Prenatal Diagnosis最新文献

{"title":"Short- and Long-Term Outcomes of Prenatally Identified Congenital Aqueductal Stenosis by Fetal MRI.","authors":"Noah J Smith, Usha D Nagaraj, Beth M Kline-Fath, Karin S Bierbrauer, Mounira Habli, Charu Venkatesan","doi":"10.1002/pd.6690","DOIUrl":"https://doi.org/10.1002/pd.6690","url":null,"abstract":"<p><strong>Objective: </strong>Providing accurate prenatal prognostication for expectant parents is challenging due to limited literature on factors impacting outcomes in children with congenital aqueductal stenosis (CAS). This study stratified CAS patients into isolated or complex categories (presence of additional intra- or extra-cranial anomalies or genetic syndromes) and evaluated both short- and long-term outcomes. Additionally, the role of ventricular rupture was assessed.</p><p><strong>Methods: </strong>This was a single center retrospective-cohort study of CAS patients who underwent fetal MRI over a 10-year period.</p><p><strong>Results: </strong>Of 140 patients with CAS, 107 (76%) were complex and 33 (24%) were isolated. There were no differences in the size of ventricular enlargement or incidence of ventricular rupture between the two groups. 14 pregnancies were terminated, 9 experienced fetal demise/stillbirth, and there were 21 post-natal deaths. Outcomes at the time of hospital discharge were available for 86 patients and long-term follow-up data for 64. CSF diversion (via ventriculoperitoneal shunt) was performed in 95% of complex and 71% of isolated CAS patients. Acutely, no differences were noted in seizures (complex: 10%; isolated: 18%) or respiratory support but there was an increased risk for feeding support. Risks for non-ambulatory status (complex: 32% vs. isolated: 0%), epilepsy (complex: 56% vs. isolated: 19%) and long-term gastrostomy tube assisted feeding (complex: 25.5% vs. isolated: 0%) were significantly greater with complex CAS. The presence of rupture did not impact clinical outcome.</p><p><strong>Conclusion: </strong>Poor clinical outcome was associated with complex CAS. Ventricular rupture alone did not portend a poor outcome. Prenatal counseling can tailor prognostication by CAS type.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472961","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":"Prenatal Diagnosis of Warsaw Breakage Syndrome: Fetal Compound Heterozygous Variants in the DDX11 Gene Associated With Growth Restriction, Cerebral, and Extra-Cerebral Malformations.","authors":"C Kratochwila, L Pomar, S Lebon, C Gengler, D C Pavlidou, J-M Good, C Kumps, J Sichitiu","doi":"10.1002/pd.6684","DOIUrl":"https://doi.org/10.1002/pd.6684","url":null,"abstract":"<p><p>Warsaw Breakage Syndrome (WABS) is a rare autosomal recessive cohesinopathy characterized by growth retardation and congenital anomalies. This report aims to highlight the prenatal diagnosis of WABS through ultrasound findings and genetic testing. We report a case of prenatal diagnosis of WABS in a 24-week gestation fetus exhibiting microcephaly, delayed sulcation, short corpus callosum, cerebellar vermis hypoplasia and intrahepatic portal-systemic shunts. The couple had a history of a prior pregnancy termination due to severe intrauterine growth restriction and cerebral malformations. Whole exome sequencing revealed compound heterozygous pathogenic variants [NM_030653.4:c.1403dupT, p.(Ser469Valfs*32) and c.1672C>T, p.(Arg558*)] in the DDX11 gene, consistent with WABS. The same pathogenic variants were identified in the prior terminated fetus upon subsequent analysis. Postmortem examination of the proband confirmed the prenatal ultrasound findings. This case expands the understanding of the prenatal phenotypic spectrum of WABS by identifying specific cerebral and extracerebral anomalies associated with pathogenic variants in the DDX11 gene. Incorporating advanced genetic diagnostics like whole exome sequencing into prenatal care provides valuable information for genetic counseling and management of rare genetic disorders.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472960","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":"Application of Genetic Origin Analysis of Copy Number Variations in Non-Invasive Prenatal Testing.","authors":"Jing Wang, Qing-Wen Zhu, Ai-Ming Cui, Meng-Si Lin, Hai-Qin Lou","doi":"10.1002/pd.6688","DOIUrl":"https://doi.org/10.1002/pd.6688","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to assess the application of origin analysis of copy number variations (CNVs) in non-invasive prenatal testing (NIPT) and provide a basis for expanding the clinical application of NIPT.</p><p><strong>Method: </strong>We enrolled 35,317 patients who underwent NIPT between January 2019 and March 2023. Genome sequencing of copy number variation (CNV-Seq) analysis was performed using the CNV calling pipeline to identify subchromosomal abnormalities in maternal plasma. Genetic origin was determined by comparing the chimaerism ratio of CNV and the concentration of cell-free foetal DNA (cffDNA). All pregnant women with a high risk of CNV, as indicated by the NIPT, were informed of their genetic origins. Amniocentesis was recommended for detecting the CNVs in foetal chromosomes, and pregnancy outcomes were tracked.</p><p><strong>Results: </strong>A total of 109 pregnancies showed clinically significant positive results for CNV after NIPT, including 65 cases of maternal/foetal (M/F)-CNVs and 44 cases of F-CNVs. The occurrence of M/F-CNVs was independent of age, screening (serological or ultrasound) indications for abnormalities, and mode of pregnancy. The incidence of pathogenic/likely pathogenic (P/LP)-F-CNVs was high in cases where serological screening indicated intermediate, high-risk, or abnormal US findings (p < 0.05). In the M/F-CNV group, most of the P/LP-CNVs were small fragments with low penetrance; 55 (84.62%) were less than 5 Mb in size, and nine (13.85%) were between 5 and 10 Mb. In the F-CNV group, foetal P/LP-CNV was detected in 36 of 42 cases undergoing prenatal diagnosis, and no significant bias was noted in the size distribution of P/LP-F-CNV fragments. The prenatal diagnostic rate and positive predictive value in the F-CNV group were 95.45% and 85.71%, respectively, which were significantly different from those in the M/F group (26.15% and 52.95%), respectively (p < 0.05).</p><p><strong>Conclusions: </strong>Genetic origin analysis of CNV can effectively improve adherence to prenatal diagnosis in pregnant women and the accuracy of prenatal diagnosis.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472957","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":"Aberrant Fetal Brain Sulcus Formation: A Clue to the Diagnosis of Sotos Syndrome.","authors":"Caiqun Luo, Yang Liu, Hui Wang, LiYuan Chen, XiaoXia Wu, Qian Geng, Huaxuan Wen, Shengli Li, Weiqing Wu, Mei Zhong","doi":"10.1002/pd.6686","DOIUrl":"https://doi.org/10.1002/pd.6686","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to elucidate two distinct fetal ultrasound features associated with aberrant brain sulcus formation as potential prenatal markers for Sotos syndrome caused by mutations in the NSD1 gene.</p><p><strong>Method: </strong>This retrospective study investigated three fetuses across two pregnancies, including a pair of monochorionic diamniotic twins, all diagnosed with Sotos syndrome via whole exome sequencing (WES). Comprehensive clinical and laboratory data were collected and analyzed. Each fetus underwent a series of specialized neurosonographic assessments to evaluate the development of the cerebral cortex.</p><p><strong>Results: </strong>All three fetuses exhibited aberrant brain sulcus formation characterized by Sylvian fissure (SF) abnormalities and shallow parietooccipital sulcus (POS). WES revealed the presence of two de novo NSD1 variants in these fetuses.</p><p><strong>Conclusions: </strong>Fetal aberrant brain sulcus formation may represent a distinctive ultrasound feature indicative of Sotos syndrome, thereby offering additional diagnostic insights for the identification of this condition.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472942","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":"Contemporary Outcomes of a National Fetal Spina Bifida Surgery Service.","authors":"Charlotte C Kik, Yada Kunpalin, Abhaya V Kulkarni, Abby Varghese, Nimrah Abbasi, Greg Ryan, Philip L J Dekoninck, Paige T Church, Armaan Malhotra, Kamini Raghuram, Edmond Kelly, Tim Van Mieghem","doi":"10.1002/pd.6689","DOIUrl":"https://doi.org/10.1002/pd.6689","url":null,"abstract":"<p><strong>Objective: </strong>To assess contemporary outcomes of fetuses who underwent open fetal spina bifida surgery in Canada.</p><p><strong>Methods: </strong>Our clinical program prospectively collected outcomes of all consecutive fetuses who underwent open fetal spina bifida closure at the Ontario Fetal Center in Toronto and who were at least 1 year of age at the time of postnatal follow-up. We gathered information on the need for hydrocephalus treatment, motor function, bladder function, as well as neurodevelopment (Ages and Stages Questionnaire and Bayley's scales of infant development). Developmental outcomes were categorized as \"Typical Development,\" \"Possible Delay,\" or \"Significantly Delayed.\"</p><p><strong>Results: </strong>Between 2017 and 2022, 41 fetuses underwent open fetal spina bifida closure. Twenty-four patients (58.5%) responded to the questionnaire at a median age of 46.5 months. Eight children (33.3%) required CSF diversion procedures. Bladder management included clean intermittent catheterization (43.5%), spontaneous voiding (34.8%), or both (21.7%), with 43.5% needing medication for overactive bladder. All patients could sit independently, with 50% walking outside and 50% crawling indoors. Among those walking outdoors (50%), 25% did so without orthotics or aid, 58.3% with orthotics, and 16.7% required additional walking aids. Most children demonstrated typical communication and problem-solving skills (79.2%), while gross motor development was significantly delayed in 91.7% of cases. Fine motor skills varied, with 56.5% showing typical development and 34.8% possibly experiencing delays.</p><p><strong>Conclusions: </strong>This study showed a mixed developmental profile among patients who underwent open fetal spina bifida repair, consistent with the MOMs trial findings.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472958","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":"Predictive Indicators and Outcomes of Pregnancies Affected by Stage I Twin-Twin Transfusion Syndrome Treated With Fetoscopic Laser Photocoagulation.","authors":"Maiko Wagata, Seiji Wada, Haruhiko Sago, Makiko Shimabukuro, Masahiko Nakata, Shigenori Iwagaki, Yuichiro Takahashi, Hiroko Konno, Takeshi Murakoshi, Keisuke Ishii","doi":"10.1002/pd.6691","DOIUrl":"https://doi.org/10.1002/pd.6691","url":null,"abstract":"<p><strong>Objective: </strong>The significance of fetoscopic laser photocoagulation (FLP) in stage I twin-twin transfusion syndrome (TTTS) remains controversial. This study aimed to clarify the outcomes and prognostic factors of stage I TTTS after FLP.</p><p><strong>Method: </strong>We conducted a retrospective cohort study on patients with stage I TTTS who underwent FLP in Japan. The primary outcome was neonatal survival at 28 days. The adjusted odds ratios (aOR) of pre- and intraoperative factors for mortality in recipient and donor twins were calculated.</p><p><strong>Results: </strong>This study included 272 twin pairs. The survival rate of at least one twin and both twins was 98% (267 pairs) and 85% (232 pairs), respectively. Survival of the recipient twin was observed in 253 cases (93%). No factor was associated with the mortality of the recipients. Among the donor twins, 246 (90%) survived. Preoperative twin anemia-polycythemia sequence (aOR, 17.45; 95% CI, 3.16-96.31) and arterio-arterial vascular anastomosis (AAA) identified at FLP (aOR, 2.78; 95% CI, 1.10-7.06) were independently associated with mortality of the donors.</p><p><strong>Conclusion: </strong>The neonatal survival rate for both recipient and donor twins was > 90% among patients with stage I TTTS who underwent FLP. AAA is a risk factor for mortality in donors following FLP, though the pathophysiology of AAA remains to be clarified.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472959","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 Challenges of Performing Exome Sequencing in Structurally Normal Fetuses.","authors":"Natalie Chandler, Muriel Holder-Espinasse, Fionnuala Mone","doi":"10.1002/pd.6687","DOIUrl":"https://doi.org/10.1002/pd.6687","url":null,"abstract":"","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406802","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":"Prenatal Phenotypic Analysis of Branchio-Oto-Renal Spectrum Disorder Attributable to EYA1 Gene Pathogenic Variants and Systematic Literature Review.","authors":"Yuan Tian, Yuexia Lv, Handuo Wang, Jia Che, Fangying Cui, Jing Guo, Weifang Tian, Jia Peng, Bo Yang, Haiyu Li, Baixue Zhou, Xiaolu Zhu, Xueyin Cui, Ling Liu","doi":"10.1002/pd.6673","DOIUrl":"https://doi.org/10.1002/pd.6673","url":null,"abstract":"<p><strong>Background: </strong>Branchio-oto-renal (BOR) spectrum disorders are linked to pathogenic variants in the EYA1 gene, presenting significant challenges for prenatal ultrasound screening due to their phenotypic variability and complexity. Understanding these disorders' phenotypic expressions and genetic foundations is crucial.</p><p><strong>Methods: </strong>Our study included pregnant women who underwent fetal whole-exome sequencing at the Department of Medical Genetics and Prenatal Diagnosis, The Third Affiliated Hospital of Zhengzhou University, Henan, China between January 2023 and March 2024. We identified a novel EYA1 gene pathogenic variant and conducted a systematic literature review of all reported prenatal cases associated with EYA1-related diseases, focusing on the detectability of these conditions in prenatal ultrasound. Additionally, we systematically reviewed case reports related to the EYA1 gene, emphasizing missense pathogenic variants for functional predictions and locus position analysis.</p><p><strong>Results: </strong>Our research discovered a new pathogenic variant within the EYA1 gene, highlighting the difficulty of detecting BOR spectrum disorder phenotypes through prenatal ultrasound due to their subtle manifestations. We found that amniotic fluid anomalies and cardiac abnormalities are more prevalent in prenatal cases compared to postnatal cases. A critical region within the EYA Homologous Region (eyaHR) was identified, where missense pathogenic variants significantly affect protein stability, indicating a crucial area associated with the severity of phenotypic expression in EYA1 gene-associated disorders.</p><p><strong>Conclusion: </strong>This study enhances the understanding of the genetic landscape of BOR spectrum disorders and suggests that certain phenotypic markers and genetic regions may be pivotal in improving prenatal screening and diagnosis for EYA1-related diseases.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406801","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 Potential of Tele-Ultrasound, Handheld and Self-Operated Ultrasound in Pregnancy Care: A Systematic Review.","authors":"Shariva S Kariman, Josephus F M van den Heuvel, Bauke M E Adriaanse, Dick Oepkes, Mireille N Bekker","doi":"10.1002/pd.6679","DOIUrl":"https://doi.org/10.1002/pd.6679","url":null,"abstract":"<p><strong>Objective: </strong>To explore the use of tele-ultrasound and handheld or self-operated ultrasound in pregnancy.</p><p><strong>Methods: </strong>A systematic search provided 31 studies. The risk of bias for each study was assessed. Results were analyzed and presented in a narrative overview in four domains: tele-ultrasound, patient-operated ultrasound, handheld devices and low- and middle-income countries (LMIC).</p><p><strong>Results: </strong>The quality of studies was generally low or fair based on the NIH Quality Assessment Tools. Fetal tele-ultrasound services (11 studies) are feasible and especially helpful in rural areas or with increased centralization of specialist care. Three studies with patient-operated ultrasound concluded its feasibility with good-to-high experiences. The use of handheld devices in pregnancy (eight studies) showed similar ultrasound results when compared to standard devices. In LMICs, innovative use of ultrasound (nine studies) can facilitate access to obstetric care performed by trained as well as unskilled caregivers combined with remote evaluation by an expert.</p><p><strong>Conclusions: </strong>Innovations in ultrasound in pregnancy care have shown promising results for application. Although most studies demonstrated benefits for pregnant women or care providers, high-level evidence is scarce. High-quality studies on innovations are needed to assess medical outcomes, patient and provider experiences and costs.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401101","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":"Confined Placental Mosaicism Detected With Non-Invasive Prenatal Testing: Is There an Association Between Mosaic Ratio and Pregnancy Outcome?","authors":"Geerke M Eggenhuizen, Attie T J I Go, Mariëtte J V Hoffer, Eveline Goedegebuur-Zwalua, Malgorzata I Srebniak, Diane Van Opstal","doi":"10.1002/pd.6680","DOIUrl":"https://doi.org/10.1002/pd.6680","url":null,"abstract":"<p><strong>Objective: </strong>Confined placental mosaicism (CPM) is associated with an increased risk for pregnancy complications, such as fetal growth restriction (FGR), preterm birth and hypertensive disorders. Pregnancies with possible CPM can be identified with non-invasive prenatal testing (NIPT). We performed a retrospective cohort study to investigate whether the mosaic ratio, as calculated with the Veriseq v2 used for NIPT, can predict adverse pregnancy outcomes in cases of CPM.</p><p><strong>Method: </strong>A mosaic ratio for trisomies detected by NIPT and obstetric data such as fetal growth, structural fetal anomalies and birthweight were retrospectively studied in a cohort of patients with CPM diagnosed between February 2021 and October 2023. Structural and sex chromosomal aberrations were not included in this study.</p><p><strong>Results: </strong>Of 122 CPM cases, 52 cases (42.6%) showed adverse perinatal outcomes, including FGR, low birthweight, hypertensive disorders, or preterm birth. A significantly higher mosaic ratio was found in the adverse outcome group compared to those with normal outcome, but a clear-cut threshold could not be set, except potentially for trisomy 16.</p><p><strong>Conclusion: </strong>There is an association between the mosaic ratio and adverse pregnancy outcomes in cases of CPM. However, without a clear-cut threshold, it cannot be used for the individual patient for differentiation between CPM with and without clinical consequences.</p>","PeriodicalId":20387,"journal":{"name":"Prenatal Diagnosis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401099","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}