Nanogrooved microdiscs for bottom-up modulation of osteogenic differentiation

Grooved topographical features have effectively modulated cell differentiation on two-dimensional substrates. To transpose patterning into a 3D environmment, nanogrooved microdiscs, "topodiscs", are produced as cell carriers for bottom-up cell-mediated assembly. While enhancing cell proliferation, topodiscs led to the formation of bone-like aggregates, even in culture medium lacking osteoinductive factors.publishe

Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-Adjusted life-years for 29 cancer groups, 1990 to 2017 : A systematic analysis for the global burden of disease study

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-Adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572000 deaths and 15.2 million DALYs), and stomach cancer (542000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601000 deaths and 17.4 million DALYs), TBL cancer (596000 deaths and 12.6 million DALYs), and colorectal cancer (414000 deaths and 8.3 million DALYs). Conclusions and Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care. © 2019 American Medical Association. All rights reserved.Peer reviewe

Hipster microcarriers: exploring geometrical and topographical cues of non-spherical microcarriers in biomedical applications

Structure and organisation are key aspects of the native tissue environment, which ultimately condition cell fate via a myriad of processes, including the activation of mechanotransduction pathways. By modulating the formation of integrin-mediated adhesions and consequently impacting cell contractility, engineered geometrical and topographical cues may be introduced to activate downstream signalling and ultimately control cell morphology, proliferation, and differentiation. Microcarriers appear as attractive vehicles for cell-based tissue engineering strategies aiming to modulate this 3D environment, but also as vehicles for cell-free applications, given the ease in tuning their chemical and physical properties. In this review, geometry and topography are highlighted as two preponderant features in actively regulating interactions between cells and the extracellular matrix. While most studies focus on the 2D environment, we focus on how the incorporation of these strategies in 3D systems could be beneficial. The techniques applied to design 3D microcarriers with unique geometries and surface topographical cues are covered, as well as specific tissue engineering approaches employing these microcarriers. In fact, successfully achieving a functional histoarchitecture may depend on a combination of fine-tuned geometrically shaped microcarriers presenting intricately tailored topographical cues. Lastly, we pinpoint microcarrier geometry as a key player in cell-free biomaterial-based strategies, and its impact on drug release kinetics, the production of steerable microcarriers to target tumour cells, and as protein or antibody biosensors.publishe

Cell behavior within nanogrooved sandwich culture system

Grooved topography and inherent cell contact guidance has shown promising results regarding cell proliferation, morphology, and lineage‐specific differentiation. Yet these approaches are limited to 2D applications. Sandwich‐culture conditions are developed to bridge the gap between 2D and 3D culture, enabling both ventral and dorsal cell surface stimulation. The effect of grooved surface topography is accessed on cell orientation and elongation in a highly controlled manner, with simultaneous and independent stimuli on two cell sides. Nanogrooved and non‐nanogrooved substrates are assembled into quasi‐3D systems with variable relative orientations. A plethora of sandwich‐culture conditions are created by seeding cells on lower, upper, or both substrates. Software image analysis demonstrates that F‐actin of cells acquires the orientation of the substrate on which cells are initially seeded, independently from the orientation of the second top substrate. Contrasting cell morphologies are observed, with a higher elongation for nanogrooved 2D substrates than nanogrooved sandwich‐culture conditions. Correlated with an increased pFAK activity and vinculin staining for sandwich‐culture conditions, these results point to an enhanced cell surface stimulation versus control conditions. The pivotal role of initial cell‐biomaterial contact on cellular alignment is highlighted, providing important insights for tissue engineering strategies aiming to guide cellular response through mechanotransduction approaches

Mechanical Properties of Ca-Saturated Hydrogels with Functionalized Alginate

In this work, the mechanical properties and stability of alginate hydrogels containing functionalized alginates (peptide and β-cyclodextrin) were studied. There is an increasing interest in the modification of alginates to add functions such as cell attachment and increased solubility of hydrophobic drugs, for better performance in tissue engineering and drug release, respectively. Functionalization was achieved in this study via periodate oxidation followed by reductive amination, previously shown to give a high and controllable degree of substitution. Young’s modulus and the stress at rupture of the hydrogels were in general lowered when exchanging native alginate with the modified alginate. Still, the gel strength could be adjusted by the fraction of modified alginate in the mixed hydrogels as well as the degree of oxidation. No notable difference in deformation at rupture was observed while syneresis was influenced by the degree of oxidation and possibly by the nature and amount of the grafted molecules. The mixed hydrogels were less stable than hydrogels with only native alginate, and modified alginate was released from the hydrogels. Furthermore, the hydrogels in general rather disintegrated than swelled upon saline treatments

Mechanical Properties of Ca-Saturated Hydrogels with Functionalized Alginate

In this work, the mechanical properties and stability of alginate hydrogels containing functionalized alginates (peptide and β-cyclodextrin) were studied. There is an increasing interest in the modification of alginates to add functions such as cell attachment and increased solubility of hydrophobic drugs, for better performance in tissue engineering and drug release, respectively. Functionalization was achieved in this study via periodate oxidation followed by reductive amination, previously shown to give a high and controllable degree of substitution. Young’s modulus and the stress at rupture of the hydrogels were in general lowered when exchanging native alginate with the modified alginate. Still, the gel strength could be adjusted by the fraction of modified alginate in the mixed hydrogels as well as the degree of oxidation. No notable difference in deformation at rupture was observed while syneresis was influenced by the degree of oxidation and possibly by the nature and amount of the grafted molecules. The mixed hydrogels were less stable than hydrogels with only native alginate, and modified alginate was released from the hydrogels. Furthermore, the hydrogels in general rather disintegrated than swelled upon saline treatments

Body mass index, triglyceride-glucose index, and prostate cancer death: a mediation analysis in eight European cohorts.

Funder: World Cancer Research Fund (WCRF UK); doi: https://doi.org/10.13039/501100000321Funder: Vetenskapsrådet (Swedish Research Council); doi: https://doi.org/10.13039/501100004359Funder: Crafoordska Stiftelsen (Crafoord Foundation); doi: https://doi.org/10.13039/501100003173Funder: Swedish Prostate Cancer Federation Märta Winkler FoundationFunder: Cancerfonden (Swedish Cancer Society); doi: https://doi.org/10.13039/501100002794Funder: Forskningsrådet om Hälsa, Arbetsliv och Välfärd (Swedish Research Council for Health, Working Life and Welfare); doi: https://doi.org/10.13039/501100006636BACKGROUND: Insulin resistance is a hypothesised biological mechanism linking obesity with prostate cancer (PCa) death. Data in support of this hypothesis is limited. METHODS: We included 259,884 men from eight European cohorts, with 11,760 incident PCa's and 1784 PCa deaths during follow-up. We used the triglyceride-glucose (TyG) index as indicator of insulin resistance. We analysed PCa cases with follow-up from PCa diagnosis, and the full cohort with follow-up from the baseline cancer-free state, thus incorporating both PCa incidence and death. We calculated hazard ratios (HR) and the proportion of the total effect of body mass index (BMI) on PCa death mediated through TyG index. RESULTS: In the PCa-case-only analysis, baseline TyG index was positively associated with PCa death (HR per 1-standard deviation: 1.11, 95% confidence interval (CI); 1.01-1.22), and mediated a substantial proportion of the baseline BMI effect on PCa death (HRtotal effect per 5-kg/m2 BMI: 1.24; 1.14-1.35, of which 28%; 4%-52%, mediated). In contrast, in the full cohort, the TyG index was not associated with PCa death (HR: 1.03; 0.94-1.13), hence did not substantially mediate the effect of BMI on PCa death. CONCLUSIONS: Insulin resistance could be an important pathway through which obesity accelerates PCa progression to death

Bioengineered hierarchical bonelike compartmentalized microconstructs using nanogrooved microdiscs

Fabrication of vascularized large-scale constructs for regenerative medicine remains elusive since most strategies rely solely on cell self-organization or overly control cell positioning, failing to address nutrient diffusion limitations. We propose a modular and hierarchical tissue-engineering strategy to produce bonelike tissues carrying signals to promote prevascularization. In these 3D systems, disc-shaped microcarriers featuring nanogrooved topographical cues guide cell behavior by harnessing mechanotransduction mechanisms. A sequential seeding strategy of adipose-derived stromal cells and endothelial cells is implemented within compartmentalized, liquefied-core macrocapsules in a self-organizing and dynamic system. Importantly, our system autonomously promotes osteogenesis and construct's mineralization while promoting a favorable environment for prevascular-like endothelial organization. Given its modular and self-organizing nature, our strategy may be applied for the fabrication of larger constructs with a highly controlled starting point to be used for local regeneration upon implantation or as drug-screening platforms.publishe

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BackgroundEstimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period.Methods22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution.FindingsGlobal all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations.InterpretationGlobal adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic