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Background: Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti-factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown. Objectives: The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome. Methods: In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates. Results: We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti-recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; P < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; P < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome. Conclusion: Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.

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BACKGROUND: Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high-responding inhibitor (PwHA-HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI (∆tinhi-ITI ) is debatable. OBJECTIVE: The aim of this study was to evaluate this association among a large cohort of severe PwHA-HRi. METHODS: Severe (factor VIII activity level <1%) PwHA-HRi on ITI (n = 142) were enrolled in 15 hemophilia treatment centers. PwHA-HRi were treated according to the Brazilian ITI Protocol. ITI outcomes were defined as success (i.e., recovered responsiveness to exogenous FVIII) and failure (i.e., no responsiveness to exogenous FVIII and requirement of bypassing agents to control bleeding). RESULTS: Median ages at inhibitor detection and at ITI start were 3.2 years (interquartile range [IQR], 1.6-8.1) and 6.9 years [IQR, 2.6-20.1), respectively. PwHA-HRi were stratified according to ∆tinhi-ITI quartiles: first (0.0-0.6 year), second (>0.6-1.7 year), third (>1.7-9.2 years), and fourth quartile (>9.2-24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. CONCLUSION: In conclusion, delayed ITI start is not associated with failure of ITI in PwHA-HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start.

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Hemophilia A (HA) is an inherited bleeding disorder which requires continuous replacement with factor (F) VIII concentrate. The main complication of HA is the development of neutralizing alloantibodies which inhibit FVIII activity (inhibitors). The objective of this study was to investigate the effect of the first FVIII infusions on immunological biomarkers in previously untreated patients with HA. Plasma samples were collected at enrollment before any FVIII infusion (T0) and at inhibitor development (INB +/T1) or up to 35 exposure days without inhibitors (INB -/T1). Anti-FVIII antibodies (immunoglobulin M, immunoglobulin G [IgG] 1, IgG3, and IgG4), chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10), and cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, interferon-γ, tumor necrosis factor, and IL-17) were assessed. A total of 71 children with severe HA were included, of whom 28 (39.4%) developed inhibitors. Plasma levels of anti-FVIII IgG4, IL-6, and CXCL8 were higher at INB +/T1 when compared with INB -/T1. This group presented a mixed cytokine profile and higher plasma levels of CXCL9 and CXL10 when compared with INB +/T1. We conclude that exposure to FVIII triggers a proinflammatory response mediated by IL-6 and CXCL8 in patients with HA who developed inhibitors. Regardless of inhibitor status, the immune system of all HA patients is stimulated after infusions of FVIII.

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Since 2015 Brazil has experienced the social repercussions of the Zika virus epidemic, thus raising a debate about: difficulties of diagnosis; healthcare access for children with Zika Congenital Syndrome (ZCS); the search for benefits by affected families; social and gender inequalities; and a discussion on reproductive rights, among others. The objective of this article is to analyse access to specialized health services for the care of children born with ZCS in three North-eastern states of Brazil. This is an exploratory cross-sectional study which analyses recorded cases of microcephaly at the municipal level between 2015 and 2017. Most of the cases of ZCS were concentrated on the Northeast coast. Rio Grande do Norte and Paraiba had the highest incidence of microcephaly in the study period. The states of Bahia, Paraiba and Rio Grande do Norte were selected for their high incidence of microcephaly due to the Zika Virus. Socio-territorial vulnerability was stratified using access to microcephaly diagnosis and treatment indicators. The specialized care network was mapped according to State Health Secretaries Protocols. A threshold radius of 100 km was stablished as the maximum distance from municipalities centroids to specialised health care for children with microcephaly. Prenatal coverage was satisfactory in most of the study area, although availability of ultrasound equipment was uneven within states and health regions. Western Bahia had the lowest coverage of ultrasound equipment and lacked health rehabilitation services. ZCS's specialized health services were spread out over large areas, some of which were outside the affected patients' home municipalities, so displacements were expensive and very time consuming, representing an extra burden for the affected families. This study is the first to address accessibility of children with microcephaly to specialised health care services and points to the urgent need to expand coverage of these services in Brazil, especially in the northeastern states, which are most affected by the epidemic.

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Resumo O objetivo deste artigo é analisar a influência dos determinantes socioambientais da saúde na incidência de malária por Plasmodium vivax na fronteira franco-brasileira. O estudo foi realizado entre 2011 e 2015, no município de Oiapoque (AP), na Amazônia brasileira. Foram incluídos na amostra 253 indivíduos de ambos os sexos, de 10 a 60 anos de idade. Houve predominância de 63,64% (161/253) de casos de malária em adultos do sexo masculino. A faixa etária mais acometida foi de 20 a 29 anos, com 30% (76/253); 84,6% (214/253) dos pacientes não concluíram o ensino médio, e 29,6% (75/253) não concluíram o ensino primário. No aspecto ambiental, houve correlação negativa entre as precipitações pluviométricas e a incidência da malária por P. vivax (p=0,0026). Em termos de mobilidade, constatou-se considerável proporção de migrantes provenientes dos estados do Pará e do Maranhão (55,73%; 141/253). Por fim, os dados apontaram que 31,23% (79/253) dos casos de malária foram importados da Guiana Francesa. Em síntese, a transmissão da malária na fronteira franco-brasileira envolve fatores ecológico-ambientais, biológicos e sociais que se expressam na elevada vulnerabilidade social da população que vive e circula na zona fronteiriça, favorecendo a ocorrência de surtos e a permanência da enfermidade.

Abstract This study analyzes the influence of socio-environmental health determinants on the maintenance of Plasmodium vivax malaria at the borders between French Guiana and Brazil. This study was carried out between 2011 and 2015 in the city of Oiapoque, Amapá, situated in the Brazilian Amazon region. The sample included 253 individuals of both sexes aged between 10 and 60 years. The disease was predominant in 63.64% (161/253) adult males. The most affected age group was 20 to 29 years old, with 30% (76/253). About 84.6% did not complete high school, while 29.6% (75/253) of the cases had not finished the first degree. Concerning the environmental aspect, negative correlation was observed between rainfall and the incidence of P. vivax malaria (p=0.0026). In terms of mobility, there was a considerable influx of migrants from the states of Pará and Maranhão, with 55.73% (141/253). Lastly, the data indicated that 31.23% (79/253) of malaria cases were imported from French Guiana. In summary, the transmission of malaria in these particular borders involved ecological, environmental, biological and social factors, which are expressed in the high social vulnerability of the population living and circulating in the border zone, favoring the occurrence of outbreaks and the maintenance of the disease.

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BACKGROUND: The epidemiological surveillance of malaria is a necessary intervention for eliminating the disease from the planet. The international border zones of the Amazon continue to be highly vulnerable to malaria since population mobility impedes elimination. Although in the past few years, cases of malaria have had an essential reduction in Brazil, this trend was not confirmed in municipalities along the border. This study aimed to establish the epidemiology of the disease during the last 13 years in Oiapoque, a Brazilian municipality at the international border with French Guiana, an overseas department, to develop strategies for the control/elimination of malaria in these areas. RESULTS: Data collected from 2003 to 2015 from the Malaria Epidemiological Surveillance System was used. It was found that, despite the important reduction in cases (68.1%), the annual parasite index remained a high epidemiological risk. The disease is seasonal in that the period of highest transmission occurs between September and December. Between 2003 and 2015, eight outbreaks were identified, with one of these lasting 15 months between August 2006 and October 2007. There were changes in the epidemiological profile, with imported cases representing 67.7% of cases from 2003 to 2007 and representing 32.9% of cases from 2008 to 2015 (p < 0.01). The greatest number of cases was among Brazilians coming from the artisanal gold mines of French Guiana. There were also changes in the profile of autochthonous malaria with an increase in urban cases from 14.3% in 2003 to 32.3% in 2015 (p < 0 .01). The burden of malaria in indigenous areas was also very high (67.3% in rural areas) in 2015. There were changes in the parasite species profile with a significant decrease of cases of Plasmodium falciparum (p = 0.01). Children under 15 years old, representing 9.7% of cases at the onset of the study, accounted for 34.2% of case notifications (p < 0.01) in 2015. Also, 74% of cases in 2003 and 55.9% in 2015 (p < 0.01) were among men. CONCLUSIONS: The fragility of local health services in cross-border areas continues to be an obstacle for malaria elimination.

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Previous cross-sectional studies showed that some patients with haemophilia A (HA) without inhibitor presented a pro-inflammatory profile during factor VIII (FVIII) replacement therapy. Furthermore, an anti-inflammatory/regulatory state was described in HA patients after inhibitor development. However, no study investigated the levels of these biomarkers before exposure to exogenous FVIII. This study investigated the immunological profile of previously untreated patients (PUPs) with HA in comparison with non-haemophiliac boys. A panel of chemokines and cytokines was evaluated in the plasma of 40 PUPs with HA and 47 healthy controls. The presence of microparticles was assessed in the plasma of 32 PUPs with HA and 47 healthy controls. PUPs with HA presented higher levels of CXCL8 (IL8), IL6, IL4, IL10, IL2, IL17A (IL17), and lower levels of CXCL10 (IP-10) and CCL2 (MCP-1) than the age-matched healthy controls (P < 0·05). We also observed higher levels of microparticles derived from endothelium, erythrocytes, platelets, leucocytes, neutrophils, and T lymphocytes in patients in comparison with controls (P < 0·05). Compared with controls, PUPs with HA presented a distinct immunological profile, characterized by a prominent pro-inflammatory status that appears to be regulated by IL4 and IL10.

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There are few studies about transvaginal ultrasound-guided follicle aspiration in equine medicine regarding potential complications to future fertility of aspirated mares. In order to evaluate the effect of follicular aspiration on subsequent fertility in mares, two experiments were conducted. In Experiment I, fifteen Criollo mares were allocated to one of three groups according to the diameter of the aspirated follicle during estrus: 25-29mm (n=4; Group 1); 30-34mm (n=6; Group 2); > 35mm (n=5; Group 3) and control group (n=15; Group 4). In Experiment II, the follicular aspiration was attempted in twenty-five mares during diestrous, when at least four follicles (> 5mm) were seen in the transrectal ultrasonography of both ovaries. All visible follicles, between 4 and 8 mm, were aspirated. Thirty-one mares served as control. In Experiments I and II, the pregnancy rates in the following cycle after aspiration were 75.0% (Group 1), 83.3% (Group 2), 60.0% (Group 3), and 73.3% (Group 4 - Control); and 76.0% in the aspirated diestrous group and 77.4% in the control group (non aspirated), respectively. On both experiments, pregnancy rates were similar (P>0.05) in treated and control mares. The results of this study show that the conception rates of the first estrus period following follicular aspiration are not affected by the procedure.

Há poucos estudos sobre aspiração folicular transvaginal guiada por ultrassom na medicina equina abordando complicações futuras na fertilidade das éguas aspiradas. Com o objetivo de avaliar o efeito da aspiração folicular na fertilidade das éguas, foram conduzidos dois experimentos. No experimento I, 15 éguas da raça Crioula foram distribuídas em três grupos de acordo com o diâmetro do folículo aspirado durante o estro: 25-29mm (n=4; grupo 1); 30-34mm (n=6; grupo 2); > 35mm (n=5; grupo 3) e grupo controle (n=15; grupo 4). No experimento II, a aspiração folicular foi realizada em 25 éguas durante o diestro quando pelo menos 4 folículos (>5mm) foram observados na ultrassonografia transretal em ambos os ovários. Foram aspirados todos os folículos visíveis, entre 4 e 8 mm. Trinta e uma éguas serviram como controle. No experimento I, a taxa de prenhez no ciclo seguinte a aspiração foi de 75% (grupo 1), 83,3% (grupo 2), 60% (grupo 3), e 73,3% (grupo 4). No experimento II foi de 76% no grupo aspirado e 77,4% no grupo controle (não aspirado). Em ambos os experimentos, as taxas de prenhez foram similares (P>0,05). Os resultados mostram que a taxa de concepção no primeiro ciclo após a aspiração folicular não é afetada pelo procedimento.

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There are few studies about transvaginal ultrasound-guided follicle aspiration in equine medicine regarding potential complications to future fertility of aspirated mares. In order to evaluate the effect of follicular aspiration on subsequent fertility in mares, two experiments were conducted. In Experiment I, fifteen Criollo mares were allocated to one of three groups according to the diameter of the aspirated follicle during estrus: 25-29mm (n=4; Group 1); 30-34mm (n=6; Group 2); > 35mm (n=5; Group 3) and control group (n=15; Group 4). In Experiment II, the follicular aspiration was attempted in twenty-five mares during diestrous, when at least four follicles (> 5mm) were seen in the transrectal ultrasonography of both ovaries. All visible follicles, between 4 and 8 mm, were aspirated. Thirty-one mares served as control. In Experiments I and II, the pregnancy rates in the following cycle after aspiration were 75.0% (Group 1), 83.3% (Group 2), 60.0% (Group 3), and 73.3% (Group 4 - Control); and 76.0% in the aspirated diestrous group and 77.4% in the control group (non aspirated), respectively. On both experiments, pregnancy rates were similar (P>0.05) in treated and control mares. The results of this study show that the conception rates of the first estrus period following follicular aspiration are not affected by the procedure.(AU)

Há poucos estudos sobre aspiração folicular transvaginal guiada por ultrassom na medicina equina abordando complicações futuras na fertilidade das éguas aspiradas. Com o objetivo de avaliar o efeito da aspiração folicular na fertilidade das éguas, foram conduzidos dois experimentos. No experimento I, 15 éguas da raça Crioula foram distribuídas em três grupos de acordo com o diâmetro do folículo aspirado durante o estro: 25-29mm (n=4; grupo 1); 30-34mm (n=6; grupo 2); > 35mm (n=5; grupo 3) e grupo controle (n=15; grupo 4). No experimento II, a aspiração folicular foi realizada em 25 éguas durante o diestro quando pelo menos 4 folículos (>5mm) foram observados na ultrassonografia transretal em ambos os ovários. Foram aspirados todos os folículos visíveis, entre 4 e 8 mm. Trinta e uma éguas serviram como controle. No experimento I, a taxa de prenhez no ciclo seguinte a aspiração foi de 75% (grupo 1), 83,3% (grupo 2), 60% (grupo 3), e 73,3% (grupo 4). No experimento II foi de 76% no grupo aspirado e 77,4% no grupo controle (não aspirado). Em ambos os experimentos, as taxas de prenhez foram similares (P>0,05). Os resultados mostram que a taxa de concepção no primeiro ciclo após a aspiração folicular não é afetada pelo procedimento.(AU)

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RESUMO

There are few studies about transvaginal ultrasound-guided follicle aspiration in equine medicine regarding potential complications to future fertility of aspirated mares. In order to evaluate the effect of follicular aspiration on subsequent fertility in mares, two experiments were conducted. In Experiment I, fifteen Criollo mares were allocated to one of three groups according to the diameter of the aspirated follicle during estrus: 25-29mm (n=4; Group 1); 30-34mm (n=6; Group 2); > 35mm (n=5; Group 3) and control group (n=15; Group 4). In Experiment II, the follicular aspiration was attempted in twenty-five mares during diestrous, when at least four follicles (> 5mm) were seen in the transrectal ultrasonography of both ovaries. All visible follicles, between 4 and 8 mm, were aspirated. Thirty-one mares served as control. In Experiments I and II, the pregnancy rates in the following cycle after aspiration were 75.0% (Group 1), 83.3% (Group 2), 60.0% (Group 3), and 73.3% (Group 4 - Control); and 76.0% in the aspirated diestrous group and 77.4% in the control group (non aspirated), respectively. On both experiments, pregnancy rates were similar (P>0.05) in treated and control mares. The results of this study show that the conception rates of the first estrus period following follicular aspiration are not affected by the procedure.

Há poucos estudos sobre aspiração folicular transvaginal guiada por ultrassom na medicina equina abordando complicações futuras na fertilidade das éguas aspiradas. Com o objetivo de avaliar o efeito da aspiração folicular na fertilidade das éguas, foram conduzidos dois experimentos. No experimento I, 15 éguas da raça Crioula foram distribuídas em três grupos de acordo com o diâmetro do folículo aspirado durante o estro: 25-29mm (n=4; grupo 1); 30-34mm (n=6; grupo 2); > 35mm (n=5; grupo 3) e grupo controle (n=15; grupo 4). No experimento II, a aspiração folicular foi realizada em 25 éguas durante o diestro quando pelo menos 4 folículos (>5mm) foram observados na ultrassonografia transretal em ambos os ovários. Foram aspirados todos os folículos visíveis, entre 4 e 8 mm. Trinta e uma éguas serviram como controle. No experimento I, a taxa de prenhez no ciclo seguinte a aspiração foi de 75% (grupo 1), 83,3% (grupo 2), 60% (grupo 3), e 73,3% (grupo 4). No experimento II foi de 76% no grupo aspirado e 77,4% no grupo controle (não aspirado). Em ambos os experimentos, as taxas de prenhez foram similares (P>0,05). Os resultados mostram que a taxa de concepção no primeiro ciclo após a aspiração folicular não é afetada pelo procedimento.

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This article aims to analyze the malaria surveillance situation on the triple border between Brazil, Colombia, and Peru. This was a qualitative study using questionnaires in the border towns in 2011. The results were analyzed with the SWOT matrix methodology, pointing to significant differences between the malaria surveillance systems along the border. Weaknesses included lack of linkage between actors, lack of trained personnel, high turnover in teams, and lack of malaria specialists in the local hospitals. The study also showed lack of knowledge on malaria and its prevention in the local population. The strengths are the inclusion of new institutional actors, improvement of professional training, distribution of insecticide-treated bed nets, and possibilities for complementary action between surveillance systems through cooperation between health teams on the border. Malaria control can only be successful if the region is dealt with as a whole.

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O objetivo deste artigo é analisar a situação da vigilância da malária na tríplice fronteira entre Brasil, Colômbia e Peru. É um estudo qualitativo com aplicação de questionários em cidades da fronteira realizado em 2011. Os resultados foram analisados pela metodologia DOFA e apontaram diferenças significativas entre os sistemas de vigilância da malária na fronteira. Observou-se como debilidades a desarticulação entre atores responsáveis, a insuficiência de pessoal treinado, a alta rotatividade das equipes e a falta de médicos especialistas em malária nos hospitais locais. Verificou-se ainda o desconhecimento sobre a malária e suas formas de prevenção na população entrevistada. As fortalezas são a inserção de novos atores institucionais, a melhora da qualificação profissional, a distribuição de mosquiteiros impregnados e possibilidades de complementaridade entre os sistemas de vigilância a serem aproveitadas pela cooperação entre as equipes de saúde da fronteira, pois o controle da malária só pode ter sucesso tomando-se esta região em seu conjunto.

This article aims to analyze the malaria surveillance situation on the triple border between Brazil, Colombia, and Peru. This was a qualitative study using questionnaires in the border towns in 2011. The results were analyzed with the SWOT matrix methodology, pointing to significant differences between the malaria surveillance systems along the border. Weaknesses included lack of linkage between actors, lack of trained personnel, high turnover in teams, and lack of malaria specialists in the local hospitals. The study also showed lack of knowledge on malaria and its prevention in the local population. The strengths are the inclusion of new institutional actors, improvement of professional training, distribution of insecticide-treated bed nets, and possibilities for complementary action between surveillance systems through cooperation between health teams on the border. Malaria control can only be successful if the region is dealt with as a whole.

El objetivo de este trabajo es analizar la situación de la vigilancia de la malaria en la triple frontera entre Brasil, Colombia y Perú. Se trata de un estudio cualitativo con cuestionarios en las ciudades fronterizas, llevado a cabo en 2011. Los resultados se analizaron mediante la metodología DOFA y mostraron diferencias significativas entre los sistemas de vigilancia de la malaria en la frontera. Se observaron debilidades como una desconexión entre el personal responsable y capacitado insuficientemente, la alta rotación de personal y la falta de médicos expertos en malaria en los hospitales locales. También hubo falta de conocimiento sobre la malaria y su prevención en la población entrevistada. Los puntos fuertes son la inclusión de nuevos actores institucionales, la mejora de la cualificación del personal, la distribución de mosquiteros impregnados y oportunidades de complementariedad entre los sistemas de vigilancia para que fueran disfrutados cooperativamente entre los equipos de salud de la frontera, porque el control de la malaria sólo puede tener éxito mediante la adopción de medidas de esta índole.

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