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São Paulo (SP), 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 SP, 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 SP, we generated and analysed virus genomic data and epizootic case data from NHP in SP. We report the occurrence of three spatiotemporally distinct phases of the outbreak in SP prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in SP, mostly sampled from non-human primates 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 SP state at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern SP 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 SP state. Our results shed light on the sylvatic transmission of yellow fever in highly fragmented forested regions in SP state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species. Competing Interest Statement The authors have declared no competing interest.

A major outbreak of yellow fever (YF) occurred in Brazil during 2016-2018. Epizootics in New World nonhuman primates are sentinel events for YF virus circulation. However, genus-specific susceptibilities and suitability for YF surveillance remain poorly understood. We obtained and compared epidemiologic, histopathologic, immunohistochemical, and molecular results from 93 human and 1,752 primate cases submitted during the recent YF outbreak in Brazil (2017), with the support of the Brazilian National YF Surveillance Program. We detected heterogeneous YF-associated profiles among the various genera of primates we analyzed. Alouatta primates were the most reliable sentinel; Sapajus and Callicebus primates had higher viral loads but lower proportional mortality rates. Callithrix primates were the least sensitive, showing lower viral loads, lower proportional mortality rates, and no demonstrable YF virus antigen or extensive lesions in liver, despite detectable viral RNA. These differences in susceptibility, viral load, and mortality rates should be considered in strategic surveillance of epizootics and control measures for YF.

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.

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.

The impact of incident sudden cardiac death (SCD) on the predictive accuracy of prognostic risk scores for patients with chronic heart failure (HF) has rarely been examined. We assessed the relationship between estimated probability of death and modes of death in this population, as well as the predictors of death and survival in prognostic outliers. The MAGGIC 3-year probability of death was estimated in 6,859 participants of the GISSI-HF trial (mean age 67±11 years, 78% men, 91% with ejection fraction <40%, mean follow-up 3.5±1.3 years, observed mortality 28.4%). The incidence of SCD progressively decreased with increased probability of death, and occurred in 52.5% of patients estimated at low-risk (N = 61 with probability <14%) vs. in 23.5% of the high-risk ones (N = 375 with probability >56%, P < .0001). On the contrary, death from worsening HF was significantly more frequent in the latter group (19.7% vs. 46.1%, P < .0001). The overall predictive accuracy of the MAGGIC model improved after excluding deaths from SCD (AUC from 0.731 to 0.760, P = .0034). Among patients estimated at low-risk (N = 61 dead, 743 alive), independent predictors of death were older age, longer history of HF, higher serum uric acid and chronic obstructive pulmonary disease. The only predictor of survival in patients estimated at high-risk (N = 210 alive, 375 dead) was higher systolic blood pressure. The MAGGIC risk score demonstrated its scarce ability to capture SCD, particularly in chronic HF patients estimated at low risk of death. Newer and better prognostic tools in the evolving horizon of HF are needed.

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.