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      High prevalence and mortality due to Histoplasma capsulatum in the Brazilian Amazon: An autopsy study

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          Abstract

          Background

          Histoplasmosis is acquired by inhalation of spores of the dimorphic fungus Histoplasma spp. Although this pathogen is distributed worldwide, it is more prevalent in the Americas. However, the real burden of histoplasmosis remains undefined in many endemic regions.

          Methodology

          We conducted a series of 61 autopsies to individuals who died in a hospital in the Brazilian Amazon focused on infectious diseases. We performed a detailed histological and microbiological evaluation with genetic characterization of Histoplasma strains with the aim to evaluate the contribution of histoplasmosis to morbidity and mortality. Additionally, we assessed the clinicopathological correlation.

          Principal findings

          Evidence of Histoplasma infection was detected in 21 patients (34%). Eight cases were disseminated infections, all of them occurred in HIV-positive patients. Six cases were localized histoplasmosis, limited to the lungs. In seven patients Histoplasma DNA was detected by PCR in patients with no histological lesions. Histoplasma infection was detected in 38% of HIV-positive patients and was a major contributor to death in 22% of them. Lungs, liver and spleen were affected in all cases of disseminated histoplasmosis. Phylogenetic analysis of the strains suggested a high diversity of Histoplasma species circulating in the Brazilian Amazon. Histoplasmosis was clinically missed in 75% of the disseminated infections.

          Conclusions

          The high incidence of histoplasmosis, the low index of clinical suspicion, and the severity of the disseminated disease highlight the need of proactively implementing sensitive routine screening methods for this pathogen in endemic areas. Antifungal prophylaxis against Histoplasma should be encouraged in the severely immunocompromised HIV patients in these areas. In conclusion, substantial mortality is associated with disseminated histoplasmosis among HIV-positive patients in the Brazilian Amazon.

          Author summary

          Histoplasmosis is a fungal infection caused by inhalation of spores of the fungus Histoplasma spp. It occurs in specific endemic areas, such as areas of USA, Africa and Latin America. However, the real burden of histoplasmosis remains unknown in many endemic regions. Clinically, histoplasmosis is frequently misdiagnosed as tuberculosis. The current study was carried out to explore the frequency and characteristics of Histoplasma infection in a series of autopsies conducted in the Brazilian Amazon. We found evidence of Histoplasma infection in one-third of the deceased patients. A significant proportion of the cases were disseminated infections, with extensive involvement and severe damage of most organs. All these disseminated infections occurred in HIV-positive patients. Strikingly, histoplasmosis was clinically missed in more than two-thirds of these patients and had an extremely high mortality. In conclusion, the high frequency and mortality of histoplasmosis, together with the frequent misdiagnosis of the disease, highlight the need of implementation of sensitive screening methods for Histoplasma in HIV patients in endemic areas. Additionally, antifungal prophylaxis against Histoplasma should be encouraged in the severely immunocompromised HIV patients in these areas.

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          Most cited references44

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          IQ-TREE: A Fast and Effective Stochastic Algorithm for Estimating Maximum-Likelihood Phylogenies

          Large phylogenomics data sets require fast tree inference methods, especially for maximum-likelihood (ML) phylogenies. Fast programs exist, but due to inherent heuristics to find optimal trees, it is not clear whether the best tree is found. Thus, there is need for additional approaches that employ different search strategies to find ML trees and that are at the same time as fast as currently available ML programs. We show that a combination of hill-climbing approaches and a stochastic perturbation method can be time-efficiently implemented. If we allow the same CPU time as RAxML and PhyML, then our software IQ-TREE found higher likelihoods between 62.2% and 87.1% of the studied alignments, thus efficiently exploring the tree-space. If we use the IQ-TREE stopping rule, RAxML and PhyML are faster in 75.7% and 47.1% of the DNA alignments and 42.2% and 100% of the protein alignments, respectively. However, the range of obtaining higher likelihoods with IQ-TREE improves to 73.3-97.1%.
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            ModelFinder: Fast Model Selection for Accurate Phylogenetic Estimates

            Model-based molecular phylogenetics plays an important role in comparisons of genomic data, and model selection is a key step in all such analyses. We present ModelFinder, a fast model-selection method that greatly improves the accuracy of phylogenetic estimates. The improvement is achieved by incorporating a model of rate-heterogeneity across sites not previously considered in this context, and by allowing concurrent searches of model-space and tree-space.
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              Occurrence of the potent mutagens 2- nitrobenzanthrone and 3-nitrobenzanthrone in fine airborne particles

              Polycyclic aromatic compounds (PACs) are known due to their mutagenic activity. Among them, 2-nitrobenzanthrone (2-NBA) and 3-nitrobenzanthrone (3-NBA) are considered as two of the most potent mutagens found in atmospheric particles. In the present study 2-NBA, 3-NBA and selected PAHs and Nitro-PAHs were determined in fine particle samples (PM 2.5) collected in a bus station and an outdoor site. The fuel used by buses was a diesel-biodiesel (96:4) blend and light-duty vehicles run with any ethanol-to-gasoline proportion. The concentrations of 2-NBA and 3-NBA were, on average, under 14.8 µg g−1 and 4.39 µg g−1, respectively. In order to access the main sources and formation routes of these compounds, we performed ternary correlations and multivariate statistical analyses. The main sources for the studied compounds in the bus station were diesel/biodiesel exhaust followed by floor resuspension. In the coastal site, vehicular emission, photochemical formation and wood combustion were the main sources for 2-NBA and 3-NBA as well as the other PACs. Incremental lifetime cancer risk (ILCR) were calculated for both places, which presented low values, showing low cancer risk incidence although the ILCR values for the bus station were around 2.5 times higher than the ILCR from the coastal site.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: SoftwareRole: VisualizationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                5 April 2021
                April 2021
                : 15
                : 4
                : e0009286
                Affiliations
                [1 ] ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
                [2 ] Department of Pathology, Hospital Clinic of Barcelona, Universitat de Barcelona, Barcelona, Spain
                [3 ] Department of Microbiology, Hospital Clinic of Barcelona, Universitat de Barcelona, Barcelona, Spain
                [4 ] Universidade do Estado do Amazonas, Manaus, Brazil
                [5 ] Fundação de Medicina Tropical Doutor Heitor Viera Dourado, Manaus, Brazil
                [6 ] Fundação Centro de Controle de Oncologia do Amazonas, Manaus, Brazil
                [7 ] Instituto de Pesquisas Leônidas & Maria Deane, Fiocruz, Manaus, Brazil
                [8 ] The Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, United States of America
                [9 ] Núcleo de Medicina Tropical, Faculdade de Medicina, Universidade de Brasília, Brasilia, Brazil
                [10 ] Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
                [11 ] ICREA, Catalan Institution for Research and Advanced Studies, Barcelona, Spain
                [12 ] Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Sant Joan de Déu (University of Barcelona), Barcelona, Spain
                [13 ] Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
                National Institute for Communicable Diseases, Johannesburg, South Africa, SOUTH AFRICA
                Author notes

                The authors have declared that no competing interests exist.

                ‡ JO and MJM also contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-5030-3526
                https://orcid.org/0000-0001-9519-6082
                https://orcid.org/0000-0001-9409-7322
                https://orcid.org/0000-0002-9657-939X
                https://orcid.org/0000-0001-7849-6112
                https://orcid.org/0000-0003-3374-9985
                https://orcid.org/0000-0003-1763-3464
                https://orcid.org/0000-0002-9284-8601
                https://orcid.org/0000-0001-6675-3425
                https://orcid.org/0000-0002-2943-3550
                https://orcid.org/0000-0002-8589-5936
                https://orcid.org/0000-0001-9992-6951
                https://orcid.org/0000-0002-1863-6379
                https://orcid.org/0000-0002-9970-1880
                https://orcid.org/0000-0002-8025-3926
                https://orcid.org/0000-0003-0875-7596
                https://orcid.org/0000-0002-4820-7954
                https://orcid.org/0000-0002-0682-1075
                Article
                PNTD-D-20-01964
                10.1371/journal.pntd.0009286
                8049479
                33819269
                22dd06de-fd80-486d-a162-7b9886bf7af9
                © 2021 Rakislova et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 November 2020
                : 2 March 2021
                Page count
                Figures: 3, Tables: 3, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: OPP1067522
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: OPP1128001
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: PI12/00757
                Award Recipient :
                Funded by: Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) of Generalitat de Catalunya
                Award ID: 2017SGR794
                Award Recipient :
                This work was supported by the Bill & Melinda Gates Foundation [grant numbers OPP1067522 to QB, OPP1128001 to JO], and by the Instituto de Salud Carlos III [grant number PI12/00757 to CM], and the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) of Generalitat de Catalunya [grant number 2017SGR794 to M.J.M.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                2021-04-15
                All relevant data are within the paper. Additional data is available under request, according to the Consortium agreement signed among the CaDMIA project partnership. Data use and transfer is monitored by ISGlobal's Data Management and Biostatistics Unit (contact e-mail: ubioesdm@ 123456isglobal.org ).

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