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1.
Proc Natl Acad Sci U S A ; 114(52): E11267-E11275, 2017 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-29229808

RESUMO

Insecticide-based interventions have contributed to ∼78% of the reduction in the malaria burden in sub-Saharan Africa since 2000. Insecticide resistance in malaria vectors could presage a catastrophic rebound in disease incidence and mortality. A major impediment to the implementation of insecticide resistance management strategies is that evidence of the impact of resistance on malaria disease burden is limited. A cluster randomized trial was conducted in Sudan with pyrethroid-resistant and carbamate-susceptible malaria vectors. Clusters were randomly allocated to receive either long-lasting insecticidal nets (LLINs) alone or LLINs in combination with indoor residual spraying (IRS) with a pyrethroid (deltamethrin) insecticide in the first year and a carbamate (bendiocarb) insecticide in the two subsequent years. Malaria incidence was monitored for 3 y through active case detection in cohorts of children aged 1 to <10 y. When deltamethrin was used for IRS, incidence rates in the LLIN + IRS arm and the LLIN-only arm were similar, with the IRS providing no additional protection [incidence rate ratio (IRR) = 1.0 (95% confidence interval [CI]: 0.36-3.0; P = 0.96)]. When bendiocarb was used for IRS, there was some evidence of additional protection [interaction IRR = 0.55 (95% CI: 0.40-0.76; P < 0.001)]. In conclusion, pyrethroid resistance may have had an impact on pyrethroid-based IRS. The study was not designed to assess whether resistance had an impact on LLINs. These data alone should not be used as the basis for any policy change in vector control interventions.


Assuntos
Anopheles , Resistência a Medicamentos , Inseticidas , Malária Falciparum , Controle de Mosquitos/economia , Nitrilas , Fenilcarbamatos , Piretrinas , Animais , Criança , Pré-Escolar , Custos e Análise de Custo , Feminino , Humanos , Incidência , Inseticidas/economia , Inseticidas/farmacologia , Malária Falciparum/economia , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Masculino , Nitrilas/economia , Nitrilas/farmacologia , Fenilcarbamatos/economia , Fenilcarbamatos/farmacologia , Piretrinas/economia , Piretrinas/farmacologia , Sudão/epidemiologia
2.
Dig Dis Sci ; 64(7): 1809-1814, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30746632

RESUMO

BACKGROUND AND AIMS: IBD patients with inadequately treated disease often relapse and require hospitalizations for further management. The purpose of this practice review was to determine whether personalized IBD care improved patient outcomes as measured by IBD-related hospitalizations. METHODS: A dedicated IBD clinic was created for personalized patient care in a tertiary veterans health care center in 2014. In the first year, the care program consisted of patient-centered medical home (PCMH). In the second year, personalized biologic therapy was incorporated into the program, based on the severity of mucosal barrier dysfunction measured by probe-based confocal laser endomicroscopy (pCLE) analysis of the terminal ileum during colonoscopy. IBD-related hospitalizations during these 2 years were compared to the year before the care program. RESULTS: The IBD-related admissions at baseline, year 1 and 2 of the program were: total number of admissions of 25, 24, 8 (P = 0.03) per year, total number of hospital days of 177, 144, 31 days per year (P < 0.01), median length of stay 7, 4, and 2 days per visit (P = 0.013), respectively. Patients had significant increases in serum hemoglobin (11.5 ± 2.7, 11.9 ± 2.6, 14.0 ± 1.4 g/dl; P = 0.035), albumin (2.7 ± 0.7, 3.0 ± 0.6 g/dl 3.7 ± 0.8 g/dl; P = 0.031) and body mass index (26.6 ± 2.9, 28.1 ± 5.9; 34.0 ± 10.8; P = 0.047). CONCLUSIONS: Personalized IBD care incorporating a PCMH model and tailored biologic therapy based on pCLE findings of mucosal barrier dysfunction significantly reduced IBD-related hospitalizations.


Assuntos
Instituições de Assistência Ambulatorial , Produtos Biológicos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Avaliação de Processos e Resultados em Cuidados de Saúde , Admissão do Paciente , Assistência Centrada no Paciente , Serviços de Saúde para Veteranos Militares , Adulto , Idoso , Idoso de 80 Anos ou mais , Produtos Biológicos/efeitos adversos , Tomada de Decisão Clínica , Colonoscopia , Feminino , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Mucosa Intestinal/patologia , Tempo de Internação , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Seleção de Pacientes , Valor Preditivo dos Testes , Avaliação de Programas e Projetos de Saúde , Indicadores de Qualidade em Assistência à Saúde , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
4.
Toxicon ; 237: 107535, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38040061

RESUMO

The goal to reduce the burden of snakebite envenoming is challenged by the gaps in evidence for clinical care and public health. These evidence gaps and the absence of a strong network are illustrated by bibliometrics. The African Snakebite Alliance is a multidisciplinary group focusing on research themes which will generate evidence needed to shape policy and practice.


Assuntos
Mordeduras de Serpentes , Humanos , Mordeduras de Serpentes/epidemiologia , Antivenenos/uso terapêutico , Saúde Pública
5.
PLoS Negl Trop Dis ; 18(2): e0011957, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38363794

RESUMO

BACKGROUND: Lymphatic filariasis (LF) is a parasitic disease transmitted by mosquitoes, causing severe pain, disfiguring, and disabling clinical conditions such as lymphoedema and hydrocoele. LF is a global public health problem affecting 72 countries, primarily in Africa and Asia. Since 2000, the World Health Organization (WHO) has led the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to support all endemic regions. This paper focuses on the achievements of the Malawi LF Elimination Programme between 2000 and 2020 to eliminate LF as a public health problem, making it the second sub-Saharan country to receive validation from the WHO. METHODOLOGY/PRINCIPAL FINDINGS: The Malawi LF Programme addressed the widespread prevalence of LF infection and disease across the country, using the recommended WHO GPELF strategies and operational research initiatives in collaboration with key national and international partners. First, to stop the spread of infection (i.e., interrupt transmission) and reduce the circulating filarial antigen prevalence from as high as 74.4% to below the critical threshold of 1-2% prevalence, mass drug administration (MDA) using a two-drug regime was implemented at high coverage rates (>65%) of the total population, with supplementary interventions from other programmes (e.g., malaria vector control). The decline in prevalence was monitored and confirmed over time using several impact assessment and post-treatment surveillance tools including the standard sentinel site, spot check, and transmission assessment surveys and alternative integrated, hotspot, and easy-access group surveys. Second, to alleviate suffering of the affected populations (i.e., control morbidity) the morbidity management and disability prevention (MMDP) package of care was implemented. Specifically, clinical case estimates were obtained via house-to-house patient searching activities; health personnel and patients were trained in self-care protocols for lymphoedema and/or referrals to hospitals for hydrocoele surgery; and the readiness and quality of treatment and services were assessed with new survey tools. CONCLUSIONS: Malawi's elimination of LF will ensure that future generations are not infected and suffer from the disfiguring and disabling disease. However, it will be critical that the Malawi LF Elimination programme remains vigilant, focussing on post-elimination surveillance and MMDP implementation and integration into routine health systems to support long-term sustainability and ongoing success. SUMMARY: Lymphatic filariasis, also known as elephantiasis, is a disabling, disfiguring, and painful disease caused by a parasite that infected mosquitoes transmit to millions of people worldwide. Since 2000, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) has supported endemic countries such as Malawi in south-eastern Africa, to eliminate the disease as a public health problem. The Malawi National LF Elimination Programme has worked tirelessly over the past two decades to implement the GPELF recommended strategies to interrupt the transmission with a two-drug regime, and to alleviate suffering in patients with lymphoedema and/or hydrocoele through morbidity management and disability prevention. Additionally, the LF Programme has collaborated with national and international stakeholders to implement a range of supplementary operational research projects to address outstanding knowledge gaps and programmatic barriers. In 2020, the World Health Organisation validated that Malawi had successfully eliminated LF as a public health problem, making it the second country in sub-Saharan Africa to achieve this, which is remarkable given that Malawi previously had very high infection rates. The LF Programme now remains vigilant, putting its efforts towards post-elimination surveillance and the continued implementation of care for patients with chronic conditions. Malawi's elimination of LF will ensure that future generations are not affected by this devastating disease.


Assuntos
Anopheles , Filariose Linfática , Linfedema , Malária , Animais , Humanos , Filariose Linfática/tratamento farmacológico , Filariose Linfática/epidemiologia , Filariose Linfática/prevenção & controle , Saúde Pública , Malaui/epidemiologia , Mosquitos Vetores , Cegueira
6.
PLoS Negl Trop Dis ; 17(12): e0011838, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38091347

RESUMO

Snakebite envenoming is a debilitating neglected tropical disease disproportionately affecting the rural poor in low and middle-income countries in the tropics and sub-tropics. Critical questions and gaps in public health and policy need to be addressed if major progress is to be made towards reducing the negative impact of snakebite, particularly in the World Health Organisation (WHO) Africa region. We engaged key stakeholders to identify barriers to evidence-based snakebite decision making and to explore how development of research and policy hubs could help to overcome these barriers. We conducted an electronic survey among 73 stakeholders from ministries of health, health facilities, academia and non-governmental organizations from 15 countries in the WHO Africa region. The primary barriers to snakebite research and subsequent policy translation were limited funds, lack of relevant data, and lack of interest from policy makers. Adequate funding commitment, strong political will, building expert networks and a demand for scientific evidence were all considered potential factors that could facilitate snakebite research. Participants rated availability of antivenoms, research skills training and disease surveillance as key research priorities. All participants indicated interest in the development of research and policy hubs and 78% indicated their organization would be willing to actively participate. In conclusion, our survey affirms that relevant stakeholders in the field of snakebite perceive research and policy hubs as a promising development, which could help overcome the barriers to pursuing the WHO goals and targets for reducing the burden of snakebite.


Assuntos
Mordeduras de Serpentes , Humanos , Mordeduras de Serpentes/epidemiologia , Mordeduras de Serpentes/prevenção & controle , Antivenenos/uso terapêutico , África/epidemiologia , Organização Mundial da Saúde , Saúde Pública
7.
PLoS Negl Trop Dis ; 17(11): e0011732, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37948462

RESUMO

BACKGROUND: Halving snakebite morbidity and mortality by 2030 requires countries to develop both prevention and treatment strategies. The paucity of data on the global incidence and severity of snakebite envenoming causes challenges in prioritizing and mobilising resources for snakebite prevention and treatment. In line with the World Health Organisation's 2019 Snakebite Strategy, this study sought to investigate Eswatini's snakebite epidemiology and outcomes, and identify the socio-geographical factors associated with snakebite risk. METHODOLOGY: Programmatic data from the Ministry of Health, Government of Eswatini 2019-2021, was used to assess the epidemiology and outcomes of snakebite in Eswatini. We developed a snake species richness map from the occurrence data of all venomous snakes of medical importance in Eswatini that was subjected to niche modelling. We formulated four risk indices using snake species richness, various geospatial datasets and reported snakebites. A multivariate cluster modelling approach using these indices was developed to estimate risk of snakebite and the outcomes of snakebite in Eswatini. PRINCIPAL FINDINGS: An average of 466 snakebites was recorded annually in Eswatini. Bites were recorded across the entire country and peaked in the evening during summer months. Two cluster risk maps indicated areas of the country with a high probability of snakebite and a high probability of poor snakebite outcomes. The areas with the highest rate of snakebite risk were primarily in the rural and agricultural regions of the country. SIGNIFICANCE: These models can be used to inform better snakebite prevention and treatment measures to enable Eswatini to meet the global goal of reducing snakebite morbidity and mortality by 50% by 2030. The supply chain challenges of antivenom affecting southern Africa and the high rates of snakebite identified in our study highlight the need for improved snakebite prevention and treatment tools that can be employed by health care workers stationed at rural, community clinics.


Assuntos
Mordeduras de Serpentes , Animais , Humanos , Mordeduras de Serpentes/terapia , Essuatíni , Serpentes , Antivenenos/uso terapêutico , Saúde Global
8.
Rand Health Q ; 9(3): 18, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35837514

RESUMO

The Military Health System (MHS), through its global network of facilities and providers, meets the health care needs of more than 9 million service members and their dependents during peacetime. It is also responsible for treating casualties during combat operations and in the aftermath of disasters and humanitarian crises. The 2018 National Defense Strategy emphasizes a need to prepare for future combat operations that could be distinctly different from those of the past few decades. The evolving security environment is characterized by precision missile strike capabilities and a risk that adversaries will target critical military infrastructure. These types of attacks could significantly degrade U.S. combat capabilities and significantly increase casualties. There is a range of opportunities for the MHS to align its capabilities to address potential future threats. But to implement effective mitigation strategies, it requires an understanding of the numbers and types of casualties it can expect in a future combat operation, the capability and capacity to treat and evacuate casualties, the network of storage facilities and transportation assets to ensure access to medical supplies, the capacity and capabilities of the U.S. health care system overall, and gaps in the medical supply industrial base. A thorough analysis of these sources of risk highlights how the MHS can build a more agile and resilient medical support capability so that it can continue to provide the best care possible to the warfighter both at home and in combat.

9.
PLoS Negl Trop Dis ; 16(9): e0010496, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36108067

RESUMO

BACKGROUND: Snakebite is a major public health concern in Eswatini, where treatment relies upon one antivenom-SAIMR Polyvalent. Although effective in treating snakebite, SAIMR Polyvalent is difficult to source outside its manufacturing country (South Africa) and is dauntingly expensive. We compared the preclinical venom-neutralising efficacy of two alternative antivenoms with that of SAIMR Polyvalent against the lethal and tissue-destructive effects of venoms from five species of medically important snakes using in vivo murine assays. The test antivenoms were 'Panafrican' manufactured by Instituto Clodomiro Picado and 'PANAF' manufactured by Premium Serums & Vaccines. PRINCIPAL FINDINGS: In vivo murine preclinical studies identified both test antivenoms were equally or more effective than SAIMR Polyvalent at neutralising lethal and tissue-destructive effects of Naja mossambica venom. Both test antivenoms were less effective than SAIMR Polyvalent at neutralising the lethal effects of Bitis arietans, Dendroaspis polylepis, Hemachatus haemachatus and Naja annulifera venoms, but similarly effective at neutralising tissue damage induced by B. arietans and H. haemachatus venoms. In vitro immunological assays identified that the titres and toxin-specificities of immunoglobulins (iGs) in the test antivenoms were comparable to that of SAIMR Polyvalent. Plasma clotting disturbances by H. haemachatus and N. mossambica were neutralised by the test antivenoms, whereas SAIMR Polyvalent failed to neutralise this bioactivity of N. mossambica venom. B. arietans SVMP activity was equally reduced by all three antivenoms, and H. haemachatus and N. mossambica PLA2 activities were neutralised by all three antivenoms. CONCLUSIONS: While both Panafrican and PANAF antivenoms exhibited promising preclinical efficacies, both were less poly-specifically effective than SAIMR Polyvalent in these murine assays. The efficacy of these antivenoms against the lethal and tissue-destructive effects of N. mossambica venom, the most common biting species in Eswatini, identify that Panafrican and PANAF antivenoms offer effective alternatives to SAIMR Polyvalent for the treatment of snakebite in Eswatini, and potentially for neighbouring countries.


Assuntos
Mordeduras de Serpentes , Viperidae , Animais , Antivenenos/farmacologia , Antivenenos/uso terapêutico , Essuatíni , Camundongos , Fosfolipases A2 , Mordeduras de Serpentes/tratamento farmacológico
10.
Rheumatology (Oxford) ; 49(11): 2204-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20688804

RESUMO

OBJECTIVES: Currently, there are no prospective studies exploring the prognosis of patients with juvenile primary FM syndrome (JPFS) or their physical, emotional and social outcomes as they enter the early adult years. The primary objective of this study was to assess long-term outcomes of a paediatric sample of clinically referred JPFS patients and their matched healthy controls. METHODS: Participants were 48 youths (current mean age = 19 years) diagnosed with JPFS in childhood or adolescence and 43 healthy controls matched in age, gender and race. The average length of follow-up was 3.67 years (range 2-6 years). Participants completed online (web-based) self-report questionnaires about current pain and physical symptoms, health status, anxiety, depressive symptoms and current and past treatments. RESULTS: Results showed that 62.5% of participants in the JPFS group continued to experience widespread pain and 60.4% reported having all the cardinal features of FM syndrome (including widespread pain, poor sleep and fatigue) at follow-up. The JPFS group reported significantly lower scores on all measures of health status and physical functioning compared with healthy controls and significantly greater symptoms of anxiety and depression. CONCLUSION: The results of this controlled follow-up study demonstrate that symptoms of FM appear to be chronic in a majority of clinically referred JPFS patients and the associated physical and emotional impairment can also be persistent. Implications for treatment and the need for further prospective longitudinal studies are discussed.


Assuntos
Fibromialgia/fisiopatologia , Transtornos do Humor/etiologia , Medição da Dor/psicologia , Adolescente , Estudos de Casos e Controles , Feminino , Fibromialgia/complicações , Fibromialgia/psicologia , Seguimentos , Humanos , Relações Interpessoais , Masculino , Transtornos do Humor/psicologia , Psicologia do Adolescente , Autoimagem , Isolamento Social/psicologia , Síndrome , Adulto Jovem
11.
Rand Health Q ; 8(3): 9, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31205809

RESUMO

The Joint military community provides a wide array of medical support services to its personnel, including the transfusion of blood and blood products. Ensuring that blood remains available and safe for transfusion requires sophisticated logistical support, especially for the military community's provision of blood to medical operations around the globe. However, that supply chain may become brittle in future potential operating environments, such as large-scale combat operations where adversaries may contest the U.S. military's freedom of movement. This study describes the elements in the military's current blood supply chain and outlines a framework for assessing its performance. Through that lens, the authors then explore an array of approaches offering promise in improving the resiliency of the blood supply chain, including alternative concepts of operation and technologies. By understanding the mechanisms that underlie blood supply chain resilience, the Joint medical community can be better positioned to tailor a robust portfolio of resiliency investments. Such a portfolio would better ensure the availability and safety of blood and blood products under a wide array of stressors and threats to the system.

12.
Arthritis Res Ther ; 21(1): 156, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238969

RESUMO

BACKGROUND: GATA3 is a transcription factor that is important during development and plays a role in differentiation and activity of immune cells, particularly T cells. Abnormal T cell function is found in autoimmune arthritis. We present the first known case of autoimmune arthritis associated with a novel GATA3 mutation. METHODS: Whole exome sequencing of the proband was performed on a clinical basis. Peripheral blood mononuclear cells (PBMCs) were collected from the proband, healthy sibling, and parent. cDNA prepared from RNA was analyzed with polymerase chain reaction and Sanger sequencing. Intracellular proteins were assessed by immunoblot of PBMC homogenates. GATA3 in vitro activity was measured in HeLa cell cultures expressing a mammalian expression vector containing GATA3 or mutants generated by site-directed mutagenesis. GATA3 transcriptional activity was examined using a luciferase reporter assay system. T helper cell ex vivo function was evaluated by stimulating PBMCs to differentiate into effector T cells along Th0, Th1, Th2, and Th17 lineages, and re-stimulating effector cells to secrete cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay. RESULTS: The proband is the first known case of autoimmune arthritis associated with a mutation in GATA3. The proband M401VfsX106 protein is expressed and has a dominant negative function on GATA3 transcriptional activity. The proband PBMCs have markedly increased differentiation along the Th1 and Th17 pathways, with decreased differentiation along the Th2 pathway. Unexpectedly, Th0 cells from the proband express high levels of IFNγ. CONCLUSIONS: Our research presents the first known case of autoimmune arthritis associated with a mutation in GATA3. This work expands the phenotypic spectrum of GATA3 mutations. It reveals the novel insight that decreased and altered GATA3 activity coincides with autoimmune arthritis. This work suggests that modulation of GATA3 may be a therapeutic approach for patients with autoimmune arthritis.


Assuntos
Artrite Juvenil/genética , Doenças Autoimunes/genética , Autoimunidade , DNA/genética , Fator de Transcrição GATA3/genética , Mutação , Artrite Juvenil/imunologia , Artrite Juvenil/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Pré-Escolar , Citocinas/metabolismo , Análise Mutacional de DNA , Fator de Transcrição GATA3/metabolismo , Humanos , Masculino
13.
Parasit Vectors ; 11(1): 122, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29499751

RESUMO

BACKGROUND: Long-lasting insecticidal nets (LLINs) (with pyrethroids) and indoor residual spraying (IRS) are the cornerstones of the Sudanese malaria control program. Insecticide resistance to the principal insecticides in LLINs and IRS is a major concern. This study was designed to monitor insecticide resistance in Anopheles arabiensis from 140 clusters in four malaria-endemic areas of Sudan from 2011 to 2014. All clusters received LLINs, while half (n = 70), distributed across the four regions, had additional IRS campaigns. METHODS: Anopheles gambiae (s.l.) mosquitoes were identified to species level using PCR techniques. Standard WHO insecticide susceptibility bioassays were carried out to detect resistance to deltamethrin (0.05%), DDT (4%) and bendiocarb (0.1%). TaqMan assays were performed on random samples of deltamethrin-resistant phenotyped and pyrethrum spray collected individuals to determine Vgsc-1014 knockdown resistance mutations. RESULTS: Anopheles arabiensis accounted for 99.9% of any anopheline species collected across all sites. Bioassay screening indicated that mosquitoes remained susceptible to bendiocarb but were resistance to deltamethrin and DDT in all areas. There were significant increases in deltamethrin resistance over the four years, with overall mean percent mortality to deltamethrin declining from 81.0% (95% CI: 77.6-84.3%) in 2011 to 47.7% (95% CI: 43.5-51.8%) in 2014. The rate of increase in phenotypic deltamethrin-resistance was significantly slower in the LLIN + IRS arm than in the LLIN-only arm (Odds ratio 1.34; 95% CI: 1.02-1.77). The frequency of Vgsc-1014F mutation varied spatiotemporally with highest frequencies in Galabat (range 0.375-0.616) and New Halfa (range 0.241-0.447). Deltamethrin phenotypic-resistance correlated with Vgsc-1014F frequency. CONCLUSION: Combining LLIN and IRS, with different classes of insecticide, may delay pyrethroid resistance development, but the speed at which resistance develops may be area-specific. Continued monitoring is vital to ensure optimal management and control.


Assuntos
Anopheles/efeitos dos fármacos , Resistência a Inseticidas/genética , Malária/prevenção & controle , Controle de Mosquitos , Mosquitos Vetores/efeitos dos fármacos , Animais , Anopheles/genética , Bioensaio , Feminino , Mosquiteiros Tratados com Inseticida , Inseticidas/farmacologia , Malária/epidemiologia , Mosquitos Vetores/parasitologia , Nitrilas/farmacologia , Piretrinas/farmacologia , Sudão/epidemiologia
14.
Eur J Med Chem ; 157: 1202-1213, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30193218

RESUMO

The West Nile virus (WNV) has spread throughout the world causing neuroinvasive diseases with no treatments available. The viral NS2B-NS3 protease is essential for WNV survival and replication in host cells and is a promising drug target. Through an enzymatic screen of the National Institute of Health clinical compound library, we report the discovery of zafirlukast, an FDA approved treatment for asthma, as an inhibitor for the WNV NS2B-NS3 protease. Zafirlukast was determined to inhibit the protease through a mixed mode mechanism with an IC50 value of 32 µM. A structure activity relationship study of zafirlukast revealed the cyclopentyl carbamate and N-aryl sulfonamide as structural elements crucial for NS2B-NS3 protease inhibition. Replacing the cyclopentyl with a phenyl improved inhibition, resulting in an IC50 of 22 µM. Experimental and computational docking analysis support the inhibition model of zafirlukast and analogs binding at an allosteric site on the NS3 protein, thereby disrupting the NS2B cofactor from binding, resulting in protease inhibition.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Inibidores de Proteases/farmacologia , Compostos de Tosil/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus do Nilo Ocidental/enzimologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Indóis , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenilcarbamatos , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , RNA Helicases/antagonistas & inibidores , RNA Helicases/metabolismo , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade , Sulfonamidas , Compostos de Tosil/síntese química , Compostos de Tosil/química , Proteínas não Estruturais Virais/metabolismo
16.
Infect Dis Poverty ; 6(1): 52, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28457226

RESUMO

It is widely known that the recent Ebola Virus Disease (EVD) in West Africa caused a serious disruption to the national health system, with many of ongoing disease focused programmes, such as mass drug administration (MDA) for onchocerciasis (ONC), lymphatic filariasis (LF) and schistosomiasis (SCH), being suspended or scaled-down. As these MDA programmes attempt to restart post-EVD it is important to understand the challenges that may be encountered. This commentary addresses the opinions of the major health sectors involved, as well as those of community members, regarding logistic needs and challenges faced as these important public health programmes consider restarting. There appears to be a strong desire by the communities to resume NTD programme activities, although it is clear that some important challenges remain, the most prominent being those resulting from the severe loss of trained staff.


Assuntos
Surtos de Doenças/prevenção & controle , Saúde Global , Doença pelo Vírus Ebola , Doenças Negligenciadas , Serviços Preventivos de Saúde , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Ebolavirus , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Libéria , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/prevenção & controle
17.
Parasit Vectors ; 10(1): 172, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28381279

RESUMO

BACKGROUND: Loiasis is a filarial disease caused Loa loa. The main vectors are Chrysops silacea and C. dimidiata which are confined to the tropical rainforests of Central and West Africa. Loiasis is a mild disease, but individuals with high microfilaria loads may suffer from severe adverse events if treated with ivermectin during mass drug administration campaigns for the elimination of lymphatic filariasis and onchocerciasis. This poses significant challenges for elimination programmes and alternative interventions are required in L. loa co-endemic areas. The control of Chrysops has not been considered as a viable cost-effective intervention; we reviewed the current knowledge of Chrysops vectors to assess the potential for control as well as identified areas for future research. RESULTS: We identified 89 primary published documents on the two main L. loa vectors C. silacea and C dimidiata. These were collated into a database summarising the publication, field and laboratory procedures, species distributions, ecology, habitats and methods of vector control. The majority of articles were from the 1950-1960s. Field studies conducted in Cameroon, Democratic Republic of Congo, Equatorial Guinea, Nigeria and Sudan highlighted that C. silacea is the most important and widespread vector. This species breeds in muddy streams or swampy areas of forests or plantations, descends from forest canopies to feed on humans during the day, is more readily adapted to human dwellings and attracted to wood fires. Main vector targeted measures proposed to impact on L. loa transmission included personal repellents, household screening, indoor residual spraying, community-based environmental management, adulticiding and larviciding. CONCLUSIONS: This is the first comprehensive review of the major L. loa vectors for several decades. It highlights key vector transmission characteristics that may be targeted for vector control providing insights into the potential for integrated vector management, with multiple diseases being targeted simultaneously, with shared human and financial resources and multiple impact. Integrated vector management programmes for filarial infections, especially in low transmission areas of onchocerciasis, require innovative approaches and alternative strategies if the elimination targets established by the World Health Organization are to be achieved.


Assuntos
Dípteros/fisiologia , Insetos Vetores/fisiologia , Loa/fisiologia , Loíase/transmissão , Oncocercose/transmissão , Distribuição Animal , Animais , Dípteros/parasitologia , Erradicação de Doenças , Ecologia , Humanos , Insetos Vetores/parasitologia , Loíase/parasitologia , Loíase/prevenção & controle , Oncocercose/parasitologia , Oncocercose/prevenção & controle
18.
PLoS Negl Trop Dis ; 11(5): e0005599, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28552961

RESUMO

BACKGROUND: The cornerstone of current schistosomiasis control programmes is delivery of praziquantel to at-risk populations. Such preventive chemotherapy requires accurate information on the geographic distribution of infection, yet the performance of alternative survey designs for estimating prevalence and converting this into treatment decisions has not been thoroughly evaluated. METHODOLOGY/PRINCIPAL FINDINGS: We used baseline schistosomiasis mapping surveys from three countries (Malawi, Côte d'Ivoire and Liberia) to generate spatially realistic gold standard datasets, against which we tested alternative two-stage cluster survey designs. We assessed how sampling different numbers of schools per district (2-20) and children per school (10-50) influences the accuracy of prevalence estimates and treatment class assignment, and we compared survey cost-efficiency using data from Malawi. Due to the focal nature of schistosomiasis, up to 53% simulated surveys involving 2-5 schools per district failed to detect schistosomiasis in low endemicity areas (1-10% prevalence). Increasing the number of schools surveyed per district improved treatment class assignment far more than increasing the number of children sampled per school. For Malawi, surveys of 15 schools per district and 20-30 children per school reliably detected endemic schistosomiasis and maximised cost-efficiency. In sensitivity analyses where treatment costs and the country considered were varied, optimal survey size was remarkably consistent, with cost-efficiency maximised at 15-20 schools per district. CONCLUSIONS/SIGNIFICANCE: Among two-stage cluster surveys for schistosomiasis, our simulations indicated that surveying 15-20 schools per district and 20-30 children per school optimised cost-efficiency and minimised the risk of under-treatment, with surveys involving more schools of greater cost-efficiency as treatment costs rose.


Assuntos
Quimioprevenção/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Praziquantel/uso terapêutico , Esquistossomose/prevenção & controle , Inquéritos e Questionários/normas , Adolescente , Criança , Pré-Escolar , Côte d'Ivoire/epidemiologia , Feminino , Humanos , Libéria/epidemiologia , Modelos Logísticos , Malaui/epidemiologia , Masculino , Guias de Prática Clínica como Assunto , Esquistossomose/epidemiologia , Instituições Acadêmicas , Organização Mundial da Saúde
20.
PLoS Negl Trop Dis ; 9(3): e0003642, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25785587

RESUMO

BACKGROUND: The prevalence of Wuchereria bancrofti, which causes lymphatic filariasis (LF) in The Gambia was among the highest in Africa in the 1950s. However, surveys conducted in 1975 and 1976 revealed a dramatic decline in LF endemicity in the absence of mass drug administration (MDA). The decline in prevalence was partly attributed to a significant reduction in mosquito density through the widespread use of insecticidal nets. Based on findings elsewhere that vector control alone can interrupt LF, we asked the question in 2013 whether the rapid scale up in the use of insecticidal nets in The Gambia had interrupted LF transmission. METHODOLOGY/PRINCIPAL FINDING: We present here the results of three independently designed filariasis surveys conducted over a period of 17 years (1997-2013), and involving over 6000 subjects in 21 districts across all administrative divisions in The Gambia. An immunochromatographic (ICT) test was used to detect W. bancrofti antigen during all three surveys. In 2001, tests performed on stored samples collected between 1997 and 2000, in three divisions, failed to show positive individuals from two divisions that were previously highly endemic for LF, suggesting a decline towards extinction in some areas. Results of the second survey conducted in 2003 showed that LF was no longer endemic in 16 of 21 districts surveyed. The 2013 survey used a WHO recommended LF transmission verification tool involving 3180 6-7 year-olds attending 60 schools across the country. We demonstrated that transmission of W. bancrofti has been interrupted in all 21 districts. CONCLUSIONS: We conclude that LF transmission may have been interrupted in The Gambia through the extensive use of insecticidal nets for malaria control for decades. The growing evidence for the impact of malaria vector control activities on parasite transmission has been endorsed by WHO through a position statement in 2011 on integrated vector management to control malaria and LF.


Assuntos
Erradicação de Doenças/métodos , Filariose Linfática/epidemiologia , Insetos Vetores/efeitos dos fármacos , Mosquiteiros Tratados com Inseticida/estatística & dados numéricos , Inseticidas/farmacologia , Controle de Mosquitos/métodos , Wuchereria bancrofti , Adulto , Animais , Gâmbia/epidemiologia , Humanos , Masculino , Prevalência , Inquéritos e Questionários , Wuchereria bancrofti/imunologia
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