Haemophilia最新文献

{"title":"Abstract","authors":"","doi":"10.1111/hae.15148","DOIUrl":"10.1111/hae.15148","url":null,"abstract":"","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 S1","pages":"4-229"},"PeriodicalIF":3.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058860","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":"Operationalising a Haemophilia Gene Editing Lexicon for Practical Use.","authors":"William McKeown, Cedric Hermans, Carmen Unzu, Mark A Kay, Flora Peyvandi, Penni Smith, Wolfgang Miesbach, Glenn F Pierce, Kate Khair, Leonard A Valentino, Steven W Pipe, Monisha Pillai, Micheala Jones, Virginie Delwart, Anil Sindhurakar, David E Gutstein, Craig M Kessler","doi":"10.1111/hae.15155","DOIUrl":"https://doi.org/10.1111/hae.15155","url":null,"abstract":"<p><strong>Introduction: </strong>Gene editing therapies offer the possibility of substantial improvement in treatment and quality of life for people with haemophilia (PWH) in a landscape of dynamic therapeutic advancement. Developing a common and understandable language to discuss gene editing will be essential to ensure these treatments can be deployed in a safe and effective manner with fully informed and shared decision-making between healthcare professionals (HCPs) and PWH. A lexicon explaining and clarifying key concepts is one potential tool to address these aims. Here we evaluate how a gene editing lexicon could be deployed to maximise impact and improve patient outcomes.</p><p><strong>Aim: </strong>To operationalise the gene editing lexicon for successful adoption by the haemophilia community.</p><p><strong>Methods: </strong>Through an innovative, iterative process, representatives from the haemophilia community, including multidisciplinary HCPs, PWH, and caregivers, with support from language strategy experts, developed a gene editing lexicon and evaluated operational aspects for real-world adoption of this resource.</p><p><strong>Results: </strong>A gene editing lexicon was developed, including infographics illustrating key concepts. Infographics were adapted from the lexicon to further clarify and communicate these concepts. Infographics were found to be a potentially vital tool for enhancing the practical use of the lexicon to promote shared decision-making and attain informed consent for gene editing therapies.</p><p><strong>Conclusion: </strong>A gene editing lexicon shows promise for improving the understanding of gene editing for all stakeholders in the haemophilia community. Ensuring the lexicon remains up to date with current therapies and appropriate strategies for adoption such as infographics will enable this resource to have maximum impact.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046426","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":"Haemophilia Infants Gross Motor Development: Comparisons With Full-Term and Preterm Infants of the Same Nationality.","authors":"Dimitrios Syrengelas, Athina Dettoraki, Aikaterini Michalopoulou, Paraskevi Kleisiouni, Tania Siahanidou, Christina T Moschou, Miltiades A Kyprianou, Platon Peristeris, Helen Pergantou","doi":"10.1111/hae.15149","DOIUrl":"https://doi.org/10.1111/hae.15149","url":null,"abstract":"<p><strong>Introduction: </strong>Infants with haemophilia, due to parental overprotection, have difficulty developing their full motor repertoire of typical gross motor development. It is of great clinical importance to evaluate the motor development of these infants with a standardized assessment tool.</p><p><strong>Aim: </strong>To study the gross motor development in infants with haemophilia, using the Alberta Infant Motor Scale (AIMS) and compare it with full-term (FT) and preterm infants (PT).</p><p><strong>Methods: </strong>Fifteen FT infants with severe or moderate haemophilia A and B were assessed with the AIMS (Group D). The scale is already standardized in FT Greek infants (Group A). Two groups of PT infants were also included, with gestational age >32 weeks and ≤32 weeks, Groups B and C, respectively. The mean Z-scores were tested with the ANOVA procedure, followed by post hoc pairwise comparisons with Bonferroni correction.</p><p><strong>Results: </strong>The four groups had significantly different mean Z-scores. Infants in Group A had a mean Z-score of 0 ± 1. Infants in Group B lagged significantly behind by one standard deviation. Preterm infants in Group C had a mean Z-score significantly lower than Group B. Infants in Group D had a mean Z-score significantly lower than Group C.</p><p><strong>Conclusions: </strong>Motor development in infants with haemophilia significantly lags behind both FT and PT infants. Differences in AIMS scores could be attributed to the reduction of movement activity, since infants with haemophilia are often deprived of certain positions, being held and carried in the parents' arms, as well as from free play time on the floor.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046420","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":"Comparison of Single Knee Arthroplasty and Bilateral Knee Arthroplasty in Haemophiliacs During a Single Operation: A Systematic Review and Meta-Analysis.","authors":"Yi Zhang, Hang Pei, Chao Wang, Guanyin Wang, Zan Shen, Jiang Hua, Bangjian He","doi":"10.1111/hae.15150","DOIUrl":"https://doi.org/10.1111/hae.15150","url":null,"abstract":"<p><strong>Background: </strong>Arthroplasty is the standard treatment for end-stage haemophilic knee arthritis; however, the choice between single knee arthroplasty (SKA) and bilateral knee arthroplasty (BKA) in a single operation remains controversial due to the risks specific to haemophiliacs.</p><p><strong>Methods: </strong>Two independent researchers conducted searches across CNKI, CBM, Wanfang, PubMed, Cochrane Library, Embase, and Web of Science, with the last search performed on 15 October 2024. Study results include joint function, complication and various cost. Literature quality was assessed using the Newcastle-Ottawa Scale (NOS). Outcomes were evaluated with fixed-effects or random-effects models, while heterogeneity and publication bias were also assessed.</p><p><strong>Results: </strong>Nine studies involving 309 haemophilia patients were included, with 166 in SKA group and 143 in BKA group. No statistically significant differences were observed between the SKA and BKA groups in range of motion (95% CI: -0.22 [-3.57, 3.13], p = 0.90), Hospital for Special Surgery score (95% CI: -2.13 [-4.89, 0.64], p = 0.13), flexion degree (95% CI: -2.38 [-7.22, 2.46], p = 0.33), cost (95% CI: -0.24 [-0.94, 0.45], p = 0.49), complication rate (95% CI: 1.31 [-0.79, 2.17], p = 0.29), hospital stay (95% CI: 0.25 [-2.06, 2.57], p = 0.83), and coagulation factor usage (p = 0.49). However, The SKA group outperformed the BKA group in terms of operative time, postoperative drainage, and transfusion volume (p < 0.001).</p><p><strong>Conclusions: </strong>Our study indicates that, apart from differences in operative time, transfusion volume, and blood loss, SKA and BKA show no significant differences in postoperative joint function, complication rates, or costs.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046411","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":"Deceased Donor With Hemophilia A: To Consider or Not for Liver Donation.","authors":"Jagadeesh Menon, Prithviraj Nabi, Naresh Shanmugam, Ashwin Rammohan, Rajesh Rajalingam, Mohamed Rela","doi":"10.1111/hae.15154","DOIUrl":"https://doi.org/10.1111/hae.15154","url":null,"abstract":"","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046413","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":"Factor VIII Antibodies Demonstrate Type I or Type II Kinetics in Acquired Haemophilia A.","authors":"Kirollos Kamel, Sofia Sardo Infirri, Anne Riddell, Pratima Chowdary, Paul Batty","doi":"10.1111/hae.15144","DOIUrl":"https://doi.org/10.1111/hae.15144","url":null,"abstract":"<p><strong>Background: </strong>Acquired haemophilia A (AHA) is an acquired bleeding disorder resulting from autoantibodies against Factor VIII (FVIII). Previous studies have reported differences in FVIII inhibitor kinetics (type I or type II) in AHA compared to severe haemophilia A.</p><p><strong>Aim: </strong>To characterise inhibitor kinetics in AHA and evaluate the proportions displaying type I, II or indeterminate kinetics.</p><p><strong>Methods: </strong>Single-centre retrospective study of inhibitor kinetics in adults with AHA. Type I kinetics were defined as linear FVIII inhibition with ≥ 97% FVIII inactivation. Type II kinetics were defined as non-linear kinetics and inability to completely neutralise FVIII. Inhibitor titres were calculated using two methods outlined by the International Council for Standardisation in Haematology.</p><p><strong>Results: </strong>Baseline samples from 34 patients were included. Fifteen samples (44.1%) exhibited type I kinetics, 16 samples (47.1%) exhibited type II kinetics and 3 (8.8%) were indeterminate. Plateau mean residual FVIII:C was higher for inhibitors displaying type II compared to type I kinetics (18.6 vs. 2.9 IU/dL, p < 0.0001). Non-linear regression using a dose-response curve without categorisation for kinetics type yielded a poor fit (R² = 38%), which improved with refitting using categories of type I or II kinetics that explained 87% and 85% of the variability. The median difference in inhibitor titre between the two reporting methods was 5% and 15% in the type I and II kinetics groups, respectively.</p><p><strong>Conclusion: </strong>FVIII autoantibodies demonstrate either type I or type II kinetics. Greater discrepancy in reported inhibitor titres depending on the method used is seen for inhibitors with type II kinetics.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983208","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":"Low-Dose Emicizumab Versus Low-/Intermediate-Dose Factor VIII Secondary Prophylaxis for Noninhibitor Haemophilia A Patients With Severe Bleeding Phenotype","authors":"Nuchanun Kessakorn,&nbsp;Itsaraet Gosriwatana,&nbsp;Nuttarak Sasipong,&nbsp;Chonlatis Srichumpuang,&nbsp;Chatphatai Moonla,&nbsp;Darintr Sosothikul","doi":"10.1111/hae.15146","DOIUrl":"10.1111/hae.15146","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Subcutaneous emicizumab, a factor VIII (FVIII)-mimicking bispecific monoclonal antibody, can effectively prevent bleeds in haemophilia A (HA) patients with/without inhibitors; however, its standard-dose regimens are financially burdensome. Low-dose emicizumab prophylaxis may alternatively be applied to noninhibitor HA patients in resource-limited settings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>During 2023, Thai patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype (historical annualized bleeding rate [ABR] &gt;5 bleeds/year before regular FVIII prophylaxis) who received low-/intermediate-dose FVIII secondary prophylaxis ≥8 months were enrolled. After the 4-day washout period, low-dose emicizumab prophylaxis (2.0–2.5 mg/kg every fortnight for two loading doses, then every 4 weeks) was implemented for 8 months. Pre-/post-emicizumab ABR, annualized joint bleeding rates (AJBR), haemophilia joint health scores (HJHS) and haemophilia-specific quality-of-life (QoL) scores were analysed. Emicizumab plasma levels on modified one-stage FVIII assays were also monitored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In 15 subjects, ABR (median of differences, −2 bleeds/year; interquartile range, −3 to 0; <i>p</i> = 0.002), but not AJBR (<i>p</i> = 0.07), were reduced after switching to low-dose emicizumab prophylaxis, although the pre-dose emicizumab plasma levels at the steady state, achieved since week 12, were modest (median monthly level, 8.4 µg/mL; interquartile range, 4.3–10.4). Concurrently, HJHS (<i>p</i> = 0.008) and QoL score (<i>p </i>&lt; 0.001) were decreased, and 46.7% had zero bleeds while receiving low-dose emicizumab.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Low-dose emicizumab, compared to low-/intermediate-dose FVIII secondary prophylaxis, meaningfully improves bleeding prevention, joint health and QoL in patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype. This regimen potentially helps address previously unmet needs in HA care among low-to-middle-income countries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ClinicalTrials.gov identifier NCT06155955.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"122-131"},"PeriodicalIF":3.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907093","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":"Successful Orthopaedic Surgeries With World Federation of Haemophilia Humanitarian Aid Program in Resource-Limited Settings","authors":"Rema Ganapathi,&nbsp;Neeraj Sidharthan,&nbsp;Jecko Thachil","doi":"10.1111/hae.15141","DOIUrl":"10.1111/hae.15141","url":null,"abstract":"","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"162-165"},"PeriodicalIF":3.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907102","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":"Mortality in Haemophilia Patients in India: A National Cohort Study","authors":"Shrimati Shetty,&nbsp;Cecil Ross,&nbsp;M. Joseph John,&nbsp;Shrinath Kshirsagar,&nbsp;Nimish Kulkarni,&nbsp;D. S. Pavitra,&nbsp;Diksha Sarwan,&nbsp;P. K. Misha,&nbsp;Antony Paul,&nbsp;Apurva More,&nbsp;Nazish Kaunchale,&nbsp;Magdalene D'silva,&nbsp;Shrushti Masurkar,&nbsp;Shruti Kharat,&nbsp;Kranti Patil,&nbsp;Shalaka Patel,&nbsp;Priti Mehendale,&nbsp;Prachi Sarvaiya,&nbsp;Savita Rangarajan","doi":"10.1111/hae.15143","DOIUrl":"10.1111/hae.15143","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Mortality and morbidity in persons with haemophilia (PWH) have decreased due to improved diagnosis and treatment along with comprehensive population outreach efforts, but the impact is not uniform in different countries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The study aims to assess all-cause and intracranial haemorrhage (ICH)-specific mortality of PWH in India.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This is a retrospective, observational, multi-centric cohort study of 1020 haemophilia patients from three centres in India. The mortality data in the family was collected from personal interviews, and subsequently confirmed with the corresponding haemophilia treatment centres (HTCs). The demographic and clinical data, along with other comorbidities, were collected from the medical records.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 170 reported deaths, 73 (42.9%) were caused by ICH, and 44 (25.9%) resulted from accidents or trauma. Gastrointestinal (GI) bleeding was the third most common cause of death, accounting for 27 cases (15.9%). The average and median ages at death were 27.7 and 26 years, respectively. None of the deceased cases were receiving any prophylactic or immune tolerance induction (ITI) therapy, and all had severe haemophilia. In addition, the prevalence of inhibitors and hypertension was significantly higher in deceased cases compared to that in the general haemophilia population (<i>p</i> &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Severity of haemophilia, episodic treatment, hypertension and inhibitors showed significant association with mortality. ICH continues to be the leading cause of death among haemophilia patients in the country. This underscores the challenges in managing haemophilia and the need for improved treatment strategies to increase the life expectancy of PWH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"132-139"},"PeriodicalIF":3.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907099","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":"Cross-Cultural Translation of the Adolescent Menstrual Bleeding Questionnaire (AMBQ)","authors":"Chelsea Howie,&nbsp;Hannah Cameron,&nbsp;Mandy Bouchard,&nbsp;Victoria Price,&nbsp;Nancy L. Young,&nbsp;Meghan Pike","doi":"10.1111/hae.15145","DOIUrl":"10.1111/hae.15145","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Heavy menstrual bleeding (HMB) affects up to 37% of adolescents. Given the paucity of available tools to assess health-related quality of life (HRQoL) in adolescents with HMB, we developed the adolescent menstrual bleeding questionnaire (aMBQ), a valid and reliable measure of bleeding-related quality of life. The aim of this study was cross-cultural translation and adaptation of the English aMBQ into French to ensure accessibility for more Canadian adolescents who menstruate.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A five-step process was followed: (1) forward translation from English to Canadian French; (2) backward translation from French to English; (3) review of source and translated aMBQ to create a reconciled version; (4) cognitive debriefing to ensure linguistic and clinical equivalence and (5) review of cognitive debriefings to produce the final version of the French aMBQ. Results of cognitive debriefings were reviewed after every three participants; items were revised if presented as an issue by ≥2 participants. These changes were implemented and tested in cognitive debriefings until saturation was reached.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Linguistic changes were made to nine (33%) of the questions and one (3.7%) answer options. Major changes were made to four of the 27 questions (15%), and minor changes were made to five of the 27 questions (19%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Professional translators, clinical experts and patient input through cognitive debriefing are pivotal to successful cross-cultural translation. Results of cognitive debriefing interviews suggest the French aMBQ is easily understood and confirms its face validity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"118-121"},"PeriodicalIF":3.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881884","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}