52,679 research outputs found

    Science, Technology and Innovation for Public Health in Africa

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    "African countries face formidable challenges in public health, particularly with the rapid spread of HIV/AIDS and the persistence of malaria and related killer diseases such as tuberculosis which wreck havoc with people’s lives. Other challenges the African countries are experiencing include the deterioration of health infrastructures and low and declining investments in health research. For many of these countries, this state of affairs has resulted in a considerable drop in life expectancy in the last two decades. This is particularly so in the sub-Saharan Africa where the burden of disease is pervasive and most pronounced..."NEPA

    Determinantes genéticos de resistência cruzada entre a terapêutica da malaria com novos compostos

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    Tese de doutoramento em Envelhecimento e Doen√ßas Cr√≥nicasIn 2019, malaria caused half a million deaths worldwide, being elimination hampered by the ability of Plasmodium falciparum to evolve antimalarial resistance. The efficacy of artemisinin-based combination therapies (ACT) helped to reduce malaria mortality, however, resistance is a reality. Being ACT efficacy threatened, efforts to define the molecular basis of multidrug resistance and the search for new compound, ideally with new mechanisms of action, are urgently in need. Within the parasite, most of the available antimalarials act at the host‚Äôs intraerythrocytic stage. Here, many drugs are housed in the digestive vacuole of the parasite with flux promoted by transporter proteins, such as the Plasmodium falciparum multidrug resistance protein 1 (PfMDR1), a well-known ACT resistance player. We explored the interplay of known pfmdr1 resistance markers, namely, gene copy number variation with N86Y and Y184F single nucleotide polymorphisms to unravel the complex traits that might serve to maximize ACT resistance. Using genomic epidemiology, a global prevalence and temporal changes of pfmdr1 polymorphisms were assessed and, taking into account the information from this database, through a gene editing approach, we create in vitro edited parasite lines to evaluate the impact of these polymorphisms in the kinetics of the transporter. This data provided evidence of specific multicopy PfMDR1 with N86/184F haplotype, geographic selection and expansion in Southeast Asia. The genetic tools created could help on finding drugs with potential of reverting a multidrug resistance phenotype, as the herein explored synthetic compounds derived from steroids, a class of molecules with relevant biological activities. Structure‚Äďactivity relationship led to the synthesis of steroid derivatives with promising antimalarial activity against the blood stage of the parasite‚Äôs life cycle with high selectivity and independent of PfMDR1. Exploring possible mechanisms of action of the best compound, revealed induction of oxidative stress inside the parasite and interference with the metabolic process that leads to hemozoin formation inside the digestive vacuole of the parasite. Overall, the findings presented could help tailor and optimize present antimalarial drug usage by taking into account the regional prevalence of pfmdr1 polymorphisms and highlights the high potential of the newly developed compounds, thereby underscoring the possibility to develop new antimalarial drugs based on steroids.Em 2019, a mal√°ria causou meio milh√£o de mortes mundialmente, sendo a elimina√ß√£o dificultada pela capacidade do Plasmodium falciparum desenvolver resist√™ncia aos antimal√°ricos atuais. A efic√°cia da terapia de combina√ß√£o baseadas em artemisinina (ACT) ajudou a reduzir a mortalidade provocada pela mal√°ria, no entanto, a resist√™ncia √© uma realidade. A efic√°cia do ACT est√° comprometida, as tentativas para definir as bases moleculares da multirresist√™ncia e a procura por novos compostos, idealmente com novos mecanismos de a√ß√£o, s√£o urgentes. No parasita, a maioria dos antimal√°ricos atua no estadio intra-eritroc√≠tico. Muitos s√£o alojados no vac√ļolo digestivo do parasita atrav√©s do fluxo promovido por prote√≠nas transportadoras, como a ‚ÄúPlasmodium falciparum multidrug resistance protein 1‚ÄĚ (PfMDR1), um fator envolvido na resist√™ncia aos ACTs. Neste trabalho foi explorada a intera√ß√£o de marcadores de resist√™ncia conhecidos no pfmdr1, ou seja, varia√ß√£o do n√ļmero de c√≥pias do gene com polimorfismos no nucle√≥tido N86Y e Y184F para tentar descobrir as caracter√≠sticas que ajudam a maximizar a resist√™ncia aos ACTs. Usando epidemiologia gen√≥mica, a preval√™ncia e altera√ß√Ķes temporais dos polimorfismos no pfmdr1 foram avaliadas tendo em considera√ß√£o a informa√ß√£o obtida desta base de dados, atrav√©s de edi√ß√£o de genes, geramos in vitro parasitas editados para avaliar o impacto desses polimorfismos na cin√©tica do transportador. Isto desvendou evid√™ncias acerca do hapl√≥tipo espec√≠fico de multic√≥pias com N86/184F, sobre a sele√ß√£o geogr√°fica e expans√£o no Sudeste Asi√°tico. As ferramentas gen√©ticas criadas podem auxiliar na descoberta de f√°rmacos com potencial para reverter o fen√≥tipo de resist√™ncia, como os compostos sint√©ticos derivados de ester√≥ides explorados nesta tese, uma classe de mol√©culas com atividade biol√≥gica relevante. A rela√ß√£o estrutura-atividade levou √† s√≠ntese de ester√≥ides com uma atividade promissora contra o estadio intra-eritroc√≠tico do ciclo de vida do parasita com grande seletividade e independ√™ncia do PfMDR1. Os mecanismos de a√ß√£o do melhor composto foi tamb√©m explorados, revelando indu√ß√£o de stress oxidativo no parasita e uma interfer√™ncia no processo metab√≥lico que leva √† forma√ß√£o de hemozo√≠na. Concluindo, os resultados apresentados podem ajudar a adaptar e otimizar o uso dos antimal√°ricos atuais, tendo em considera√ß√£o a preval√™ncia regional dos polimorfismos no pfmdr1 e, destaca tamb√©m o grande potencial dos compostos recentemente desenvolvidos, demonstrando a possibilidade de desenvolver novos antimal√°ricos baseados em ester√≥ides.Financial support was provided by grants from the PD/BD/127826/2016, ICVS Scientific Microscopy Platform, member of the national infrastructure PPBI - Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122; by National funds, through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020; by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF

    Proteome-wide antigenic profiling in Ugandan cohorts identifies associations between age, exposure intensity, and responses to repeat-containing antigens in Plasmodium falciparum

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    Protection against Plasmodium falciparum, which is primarily antibody-mediated, requires recurrent exposure to develop. The study of both naturally acquired limited immunity and vaccine induced protection against malaria remains critical for ongoing eradication efforts. Towards this goal, we deployed a customized P. falciparum PhIP-seq T7 phage display library containing 238,068 tiled 62-amino acid peptides, covering all known coding regions, including antigenic variants, to systematically profile antibody targets in 198 Ugandan children and adults from high and moderate transmission settings. Repeat elements ‚Äď short amino acid sequences repeated within a protein ‚Äď were significantly enriched in antibody targets. While breadth of responses to repeat-containing peptides was twofold higher in children living in the high versus moderate exposure setting, no such differences were observed for peptides without repeats, suggesting that antibody responses to repeat-containing regions may be more exposure dependent and/or less durable in children than responses to regions without repeats. Additionally, short motifs associated with seroreactivity were extensively shared among hundreds of antigens, potentially representing cross-reactive epitopes. PfEMP1 shared motifs with the greatest number of other antigens, partly driven by the diversity of PfEMP1 sequences. These data suggest that the large number of repeat elements and potential cross-reactive epitopes found within antigenic regions of P. falciparum could contribute to the inefficient nature of malaria immunity

    The Design, Synthesis and Evaluation of Novel Metalloaminopeptidase Inhibitors

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    Approximately 247 million infections and 619,000 deaths associated with malaria were recorded in 2021. Malaria caused by Plasmodium falciparum has two enzymes, PfA-M1 and PfA-M17, which play vital roles in the fitness and survival of malaria parasites. Inhibition of PfA-M1 and PfA-M17 results in parasite death. Using the structures of PfA-M1 and PfA-M17, a range of new inhibitors were designed, synthesised, and evaluated for use as potential antimalarial agents. Several of these new compounds were found to be potent inhibitors of PfA-M1 and inhibited malaria parasites, with this work paving the way towards a new class of antimalarial therapy

    Environmental surveillance for Salmonella Typhi as a tool to estimate the incidence of typhoid fever in low-income populations.

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    Background: The World Health Organisation recommends prioritised use of recently prequalified typhoid conjugate vaccines in countries with the highest incidence of typhoid fever. However, representative typhoid surveillance data are lacking in many low-income countries because of the costs and challenges of diagnostic clinical microbiology. Environmental surveillance (ES) of Salmonella Typhi in sewage and wastewater using molecular methods may offer a low-cost alternative, but its performance in comparison with clinical surveillance has not been assessed. Methods: We developed a harmonised protocol for typhoid ES and its implementation in communities in India and Malawi where it will be compared with findings from hospital-based surveillance for typhoid fever. The protocol includes methods for ES site selection based on geospatial analysis, grab and trap sample collection at sewage and wastewater sites, and laboratory methods for sample processing, concentration and quantitative polymerase chain reaction (PCR) to detect Salmonella Typhi. The optimal locations for ES sites based on digital elevation models and mapping of sewage and river networks are described for each community and their suitability confirmed through field investigation. We will compare the prevalence and abundance of Salmonella Typhi in ES samples collected each month over a 12-month period to the incidence of blood culture confirmed typhoid cases recorded at referral hospitals serving the study areas. Conclusions: If environmental detection of Salmonella Typhi correlates with the incidence of typhoid fever estimated through clinical surveillance, typhoid ES may be a powerful and low-cost tool to estimate the local burden of typhoid fever and support the introduction of typhoid conjugate vaccines. Typhoid ES could also allow the impact of vaccination to be assessed and rapidly identify circulation of drug resistant strains

    Un equipo del ISCIII participa en una investigaci√≥n internacional que revela el primer ‚Äėmapa‚Äô gen√≥mico del par√°sito causante de la babesiosis

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    Noticia publicada en la web del ISCIII, el 24/04/2023.Un equipo del Centro Nacional de Microbiolog√≠a (CNM) del Instituto de Salud Carlos III (ISCIII) ha participado en una investigaci√≥n internacional que ha desvelado la primera secuencia completa y la estructura tridimensional (3D) del genoma del par√°sito Babesia duncani‚Äč, microorganismo causante de la babesiosis, una enfermedad similar a la malaria. Los resultados de este estudio, que se ha coordinado desde las universidades de Yale y California, en Estados Unidos, acaban de publicarse en la revista Nature Microbiology.N

    A Stylistic Analysis of President Nana Addo Dankwa Akufo-Addo’s Update on Ghana’s Enhanced Response to Covid-19 Pandemic

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    This paper analyzes President Nana Addo Dankwa Akufo-Addo’s speech update on Ghana’s enhanced response to Covid-19 pandemic through a stylistic framework. The paper adopts a qualitative method with the aim of finding out the linguistic features ingrained in the speaker’s speech and its effect on the speech to the audience. The study reveals that the selected speech embodies a bevy of (these) linguistic elements: Graphology, syntactic features (multiple sentence, complex sentence, compound sentence), phrases, pronouns, modal verbs, coordinating conjunction and literary devices - repetition, parallel structures and simile. Consequently, the study reveals that the linguistic tools launched in the speaker’s speech help him to carry out his intention to the audience; and as well enables him to win a score of admiration from the audience during the era of COVID-19. The findings of this study have implication on formal stylistics. Thus, it contributes to knowledge on stylistic analysis of presidential speeches in Ghana and by extension, Africa. Keywords: Covid-19, language, speech, Stylistics. DOI: 10.7176/JLLL/97-01 Publication date:March 31st 202

    Impact of Population Based Indoor Residual Spraying with and without Mass Drug Administration with Dihydroartemisinin-Piperaquine on Malaria Prevalence in a High Transmission Setting: A Quasi-Experimental Controlled Before-and-After Trial in Northeastern Uganda

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    Background: Declines in malaria burden in Uganda have slowed. Modelling predicts that indoor residual spraying (IRS) and mass drug administration (MDA), when co-timed, have synergistic impact. This study investigated additional protective impact of population-based MDA on malaria prevalence, if any, when added to IRS, as compared with IRS alone and with standard of care (SOC). Methods: The 32-month quasi-experimental controlled before-and-after trial enrolled an open cohort of residents (46,765 individuals, 1st enumeration and 52,133, 4th enumeration) of Katakwi District in northeastern Uganda. Consented participants were assigned to three arms based on residential subcounty at study start: MDA+IRS, IRS, SOC. IRS with pirimiphos methyl and MDA with dihydroartemisinin- piperaquine were delivered in 4 co-timed campaign-style rounds 8‚ÄČmonths apart. The primary endpoint was population prevalence of malaria, estimated by 6 cross-sectional surveys, starting at baseline and preceding each subsequent round. Results: Comparing malaria prevalence in MDA+IRS and IRS only arms over all 6 surveys (intention-to-treat analysis), roughly every 6‚ÄČmonths post-interventions, a geostatistical model found a significant additional 15.5% (95% confidence interval (CI): [13.7%, 17.5%], Z‚ÄČ=‚ÄČ9.6, p‚ÄČ=‚ÄČ5e‚ąí20) decrease in the adjusted odds ratio (aOR) due to MDA for all ages, a 13.3% reduction in under 5‚Äôs (95% CI: [10.5%, 16.8%], Z‚ÄČ=‚ÄČ4.02, p‚ÄČ=‚ÄČ5e‚ąí5), and a 10.1% reduction in children 5‚Äď15 (95% CI: [8.5%, 11.8%], Z‚ÄČ=‚ÄČ4.7, p‚ÄČ=‚ÄČ2e‚ąí5). All ages residents of the MDA + IRS arm enjoyed an overall 80.1% reduction (95% CI: [80.0%, 83.0%], p = 0.0001) in odds of qPCR confirmed malaria compared with SOC residents. Secondary difference-in-difference analyses comparing surveys at different timepoints to baseline showed aOR (MDA + IRS vs IRS) of qPCR positivity between 0.28 and 0.66 (p \u3c 0.001). Of three serious adverse events, one (nonfatal) was considered related to study medications. Limitations include the initial non-random assignment of study arms, the single large cluster per arm, and the lack of an MDA-only arm, considered to violate equipoise. Conclusions: Despite being assessed at long time points 5‚Äď7‚ÄČmonths post-round, MDA plus IRS provided significant additional protection from malaria infection over IRS alone. Randomized trials of MDA in large areas undergoing IRS recommended as well as cohort studies of impact on incidence

    Annual number of malaria cases trend in the irrigated and non-irrigated villages, South Ethiopia, 2013‚Äď2020.

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    Annual number of malaria cases trend in the irrigated and non-irrigated villages, South Ethiopia, 2013‚Äď2020.</p
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