Drug Safety最新文献

{"title":"The Extent and Magnitude of Bias in Case-Crossover Studies of Real-World Non-transient Medications Patterns: A Simulation Study with Real-World Examples.","authors":"Hsiao-Ching Huang, Mina Tadrous, Saria Awadalla, Daniel Touchette, Glen T Schumock, Todd A Lee","doi":"10.1007/s40264-025-01597-8","DOIUrl":"https://doi.org/10.1007/s40264-025-01597-8","url":null,"abstract":"<p><strong>Introduction: </strong>A case-crossover study is a self-controlled design most appropriate for evaluating transient medication exposures. However, it has increasingly been used in studies of chronic medications and can cause bias in effect estimates that vary based on the pattern of medication use. The goal of this study was to evaluate the magnitude of this bias across different medication-use patterns.</p><p><strong>Objective: </strong>To quantify the magnitude of the bias introduced by different medication patterns and evaluate different case-crossover approaches to mitigate the bias.</p><p><strong>Methods: </strong>We conducted a simulation study evaluating the bias introduced by (1) seven common medication patterns separately, and (2) cohort with 15 different patterns combined. We evaluated each scenario under risk ratios of 0.50, 0.75, 1.00, 1.50, and 2.00. Each approach was analyzed using conditional logistic regression comparing the probability of exposure on the outcome day to 30 days prior. A case-time-control design was used in each of the scenarios. Sensitivity analysis was performed to evaluate the impact on the estimates when changing the length of the risk and control windows. We conducted a real-world example focusing on sodium-glucose co-transporter-2 inhibitor users as real-world examples.</p><p><strong>Results: </strong>The case-crossover design resulted in unbiased estimates when patterns were consistent with transient exposures but were biased upward with prolonged exposure patterns. The magnitude of the bias varies by patterns or pattern combinations. When evaluating prolonged exposures individually or combined as a cohort with mixture patterns, case-time-control with extended risk and control window (30 days) produced unbiased results (mean bias ≤ 0.03).</p><p><strong>Conclusion: </strong>Researchers who use the case-crossover design to evaluate non-transient exposures should implement recommended methods to account for biases.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834507","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":"Advancing Pharmacovigilance Practice in Africa: Moving from Data Collection to Data-Driven Decision Making-Report from the 5th ISoP Africa Chapter Meeting.","authors":"Helen Byomire Ndagije, Sheila Ampaire, George Tsey Sabblah, Comfort Ogar, Jayesh Manharlal Pandit, Nimisha Kotecha, Mulugeta Russom, Victoria Prudence Nambasa, Claris Ambale, Dorothy Aywak, Peter U Bassi, Wangui Mathenge, Johanna C Meyer, Christabel Khaemba, Emmaculate Kwikiriza, Julius Mayengo, Joanitah Atuhaire, David Nahamya, Omar Aimer, Angela Caro-Rojas","doi":"10.1007/s40264-025-01598-7","DOIUrl":"https://doi.org/10.1007/s40264-025-01598-7","url":null,"abstract":"","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811946","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":"Pharmacovigilance in Cell and Gene Therapy: Evolving Challenges in Risk Management and Long-Term Follow-Up.","authors":"Emile Youssef, Kari Weddle, Lisa Zimmerman, Dannelle Palmer","doi":"10.1007/s40264-025-01596-9","DOIUrl":"https://doi.org/10.1007/s40264-025-01596-9","url":null,"abstract":"<p><p>Cell and gene therapies, including CAR T-cells, CRISPR-based genome editing, and next-generation viral and non-viral delivery platforms, are transforming treatment paradigms across cancer, rare genetic disorders, immune dysregulation, and neurodegenerative disease. These therapies offer curative potential but also present safety challenges owing to prolonged biological activity, systemic immune engagement, and lasting genomic alterations. This review examines the range of related toxicities, including immune complications, genotoxicity, and organ-specific effects, with attention to atypical presentations, gaps in clinical trial safety capture, and disparities in global long-term follow-up infrastructure. Central to our analysis is a risk-adaptive, digitally enabled pharmacovigilance model that incorporates real-world data, artificial intelligence-based signal detection, and seamless pediatric-to-adult follow-up to proactively protect patients while supporting innovation. Integrated safety dashboards, pediatric transition roadmaps, and predictive monitoring tools are proposed as practical solutions to improve coordination among sponsors, regulators, and clinical sites. We also outline best practices for aligning risk evaluation and mitigation strategies with risk management plans and examine how wearable biosensors, electronic patient-reported outcomes, and multi-omics biomarkers contribute to near real-time safety surveillance. Ethical priorities such as informed consent, data privacy, and equitable access are addressed throughout. By positioning pharmacovigilance as a proactive and predictive foundation within the therapeutic landscape, this review offers a forward-looking blueprint to advance innovation while ensuring long-term patient safety.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811948","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":"Meeting Report: Herbal and Dietary Supplement Safety Surveillance Summit.","authors":"Dina Halegoua-DeMarzio, Andrew Stolz, Bharati Avula, Ikhlas Khan, Victor Navarro","doi":"10.1007/s40264-025-01589-8","DOIUrl":"https://doi.org/10.1007/s40264-025-01589-8","url":null,"abstract":"","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811947","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":"A Scoping Review of Published Literature on the Contributions of the Natural Health Products (NHPs) Industry to Pharmacovigilance for NHPs.","authors":"Xin Yi Lim, Sanyogita Ram, Shane Scahill, Joanne Barnes","doi":"10.1007/s40264-025-01587-w","DOIUrl":"https://doi.org/10.1007/s40264-025-01587-w","url":null,"abstract":"<p><strong>Background: </strong>The natural health products (NHPs) industry is a key stakeholder in pharmacovigilance for NHPs. However, the specific contributions that the NHPs industry makes to pharmacovigilance for NHPs are not well-understood.</p><p><strong>Objective: </strong>This scoping review aimed to identify and map published literature describing the contributions of the NHPs industry to pharmacovigilance activities for NHPs. Assessment of benefit-harm balance for individual NHPs/natural ingredients is outside the scope of this review.</p><p><strong>Methods: </strong>Using predetermined keywords and Medical Subject Headings, seven international electronic biomedical journal databases were searched to identify articles describing the contributions of the NHPs industry to pharmacovigilance for NHPs in relation to product surveillance and stakeholders' views on the NHPs industry and its pharmacovigilance activities.</p><p><strong>Results: </strong>Of the 2285 records identified, 40 articles (representing 40 studies) met the inclusion criteria for this review. Among these, 33 described post-marketing surveillance activities and seven explored stakeholders' views. Of the articles describing post-marketing surveillance studies, 22 were authored and/or sponsored by the industry; the remaining 11 involved contributions from the NHPs industry in the form of safety data submitted as spontaneous reports to a national or state pharmacovigilance database. Contributions of the NHPs industry were primarily through passive surveillance via spontaneous reporting. In total, 13 active surveillance studies were undertaken by the NHPs industry, mainly in clinical care settings such as medical centres, hospitals, and private practices, and were focused on single products. There were limited findings relating to stakeholders' views on pharmacovigilance and the NHPs industry's involvement.</p><p><strong>Conclusions: </strong>The NHPs industry contributes to pharmacovigilance for NHPs primarily through passive surveillance measures. Active surveillance involving the NHPs industry was typically undertaken in non-community settings. Additional research exploring stakeholders' views on and preparedness for participating in active surveillance involving the industry, focusing particularly on models based on the consumer-industry reporting pathway, could identify new strategies for strengthening post-marketing safety monitoring for NHPs.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798497","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":"7th Symposium ISoP Latin American Chapter \"Advancing Pharmacovigilance Innovation in Latin America\" August 20-22, 2025 Mérida, Yucatán, Mexico.","authors":"","doi":"10.1007/s40264-025-01595-w","DOIUrl":"https://doi.org/10.1007/s40264-025-01595-w","url":null,"abstract":"","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788548","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 Impact of COVID-19 and COVID-19 Vaccination on Detection, Assessment, and Management of Suspected Acute Drug-Induced Liver Injury Occurring during Clinical Trials: Consensus Recommendations from the IQ DILI Initiative.","authors":"Melissa Palmer, Daniel Seekins, Mark Avigan, John Marcinak, Don C Rockey, Arie Regev, Vineet K Shastri, James H Lewis, Ajit Dash","doi":"10.1007/s40264-025-01591-0","DOIUrl":"https://doi.org/10.1007/s40264-025-01591-0","url":null,"abstract":"<p><p>While the acute impact of the coronavirus disease 2019 (COVID-19) pandemic has waned, implications for clinical trials remain. In particular, guidance for evaluation of elevated liver tests due to COVID-19, its treatments, and COVID-19 vaccination is lacking. The IQ DILI Initiative, composed of experts from academia, regulatory agencies, and industry herein propose recommendations to address this gap. Extensive literature review was conducted and structured discussions were held between IQ DILI industry members, regulators, and academic experts in hepatology and DILI. Liver-related manifestations in nonhospitalized patients with COVID-19 are highly varied. Evidence of liver injury may occur after COVID-19 symptoms resolve and testing is negative. Treatments for COVID-19 may cause liver injury or alter pharmacokinetics. COVID-19 vaccination has been associated with rare but clear hepatotoxicity, typically consistent with drug-induced autoimmune-like hepatitis, although other presentations, severity, latency, and time to resolution have been reported. Liver injury occurred with mRNA and viral vector vaccines, and in individuals with and without underlying autoimmune or liver diseases. Drug developers and investigators should be aware of the potential liver-related manifestations related to COVID-19, its treatments, and COVID-19 vaccination, as this may impact study eligibility and causality assessment during a trial. COVID-19 testing should be considered part of DILI causality assessment, as a positive test may prevent premature termination of the investigational drug. Since clinical trial participants may not consider vaccinations in their medical history, specific inquiry about their receipt is important when liver tests are abnormal during screening and as part of DILI causality assessment.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783798","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":"Teratogenic Risk Impact Mitigation (TRIM): Development of Explicit Criteria to Facilitate Decisions Regarding Teratogenic Risk Mitigation Strategies.","authors":"Celeste L Y Ewig, Yanning Wang, Nicole E Smolinski, Gita A Toyserkani, Cynthia LaCivita, Leila Lackey, Sara Eggers, Leyla Sahin, Reem S Abu-Rustum, Brian T Bateman, Anick Berard, Christina D Chambers, Beth Choby, Elizabeth A Conover, Michael F Greene, Sonia Hernández-Díaz, Denise J Jamieson, Sarah G Običan, Janine E Polifka, Kay Roussos-Ross, Jeanne S Sheffield, Sharon Voyer Lavigne, Ellen M Zimmermann, Susan B Laffan, Anthony M DeLise, Alicia W Gilsenan, Tarek A Hammad, Christian Hampp, Janet R Hardy, Caitlin A Knox, Kristine Shields, Meredith Y Smith, Rachel E Sobel, Melissa S Tassinari, Judith C Maro, Sonja A Rasmussen, Almut G Winterstein","doi":"10.1007/s40264-025-01581-2","DOIUrl":"https://doi.org/10.1007/s40264-025-01581-2","url":null,"abstract":"<p><strong>Background: </strong>Preventing fetal exposure to teratogenic medications is an important target for risk mitigation efforts. Decisions about risk mitigation efforts specific to teratogenic medications are complex.</p><p><strong>Objectives: </strong>The Teratogenic Risk Impact and Mitigation (TRIM) tool was developed as an innovative decision support tool to facilitate prioritization of teratogenic medications for risk mitigation strategies.</p><p><strong>Methods: </strong>We employed a modified Delphi study design involving experts across teratology, obstetrics/gynecology, and medication safety. Panelists proposed decision criteria in three focus groups, followed by e-Delphi rounds to reach a consensus on criteria regarding three dimensions: (1) completeness; (2) relevance; and (3) distinctiveness. Aggregated feedback from each round was used to inform revision of the criteria in subsequent rounds.</p><p><strong>Results: </strong>A total of 33 candidate criteria proposed by 32 focus group participants were organized into ten distinct criteria for the Delphi process. Consensus (defined as > 85% agreement on all three dimensions) was reached after three e-Delphi rounds, resulting in six criteria: (1) background use among persons of reproductive potential; (2) overall medication benefit considering severity of the indication and availability of alternatives; (3) seriousness of the teratogenic outcome; (4) risk of the teratogenic outcome; (5) certainty regarding teratogenicity; and (6) the risk of exposure during pregnancy.</p><p><strong>Conclusions: </strong>We established measurable criteria to inform decisions when prioritizing teratogenic medications for risk mitigation programs. Criteria are consensus based and consistent with relevant regulatory guidance. Future work will operationalize these criteria and determine specific weights to facilitate medication-specific TRIM scores. Through its explicit framework, the TRIM tool may support consistent, transparent, and rational decision making and help optimize the contribution of risk mitigation programs to public health.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783797","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":"How does the Content and Dissemination of Communications on the Risks of Medicines Affect Prescriber Awareness, Knowledge, and Behaviour: A Systematic Review.","authors":"Lucy T Perry, Annim Mohammad, Ashleigh Hooimeyer, Eliza J McEwin, Barbara Mintzes","doi":"10.1007/s40264-025-01588-9","DOIUrl":"https://doi.org/10.1007/s40264-025-01588-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Medicines have important and sometimes lifesaving health benefits. They can also be the cause of harm and injury due to adverse drug reactions (ADRs). Effective communication of medicine risks is crucial to informed prescribing decisions and the protection of patient health. Clinicians must receive, interpret, and then implement these communications to achieve desired outcomes; however, this has not always been successful. Therefore, it is important to understand how the content of risk communication about medicines and the methods of dissemination may affect prescribers' awareness, knowledge, and behaviours.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Aims: &lt;/strong&gt;This systematic review provides an overview of the effect of content and dissemination of risk communications about medicines on prescribers' awareness, knowledge, and behaviour and ultimately on patient health.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A systematic review was conducted. Studies were included if they were randomised controlled trials investigating the effect of the content or dissemination of risk communications about medicines on prescribers' knowledge, awareness, and behaviour. MEDLINE, Embase, and PsycINFO via Ovid, Scopus, and Web of Science databases were searched up to December 2024. Data on intervention type, study design, prescriber type, and outcomes were extracted. Outcomes were synthesised, and meta-analysis was undertaken where results allowed for this.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Twenty-three studies met the inclusion criteria: ten investigated the content of risk communication, ten investigated dissemination methods, and three investigated both. Twenty-one studies assessed prescribing behaviours, and one study each assessed clinicians' awareness and knowledge, respectively. Two studies evaluated how risk communication content and its delivery to clinicians affected patient health outcomes. Interventions included computerised clinical systems, risk assessment tools, alerting systems, targeted messaging, and education. Visual risk assessment tools and targeted education reduced ADR rates, improving patient health. Alerts to change clinical monitoring and assessment behaviour were modestly effective (relative risk [RR] 1.03; 95% confidence interval [CI] 1.01-1.05). Multicomponent approaches also positively affected prescribing behaviours. Targeted messages, such as audit and feedback, improved clinicians' awareness of risk communications. Computer alerts and risk assessments that were interruptive and easily accessed in workflows or provided actions or information to avoid or minimise risk to patients did not significantly change prescribing (RR 1.50; 95% CI 0.87-2.60 and RR 1.41; 95% CI 0.89-2.24). However, study heterogeneity and small sample sizes limited the power to detect differences.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;There is limited evidence from randomised controlled trials comparing the effectiveness of drug risk communication strategies targeting p","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774936","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":"Uncovering the Hidden Hurdles: Exploring Challenges in Pediatric Pharmacovigilance in the Netherlands.","authors":"Anne T M Dittrich, Yvet Kroeze, Michel A A P Willemsen, Jos M Th Draaisma, Eugène P van Puijenbroek, D Maroeska W M Te Loo","doi":"10.1007/s40264-025-01593-y","DOIUrl":"https://doi.org/10.1007/s40264-025-01593-y","url":null,"abstract":"<p><strong>Introduction: </strong>The use of drugs carries risks, as adverse drug reactions (ADRs) can occur. In the Netherlands, a voluntary pharmacovigilance system is in place, allowing healthcare professionals and patients to report (suspected) ADRs. Previous research has highlighted underreporting as a significant problem; however, barriers for ADR reporting are not clear.</p><p><strong>Objectives: </strong>The aim was to assess perceptions of ADR reporting among pediatricians (in training), to identify barriers hindering reporting, and to study differences between our hospital and other Dutch hospitals.</p><p><strong>Methods: </strong>A cross-sectional survey was conducted among pediatricians (in training) in the Netherlands. The study questionnaire was based on a validated questionnaire and adjusted for the Dutch context, addressing aspects related to ADR reporting, attitudes toward ADRs in work environment, personal vision, reasons for nonreporting, and future perspectives.</p><p><strong>Results: </strong>A dataset of 127 respondents was included. Of these, 93% reported knowing how to report an ADR. Overall, 95% believed that reporting ADRs has the potential to enhance knowledge and improve drug safety, and 93% acknowledged the overall importance of ADR reporting. However, 19% of respondents indicated that they had never reported an ADR. The most commonly cited reason (61%) for not reporting was prior knowledge of the ADR. Other barriers included uncertainty about whether a symptom constituted an ADR, the perception that the ADR was not severe, and time constraints.</p><p><strong>Conclusions: </strong>This study highlights the importance of addressing barriers to ADR reporting in pediatric healthcare. While healthcare professionals recognize the significance of ADR reporting, several impediments hinder their reporting efforts.</p>","PeriodicalId":11382,"journal":{"name":"Drug Safety","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768486","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}