Pediatric Research最新文献

{"title":"Family reflections: living with Marfan syndrome.","authors":"Garrett Langford","doi":"10.1038/s41390-025-04007-y","DOIUrl":"https://doi.org/10.1038/s41390-025-04007-y","url":null,"abstract":"","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780838","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":"Causal relationship between gut microbiota, metabolites, and short stature: a Mendelian randomization study.","authors":"Zhimin Zheng, Hao Sun, Panpan Zhang, Fan Cao, Xuwu Xiao, Tingting Zhao","doi":"10.1038/s41390-025-03985-3","DOIUrl":"10.1038/s41390-025-03985-3","url":null,"abstract":"<p><strong>Background: </strong>Previous evidence suggests close relationships between the gut microbiota and short stature, but the causal relationship between them remains unclear. Our study performed Mendelian randomization (MR) analysis to investigate the causal relationships between gut microbiota, blood metabolites, and short stature, and to identify the potential role of blood metabolites as mediators.</p><p><strong>Methods: </strong>We extracted summary-level data for 119 genera gut microbiota, 309 blood metabolites, and short stature from published genome-wide association studies (GWASs). We applied two-sample MR to infer the causal links, and a two-step MR was employed to quantify the proportion of the effect of gut microbiota on short stature mediated by blood metabolites.</p><p><strong>Results: </strong>Increased Prevotella9, Alloprevotella, FamilyXIIIAD3011group, 3-(4-hydroxyphenyl) lactate, and cyclo (leu-pro) were potentially associated with higher short stature risk while Parasutterella, Clostridium sensu stricto 1, Roseburia, caffeine, laurate (12:0), and 4-hydroxyhippurate were related to lower short stature risk. Mediation analysis indicated that 4-hydroxyhippurate levels acted as a mediator between Clostridium sensu stricto 1 and short stature, with an indirect effect proportion of 43.03%.</p><p><strong>Conclusion: </strong>Our study demonstrates the causal relationships among gut microbiota, blood metabolites, and short stature, and computes the proportion of the effect mediated by blood metabolites, provides new insights for studying the gut-bone axis theory in short stature.</p><p><strong>Impact: </strong>Our study used Mendelian randomization to demonstrate a causal relationship between gut microbiota, blood metabolites and short stature and identified a mediating role for metabolites. Current studies on the relationship between gut microbiota and short stature are observational and cannot infer causality, our research provides new evidence for this problem. This is the first Mendelian randomization study of gut microbiota, blood metabolites and short stature, providing new insights into the gut-skeletal axis theory of short stature.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780822","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":"Dose-related systemic and cerebral hemodynamic effects of norepinephrine in newborn piglets with hypoxia-reoxygenation.","authors":"Po-Yin Cheung, Marwa Ramsie, Tze-Fun Lee, Megan O'Reilly, Georg M Schmölzer","doi":"10.1038/s41390-025-04010-3","DOIUrl":"https://doi.org/10.1038/s41390-025-04010-3","url":null,"abstract":"<p><strong>Background: </strong>Little is known regarding systemic and regional hemodynamic effects of norepinephrine (NE) in hypotensive neonates after hypoxia-reoxygenation (H-R). We hypothesized that NE would improve cardiac function, systemic and cerebral hemodynamics without aggravating hyperlactatemia during H-R, compared with epinephrine (EPI).</p><p><strong>Methods: </strong>In an established model of neonatal H-R, piglets were treated with either NE (0.05, 0.1 and 0.2 µg/kg/min), EPI (0.1 µg/kg/min) or saline for 2 h during reoxygenation in a blinded, randomized fashion (n = 8/group). Systemic hemodynamics, carotid blood flow, cerebral oxygenation, and cardiac contractile function were continuously measured. Myocardial, cerebral, renal and intestinal tissues were analyzed for lactate and oxidative stress levels.</p><p><strong>Results: </strong>Norepinephrine (0.1 and 0.2 µg/kg/min) and EPI increased mean arterial pressure and cardiac output with corresponding changes in left ventricular systolic, but not diastolic, function. Norepinephrine at 0.1 µg/kg/min had the optimal systemic hemodynamic effects and cerebral perfusion with lower plasma lactate. Tissue lactate and oxidative stress levels were not different.</p><p><strong>Conclusions: </strong>In newborn piglets with H-R, NE improved cardiac contractile function, cardiac output, blood pressure, and cerebral perfusion in a dose-related manner. Clinical studies of NE on systemic and regional hemodynamic effects in asphyxiated neonates are required to confirm the findings in this pre-clinical study.</p><p><strong>Impact: </strong>In an established model of neonatal hypoxia-reoxygenation, 2-h infusion of norepinephrine at 0.05-0.2 µg/kg/min has dose-related increases in cardiac systolic contractile function and systemic blood pressure with corresponding improvements in cerebral perfusion in newborn piglets, without significant changes in ischemic and oxidative stress markers in tissues. The hemodynamic effects of norepinephrine are comparable to those of epinephrine which causes increased plasma lactate. While norepinephrine is an effective inotropic vasopressor in the treatment of hypotensive shock in neonates with hypoxia-reoxygenation, studies are required to confirm its effects and safety in prolonged administration in clinical trials.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780823","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":"Bronchopulmonary dysplasia: signatures of monocyte-macrophage reactivity and tolerance define novel placenta-lung endotypes.","authors":"Karen K Mestan, Abhineet M Sharma, Sarah Lazar, Sonalisa Pandey, Mana M Parast, Louise C Laurent, Lawrence S Prince, Debashis Sahoo","doi":"10.1038/s41390-025-04025-w","DOIUrl":"https://doi.org/10.1038/s41390-025-04025-w","url":null,"abstract":"<p><strong>Background: </strong>Bronchopulmonary dysplasia (BPD) is a complex disease involving aberrant immune responses across the lifespan, but these mechanisms are challenging to follow in human infants. Leveraging novel Signatures of Macrophage Reactivity and Tolerance (SMaRT), we hypothesized that distinct profiles of immune cell polarization in blood and lung are associated with BPD.</p><p><strong>Methods: </strong>Published transcriptomic datasets of cord blood-derived monocytes (CB-MNC), peripheral blood monocytes (PBMC) and tracheal aspirate-derived lung macrophages were linked to placental inflammatory (PID) and vascular (PVD) disease states using Amsterdam criteria, and BPD outcomes using NIH consensus criteria. Datasets were integrated using SMaRT to investigate monocyte-macrophage polarization tracked over the neonatal course.</p><p><strong>Results: </strong>At birth and day 1 (D1), CB-MNCs and lung macrophages exhibited significant reactivity with PID versus PVD. After D14, macrophages from PID versus PVD-exposed infants exhibited reactive phenotypes (p = 0.002), with convergence towards original placental disease. Macrophages exhibited reactivity with BPD on D1-D7 (p = 0.007), but no difference after D14. At birth, CB-MNCs from BPD patients exhibited tolerance, which persisted in PBMCs throughout the neonatal period.</p><p><strong>Conclusion: </strong>Inflammatory versus vascular-mediated processes in developing lungs are influenced by immune cells programmed by distinct placental disease states. Circulating monocytes may play a role in attenuating macrophage reactivity towards a tolerant phenotype.</p><p><strong>Impact: </strong>Bronchopulmonary dysplasia is a complex, multifactorial chronic lung disease in which the mechanisms of placenta-lung crosstalk are poorly understood. This study uses novel AI approaches to understand how fetal monocytes and lung macrophages contribute to the pathogenesis of BPD. The study identified changes in macrophage reactivity versus tolerance that could explain the heterogeneity and adaptability of immune cells and the placenta in modulating health and disease in the developing fetus and neonate.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772937","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":"Screen habits and effects on sensory profiles in 6- to 36-month-old toddlers.","authors":"Estelle Gillioz, Edouard Gentaz, Fleur Lejeune","doi":"10.1038/s41390-025-04024-x","DOIUrl":"10.1038/s41390-025-04024-x","url":null,"abstract":"<p><strong>Background: </strong>The pervasive presence of screens in toddlers' environments leads to earlier, longer, and more varied exposure to digital devices. Although they provide toddlers with developmentally inappropriate visual and auditory stimulations, only one study has investigated the effect of these screens on their sensory development. The current research, therefore, explores the links between screen use habits and sensory profiles in 6- to 36-month-old toddlers.</p><p><strong>Methods: </strong>Data were collected online using two questionnaires: a questionnaire designed to gather information regarding the use of screens within households and the Dunn's Infant/Toddler Sensory Profile 2 Questionnaire to assess the toddlers' sensory profile.</p><p><strong>Results: </strong>Significant differences in sensory processing based on screen exposure were found: 6- to 18-month-old toddlers showed higher sensitivity and registration scores related to greater direct screen exposure, while 19- to 36-month-old toddlers principally showed higher seeking scores related to greater direct and background screen exposure.</p><p><strong>Conclusion: </strong>These behavioral patterns suggest that excessive screen exposure may impact sensory processing, reducing opportunities for active, multisensory interactions essential for development, emphasizing the need for guidelines to manage screen use in early childhood to promote optimal sensory and cognitive development.</p><p><strong>Impact: </strong>Early screen exposure and sensory processing of 6- to 36-month-old toddlers are linked Potential risks of excessive screen exposure time in toddlerhood could include behavioral problems and hyperactivity through sensory over-responsivity patterns Monitoring and managing screen use in early childhood is crucial for optimal development and to reduce the risk of behavioral disorders in a digital age.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772886","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":"Neonatal encephalopathy in India: spatiotemporal variations in declining mortality.","authors":"Ramesh Vidavalur, Vinod K Bhutani","doi":"10.1038/s41390-025-04009-w","DOIUrl":"https://doi.org/10.1038/s41390-025-04009-w","url":null,"abstract":"<p><strong>Background: </strong>United Nations Sustainable Development Goals (SDGs) target reduction of global neonatal and infant mortality. We examined trends in both neonatal/overall infant mortality (NMR/IMR) and those related to neonatal encephalopathy (NE) for India.</p><p><strong>Methods: </strong>NE mortality data (1990-2019), stratified by age (0-6 days, 7-27 days) and location, were sourced from the Global Health Data Exchange. Birth cohort data were obtained from the UN Population Prospects. NE-NMR trends were analyzed using joinpoint regression to estimate annual percent change (APC) and average APC (AAPC). Pearson correlation assessed relationships between NE-NMR and sociodemographic index (SDI) or composite coverage index (CCI).</p><p><strong>Results: </strong>Of 811 million live births (1990-2019), 4.3 million deaths (uncertainty interval [UI]: 3.6-5.3 million) were NE-related. NE-NMR declined from 6.7 to 3.5 (47.5%, AAPC: -2.2%)], while all-cause NMR and IMR declined from 57.3 to 21.6 (62.6%; AAPC: -3.3%) and from 83.2 to 29.9 (64.1%, AAPC: -3.5%) per 1000 livebirths, respectively. NE-NMR correlated inversely with SDI (R² = 0.57, p < 0.01) but not with CCI (R² = 0.08, p = 0.13). Regional disparities persisted.</p><p><strong>Conclusions: </strong>NE-related neonatal mortality declines, though significant, lags overall neonatal and infant mortality improvements. Sustained, focused and community-oriented efforts are critical to closing these disparities to meet India's SDG targets.</p><p><strong>Impact: </strong>India has achieved significant reductions in neonatal encephalopathy (NE) and all-cause neonatal mortality over the past three decades. From 1990 to 2019, infant mortality rate (IMR) declined from 83 to 29 per 1000 livebirths though NE's share of IMR increased from 8% to 11.8%. Significant interstate variations in NE mortality persist, highlighting the need for targeted state-specific healthcare strategies. NE mortality strongly correlates with sociodemographic development, reflecting the critical role of broad social and economic progress. Strategic and sustained investments in healthcare systems are vital to closing data gaps, reducing disparities, and achieving single-digit neonatal mortality rates by 2030.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764587","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":"Higher risk of metabolic syndrome in children and adolescents and polymorphisms in the fat mass and obesity-associated gene: a systematic review and meta-analysis.","authors":"Yongyan Song, Shujin Li, Hao Liu, Xinyu Liu, Jing Li, Yunhan Wang, Jin Yang","doi":"10.1038/s41390-025-04020-1","DOIUrl":"10.1038/s41390-025-04020-1","url":null,"abstract":"<p><strong>Background: </strong>The relationship between polymorphisms in fat mass and obesity-associated gene (FTO) and the components of metabolic syndrome (MetS) has been explored among children and adolescents, but the results are inconsistent and inconclusive.</p><p><strong>Methods: </strong>Electronic databases including Medline, Scopus, Embase, Web of Science, CNKI, and Google Scholar were searched for eligible studies, and data were extracted from each study. Standardized mean differences were calculated to examine the differences in the components of MetS between FTO genotypes.</p><p><strong>Results: </strong>Forty-six studies (45,100 subjects), seven studies (4216 subjects), and six studies (2699 subjects) were included in the meta-analyses for FTOrs9939609, FTOrs1421085, and FTOrs17817449 polymorphisms, respectively. A-allele carriers of FTOrs9939609 polymorphism had higher levels of waist circumference (WC), systolic blood pressure, and fasting blood glucose, but lower levels of high-density lipoprotein cholesterol (HDL-C) than TT homozygotes (p < 0.05 for all). C-allele carriers of FTOrs1421085 polymorphism had higher levels of WC and lower levels of HDL-C than TT homozygotes (p < 0.05 for both). No significant associations between FTOrs17817449 polymorphism and the components of MetS were detected.</p><p><strong>Conclusion: </strong>The meta-analysis demonstrates that A allele of FTOrs9939609 and C allele of FTOrs1421085 polymorphisms confer a higher risk of MetS among children and adolescents.</p><p><strong>Impact statement: </strong>Genetic polymorphisms are closely related to metabolic syndrome in children and adolescents. The rs9939609 polymorphism in fat mass and obesity-associated gene is apparently associated with a higher risk of metabolic syndrome among children and adolescents. The findings of this study can provide reference for gene diagnosis and gene therapy of metabolic syndrome in children and adolescents.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764585","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":"Advancing neonatal autopsy by strengthening physician belief and fostering effective family communication.","authors":"Panagiotis Kratimenos, Gabriele Simonti, Hannah C Kinney","doi":"10.1038/s41390-025-04031-y","DOIUrl":"10.1038/s41390-025-04031-y","url":null,"abstract":"<p><p>With decreasing rates of neonatal autopsies, it is crucial to raise awareness among medical professionals about the fundamental information obtained from this procedure. Despite new medical advancements, an autopsy is still one of the most reliable methods to determine cause of death. Yet physicians and medical students receive limited exposure and training regarding the value of neonatal autopsies, which likely is contributing to the declining number of autopsies in the United States. Additionally, the emotional state of parents around the death of their infant can increase the discomfort healthcare professionals feel about broaching autopsy conversations with the family. Thus, it is pivotal for physicians and other clinicians to be aware of the benefits of neonatal autopsies and become comfortable communicating this information to families in a timely and appropriate manner. In this article, we provide recommendations to fill these knowledge and communication gaps by presenting common concerns and considerations surrounding autopsy discussion and how to address them. Included are example scripts for conversations that model requesting consent for autopsy at a painful time. This article is intended for neonatologists and pediatricians, as well as other healthcare professionals and trainees. IMPACT: Neonatal autopsies are vital yet often overlooked. This article presents challenges that physicians face in discussing the autopsy process with grieving families and offers practical insights into these complex conversations.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753982","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":"Wanted: multi-dimensional resolution for BPD-PH \"omics\".","authors":"Anne Hilgendorff, Laurie C Eldredge, Jennifer M S Sucre","doi":"10.1038/s41390-025-03898-1","DOIUrl":"https://doi.org/10.1038/s41390-025-03898-1","url":null,"abstract":"","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753989","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":"Whole blood biophysical immune profiling of newborn infants correlates with immune responses.","authors":"Kerwin Kwek Zeming, Genevieve Llanora, Kaiyun Quek, Chin Ren Goh, Nicholas Zhi Heng Ng, Jongyoon Han, Kee Thai Yeo","doi":"10.1038/s41390-025-03952-y","DOIUrl":"https://doi.org/10.1038/s41390-025-03952-y","url":null,"abstract":"<p><strong>Background: </strong>There is a current, absence of reliable, blood-sparing, diagnostic tools to measure and trend real-time changes in the levels of inflammation and its effects on the immune cells in the infant.</p><p><strong>Methods: </strong>We deployed the BiophysicaL Immune Profiling for Infants (BLIPI) system in the neonatal intensive care unit to describe immune cell biophysical profiles using 50 microliters of blood per sample from term and preterm infants.</p><p><strong>Results: </strong>A total of 19 infants (8 term, 11 preterm) were recruited and 24 blood samples were collected in their first month. Based on the profiles of immune cells' size and deformation, there was a clear distinction between term and preterm infants, with 48/50 markers significantly different. A preterm infant with late-onset bacterial sepsis had notable size and deformability differences compared to the rest of the preterm cohort. There was a significant correlation between immune cell biophysical profiles and clinical markers such as C-reactive protein, white blood cell counts, and immature-to-total neutrophil (I:T) ratios, with Pearson correlation coefficients for linear regression models of 0.98, 0.97 and 0.94 respectively.</p><p><strong>Conclusion: </strong>This study highlights the potential for the biophysical immune cell profiling system to provide an overview of the infant's current immune activation and response.</p><p><strong>Impact: </strong>We present a novel, minimally invasive diagnostic system that leverages the physical properties of immune cells to provide a rapid and direct assessment of the immune status, requiring 20 times less blood volume than standard tests. This study demonstrates the potential of a compact, deployable system that is capable of performing biophysical profiling to assess immune cell activation in term and preterm infants, by revealing distinct differences in cell size and deformation between groups. The system's sensitive, quantitative measures were correlated with routine clinical biomarkers, highlighting its ability to provide a rapid, minimally invasive, real-time monitoring of neonatal immune status.</p>","PeriodicalId":19829,"journal":{"name":"Pediatric Research","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753992","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}