Clinical Endocrinology最新文献

{"title":"A Novel Molecular Regulatory Network in Bone Marrow Mesenchymal Stem Cells for Age-Related Osteoporosis.","authors":"Ming-Dong Gao, Xiao-Jun Wang, Peng-Biao Li, Qian-Qian Dong, Li-Min Tian","doi":"10.1111/cen.15239","DOIUrl":"https://doi.org/10.1111/cen.15239","url":null,"abstract":"<p><strong>Background: </strong>This study evaluates the miRNA-mRNA regulatory networks that potentially influence the senescence mechanisms of bone marrow mesenchymal stem cells (BMSCs) in age-related osteoporosis (ARO). By identifying these networks, the study aims to offer new molecular markers and therapeutic targets for ARO.</p><p><strong>Methods: </strong>Five mRNA datasets were analyzed to identify common differentially expressed genes associated with senescence and osteoporosis. Seven hub genes were found to be enriched in the PI3K-Akt signaling pathway, and 22 hub miRNAs potentially regulating these genes. Primary BMSCs were harvested and cultured from seven younger, non-osteoporotic individuals and six older adults with osteoporosis. Expression levels of the hub genes and miRNAs were validated using quantitative real-time polymerase chain reaction (qRT-PCR).</p><p><strong>Results: </strong>Expression analysis showed that integrin subunit beta 3 (ITGB3), receptor tyrosine kinase ligand (KITLG), platelet-derived growth factor (PDGFB), and their associated regulatory miRNAs, exhibited significant differences between the two BMSC groups.</p><p><strong>Conclusion: </strong>A newly identified miRNA-mRNA regulatory network may mediate ARO via the PI3K-Akt signaling pathway in BMSCs. These molecular insights provide a foundation for potential therapeutic interventions targeting age-related osteoporosis.</p>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718131","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":"Patient Participation in Urine Specific Gravity Screening for Arginine Vasopressin Deficiency in an Inpatient Neurosurgical Clinic.","authors":"Jeanne-Marie Nollen, Anja H Brunsveld-Reinders, Nienke R Biermasz, Marco J T Verstegen, Eline Leijtens, Wilco C Peul, Ewout W Steyerberg, Wouter R van Furth","doi":"10.1111/cen.15241","DOIUrl":"https://doi.org/10.1111/cen.15241","url":null,"abstract":"<p><strong>Objective: </strong>Detecting hypotonic urine (specific gravity < 1005 g/L) is crucial for the early identification of arginine vasopressin deficiency (AVP-deficiency), a common complication after pituitary surgery. This study aimed to evaluate the agreement between urine specific gravity measurements taken by patients using urine test strips and those taken by nurses using a refractometer, to assess the reliability of patient-conducted measurements for diagnosing this condition.</p><p><strong>Design: </strong>A prospective cohort study was conducted in a neurosurgical ward.</p><p><strong>Patients: </strong>The study included 110 participants who collectively provided 609 specific gravity measurements.</p><p><strong>Measurements: </strong>Specific gravity measurements were taken using Combur-10 urine test strips by patients and using an ATAGO MASTER-SUR/Nα refractometer by nurses. Agreement was analysed using Weighted Kappa and intraclass correlation coefficient (ICC).</p><p><strong>Results: </strong>Moderate agreement was found between patient-conducted measurements and those from the refractometer (Kappa = 0.47, ICC = 0.69). Substantial to good agreement was observed between patient and nurse measurements using urine test strips (Kappa = 0.82, ICC = 0.89). A threshold of 1.015 g/L in test strip measurements ensured no cases of hypotonic urine were missed, reducing the need for nurse-led testing by 50%. Patient satisfaction was high (mean 7.8), while nurse satisfaction was lower (mean 6.4).</p><p><strong>Conclusions: </strong>Although patients are less accurate than nurses in measuring specific gravity, they can reliably screen for hypotonic urine in AVP-deficiency diagnostics using urine test strips. A higher cut-off point improves diagnostic accuracy, enhances patient participation and reduces the screening workload for nurses.</p>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718181","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":"Ketotic Hypoglycaemia Following Sleeve Gastrectomy.","authors":"Jinwen He, Liza Phillips, Janelle Nisbet, Adam Morton","doi":"10.1111/cen.15232","DOIUrl":"https://doi.org/10.1111/cen.15232","url":null,"abstract":"<p><p>Post-bariatric surgery hypoglycaemia is typically mediated by hyperinsulinaemia, although the exact mechanisms are incompletely understood. Two cases of non-insulin mediated, ketotic hypoglycaemia following sleeve gastrectomy are presented. After fasting for 40 and 65 h, respectively, both patients developed symptomatic hypoglycaemia, with corresponding low insulin, low c-peptide and elevated beta-hydroxybutyrate levels. Morning cortisol and IGF1 levels were normal. Potential mechanisms for ketotic hypoglycaemia following bariatric surgery include reduction in hepatic, renal and intestinal gluconeogenesis, or alternatively an underlying inborn error of metabolism such as a glycogen storage disorder unmasked by bariatric surgery. Most glycogen storage disorders present in childhood, but there have been rare case reports of glycogen storage disorders types I, III and IX diagnosed in adulthood. Neither of the above cases had other features of a glycogen storage disorder such as elevated lactate, hyperuricaemia, hypertriglyceridaemia, hepatomegaly, myopathy or an indicative family history. Both patients trialled first-line dietary management, which was inadequate in managing hypoglycaemia. Treatment with the glucagon-like peptide-1 receptor agonist semaglutide resulted in the resolution of hypoglycaemic episodes in one patient, and a significant reduction in hypoglycaemic episodes in the other patient.</p>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699824","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":"Risk of Dementia in Non-Overtly Functional Adrenal Tumours (NOFAT)-Reply.","authors":"Hadis Mirzaei, Jekaterina Patrova, Buster Mannheimer, Jonatan D Lindh, Henrik Falhammar","doi":"10.1111/cen.15243","DOIUrl":"https://doi.org/10.1111/cen.15243","url":null,"abstract":"","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708887","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":"Transsphenoidal Surgery for Pituitary Neuroendocrine Tumours (PiTNETs) in a Tertiary Hospital: Are There Differences Between Young and Elderly Patients?","authors":"Inés Borrego-Soriano, Paola Parra-Ramírez, Patricia Martín-Rojas-Marcos, Carlos Pérez-López, Pablo García-Feijoo, Cristina Álvarez-Escolá","doi":"10.1111/cen.15242","DOIUrl":"https://doi.org/10.1111/cen.15242","url":null,"abstract":"<p><strong>Objective: </strong>The incidence of pituitary neuroendocrine tumours (PiTNET) in elderly patients is rising, but treatment recommendations and data of outcomes are limited. This study aimed to compare the clinical characteristics and surgical outcomes of elderly and younger patients.</p><p><strong>Design: </strong>Retrospective and observational study.</p><p><strong>Patients: </strong>One hundred twenty-four adults underwent transsphenoidal surgery due to PiTNET in our hospital from 2018 to 2023.</p><p><strong>Measurements: </strong>We stratified the population according to age and compared the clinical features and surgical outcomes.</p><p><strong>Results: </strong>Thirty-two patients (25.8%) were 65 years or older. Elderly patients had a lower rate of hormonal excess (15.6% vs. 60.9%, p < 0.001) and a higher rate of hypopituitarism (43.8% vs. 8.7%, p < 0.001), with a greater median number of affected axis (3 vs. 1, p < 0.001). Only the rate of ACTH excess was different between groups (0 vs. 26.1%, p = 0.003). The most common surgical indication in elderly patients was visual impairment (31.3%) compared to functionality in younger individuals (42.4%, p = 0.012). There were no differences in the Knosp grade, but elderly patients had a higher rate of macroadenomas (84.4% vs. 58.7%, p = 0.002). In the immediate postsurgical period, there were no differences in the rate of surgical or hormonal complications, or in the hospital stay. Ki67 was lower in elderly patients (1.44% vs. 2.77%, p = 0.045). After 6-12 months, there were no differences in the tumour resection rate, visual improvement, or hormonal status.</p><p><strong>Conclusion: </strong>With experienced surgical and endocrinological care, transsphenoidal surgery for elderly patients with PiTNET is effective and safe.</p>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699840","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":"The Utility of Magnetic Resonance Imaging for Hypophysitis Secondary to Immune Checkpoint Inhibitor Use.","authors":"Qi Yang Damien Qi, Jeevan Vettivel, Krisha Solanki, Anna Davis, Anthony W Russell, Leon A Bach","doi":"10.1111/cen.15240","DOIUrl":"https://doi.org/10.1111/cen.15240","url":null,"abstract":"<p><strong>Objective: </strong>Immune checkpoint inhibitor (ICI) therapy is an efficacious cancer treatment, often resulting in autoimmune off-target effects. Magnetic resonance imaging (MRI) has been a recommended investigation for ICI-related hypophysitis. We sought to identify the frequency of identifiable MRI changes.</p><p><strong>Design: </strong>A retrospective case-control audit was performed of individuals who received one or more ICI between January 2018 and December 2023 at a single tertiary referral centre in Melbourne, Australia.</p><p><strong>Patients: </strong>Individuals requiring hormone supplementation were screened for hypophysitis. A randomly selected control group receiving ICI demonstrated normal pituitary function at the time of MRI.</p><p><strong>Measurements and results: </strong>Fifty-four (6.9%) of 778 individuals who received ICI therapy were diagnosed with ICI-related hypophysitis. 43 had an MRI examining the pituitary gland within 2 months. Four (9.3%) had initial reporting consistent with hypophysitis. Upon re-examination by an MRI-Fellowship trained radiologist, a further 6 (total 10, 23%) had acute hypophysitis changes. Among the control group, 45 of 46 individuals had an MRI within 2 months of normal pituitary biochemistry. All initial MRI reports were normal, but upon review 1 (2.2%) had acute hypophysitis abnormalities, with a significant difference between groups (10/43 vs 1/45, p = 0.003). Within the control group, a further 10 (22%) individuals had an atrophic pituitary and/or empty sella. No other significant pituitary pathology, including pituitary metastasis, was identified.</p><p><strong>Conclusions: </strong>Although changes were observed in a minority of patients with hypophysitis, MRI provides minimal additional clinically meaningful information, so it could be reserved for atypical cases or those with persisting symptoms despite adequate supplementation.</p>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691370","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":"Moderate to Severe Short Stature and Joint Involvement in Individuals With ACAN Deletions.","authors":"Lucia Sentchordi-Montané, Francisca Díaz-Gonzalez, Silvia Modamio-Høybjør, Julián Nevado, Flavia Machado-Fernandes, Atilano Carcavilla, María Salcedo, Jorge Saraiva, Sarina G Kant, Christian de Bruin, Hermine A van Duyvenvoorde, Iris González-Cabaleiro, Lourdes Rey-Cordo, José Luis Chamorro-Martín, Vanesa Cancela-Muñiz, José Juan Alcón-Sáez, Manuel Parrón-Pajares, Sergio B Sousa, Karen E Heath","doi":"10.1111/cen.15237","DOIUrl":"https://doi.org/10.1111/cen.15237","url":null,"abstract":"<p><strong>Objective: </strong>In recent years, numerous heterozygous ACAN variants have been identified in individuals with short stature. The phenotypic spectrum includes mild to moderate short stature, advanced to delayed bone age, mild dysmorphic features, brachydactyly and/or other mild skeletal defects and joint pathology in early adulthood which often requires surgery. However, only one multiexonic ACAN deletion has been reported to date, in a family with short stature, advanced bone age in childhood and early osteoarthritis and spine deformity in the father. Here, we describe 15 individuals from 6 families with ACAN deletions.</p><p><strong>Design, patients and measurements: </strong>All probands were referred for short stature to paediatric endocrinology and genetic clinics in different European hospitals. After molecular studies detected the deletion, segregation studies were performed when available. Clinical and radiological features were evaluated in all cases.</p><p><strong>Results: </strong>Three complete and three intragenic deletions were detected. Patients present with moderate to severe short stature, mildly disproportionate growth and mild dysmorphic features. The majority suffer from joint involvement (osteochondritis dissecans and/or early onset osteoarthritis) which has required early surgical intervention.</p><p><strong>Conclusions: </strong>Although individuals with heterozygous ACAN deletions exhibit phenotypic variability, it is noticeable that they present with a quite homogeneous and age-dependent phenotype with a high proportion of severe joint problems.</p>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699828","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":"\"Risk of Dementia in Non-Overtly Functional Adrenal Tumour (NOFAT)\".","authors":"Elena Notarianni","doi":"10.1111/cen.15244","DOIUrl":"https://doi.org/10.1111/cen.15244","url":null,"abstract":"","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691368","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":"Approach to the Management of Gastrointestinal Manifestations in Patients With Phaeochromocytoma and Paraganglioma.","authors":"Monica Majumder, Cherie Chiang, Grace Kong, Michael Michael, Nirupa Sachithanandan, Emma Boehm","doi":"10.1111/cen.15235","DOIUrl":"https://doi.org/10.1111/cen.15235","url":null,"abstract":"<p><strong>Objective: </strong>Managing gastrointestinal symptoms in patients with phaeochromocytoma and paraganglioma (PPGL) is challenging due to the risk of catecholaminergic crisis with many commonly prescribed medications, especially in functional tumours. We reviewed gastrointestinal symptom management and outcomes in PPGL patients at our centre and developed recommendations based on a literature review and our experience.</p><p><strong>Design, patients, measurement: </strong>A single-centre retrospective analysis of the management of gastrointestinal symptoms in patients with PPGL between 2019 and 2024 was completed. A literature review of gastrointestinal manifestations in PPGL was undertaken.</p><p><strong>Results: </strong>Twenty-four individuals with PPGL admitted for radionuclide therapy, chemotherapy, surgery or other medical illness were included. Eighteen (75%) had metastatic disease. Fifty administration events of antiemetics for nausea or vomiting occurred. Two patients had acute colonic pseudo-obstruction. Dopamine antagonists (metoclopramide) and corticosteroids (dexamethasone) were administered to 10 and 9 patients, respectively, the majority of whom were alpha-blocked (n = 7) or had a dopaminergic/biochemically silent phenotype (n = 10). A patient with noradrenergic PPGL experienced a hypertensive episode following high-dose dexamethasone. No patients with biochemically negative/dopaminergic phenotypes or on alpha blockade experienced an antiemetic-related adverse event. Published evidence of dopamine antagonists and corticosteroids precipitating catecholaminergic crisis was mostly limited to case reports. While low-risk antiemetics (serotonin, histamine or neurokinin antagonists) are preferable, we found higher-risk antiemetics (dexamethasone and metoclopramide) can be cautiously administered in patients with a biochemically negative/dopaminergic phenotype or in those on adequate alpha blockade. Limited case reports demonstrated anti-cholinergic agents were beneficial for the management of acute colonic pseudo-obstruction.</p><p><strong>Conclusions: </strong>Optimal management of gastrointestinal symptoms in PPGL should consider disease characteristics such as primary location, secretory profile, alpha blockade and medication profile.</p>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691369","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":"Morning Salivary Cortisone Versus Serum Cortisol in the Overnight Dexamethasone Suppression Test (ODNST): Evaluation in a Clinical Setting.","authors":"Mathilde Mordaunt, Adrian Heald, Waseem Majeed, Rupinder Kochhar, Akheel Syed, Rajshekhar N Mudaliar, Ramadan Alshames, Fahmy Hanna, David Marshall, Brian Keevil, Anthony A Fryer","doi":"10.1111/cen.15233","DOIUrl":"https://doi.org/10.1111/cen.15233","url":null,"abstract":"<p><strong>Introduction: </strong>Saliva hormone measurement is increasingly being applied in everyday clinical practice. In relation to salivary cortisone measurement, there is a particular advantage, with minimal chance of cross-reaction with prescribed glucocorticoids and greater convenience. We evaluated the utility of salivary cortisone measurement in patients undergoing an overnight dexamethasone suppression test (ONDST).</p><p><strong>Methods: </strong>Individuals undergoing an ONDST had parallel measurement of serum cortisol and salivary cortisone at 0900 following midnight dexamethasone (1 mg). Salivary cortisone was measured by electrospray positive liquid chromatography tandem mass spectrometry. The threshold for adequate suppression of salivary cortisone was< 2.7nmol/L; serum cortisol was< 50nmol/L.</p><p><strong>Results: </strong>Results for 34 individuals which included 21% men (mean age 49.4 years) and 79% women (mean age 56.7 years) were analysed. Serum cortisol did not suppress in 22/34 cases. Salivary cortisone did not suppress in two of the cases where cortisol did suppress. We found a strong correlation between 0900 salivary cortisone and serum cortisol after 1 mg ONDST (r² = 0.65, p = 0.009). When performance of post-dexamethasone salivary cortisone (< 2.7nmol/L) alone in relation to suppression of serum cortisol (< 50nmol/L) was analysed all but 2 individuals were correctly classified. They had values for post dexamethasone salivary cortisone/serum cortisol of respectively 5.9/23 nmol/L (presented with unexplained fatigue, case 25) and 7/32 nmol/L (investigated for cyclical Cushing's Syndrome that was excluded, case 29). Agreement was 94.1%, kappa 0.87, p < 0.0001. The sensitivity of salivary cortisone for potential Cushing's syndrome as indicated by the post-dexamethasone 0900 serum cortisol was 100% (all cases of potential cortisol excess (0900 cortisol > 50nmol/L) were picked up) and specificity of 84.6% with a positive predictive value of 90.5% of salivary cortisone (using serum cortisol as the standard) and negative predictive value of 100% in relation to ruling out cortisol excess.</p><p><strong>Conclusion: </strong>We have provided further evidence that ONDST salivary cortisone has potential to be the first-line test for suspected Cushing's syndrome, not requiring venepuncture or attendance at hospital, with 100% sensitivity and reasonable specificity. Application of the salivary cortisone test has the potential for significant savings of money and time in this and other contexts.</p>","PeriodicalId":10346,"journal":{"name":"Clinical Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669476","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}