Evaluation of the efficacy of a new insecticide paint against malaria vectors

La malaria continúa siendo un problema de salud pública global. Se calcula que en el mundo hay 3.300 millones de personas en 97 países y territorios que corren el riesgo de padecer el paludismo, y que para 1.200 millones ese riesgo es elevado (WHO, 2014). El control de la malaria a gran escala está altamente basado en al control del vector, principalmente mediante el uso de mosquiteras tratadas con insecticidas de larga duración (LLINs), y en menor medida, el Rociamiento Residual Intradomiciliario. Todos los tratamientos recomendados de LLINs y la mayoría del Rociamiento Residual Intradomiciliario se basan en el uso de piretroides. La creciente resistencia de los vectores de malaria a los piretroides detectada en muchos países de África, así como las limitaciones operativas de los LLINs y el Rociamiento Residual Intradomiciliario, como el uso inadecuado y la necesidad de equipo especializado, respectivamente, señalan la conveniencia de investigar el potencial de productos y estrategias diferentes frente a los vectores del parásito de la malaria. Con este propósito, se ha estudiado la pintura insecticida Inesfly 5A IGRTM, que contiene dos organofosfatos (OPs), clorpírifos (1.5%) y diazinón (1.5%) y un IGR piriproxifeno (0.063%), en una serie de proyectos realizados en Costa de Marfil, Francia, Benín y Burkina Faso: Las primeras pruebas con Inesfly 5A IGRTM se realizaron en el laboratorio siguiendo los protocolos de Fase I del Plan de Evaluación de Pesticidas de la OMS (WHOPES) y mostraron la importancia de la porosidad de los materiales en la eficacia a largo plazo. Las siguientes pruebas se realizaron en el laboratorio en el Insituto LIN en Francia (Fase I) con cepas resistentes y susceptibles a los OPs del mosquito plaga urbano Culex quinquefaciatus (Say, 1823). La cepa resistente era homozigota para el gen de resistencia ace-1R involucrado en la resistencia a los OPs. En el laboratorio, un año tras el tratamiento con Inesfly 5A IGR™, la mortalidad diferida se matuvo elevada, 93–100%, incluso contra las cepa resistente a los OPs sobre superficies no porosas como el plástico y la madera. En superficies porosas como el cemento, las tasas de mortalidad fueron bajas 12 meses tras el tratamiento independientemente de la dosis y el nivel de resistencia. Las tasas de fecundidad, fertilidad y emergencia de adultos se vieron reducidas justo después del tratamiento a la dosis menor (p < 10–3), ya que a la dosis mayor las hembras expuestas a los bioensayos no sobrevivieron en suficiente número. Nueve meses tras el tratamiento, la tasa de fecundidad se redujo en ambas dosis (p < 10–3), y la tasa de emergencia se redujo en la dosis mayor (p < 10–3). Las evaluaciones en Fase II se realizaron en casas experimentales en el terreno en Bénin contra poblaciones del principal vector del parásito de la malaria, Anopheles gambiae Giles, 1902, y Cx. quinquefasciatus. Ambas poblaciones, An. gambiae y Cx. quinquefasciatus, son resistentes a los piretrinoides con elevadas frecuencias de kdr. En el terreno, seis meses tras el tratamiento con Inesfly 5A IGR™, las tasas de mortalidad se mantuvieron a 90–100% en superficies no porosas de cemento, en poblaciones de mosquitos resistentes a pirotrides. Nueve meses después del tratamiento, las tasas de mortalidad en las casas experimentales tratadas con dos capas de pintura insecticida todavía ascendía al 90–93% en An. gambiae y un 55% en Cx. quinquefasciatus, ambos resistentes a piretroides. La evaluación de la mortalidad espacial ha sido el tema de un estudio paralelo para desarrollar un modelo de valoración sobre el efecto letal que pueden tener los productos insecticidas en la distancia, tanto en el laboratorio como sobre el terreno, a estos tests les hemos denominado evaluación de la mortalidad espacial. Durante 12 meses, una elevada mortalidad espacial se observó a largo plazo (96–100%) contra poblaciones de An. gambiae y Cx. quinquefasciatus susceptibles a los piretrinoides colocados a distancias de un metro durante la noche, sin entrar en contacto directo con las superficies tratadas. Recomendaciones para añadir la evaluación de la mortalidad espacial a la batería de tests comúnmente realizados en los protocolos WHOPES fueron publicadas. Basado en los buenos resultados obtenidos en los estudios de las Fases I y II, y con objeto de apoyar las iniciativas de salud pública basadas en LLINs, se realizaron dos estudios piloto para evaluar la eficacia de Inesfly 5A IGRTM combinada con LLINs en casas reales tratadas con pirotroides en las aldeas VK1 y VK3 en Burkina Faso. En la aldea VK1, el interior de las casas fue tratado con una o dos capas de pintura sobre un número de superficies diferentes (paredes versus paredes y techo). En la otra aldea, VK3, únicamente las ventanas y puertas fueron tratadas con una capa. En la aldea VK1, donde se trató el interior de las casas, la combinación de Inesfly 5A IGR™ y LLINs resultó en una mortalidad a largo plazo de 12 meses, con una tasa de mortalidad de 80% durante las capturas de mosquitos contra poblaciones de mosquitos Anopheles coluzzii Coetzee & Wikerson, 2013, el vector local de la malaria resistente a los piretrinoides con altas frecuencias de kdr. Por otra parte, la aplicación de Inesfly 5A IGRTM en el exterior de ventanas y puertas en VK3 logró una eficacia letal de 80% durante apenas 2 meses contra An. coluzzii resistentes a piretroides. Entomológicamente, estos estudios piloto aportaron una información valiosa concluyendo que el interior de las casas, y no únicamente puertas y ventanas, deberá ser tratado en la siguiente evaluación a gran escala del estudio de Fase III. En términos socio-epidemiológicos, en preparación para el estudio de Fase III, treinta y dos localizaciones/aldeas cumplieron los requisitos del estudio: al menos 100 niños por aldea de edades comprendidas entre los 6 meses y los 14 años (para asegurar 30 sujetos evaluables al final des estudio), las aldeas estaban al menos a 1–2 km de distancia, las aldeas eran accesibles por carretera y sus habitantes mostraron un interés en participar. La Fase III de este estudio se llevará a cabo para valorar el impacto de la combinación de la pintura insecticida de organofosforados junto con LLINs tratadas con piretroides en la reducción real de la incidencia de malaria en niños de edades comprendidas entre los 6 meses y los 14 años en África del Oeste donde la malaria es holoendémica y los vectores son resistentes a piretroides.Malaria continues to be a serious public health concern worldwide. An estimated 3.3 billion people in 97 countries and territories are at risk of malaria, and 1.2 billion are at high risk (WHO, 2014). Mosquitoes are the main malaria parasite vector; and control on a large scale is essentially achieved using Long-Lasting Insecticide- Treated Nets (LLINs) and, to a lesser extent, Indoor Residual Spraying (IRS). All recommended LLINs and most IRS interventions consist of the use of pyrethroids. However, the increased resistance of malaria vectors to pyrethroids reported in many African countries—along with operational constraints to LLINs and IRS, such as inadequate use, or the need of specialized equipment—suggest the need to study the potential of different products and strategies. To this end, a new product has been tested: the insecticide paint Inesfly 5A IGR, which contains two organophosphates (OPs), chlorpyrifos (1.5%), and diazinon (1.5%); plus an Insect Growth Regulator (IGR), pyriproxyfen (0.063%). Inesfly 5A IGR was tested in a series of laboratory studies performed in France and several African countries, following Phase I of the WHO Pesticide Evaluation Scheme (WHOPES) procedures in Côte d’Ivoire. The first tests showed the importance of the porosity of the materials to which the paint is applied. The next Phase I tests were performed in the laboratory of the Laboratoire de Lutte contres des Insectes Nuisibles (LIN) in France. The mosquitoes used were two strains of the urban pest mosquito Culex quinquefasciatus (Say, 1823): one susceptible to OPs, and one resistant to them (a homozygote for the ace-1R gene resistant to OPs and carbamates). One year after treatment with insecticide paint (IP), delayed mortality was still 93–100%—even for OP-resistant females, and even on non-porous surfaces such as hard plastic or softwood. On porous surfaces such as cement, death rates were still low 12 months after treatment, regardless of dose or resistance status. Fecundity, fertility and adult emergence were reduced right after treatment even at the lower dose (p<10–3), since females exposed to the higher dose during bioassays did not survive in enough numbers. A reduction in fecundity was still observed 9 months after treatment at both doses (p<10–3), and adult emergence was reduced at the higher dose (p<10–3). Phase II field tests were performed in experimental huts in the field in Bénin, against populations of Anopheles gambiae (Giles, 1902) and Cx. quinquefasciatus. Both populations were resistant to pyrethroids with high knockdown resistance (kdr) frequencies. In the field, 6 months after treatment with Inesfly 5A IGR, mortality rates of both pyrethroid-resistant mosquito strains were still 90–100% on porous cement surfaces. Nine months after treatment, mortality rates in experimental huts treated with 2 layers of insecticide paint were still about 90–93% against pyrethroid-resistant An. gambiae, and 55% against resistant Cx. quinquefasciatus. A parallel study assessed spatial mortality, with the goal of developing a model to assess the killing effect of insecticide products at a distance. This test, performed both in the laboratory and in the field, obtained high long-term mortality (96–100%) for 12 months in the field against pyrethroid-susceptible An. gambiae and Cx. quinquefasciatus. The mosquitoes never came in direct contact with treated surfaces, being kept at a distance of at least 1 metre overnight. Suggestions to include these tests as part of WHOPES were published accordingly. Based on the good results obtained during Phase I and II studies, and in an effort to support LLIN-based public health initiatives, two pilot studies were performed in the field to assess the efficacy of Inesfly 5A IGR in combination with pyrethroid-treated LLINs. The studies took place in houses in two villages in the Kou Valley, in Burkina Faso, VK1 and VK3. In the VK1 village, house interiors were treated with 1 or 2 layers of insecticide paint on different surfaces: walls alone, or walls plus ceiling. In the VK3 village, only windows and doors were treated, with only 1 layer of paint. The VK1results showed that where houses were treated and LLINs were used, the combination yielded a long-term mortality rate of 80% over 12 months against Anopheles coluzzii (Coetzee & Wikerson, 2013), the local pyrethroid-resistant malaria vector. But at VK3, treating windows and doors alone yielded a killing efficacy of 80% for only 2 months against An. coluzzii. In entomological terms, these pilot studies provided useful information to conclude that treating walls and ceilings, not just doors and windows, is needed for the forthcoming large-scale WHOPES Phase III evaluation. In terms of preparation for the WHOPES Phase III study, 32 sites met the four socio- epidemiological criteria for inclusion: villages had at least 100 children, from 6 months to 14 years old (to ensure at least 30 evaluable subjects at the end of the study); villages were at least 1–2 km from each other; villages could be accessed by road; and residents had expressed an interest in participating. The Phase III study will assess what impact the combination of treatments— insecticide paint applied to house interiors, and pyrethroid-treated LLINs—may have on reducing the incidence of malaria, in a West African area where malaria is holoendemic, and vectors are resistant to pyrethroids with high kdr frequencies. The specific targets of the study will be children aged 6 months to 14 years

Efficacy of an insecticide paint against insecticide-susceptible and resistant mosquitoes - Part 1: Laboratory evaluation

<p>Abstract</p> <p>Background</p> <p>The main malaria vector <it>Anopheles gambiae </it>and the urban pest nuisance <it>Culex quinquefasciatus </it>are increasingly resistant to pyrethroids in many African countries. There is a need for new products and strategies. Insecticide paint Inesfly 5A IGR™, containing two organophosphates (OPs), chlorpyrifos and diazinon, and insect growth regulator (IGR), pyriproxyfen, was tested under laboratory conditions for 12 months following WHOPES Phase I procedures.</p> <p>Methods</p> <p>Mosquitoes used were laboratory strains of <it>Cx. quinquefasciatus </it>susceptible and resistant to OPs. The paint was applied at two different doses (1 kg/6 m²and 1 kg/12 m²) on different commonly used surfaces: porous (cement and stucco) and non-porous (softwood and hard plastic). Insecticide efficacy was studied in terms of delayed mortality using 30-minute WHO bioassay cones. IGR efficacy on fecundity, fertility and larval development was studied on OP-resistant females exposed for 30 minutes to cement treated and control surfaces.</p> <p>Results</p> <p>After treatment, delayed mortality was high (87-100%) even against OP-resistant females on all surfaces except cement treated at 1 kg/12 m². Remarkably, one year after treatment delayed mortality was 93-100% against OP-resistant females on non-porous surfaces at both doses. On cement, death rates were low 12 months after treatment regardless of the dose and the resistance status. Fecundity, fertility and adult emergence were reduced after treatment even at the lower dose (p < 10^{^-3}). A reduction in fecundity was still observed nine months after treatment at both doses (p < 10^{^-3}) and adult emergence was reduced at the higher dose (p < 10^{^-3}).</p> <p>Conclusions</p> <p>High mortality rates were observed against laboratory strains of the pest mosquito <it>Cx. quinquefasciatus </it>susceptible and resistant to insecticides. Long-term killing remained equally important on non-porous surfaces regardless the resistance status for over 12 months. The paint's effect on fecundity, fertility and adult emergence may continue to provide an additional angle of attack in reducing overall population densities when the lethal effect of OPs diminishes over time. Some options on how to deal with porous materials are given. Implications in vector control are discussed.</p

Evaluation of the primitive fraction by functional in vitro assays at the RNA and DNA level represents a novel tool for complementing molecular monitoring in chronic myeloid leukemia

Quantification of BCR-ABL1 mRNA levels in peripheral blood of chronic myeloidleukemia patients is a strong indicator of response to tyrosine-kinase inhibitors (TKI)treatment. However, additional prognostic markers are needed in order to better classify patients. The hypothesis of leukemic stem cells (LSCs) heterogeneity and persistence, suggests that their functional evaluation could be of clinical interest. In this work, we assessed the primitive and progenitor fractions in patients at diagnosis and during TKI treatment using functional in vitro assays, defining a ?functional leukemic burden? (FLB). We observed that the FLB was reduced in vivo in both fractions upon treatment. However, different FLB levels were observed among patients according to their response to treatment, suggesting that quantification of the FLB could complement early molecular monitoring. Given that FLB assessment is limited by BCR-ABL1 mRNA expression levels, we developed a novel detection method of primitive cells at the DNA level, using patient-specific primers and direct nested PCR in colonies obtained from functional in vitro assays. We believe that this methodcould be useful in the context of discontinuation trials, given that it is unknown whether the persistent leukemic clone represents LSCs, able to resume the leukemia upon TKI removal.Fil: Ruiz, María Sol. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Sanchez, María Belén. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina. Argenomics; ArgentinaFil: Gutierrez, Leandro German. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Instituto Alexander Fleming, Bs. As.; ArgentinaFil: Koile, Daniel Isaac. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Yankilevich, Patricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Mosqueira, Celeste. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Cranco, Santiago. Fundaleu; ArgentinaFil: Custidiano, María del Rosario. Hospital Italiano de La Plata; ArgentinaFil: Freitas, Josefina. Provincia de Buenos Aires. Hospital Nacional Profesor A. Posadas; ArgentinaFil: Foncuberta, Cecilia. Instituto Alexander Fleming; ArgentinaFil: Moiraghi, Beatriz. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Pavlovsky, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pérez, Mariel Ana. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Ventriglia, Verónica. Provincia de Buenos Aires. Hospital Nacional Profesor A. Posadas; Argentina; ArgentinaFil: Sánchez Ávalos, Julio César Américo. Instituto Alexander Fleming; ArgentinaFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Bianchini, Michele. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentin

Design and challenges of a large HIV prevention clinical study on mother-to-child transmission: ANRS 12397 PROMISE-EPI study in Zambia and Burkina Faso

Under embargo until: 2022-04-23Post-natal HIV infection through breastfeeding remains a challenge in many low and middle-income countries, particularly due to non-availability of alternative infant feeding options and the suboptimal Prevention of Mother to Child Transmission of HIV-1 (PMTCT) cascade implementation and monitoring. The PROMISE-EPI study aims to address the latter by identifying HIV infected mothers during an almost never-missed visit for their infant, the second extended program on immunization visit at 6–8 weeks of age (EPI-2). The study is divided into 3 components inclusive of an open-label randomized controlled trial aiming to assess the efficacy of a responsive preventive intervention compared to routine intervention based on the national PMTCT guidelines for HIV-1 uninfected exposed breastfeeding infants. The preventive intervention includes: a) Point of care testing for early infant HIV diagnosis and maternal viral load; b) infant, single-drug Pre-Exposure Prophylaxis (PrEP) (lamivudine) if mothers are virally unsuppressed. The primary outcome is HIV-transmission rate from EPI-2 to 12 months. The study targets to screen 37,000 mother/infant pairs in Zambia and Burkina Faso to identify 2000 mother/infant pairs for the clinical trial. The study design and challenges faced during study implementation are described, including the COVID-19 pandemic and the amended HIV guidelines in Zambia in 2020 (triple-drug PrEP in HIV exposed infants guided by quarterly maternal viral load). The changes in the Zambian guidelines raised several questions including the equipoise of PrEP options, the standard of care-triple-drug (control arm in Zambia) versus the study-single-drug (intervention arm).acceptedVersio

Cegueira silenciosa: revisão narrativa e estudo epidemiológico do glaucoma no Brasil entre 2017 e 2022: Silent blindness: narrative review and study epidemiology of glaucoma in Brazil between 2017 and 2022

Considerado um problema de saúde pública por representar importante causa de cegueira irreversível, além de demandar altos gastos ao Sistema Único de Saúde, o glaucoma urge atenção especializada no Brasil. Objetivou-se, primeiramente, alcançar perspectivas específicas no que tange ao glaucoma, abrangendo questões etiológicas, fisiopatológicas, clínico-sintomatológicas, comportamentais, diagnósticas, técnicas terapêuticas, além de levantar dados epidemiológicos acerca da prevalência do glaucoma. As tabulações de dados advindas do DATASUS-TabNet evidenciam as seguintes variáveis atreladas à doença: história familiar positiva, faixa etária acima de 45 anos, acometimento majoritário em indivíduos do sexo masculino, etnia negra, preponderância na região Sudeste do Brasil, escolaridade limitada e recorrência alinhada a fatores de risco comportamentais presentes ao longo da vida. O diagnóstico perfaz a realização de exame oftalmológico atrelado a exames complementares. Em relação ao acompanhamento e ao tratamento, é fundamental uma postura individualizada para o direcionamento de condutas especializadas para cada paciente

Efficacy of an insecticide paint against malaria vectors and nuisance in West Africa - Part 2: Field evaluation

<p>Abstract</p> <p>Background</p> <p>Widespread resistance of the main malaria vector <it>Anopheles gambiae </it>to pyrethroids reported in many African countries and operational drawbacks to current IRS methods suggest the convenience of exploring new products and approaches for vector control. Insecticide paint Inesfly 5A IGR™, containing two organophosphates (OPs), chlorpyrifos and diazinon, and one insect growth regulator (IGR), pyriproxyfen, was tested in Benin, West Africa, for 12 months.</p> <p>Methods</p> <p>Field trials were conducted in six experimental huts that were randomly allocated to one or two layers of insecticide at 1 Kg/6 m²or control. Evaluations included: (i) early mosquito collection, (ii) mosquito release experiments, (iii) residual efficacy tests and (iv) distance tests. Early mosquito collections were performed on local populations of pyrethroid-resistant <it>An. gambiae </it>and <it>Culex quinquefasciatus</it>. As per WHOPES phase II procedures, four entomological criteria were evaluated: deterrence, excito-repellence, blood-feeding inhibition and mortality. Mosquito release experiments were done using local malaria-free <it>An. gambiae </it>females reared at the CREC insectarium. Residual efficacy tests and distance tests were performed using reference susceptible strains of <it>An. gambiae </it>and <it>Cx. quinquefasciatus</it>.</p> <p>Results</p> <p>Six months after treatment, mortality rates were still 90-100% against pyrethroid-resistant mosquito populations in experimental huts. At nine months, mortality rates in huts treated with two layers was still about 90-93% against <it>An. gambiae </it>and 55% against <it>Cx. quinquefasciatus</it>. Malaria-free local mosquito release experiments yielded a 90% blood-feeding inhibition in the absence of a physical barrier. A long-term residual efficacy of 12 months was observed by WHO-bioassays in huts treated with two layers (60-80%). Mortality after an overnight exposition at distances of 1 meter was 96-100% for up to 12 months.</p> <p>Conclusion</p> <p>The encouraging results obtained on the insecticide paint Inesfly 5A IGR™ in terms of mortality, be it in direct contact or at a distance, and its new operational approach could constitute an additional option in malaria control efforts in areas of pyrethroid resistance. Phase III studies will be performed to assess the product's epidemiological impact and sociological acceptance.</p

Recommendations for the diagnosis and radiological follow-up of pituitary neuroendocrine tumours Recomendaciones sobre el diagnóstico y seguimiento radiológico de los tumores neuroendocrinos hipofisarios

Pituitary neuroendocrine tumours (PitNETs) constitute a heterogeneous group of tumours with a gradually increasing incidence, partly accounted for by more sensitive imaging techniques and more extensive experience in neuroradiology in this regard. Although most PitNETs are indolent, some exhibit aggressive behaviour, and recurrence may be seen after surgical removal. The changes introduced in the WHO classification in 2017 and terminological debates in relation to neuroendocrine tumours warrant an update of the guidelines for the diagnosis, preoperative and postoperative management, and follow-up of response to treatment of PitNETs. This multidisciplinary document, an initiative of the Neuroendocrinology area of the Sociedad Española de Endocrinología y Nutrición [Spanish Society of Endocrinology and Nutrition] (SEEN), focuses on neuroimaging studies for the diagnosis, prognosis and follow-up of PitNETs. The basic requirements and elements that should be covered by magnetic resonance imaging are described, and a minimum radiology report to aid clinicians in treatment decision-making is proposed. This work supplements the consensus between the Neuroendocrinology area of the SEEN and the Sociedad Española de Anatomía Patológica [Spanish Society of Pathology] for the pathological study of PitNETs