20 research outputs found

    Um modelo estocástico para a migração de células individuais

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    O estudo de processos biológicos que produzem a dinâmica de sistemas vivos utilizando ferramentas matemáticas e computacionais é uma área de grande interesse da ciência moderna, e a mobilidade celular é um de seus temas principais, pois está presente em diversos processos de tecidos saudáveis e de doenças, como no desenvolvimento do câncer. A partir de dados experimentais de diversos laboratórios com diferentes tipos de células aplicando técnicas de análise estatística, foi proposta uma modificação na teoria canônica para ajustar o comportamento das células para escalas de tempo pequenas. Também foi desenvolvido um modelo computacional em ambiente virtual CompuCell3D para a simulação de migração de células eucariontes sobre substrato plano, utilizando método de Monte Carlo. Diferente de outros modelos apresentados na literatura, este modelo é tridimensional e simula o comportamento de uma célula composta pelas organelas intracelulares que estão envolvidas na biomecânica do movimento celular. As simulações reproduzem, espontaneamente, o processo de quebra de simetria que permite que a célula comece a migrar de forma persistente. Ainda assim, as simulações apresentaram baixo custo computacional, gerando a perspectiva de implementação para o estudo do movimento coletivo de células ou de engenharia de tecidos. São apresentados todos os passos necessários para a implementação de simulações de mobilidade celular em ambiente CompuCell3D. Os resultados da tese indicam um protocolo para a medida de mobilidade celular que possibilita a comparação entre os resultados de diferentes experimentos ou simulações apenas por um parâmetro adimensional. Este protocolo evita erros como na determinação da velocidade média das células. Os resultados das simulações indicam a existência de uma correlação entre a polarização da célula e o seu deslocamento futuro, no entanto, esta correlação ainda não está totalmente caraterizada.The study of biological processes that produce the dynamics of living systems using mathematical and computational tools is an area of great interest in modern science, and cell mobility is one of its main themes, as it is present in several healthy tissue processes and diseases, as in the development of cancer. Based on experimental data from different laboratories with different types of cells applying statistical analysis techniques, a modification in the canonical theory has been proposed to adjust the behavior of cells for small time scales. A computational model in a virtual environment CompuCell3D was also developed to simulate the migration of eukaryotic cells on a flat substrate, using the Monte Carlo method. Unlike other models presented in the literature, this model is three-dimensional and simulates the behavior of a cell composed of intracellular organelles that are involved in the biomechanics of cell movement. The simulations spontaneously reproduce the symmetry breaking process that allows the cell to start migrating persistently. Even so, the simulations showed low computational cost, generating the prospect of implementation for the study of the collective movement of cells or tissue engineering. All the necessary steps for the implementation of cell mobility simulations in a CompuCell3D environment are presented. The results of the thesis indicate a protocol for the measurement of cellular mobility that makes it possible to compare the results of different experiments or simulations using only one dimensionless parameter. This protocol avoids errors as in the determination of the average speed of the cells. The results of the simulations still indicate the existence of a correlation between the polarization of the cell and its future displacement; however, this correlation is not yet fully characterized

    Instantaneous cell migration velocity may be ill-defined

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    Cell crawling is critical to biological development, homeostasis and disease. In many cases, cell trajectories are quasi-random-walk. In vitro assays on flat surfaces often described such quasi-random-walk cell trajectories as approximations to a solution of a Langevin process. However, experiments show quasi-diffusive behavior at small timescales, indicating that instantaneous velocity and velocity autocorrelations are not well-defined. We propose to characterize mean-squared cell displacement using a modified F\"urth equation with three temporal and spatial regimes: short- and long-time/range diffusion and intermediate time/range ballistic motion. This analysis collapses mean-squared displacements of previously published experimental data onto a single-parameter family of curves, allowing direct comparison between movement in different cell types, and between experiments and numerical simulations. Our method also show that robust cell-motility quantification requires an experiment with a maximum interval between images of a few percent of the cell-motion persistence time or less, and a duration of a few orders-of-magnitude longer than the cell-motion persistence time or more.Comment: 5 pages, plus Supplemental materia

    Shape-velocity correlation defines polarization in migrating cell simulations

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    Cell migration plays essential roles in development, wound healing, diseases, and in the maintenance of a complex body. Experiments in collective cell migration generally measure quantities such as cell displacement and velocity. The observed short-time diffusion regime for mean square displacement in single-cell migration experiments on flat surfaces calls into question the definition of cell velocity and the measurement protocol. Theoretical results in stochastic modeling for single-cell migration have shown that this fast diffusive regime is explained by a white noise acting on displacement on the direction perpendicular to the migrating cell polarization axis (not on velocity). The prediction is that only the component of velocity parallel to the polarization axis is a well-defined quantity, with a robust measurement protocol. Here, we ask whether we can find a definition of a migrating-cell polarization that is able to predict the cell's subsequent displacement, based on measurements of its shape. Supported by experimental evidence that cell nucleus lags behind the cell center of mass in a migrating cell, we propose a robust parametrization for cell migration where the distance between cell nucleus and the cell's center of mass defines cell shape polarization. We tested the proposed methods by applying to a simulation model for three-dimensional cells performed in the CompuCell3D environment, previously shown to reproduce biological cells kinematics migrating on a flat surface

    Growth laws and self-similar growth regimes of coarsening two-dimensional foams: Transition from dry to wet limits

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    We study the topology and geometry of two dimensional coarsening foams with arbitrary liquid fraction. To interpolate between the dry limit described by von Neumann's law, and the wet limit described by Marqusee equation, the relevant bubble characteristics are the Plateau border radius and a new variable, the effective number of sides. We propose an equation for the individual bubble growth rate as the weighted sum of the growth through bubble-bubble interfaces and through bubble-Plateau borders interfaces. The resulting prediction is successfully tested, without adjustable parameter, using extensive bidimensional Potts model simulations. Simulations also show that a selfsimilar growth regime is observed at any liquid fraction and determine how the average size growth exponent, side number distribution and relative size distribution interpolate between the extreme limits. Applications include concentrated emulsions, grains in polycrystals and other domains with coarsening driven by curvature

    Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

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    : The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

    Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

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    Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill & Melinda Gates Foundation

    Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

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    Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

    Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

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    Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

    Dinâmica do crescimento de espumas molhadas

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    O estudo dos sistemas que apresentam padrões celulares é motivado pela frequência com que são encontrados na natureza, bem como sua grande aplicabilidade tecnológica. Sistemas celulares biológicos, sólidos policristalinos, espumas, entre outros, têm em comum uma estrutura formada por domínios, e diferentes regimes estruturais e de dinâmica para diferentes frações entre as fases envolvidas. A maioria dos trabalhos publicados até hoje se limitou aos casos limites de diluição entre as fases do sistema, ou seja, ao limite em que a fase celular está muito diluída, caracterizando o Amadurecimento de Ostwald (ou do inglês, Ostwald Ripening), e o limite oposto, quando os domínios estão em contato direto entre si, e que o seu crescimento é descrito pela lei de von Neumann-Mullins. Este trabalho compila os conhecimentos sobre a estrutura e a dinâmica desta classe de sistemas, e explora os efeitos decorrentes das frações entre as fases. Também apresenta os resultados obtidos pelas simulações realizadas utilizando o modelo GGH, para diversas frações entre fases e que reproduzem os resultados conhecidos para os casos limites, bem como mostram que o crescimento em escala não é algo específico destes limites. E, por final, apresenta uma tentativa de escrever uma expressão matemática para a taxa de crescimento dos domínios que conecte as teorias limites, como sendo apenas função de variáveis relacionadas à sua geometria.The study of systems that exhibit cellular patterns is motivated not only by the frequency with which they are found in nature, but also by their wide application in technology. Biological systems, policrystal solids, soap froth, and others, have in common a structure formed by domains, and different structural and dynamic regimes for different fractions between the phases in the system. Most studies have been limited to the limit cases where the dilution between the phases of the system, i.e., the threshold at which cell phase is very dilute, featuring Ostwald Ripening, and the opposite limit, when the domains are in direct contact with each other, and where its growth is described by the law of von Neumann-Mullins. This work compiles the knowledge of the structure and dynamics of this class of systems, and explores the effects of the different fractions between the phases. It also presents the results obtained by simulations using the GGH model for these various fractions between regimes and reproducing the known results for the limiting cases and showing that the scale growth is not specific to these limits. Yet, it presents, an attempt to write a mathematical expression for the rate of growth of the areas that connect the limit theories through a function of the variables related to the system geometry
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