Investigation of the responsiveness of liquid-crystalline nanoparticles to triggers of biomedical interest by the incorporation of cleavable surfactants

Orientadores: Watson Loh, Fernanda PolettoDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de QuímicaResumo: Sistemas dispersos de fases cúbicas bicontínuas, denominados cubossomas, apresentam taxa de liberação de fármacos muito rápida se comparada às taxas das demais fases líquido-cristalinas. Logo, visando evitar maiores efeitos colaterais associados à liberação acelerada do fármaco incorporado ao sistema, é interessante que a fase cúbica bicontínua seja formada apenas no local de ação desejado. Nesta dissertação, foram propostos novos sistemas dispersos de fases líquido-cristalinas com capacidade de resposta a estímulos como a presença de lipases ou variação da concentração de íons H+, visando liberação sustentada de fármacos. A fase lipídica de tais sistemas foi constituída majoritariamente por fitantriol, composto que forma fases cúbicas bicontínuas reversas em regime diluído sob temperatura fisiológica e resiste à hidrólise causada por enzimas ou concentração de íons H+. Neste contexto, este trabalho exibiu as seguintes etapas: i) produção de cubossomas com estabilidade cinética adequada, ii) uso de aditivos cliváveis para transição de fase do sistema, convertendo fase cúbica bicontínua em outra fase de liberação mais lenta, iii) verificação da hidrólise dos aditivos pela ação de gatilhos, como enzimas e variação na concentração de íons H+ de modo a gerar nova transição para fase de liberação mais rápida e iv) correlação da estrutura de fase com a cinética de liberação da molécula modelo sal sódico de fluoresceína. Visando promover mudança de fase em relação ao sistema cúbico inicial, foram preparadas formulações baseadas na formulação original de fitantriol e Pluronic® F-127 como estabilizante, adicionando-se os surfactantes sulfossuccinato sódico de dioctila (AOT) e éster decílico do cloridrato de betaína (DBC) como aditivos. A escolha desses compostos foi pautada em sua biocompatibilidade e presença da ligação éster, a qual pode ser hidrolisada pelo uso dos gatilhos supracitados. Concentrações específicas de AOT e DBC foram capazes de promover transição do sistema de cubossoma para niossoma (dispersão de fase lamelar), de liberação mais lenta. Posteriormente, os estudos objetivaram nova mudança de fase mediante hidrólise dos aditivos através de gatilhos químico (pH: 3,9 a 8,5) e bioquímico (lipases de Candida antarctica e Rhizomucor miehei). A síntese de um pró-fármaco (fármaco administrado em forma inativa, sendo ativado apenas após biotransformação), éster decílico de indometacina, foi realizada e o mesmo foi incorporado aos sistemas dispersos com o objetivo de avaliar a resposta à presença dos gatilhos. Foi verificado que os sistemas contendo AOT são sensíveis ao meio alcalino, o qual levou à formação de mistura de fases, hexagonal reversa e cúbica micelar reversa. Os sistemas com DBC, por sua vez, se mostraram sensíveis aos meios neutros e alcalinos, formando fase hexagonal reversa. Por fim, os sistemas contendo o pró-fármaco não sofreram modificações em resposta à concentração de íons H+. No que concerne à ação das enzimas sobre os aditivos, mudanças de fase não foram detectadas. A última etapa do trabalho consistiu em correlacionar o perfil cinético de liberação de sal sódico de fluoresceína a partir de nanopartículas com diferentes estruturas de fase. A formulação contendo DBC foi a mais promissora, apresentando potencial como plataforma para liberação sustentada de fármacos em compartimentos neutros/alcalinos do organismoAbstract: Dispersed systems of bicontinuous cubic phases, called cubosomes, display a faster of drug release rate than those generated by other liquid-crystalline phases. Therefore, in order to avoid greater side effects associated with the accelerated release of the drug incorporated into the system, it is required that the bicontinuous cubic phase be formed only at the desired site of action. In this dissertation, dispersed systems of liquid-crystalline phases were studied for the sustained release of drugs with responsiveness to stimulus such as presence of lipases or changes in the concentration of ions H+. These systems were contained phytantriol, compound capable of forming reverse bicontinuous cubic phases in diluted solutions at physiological temperature and resists the hydrolysis caused by enzymes or concentration of ions H+. In this respect, this work presented the following steps: i) production of cubosomes with adequate kinetic stability, ii) application of cleavable additives for phase transition of the system, converting the cubosomes into a slow releasing phase, iii) hydrolysis of the additives by the action of enzymes and changes in the concentration of ions H+ to generate a new transition to a fast releasing phase, and iv) correlation of the phase transitions with the release kinetics of the model molecule sodium salt of fluorescein. In order to promote phase change over the initial cubic system, formulations based on the original formulation of phytantriol and Pluronic® F-127 as stabilizer were prepared by adding the dioctyl sulfosuccinate sodium salt (AOT) and decyl betainate chloride (DBC). The use of these compounds was based on their biocompatibility and the presence of ester bonds that may be hydrolyzed by the use of the aforementioned triggers. Specific concentrations of AOT and DBC were able to promote the cubosome-to-niosome (lamellar phase dispersion) transition, producing a slow releasing system. Subsequently, the studies were directed towards new transition to a fast releasing phase through the hydrolysis of the additives mediated by chemical (pH: 3,9 to 8,5) and biochemical (enzymes of Candida antarctica e Rhizomucor miehei) triggers. The synthesis of the prodrug (drug administered in inactive mode, which is activated only after biotransformation), indomethacin decyl ester, for incorporation into the dispersed systems was also proposed in order to evaluate the responsiveness caused by the prodrug as an additive. We verified that the systems with AOT were sensitive to alkaline medium leading to the formation of a mixture of reverse hexagonal and reverse micellar cubic phases. DBC systems were sensitive to neutral and alkaline media, forming reverse hexagonal phase. Finally, the systems containing the prodrug were not modified in response to the concentration of ions H+. With regards to the action of the enzymes on the additives, phase changes were not detected when the enzyme was added to the formulations. The last step of the project was to correlate the kinetic profile of sodium salt release of fluorescein from nanoparticles with different phase structures. The formulation containing DBC was the most promising, presenting potential as platform for sustained release of drugs in neutral/alkaline compartments of the organismMestradoFísico-QuímicaMestra em QuímicaFAPES

Perfil de liderança do enfermeiro: concepção dos técnicos de enfermagem/ Nurse leadership profile: conception of nursing technicians

Objetivo: Avaliar a concepção dos técnicos de Enfermagem acerca do perfil de liderança do profissional enfermeiro diante de diferentes atuações. Método: Estudo tipo transversal de natureza descritiva. A população analisada foram 58 técnicos de enfermagem, sendo 49 atuantes em áreas distintas de um Hospital de alta complexidade e 09 em Unidades Básicas de Saúde. A coleta dos dados ocorreu por meio de questionário elaborado previamente pelos autores. Resultados: Quanto ao estilo de liderança, observou-se nas Unidades Básicas de Saúde, o seguinte resultado: 56 % (N=5) dos entrevistados, afirmaram que os enfermeiros possuem um perfil democrático, enquanto na área hospitalar, 45% (N=22) afirmaram que os enfermeiros possuem um perfil auto­­crático. Conclusão: Na Atenção Básica ou na rede hospitalar, o perfil de liderança adotado pelo enfermeiro, deve oferecer condições que auxiliem na realização das atividades, na construção de um ambiente saudável, que estimule o comprometimento da equipe no alcance dos objetivos comuns.

Cartografia e diplomacia: usos geopolíticos da informação toponímica (1750-1850)

O artigo explora dimensões geopolíticas da toponímia, registradas em documentos cartográficos, desde as reformas empreendidas pelo consulado pombalino em meados do século XVIII, até às primeiras décadas do século XIX, em meio ao processo de afirmação do Estado imperial pós-colonial.This paper explores the geopolitical dimensions of toponymy as registered in cartographic documents dating from the reforms pushed through by the consulate of Marquis of Pombal in the mid 18th century to the early decades of the 19th century, as the post-colonial imperial State established itself

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Práticas Educomunicativas

Esta publicação pretende divulgar as práticas educomunicativas realizadas em diferentes regiões do país e que estão sendo implantadas por nossos associados. O e-book Práticas Educomunicativas, que visa oferecer um material de uso prático que possa servir de apoio pedagógico em diferentes contextos, escolar ou de ações junto a instituições, apresenta 20 artigos de profissionais e pesquisadores que implementam ações que inter-relacionam comunicação e educação no contexto da educação apontando as experiências e processos de educomunicação e valorizando desta forma, o trabalho realizado por cada educomunicador oferecendo, ao leitor, um material de uso prático que possa servir de apoio pedagógico em diferentes contextos

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt