Experimental Dermatology最新文献

{"title":"Correction to ‘Dose escalation of biologic treatment in patients with moderate-to-severe psoriasis in Japan’","authors":"","doi":"10.1111/exd.15139","DOIUrl":"10.1111/exd.15139","url":null,"abstract":"<p>Tada Y, Soliman AM, Ishii K, Sakuma R, Pinter A, Davis M, Nunag D, Buessing M, Puig L, Imafuku S. Dose escalation of biologic treatment in patients with moderate-to-severe psoriasis in Japan. Exp Dermatol. 2024 May;33(5):e15067. doi: 10.1111/exd.15067. PMID: 38757460.</p><p>\u0000 https://onlinelibrary.wiley.com/doi/10.1111/exd.15067\u0000 </p><p>In addition, also in Experimental Design, ‘gusekumab’ is misspelled and should be ‘guselkumab’.</p><p>We apologize for this error; however, note that it has no impact on the results of the study and the findings are unchanged.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.15139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626518","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":"Melanin accumulation in acanthotic seborrheic keratosis: Reduced proliferation and early differentiation of keratinocytes and increased number of melanocytes","authors":"Mizuki Ueno,&nbsp;Yu Gabe,&nbsp;Megumi Tobiishi,&nbsp;Aya Komiya,&nbsp;Takuo Yuki,&nbsp;Keigo Kawabata,&nbsp;Yoshito Takahashi,&nbsp;Tamio Suzuki","doi":"10.1111/exd.15138","DOIUrl":"10.1111/exd.15138","url":null,"abstract":"<p>Seborrheic keratosis (SK) is a common benign tumour, often associated with hyperpigmentation. To investigate the mechanism of melanin accumulation in SK, we have conducted comprehensive gene expression and histological analyses. We obtained five pairs of skin samples, including non-lesional and SK samples, from the backs of three male Japanese participants aged 40–59 years. To examine melanocytes and keratinocytes in SK, three pairs of skin samples were separated by laser capture microdissection into the basal layer and the other layer in the epidermis. We performed a comprehensive gene expression analysis to identify differentially expressed genes between non-lesional and SK skin, followed by gene ontology and pathway analysis. We found abnormal morphogenesis and cell proliferation in the basal layer, along with increased immune response and impaired cell differentiation and metabolism in the other layer of SK. We focused on cell proliferation and differentiation, as these are directly associated with melanin accumulation. Immunohistochemical analyses of Ki67, keratin 10, and keratin 14 demonstrated the decreases in the proliferation and early differentiation of the epidermis. Contrarily, no significant changes were observed in terminal differentiation markers, filaggrin and loricrin. Although the number of melanocytes was higher in SK than in non-lesional skin, melanogenic activity showed no difference. These results indicated that melanin accumulation in SK is caused by delayed melanin excretion due to reduced turnover around the basal and spinous layers of the epidermis and melanin production due to an increased number of melanocytes. Our findings provide new insights for therapeutic approaches in SK.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616143","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":"Topical use of tobramycin: A possible innovative treatment of severe skin chronic ulcers","authors":"Corrado Cirielli,&nbsp;Francesco Facchiano,&nbsp;Mauro Picardo,&nbsp;Marco Benedetto,&nbsp;Roberto Tagliaferri,&nbsp;Stefano Tagliaferri,&nbsp;Giuseppe Piccinni,&nbsp;Annarita Panebianco,&nbsp;Antonio Facchiano","doi":"10.1111/exd.15131","DOIUrl":"10.1111/exd.15131","url":null,"abstract":"","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616144","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":"Increased loss-of-function filaggrin gene mutation prevalence in atopic dermatitis patients across northern latitudes indicates genetic fitness: A systematic review and meta-analysis","authors":"Casper Milde Khatib,&nbsp;Amalie Wandel Klein-Petersen,&nbsp;Amalie Thorsti Møller Rønnstad,&nbsp;Alexander Egeberg,&nbsp;Maria Oberländer Christensen,&nbsp;Jonathan Ian Silverberg,&nbsp;Simon Francis Thomsen,&nbsp;Alan David Irvine,&nbsp;Jacob Pontoppidan Thyssen","doi":"10.1111/exd.15130","DOIUrl":"10.1111/exd.15130","url":null,"abstract":"<p>Loss-of-function (LoF) mutations in the filaggrin gene (<i>FLG</i>) constitute the strongest genetic risk for atopic dermatitis (AD). A latitude-dependent difference in the prevalence of LoF <i>FLG</i> mutations was systematically evaluated. A systematic review and meta-analysis were performed to estimate the prevalence of LoF <i>FLG</i> mutations in AD patients and the general population by geography and ethnicity. Risk of bias was assessed by Newcastle-Ottawa Scale and Jadad score. StatsDirect, version 3 software was used to calculate all outcomes. PubMed and EMBASE were searched until 9^th December 2021. Studies were included if they contained data on the prevalence of LoF <i>FLG</i> mutations in AD patients or from the general population or associations between AD and LoF <i>FLG</i> mutations and were authored in English. Overall, 248 studies and 229 310 AD patients and individuals of the general population were included in the quantitative analysis. The prevalence of LoF <i>FLG</i> mutations was 19.1% (95% CI, 17.3–21.0) in AD patients and 5.8% (95% CI, 5.3–6.2) in the general population. There was a significant positive association between AD and LoF <i>FLG</i> mutations in all latitudes in the Northern hemisphere, but not in all ethnicities. The prevalence of LoF <i>FLG</i> mutations became gradually more prevalent in populations residing farther north of the Equator but was negligible in Middle Easterners and absent in most African populations. <i>FLG</i> LoF mutations are common and tend to increase with northern latitude, suggesting potential clinical implications for future AD management. The existence of possible genetic fitness from <i>FLG</i> LoF mutations remains unknown.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.15130","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579366","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":"Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease","authors":"Yael Renert-Yuval,&nbsp;Juana Gonzalez,&nbsp;Sandra Garcet,&nbsp;Samuel C. Williams,&nbsp;Ariana Moreno,&nbsp;James G. Krueger","doi":"10.1111/exd.15129","DOIUrl":"10.1111/exd.15129","url":null,"abstract":"<p>Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA⁺ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.15129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563085","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":"Metabolic dynamics in psoriatic epidermis: Enhanced glucose and lactate uptake, glycolytic pathway and TCA cycle dynamics","authors":"Satoshi Nakamizo,&nbsp;Hiromi Doi,&nbsp;Kenji Kabashima","doi":"10.1111/exd.15127","DOIUrl":"10.1111/exd.15127","url":null,"abstract":"&lt;p&gt;Psoriasis, a prevalent chronic inflammatory skin disorder, impacts approximately 2%–3% of the global population.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This disease is marked by an expedited proliferation of keratinocytes and a significantly shortened turnover time. Additionally, a notable association exists between psoriasis and metabolic syndrome, with a considerable portion of patients displaying obesity.&lt;/p&gt;&lt;p&gt;Prior research has underscored the importance of glucose uptake in the proliferation of keratinocytes.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Conversely, the tricarboxylic acid (TCA) cycle are crucial for the differentiation of these cells.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; In the context of psoriasis, an increase in GLUT1 expression has been observed, correlating with heightened severity scores, suggesting an enhanced glycolytic activity.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The glycolytic pathway facilitates the conversion of glucose into ATP and lactate, the latter of which is either expelled from the cell via MCT4 or reabsorbed through MCT1.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Once inside the cell, lactate contributes to ATP production through the TCA cycle. An in-depth understanding of the alterations and dynamics within these metabolic pathways, including glycolysis, the TCA cycle and lactate transport, is essential for a comprehensive grasp of the pathophysiology of psoriasis. However, the precise mechanisms through which lactate is metabolized in psoriatic keratinocytes remain unclear, highlighting a significant gap in our understanding of the disease's metabolic foundations.&lt;/p&gt;&lt;p&gt;To delve deeper into the metabolic processes in keratinocytes of psoriasis vulgaris at a single-cell resolution, we re-analysed publicly available single-cell RNA sequencing data from prior psoriasis studies (GSE162183),&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; focusing specifically on epidermal keratinocytes (Figure S1a,b). We discovered significant gene expression differences between healthy individuals and psoriasis patients in both undifferentiated and differentiated epidermal keratinocytes (Figure S1a). Analysis of gene expression profiles in these cells revealed a marked upregulation of glucose transporter genes (e.g. SLC2A1) and cell proliferation markers (e.g. MKI67) in the undifferentiated keratinocytes of psoriatic lesions (Figure S1c). Additionally, the expression of inflammatory markers, such as KRT16 and S100A7, was significantly elevated in the differentiated keratinocytes within the psoriatic epidermis. Subsequent pathway analysis of the upregulated genes in each cell type indicated an elevation of genes related to cell proliferation in psoriatic undifferentiated keratinocytes, while genes associated with aerobic respiration were upregulated in both undifferentiated and differentiated keratinocytes (Figure 1A).&lt;/p&gt;&lt;p&gt;Further investigation into the gene expression related to representative metabolic pathways, specifically glycolysis and the TCA cycle, in these keratinocytes revealed an upregulation in psorias","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/exd.15127","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554460","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":"Pulmonary interstitial lesions in pemphigus mouse model: Verifying pemphigus may not be only limited to skin and mucosa","authors":"Chang Tang,&nbsp;Lanting Wang,&nbsp;Qingmei Liu,&nbsp;Zihua Chen,&nbsp;Jin Yang,&nbsp;Haiqing Gao,&nbsp;Chenggong Guan,&nbsp;Shan He,&nbsp;Luyao Zhang,&nbsp;Shenyuan Zheng,&nbsp;Fanping Yang,&nbsp;Shengan Chen,&nbsp;Li Ma,&nbsp;Zhen Zhang,&nbsp;Ying Zhao,&nbsp;Jiucun Wang,&nbsp;Xiaoqun Luo","doi":"10.1111/exd.15136","DOIUrl":"10.1111/exd.15136","url":null,"abstract":"<p>Interstitial lung disease (ILD) has been identified as a prevalent complication and significant contributor to mortality in individuals with pemphigus. In this study, a murine model of pemphigus was developed through the subcutaneous administration of serum IgG obtained from pemphigus patients, allowing for an investigation into the association between pemphigus and ILD. Pulmonary interstitial lesions were identified in the lungs of a pemphigus mouse model through histopathology, RT-qPCR and Sircol assay analyses. The severity of these lesions was found to be positively associated with the concentration of IgG in the injected serum. Additionally, DIF staining revealed the deposition of serum IgG in the lung tissue of pemphigus mice, indicating that the subcutaneous administration of human IgG directly impacted the lung tissue of the mice, resulting in damage. This study confirms the presence of pulmonary interstitial lesions in the pemphigus mouse model and establishes a link between pemphigus and ILD.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554461","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":"Analysis of risk factors related to chronic non-healing wound infection and the construction of a clinical prediction model","authors":"Jing Liu,&nbsp;Qiang He,&nbsp;Gaijuan Guo,&nbsp;Chunbao Zhai","doi":"10.1111/exd.15102","DOIUrl":"10.1111/exd.15102","url":null,"abstract":"<p>This study is aimed to analyse the risk factors associated with chronic non-healing wound infections, establish a clinical prediction model, and validate its performance. Clinical data were retrospectively collected from 260 patients with chronic non-healing wounds treated in the plastic surgery ward of Shanxi Provincial People's Hospital between January 2022 and December 2023 who met the inclusion criteria. Risk factors were analysed, and a clinical prediction model was constructed using both single and multifactor logistic regression analyses to determine the factors associated with chronic non-healing wound infections. The model's discrimination and calibration were assessed via the concordance index (C-index), receiver operating characteristic (ROC) curve and calibration curve. Multivariate logistic regression analysis identified several independent risk factors for chronic non-healing wound infection: long-term smoking (odds ratio [OR]: 4.122, 95% CI: 3.412–5.312, <i>p</i> &lt; 0.05), history of diabetes (OR: 3.213, 95% CI: 2.867–4.521, <i>p</i> &lt; 0.05), elevated C-reactive protein (OR: 2.981, 95% CI: 2.312–3.579, <i>p</i> &lt; 0.05), elevated procalcitonin (OR: 2.253, 95% CI: 1.893–3.412, <i>p</i> &lt; 0.05) and reduced albumin (OR: 1.892, 95% CI: 1.322–3.112, <i>p</i> &lt; 0.05). The clinical prediction model's C-index was 0.762, with the corrected C-index from internal validation using the bootstrap method being 0.747. The ROC curve indicated an area under the curve (AUC) of 0.762 (95% CI: 0.702–0.822). Both the AUC and C-indexes ranged between 0.7 and 0.9, suggesting moderate-to-good predictive accuracy. The calibration chart demonstrated a good fit between the model's calibration curve and the ideal curve. Long-term smoking, diabetes, elevated C-reactive protein, elevated procalcitonin and reduced albumin are confirmed as independent risk factors for bacterial infection in patients with chronic non-healing wounds. The clinical prediction model based on these factors shows robust performance and substantial predictive value.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554459","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":"Spinal histamine H4 receptor mediates chronic pruritus via p-ERK in acetone–ether–water (AEW)-induced dry skin mice","authors":"Ting-Ting Wang,&nbsp;Zi-Yang Li,&nbsp;Dan-Dan Hu,&nbsp;Xian-Yun Xu,&nbsp;Ning-Jing Song,&nbsp;Gang-Qiang Li,&nbsp;Ling Zhang","doi":"10.1111/exd.15128","DOIUrl":"10.1111/exd.15128","url":null,"abstract":"<p>Dry skin is common to many pruritic diseases and is difficult to improve with oral traditional antihistamines. Recently, increasing evidence indicated that histamine H4 receptor (H4R) plays an important role in the occurrence and development of pruritus. Extracellular signal-regulated kinase (ERK) phosphorylation activation in the spinal cord mediates histamine-induced acute and choric itch. However, whether the histamine H4 receptor regulates ERK activation in the dry skin itch remains unclear. In the study, we explore the role of the histamine H4 receptor and p-ERK in the spinal cord in a dry skin mouse model induced by acetone–ether–water (AEW). q-PCR, Western blot, pharmacology and immunofluorescence  were applied in the study. We established a dry skin itch model by repeated application of AEW on the nape of neck in mice. The AEW mice showed typically dry skin histological change and persistent spontaneous scratching behaviour. Histamine H4 receptor, instead of histamine H1 receptor, mediated spontaneous scratching behaviour in AEW mice. Moreover, c-Fos and p-ERK expression in the spinal cord neurons were increased and co-labelled with GRPR-positive neurons in AEW mice. Furthermore, H4R agonist 4-methyhistamine dihydrochloride (4-MH)induced itch. Both 4-MH-induced itch and the spontaneous itch in AEW mice were blocked by p-ERK inhibitor U0126. Finally, intrathecal H4R receptor antagonist JNJ7777120 inhibited spinal p-ERK expression in AEW mice. Our results indicated that spinal H4R mediates itch via ERK activation in the AEW-induced dry skin mice.</p>","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554462","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":"Decreased serum IL-38 levels in pemphigus vulgaris","authors":"Toyoki Yamamoto,&nbsp;Lixin Li,&nbsp;Yukiko Ito,&nbsp;Shinichi Sato,&nbsp;Sayaka Shibata","doi":"10.1111/exd.15132","DOIUrl":"10.1111/exd.15132","url":null,"abstract":"","PeriodicalId":12243,"journal":{"name":"Experimental Dermatology","volume":"33 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497547","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}