Reproductive Sciences最新文献

{"title":"Mass Spectrometric Analysis of Clomiphene Citrate-induced Changes in the Secretome Profile of PAX8-positive Human Fallopian Tube Secretory Epithelial Cells and Identification of Biomarkers Relevant to Reproduction and Pregnancy.","authors":"Opalina Roy, Shruthi Ammankallu, Vanya Kadla Narayana, Chinmaya Narayana, Shripad Hebbar, Prashanth K Adiga, Manjunath B Joshi, Jeevan Gowda, Anujith Kumar, Satish Kumar Adiga, Megan Ritting, Nagarajan Kannan, Thottethodi Subrahmanya Keshava Prasad, Guruprasad Kalthur","doi":"10.1007/s43032-025-01884-w","DOIUrl":"10.1007/s43032-025-01884-w","url":null,"abstract":"<p><p>Clomiphene citrate (CC) is commonly used for infertility treatments, particularly in intrauterine insemination (IUI) and in vitro fertilization (IVF) programs. Despite its effectiveness in inducing ovulation, it is reported to have a low pregnancy rate compared to letrozole. Further, risks of ectopic pregnancy, miscarriage, and fetal malformations have been reported in CC-induced fertility treatment cycles. The present study aimed at understanding whether these effects are associated with CC-induced changes in the secretome profile of the human PAX8-positive fallopian tube secretory epithelial cells (hPFTSECs). Fallopian tube tissues from healthy women who underwent postpartum tubectomy were enzymatically dissociated and cultured with CC, and their secretomes were analyzed by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to identify CC-induced alterations. Proteomic analysis identified a total of 1549 proteins in the secretome pool of hPFTSECs cultured in vitro and 258 proteins were found to be differentially abundant in response to CC. KEGG and REACTOME analysis revealed that the differentially abundant proteins (DAPs) were mainly associated with pathways such as estrogen signaling, cell cycle and DNA damage. Further, candidate proteins associated with ovulation, embryo development, embryo implantation, pregnancy complications, ectopic pregnancy, sperm functions, apoptosis, senescence, and ovarian cancers were identified. CC exposure induced changes in secretome profile of hPFTSECs may affect the female reproductive health by potentially altering the tubal microenvironment. The study was registered in the Clinical Trials Registry of India (CTRI) under the registration number CTRI/2020/11/028791 on 02/11/2020.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2423-2441"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275784","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":"Beneficial Effects of Alchemilla vulgaris in DHEA-Induced Rat Model of Polycystic Ovary Syndrome.","authors":"Zeynep Ece Utkan Korun, Semil Selcen Gocmez, Selenay Furat, Kubra Kavram Sarihan, Fatma Ceyla Eraldemir, Huseyin Askin Akpulat, Deniz Sahin, Sule Yildiz","doi":"10.1007/s43032-025-01885-9","DOIUrl":"10.1007/s43032-025-01885-9","url":null,"abstract":"<p><p>Alchemilla vulgaris has traditionally been used to treat gynecologic diseases. The anti-inflammatory and vasorelaxant effects of the extract of A. vulgaris (AVE) have been reported in previous studies. This study aimed to investigate the effects of A. vulgaris on PCOS, one of the most common metabolic disorders in adult women of reproductive age, accompanied by inflammation and vascular endothelial dysfunction, in an experimental animal model. Three groups of prepubertal female Wistar rats were established: PCOS, Control, and PCOS + AVE groups. Subcutaneous dehydroepiandrosterone (DHEA) was administered for 35 days to the PCOS and PCOS + AVE groups. The rats in the PCOS + AVE group were orally administered AVE (50 mg/100 g bw/day) for 35 days. Systemic blood pressure, vascular endothelial function, ovarian morphology, and endocrine biomarker levels were measured at the end of the experiment. TNF-α levels were also evaluated in the thoracic aorta and ovaries. Hormonal imbalances, ovarian morphological changes, and endothelial dysfunction were observed in the PCOS group, which returned to the controls after AVE treatment. Furthermore, AVE attenuated the aortic and ovarian levels of TNF-α in the PCOS group. Our study suggests that AVE may have beneficial effects in the treatment of PCOS due to its anti-inflammatory and vasculoprotective properties.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2453-2466"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476531","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":"Effect of Nifedipine in Preventing Ovarian Hyperstimulation Syndrome through TRPC1 Ion Channel Inhibition.","authors":"Emel Kocal, Remzi Atilgan, Şehmus Pala, Melike Aslan, Tuncay Kuloğlu, Nevin Ilhan, Ebru Etem Önalan, Serhat Hançer, Gizem Kaymaz Bircan","doi":"10.1007/s43032-025-01913-8","DOIUrl":"10.1007/s43032-025-01913-8","url":null,"abstract":"<p><p>Ovarian hyperstimulation syndrome (OHSS) is a life-threatening complication that usually develops as a result of triggering ovulation with human chorionic gonadotropin (hCG) after gonadotropin treatment, and in whose pathophysiology vascular endothelial growth factor (VEGF) and inflammatory mediators play a role. Nifedipine, used especially in the treatment of hypertension, is a calcium channel blocker. Nifedipine also has anti-inflammatory effects via transient receptor potential canonical (TRPC1) ion channel inhibition. VEGF also regulates the angiogenic process through TRPC channels. In our study, we investigated the potential of nifedipine to prevent OHSS due to its TRPC1 blocking effect and anti-inflammatory effects. A total of 28 rats were randomly divided into four equal groups. Group (G) 1 control group (n = 7). Rats in G2 (n = 7) were administered 30 IU pregnant mare serum gonadotropin for 4 days and OHSS was induced by administering 30 IU hCG on the fifth day. Rats in G3 (n = 7) were induced to have OHSS and were given 100 μg/kg oral cabergoline, while rats in G4 (n = 7) were induced to have OHSS and were given 20 mg/kg intraperitoneal nifedipine. On the fifth day, all rats were decapitated and VEGF, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and hypoxia-inducible factor (HIF)-1α levels were measured in their serum and tissues. TRPC1 gene expression and immunohistochemical analysis were performed in ovarian tissue. We showed that nifedipine inhibited VEGF and some inflammatory factor levels more than cabergoline. We showed that nifedipine may achieve these effects through TRPC1 blockade and suppression of inflammatory factors.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2375-2387"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326739","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":"Expression Patterns and Functional Implications of CMTM2 in Human Testis and Sperm.","authors":"Liu XueXia, Gong BenJiao, Zhang XueYing, Zhu Peng, Liu FuJun","doi":"10.1007/s43032-025-01852-4","DOIUrl":"10.1007/s43032-025-01852-4","url":null,"abstract":"<p><p>The CMTM family plays pivotal roles in various physiological and pathological processes, including those associated with the male reproductive system. Among them, CMTM2 exhibits specific expression in testicular tissue; however, its relationship with spermatogenesis, sperm function, and the underlying molecular mechanisms remains unclear. This study systematically investigated the localization of CMTM2 in human testis and sperm, as well as its correlation with spermatogenesis and sperm quality. The results revealed that CMTM2 expression was specifically localized in human testis, predominantly in germ cells, with significantly lower levels observed in sperm from patients with asthenozoospermia and teratozoospermia compared to normospermic individuals. Immunofluorescence analysis revealed that CMTM2 was predominantly localized in the middle piece of sperm, with significant reductions in infertile samples. Western blot analysis confirmed decreased CMTM2 levels in sperm from asthenozoospermia, oligozoospermia, and teratozoospermia patients, indicating a strong correlation between CMTM2 expression and sperm quality. Furthermore, CMTM2 expression positively correlated with sperm progressive motility, but not with sperm concentration, suggesting its potential role in regulating sperm motility in both normal and asthenozoospermia patients. The findings suggested a significant correlation between the CMTM2 expression and spermatogenesis as well as sperm quality, thereby providing valuable insights for further investigations into the molecular mechanisms involved. These results lay a foundational basis for exploring the potential roles of other members within the CMTM family in male reproduction.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2388-2396"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754368","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":"Clinical Characteristics and Molecular Aetiology of Cytochrome P450 Oxidoreductase Deficiency Diagnosed in 46,XX Patients.","authors":"Duoduo Zhang, Leilei Ding, Shan Deng, Qinjie Tian","doi":"10.1007/s43032-025-01878-8","DOIUrl":"10.1007/s43032-025-01878-8","url":null,"abstract":"<p><p>P450 oxidoreductase deficiency (PORD) affects cytochrome enzyme activities, causing various symptoms, such as adrenal insufficiency, disorders of sex development and skeletal malformations. This study aims to elucidate the clinical manifestations, genotype characteristics, diagnosis and management of 46,XX karyotype patients with PORD in China. A retrospective study included twelve 46,XX PORD patients in a Chinese tertiary medical center from 2004 to 2024. The patients' clinical characteristics were summarized based on manifestations, hormone profiles, and responses to treatments. The age of first visit was 7-31 years. Except for one young girl presenting with ambiguous genitalia since born, 11 patients presented with either abnormal menses or multiple ovarian cysts. Six patients showed masculinization of their external genitalia, and ten patients showed varying degrees of skeletal deformity. Progesterone was elevated and ovarian reserve was poor in all patients. The most frequent POR variant, c.1370G > A, located in exon 11 occurred in 11/12 patients with an allele frequency of 87.5% (21/24). Two novel nonsense mutations, c.1684dupG and c.2040dupC, were identified and assessed as pathogenic and likely pathogenic by ACMG, respectively. The c.1370G > A might be a dominant mutation type of POR in China. Female patients with PORD have a vulnerable ovarian reserve, and their ovarian macrocysts can be managed conservatively for fertility preservation. This study specifically focuses on PORD in 46,XX Chinese individuals, which implies its genetic causes with novel genetic findings and summarizes the puzzling spectrum of clinical manifestations.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2474-2483"},"PeriodicalIF":2.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326738","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":"Mass Spectrometry-Based Untargeted Metabolomics Identifies Distinct Metabolic Signatures in Infertility: A Comparative Analysis of PCOS, POR, and NOR.","authors":"Metin Demirel, Mehtap Alim, Fatmanur Koktasoglu, Nil Atakul, Ebru Guner, Ayse Nur Işık Aydın, Sanem Naz Kafali, Yildız Atamer, Sahabettin Selek","doi":"10.1007/s43032-025-01908-5","DOIUrl":"10.1007/s43032-025-01908-5","url":null,"abstract":"<p><strong>Background: </strong>Infertility affects approximately 15% of reproductive-age couples, with polycystic ovary syndrome and poor ovarian reserve being major contributing factors. Metabolomic profiling of follicular fluid offers insights into the underlying metabolic disturbances associated with these infertility phenotypes. This study aims to identify metabolic biomarkers distinguishing PCOS, POR, and male factor infertility, which may facilitate improved diagnostic and therapeutic strategies.</p><p><strong>Methods: </strong>A total of 119 participants were categorized into three groups: PCOS (n = 39), POR (n = 40), and NOR (n = 40). Liquid chromatography-high-resolution mass spectrometry was used for untargeted metabolomic profiling. Metabolites were identified using HMDB, MassBank, and MoNA, while pathway analysis was performed using KEGG. Statistical analyses were conducted using R and Python, including one-way ANOVA, t-tests, and Mann-Whitney U tests, with False Discovery Rate correction applied.</p><p><strong>Results: </strong>Distinct metabolic alterations were observed among the groups. Trehalose-6-phosphate, taurocholate, and N,N-dimethylglycine emerged as the most significantly altered metabolites, showing strong discriminatory potential between PCOS and POR. PCOS patients exhibited reduced levels of taurocholate, mycalemide, and trehalose-6-phosphate, whereas NOR patients showed elevated levels of N,N-dimethylglycine and argininosuccinate. The POR group demonstrated increased levels of 1-methyl-2-pyrrolidone and haplopine, along with a broader metabolite distribution.</p><p><strong>Conclusion: </strong>This study reveals phenotype-specific metabolic signatures in PCOS and POR, identifying taurocholate, mycalemide, and N,N-dimethylglycine as potential follicular biomarkers. These findings contribute to a deeper understanding of the metabolic basis of infertility and highlight the potential of follicular fluid metabolomics for precision medicine in reproductive health.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2270-2282"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333803","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":"SCM-198 Inhibits EMS Development by Reversing Decreased Proportions of IFN-γ⁺T Cells and CCR5⁺T Cells.","authors":"Yewei Lu, Yunyun Li, Yue Li, Yikong Lin, Xiaolin Wang, Yizhun Zhu, Beihua Wang, Meirong Du","doi":"10.1007/s43032-025-01823-9","DOIUrl":"10.1007/s43032-025-01823-9","url":null,"abstract":"<p><p>Endometriosis is a common gynecological disease that causes severe pain and infertility. However, the available treatments for EMS are limited. SCM-198, a synthetic form of leonurine, possesses various abilities, including anti-inflammatory, immunomodulatory, antioxidant, anti-fibrotic, and anti-proliferative effects. Previous studies have shown that SCM-198 can inhibit the growth of ectopic lesions, but the specific mechanism remains unknown. The results of our studies indicate that SCM-198 significantly suppresses the endometriotic growth of EMS mice. Enrichment analysis of RNA-seq indicates that SCM-198 is involved in T cell differentiation, activation, cytokine production, stimulation of chemotaxis, and migration. Flow cytometry reveals that SCM-198 reverses the decreased proportions of IFN-γ + T cells and CCR5 + T cells in ectopic lesions. RNA-seq analysis shows that SCM-198 enhances the expression of CCL5 in the ectopic lesions, and western blot is conducted to verify this conclusion both in vivo and in vitro. These findings demonstrate that SCM-198 reverses the decreased proportions of IFN-γ + T cells and CCR5 + T cells, alleviating the growth of mouse ectopic lesions, and the changes in CCR5 + T cells are likely due to the reduced expression of CCL5.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2180-2189"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670913","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":"Can a Diet, Nutrition and Supplement Program Prevent Uterine Fibroid Recurrence? Pilot Results of the LIFE Program.","authors":"Margot Bellon, Elaine Salamanca, Steven Friedman, Michael Chan, Taraneh Shirazian","doi":"10.1007/s43032-025-01904-9","DOIUrl":"10.1007/s43032-025-01904-9","url":null,"abstract":"<p><p>The objective of this prospective, longitudinal cohort study was to evaluate the pilot effects of a 24-month exercise and nutrition intervention, called the Lifestyle Intervention for Fibroid Elimination Program (LIFE), at NYU Langone Health's Center for Fibroid Care. Specifically, we evaluate the impact on quality of life (QOL), symptom severity (SS), and clinical lab markers in 22 fibroid patients. Patients who underwent a procedure within 3 months of the start of the LIFE Program and completed up to 12 months of the program were included in this study. Participants were excluded if currently pregnant, postmenopausal, or had dietary restrictions or physical constraints that prevented them from participating fully in the intervention. This intervention required participants to follow a prescribed nutrition and exercise regimen for up to 12 months and attend at least 2 office visits with a physician. Participants also completed two quality of life questionnaires and regular ultrasound imaging. The demographic breakdown of our study cohort was 63.6% Black and 18.2% Hispanic/LatinX. A clinically meaningful improvement in QOL and symptom severity was found within the first year of the LIFE program. The QOL sub-scale scores that showed the greatest improvement were concern and energy/mood. Vitamin D lab values also showed a clinically meaningful improvement. The LIFE Program was associated with a reduction in symptom burden and an improvement in quality of life up to 12 months after a procedural fibroid intervention, yielding insight into how a lifestyle intervention may be an effective adjunct in improving patient quality of life.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2216-2222"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336898","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":"Correction: Evaluation of an Updated Gene Panel as a Diagnostic Tool for Both Male and Female Infertility.","authors":"Özlem Okutman, Ali Sami Gürbüz, Ahmet Salvarci, Umut Büyük, Halil Ruso, Timur Gürgan, Julien Tarabeux, Anne-Sophie Leuvrey, Elsa Nourisson, Cécile Lang, Jean Muller, Stephane Viville","doi":"10.1007/s43032-025-01881-z","DOIUrl":"10.1007/s43032-025-01881-z","url":null,"abstract":"","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2513"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101123","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":"Macrophage Plasticity and Extracellular Vesicles in Endometriosis: Immunopathology and Therapeutic Perspectives.","authors":"Saba Safdarpour, Parisa Nadri, Nima Azari-Dolatabad","doi":"10.1007/s43032-025-01896-6","DOIUrl":"10.1007/s43032-025-01896-6","url":null,"abstract":"<p><p>Endometriosis, as a chronic gynecological condition, includes irregular endometrial cell growth beyond the uterus, which creates pelvic pain and infertility, together with inflammatory disease throughout the body. Currently, about 10% of all women worldwide experience this disease, but scientists have not determined its natural causes. Importantly, the development of endometriosis depends significantly on the dysfunction of the immune system, which results in impaired macrophage activity. Specifically, endometriotic lesions contain M2-like macrophages, supporting tissue reconstruction along new blood vessel formation and evading immune responses. Moreover, the survival of lesions and the processes of neurogenesis and inflammation depend on the actions of macrophage-derived extracellular vesicles (EVs) as well as cytokines and growth factors. In this context, this review investigates the process of macrophage polarization and details the cellular interactions found in endometriotic tissue environments and their therapeutic capacity. Ultimately, understanding the underlying mechanisms of disease will facilitate the development of immunomodulatory therapies aimed at reducing symptoms and improving clinical outcomes.</p>","PeriodicalId":20920,"journal":{"name":"Reproductive Sciences","volume":" ","pages":"2065-2079"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249305","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}