informed consent. Regardless of whether individuals are recently diagnosed (and undergoing treatment) or previously treated (and completed treatment years prior), they are eligible to enroll in the Registry through this arm.

THE PHYSICIAN DRIVEN ARM

INTO-HLH will collaborate with the NACHO network of centers in North America to enroll primarily recently diagnosed patients undergoing treatment.  Deceased patients will also be eligible to be enrolled in this arm. Those who have completed therapy in prior years are encouraged to self-enroll through the Patient Powered Arm. If you practice at other sites, in other specialties, or represent other networks, and would be interested in collaborating, please contact us.

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INTO-HLH will collaborate with the NACHO network of centers in North America to enroll primarily recently diagnosed patients undergoing treatment
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INTO-HLH will collaborate with the NACHO network of centers in North America to enroll primarily recently diagnosed patients undergoing treatment.

SPOTLIGHT ON RESEARCH

We highlight a few recent papers of clinical or scientific merit. Under show more is a longer (but not exhaustive) list of mostly historical papers on HLH of significant interest. Publication in this area continues to expand.

Challenges of diagnosing HLH

We need more efficient ways to diagnose HLH. While improved clinical criteria will eventually help, the process starts with clinicians more clearly understanding what HLH is and what it is not.

Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO).  Jordan MB, Allen CE, Greenberg J, et al. Pediatr Blood Cancer. 2019;66(11):e27929. doi:10.1002/pbc.27929

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We need more efficient ways to diagnose HLH. The process starts with clinicians more clearly understanding what HLH is and what it is not

Publication

HLH after CAR T-cell therapy

HLH after CAR T-cells are increasingly recognized. This series describes an unusual cluster of such patients and offers concepts for distinguishing from ‘routine’ CRS.
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REVIEWS

  1. Ehl S, Astigarraga I, von Bahr Greenwood T, Hines M, Horne A, Ishii E, Janka G, Jordan MB, La Rosée P, Lehmberg K, Machowicz R, Nichols KE, Sieni E, Wang Z, Henter JI. Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract. 2018 Sep-Oct;6(5):1508-1517. doi: 10.1016/j.jaip.2018.05.031. Epub 2018 Jul 4. PMID: 30201097.
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  2. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-4052. doi:10.1182/blood-2011-03-278127
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CLINICAL STUDIES

  1. Lin H, Scull BP, Goldberg BR, et al. IFN-γ signature in the plasma proteome distinguishes pediatric hemophagocytic lymphohistiocytosis from sepsis and SIRS. Blood Adv. 2021;5(17):3457-3467. doi:10.1182/bloodadvances.2021004287
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  2. Chaturvedi V, Marsh RA, Zoref-Lorenz A, et al. T-cell activation profiles distinguish hemophagocytic lymphohistiocytosis and early sepsis. Blood. 2021;137(17):2337-2346. doi:10.1182/blood.2020009499
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  3. Allen CE, Marsh R, Dawson P, et al. Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies. Blood. 2018;132(13):1438-1451. doi:10.1182/blood-2018-01-828277
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  4. Chinn IK, Eckstein OS, Peckham-Gregory EC, et al. Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis. Blood. 2018;132(1):89-100. doi:10.1182/blood-2017-11-814244
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  5. Hartz B, Marsh R, Rao K, Henter JI, Jordan M, Filipovich L, Bader P, Beier R, Burkhardt B, Meisel R, Schulz A, Winkler B, Albert MH, Greil J, Karasu G, Woessmann W, Corbacioglu S, Gruhn B, Holter W, Kühl JS, Lang P, Seidel MG, Veys P, Löfstedt A, Ammann S, Ehl S, Janka G, Müller I, Lehmberg K. The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis. Blood. 2016 Jun 23;127(25):3281-90. doi: 10.1182/ blood-2015-12-684498. Epub 2016 Apr 20. PMID: 27099148; PMCID: PMC5291300.
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  6. Marsh RA, Kim MO, Liu C, Bellman D, Hart L, Grimley M, Kumar A, Jodele S, Myers KC, Chandra S, Leemhuis T, Mehta PA, Bleesing JJ, Davies SM, Jordan MB, Filipovich AH. An intermediate alemtuzumab schedule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis. Biol Blood Marrow Transplant. 2013 Nov;19(11):1625-31. doi: 10.1016/ j.bbmt.2013.09.001. Epub 2013 Sep 10. PMID: 24035782; PMCID: PMC4167781.
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  7. Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, Lee ND, Khan SP, Lawrence J, Mo JQ, Bleesing JJ, Filipovich AH, Jordan MB. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013 Jan;60(1):101-9. doi: 10.1002/pbc.24188. Epub 2012 Apr 22. PMID: 22522603; PMCID: PMC3410971.
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  8. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4):428-435. doi:10.1111/j.1651-2227.1991.tb11878.x
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  9. Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, Yamamoto K, Horiuchi H, Takada K, Ohshima K, Nakamura S, Kinukawa N, Oshimi K, Kawa K. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2007 Jul;86(1):58-65. doi: 10.1532/IJH97.07012. PMID: 17675268.
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PRECLINICAL STUDIES

  1. Chaturvedi V, Lakes N, Tran M, Castillo N, Jordan MB. JAK inhibition for murine HLH requires complete blockade of IFN-γ signaling and is limited by toxicity of JAK2 inhibition. Blood. 2021 Sep 23;138(12):1034-1039. doi: 10.1182/ blood.2020007930. PMID: 34232994.
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  2. Meyer LK, Verbist KC, Albeituni S, Scull BP, Bassett RC, Stroh AN, Tillman H, Allen CE, Hermiston ML, Nichols KE. JAK/ STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation. Blood. 2020 Aug 6;136(6):657-668. doi: 10.1182/blood.2020006075. PMID: 32530039; PMCID: PMC7414590.
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  3. Maschalidi S, Sepulveda FE, Garrigue A, Fischer A, de Saint Basile G. Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood. 2016 Jul 7;128(1):60-71. doi: 10.1182/ blood-2016-02-700013. Epub 2016 May 24. PMID: 27222478.
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  4. Das R, Guan P, Sprague L, Verbist K, Tedrick P, An QA, Cheng C, Kurachi M, Levine R, Wherry EJ, Canna SW, Behrens EM, Nichols KE. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood. 2016 Mar 31;127(13):1666-75. doi: 10.1182/blood-2015-12-684399. Epub 2016 Jan 29. PMID: 26825707; PMCID: PMC4817310.
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  5. Terrell CE, Jordan MB. Mixed hematopoietic or T-cell chimerism above a minimal threshold restores perforin- dependent immune regulation in perforin-deficient mice. Blood. 2013;122(15):2618-2621. doi:10.1182/ blood-2013-06-508143
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  6. Terrell CE, Jordan MB. Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. Blood. 2013;121(26):5184-5191. doi:10.1182/blood-2013-04-495309
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  7. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104(3):735-743. doi:10.1182/ blood-2003-10-3413
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REVIEWS

  1. De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. Targeting interferon-γ in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol. 2021;17(11):678-691. doi:10.1038/s41584-021-00694-z
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  2. Nikiforow S, Berliner N. To "Lump" or to "Split" in Macrophage Activation Syndrome and Hemophagocytic Lymphohistiocytosis. Arthritis Rheumatol. 2020;72(2):206-209. doi:10.1002/art.41106
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CLINICAL STUDIES

  1. Ravelli A, Minoia F, Davì S, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2016;68(3):566-576. doi:10.1002/art.39332
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  2. Lam MT, Coppola S, Krumbach OHF, Prencipe G, Insalaco A, Cifaldi C, Brigida I, Zara E, Scala S, Di Cesare S, Martinelli S, Di Rocco M, Pascarella A, Niceta M, Pantaleoni F, Ciolfi A, Netter P, Carisey AF, Diehl M, Akbarzadeh M, Conti F, Merli P, Pastore A, Levi Mortera S, Camerini S, Farina L, Buchholzer M, Pannone L, Cao TN, Coban-Akdemir ZH, Jhangiani SN, Muzny DM, Gibbs RA, Basso-Ricci L, Chiriaco M, Dvorsky R, Putignani L, Carsetti R, Janning P, Stray-Pedersen A, Erichsen HC, Horne A, Bryceson YT, Torralba-Raga L, Ramme K, Rosti V, Bracaglia C, Messia V, Palma P, Finocchi A, Locatelli F, Chinn IK, Lupski JR, Mace EM, Cancrini C, Aiuti A, Ahmadian MR, Orange JS, De Benedetti F, Tartaglia M. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function.  J Exp Med. 2019 Dec 2;216(12):2778-2799. doi: 10.1084/jem.20190147. Epub 2019 Oct 10.PMID: 31601675
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REVIEWS

  1. La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477. doi:10.1182/blood.2018894618
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  2. Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood. 2015;125(19):2908-2914. doi:10.1182/blood-2015-01-551622
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CLINICAL STUDIES

  1. Knaak C, Nyvlt P, Schuster FS, Spies C, Heeren P, Schenk T, Balzer F, La Rosée P, Janka G, Brunkhorst FM, Keh D, Lachmann G. Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore. Crit Care. 2020 May 24;24(1):244. doi: 10.1186/s13054-020-02941-3. PMID: 32448380; PMCID: PMC7245825.
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  2. Miller PG, Niroula A, Ceremsak JJ, et al. Identification of germline variants in adults with hemophagocytic lymphohistiocytosis. Blood Adv. 2020;4(5):925-929. doi:10.1182/bloodadvances.2019001272
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  3. Miller PG, Sperling AS, Gibson CJ, et al. Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis. Blood. 2020;136(26):3051-3055. doi:10.1182/blood.2020008206
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  4. Schram AM, Comstock P, Campo M, et al. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. Br J Haematol. 2016;172(3):412-419. doi:10.1111/bjh.13837
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  5. Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, Coppo P, Hejblum G. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014 Sep;66(9):2613-20. doi: 10.1002/art.38690. PMID: 24782338.
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  6. Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014 Apr 26;383(9927):1503-1516. doi: 10.1016/S0140-6736(13)61048-X. Epub 2013 Nov 27. Erratum in: Lancet. 2014 Apr 26;383(9927):1464. PMID: 24290661.
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REVIEWS

  1. Setiadi A, Zoref-Lorenz A, Lee CY, Jordan MB, Chen LYC. Malignancy-associated haemophagocytic lymphohistiocytosis. Lancet Haematol. 2022;9(3):e217-e227. doi:10.1016/S2352-3026(21)00366-5
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  2. Daver N, McClain K, Allen CE, et al. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer. 2017;123(17):3229-3240. doi:10.1002/cncr.30826
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  3. Lehmberg, K., Nichols, K. E., Henter, J. I., Girschikofsky, M., Greenwood, T., Jordan, M., Kumar, A., Minkov, M., La Rosée, P., Weitzman, S., & Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society (2015). Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica, 100(8), 997–1004. https://doi.org/10.3324/haematol.2015.123562
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CLINICAL STUDIES

  1. Tamamyan GN, Kantarjian HM, Ning J, et al. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: Relation to hemophagocytosis, characteristics, and outcomes. Cancer. 2016;122(18):2857-2866. doi:10.1002/cncr.30084
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REVIEWS

  1. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020 Dec 3;383(23):2255-2273. doi: 10.1056/NEJMra2026131. PMID: 33264547; PMCID: PMC7727315.
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  2. Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan KF, Caricchio R, Mahmud S, Hazen MM, Halyabar O, Hoyt KJ, Han J, Grom AA, Gattorno M, Ravelli A, De Benedetti F, Behrens EM, Cron RQ, Nigrovic PA. On the Alert for Cytokine Storm: Immunopathology in COVID-19. Arthritis Rheumatol. 2020 Jul;72(7):1059-1063. doi: 10.1002/art.41285. Epub 2020 May 10. PMID: 32293098; PMCID: PMC7262347.
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CLINICAL STUDIES

  1. Kevin O McNerney, Amanda M DiNofia, David T Teachey, Stephan A Grupp, Shannon L Maude  Potential Role of IFNγ Inhibition in Refractory Cytokine Release Syndrome Associated with CAR T-cell Therapy. Blood Cancer Discov. 2022 Mar 1;3(2):90-94. doi: 10.1158/2643-3230.BCD-21-0203. PMID: 35015687  DOI: 10.1158/2643-3230.BCD-21-0203
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  2. Diorio C, Shraim R, Vella LA, et al. Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat Commun. 2021;12(1):7222. Published 2021 Dec 10. doi:10.1038/s41467-021-27544-6
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  3. Rodriguez-Smith JJ, Verweyen EL, Clay GM, et al. Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study. Lancet Rheumatol. 2021;3(8):e574-e584. doi:10.1016/S2665-9913(21)00139-9
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  4. Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, Przepiorka D, Farrell AT, Pazdur R. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. Oncologist. 2018 Aug;23(8):943-947. doi: 10.1634/theoncologist.2018-0028. Epub 2018 Apr 5. PMID: 29622697; PMCID: PMC6156173.
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  5. Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert Rev Clin Immunol. 2019 Aug;15(8):813-822. doi: 10.1080/1744666X.2019.1629904. Epub 2019 Jun 20. PMID: 31219357; PMCID: PMC7936577.
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PRECLINICAL STUDIES 

  1. Bailey SR, Vatsa S, Larson RC, Bouffard AA, Scarfò I, Kann MC, Berger TR, Leick MB, Wehrli M, Schmidts A, Silva H, Lindell KA, Demato A, Gallagher KME, Frigault MJ, Maus MV. Blockade or Deletion of IFNγ Reduces Macrophage Activation without Compromising CAR T-cell Function in Hematologic Malignancies. Blood Cancer Discov. 2022 Mar 1;3(2):136-153. doi: 10.1158/2643-3230.BCD-21-0181. PMID: 35015685.
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Collaborate with us

By collaborating with us, together we will:

  • Enhance clinical understanding on the natural history of HLH disease, treatment patterns, and outcomes
  • Provide evidence to support the clinical decision-making process in the management of HLH
  • Rich data source to meet current and future research needs
  • Broaden and strengthen the network of physicians collaborating in HLH

If you are interested in collaborating, please contact us through our contact page

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