Internal validity of clinical trials for Plasmodium vivax malaria treatment

Resistência parasitária pode ser definida como a habilidade da cepa parasitária de sobreviver e/ou multiplicar, a despeito da administração e absorção da medicação dada em doses iguais ou superiores àquelas usualmente recomendadas, porém dentro do limite de tolerância dos indivíduos. Assim sendo, o desenho de estudo ideal para monitorizar a emergência da resistência parasitária aos antimaláricos deveria utilizar controles históricos ou alguma informação prévia (baseline) válida. Além disso, é fundamental que se tenha algum tipo de controle sobre os demais determinantes de falha terapêutica, não diretamente relacionados ao fenômeno biológico da resistência do parasita, os quais poderiam variar através do tempo e teriam potencial de distorcer a interpretação dos resultados de estudos dessa natureza. No presente artigo são feitas considerações sobre a validade interna de estudos que objetivam avaliar a emergência da resistência in vivo do Plasmodium vivax à doses padronizadas de primaquina usadas rotineiramente pelos serviços de saúde. Poucos foram os estudos que atentaram para a necessidade de controlar os determinantes externos da falha terapêutica, ou que se preocuparam em comparar os resultados encontrados com as taxas de cura historicamente observadas em uma dada região geográfica. Assim, recomenda-se que maior ênfase seja dada à validade interna (e limitações) das conclusões de estudos dessa natureza. _______________________________________________________________________________________ ABSTRACTParasite resistance can be defined as the ability of a parasite strain to survive and/or to multiply despite the administration and absorption of a drug given in doses equal or higher than those usually recommended, but within the limits of tolerance of the patients. Therefore, the ideal study design to be used to monitor emergence of parasite resistance would use historical controls or any valid baseline data. Moreover, it is desirable to have some control of remaining determinants of therapeutic failure, not related to biological parasite resistance, which could vary over time and would have potential to distort the analysis for detecting emergence of parasite resistance. Here we comment on the internal validity of studies, which aim to assess the in vivo Plasmodium vivax emergence of resistance to standard doses of primaquine used routinely by health services. Few studies have paid attention to the need to control for other determinant factors of therapeutic failures or made any attempt to compare current findings with cure failure rates of historical controls from a given geographical area. Therefore, attention to the internal validity (and limitations) of study conclusions in these types of study is strongly advised

Polymorphism at the apical membrane antigen 1 locus reflects the world population history of Plasmodium vivax

<p>Abstract</p> <p>Background</p> <p>In malaria parasites (genus <it>Plasmodium</it>), <it>ama-1 </it>is a highly polymorphic locus encoding the Apical Membrane Protein-1, and there is evidence that the polymorphism at this locus is selectively maintained. We tested the hypothesis that polymorphism at the <it>ama-1 </it>locus reflects population history in <it>Plasmodium vivax</it>, which is believed to have originated in Southeast Asia and is widely geographically distributed. In particular, we tested for a signature of the introduction of <it>P. vivax </it>into the New World at the time of the European conquest and African slave trade and subsequent population expansion.</p> <p>Results</p> <p>One hundred and five ama<it>-1 </it>sequences were generated and analyzed from samples from six different Brazilian states and compared with database sequences from the Old World. Old World populations of <it>P. vivax </it>showed substantial evidence of population substructure, with high sequence divergence among localities at both synonymous and nonsynonymous sites, while Brazilian isolates showed reduced diversity and little population substructure.</p> <p>Conclusion</p> <p>These results show that genetic diversity in <it>P. vivax </it>AMA-1 reflects population history, with population substructure characterizing long-established Old World populations, whereas Brazilian populations show evidence of loss of diversity and recent population expansion.</p> <p>Note</p> <p>Nucleotide sequence data reported is this paper are available in the GenBank™ database under the accession numbers <ext-link ext-link-type="gen" ext-link-id="EF031154">EF031154</ext-link> – <ext-link ext-link-type="gen" ext-link-id="EF031216">EF031216</ext-link> and <ext-link ext-link-type="gen" ext-link-id="EF057446">EF057446</ext-link> – <ext-link ext-link-type="gen" ext-link-id="EF05487">EF057487</ext-link></p

Safety, efficacy and pharmacokinetic evaluations of a new coated chloroquine tablet in a single-arm open-label non-comparative trial in Brazil: a step towards a user-friendly malaria vivax treatment

Additional file 1. Co-blister preliminary design. The figure provided is an illustrative package design of the chloroquine and primaquine co-blister

Increased polyclonal immunoglobulin reactivity toward human and bacterial proteins is associated with clinical protection in human Plasmodium infection

BACKGROUND: Polyclonal B-cell activation is well known to occur in Plasmodium infections, but its role in pathogenesis or protection remains unclear. However, protective properties of natural antibodies have previously been demonstrated in other contexts. METHODS: Sera from asymptomatic and symptomatic Plasmodium-infected subjects locally detected in a survey study in the Brazilian Amazon, and from unexposed and exposed but presently uninfected control subjects, were assayed by a standardized quantitative immunoblot method allowing simultaneous detection of IgG or IgM reactivity to a large number of parasite-unrelated proteins. RESULTS: In subjects free of coinfection with hepatitis B virus, IgG reactivity to human brain antigens and Escherichia coli proteins was strikingly enhanced in asymptomatic Plasmodium-infected individuals when compared to such with clinical malaria symptoms, or to uninfected control subjects. This difference was most characteristic for limited exposure times (less than ten years locally, or 20 years in endemic areas). It was more significant than a similar trend found for IgG to Plasmodium falciparum antigens, and unrelated to parasitaemia levels. Asymptomatic subjects with comparatively short exposure characteristically showed relatively elevated IgG versus IgM reactivity. Polyclonal IgG reactivity appears triggered by previous P. falciparum but not Plasmodium vivax malaria. CONCLUSION: The observed difference in polyclonal antibody production seems related to intrinsic activation states of infected individuals, rather than to parasite-antigen specific immune responses. However, it appears influenced by preceding stimuli. This supports the idea that acquired clinical immunity may not exclusively depend on antigen-specific responses, but also on the individual polyclonal reaction

Simultaneous infection of human host with genetically distinct isolates of Paracoccidioides brasiliensis

This study is the first report on genetic differences between isolates of Paracoccidioides brasiliensis from a single patient. We describe a simultaneous infection with genetically distinct isolates of P. brasiliensis in a patient with chronic paracoccidioidomycosis. The clinical isolates were obtained from lesions in different anatomical sites and were characterised by random amplified polymorphic DNA (RAPD) analysis. The RAPD technique can be helpful for distinguishing between clinical isolates. Different random primers were used to characterise these clinical isolates. The RAPD patterns allowed for differentiation between isolates and the construction of a phenetic tree, which showed more than 28% genetic variability in this fungal species, opening new possibilities for clinical studies of P. brasiliensis. Based on these results and preliminary clinical findings, we suggest that different genotypes of P. brasiliensis might infect the same patient, inducing the active form of the disease.Universidade Federal de Mato Grosso Faculdade de Ciências Médicas Laboratório de MicologiaUniversidade Federal de São Paulo (UNIFESP) Departamento de Microbiologia, Imunologia e ParasitologiaUniversidade de Cuiabá Hospital Geral Universitário Laboratório de MicologiaUNIFESP, Depto. de Microbiologia, Imunologia e ParasitologiaSciEL

Visceral leishmaniasis in a Brazilian endemic area: an overview of occurrence, HIV coinfection and lethality

The Brazilian municipality of Rondonópolis, Mato Grosso State, represents an important visceral leishmaniasis (VL) endemic area. This study described epidemiological and clinical aspects of the occurrence, VL/HIV coinfection and lethality related to VL in Rondonópolis. Data from autochthonous cases reported between 2011 and 2016 were obtained from official information systems. During this period, 81 autochthonous cases were reported, with decreasing incidence through 2016. Contrastingly, the lethality rate was 8.6% overall, but varied widely, reaching a peak (20%) in 2016. Almost 10% of patients had VL/HIVcoinfection. The occurrence of VL prevailed among men (56.8%), brown-skinned (49.4%), urban residents (92.6%), aged 0-4 years (33.3%). Housewives or retired (29.6%) were the most affected occupational groups. Lower age was the main difference among the total VL cases and those who were coinfected or died. Clinically, fever, weakness and splenomegaly were more frequent among all VL cases and VL/HIV coinfected individuals. Bacterial infections (p=0.001) and bleeding (

Síndrome de Burnout e qualidade de vida dos profissionais da atenção primária à saúde durante a pandemia de COVID-19, em município da Amazônia Brasileira

Introdução: Não bastassem as demandas de saúde tradicionalmente existentes na rede de Atenção Primária à Saúde (APS), uma pandemia viral de COVID-19 emergiu em 2019, acometendo centenas de milhares de indivíduos em todo o país, elevando sobremaneira a carga de trabalho desses profissionais. Objetivo: Avaliar a qualidade de vida e a prevalência da síndrome de burnout entre profissionais da APS de um município de médio porte da Amazônia brasileira, durante a pandemia de COVID-19. Método: Em estudo descritivo transversal, realizado no ano de 2021, com metodologia quantitativa, foram identificadas as características biopsicossociais de 164 profissionais envolvidos com a APS do município de Ji-Paraná, estado de Rondônia. Para investigar as dimensões descritas na síndrome de burnout, foi utilizado o inventário de burnout de Maslach. Para avaliação da percepção dos participantes sobre a sua qualidade de vida (QV), foi aplicado o questionário da Organização Mundial da Saúde sobre a qualidade de vida (WHOQOL-bref). Resultados: O domínio na QV com maior impacto negativo foi o ambiental. Em relação as dimensões existentes na síndrome de burnout, verificou-se que 33,5% cursam com alto grau de exaustão emocional e 84,4% apresentam alto grau de despersonalização. Conclusão: Constatou-se que a QV dos profissionais da APS foi comprometida principalmente no domínio ambiental e foi alto o grau de despersonalização na avaliação da síndrome de burnout, embora a percepção de realização profissional desses indivíduos permaneça alta

Contagem de borda e regra Dowdall: metodologia justa para a priorização de temas educacionais a serem ofertados para profissionais da atenção primária em saúde / Borda count and Dowdall rule: a fair methodology for prioritizing educational topics to be offered to primary health care professionals

Considerando a diversidade dos problemas de saúde existentes num dado território, a eleição e priorização de temas educacionais para a capacitação de profissionais de saúde constitui um desafio para os gestores de saúde. Espera-se que o método utilizado para esse fim deve buscar atender a diversidade e a escolha consensual da clientela. O presente estudo propõe a aplicação de uma nova metodologia para a priorização de temas educacionais a serem ofertados pelo Telessaúde Mato Grosso (Telessaúde-MT) aos profissionais vinculados à atenção primária em saúde (APS) de todo o estado. Para tanto, foi utilizada a chamada contagem de Borda e a regra Dowdall, baseadas em uma alternativa matemática de ponderação das escolhas, amplamente aceitável ou consensual, em vez de outra, preferida por uma maioria dos clientes, mas que não representa o consenso dos participantes. Todos os 14.054 profissionais de saúde das 977 Unidades Básicas de Saúde de Mato Grosso, identificadas no Cadastro Nacional de Estabelecimentos de Saúde, foram elegíveis para o estudo. Um formulário estruturado foi enviado a cada profissional, contendo questões sobre dados demográficos, ocupacionais e sobre temas relacionados às condições sensíveis à APS (CSAPS), os quais consideram relevantes para o programa de Tele-educação do Telessaúde-MT. Respostas válidas foram obtidas de 1221 (8,7%) profissionais que atenderam ao critério de estarem envolvidos na APS. Houve predominância do gênero feminino e de profissionais com mais de cinco anos de atuação na APS. A análise aqui apresentada restringe aos questionários respondidos pelos profissionais médicos (n=74) e enfermeiros (n=159). Pelo sistema plural, 59 temas clínicos de CSAPS foram ranqueados em ordem de prioridades por esses profissionais, com destaque para manejo das arboviroses endêmicas em primeira escolha (42 votos), seguido de exame citopatológico uterino com 36 votos, infecções sexualmente transmissíveis com 35 votos, hipertensão arterial sistêmica com 20 votos e depressão, com 16 votos. No entanto, após ranqueamento das escolhas e análise pela contagem de Borda e regra Dowdall, observou-se que o ranqueamento mudou, respectivamente, para 698 pontos e 59,8 pontos para arboviroses endêmicas, 1.084 e 74,9 pontos exame citopatológico uterino, 1.148 e 78,7 pontos para IST, 705 e 48,2 pontos hipertensão arterial sistêmica e 743 e 47,3 pontos para depressão. Portanto, constatou-se que usando a eleição por ordem de mérito, o tema mais votado foi IST, seguido de exame citopatológico uterino. Manejo das arboviroses endêmicas mudou para a última posição na contagem de Borda e para a terceira na regra Dowdall. Por serem métodos de eleição sabidamente mais consensuais, sua utilização no contexto da educação permanente em saúde de profissionais da atenção primária resulta em um ordenamento temático mais assertivo para atender as necessidades dos alunos

Allele-specific antibodies to Plasmodium vivax merozoite surface protein-1: prevalence and inverse relationship to haemoglobin levels during infection.

BACKGROUND: Antigenic polymorphisms are considered as one of the main strategies employed by malaria parasites to escape from the host immune responses after infections. Merozoite surface protein-1 (MSP-1) of Plasmodium vivax, a promising vaccine candidate, is a highly polymorphic protein whose immune recognition is not well understood. METHODS AND RESULTS: The IgG responses to conserved (MSP-119) and polymorphic (block 2 and block 10) epitopes of PvMSP-1 were evaluated in 141 P. vivax infected patients. Ten recombinant proteins corresponding to block 2 (variants BR07, BP29, BP39, BP30, BEL) and block 10 (BR07, BP29, BP39, BP01, BP13) often observed in Brazilian P. vivax isolates were assessed by ELISA in order to determine levels of specific antibodies and their respective seroprevalence. The magnitude and the frequency of variant-specific responses were very low, except for BR07 variant (>40%), which was the predominant haplotype as revealed by block 10 PvMSP-1 gene sequencing. By contrast, 89% of patients had IgG against the C-terminal conserved domain (PvMSP-119), confirming the high antigenicity of this protein. Using multiple linear and logistic regression models, there was evidence for a negative association between levels of haemoglobin and several IgG antibodies against block 2 variant antigens, with the strongest association being observed for BP39 allelic version. This variant was also found to increase the odds of anaemia in these patients. CONCLUSIONS: These findings may have implications for vaccine development and represent an important step towards a better understanding of the polymorphic PvMSP-1 domain as potential targets of vaccine development. These data highlight the importance of extending the study of these polymorphic epitopes of PvMSP-1 to different epidemiological settings

Clinical epidemiological profile of snake bite occurred in Cacoal county Rondônia, Brazil, 2011 and 2015

The main objective of this study is to describe the clinical and epidemiological profile of snakebite poisoning occurred in Cacoal, state of Rondonia, Brazil. Data were obtained from the National Surveillance Disease System (SINAN) of the Brazilian Ministry of Health, in which were found 72 notified cases of snake bites between 2011-2015. Most accidents was caused by snakes of Both rops and Lachesis genera, accounting for 75.0% and 6.9%, respectively. The snakebite incidence was higher in men, aged between 41 and 60 years old. The most affected site of the bite was the feet and the most prevalent clinical manifestations were local pain, swelling, bruise and vagal symptoms. All patients were treated with specific anti venom serum, except those whose bite was provoked by unknown snakes, which received the snake polyvalent anti venom. Local and/or systemic complications were not registered and all patients were considered cured. In the analyzed documentation, there was no information on the patient outcome. Therefore, the patients with snakebites from the Cacoal County have the same clinical and epidemiological profile described in many localities of the Brazilian Amazon. However, it is necessary to make the health team aware for the correct completion of the reporting forms, as well as starting the patient’s follow-up, in order to register their clinical outcom