Journal of Cardiovascular Pharmacology最新文献

{"title":"Dihydrotestosterone Pretreatment Diminishes the Severity of Drug-Induced Torsades de Pointes.","authors":"James E Tisdale, Heather A Jaynes, Brian R Overholser, Kevin M Sowinski, Richard J Kovacs","doi":"10.1097/FJC.0000000000001716","DOIUrl":"https://doi.org/10.1097/FJC.0000000000001716","url":null,"abstract":"<p><p>Testosterone and dihydrotestosterone (DHT) attenuate drug-induced lengthening of ventricular repolarization, but it is unknown whether they influence drug-induced torsades de pointes (TdP). We tested the hypothesis that DHT reduces the incidence and severity of drug-induced TdP. Male New Zealand white rabbits underwent orchiectomy and were implanted with two subcutaneous sustained-release pellets containing DHT 50 mg (100 mg, n=23) or placebo (n=20). After 7 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Dofetilide 100 nM was perfused for 30 minutes. Median (Q1, Q3) serum DHT concentrations were higher in DHT-treated rabbits [314.0 (232.5, 388.6) versus 32.5 (28.5, 36.2) ng/dL, p<0.0001]. The incidence of TdP in the DHT and placebo groups was 6/23 (26%) versus 8/20 (40%), respectively (p=0.33). In hearts that developed TdP, the median (Q1, Q3) number of episodes was lower in the DHT group [2 (2, 3.5) versus 18.5 (12.5, 20.5), p=0.01]. The median time to first TdP episode was longer [18.5 (17.3, 21.3) versus 10.5 (12.5, 20.5) minutes, p=0.01] and the TdP burden (median total number of TdP beats per heart) was lower in the DHT group [11.5 (9.5-46.5) versus 271 (99.3-440.3) beats, p=0.007]. Pre-dofetilide Fridericia-corrected QT (QTF) intervals were shorter in the DHT group [377 (366, 390) vs 385 (378, 401) ms, p=0.02]. Maximum QTF interval during dofetilide perfusion was shorter in the DHT group [399 (390, 410) vs 414 (399, 442) ms, p=0.007]. In conclusion, DHT diminishes the severity of dofetilide-induced TdP.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylphenidate and high intensity interval training alone and in combination ameliorate the tramadol- induced cardiac side effects in male rats: the role of oxidative stress and mitochondria function.","authors":"Gholamreza Sepehri, Sara Shirazpour, Farzaneh Rostamzadeh, Homa Jafari, Maryam Iranpour","doi":"10.1097/FJC.0000000000001715","DOIUrl":"https://doi.org/10.1097/FJC.0000000000001715","url":null,"abstract":"<p><p>Tramadol, a widely prescribed analgesic for moderate to severe pain, is associated with significant cardiovascular risks. This study investigated the effects of high-intensity interval training (HIIT), methylphenidate (MPH), and their combination on oxidative stress and mitochondrial quality in the hearts of male Wistar rats subjected to long-term tramadol treatment. Experimental groups included control (CTL), MPH, tramadol (TR), HIIT, MPH+HIIT, TR+HIIT, and MPH+TR+HIIT. Rats underwent HIIT; 5 days per week for 8 weeks. Real-time PCR was used to quantify MFN-2, DRP-1, PINK-1, and Parkin mRNA levels. Superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities, and malondialdehyde (MDA) levels were measured using colorimetry. Histopathological evaluations were assessed for cardiac damage and fibrosis by H&E and Masson's trichrome staining. Tramadol significantly decreased SOD and GPX activities and increased MDA levels compared with the CTL group. Both HIIT and MPH, either alone or in combination, were associated with a significant increase in SOD and GPX and a reduction of MDA levels. Both HIIT and MPH partially repaired the tramadol-induced changes in mRNA expression of DRP-1, and PINK-1. In addition, HIIT, MPH, and their combination significantly reversed histopathological changes associated with long-term tramadol use. These findings suggested that tramadol administration associated with a significant increase in oxidative stress parameters and cardiac damage in heart tissues of rats, which could be ameliorated by HIIT, MPH alone, or their combination.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relaxant effect of menthol on the pudendal artery and corpus cavernosum of lean and db/db mice: A refreshing approach to diabetes-associated erectile dysfunction.","authors":"Fênix Alexandra de Araujo, Raiana Anjos Moraes, Liliane Barreto da Silva, Rafael Leonne Cruz de Jesus, Laena Pernomian, Tiago Januário Costa, Camilla F Wenceslau, Fernanda Priviero, R Clinton Webb, Cameron G McCarthy, Darízy Flávia Silva","doi":"10.1097/FJC.0000000000001709","DOIUrl":"https://doi.org/10.1097/FJC.0000000000001709","url":null,"abstract":"<p><strong>Abstract: </strong>Erectile dysfunction is one of the most underestimated complications of diabetes. Menthol, known for its cooling sensation, is commonly featured in products that claim to enhance sexual performance, yet its effects on penile vasculature lack scientific validation. This study aimed to evaluate whether menthol induces relaxation in the corpus cavernosum and pudendal arteries isolated from diabetic mice. Male lean and db/db mice (20-24 weeks old) were used. Assessments included murinometric data, histology, confocal microscopy to evaluate arterial structure, DHE staining for reactive oxygen species (ROS), immunofluorescence, and Western blotting for TRPM8 expression. The isometric force was measured on a wire myograph (pudendal artery) or organ bath (corpus cavernosum). Our results demonstrated that menthol induced a similar relaxation in pudendal arteries from db/db and lean, although it had a reduced effect in the corpus cavernosum from db/db. The db/db exhibited distinct structural and functional phenotypes characterized by increased fibrosis, ROS levels in the corpus cavernosum, and reduced relaxation to acetylcholine and sildenafil in pudendal arteries. TRPM8 was expressed but it seems not to be the exclusive target for menthol-induced relaxation in the corpus cavernosum of lean mice and in the pudendal arteries of both groups. Furthermore, menthol pre-exposure decreased the efficacy of phenylephrine in pudendal arteries from both groups and in the corpus cavernosum of lean mice, without affecting the potency or efficacy of acetylcholine. These findings suggest that menthol-induced relaxation and reduction of phenylephrine efficacy may hold promise for decreasing penile vascular resistance and enhancing blood flow to the penis.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Invited Article: Al guided Dual Antiplatelet Therapy and Anticoagulation.","authors":"Nicholas Huerta, Shaikh B Iqbal, Shiavax J Rao, Ameesh Isath, Benjamin S Glicksberg, Chayakrit Krittanawong","doi":"10.1097/FJC.0000000000001710","DOIUrl":"https://doi.org/10.1097/FJC.0000000000001710","url":null,"abstract":"<p><p>Artificial intelligence (AI) has emerged as a transformative tool in healthcare through data analysis, pattern recognition and predictive modeling capabilities. AI-driven approaches have the potential to positively transform patient care through personalized treatment regimens comprising antiplatelet and anticoagulant therapy. This review explores the integration of AI in guiding antithrombotic therapies, highlighting the potential to improve patient outcomes through personalized medicine. Following a rigorous screening process, a total of 15 studies from the PubMed database were included in the review. We further explore studies investigating the role of Al in anticoagulation choices for acute coronary syndrome, during PCI and for long-term treatment. We also explore studies of antiplatelet agent selection and duration, as well as AI-guided platelet function testing and genotyping. The few studies that exist have demonstrated the integration of AI into antiplatelet and anticoagulation therapy holds substantial promise for enhancing patient-specific treatment strategies in cardiovascular care. AI can provide predictive insights that could surpass less objective traditional approaches in accuracy and personalization. Furthermore, the development of AI-driven tools for therapy duration assessment, genetic testing, and mobile applications for patient monitoring underscores AI's role in supporting real-time clinical decision-making and improving patient adherence. Future studies will be crucial in order to address the current limitations in applicability and validate these AI systems with respect to patient centered outcomes.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the Role of In-hospital Bleeding in Acute Coronary Syndromes.","authors":"Felice Gragnano, Paolo Calabrò, Dominick J Angiolillo","doi":"10.1097/FJC.0000000000001685","DOIUrl":"10.1097/FJC.0000000000001685","url":null,"abstract":"","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"319-321"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Different Doses of Dexmedetomidine on Atrial Fibrillation in Adults After Cardiac Surgery.","authors":"Xinling Zhang, Jian Liu, Yafei Shi, Huirong Wang, Fei Wang, Wenzhu Wang","doi":"10.1097/FJC.0000000000001674","DOIUrl":"10.1097/FJC.0000000000001674","url":null,"abstract":"<p><strong>Abstract: </strong>In this study, we compared the effects of various doses of dexmedetomidine on the incidence of atrial fibrillation (AF) after cardiac surgery in adults. A total of 224 adult patients who underwent elective cardiac surgery were randomly assigned to two groups. The DEX0.5 group received a continuous infusion of dexmedetomidine at a rate of 0.5 μg·kg⁻ 1 ·h⁻ 1 , while the DEX1 group received it at a rate of 1 μg·kg⁻ 1 ·h⁻ 1 during the induction of anesthesia, which was maintained for 24 hours. The primary outcome was the incidence of AF, while the secondary outcomes included other tachyarrhythmias, bradycardia, hypotension, duration of mechanical ventilation, time spent in the cardiac care unit, and length of hospitalization. A total of 101 patients were included in the DEX0.5 group, while 104 patients were included in the DEX1 group. The incidence of AF was significantly lower in the DEX1 group compared with the DEX0.5 group (10.6% vs. 21.8%, P = 0.029). In addition, the duration of mechanical ventilation was shorter in the DEX1 group than in the DEX0.5 group (8.9 vs. 15.2 hours, P = 0.018). Logistic regression analyses were conducted to investigate the factors influencing AF. The results indicated that the dose of dexmedetomidine was the only independent predictor (odds ratio = 0.394, 95% confidence interval 0.172 to 0.903, P = 0.028). Compared with a continuous infusion of 0.5 μg·kg⁻ 1 ·h⁻ 1 , this study suggested that administering dexmedetomidine at a dose of 1 μg·kg⁻ 1 ·h⁻ 1 for 24 hours is effective in reducing the incidence of AF after cardiac surgery.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"350-357"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of In-Hospital Bleeding on Postdischarge Therapies and Prognosis in Acute Coronary Syndromes.","authors":"Luigi Spadafora, Matteo Betti, Fabrizio D'Ascenzo, Gaetano De Ferrari, Ovidio De Filippo, Carlo Gaudio, Carlos Collet, Pierre Sabouret, Pierfrancesco Agostoni, Carlo Zivelonghi, Bianca Pernice, Gianmarco Sarto, Beatrice Simeone, Erica Rocco, Federico Russo, Salvatore Giordano, Nicola Pierucci, Alberto Testa, Stefano Cacciatore, Giuseppe Biondi-Zoccai, Marco Bernardi","doi":"10.1097/FJC.0000000000001678","DOIUrl":"10.1097/FJC.0000000000001678","url":null,"abstract":"<p><strong>Abstract: </strong>Acute coronary syndromes (ACS) continue to pose significant challenges for clinical practitioners, particularly regarding the prediction of mid- to long-term outcomes. This study aims to investigate the impact of in-hospital bleeding (IHB) at 1-year follow-up in patients admitted for ACS. Data from 23,270 patients enrolled in the international PRAISE registry and discharged after ACS were analyzed. A total of 1060 patients experienced IHB, whereas 18,765 did not; 3445 were excluded because of missing data. The primary endpoint was all-cause mortality at 1 year. Secondary endpoints included major bleeding, reinfarction, and composite endpoints at 1 year. Patients with IHB were older, more frequently female, and had a higher prevalence of cardiovascular risk factors (all P < 0.05). At discharge, IHB patients were less likely to receive optimal medical therapy. At the 1-year follow-up, all-cause mortality, major bleeding, and reinfarction were significantly higher in the IHB group (all P s < 0.001). Bivariate analysis showed a strong association between IHB and all the outcomes of interest (all odds ratios >1; all P s < 0.001). These associations remained significant even after adjusting for several covariates, except for reinfarction (odds ratio 1.3; 95% confidence interval 0.9-2.11; P = 0.149). Age, female sex, hypertension, and peripheral artery disease were found to be independent predictors of IHB, whereas drug-eluting stent implantation, radial access, and left ventricular ejection fraction were identified as protective factors. IHB is a hallmark of frailty in patients with ACS; therefore, greater attention should be given during follow-up to patients experiencing this condition.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"322-328"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac Immunotherapy, Immuno-Cardiology, and the Future of Cardiovascular Pharmacology.","authors":"Giuseppe Biondi-Zoccai, Brittany N Weber, Antonio Abbate, George W Booz","doi":"10.1097/FJC.0000000000001687","DOIUrl":"10.1097/FJC.0000000000001687","url":null,"abstract":"<p><strong>Abstract: </strong>Immuno-cardiology is an emerging field that explores the interplay between the immune system, inflammation, and cardiovascular health/disease, aiming to develop innovative therapies for preventing and treating cardiac diseases. Indeed, chronic inflammation and immune dysregulation play pivotal roles in most cardiovascular conditions, including arrhythmias, atherothrombosis, ischemic heart disease, heart failure, and valve disease. Recent advances in immune-based therapies, including chimeric antigen receptor-T and chimeric antigen receptor-macrophage technologies, have demonstrated potential in impacting on cardiac fibrosis and thus improving surrogate end points in preclinical studies. Immune checkpoint inhibitors, while already established as an effective intervention in oncology, present challenges in their cardiovascular applications because of cardiotoxic side effects, highlighting the need for dedicated cardioprotective strategies or further molecular refinements. Nanoparticle-based delivery systems and cytokine-targeted therapies may offer precise modulation of immune responses, while gut microbiota interventions could exploit the systemic impact of inflammation on cardiovascular health. Despite these quite promising advances, barriers such as safety, scalability, and patient-specific responses must be addressed, and thus precision and personalized approaches will be crucial to overcoming these challenges and ensuring safe and also equitable access. By leveraging interdisciplinary collaboration and technological innovations, immuno-cardiology holds the promise of transforming the prevention and treatment landscape for cardiac diseases, paving the way for improved outcomes and quality of life for patients worldwide.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"308-311"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12138625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decastatin, a Novel Non-Collagenous 1 Domain From Collagen Type X, Harbors a Specific Fragment With Antiangiogenic Properties.","authors":"Stine Marie Jansen, Rastislav Pitek, Morten Asser Karsdal, Kim Henriksen","doi":"10.1097/FJC.0000000000001683","DOIUrl":"10.1097/FJC.0000000000001683","url":null,"abstract":"<p><strong>Abstract: </strong>The NC1 domains of collagens have been shown to possess antiangiogenic potential and, therefore, are of therapeutic interest for cancer. However, endostatin and other NC1 domains have not been successful in clinical tests. Therefore, we used evolutionary conservation to perform molecular deconstruction of the domains to further understand their structure-activity relationship, thereby deciphering their antiangiogenic potential. Homology exploration revealed that collagen type X contains a highly interesting NC1 domain (decastatin), with several sequences showing significant homology with vastatin, which is a known collagen type VIII-derived NC1 domain. For comparison, endostatin and vastatin were split into fragments, some of which contained highly conserved regions. The testing of these peptides revealed that the peptides containing conserved regions induced signaling, and fragment 4 of decastatin showed the highest potency of all fragments, with a calculated inhibitory concentration value of 2.7 μM in the human umbilical vein endothelial cell-based tube formation assay, which is like that of an intact NC1 domain. Notably, the corresponding fragment from vastatin (V4) also inhibited tube formation, suggesting that this region is of therapeutic interest. In summary, we used evolutionary conservation to identify a novel NC1 domain of collagen type X, a collagen playing a role in angiogenesis of the growth plate. Furthermore, we provided data indicating that the antiangiogenic activity of NC1 domain-derived peptides reside within their conserved domains. As a result, we identified a fragment called Decastatin fragment 4 (D4) derived from the NC1 domain of collagen type X, and which has potent antiangiogenic activity.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"369-380"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Game Changer for Resistant Hypertension: The Rise of Aprocitentan.","authors":"Ali H Eid","doi":"10.1097/FJC.0000000000001679","DOIUrl":"10.1097/FJC.0000000000001679","url":null,"abstract":"<p><strong>Abstract: </strong>Hypertension is a major risk factor for cardiovascular disease, and a major contributor to global morbidity and mortality. In particular, resistant hypertension (rHTN), defined as blood pressure that remains elevated despite treatment with at least three antihypertensive agents including a diuretic, continues to be a major pharmacotherapeutic challenge. Traditional antihypertensive drugs often fail in patients with rHTN, underscoring the need for novel therapies. This is a brief mini-review of aprocitentan, a new drug that promises a glimmer of hope for patients with rHTN. This drug is a dual endothelin (ET) receptor antagonist that blocks both ET A and ET B receptors. Given that these two receptors are critical players in vasotone regulation, antagonizing them, such as by aprocitentan, would be expected to significantly reduce blood pressure in patients with rHTN. Indeed, the PRECISION clinical trial demonstrated aprocitentan's superior effectiveness in reducing blood pressure in resistant patients, and the effects were sustained. Aprocitentan has been recently FDA-approved, marking a major milestone in hypertension management, offering hope for patients with difficult-to-treat hypertension.</p>","PeriodicalId":15212,"journal":{"name":"Journal of Cardiovascular Pharmacology","volume":" ","pages":"312-315"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}