Sheep Models of F508del and G542X Cystic Fibrosis Mutations Show Cellular Responses to Human Therapeutics

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The F508del and G542X are the most common mutations found in US patients, accounting for 86.4% and 4.6% of all mutations, respectively. The F508del causes deletion of the phenylalanine residue at position 508 and is associated with impaired CFTR protein folding. The G542X is a nonsense mutation that introduces a stop codon into the mRNA, thus preventing normal CFTR protein synthesis. Here, we describe the generation of CFTRF508del/F508del and CFTRG542X/G542X lambs using CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). First, we introduced either F508del or G542X mutations into sheep fetal fibroblasts that were subsequently used as nuclear donors for SCNT. The newborn CF lambs develop pathology similar to CFTR−/− sheep and CF patients. Moreover, tracheal epithelial cells from the CFTRF508del/F508del lambs responded to a human CFTR (hCFTR) potentiator and correctors, and those from CFTRG542X/G542X lambs showed modest restoration of CFTR function following inhibition of nonsense-mediated decay (NMD) and aminoglycoside antibiotic treatments. Thus, the phenotype and electrophysiology of these novel models represent an important advance for testing new CF therapeutics and gene therapy to improve the health of patients with this life-limiting disorder

The sustainable materials roadmap

Over the past 150 years, our ability to produce and transform engineered materials has been responsible for our current high standards of living, especially in developed economies. However, we must carefully think of the effects our addiction to creating and using materials at this fast rate will have on the future generations. The way we currently make and use materials detrimentally affects the planet Earth, creating many severe environmental problems. It affects the next generations by putting in danger the future of the economy, energy, and climate. We are at the point where something must drastically change, and it must change now. We must create more sustainable materials alternatives using natural raw materials and inspiration from nature while making sure not to deplete important resources, i.e. in competition with the food chain supply. We must use less materials, eliminate the use of toxic materials and create a circular materials economy where reuse and recycle are priorities. We must develop sustainable methods for materials recycling and encourage design for disassembly. We must look across the whole materials life cycle from raw resources till end of life and apply thorough life cycle assessments (LCAs) based on reliable and relevant data to quantify sustainability. We need to seriously start thinking of where our future materials will come from and how could we track them, given that we are confronted with resource scarcity and geographical constrains. This is particularly important for the development of new and sustainable energy technologies, key to our transition to net zero. Currently 'critical materials' are central components of sustainable energy systems because they are the best performing. A few examples include the permanent magnets based on rare earth metals (Dy, Nd, Pr) used in wind turbines, Li and Co in Li-ion batteries, Pt and Ir in fuel cells and electrolysers, Si in solar cells just to mention a few. These materials are classified as 'critical' by the European Union and Department of Energy. Except in sustainable energy, materials are also key components in packaging, construction, and textile industry along with many other industrial sectors. This roadmap authored by prominent researchers working across disciplines in the very important field of sustainable materials is intended to highlight the outstanding issues that must be addressed and provide an insight into the pathways towards solving them adopted by the sustainable materials community. In compiling this roadmap, we hope to aid the development of the wider sustainable materials research community, providing a guide for academia, industry, government, and funding agencies in this critically important and rapidly developing research space which is key to future sustainability.journal articl

Efficacy and Safety of Artemether-Lumefantrine in the Treatment of Acute, Uncomplicated Plasmodium falciparum Malaria: A Pooled Analysis

Randomized trials have confirmed the efficacy and safety of artemether-lumefantrine (AL) for treatment of uncomplicated Plasmodium falciparum malaria. Data from seven studies supported by Novartis (1996–2007), including 647 adults (> 16 years of age, 83.3% completed the study) and 1,332 children (≤ 16 years of age, 89.3% completed the study) with microscopically confirmed uncomplicated P. falciparum malaria and treated with the recommended regimen of AL, were pooled. The 28-day polymerase chain reaction–corrected parasitologic cure rate (primary efficacy endpoint) was 97.1% (495 of 510) in adults and 97.3% (792 of 814) in children (evaluable population). Gametocytemia prevalence after day was 4.2% (23 of 554) in adults and 0.9% (8 of 846) in children. No noteworthy safety signals were observed. Serious adverse events occurred in 1.4% of the adults and 1.3% of the children. This study is the largest data set to date assessing AL therapy for treatment of acute uncomplicated P. falciparum malaria. Artemether-lumefantrine showed high cure rates and rapid resolution of parasitemia, fever, and gametocytemia in adults and children, and showed an excellent safety and tolerability profile

So Different, yet So Similar: Meta-Analysis and Policy Modeling of Willingness to Participate in Clinical Trials among Brazilians and Indians

BACKGROUND: With the global expansion of clinical trials and the expectations of the rise of the emerging economies known as BRICs (Brazil, Russia, India and China), the understanding of factors that affect the willingness to participate in clinical trials of patients from those countries assumes a central role in the future of health research. METHODS: We conducted a systematic review and meta-analysis (SRMA) of willingness to participate in clinical trials among Brazilian patients and then we compared it with Indian patients (with results of another SRMA previously conducted by our group) through a system dynamics model. RESULTS: Five studies were included in the SRMA of Brazilian patients. Our main findings are 1) the major motivation for Brazilian patients to participate in clinical trials is altruism, 2) monetary reimbursement is the least important factor motivating Brazilian patients, 3) the major barrier for Brazilian patients to not participate in clinical trials is the fear of side effects, and 4) Brazilian patients are more likely willing to participate in clinical trials than Indians. CONCLUSION: Our study provides important insights for investigators and sponsors for planning trials in Brazil (and India) in the future. Ignoring these results may lead to unnecessary fund/time spending. More studies are needed to validate our results and for better understanding of this poorly studied theme

Estimación de la concentración media diaria de material particulado fino en la región del Complejo Industrial y Portuario de Pecém, Ceará, Brasil

A exposição ao material particulado fino (MP2,5) está associada a inúmeros desfechos à saúde. Desta forma, monitoramento da concentração ambiental do MP2,5 é importante, especialmente em áreas amplamente industrializadas, pois abrigam potenciais emissores do MP2,5 e de substâncias com potencial de aumentar a toxicidade de partículas já suspensas. O objetivo desta pesquisa é estimar a concentração diária do MP2,5 em três áreas de influência do Complexo Industrial e Portuário do Pecém (CIPP), Ceará, Brasil. Foi aplicado um modelo de regressão não linear para a estimativa do MP2,5, por meio de dados de profundidade óptica monitorados por satélite. As estimativas foram realizadas em três áreas de influência (Ai) do CIPP (São Gonçalo do Amarante – Ai I, Paracuru e Paraipaba – Ai II e Caucaia – Ai III, no período de 2006 a 2017. As médias anuais das concentrações estimadas foram inferiores ao estabelecido pela legislação nacional em todas as Ai (8µg m-3). Em todas as Ai, os meses referentes ao período de seca (setembro a fevereiro) apresentaram as maiores concentrações e uma predominância de ventos leste para oeste. Os meses que compreendem o período de chuva (março a agosto) apresentaram as menores concentrações e ventos menos definidos. As condições meteorológicas podem exercer um papel importante nos processos de remoção, dispersão ou manutenção das concentrações do material particulado na região. Mesmo com baixas concentrações estimadas, é importante avaliar a constituição das partículas finas dessa região, bem como sua possível associação a efeitos adversos à saúde da população local.Exposure to fine particulate matter (PM2.5) is associated with numerous negative health outcomes. Thus, monitoring the environmental concentration of PM2.5 is important, especially in heavily industrialized areas, since they harbor potential emitters of PM2.5 and substances with the potential to increase the toxicity of already suspended particles. This study aims to estimate daily concentrations of PM2.5 in three areas under the influence of the Industrial and Port Complex of Pecém (CIPP), Ceará State, Brazil. A nonlinear regression model was applied to estimate PM2.5, using satellitemonitored optical depth data. Estimates were performed in three areas of influence (Ai) of the CIPP (São Gonçalo do Amarante – AiI, Paracuru and Paraipaba – AiII, and Caucaia – AiIII), from 2006 to 2017. Estimated mean annual concentrations were lower than established by Brazil’s national legislation in all three Ai (8µg m-³). In all the Ai, the months of the dry season (September to February) showed the highest concentrations and a predominance of east winds, while the months of the rainy season (March to August) showed the lowest concentrations and less defined winds Weather conditions can play an important role in the removal, dispersal, or maintenance of concentrations of particulate matter in the region. Even at low estimated concentrations, it is important to assess the composition of fine participles in this region and their possible association with adverse health outcomes in the local population.La exposición al material particulado fino (MP2,5) está asociada a innumerables problemas de salud. Por ello, la supervisión de la concentración ambiental del MP2,5 es importante, especialmente en áreas ampliamente industrializadas, puesto que albergan potenciales emisores de MP2,5 y de sustancias con potencial de aumentar la toxicidad de partículas ya suspendidas. El objetivo de esta investigación es estimar la concentración diaria del MP2,5 en tres áreas de influencia del Complejo Industrial y Portuario de Pecém (CIPP), Ceará, Brasil. Se aplicó un modelo de regresión no lineal para la estimación del MP2,5, mediante datos de profundidad óptica supervisados por satélite. Las estimaciones fueron realizadas en tres áreas de influencia (Ai) del CIPP (São Gonçalo do Amarante – Ai I, Paracuru y Paraipaba – Ai II y Caucaia – Ai III en el período de 2006 a 2017. Las medias anuales de las concentraciones estimadas fueron inferiores a lo establecido por la legislación nacional en todas las Ai (8µg m-³). En todas las Ai, los meses referentes al período de sequía (de setiembre a febrero) presentaron las mayores concentraciones y una predominancia de vientos este a oeste, los meses que comprenden el período de lluvia (marzo a agosto) presentaron las menores concentraciones y vientos menos definidos. Las condiciones meteorológicas pueden ejercer un papel importante en los procesos de eliminación, dispersión o mantenimiento de las concentraciones del material particulado en la región. Incluso con bajas concentraciones estimadas es importante que se evalúe la constitución de las partículas finas de esta región, así como su posible asociación con efectos adversos para la salud de la población local

Acceptability of self-conducted home-based HIV testing among men who have sex with men in Brazil: data from an on-line survey

The Brazilian HIV/AIDS epidemic is concentrated among men who have sex with men (MSM), however HIV testing rates among MSM are not commensurate with their risk. Strategies to expand early diagnosis may include use of self-conducted home-based testing kits, which are now available for purchase in the US. In April 2011 we conducted a survey with Brazilian MSM using Facebook to assess HIV testing preferences and acceptability of home-based testing. Among 356 previously tested, HIV-negative MSM, 47% reported a preference for home-based testing, 27% preferred clinic-based testing, and 26% had no preference. Less frequent testers and those who had considered testing but failed to test were more likely to prefer home-based testing. Close to 90% reported that they would use self-test kits; 62% and 54% said they would use home-based testing to make choices about unprotected sex with regular and new partners, respectively. Concerns included difficulty to understand the tests (32%) and receiving results alone (23%). Overall, home-based testing may appeal to MSM and result in increased testing frequency. Research on feasibility and utilization of self-tests in practice is needed