In the matter of the request of Liberty Mutual Fire Insurance Company, a Massachusetts domestic stock insurance company, to redomesticate to the state of Wisconsin

Submitted by Nuzia Santos ([email protected]) on 2018-08-24T16:36:28Z No. of bitstreams: 1 Phosphatidyl Inositol 3 Kinase-Gamma Balances.pdf: 10035595 bytes, checksum: 5a61fb2c618990d4314d36db3868ee2e (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2018-08-24T16:44:27Z (GMT) No. of bitstreams: 1 Phosphatidyl Inositol 3 Kinase-Gamma Balances.pdf: 10035595 bytes, checksum: 5a61fb2c618990d4314d36db3868ee2e (MD5)Made available in DSpace on 2018-08-24T16:44:27Z (GMT). No. of bitstreams: 1 Phosphatidyl Inositol 3 Kinase-Gamma Balances.pdf: 10035595 bytes, checksum: 5a61fb2c618990d4314d36db3868ee2e (MD5) Previous issue date: 2018Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Fisiologia e Biofísica. Laboratório de Imunologia e Mecânica Pulmonar. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brazil / UNIFRANZ. Coordinación Nacional de Investigación. La Paz, Bolivia.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Morfologia. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade de São Paulo. Departamento de Farmacologia. Laboratório de Inflamação e Dor. Universidade de São Paulo. Ribeirão Preto, SP, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Imunologia de Doenças Virais. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Biologia Geral. Belo Horizonte, MG, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de RNA de Interferência Belo Horizonte, MG, Brazil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto René Rachou. Laboratório de Imunologia de Doenças Virais. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Análises Clínicas e Toxicológicas. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Fisiologia e Biofísica. Laboratório de Imunologia e Mecânica Pulmonar. Belo Horizonte, MG, Brazil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Laboratório de Imunofarmacologia. Belo Horizonte, MG, Brazil.Influenza A virus (IAV) infection causes severe pulmonary disease characterized by intense leukocyte infiltration. Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes, involved in cell growth, survival, and migration. Class IB PI3K or phosphatidyl inositol 3 kinase-gamma (PI3Kγ), mainly expressed by leukocytes, is involved in cell migration during inflammation. Here, we investigated the contribution of PI3Kγ for the inflammatory and antiviral responses to IAV. PI3Kγ knockout (KO) mice were highly susceptible to lethality following infection with influenza A/WSN/33 H1N1. In the early time points of infection, infiltration of neutrophils was higher than WT mice whereas type-I and type-III IFN expression and p38 activation were reduced in PI3Kγ KO mice resulting in higher viral loads when compared with WT mice. Blockade of p38 in WT macrophages infected with IAV reduced levels of interferon-stimulated gene 15 protein to those induced in PI3Kγ KO macrophages, suggesting that p38 is downstream of antiviral responses mediated by PI3Kγ. PI3Kγ KO-derived fibroblasts or macrophages showed reduced type-I IFN transcription and altered pro-inflammatory cytokines suggesting a cell autonomous imbalance between inflammatory and antiviral responses. Seven days after IAV infection, there were reduced infiltration of natural killer cells and CD8+ T lymphocytes, increased concentration of inflammatory cytokines in bronchoalveolar fluid, reduced numbers of resolving macrophages, and IL-10 levels in PI3Kγ KO. This imbalanced environment in PI3Kγ KO-infected mice culminated in enhanced lung neutrophil infiltration, reactive oxygen species release, and lung damage that together with the increased viral loads, contributed to higher mortality in PI3Kγ KO mice compared with WT mice. In humans, we tested the genetic association of disease severity in influenza A/H1N1pdm09-infected patients with three potentially functional PIK3CG single-nucleotide polymorphisms (SNPs), rs1129293, rs17847825, and rs2230460. We observed that SNPs rs17847825 and rs2230460 (A and T alleles, respectively) were significantly associated with protection from severe disease using the recessive model in patients infected with influenza A(H1N1)pdm09. Altogether, our results suggest that PI3Kγ is crucial in balancing antiviral and inflammatory responses to IAV infection

Cohort-profile: Household transmission of SARS-CoV-2 in a low-resource community in Rio de Janeiro, Brazil.

PURPOSE: To better understand the household transmission of SARS-COV-2 in a low-resource community in Rio de Janeiro during the COVID-19 pandemic (2020-2022). PARTICIPANTS: This is an open prospective cohort study of children ≤12 years old and their household contacts. During home visits over 24 months, we collected data on sociodemographic characteristics, behavioural data, clinical manifestations of SARS-CoV-2, vaccination status, SARS-CoV-2 (reverse transcription-polymerase chain reaction) RT-PCR and anti-S antibody tests. Among adults, the majority of participants were women (62%). FINDINGS TO DATE: We enrolled 845 families from May 2020 to May 2022. The median number of residents per household was four. The median household density, defined as the number of persons per room, was 0.95. The risk of SARS-CoV-2 occurrence was higher in households with a high number of persons per room. Children were not the principal source of SARS-CoV-2 infections in their households during the first wave of the pandemic. FUTURE PLANS: Future studies will investigate cellular and humoral immune responses to locally circulating SARS-CoV-2 variants, which is relevant for the design of vaccines, antivirals and monoclonal antibodies. We will also engage in outreach to encourage vaccination as a means of limiting the transmission of novel SARS-CoV-2 variants and other emerging pathogens

H1N1pdm Influenza Infection in Hospitalized Cancer Patients: Clinical Evolution and Viral Analysis

BACKGROUND: The novel influenza A pandemic virus (H1N1pdm) caused considerable morbidity and mortality worldwide in 2009. The aim of the present study was to evaluate the clinical course, duration of viral shedding, H1N1pdm evolution and emergence of antiviral resistance in hospitalized cancer patients with severe H1N1pdm infections during the winter of 2009 in Brazil. METHODS: We performed a prospective single-center cohort study in a cancer center in Rio de Janeiro, Brazil. Hospitalized patients with cancer and a confirmed diagnosis of influenza A H1N1pdm were evaluated. The main outcome measures in this study were in-hospital mortality, duration of viral shedding, viral persistence and both functional and molecular analyses of H1N1pdm susceptibility to oseltamivir. RESULTS: A total of 44 hospitalized patients with suspected influenza-like illness were screened. A total of 24 had diagnosed H1N1pdm infections. The overall hospital mortality in our cohort was 21%. Thirteen (54%) patients required intensive care. The median age of the studied cohort was 14.5 years (3-69 years). Eighteen (75%) patients had received chemotherapy in the previous month, and 14 were neutropenic at the onset of influenza. A total of 10 patients were evaluated for their duration of viral shedding, and 5 (50%) displayed prolonged viral shedding (median 23, range=11-63 days); however, this was not associated with the emergence of a resistant H1N1pdm virus. Viral evolution was observed in sequentially collected samples. CONCLUSIONS: Prolonged influenza A H1N1pdm shedding was observed in cancer patients. However, oseltamivir resistance was not detected. Taken together, our data suggest that severely ill cancer patients may constitute a pandemic virus reservoir with major implications for viral propagation

A Research and Development (R&D) roadmap for influenza vaccines: Looking toward the future

Improved influenza vaccines are urgently needed to reduce the burden of seasonal influenza and to ensure a rapid and effective public-health response to future influenza pandemics. The Influenza Vaccines Research and Development (R&D) Roadmap (IVR) was created, through an extensive international stakeholder engagement process, to promote influenza vaccine R&D. The roadmap covers a 10-year timeframe and is organized into six sections: virology; immunology; vaccinology for seasonal influenza vaccines; vaccinology for universal influenza vaccines; animal and human influenza virus infection models; and policy, finance, and regulation. Each section identifies barriers, gaps, strategic goals, milestones, and additional R&D priorities germane to that area. The roadmap includes 113 specific R&D milestones, 37 of which have been designated high priority by the IVR expert taskforce. This report summarizes the major issues and priority areas of research outlined in the IVR. By identifying the key issues and steps to address them, the roadmap not only encourages research aimed at new solutions, but also provides guidance on the use of innovative tools to drive breakthroughs in influenza vaccine R&D.publishedVersio

H1N1pdm09 Adjuvanted Vaccination in HIV-Infected Adults: A Randomized Trial of Two Single versus Two Double Doses

Since human immunodeficiency virus (HIV)-infected individuals are at increased risk of severe disease from pandemic influenza A (H1N1pdm09), vaccination was recommended as a prevention strategy. The aim of the present study was to evaluate the safety, immunogenicity and persistence of the immune response after vaccination against pandemic influenza A (H1N1pdm09) with an adjuvanted vaccine in human immunodeficiency virus (HIV)-infected adults using two single and two double doses.Open label, randomized trial to evaluate the immune response following H1N1pdm09 vaccination in HIV-infected participants compared to HIV-negative controls (NCT01155037). HIV-infected participants were randomized to receive 2 single (3.75 µg hemagglutinin) or 2 double (7.5 µg hemagglutinin) doses of the vaccine, 21 days apart. Controls received one dose of the vaccine. The primary endpoint was seroconversion as measured by hemagglutination inhibition assay. Two hundred fifty six HIV-infected participants (129 and 127 randomized to single and double doses, respectively) and 71 HIV-negative controls were enrolled. Among HIV-infected participants, seroconversion increased from 46.7% and 51.7% after the first dose to 77.2% and 83.8% after the second dose of the vaccine using single and double doses, respectively. Participants aged >40 years showed higher seroconversion compared to younger participants. Seroconversion among HIV-infected women and those with nadir CD4<200 cells/mm(3) was significantly higher with double doses. Persistence of protective antibodies six months after vaccination was achieved by 80% and 89.9% of the HIV-infected participants who received single and double doses, respectively.Our results support the recommendation of two double doses of adjuvanted H1N1pdm09 vaccine for HIV-infected individuals, particularly women, and those aged >40 years or with nadir CD4<200 cells/mm(3), to achieve antibody levels that are both higher and more sustained.ClinicalTrials.gov NCT01155037

Fiocruz in Antarctica – health and environmental surveillance facing the challenges of the 21st century

Abstract FioAntar, FIOCRUZ’s research project in Antarctica, is based on the One Health approach. FioAntar aims to generate relevant information that will help reduce the risk of future pandemics and improve the search for chemical compounds and new biological molecules. After four expeditions to Antarctica under the scope of PROANTAR, Fiocruz has identified Influenza H11N2 virus in environmental fecal samples, as well as Histoplasma capsulatum and Bacillus cereus in soil samples. In addition, in a prospective virome analysis from different lakes in the South Shetland Islands, six viral orders were described, supporting future research related to the biodiversity and viral ecology in this extreme ecosystem. Our findings of environmental pathogens of public health importance are a warning about the urgency of establishing a surveillance agenda on zoonoses in Antarctica due to the imminent risks that ongoing environmental and climate changes impose on human health across the planet. FioAntar strives to establish a comprehensive surveillance program across Antarctica, monitoring circulation of pathogens with the potential to transcend continent boundaries, thereby mitigating potential spread. For Fiocruz, Antarctica signifies a new frontier, teeming with opportunities to explore novel techniques, refine established methodologies, and cultivate invaluable knowledge

Long COVID-19 syndrome associated with Omicron XBB.1.5 infection: a case report.

BACKGROUND: There is interest in lingering non-specific symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, referred to as Long coronavirus disease 2019 (Long COVID-19). It remains unknown whether the risk of Long COVID-19 is associated with pre-existing comorbidities or initial COVID-19 severity, including infections due to new Omicron lineages which predominated in 2023. OBJECTIVES: The aim of this case report was to characterize the clinical features of acute XBB.1.5 infection followed by Long COVID-19. METHODS: We followed a 73-year old female resident of Rio de Janeiro with laboratory-confirmed SARS-CoV-2 during acute infection and subsequent months. The SARS-CoV-2 lineage was determined by genome sequencing. FINDINGS: The participant denied comorbidities and had completed a two-dose vaccination schedule followed by two booster doses eight months prior to SARS-CoV-2 infection. Primary infection by viral lineage XBB.1.5. was clinically mild, but the participant subsequently reported persistent fatigue. MAIN CONCLUSIONS: This case demonstrates that Long COVID-19 may develop even after mild disease due to SARS-CoV-2 in fully vaccinated and boosted individuals without comorbidities. Continued monitoring of new SARS-CoV-2 lineages and associated clinical outcomes is warranted. Measures to prevent infection should continue to be implemented including development of new vaccines and antivirals effective against novel variants