Pediatric Drugs最新文献

{"title":"Isavuconazole: Real-World Data and Clinical Considerations for Pediatric Patients.","authors":"Lorenzo Chiusaroli, Danila Seidel, Daniel Ebrahimi-Fakhari, Luise Martin, Karoline Ehlert, Andreas H Groll, Zoi Dorothea Pana","doi":"10.1007/s40272-026-00780-3","DOIUrl":"https://doi.org/10.1007/s40272-026-00780-3","url":null,"abstract":"<p><p>Isavuconazole (ISAV) is a broad-spectrum triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis and has recently received approval for use in children ≥1 year of age. Pediatric approval was based on limited registration data, underscoring the importance of real-world evidence to better define efficacy and safety in children and adolescents. In this manuscript, we reviewed pediatric registration trials and real-world studies evaluating ISAV, with a focus on treatment and prophylaxis indications, pharmacokinetics, and safety. The literature review was conducted using PubMed, Embase, and Cochrane databases to identify relevant real-world and clinical studies published between January 1, 2005, and October 31, 2025. Studies reporting ISAV use in patients <18 years of age, including registration trials, observational cohorts, case series, and pharmacokinetic-pharmacodynamic studies, were included. Twenty-six real-world publications and two clinical registration trials met inclusion criteria. Among the real-world publications, ISAV was used for treatment in 23 studies and for prophylaxis in 5 studies, while 17 studies evaluated drug exposure or pharmacokinetics (several studies involved more than one mode of administration). Most patients had underlying hematologic or oncologic conditions. Across heterogeneous study populations and outcome definitions, complete or partial response was reported descriptively in approximately 72% of evaluable patients treated for invasive fungal disease, with breakthrough fungal infections reported in approximately 10% of patients receiving prophylaxis. Adverse events were generally mild and predominantly consisted of reversible hepatic laboratory abnormalities; serious drug-related toxicity, including one reported case of acute liver failure, was rare. Pharmacokinetic data demonstrated predictable exposure and achievement of target plasma concentrations in the majority of patients. Taken together, current evidence, although limited and derived largely from retrospective and salvage-treatment cohorts, suggests promising clinical activity and generally favorable tolerability of ISAV for invasive mold infections in pediatric populations. Real-world data support its use as a therapeutic option in selected patients, while underscoring the need for prospective studies to confirm efficacy, optimize dosing, and assess long-term safety.</p>","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207483","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":"Pharmacological Interventions for Acute Stress Disorder and for the Prevention and Treatment of Post-traumatic Stress Disorder in Children and Adolescents: A Narrative Review.","authors":"Charles Tesnières, Hala Kerbage, Eric Bui, Julie Rolling","doi":"10.1007/s40272-026-00777-y","DOIUrl":"https://doi.org/10.1007/s40272-026-00777-y","url":null,"abstract":"<p><p>Traumatic events are common during childhood and adolescence and may lead to acute stress disorder (ASD) or post-traumatic stress disorder (PTSD), both associated with developmental, cognitive and functional impairment. Although trauma-focused psychotherapies are recommended as first-line treatments, pharmacological interventions are frequently used in clinical practice despite limited evidence in paediatric populations. To review the evidence on pharmacological interventions for the prevention and treatment of paediatric ASD and PTSD, we reviewed the literature published up to December 2025. Eligible studies included participants aged younger than 18 years and evaluated pharmacological interventions targeting ASD, PTSD prevention or PTSD treatment. After screening and a full-text review, 75 publications were included. Given the methodological heterogeneity, findings were synthesised narratively. Evidence for pharmacological interventions in paediatric trauma-related disorders remains limited and heterogeneous. For PTSD prevention, only limited data support sertraline and, in the context of ASD, imipramine. Limited data also suggest that opioids used for pain management after trauma may reduce subsequent PTSD risk. Early opioid (morphine) exposure for pain management was also associated with lower subsequent severity symptoms in observational paediatric burn studies. Evidence for PTSD treatment is weaker. Anticonvulsants (sodium valproate, carbamazepine, oxcarbazepine, lamotrigine), antipsychotics (clozapine, quetiapine, aripiprazole), glutamatergics (D-cycloserine, ketamine, ifenprodil), propranolol and cannabidiol do not appear to provide sufficient benefit for routine use. Alpha-adrenergic agents (prazosin, clonidine, guanfacine) have shown preliminary signals of benefit, particularly for hyperarousal and trauma-related sleep disturbances. However, these findings are based on non-randomised and uncontrolled studies. Antidepressants (sertraline, citalopram) show mixed results; among them, citalopram was associated with symptomatic improvement in one small open-label study and one case series. These findings should be considered preliminary and hypothesis generating. No pharmacological treatment has sufficient evidence to warrant routine recommendation for paediatric PTSD and ASD. Pharmacotherapy should therefore be considered only as an adjunct to trauma-focused psychotherapy in selected clinical situations. Further randomised controlled trials are needed.</p>","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195962","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":"Efficacy of Ibuprofen Versus Acetaminophen for Acute Fever Management in Febrile Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials.","authors":"Gian Luigi Marseglia, Paola Giovanna Marchisio, Gregorio Paolo Milani, Michele Miraglia Del Giudice, Irene Schiavetti, Giorgio Ciprandi","doi":"10.1007/s40272-026-00773-2","DOIUrl":"https://doi.org/10.1007/s40272-026-00773-2","url":null,"abstract":"<p><strong>Background: </strong>Ibuprofen and acetaminophen are the most widely used antipyretic agents in pediatric practice. Despite their common use, comparative evidence on their relative efficacy in febrile children remains heterogeneous, and clinical recommendations vary across guidelines and countries.</p><p><strong>Objective: </strong>We aimed to evaluate the comparative antipyretic efficacy of ibuprofen versus acetaminophen in febrile children through a systematic review and meta-analysis restricted to randomized controlled trials.</p><p><strong>Methods: </strong>A systematic search was conducted in Scopus, PubMed, and Web of Science using a predefined strategy combining terms for ibuprofen, paracetamol/acetaminophen, fever/febrile/pyrexia, and pediatric populations. The primary outcome was the proportion of children afebrile at 4 h. Continuous outcomes included temperature reduction at 4 h, time without fever during the first 4 h, and time-weighted summary temperature differences over 0-8 h. The study protocol was registered in PROSPERO (CRD420261353471).</p><p><strong>Results: </strong>A total of 479 records were identified; after duplicate removal and screening, seven studies were included in the quantitative synthesis. For the primary outcome of afebrile status at 4 h, the pooled risk ratio was 1.26 (95% confidence interval [CI] 0.88-1.80; p = 0.106). Temperature reduction at 4 h was significantly greater with ibuprofen (mean difference 0.31 °C, p = 0.024). The time-weighted summary temperature outcome over 0-8 h numerically favored ibuprofen but did not reach statistical significance (mean difference - 3.52, 95% CI - 21.24 to 14.21; p = 0.240; I² = 57.6%). An exploratory standardized mean difference analysis across heterogeneous continuous outcomes (seven comparisons) yielded a near-null pooled effect (Hedges' g - 0.08, 95% CI - 0.40 to 0.25; p = 0.645; I² = 84.0%).</p><p><strong>Conclusions: </strong>The primary outcome-the proportion of children achieving afebrile status at 4 h-did not differ significantly between ibuprofen and acetaminophen (risk ratio 1.26, 95% CI 0.88-1.80; p = 0.106). Ibuprofen produced a statistically greater reduction in temperature at 4 h compared with acetaminophen (mean difference 0.31 °C), although this difference is unlikely to be clinically meaningful. These findings suggest a marginal quantitative advantage of ibuprofen to decrease body temperature, without a clinically significant difference between the two agents.</p>","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183108","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":"Correction: Effectiveness and Safety of IL‑17A Inhibitors in Pediatric Psoriasis: A Real‑World, Multicenter, International Study.","authors":"Vito Di Lernia, Bertille Bonniaud, Eve Puzenat, Christine Bodemer, Morgane Seyler, Marieke M B Seyger, Mathilde Tardieu, Helena Iznardo, Francesca Satolli, Paula C Luna, Olivier Carpentier, Ouafa Hocar, Tiago Torres, Iria Neri, Luca Stingeni, Cristina Bertoli, Alain Beauchet, Emmanuel Mahé","doi":"10.1007/s40272-026-00774-1","DOIUrl":"https://doi.org/10.1007/s40272-026-00774-1","url":null,"abstract":"","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182746","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":"Exclusion by Design: Regulatory Reform and Evolving Frameworks for Clinical Trials in Pregnancy.","authors":"Gregory L Kearns, Agnes Saint-Raymond","doi":"10.1007/s40272-026-00779-w","DOIUrl":"https://doi.org/10.1007/s40272-026-00779-w","url":null,"abstract":"<p><p>Maternal-fetal pharmacology remains a critically underdeveloped domain, largely because ethical, regulatory, and methodological barriers impede evidence generation in pregnant populations (hereafter women). Pregnant women continue to be routinely excluded from clinical trials, creating both a knowledge and an evidence gap that can adversely affect maternal and neonatal outcomes. Despite significant regulatory advances in both encouraging trial inclusion and improving labeling [1], for example through the implementation of the US Pregnancy and Lactation Labeling Rule, substantial gaps and a lack of harmonization persist in pharmacologic, safety, and efficacy data for medications used during pregnancy and lactation. This targeted commentary examines the current state of medication use in pregnant women and their fetuses, the regulatory landscape, and the challenges that impede the development of new research in maternal-fetal pharmacology. We also identify the regulatory conundrum in selected countries worldwide and propose new strategies to improve evidence generation and regulatory decision making for this protected population.</p>","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113499","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":"Repeated-Dose High-Dose Ivermectin Pharmacokinetics and Safety in Children with Acute Dengue.","authors":"Keswadee Lapphra, Dumrong Mairiang, Joel Tarning, Dararat Prayongkul, Chunya Puttikhunt, Adisak Songjaeng, Tanapan Prommool, Nattaya Tangthawornchaikul, Kulkanya Chokephaibulkit, Panisadee Avirutnan","doi":"10.1007/s40272-026-00771-4","DOIUrl":"https://doi.org/10.1007/s40272-026-00771-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Ivermectin has shown anti-dengue virus activity in experimental systems, and an adult dengue trial found faster clearance of circulating non-structural protein 1 (NS1) without improvement in viremia or clinical outcomes. Pediatric pharmacokinetic and safety data for repeated high-dose regimens remain limited. We characterized repeated-dose ivermectin pharmacokinetics and safety in children with acute uncomplicated dengue weighing ≥15 kg.</p><p><strong>Methods: </strong>In this prospective, open-label, sequential dose-escalation study, children aged 1-15 years who presented within 72 h of fever onset and met the protocol laboratory-confirmation criteria for dengue received ivermectin 400 or 600 μg/kg once daily for 3 days. Noncompartmental analyses estimated exposure and peak concentrations from intensive plasma sampling. Exploratory analyses examined associations between exposure and viremia and NS1 trajectories during the first 48 h after dose 1; the study was not designed or powered to evaluate antiviral efficacy.</p><p><strong>Results: </strong>All 24 children completed follow-up and experienced at least one adverse event; most events were consistent with acute dengue. Six participants (25%) experienced serious adverse events consisting of grade 4 neutropenia; all participants were clinically well, required no neutropenia-specific treatment, and showed improvement at the next available assessment or follow-up. No serious adverse event was assessed as related to ivermectin. One asymptomatic grade 1 QTc-prolongation adverse event was recorded and required no intervention. Exposure increased with dose: median 0-48-h area under the concentration-time curve (AUC_last) was 1316.49 and 2129.41 ng·h/mL at 400 and 600 μg/kg, respectively, and corresponding maximum observed concentrations (C_max) were 107.50 and 165.50 ng/mL. Dose-normalized parameters showed no clear relationship with body weight. Analyses confined to the first 48 h identified no clear exposure-response association with viremia or NS1 trajectories.</p><p><strong>Conclusions: </strong>In children weighing ≥15 kg with acute uncomplicated dengue, ivermectin exposure increased with administered dose, while dose-normalized AUC_last and C_max showed no clear relationship with body weight across the studied range. Pharmacokinetics and Pharmacodynamics of Ivermectin in Pediatric Dengue Patients (PKIDEN) therefore fills an important dengue-specific pediatric clinical pharmacology gap and provides repeated-dose exposure and safety reference data that may inform dose selection, exposure interpretation, and safety monitoring in future studies. The study was not designed to determine antiviral efficacy or clinical benefit.</p><p><strong>Trial registry: </strong>ClinicalTrials.gov: NCT03432442; first posted February 14, 2018.</p>","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025785","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":"Real-World Outcomes of Ocrelizumab and Ofatumumab Treatment in Pediatric-Onset Multiple Sclerosis.","authors":"Vivien X Xie Cherng, Claire Har, Hayley Roper, Alexandra B Kornbluh, Ilana Kahn","doi":"10.1007/s40272-026-00778-x","DOIUrl":"https://doi.org/10.1007/s40272-026-00778-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Ocrelizumab and ofatumumab are highly effective disease-modifying therapies (DMTs) for adult-onset multiple sclerosis and are increasingly used in pediatric-onset multiple sclerosis. However, there is a paucity of data on their safety and efficacy in pediatric-onset multiple sclerosis. We aimed to describe real-world outcomes of ocrelizumab and ofatumumab in a single center cohort of patients with pediatric-onset multiple sclerosis.</p><p><strong>Methods: </strong>A retrospective cohort study of pediatric patients evaluated at Children's National Hospital between 2015 and 2026 who fulfilled 2017 McDonald criteria for relapsing-remitting multiple sclerosis and were treated with either ocrelizumab or ofatumumab. Patients were included regardless of whether they were treatment naïve or switching from a prior DMT. Primary outcomes were clinical relapse or radiologic worsening with new/enlarging T2 or gadolinium-enhancing lesions on magnetic resonance imaging. Secondary outcomes included safety and tolerability outcomes characterized by frequency and severity of infections, medication side effects, and hypogammaglobulinemia. Statistical analysis included descriptive statistics and an exploratory Kaplan-Meier survival analysis.</p><p><strong>Results: </strong>Forty-one patients were included, with mean age at diagnosis of 15 years (range 8-17 years). There were 32/41 (78%) patients treated with ocrelizumab and 9/41 (22%) treated with ofatumumab; 22/41 (54%) received these agents as first-line DMTs. There were 19/41 (46%) patients prescribed a previous DMT, and radiologic worsening/clinical relapse was the most common reason for switching (9/19, 47%). Only 1/41 (2%) experienced a clinical relapse occurring > 3 months after ocrelizumab initiation, with an annualized relapse rate of 0.012. There were 3/41 (7%) patients who had new or enlarged T2 hyperintense lesions after re-baseline magnetic resonance imaging. There were 5/41 (12%) patients who experienced an infusion or injection-site reaction, which were all mild and managed conservatively. No patients discontinued ocrelizumab or ofatumumab because of adverse events.</p><p><strong>Conclusions: </strong>These results provide descriptive real-word data on the use of ocrelizumab and ofatumumab, especially when used as a first-line DMT in pediatric-onset multiple sclerosis. Although limited by a short follow-up period, our real-world findings provide safety and effectiveness data to inform DMT selection and shared decision making with families.</p>","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017656","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":"Managing Sjögren's Disease in Pediatric Patients.","authors":"Sara M Stern, Ludovic Trinquart, Hermine I Brunner, Marisha E Palm, Nora G Singer","doi":"10.1007/s40272-026-00772-3","DOIUrl":"https://doi.org/10.1007/s40272-026-00772-3","url":null,"abstract":"<p><p>Over the past decade, therapeutic development in adult Sjögren's disease (SjD) has accelerated substantially. Multiple targeted agents directed at B-cell survival, co-stimulation, autoantibody recycling, and immune regulation are advancing through late-phase clinical development. As of August 2026, there are no US Food and Drug Administration-approved disease-modifying or immunomodulatory therapies specifically indicated to treat the underlying autoimmunity of SjD. US Food and Drug Administration approvals in adults are limited to symptomatic treatment of sicca (dryness) symptoms, particularly xerostomia (dry mouth). Treatment of childhood SjD remains off-label and is supported by a limited evidence base consisting largely of case reports, case series, registry abstracts, and clinician survey data. B-cell-targeted medicines and conventional disease-modifying anti-rheumatic drugs have been used off-label in SjD, including childhood SjD. In this review, we compare the clinical phenotype of childhood SjD with adult SjD, summarize the therapies currently used in children and the evidence supporting them, and propose a framework for prioritizing adult SjD therapeutics for pediatric development. The inflammatory phenotype of childhood SjD provides a strong biologic rationale for the study of selected targeted therapies, while underscoring the need for staged pediatric development, phenotype-enriched trials, and outcome measures suited to glandular and systemic disease in children. The highest-priority candidates for pediatric study are discussed based on available adult data and current approval in children for other pediatric diseases.</p>","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017684","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":"Authors' Reply to Kaplan Comment on \"Safety and Efficacy of Oral Ferric Maltol and Ferrous Sulfate for Iron Deficiency Anemia in Infants, Children and Adolescents: A Multicenter Randomized Trial\".","authors":"Richard K Russell","doi":"10.1007/s40272-026-00775-0","DOIUrl":"https://doi.org/10.1007/s40272-026-00775-0","url":null,"abstract":"","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002068","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":"Comment on \"Safety and Efficacy of Oral Ferric Maltol and Ferrous Sulfate for Iron Deficiency Anemia in Infants, Children and Adolescents: A Multicenter Randomized Trial\".","authors":"Fatih Kaplan","doi":"10.1007/s40272-026-00776-z","DOIUrl":"10.1007/s40272-026-00776-z","url":null,"abstract":"","PeriodicalId":19955,"journal":{"name":"Pediatric Drugs","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002073","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}