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Ludmila Pierdevara,1 Ana María Porcel-Gálvez,2 Alexandra Maria Ferreira da Silva,1 Sérgio Barrientos Trigo,3 Margarida Eiras4 1Escuela Internacional de Doctorado, Universidad de Sevilla, Sevilla, Spain; 2Nursing Department, Escuela Internacional de Doctorado, University of Seville, Sevilla, Spain; 3Department of Nursing, Escuela Internacional de Doctorado, University of Seville, Sevilla, Spain; 4H&RC ESTeSL-IPL, Lisbon, PortugalCorrespondence: Ludmila Pierdevara Praça do Poder Local, Lote 7ª, 6º Frente, Lagos 8600-524, PortugalTel +351 963605271Email pierdevara@hotmail.comPurpose: To adapt and validate the Global Trigger Tool (IHI-GTT), which identifies and analyzes adverse events (AE) in hospitalized patients and their measurement properties in the Portuguese context.Methods: A retrospective cross-sectional study was based on a random sample of 90 medical records. The stages of translation and cross-cultural adaptation of the IHI-GTT were based on the Cross-Cultural Adaptation Protocol that originated from the Portuguese version, GTT-PT, for the hospital context in medical-surgical departments. Internal consistency, reliability, reproducibility, diagnostic tests, and discriminatory predictive value were investigated.Results: The final phase of the GTT-PT showed insignificant inconsistencies. The pre-test phase confirmed translation accuracy, easy administration, effectiveness in identifying AEs, and relevance of integrating it into hospital risk management. It had a sensitivity of 97.8% and specificity of 74.8%, with a cutoff point of 0.5, an accuracy of 83%, and a positive predictive value of 69.8% and a negative predictive value of 0.98%.Conclusion: The GTT-PT is a reliable, accurate, and valid tool to identify AE, with robust measurement properties.Keywords: medical errors, patient safety, risk management

Background: Understanding how urban environments influence people's health, especially as individuals age, can help identify ways to improve health in the rapidly urbanizing and rapidly aging populations., Objectives: To investigate the association between age and self-reported health (SRH) in adults living in Latin-American cities and whether gender and city-level socioeconomic characteristics modify this association., Methods: Cross-sectional analyses of 71,541 adults aged 25-97 years, from 114 cities in 6 countries (Argentina, Brazil, Colombia, Chile, El Salvador, and Guatemala), as part of the Salud Urbana en America Latina (SALURBAL) Project. We used individual-level age, gender, education, and self-reported health (SRH) data from harmonized health surveys. As proxies for socioeconomic environment we used a city-level socioeconomic index (SEI) calculated from census data, and gross domestic product (GDP) per-capita. Multilevel Poisson models with a robust variance were used to estimate relative risks (RR), with individuals nested in cities and binary SRH (poor SHR vs. good SRH) as the outcome. We examined effect modification by gender and city-level socioeconomic indicators., Results: Overall, 31.4% of the sample reported poor SRH. After adjusting for individual-level education, men had a lower risk of poor SRH (RR = 0.76; CI 0.73-0.78) compared to women, and gender modified the association between age and poor SRH (p-value of interaction < 0.001). In gender stratified models, the association between older age and poor SRH was more pronounced in men than in women, and in those aged 25-65 than among those 65+ (RR/10 years = 1.38 vs. 1.10 for men, and RR/10 years = 1.29 vs. 1.02 for women). Living in cities with higher SEI or higher GDP per-capita was associated with a lower risk of poor SRH. GDP per-capita modified the association between age (25-65) and SRH in men and women, with SEI the interaction was less clear., Conclusions: Across cities in Latin America, aging impact on health is significant among middle-aged adults, and among men. In both genders, cities with lower SEI or lower GDP per-capita were associated with poor SRH. More research is needed to better understand gender inequalities and how city socioeconomic environments, represented by different indicators, modify exposures and vulnerabilities associated with aging., (© 2022. The Author(s).)

Increased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation and bone-resorbing activities. Transferrin receptor 1 (Tfr1) mediates cellular iron uptake through endocytosis of iron-loaded transferrin, and its expression increases during osteoclast differentiation. Nonetheless, the precise functions of Tfr1 and Tfr1-mediated iron uptake in osteoclast biology and skeletal homeostasis remain incompletely understood. To investigate the role of Tfr1 in osteoclast lineage cells in vivo and in vitro, we crossed Tfrc (encoding Tfr1)-floxed mice with Lyz2 (LysM)- Cre and Cathepsin K ( Ctsk )-Cre mice to generate Tfrc conditional knockout mice in myeloid osteoclast precursors (Tfr1 ΔLysM ) or differentiated osteoclasts (Tfr1 ΔCtsk ), respectively. Skeletal phenotyping by µCT and histology unveiled a significant increase in trabecular bone mass with normal osteoclast number in long bones of 10-week-old young and 6-month-old adult female but not male Tfr1 ΔLysM mice. Although high trabecular bone volume in long bones was observed in both male and female Tfr1 ΔCtsk mice, this phenotype was more pronounced in female knockout mice. Consistent with this gender-dependent phenomena, estrogen deficiency induced by ovariectomy decreased trabecular bone mass in Tfr1 ΔLysM mice. Mechanistically, disruption of Tfr1 expression attenuated mitochondrial metabolism and cytoskeletal organization in mature osteoclasts in vitro by attenuating mitochondrial respiration and activation of the Src-Rac1-WAVE regulatory complex axis, respectively, leading to decreased bone resorption with little impact on osteoclast differentiation. These results indicate that Tfr1-mediated iron uptake is specifically required for osteoclast function and is indispensable for bone remodeling in a gender-dependent manner., Competing Interests: BD, LW, TF, JZ, NA, KK, RL, SM, RE, MJ, XW, JF, TB, JG, AK, LG, WX, HZ No competing interests declared, SM Reviewing editor, eLife

Supplemental Digital Content is available in the text., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Osteoclasts are multinucleated cells of the monocyte/macrophage lineage that degrade bone. Here, we used lineage tracing studies-labelling cells expressing Cx3cr1, Csf1r or Flt3-to identify the precursors of osteoclasts in mice. We identified an erythromyeloid progenitor (EMP)-derived osteoclast precursor population. Yolk-sac macrophages of EMP origin produced neonatal osteoclasts that can create a space for postnatal bone marrow haematopoiesis. Furthermore, EMPs gave rise to long-lasting osteoclast precursors that contributed to postnatal bone remodelling in both physiological and pathological settings. Our single-cell RNA-sequencing data showed that EMP-derived osteoclast precursors arose independently of the haematopoietic stem cell (HSC) lineage and the data from fate tracking of EMP and HSC lineages indicated the possibility of cell-cell fusion between these two lineages. Cx3cr1 + yolk-sac macrophage descendants resided in the adult spleen, and parabiosis experiments showed that these cells migrated through the bloodstream to the remodelled bone after injury.

Objective: To analyze the adolescent motherhood trend and associated factors in under-100 000-inhabitants communities., Materials and Methods: Cross-sectional analysis of 16 686 women in under-100 000-inhabitants communities in Encuesta Nacional de Salud y Nutrición (Ensanut) 2006, 2012 and 100k 2018. We adjusted robust Poisson models with adolescent motherhood as dependent variable for women aged 12-19 and 20-24., Results: Attending school and using modern contraceptives decrease adolescent motherhood prevalence in both age groups. Among adolescent girls, having a health financing scheme, and early sexual debut in the case of adults, is positively associated with adolescent motherhood., Conclusions: It is necessary to strengthen public policies seeking to modify structural factors that provide life choices, and to maintain and strengthen the actions and coverage proposed by Estrategia Nacional para la Prevención del Embarazo en Adolescentes (ENAPEA) targeting this population., Competing Interests: Declaration of conflict of interests. The authors declare that they have no conflict of interests.

β-catenin protein needs to be precisely regulated for effective fracture repair. The pace of fracture healing slows with age, associated with a transient increase in β-catenin during the initial phase of the repair process. Here we examined the ability of pharmacologic agents that target β-catenin to improve the quality of fracture repair in old mice. 20 month old mice were treated with Nefopam or the tankyrase inhibitor XAV939 after a tibia fracture. Fractures were examined 21 days later by micro-CT and histology, and 28 days later using mechanical testing. Daily treatment with Nefopam for three or seven days but not ten days improved the amount of bone present at the fracture site, inhibited β-catenin protein level, and increased colony forming units osteoblastic from bone marrow cells. At 28 days, treatment increased the work to fracture of the injured tibia. XAV939 had a more modest effect on β-catenin protein, colony forming units osteoblastic, and the amount of bone at the fracture site. This data supports the notion that high levels of β-catenin in the early phase of fracture healing in old animals slows osteogenesis, and suggests a pharmacologic approach that targets β-catenin to improve fracture repair in the elderly.

The pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Here we report that young macrophage cells produce factors that promote osteoblast differentiation of old bone marrow stromal cells. Heterochronic parabiosis exploiting young mice in which macrophages can be depleted and fractionated bone marrow transplantation experiments show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Proteomic analysis of the secretomes identify differential proteins secreted between old and young macrophages, such as low-density lipoprotein receptor-related protein 1 (Lrp1). Lrp1 is produced by young cells, and depleting Lrp1 abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp1 improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice.

The dynorphin (DYN) peptide family includes opioid and non-opioid peptides, yet the physiological role of the non-opioid DYN peptides remains poorly understood. Recent evidence shows that administering the non-opioid peptide DYN-A 2-17 into the paraventricular hypothalamic nucleus (PVN) simultaneously increased short-term intake of standard rodent chow and spontaneous physical activity (SPA). The present studies aimed to expand upon the mechanisms and role of DYN-A 2-17 on food intake and energy expenditure. Injection of DYN-A 2-17 in PVN increased SPA, energy expenditure and wheel running in the absence of food. Repeated DYN-A 2-17 injection in PVN increased short-term chow intake, but this effect habituated over time and failed to alter cumulative food intake, body weight or adiposity. Pre-treatment with a CRF receptor antagonist into PVN blocked the effects of DYN-A 2-17 on food intake while injection of DYN-A 2-17 in PVN increased plasma ACTH. Finally, as DYN peptides are co-released with orexin peptides, we compared the effects of DYN-A 2-17 to orexin-A and the opioid peptide DYN-A 1-13 on food choice and intake in PVN when palatable snacks and chow were available. DYN-A 1-13 selectively increased intake of palatable snacks. DYN-A 2-17 and orexin-A decreased palatable snack intake while orexin-A also increased chow intake. These findings demonstrate that the non-opioid peptide DYN-A 2-17 acutely regulates physical activity, energy expenditure and food intake without long-term effects on energy balance. These data also propose different roles of opioid, non-opioid DYN and orexin peptides on food choice and intake when palatable and non-palatable food options are available., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

We aimed to estimate the population fraction of poor early child health and developmental outcomes attributable to maternal depressive symptoms (DS) contrasting it between low- and middle/high-income households. We used a nationally representative probabilistic sample of 4240 children younger than 5 years old and their mothers, derived from the Mexican National Health and Nutrition Survey Data (ENSANUT 2012). Complex survey design, sampling, and analytic weights were taken into account in analyses. DS was measured by CESD-7. Child outcomes were as follows: breastfeeding, attending well-child check-ups, respiratory disease, diarrhea and general health problems, immunization, accidents, growth, obesity, and food insecurity. Prevalence of DS among mothers was 21.36%. In low-SES households, DS was associated with higher risk of never being breastfed (RR = 1.77; p < .05), health problems (RR = 1.37; p < .05), acute respiratory disease (RR = 1.51; p < .05), accidents requiring child hospitalization (RR = 2.16; p < .01), and moderate or severe food insecurity (RR = 1.58; p < .001). In medium- or high-SES households, DS was associated with higher risk of never attending a developmental check-up (RR = 2.14; p < .05) and moderate or severe food insecurity (RR = 1.75; p < .01). Population risks attributable to DS ranged from 2.30 to 17.45%. Prevention of DS could lead to reduction of problematic early childhood outcomes in both low and medium/high SES.

Objective:: To describe the methodology and the implementation survey results from National Survey of Children and Women Mexico's (ENIM 2015)., Materials and Methods:: The ENIM 2015 is a probability survey with multistage, stratified and cluster sample, with regional, rural and urban strata, and indigenous population representation.We applied questionnaires to get information from the household, women aged 15 to 49 years, children under five years and children and adolescents aged 5-17 years., Results:: The response rate for households and women was 94%, obtaining information from 10 760 households and 12 110 women; while for children and adolescents and children under five years was 98%, 11 607 and 8 066, respectively., Conclusion:: The ENIM 2015 probabilistic design allows generate indicators that can be stratified into five regions, rural and urban strata and from indigenous population, as well as a baseline for 15 indicators of the ODS.

Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in vivo. Surprisingly, we found that decreased iron, due to inactivation of Tfr1, was associated with severe cardiac consequences. Mice lacking Tfr1 in the heart died in the second week of life and had cardiomegaly, poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy. The phenotype could only be rescued by aggressive iron therapy, but it was ameliorated by administration of nicotinamide riboside, an NAD precursor. Our findings underscore the importance of both Tfr1 and iron in the heart, and may inform therapy for patients with heart failure., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Divalent metal-ion transporter-1 (DMT1) is a widely expressed iron-preferring membrane-transport protein that serves a critical role in erythroid iron utilization. We have investigated its role in intestinal metal absorption by studying a mouse model lacking intestinal DMT1 (i.e., DMT1(int/int)). DMT1(int/int) mice exhibited a profound hypochromic-microcytic anemia, splenomegaly, and cardiomegaly. That the anemia was due to iron deficiency was demonstrated by the following observations in DMT1(int/int) mice: 1) blood iron and tissue nonheme-iron stores were depleted; 2) mRNA expression of liver hepcidin (Hamp1) was depressed; and 3) intraperitoneal iron injection corrected the anemia, and reversed the changes in blood iron, nonheme-iron stores, and hepcidin expression levels. We observed decreased total iron content in multiple tissues from DMT1(int/int) mice compared with DMT1(+/+) mice but no meaningful change in copper, manganese, or zinc. DMT1(int/int) mice absorbed (64)Cu and (54)Mn from an intragastric dose to the same extent as did DMT1(+/+) mice but the absorption of (59)Fe was virtually abolished in DMT1(int/int) mice. This study reveals a critical function for DMT1 in intestinal nonheme-iron absorption for normal growth and development. Further, this work demonstrates that intestinal DMT1 is not required for the intestinal transport of copper, manganese, or zinc., (Copyright © 2015 the American Physiological Society.)

Transferrin receptor (Tfr1) is ubiquitously expressed, but its roles in non-hematopoietic cells are incompletely understood. We used a tissue-specific conditional knockout strategy to ask whether skeletal muscle required Tfr1 for iron uptake. We found that iron assimilation via Tfr1 was critical for skeletal muscle metabolism, and that iron deficiency in muscle led to dramatic changes, not only in muscle, but also in adipose tissue and liver. Inactivation of Tfr1 incapacitated normal energy production in muscle, leading to growth arrest and a muted attempt to switch to fatty acid β oxidation, using up fat stores. Starvation signals stimulated gluconeogenesis in the liver, but amino acid substrates became limiting and hypoglycemia ensued. Surprisingly, the liver was also iron deficient, and production of the iron regulatory hormone hepcidin was depressed. Our observations reveal a complex interaction between iron homeostasis and metabolism that has implications for metabolic and iron disorders.