Special Issue "Histoplasma and Histoplasmosis 2020"

A special issue of Journal of Fungi (ISSN 2309-608X). This special issue belongs to the section "Fungal Pathogenesis and Disease Control".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 13598

Special Issue Editors

Dr. Nathan C. Bahr
E-Mail Website
Guest Editor
Division of Infectious Diseases, Department of Medicine, University of Kansas Medical Center, Kansas City, KS, USA
Interests: histoplasma and histoplasmosis; TB meningitis; cryptococcal meningitis; diagnostic testing; opportunistic infections
Prof. Dr. Mathieu Nacher
E-Mail Website
Guest Editor
Medicine Department, Ecosystemes Amazoniens et Pathologie Tropicale, EA 3593, Labex CEBA, University of French Guiana, Cayenne, French Guiana, Fracne
Interests: HIV infectious diseases; malaria; AIDS; Plasmodium; Falciparum malaria; Vivax malaria
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Special Issue Information

Dear Colleagues,

Histoplasmosis is often described as having a narrow endemic area. The era of HIV and the ever increasing use of immune suppressive medications have shown us that this way of thinking isn’t accurate. In fact, though histoplasmosis is certainly more frequent in certain areas of the world, the disease has been detected nearly worldwide. In Latin America, it is the most frequent cause of mortality among those with advanced HIV but is frequently mis-diagnosed as ‘culture-negative’ tuberculosis. In much of the world, the lack of readily available rapid diagnostic tests is a major barrier to diagnosis of histoplasmosis. Diagnostic difficulties aside, therapeutics are also problematic. Liposomal amphotericin b is mostly unavailable for severe presentations. Itraconazole is the treatment of choice in many situations but can be difficult for patients to tolerate and is frequently implicated in drug interactions.

Are there better treatments and are any of the new antifungal medications candidates to improve treatment tolerability? Why are we missing so many cases and is it really as straightforward as needing better diagnostic tests? What actual progress has been made in reducing the burden of disease worldwide? Can we prevent histoplasmosis? Why do the seemingly rare immunologic manifestations of histoplasmosis occur?

This Special Issue of the Journal of Fungi will seek to answer some basic and important questions about histoplasmosis to which the answers are not yet known in hopes of increasing our knowledge of the disease and making progress towards decreasing the worldwide burden.

Sincerely,

Dr. Nathan C. Bahr
Prof. Dr. Mathieu Nacher
Guest Editors

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Keywords

  • Histoplasma
  • histoplasmosis
  • endemic fungi
  • opportunistic infections
  • AIDS
  • fungal epidemiology

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Published Papers (12 papers)

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Research

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Article
Detection of Cytokines and Collectins in Bronchoalveolar Fluid Samples of Patients Infected with Histoplasma capsulatum and Pneumocystis jirovecii
J. Fungi 2021, 7(11), 938; https://doi.org/10.3390/jof7110938 - 04 Nov 2021
Viewed by 553
Abstract
Histoplasmosis and pneumocystosis co-infections have been reported mainly in immunocompromised humans and in wild animals. The immunological response to each fungal infection has been described primarily using animal models; however, the host response to concomitant infection is unknown. The present work aimed to [...] Read more.
Histoplasmosis and pneumocystosis co-infections have been reported mainly in immunocompromised humans and in wild animals. The immunological response to each fungal infection has been described primarily using animal models; however, the host response to concomitant infection is unknown. The present work aimed to evaluate the pulmonary immunological response of patients with pneumonia caused either by Histoplasma capsulatum, Pneumocystis jirovecii, or their co-infection. We analyzed the pulmonary collectin and cytokine patterns of 131 bronchoalveolar lavage samples, which included HIV and non-HIV patients infected with H. capsulatum, P. jirovecii, or both fungi, as well as healthy volunteers and HIV patients without the studied fungal infections. Our results showed an increased production of the surfactant protein-A (SP-A) in non-HIV patients with H. capsulatum infection, contrasting with HIV patients (p < 0.05). Significant differences in median values of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, IL-33, IL-13, and CXCL8 were found among all the groups studied, suggesting that these cytokines play a role in the local inflammatory processes of histoplasmosis and pneumocystosis. Interestingly, non-HIV patients with co-infection and pneumocystosis alone showed lower levels of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, and IL-23 than histoplasmosis patients, suggesting an immunomodulatory ability of P. jirovecii over H. capsulatum response. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Article
Cytological Spectrum of Pulmonary Histoplasmosis Diagnosed by Bronchoalveolar Lavage: 12 Years of Experience in French Guiana
J. Fungi 2021, 7(7), 576; https://doi.org/10.3390/jof7070576 - 19 Jul 2021
Viewed by 654
Abstract
Disseminated histoplasmosis is a major cause of mortality in HIV-infected patients. Rapid and efficient diagnosis of Histoplasma capsulatum is crucial. Cytopathology is available in most hospitals and represents a rapid diagnostic alternative. In this study, we reviewed 12 years of experience to describe [...] Read more.
Disseminated histoplasmosis is a major cause of mortality in HIV-infected patients. Rapid and efficient diagnosis of Histoplasma capsulatum is crucial. Cytopathology is available in most hospitals and represents a rapid diagnostic alternative. In this study, we reviewed 12 years of experience to describe the cytology of histoplasmosis diagnosed by bronchoalveolar lavage (BAL) in relation to patient characteristics. BAL-diagnosed pulmonary histoplasmosis concerned 17 patients (14 HIV+). BAL cellularity ranged from 76,000 to 125,000 cells/mL in HIV patients, and 117,000 to 160,000 cells/mL in non-HIV patients. Macrophages predominated in all HIV patients (from 60% to 88%), lymphocytic infiltrates ranged from 5% to 15%, and neutrophils were very heterogeneous (from 2% to 32%). The number of H. capsulatum at hot spots seemed greater in HIV-infected than in immunocompetent patients (9 to 375 vs. 4 to 10) and were inversely proportional to the CD4 counts. Yeasts were both intracellular and extracellular in 85.7% of the HIV patients. This is the most comprehensive series detailing the cytological aspects of BAL in the diagnosis of H. capsulatum, focusing on the number of yeasts and their clustering pattern. The cytological examination of the Gomori-Grocott-stained BAL allows a reliable diagnosis of histoplasmosis. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Article
New Histoplasma Diagnostic Assays Designed via Whole Genome Comparisons
J. Fungi 2021, 7(7), 544; https://doi.org/10.3390/jof7070544 - 09 Jul 2021
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Abstract
Histoplasmosis is a systemic fungal disease caused by the pathogen Histoplasma spp. that results in significant morbidity and mortality in persons with HIV/AIDS and can also affect immunocompetent individuals. Although some PCR and antigen-detection assays have been developed, conventional diagnosis has largely relied [...] Read more.
Histoplasmosis is a systemic fungal disease caused by the pathogen Histoplasma spp. that results in significant morbidity and mortality in persons with HIV/AIDS and can also affect immunocompetent individuals. Although some PCR and antigen-detection assays have been developed, conventional diagnosis has largely relied on culture, which can take weeks. Our aim was to provide a proof of principle for rationally designing and standardizing PCR assays based on Histoplasma-specific genomic sequences. Via automated comparisons of aligned genome contigs/scaffolds and gene (sub)sequences, we identified protein-coding genes that are present in existing sequences of Histoplasma strains but not in other genera. Two of the genes, PPK and CFP4, were used for designing primer sets for conventional and real-time PCR assays. Both resulted in a 100% analytical specificity in vitro and detected 62/62 H. capsulatum isolates using purified DNA. We also obtained positive detections of 2/2 confirmed H. capsulatum clinical FFPE (formalin-fixed paraffin-embedded) samples using both primer sets. Positive control plasmid 10-fold serial dilutions confirmed the analytical sensitivity of the assays. The findings suggest that these novel primer sets should allow for detection sensitivity and reduce false positive results/cross-reactions. New assays for detecting pathogenic fungi, constructed along these lines, could be simple and affordable to implement. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Article
Long-Term Mortality after Histoplasma Infection in People with HIV
J. Fungi 2021, 7(5), 369; https://doi.org/10.3390/jof7050369 - 08 May 2021
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Abstract
Histoplasmosis is a common opportunistic infection in people with HIV (PWH); however, no study has looked at factors associated with the long-term mortality of histoplasmosis in PWH. We conducted a single-center retrospective study on the long-term mortality of PWH diagnosed with histoplasmosis between [...] Read more.
Histoplasmosis is a common opportunistic infection in people with HIV (PWH); however, no study has looked at factors associated with the long-term mortality of histoplasmosis in PWH. We conducted a single-center retrospective study on the long-term mortality of PWH diagnosed with histoplasmosis between 2002 and 2017. Patients were categorized into three groups based on length of survival after diagnosis: early mortality (death < 90 days), late mortality (death ≥ 90 days), and long-term survivors. Patients diagnosed during or after 2008 were considered part of the modern antiretroviral therapy (ART) era. Insurance type (private vs. public) was a surrogate indicator of socioeconomic status. Out of 54 PWH infected with histoplasmosis, overall mortality was 37%; 14.8% early mortality and 22.2% late mortality. There was no statistically significant difference in survival based on the availability of modern ART (p = 0.60). Insurance status reached statistical significance with 38% of survivors having private insurance versus only 8% having private insurance in the late mortality group (p = 0.05). High mortality persists despite the advent of modern ART, implicating a contribution from social determinants of health, such as private insurance. Larger studies are needed to elucidate the role of these factors in the mortality of PWH. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
Communication
Summary of Guidelines for Managing Histoplasmosis among People Living with HIV
J. Fungi 2021, 7(2), 134; https://doi.org/10.3390/jof7020134 - 12 Feb 2021
Cited by 1 | Viewed by 1738
Abstract
Histoplasmosis is a frequent fungal opportunistic infection in people living with HIV (PLHIV), associated every year to a total of 5% to 15% of AIDS-related deaths among this population. In 2020, the first global guidelines for diagnosing and managing disseminated histoplasmosis among PLHIV [...] Read more.
Histoplasmosis is a frequent fungal opportunistic infection in people living with HIV (PLHIV), associated every year to a total of 5% to 15% of AIDS-related deaths among this population. In 2020, the first global guidelines for diagnosing and managing disseminated histoplasmosis among PLHIV was published. This document recommends (1) detection of circulating Histoplasma antigens as the recommended laboratory assay to diagnose histoplasmosis among PLHIV; (2) the use of liposomal amphotericin for induction therapy in severe or moderately severe disease, followed by a maintenance therapy with itraconazole for 12 months; a shorter maintenance therapy could be considered if the patient is clinically stable and if immune status has improved; (3) antiretroviral therapy initiation as soon as possible among patients with histoplasmosis without involvement of central nervous system; and (4) that for the treatment of co-infection with histoplasmosis and tuberculosis (TB), treatment of TB should be initiated according to the World Health Organization treatment guidelines. Appropriate health education of providers, supportive supervision, and policy guidance for the care of PLHIV are required. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Article
Risk Factors for Mortality among HIV-Infected Patients with Disseminated Histoplasmosis
J. Fungi 2020, 6(4), 326; https://doi.org/10.3390/jof6040326 - 30 Nov 2020
Cited by 3 | Viewed by 691
Abstract
Identifying prognostic factors is important in order to guide the choice of first-line therapy for disseminated histoplasmosis. Our objective was to identify factors associated with death among a cohort of 330 patients compiled over 34 years of clinical practice in French Guiana. Survival [...] Read more.
Identifying prognostic factors is important in order to guide the choice of first-line therapy for disseminated histoplasmosis. Our objective was to identify factors associated with death among a cohort of 330 patients compiled over 34 years of clinical practice in French Guiana. Survival analysis was performed with death as the failure event and date of symptom onset as the origin event. Incidence rates were and Cox proportional hazards models were computed. Overall, 330 HIV-infected patients with disseminated histoplasmosis were included in the analysis, with 126 deaths occurring. One-quarter of all patients died within 6 months of the first symptoms. Patients with dyspnea, renal failure, arterial blood pressure < 90 mmHG, and a WHO performance score > 2 had a greater incidence of death. Bivariate analyses showed that patients with increased LDH, low hemoglobin, low serum protein, low CD4 counts, and low platelets tended to have a greater incidence of death. After adjusting for potential confounders, patients with dyspnea, a WHO performance score > 2, serum protein < 60 g/L, and hemoglobin < 8.9 g/dL had an increased risk of dying. The interaction terms showed that patients treated with liposomal amphotericin B had a marked reduction in death among patients with renal failure; among renal failure patients, the elevation of LDH was associated with a significant risk of death. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Article
Detection of Histoplasma DNA from Tissue Blocks by a Specific and a Broad-Range Real-Time PCR: Tools to Elucidate the Epidemiology of Histoplasmosis
J. Fungi 2020, 6(4), 319; https://doi.org/10.3390/jof6040319 - 27 Nov 2020
Cited by 3 | Viewed by 944
Abstract
Lack of sensitive diagnostic tests impairs the understanding of the epidemiology of histoplasmosis, a disease whose burden is estimated to be largely underrated. Broad-range PCRs have been applied to identify fungal agents from pathology blocks, but sensitivity is variable. In this study, we [...] Read more.
Lack of sensitive diagnostic tests impairs the understanding of the epidemiology of histoplasmosis, a disease whose burden is estimated to be largely underrated. Broad-range PCRs have been applied to identify fungal agents from pathology blocks, but sensitivity is variable. In this study, we compared the results of a specific Histoplasma qPCR (H. qPCR) with the results of a broad-range qPCR (28S qPCR) on formalin-fixed, paraffin-embedded (FFPE) tissue specimens from patients with proven fungal infections (n = 67), histologically suggestive of histoplasmosis (n = 36) and other mycoses (n = 31). The clinical sensitivity for histoplasmosis of the H. qPCR and the 28S qPCR was 94% and 48.5%, respectively. Samples suggestive for other fungal infections were negative with the H. qPCR. The 28S qPCR did not amplify DNA of Histoplasma in FFPE in these samples, but could amplify DNA of Emergomyces (n = 1) and Paracoccidioides (n = 2) in three samples suggestive for histoplasmosis but negative in the H. qPCR. In conclusion, amplification of Histoplasma DNA from FFPE samples is more sensitive with the H. qPCR than with the 28S qPCR. However, the 28S qPCR identified DNA of other fungi in H. qPCR-negative samples presenting like histoplasmosis, suggesting that the combination of both assays may improve the diagnosis. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Review

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Review
Occupational Histoplasmosis: Epidemiology and Prevention Measures
J. Fungi 2021, 7(7), 510; https://doi.org/10.3390/jof7070510 - 26 Jun 2021
Cited by 2 | Viewed by 922
Abstract
In areas where Histoplasma is endemic in the environment, occupations involving activities exposing workers to soil that contains bird or bat droppings may pose a risk for histoplasmosis. Occupational exposures are frequently implicated in histoplasmosis outbreaks. In this paper, we review the literature [...] Read more.
In areas where Histoplasma is endemic in the environment, occupations involving activities exposing workers to soil that contains bird or bat droppings may pose a risk for histoplasmosis. Occupational exposures are frequently implicated in histoplasmosis outbreaks. In this paper, we review the literature on occupationally acquired histoplasmosis. We describe the epidemiology, occupational risk factors, and prevention measures according to the hierarchy of controls. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Review
Histoplasmosis Diagnosed in Europe and Israel: A Case Report and Systematic Review of the Literature from 2005 to 2020
J. Fungi 2021, 7(6), 481; https://doi.org/10.3390/jof7060481 - 14 Jun 2021
Cited by 2 | Viewed by 998
Abstract
Human histoplasmosis is a mycosis caused by two distinct varieties of a dimorphic fungus: Histoplasma capsulatum var. capsulatum and H. capsulatum var. duboisii. In Europe, it is usually imported by migrants and travellers, although there have been some autochthonous cases, especially in [...] Read more.
Human histoplasmosis is a mycosis caused by two distinct varieties of a dimorphic fungus: Histoplasma capsulatum var. capsulatum and H. capsulatum var. duboisii. In Europe, it is usually imported by migrants and travellers, although there have been some autochthonous cases, especially in Italy; however, most European physicians are unfamiliar with its clinical and pathological picture, particularly among immunocompromised patients without HIV infection. This systematic review of all the cases of histoplasmosis reported in Europe and Israel between 2005 and 2020 identified 728 cases diagnosed in 17 European countries and Israel described in 133 articles. The vast majority were imported (mainly from Central and South America), but there were also seven autochthonous cases (six in Europe and one in Israel). The patients were prevalently males (60.4%), and their ages ranged from 2 to 86 years. The time between leaving an endemic region and the diagnosis of histoplasmosis varied from a few weeks to more than 40 years. Progressive disseminated histoplasmosis was the most frequent clinical picture among people living with HIV infection (89.5%) or a different immunocompromising condition (57.1%), but it was also recorded in 6.2% of immunocompetent patients. Twenty-eight cases were caused by Histoplasma duboisii. Immunocompromised patients without HIV infection had the worst outcomes, with a mortality rate of 32%. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Review
Paediatric Histoplasmosis 2000–2019: A Review of 83 Cases
J. Fungi 2021, 7(6), 448; https://doi.org/10.3390/jof7060448 - 04 Jun 2021
Cited by 1 | Viewed by 857
Abstract
Histoplasmosis is an endemic fungal infection that is confined to specific geographical regions. Histoplasma spp. are primary pathogens that cause disease in both immunocompetent and immunocompromised patients, ranging from a single-organ (mostly affecting the lungs) infection to life-threatening disseminated disease. Knowledge about the [...] Read more.
Histoplasmosis is an endemic fungal infection that is confined to specific geographical regions. Histoplasma spp. are primary pathogens that cause disease in both immunocompetent and immunocompromised patients, ranging from a single-organ (mostly affecting the lungs) infection to life-threatening disseminated disease. Knowledge about the clinical epidemiology relies on data from adult populations; little is known about the patient and disease characteristics in the paediatric population. Therefore, a structured review of published cases of paediatric histoplasmosis between 2000 and 2019 was performed. A literature search of PubMed was conducted and the epidemiological and clinical data from 83 cases were analysed. The mean age at presentation was 9.5 ± 5.5 years, and 51% were girls. Two-thirds of the children were immunocompromised. The majority of children presented with disseminated disease. The most frequently observed clinical symptoms were respiratory symptoms, alongside non-specific systemic features, including fever, myalgia, fatigue and weight loss. The mortality rate was 11%. Histoplasmosis affects children of any age. Being immunocompromised is a risk factor for severe and disseminated disease. The lack of specific presenting features leads to underreporting and delay in diagnosis. To improve the recognition and outcome of histoplasmosis in childhood, increased awareness and surveillance systems are warranted. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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Review
Treatment and Prevention of Histoplasmosis in Adults Living with HIV
J. Fungi 2021, 7(6), 429; https://doi.org/10.3390/jof7060429 - 28 May 2021
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Abstract
Histoplasmosis causes life-threatening disseminated infection in adult patients living with untreated HIV. Although disease incidence has declined dramatically in countries with access to antiretroviral therapy, histoplasmosis remains prevalent in many resource-limited regions. A high index of suspicion for histoplasmosis should be maintained in [...] Read more.
Histoplasmosis causes life-threatening disseminated infection in adult patients living with untreated HIV. Although disease incidence has declined dramatically in countries with access to antiretroviral therapy, histoplasmosis remains prevalent in many resource-limited regions. A high index of suspicion for histoplasmosis should be maintained in the setting of a febrile multisystem illness in severely immunosuppressed patients, particularly in persons with hemophagocytic lymphohistiocytosis. Preferred treatment regimens for initial therapy include liposomal amphotericin B for severe disease, or itraconazole for mild to moderate disease. Subsequently, itraconazole maintenance therapy should be administered for at least one year and then discontinued if CD4 count increases to ≥150 cells/µL. Antiretroviral therapy, which improves outcome when administered together with an antifungal agent, should be instituted immediately, as the risk of triggering Immune Reconstitution Syndrome is low. The major risk factor for relapsed infection is nonadherence. Itraconazole prophylaxis reduces risk for histoplasmosis in patients with CD4 counts <100/µL but is not associated with survival benefit and is primarily reserved for use in outbreaks. Although most patients with histoplasmosis have not had recognized high-risk exposures, avoidance of contact with bird or bat guano or inhalation of aerosolized soil in endemic regions may reduce risk. Adherence to effective antiretroviral therapy is the most important strategy for reducing the incidence of life-threatening histoplasmosis. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)

Other

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Case Report
Coronavirus Disease 2019 (COVID-19) in a Patient with Disseminated Histoplasmosis and HIV—A Case Report from Argentina and Literature Review
J. Fungi 2020, 6(4), 275; https://doi.org/10.3390/jof6040275 - 10 Nov 2020
Cited by 24 | Viewed by 1808
Abstract
The disease caused by the new SARS-CoV-2, known as Coronavirus disease 2019 (COVID-19), was first identified in China in December 2019 and rapidly spread around the world. Coinfections with fungal pathogens in patients with COVID-19 add challenges to patient care. We conducted a [...] Read more.
The disease caused by the new SARS-CoV-2, known as Coronavirus disease 2019 (COVID-19), was first identified in China in December 2019 and rapidly spread around the world. Coinfections with fungal pathogens in patients with COVID-19 add challenges to patient care. We conducted a literature review on fungal coinfections in patients with COVID-19. We describe a report of a patient with disseminated histoplasmosis who was likely infected with SARS-CoV-2 and experienced COVID-19 during hospital care in Buenos Aires, Argentina. This patient presented with advanced HIV disease, a well-known factor for disseminated histoplasmosis; on the other hand, we suspected that COVID-19 was acquired during hospitalization but there is not enough evidence to support this hypothesis. Clinical correlation and the use of specific Histoplasma and COVID-19 rapid diagnostics assays were key to the timely diagnosis of both infections, permitting appropriate treatment and patient care. Full article
(This article belongs to the Special Issue Histoplasma and Histoplasmosis 2020)
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