Genomic Surveillance of Yellow Fever Virus Epizootic in São Paulo, Brazil, 2016 – 2018

São Paulo, a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in São Paulo, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spillover to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo, we generated and analysed virus genomic data and epizootic case data from NHPs in São Paulo. We report the occurrence of three spatiotemporally distinct phases of the outbreak in São Paulo prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in São Paulo, mostly sampled from NHPs between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in São Paulo at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern São Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of São Paulo state. Our results shed light on the sylvatic transmission of YFV in highly fragmented forested regions in São Paulo state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species

Genomic Surveillance of Yellow Fever Virus Epizootic in São Paulo, Brazil, 2016 – 2018

São Paulo, a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in São Paulo, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spillover to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo, we generated and analysed virus genomic data and epizootic case data from NHPs in São Paulo. We report the occurrence of three spatiotemporally distinct phases of the outbreak in São Paulo prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in São Paulo, mostly sampled from NHPs between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in São Paulo at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern São Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of São Paulo state. Our results shed light on the sylvatic transmission of YFV in highly fragmented forested regions in São Paulo state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species.ISSN:1553-7374ISSN:1553-736

Propranolol for familial cerebral cavernous malformation (Treat_CCM): Study protocol for a randomized controlled pilot trial

Background: Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. Methods: Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40-80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). Discussion: Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial. Trial registration: ClinicalTrails.gov, NCT03589014. Retrospectively registered on 17 July 2018

Zika virus in the Americas: early epidemiological and genetic findings

Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas

Zika virus in the Americas: early epidemiological and genetic findings

Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas

Zika virus in the Americas: Early epidemiological and genetic findings

Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015 and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. Using next generation sequencing we generated seven Brazilian ZIKV genomes, sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, estimated to have occurred between May-Dec 2013, more than 12 months prior to the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV endemic areas, and with reported outbreaks in Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology in the Americas of this emerging virus

Zika virus in the Americas: early epidemiological and genetic findings

International audienceBrazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ̃30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015 and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. Using next generation sequencing we generated seven Brazilian ZIKV genomes, sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, estimated to have occurred between May-Dec 2013, more than 12 months prior to the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV endemic areas, and with reported outbreaks in Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology in the Americas of this emerging virus

Prognostic impact of diabetes and prediabetes on survival outcomes in patients with chronic heart failure: a post-hoc analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial

Background-The independent prognostic impact of diabetes mellitus (DM) and prediabetes mellitus (pre-DM) on survival outcomes in patients with chronic heart failure has been investigated in observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre-DM on survival outcomes in the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial.Methods and Results-We assessed the risk of all-cause death and the composite of all-cause death or cardiovascular hospitalization over a median follow-up period of 3.9 years among the 6935 chronic heart failure participants of the GISSI-HF trial, who were stratified by presence of DM (n= 2852), pre-DM (n= 2013), and non-DM (n= 2070) at baseline. Compared with non-DM patients, those with DM had remarkably higher incidence rates of all-cause death (34.5% versus 24.6%) and the composite end point (63.6% versus 54.7%). Conversely, both event rates were similar between non-DM patients and those with pre-DM. Cox regression analysis showed that DM, but not pre-DM, was associated with an increased risk of all-cause death (adjusted hazard ratio, 1.43; 95% CI, 1.28-1.60) and of the composite end point (adjusted hazard ratio, 1.23; 95% CI, 1.13-1.32), independently of established risk factors. In the DM subgroup, higher hemoglobin A1c was also independently associated with increased risk of both study outcomes (all-cause death: adjusted hazard ratio, 1.21; 95% CI, 1.02-1.43; and composite end point: adjusted hazard ratio, 1.14; 95% CI, 1.01-1.29, respectively).Conclusions-Presence of DM was independently associated with poor long-term survival outcomes in patients with chronic heart failure

Zika virus in the Americas: Early epidemiological and genetic findings

Submitted by sandra infurna ([email protected]) on 2016-06-21T16:53:42Z No. of bitstreams: 1 gonzalo2_bello_etal_IOC_2016.pdf: 1066180 bytes, checksum: d43c1cf1b828de79e634ed276cc62178 (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-06-21T17:27:43Z (GMT) No. of bitstreams: 1 gonzalo2_bello_etal_IOC_2016.pdf: 1066180 bytes, checksum: d43c1cf1b828de79e634ed276cc62178 (MD5)Made available in DSpace on 2016-06-21T17:27:43Z (GMT). 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No. of bitstreams: 3 license.txt: 2991 bytes, checksum: 5a560609d32a3863062d77ff32785d58 (MD5) gonzalo2_bello_etal_IOC_2016.pdf: 1066180 bytes, checksum: d43c1cf1b828de79e634ed276cc62178 (MD5) gonzalo2_bello_etal_IOC_2016.pdf.txt: 51037 bytes, checksum: bebf604bcb5623ddff92fec2bebc02a5 (MD5) Previous issue date: 2016Ministério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, Brasil / University of Oxford. Department of Zoology. Oxford, UK.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.University of Oxford. Department of Zoology. Oxford, UK.Universidade de São Paulo. Instituto Adolfo Lutz. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto Adolfo Lutz. São Paulo, SP, Brasil.University of Oxford. Department of Zoology. Oxford, UK.University of Oxford. Department of Zoology. Oxford, UK.University of Oxford. Department of Zoology. Oxford, UK.University of Oxford. Wellcome Trust Centre for Human Genetics. Oxford, UK.University of Oxford. Wellcome Trust Centre for Human Genetics. Oxford, UK.Universidade de São Paulo. Instituto Adolfo Lutz. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto Adolfo Lutz. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto Adolfo Lutz. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto Adolfo Lutz. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto Adolfo Lutz. São Paulo, SP, Brasil.Universidade de São Paulo. Instituto Adolfo Lutz. São Paulo, SP, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.University of Oxford. Department of Zoology. Oxford, UK / Metabiota. San Francisco, CA 94104, USA.University of Oxford. Department of Zoology. Oxford, UK.University of Oxford. Department of Zoology. Oxford, UK.Fundação Oswaldo Cruz. Salvador, BA, Brasil.Universidade Estadual de Feira de Santana, Feira de Santana. Departamento de Saúde. Centro de Pós-Graduação em Saúde Coletiva. Feira de Santana, BA, Brasil.Fundação Oswaldo Cruz. Salvador, BA, Brasil.University of Washington. Institute for Health Metrics and Evaluation,. Seattle, WA, USA / University of Oxford. Wellcome Trust Centre for Human Genetics. Oxford, UK.Ministério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, Brasil.Ministério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, BrasilMinistério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, BrasilMinistério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, BrasilMinistério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, BrasilMinistério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, BrasilMinistério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, BrasilMinistério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, BrasilMinistério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de AIDS e Imunologia Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de AIDS e Imunologia Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de AIDS e Imunologia Molecular. Rio de Janeiro, RJ, Brasil.Li Ka Shing Knowledge Institute. St. Michael’s Hospital. Toronto, Canada / University of Toronto. Department of Medicine. Division of Infectious Diseases. Toronto, Canada.University of Toronto.Dalla Lana School of Public Health. Toronto, Canada;Brasil. Ministério da Saúde. Brasília, DF, Brasil.Brasil. Ministério da Saúde. Brasília, DF, Brasil.University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA.University of Oxford. Department of Zoology. Oxford, UK / Metabiota. San Francisco, CA 94104, USA.Ministério da Saúde. Instituto Evandro Chagas, Centro de Inovação tecnológica. Ananindeua, PA, Brasil / University of Texas Medical Branch. Department of Pathology. Galveston, TX, USA.Ministério da Saúde. Instituto Evandro Chagas. Departamento de Arbovirologia e Febres Hemorrágicas. Ananindeua, PA, Brasil.Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015 and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. Using next generation sequencing we generated seven Brazilian ZIKV genomes, sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, estimated to have occurred between May-Dec 2013, more than 12 months prior to the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV endemic areas, and with reported outbreaks in Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology in the Americas of this emerging virus