Evaluation of humoral and cellular immune responses to P.berghei-based whole-sporozoite malaria vaccination in rhesus macaques

A malária é uma doença infecciosa transmitida por mosquitos que continua a ser uma das doenças infecciosas mais impactantes do mundo, matando milhares de pessoas todos os anos. Apesar de todos os esforços para controlar esta doença, como quimioprofilaxia e medidas de controlo de vetores, a falta de conhecimento sobre as respostas imunes desencadeadas pelo parasita Plasmodium dificulta o desenvolvimento de uma vacina eficaz contra a malária, que é necessária com urgência. A natureza assintomática e altamente imunogénica do estadio hepático da infecção por Plasmodium torna-o num alvo ideal para o desenvolvimento da vacina contra a malária. Prudêncio lab do Instituto de Medicina Molecular (IMM) desenvolveu um novo candidato a vacina contra a malária de esporozoito inteiro que tem como alvo o estágio hepático, a PbVAC. Na qual o parasita roedor P. berghei expressa a proteína circunsporozoítica de superfície do P. falciparum (PfCSP), altamente imunogénica, de modo a promover respostas imunitárias específicas para PfCSP, assim como respostas cruzadas entre espécies, que podem proteger contra uma infecção subsequente por P. falciparum. Estudos pré-clínicos em modelos de infecção em murganhos e coelhos mostraram que PbVac é capaz de infectar e desenvolver-se em hepatócitos sem estabelecer uma infecção no estadio sanguíneo. Para imitar o que acontece no fígado humano, os macacos rhesus (Macaca mulatta) foram usados para um teste pré-clínico de P. berghei wild-type (WT) e esporozoítos PbVac geneticamente modificados, como estratégia para induzir imunidade contra P. falciparum. Este estudo tem como objetivo investigar e comparar as respostas imunes humorais e celulares entre animais imunizados e não imunizados. Primeiro, confirmamos que os esporozoítos do PbWT são capazes de infectar hepatócitos do macaco rhesus in vivo. Posteriormente, os macacos rhesus foram imunizados por picada de mosquito com PbVac ou PbWT e seguidos por 21 semanas, em paralelo com animais não imunizados. Células mononucleares do sangue periférico (PBMCs) e plama foram coletadas periodicamente e células do fígado e esplenócitos foram coletados na eutanásia. Foi realizada uma comparação do plasma pré e pós 3 imunizações para analisar as respostas humorais quantificando IgGs específicas para esporozoítos. As composições dos compartimentos imunes do sangue periférico, fígado e baço foram analisadas por imunofenotipagem e respostas imunes celulares específicas contra esporozoítos PbVAC, PbWT e Pf foram avaliadas em PBMCs e células hepáticas utilizando um ensaio intracelular de citocinas. As imunizações foram seguras, sem alterações relevantes nos parâmetros de segurança avaliados, e nenhuma infecção relevante foi encontrada. Mostramos que as imunizações contra PbWT e PbVac são capazes de provocar uma resposta humoral contra o antigénio em macacos. É importante ressaltar que a geração de anticorpos anti-esporozoítos Pf observados em animais imunizados com PbVac- mas não com PbWT indica que a PfCS pode desempenhar um papel significativo nas respostas humorais à vacina. Quanto ao papel da imunidade celular desencadeada por essas imunizações, nem o perfil fenotípico geral, nem a magnitude e especificidade das respostas celulares aos agentes de imunização ou a Pf foram significativamente alteradas após a imunização. Em contraste com o que alguns ensaios em humanos relataram, não encontramos expansão da população de células T γδ após a imunização. No entanto, encontramos alterações fenotípicas nas células linfóides inatas (ILCs), que diminuíram significativamente, e um aumento nas células T CD4+ nos PBMCs. No geral, os nossos resultados indicam que a imunização com PbVac representa uma plataforma de vacinação segura que gera respostas imunes humorais a Pf. Manipulação adicional da estratégia de imunização com PbVac, como dose ou modo de administração, pode melhorar significativamente as suas respostas imunológicas humorais e celulares, contribuindo assim para o desenvolvimento de uma vacina eficiente contra a malária.Malaria is a mosquito-borne infectious disease that remains one of the most impactful infectious diseases globally, killing thousands of people every year. Despite all efforts to control this disease, such as chemoprophylaxis and vector control measures, the lack of knowledge about the immune responses triggered by the Plasmodium parasite hinders the development of an urgently needed efective malaria vaccine. The asymptomatic and highly immunogenic nature of the liver stage of Plasmodium infection makes it an ideal target for malaria vaccine development. The Instituto de Medicina Molecular (IMM)’s Prudêncio lab has developed a new pre-erythrocytic whole-sporozoite malaria vaccine candidate, PbVac, in which the rodent P. berghei parasite expresses the highly immunogenic P. falciparum surface circumsporozoite protein (PfCS in order to promote PfCS-specific and cross-species immune responses that may protect against a subsequent P. falciparum infection. Pre-clinical studies in mouse and rabbit models of infection have shown that PbVac is able to infect and develop in hepatocytes without establishing a blood stage infection. In order to mimic what happens in the human liver, rhesus macaques (Macaca mulatta) were used for a pre-clinical analysis of P. berghei wild-type (WT) and genetically modified PbVac sporozoites, as a strategy to induce immunity to P. falciparum. This study aims to investigate and compare the humoral and cellular-associated immune responses between immunized and non-immunized animals. First, the ability of PbWT sporozoites to infect rhesus macaque hepatocytes in vivo was confirmed. Subsequently, rhesus macaques were immunized by mosquito bite with PbVAC or PbWT and followed for 21 weeks, in parallel with non-immunized animals. Peripheral blood mononuclear cells (PBMCs) and plasma were collected periodically, and liver cells and splenocytes were collected at euthanasia. A comparison between plasma pre- and post- 3 immunizations was performed to analyze humoral responses through quantification of specific IgGs for sporozoites. The compositions of the peripheral blood, liver and spleen immune compartments were analyzed by immunophenotyping, and specific cellular immune responses against PbVAC, PbWT and Pf sporozoites were assessed in PBMCs and liver cells by an intracellular cytokine assay.Immunizations were safe, with no relevant changes in the safety parameters evaluated, and no breakthrough infections were found. We show that both PbWT and PbVac immunizations are capable of eliciting a humoral response against the immunogen in monkeys. Importantly, the generation of anti-Pf sporozoites antibodies observed in PbVac- but not PbWT-immunized animals indicates that PfCS may play a significant role in humoral responses to the vaccine. As for the role of cellular immunity elicited by these immunizations, neither the overall phenotypic profile nor the magnitude and specificity of cellular responses to the immunization agents or to Pf were significanty altered upon immunization. In contrast to what some human trials have reported, we found no expansion of the γδ T cell population upon immunization. However we found phenotypic changes in innate lymphoid cells ILCs, which decreased significantly, and an increase in CD4+ T cells in PBMCs. Overall, our results indicate that PbVac immunization represents a safe vaccination platform that generates humoral immune responses to Pf. Additional manipulation of the PbVac immunization strategy, such as dose or mode of administration, may significantly enhance its humoral as well as cellular immune responses, thus contributing to the development of an efficient malaria vaccine

Manifestações bucais em pacientes portadores de Diabetes Mellitus / Oral manifestations in Diabetes Mellitus patients

A deficiência total ou parcial da produção de insulina pelo pâncreas pode caracterizar o distúrbio metabólico crônico conhecido como Diabetes Mellitus (DM), que é desencadeado por fatores genéticos associados a fatores ambientais. Nos casos de Diabetes mellitus do tipo 1 (DM1) há ampla destruição autoimune de células β pancreáticas, com deficiência total da insulina. Enquanto no Diabetes Mellitus tipo 2 (DM2) ocorre defeitos na ação da insulina e comprometimento parcial da secreção da insulina. Dentre os diversos sinais e sintomas sistêmicos, é de especial importância para a Odontologia a identificação de manifestações bucais, como: doença periodontal, xerostomia, candidíase, halitose, glossodínea, glossite migratória benigna e outras menos comuns. O objetivo desse trabalho é compreender a etiopatogenia e as principais características clínicas das lesões bucais relacionadas ao DM por meio de revisão sistemática da literatura, visando o correto diagnóstico e o tratamento mais adequado

The Microcephaly Epidemic Research Group Paediatric Cohort (MERG-PC): A Cohort Profile.

This cohort profile aims to describe the ongoing follow-up of children in the Microcephaly Epidemic Research Group Paediatric Cohort (MERG-PC). The profile details the context and aims of the study, study population, methodology including assessments, and key results and publications to date. The children that make up MERG-PC were born in Recife or within 120 km of the city, in Pernambuco/Brazil, the epicentre of the microcephaly epidemic. MERG-PC includes children from four groups recruited at different stages of the ZIKV microcephaly epidemic in Pernambuco, i.e., the Outpatient Group (OG/n = 195), the Microcephaly Case-Control Study (MCCS/n = 80), the MERG Pregnant Women Cohort (MERG-PWC/n = 336), and the Control Group (CG/n = 100). We developed a comprehensive array of clinical, laboratory, and imaging assessments that were undertaken by a 'task force' of clinical specialists in a single day at 3, 6, 12, 18 months of age, and annually from 24 months. Children from MCCS and CG had their baseline assessment at birth and children from the other groups, at the first evaluation by the task force. The baseline cohort includes 711 children born between February 2015 and February 2019. Children's characteristics at baseline, excluding CG, were as follows: 32.6% (184/565) had microcephaly, 47% (263/559) had at least one physical abnormality, 29.5% (160/543) had at least one neurological abnormality, and 46.2% (257/556) had at least one ophthalmological abnormality. This ongoing cohort has contributed to the understanding of the congenital Zika syndrome (CZS) spectrum. The cohort has provided descriptions of paediatric neurodevelopment and early epilepsy, including EEG patterns and treatment response, and information on the frequency and characteristics of oropharyngeal dysphagia; cryptorchidism and its surgical findings; endocrine dysfunction; and adenoid hypertrophy in children with Zika-related microcephaly. The study protocols and questionnaires were shared across Brazilian states to enable harmonization across the different studies investigating microcephaly and CZS, providing the opportunity for the Zika Brazilian Cohorts Consortium to be formed, uniting all the ZIKV clinical cohorts in Brazil

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants.

BACKGROUND: Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. METHODS: We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. FINDINGS: The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. INTERPRETATION: Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. FUNDING: WHO

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. Copyright (C) 2021 World Health Organization; licensee Elsevier

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings