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  • Oxford University Press (OUP)  (10)
  • English  (10)
  • 2020-2024  (10)
  • 1
    In: EP Europace, Oxford University Press (OUP), Vol. 22, No. 12 ( 2020-12-23), p. 1864-1872
    Abstract: We aimed at addressing the role of late gadolinium enhancement (LGE) in arrhythmic risk stratification of LMNA-associated cardiomyopathy (CMP). Methods and results We present data from a multicentre national cohort of patients with LMNA mutations. Of 164 screened cases, we finally enrolled patients with baseline cardiac magnetic resonance (CMR) including LGE sequences [n = 41, age 35 ± 17 years, 51% males, mean left ventricular ejection fraction (LVEF) by echocardiogram 56%]. The primary endpoint of the study was follow-up (FU) occurrence of malignant ventricular arrhythmias [MVA, including sustained ventricular tachycardia (VT), ventricular fibrillation, and appropriate implantable cardioverter-defibrillator (ICD) therapy] . At baseline CMR, 25 subjects (61%) had LGE, with non-ischaemic pattern in all of the cases. Overall, 23 patients (56%) underwent ICD implant. By 10 ± 3 years FU, eight patients (20%) experienced MVA, consisting of appropriate ICD shocks in all of the cases. In particular, the occurrence of MVA in LGE+ vs. LGE− groups was 8/25 vs. 0/16 (P = 0.014). Of note, no significant differences between LGE+ and LGE− patients were found in currently recognized risk factors for sudden cardiac death (male gender, non-missense mutations, baseline LVEF & lt;45% and non-sustained VT), all P-value & gt;0.05. Conclusions In LMNA-CMP patients, LGE at baseline CMR is significantly associated with MVA. In particular, as suggested by this preliminary experience, the absence of LGE allowed to rule-out MVA at 10 years mean FU.
    Type of Medium: Online Resource
    ISSN: 1099-5129 , 1532-2092
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2002579-8
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  • 2
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 23, No. Supplement_G ( 2021-12-08)
    Abstract: Mitochondrial A-kinase anchoring proteins (mitoAKAP) encoded by the Akap1 gene promote Protein Kinase A mitochondrial targeting, regulating mitochondrial structure and function, reactive oxygen species production, and cardiomyocyte survival. Whether mitoAKAP levels play a role in cardiac ageing, gut barrier integrity and gut microbiota composition is currently unknown. The aim of this study was to highlight the complex interplay between cardiac dysfunction, gut barrier integrity, gut microbiota composition and ageing in young (6-month-old, 6 m) and old (24-month-old, 24 m) wild type (wt) and Akap1 heterozygous mice (Akap1+/−). Methods and results Cardiac function was noninvasively analysed by echocardiography in 6 m and 24 m wt and Akap1+/− mice. Gut microbial DNA was extracted and gut microbiota composition was analysed by Illumina Mi-Seq analysis. Bioinformatics analysis was carried out to identify major intestinal populations. Alpha diversity within each sample was determined, and then analysed according to genotype and age; then, inter-sample diversity was determined. For each dataset, we used UniFrac to calculate the differences between microbial communities based on phylogenetic distance between taxa sets in a phylogenetic tree. Bioinformatics analyses were performed using the analysis of similarities (ANOSIM). To evaluate the role of mitoAKAPs in intestinal permeability, we analysed intestinal junction proteins expression levels in colon samples of all groups. Variance analysis was performed to determine significance among the groups. Partial loss of Akap1 accelerated the progression of cardiac dysfunction in 24 m mice, as demonstrated by a significantly lower % fractional shortening (%FS) compared to 24 m wt mice (%FS, wt 6 m: 60 ± 3; Akap1−/+ 6 m: 58 ± 5; wt 24 m: 49 ± 6*; Akap1−/+ 24 m: 39 ± 12*§; *P  & lt; 0.05 vs. wt 6 m; §P  & lt; 0.05 vs. wt 24 m). In 24 m Akap1+/− mice, ageing was associated to enhanced colon permeability, as shown by reduced levels of Ocln and Tjp1 mRNA expression. A principal Co-ordinate analysis of faecal samples based on their unweighted UniFrac distances revealed that samples from Akap1+/− 24 m mice cluster apart from wt 24 m samples, suggesting that Akap1+/− 24 m mice exhibit a different assortment of microbial communities. This observation was supported by ANOSIM R statistic that revealed significant differences in gut microbiota composition between wt and Akap1+/− 24 m mice (ANOSIM R = 0.475, P = 0.023), while no significant differences in bacterial assortment were identified between wt and Akap1+/− 6 m mice. We analysed the differences in abundance of all 2042 Operational Taxonomic Units (OTUs) between age-matched wt and Akap1+/−. We identified 10 OTUs differently represented in wt and Akap1+/− 6 m mice, while a bigger set of bacterial OTUs (19) were different between wt and Akap1+/− 24 m mice. Consistent with previous results in patients with heart failure, we identified Clostridiales, Blautia producta, and R. Torques among differently regulated species. These results are in accordance with previous data on patients with heart failure (HF). Conclusions Partial Akap1 deletion plays an important role in the progression towards HF and modulates colon permeability and gut microbiota composition during ageing. This work highlights the complex interplay between gut microbiota and development of cardiac dysfunction, and characterization of these processes might lead to the development of new diagnostic and therapeutic approaches for cardiac dysfunction.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 3
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: Despite optimal therapy, heart failure (HF) remains a relentless and deadly disease. Given the relative inaccessibility of myocardial human tissues, identification of circulating biomarkers mirroring myocardial pathological signaling pathways, especially in peripheral blood mononuclear cells (PBMC) is expected to be extremely relevant. Small Nucleolar RNAs (snoRNAs) have been shown to play important roles in various cellular physiological processes. However, the connection between snoRNAs and pathological dysfunction in the heart or peripheral blood mononuclear cells (PBMC) is still poorly understood. Purpose To identify novel circulating PBMC biomarkers linked to myocardial dysfunction and HF. Methods : Myocardial left ventricle (LV) samples and PBMC were obtained from patients affected by ischemic HF (HF, n =13) undergoing heart transplantation and control donors (CD, n=7) and analyzed by RNA sequencing analysis (RNASeq). SNORD3A expression levels in the different groups were evaluated by quantitative real-time PCR. HF was induced in 8-week-old wild type C57BL/6 mice by transverse aortic constriction (TAC). Sham-operated mice (sham) were used as controls. After twelve-week-TAC (12w) or sham operation, mice were anesthetized, cardiac function was analyzed by echocardiography, and cardiac/PBMC samples were collected after sacrifice. In order to test the role of SNORD3A in cardiomyocyte hypoxia, H9C2 cardiomyoblasts were transfected with SNORD3A-targeted antisense oligonucleotides (ASO) and cell survival was analyzed. Results RnaSeq analysis identified a small set of genes differentially expressed in the heart and PBMC from HF patients. Among these, SNORD3A was up-regulated in cardiac and PBMC samples from HF patients compared to CD (Figure 1A). Similarly, in murine HF induced by 12w TAC, SNORD3A levels were increased by rtPCR, both in the heart and PBMC (Figure 1B). SNORD3A expression levels were also significantly increased in H9C2 cells exposed to in vitro hypoxia (Figure 1C). Interestingly, H9C2 transfection with SNORD3A-specific ASO significantly reduced hypoxia-induced SNORD3A upregulation and reduced hypoxia-induced cell death (Figure 1D). Conclusions In this study, we identify SNORD3A as a novel possible biomarker in human HF, similarly up-regulated in the heart and PBMC, induced by hypoxia in vitro and modulating cell survival.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2141255-8
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  • 4
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 23, No. Supplement_G ( 2021-12-08)
    Abstract: Despite optimal therapy, heart failure (HF) remains a relentless and deadly disease. Given the relative inaccessibility of myocardial human tissues, identification of circulating biomarkers mirroring myocardial pathological signalling pathways, especially in peripheral blood mononuclear cells (PBMC) is expected to be extremely relevant. Small Nucleolar RNAs (snoRNAs) have been shown to play important roles in various cellular physiological processes. However, the connection between snoRNAs and pathological dysfunction in the heart or peripheral blood mononuclear cells (PBMC) is still poorly understood. To identify novel circulating PBMC biomarkers linked to myocardial dysfunction and HF. Methods Myocardial left ventricle (LV) samples and PBMC were obtained from patients affected by ischaemic HF (HF, n = 13) undergoing heart transplantation and control donors (CD, n = 7) and analysed by RNA sequencing analysis (RNASeq). SNORD3A expression levels in the different groups were evaluated by quantitative real-time PCR. HF was induced in 8-week-old wild type C57BL/6 mice by transverse aortic constriction (TAC). Sham-operated mice (sham) were used as controls. After 12-week-TAC (12w) or sham operation, mice were anesthetized, cardiac function was analysed by echocardiography, and cardiac/PBMC samples were collected after sacrifice. In order to test the role of SNORD3A in cardiomyocyte hypoxia, H9C2 cardiomyoblasts were transfected with SNORD3A-targeted antisense oligonucleotides (ASO) and cell survival was analysed. Results RNASeq analysis identified a small set of genes differentially expressed in the heart and PBMC from HF patients. Among these, SNORD3A was up-regulated in cardiac and PBMC samples from HF patients compared to CD (Figure 1A). Similarly, in murine HF induced by 12w TAC, SNORD3A levels were increased by rtPCR, both in the heart and PBMC (Figure 1B). SNORD3A expression levels were also significantly increased in H9C2 cells exposed to in vitro hypoxia (Figure 1C). Interestingly, H9C2 transfection with SNORD3A-specific ASO significantly reduced hypoxia-induced SNORD3A up-regulation and reduced hypoxia-induced cell death (Figure 1D). Conclusions In this study, we identify SNORD3A as a novel possible biomarker in human HF, similarly up-regulated in the heart and PBMC, induced by hypoxia in vitro and modulating cell survival.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2141255-8
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  • 5
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: The most commonly used method to assess peripheral oxygen saturation (SpO2) in clinical practice is pulse oximetry. Smartwatches are widespread and are increasingly being used for digital health information. The smartwatch Apple Watch 6 was developed with a new sensor and an app that allows taking on-demand readings of blood oxygen and background readings, day and night. Aims The primary aim of the study was the head-to-head comparison of the measurements of SpO2 and heart rate (HR) by the smartwatch and the standard pulse oximeter. The secondary aim was the comparison of the measurements of SpO2 and HR between subgroups (lung disease, cardiovascular disease, healthy subjects). Methods and results We enrolled study participants with lung or cardiovascular disease and healthy subjects. A total of 265 subjects were screened for enrollment in this study. After screening, 257 subjects were included in the present study. The measurements of SpO2 and HR were obtained with the Apple Watch 6 and the Nellcor system and taken within 1 minute of each other in order to ensure comparability between the two devices. The correlation between the two technologies was assessed using linear regression and estimated with Pearson analysis for normally distributed data and Spearman analysis for nonparametric data. A plot of the differences between techniques was created according to the method described by J.M. Bland and D.G. Altmann. We observed a strong positive correlation between the smartwatch and the standard commercial device in the evaluation of SpO2 measurements (r=0.89, p & lt; 0.0001; Figure 1A) and HR measurements (r=0.98, p & lt; 0.0001; Figure 1B). A very good concordance was found between SpO2 (bias, -0.2289; SD, 1.66; lower limit, -3.49; and upper limit, 3.04; Figure 2A) and HR (bias, -0.1052; SD, 2.93; lower limit, -5.84; and upper limit, 5.63; Figure 2B) measured by the smartwatch in comparison with the standard commercial device using Bland–Altman analysis. We observed similar agreements and concordance even in the different subgroups. Conclusions In conclusion, our study demonstrates the feasibility and agreement of the Apple Watch 6 compared with the standard device used to assess SpO2 in patients with cardiovascular or lung diseases and in healthy subjects.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 6
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: Ataxia Telangiectasia Mutated (ATM) protein kinase is the major sensor of DNA damage response (DDR) and oxidative stress, variously implicated in cellular metabolism. Previous studies on ATM functions in the heart have produced conflicting results. Here we hypothesized that ATM might regulate cardiomyocyte metabolic homeostasis and function. Methods Atm-mutated mice (Atm-/-) and their wild-type littermates (Atm+/+) were used to assess the effects of ATM inactivation on cardiomyocyte hypertrophy, cardiac structure, function, DDR and metabolism under sham conditions or after pressure overload by transverse aortic constriction (TAC). Results ATM inactivation induced cardiomyocyte hypertrophy (FIG.1 A), fetal gene expression re-activation and a specific metabolomic signature in the heart, characterized by significant accumulation of pyruvate, branched chain amino-acids, short-medium acyl-carnitines and metabolites of tricarboxylic acid cycle (FIG.1 C, D),. Importantly, pyruvate was trapped in the cytosol because mitochondrial carriers were suppressed and the enzymes that process pyruvate were dysregulated. As a consequence of pyruvate metabolic block, fatty acids oxidation was inefficient and resulted in the accumulation of acyl-carnitines and insulin resistance. Although these metabolic changes were present constitutively in Atm-/- mice, they were amplified by TAC, which rapidly induced heart failure (FIG.1 B) in Atm-/- mice. ATM inactivation also increased basal and TAC-induced genomic stress in cardiomyocytes, as shown by the levels of p-γ-H2AX, 8-oxodG glycosylase (OGG1/2) and apurinic site nuclease (APE1). Cardiac metabolic changes induced by ATM loss (rise of pyruvate, lactate and succinate levels) were also present in Atm-/- brains, although the basal conditions were different. Conclusions ATM rewires the metabolism of cardiac cells by inducing glycolysis and fatty acids oxidation. Combining metabolomic, DNA damage and cardiac phenotypes, we deduce that ATM stimulates glycolysis to repair DNA lesions and protect the heart against stress-induced dysfunction.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2141255-8
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  • 7
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: Mitochondrial A-kinase anchoring proteins (mitoAKAP) encoded by the Akap1 gene promote Protein Kinase A mitochondrial targeting, regulating mitochondrial structure and function, reactive oxygen species production and cardiomyocyte survival. Whether mitoAKAP levels play a role in cardiac aging, gut barrier integrity and gut microbiota composition is currently unknown. Purpose The aim of this study was to highlight the complex interplay between cardiac dysfunction, gut barrier integrity, gut microbiota composition and aging in young (6-month-old, 6m) and old (24-month-old, 24m) wild type (wt) and Akap1 heterozygous mice (Akap1+/-). Methods Cardiac function was noninvasively analyzed by echocardiography in 6m and 24m wt and Akap1+/- mice. Gut microbial DNA was extracted and gut microbiota composition was analyzed by Illumina Mi-Seq analysis. Bioinformatics analysis was carried out to identify major intestinal populations. Alpha diversity within each sample was determined, and then analyzed according to genotype and age; then, inter-sample diversity was determined. For each dataset, we used UniFrac to calculate the differences between microbial communities based on phylogenetic distance between taxa sets in a phylogenetic tree. Bioinformatics analyses were performed using the analysis of similarities (ANOSIM). To evaluate the role of mitoAKAPs in intestinal permeability, we analyzed intestinal junction proteins expression levels in colon samples of all groups. Variance analysis was performed to determine significance among the groups. Results Partial loss of Akap1 accelerated the progression of cardiac dysfunction in 24m mice, as demonstrated by a significantly lower % fractional shortening (%FS) compared to 24m wt mice (%FS, wt 6m: 60±3; Akap1-/+ 6m: 58±5; wt 24m: 49±6*; Akap1-/+ 24m: 39±12*§; *p & lt;0.05 vs. wt 6m; §p & lt;0.05 vs. wt 24m). In 24m Akap1+/- mice, aging was associated to enhanced colon permeability, as shown by reduced levels of Ocln and Tjp1 mRNA expression. A principal coordinate analysis of fecal samples based on their unweighted UniFrac distances revealed that samples from Akap1+/- 24m mice cluster apart from wt 24m samples, suggesting that Akap1+/- 24m mice exhibit a different assortment of microbial communities. This observation was supported by ANOSIM R statistic that revealed significant differences in gut microbiota composition between wt and Akap1+/- 24m mice (ANOSIM R=0.475, P=0.023), while no significant differences in bacterial assortment were identified between wt and Akap1+/- 6m mice. We analyzed the differences in abundance of all 2,042 Operational Taxonomic Units (OTUs) between age-matched wt and Akap1+/-. We identified 10 OTUs differently represented in wt and Akap1+/- 6m mice, while a bigger set of bacterial OTUs (19) were different between wt and Akap1+/-24m mice. Consistent with previous results in patients with heart failure, we identified Clostridiales, Blautia producta and R. Torques among differently regulated species. These results are in accordance with previous data on patients with heart failure (HF). Conclusion Partial Akap1 deletion plays an important role in the progression toward HF and modulates colon permeability and gut microbiota composition during aging. This work highlights the complex interplay between gut microbiota and development of cardiac dysfunction, and characterization of these processes might lead to the development of new diagnostic and therapeutic approaches for cardiac dysfunction.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2141255-8
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  • 8
    In: NAR Genomics and Bioinformatics, Oxford University Press (OUP), Vol. 5, No. 2 ( 2023-03-29)
    Abstract: Identifying cell types based on expression profiles is a pillar of single cell analysis. Existing machine-learning methods identify predictive features from annotated training data, which are often not available in early-stage studies. This can lead to overfitting and inferior performance when applied to new data. To address these challenges we present scROSHI, which utilizes previously obtained cell type-specific gene lists and does not require training or the existence of annotated data. By respecting the hierarchical nature of cell type relationships and assigning cells consecutively to more specialized identities, excellent prediction performance is achieved. In a benchmark based on publicly available PBMC data sets, scROSHI outperforms competing methods when training data are limited or the diversity between experiments is large.
    Type of Medium: Online Resource
    ISSN: 2631-9268
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 3009998-5
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  • 9
    In: British Journal of Surgery, Oxford University Press (OUP), ( 2023-11-14)
    Abstract: The association between volume, complications and pathological outcomes is still under debate regarding colorectal cancer surgery. The aim of the study was to assess the association between centre volume and severe complications, mortality, less-than-radical oncologic surgery, and indications for neoadjuvant therapy. Methods Retrospective analysis of 16,883 colorectal cancer cases from 80 centres (2018–2021). Outcomes: 30-day mortality; Clavien-Dindo grade & gt;2 complications; removal of ≥ 12 lymph nodes; non-radical resection; neoadjuvant therapy. Quartiles of hospital volumes were classified as LOW, MEDIUM, HIGH, and VERY HIGH. Independent predictors, both overall and for rectal cancer, were evaluated using logistic regression including age, gender, AJCC stage and cancer site. Results LOW-volume centres reported a higher rate of severe postoperative complications (OR 1.50, 95% c.i. 1.15–1.096, P = 0.003). The rate of ≥ 12 lymph nodes removed in LOW-volume (OR 0.68, 95% c.i. 0.56–0.85, P & lt; 0.001) and MEDIUM-volume (OR 0.72, 95% c.i. 0.62–0.83, P & lt; 0.001) centres was lower than in VERY HIGH-volume centres. Of the 4676 rectal cancer patients, the rate of ≥ 12 lymph nodes removed was lower in LOW-volume than in VERY HIGH-volume centres (OR 0.57, 95% c.i. 0.41–0.80, P = 0.001). A lower rate of neoadjuvant chemoradiation was associated with HIGH (OR 0.66, 95% c.i. 0.56–0.77, P & lt; 0.001), MEDIUM (OR 0.75, 95% c.i. 0.60–0.92, P = 0.006), and LOW (OR 0.70, 95% c.i. 0.52–0.94, P = 0.019) volume centres (vs. VERY HIGH). Conclusion Colorectal cancer surgery in low-volume centres is at higher risk of suboptimal management, poor postoperative outcomes, and less-than-adequate oncologic resections. Centralisation of rectal cancer cases should be taken into consideration to optimise the outcomes.
    Type of Medium: Online Resource
    ISSN: 0007-1323 , 1365-2168
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2006309-X
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  • 10
    In: Bioinformatics, Oxford University Press (OUP), Vol. 36, No. Supplement_2 ( 2020-12-30), p. i919-i927
    Abstract: Recent technological advances have led to an increase in the production and availability of single-cell data. The ability to integrate a set of multi-technology measurements would allow the identification of biologically or clinically meaningful observations through the unification of the perspectives afforded by each technology. In most cases, however, profiling technologies consume the used cells and thus pairwise correspondences between datasets are lost. Due to the sheer size single-cell datasets can acquire, scalable algorithms that are able to universally match single-cell measurements carried out in one cell to its corresponding sibling in another technology are needed. Results We propose Single-Cell data Integration via Matching (SCIM), a scalable approach to recover such correspondences in two or more technologies. SCIM assumes that cells share a common (low-dimensional) underlying structure and that the underlying cell distribution is approximately constant across technologies. It constructs a technology-invariant latent space using an autoencoder framework with an adversarial objective. Multi-modal datasets are integrated by pairing cells across technologies using a bipartite matching scheme that operates on the low-dimensional latent representations. We evaluate SCIM on a simulated cellular branching process and show that the cell-to-cell matches derived by SCIM reflect the same pseudotime on the simulated dataset. Moreover, we apply our method to two real-world scenarios, a melanoma tumor sample and a human bone marrow sample, where we pair cells from a scRNA dataset to their sibling cells in a CyTOF dataset achieving 90% and 78% cell-matching accuracy for each one of the samples, respectively. Availability and implementation https://github.com/ratschlab/scim. Supplementary information Supplementary data are available at Bioinformatics online.
    Type of Medium: Online Resource
    ISSN: 1367-4803 , 1367-4811
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1468345-3
    SSG: 12
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