Endocrine Practice最新文献

{"title":"Diagnosis and Phenotypes of Idiopathic Diabetes: A Systematic Review.","authors":"Rana El Nahas, Ghalia Missous, Mohannad Al-Tarakji, Mohamed Said-Ghali, Khalid Hussain, Nicholas van Panhuys, Laura Herrero, Meritxell Espino-Guarch","doi":"10.1016/j.eprac.2025.06.009","DOIUrl":"10.1016/j.eprac.2025.06.009","url":null,"abstract":"<p><strong>Objective: </strong>Diabetes classification includes various forms, primarily type 1 and type 2, along with atypical types like type-1b diabetes (T1bD), which lack classic autoimmune markers or high-risk human leukocyte antigen (HLA) alleles, presenting diagnostic challenges and suggesting alternative pathogenic mechanisms. This review explores the potential genetic basis of these cases and the need for comprehensive testing.</p><p><strong>Methods: </strong>Seventeen studies, including case reports, cross-sectional, and cohort studies, were analyzed from PubMed, Web of Science, and Scopus databases up to March 14, 2024, covering 290 T1bD cases.</p><p><strong>Results: </strong>The cases were reclassified using the American Diabetes Association's criteria (autoantibody-negative, onset <35 years old, nonobese, and not HLA-associated). Genetic testing results were reviewed, focusing on identified mutations. Reclassification identified 201 T1bD cases, of which 30% of autoantibody-negative T1bD cases had pathogenic variants linked to monogenic diabetes, such as maturity-onset diabetes of the young, and mutations in INS, KCNJ11, and KLF1 genes linked to neonatal diabetes. Only 60 T1bD cases underwent exome sequencing, and none had whole genome sequencing, indicating limited genetic exploration.</p><p><strong>Conclusion: </strong>A significant proportion of T1bD cases may have an undetermined genetic basis, emphasizing the need for more comprehensive diagnostic assessments. Increased use of advanced genetic screening, such as whole genome sequencing, and data sharing are vital for improving diagnosis and management, potentially enabling personalized treatment for idiopathic diabetes.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483667","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":"Comparative Effectiveness of Glucagon-like Peptide-1- Receptor Agonists in Patients With Heart Failure With Preserved or Minimally Reduced Ejection Fraction: A Comprehensive Bayesian Network Meta-Analysis and Network Meta-Regression.","authors":"Ibrahim Khalil, M Rafiqul Islam, A B M Kamrul-Hasan, Lakshmi Nagendra, Sunjida Amin Promi, Md Abu Sayed, Mohd Turzo Rahman, Nowrin Sultana, Noshin Anjum Tasmi, Manisha Das, Salsabil Tarannum, Rajendronath Dey, Deep Dutta","doi":"10.1016/j.eprac.2025.06.005","DOIUrl":"10.1016/j.eprac.2025.06.005","url":null,"abstract":"<p><strong>Objectives: </strong>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown beneficial effects on clinical outcomes in patients with heart failure (HF) with preserved ejection fraction (HFpEF) or minimally reduced ejection fraction (HFmrEF). This network meta-analysis (NMA) aimed to consolidate evidence from RCTs assessing the effects of GLP-1 RAs in HFpEF and HF with reduced ejection fraction.</p><p><strong>Methods: </strong>Several databases were searched comprehensively for relevant RCTs. A Bayesian NMA was conducted using R, and meta-regression was employed to investigate potential sources of heterogeneity. Statistical significance was evaluated using 95% credible intervals (CrIs) and surface under the cumulative ranking curve to rank treatment effectiveness. The primary outcome was hospitalization for HF (HHF).</p><p><strong>Results: </strong>Eight reports from 6 Phase 3 RCTs (N = 24 099), mostly with low risks of bias, were included. Compared to placebo, semaglutide reduced the risk of HHF (HR 0.52, 95% CrI [0.25, 0.87]), while tirzepatide (HR 0.51, 95% CrI [0.16, 1.24]) and exenatide (HR 0.82, 95% CrI [0.33, 1.73]) demonstrated no effect. Semaglutide and exenatide, but not tirzepatide, reduced the risk of all-cause mortality. None affected cardiovascular mortality. Semaglutide decreased the risk of worsening of HF events; tirzepatide did not. Tirzepatide and semaglutide enabled weight loss; however, only semaglutide notably enhanced the 6-minute walk distance. According to the surface under the cumulative ranking curve values, tirzepatide ranked highest for reducing HHF and body weight, semaglutide for decreasing cardiovascular mortality and worsening of HF events and improving the 6-minute walk distance, and exenatide for reducing all-cause mortality.</p><p><strong>Conclusion: </strong>GLP-1 RAs provide significant benefits for patients with HFpEF or HFmrEF, with semaglutide offering more advantages than tirzepatide and exenatide.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483666","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":"Thyroid Emergencies: A Narrative Review.","authors":"Margaret L Kruithoff, Benjamin J Gigliotti","doi":"10.1016/j.eprac.2025.06.010","DOIUrl":"10.1016/j.eprac.2025.06.010","url":null,"abstract":"<p><strong>Introduction: </strong>Myxedema coma and thyroid storm are rare thyroid emergencies associated with considerable mortality and morbidity.</p><p><strong>Results: </strong>Myxedema coma is a state of decompensated hypothyroidism with widespread multi-organ dysfunction, including impaired consciousness, mixed respiratory failure, and hypothermia. Thyroid storm is the extreme state of thyrotoxicosis occurring when a patient's metabolic, thermoregulatory, and cardiovascular compensatory mechanisms are surpassed; clinical features include hyperthermia, neuropsychiatric symptoms, and tachyarrhythmias. Thyroid emergencies usually result from a precipitating event or trigger transforming a previously compensated hypothyroid or thyrotoxic state. Supportive care for the cardiovascular, respiratory, and thermoregulatory manifestations, as well as possible intercurrent illness or adrenal insufficiency, plays a lead role in the management. For myxedema coma, treatment typically includes high-dose levothyroxine with the addition of liothyronine for critically ill patients. Management of thyroid storm is multipronged and stepwise, consisting of first-line thionamide and beta-adrenergic receptor antagonist therapy, followed by inorganic iodine, cholestyramine, plasmapheresis, or emergent thyroidectomy in appropriate severely ill patients.</p><p><strong>Conclusions: </strong>This review provides an updated narrative overview of the diagnosis and management of myxedema coma and thyroid storm.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483668","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":"Thyroid Eye Disease: Management, Advances, and Future Opportunities.","authors":"Tamaryn Fox, Andrea Lora Kossler, Chrysoula Dosiou","doi":"10.1016/j.eprac.2025.06.011","DOIUrl":"10.1016/j.eprac.2025.06.011","url":null,"abstract":"<p><p>Thyroid eye disease (TED), the most common extrathyroidal manifestation of Graves disease, is a debilitating autoimmune condition that significantly impacts quality of life and can threaten vision. This review highlights advances in the understanding of TED, particularly in pathophysiology, emerging treatments, novel surgical techniques, and the use of imaging and artificial intelligence (AI). Teprotumumab, the first Food and Drug Administration-approved drug for TED, has shown effectiveness in reducing proptosis, improving diplopia, and enhancing quality of life. Other therapies in development include alternative insulin-like growth factor-1 receptor antagonists, FcRn inhibitors, interleukin pathway antagonists, and thyroid-stimulating hormone receptor inhibitors, all of which offer promising potential. Surgical approaches, such as orbital decompression and eyelid correction, have also evolved, with minimally invasive techniques gaining favor. Diagnostic advancements in biomarkers could further enhance early detection and disease monitoring. AI tools for assessing disease severity and predicting treatment outcomes are also emerging. Despite significant progress in molecular understanding and treatment options, TED remains complex and continued research is essential to improve diagnostic precision and therapeutic outcomes.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483669","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 Pituitary Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.","authors":"Zhe Li, Ziang Liu, Hongxia Wei, Shuqing Jin, Yuchen Sun, Yi Zhang, Yunfeng Liu","doi":"10.1016/j.eprac.2025.06.008","DOIUrl":"10.1016/j.eprac.2025.06.008","url":null,"abstract":"<p><strong>Objectives: </strong>Immune checkpoint inhibitor (ICI)-induced hypophysitis is one of the common endocrine immune-related adverse events (irAEs). Our goal is to evaluate the risk of pituitary irAEs caused by ICIs.</p><p><strong>Methods: </strong>The relevant literatures were retrieved from PubMed, Embase, and Cochrane Library from inception to October 31, 2024. References were screened according to inclusion and exclusion criteria, and study data were extracted. Meta-analysis was performed using Revman 5.3 and Stata 18.0 software.</p><p><strong>Results: </strong>A total of 21 prospective single-arm trials and 17 randomized controlled trials (RCTs) were included. In single-arm trials, the incidence of hypophysitis (4.00%) and hypopituitarism (3.84%) caused by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors was the highest in monotherapy, and the incidence of hypophysitis caused by programmed cell death 1 (PD-1) inhibitors plus CTLA-4 inhibitors was the highest in ICI combination therapy (9.36%). In RCTs, the risk of pituitary irAEs caused by ICIs was higher than that of the control group (relative risk = 10.09, 95% CI: 6.90-14.75). Compared with monotherapy, ICI combination therapy has a higher risk of pituitary irAEs (relative risk = 5.42, 95% CI: 3.36-8.73). In monotherapy, CTLA-4 inhibitors caused the highest incidence of hypophysitis and hypopituitarism, reaching 16.17% and 1.75%, respectively. Furthermore, the severity of adverse pituitary irAEs caused by CTLA-4 inhibitors was also the highest (5.12% in single-arm trials, 16.35% in RCTs).</p><p><strong>Conclusions: </strong>The results showed that ICIs are associated with a significantly higher risk of pituitary irAEs, and ICI combination may further increase the risk. In monotherapy, CTLA-4 inhibitors caused the highest incidence and severity of pituitary irAEs, while PD-L1 inhibitors caused the lowest. In combination therapy, PD-1 inhibitors combined with CTLA-4 inhibitors resulted in a higher incidence of hypophysitis.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324817","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":"Consensus Thyroid Nodule Radiofrequency Ablation Reporting Guidelines Established Using a Delphi Approach.","authors":"Kendyl Carlisle, Rebecca Kowalski, Qing Lina Hu-Bianco, Sophie Y Dream, Jonathon O Russell, Steven P Hodak, Jennifer H Kuo, Yinin Hu","doi":"10.1016/j.eprac.2025.06.006","DOIUrl":"10.1016/j.eprac.2025.06.006","url":null,"abstract":"<p><strong>Objectives: </strong>Radiofrequency ablation (RFA) has become increasingly utilized for thyroid nodules. However, best practice recommendations on data collection and outcomes reporting are lacking. The objective of this study was to generate consensus guidelines for thyroid RFA data collection for purposes of quality assurance and collaborative research.</p><p><strong>Methods: </strong>We recruited a multidisciplinary panel of experienced RFA practitioners through the North American Society for Interventional Thyroidology. Using a modified Delphi process, experts created and iteratively revised a data collection form encompassing items from the pre-, intra-, and postprocedural phases. Emphasis was placed on parameters that are readily available to both community and academic-based practitioners. Items with > 70% (strongly-agree) or 100% (agree) consensus for inclusion were retained. The Delphi process and the final reporting instrument were built on REDCap.</p><p><strong>Results: </strong>Ten panelists from 9 institutions performing a median of 22.5 cases/year completed 5 Delphi rounds. All panelists voted strongly-agree for retention on 63% (n = 37) of included items. The final instrument was divided into 3 forms: 1. Preprocedure (n = 18 items), 2. Immediate postprocedure (n = 9 items), and 3. Follow-up (n = 10 items).</p><p><strong>Conclusions: </strong>Adoption of these 3 new thyroid RFA data collection forms by new and established interventionalists may facilitate collaboration, standardized outcomes reporting, and clinical trial design.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324816","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 Future of Automated Insulin Delivery Systems.","authors":"Michael S Hughes, Carol J Levy","doi":"10.1016/j.eprac.2025.05.752","DOIUrl":"10.1016/j.eprac.2025.05.752","url":null,"abstract":"<p><p>Automated insulin delivery (AID) systems have revolutionized diabetes care by integrating continuous glucose monitoring, insulin pumps, and advanced algorithms to improve glycemic outcomes and reduce user burden. Early commercial AID systems were developed with a conservative approach, prioritizing safety and regulatory approval over full automation or extensive customization. While these systems significantly improved diabetes management, they still face limitations, including incomplete automation, accessibility barriers, and the need for better adaptation to diverse user needs and lifestyles. These challenges are now catalyzing development of next-generation AID technologies with a focus on achieving full automation, greater personalization, and broader accessibility. This review examines key limitations of current AID systems and explores future directions, including fully closed-loop control, novel insulin formulations, multi-hormonal systems, advanced sensor technologies, and integration of wearable and artificial intelligence tools. By addressing these challenges, future AID systems have the potential to deliver better effectiveness and equity in diabetes care for all individuals requiring insulin therapy.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324818","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":"Dental Implant Failure and Medication-Related Osteonecrosis of the Jaw Related to Dental Implants in Patients Taking Antiresorptive Therapy for Osteoporosis: A Systematic Review and Meta-Analysis.","authors":"Reza Mirza, Mohamed El Rabbany, Dalal S Ali, Sotirios Tetradis, Archibald Morrison, Salvatore Ruggiero, Rasha Alnajimi, Aliya A Khan, Gordon Guyatt","doi":"10.1016/j.eprac.2025.06.003","DOIUrl":"10.1016/j.eprac.2025.06.003","url":null,"abstract":"<p><strong>Objectives: </strong>To inform the 2024 International Task Force on Osteonecrosis of the Jaw update, we conducted a systematic review and meta-analysis evaluating dental implant failure and medication-related osteonecrosis of the jaw (MRONJ) related to antiresorptive therapy for osteoporosis.</p><p><strong>Methods: </strong>We searched 5 databases (1946-2024) for interventional and noninterventional studies reporting rates of dental implant failure or osteonecrosis in those with osteoporosis or osteopenia. Two reviewers independently screened all titles, abstracts, and full texts. Risk of bias was assessed using the modified Ottawa-Newcastle scale, and the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.</p><p><strong>Results: </strong>We found 793 unique citations. Nine studies (n = 655) were included in the implant failure analysis. Random-effects meta-analysis revealed wide confidence intervals (CIs) for implant failure among those exposed to antiresorptives (relative risk, 0.82; 95% CI, 0.52-1.28; P = .38, very low certainty). Sensitivity analysis at the level of implant suggested that antiresorptives reduce implant failure (relative risk, 0.53; 95% CI, 0.34-0.81; P = .003, very low certainty). We identified 186 cases of MRONJ in implant recipients. The pooled rate of MRONJ following implantation in those exposed to antiresorptive therapy was 0.5% pooled from 21 cohorts. A single report of risk-adjusted MRONJ found that bisphosphonates increased MRONJ by 3 cases per 1000 patients (adjusted hazard ratio, 4.09; 95% CI, 2.75-6.09; P < .001, moderate certainty).</p><p><strong>Conclusions: </strong>The low-certainty evidence suggests that antiresorptive therapy for osteoporosis reduces dental implant failure. Bisphosphonates are associated with MRONJ in patients with osteoporosis receiving dental implants with moderate certainty.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144283020","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 Evolution of Our Understanding of the Nuances of Pathologic Cortisol Secretion.","authors":"Lewis S Blevins","doi":"10.1016/j.eprac.2025.06.002","DOIUrl":"10.1016/j.eprac.2025.06.002","url":null,"abstract":"<p><p>Over a century has passed since Harvey Cushing reported and described the findings in his patient that led to his name being ascribed to the clinical syndrome we call Cushing syndrome. Decades of study have led to a greater understanding of the nuances of cortisol secretion associated with the various conditions that result in either relative or overt hypercortisolism. Referencing \"Cushing syndrome,\" and failing to recognize the subtle presentations of disordered cortisol secretion, leads to delays in diagnosis and treatment and excess morbidity in affected patients.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144283021","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":"A Review of Real-World Evidence About the Use of Automated Insulin Delivery Systems in People With Type 1 Diabetes.","authors":"Sonia Gera, Jaisree Iyer, Seema Meighan, Christine A March, Brynn E Marks","doi":"10.1016/j.eprac.2025.06.004","DOIUrl":"10.1016/j.eprac.2025.06.004","url":null,"abstract":"<p><strong>Introduction: </strong>Automated insulin delivery systems (AID) have revolutionized type 1 diabetes (T1D) management. Guidelines support offering AID to all people with T1D and engaging in shared decision making when choosing among the available AID systems.</p><p><strong>Results: </strong>In clinical trials, AID has been shown to improve glycemic control and reduce hypoglycemia while also improving quality of life. However, participants in clinical trials do not accurately reflect the entire T1D population and outcomes from these controlled may not generalize to clinical care. A growing body of real-world evidence seeks to understand the effect of AID systems on glycemia and person-reported outcome measures in real-world populations. These real-world studies highlight the effect of differences in engagement with AID, including time in automated mode and boluses per day, considerations about AID system selection, and approaches to educate people with T1D.</p><p><strong>Conclusion: </strong>In this review, we compare glycemic and person reported outcomes in clinical trials and the real-world studies, with consideration of the effects of different systems according to user characteristics. We also review the current state of device selection and education for people with diabetes, their caregivers, and clinicians. Lastly, we summarize key findings across AID systems and opportunities for further research.</p>","PeriodicalId":11682,"journal":{"name":"Endocrine Practice","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144283019","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}