Persistent high mortality rates for Diabetes Mellitus and Hypertension after excluding deaths associated with COVID-19 in Brazil, 2020-2022.

INTRODUCTION: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) posed a significant public health challenge globally, with Brazil being no exception. Excess mortality during this period reached alarming levels. Cardiovascular diseases (CVD), Systemic Hypertension (HTN), and Diabetes Mellitus (DM) were associated with increased mortality. However, the specific impact of DM and HTN on mortality during the pandemic remains poorly understood. METHODS: This study analyzed mortality data from Brazil's mortality system, covering the period from 2015 to 2022. Data included all causes of death as listed on death certificates, categorized by International Classification of Diseases 10th edition (ICD-10) codes. Population data were obtained from the Brazilian Census. Mortality ratios (MRs) were calculated by comparing death rates in 2020, 2021, and 2022 to the average rates from 2015 to 2019. Adjusted MRs were calculated using Poisson models. RESULTS: Between 2015 and 2022, Brazil recorded a total of 11,423,288 deaths. Death rates remained relatively stable until 2019 but experienced a sharp increase in 2020 and 2021. In 2022, although a decrease was observed, it did not return to pre-pandemic levels. This trend persisted even when analyzing records mentioning DM, HTN, or CVD. Excluding death certificates mentioning COVID-19 codes, the trends still showed increases from 2020 through 2022, though less pronounced. CONCLUSION: This study highlights the persistent high mortality rates for DM and HTN in Brazil during the years 2020-2022, even after excluding deaths associated with COVID-19. These findings emphasize the need for continued attention to managing and preventing DM and HTN as part of public health strategies, both during and beyond the COVID-19 pandemic. There are complex interactions between these conditions and the pandemic's impact on mortality rates.

The effectiveness of COVID-19 vaccines against severe cases and deaths in Brazil from 2021 to 2022: a registry-based study.

Background: Brazil started the COVID-19 mass vaccination in January 2021 with CoronaVac and ChAdOx1, followed by BNT162b2 and Ad26.COV2.S vaccines. By the end of 2021, more than 317 million vaccine doses were administered in the adult population. This study aimed at estimating the effectiveness of the primary series of COVID-19 vaccination and booster shots in protecting against severe cases and deaths in Brazil during the first year of vaccination. Methods: A cohort dataset of over 158 million vaccination and severe cases records linked from official national registries was analyzed via a mixed-effects Poisson model, adjusted for age, state of residence, time after immunization, and calendar time to estimate the absolute vaccine effectiveness of the primary series of vaccination and the relative effectiveness of the booster. The method permitted analysis of effectiveness against hospitalizations and deaths, including in the periods of variant dominance. Findings: Vaccine effectiveness against severe cases and deaths remained over 25% and 50%, respectively, after 19 weeks from primary vaccination of BNT162b2, ChAdOx1, or CoronaVac vaccines. The boosters conferred greater protection than the primary series of vaccination, with heterologous boosters providing marginally greater protection than homologous. The effectiveness against hospitalization during the Omicron dominance in the 60+ years old population started at 61.7% (95% CI, 26.1-86.2) for ChAdOx1, 95.6% (95% CI, 82.4-99.9) for CoronaVac, and 72.3% (95% CI, 51.4-87.4) for the BNT162b2 vaccine. Interpretation: This study provides real-world evidence of the effectiveness of COVID-19 vaccination in Brazil, including during the Omicron wave, demonstrating protection even after waning effectiveness. Comparisons of the effectiveness among different vaccines require caution due to potential bias effects related to age groups, periods in the pandemic, and eventual behavioural changes. Funding: Fundação Oswaldo Cruz (FIOCRUZ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Pan American Health Organization (PAHO), Departamento de Ciência e Tecnologia da Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde do Ministério da Saúde do Brasil (DECIT/SCTIE/MS).

On the normalized power prior.

The power prior is a popular tool for constructing informative prior distributions based on historical data. The method consists of raising the likelihood to a discounting factor in order to control the amount of information borrowed from the historical data. However, one often wishes to assign this discounting factor a prior distribution and estimate it jointly with the parameters, which in turn necessitates the computation of a normalizing constant. In this article, we are concerned with how to approximately sample from joint posterior of the parameters and the discounting factor. We first show a few important properties of the normalizing constant and then use these results to motivate a bisection-type algorithm for computing it on a fixed budget of evaluations. We give a large array of illustrations and discuss cases where the normalizing constant is known in closed-form and where it is not. We show that the proposed method produces approximate posteriors that are very close to the exact distributions and also produces posteriors that cover the data-generating parameters with higher probability in the intractable case. Our results suggest that the proposed method is an accurate and easy to implement technique to include this normalization, being applicable to a large class of models. They also reinforce the notion that proper inclusion of the normalizing constant is crucial to the drawing of correct inferences and appropriate quantification of uncertainty.

Identification of priority groups for COVID-19 vaccination in Brazil. / Identificação de grupos prioritários para a vacinação contra COVID-19 no Brasil.

In a context of community transmission and shortage of vaccines, COVID-19 vaccination should focus on directly reducing the morbidity and mortality caused by the disease. It was thus essential to define priority groups for vaccination by the Brazilian National Immunization Program (PNI in Portuguese), based on the risk of hospitalization and death from the disease. We calculated overrisk according to sex, age group, and comorbidities using hospitalization and death records from severe acute respiratory illness with confirmation of COVID-19 (SARI-COVID) in all of Brazil in the first 6 months of the epidemic. Higher overrisk was associated with male sex (hospitalization = 1.1 and death = 1.2), age over 45 years for hospitalization (OvRag ranging from 1.1 to 8.5), and age over 55 year for death (OvRag ranging from 1.5 to 18.3). In the groups with comorbidities, chronic kidney disease, diabetes mellitus, cardiovascular disease, and chronic lung disease were associated with overrisk, while there was no such evidence for asthma. Chronic kidney disease or diabetes and age over 60 showed an even stronger association, reaching overrisk of death 14 and 10 times greater than in the general population, respectively. For all the comorbidities, there was higher overrisk at older ages, with a downward gradient in the oldest age groups. This pattern was reversed when examining overrisk in the general population, for both hospitalization and death. The current study provided evidence of overrisk of hospitalization and death from SARI-COVID, assisting the definition of priority groups for COVID-19 vaccination.

Em um contexto de transmissão comunitária e escassez de vacinas, a vacinação contra a COVID-19 deve focar na redução direta da morbidade e da mortalidade causadas pela doença. Portanto, é fundamental a definição de grupos prioritários para a vacinação pelo Programa Nacional de Imunizações (PNI), baseada no risco de hospitalização e óbito pela doença. Para tal, calculamos o sobrerrisco por sexo, faixa etária e comorbidades por meio dos registros de hospitalização e óbito por síndrome respiratória aguda grave com confirmação de COVID-19 (SRAG-COVID) em todo o Brasil nos primeiros seis meses de epidemia. Apresentaram maior sobrerrisco pessoas do sexo masculino (hospitalização = 1,1 e óbito = 1,2), pessoas acima de 45 anos para hospitalização (SRfe variando de 1,1 a 8,5) e pessoas acima de 55 anos para óbitos (SRfe variando de 1,5 a 18,3). Nos grupos de comorbidades, doença renal crônica, diabetes mellitus, doença cardiovascular e pneumopatia crônica conferiram sobrerrisco, enquanto para asma não houve evidência. Ter doença renal crônica ou diabetes mellitus e 60 anos ou mais mostrou-se um fator ainda mais forte, alcançando sobrerrisco de óbito 14 e 10 vezes maior do que na população geral, respectivamente. Para todas as comorbidades, houve um sobrerrisco mais alto em idades maiores, com um gradiente de diminuição em faixas mais altas. Esse padrão se inverteu quando consideramos o sobrerrisco em relação à população geral, tanto para hospitalização quanto para óbito. O presente estudo forneceu evidências a respeito do sobrerrisco de hospitalização e óbito por SRAG-COVID, auxiliando na definição de grupos prioritários para a vacinação contra a COVID-19.

En un contexto de transmisión comunitaria y escasez de vacunas, la vacunación contra la COVID-19 debe enfocarse en la reducción directa de la morbilidad y de la mortalidad causadas por la enfermedad. Por lo tanto, es fundamental la definición de grupos prioritarios para la vacunación por el Programa Nacional de Inmunizaciones (PNI), basada en el riesgo de hospitalización y óbito por la enfermedad. Para tal fin, calculamos el sobrerriesgo por sexo, franja de edad y comorbilidades mediante los registros de hospitalización y óbito por síndrome respiratorio agudo grave con confirmación de COVID-19 (SRAG-COVID) en todo Brasil, durante los primeros seis meses de epidemia. Presentaron mayor sobrerriesgo personas del sexo masculino (hospitalización = 1,1 y óbito = 1,2), personas por encima de 45 años para hospitalización (SRfe variando de 1,1 a 8,5) y personas por encima de 55 años para óbitos (SRfe variando de 1,5 a 18,3). En los grupos de comorbilidades, enfermedad renal crónica, diabetes mellitus, enfermedad cardiovascular y neumopatía crónica ofrecieron sobrerriesgo, mientras que para el asma no hubo evidencia. Sufrir una enfermedad renal crónica o diabetes mellitus y tener 60 años o más mostró un factor todavía más fuerte, alcanzando sobrerriesgo de enfermedad 14 y 10 veces mayor que en la población general, respectivamente. Para todas las comorbilidades, hubo un sobrerriesgo más alto en edades mayores, con un gradiente de disminución en franjas más altas. Este patrón se invirtió cuando consideramos el sobrerriesgo en relación con la población general, tanto para hospitalización como para óbito. El presente estudio proporcionó evidencias respecto al sobrerriesgo de hospitalización y óbito por SRAG-COVID, ayudando en la definición de grupos prioritarios para la vacunación contra la COVID-19.

Identificação de grupos prioritários para a vacinação contra COVID-19 no Brasil / Identificación de grupos prioritarios para la vacunación contra la COVID-19 en Brasil / Identification of priority groups for COVID-19 vaccination in Brazil

Em um contexto de transmissão comunitária e escassez de vacinas, a vacinação contra a COVID-19 deve focar na redução direta da morbidade e da mortalidade causadas pela doença. Portanto, é fundamental a definição de grupos prioritários para a vacinação pelo Programa Nacional de Imunizações (PNI), baseada no risco de hospitalização e óbito pela doença. Para tal, calculamos o sobrerrisco por sexo, faixa etária e comorbidades por meio dos registros de hospitalização e óbito por síndrome respiratória aguda grave com confirmação de COVID-19 (SRAG-COVID) em todo o Brasil nos primeiros seis meses de epidemia. Apresentaram maior sobrerrisco pessoas do sexo masculino (hospitalização = 1,1 e óbito = 1,2), pessoas acima de 45 anos para hospitalização (SRfe variando de 1,1 a 8,5) e pessoas acima de 55 anos para óbitos (SRfe variando de 1,5 a 18,3). Nos grupos de comorbidades, doença renal crônica, diabetes mellitus, doença cardiovascular e pneumopatia crônica conferiram sobrerrisco, enquanto para asma não houve evidência. Ter doença renal crônica ou diabetes mellitus e 60 anos ou mais mostrou-se um fator ainda mais forte, alcançando sobrerrisco de óbito 14 e 10 vezes maior do que na população geral, respectivamente. Para todas as comorbidades, houve um sobrerrisco mais alto em idades maiores, com um gradiente de diminuição em faixas mais altas. Esse padrão se inverteu quando consideramos o sobrerrisco em relação à população geral, tanto para hospitalização quanto para óbito. O presente estudo forneceu evidências a respeito do sobrerrisco de hospitalização e óbito por SRAG-COVID, auxiliando na definição de grupos prioritários para a vacinação contra a COVID-19.

En un contexto de transmisión comunitaria y escasez de vacunas, la vacunación contra la COVID-19 debe enfocarse en la reducción directa de la morbilidad y de la mortalidad causadas por la enfermedad. Por lo tanto, es fundamental la definición de grupos prioritarios para la vacunación por el Programa Nacional de Inmunizaciones (PNI), basada en el riesgo de hospitalización y óbito por la enfermedad. Para tal fin, calculamos el sobrerriesgo por sexo, franja de edad y comorbilidades mediante los registros de hospitalización y óbito por síndrome respiratorio agudo grave con confirmación de COVID-19 (SRAG-COVID) en todo Brasil, durante los primeros seis meses de epidemia. Presentaron mayor sobrerriesgo personas del sexo masculino (hospitalización = 1,1 y óbito = 1,2), personas por encima de 45 años para hospitalización (SRfe variando de 1,1 a 8,5) y personas por encima de 55 años para óbitos (SRfe variando de 1,5 a 18,3). En los grupos de comorbilidades, enfermedad renal crónica, diabetes mellitus, enfermedad cardiovascular y neumopatía crónica ofrecieron sobrerriesgo, mientras que para el asma no hubo evidencia. Sufrir una enfermedad renal crónica o diabetes mellitus y tener 60 años o más mostró un factor todavía más fuerte, alcanzando sobrerriesgo de enfermedad 14 y 10 veces mayor que en la población general, respectivamente. Para todas las comorbilidades, hubo un sobrerriesgo más alto en edades mayores, con un gradiente de disminución en franjas más altas. Este patrón se invirtió cuando consideramos el sobrerriesgo en relación con la población general, tanto para hospitalización como para óbito. El presente estudio proporcionó evidencias respecto al sobrerriesgo de hospitalización y óbito por SRAG-COVID, ayudando en la definición de grupos prioritarios para la vacunación contra la COVID-19.

In a context of community transmission and shortage of vaccines, COVID-19 vaccination should focus on directly reducing the morbidity and mortality caused by the disease. It was thus essential to define priority groups for vaccination by the Brazilian National Immunization Program (PNI in Portuguese), based on the risk of hospitalization and death from the disease. We calculated overrisk according to sex, age group, and comorbidities using hospitalization and death records from severe acute respiratory illness with confirmation of COVID-19 (SARI-COVID) in all of Brazil in the first 6 months of the epidemic. Higher overrisk was associated with male sex (hospitalization = 1.1 and death = 1.2), age over 45 years for hospitalization (OvRag ranging from 1.1 to 8.5), and age over 55 year for death (OvRag ranging from 1.5 to 18.3). In the groups with comorbidities, chronic kidney disease, diabetes mellitus, cardiovascular disease, and chronic lung disease were associated with overrisk, while there was no such evidence for asthma. Chronic kidney disease or diabetes and age over 60 showed an even stronger association, reaching overrisk of death 14 and 10 times greater than in the general population, respectively. For all the comorbidities, there was higher overrisk at older ages, with a downward gradient in the oldest age groups. This pattern was reversed when examining overrisk in the general population, for both hospitalization and death. The current study provided evidence of overrisk of hospitalization and death from SARI-COVID, assisting the definition of priority groups for COVID-19 vaccination.

Estimating effective population size changes from preferentially sampled genetic sequences.

Coalescent theory combined with statistical modeling allows us to estimate effective population size fluctuations from molecular sequences of individuals sampled from a population of interest. When sequences are sampled serially through time and the distribution of the sampling times depends on the effective population size, explicit statistical modeling of sampling times improves population size estimation. Previous work assumed that the genealogy relating sampled sequences is known and modeled sampling times as an inhomogeneous Poisson process with log-intensity equal to a linear function of the log-transformed effective population size. We improve this approach in two ways. First, we extend the method to allow for joint Bayesian estimation of the genealogy, effective population size trajectory, and other model parameters. Next, we improve the sampling time model by incorporating additional sources of information in the form of time-varying covariates. We validate our new modeling framework using a simulation study and apply our new methodology to analyses of population dynamics of seasonal influenza and to the recent Ebola virus outbreak in West Africa.

Description and comparison of demographic characteristics and comorbidities in SARI from COVID-19, SARI from influenza, and the Brazilian general population. / SRAG por COVID-19 no Brasil: descrição e comparação de características demográficas e comorbidades com SRAG por influenza e com a população geral.

The study aims to describe patients hospitalized for severe acute respiratory illness (SARI) due to COVID-19 (SARI-COVID) in Brazil according to demographic characteristics and comorbidities up to the 21st Epidemiological Week of 2020. The study aimed to compare these characteristics with those of patients hospitalized for SARI due to influenza in 2019/2020 (SARI-FLU) and with the Brazilian general population. The proportions of demographic characteristics, comorbidities, and pregnant and postpartum women among patients hospitalized for SARI-COVID and SARI-FLU were obtained from the SIVEP-Gripe database, and the estimates for the Brazilian population were obtained from the population projections performed by Brazilian Institute of Geography and Statistics, Information System on Live Birth data, and nationwide surveys. Compared to the Brazilian population, patients hospitalized for SARI-COVID showed a higher proportion of males, elderly individuals and those aged 40 to 59 years, comorbidities (diabetes mellitus, cardiovascular disease, chronic kidney disease, and chronic lung diseases), and pregnant/postpartum women. Compared to the general population, Brazilians hospitalized for SARI-FLU showed higher prevalence rates of ages 0 to 4 years or over 60 years, white race/color, comorbidities (diabetes, chronic kidney disease, asthma, and other chronic lung diseases), and pregnant/postpartum women. The data suggest that these groups are evolving to more serious forms of the disease, so that longitudinal studies are extremely relevant for investigating this hypothesis and supporting appropriate public health policies.

SRAG por COVID-19 no Brasil: descrição e comparação de características demográficas e comorbidades com SRAG por influenza e com a população geral / IRAG por COVID-19 en Brasil: descripción y comparación de características demográficas y comorbilidades con el IRAG por influenza y con la población general / Description and comparison of demographic characteristics and comorbidities in SARI from COVID-19, SARI from influenza, and the Brazilian general population

O presente estudo tem o objetivo de descrever os pacientes hospitalizados por síndrome respiratória aguda grave (SRAG) em decorrência da COVID-19 (SRAG-COVID), no Brasil, quanto às suas características demográficas e comorbidades até a 21ª Semana Epidemiológica de 2020. Buscou-se comparar essas características com as dos hospitalizados por SRAG em decorrência da influenza em 2019/2020 (SRAG-FLU) e com a população geral brasileira. As frequências relativas das características demográficas, comorbidades e de gestantes/puérperas entre os pacientes hospitalizados por SRAG-COVID e SRAG-FLU foram obtidas por meio do Sistema de Informação de Vigilância Epidemiológica da Gripe (SIVEP-Gripe), e as estimativas para a população geral brasileira foram obtidas por meio de projeções populacionais realizadas pelo Instituto Brasileiro de Geografia e Estatística, dados do Sistema de Informações sobre Nascidos Vivos e de pesquisas de âmbito nacional. Entre os hospitalizados por SRAG-COVID, observou-se uma elevada proporção, em relação ao perfil da população geral brasileira, de indivíduos do sexo masculino, idosos ou com 40 a 59 anos, com comorbidades (diabetes mellitus, doença cardiovascular, doença renal crônica e pneumopatias crônicas) e de gestantes/puérperas. Já entre os hospitalizados por SRAG-FLU, observou-se prevalências superiores às populacionais de indivíduos de 0 a 4 anos de idade ou idosos, de raça ou cor branca, com comorbidades (diabetes mellitus, doença renal crônica, asma e outras pneumopatias crônicas) e de gestantes/puérperas. Esses grupos podem estar evoluindo para casos mais graves da doença, de forma que estudos longitudinais na área são de extrema relevância para investigar esta hipótese e melhor subsidiar políticas públicas de saúde.

El objetivo del presente estudio es describir a los pacientes hospitalizados por infección respiratoria aguda grave (IRAG) a consecuencia de la COVID-19 (IRAG-COVID), en Brasil, respecto a sus características demográficas y comorbilidades hasta la 21ª Semana Epidemiológica de 2020. Se buscó comparar estas características con las de los hospitalizados por SRAS, a consecuencia de la influenza en 2019/2020 (IRAG-FLU) y con la población general brasileña. Las frecuencias relativas de las características demográficas, comorbilidades y de embarazadas/puérperas entre los pacientes hospitalizados por IRAG-COVID y IRAG-FLU se obtuvieron mediante el Sistema de Información de la Vigilancia Epidemiológica de la Gripe (SIVEP-Gripe), y las estimaciones para la población general brasileña se consiguieron mediante proyecciones poblacionales realizadas por el Instituto Brasileño de Geografía e Estadística, datos del Sistema de Informaciones sobre Nascidos Vivos y de investigaciones de ámbito nacional. Entre los hospitalizados por IRAG-COVID, se observó una elevada proporción, respecto al perfil de la población general brasileña, de individuos del sexo masculino, ancianos o con 40 a 59 años, con comorbilidades (diabetes mellitus, enfermedad cardiovascular, enfermedad renal crónica y neumopatías crónicas) y de embarazadas/puérperas. Ya entre los hospitalizados por IRAG-FLU, se observaron prevalencias superiores a las poblacionales de individuos de 0 a 4 años de edad o ancianos, de raza o color blanco, con comorbilidades (diabetes mellitus, enfermedad renal crónica, asma y otras neumopatías crónicas) y de embarazadas/puérperas. Estos grupos pueden estar evolucionando hacia casos más graves de la enfermedad, por ello, los estudios longitudinales en esta área son de extrema relevancia para investigar esta hipótesis y apoyar mejor las políticas públicas de salud.

The study aims to describe patients hospitalized for severe acute respiratory illness (SARI) due to COVID-19 (SARI-COVID) in Brazil according to demographic characteristics and comorbidities up to the 21st Epidemiological Week of 2020. The study aimed to compare these characteristics with those of patients hospitalized for SARI due to influenza in 2019/2020 (SARI-FLU) and with the Brazilian general population. The proportions of demographic characteristics, comorbidities, and pregnant and postpartum women among patients hospitalized for SARI-COVID and SARI-FLU were obtained from the SIVEP-Gripe database, and the estimates for the Brazilian population were obtained from the population projections performed by Brazilian Institute of Geography and Statistics, Information System on Live Birth data, and nationwide surveys. Compared to the Brazilian population, patients hospitalized for SARI-COVID showed a higher proportion of males, elderly individuals and those aged 40 to 59 years, comorbidities (diabetes mellitus, cardiovascular disease, chronic kidney disease, and chronic lung diseases), and pregnant/postpartum women. Compared to the general population, Brazilians hospitalized for SARI-FLU showed higher prevalence rates of ages 0 to 4 years or over 60 years, white race/color, comorbidities (diabetes, chronic kidney disease, asthma, and other chronic lung diseases), and pregnant/postpartum women. The data suggest that these groups are evolving to more serious forms of the disease, so that longitudinal studies are extremely relevant for investigating this hypothesis and supporting appropriate public health policies.

Natural infection by the protozoan Leptomonas wallacei impacts the morphology, physiology, reproduction, and lifespan of the insect Oncopeltus fasciatus.

Trypanosomatids are protozoan parasites that infect thousands of globally dispersed hosts, potentially affecting their physiology. Several species of trypanosomatids are commonly found in phytophagous insects. Leptomonas wallacei is a gut-restricted insect trypanosomatid only retrieved from Oncopeltus fasciatus. The insects get infected by coprophagy and transovum transmission of L. wallacei cysts. The main goal of the present study was to investigate the effects of a natural infection by L. wallacei on the hemipteran insect O. fasciatus, by comparing infected and uninfected individuals in a controlled environment. The L. wallacei-infected individuals showed reduced lifespan and morphological alterations. Also, we demonstrated a higher infection burden in females than in males. The infection caused by L. wallacei reduced host reproductive fitness by negatively impacting egg load, oviposition, and eclosion, and promoting an increase in egg reabsorption. Moreover, we associated the egg reabsorption observed in infected females, with a decrease in the intersex gene expression. Finally, we suggest alterations in population dynamics induced by L. wallacei infection using a mathematical model. Collectively, our findings demonstrated that L. wallacei infection negatively affected the physiology of O. fasciatus, which suggests that L. wallacei potentially has a vast ecological impact on host population growth.

MERS-CoV spillover at the camel-human interface.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus from camels causing significant mortality and morbidity in humans in the Arabian Peninsula. The epidemiology of the virus remains poorly understood, and while case-based and seroepidemiological studies have been employed extensively throughout the epidemic, viral sequence data have not been utilised to their full potential. Here, we use existing MERS-CoV sequence data to explore its phylodynamics in two of its known major hosts, humans and camels. We employ structured coalescent models to show that long-term MERS-CoV evolution occurs exclusively in camels, whereas humans act as a transient, and ultimately terminal host. By analysing the distribution of human outbreak cluster sizes and zoonotic introduction times, we show that human outbreaks in the Arabian peninsula are driven by seasonally varying zoonotic transfer of viruses from camels. Without heretofore unseen evolution of host tropism, MERS-CoV is unlikely to become endemic in humans.

Virus genomes reveal factors that spread and sustained the Ebola epidemic.

The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.

Ebola Virus Glycoprotein with Increased Infectivity Dominated the 2013-2016 Epidemic.

The magnitude of the 2013-2016 Ebola virus disease (EVD) epidemic enabled an unprecedented number of viral mutations to occur over successive human-to-human transmission events, increasing the probability that adaptation to the human host occurred during the outbreak. We investigated one nonsynonymous mutation, Ebola virus (EBOV) glycoprotein (GP) mutant A82V, for its effect on viral infectivity. This mutation, located at the NPC1-binding site on EBOV GP, occurred early in the 2013-2016 outbreak and rose to high frequency. We found that GP-A82V had heightened ability to infect primate cells, including human dendritic cells. The increased infectivity was restricted to cells that have primate-specific NPC1 sequences at the EBOV interface, suggesting that this mutation was indeed an adaptation to the human host. GP-A82V was associated with increased mortality, consistent with the hypothesis that the heightened intrinsic infectivity of GP-A82V contributed to disease severity during the EVD epidemic.

Higher incidence of Zika in adult women than adult men in Rio de Janeiro suggests a significant contribution of sexual transmission from men to women.

OBJECTIVES: The recent emergence of Zika in Brazil and its association with an increased rate of congenital malformations has raised concerns over its impact on the birth rate in the country. Using data on the incidence of Zika in 2015-2016 and dengue in 2013 and 2015-2016 for the city of Rio de Janeiro (population 6.4 million), a massive increase of Zika in women compared to men was documented. METHODS: The age-adjusted incidence was compared between men and women. A negative binomial Poisson generalized linear model was fitted to the Zika incidence data to determine the significance of sexual transmission statistically. RESULTS: Even after correcting for the bias due to the systematic testing of pregnant women for Zika, there were found to be 90% more registered cases per 100000 women than men in the sexually active age group (15-65 years); this was not the case for age groups <15 years and >65 years. Assuming that infected men transmit the disease to women in their semen, but that the converse is not true, some extra incidence in women is to be expected. An alternate hypothesis would be that women visit doctors more often than men. To test this, the incidence of dengue fever was compared in men and women in 2015 and in 2013 (before Zika reached Rio de Janeiro): in both years, women were 30% more likely to be reported with dengue. CONCLUSION: Women in the sexually active age group are far more likely to get Zika than men (+90% increase); sexual transmission is the most probable cause. Women in the 15-65 years age group are also 30% more likely to be reported with dengue than men, which is probably due to women being more careful with their health.

Comment on "Mutation rate and genotype variation of Ebola virus from Mali case sequences".

Hoenen et al (Reports, 3 April 2015, p. 117; published online 26 March) suggested that the Ebola virus Makona responsible for the West African epidemic evolved more slowly than previously reported. We show that this was based on corrupted data. An erratum provided a rate compatible with the initial and later, more precise, estimates but did not correctly state the nature of the error.

Estimating the Attack Ratio of Dengue Epidemics under Time-varying Force of Infection using Aggregated Notification Data.

Quantifying the attack ratio of disease is key to epidemiological inference and public health planning. For multi-serotype pathogens, however, different levels of serotype-specific immunity make it difficult to assess the population at risk. In this paper we propose a Bayesian method for estimation of the attack ratio of an epidemic and the initial fraction of susceptibles using aggregated incidence data. We derive the probability distribution of the effective reproductive number, Rt, and use MCMC to obtain posterior distributions of the parameters of a single-strain SIR transmission model with time-varying force of infection. Our method is showcased in a data set consisting of 18 years of dengue incidence in the city of Rio de Janeiro, Brazil. We demonstrate that it is possible to learn about the initial fraction of susceptibles and the attack ratio even in the absence of serotype specific data. On the other hand, the information provided by this approach is limited, stressing the need for detailed serological surveys to characterise the distribution of serotype-specific immunity in the population.

πBUSS: a parallel BEAST/BEAGLE utility for sequence simulation under complex evolutionary scenarios.

BACKGROUND: Simulated nucleotide or amino acid sequences are frequently used to assess the performance of phylogenetic reconstruction methods. BEAST, a Bayesian statistical framework that focuses on reconstructing time-calibrated molecular evolutionary processes, supports a wide array of evolutionary models, but lacked matching machinery for simulation of character evolution along phylogenies. RESULTS: We present a flexible Monte Carlo simulation tool, called πBUSS, that employs the BEAGLE high performance library for phylogenetic computations to rapidly generate large sequence alignments under complex evolutionary models. πBUSS sports a user-friendly graphical user interface (GUI) that allows combining a rich array of models across an arbitrary number of partitions. A command-line interface mirrors the options available through the GUI and facilitates scripting in large-scale simulation studies. πBUSS may serve as an easy-to-use, standard sequence simulation tool, but the available models and data types are particularly useful to assess the performance of complex BEAST inferences. The connection with BEAST is further strengthened through the use of a common extensible markup language (XML), allowing to specify also more advanced evolutionary models. To support simulation under the latter, as well as to support simulation and analysis in a single run, we also add the πBUSS core simulation routine to the list of BEAST XML parsers. CONCLUSIONS: πBUSS offers a unique combination of flexibility and ease-of-use for sequence simulation under realistic evolutionary scenarios. Through different interfaces, πBUSS supports simulation studies ranging from modest endeavors for illustrative purposes to complex and large-scale assessments of evolutionary inference procedures. Applications are not restricted to the BEAST framework, or even time-measured evolutionary histories, and πBUSS can be connected to various other programs using standard input and output format.

Spatiotemporal dynamics of DENV-2 Asian-American genotype lineages in the Americas.

The Asian/American (AS/AM) genotype of dengue virus type 2 (DENV-2) has been evolving in the Americas over the last 30 years, leading to several waves of dengue epidemics and to the emergence of different viral lineages in the region. In this study, we investigate the spatiotemporal dissemination pattern of the DENV-2 lineages at a regional level. We applied phylogenetic and phylogeographic analytical methods to a comprehensive data set of 582 DENV-2 E gene sequences of the AS/AM genotype isolated from 29 different American countries over a period of 30 years (1983 to 2012). Our study reveals that genetic diversity of DENV-2 AS/AM genotype circulating in the Americas mainly resulted from one single founder event and can be organized in at least four major lineages (I to IV), which emerged in the Caribbean region at the early 1980s and then spread and die out with different dynamics. Lineages I and II dominate the epidemics in the Caribbean region during the 1980s and early 1990 s, lineage III becomes the prevalent DENV-2 one in the Caribbean and South America during the 1990 s, whereas lineage IV dominates the epidemics in South and Central America during the 2000s. Suriname and Guyana seem to represent important entry points for DENV-2 from the Lesser Antilles to South America, whereas Venezuela, Brazil and Nicaragua were pointed as the main secondary hubs of dissemination to other mainland countries. Our study also indicates that DENV-2 AS/AM genotype was disseminated within South America following two main routes. The first route hits Venezuela and the western side of the Andes, while the second route mainly hits Brazil and the eastern side of the Andes. The phenomenon of DENV-2 lineage replacement across successive epidemic outbreaks was a common characteristic in all American countries, although the timing of lineage replacements greatly vary across locations.

Demographic profile of sylvatic yellow fever in Brazil from 1973 to 2008.

BACKGROUND: Yellow fever is an acute, frequently fatal, febrile arbovirosis that in Brazil occurs only in the sylvatic form. Sylvatic yellow fever (SYF) appears in sporadic outbreaks over a large area of Brazil. In this paper, we analyze the demographic profile of 831 SYF cases that occurred between 1973 and 2008, to determine which segments of the exposed population are at greater risk. METHODS: Data were statistically analyzed and were also geo-referenced in order to observe their spatial pattern. The basic reproductive number of infections, R0, was estimated by the ratio between average life expectancy and the average age of the cases. RESULTS: SYF cases showed a modal profile of young male adults, approximately 30 years of age, living in rural areas of the states of Pará, Goiás, Maranhão and Minas Gerais, who were unvaccinated or whose vaccination was out of date. The disease showed a high mortality rate (51%, 421/831) among the notified cases, with death occurring on around the seventh day of illness for most patients. The R0 for SYF was estimated at approximately 2.4. CONCLUSION: The results of this study suggest that lack of vaccination coverage is a major risk factor for SYF, and that the groups most at risk are migrant laborers, farm workers and tourists.

Phylogeography of foot-and-mouth disease virus serotype O in Ecuador.

Foot-and-mouth disease virus (FMDV) is the causative agent of the most important disease of domestic cattle, foot-and-mouth disease. In Ecuador, FMDV is maintained at an endemic state, with sporadic outbreaks. To unravel the tempo and mode of FMDV spread within the country we conducted a Bayesian phylogeographic analysis using a continuous time Markov chain (CTMC) to model the diffusion of FMDV between Ecuadorian provinces. We implement this framework through Markov chain Monte Carlo available in the BEAST package to study 90 FMDV serotype O isolates from 17 provinces in the period 2002-2010. The Bayesian approach also allowed us to test hypotheses on the mechanisms of viral spread by incorporating environmental and epidemiological data in our prior distributions and perform Bayesian model selection. Our analyses suggest an intense flow of viral strains throughout the country that is possibly coupled to animal movements and ecological factors, since most of inferred viral spread routes were in Coast and Highland regions. Moreover, our results suggest that both short- and long-range spread occur within Ecuador. The province of Esmeraldas, in the border with Colombia and where most animal commerce is done, was found to be the most probable origin of the circulating strains, pointing to a transboundary behavior of FMDV in South America. These findings suggest that uncontrolled animal movements can create a favorable environment for FMDV maintenance and pose a serious threat to control programmes. Also, we show that phylogeographic modeling can be a powerful tool in unraveling the spatial dynamics of viruses and potentially in controlling the spread of these pathogens.