Frontiers in Endocrinology最新文献

{"title":"Corrigendum: Is choline kinase alpha a drug target for obesity?","authors":"Juan Carlos Lacal, Salam A Ibrahim, Tahl Zimmerman","doi":"10.3389/fendo.2025.1580595","DOIUrl":"https://doi.org/10.3389/fendo.2025.1580595","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fendo.2024.1492753.].</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1580595"},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIMP2 rs2277698 polymorphism associated with adverse IVF outcomes in Han Chinese women.","authors":"Chun-I Lee, Yu-Jen Lee, Tsung-Hsien Lee, Chi-Ying Lee, Hui-Mei Tsao, En-Hui Cheng, Chun-Chia Huang, Shun-Fa Yang, Maw-Sheng Lee","doi":"10.3389/fendo.2025.1542534","DOIUrl":"10.3389/fendo.2025.1542534","url":null,"abstract":"<p><strong>Background: </strong>Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are critical regulators of extracellular matrix (ECM) proteolysis and play a pivotal role in trophoblast invasion during embryo implantation. This study aimed to investigate the effects of single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes on clinical outcomes in women undergoing <i>in vitro</i> fertilization (IVF).</p><p><strong>Methods: </strong>This retroprospective study included 1014 women undergoing their first fresh IVF cycle without donor eggs at Lee Women's Hospital between January 2014 and December 2015. Peripheral blood samples were collected from all participants for DNA extraction and SNP genotyping using real-time polymerase chain reaction. The study focused on three SNPs: TIMP1 (rs4898 C/T), TIMP2 (rs2277698 C/T), and MMP2 (rs243865 C/T). Associations between these SNPs and IVF outcomes, including clinical pregnancy, embryo implantation, abortion, and live birth rates, were analyzed.</p><p><strong>Results: </strong>Among 560 patients analyzed, no significant differences were observed in baseline characteristics between the live birth and non-live birth groups. However, the minor alleles (CT+TT) of MMP2 (rs243865) and TIMP2 (rs2277698) were significantly more frequent in the non-live birth group (MMP2: 24.4% vs. 17.7%, p = 0.044; TIMP2: 48.1% vs. 34.4%, <i>p</i> = 0.001). In contrast, no significant differences in the genotype distribution of TIMP1 (rs4898) were noted between the groups. Logistic regression analysis identified the minor T allele of TIMP2 as a significant predictor of non-live birth (adjusted odds ratio: 1.725; 95% CI: 1.217-2.445; <i>p</i> = 0.002). Combined genotypes of MMP2/TIMP2, such as CC/CT+TT and CT+TT/CT+TT, were associated with an increased risk of non-live birth, even after adjusting for covariates.</p><p><strong>Conclusions: </strong>The study demonstrates that the minor T allele of TIMP2 (rs2277698 C/T) is associated with poor IVF outcomes, particularly non-live birth. This finding highlights the potential role of genetic variations in TIMP2 in influencing clinical outcomes of IVF. Further research is warranted to elucidate the underlying mechanisms in larger and more diverse populations.</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1542534"},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11948279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-ocular biomarkers for early diagnosis of diabetic retinopathy by non-invasive methods.","authors":"Huaixue Gou, Juping Liu","doi":"10.3389/fendo.2025.1496851","DOIUrl":"10.3389/fendo.2025.1496851","url":null,"abstract":"<p><p>Diabetic retinopathy (DR) is the predominant vision-threatening complication in individuals with diabetes mellitus. Timely diagnosis and intervention facilitate the prevention of diabetes-associated visual impairment. Classical imaging methods may prevent the timely detection of DR due to shortages of specialized facilities and retinal specialists, particularly in remote areas. In recent years, research on biomarkers related to DR has rapidly developed, playing an important role in risk assessment and early detection of the disease. Some ocular biomarkers from the vitreous body or aqueous humor were invasive, which hampered their application in clinical practice. Meanwhile, biomarkers based on omics were limited by their uneasily accessible use and complicated variables with a relatively low degree of reproducibility. As modern technology progresses, advanced non-ocular biomarkers of DR have established a comprehensive platform for the prompt identification of DR, independent of ophthalmic professionals or devices and accessible to non-ophthalmologists during community screenings. This review focuses on biomarkers derived from non-ocular sample sources, such as nailfold and skin, accessible through non-invasive methods, to reveal if they can be considered as an effective option for the early identification of DR by non-ophthalmologists in community screening initiatives.</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1496851"},"PeriodicalIF":3.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating shear wave elastography into clinical prediction of Graves' disease recurrence: a novel risk scoring system.","authors":"Xiao-Yun Zha, Ze-Hong Xu, Jia-Jia Dong, Liang-Xiao Xie, Peng-Bin Lai, Chang-Shun Wei, Hua-Qiang Zheng, Duo-Bin Huang, Jin-Zhi Wu","doi":"10.3389/fendo.2025.1551983","DOIUrl":"10.3389/fendo.2025.1551983","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to evaluate the utility of shear wave elastography (SWE) in predicting the recurrence risk of Graves' disease(GD), to construct a recurrence risk prediction model that integrates SWE and clinical characteristics, and to develop a risk scoring system aimed at enhancing the survival rate of patients with GD following drug treatment and prognosis management.</p><p><strong>Methods: </strong>A prospective cohort study was conducted involving with 169 patients diagnosed with first-episode GD. By analyzing SWE parameters, three-dimensional thyroid volume, TRAb levels, and other clinical indicators, the Cox proportional hazards model was used to construct a recurrence risk prediction model for GD. Bootstrap resampling was employed to verify the model's reliability. A simple recurrence risk scoring system was also developed based on independent risk factors for clinical use.</p><p><strong>Results: </strong>The study identified several factors significantly associated with GD recurrence: age <35 years, a family history of GD, an initial TRAb level≧15 IU/ml, a thyroid volume≧19 cm³, an initial SWE≧2.0 m/s, and a TSH(thyroid stimulating hormone) normalization duration <4 months. Notably, SWE was found to be a strong predictor, with patients exhibiting SWE ≥2.0 m/s having a recurrence risk that is 4.54 times greater than those with lower values. Based on these risk factors, a scoring system was developed with a cutoff of 4 points for recurrence risk, demonstrating a sensitivity of 74% and a specificity of 91.8%. The area under the curve (AUC) of the final model was 0.91, indicating high predictive accuracy.</p><p><strong>Conclusions: </strong>SWE is an independent predictor of recurrence risk in GD. When combined with traditional clinical indicators, it significantly enhances the predictive capability for GD recurrence. The risk score model provides a simple and effective tool for individualized management and optimization of treatment strategies.</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1551983"},"PeriodicalIF":3.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between triglyceride glucose-waist height ratio and stroke: a population-based study.","authors":"Fangyuan Xu, Xingxing Su, Fan Dai, Yu Ye, Peijia Hu, Hongliang Cheng","doi":"10.3389/fendo.2025.1510493","DOIUrl":"10.3389/fendo.2025.1510493","url":null,"abstract":"<p><strong>Background: </strong>Stroke poses a substantial threat to global public health. The triglyceride glucose-waist height ratio (TyG-WHtR), which incorporates the TyG metric with obesity-related WHtR, has demonstrated superior diagnostic and predictive value compared to the TyG index alone. Nevertheless, there is still a lack of in-depth exploration into the relationship between TyG-WHtR and stroke. This study seeks to address this gap by extracting information from the National Health and Nutrition Examination Survey (NHANES) to elucidate the potential association between TyG-WHtR levels and stroke.</p><p><strong>Methods: </strong>This study included 8,757 individuals from four research cycles conducted between 2011 and 2018. To examine the potential relationship between TyG-WHtR and stroke, we conducted multivariable logistic regression analysis. In addition, smooth curve fitting was applied to display the nonlinear association. Subgroup analyses and sensitivity analyses contributed to examining the robustness and consistency of the relationship between TyG-WHtR and stroke. The receiver operating characteristic (ROC) curves were employed to evaluate the diagnostic capability of TyG-WHtR and TyG.</p><p><strong>Results: </strong>After adjusting for relevant covariates, a positive association between TyG-WHtR levels and stroke occurrence was observed (OR: 1.26, 95% CI: 1.02-1.55). Specifically, each unit increase in TyG-WHtR was associated with a 26% higher likelihood of stroke. The findings of sensitivity analysis further demonstrated the stability of this positive relationship. Subgroup analysis revealed that this association was significant among participants who did not engage in moderate exercise and those without coronary heart disease or angina pectoris. ROC analysis demonstrated that TyG-WHtR exhibited superior predictive value compared to TyG.</p><p><strong>Conclusion: </strong>This study identified an association between elevated TyG-WHtR levels and an increased prevalence of stroke, suggesting that TyG-WHtR may serve as a valuable predictive tool for stroke risk, with potential implications for clinical prevention and early intervention.</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1510493"},"PeriodicalIF":3.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-sectional study on the association between the fibrosis-4 index and co-occurring myocardial infarction in Chinese patients with type 2 diabetes mellitus.","authors":"Ziyi Sun, Jin Zhang, Jinlong Duan, Qingqing Wang, Zhangjun Yun, Jianguo Lin, Yuhan Yang, WenXi Zuo, Zeqi Wang, Xingjiang Xiong, Kuiwu Yao","doi":"10.3389/fendo.2025.1551472","DOIUrl":"10.3389/fendo.2025.1551472","url":null,"abstract":"<p><strong>Background: </strong>Previous studies indicated that the Fibrosis-4 Index (FIB-4), an evaluation metric for liver fibrosis, is associated with adverse outcomes in coronary artery disease. However, the correlation between FIB-4 and myocardial infarction (MI) in Chinese patients with Type 2 Diabetes Mellitus (T2DM) has not been well-defined. Thus, this study aims to elucidate the association between FIB-4 and MI in Chinese T2DM patients.</p><p><strong>Methods: </strong>Cross-sectional data were collected from T2DM patients at two hospitals in China, designated as the discovery and validation centers. The exposure variable, FIB-4 index, was derived from patient age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count. This index was stratified into four distinct clusters via k-means clustering analysis. The primary outcome was defined as the incidence of co-occurring MI. Logistic and restricted cubic spline regression was conducted to assess the association between the FIB-4 index and MI in Chinese T2DM patients.</p><p><strong>Results: </strong>In the discovery phase, data were analyzed from 2,980 T2DM patients, including 1,114 females (37.38%), with 58 years average age (SD: 10.4). Among them, 190 were also MI patients. Based on the fully adjusted logistic regression analysis, the odds ratio (OR) for the second cluster was 1.00 (95% CI, 0.60-1.40); for the third cluster, it was 1.94 (95% CI, 1.32-2.57), and for the poorest controlled cluster it was 16.18 (95% CI, 14.97-17.39) in comparison to the best-controlled cluster of FIB-4. Restricted cubic spline regression revealed a linear relationship between the FIB-4 index and MI risk. Subgroup analysis demonstrated that this association was significant in elderly adults, females with high BMI, and those with comorbidities such as hypertension, coronary artery disease, and chronic heart failure. These findings yield consistent results in the validation set (n = 224).</p><p><strong>Conclusions: </strong>Among Chinese patients with T2DM, elevated FIB-4 levels have been independently associated with MI, particularly among females and individuals with concomitant hypertension. Consequently, the FIB-4 index is anticipated to serve as a promising tool for early detection and risk stratification in this population.</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1551472"},"PeriodicalIF":3.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile acid signaling in skeletal muscle homeostasis: from molecular mechanisms to clinical applications.","authors":"Feng Jia, Xiangliang Liu, Yahui Liu","doi":"10.3389/fendo.2025.1551100","DOIUrl":"10.3389/fendo.2025.1551100","url":null,"abstract":"<p><p>The intricate relationship between bile acid metabolism and skeletal muscle function has emerged as a crucial area of research in metabolic health. This review synthesizes current evidence highlighting the fundamental role of bile acids as key signaling molecules in muscle homeostasis and their therapeutic potential in muscle-related disorders. Recent advances in molecular biology and metabolomics have revealed that bile acids, beyond their classical role in lipid absorption, function as essential regulators of muscle mass and function through multiple signaling pathways, particularly via the nuclear receptor FXR and membrane receptor TGR5. Clinical studies have demonstrated significant associations between altered bile acid profiles and muscle wasting conditions, while experimental evidence has elucidated the underlying mechanisms linking bile acid signaling to muscle protein synthesis, energy metabolism, and regeneration capacity. We critically examine the emerging therapeutic strategies targeting bile acid pathways, including receptor-specific agonists, microbiome modulators, and personalized interventions based on individual bile acid profiles. Additionally, we discuss novel diagnostic approaches utilizing bile acid-based biomarkers and their potential in early detection and monitoring of muscle disorders. This review also addresses current challenges in standardization and clinical translation while highlighting promising future directions in this rapidly evolving field. Understanding the bile acid-muscle axis may provide new opportunities for developing targeted therapies for age-related muscle loss and metabolic diseases.</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1551100"},"PeriodicalIF":3.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post translational modification regulation of transcription factors governing pancreatic β-cell identity and functional mass.","authors":"Alicia Wong, Emilyn U Alejandro","doi":"10.3389/fendo.2025.1562646","DOIUrl":"10.3389/fendo.2025.1562646","url":null,"abstract":"<p><p>Dysfunction of the insulin-secreting β-cells is a key hallmark of Type 2 diabetes (T2D). In the natural history of the progression of T2D, factors such as genetics, early life exposures, lifestyle, and obesity dictate an individual's susceptibility risk to disease. Obesity is associated with insulin resistance and increased demand for insulin to maintain glucose homeostasis. Studies in both mouse and human islets have implicated the β-cell's ability to compensate through proliferation and survival (increasing functional β-cell mass) as a tipping point toward the development of disease. A growing body of evidence suggests the reduction of β-cell mass in T2D is driven majorly by loss of β-cell identity, rather than by apoptosis alone. The development and maintenance of pancreatic β-cell identity, function, and adaptation to stress is governed, in part, by the spatiotemporal expression of transcription factors (TFs), whose activity is regulated by signal-dependent post-translational modifications (PTM). In this review, we examine the role of these TFs in the developing pancreas and in the mature β-cell. We discuss functional implications of post-translational modifications on these transcription factors' activities and how an understanding of the pathways they regulate can inform therapies to promoteβ-cell regeneration, proliferation, and survival in diabetes.</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1562646"},"PeriodicalIF":3.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Oxytocin and metabolic dysregulation: from pathophysiology to pharmacotherapy.","authors":"James E Blevins, Pawel K Olszewski","doi":"10.3389/fendo.2025.1579937","DOIUrl":"10.3389/fendo.2025.1579937","url":null,"abstract":"","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1579937"},"PeriodicalIF":3.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11932911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk of TGF-β and somatostatin signaling in adenocarcinoma and neuroendocrine tumors of the pancreas: a brief review.","authors":"Hendrik Ungefroren, Harpal Randeva, Hendrik Lehnert, Jörg Schrader, Jens-Uwe Marquardt, Björn Konukiewitz, Ralf Hass","doi":"10.3389/fendo.2025.1511348","DOIUrl":"10.3389/fendo.2025.1511348","url":null,"abstract":"<p><p>Although the vast majority of cancers affecting the human pancreas are pancreatic ductal adenocarcinomas (PDAC), there are several other cancer types originating from non-exocrine cells of this organ, <i>i.e.</i>, pancreatic neuroendocrine tumors (panNET). Genomic analyses of PDAC and panNET revealed that certain signaling pathways such as those triggered by transforming growth factor-β (TGF-β) are frequently altered, highlighting their crucial role in pancreatic tumor development. In PDAC, TGF-β plays a dual role acting as a tumor suppressor in healthy tissue and early stages of tumor development but as a promoter of tumor progression in later stages. This peptide growth factor acts as a potent inducer of epithelial-to-mesenchymal transition (EMT), a developmental program that transforms otherwise stationary epithelial cells to invasive mesenchymal cells with enhanced metastatic potential. TGF-β signals through both the canonical Smad pathway involving the receptor-regulated Smad proteins, SMAD2 and SMAD3, and the common-mediator Smad, SMAD4, as well as Smad-independent pathways, <i>i.e.</i>, ERK1/2, PI3K/AKT, and somatostatin (SST). Accumulating evidence indicates an intimate crosstalk between TGF-β and SST signaling, not only in PDAC but, more recently, also in panNET. In this work, we review the available evidence on signaling interactions between both pathways, which we believe are of potential but as yet insufficiently appreciated importance for pancreatic cancer development and/or progression as well as novel therapeutic approaches.</p>","PeriodicalId":12447,"journal":{"name":"Frontiers in Endocrinology","volume":"16 ","pages":"1511348"},"PeriodicalIF":3.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}