Evaluation of Commercial Ropes Applied as Artificial Tendons in Robotic Rehabilitation Orthoses

International audienceThis study aims to present the design, selection and testing of commercial ropes (artificial tendons) used on robotic orthosis to perform the hand movements for stroke individuals over upper limb rehabilitation. It was determined the load applied in the rope would through direct measurements performed on four individuals after stroke using a bulb dynamometer. A tensile strength test was performed using eight commercial ropes in order to evaluate the maximum breaking force and select the most suitable to be used in this application. Finally, a pilot test was performed with a user of the device to ratify the effectiveness of the rope. The load on the cable was 12.38 kgf (121.4 N) in the stroke-affected hand, which is the maximum tensile force that the rope must to supports. Paragliding rope (DuPont™ Kevlar ® ) supporting a load of 250 N at a strain of 37 mm was selected. The clinical test proved the effectiveness of the rope, supporting the requested efforts, without presenting permanent deformation, effectively performing the participant’s finger opening

Emerging Infectious Diseases

Submitted by Nuzia Santos ([email protected]) on 2019-08-29T13:45:36Z No. of bitstreams: 1 17DD Yellow Fever Revaccination .pdf: 1335209 bytes, checksum: 7ab0df367d542e9e0b0d0acf6363a5d8 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2019-08-29T13:53:35Z (GMT) No. of bitstreams: 1 17DD Yellow Fever Revaccination .pdf: 1335209 bytes, checksum: 7ab0df367d542e9e0b0d0acf6363a5d8 (MD5)Made available in DSpace on 2019-08-29T13:53:35Z (GMT). No. of bitstreams: 1 17DD Yellow Fever Revaccination .pdf: 1335209 bytes, checksum: 7ab0df367d542e9e0b0d0acf6363a5d8 (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil / Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Prefeitura de Belo Horizonte. Secretaria Municipal de Saúde. Belo Horizonte, MG, Brasil.Estado de Minas Gerais. Secretaria de Saúde. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos . Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos . Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos . Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos . Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos . Rio de Janeiro, RJ, Brasil.Universidade Federal de Alfenas. Alfenas, MG, Brasil.Universidade de Brasília. Brasília, DF, Brasil.Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Brasília, DF, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Brasília, DF, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.We evaluated the duration of neutralizing antibodies and the status of 17DD vaccine–specific T- and B-cell memory following primary and revaccination regimens for yellow fever (YF) in Brazil. We observed progressive decline of plaque-reduction neutralization test (PRNT) seropositivity and of the levels of effector memory CD4+ and CD8+ T cells, as well as interferon-γ+CD8+ T cells, 10 years after primary vaccination. Revaccination restored PRNT seropositivity as well as the levels of effector memory CD4+, CD8+, and interferon-γ+CD8+ T cells. Moreover, secondary or multiple vaccinations guarantee long-term persistence of PRNT positivity and cell-mediated memory 10 years after booster vaccination. These findings support the relevance of booster doses to heighten the 17DD-YF–specific immune response to guarantee the long-term persistence of memory components. Secondary or multiple vaccinations improved the correlates of protection triggered by 17DD-YF primary vaccination, indicating that booster regimens are needed to achieve efficient immunity in areas with high risk for virus transmission

Short-lived immunity after 17DD Yellow Fever single dose indicates that booster vaccination may be required to guarantee protective immunity in children

Submitted by Priscila Nascimento ([email protected]) on 2019-10-01T19:14:22Z No. of bitstreams: 1 Short-Lived_Immunity_After_17DD_Yellow_Fever_Singl.pdf: 3383889 bytes, checksum: 0a90002bb16cb94aad75a9789f4bd242 (MD5)Approved for entry into archive by Priscila Nascimento ([email protected]) on 2019-10-01T19:54:22Z (GMT) No. of bitstreams: 1 Short-Lived_Immunity_After_17DD_Yellow_Fever_Singl.pdf: 3383889 bytes, checksum: 0a90002bb16cb94aad75a9789f4bd242 (MD5)Made available in DSpace on 2019-10-01T19:54:22Z (GMT). No. of bitstreams: 1 Short-Lived_Immunity_After_17DD_Yellow_Fever_Singl.pdf: 3383889 bytes, checksum: 0a90002bb16cb94aad75a9789f4bd242 (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Secretaria Municipal de Saúde de Belo Horizonte. Belo Horizonte, MG, Brasil.Secretaria do Estado de Saúde de Minas Gerais. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Universidade de Brasília. Faculdade de Medicina. Brasília, DF, Brasil.Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Imunização e Doenças Transmissíveis. Brasília, DF, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Programa Nacional de Imunizações. Brasília, DF, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.A vacinação contra a febre amarela (YF) é recomendada para pessoas que vivem em áreas endêmicas e representa a estratégia mais eficaz para reduzir o risco de infecção. Estudos anteriores alertaram que os regimes de reforço devem ser considerados para garantir a persistência a longo prazo dos componentes de memória específicos da 17DD-YF em adultos que vivem em áreas com circulação do vírus da YF. Considerando as menores taxas de soroconversão observadas em crianças (9 a 12 meses de idade) em comparação aos adultos, este estudo foi desenvolvido para acessar a duração da imunidade em crianças vacinadas em dose única em um período de 10 anos de seção transversal . Os níveis de anticorpos neutralizantes (PRNT) e o status fenotípico / de memória funcional das células T e B foram medidos no início, 30 a 45 dias, 1, 2, 4, 7 e 10 anos após a vacinação primária. Os resultados revelaram que uma dose única induziu 85% de soropositividade entre 30 e 45 dias e uma diminuição progressiva dependente do tempo foi observada em apenas 2 anos e diminui para valores críticos (abaixo de 60%) em períodos de tempo ≥ 4 anos . Além disso, a imunidade celular específica de YF de curta duração, mediada pelas células T e B de memória, também foi observada após 4 anos. A análise de probabilidade prevista e a memória resultante enfatizam que os correlatos de proteção (PRNT; células T CD8 + com memória efetiva; células B com memória não clássica) diminuem para valores críticos dentro de ≥4 anos após a vacinação primária. Juntos, esses resultados demonstram claramente o declínio da resposta da memória específica da 17DD-YF ao longo do tempo em crianças vacinadas principalmente entre 9 e 12 meses de idade e suportam a necessidade de um regime de reforço para garantir a persistência a longo prazo dos componentes da memória para crianças que vivem em áreas com alto risco de transmissão YF.The Yellow Fever (YF) vaccination is recommended for people living in endemic areas and represents the most effective strategy to reduce the risk of infection. Previous studies have warned that booster regimens should be considered to guarantee the long-term persistence of 17DD-YF-specific memory components in adults living in areas with YF-virus circulation. Considering the lower seroconversion rates observed in children (9–12 months of age) as compared to adults, this study was designed in order to access the duration of immunity in single-dose vaccinated children in a 10-years cross-sectional time-span. The levels of neutralizing antibodies (PRNT) and the phenotypic/functional memory status of T and B-cells were measured at a baseline, 30–45 days, 1, 2, 4, 7, and 10 years following primary vaccination. The results revealed that a single dose induced 85% of seropositivity at 30–45 days and a progressive time-dependent decrease was observed as early as 2 years and declines toward critical values (below 60%) at time-spans of ≥4-years. Moreover, short-lived YF-specific cellular immunity, mediated by memory T and B-cells was also observed after 4-years. Predicted probability and resultant memory analysis emphasize that correlates of protection (PRNT; effector memory CD8+ T-cells; non-classical memory B-cells) wane to critical values within ≥4-years after primary vaccination. Together, these results clearly demonstrate the decline of 17DD-YF-specific memory response along time in children primarily vaccinated at 9–12 months of age and support the need of booster regimen to guarantee the long-term persistence of memory components for children living in areas with high risk of YF transmission

Multi-parameter approach to evaluate the timing of memory status after 17DD-YF primary vaccination

Submitted by Priscila Nascimento ([email protected]) on 2018-06-20T18:10:46Z No. of bitstreams: 1 Multi-parameter_approach_to_evaluate_the_timing_of.pdf: 8388797 bytes, checksum: 234fb0f5fbecbf0d6e239427b5c7095d (MD5)Approved for entry into archive by Priscila Nascimento ([email protected]) on 2018-06-20T18:52:14Z (GMT) No. of bitstreams: 1 Multi-parameter_approach_to_evaluate_the_timing_of.pdf: 8388797 bytes, checksum: 234fb0f5fbecbf0d6e239427b5c7095d (MD5)Made available in DSpace on 2018-06-20T18:52:14Z (GMT). No. of bitstreams: 1 Multi-parameter_approach_to_evaluate_the_timing_of.pdf: 8388797 bytes, checksum: 234fb0f5fbecbf0d6e239427b5c7095d (MD5) Previous issue date: 2018Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou.Belo Horizonte, Minas Gerais, Brasil.Governo do Estado de Minas Gerais. Secretaria de Estado de Saúde. Belo Horizonte, Minas Gerais, Brasil.Universidade Federal de Alfenas. Alfenas, Minas Gerais, Brasil.Universidade Federal de Uberlândia. Laboratório de Bioinformática e Análises Moleculares. Uberlândia, Minas Gerais, Brasil.Food and Drug Administration. Center for Biologics Evaluation and Research. Silver Spring, Maryland, United States of America.Instituto de Biologia do Exército. Rio de Janeiro, Rio de Janeiro, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Brasília, DF, Brasil.Universidade de Brasília. Brasília, DF, Brasil.Instituto Evandro Chagas. Ananindeua, Pará, Brasil.Fundação Oswaldo Cruz. Diretoria Regional de Brasília. Brasília, DF, Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública. Rio de Janeiro, RJ, Brasil.Nesta investigação, as técnicas melhoradas por máquina foram aplicadas para trazer insights científicos para identificar um conjunto mínimo de biomarcadores relacionados à memória fenotípica / funcional para o acompanhamento pós-vacinação da vacinação contra a febre amarela (FA). Para este propósito, o estado de memória das células T circulantes (Naïve / efetor-precoce / Memória-Central / Memória Efetiva) e células B (Naïve / memória não clássica / memória clássica) juntamente com o perfil de citocinas (IFN / TNF / IL-5 / IL-10) foram monitorizados antes do NV (dia 0) e em pontos de tempo distintos após a vacinação primária com 17DD-YF - VP (dia30-45); PV (ano1-9) e PV (ano10-11). Um conjunto de biomarcadores (eEfCD4; EMCD4; CMCD19; EMCD8; IFNCD4; IL-5CD8; TNFCD4; IFNCD8; TNFCD8; IL-5CD19; IL-5CD4) foi observado em PV (dia30-45), mas não em NV (dia0) , com a maioria deles ainda observada em VP (ano1-9). Deficiências de biomarcadores fenotípicos / funcionais foram observadas em NV (dia 0), enquanto a falta total de atributos relacionados à memória foi observada na PV (ano10-11), independentemente da idade na vacinação primária. Análise de diagrama de Venn pré-selecionada 10 atributos (eEfCD4, EMCD4, CMCD19, EMCD8, IFNCD4, IL-5CD8, TNFCD4, IFNCD8, TNFCD8 e IL-5CD4), dos quais a média geral apresentou moderada precisão para discriminar PV (dia30-45) e PV (year1-9) de NV (day0) e PV (year10-11). Abordagens multi-parâmetro e algoritmos de árvore de decisão definiram os atributos EMCD8 e IL-5CD4 como os dois principais preditores com desempenho moderado. Juntamente com os títulos PRNT, os dois principais biomarcadores levaram a um status de memória resultante observado em 80% e 51% dos voluntários em PV (dia30-45) e PV (ano1-9), contrastando com 0% e 29% encontrados em NV ( day0) e PV (year10-11), respectivamente. A deficiência de atributos relacionados à memória observada na PV (year10-11) ressalta a diminuição conspícua dependente do tempo da memória resultante após a vacinação primária com 17DD-YF, que pode ser útil para monitorar potenciais correlatos de proteção em áreas sob risco de transmissão da FA.In this investigation, machine-enhanced techniques were applied to bring about scientific insights to identify a minimum set of phenotypic/functional memory-related biomarkers for post-vaccination follow-up upon yellow fever (YF) vaccination. For this purpose, memory status of circulating T-cells (Naïve/early-effector/Central-Memory/Effector-Memory) and Bcells (Naïve/non-Classical-Memory/Classical-Memory) along with the cytokine profile (IFN/ TNF/IL-5/IL-10) were monitored before-NV(day0) and at distinct time-points after 17DD-YF primary vaccinationÐPV(day30-45); PV(year1-9) and PV(year10-11). A set of biomarkers (eEfCD4; EMCD4; CMCD19; EMCD8; IFNCD4; IL-5CD8; TNFCD4; IFNCD8; TNFCD8; IL-5CD19; IL-5CD4) were observed in PV(day30-45), but not in NV(day0), with most of them still observed in PV(year1-9). Deficiencies of phenotypic/functional biomarkers were observed in NV(day0), while total lack of memory-related attributes was observed in PV (year10-11), regardless of the age at primary vaccination. Venn-diagram analysis preselected 10 attributes (eEfCD4, EMCD4, CMCD19, EMCD8, IFNCD4, IL-5CD8, TNFCD4, IFNCD8, TNFCD8 and IL-5CD4), of which the overall mean presented moderate accuracy to discriminate PV(day30-45)&PV(year1-9) from NV(day0)&PV(year10-11). Multi-parameter approaches and decision-tree algorithms defined the EMCD8 and IL-5CD4 attributes as the top-two predictors with moderated performance. Together with the PRNT titers, the toptwo biomarkers led to a resultant memory status observed in 80% and 51% of volunteers in PV(day30-45) and PV(year1-9), contrasting with 0% and 29% found in NV(day0) and PV (year10-11), respectively. The deficiency of memory-related attributes observed at PV (year10-11) underscores the conspicuous time-dependent decrease of resultant memory following17DD-YF primary vaccination that could be useful to monitor potential correlates of protection in areas under risk of YF transmission

Booster dose after 10 years is recommended following 17DD-YF primary vaccination

Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiologicos Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiologicos Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Governo do Estado de Minas Gerais. Secretaria de Estado de Saúde. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiologicos Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiologicos Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiologicos Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Universidade Federal de Alfenas. Alfenas, MG, Brasil.Instituto de Biologia do Exercito. Rio de Janeiro, RJ, Brasil.Instituto de Biologia do Exercito. Rio de Janeiro, RJ, Brasil.Instituto de Biologia do Exercito. Rio de Janeiro, RJ, Brasil.Instituto de Biologia do Exercito. Rio de Janeiro, RJ, Brasil.Instituto de Biologia do Exercito. Rio de Janeiro, RJ, Brasil.Instituto de Biologia do Exercito. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Assessoria Clínica de Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiologicos Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiologicos Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Assessoria Clínica de Bio-Manguinhos. Rio de Janeiro, RJ, Brasil.Ministerio da Saude. Secretaria de Vigilancia em Saude. Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Brasil.Universidade de Brasília. Brasilia, DF, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Instituto Evandro Chagas. Ananindeua, PA, Brasil.US Food and Drug Administration. Center for Biologics Evaluation and Research. Silver Spring, MD USAFundação Oswaldo Cruz. Diretoria Regional de Brasília. Brasília, DF, Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Publica. Rio de Janeiro, DF, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Renê Rachou. Belo Horizonte, MG, Brasil.A single vaccination of Yellow Fever vaccines is believed to confer life-long protection. In this study, results of vaccinees who received a single dose of 17DD-YF immunization followed over 10 y challenge this premise. YF-neutralizing antibodies, subsets of memory T and B cells as well as cytokine-producing lymphocytes were evaluated in groups of adults before (NVday0) and after (PVday30-45, PVyear1-4, PVyear5-9, PVyear10-11, PVyear12-13) 17DD-YF primary vaccination. YF-neutralizing antibodies decrease significantly from PVyear1-4 to PVyear12-13 as compared to PVday30-45, and the seropositivity rates (PRNT≥2.9Log10mIU/mL) become critical (lower than 90%) beyond PVyear5-9. YF-specific memory phenotypes (effector T-cells and classical B-cells) significantly increase at PVday30-45 as compared to na've baseline. Moreover, these phenotypes tend to decrease at PVyear10-11 as compared to PVday30-45. Decreasing levels of TNF-α(+) and IFN-γ(+) produced by CD4(+) and CD8(+) T-cells along with increasing levels of IL-10(+)CD4(+)T-cells were characteristic of anti-YF response over time. Systems biology profiling represented by hierarchic networks revealed that while the na've baseline is characterized by independent micro-nets, primary vaccinees displayed an imbricate network with essential role of central and effector CD8(+) memory T-cell responses. Any putative limitations of this cross-sectional study will certainly be answered by the ongoing longitudinal population-based investigation. Overall, our data support the current Brazilian national immunization policy guidelines that recommend one booster dose 10 y after primary 17DD-YF vaccination

Multi-parameter approach to evaluate the timing of memory status after 17DD-YF primary vaccination

<div><p>In this investigation, machine-enhanced techniques were applied to bring about scientific insights to identify a minimum set of phenotypic/functional memory-related biomarkers for post-vaccination follow-up upon yellow fever (YF) vaccination. For this purpose, memory status of circulating T-cells (Naïve/early-effector/Central-Memory/Effector-Memory) and B-cells (Naïve/non-Classical-Memory/Classical-Memory) along with the cytokine profile (IFN/TNF/IL-5/IL-10) were monitored before-NV(day0) and at distinct time-points after 17DD-YF primary vaccination—PV(day30-45); PV(year1-9) and PV(year10-11). A set of biomarkers (eEfCD4; EMCD4; CMCD19; EMCD8; IFNCD4; IL-5CD8; TNFCD4; IFNCD8; TNFCD8; IL-5CD19; IL-5CD4) were observed in PV(day30-45), but not in NV(day0), with most of them still observed in PV(year1-9). Deficiencies of phenotypic/functional biomarkers were observed in NV(day0), while total lack of memory-related attributes was observed in PV(year10-11), regardless of the age at primary vaccination. Venn-diagram analysis pre-selected 10 attributes (eEfCD4, EMCD4, CMCD19, EMCD8, IFNCD4, IL-5CD8, TNFCD4, IFNCD8, TNFCD8 and IL-5CD4), of which the overall mean presented moderate accuracy to discriminate PV(day30-45)&PV(year1-9) from NV(day0)&PV(year10-11). Multi-parameter approaches and decision-tree algorithms defined the EMCD8 and IL-5CD4 attributes as the top-two predictors with moderated performance. Together with the PRNT titers, the top-two biomarkers led to a resultant memory status observed in 80% and 51% of volunteers in PV(day30-45) and PV(year1-9), contrasting with 0% and 29% found in NV(day0) and PV(year10-11), respectively. The deficiency of memory-related attributes observed at PV(year10-11) underscores the conspicuous time-dependent decrease of resultant memory following17DD-YF primary vaccination that could be useful to monitor potential correlates of protection in areas under risk of YF transmission.</p></div

Changes in neutralizing antibody titers and phenotypic/functional memory-related biomarkers at distinct time-points after primary 17DD-YF vaccination.

<p>Correlation analyses were performed to validate the time-dependent decline in (A) neutralizing antibody titers and 17DD-YF Memory-related (B) phenotypic and (C) functional features. Data are expressed as scattering distribution of individual values along distinct time-points after 17DD-YF primary vaccination against neutralizing antibody titers (PRNT) as well as phenotypic and functional features (YF-Ag/CC Index). Spearman’s correlation test was applied to identify significant time-dependent loss of memory-related biomarkers. Correlation indices (p and r) along with the 95% confidence band of the best-fit line are provided in the figure. Attributes with higher correlation indices (r values) are highlighted with gray background.</p

Overall 17DD-YF memory-related biomarker signatures at distinct time-points after primary vaccination.

<p>The phenotypic/functional biomarker signatures were built taking the proportion of subjects above the cut-off edges defined for each attribute, calculated as the median index value (17DD-YF/Control) for the study population. Diagrams were constructed for all study groups to calculate the proportion (%) of volunteers above the median cut-off indices for each biomarker (gray-shaded spots). (A) The PV(day30-45) group was used to construct the memory-related phenotypic and functional biomarker signatures and draw the reference curves, used for comparative analysis amongst the study groups, (B) NV(day0), (C) PV(year1-9) and (D) PV(year10-11). Hatched cells represent unavailable results. Data mining was carried out as proposed previously by Luiza-Silva et al., (2011), selecting from the PV(day30-45) reference curves, those biomarkers with more than 50% of volunteers above the cut-off index (surrounded by dashed rectangles). Comparative analysis amongst the study groups were carried out considering only the selected set of relevant biomarkers from the phenotypic and functional reference curves. Substantial change in the set of relevant biomarkers were highlighted by (*) when the proportion of subjects above the cut-off fell below 50%. The common set of relevant biomarkers on each study group was underscored in bold font.</p

Major phenotypic/functional biomarkers useful to monitor the memory status following primary 17DD-YF vaccination.

<p>(A) Decision tree analysis was carried out to identify root attributes [Ellipses] for phenotypic/functional (P&F) biomarkers amongst NV(day0)&PV(year10-11) [white rectangle] and PV(day30-45)&PV(year1-9) [black rectangle], considered biomarkers to discriminate unprotected from protected subjects. Leave-one-out-cross-validation analysis (LOOCV) was employed to minimize biased performance estimates by using all data set for decision tree model fitting. EMCD8 and IL-5CD4 were selected as major phenotypic and functional 17DD-YF Memory-related biomarkers, respectively. (B) Heatmaps were built, taking the mean index of the top-two phenotypic/functional biomarkers (EMCD8 & IL-5CD4) and demonstrating the proportion (%) of volunteers ranging from low (White) to high (Gray) YF-Ag/CC index. A scatter plot was constructed to show the sensitivity (Gray Circle) and specificity (White Circle) of the top-two biomarkers, employing the cut-off edge (Mean Index = 1.3) provided by the ROC curve analysis. (C) Resultant memory status was defined for each subject, considering the top-two biomarkers (Mean Index >1.3) and PRNT (>2.9 Log mIU/mL, according to Simões et al., 2012). Column statistics were used to calculate the proportion of subjects displaying differing categories of resultant memory, referred as none, top-two biomarkers—P&F, PRNT and both. (D) Pie charts illustrated the overall resultant memory status within each category, as determined by the top-two biomarkers and PRNT. Significant differences at p<0.05 (Chi-square test) of resultant memory status amongst study groups were represented by letters “a”, b”, “c” and “d” in comparison to NV(day0), PV(day30-45), PV(year1-9) and PV(year10-11), respectively.</p

17DD-YF memory-related biomarker signatures according to the age at primary vaccination.

<p>The memory-related biomarker signatures were constructed using the proportion of subjects above the cut-off edges defined for each attribute, calculated as the median index value (17DD-YF/Control) for the study population. The signatures were constructed for phenotypic/functional biomarkers, compiling the proportion (%) of volunteer above the median cut-off indices. The memory-related biomarker signatures, constructed for the PV(day30-45) group, were used as the reference curves for comparative analysis amongst the PV(year10-11) subgroups, categorized according to the age at primary vaccination, including (A) 20–30 years old, (B) 31–40 years old and (C) 41–74 years old. Comparative analysis were carried out considering only the set of relevant biomarkers pre-selected from the phenotypic/functional reference curves (surrounded by dashed rectangles), including those biomarkers with more than 50% of volunteers above the cut-off index in the PV(day30-45) reference curves (surrounded by dashed rectangles). Substantial changes in the set of relevant biomarkers were underscored by (*) when the proportion of subjects above the cut-off fell below 50%. The common set of relevant biomarkers on each study group was underscored in bold font.</p