Ocular SurfacePub Date : 2024-10-01DOI: 10.1016/j.jtos.2024.11.004
Jiani Li , Xiaorui Bao , Shujia Guo , Yuhan Huang , Caihong Huang , Jiaoyue Hu , Zuguo Liu
{"title":"Cell death pathways in dry eye disease: Insights into ocular surface inflammation","authors":"Jiani Li , Xiaorui Bao , Shujia Guo , Yuhan Huang , Caihong Huang , Jiaoyue Hu , Zuguo Liu","doi":"10.1016/j.jtos.2024.11.004","DOIUrl":"10.1016/j.jtos.2024.11.004","url":null,"abstract":"<div><div>Dry eye disease (DED) is increasingly prevalent, with inflammation playing a crucial role in its pathogenesis. Severe cases of DED result in significant ocular discomfort and visual impairment due to damage and loss of ocular surface epithelial cells. The precise mechanisms underlying the loss of these epithelial cells remain a subject of ongoing research and debate. Programmed cell death (PCD) mechanisms, including pyroptosis, apoptosis, and necroptosis, are known to be critical in maintaining ocular surface homeostasis and responding to stressors in DED. The concept of PANoptosis, which integrates elements of various PCD pathways, has been implicated in the development of numerous systemic diseases, including infections, cancer, neurodegenerative, and inflammatory conditions. It also provides novel insights into the inflammatory processes underlying DED. This review highlights the crosstalk of PCD pathways in DED, particularly the significance of PANoptosis in ocular inflammation and its potential as a therapeutic target for more effective interventions.</div></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 535-544"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-10-01DOI: 10.1016/j.jtos.2024.09.005
Raoul K. Khanna , Sophie Catanese , Geoffroy Mortemousque , Camille Dupuy , Antoine Lefevre , Patrick Emond , Stéphane Beltran , Valérie Gissot , Pierre-Jean Pisella , Hélène Blasco , Philippe Corcia
{"title":"Metabolomics of basal tears in amyotrophic lateral sclerosis: A cross-sectional study","authors":"Raoul K. Khanna , Sophie Catanese , Geoffroy Mortemousque , Camille Dupuy , Antoine Lefevre , Patrick Emond , Stéphane Beltran , Valérie Gissot , Pierre-Jean Pisella , Hélène Blasco , Philippe Corcia","doi":"10.1016/j.jtos.2024.09.005","DOIUrl":"10.1016/j.jtos.2024.09.005","url":null,"abstract":"<div><h3>Purpose</h3><div>Amyotrophic lateral sclerosis (ALS) clinical variability, along with the lack of conclusive diagnostic instruments, result in average diagnosis delays of 9 months. This study aimed to assess whether metabolomic profiling of basal tears in ALS patients could act as a biological marker for diagnosing ALS, predicting prognosis, and discriminating between endophenotypes.</div></div><div><h3>Methods</h3><div>A single-center prospective case-control study was conducted in France from September 2021 to March 2023 including patients with ALS according to the revised EI Escorial criteria. Two microliters of basal tears were collected using microcapillary glass tubes and analyzed with ultra-high performance liquid chromatography coupled with mass spectrometry. Both univariate and multivariate analyses were performed.</div></div><div><h3>Results</h3><div>Twenty-five patients with ALS and 30 controls were included. No significant differences in metabolite levels were found between ALS and control groups (p > 0.05). The basal tear metabolome significantly discriminated bulbar and spinal forms of ALS based on 6 metabolites, among which 5 were decreased (aniline, trigonelline, caffeine, theophylline and methyl beta-D-galactoside) in the bulbar form and 1 was decreased in the spinal form (dodecanedioic acid).</div></div><div><h3>Conclusion</h3><div>This study represents the first prospective analysis of basal tear metabolomics in individuals with ALS. Despite the inability to distinguish between ALS patients and controls based on metabolic signatures, these findings could contribute to understanding the phenotypic diversity of ALS. Notably, distinct metabolic profiles were identified that differentiate between the bulbar and spinal forms of the disease.</div></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 363-369"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-10-01DOI: 10.1016/j.jtos.2024.09.010
Lin Cong , Benxiang Qi , Wenhui Ma , Zhongmei Ren , Qian Liang , Qingjun Zhou , Bi Ning Zhang , Lixin Xie
{"title":"Preventing and treating neurotrophic keratopathy by a single intrastromal injection of AAV-mediated gene therapy","authors":"Lin Cong , Benxiang Qi , Wenhui Ma , Zhongmei Ren , Qian Liang , Qingjun Zhou , Bi Ning Zhang , Lixin Xie","doi":"10.1016/j.jtos.2024.09.010","DOIUrl":"10.1016/j.jtos.2024.09.010","url":null,"abstract":"<div><h3>Purpose</h3><div>Neurotrophic keratopathy (NK) is a degenerative corneal condition resulting from corneal nerve injury. Current therapies, including the recombinant human nerve growth factor (rhNGF) therapy, requires continuous administration. This study aims to develop a novel and highly effective gene therapy strategy for the prevention and treatment of NK.</div></div><div><h3>Methods</h3><div>Adeno-associated virus (AAV) was transduced into corneal stromal cells by intrastromal injection. Three dimensional corneal wholemount imaging with co-immunostaining of ZO-1 and tubulin was utilized to assess the transduction of AAV.rh10. The efficacy of prevention and treatment of NK by a single intrastromal injection of AAV-Ngf was tested using capsaicin mouse model, herpes simplex keratitis (HSK) model, type Ⅱ diabetes model and alkali burn model. rhNGF eye drops served as the positive control.</div></div><div><h3>Results</h3><div>Intrastromal injection of AAV.rh10 efficiently transduced the subepithelial nerve plexus and retrogradely transported to the trigeminal ganglion (TG). A single injection of AAV.rh10-Ngf can significantly promote corneal nerve repair, accelerate corneal epithelial repair, reduce corneal stromal edema, and improve corneal sensitivity across the four NK models. The therapeutic effects were consistent with those achieved by continuous administration of rhNGF drops by 6 times daily.</div></div><div><h3>Conclusions</h3><div>This proof-of-concept study demonstrates that AAV.rh10-Ngf gene therapy is a promising method for preventing and treating of NK. Our results underline the potential for developing clinical trials to further explore the safety and efficacy of such gene therapy.</div></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 406-414"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-10-01DOI: 10.1016/j.jtos.2024.10.005
Cameron Pedersen , Victoria T. Chen , Paula Herbst , Runze Zhang , Amr Elfert , Abhi Krishan , Dimitri T. Azar , Jin-Hong Chang , Wen-Yang Hu , Tobias P. Kremsmayer , Elmira Jalilian , Ali R. Djalilian , Victor H. Guaiquil , Mark I. Rosenblatt
{"title":"Target specification and therapeutic potential of extracellular vesicles for regulating corneal angiogenesis, lymphangiogenesis, and nerve repair","authors":"Cameron Pedersen , Victoria T. Chen , Paula Herbst , Runze Zhang , Amr Elfert , Abhi Krishan , Dimitri T. Azar , Jin-Hong Chang , Wen-Yang Hu , Tobias P. Kremsmayer , Elmira Jalilian , Ali R. Djalilian , Victor H. Guaiquil , Mark I. Rosenblatt","doi":"10.1016/j.jtos.2024.10.005","DOIUrl":"10.1016/j.jtos.2024.10.005","url":null,"abstract":"<div><div>Extracellular vesicles, including exosomes, are small extracellular vesicles that range in size from 30 nm to 10 μm in diameter and have specific membrane markers. They are naturally secreted and are present in various bodily fluids, including blood, urine, and saliva, and through the variety of their internal cargo, they contribute to both normal physiological and pathological processes. These processes include immune modulation, neuronal synapse formation, cell differentiation, cancer metastasis, angiogenesis, lymphangiogenesis, progression of infectious disease, and neurodegenerative disorders like Alzheimer's and Parkinson's disease. In recent years, interest has grown in the use of exosomes as a potential drug delivery system for various diseases and injuries. Importantly, exosomes originating from a patient's own cells exhibit minimal immunogenicity and possess remarkable stability along with inherent and adjustable targeting capabilities. This review explores the roles of exosomes in angiogenesis, lymphangiogenesis, and nerve repair with a specific emphasis on these processes within the cornea. Furthermore, it examines exosomes derived from specific cell types, discusses the advantages of exosome-based therapies in modulating these processes, and presents some of the most established methods for exosome isolation. Exosome-based treatments are emerging as potential minimally invasive and non-immunogenic therapies that modulate corneal angiogenesis and lymphangiogenesis, as well as enhance and accelerate endogenous corneal nerve repair.</div></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 459-476"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142484788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Simple limbal epithelial transplantation versus cultivated limbal epithelial transplantation in ocular burns","authors":"Namrata Sharma , Renu Venugopal , Sujata Mohanty , K. Priyadarshini , Ritu Nagpal , Deepali Singhal , Aafreen Bari , Tanuj Dada , Prafulla Kumar Maharana , Tushar Agarwal , Ashish Dutt Upadhyay","doi":"10.1016/j.jtos.2024.10.007","DOIUrl":"10.1016/j.jtos.2024.10.007","url":null,"abstract":"<div><h3>Purpose</h3><div>To compare the outcomes of simple limbal epithelial transplantation (SLET) with cultivated limbal epithelial transplantation (CLET) for the management of total limbal stem cell deficiency (LSCD) in eyes with unilateral ocular burns.</div></div><div><h3>Design</h3><div>Randomized controlled trial.</div></div><div><h3>Methods</h3><div>100 patients (100 eyes) with unilateral total LSCD following ocular burns undergoing autologous Limbal Stem Cell Transplantation (LSCT) were enrolled and randomized into SLET and CLET groups. Restoration of an epithelized ocular surface was the primary outcome measure. Occurrences of progressive conjunctivalization and persistent epithelial defects postoperatively were considered surgical failures.</div></div><div><h3>Results</h3><div>Mean age was 20.2 ± 13.1 years (SLET) and 22.6 ± 14.3 years (CLET) (p = 0.363). Alkali burn was the most common causative factor in both groups and had comparable mean logMAR BCVA at presentation [SLET: 2.33 ± 0.5, CLET: 2.23 ± 1.48 (p = 0.652)]. Median time interval between injury and surgical intervention was 18 months (SLET) and 12 months (CLET) (p = 0.06). 88 % eyes in SLET group maintained a stable ocular surface at 1 year period versus CLET group (86 %) (p = 0.999). Mean logMAR BCVA significantly improved in both groups with SLET having significantly better BCVA versus CLET at 6 months (p = 0.0390), 1 year (p = 0.0001), 2 year (p = 0.0001) and 3 years (p = 0.0001) follow up. Kaplan-Meier survival analysis was statistically insignificant amongst the 2 groups (p = 0.590).</div></div><div><h3>Conclusions</h3><div>Compared to CLET, SLET is equally efficacious in restoring and maintaining a stable ocular surface in eyes with total LSCD due to ocular burns, with the added advantage of providing superior visual outcomes.</div></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 504-509"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142515695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-10-01DOI: 10.1016/j.jtos.2024.11.003
Mohammad Javed Ali, Ali Djalilian
{"title":"Readership awareness series – paper 14: The submission Dilemma - How to choose a journal?","authors":"Mohammad Javed Ali, Ali Djalilian","doi":"10.1016/j.jtos.2024.11.003","DOIUrl":"10.1016/j.jtos.2024.11.003","url":null,"abstract":"","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 521-522"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cytarabine chemotherapy induces meibomian gland dysfunction","authors":"Ren Liu , Jianwen Xue , Jiaxu Han, Mengqian Tu, Wenhui Wang, Ziyan Chen, Xiaobing Qian, Bing Xiao, Lingyi Liang","doi":"10.1016/j.jtos.2024.10.002","DOIUrl":"10.1016/j.jtos.2024.10.002","url":null,"abstract":"<div><h3>Purpose</h3><div>Cytarabine (Ara-C) chemotherapy causes symptoms resembling meibomian gland dysfunction (MGD), suggesting potential associations between Ara-C and MGD. In this study, the pathological effects of Ara-C on MGD were investigated in a rodent model.</div></div><div><h3>Methods</h3><div>Mice received Ara-C with or without rosiglitazone (PPARγ agonist) for 7 consecutive days. Slit-lamp biomicroscope was used for ocular examinations. Immunofluorescence detected acinar cell proliferation, differentiation, and ductal keratinization in the meibomian gland (MG). Lipid accumulation was evaluated by Oil Red O and LipidTox staining. Lipogenic status, FoxO1/FoxO3a cellular localization, and oxidative stress were visualized via immunohistochemistry. Western blotting assessed relative protein expression and AKT/FoxO1/FoxO3a pathway phosphorylation.</div></div><div><h3>Results</h3><div>Ara-C (50 mg/kg) did not affect mouse survival but induced damage to ocular surface microenvironment, including corneal epithelial defects, MG orifice plugging and acinar dropout, and lacrimal gland (LG) dysfunction. Ara-C intervention inhibited proliferation and caused progenitor loss in the MG, as evidenced by reduced PCNA + labeling and P63+/Lrig1+ basal cell numbers. The MG ducts of Ara-C-treated mice exhibited marked dilatation, lipid deposition, and hyperkeratinization (K1/K10 overexpression). Ara-C disrupted MG lipid metabolism by downregulating PPARγ and its downstream lipogenic targets AWAT2/SOAT1/ELOVL4 and upregulating HMGCR. Dephosphorylation of AKT and the subsequent nuclear translocation of FoxO1/FoxO3a contributed to Ara-C-induced PPARγ downregulation. Ara-C triggered oxidative stress with increases in 4-HNE and 8-OHdG and Keap1/Nrf2/HO-1/SOD1 axis dysregulation. Rosiglitazone treatment ameliorated MGD-associated pathological manifestations, LG function, MG lipid metabolism, and oxidative stress in Ara-C-exposed mice.</div></div><div><h3>Conclusions</h3><div>Systemic Ara-C chemotherapy exerted topical cytotoxic effects on the ocular surface, and PPARγ restoration by rosiglitazone mitigated Ara-C-induced MGD alterations.</div></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 444-458"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ocular SurfacePub Date : 2024-10-01DOI: 10.1016/j.jtos.2024.09.001
Sukanya Jaiswal , Isabelle Jalbert , Nicholas Olsen , Anthea Burnett , Blanka Golebiowski
{"title":"Blinded by smoke: Wildfire smoke exposure and eye irritation in australian wildland firefighters","authors":"Sukanya Jaiswal , Isabelle Jalbert , Nicholas Olsen , Anthea Burnett , Blanka Golebiowski","doi":"10.1016/j.jtos.2024.09.001","DOIUrl":"10.1016/j.jtos.2024.09.001","url":null,"abstract":"<div><h3>Purpose</h3><div>Wildfire occurrence is increasing worldwide, putting firefighters and general public at increased risk of eye injuries from smoke exposure. This study explored ocular symptoms and use of protective eyewear amongst wildland firefighters in Australia.</div></div><div><h3>Methods</h3><div>Australian wildland firefighters were invited to complete an online survey about the occurrence of eye irritation, use of protective eyewear and behaviours associated with occupational smoke exposure. Responses were analysed using logistic regression and qualitative inductive content analysis.</div></div><div><h3>Results</h3><div>338 wildland firefighters completed the survey. Eye irritation was reported by 90 % of firefighters at least <em>sometimes</em> during work and by 70 % after work. Frequency of eye irritation was greater amongst females than males (OR 2.01, CI 1.22–3.31, p < 0.001). Protective eyewear was used <em>often</em> or <em>always</em> by 67 % of firefighters on the fireground, however 55 % had to remove their protective eyewear due to sweat, fogging or another reason. Goggles were more likely to be removed compared to sunglasses and safety glasses (OR 4.28, CI 2.75–6.68, p < 0.001).</div><div>Firefighters reported that, at times smoke exposure necessitated eye closure and impaired vision on the fireground. Firefighters also reported that protective eyewear helped to reduce eye symptoms, but its consistent use on the fireground was difficult. The severity and recovery from eye symptoms varied between participants.</div></div><div><h3>Conclusion</h3><div>Australian wildland firefighters frequently experience eye irritation from smoke exposure, and this can affect operational capabilities. These findings can support the development of evidence-based strategies to help protect and aid recovery of the eye surface following smoke exposure.</div></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 381-391"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142305334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Adipose-derived mesenchymal stromal cells: A study on safety and efficacy in ocular inflammation","authors":"Robert M. Rusch , Emi Inagaki , Hiroko Taniguchi , Saki Sakakura , Rie Tamai , Hidenori Nonaka , Shota Shimizu , Shinri Sato , Yoko Ogawa , Hirayama Masatoshi , Kazuno Negishi , Hideyuki Okano , Shigeto Shimmura","doi":"10.1016/j.jtos.2024.11.001","DOIUrl":"10.1016/j.jtos.2024.11.001","url":null,"abstract":"<div><h3>Purpose</h3><div>This study explores the application of adipose-derived mesenchymal stromal cells (adMSCs) as a therapy for ocular inflammatory diseases utilizing a chronic GVHD model.</div></div><div><h3>Methods</h3><div>Human adMSCs were administered via subconjunctival injection into mice with chronic ocular GVHD. Clinical scores and changes in T cell populations were analyzed.</div></div><div><h3>Results</h3><div>The study showed significant improvement in corneal integrity, including epithelial damage, opacity, thickness, and structure, after subconjunctival adMSC transplantation. Additionally, adMSC transplantation increased CD45<sup>+</sup> and Foxp3<sup>+</sup> Tregs while decreasing CD4<sup>+</sup> T cells, 1IL17A<sup>+</sup> Th17 cells, and IFNγ<sup>+</sup> Th1 cells in local cervical lymph nodes. Moreover, adMSC-conditioned media enhanced wound closure and cell migration toward the wound bed <em>in vitro</em>. The cells disappeared within a week suggesting that trophic factors were involved.</div></div><div><h3>Conclusion</h3><div>The dual benefit of adMSCs in immune-related ocular disorders underscores their potential for clinical application. This study focuses on subconjunctival delivery, effects of adMSCs and migration post-injection, with implications for optimizing cellular therapy application. The observed dual action, combining immunomodulation and tissue repair enhancement, underscores holistic approach of adMSC therapy in regenerative medicine, making it a potent treatment for diseases involving inflammation and tissue damage in the ocular surface.</div></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"34 ","pages":"Pages 523-534"},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}