BioDrugs最新文献

{"title":"Use of Semaglutide (Wegovy) in Adults in France: A Nationwide Drug Utilization Study.","authors":"Nadia Haddy, Hugo Jourdain, David Desplas, Marion Bertrand, Marie-Joelle Jabagi, Claire Rives-Lange, Mahmoud Zureik","doi":"10.1007/s40259-024-00699-6","DOIUrl":"10.1007/s40259-024-00699-6","url":null,"abstract":"<p><strong>Background: </strong>Glucagon-like peptide 1 receptor agonists have shown promising results in obesity treatment. In France, semaglutide 2.4-mg (Wegovy) has benefited from an early-access program from July 2022 to September 2023.</p><p><strong>Objective: </strong>This study aimed to describe the user profile of semaglutide 2.4-mg and the dosage patterns under real-world conditions during this period.</p><p><strong>Methods: </strong>Between July 2022 and September 2023, semaglutide 2.4-mg initiators were identified through the nationwide APMO database (Accès Précoce-Médicaments Onéreux), built from the French National Health Data System (SNDS). The cohort was followed up until 31 December 2023. A sequence analysis was used to build clusters of dose escalation regimens.</p><p><strong>Results: </strong>Among the 6990 adult patients who started treatment, the median age was 49.0 years, with a majority of women (65.8%). The study revealed significant regional variations in initiation rates, with the highest in Ile-de-France (including Paris). Three groups of users were identified: standard adherence (74.5%), early discontinuation (13.0%), and high-dose initiation (12.5%). Factors influencing these clusters included age, with younger patients (25-34 years) more likely to discontinue early (odds ratio: 1.35 [95% confidence interval 1.05-1.75]). The use of anti-emetics during the first 5 months of the follow-up period was higher in the early-discontinuation group (15.7%) compared with the high-dose initiation group (9.0%) and standard adherence group (12.3%).</p><p><strong>Conclusions: </strong>This study involved a substantial number of real-life semaglutide 2.4-mg users and highlights the importance of monitoring treated patients from a public health perspective, given the broad prescription to come and the potential risks associated with misuse.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"321-332"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New and Emerging Biological Therapies for Myasthenia Gravis: A Focussed Review for Clinical Decision-Making.","authors":"Lea Gerischer, Paolo Doksani, Sarah Hoffmann, Andreas Meisel","doi":"10.1007/s40259-024-00701-1","DOIUrl":"10.1007/s40259-024-00701-1","url":null,"abstract":"<p><p>Myasthenia gravis (MG) is a rare autoimmune disease characterised by exertion-induced muscle weakness that can lead to potentially life-threatening myasthenic crises. Detectable antibodies are directed against specific postsynaptic structures of the neuromuscular junction. MG is a chronic condition that can be improved through therapies, but to date, not cured. Standard treatment has been unchanged for decades and includes symptomatic treatment with acetylcholine-esterase inhibitors and disease-modifying treatment with steroids, steroid-sparing immunosuppressants and thymectomy. Overall, a relevant proportion of patients does not achieve a satisfactory clinical improvement under standard treatment. Additionally, long-term therapy with steroids can cause significant side effects and latency to clinical improvement with standard steroid-sparing immunosuppressants and after thymectomy can take months to years. In recent years, treatment of MG has changed fundamentally due to improved evidence from phase 3 trials and the regulatory approval of complement inhibitors and FcRn inhibitors as add-on treatment options. This provides new optimism for substantially more patients reaching minimal manifestation status and has led to a shift in treatment strategy with more targeted therapies being employed early in the course of the disease, especially in patients with high disease activity. In this focussed review, we provide an overview of the diagnosis, classification and standard treatment of MG, followed by data from randomised controlled trials on the modern drugs already available for therapy and those still in the final stages of clinical development. In the second part, we provide an overview of real-world data for already approved therapies and outline how the availability of new biologicals is changing both clinical decision-making and patient journey.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"185-213"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Automated Tool for Glycosimilarity Assessment of mAb Therapeutic Biosimilars: Trastuzumab and Bevacizumab as Case Studies.","authors":"Anuj Shrivastava, Sanjeet S Patil, Rohan Shah, Anurag S Rathore","doi":"10.1007/s40259-025-00704-6","DOIUrl":"10.1007/s40259-025-00704-6","url":null,"abstract":"<p><strong>Background: </strong>With the expiration of patents for multiple biotherapeutics, biosimilars are gaining traction globally as cost-effective alternatives to the original products. Glycosylation, a critical quality attribute, makes glycosimilarity assessment pivotal for biosimilar development. Given the complexity of glycoanalytical profiles, assessing glycosimilarity is nontrivial.</p><p><strong>Objective: </strong>This study proposes a Python-based automated tool for rapid estimation of glycosimilarity index (GI).</p><p><strong>Materials and methods: </strong>A comprehensive analytical glycosimilarity comparison of the trastuzumab originator product, Herclon (Roche), with five marketed biosimilars:Trasturel (Reliance Life Sciences), Canmab (Biocon), Vivitra (Zydus Ingenia), Hertraz (Mylan), and Biceltis (Cipla), has been performed. Similarly, a comparison between the bevacizumab originator product, Avastin (Roche), and its five biosimilars: Abevmy (Mylan), Krabeva (Biocon), Ivzumab (RPG LifeSciences), Bryxta (Zydus), and Advamab (Alkem Labs), is presented. Glycan profile  has been assessed using liquid chromatography-fluorescence detection, and the  data have been integrated using the XGBoost-machine learning algorithm to quantify glycan composition. The GI has been calculated by combining profile similarity and compositional similarity, estimated on the basis of the criticality and tolerance of each glycan.</p><p><strong>Results: </strong>The tool enabled rapid GI estimation (< 1 min/sample) with reduced errors compared with Excel (> 10 min/sample). Biosimilars exhibited high GI with several exceeding 95%, while the lowest GI observed were 87.80% for trastuzumab and 92.39% for bevacizumab.</p><p><strong>Conclusions: </strong>The Python-based tool offers a high-throughput and a reliable platform for glycosimilarity assessment, outperforming traditional analysis. Minor variations in glycosylation patterns were observed among the biosimilars, suggesting a modest glycosimilarity variation (GI range between 80 and 100%). However, the limited number of innovator batches analyzed constrained the establishment of definitive tolerance limits. Future studies should focus on analyzing larger datasets to improve accuracy and define precise tolerance limits, enhancing the tool's reliability and its potential to accelerate biosimilar development.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"333-345"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Path to Accessible Care: Development and Impact of Eculizumab Biosimilars for Paroxysmal Nocturnal Hemoglobinuria and Atypical Hemolytic Uremic Syndrome.","authors":"Jun Ho Jang, Bing Han, Jinah Jung, Paola Russo, Austin G Kulasekararaj","doi":"10.1007/s40259-025-00707-3","DOIUrl":"10.1007/s40259-025-00707-3","url":null,"abstract":"<p><p>Eculizumab, a humanized monoclonal antibody targeting complement C5, is the first approved drug for complement-mediated diseases and indicated to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorder. The introduction of eculizumab has improved the prognosis of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to near-normal life expectancy and quality of life. Administration of eculizumab resulted in a rapid and sustained reduction in hemolytic activity and a consequent risk of thrombosis in paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy in atypical hemolytic uremic syndrome, respectively. Nevertheless, many patients still have difficulty accessing eculizumab treatment because of its high costs. Biosimilars to reference eculizumab may increase patient access to treatment by creating market competition and eventually decreasing treatment costs. Clinical use of biosimilars in Europe in the last 15 years has demonstrated that they are as safe and effective as their reference products, and can also drive cost reductions and increase patients' access to treatment. This review aims to increase awareness about the importance of biosimilars of reference eculizumab and their entry for use in patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome based on the accumulated experience of other previously approved biosimilars, and to provide an overview of the stringent biosimilar development pathway in general and the concept of extrapolation in particular.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"281-295"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Islet Cell Replacement and Regeneration for Type 1 Diabetes: Current Developments and Future Prospects.","authors":"Arthur Rech Tondin, Giacomo Lanzoni","doi":"10.1007/s40259-025-00703-7","DOIUrl":"10.1007/s40259-025-00703-7","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas, leading to insulin deficiency and chronic hyperglycemia. The main current therapeutic strategies for clinically overt T1D - primarily exogenous insulin administration combined with blood glucose monitoring - fail to fully mimic physiological insulin regulation, often resulting in suboptimal or insufficient glycemic control. Islet cell transplantation has emerged as a promising avenue for functionally replacing endogenous insulin production and achieving long-term glycemic stability. Here, we provide an overview of current islet replacement strategies, ranging from islet transplantation to stem cell-derived islet cell transplantation, and highlight emerging approaches such as immunoengineering. We examine the advancements in immunosuppressive protocols to enhance graft survival, innovative encapsulation, and immunomodulation techniques to protect transplanted islets, and the ongoing challenges in achieving durable and functional islet integration. Additionally, we discuss the latest clinical outcomes, the potential of gene editing technologies, and the emerging strategies for islet cell regeneration. This review aims to highlight the potential of these approaches to transform the management of T1D and improve the quality of life of individuals affected by this condition.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"261-280"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TL1A Inhibition in Inflammatory Bowel Disease: A Pipeline Review.","authors":"Virginia Solitano, Maria Manuela Estevinho, Federica Ungaro, Fernando Magro, Silvio Danese, Vipul Jairath","doi":"10.1007/s40259-025-00706-4","DOIUrl":"10.1007/s40259-025-00706-4","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), remains challenging to manage, with a substantial proportion of patients not responding to conventional therapies or developing complications. The tumor necrosis factor (TNF) superfamily member TL1A has emerged as an important player in the pathogenesis of IBD, influencing pathways of inflammation and fibrosis. This leading article reviews the role of TL1A in IBD, evaluates the efficacy of anti-TL1A therapies in clinical trials, and discusses future directions for research and treatment. TL1A is implicated in IBD through its interaction with death domain receptor 3 (DR3), promoting T-cell activation and contributing to both inflammatory responses and fibrotic changes. Phase 2 clinical trials of anti-TL1A agents have demonstrated promising results, showing improvements in endoscopic and histologic outcomes for both UC and CD. Phase 2 and 3 clinical trials are ongoing, which are expected to provide further clarity on the efficacy and safety of TL1A-targeting agents in treating IBD.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"171-183"},"PeriodicalIF":5.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Biological Therapy for Psoriasis on the Development of Psoriatic Arthritis: A Population-Based Cohort Study.","authors":"Yongtai Cho, Suneun Park, Kyungyeon Jung, Jeong-Eun Lee, Jieun Woo, Ju Hwan Kim, Ju-Young Shin","doi":"10.1007/s40259-024-00689-8","DOIUrl":"10.1007/s40259-024-00689-8","url":null,"abstract":"<p><strong>Background: </strong>Evidence comparing the impact of various biologics for psoriasis on the progression to psoriatic arthritis (PsA) is limited. We therefore assessed the risk of PsA associated with interleukin (IL)-23 inhibitor, IL-17 inhibitor, or IL-12/23 inhibitor use compared with tumor necrosis factor (TNF) inhibitor use among patients with psoriasis.</p><p><strong>Methods: </strong>This population-based cohort study used the nationwide claims database from South Korea (2007-2023). New users of IL or TNF inhibitors with psoriasis who did not have PsA or other inflammatory arthritis were categorized into each class of the IL inhibitors for comparison with TNF inhibitor users. The outcome measured was the development of incident PsA. We calculated multinomial overlap weights to balance predefined covariates. Hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models.</p><p><strong>Results: </strong>We identified 9499 patients with psoriasis (mean age 45.1 years; 33.6% female), of whom 3913 (41.2%), 2126 (22.4%), 2773 (28.8%), and 727 (7.7%) were exposed to IL-23 inhibitor, IL-17 inhibitor, IL-12/23 inhibitor, and TNF inhibitor, respectively. PsA developed in 281 (3.0%) patients during 23,275 person-years. The weighted HR for any IL inhibitors was 0.40 (95% CI 0.25-0.62), with specific HRs of 0.22 (95% CI 0.13-0.37), 0.47 (95% CI 0.28-0.80), and 0.46 (95% CI 0.29-0.74) for IL-23 inhibitor, IL-17 inhibitor, and IL-12/23 inhibitor, respectively. IL-23 inhibitors exhibited the greatest rate difference of - 2.61 (95% CI - 3.67 to - 1.55) cases of PsA per 100 person-years.</p><p><strong>Conclusions: </strong>The use of IL inhibitors, particularly IL-23 inhibitors, compared with TNF inhibitors, was associated with a lower risk of developing PsA.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"143-152"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Comparative Analysis of Trastuzumab Originator and Biosimilars: Safety, Efficacy, and Cost Effectiveness.","authors":"Tomoka Mamori, Maki Tanioka, Kenji Takada, Hirofumi Hamano, Takahiro Tsukioki, Yuko Takahashi, Tsuguo Iwatani, Tadahiko Shien, Shinichi Toyooka","doi":"10.1007/s40259-024-00686-x","DOIUrl":"10.1007/s40259-024-00686-x","url":null,"abstract":"<p><strong>Background: </strong>Despite the global use of trastuzumab biosimilars, concerns remain regarding their efficacy and safety. In particular, when used concurrently with pertuzumab, trastuzumab biosimilars lack extensive real-world data and safety information. Additionally, as cancer drug expenditures continue to rise worldwide, cost savings from biosimilars have become increasingly important.</p><p><strong>Objective: </strong>This study aims to assess the safety, efficacy, and cost effectiveness of trastuzumab originators and their biosimilars in real-world clinical settings, focusing on a large patient population.</p><p><strong>Methods: </strong>The analysis included 31,661 patients with HER2-positive breast cancer from the Medical Data Vision Co., Ltd. database in Japan. Additionally, adverse event reports for the trastuzumab originator and its biosimilars were obtained for 58,799 patients from the World Health Organization's VigiBase, the global adverse event reporting database.</p><p><strong>Results: </strong>No significant differences were observed in heart failure hospitalizations, liver dysfunction, or infusion reaction rates in both the Medical Data Vision Co., Ltd. database and the World Health Organization's VigiBase. In the Medical Data Vision Co., Ltd. database, the addition of pertuzumab did not significantly influence the incidence of adverse events, and the use of biosimilars significantly reduced medical costs, with no significant difference in breast cancer recurrence rates.</p><p><strong>Conclusions: </strong>By analyzing two large and diverse datasets from multiple perspectives, we obtained reliable results that the trastuzumab originator and its biosimilars have similar safety profiles. The concurrent use of pertuzumab was also found to be safe. The use of biosimilars can lead to cost savings. These findings provide crucial insights for the evaluation and adoption of biosimilars in clinical practice.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"131-142"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Dystrophin- and Utrophin-Based Therapeutic Approaches for Treatment of Duchenne Muscular Dystrophy: A Comparative Review.","authors":"Sylwia Szwec, Zuzanna Kapłucha, Jeffrey S Chamberlain, Patryk Konieczny","doi":"10.1007/s40259-024-00693-y","DOIUrl":"10.1007/s40259-024-00693-y","url":null,"abstract":"","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"167"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accelerating CAR-T Cell Therapies with Small-Molecule Inhibitors.","authors":"Katrin Mestermann, Andoni Garitano-Trojaola, Michael Hudecek","doi":"10.1007/s40259-024-00688-9","DOIUrl":"10.1007/s40259-024-00688-9","url":null,"abstract":"<p><p>Chimeric antigen receptor T-cell therapies have markedly improved the survival rates of patients with B-cell malignancies. However, their efficacy in other hematological cancers, such as acute myeloid leukemia, and in solid tumors has been limited. Key obstacles include the downregulation or loss of antigen expression on cancer cells, restricted accessibility to target cells, and the poor persistence of these \"living drugs\" because of the highly immunosuppressive tumor microenvironment. Additionally, manufacturing these immunotherapies presents significant challenges, and patients frequently experience side effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This review emphasizes the potential of small-molecule inhibitors, many of which are already approved for clinical use, to facilitate chimeric antigen receptor T-cell manufacturing, enhance their anti-tumor efficacy, and mitigate their side effects. Although substantial work remains, the robust pre-clinical data and the growing clinical interest suggest significant promise for using cancer signaling pathway inhibitors to enhance and refine chimeric antigen receptor T-cell therapy for both hematological and solid tumors. Exploring these combination strategies could lead to more effective therapies, offering new hope for patients with resistant forms of cancer.</p>","PeriodicalId":9022,"journal":{"name":"BioDrugs","volume":" ","pages":"33-51"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}