Carolina Garcia-Vidal , Antonio Gallardo-Pizarro , Tommaso Francesco Aiello , Ana Martinez-Urrea , Christian Teijon-Lumbreras , Patricia Monzo-Gallo
{"title":"Experience with isavuconazole in the treatment of mucormycosis and breakthrough fungal infections","authors":"Carolina Garcia-Vidal , Antonio Gallardo-Pizarro , Tommaso Francesco Aiello , Ana Martinez-Urrea , Christian Teijon-Lumbreras , Patricia Monzo-Gallo","doi":"10.1016/j.riam.2025.01.005","DOIUrl":"10.1016/j.riam.2025.01.005","url":null,"abstract":"<div><div>Isavuconazole, a triazole-class antifungal, is effective and safe for both primary treatment and salvage therapy in a variety of fungal infections. This article reviews recent knowledge on the role of this antifungal in the treatment of mucormycosis and breakthrough invasive fungal infections (bIFI) during antifungal therapy. Isavuconazole has demonstrated favorable clinical outcomes and a good safety profile in various patient populations with mucormycosis, including those with comorbidities such as diabetes mellitus or severe immunosuppression. Particularly noteworthy is the fact that drug interactions in patients with mucormycosis, where a solid organ transplant was a predisposing factor, have been effectively managed. In the treatment of bIFIs, the use of isavuconazole requires a thoughtful reflection about the fungal species involved and their susceptibility profiles. This is highly dependent on the antifungal agent administered before the onset of bIFI. Early diagnosis and appropriate antifungal therapy are essential to improve outcomes in patients with mucormycosis and bIFIs. Isavuconazole represents a valuable option for managing these complex infections.</div></div>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":"42 1","pages":"Pages 51-54"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francisco Javier Candel , Mayra Matesanz , José Mensa , José Ramón Azanza
{"title":"Pharmacokinetic novelties of isavuconazole. Use in special situations","authors":"Francisco Javier Candel , Mayra Matesanz , José Mensa , José Ramón Azanza","doi":"10.1016/j.riam.2025.02.003","DOIUrl":"10.1016/j.riam.2025.02.003","url":null,"abstract":"<div><div>Isavuconazole, a next generation triazole, exhibits unique pharmacokinetic and pharmacodynamic properties that make it ideal for treating invasive fungal infections in critically ill and immunocompromised patients. This antifungal agent stands out for its broad spectrum of activity, which includes filamentous fungi such as <em>Aspergillus</em> and Mucorales, with an efficacy comparable to that of voriconazole and additional advantages against these pathogens. Its high oral bioavailability (close to 100%), prolonged half-life (>100<!--> <!-->h), and linear, predictable pharmacokinetic profile minimize the need for frequent dose adjustments and therapeutic monitoring. Its lipophilic structure facilitates penetration into key tissues, such as the central nervous system and pulmonary tissue, as validated by clinical studies showing survival rates exceeding 70% in patients with complicated invasive fungal infection. Its use is safe in populations with renal impairment, mild to moderate hepatic impairment, paediatrics, and obesity, although dose adjustment is recommended for severe hepatic impairment. Recent studies in critically ill patients undergoing extracorporeal membrane oxygenation or continuous renal replacement therapy have revealed moderate reductions in plasma concentration, without significant clinical impact. Adaptive dosing strategies have been proposed to optimize efficacy in these cases. Compared to other triazoles, isavuconazole demonstrates a robust safety profile, with lower incidences of hepatotoxicity and neurotoxicity. Its antifungal activity, favorable pharmacokinetics, and excellent safety profile underscore its role as a reference antifungal agent, particularly in challenging clinical scenarios.</div></div>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":"42 1","pages":"Pages 37-44"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pharmacological interactions of isavuconazole","authors":"José Ramón Azanza Perea","doi":"10.1016/j.riam.2025.04.001","DOIUrl":"10.1016/j.riam.2025.04.001","url":null,"abstract":"<div><div>The interactions between the various drugs a patient receives at any given time are crucial for justifying treatments, especially considering the often severe adverse effects associated with them. These interactions are particularly significant for azole antifungals, such as voriconazole, fluconazole, posaconazole, and itraconazole. The most recently marketed azole, isavuconazole, stands out due to its lower inhibitory effect on various CYP450 enzymes and transport proteins. While it can induce some isoenzymes of the CYP450 superfamily, its impact is minimal. As a result, we can conclude that its interactions with other drugs are less pronounced, which reduces the need for treatment adjustments or dose modifications. Additionally, isavuconazole boasts high oral bioavailability, an extensive volume of distribution, and a notably long elimination half-life. A significant side effect common to all azoles, but not associated with isavuconazole, is the prolongation of the QTc interval, which can sometimes lead to the risk of Torsades de Pointes. These advantages make isavuconazole the preferred antifungal choice for patients on multiple medications.</div></div>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":"42 1","pages":"Pages 45-50"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Current and future use of isavuconazole in children and adolescents","authors":"Natalia Mendoza-Palomar, Pere Soler-Palacín","doi":"10.1016/j.riam.2025.04.002","DOIUrl":"10.1016/j.riam.2025.04.002","url":null,"abstract":"<div><div>Invasive fungal infections (IFI) present significant challenges in newborn, children and adolescents, particularly in immunocompromised patients, such as those with some primary immunodeficiencies or hematologic malignancies, and those who undergo hematopoietic stem cell transplantation. Isavuconazole (ISA), a broad-spectrum triazole antifungal, has emerged as an effective alternative for treating IFI in adults, especially those caused by <em>Aspergillus</em> and Mucorales. Recent approvals by the Food and Drug Administration (2023) and the European Medicines Agency (2024) have extended the use of ISA to paediatric populations, offering an important addition to the current treatment options. Two clinical trials have assessed ISA in paediatric patients, showing it is generally well tolerated, with an acceptable safety profile. While adverse events are primarily gastrointestinal and hepatic, they are less frequent than those associated with voriconazole or liposomal amphotericin B. According to pharmacokinetic studies, drug clearance is faster in children, particularly in those under 35<!--> <!-->kg; thus, doses require careful modification.</div><div>ISA may represent a crucial advancement in the treatment of paediatric IFIs, but therapeutic drug monitoring remains essential due to variability in drug concentrations.</div></div>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":"42 1","pages":"Pages 32-36"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Impact of current clinical guidelines on the management of invasive fungal disease","authors":"Santiago de Cossio Tejido , Miguel Salavert Lletí","doi":"10.1016/j.riam.2025.02.002","DOIUrl":"10.1016/j.riam.2025.02.002","url":null,"abstract":"<div><div>Isavuconazole is a new broad-spectrum antifungal triazole with a better safety profile in terms of drug–drug interactions, adverse effects, and tolerance compared to other azoles. Increasing evidence supports the usefulness of isavuconazole in the treatment of invasive fungal diseases. In this review, we aim to analyze the influence of this new evidence on the main clinical guidelines. We reviewed the most recent consensus guidelines issued by the major infectious diseases societies worldwide, focusing on the novelties regarding the recommendations for the use of isavuconazole in different invasive fungal infections and management strategies.</div><div>Isavuconazole has been included as first-line therapy for invasive aspergillosis, with slight differences in preference for voriconazole or isavuconazole depending on the clinical scenario. In mucormycosis, isavuconazole is considered an alternative first-line therapy to liposomal amphotericin B, especially in those patients with underlying renal impairment. Additionally, the use of isavuconazole is suggested in salvage scenario for both conditions, and the combination with other mold-active drugs is considered. The guidelines report the promising results obtained with the use of this drug for treating mycoses caused by other molds and rare yeasts, as well as endemic mycoses, but since solid evidence is still lacking, the recommendations in this area are generally weak.</div><div>Isavuconazole is a suitable therapeutic option for invasive fungal infections, offering efficacy against a range of pathogens, including <em>Aspergillus</em> and fungi within the order Mucorales. Its safety profile and its favorable drug interaction profile make it a valuable alternative to traditional agents like voriconazole or liposomal amphotericin B in certain scenarios. However, continued research is essential to better understand its role in combination therapies and to assess its effectiveness against other fungal species.</div></div>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":"42 1","pages":"Pages 15-21"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fernanda A Oliveira, Andrea R Bernardes-Engemann, Fernando Almeida-Silva, Beatriz da S Motta, Marcos A Almeida, Marcus M Teixeira, Andrea d'Avila Freitas, Kim M Geraldo, Valdiléa G Veloso, Beatriz Grinsztejn, Marcel de Souza Borges Quintana, Rodrigo Almeida-Paes, Rosely M Zancopé-Oliveira
{"title":"Isolation of fungi from the Trichosporonaceae family in urine samples from COVID-19 patients: Should we worry about it?","authors":"Fernanda A Oliveira, Andrea R Bernardes-Engemann, Fernando Almeida-Silva, Beatriz da S Motta, Marcos A Almeida, Marcus M Teixeira, Andrea d'Avila Freitas, Kim M Geraldo, Valdiléa G Veloso, Beatriz Grinsztejn, Marcel de Souza Borges Quintana, Rodrigo Almeida-Paes, Rosely M Zancopé-Oliveira","doi":"10.1016/j.riam.2024.10.003","DOIUrl":"10.1016/j.riam.2024.10.003","url":null,"abstract":"<p><strong>Background: </strong>Trichosporon genus encompasses emergent fungal pathogens with an increased incidence that concerns potential multi-drug resistance and mortality, especially in immunocompromised patients. COVID-19 is a disease of pandemic proportions with complications related to cytokine storm and lymphopenia.</p><p><strong>Aims: </strong>To study the isolation of fungi within the Trichosporanaceae family in patients infected with SARS-CoV-2.</p><p><strong>Methods: </strong>In this work we recovered 35 fungal isolates belonging to the Trichosporonaceae family from urine samples of 32 patients hospitalized due to COVID-19 complications. We evaluated their mycological characteristics, as well as the patient's clinical aspects.</p><p><strong>Results: </strong>Trichosporon asahii was the main species identified, followed by Cutaneotrichosporon jirovecii and Trichosporon inkin, respectively. The blood cultures of 20 of these patients were all negative for fungi. Isolation of Trichosporonaceae fungi in urine was associated with high COVID-19 severity. The antifungal susceptibility test showed low MIC values for voriconazole, an antifungal in the first-line treatment of trichosporonosis. In contrast, high MIC values were found in the case of amphotericin B and 5-fluorocytosine in all the species, except for C. jirovecii. Since invasive trichosporonosis was not confirmed, none of the patients were given an antifungal treatment, without affecting the outcome of the patients.</p><p><strong>Conclusions: </strong>Our results suggest that the isolation in urine of fungi from the Trichosporonaceae family may be associated to more severe forms of the disease COVID-19, but not with an increase in death rate. However, these isolates do not seem to be linked to urinary infections, therefore no antifungal therapy is mandatory in these cases.</p>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":" ","pages":"58-67"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"[Clinical problems in Medical Mycology: Problem number 57].","authors":"Gabriela Santiso, Fernando Messina, Matías Gastón Pérez, Daniela Masini, Mercedes Romero, Emanuel Marin, Alicia Arechavala","doi":"10.1016/j.riam.2025.01.001","DOIUrl":"10.1016/j.riam.2025.01.001","url":null,"abstract":"<p><p>A 48-year-old man with no relevant medical history went to a general acute hospital seeking medical attention. He had fever, cough, and chest pain. A chest X-ray revealed pleural effusion, which prompted a puncture and a subsequent culture of the sample; antibiotic treatment was prescribed. Despite the treatment, the man remained febrile, and a new clinical examination suggested a probable onychomycosis of all 20 nails. A rapid HIV test was carried out. The culture from the pleural puncture showed yeast growth identified as Cryptococcus sp., revealing a disseminated disease with central nervous involvement, thus leading to an early diagnosis with a better prognosis.</p>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":" ","pages":"83-85"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stella Wolfgruber, Jon Salmanton-García, Marius Paulin Ngouanom Kuate, Martin Hoenigl, Jose Guillermo Pereira Brunelli
{"title":"Antifungal pipeline: New tools for the treatment of mycoses.","authors":"Stella Wolfgruber, Jon Salmanton-García, Marius Paulin Ngouanom Kuate, Martin Hoenigl, Jose Guillermo Pereira Brunelli","doi":"10.1016/j.riam.2024.11.001","DOIUrl":"10.1016/j.riam.2024.11.001","url":null,"abstract":"<p><p>Fungal infections are becoming an escalating public health challenge, particularly among immunocompromised individuals. The partially limited efficacy of current antifungal treatments, their potential adverse effects, and the increasing problem of resistance emphasize the need for new treatment options. Existing antifungal classes-allylamines, azoles, echinocandins, polyenes, and pyrimidine analogs-face challenges due to their similarity with human cells and rising resistance. New antifungal agents, such as ibrexafungerp, rezafungin, oteseconazole, and miltefosine, offer novel mechanisms of action along with reduced toxicity. While antifungal resistance is a growing global concern, fungal infections in low- and middle-income countries (LMICs) present specific challenges with high rates of opportunistic infections like cryptococcosis and endemic mycoses such as histoplasmosis. The World Health Organization's fungal priority pathogens list highlights the prevalence of these infections in LMICs, where limited access to antifungal drugs and misuse are common. This review provides a comprehensive overview of these new agents and their mechanisms, and explores the challenges and roles of antifungal drugs in LMICs, where the burden of fungal infections is high. Continued research and development are essential to address the rising incidence and resistance of fungal infections globally.</p>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":" ","pages":"68-78"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maximiliano Gabriel Castro, Erwin Alexander Rottoli, María José Sadonio, Melina Beloso, Andrea Gómez Colussi, María Fernanda Argarañá, Federico Rafael Galluccio
{"title":"Series of cases of disseminated histoplasmosis in people living with the human immunodeficiency virus: A neglected endemic in Latin America and the Caribbean.","authors":"Maximiliano Gabriel Castro, Erwin Alexander Rottoli, María José Sadonio, Melina Beloso, Andrea Gómez Colussi, María Fernanda Argarañá, Federico Rafael Galluccio","doi":"10.1016/j.riam.2025.01.002","DOIUrl":"10.1016/j.riam.2025.01.002","url":null,"abstract":"<p><strong>Background: </strong>Disseminated histoplasmosis is a common infection in people living with human immunodeficiency virus (HIV) in Latin America and the Caribbean.</p><p><strong>Aims: </strong>To examine the clinical characteristics and outcomes of disseminated histoplasmosis in people living with HIV focusing on delayed diagnoses.</p><p><strong>Methods: </strong>A descriptive study in a public hospital in Santa Fe (Argentina) was conducted between 2017 and 2023. Disseminated histoplasmosis was diagnosed through direct examination and/or culture of blood, respiratory secretions, bone marrow, or skin samples.</p><p><strong>Results: </strong>Twenty-one patients were included (median age: 34 years; 61.9% male). Ten (47.6%) patients were under antiretroviral therapy, but were non-adherent. The median CD4+ count was 10cells/mm<sup>3</sup>. Fever was the prevailing symptom (19, 90.5%), with a median duration of 30 days. Visceromegalies were observed in 11 patients (52.4%), lymphadenopathy in 10 (47.6%), and skin lesions in 11 (52.4%). All patients had anemia, and 13 (61.9%) had liver function abnormalities. Diagnosis was made through the scraping of mucocutaneous lesions in 11 patients (52.4%). Eight patients (38.1%) were admitted to the Intensive Care Unit, and six (28.6%) died. Five patients (23.8%) had delayed diagnoses.</p><p><strong>Conclusions: </strong>Disseminated histoplasmosis may be underdiagnosed due to its subacute course and nonspecific clinical presentation. A high index of suspicion is essential, particularly in people living with the HIV.</p>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":" ","pages":"79-82"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Beatriz Gálvez, Consuelo Ferrer, Violeta Esteban, José Noberto Sancho-Chust, Beatriz Amat, Eusebi Chiner, Maria Francisca Colom
{"title":"Pneumocystis jirovecii in the lower respiratory tract of immunocompetent individuals.","authors":"Beatriz Gálvez, Consuelo Ferrer, Violeta Esteban, José Noberto Sancho-Chust, Beatriz Amat, Eusebi Chiner, Maria Francisca Colom","doi":"10.1016/j.riam.2024.10.002","DOIUrl":"10.1016/j.riam.2024.10.002","url":null,"abstract":"<p><strong>Background: </strong>Pneumocystis jirovecii colonization rates in healthy patients are unclear. Previously published studies suggest that the fungus could play a role in the physiopathology and progression of chronic respiratory diseases.</p><p><strong>Aims: </strong>The goal of this study was to determine the prevalence of colonization by this fungus in the lower respiratory tract of immunocompetent patients who are not at risk of dysbiosis.</p><p><strong>Methods: </strong>The presence of P. jirovecii was confirmed in the bronchoalveolar lavage (BAL) samples from adults who underwent bronchoscopy for non-infectious reasons, had no immunosuppressive factors, and had not been on antibiotic treatment for at least one month. The results were compared with those obtained in the study on the presence of Pneumocystis in environmental dust samples obtained by swabbing surfaces in the participating subjects' domestic settings. Real-time PCR was the technique used for detecting the fungus in both types of samples.</p><p><strong>Results: </strong>A total of 97 BAL samples and 49 domestic environment samples were studied. The medical reasons for needing a bronchoscopy were, mainly, the examination of both pulmonary neoplasm in 55 patients (57%) and diffuse interstitial lung disease in 21 patients (22%). The overall prevalence of P. jirovecii in our population was 7.22% in BAL samples and 0% in domestic samples.</p><p><strong>Conclusions: </strong>The presence of P. jirovecii in the lower respiratory tract is relevantly linked with the patient's immune status, not with an underlying pathology. Prevalence is low in immunocompetent individuals who do not have any infectious pathology and are not having antimicrobial treatments. Our results do not enable us to figure out which the environmental niche of P. jirovecii is.</p>","PeriodicalId":21291,"journal":{"name":"Revista Iberoamericana De Micologia","volume":" ","pages":"51-57"},"PeriodicalIF":1.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}