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- Influence of Functional Variations in Genes of Neurotrophins and Neurotransmitter Systems on the Development of Retinopathy of PrematurityPublication . Fevereiro-Martins, M; Santos, AC; Marques-Neves, C; Guimarães, H; Bicho, Mfirst_pagesettingsOrder Article Reprints Open AccessArticle Influence of Functional Variations in Genes of Neurotrophins and Neurotransmitter Systems on the Development of Retinopathy of Prematurity by Mariza Fevereiro-Martins 1,2,3,4,*,Ana Carolina Santos 1,2ORCID,Carlos Marques-Neves 1,2,5,Hercília Guimarães 6ORCID,Manuel Bicho 1,2,3ORCID andon behalf of the GenE-ROP Study Group † 1 Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal 2 Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental-ISAMB, Laboratório Associado Terra, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal 3 Instituto de Investigação Científica Bento da Rocha Cabral, Calçada Bento da Rocha Cabral 14, 1250-012 Lisboa, Portugal 4 Departamento de Oftalmologia, Hospital Cuf Descobertas, Rua Mário Botas, 1998-018 Lisboa, Portugal 5 Centro de Estudos das Ciências da Visão, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, Piso 1C, 1649-028 Lisboa, Portugal 6 Departamento de Ginecologia-Obstetrícia e Pediatria, Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal * Author to whom correspondence should be addressed. † Collaborators of the study group are included in the Acknowledgments. Int. J. Mol. Sci. 2025, 26(3), 898; https://doi.org/10.3390/ijms26030898 Submission received: 7 December 2024 / Revised: 20 January 2025 / Accepted: 20 January 2025 / Published: 22 January 2025 (This article belongs to the Special Issue Molecular Aspects of Retinopathy and Protection) Downloadkeyboard_arrow_down Browse Figure Review Reports Versions Notes Abstract Retinal neurodevelopment, vascularization, homeostasis, and stress response are influenced by factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and erythropoietin (EPO). As retinopathy of prematurity (ROP) is a neurovascular retinal disease, this study analyzed the contributions of NGF (rs6330), BDNF (rs7934165), TH (rs10770141), and EPO (rs507392) genetic functional polymorphisms to the modulation of hematological and biochemical parameters of the first week of life and their association with ROP development. A multicenter cohort of 396 preterm infants (gestational age < 32 weeks or birth weight < 1500 g) was genotyped using MicroChip DNA and iPlex MassARRAY® platform. Multivariate regression followed univariate assessment of ROP risk factors. NGF (GG) genotype was associated with a higher ROP risk (OR = 1.79), which increased further (OR = 2.38) when epistatic interactions with TH (allele C) and BDNF (allele G) were present. Significant circulating biomarker differences, including bilirubin, erythrocytes, monocytes, neutrophils, lymphocytes, and platelet markers, were found between ROP and non-ROP groups, with variations depending on the polymorphism. These findings suggest that NGF (rs6330) and its interactions with related genes contribute to ROP risk, providing valuable insights into the genetic and biological mechanisms underlying the disease and identifying potential predictive biomarkers.
- Fetal Hemoglobin as a Predictive Biomarker for Retinopathy of Prematurity: A Prospective Multicenter Cohort Study in PortugalPublication . Fevereiro-Martins, M; Aguiar, L; Inácio, Â; Cardoso, C; Santos, AC; Marques-Neves, C; Guimarães, H; Pinto, R; Bicho, MBackground/Objectives: Retinopathy of prematurity (ROP) is a leading cause of vision impairment in preterm infants, with its pathogenesis linked to oxygen exposure. Red blood cell (RBC) transfusions, commonly performed in neonatal intensive care units (NICUs), reduce fetal hemoglobin (HbF) fraction, altering oxygen dynamics and potentially contributing to ROP. We aimed to investigate the relationship between RBC transfusions, HbF percentage, and ROP, evaluating HbF as a potential predictive biomarker. Methods: A multicenter, prospective study was conducted across eight Portuguese NICUs, involving infants born at <32 weeks gestational age (GA) or <1500 g. ROP staging followed the International Classification of ROP (ICROP2). Clinical data were collected during hospitalization, and HbF fractions were measured from blood samples in the first four weeks of life using standardized methods. Infants were stratified by ROP presence and treatment requirement. Statistical analysis was performed using SPSS 28.0, with p < 0.05. Results: Eighty-two infants (mean GA: 28.1 ± 2.1 weeks, birth weight: 1055.8 ± 258.3 g) were included. Among them, 29 (35.4%) presented ROP and 4 (4.9%) required treatment. Infants with ROP had more RBC transfusions and lower HbF percentages than those without ROP (p < 0.05). Lower HbF was associated with more RBC transfusions (p < 0.001). Kaplan-Meier survival curves showed a higher ROP risk in infants with reduced HbF (p < 0.05). Conclusions: Low HbF percentage in the first four weeks of life may increase ROP risk in preterm infants. HbF could serve as a biomarker for ROP prediction. Interventions preserving HbF may reduce ROP risk. Further studies are needed to validate HbF as a biomarker and refine prevention strategies.
- Global change, climate change, and asthma in children: Direct and indirect effects - A WAO Pediatric Asthma Committee ReportPublication . Le Souëf, PN; Adachi, Y; Anastasiou, E; Ansotegui, IJ; Badellino, HA; Banzon, T; Beltrán, CP; D'Amato, G; El-Sayed, ZA; Gómez, RM; Hossny, E; Kalayci, Ö; Morais-Almeida, M; Nieto-Garcia, A; Peden, DB; Phipatanakul, W; Wang, JY; Wan, IJ; Wong, G; Xepapadaki, P; Papadopoulos, NGThe twenty-first century has seen a fundamental shift in disease epidemiology with anthropogenic environmental change emerging as the likely dominant factor affecting the distribution and severity of current and future human disease. This is especially true of allergic diseases and asthma with their intimate relationship with the natural environment. Climate change-related variables including increased ambient temperature, heat waves, extreme weather events, air pollution, and rainfall distribution, all can directly affect asthma in children, but each of these variables also indirectly affects asthma via alterations in pollen production and release, outdoor allergen exposure or the microbiome. Air pollution, with its many and varied respiratory consequences, is likely to have the greatest effect, as it has increased globally due to rapid increases in fossil fuel combustion, global population, crowding, and megacities, as well as forest burning and trees succumbing to an increasingly hostile environment. Human activities have also caused substantial deterioration of the global microbiome with reductions in biodiversity for molds, bacteria, and viruses. Reduced microbiome diversity has, in turn, been associated with increases in Th2 allergic responses and allergic disease. The collective effect of these changes has already shifted allergy and asthma disease patterns. Given that changes in climate have been relatively small to date, the unavoidable, much greater shifts in climate in the future are concerning. Determining the relative scale of the direct versus indirect effects of climate change variables is needed if effective avoidance and adaptive measures are to be implemented. This would also require much more basic, epidemiological, and clinical research to understand the causal mechanisms, the most relevant climate factors involved, the regions most affected and, most importantly, effective and actionable adaptation measures. We suggest that allergy and respiratory health workers should follow current guidance to reduce present risks related to climate change and watch for new recommendations to reduce future risks. Since the respiratory system is the one most affected by climate change, they also need to call for more research in this area and show strong leadership in advocating for urgent action to protect children by reducing or reversing factors that have led to our deteriorating climate.
- European Society of Endocrinology Curriculum and Training Recommendation in EndocrinologyPublication . Luger, A; Durkan, M; Christ-Crain, M; Marques, PThe European Society of Endocrinology (ESE) and the Union Européenne des Médecins Spécialistes (U.E.M.S.) Section and Board of Endocrinology have produced a Curriculum and Training Recommendation in Endocrinology to provide updated recommendations concerning the content and structure of postgraduate training. Cornerstones of the Curriculum are the integrity of Endocrinology not to be divided into subspecialties such as diabetology or thyroidology, recommendation of 6 years full-time training comprising 1-3 years (preferably 2-3 years) of General Internal Medicine followed by 3-5 years of specialist training in Endocrinology across 13 core areas. In addition to knowledge and experience in the many fields of Endocrinology, the Curriculum includes specific attitudes, communication skills, training to work in and lead multidisciplinary teams, resource management, quality assurance, human-error management, and critical incidents reporting as well as the commitment to life-long learning expected from a trainee and from an Endocrinologist. The Curriculum also includes requirements for training centres, for assessment of training and for competencies of trainers. The aim of the ESE Curriculum and Training Recommendation in Endocrinology is to harmonise postgraduate training and help provide the best medical care for patients with endocrine diseases across Europe.
- Enhancing precision in hysteroscopic surgery: The role of intraoperative ultrasoundPublication . Ferreira de Castro, L; Santos, I; Laganà, AS; de Vree, B; van Herendael, BJ; Djokovic, DHysteroscopy stands as the gold-standard approach for managing intrauterine pathology. However, in complex clinical cases, hysteroscopic evaluation alone may prove insufficient for the safest and successful patient management. Intraoperative ultrasound (IOUS) has emerged as a valuable adjunct to hysteroscopic surgery, offering real-time visualization of endometrial cavity, uterine walls and instruments within the uterine cavity, enabling precise delineation of anatomical structures, and helping to assess the extent of pathology during intricate interventions. This review aims to comprehensively assess the applications, efficacy and utility of IOUS in hysteroscopic surgery. Available evidence indicates that in hysteroscopic myomectomy, IOUS significantly reduces the risk of uterine perforation, particularly in submucosal FIGO 2 myomas, and enhances the likelihood of a single-step procedure. During hysteroscopic metroplasty, ultrasound guidance decreases the chance of incomplete uterine septum resection. In the hysteroscopic management of severe Asherman syndrome, IOUS reduces the risk of uterine perforation or false passage. For cesarean scar pregnancy (CSP), ultrasound is crucial in defining the most appropriate surgical approach and is effective in guiding the hysteroscopic treatment of endogenic CSP. The use of IOUS in hysteroscopy proves valuable in complex cases where the risk of uterine perforation or incomplete procedure is increased.
- An increase in paediatric arthroscopy in Europe: Experience of the EPOS Sport Study GroupPublication . Turati, M; Crippa, M; Nicolaou, N; Tassistro, E; Sinikumpu, J; Courvoisier, A; Mumme, M; Duart, J; Thüsing, M; Bigoni, M; Accadbled, F
- Retinopathy of Prematurity in Eight Portuguese Neonatal Intensive Care Units: Incidence, Risk Factors, and Progression—A Prospective Multicenter StudyPublication . Fevereiro-Martins, M; Santos, ACa; Marques-Neves, C; Bicho, M; Guimarães, HBackground/objectives: Retinopathy of prematurity (ROP) is a retinal neovascular disease affecting preterm infants. Identifying risk factors for its development and progression is critical for effective screening and prevention. This study aimed to analyze the incidence of ROP and identify key risk factors for its development and progression. Methods: We conducted a prospective, observational cohort study on 455 neonates (gestational age [GA] < 32 weeks or birth weight < 1500 g) across eight Portuguese NICUs. Results: ROP incidence was 37.8%, with 4.6% requiring treatment. Multivariate analysis identified low GA and the number of red blood cell (RBC) transfusions as significant factors for ROP development and progression. After adjusting for these variables, platelet transfusions, high maximum fraction of inspired oxygen (FiO2) in the second week, and surfactant use remained significantly associated with ROP development, while early and late sepsis, maternal chronic hypertension, and delayed enteral nutrition were associated with progression to ROP requiring treatment. Conclusions: These findings underscore the importance of addressing low GAs and adult RBC transfusions in ROP risk management and suggest that maximum FiO2, platelet transfusions, and sepsis also play crucial roles. Larger studies are needed to validate these results and explore preventive interventions, particularly regarding the impact of multiple adult RBC transfusions on fetal hemoglobin percentages.
- Global change, climate change, and asthma in children: Direct and indirect effects - A WAO Pediatric Asthma Committee ReportPublication . Le Souëf, PN; Adachi, Y; Anastasiou, E; Ansotegui, IJ; Badellino, HA; Banzon, T; Beltrán, CP; D'Amato, G; El-Sayed, ZA; Gómez, RM; Hossny, E; Kalayci, Ö; Morais-Almeida, M; Nieto-Garcia, A; Peden, DB; Phipatanakul, W; Wang, JY; Wan, IJ; Wong, G; Xepapadaki, P; Papadopoulos, NGThe twenty-first century has seen a fundamental shift in disease epidemiology with anthropogenic environmental change emerging as the likely dominant factor affecting the distribution and severity of current and future human disease. This is especially true of allergic diseases and asthma with their intimate relationship with the natural environment. Climate change-related variables including increased ambient temperature, heat waves, extreme weather events, air pollution, and rainfall distribution, all can directly affect asthma in children, but each of these variables also indirectly affects asthma via alterations in pollen production and release, outdoor allergen exposure or the microbiome. Air pollution, with its many and varied respiratory consequences, is likely to have the greatest effect, as it has increased globally due to rapid increases in fossil fuel combustion, global population, crowding, and megacities, as well as forest burning and trees succumbing to an increasingly hostile environment. Human activities have also caused substantial deterioration of the global microbiome with reductions in biodiversity for molds, bacteria, and viruses. Reduced microbiome diversity has, in turn, been associated with increases in Th2 allergic responses and allergic disease. The collective effect of these changes has already shifted allergy and asthma disease patterns. Given that changes in climate have been relatively small to date, the unavoidable, much greater shifts in climate in the future are concerning. Determining the relative scale of the direct versus indirect effects of climate change variables is needed if effective avoidance and adaptive measures are to be implemented. This would also require much more basic, epidemiological, and clinical research to understand the causal mechanisms, the most relevant climate factors involved, the regions most affected and, most importantly, effective and actionable adaptation measures. We suggest that allergy and respiratory health workers should follow current guidance to reduce present risks related to climate change and watch for new recommendations to reduce future risks. Since the respiratory system is the one most affected by climate change, they also need to call for more research in this area and show strong leadership in advocating for urgent action to protect children by reducing or reversing factors that have led to our deteriorating climate.
- Retinopathy of prematurity: contribution of inflammatory and genetic factorsPublication . Fevereiro-Martins, M; Guimarães, H; Marques-Neves, C; Bicho, MRetinopathy of prematurity (ROP) is a retinal vasoproliferative disorder that represents an important cause of childhood visual impairment and blindness. Although oxidative stress has long been implicated in ROP etiology, other prenatal and perinatal factors are also involved. This review focuses on current research involving inflammation and genetic factors in the pathogenesis of ROP. Increasing evidence suggests that perinatal inflammation or infection contributes to ROP pathogenesis. Cytokines and chemokines with a fundamental role in inflammatory responses and that significantly contributing to angiogenesis are analyzed. Microglia cells, the retinal-resident macrophages, are crucial for retinal homeostasis, however, under sustained pathological stimuli release exaggerated amounts of inflammatory mediators and can promote pathological neovascularization. Current modulation of angiogenic cytokines, such as treatment with antibodies to vascular endothelial growth factor (anti-VEGF), has shown efficacy in the treatment of ocular neovascularization; however, some patients are refractory to anti-VEGF agents, suggesting that other angiogenic or anti-angiogenic cytokines need to be identified. Much evidence suggests that genetic factors contribute to the phenotypic variability of ROP. Several studies have implicated the involvement of candidate genes from different signaling pathways in the development of ROP. However, a genetic component with a major impact on ROP has not yet been discovered. Most studies have limitations and did not replicate results. Future research involving bioinformatics, genomics, and proteomics may contribute to finding more genes associated with ROP and may allow discovering better solutions in the management and treatment of ROP.
- Retinopathy of Prematurity in Eight Portuguese Neonatal Intensive Care Units: Incidence, Risk Factors, and Progression—A Prospective Multicenter StudyPublication . Fevereiro-Martins, M; Santos, AC; Marques-Neves, C; Bicho, M; Guimarães, HBackground/Objectives: Retinopathy of prematurity (ROP) is a retinal neovascular disease affecting preterm infants. Identifying risk factors for its development and progression is critical for effective screening and prevention. This study aimed to analyze the incidence of ROP and identify key risk factors for its development and progression. Methods: We conducted a prospective, observational cohort study on 455 neonates (gestational age [GA] < 32 weeks or birth weight < 1500 g) across eight Portuguese NICUs. Results: ROP incidence was 37.8%, with 4.6% requiring treatment. Multivariate analysis identified low GA and the number of red blood cell (RBC) transfusions as significant factors for ROP development and progression. After adjusting for these variables, platelet transfusions, high maximum fraction of inspired oxygen (FiO2) in the second week, and surfactant use remained significantly associated with ROP development, while early and late sepsis, maternal chronic hypertension, and delayed enteral nutrition were associated with progression to ROP requiring treatment. Conclusions: These findings underscore the importance of addressing low GAs and adult RBC transfusions in ROP risk management and suggest that maximum FiO2, platelet transfusions, and sepsis also play crucial roles. Larger studies are needed to validate these results and explore preventive interventions, particularly regarding the impact of multiple adult RBC transfusions on fetal hemoglobin percentages.