Reproductive Sciences最新文献

{"title":"Cervical Pessary Versus Vaginal Progesterone to Prevent Preterm Birth in Women with a Singleton Pregnancy and a Short Cervix: A Systematic Review and Meta-Analysis.","authors":"Ahmed Abu-Zaid, Saeed Baradwan, Bandr Hafedh, Afaf Tawfiq, Ghaidaa Farouk Hakeem, Alya Alkaff, Mohamed Abuzaid, Afnan Baradwan, Lolwa Almonayea, Shahad Alfadhli, Hessa Alqaed, Osama Alomar","doi":"10.1007/s43032-025-01929-0","DOIUrl":"10.1007/s43032-025-01929-0","url":null,"abstract":"<p><p>Vaginal progesterone (VP) is the recommended intervention for preventing preterm birth (PTB) in women with short cervix and singleton pregnancy. However, cervical pessary (CP) has been proposed as a simpler alternative. This study compares the efficacy and safety of both interventions. A systematic review and meta-analysis included randomized controlled trials (RCTs) from PubMed, CENTRAL, Scopus, Google Scholar, and Web of Science (up to November 2024). Based on heterogeneity, fixed- or random-effects models were used to analyze dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD), both with 95% confidence intervals (CI). Five RCTs with 1,427 patients were analyzed. No significant differences were found between CP and VP in PTB before 37 weeks (RR: 1.08, 95% CI: 0.87, 1.34), 34 weeks (RR: 1.08, 95% CI: 0.80, 1.44), or 28 weeks (RR: 1.42, 95% CI: 0.86, 2.33), time from randomization to delivery (MD: -0.13 h, 95% CI: -6.08, 5.82), maternal infection (RR: 0.98, 95% CI: 0.74, 1.30), neonatal/fetal mortality (RR: 1.19, 95% CI: 0.69, 2.06), neonatal sepsis (RR: 0.73, 95% CI: 0.36, 1.50), intraventicular hemorrhage (IVH; RR: 1.02, 95% CI: 0.23, 4.42), or necrotizing enterocolitis (NEC; RR: 3.36, 95% CI: 0.93, 12.22). However, CP significantly increased vaginal bleeding (RR: 2.79, 95% CI: 1.35, 5.77, p = 0.01). CP showed no clinical benefit in prolonging pregnancy, reducing PTB rates, or improving maternal or neonatal outcomes compared to VP. CP was associated with an increased risk of vaginal bleeding. However, these findings should be interpreted cautiously due to limited data.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2540-2557"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643178","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":"Expression and Regulatory Roles of SKAP2 and Cortactin in Mouse Ovarian Tissue and Oocyte Maturation.","authors":"Ying Feng, Xinyi Hang, Zhumei Sheng, Yu Chen, Xuejing Jin","doi":"10.1007/s43032-025-01925-4","DOIUrl":"10.1007/s43032-025-01925-4","url":null,"abstract":"<p><p>Oocyte maturation is a critical phase in mammalian reproduction. Src kinase-associated phosphoprotein 2 (SKAP2) and cortactin, both cytoskeletal regulatory proteins that play pivotal roles in cell motility and signal transduction. However, their specific functions and mechanisms during oocyte maturation are currently unknown. This study revealed the roles of SKAP2 and cortactin in the oocyte maturation process. To investigate the distribution, activity, and functional significance of SKAP2 during murine oocyte asymmetric division, ovarian tissues were infected with lentiviruses expressing SKAP2 and cortactin shRNA. Cell morphology was analyzed to assess the expression and distribution of cyclins, SKAP2, Wiskott-Aldrich syndrome protein family member 2 (WAVE2), and cortactin. Additionally, the levels of SKAP2, Cyclin A, Cyclin B, Cyclin-dependent kinase 1 (CDK1), and Polo-like kinase 1 (PLK1) were quantified using qPCR and western blotting. SKAP2 was highly expressed in ovarian tissues and oocytes. Knockdown of SKAP2 significantly impaired oocyte maturation and altered the expression of key cell cycle proteins. SKAP2 regulates oocyte maturation and division by modulating cell cycle proteins and interacting with WAVE2 and cortactin. SKAP2 and cortactin are important in the regulatory mechanisms of oocyte maturation, these findings offer potential targets and strategies for advancing reproductive technologies and treating reproductive disorders.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2763-2778"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homeobox C6 is Up-Regulated and Affects the Pathogenesis of Endometriosis.","authors":"Jianfa Jiang, Luyao Zhang, Lijie Li","doi":"10.1007/s43032-025-01918-3","DOIUrl":"10.1007/s43032-025-01918-3","url":null,"abstract":"<p><p>Endometriosis is one of the most common, difficult, and complicated gynecological disorders. The present study investigated the expression of HOXC6 in endometriosis and described its possible role in its pathogenesis. Ectopic and eutopic endometrial samples from 21 patients with endometriosis and a control endometrium from 15 women without endometriosis were collected. HOXC6 expression in endometrial tissue was analyzed with immunohistochemistry and quantitative reverse transcription polymerase chain reaction. HOXC6's silencing in endometriotic stromal cells (ESC) was established with small interfering RNA (siRNA) to detect the effect on proliferation, adhension, invasion, and migration using CCK-8, adhesion, wound healing, and transwell assays. Western blotting was performed to detect the expression of related molecules after the down-regulation of HOXC6. HOXC6 mRNA and protein expression levels in the ectopic endometrial samples were significantly higher in women with endometriosis than in controls, while the levels in the eutopic endometrial tissues of the same patients did not significantly differ from those in non-endometriotic patients. The knockdown of HOXC6 expression inhibited the proliferation, adhesion, migration, and invasion of ESC. The results indicated that HOXC6 down-expression decreased the expression of N-cadherin and vimentin, whereas the expression of E-cadherin increased. HOXC6 down-expression also decreased the expression levels of TGF-β1 and phosphorylated SMAD2/SMAD3. In conclusion, HOXC6 was overexpressed in endometriosis and might therefore promote the proliferation, adhesion, invasion, and migration of ESC via the TGF-β1/smad signaling pathway. These findings present a new perspective and may therefore inspire further study of the endometriosis mechanism.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2574-2582"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497958","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":"Optimal Exercise Intensity for Enhancing Sperm Parameters: A Network Meta-Analysis of Rodent Studies.","authors":"Yinchu Hu, Ruiqiong Li, Mimi Chen, Yidong Chen, Qi Wang, Xiaowei Zhang, Yanhui Lu, Mingjie Yao, Yao Dang, Lihua Ren","doi":"10.1007/s43032-025-01926-3","DOIUrl":"10.1007/s43032-025-01926-3","url":null,"abstract":"<p><p>Exercise training as a potential intervention to improve male reproductive health, its efficacy appears to be contingent on exercise intensity. However, the optimal training intensity remains poorly defined. Hence, this study aimed to identify the optimal exercise intensity for improving sperm parameters through network meta-analysis of rodent studies. The comprehensive search across eight databases ultimately identified 35 eligible studies, coving four different exercises: low-intensity continuous training (LICT), moderate-intensity continuous training (MICT), high-intensity continuous training (HICT), and high-intensity interval training (HIIT). The network meta-analysis indicated that MICT showed superior efficacy versus HICT in terms of sperm concentration (MD: 15.28, 95% CI: 2.52-28.04). The surface under the cumulative ranking curve (SUCRA) value, an indicator to quantify the relative ranking probability of interventions, indicated the highest probability of MICT being optimal training for increasing sperm concentration in both healthy (SUCRA 77.6%) and unhealthy groups (SUCRA 80.1%). Additionally, MICT (MD: 12.23, 95% CI: 7.97-16.48) and HIIT (MD: 10.94, 95% CI: 1.10, 20.78) were superior to sedentary control in improving sperm motility. However, HICT was associated with a significant reduction in normal sperm morphology compared to sedentary control (MD: -10.05, 95% CI: -19.53- -0.58) and MICT (MD: -17.25, 95% CI: -32.17- -2.33). These preclinical results position MICT as the preferred exercise modality for sperm quality improvement, with HIIT as an alternative. However, environmental and lifestyle confounders unique to humans require careful attention when extrapolating these findings to human populations.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2528-2539"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554303","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":"Unraveling the Regulatory Function of MicroRNAs in Reproductive System Apoptosis and Their Implications for Infertility.","authors":"Hadis Musavi, Maryam Ezzati, Sheyda Hoseinnia, Mandana Zafari, Zeinab Vahidinia, Melika Izadpanah","doi":"10.1007/s43032-025-01897-5","DOIUrl":"10.1007/s43032-025-01897-5","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are small non-coding RNA molecules that modulate gene expression and are essential in numerous biological functions, including reproductive functions. Alterations in miRNA expression can affect ovarian function, sperm development, and implantation processes, potentially leading to different diseases and consequently infertility. Researches have indicated that certain microRNAs play a crucial role in the regulation of hormones and proteins that are vital for reproductive processes, suggesting that dysregulation of these miRNAs may contribute to infertility in both men and women. Some miRNAs are able to promote apoptosis, while others may inhibit this process. They can control the expression of genes associated with programmed cell death, thereby influencing the health of oocytes and sperm. Dysfunction of some micro RNAs may lead to increased apoptosis and decreased fertility. The aim of this study was to investigate microRNAs involved in the regulation of apoptosis in male and female reproductive system cells, and to evaluate their association with infertility-related disorders.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2515-2527"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554304","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":"Integrated Analysis of Lactate-Related Genes Identifies S100A4 as a Novel Marker Promoting the Migration and Invasion of Endometrial Stromal Cell in Endometriosis.","authors":"Xiuping Wang, Yue Chen, Qingyue Wu, Xiwen Wang, Yanyun Wu, Hengwei Liu","doi":"10.1007/s43032-025-01914-7","DOIUrl":"10.1007/s43032-025-01914-7","url":null,"abstract":"<p><p>Endometriosis is a prevalent gynecological disorder worldwide that significantly impairs the quality of life of patients and imposes a substantial economic burden. The limited efficacy and adverse effects of current pharmacological and surgical treatments highlight the urgent need for alternative diagnostic biomarkers and therapeutic targets. Recent evidence indicates that metabolic reprogramming, particularly lactate metabolism, plays a crucial role in the development and progression of endometriosis. In this study, we employed differential expression analysis to identify differentially expressed genes in endometriosis patients, and used Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest (RF) for feature selection and model construction. Five key genes (MRPS2, YARS2, SLC3A1, CALD1, and S100A4) were validated as highly accurate diagnostic markers. Furthermore, we conducted in-depth analysis of the regulatory activity of these key lactate metabolism-related genes and their association with immune infiltration. Additionally, we constructed a lncRNA-miRNA gene regulatory network, providing insights into the molecular mechanisms and potential therapeutic strategies. Among these key lactate metabolism-related genes, S100A4 was found to be significantly upregulated in the lesions of endometriosis and plays a pivotal role in regulating cellular invasion and metabolic reprogramming in endometriosis. Silencing of S100A4 significantly inhibited the migration and invasion ability of endometrial stromal cells, whereas overexpression of S100A4 reversed this inhibitory effect. This finding further underscores the importance of S100A4 as a potential therapeutic target. In conclusion, this study highlights the potential value of lactate-related genes as diagnostic biomarkers and therapeutic targets, especially targeting the S100A4 gene in endometrial stromal cells, which may serve as an effective therapeutic strategy to inhibit the progression of endometriosis, offering new directions for future clinical diagnosis and treatment.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2558-2573"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609170","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":"Implementation of a Program for Combined Intra-Gestational and Systemic Methotrexate Injection to Treat Non-Tubal Ectopic Pregnancy: A Report of Outcomes and Feasibility.","authors":"Michael Strug, Jie Deng, Brent Monseur, Ruben Alvero, Lusine Aghajanova","doi":"10.1007/s43032-025-01920-9","DOIUrl":"10.1007/s43032-025-01920-9","url":null,"abstract":"<p><p>Non-tubal ectopic pregnancies (NTEP) are a rare and life-threatening subset of ectopic pregnancies, with their clinical management poorly defined. This study evaluated the effectiveness of combined methotrexate injection (intra-gestational/systemic) for NTEP in an outpatient setting. In this case series (January 2019-December 2023), our institution introduced a program to treat NTEP using ultrasound-guided transvaginal intra-gestational methotrexate injection (100 mg) and intramuscular methotrexate (25 mg) with fetal intracardiac potassium chloride, if cardiac activity present. The primary outcome was the resolution of hCG levels without emergency surgery while secondary outcomes included safety, residual products of conception and future fertility. Twenty patients with NTEP (cesarean scar, n = 11; cervical, n = 5; interstitial, n = 4) were treated. The success rate was 95% (19/20), with one patient requiring emergency uterine artery embolization for acute hemorrhage one-month post-procedure, despite decreasing hCG. Acute hemorrhage occurred in 10% (2/20) of patients but resolved without hysterectomy. The median time to negative hCG was 80 days (IQR 51-112) with cesarean scar pregnancy taking longer to resolve (p = 0.047). Residual products of conception were observed in all patients who had follow up ultrasound (10/10). Of those who attempted to conceive afterward, 78% (7/9) achieved pregnancy within the study period. In conclusion, combined methotrexate for treatment of NTEP is a safe, effective, and fertility-sparing approach with promising future pregnancy outcomes. Complications warrant close surveillance until pregnancy resolution. Fertility clinics are well-suited to offer this non-surgical treatment in an outpatient setting.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2685-2691"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637839","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":"Peptidomic and Proteomic Signatures in Human Blood Serum, Follicular Fluid and Spent Media: A Study of Embryo Development Competency after In Vitro Fertilization.","authors":"Paweena Thuwanut, Porntip Sirayapiwat, Sittiruk Roytrakul, Punkavee Tuntiviriyapun, Chanakarn Suebthawinkul, Nuttanun Panyawongudom, Wisan Sereepapong","doi":"10.1007/s43032-025-01933-4","DOIUrl":"10.1007/s43032-025-01933-4","url":null,"abstract":"<p><p>This research aimed to investigate peptide barcodes and proteomic profiles in blood serum, follicular fluid, and spent media from infertile patients, focusing on their potential to retrieve good-quality embryo during in vitro fertilization (IVF). Biological samples were collected from 30 participants, equally comprising individuals who retrieved mature oocyte and developed or did not develop to good-quality blastocyst. Analysis of peptide barcodes and proteomic profiles was conducted using MALDI-TOF MS and nano-LC-ESI MS/MS. Subsequently, data peptide mass peak patterns, proteins and protein interaction networks were generated. Primary results in participants with good embryo development competency indicated that 448 of 1,792 peptide mass peaks were up-regulated in blood serum, 76 of 1,793 peptides in follicular fluid, and 51 of 1,610 peptides in spent media (fold-change ≥ 1.0, P < 0.05). Up-regulated proteins including angiomotin in blood serum, capping protein and janus kinase in follicular fluid were identified (edge confidence scores > 0.90). Additionally, spent media showed unique protein network involving ATP-dependent RNA helicase DDX19A and ankyrin repeat proteins via ubiquitin C protein (edge confidence score > 0.80). In conclusion, identified peptide barcodes and protein interaction networks in this study may offer novel insights into molecular mechanisms underlying embryo development competency after IVF treatment.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2654-2668"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643273","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":"Placenta - A Competent, But Not Infallible, Antiviral and Antiparasitic Barrier.","authors":"Christian Castillo, Helena Hae Jin Chi, Larissa Bornia Ghilardi, Ana Liempi, Maria Notomi Sato, Ulrike Kemmerling, Estela Bevilacqua","doi":"10.1007/s43032-025-01921-8","DOIUrl":"10.1007/s43032-025-01921-8","url":null,"abstract":"","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2669-2684"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637840","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":"m5C-Modified lncRNA SNHG15 Promotes Ovarian Cancer Progression Via the miR-545-3p/PD-L1 Axis.","authors":"Li Chen, Ruifeng Ma, Lei Wu, Dandan Wang, Jingchao Li, Li Guo","doi":"10.1007/s43032-025-01919-2","DOIUrl":"10.1007/s43032-025-01919-2","url":null,"abstract":"<p><p>Ovarian cancer (OC) poses a health burden of women. Long non-coding RNA SNHG15 has been reported to promote OC progression; however, its effect on immune evasion remains unknown. Here, we investigated the effect of SNHG15 on OC cell immune evasion and the underlying mechanism. Cell phenotypes were assessed using cell counting kit-8, colony formation, lactate dehydrogenase cytotoxicity, and enzyme-linked immunosorbent assays. The mechanism was evaluated by dual-luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), methylated RIP, and RNA stability assay. The role in vivo was analyzed using tumor-bearing mice. The results showed that SNHG15 and PD-L1 levels were increased, while miR-545-3p expression was reduced in OC. SNHG15 was a sponge of miR-545-3p, and PD-L1 was a downstream target of SNHG15. Knockdown of SNHG15 suppressed OC cell proliferation, and enhanced cytotoxicity and pro-inflammatory response of CD8⁺ T cells, whereas miR-545-3p downregulation reversed these cellular behaviors. Moreover, PD-L1 reversed the cell phenotypes induced by miR-545-3p. Additionally, SNHG15 was modified by m5C, which was mediated by NSUN2. Furthermore, SNHG15 knockdown impeded tumor growth in mice. In conclusion, m5C-methylated lncRNA SNHG15 promotes OC progression by accelerating cell proliferation and immune evasion via the miR-545-3p/PD-L1 axis, demonstrating a tumor-promoting function of SNHG15 in OC.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2595-2606"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485736","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}