Publications by authors named "Giulia Gobbo"

15 Publications

  • Page 1 of 1

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

J Hepatol 2021 Jul 30. Epub 2021 Jul 30.

Gastroenterology Unit, ASL Latina, Department of Translational and Precision Medicine, "Sapienza" University of Rome, Italy.

Background & Aims: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model.

Methods: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses.

Results: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD.

Conclusions: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed.

Lay Summary: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.
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http://dx.doi.org/10.1016/j.jhep.2021.07.018DOI Listing
July 2021

Mistakes Are Common; Should We Worry about Them?

Trends Mol Med 2021 08 11;27(8):721-722. Epub 2021 May 11.

British Columbia (BC) Children's Hospital Research Institute, 950 W 28th Ave., Vancouver V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, 4500 Oak St., Vancouver V6H 3N1, Canada.

Mutations arising early in human development are surprisingly common, but most often are confined to the placenta. These mutations provide clues to the normal developmental processes leading to a healthy placenta, despite these features being shared in common with cancer.
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http://dx.doi.org/10.1016/j.molmed.2021.04.008DOI Listing
August 2021

Abdominal obesity phenotype is associated with COVID-19 chest X-ray severity score better than BMI-based obesity.

Eat Weight Disord 2021 Apr 5. Epub 2021 Apr 5.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami, Coral Gables, FL, USA.

Purpose: Chest X-ray (CXR) severity score and BMI-based obesity are predictive risk factors for COVID-19 hospital admission. However, the relationship between abdominal obesity and CXR severity score has not yet been fully explored.

Methods: This retrospective cohort study analyzed the association of different adiposity indexes, including waist circumference and body mass index (BMI), with CXR severity score in 215 hospitalized patients with COVID-19.

Results: Patients with abdominal obesity showed significantly higher CXR severity scores and had higher rates of CXR severity scores ≥ 8 compared to those without abdominal obesity (P < 0.001; P = 0.001, respectively). By contrast, patients with normal weight, with overweight and those with BMI-based obesity showed no significant differences in either CXR severity scores or in the rates of CXR severity scores ≥ 8 (P = 0.104; P = 0.271, respectively). Waist circumference and waist-to-height ratio (WHtR) correlated more closely with CXR severity scores than BMI (r = 0.43, P < 0.001; r = 0.41, P < 0.001; r = 0.17, P = 0.012, respectively). The area under the curves (AUCs) for waist circumference and WHtR were significantly higher than that for BMI in identifying a high CXR severity score (≥ 8) (0.68 [0.60-0.75] and 0.67 [0.60-0.74] vs 0.58 [0.51-0.66], P = 0.001). A multivariate analysis indicated abdominal obesity (risk ratio: 1.75, 95% CI: 1.25-2.45, P < 0.001), bronchial asthma (risk ratio: 1.73, 95% CI: 1.07-2.81, P = 0.026) and oxygen saturation at admission (risk ratio: 0.96, 95% CI: 0.94-0.97, P < 0.001) as the only independent factors associated with high CXR severity scores.

Conclusion: Abdominal obesity phenotype is associated with a high CXR severity score better than BMI-based obesity in hospitalized patients with COVID-19. Therefore, when visiting the patient in a hospital setting, waist circumference should be measured, and patients with abdominal obesity should be monitored closely. Level of evidence Cross-sectional descriptive study, Level V.
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http://dx.doi.org/10.1007/s40519-021-01173-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020829PMC
April 2021

Confined placental mosaicism involving multiple de novo copy number variants associated with fetal growth restriction: A case report.

Am J Med Genet A 2021 06 22;185(6):1908-1912. Epub 2021 Mar 22.

BC Children's Hospital Research Institute, Vancouver, Canada.

The presence of multiple large (>1 Mb) copy number variants (CNVs) in non-malignant tissue is rare in human genetics. We present a liveborn male with a birth weight below the first percentile associated with placental mosaicism involving eight 2.4-3.9 Mb de novo duplications. We found that the duplications likely co-localized to the same cells, were mosaic in the placenta, and impacted maternal and paternal chromosomes. In addition, 27.4 Mb and 240 genes were duplicated in affected cells, including candidate placental genes KISS1 and REN. We ruled out involvement of homologous recombination-based mechanisms or an altered epigenome in generating the CNVs. This case highlights the diversity of genetic abnormalities in the human placenta and the gaps in our knowledge of how such errors arise.
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http://dx.doi.org/10.1002/ajmg.a.62183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251599PMC
June 2021

Genomic imbalances in the placenta are associated with poor fetal growth.

Mol Med 2021 01 7;27(1). Epub 2021 Jan 7.

The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay St, Toronto, M5G 0A4, Canada.

Background: Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth.

Methods: We used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR.

Results: Aneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5-107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3.

Conclusions: We conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.
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http://dx.doi.org/10.1186/s10020-020-00253-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792164PMC
January 2021

A Monocentric Retrospective Observational Study of Comorbidities in Patients Affected by Autoimmune Bullous Diseases.

In Vivo 2020 Jul-Aug;34(4):2113-2118

Unit of Dermatology, University of Padua, Padua, Italy

Background/aim: Autoimmune bullous diseases (AIBDs) of the skin and mucosae include a heterogeneous group of chronic diseases, which could be associated with various comorbidities. The purpose of this study was to evaluate the comorbidity profiles of patients affected by AIBDs, who referred to the Dermatological Clinic of Padua from December 2015 to June 2018.

Patients And Methods: A monocentric retrospective observational study was conducted on 157 patients with diagnosis of AIBDs. Patients' comorbidities were investigated during the periodic visits of follow-up and through the analysis of computerized medical records.

Results: Among the 157 patients, 40 (25.5%) were diagnosed with PV, 15 (9.6%) with PF, and 102 (64.9%) with BP. Nine different comorbidities were observed, but only two of these were statistically significantly associated with BP: type 2 diabetes (p=0.0142) and neuropsychiatric disorders (p=0.015).

Conclusion: BP is statistically significantly associated with type 2 diabetes mellitus and neuropsychiatric diseases. The correlation with neuropsychiatric pathologies is interesting for the possible bidirectional role in their etiology. The association with type 2 diabetes mellitus could suggest more caution in the administration of systemic corticosteroids, especially in elderly patients.
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http://dx.doi.org/10.21873/invivo.12016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439873PMC
June 2021

The significance of the placental genome and methylome in fetal and maternal health.

Hum Genet 2020 Sep 25;139(9):1183-1196. Epub 2019 Sep 25.

BC Children's Hospital Research Institute, 950 West 28th Ave, Vancouver, BC, V5Z 4H4, Canada.

The placenta is a crucial organ for supporting a healthy pregnancy, and defective development or function of the placenta is implicated in a number of complications of pregnancy that affect both maternal and fetal health, including maternal preeclampsia, fetal growth restriction, and spontaneous preterm birth. In this review, we highlight the role of the placental genome in mediating fetal and maternal health by discussing the impact of a variety of genetic alterations, from large whole-chromosome aneuploidies to single-nucleotide variants, on placental development and function. We also discuss the placental methylome in relation to its potential applications for refining diagnosis, predicting pathology, and identifying genetic variants with potential functional significance. We conclude that understanding the influence of the placental genome on common placental-mediated pathologies is critical to improving perinatal health outcomes.
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http://dx.doi.org/10.1007/s00439-019-02058-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093232PMC
September 2020

Accurate ethnicity prediction from placental DNA methylation data.

Epigenetics Chromatin 2019 08 9;12(1):51. Epub 2019 Aug 9.

Department of Medical Genetics, University of British Columbia, C201-4500 Oak Street, Vancouver, BC, V6H 3N1, Canada.

Background: The influence of genetics on variation in DNA methylation (DNAme) is well documented. Yet confounding from population stratification is often unaccounted for in DNAme association studies. Existing approaches to address confounding by population stratification using DNAme data may not generalize to populations or tissues outside those in which they were developed. To aid future placental DNAme studies in assessing population stratification, we developed an ethnicity classifier, PlaNET (Placental DNAme Elastic Net Ethnicity Tool), using five cohorts with Infinium Human Methylation 450k BeadChip array (HM450k) data from placental samples that is also compatible with the newer EPIC platform.

Results: Data from 509 placental samples were used to develop PlaNET and show that it accurately predicts (accuracy = 0.938, kappa = 0.823) major classes of self-reported ethnicity/race (African: n = 58, Asian: n = 53, Caucasian: n = 389), and produces ethnicity probabilities that are highly correlated with genetic ancestry inferred from genome-wide SNP arrays (> 2.5 million SNP) and ancestry informative markers (n = 50 SNPs). PlaNET's ethnicity classification relies on 1860 HM450K microarray sites, and over half of these were linked to nearby genetic polymorphisms (n = 955). Our placental-optimized method outperforms existing approaches in assessing population stratification in placental samples from individuals of Asian, African, and Caucasian ethnicities.

Conclusion: PlaNET provides an improved approach to address population stratification in placental DNAme association studies. The method can be applied to predict ethnicity as a discrete or continuous variable and will be especially useful when self-reported ethnicity information is missing and genotyping markers are unavailable.
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http://dx.doi.org/10.1186/s13072-019-0296-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688210PMC
August 2019

Association of a placental Interleukin-6 genetic variant (rs1800796) with DNA methylation, gene expression and risk of acute chorioamnionitis.

BMC Med Genet 2019 02 22;20(1):36. Epub 2019 Feb 22.

BC Children's Hospital Research Institute, 950 W 28th Ave, Vancouver, BC, V5Z 4H4, Canada.

Background: Acute chorioamnionitis (aCA), inflammation of the placenta and fetal membranes, is a frequently reported lesion in preterm deliveries. Genetic variants in innate immune system genes such as Interleukin-6 (IL6) may contribute to the placenta's inflammatory response, thus predisposing some pregnancies to aCA. These genetic variants may modulate molecular processes such as DNA methylation and gene expression, and in turn might affect susceptibility to aCA. Currently, there is remarkably little research on the role of fetal (placental) genetic variation in aCA. We aimed to explore the associations between genetic variants in candidate immune-system genes and susceptibility towards inflammatory responses in the placenta, which is linked to a strong inflammatory response in the newborn.

Methods: DNA samples from 269 placentas (72 aCA cases, 197 non-aCA cases) were collected for this study. Samples were genotyped at 55 ancestry informative markers (AIMs) and 16 additional single nucleotide polymorphisms (SNPs) in 12 candidate innate immune system genes using the Sequenom iPLEX Gold Assay. Publicly available datasets were used to obtain DNA methylation (GSE100197, GSE74738, GSE115508, GSE44667, GSE98224) and gene expression data (GSE44711, GSE98224).

Results: Differences in IL6 placental allele frequencies were associated with aCA (rs1800796, p = 0.04) with the CC genotype specifically implicated (OR = 3.1; p = 0.02). In a subset of the placental samples (n = 67; chorionic villi), we showed that the IL6 SNP (rs1800796) was associated with differential DNA methylation in five IL6-related CpG sites (cg01770232, cg02335517, cg07998387, cg13104385, and cg0526589), where individuals with a CC genotype showed higher DNA methylation levels than individuals carrying the GG genotype. Using two publicly available datasets, we observed that the DNA methylation levels at cg01770232 negatively correlated with IL6 gene expression in the placenta (r = - 0.67, p < 0.004; r = - 0.56, p < 2.937e-05).

Conclusions: We demonstrated that the minor C allele at the IL6 SNP (rs1800796), which is largely limited to East Asian populations, is associated with the presence of aCA. This SNP was associated with increased DNA methylation at a nearby MEPC2 binding site, which was also associated with decreased expression of IL6 in the placenta. Decreased expression of IL6 may increase vulnerability to microbial infection. Additional studies are required to confirm this association in Asian populations with larger sample sizes.
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http://dx.doi.org/10.1186/s12881-019-0768-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387541PMC
February 2019

Considerations when processing and interpreting genomics data of the placenta.

Placenta 2019 09 7;84:57-62. Epub 2019 Jan 7.

BC Children's Hospital Research Institute, 950 West 28th Ave, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, 4500, Oak Street, Vancouver, BC V6H3N1, Canada. Electronic address:

The application of genomic approaches to placental research has opened exciting new avenues to help us understand basic biological properties of the placenta, improve prenatal screening/diagnosis, and measure effects of in utero exposures on child health outcomes. In the last decade, such large-scale genomic data (including epigenomics and transcriptomics) have become more easily accessible to researchers from many disciplines due to the increasing ease of obtaining such data and the rapidly evolving computational tools available for analysis. While the potential of large-scale studies has been widely promoted, less attention has been given to some of the challenges associated with processing and interpreting such data. We hereby share some of our experiences in assessing data quality, reproducibility, and interpretation in the context of genome-wide studies of the placenta, with the aim to improve future studies. There is rarely a single "best" approach, as that can depend on the study question and sample cohort. However, being consistent, thoroughly assessing potential confounders in the data, and communicating key variables in the methods section of the manuscript are critically important to help researchers to collaborate and build on each other's work.
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http://dx.doi.org/10.1016/j.placenta.2019.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612459PMC
September 2019

No evidence for association of 677C>T and 1298A>C variants with placental DNA methylation.

Clin Epigenetics 2018 13;10:34. Epub 2018 Mar 13.

1BC Children's Hospital Research Institute, 950 W 28th Ave, Vancouver, BC V5Z 4H4 Canada.

Background: 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in one-carbon metabolism that ensures the availability of methyl groups for methylation reactions. Two single-nucleotide polymorphisms (SNPs) in the gene, 677C>T and 1298A>C, result in a thermolabile enzyme with reduced function. These variants, in both the maternal and/or fetal genes, have been associated with pregnancy complications including miscarriage, neural tube defects (NTDs), and preeclampsia (PE), perhaps due to altered capacity for DNA methylation (DNAm). In this study, we assessed the association between 677TT and 1298CC genotypes and risk of NTDs, PE, or normotensive intrauterine growth restriction (nIUGR). Additionally, we assessed whether these high-risk genotypes are associated with altered DNAm in the placenta.

Results: In 303 placentas screened for this study, we observed no significant association between the occurrence of NTDs ( = 55), PE (early-onset:  = 28, late-onset:  = 20), or nIUGR ( = 21) and placental (fetal) 677TT or 1298CC genotypes compared to healthy pregnancies ( = 179), though a trend of increased 677TT genotype in PE/IUGR together was observed (OR 2.53,  = 0.048). DNAm was profiled in 10 high-risk 677 (677TT + 1298AA), 10 high-risk 1298 (677CC + 1298CC), and 10 reference (677CC + 1298AA) genotype placentas. Linear modeling identified no significantly differentially methylated sites between high-risk 677 or 1298 and reference placentas at a false discovery rate < 0.05 and Δβ ≥ 0.05 using the Illumina Infinium HumanMethylation450 BeadChip. Using a differentially methylated region analysis or separating cytosine-guanine dinucleotides (CpGs) by CpG density to reduce multiple comparisons also did not identify differential methylation. Additionally, there was no consistent evidence for altered methylation of repetitive DNA between high-risk and reference placentas.

Conclusions: We conclude that large-scale, genome-wide disruption in DNAm does not occur in placentas with the high-risk 677TT or 1298CC genotypes. Furthermore, there was no evidence for an association of the 1298CC genotype and only a tendency to higher 677TT in pregnancy complications of PE/IUGR. This may be due to small sample sizes or folate repletion in our Canadian population attenuating effects of the high-risk variants. However, given our results and the conflicting results in the literature, investigations into alternative mechanisms that may explain the link between variants and pregnancy complications, or in populations at risk of folate deficiencies, are warranted.
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http://dx.doi.org/10.1186/s13148-018-0468-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851070PMC
February 2019

Review: placental biomarkers for assessing fetal health.

Hum Mol Genet 2017 10;26(R2):R237-R245

BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.

The placenta is a multifunctional organ that regulates key aspects of pregnancy maintenance and fetal development. As the placenta is in direct contact with maternal blood, cellular products (DNA, RNA, proteins, etc.) from the placenta can enter maternal circulation by a variety of ways. The application of serum proteins and circulating placental derived DNA has been well demonstrated for the diagnosis of aneuploidy, and there is great interest in exploring the use of placental biomarkers for the prediction of a range of fetal health parameters. In this review, we discuss how placental biomarkers might be used for the diagnosis and early detection of preeclampsia, fetal growth restriction and inflammation associated with preterm birth. We emphasize how increased understanding of the underlying placental biology can aid in the interpretation of such approaches and development of new biomarkers that can help predict the onset of pregnancy and neonatal health concerns before they manifest.
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http://dx.doi.org/10.1093/hmg/ddx210DOI Listing
October 2017

The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome.

J Hepatol 2009 Sep 26;51(3):475-82. Epub 2009 May 26.

Department of Internal Medicine, IRCCS Policlinico San Donato, University of Milan, 20097 San Donato Milanese, Milan, Italy.

Background/aims: Some evidence suggests that the systemic inflammatory response syndrome (SIRS) contributes to the poor outcome of cirrhotic patients. We studied 141 cirrhotic patients consecutively admitted to a tertiary referral centre assessing prevalence of SIRS and its relationship with in-hospital outcome.

Methods: Presence of SIRS was assessed on admission and during hospital stay. Main clinical outcomes were death and development of portal hypertension-related complications.

Results: Thirty-nine patients met SIRS criteria. SIRS was present on admission in 20 of 141 patients (14.1%), whereas it occurred during hospital stay in 19 of 121 (15.7%). SIRS was correlated with bacterial infection at admission (p=0.02), jaundice (p=0.011), high serum creatinine levels (p=0.04), high serum bilirubin levels (p=0.002), high international normalized ratio (p=0.046), high model of end-stage liver disease (MELD) score (p=0.001), and high SOFA score (p=0.003). During a follow-up of 14+/-8 days, 16 patients died (11%), 7 developed portal hypertension-related bleeding (5%), 16 hepatic encephalopathy (11%), and 5 hepatorenal syndrome type-1 (3.5%). SIRS was correlated both to death (p<0.001) and to portal hypertension-related complications (p<0.001). On multivariate analysis, SIRS and MELD were independently associated with death.

Conclusions: SIRS frequently occurs in patients with advanced cirrhosis and is associated with a poor outcome.
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http://dx.doi.org/10.1016/j.jhep.2009.04.017DOI Listing
September 2009
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