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Scientific evidence on hepatitis Delta in Brazil: integrative literature review

Abstract

Objective:

Describe the level of scientific evidence on infections by the hepatitis Delta virus (HDV) in Brazil.

Methods:

Integrative literature review, with research in the databases of the Medical Literature Analysis and Retrieval System Online, Latin American and Caribbean Center on Health Sciences Information, Scientific Eletronic Library Online and Scopus, with analysis focusing on the leveling of the methodological rigor according to the model of Melnyk and Fineout-Overholt.

Results:

The search revealed an average of two publications a year between 1987 and 2017. We selected 33 articles, the majority (91%) presented level of evidence VI. The publications were concentrated in the area of tropical medicine (46%) and virology (15%). The authors of 85% of the studies were medical professionals and the most common design was the descriptive/cross-sectional (69.6%).

Conclusion:

Scientific literature on HDV infections in Brazil is focused on prevalence studies, showing incipiency regarding the production of studies with stricter guidelines, such as clinical trials.

Keywords
Hepatitis D; Hepatitis B; Brazil

Resumo

Objetivo:

Descrever o nível de evidência científica sobre a infecção por vírus da hepatite Delta (VHD) no Brasil.

Métodos:

Revisão integrativa da literatura, com buscas realizadas nas bases de dados do Medical Literature Analysis and Retrieval System Online, Literatura Latino-americana e do Caribe em Ciências da Saúde, Scientific Eletronic Library Online e Scopus, com análise centrada no nivelamento do rigor metodológico de acordo com o modelo de Melnyk e Fineout-Overholt.

Resultados:

A busca revelou uma média de duas publicações por ano no intervalo entre 1987 e 2017. Foram selecionados 33 artigos, tendo a maioria (91%) apresentado nível de evidência VI. As publicações ficaram concentradas em periódicos da área de medicina tropical (46%) e virologia (15%). Dos trabalhos, 85% tinha profissional médico com autor e o delineamento mais encontrado foi o descritivo/transversal (69,6%).

Conclusão:

A produção científica sobre a infecção por VHD no Brasil está centrada em estudos de prevalência, mostrando-se incipiente quanto à produção de estudos com delineamentos mais rígidos como ensaios clínicos.

Descritores
Hepatite D; Hepatite B; Brasil

Introduction

By analyzing the serum of patients infected with the hepatitis B virus (HBV), the Italian researcher Mario Rizzetto described a new antigen-antibody system in the 1970's, the system was named antigen/antibody Delta.(11. Rizzetto M, Canese MG, Aricò S, Crivelli O, Trepo C, Bonino F, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut. 1977; 18(12):997-1003.) Subsequent studies revealed that that the discovery was not of another component of HBV, but of a new virus: the hepatitis Delta virus (HDV).(22. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010; 7(1):31-40.)

The HDV needs the HBV to infect humans, because it uses the surface antigen (HBsAg) on the process of pathogenesis.(22. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010; 7(1):31-40.) The viral structure is composed by a single-stranded ribonucleic acid (RNA) (33. Rizzetto M. Hepatitis D Virus: Introduction and Epidemiology. Cold Spring Harb Perspect Med. 2015; 5(7):a021576.), measuring between 35nm and 37nm, it produces two antigens of known clinical importance: the small Delta antigen (HDAg-S), which acts in the process of viral replication, and the large Delta antigen (HDAg-L) which, through the interaction with HBsAg, acts on the assembly of RNA.(44. Alfaiate D, Dény P, Durantel D. Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options. Antiviral Res. 2015; 122:112-29.)

HDV infection occurs by parenteral exposure and is considered a co-infection when it occurs on the primary or acute phase of HBV infection and as a superinfection when it occurs in chronic hepatitis B.(22. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010; 7(1):31-40.)

The interaction between the HDV and HBV is not fully understood yet, especially due to the fact that both viruses compete for HBsAg to assemble new viral structures.(55. Huang CR. Hepatitis D virus infection, replication and crosstalk with the hepatitis B virus. World J Gastroenterol. 2014; 20(40):14589.) Furthermore, studies indicate that the HDV is related to the early development of serious conditions of hepatic diseases, such as: Cirrhosis, hepatocellular carcinoma (HCC) and fulminant hepatitis.(66. Rizzetto M, Alavian SM. Hepatitis Delta. Clin Liver Dis. 2013; 17(3):475-87.,77. De Oliveira MS, Do Valle SD, Silva RP, De Figueiredo EN. Hepatite B e a superinfecção por vírus D em pacientes crônicos na Amazônia ocidental brasileira. Rev Epidemiol Control Infec [Internet]. 2015 [citado 2016 Abr 17];5(2). Disponível em: http://online.unisc.br/seer/index.php/epidemiologia/article/view/5442.
http://online.unisc.br/seer/index.php/ep...
)

The hepatitis cases caused by HDV associated with HBV represent a serious worldwide public health problem, generating continuous demands to health services, in addition to considerable losses in the quality of life of infected patients, also showing high mortality rates.(88. Crispim MA, Fraiji NA, Campello SC, Schriefer NA, Stefani MM, Kiesslich D. Molecular epidemiology of hepatitis B and hepatitis delta viruses circulating in the Western Amazon region, North Brazil. BMC Infect Dis. 2014; 14:94.)

This kind of infection is distributed around the globe; HBV, the required element for HDV infection, is estimated to have already infected 2 billion individuals worldwide, of which 300 to 400 million are chronic carriers and 15 to 20 million are infected with the HDV(22. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010; 7(1):31-40.,99. Oliveira MS, Silva RP, Valle SD, Figueiredo EN, Fram D. Chronic hepatitis B and D: prognosis according to Child-Pugh score. Rev Bras Enferm. 2017; 70(5):1048-53.), with an annual number of deaths estimated between 620,000 and 1 million.(1010. Scaglione SJ, Lok AS. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology. 2012; 142(6):1360-8.)

The HDV has worldwide distribution with variable prevalence. Two countries of Central Europe, Romania and Hungary, present, respectively, 47.6% and 13.9% of patients with positive HBsAg infected with HDV. West and central Africa, present infection ranging from 1.3% in Nigeria to 66% in Gabon. 20% of patients with positive HBsAg in Egypt are infected. In Asia, the prevalence reaches 66.7% in Taiwan and 82% in Mongolia. (44. Alfaiate D, Dény P, Durantel D. Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options. Antiviral Res. 2015; 122:112-29.) The distribution in South America is variable, but high indicators are found across the entire Amazon basin, especially in the Western Brazilian Amazon, where the seropositivity to HDV can reach up to 85% of patients with positive HBsAg in some communities.(44. Alfaiate D, Dény P, Durantel D. Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options. Antiviral Res. 2015; 122:112-29.,88. Crispim MA, Fraiji NA, Campello SC, Schriefer NA, Stefani MM, Kiesslich D. Molecular epidemiology of hepatitis B and hepatitis delta viruses circulating in the Western Amazon region, North Brazil. BMC Infect Dis. 2014; 14:94.,1111. di Filippo Villa D, Cortes-Mancera F, Payares E, Montes N, de la Hoz F, Arbelaez MP, et al. Hepatitis D virus and hepatitis B virus infection in Amerindian communities of the Amazonas state, Colombia. Virol J. 2015; 12:172.)

Dating back to the mid-18th century, historical accounts record deaths of members of the French Royal Academy of Science by a disease described acute icteric fever, during an expedition through the Amazon River, in Brazil.(1212. Fonseca JC. Histórico das hepatites virais. Rev Soc Bras Med Trop. 2010; 43(3):322-30.) During the second half of the 20th century, studies describe a serious icteric condition, of rapid evolution and with death records of five days after the initial symptoms in the city of Lábrea, in the interior of the state of Amazonas. The condition was initially named as Labrea black fever,(1313. Fonseca JC, Ferreira LC, Guerra AL, Passos LM, Simonetti JP. Hepatite fulminante e febre negra de Lábrea: estudo de 5 casos procedentes de Codajás, Amazonas, Brasil. Rev Soc Bras Med Trop. 1983; 16(3):144-7.) but the cases were investigated and in 1987 it was confirmed that the Labrea black fever was, in fact, fulminant hepatitis caused by infection of the HDV in patients with HBV.(1414. Bensabath G. Hepatitis Delta virus infection and Labrea hepatitis: prevalence and role in fulminant hepatitis in the Amazon Basin. JAMA. 1987; 258(4):479.)

Nowadays, despite the infection being recorded throughout the Brazilian territory and 77% of the cases occurring in the northern region, researchers claim that despite the high endemic indicators of HDV infection, the condition is neglected by health services.(1515. Cicero MF, Pena NM, Santana LC, Arnold R, Azevedo RG, Leal ÉS, et al. Is Hepatitis Delta infections important in Brazil? BMC Infect Dis [Internet]. 2016 [cited 2017 Sep 28];16(1). Available from: http://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-1856-9.
http://bmcinfectdis.biomedcentral.com/ar...
)

Given the Brazilian context, resources available from the Brazilian Unified Health System and recognizing HDV infection as a major public health problem, the objective of this study was to, through an integrative review: describe the level of scientific evidence on HDV infection in Brazil to provide awareness on the theme to health professionals and public administrators, as well as serving as a parameter of good research and assistance practices for the development of health policies.

Methods

Integrative literature review with the theme “level of scientific evidence on HDV infection in Brazil” between the years of 1987 and 2017. The search was performed in September 2017 and went through six methodological steps, according to criteria outlined in national and international scientific literature (Figure 1).(1616. Alcalá Pompeo D, Rossi LA, Galvão CM. Revisão integrativa: etapa inicial do processo de validação de diagnóstico de enfermagem. Acta Paul Enferm. 2009; 22(4):434-8.

17. Hopia H, Latvala E, Liimatainen L. Reviewing the methodology of an integrative review. Scand J Caring Sci. 2016; 30(4):662-9.

18. Mendes KD, Silveira RC, Galvão CM. Revisão integrativa: método de pesquisa para a incorporação de evidências na saúde e na enfermagem. Texto Contexto Enferm. 2008; 17(4):758-64.
-1919. Souza MT de, Silva MD, Carvalho R. Integrative review: what is it? How to do it? einstein (São Paulo). 2010; 8(1):102-6.)

Figure 1
Methodological stages of the research

The first stage was to elaborate the guiding question: “what is the level of scientific evidence on HDV infection in Brazil?”. Then, we set the keywords according to the Health Sciences Descriptors (DeCS) and the Medical Subject Headings (MeSH), they are: Hepatitis D; Hepatitis B and Brazil.

On the second stage we defined the databases for searching and the eligibility criteria. For this, were considered eligible the scientific articles found through the descriptors defined on the first step, published in English, Portuguese and Spanish, the search was restricted to the Brazilian territory, the approach focused on hepatitis D or HDV and abstract available in the following databases: Medical Literature Analysis and Retrieval System Online (Medline), Latin American and Caribbean Center on Health Sciencies Information (LILACS), Scientific Electronic Library Online (SciELO) and Scopus (Elsevier).

For the third stage we considered the formulation of a framework proposed by Souza, Silva and Carvalho(1919. Souza MT de, Silva MD, Carvalho R. Integrative review: what is it? How to do it? einstein (São Paulo). 2010; 8(1):102-6.) to organize the database and present the results (Chart 1), in addition to the classification of evidence models based on the model of Melnyk and Fineout-Overholt.(2020. Melnyk BM, Fineout-Overholt E. Evidencebased practice in nursing & healthcare. A guide to best practice. Philadelphia: Lippincot Williams & Wilkins; 2005. Making the case for evidence based practice. p.239-344.)

Chart 1
Characterization of publications on hepatitis D in Brazil, according to reference, thematic considerations, type of study and level of evidence

Evidence from systematic review or meta-analysis of all relevant randomized clinical trials controlled or from clinical guidelines based on systematic reviews of randomized controlled clinical trials:

  • I- Evidence from at least one controlled and well-designed randomized clinical trial;

  • II- Evidence from clinical trials well designed without randomization;

  • III- Evidence from well-designed cohort and case-control studies;

  • IV- Evidence from systematic review of descriptive and qualitative studies;

  • V- Evidence from a single descriptive or qualitative study;

  • IV- Evidence from the opinion of authorities and/or from a report of committees of experts.

During the fourth stage we read the abstracts and applied the eligibility criteria, as set by the protocol on figure 1, the result was 33 selected studies.

On the fifth stage the discussion of data found was had and on the sixth stage we built the descriptive document of this review.

Results

The selected studies are summarized (Chart 1), considering information such as title, author(s), journal in which it was published, thematic considerations and the classification of the level of evidence.

The studies analyzed (Chart 1) were organized to facilitate the better reading of the results. The selected studies were published between the years of 1987 and 2017; there were no studies selected for the years 1993, 1997, 1998, 2003, 2010, 2013 and 2016. We observed an average publication of two studies per year on the other years, and 2014 presented the greater volume of publications, with four studies.

Observing the academic training of the main author of the study, 85% of the studies were from medical professionals, 6% from biomedical professionals, 3% from nurses, 3% from pharmacists/biochemists and 3% from biologists.

The research were published in eight categories of journals, 46% of the area of tropical medicine, 15% of the area of virology, 12% of the area of infectious diseases, 9% of the area of medical sciences, 9% of the area of public health, 3% of the area of hepatology, 3% of the area of nursing and 3% of the area of biomedicine.

Regarding research design, 69.6% were cross-sectional studies, 15.2% were literature reviews, 6.1% were case-control studies, 6.1% were case reports and 3% were clinical trials.

By classifying the level of evidence according to the method adopted, we observed that: 91% of the studies were of type VI, i.e., evidence derived from a single descriptive or qualitative study; 6% were of type IV, evidences from well designed cohort and case-control studies; and 3% of type III, i.e., evidences from well designed clinical trials without randomization.

Discussion

The result of this integrative review depicts the scientific production on HDV infection in Brazil over the past three decades, and, despite being a major cause of severe complications of hepatic disease in patients with hepatitis B and variable distribution, with areas of high prevalence on the country,(22. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010; 7(1):31-40.,5151. Alvarado-Mora MV, Romano CM, Gomes-Gouvêa MS, Gutierrez MF, Carrilho FJ, Pinho JR. Dynamics of Hepatitis D (delta) virus genotype 3 in the Amazon region of South America. Infect Genet Evol. 2011; 11(6):1462-8.,5252. Silva AL, Vitorino RR, Esperidião-Antonio V, Santos ET, Santana LA, Henriques BD, et al. Hepatites virais: B, C e D: atualização. Rev Soc Bras Clín Méd. 2012; 10(3):206-18.) the results demonstrate a discrete scientific production.

Of the studies identified in this review, 91% correspond to the level of evidence VI, i.e., studies with descriptive cross-sectional design, most of them focused on the analysis of prevalence, resulting on a low level of evidence.(1818. Mendes KD, Silveira RC, Galvão CM. Revisão integrativa: método de pesquisa para a incorporação de evidências na saúde e na enfermagem. Texto Contexto Enferm. 2008; 17(4):758-64.,2020. Melnyk BM, Fineout-Overholt E. Evidencebased practice in nursing & healthcare. A guide to best practice. Philadelphia: Lippincot Williams & Wilkins; 2005. Making the case for evidence based practice. p.239-344.)

The main areas of production are concentrated in tropical medicine journals. Brazil is a tropical country and still bears a high burden of communicable diseases.(5353. Mendes EV. As redes de atenção à saúde. Ciênc Saúde Coletiva. 2010; 15(5):2297-305.) Although advances on the control of vaccine-preventable diseases and HIV infection are seen on the last two decades, infectious diseases still constitute a serious public health problem in the country.(5454. Victora CG, Barreto ML, Leal MC, Monteiro CA, Schmidt MI, Paim J, et al. Condições de saúde e inovações nas políticas de saúde no Brasil: o caminho a percorrer. Lancet. 2011;(Supl Saúde no Brasil 6):90-102. DOI:10.1016/S0140-6736(11)60055-X.
https://doi.org/10.1016/S0140-6736(11)60...
)

Most studies, 85%, have a medical professional as the primary author, although it is a theme inherent to the practice of medicine, due to the need for scientific research to produce good clinical practices;(5555. Paolucci El Dib R. Como praticar a medicina baseada em evidências. J Vasc Bras. 2007; 6(1):1-4.) other areas of the multidisciplinary field of health hold equal importance on the need for scientific production as a guiding mechanism for the improvement of care, especially when preventable harms, such as hepatitis D, are considered, an argument that contrasts with researchers who claim, for example, that the scientific production of nursing is still incipient in Brazil.(5656. Morais AS, Nicole AG, Braga AT, Tronchin DMR, Melleiro MM. Qualidade e avaliação em saúde: publicações em periódicos de enfermagem nas últimas duas décadas. Rev Enferm UERJ. 2008; 16(3):404-9.)

However, initiatives such as the national program for the prevention and control of viral hepatitis, which seeks the systematization of the programmatic actions in health, providing the nursing professional with protagonism and autonomy to manage care on the three levels of health care. Due to the professional assignment, there is interest in constructing health strategies from new knowledge, both in care and adequacy of public policies.(5757. Brasil. Ministério da Saúde, Secretaria de Vigilância em Saúde. Manual de aconselhamento em hepatites virais. Brasília (DF): Ministério da Saúde; 2005. 52 p.)

The World Health Organization recognizes the HBV infection, a necessary condition for the HDV infection, as a public health problem that requires urgent response, reiterating the importance of prevention, particularly through vaccine strategies, this highlights the importance of the nurse as a transforming agent in this health-dis-ease-curing process.(5858. Organização Panamericana da Saúde (OPAS)/Organização Mundial da Saúde (OMS). Novos dados sobre hepatites destacam necessidade de uma resposta global urgente [Internet]. Brasília (DF); OPAS/OMS; 2017 [cited 2017 Oct 31]. Available from: http://www.paho.org/bra/index.php?option=com_content&view=article&id=5404:novos-dados-sobre-hepatites-destacam-necessidade-de-uma-resposta-global-urgente&Itemid=812.
http://www.paho.org/bra/index.php?option...
)

However, to evaluate the quality of scientific production in health it is necessary to consider the structural and promotion conditions existing in Brazil for higher ranked classifications. This goes beyond the theme of this integrative review. Stimulating undergraduate research was only implemented in Brazil in 1988 and despite the advances in recent decades, the Brazilian scientific production faces obstacles regarding the quality of the studies produced, something directly related to the scarcity of resources.(5959. Tenório MP, Beraldi G. Iniciação científica no Brasil e nos cursos de medicina. Rev Assoc Médica Bras. 2010; 56(4):390-3.)

Additionally, when the object of analysis is a theme like HDV infection, aspects related to the quality of care and to the rational use of resources, both in the public and private sectors, end up exerting pressure on health professionals who lack contextualized scientific evidence for better performance practices.(6060. Sampaio RF, Mancini MC. Estudos de revisão sistemática: um guia para síntese criteriosa da evidência científica. Rev Bras Fisioter. 2007; 11(1):83-9.)

The production of scientific evidence, such as meta-analytic reviews or randomized clinical trials, does not exclude the importance of descriptive studies and the value of personal experiences, but evidences to care for patients subject to the evolution to severe conditions, such as those infected with HDV, are of fundamental importance to make the best clinical decisions.(5555. Paolucci El Dib R. Como praticar a medicina baseada em evidências. J Vasc Bras. 2007; 6(1):1-4.) However, we note that all of the epidemiological studies and the data on information systems must be used to understand hepatitis B and D in the country, and to support the development of individual and collective interventions that minimize the influence of the disease on the population.

Despite the importance of study reviews to synthesize research results or even the production of relevant research, actions must go beyond simply stimulating scientific production, but fundamentally, using the results of these studies as transforming elements in clinical practice.(6060. Sampaio RF, Mancini MC. Estudos de revisão sistemática: um guia para síntese criteriosa da evidência científica. Rev Bras Fisioter. 2007; 11(1):83-9.)

Conclusion

We conclude that the scientific literature on HDV infection in Brazil is centered on research with descriptive/cross-sectional design, being incipient on studies with higher levels of evidence. This information points to the need for further research focused on the definition of risk factors, drug and therapeutic analysis and the effectiveness of prevention and control programs, to sustain the adoption of innovations in public policies and healthcare.

Referências

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    Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010; 7(1):31-40.
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    Rizzetto M. Hepatitis D Virus: Introduction and Epidemiology. Cold Spring Harb Perspect Med. 2015; 5(7):a021576.
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    Alfaiate D, Dény P, Durantel D. Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options. Antiviral Res. 2015; 122:112-29.
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    Huang CR. Hepatitis D virus infection, replication and crosstalk with the hepatitis B virus. World J Gastroenterol. 2014; 20(40):14589.
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    Oliveira MS, Silva RP, Valle SD, Figueiredo EN, Fram D. Chronic hepatitis B and D: prognosis according to Child-Pugh score. Rev Bras Enferm. 2017; 70(5):1048-53.
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    Scaglione SJ, Lok AS. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology. 2012; 142(6):1360-8.
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    Fonseca JC, Ferreira LC, Guerra AL, Passos LM, Simonetti JP. Hepatite fulminante e febre negra de Lábrea: estudo de 5 casos procedentes de Codajás, Amazonas, Brasil. Rev Soc Bras Med Trop. 1983; 16(3):144-7.
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    Bensabath G. Hepatitis Delta virus infection and Labrea hepatitis: prevalence and role in fulminant hepatitis in the Amazon Basin. JAMA. 1987; 258(4):479.
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    Cicero MF, Pena NM, Santana LC, Arnold R, Azevedo RG, Leal ÉS, et al. Is Hepatitis Delta infections important in Brazil? BMC Infect Dis [Internet]. 2016 [cited 2017 Sep 28];16(1). Available from: http://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-1856-9
    » http://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-1856-9
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Publication Dates

  • Publication in this collection
    Nov-Dec 2017

History

  • Received
    08 Nov 2017
  • Accepted
    04 Dec 2017
Escola Paulista de Enfermagem, Universidade Federal de São Paulo R. Napoleão de Barros, 754, 04024-002 São Paulo - SP/Brasil, Tel./Fax: (55 11) 5576 4430 - São Paulo - SP - Brazil
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