Pediatric Research最新文献

{"title":"Severe anemia in preterm infants associated with increased bacterial virulence potential and metabolic disequilibrium.","authors":"Justin A Gibbons, Leigh-Anne M Worthington, Elizabeth G Chiu, Heather R Kates, Rico R Carter, Rachel Nelson, Min Zhang, Timothy J Garrett, Thao T B Ho","doi":"10.1038/s41390-024-03669-4","DOIUrl":"10.1038/s41390-024-03669-4","url":null,"abstract":"<p><strong>Background: </strong>Anemia in preterm infants is associated with gut dysbiosis and necrotizing enterocolitis. Our study aimed to identify the bacterial functions and metabolites that can explain the underlying mechanisms of anemia associated disease conditions.</p><p><strong>Methods: </strong>We conducted a case control study in preterm infants with cases having a hematocrit <math><mo>≤</mo></math> 25%. The control infants were matched by birth gestational age and weight. Fecal samples were collected before, at the onset, and after the onset of anemia in cases and with matched postnatal age in controls for metagenomics and metabolomics analyzes.</p><p><strong>Results: </strong>18 anemic and 20 control infants with fecal samples collected at 17 days, 5 weeks, and 7 weeks postnatal age were included. Virulence factor potential, decrease in beta diversity evolution, and larger changes in metabolome were associated with severe anemia. Metabolite abundances of N-acetylneuraminate and butyrobetaine were associated with virulence factor potential. Anemic group had decreased prostaglandin and lactic acid levels.</p><p><strong>Conclusion: </strong>Fecal omics data showed that severe anemia is associated with a pro-inflammatory gut microbiota with more virulent and less commensal anaerobic bacterial activities. Future studies can examine the link between anemia-associated dysbiosis and clinical outcomes and predict an infant-specific hematocrit threshold that negatively affects clinical outcomes.</p><p><strong>Impact: </strong>Severe anemia in preterm infants contributes to a pro-inflammatory gut with greater bacterial virulence and less commensal bacterial activities. The multiomics approach using non-invasive fecal biospecimens identified functional and metabolic changes in the gut microbiota and these mechanistic changes are plausible explanations for anemia-associated disease conditions in preterm infants. Our findings identified biological changes of the gut environment in severely anemic preterm infants that can offer guidance for clinical management.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive model development for premature infant extubation outcomes: development and analysis.","authors":"Camila S Espíndola, Yuri K Lopes, Grasiela S Ferreira, Emanuella C Cordeiro, Silvana A Pereira, Dayane Montemezzo","doi":"10.1038/s41390-024-03643-0","DOIUrl":"https://doi.org/10.1038/s41390-024-03643-0","url":null,"abstract":"<p><strong>Background: </strong>Given the knowledge of the damage caused by prolonged invasive mechanical ventilation in premature newborns, withdrawing this support as quickly as possible is important to minimize morbidity. The aim of this study was to analyze the variables associated with extubation outcomes and to develop a predictive model for successful extubation in premature newborns.</p><p><strong>Methods: </strong>Data were obtained from a multicenter study involving six public maternity hospitals. The variables with the highest correlation to the extubation outcome were used to construct the predictive model through data analysis and machine learning methods, followed by training and testing of algorithms.</p><p><strong>Results: </strong>Data were collected from 405 premature newborns. The predictive model with the best metrics was trained and tested using the variables of gestational age, birth weight, weight at extubation, congenital infections, and time on invasive mechanical ventilation, based on 393 samples according to the extubation outcome (12 were discarded due to irretrievable missing data in important attributes). The model exhibited an accuracy of 77.78%, sensitivity of 79.41%, and specificity of 60%.</p><p><strong>Conclusion: </strong>These variables generated a predictive model capable of estimating the probability of successful extubation in premature newborns.</p><p><strong>Impact: </strong>Prolonged use of invasive mechanical ventilation in preterm newborns increases morbidity/mortality rates, emphasizing the importance of early withdrawal from invasive ventilatory support. However, the decision to extubate lacks tools with higher extubation outcome precision. The use of artificial intelligence through the construction of a predictive model can assist in the decision-making process for extubating preterm newborns based on real-world data. The implementation of this tool can optimize the decision to extubate preterm newborns, promoting successful extubation and reducing preterm newborns exposure to adverse events associated with extubation failure.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early Intervention services in the era of genomic medicine: setting a research agenda.","authors":"Katherine E MacDuffie, Betty Cohn, Paul Appelbaum, Kyle B Brothers, Dan Doherty, Aaron J Goldenberg, Elizabeth Reynolds, Hadley Stevens Smith, Anne Wheeler, Joon-Ho Yu","doi":"10.1038/s41390-024-03668-5","DOIUrl":"https://doi.org/10.1038/s41390-024-03668-5","url":null,"abstract":"<p><p>Newborn genomic sequencing (NBSeq) has the potential to substantially improve early detection of rare genetic conditions, allowing for pre-symptomatic treatment to optimize outcomes. Expanding conceptions of the clinical utility of NBSeq include earlier access to behavioral early intervention to support the acquisition of core motor, cognitive, communication, and adaptive skills during critical windows in early development. However, important questions remain about equitable access to early intervention programs for the growing number of infants identified with a genetic condition via NBSeq. We review the current NBSeq public health, clinical, and research landscape, and highlight ongoing international research efforts to collect population-level data on the utility of NBSeq for healthy newborns. We then explore the challenges facing a specific Early Intervention (EI) system-the US federally supported \"Part C\" system-for meeting the developmental needs of young children with genetic diagnoses, including structural limitations related to funding, variable eligibility criteria, and lack of collaboration with newborn screening programs. We conclude with a set of questions to guide future research at the intersection of NBSeq, newborn screening, and EI, which once answered, can steer future policy to ensure that EI service systems can optimally support the developmental needs of infants impacted by broader implementation of NBSeq. IMPACT: Existing literature on the clinical benefits of genome sequencing in newborns tends to focus on earlier provision of medical interventions, with less attention to the ongoing developmental needs of very young children with genetic conditions. This review outlines the developmental needs of a growing number of children diagnosed with genetic conditions in infancy and describes the strengths and limitations of the United States Early Intervention system (IDEA Part C) for meeting those needs.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The needs of families of pediatric cancer survivors: challenges and developments in psychosocial support services.","authors":"Verena Paul, Laura Inhestern, Désirée Sigmund, Jana Winzig, Stefan Rutkowski, Gabriele Escherich, Corinna Bergelt","doi":"10.1038/s41390-024-03662-x","DOIUrl":"https://doi.org/10.1038/s41390-024-03662-x","url":null,"abstract":"<p><strong>Impact: </strong>Caru et al. emphasize the positive of physical activity during and after treatment for children with cancer, highlighting its significance for improving health outcomes. In Germany, exercise therapy has not yet been integrated into standard post-treatment care; however, efforts are underway to establish a nationwide framework that enhances these services. Given the complexity of the challenges faced by families, a family-centered approach to psychosocial support services is essential for effectively addressing their multifaceted needs.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Standardizing feeding strategies in preterm infants with birth weight >1500 g: current perspective.","authors":"Abhay Lodha","doi":"10.1038/s41390-024-03660-z","DOIUrl":"10.1038/s41390-024-03660-z","url":null,"abstract":"","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paediatric e-scooter riders at high risk of life-threatening traffic accidents.","authors":"Andrea Schuller, Anna Hohensteiner, Thomas Sator, Lorenz Pichler, Manuela Jaindl, Elisabeth Schwendenwein, Thomas Manfred Tiefenboeck, Stephan Payr","doi":"10.1038/s41390-024-03667-6","DOIUrl":"10.1038/s41390-024-03667-6","url":null,"abstract":"<p><strong>Background: </strong>This study presents the epidemiology and the development of e-scooter and non-electric scooter injuries in children and adolescents to highlight the nature and the severity of such injuries.</p><p><strong>Methods: </strong>All children and adolescents with electric or non-electric scooter related injuries between January 2019 until December 2022 were included in this single-centre study and retrospectively evaluated. An epidemiological overview including age, sex, type of scooter, injury mechanism, diagnosed injuries and surgical interventions were presented. Further, statistical comparisons of the means and proportions of injuries and the number of surgical interventions between electric and non-electric scooter riders were made.</p><p><strong>Results: </strong>The study consists of 633 children and adolescents (9.1 ± 5.0 years; 231 female, 36.5%, 402 male, 63.5%). 80.1% (8.0 ± 4.1 years) used non-electric scooters, while 19.9% (14.2 ± 4.1 years) used e-scooters. In comparison, adolescent e-scooter riders were significantly more likely to be involved in traffic accidents (non-electric scooter: 16/507; e-scooter: 21/126; p = 0.0001) and suffered severe head injuries more often (non-electric scooter: 8/134; e-scooter: 7/37; p = 0.0217) than patients riding non-electric scooters.</p><p><strong>Conclusion: </strong>Adolescent e-scooter riders were more likely to be involved in potentially life-threatening traffic accidents having a higher risk of severe head injuries requiring surgery compared to non-electric scooter riders.</p><p><strong>Impact: </strong>Adolescent e-scooter riders have a higher risk to be involved in potentially life-threatening traffic accidents than riders of non-electric scooters. E-scooter riders have a higher risk of sustaining serious head injuries requiring surgical intervention than non-electric scooter riders. The data highly recommends the implementation of prevention strategies especially educating youth and parents and wearing protective clothing. Legislation and law enforcement could help prevent such injuries and potentially life-threatening traffic accidents involving children and adolescents who ride e-scooters.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiome impact on childhood allergic rhinitis and house dust mite IgE responses.","authors":"Junyang Li, Nan Shen, Wenjun He, Yi Pan, Jing Wu, Ruike Zhao, Xi Mo, Youjin Li","doi":"10.1038/s41390-024-03645-y","DOIUrl":"https://doi.org/10.1038/s41390-024-03645-y","url":null,"abstract":"<p><strong>Background: </strong>The correlation between the gut microbiota and airway inflammation in childhood allergic rhinitis (AR), particularly concerning allergen exposure, remains insufficiently explored. This study aimed to link gut microbiota changes with house dust mite (HDM)-specific IgE responses in pediatric AR.</p><p><strong>Methods: </strong>Using metagenomic shotgun sequencing, we compared the fecal microbiota of 60 children with HDM-AR to 48 healthy controls (HC), analyzing the link to IgE reactions. We examined the effects of oral Escherichia (E.) fergusonii treatment in mice sensitized with ovalbumin and HDM on allergic symptoms, mucosal cell infiltration, Th1/Th2/Tregs balance in the spleen, serum cytokine levels, and E. fergusonii presence in feces.</p><p><strong>Results: </strong>Children with HDM-AR have a less diverse gut microbiome and lower levels of E. fergusonii compared to controls, with a negative correlation between E. fergusonii abundance and HDM-specific IgE levels. In mice sensitized with OVA and HDM, oral administration of E. fergusonii improved allergic symptoms, reduced nasal eosinophils/mast cells infiltration and adjusted Th cell populations towards a non-allergic profile in splenic lymphocytes with exception of IFN-γ change in serum.</p><p><strong>Conclusion: </strong>These findings underline the potential of targeting gut microbiota, particularly E. fergusonii, in managing childhood HDM-AR, suggesting a promising approach for future interventions.</p><p><strong>Impact: </strong>The composition and distribution of gut microbiota in children with HDM-AR are significant changed. The abundance of Escherichia genus is decreased in HDM-AR children. HDM-specific IgE levels are strongly negatively associated with E. fergusonii abundance. Oral administration of E. fergusonii effectively suppresses allergic responses in murine model. These findings offer novel insights into the diagnosis and treatment of HDM-AR, which suggested that E. fergusonii holds promise as a potential therapeutic avenue for managing HDM-AR.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A validated NICU database: recounting 50 years of clinical growth, quality improvement and research.","authors":"Kikelomo Babata, Charles R Rosenfeld, Mambarambath Jaleel, Patti J Burchfield, Marina Santos Oren, Riya Albert, L Steven Brown, Lina Chalak, Luc P Brion","doi":"10.1038/s41390-024-03624-3","DOIUrl":"https://doi.org/10.1038/s41390-024-03624-3","url":null,"abstract":"<p><p>The importance of a Neonatal Intensive Care Unit (NICU) database lies in its critical role in improving the quality of care for very preterm neonates and other high-risk newborns. These databases contain extensive information regarding maternal exposures, pregnancy complications, and neonatal care. They support quality improvement (QI) initiatives, facilitate clinical research, and track health outcomes in order to identify best practices and improve clinical guidelines. The Parkland Memorial Hospital NICU database was originally part of the Maternal and Neonatal Data Acquisition, Transmission and Evaluation project funded by the Robert Wood Johnson Foundation to assess perinatal-neonatal care in Dallas County Texas, 1977-1982. Clinical data points were defined, transcribed and validated in 1977; revalidation has occurred multiple times. Data are prospectively extracted from health records of high-risk neonates among >11,000 births annually. The database contains clinical information on >50,000 neonates, including all initially admitted to the NICU regardless of gestational age or birthweight and since 10/03/2011, all neonates admitted for observation and transferred to the term newborn nursery. The database has provided the basis for QI studies and research designed to assess and improve neonatal care. We discuss the history, evolution, administration, impact on neonatal outcomes, and future directions of our database. IMPACT: A single neonatal intensive care unit (NICU) database was designed for prospective data collection, validated and maintained for 46yrs. This database has supported quality improvement assessment, original clinical research, education and administrative requirements and impacted clinical neonatal care.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The relationships between resilience and child health behaviors in a national dataset.","authors":"Ellen L McMahon, Shelby Wallace, Lauren R Samuels, William J Heerman","doi":"10.1038/s41390-024-03664-9","DOIUrl":"https://doi.org/10.1038/s41390-024-03664-9","url":null,"abstract":"<p><strong>Background: </strong>Resilience mechanisms at the individual, family, and environmental levels may improve health outcomes despite potentially harmful stress exposure partly through the practice of positive health behaviors.</p><p><strong>Methods: </strong>We performed a secondary analysis of 2016-2021 National Survey of Children's Health data to assess the relationships between three resilience domains - child, family, neighborhood - and six health behaviors using multiple regression models adjusted for the other resilience domain(s) and potential confounders.</p><p><strong>Results: </strong>Analysis revealed significant associations between each resilience domain and multiple health behaviors in a total weighted analytic sample of 70,156,540 children. For each outcome, the odds of better health behaviors were highest with high resilience in all possible domains. For example, among children ages 0-5 years, the adjusted odds of having \"good quality\" vs. \"poor quality\" sleep for those with \"high\" resilience in all domains were 2.21 times higher (95% CI 1.78, 2.63) than for those with \"low\" resilience in all domains.</p><p><strong>Conclusions: </strong>This line of research may help to inform the design of resilience and health behavior promotion interventions by targeting multiple socio-ecological domains of influence to improve health and development outcomes in children exposed to experiences or sources of potential stress.</p><p><strong>Impact: </strong>This study assessed the associations between three socio-ecological resilience domains (child, family, and neighborhood) and six child and family health behaviors in a national dataset. Resilience exists within multiple socio-ecological levels and supports healthy functioning despite experiencing stress. Studies in adults and limited pediatric sub-populations show associations between resilience and health behaviors, which in turn influence numerous health outcomes. Resilience at three levels of socio-ecological levels was found to be associated with the performance of multiple child and family health behaviors in a nationally representative general pediatric population. These findings have important implications for child and family health promotion efforts.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preterm birth is associated with dystonic features and reduced cortical parvalbumin immunoreactivity in mice.","authors":"Kat Gemperli, Femi Folorunso, Benjamin Norin, Rebecca Joshua, Rachel Rykowski, Clayton Hill, Rafael Galindo, Bhooma R Aravamuthan","doi":"10.1038/s41390-024-03603-8","DOIUrl":"10.1038/s41390-024-03603-8","url":null,"abstract":"<p><strong>Background: </strong>Preterm birth is a common cause of dystonia. Though dystonia is often associated with striatal dysfunction after neonatal brain injury, cortical dysfunction may best predict dystonia following preterm birth. Furthermore, abnormal sensorimotor cortex inhibition is associated with genetic and idiopathic dystonias. To investigate cortical dysfunction and dystonia following preterm birth, we developed a new model of preterm birth in mice.</p><p><strong>Methods: </strong>We induced preterm birth in C57BL/6J mice at embryonic day 18.3, ~24 h early. Leg adduction variability and amplitude, metrics we have shown distinguish between dystonia from spasticity during gait in people with CP, were quantified from gait videos of mice. Parvalbumin-positive interneurons, the largest population of cortical inhibitory interneurons, were quantified in the sensorimotor cortex and striatum.</p><p><strong>Results: </strong>Mice born preterm demonstrate increased leg adduction amplitude and variability during gait, suggestive of clinically observed dystonic gait features. Mice born preterm also demonstrate fewer parvalbumin-positive interneurons and reduced parvalbumin immunoreactivity in the sensorimotor cortex, but not the striatum, suggesting dysfunction of cortical inhibition.</p><p><strong>Conclusions: </strong>These data may suggest an association between cortical dysfunction and dystonic gait features following preterm birth. We propose that our novel mouse model of preterm birth can be used to study this association.</p><p><strong>Impact: </strong>Mouse models of true preterm birth are valuable for studying clinical complications of prematurity. Mice born preterm demonstrate increased leg adduction amplitude and variability during gait, suggestive of clinically observed dystonic gait features. Mice born preterm demonstrate fewer parvalbumin-positive interneurons and reduced parvalbumin immunoreactivity in the sensorimotor cortex, suggesting dysfunction of cortical inhibition. Mice born preterm do not demonstrate changes in parvalbumin immunoreactivity in the striatum. Cortical dysfunction may be associated with dystonic gait features following preterm birth.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}