The level of an intracellular antioxidant during development determines the adult phenotype in a bird species: a potential organizer role for glutathione

Life-history traits are often involved in trade-offs whose outcome would depend on the availability of resources but also on the state of specific molecular signals. Early conditions can influence trade-offs and program the phenotype throughout the lifetime, with oxidative stress likely involved in many taxa. Here we address the potential regulatory role of a single intracellular antioxidant in lifehistory trade-offs. Blood glutathione levels were reduced in a large sample of birds (zebra finch Taeniopygia guttata) during development using the synthesis inhibitor buthionine sulfoximine (BSO). Results revealed several modifications in the adult phenotype. BSO-treated nestlings showed lower glutathione and plasma antioxidant levels. In adulthood, BSO birds endured greater oxidative damage in erythrocytes but stronger expression of a sexual signal. Moreover, adult BSO females also showed weaker resistance to oxidative stress but were heavier and showed better body condition. Results suggest that low glutathione values during growth favor the investment in traits that should improve fitness returns, probably in the form of early reproduction. Higher oxidative stress in adulthood may be endured if this cost is paid later in life. Either the presence of specific signaling mechanisms or the indirect effect of increased oxidative stress can explain our findings.Ministerio de Economía y Competitividad [MINECO], Spain). Financial support was obtained from the projects CGL-2009-10883-C02-02 and CGL2012-40229-C02-01 (MINECO).Peer Reviewe

Covariation in oxidative stress markers in the blood of nestling and adult birds

Interest in the imbalance between the production of reactive oxygen species and the state of the antioxidant machinery—that is, oxidative stress—has recently grown among comparative physiologists and evolutionary/behavioral ecologists. The number and types of markers used to estimate oxidative stress is, however, under debate. The study of covariation among these markers is necessary to better interpret the information content of each independent variable. Here, the covariation in levels of 10 blood parameters in a group of zebra finches (Taeniopygia guttata) as nestlings and adults was analyzed across a large data set. Total glutathione levels in erythrocytes were negatively correlated with plasma carotenoid values in nestlings only, supporting the implication of carotenoids in the antioxidant machinery during a particularly stressful period of life. Plasma lipid levels (triglycerides [TRGs]) as well as plasma antioxidant capacity—the latter tested with and without control for uric acid levels—showed individual consistency with age. Plasma TRG and uric acid levels were strongly correlated with plasma lipid peroxidation and antioxidant capacity, respectively, suggesting an influence of recent intake or mobilization of energy stores on these variables. The meaning of oxidative stress markers, whether corrected or uncorrected for levels of nutritional metabolites, remains to be explored. Experiments manipulating diet composition and oxidative stress are necessary to confirm or reject the hypothesized causalities.A.A.R.-H. was funded by a Formación de Personal de Investigación grant (BES-2010-035013; Ministerio de Economía y Competitividad [MINECO], Spanish government). Financial support was obtained from the projects CGL-2009-10883-C02-02 and CGL2012-40229-C02-01 (MINECO).Peer Reviewe

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

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

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

El papel de estrés oxidativo durante el desarrollo en los compromisos de historia de vida: un estudio en el diamante mandarín (Taeniopygia guttata)

Memoria presentada por Ana Ángela Romero Haro para optar al grado de doctor por la Universidad de Castilla-La Mancha.Los rasgos de historia de vida son características que un individuo manifiesta desde el nacimiento hasta la muerte y que están estrechamente ligadas a la reproducción y la supervivencia. Su expresión puede estar afectada por factores internos del individuo, es decir, por “limitaciones” y “compromisos”. Una limitación es un impedimento en la expresión de un carácter, mientras que en un compromiso la expresión de un rasgo impide la manifestación de otro. La base de estos compromisos sería el uso alternativo de recursos limitantes, pero también el daño provocado en un rasgo por la expresión de otro o ciertas señales bioquímicas que no promuevan la expresión de ambos simultáneamente. Aunque se ha señalado al estrés oxidativo como mecanismo implicado en este contexto existen pocos trabajos longitudinales que estudien su papel en diferentes compromisos durante toda la vida. En esta tesis hemos estudiado el papel del estrés oxidativo sufrido durante el desarrollo en diferentes compromisos vitales en una población de diamante mandarín en condiciones de cautividad realizando varias manipulaciones experimentales. Durante el crecimiento se disminuyeron los niveles del antioxidante glutatión. La mayoría de las consecuencias fueron apreciables solo a edad adulta y promoverían una reproducción temprana: las hembras tuvieron mayor peso y condición física y, ambos sexos, unos picos más rojos (señal sexual). Antes de la cópula se manipuló la inversión reproductiva de los machos estableciéndolos en ambientes con hembras o solo con machos. El estrés oxidativo temprano que sufrieron estos machos no afectó directamente a su inversión, pero el experimentado por el compañero de jaula produjo cambios fisiológicos y morfológicos en ellos. Más adelante, el esfuerzo reproductor de nuestras aves fue manipuladodurante la cría de sus pollos aumentando o disminuyendo el tamaño de las nidadas. Las consecuencias fueron sorprendentemente positivas para aquellos individuos cuyo nivel de estrés coincidía entre el desarrollo y la reproducción, aunque ambos ambientes fueran desfavorables. Aquellos que sufrieron una disminución del nivel de glutatión durante el desarrollo y un aumento del esfuerzo reproductor mostraron unos eritrocitos más resistentes a una hemólisis experimentada bajo estrés oxidativo. Además, los resultados también muestran que cualquier inversión en obtención de pareja puede tener a efectos a largo plazo e incluirse en el coste oxidativo de la reproducción. Por último, se detectaron profundas diferencias entre sexos al afrontar los desafíos oxidativos. La conclusión global es que la disminución de un único antioxidante durante el desarrollo puede influenciar la historia de vida de un individuo. El glutatión ha demostrado ser una molécula con un importante papel programador del fenotipo a largo plazo. En esta tesis se presenta, además, un trabajo de revisión bibliográfico sobre el coste oxidativo de la reproducción. Existen múltiples causas, mayormente metodológicas, que podrían explicar los resultados contradictorios de los trabajos experimentales actuales. Pero no podemos descartar que la reproducción podría disminuir el daño oxidativo, en determinadas circunstancias, mediante un proceso de hormesis (compensación) y/o por utilización de macromoléculas oxidadas y acumuladas para usarlas en la reproducción. Diferentes resultados encontrados en esta tesis apoyarían estas hipótesis.Peer Reviewe

Early development conditions and the oxidative cost of social context in adulthood: an experimental study in birds

Environmental conditions during early life may shape phenotype in adulthood. Early adverse conditions may increase the oxidative stress in adults, which could affect their reproductive output and survival. It has also been hypothesized that the larger the reproductive investment, the higher the oxidative stress. We tested this and the potential influence of early oxidative stress on how individuals respond to a reproductive stimulation. The synthesis of the antioxidant glutathione was inhibited in captive zebra finches (Taeniopygia guttata) during growth. In adulthood, the expression of a carotenoid-based sexual signal, bill redness, increased in both sexes, with females also being heavier than controls. The social context of control and glutathione-inhibited males was then manipulated to stimulate precopulatory reproductive investments. Males were individually caged in front of a female or another male. We predicted that males enduring lower early antioxidant levels and placed close to a female should pay the highest cost of a hypothetical increase in bill redness in terms of oxidative damage. However, early conditions only influenced the male's phenotype via their partners. Males caged with females showed increases in circulating pigment (carotenoid) levels, but only when females endured early low antioxidant values. This was probably related to the higher attractiveness of these females. Nevertheless, the bill redness of males did not differ during the social manipulation. Moreover, males facing females from any early condition group showed lower oxidative damage levels in plasma lipids. This result agrees with some findings in rodents, also in captivity. However, the effect may be due to increased triglyceride levels and body mass in males not facing females, as variation in these traits explained oxidative damage variability. The importance of considering housing conditions and life history when interpreting oxidative stress-related trade-offs is highlighted..AR was funded by a Formación de Personal de Investigación grant (BES-2010-035013; Ministerio de Economía y Competitividad, MINECO, Spanish Government). Financial support was obtained from the projects CGL-2009-10883-C02-02 and CGL2012-40229-C02-01 (MINECO, Spain).Peer Reviewe