537 results on '"F. Raimondi"'
Search Results
252. IgM and IgA enriched polyclonal immunoglobulins reduce short term mortality in extremely low birth weight infants with sepsis: a retrospective cohort study.
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Capasso L, Borrelli AC, Pirozzi MR, Bucci L, Albachiara R, Ferrara T, and Raimondi F
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- Case-Control Studies, Cohort Studies, Humans, Infant, Extremely Low Birth Weight, Infant, Newborn, Retrospective Studies, Immunoglobulin A therapeutic use, Immunoglobulin M therapeutic use, Immunoglobulins, Intravenous therapeutic use, Immunologic Factors therapeutic use, Sepsis drug therapy, Sepsis mortality
- Abstract
Background: Immunoglobulin supplementation is a debated strategy in fighting sepsis. We evaluated a polyclonal IgM and IgA enriched immunoglobulin (IgMeIVIG) preparation in reducing the short-term mortality in extremely low birth weight neonates (ELBW) with proven infection., Methods: ELBW infants born from January 2008 to December 2014 were eligible for this retrospective case-control analysis if they were symptomatic and had a positive blood culture after 72 hours of life. Patients received antibiotic treatment with or without IgMeIVIG (intravenously, 250 mg/kg/day for 3 days) within the 24 hours from clinical suspicion as per indication of the attending physician. Short-term (7 and 21 days) mortality was the study primary outcome while secondary outcomes were: mortality at discharge, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, periventricular leukomalacia, and retinopathy of prematurity., Results: Each group was composed by thirty-nine infants. Both groups were similar for antenatal steroids, mode of delivery, birth weight, gestational age and SNAPII score as indicator of disease severity. Infants receiving IgMeIVIG had a significantly lower short-term mortality compared with neonates receiving antibiotics alone: 6/39 (15%) vs. 14/39 (36%); P=0.038. No differences in other outcomes were found., Conclusions: This study shows that IgMeIVIG may have a role as adjuvant therapy in ELBW infants with proven sepsis. We warrant future prospective, blinded RCT studies where IgMeIVIG can be consistently used if needed throughout the NICU admission in ELBW septic neonates to appropriately evaluate its effect on mortality at discharge.
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- 2021
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253. Predictors of low exercise cardiac output in patients with severe pulmonic regurgitation.
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Karsenty C, Khraiche D, Jais JP, Raimondi F, Ladouceur M, Waldmann V, Soulat G, Pontnau F, Bonnet D, Iserin L, and Legendre A
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- Adolescent, Adult, Cardiac Output, Low etiology, Child, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Pulmonary Valve Insufficiency complications, Retrospective Studies, Severity of Illness Index, Young Adult, Cardiac Output, Low metabolism, Cardiac Output, Low physiopathology, Exercise Test, Oxygen Consumption, Pulmonary Valve Insufficiency metabolism, Pulmonary Valve Insufficiency physiopathology
- Abstract
Background and Objectives: Chronic pulmonic regurgitation (PR) following repair of congenital heart disease (CHD) impairs right ventricular function that impacts peak exercise cardiac index (pCI). We aimed to estimate in a non-invasive way pCI and peak oxygen consumption (pVO
2 ) and to evaluate predictors of low pCI in patients with significant residual pulmonic regurgitation after CHD repair., Method: We included 82 patients (median age 19 years (range 10-54 years)) with residual pulmonic regurgitation fraction >40%. All underwent cardiac MRI and cardiopulmonary testing with measurement of pCI by thoracic impedancemetry. Low pCI was defined <7 L/min/m2 ., Results: Low pCI was found in 18/82 patients. Peak indexed stroke volume (pSVi) tended to compensate chronotropic insufficiency only in patients with normal pCI (r=-0.31, p=0.01). Below 20 years of age, only 5/45 patients had low pCI but near-normal (≥6.5 L/min/m2 ). pVO2 (mL/kg/min) was correlated with pCI (r=0.58, p=0.0002) only in patients aged >20 years. Left ventricular stroke volume in MRI correlated with pSVi only in the group of patients with low pCI (r=0.54, p=0.02). No MRI measurements predicted low pCI. In multivariable analysis, only age predicted a low pCI (OR=1.082, 95% CI 1.035 to 1.131, p=0.001) with continuous increase of risk with age., Conclusions: In patients with severe PR, pVO2 is a partial reflection of pCI. Risk of low pCI increases with age. No resting MRI measurement predicts low haemodynamic response to exercise. Probably more suitable to detect ventricular dysfunction, pCI measurement could be an additional parameter to take into account when considering pulmonic valve replacement., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
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254. Predicting in-hospital mortality from Coronavirus Disease 2019: A simple validated app for clinical use.
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Magro B, Zuccaro V, Novelli L, Zileri L, Celsa C, Raimondi F, Gori M, Cammà G, Battaglia S, Genova VG, Paris L, Tacelli M, Mancarella FA, Enea M, Attanasio M, Senni M, Di Marco F, Lorini LF, Fagiuoli S, Bruno R, Cammà C, and Gasbarrini A
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- Adult, Aged, Aged, 80 and over, COVID-19 epidemiology, Cohort Studies, Female, Hospital Mortality, Hospitalization statistics & numerical data, Humans, Italy epidemiology, Male, Middle Aged, Mobile Applications, ROC Curve, Retrospective Studies, Risk Assessment methods, Risk Factors, SARS-CoV-2 isolation & purification, COVID-19 mortality
- Abstract
Backgrounds: Validated tools for predicting individual in-hospital mortality of COVID-19 are lacking. We aimed to develop and to validate a simple clinical prediction rule for early identification of in-hospital mortality of patients with COVID-19., Methods and Findings: We enrolled 2191 consecutive hospitalized patients with COVID-19 from three Italian dedicated units (derivation cohort: 1810 consecutive patients from Bergamo and Pavia units; validation cohort: 381 consecutive patients from Rome unit). The outcome was in-hospital mortality. Fine and Gray competing risks multivariate model (with discharge as a competing event) was used to develop a prediction rule for in-hospital mortality. Discrimination and calibration were assessed by the area under the receiver operating characteristic curve (AUC) and by Brier score in both the derivation and validation cohorts. Seven variables were independent risk factors for in-hospital mortality: age (Hazard Ratio [HR] 1.08, 95% Confidence Interval [CI] 1.07-1.09), male sex (HR 1.62, 95%CI 1.30-2.00), duration of symptoms before hospital admission <10 days (HR 1.72, 95%CI 1.39-2.12), diabetes (HR 1.21, 95%CI 1.02-1.45), coronary heart disease (HR 1.40 95% CI 1.09-1.80), chronic liver disease (HR 1.78, 95%CI 1.16-2.72), and lactate dehydrogenase levels at admission (HR 1.0003, 95%CI 1.0002-1.0005). The AUC was 0.822 (95%CI 0.722-0.922) in the derivation cohort and 0.820 (95%CI 0.724-0.920) in the validation cohort with good calibration. The prediction rule is freely available as a web-app (COVID-CALC: https://sites.google.com/community.unipa.it/covid-19riskpredictions/c19-rp)., Conclusions: A validated simple clinical prediction rule can promptly and accurately assess the risk for in-hospital mortality, improving triage and the management of patients with COVID-19., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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255. Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19.
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Brunetta E, Folci M, Bottazzi B, De Santis M, Gritti G, Protti A, Mapelli SN, Bonovas S, Piovani D, Leone R, My I, Zanon V, Spata G, Bacci M, Supino D, Carnevale S, Sironi M, Davoudian S, Peano C, Landi F, Di Marco F, Raimondi F, Gianatti A, Angelini C, Rambaldi A, Garlanda C, Ciccarelli M, Cecconi M, and Mantovani A
- Subjects
- A549 Cells, Adult, C-Reactive Protein metabolism, COVID-19 epidemiology, COVID-19 virology, Cell Line, Tumor, Cells, Cultured, Cohort Studies, Endothelial Cells metabolism, Epidemics, Female, Humans, Male, Middle Aged, Monocytes metabolism, Neutrophils metabolism, Prognosis, SARS-CoV-2 physiology, Serum Amyloid P-Component metabolism, C-Reactive Protein genetics, COVID-19 genetics, Gene Expression Profiling methods, Macrophages metabolism, SARS-CoV-2 isolation & purification, Serum Amyloid P-Component genetics
- Abstract
Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation
1-3 . The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7 . RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.- Published
- 2021
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256. 4D flow cardiac magnetic resonance in children and adults with congenital heart disease: Clinical experience in a high volume center.
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Isorni MA, Moisson L, Moussa NB, Monnot S, Raimondi F, Roussin R, Boet A, van Aerschot I, Fournier E, Cohen S, Kara M, and Hascoet S
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- Adolescent, Adult, Aged, Child, Child, Preschool, Heart, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Magnetic Resonance Imaging, Cine, Magnetic Resonance Spectroscopy, Middle Aged, Predictive Value of Tests, Reproducibility of Results, Young Adult, Heart Defects, Congenital diagnostic imaging, Heart Septal Defects
- Abstract
Background: Cardiac magnetic resonance (CMR) imaging with velocity encoding along all three directions of flow, known as 4DFlow CMR, provides both anatomical and functional information. Few data are available on the usefulness of 4DFlow CMR in everyday practice. Here, our objective was to investigate the usefulness of 4DFlow CMR for assessing congenital heart disease (CHD) in everyday practice., Methods: From 2017 to 2019, consecutive patients who underwent 4DFlow CMR were included prospectively at a single high-volume centre. The parameters recommended by an expert's consensus statement for each diagnosis (congenital valvulopathy, septal defect, complex CHD, tetralogy of Fallot, aortic abnormalities) were assessed by two blinded experienced readers. 4DFlow CMRs that provided all recommended parameters were considered successful. Inter-observer and intra-observer agreement were investigated., Results: We included 187 adults and 60 children covering broad ranges of weight (4.5-142 kg) and age (0.1-67 years). 4DFlow CMR was always the second-line imaging modality, after inconclusive echocardiography, and was successful in 231/247 (91%) patients, with no significant difference between children and adults (54/60, 90%; and 177/187, 95%; respectively; p = .13). Longer time using 4DFlow CMR at our centre was associated with success; in children, older age was also associated with exam success. There was an about 12-month learning curve in children. The success rate was lowest in neonates. Inter-observer and intra-observer agreement were substantial., Conclusion: Our results suggest that 4DFlow CMR usually provides a comprehensive assessment of CHD in adults and children. A learning curve exists for children and the investigation remains challenging in neonates., (Copyright © 2020 Elsevier B.V. All rights reserved.)
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- 2020
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257. Lung ultrasound-guided surfactant administration: time for a personalized, physiology-driven therapy.
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Raimondi F, de Winter JP, and De Luca D
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- Humans, Ultrasonography, Interventional, Lung diagnostic imaging, Pulmonary Surfactants administration & dosage, Surface-Active Agents administration & dosage, Ultrasonography methods
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- 2020
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258. Using LU score to predict extubation failure in preterm infants should consider gestational age at birth.
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Alonso-Ojembarrena A and Raimondi F
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- Gestational Age, Humans, Infant, Infant, Newborn, Lung diagnostic imaging, Ultrasonography, Ventilator Weaning, Airway Extubation, Infant, Premature
- Published
- 2020
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259. Comparison of different prediction models for the indication of implanted cardioverter defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy.
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Aquaro GD, De Luca A, Cappelletto C, Raimondi F, Bianco F, Botto N, Barison A, Romani S, Lesizza P, Fabris E, Todiere G, Grigoratos C, Pingitore A, Stolfo D, Dal Ferro M, Merlo M, Di Bella G, and Sinagra G
- Abstract
Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a high risk of sudden cardiac death. Three different prediction models for the indication of implanted cardioverter defibrillator (ICD) are now available: the 5 year ARVC risk score, the International Task Force Consensus (ITFC) criteria, and the Heart Rhythm Society (HRS) criteria. We compared these three prediction models in a validation cohort of patients with definite ARVC., Methods and Results: In a cohort of 140 patients with definite ARVC, the 5 year ARVC risk score and the ITFC and HRS criteria were compared for the prediction of a major combined endpoint of sudden cardiac death, appropriate ICD intervention, resuscitated cardiac arrest, and sustained ventricular tachycardia. During the follow-up, 65 major events occurred. The 5 year ARVC risk score with a threshold >10%, derived from the maximally selected rank statistic, predicted 62 (95%) events [odds ratio (OR) 9.1, 95% confidence interval (CI) 2.6-32, P = 0.0006], the ITFC criteria 53 (81%, OR 4.8, 95% CI 2.2-10.3, P = 0.0001), and the HRS criteria 29 (45%, OR 4.2, 95% CI 1.9-9.3, P = 0.0003). At the analysis of decision curve for ICD implantation, a 5 year ARVC risk score >10% showed a greater net benefit than the ITFC and HRS criteria over a wide range of threshold probability of events. Finally, at multivariate analysis, the 5 year ARVC risk score >10% was the only independent predictor of major events., Conclusions: The 5 year score with a threshold of >10% was more effective for predicting events than the ITFC and HRS criteria., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)
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- 2020
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260. Neonatal lung ultrasound: From paradox to diagnosis … and beyond.
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Migliaro F, Salomè S, Corsini I, De Luca D, Capasso L, Gragnaniello D, and Raimondi F
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- Humans, Infant, Newborn, Infant, Premature, Bronchopulmonary Dysplasia diagnostic imaging, Lung diagnostic imaging, Ultrasonography methods
- Published
- 2020
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261. Society for Cardiovascular Magnetic Resonance (SCMR) recommended CMR protocols for scanning patients with active or convalescent phase COVID-19 infection.
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Kelle S, Bucciarelli-Ducci C, Judd RM, Kwong RY, Simonetti O, Plein S, Raimondi F, Weinsaft JW, Wong TC, and Carr J
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- COVID-19, Coronavirus Infections epidemiology, Female, Humans, Magnetic Resonance Imaging, Male, Pandemics statistics & numerical data, Pneumonia, Viral epidemiology, Severity of Illness Index, Societies, Medical, United States, Cardiovascular Diseases diagnostic imaging, Coronavirus Infections prevention & control, Infection Control organization & administration, Magnetic Resonance Imaging, Cine standards, Pandemics prevention & control, Pneumonia, Viral prevention & control, Practice Guidelines as Topic
- Abstract
The aim of this document is to provide specific recommendations on the use of cardiovascular magnetic resonance (CMR) protocols in the era of the COVID-19 pandemic. In patients without COVID-19, standard CMR protocols should be used based on clinical indication as usual. Protocols used in patients who have known / suspected active COVID-19 or post COVID-19 should be performed based on the specific clinical question with an emphasis on cardiac function and myocardial tissue characterization. Short and dedicated protocols are recommended.
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- 2020
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262. The Effect of Liraglutide on β-Blockade for Preventing Variceal Bleeding: A Case Series.
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Vukotic R, Raimondi F, Brodosi L, Vitale G, Petroni ML, Marchesini G, and Andreone P
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- Aged, Diabetes Mellitus, Type 2 drug therapy, Drug Interactions, Esophageal and Gastric Varices complications, Esophageal and Gastric Varices drug therapy, Female, Gastrointestinal Hemorrhage complications, Gastrointestinal Hemorrhage drug therapy, Heart Rate drug effects, Humans, Hypoglycemic Agents therapeutic use, Liraglutide therapeutic use, Male, Middle Aged, Adrenergic beta-Antagonists therapeutic use, Diabetes Mellitus, Type 2 complications, Esophageal and Gastric Varices prevention & control, Gastrointestinal Hemorrhage prevention & control, Hypoglycemic Agents adverse effects, Liraglutide adverse effects, Propranolol therapeutic use
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- 2020
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263. Cardiac computed tomography angiography in the paediatric population: Expert consensus from the Filiale de cardiologie pédiatrique et congénitale (FCPC) and the Société française d'imagerie cardiaque et vasculaire diagnostique et interventionnelle (SFICV).
- Author
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Warin Fresse K, Isorni MA, Dacher JN, Pontana F, Gorincour G, Boddaert N, Jacquier A, and Raimondi F
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- Adolescent, Age Factors, Child, Child, Preschool, Computed Tomography Angiography adverse effects, Consensus, Coronary Angiography adverse effects, Heart Defects, Congenital therapy, Humans, Infant, Infant, Newborn, Predictive Value of Tests, Prognosis, Radiation Dosage, Radiation Exposure adverse effects, Reproducibility of Results, Risk Assessment, Risk Factors, Computed Tomography Angiography standards, Coronary Angiography standards, Coronary Vessels diagnostic imaging, Heart Defects, Congenital diagnostic imaging
- Abstract
This paper aims to provide a paediatric cardiac computed tomography angiography expert panel consensus based on the opinions of experts from the Société française d'imagerie cardiaque et vasculaire diagnostique et interventionnelle (SFICV) and the Filiale de cardiologie pédiatrique congénitale (FCPC). This expert panel consensus includes recommendations for indications, patient preparation, computed tomography angiography radiation dose reduction techniques and postprocessing techniques. We think that to realize its full potential and to avoid pitfalls, cardiac computed tomography angiography in children with congenital heart disease requires training and experience. Moreover, paediatric cardiac computed tomography angiography protocols should be standardized to acquire optimal images in this population with the lowest radiation dose possible, to prevent unnecessary radiation exposure. We also provide a suggested structured report and a list of acquisition protocols and technical parameters in relation to specific vendors., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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264. Prognostic Value of Magnetic Resonance Phenotype in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.
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Aquaro GD, De Luca A, Cappelletto C, Raimondi F, Bianco F, Botto N, Lesizza P, Grigoratos C, Minati M, Dell'Omodarme M, Pingitore A, Stolfo D, Ferro MD, Merlo M, Di Bella G, and Sinagra G
- Subjects
- Adult, Arrhythmogenic Right Ventricular Dysplasia physiopathology, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Cine standards, Male, Middle Aged, Prognosis, Prospective Studies, Young Adult, Arrhythmogenic Right Ventricular Dysplasia diagnostic imaging, Magnetic Resonance Imaging, Cine methods, Phenotype, Registries
- Abstract
Background: Cardiac magnetic resonance (CMR) is widely used to assess tissue and functional abnormalities in arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a ARVC risk score was proposed to predict the 5-year risk of malignant ventricular arrhythmias in patients with ARVC. However, CMR features such as fibrosis, fat infiltration, and left ventricular (LV) involvement were not considered., Objectives: The authors sought to evaluate the prognostic role of CMR phenotype in patients with definite ARVC and to evaluate the effectiveness of the novel 5-year ARVC risk score to predict cardiac events in different CMR presentations., Methods: A total of 140 patients with definite ARVC were enrolled (mean age 42 ± 17 years, 97 males) in this multicenter prospective registry. As per study design, CMR was performed in all the patients at enrollment. The novel 5-year ARVC risk score was retrospectively calculated using the patient's characteristics at the time of enrollment. During a median follow-up of 5 years (2 to 8 years), the combined endpoint of sudden cardiac death, appropriate implantable cardioverter-defibrillator intervention, and aborted cardiac arrest was considered., Results: CMR was completely negative in 14 patients (10%), isolated right ventricular (RV) involvement was found in 58 (41%), biventricular in 52 (37%), and LV dominant in 16 (12%). During the follow-up, 48 patients (34%) had major events, but none occurred in patients with negative CMR. At Kaplan-Meier analysis, patients with LV involvement (LV dominant and biventricular) had a worse prognosis than those with lone RV (p < 0.0001). At multivariate analysis, the LV involvement, a LV-dominant phenotype, and the 5-year ARVC risk score were independent predictors of major events. The estimated 5-year risk was able to predict the observed risk in patients with lone RV but underestimated the risk in those with LV involvement., Conclusions: Different CMR presentations of ARVC are associated with different prognoses. The 5-year ARVC risk score is valid for the estimation of risk in patients with lone-RV presentation but underestimated the risk when LV is involved., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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265. Pediatric cardiac computed tomography angiography: Expert consensus from the Filiale de Cardiologie Pédiatrique et Congénitale (FCPC) and the Société Française d'Imagerie Cardiaque et Vasculaire diagnostique et interventionnelle (SFICV).
- Author
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Warin-Fresse K, Isornii MA, Dacher JN, Pontana F, Gorincour G, Boddaert N, Jacquier A, and Raimondi F
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- Child, Computed Tomography Angiography, Consensus, Coronary Angiography, Humans, Radiation Dosage, Tomography, X-Ray Computed, Heart Defects, Congenital diagnostic imaging, Radiation Exposure
- Abstract
This article was designed to provide a pediatric cardiac computed tomography angiography (CCTA) expert panel consensus based on opinions of experts of the Société Française d'Imagerie Cardiaque et Vasculaire diagnostique et interventionnelle (SFICV) and of the Filiale de Cardiologie Pédiatrique Congénitale (FCPC). This expert panel consensus includes recommendations for indications, patient preparation, CTA radiation dose reduction techniques, and post-processing techniques. The consensus was based on data from available literature (original papers, reviews and guidelines) and on opinions of a group of specialists with extensive experience in the use of CT imaging in congenital heart disease. In order to reach high potential and avoid pitfalls, CCTA in children with congenital heart disease requires training and experience. Moreover, pediatric cardiac CCTA protocols should be standardized to acquire optimal images in this population with the lowest radiation dose possible to prevent unnecessary radiation exposure. We also provided a suggested structured report and a list of acquisition protocols and technical parameters in relation to specific vendors., (Copyright © 2020 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
- Full Text
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266. Imaging features of complete congenital atresia of left coronary artery.
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Raimondi F, Secinaro A, Boddaert N, and Bonnet D
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- Coronary Angiography, Humans, Coronary Vessel Anomalies diagnostic imaging
- Published
- 2020
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267. The Natural History of Hearing Disorders in Asymptomatic Congenital Cytomegalovirus Infection.
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Salomè S, Giannattasio A, Malesci R, Marciano E, Dolce P, Portella G, Continisio GI, Di Costanzo P, Capone E, Coppola C, Capasso L, and Raimondi F
- Abstract
Background and Aim: Cytomegalovirus (CMV) is the main cause of congenital infection in developed countries leading to deafness but the burden of sensorineural hearing loss (SNHL) in asymptomatic children remains incompletely characterized. Aim of this study was to evaluate the long-term audiological outcome in this group of patients. Methods: Consecutive neonates with congenital CMV infection were followed from 2002 to 2018. Patients were considered asymptomatic if free from any clinical and instrumental impairment at referral and underwent serial clinical exams, audiological evaluations and CMV-PCR determinations. Results: A cohort of 258 children was analyzed and the disease onset was asymptomatic in 125 (48%) infants. Among these, we studied 102 patients with a follow-up longer than 1 year and a median observation period of 2.8 years (range: 1-10.3 years). No patient developed a stable delayed SNHL but only 14 (14%) presented a variable hearing impairment, seven of which bilateral. The unstable SNHL was mild in 12 infants and moderate in two. Patients with fluctuating SNHL had significantly higher urine viral load ( p 0.002) and more often positive viremia ( p 0.015) than babies with stable normal hearing. Conclusions: CMV infected, asymptomatic neonates have a low risk of transient SNHL later in infancy. Positive viremia and high urine viral load at onset are significant risk factors for delayed fluctuating SNHL. These data are relevant for an appropriate follow up plan of these patients., (Copyright © 2020 Salomè, Giannattasio, Malesci, Marciano, Dolce, Portella, Continisio, Di Costanzo, Capone, Coppola, Capasso and Raimondi.)
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- 2020
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268. May We Start Early Enteral Nutrition in Critically Ill Children?
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Capasso L and Raimondi F
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- Child, Humans, Parenteral Nutrition, Parenteral Nutrition, Total, Critical Illness therapy, Enteral Nutrition
- Published
- 2020
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269. CRISPR-Directed Therapeutic Correction at the NCF1 Locus Is Challenged by Frequent Incidence of Chromosomal Deletions.
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Wrona D, Pastukhov O, Pritchard RS, Raimondi F, Tchinda J, Jinek M, Siler U, and Reichenbach J
- Abstract
Resurrection of non-processed pseudogenes may increase the efficacy of therapeutic gene editing, upon simultaneous targeting of a mutated gene and its highly homologous pseudogenes. To investigate the potency of this approach for clinical gene therapy of human diseases, we corrected a pseudogene-associated disorder, the immunodeficiency p47
phox -deficient chronic granulomatous disease (p47phox CGD), using clustered regularly interspaced short palindromic repeats-associated nuclease Cas9 (CRISPR-Cas9) to target mutated neutrophil cytosolic factor 1 ( NCF1 ). Being separated by less than two million base pairs, NCF1 and two pseudogenes are closely co-localized on chromosome 7. In healthy people, a two-nucleotide GT deletion (ΔGT) is present in the NCF1B and NCF1C pseudogenes only. In the majority of patients with p47phox CGD, the NCF1 gene is inactivated due to a ΔGT transfer from one of the two non-processed pseudogenes. Here we demonstrate that concurrent targeting and correction of mutated NCF1 and its pseudogenes results in therapeutic CGD phenotype correction, but also causes potentially harmful chromosomal deletions between the targeted loci in a p47phox -deficient CGD cell line model. Therefore, development of genome-editing-based treatment of pseudogene-related disorders mandates thorough safety examination, as well as technological advances, limiting concurrent induction of multiple double-strand breaks on a single chromosome., (© 2020 The Author(s).)- Published
- 2020
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270. Why does the Aβ peptide of Alzheimer share structural similarity with antimicrobial peptides?
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Pastore A, Raimondi F, Rajendran L, and Temussi PA
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- Alzheimer Disease immunology, Alzheimer Disease pathology, Amyloid beta-Peptides chemistry, Animals, Bacteria immunology, Bacteria pathogenicity, Brain immunology, Brain pathology, Databases, Protein, Host-Pathogen Interactions, Humans, Immunity, Innate, Models, Molecular, Peptide Fragments chemistry, Pore Forming Cytotoxic Proteins chemistry, Protein Aggregates, Protein Aggregation, Pathological, Protein Conformation, Structure-Activity Relationship, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Brain metabolism, Peptide Fragments metabolism, Pore Forming Cytotoxic Proteins metabolism
- Abstract
The Aβ peptides causally associated with Alzheimer disease have been seen as seemingly purposeless species produced by intramembrane cleavage under both physiological and pathological conditions. However, it has been increasingly suggested that they could instead constitute an ancient, highly conserved effector component of our innate immune system, dedicated to protecting the brain against microbial attacks. In this antimicrobial protection hypothesis, Aβ aggregation would switch from an abnormal stochastic event to a dysregulated innate immune response. In this perspective, we approach the problem from a different and complementary perspective by comparing the structure and sequence of Aβ(1-42) with those of bona fide antimicrobial peptides. We demonstrate that Aβ(1-42) bears convincing structural similarities with both viral fusion domains and antimicrobial peptides, as well as sequence similarities with a specific family of bacterial bacteriocins. We suggest a model of the mechanism by which Aβ peptides could elicit the immune response against microbes.
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- 2020
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271. Trends, risk factors and outcomes of healthcare-associated infections in a neonatal intensive care unit in Italy during 2013-2017.
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Scamardo MS, Dolce P, Esposito EP, Raimondi F, Triassi M, and Zarrilli R
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- Cross Infection diagnosis, Cross Infection microbiology, Female, Humans, Incidence, Infant, Newborn, Italy, Length of Stay, Male, Respiration, Artificial, Retrospective Studies, Risk Factors, Time Factors, Cross Infection epidemiology, Intensive Care Units, Neonatal
- Abstract
Background: Healthcare-associated infections (HAIs) occur frequently in intensive care units (NICUs). The aim of this study was to analyze the results of surveillance of HAIs in a III level NICU in Naples, Italy during 2013-2017 and to compare with those obtained during 2006-2010., Methods: The surveillance included 1265 neonates of all birth weight (BW) classes with > 2 days NICU stay. Infections were defined using standard Centers for Disease Control and Prevention definitions adapted to neonatal pathology., Results: A total of 125 HAIs were registered during 2013-2017 with a frequency of 9.9% and an incidence density of 3.2 per 1000 patient days. HAIs occurred in all BW classes with a decreasing trend from the lowest to the highest BW classes (p = < 0.001). Central line-associated blood stream infection (CLABSI) was the most frequent infection (69.6%), followed by ventilator associated pneumonia (VAP) (20%), urinary tract infection (UTI) (8.8%) and necrotizing enterocolitis (NEC) (1.6%). Also, CLABSI and VAP incidence density decreased from lower to highest BW classes showing a significant trend (p = 0.007). Most frequent pathogens responsible for CLABSI were: Coagulase-negative staphylococci (CONS) (25.3%), Candida parapsilosis (21.8%), Pseudomonas aeruginosa (5.7), Escherichia coli and Klebsiella pneumoniae (6.8%). No microbiological diagnosis was achieved for 20.7% of CLABSI. Pseudomonas aeruginosa (28%), Stenotrophomonas maltophilia (20%), and CONS (20%) were the most frequent pathogens responsible for VAP. CLABSI incidence density showed no differences between 2006 and 2010 and 2013-2017, while VAP incidence density for the 751-100 g BW class was higher during 2006-2010 than during 2013-2017 (p = 0.006). A higher incidence of the CLABSI caused by Gram positive bacteria (p = 0.002) or by undetermined etiology (p = 0.01) was observed during 2013-2017 than during 2006-2010, while a significant lower incidence of VAP caused by Gram-negative bacteria was found during 2013-2017 than during 2006-2010 (p = 0.007)., Conclusion: HAIs in the NICU developed in all BW classes with a decreasing trend from the lowest to the highest BW classes in both study periods. Differences in the aetiology of CLABSI and VAP were found between the two study periods. This reinforces the importance of HAIs surveillance protocol in the NICU, which monitors microbiological isolates and use of medical devices for all BW classes of neonates.
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- 2020
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272. 4D flow MRI versus conventional 2D for measuring pulmonary flow after Tetralogy of Fallot repair.
- Author
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Isorni MA, Martins D, Ben Moussa N, Monnot S, Boddaert N, Bonnet D, Hascoet S, and Raimondi F
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Echocardiography methods, Female, Four-Dimensional Computed Tomography methods, Humans, Magnetic Resonance Imaging, Cine methods, Male, Middle Aged, Retrospective Studies, Tetralogy of Fallot physiopathology, Young Adult, Echocardiography standards, Four-Dimensional Computed Tomography standards, Magnetic Resonance Imaging, Cine standards, Pulmonary Circulation physiology, Tetralogy of Fallot diagnostic imaging
- Abstract
Background: After tetralogy of Fallot (TOF) repair, pulmonary regurgitation and right ventricular function must be monitored. Conventional (2D) cardiac magnetic resonance (CMR) is currently the clinical reference method for measuring pulmonary regurgitation. However, 4DFlow CMR has been reported to provide a more comprehensive flow analysis than 2D CMR. We aimed to compare 4DFlow CMR to 2D CMR for assessing pulmonary regurgitation and flow, as well as aortic flow, in children and adults after surgical repair of TOF., Methods: Retrospective analysis of patients with repaired TOF admitted for cardiac MRI with 4DFlow acquisition from 2016 to 2018. Linear regression was used to assess correlations and Bland-Altman analyses were performed., Results: The 60 included patients had a mean age of 18.2 ± 10.4 years (range, 2-54 years). Significant correlations between the two techniques were found for pulmonary regurgitant fraction (R [2] = 0.6642, p < 0.0001), net pulmonary flow (R [2] = 0.6782, p < 0.0001), forward pulmonary flow (R [2] = 0.6185, p < 0.0001), backward pulmonary flow (R [2] = 0.8192, p < 0.0001), and aortic valve flow (R [2] = 0.6494, p < 0.0001). The Bland-Altman analysis showed no significant bias, narrow limits of agreement, and few scattered points. The correlation between pulmonary and aortic flow was better with 4DFlow CMR than with 2D CMR (R [2] = 0.8564, p < 0.0001 versus R [2] = 0.4393, p < 0,0001, respectively). Interobserver reliability was good., Conclusion: These results establish the feasibility and reliability of 4DFlow CMR for assessing pulmonary flow in a large paediatric and adult population with repaired TOF. 4DFlow CMR may be more reliable than 2D MRI for pulmonary flow assessment after TOF repair., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2020
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273. Neonatal Hyperbilirubinemia: An Updated Appraisal of National Guidelines.
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Capasso L, Palma M, Coppola C, Salomè S, Esposito V, Grappone L, and Raimondi F
- Subjects
- Child, Humans, Infant, Newborn, Hyperbilirubinemia, Neonatal diagnosis, Hyperbilirubinemia, Neonatal therapy, Kernicterus diagnosis, Kernicterus etiology, Kernicterus therapy
- Abstract
Recent reports from several developed countries have documented a resurgence of bilirubin encephalopathy causing both healthcare and forensic issues. For these reasons, many national pediatric societies have issued recommendations on the diagnosis and the treatment of clinically significant neonatal hyperbilirubinemia. The differences among individual national documents may have an impact on neonatal healthcare. This paper shortly reviews the advantages and the shortcomings of the main international guidelines with a focus on the available evidence., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2020
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274. Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases.
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Mundo L, Ambrosio MR, Raimondi F, Del Porro L, Guazzo R, Mancini V, Granai M, Jim Rocca B, Lopez C, Bens S, Onyango N, Nyagol J, Abinya N, Navari M, Ndede I, Patel K, Paolo Piccaluga P, Bob R, de Santi MM, Russell RB, Lazzi S, Siebert R, Stein H, and Leoncini L
- Subjects
- Adolescent, Adult, Aged, Burkitt Lymphoma epidemiology, Burkitt Lymphoma pathology, Child, Female, Genomics methods, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Immunophenotyping, Male, Middle Aged, Models, Molecular, Mutation, Protein Conformation, RNA, Messenger genetics, Structure-Activity Relationship, Translocation, Genetic, Young Adult, Burkitt Lymphoma genetics, Burkitt Lymphoma metabolism, Gene Expression Regulation, Neoplastic, Genes, Switch, Genes, myc
- Abstract
MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
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- 2019
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275. Auto-regulation of Rab5 GEF activity in Rabex5 by allosteric structural changes, catalytic core dynamics and ubiquitin binding.
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Lauer J, Segeletz S, Cezanne A, Guaitoli G, Raimondi F, Gentzel M, Alva V, Habeck M, Kalaidzidis Y, Ueffing M, Lupas AN, Gloeckner CJ, and Zerial M
- Subjects
- Animals, Catalytic Domain, Cell Line, Humans, Protein Binding, Protein Transport, Guanine Nucleotide Exchange Factors metabolism, Ubiquitin metabolism, rab5 GTP-Binding Proteins metabolism
- Abstract
Intracellular trafficking depends on the function of Rab GTPases, whose activation is regulated by guanine exchange factors (GEFs). The Rab5 GEF, Rabex5, was previously proposed to be auto-inhibited by its C-terminus. Here, we studied full-length Rabex5 and Rabaptin5 proteins as well as domain deletion Rabex5 mutants using hydrogen deuterium exchange mass spectrometry. We generated a structural model of Rabex5, using chemical cross-linking mass spectrometry and integrative modeling techniques. By correlating structural changes with nucleotide exchange activity for each construct, we uncovered new auto-regulatory roles for the ubiquitin binding domains and the Linker connecting those domains to the catalytic core of Rabex5. We further provide evidence that enhanced dynamics in the catalytic core are linked to catalysis. Our results suggest a more complex auto-regulation mechanism than previously thought and imply that ubiquitin binding serves not only to position Rabex5 but to also control its Rab5 GEF activity through allosteric structural alterations., Competing Interests: JL, SS, AC, GG, FR, MG, VA, MH, YK, MU, AL, CG, MZ No competing interests declared, (© 2019, Lauer et al.)
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- 2019
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276. Interconnecting Flexibility, Structural Communication, and Function in RhoGEF Oncoproteins.
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Felline A, Belmonte L, Raimondi F, Bellucci L, and Fanelli F
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- Binding Sites, Humans, Models, Molecular, Molecular Dynamics Simulation, Protein Conformation, Protein Domains, Oncogene Proteins chemistry, Rho Guanine Nucleotide Exchange Factors chemistry
- Abstract
Dbl family Rho guanine nucleotide exchange factors (RhoGEFs) play a central role in cell biology by catalyzing the exchange of guanosine 5'-triphosphate for guanosine 5'-diphosphate (GDP) on RhoA. Insights into the oncogenic constitutive activity of the Lbc RhoGEF were gained by analyzing the structure and dynamics of the protein in different functional states and in comparison with a close homologue, leukemia-associated RhoGEF. Higher intrinsic flexibility, less dense and extended structure network, and less stable allosteric communication pathways in Lbc, compared to the nonconstitutively active homologue, emerged as major determinants of the constitutive activity. Independent of the state, the essential dynamics of the two RhoGEFs is contributed by the last 10 amino acids of Dbl homology (DH) and the whole pleckstrin homology (PH) domains and tends to be equalized by the presence of RhoA. The catalytic activity of the RhoGEF relies on the scaffolding action of the DH domain that primarily turns the switch I (SWI) of RhoA on itself through highly conserved amino acids participating in the stability core and essential for function. Changes in the conformation of SWI and disorganization of the RhoA regions deputed to nucleotide binding are among the major RhoGEF effects leading to GDP release. Binding of RhoA reorganizes the allosteric communication on RhoGEF, strengthening the communication among the canonical RhoA binding site on DH, a secondary RhoA binding site on PH, and the binding site for heterotrimeric G proteins, suggesting dual roles for RhoA as a catalysis substrate and as a regulatory protein. The structure network-based analysis tool employed in this study proved to be useful for predicting potentially druggable regulatory sites in protein structures.
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- 2019
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277. Quasifree Neutron Knockout from ^{54}Ca Corroborates Arising N=34 Neutron Magic Number.
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Chen S, Lee J, Doornenbal P, Obertelli A, Barbieri C, Chazono Y, Navrátil P, Ogata K, Otsuka T, Raimondi F, Somà V, Utsuno Y, Yoshida K, Baba H, Browne F, Calvet D, Château F, Chiga N, Corsi A, Cortés ML, Delbart A, Gheller JM, Giganon A, Gillibert A, Hilaire C, Isobe T, Kahlbow J, Kobayashi T, Kubota Y, Lapoux V, Liu HN, Motobayashi T, Murray I, Otsu H, Panin V, Paul N, Rodriguez W, Sakurai H, Sasano M, Steppenbeck D, Stuhl L, Sun YL, Togano Y, Uesaka T, Wimmer K, Yoneda K, Achouri N, Aktas O, Aumann T, Chung LX, Flavigny F, Franchoo S, Gašparić I, Gerst RB, Gibelin J, Hahn KI, Kim D, Koiwai T, Kondo Y, Koseoglou P, Lehr C, Linh BD, Lokotko T, MacCormick M, Moschner K, Nakamura T, Park SY, Rossi D, Sahin E, Sohler D, Söderström PA, Takeuchi S, Törnqvist H, Vaquero V, Wagner V, Wang S, Werner V, Xu X, Yamada H, Yan D, Yang Z, Yasuda M, and Zanetti L
- Abstract
Exclusive cross sections and momentum distributions have been measured for quasifree one-neutron knockout reactions from a ^{54}Ca beam striking on a liquid hydrogen target at ∼200 MeV/u. A significantly larger cross section to the p_{3/2} state compared to the f_{5/2} state observed in the excitation of ^{53}Ca provides direct evidence for the nature of the N=34 shell closure. This finding corroborates the arising of a new shell closure in neutron-rich calcium isotopes. The distorted-wave impulse approximation reaction formalism with shell model calculations using the effective GXPF1Bs interaction and ab initio calculations concur our experimental findings. Obtained transverse and parallel momentum distributions demonstrate the sensitivity of quasifree one-neutron knockout in inverse kinematics on a thick liquid hydrogen target with the reaction vertex reconstructed to final state spin-parity assignments.
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- 2019
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278. Rare, functional, somatic variants in gene families linked to cancer genes: GPCR signaling as a paradigm.
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Raimondi F, Inoue A, Kadji FMN, Shuai N, Gonzalez JC, Singh G, de la Vega AA, Sotillo R, Fischer B, Aoki J, Gutkind JS, and Russell RB
- Subjects
- Chromogranins genetics, Computational Biology, Epistasis, Genetic, GTP-Binding Protein alpha Subunits, Gs genetics, Gene Frequency, Gene Regulatory Networks physiology, Genes, Tumor Suppressor, HEK293 Cells, Humans, Models, Molecular, Multigene Family genetics, Neoplasms mortality, Neoplasms pathology, Receptors, G-Protein-Coupled chemistry, Receptors, G-Protein-Coupled metabolism, Signal Transduction genetics, Survival Analysis, Transcription Factors genetics, Mutation physiology, Neoplasms genetics, Oncogenes genetics, Receptors, G-Protein-Coupled genetics
- Abstract
Oncodriver genes are usually identified when mutations recur in multiple tumours. Different drivers often converge in the activation or repression of key cancer-relevant pathways. However, as many pathways contain multiple members of the same gene family, individual mutations might be overlooked, as each family member would necessarily have a lower mutation frequency and thus not identified as significant in any one-gene-at-a-time analysis. Here, we looked for mutated, functional sequence positions in gene families that were mutually exclusive (in patients) with another gene in the same pathway, which identified both known and new candidate oncodrivers. For instance, many inactivating mutations in multiple G-protein (particularly G
i/o ) coupled receptors, are mutually exclusive with Gαs oncogenic activating mutations, both of which ultimately enhance cAMP signalling. By integrating transcriptomics and interaction data, we show that the Gs pathway is upregulated in multiple cancer types, even those lacking known GNAS activating mutations. This suggests that cancer cells may develop alternative strategies to activate adenylate cyclase signalling in multiple cancer types. Our study provides a mechanistic interpretation for several rare somatic mutations in multi-gene oncodrivers, and offers possible explanations for known and potential off-label cancer treatments, suggesting new therapeutic opportunities.- Published
- 2019
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279. Systolic Blood Pressure and Risk of Valvular Heart Disease: A Mendelian Randomization Study.
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Nazarzadeh M, Pinho-Gomes AC, Smith Byrne K, Canoy D, Raimondi F, Ayala Solares JR, Otto CM, and Rahimi K
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- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Heart Valve Diseases genetics, Heart Valve Diseases physiopathology, Humans, Male, Middle Aged, Risk Assessment, Blood Pressure genetics, Heart Valve Diseases epidemiology, Heart Valve Diseases etiology, Mendelian Randomization Analysis
- Abstract
Importance: Modifiable risk factors for valvular heart disease remain largely unknown, which limits prevention and treatment., Objective: To assess the association between systolic blood pressure (BP) and major valvular heart disease., Design, Setting, and Participants: A UK Biobank population-based cohort of 502 602 men and women aged 40 to 96 years at baseline was evaluated through mendelian randomization using individual participant data. Inclusion criteria were valid genetic data and BP measurements. The participants were recruited between 2006 and 2010; data analysis was performed from June 2018 to January 2019., Exposures: Systolic BP was measured during clinical assessment and instruments for the genetic effect of high BP were identified from variants that were independently (linkage disequilibrium threshold of r2<0.1) associated with systolic BP with minor allele frequency greater than 0.01. A total of 130 single-nucleotide polymorphisms that have been shown to be associated with systolic BP in a genome-wide association meta-analysis involving 1 million participants of European ancestry were selected., Main Outcomes and Measures: Incident aortic stenosis, aortic regurgitation, and mitral regurgitation, individually and combined. Cases were largely based on hospital records linked to the UK Biobank with International Classification of Diseases and Health Related Problems, Tenth Revision codes., Results: Of the 502 602 individuals screened, 329 237 participants (177 741 [53.99%] women; mean [SD] age, 56.93 [7.99] years) had valid genetic data and BP measurements; of this cohort, 3570 individuals (1.08%) had a diagnosis of valvular heart disease (aortic stenosis, 1491 [0.45%]; aortic regurgitation, 634 [0.19%]; and mitral regurgitation, 1736 [0.53%]). Each genetically associated 20-mm Hg increment in systolic BP was associated with an increased risk of aortic stenosis (odds ratio [OR], 3.26; 95% CI, 1.50-7.10), aortic regurgitation (OR, 2.59; 95% CI, 0.75-8.92), and mitral regurgitation (OR, 2.19; 95% CI, 1.07-4.47), with no evidence for heterogeneity by type of valvular heart disease (P = .90). Sensitivity analyses confirmed the robustness of the association., Conclusions and Relevance: Lifetime exposure to elevated systolic BP appears to be associated with an increased risk of major valvular heart disease.
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- 2019
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280. ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib.
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Marisi G, Petracci E, Raimondi F, Faloppi L, Foschi FG, Lauletta G, Iavarone M, Canale M, Valgiusti M, Neri LM, Ulivi P, Orsi G, Rovesti G, Vukotic R, Conti F, Cucchetti A, Ercolani G, Andrikou K, Cascinu S, Scartozzi M, and Casadei-Gardini A
- Abstract
Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 ( ANGPT2 ) and endothelial-derived nitric oxide synthase ( NOS3 ) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2 rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2 rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73-8.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73-8.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44-0.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30-0.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2 rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.
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- 2019
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281. Illuminating the Onco-GPCRome: Novel G protein-coupled receptor-driven oncocrine networks and targets for cancer immunotherapy.
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Wu V, Yeerna H, Nohata N, Chiou J, Harismendy O, Raimondi F, Inoue A, Russell RB, Tamayo P, and Gutkind JS
- Subjects
- Animals, DNA Copy Number Variations, Humans, Mutation, Neoplasms genetics, Neoplasms physiopathology, Signal Transduction, Immunotherapy, Neoplasms therapy, Receptors, G-Protein-Coupled metabolism
- Abstract
G protein-coupled receptors (GPCRs) are the largest gene family of cell membrane-associated molecules mediating signal transmission, and their involvement in key physiological functions is well-established. The ability of GPCRs to regulate a vast array of fundamental biological processes, such as cardiovascular functions, immune responses, hormone and enzyme release from endocrine and exocrine glands, neurotransmission, and sensory perception ( e.g. vision, odor, and taste), is largely due to the diversity of these receptors and the layers of their downstream signaling circuits. Dysregulated expression and aberrant functions of GPCRs have been linked to some of the most prevalent human diseases, which renders GPCRs one of the top targets for pharmaceutical drug development. However, the study of the role of GPCRs in tumor biology has only just begun to make headway. Recent studies have shown that GPCRs can contribute to the many facets of tumorigenesis, including proliferation, survival, angiogenesis, invasion, metastasis, therapy resistance, and immune evasion. Indeed, GPCRs are widely dysregulated in cancer and yet are underexploited in oncology. We present here a comprehensive analysis of GPCR gene expression, copy number variation, and mutational signatures in 33 cancer types. We also highlight the emerging role of GPCRs as part of oncocrine networks promoting tumor growth, dissemination, and immune evasion, and we stress the potential benefits of targeting GPCRs and their signaling circuits in the new era of precision medicine and cancer immunotherapies., (© 2019 Wu et al.)
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- 2019
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282. PRECOG: PREdicting COupling probabilities of G-protein coupled receptors.
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Singh G, Inoue A, Gutkind JS, Russell RB, and Raimondi F
- Subjects
- Amino Acid Sequence, Animals, Binding Sites, GTP-Binding Proteins genetics, GTP-Binding Proteins metabolism, Humans, Internet, Models, Molecular, Mutation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Engineering, Protein Interaction Domains and Motifs, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Sequence Alignment, Sequence Homology, Amino Acid, Signal Transduction, GTP-Binding Proteins chemistry, Receptors, G-Protein-Coupled chemistry, Recombinant Fusion Proteins chemistry, Software
- Abstract
G-protein coupled receptors (GPCRs) control multiple physiological states by transducing a multitude of extracellular stimuli into the cell via coupling to intra-cellular heterotrimeric G-proteins. Deciphering which G-proteins couple to each of the hundreds of GPCRs present in a typical eukaryotic organism is therefore critical to understand signalling. Here, we present PRECOG (precog.russelllab.org): a web-server for predicting GPCR coupling, which allows users to: (i) predict coupling probabilities for GPCRs to individual G-proteins instead of subfamilies; (ii) visually inspect the protein sequence and structural features that are responsible for a particular coupling; (iii) suggest mutations to rationally design artificial GPCRs with new coupling properties based on predetermined coupling features., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2019
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283. Familial intrahepatic cholestasis: New and wide perspectives.
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Vitale G, Gitto S, Vukotic R, Raimondi F, and Andreone P
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- Cholestasis, Intrahepatic physiopathology, Disease Progression, Humans, Liver physiopathology, Mutation, Exome Sequencing, ATP Binding Cassette Transporter, Subfamily B genetics, ATP Binding Cassette Transporter, Subfamily B, Member 11 genetics, Adenosine Triphosphatases genetics, Cholestasis, Intrahepatic genetics, Receptors, Cytoplasmic and Nuclear genetics
- Abstract
Background: Progressive familial intrahepatic cholestasis (PFIC) includes autosomal recessive cholestatic rare diseases of childhood., Aims: To update the panel of single genes mutations involved in familial cholestasis., Methods: PubMed search for "familial intrahepatic cholestasis" alone as well as in combination with other key words was performed considering primarily original studies and meta-analyses., Results: PFIC1 involves ATP8B1 gene encoding for aminophospholipid flippase FIC1. PFIC2 includes ABCB11 gene, encoding for protein functioning as bile salt export pump. PFIC3 is due to mutations of ABCB4 gene responsible for the synthesis of class III multidrug resistance P-glycoprotein flippase. PFIC4 and PFIC5 involve tight junction protein-2 gene and NR1H4 gene encoding for farnesoid X receptor. Benign Intrahepatic Cholestasis, Intrahepatic Cholestasis of Pregnancy and Low-phospholipid-associated cholelithiasis involve the same genes and are characterized by intermittent attacks of cholestasis, no progression to cirrhosis, reversible pregnancy-specific cholestasis and cholelithiasis in young people. Blood and liver tissue levels of bile-excreted drugs can be influenced by the presence of mutations in PFIC genes, causing drug-induced cholestasis. Mutations in PFIC genes might increase the risk of liver cancer., Conclusion: There is a high proportion of unexplained cholestasis potentially caused by specific genetic pathophysiologic pathways. The use of next generation sequencing and whole-exome sequencing could improve the diagnostic process in this setting., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)
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- 2019
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284. Illuminating G-Protein-Coupling Selectivity of GPCRs.
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Inoue A, Raimondi F, Kadji FMN, Singh G, Kishi T, Uwamizu A, Ono Y, Shinjo Y, Ishida S, Arang N, Kawakami K, Gutkind JS, Aoki J, and Russell RB
- Subjects
- Female, HEK293 Cells, Heterotrimeric GTP-Binding Proteins genetics, Humans, Male, PC-3 Cells, Receptors, G-Protein-Coupled genetics, Heterotrimeric GTP-Binding Proteins metabolism, Models, Biological, Receptors, G-Protein-Coupled metabolism, Signal Transduction
- Abstract
Heterotrimetic G proteins consist of four subfamilies (G
s , Gi/o , Gq/11 , and G12/13 ) that mediate signaling via G-protein-coupled receptors (GPCRs), principally by receptors binding Gα C termini. G-protein-coupling profiles govern GPCR-induced cellular responses, yet receptor sequence selectivity determinants remain elusive. Here, we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique Gα subunit C termini. For each receptor, we probed chimeric Gα subunit activation via a transforming growth factor-α (TGF-α) shedding response in HEK293 cells lacking endogenous Gq/11 and G12/13 proteins, and complemented G-protein-coupling profiles through a NanoBiT-G-protein dissociation assay. Interrogation of the dataset identified sequence-based coupling specificity features, inside and outside the transmembrane domain, which we used to develop a coupling predictor that outperforms previous methods. We used the predictor to engineer designer GPCRs selectively coupled to G12 . This dataset of fine-tuned signaling mechanisms for diverse GPCRs is a valuable resource for research in GPCR signaling., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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285. Congenital Lung Malformations: Unresolved Issues and Unanswered Questions.
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Annunziata F, Bush A, Borgia F, Raimondi F, Montella S, Poeta M, Borrelli M, and Santamaria F
- Abstract
Advances in prenatal and postnatal diagnosis, perioperative management, and postoperative care have dramatically increased the number of scientific reports on congenital thoracic malformations (CTM). Nearly all CTM are detected prior to birth, generally by antenatal ultrasound. After delivery, most infants do well and remain asymptomatic for a long time. However, complications may occur beyond infancy, including in adolescence and adulthood. Prenatal diagnosis is sometimes missed and detection may occur later, either by chance or because of unexplained recurrent or persistent respiratory symptoms or signs, with difficult implications for family counseling and substantial delay in surgical planning. Although landmark studies have been published, postnatal management of asymptomatic children is still controversial and needs a resolution. Our aim is to provide a focused overview on a number of unresolved issues arising from the lack of an evidence-based consensus on the management of patients with CTM. We summarized findings from current literature, with a particular emphasis on the vigorous controversies on the type and timing of diagnostic procedures, treatments and the still obscure relationship between CTM and malignancies, a matter of great concern for both families and physicians. We also present an algorithm for the assessment and follow-up of CTM detected either in the antenatal or postnatal period. A standardized approach across Europe, based on a multidisciplinary team, is urgently needed for achieving an evidence-based management protocol for CTM.
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- 2019
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286. Profiling of Epigenetic Features in Clinical Samples Reveals Novel Widespread Changes in Cancer.
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Noberini R, Restellini C, Savoia EO, Raimondi F, Ghiani L, Jodice MG, Bertalot G, Bonizzi G, Capra M, Maffini FA, Tagliabue M, Ansarin M, Lupia M, Giordano M, Osti D, Pelicci G, Chiocca S, and Bonaldi T
- Abstract
Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in cancer could have important implications for the discovery of both biomarkers for patient stratification and novel epigenetic targets. In this study, we employed mass spectrometry-based approaches to comprehensively profile histone H3 PTMs in a panel of normal and tumoral tissues for different cancer types, identifying various changes, some of which appear to be a consequence of the increased proliferation rate of tumors, while others are cell-cycle independent. Histone PTM changes found in tumors partially correlate with alterations of the gene expression profiles of HMEs obtained from publicly available data and are generally lost in culture conditions. Through this analysis, we identified tumor- and subtype-specific histone PTM changes, but also widespread changes in the levels of histone H3 K9me3 and K14ac marks. In particular, H3K14ac showed a cell-cycle independent decrease in all the seven tumor/tumor subtype models tested and could represent a novel epigenetic hallmark of cancer. ., Competing Interests: The authors declare no conflict of interest
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- 2019
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287. Aortic atresia and interrupted aortic arch communicating through external carotid anastomosis.
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Dangouloff-Ros V, Boddaert N, and Raimondi F
- Subjects
- Aorta, Thoracic abnormalities, Aortic Diseases congenital, Female, Humans, Infant, Newborn, Vascular Surgical Procedures, Anastomosis, Surgical, Aorta abnormalities, Aortic Diseases surgery, Vascular Malformations surgery
- Abstract
We describe the case of a newborn girl who displayed association of aortic atresia and interrupted aortic arch, with retrograde flow in ascending aorta, through extracranial anastomoses between vertebral arteries (arisen from descending aorta) and external carotids.
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- 2019
- Full Text
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288. Idiopathic, heritable and veno-occlusive pulmonary arterial hypertension in childhood: computed tomography angiography features in the initial assessment of the disease.
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Berteloot L, Proisy M, Jais JP, Lévy M, Boddaert N, Bonnet D, and Raimondi F
- Subjects
- Adolescent, Cardiac Catheterization, Case-Control Studies, Child, Child, Preschool, Early Diagnosis, Familial Primary Pulmonary Hypertension diagnostic imaging, Familial Primary Pulmonary Hypertension genetics, Female, Humans, Hypertension, Pulmonary genetics, Infant, Male, Predictive Value of Tests, Pulmonary Veno-Occlusive Disease genetics, Radiographic Image Interpretation, Computer-Assisted, Retrospective Studies, Sensitivity and Specificity, Computed Tomography Angiography, Hypertension, Pulmonary diagnostic imaging, Pulmonary Veno-Occlusive Disease diagnostic imaging
- Abstract
Background: In children, idiopathic and heritable pulmonary arterial hypertension present echocardiographic and heart catheterization findings similar to findings in pulmonary veno-occlusive disease., Objective: To provide a systematic analysis of CT angiography anomalies in children with idiopathic or heritable pulmonary arterial hypertension, or pulmonary veno-occlusive disease. We also sought to identify correlations between CT findings and patients' baseline characteristics., Materials and Methods: We retrospectively analyzed CT features of children with idiopathic and heritable pulmonary arterial hypertension or pulmonary veno-occlusive disease and 30 age-matched controls between 2008 and 2014. We compared CT findings and patient characteristics, including gene mutation type, and disease outcome until 2017., Results: The pulmonary arterial hypertension group included idiopathic (n=15) and heritable pulmonary arterial hypertension (n=11) and pulmonary veno-occlusive disease (n=4). Median age was 6.5 years. Children with pulmonary arterial hypertension showed enlargement of pulmonary artery and right cardiac chambers. A threshold for the ratio between the pulmonary artery and the ascending aorta of ≥1.2 had a sensitivity of 90% and a specificity of 100% for pulmonary arterial hypertension. All children with pulmonary veno-occlusive disease had thickened interlobular septa, centrilobular ground-glass opacities, and lymphadenopathy. In children with idiopathic and heritable pulmonary arterial hypertension, presence of intrapulmonary neovessels and enlargement of the right atrium were correlated with higher mean pulmonary artery pressure (P=0.011) and pulmonary vascular resistance (P=0.038), respectively. Mediastinal lymphadenopathy was associated with disease worsening within the first 2 years of follow-up (P=0.024)., Conclusion: CT angiography could contribute to early diagnosis and prediction of severity in children with pulmonary arterial hypertension.
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- 2019
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289. Defective homologous recombination DNA repair as therapeutic target in advanced chordoma.
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Gröschel S, Hübschmann D, Raimondi F, Horak P, Warsow G, Fröhlich M, Klink B, Gieldon L, Hutter B, Kleinheinz K, Bonekamp D, Marschal O, Chudasama P, Mika J, Groth M, Uhrig S, Krämer S, Heining C, Heilig CE, Richter D, Reisinger E, Pfütze K, Eils R, Wolf S, von Kalle C, Brandts C, Scholl C, Weichert W, Richter S, Bauer S, Penzel R, Schröck E, Stenzinger A, Schlenk RF, Brors B, Russell RB, Glimm H, Schlesner M, and Fröhling S
- Subjects
- Adult, Aged, Chordoma genetics, Chordoma pathology, Chromosome Mapping, DNA Breaks, Double-Stranded, DNA Mutational Analysis, Drug Resistance, Neoplasm genetics, Female, Genomic Instability, Humans, Male, Middle Aged, Phthalazines pharmacology, Piperazines pharmacology, Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Precision Medicine methods, Protein Domains genetics, Treatment Outcome, Exome Sequencing, Chordoma drug therapy, Phthalazines therapeutic use, Piperazines therapeutic use, Poly (ADP-Ribose) Polymerase-1 genetics, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Recombinational DNA Repair genetics
- Abstract
Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
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- 2019
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290. Aortic angle is associated with neo-aortic root dilatation and regurgitation following arterial switch operation.
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Martins D, Khraiche D, Legendre A, Boddaert N, Raisky O, Bonnet D, and Raimondi F
- Subjects
- Aortic Coarctation etiology, Arterial Switch Operation adverse effects, Female, Humans, Infant, Newborn, Magnetic Resonance Imaging, Cine trends, Male, Retrospective Studies, Aortic Coarctation diagnostic imaging, Arterial Switch Operation trends, Transposition of Great Vessels diagnostic imaging, Transposition of Great Vessels surgery
- Abstract
Introduction: Neo-aortic root dilatation and regurgitation are common progressive long-term complications of the arterial switch operation (ASO) for transposition of the great arteries (TGA) with increasing clinical burden. While several risk factors have been identified, most are constitutional. The acute aortic angle commonly seen after ASO might alter aortic dynamics and facilitate progression of the neo-aortic root dilatation and aortic regurgitation, but insufficient data is available. We intend to assess the effect of the aortic angle in the extent of neo-aortic root dilatation and presence of regurgitation., Methods: Retrospective analysis of TGA patients undergoing CMR after ASO at a single tertiary centre from November 2010 to July 2017., Results: 180 patients were analysed, 157 of which having adequate imaging of the aortic arch and root. Neo-aortic root Z score was normally distributed with 73% of patients having a Z score > 2. The aortic angle had a significant (p < 0,001) inverse relationship with the neo-aortic root Z score both in univariate and multivariate linear regression. Other significant associations were male gender and the concomitant presence of a VSD or a dysplastic neo-aortic valve. The presence of neo-aortic regurgitation was also inversely correlated with the aortic angle. The presence of a bicuspid neo-aortic valve was another significant association, further correlating with the more severe forms., Conclusions: Acute aortic angles associate more extensive neo-aortic root dilatation and higher incidence of regurgitation. We believe a surgical technique promoting less acute aortic angles has potential for ameliorating the long-term outcomes of TGA., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2019
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291. Understanding the role of genetic variability in LRRK2 in Indian population.
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Kishore A, Ashok Kumar Sreelatha A, Sturm M, von-Zweydorf F, Pihlstrøm L, Raimondi F, Russell R, Lichtner P, Banerjee M, Krishnan S, Rajan R, Puthenveedu DK, Chung SJ, Bauer P, Riess O, Gloeckner CJ, Kruger R, Gasser T, and Sharma M
- Subjects
- Adult, Aged, Aged, 80 and over, Alleles, Female, Gene Frequency, Genotype, Haplotypes, Humans, India, Male, Middle Aged, Mutation, Missense, Young Adult, Genetic Predisposition to Disease, Genetic Variation, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, Parkinson Disease genetics, Polymorphism, Single Nucleotide
- Abstract
Background: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations., Objectives: To resolve the role of LRRK2 in the Indian population., Methods: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene., Results: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity., Conclusions: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)
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- 2019
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292. Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.
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López C, Kleinheinz K, Aukema SM, Rohde M, Bernhart SH, Hübschmann D, Wagener R, Toprak UH, Raimondi F, Kreuz M, Waszak SM, Huang Z, Sieverling L, Paramasivam N, Seufert J, Sungalee S, Russell RB, Bausinger J, Kretzmer H, Ammerpohl O, Bergmann AK, Binder H, Borkhardt A, Brors B, Claviez A, Doose G, Feuerbach L, Haake A, Hansmann ML, Hoell J, Hummel M, Korbel JO, Lawerenz C, Lenze D, Radlwimmer B, Richter J, Rosenstiel P, Rosenwald A, Schilhabel MB, Stein H, Stilgenbauer S, Stadler PF, Szczepanowski M, Weniger MA, Zapatka M, Eils R, Lichter P, Loeffler M, Möller P, Trümper L, Klapper W, Hoffmann S, Küppers R, Burkhardt B, Schlesner M, and Siebert R
- Subjects
- Adolescent, Alternative Splicing genetics, Amino Acid Sequence, Basic Helix-Loop-Helix Transcription Factors chemistry, Basic Helix-Loop-Helix Transcription Factors metabolism, Child, Child, Preschool, Chromosome Breakpoints, Cohort Studies, DNA Methylation genetics, DNA Mutational Analysis, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, INDEL Mutation genetics, Male, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Open Reading Frames genetics, Polymorphism, Single Nucleotide genetics, Proto-Oncogene Proteins c-myc genetics, Translocation, Genetic, Whole Genome Sequencing, Burkitt Lymphoma genetics, Genome, Human, Transcriptome genetics
- Abstract
Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.
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- 2019
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293. The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma.
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Wagener R, Seufert J, Raimondi F, Bens S, Kleinheinz K, Nagel I, Altmüller J, Thiele H, Hübschmann D, Kohler CW, Nürnberg P, Au-Yeung R, Burkhardt B, Horn H, Leoncini L, Jaffe ES, Ott G, Rymkiewicz G, Schlesner M, Russell RB, Klapper W, and Siebert R
- Subjects
- ATPases Associated with Diverse Cellular Activities, Adolescent, Adult, Burkitt Lymphoma pathology, Child, Child, Preschool, DNA Helicases genetics, DNA-Binding Proteins genetics, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, Proto-Oncogene Proteins c-myc genetics, Retrospective Studies, Young Adult, Biomarkers, Tumor genetics, Burkitt Lymphoma classification, Burkitt Lymphoma genetics, Chromosome Aberrations, Chromosomes, Human, Pair 11 genetics, Mutation
- Abstract
The new recently described provisional lymphoma category Burkitt-like lymphoma with 11q aberration comprises cases similar to Burkitt lymphoma (BL) on morphological, immunophenotypic and gene-expression levels but lacking the IG- MYC translocation. They are characterized by a peculiar imbalance pattern on chromosome 11, but the landscape of mutations is not yet described. Thus, we investigated 15 MYC -negative Burkitt-like lymphoma with 11q aberration (mnBLL,11q,) cases by copy-number analysis and whole-exome sequencing. We refined the regions of 11q imbalance and identified the INO80 complex-associated gene NFRKB as a positional candidate in 11q24.3. Next to recurrent gains in 12q13.11-q24.32 and 7q34-qter as well as losses in 13q32.3-q34, we identified 47 genes recurrently affected by protein-changing mutations (each ≥3 of 15 cases). Strikingly, we did not detect recurrent mutations in genes of the ID3-TCF3 axis or the SWI/SNF complex that are frequently altered in BL, or in genes frequently mutated in germinal center-derived B-cell lymphomas like KMT2D or CREBBP An exception is GNA13 , which was mutated in 7 of 15 cases. We conclude that the genomic landscape of mnBLL,11q, differs from that of BL both at the chromosomal and mutational levels. Our findings implicate that mnBLL,11q, is a lymphoma category distinct from BL at the molecular level., (© 2019 by The American Society of Hematology.)
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- 2019
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294. Oxidative Stress and Bronchopulmonary Dysplasia: Evidences From Microbiomics, Metabolomics, and Proteomics.
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Capasso L, Vento G, Loddo C, Tirone C, Iavarone F, Raimondi F, Dani C, and Fanos V
- Abstract
Bronchopulmonary dysplasia is a major issue affecting morbidity and mortality of surviving premature babies. Preterm newborns are particularly susceptible to oxidative stress and infants with bronchopulmonary dysplasia have a typical oxidation pattern in the early stages of this disease, suggesting the important role of oxidative stress in its pathogenesis. Bronchopulmonary dysplasia is a complex disease where knowledge advances as new investigative tools become available. The explosion of the "omics" disciplines has recently affected BPD research. This review focuses on the new evidence coming from microbiomics, metabolomics and proteomics in relation to oxidative stress and pathogenesis of bronchopulmonary dysplasia. Since the pathogenesis is not yet completely understood, information gained in this regard would be important for planning an efficacious prevention and treatment strategy for the future.
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- 2019
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295. Lung Ultrasound for the Differential Diagnosis of Respiratory Distress in Neonates.
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Corsini I, Parri N, Gozzini E, Coviello C, Leonardi V, Poggi C, Giacalone M, Bianconi T, Tofani L, Raimondi F, and Dani C
- Subjects
- Diagnosis, Differential, Female, Humans, Infant, Newborn, Italy, Male, Point-of-Care Systems, Prospective Studies, Radiography, Thoracic, Time Factors, Ultrasonography, Intensive Care, Neonatal standards, Lung diagnostic imaging, Respiratory Distress Syndrome, Newborn diagnosis
- Abstract
Background: Respiratory distress (RD) is the most common neonatal illness. Lung ultrasound (LUS) is a technique previously tested in neonatal studies on RD, but literature regarding its routine clinical applicability is still lacking., Objective: To assess the concordance between LUS performed by neonatologists with different training levels and chest X-ray (CXR) for the diagnosis of RD in newborns during the first 24 h of life., Methods: We enrolled newborns with RD during the first 24 h of life. Patients underwent LUS and CXR. LUS and CXR diagnosis were compared to evaluate concordance. Twenty percent of patients received two LUS (one from an experienced and one from a novice sonographer) to calculate the interobserver agreement. The difference in time needed to reach a diagnosis with LUS and CXR, and from novice and expert operators, was measured., Results: We studied 124 patients; 134 diagnoses were reported. The concordance between LUS and CXR diagnosis was 91% (95% CI 86-96%) with a κ statistic of 0.88 (95% CI 0.81-0.94). The median time to diagnosis was shorter for LUS (9.5 min, IQR 5-15) than for CXR (50 min, IQR 33-64) (p < 0.0001). In 25/124 patients, LUS was performed by both novice and experienced sonographers with complete concordance. The median time to diagnosis was shorter for expert (9 min, IQR 5-15) than novice operators (15 min, IQR 10-20) (p < 0.0002)., Conclusion: LUS and CXR have a high concordance in the differential diagnosis of neonatal RD in the first 24 h of life. LUS has a shorter operation time than CXR., (© 2018 S. Karger AG, Basel.)
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- 2019
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296. A Multicenter Lung Ultrasound Study on Transient Tachypnea of the Neonate.
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Raimondi F, Yousef N, Rodriguez Fanjul J, De Luca D, Corsini I, Shankar-Aguilera S, Dani C, Di Guardo V, Lama S, Mosca F, Migliaro F, Sodano A, Vallone G, and Capasso L
- Subjects
- Female, Gestational Age, Humans, Infant, Newborn, Italy, Male, Prospective Studies, Lung diagnostic imaging, Transient Tachypnea of the Newborn diagnosis, Ultrasonography
- Abstract
Background and Aim: Discordant results that demand clarification have been published on diagnostic lung ultrasound (LUS) signs of transient tachypnea of the neonate (TTN) in previous cross-sectional, single-center studies. This work was conducted to correlate clinical and imaging data in a longitudinal and multicenter fashion., Methods: Neonates with a gestational age of 34-40 weeks and presenting with TTN underwent a first LUS scan at 60-180 min of life. LUS scans were repeated every 6-12 h if signs of respiratory distress persisted. Images were qualitatively described and a LUS aeration score was calculated. Clinical data were collected during respiratory distress., Results: We enrolled 65 TTN patients. Thirty-one (47.6%) had a sharp echogenicity increase in the lower lung fields (the "double lung point" or DLP sign). On admission, there was no significant difference between patients with and without DLP in Silverman scores (4 ± 1.5 vs. 4 ± 2.1; p = 0.9) or LUS scores (7.6 ± 2.6 vs. 5.6 ± 3.8; p = 0.12); PaO2/FiO2 (249 ± 93 vs. 252 ± 125; p = 0.91). All initial LUS scans (performed at the onset of distress) and 99.5% of all scans showed a regular pleural line with no consolidation, with only 1 neonate showing consolidation in the follow-up scans. The Silverman and LUS scores were significantly correlated (rho = 0.27; p = 0.02)., Conclusion: A regular pleural line with no consolidation is a consistent finding in TTN. The presence of a DLP is not essential for the LUS diagnosis of TTN. A semi-quantitative LUS score correlates well with the clinical course and could be useful in monitoring changes in lung aeration during TTN., (© 2019 S. Karger AG, Basel.)
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- 2019
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297. RSV prophylaxis in premature infants.
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Del Vecchio A, Franco C, Del Vecchio K, Umbaldo A, Capasso L, and Raimondi F
- Subjects
- Animals, Antiviral Agents administration & dosage, Antiviral Agents economics, Cost-Benefit Analysis, Hospitalization statistics & numerical data, Humans, Infant, Newborn, Palivizumab economics, Respiratory Syncytial Virus Infections economics, Respiratory Syncytial Virus Infections epidemiology, Respiratory Tract Infections epidemiology, Respiratory Tract Infections prevention & control, Respiratory Tract Infections virology, Risk Factors, Infant, Premature, Palivizumab administration & dosage, Respiratory Syncytial Virus Infections prevention & control
- Abstract
Infants born prematurely before 37 weeks of gestational age (GA) have particular anatomical, immunological and metabolic characteristics that predispose them, even in the absence of diseases at birth, to severe morbidity. Respiratory syncytial virus (RSV) is the leading cause of hospitalization for lower respiratory tract infections (LRTI) in the first year of life, as well as an important cause of respiratory outcomes as recurrent wheezing in industrialized countries or mortality in developing countries. Prematurity is an important risk factor for hospitalization for severe RSV disease, but epidemiological, environmental and demographic risk factors also play a role in RSV infection. Currently, there is no effective antiviral therapy for the treatment of RSV infection, nor the possibility of using maternal immunization or vaccination of children to prevent infection, although numerous preclinical and clinical studies are still ongoing. Passive immunization with palivizumab has been shown to be safe and effective in preventing RSV hospitalization in children at greater risk of contracting a serious infection. Costs associated with palivizumab prophylaxis and its monthly intramuscularly administration has prompted many health institutions of different countries to implement specific recommendations, with the aim of protecting at risk infants for whom RSV infection is likely to cause serious illness or death. The cost-effectiveness ratio of prophylaxis, related to reduce hospitalization costs and the impact of the burden of RSV disease worldwide, greatly affects the drafting and the adoption of specific recommendations and the adherence to them, concerning the passive immunization with palivizumab.
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- 2018
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298. Predicting the risk of emergency admission with machine learning: Development and validation using linked electronic health records.
- Author
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Rahimian F, Salimi-Khorshidi G, Payberah AH, Tran J, Ayala Solares R, Raimondi F, Nazarzadeh M, Canoy D, and Rahimi K
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, England, Female, Health Services Needs and Demand, Health Status, Humans, Male, Middle Aged, Needs Assessment, Reproducibility of Results, Risk Assessment, Risk Factors, Sex Factors, Socioeconomic Factors, Time Factors, Young Adult, Data Mining methods, Electronic Health Records, Emergency Service, Hospital, Machine Learning, Patient Admission
- Abstract
Background: Emergency admissions are a major source of healthcare spending. We aimed to derive, validate, and compare conventional and machine learning models for prediction of the first emergency admission. Machine learning methods are capable of capturing complex interactions that are likely to be present when predicting less specific outcomes, such as this one., Methods and Findings: We used longitudinal data from linked electronic health records of 4.6 million patients aged 18-100 years from 389 practices across England between 1985 to 2015. The population was divided into a derivation cohort (80%, 3.75 million patients from 300 general practices) and a validation cohort (20%, 0.88 million patients from 89 general practices) from geographically distinct regions with different risk levels. We first replicated a previously reported Cox proportional hazards (CPH) model for prediction of the risk of the first emergency admission up to 24 months after baseline. This reference model was then compared with 2 machine learning models, random forest (RF) and gradient boosting classifier (GBC). The initial set of predictors for all models included 43 variables, including patient demographics, lifestyle factors, laboratory tests, currently prescribed medications, selected morbidities, and previous emergency admissions. We then added 13 more variables (marital status, prior general practice visits, and 11 additional morbidities), and also enriched all variables by incorporating temporal information whenever possible (e.g., time since first diagnosis). We also varied the prediction windows to 12, 36, 48, and 60 months after baseline and compared model performances. For internal validation, we used 5-fold cross-validation. When the initial set of variables was used, GBC outperformed RF and CPH, with an area under the receiver operating characteristic curve (AUC) of 0.779 (95% CI 0.777, 0.781), compared to 0.752 (95% CI 0.751, 0.753) and 0.740 (95% CI 0.739, 0.741), respectively. In external validation, we observed an AUC of 0.796, 0.736, and 0.736 for GBC, RF, and CPH, respectively. The addition of temporal information improved AUC across all models. In internal validation, the AUC rose to 0.848 (95% CI 0.847, 0.849), 0.825 (95% CI 0.824, 0.826), and 0.805 (95% CI 0.804, 0.806) for GBC, RF, and CPH, respectively, while the AUC in external validation rose to 0.826, 0.810, and 0.788, respectively. This enhancement also resulted in robust predictions for longer time horizons, with AUC values remaining at similar levels across all models. Overall, compared to the baseline reference CPH model, the final GBC model showed a 10.8% higher AUC (0.848 compared to 0.740) for prediction of risk of emergency admission within 24 months. GBC also showed the best calibration throughout the risk spectrum. Despite the wide range of variables included in models, our study was still limited by the number of variables included; inclusion of more variables could have further improved model performances., Conclusions: The use of machine learning and addition of temporal information led to substantially improved discrimination and calibration for predicting the risk of emergency admission. Model performance remained stable across a range of prediction time windows and when externally validated. These findings support the potential of incorporating machine learning models into electronic health records to inform care and service planning., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JT receives funding for DPhil provided by Rhodes Trust and Clarendon Fund, is Chair on board of CHASE (incorporated association), travel grant from European Society of Hypertension, British Research Council training grant, Special Consultant for Bendelta. KR receives a stipend as a specialty consulting editor for PLOS Medicine and serves on the journal’s editorial board.
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- 2018
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299. Myocardial inflammation detected by cardiac MRI in Arrhythmogenic right ventricular cardiomyopathy: A paediatric case series.
- Author
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Martins D, Ovaert C, Khraiche D, Boddaert N, Bonnet D, and Raimondi F
- Subjects
- Adolescent, Arrhythmogenic Right Ventricular Dysplasia physiopathology, Child, Child, Preschool, Female, Humans, Male, Myocarditis physiopathology, Retrospective Studies, Arrhythmogenic Right Ventricular Dysplasia complications, Arrhythmogenic Right Ventricular Dysplasia diagnostic imaging, Magnetic Resonance Imaging, Cine methods, Myocarditis complications, Myocarditis diagnostic imaging
- Abstract
Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease with an elusive association with myocardial inflammation. A myocarditis phenotype has been well established without systematic evidence of a viral trigger. We intend to study the relationship between myocardial inflammation detected by Cardiac magnetic resonance (CMR) and ARVC in a paediatric population., Methods: Retrospective case series of all patients <18 years admitted to two CMR units for clinical suspicion of myocarditis from March 2012 to June 2017 who had genetic testing for inherited cardiomyopathies including analysis for known ARVC genes., Results: Six patients were identified experiencing myocarditis-like episodes with chest pain and troponin elevation. All had CMR evidence of active myocardial inflammation often affecting the left ventricle without identification of an infectious trigger. These episodes were likely exercise-induced in 50% of our patients and were multiple in all but one., Conclusion: We provide evidence that ARVC can present as recurrent myocarditis-like episodes with CMR evidence of myocardial inflammation despite absent infectious trigger in children. We believe they represent an active hot phase of the disease and may lead to disease progression., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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300. Studying how genetic variants affect mechanism in biological systems.
- Author
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Raimondi F and Russell RB
- Subjects
- Humans, Mutation, Nucleotides genetics, Protein Folding, Genetic Variation, Systems Biology
- Abstract
Genetic variants are currently a major component of system-wide investigations into biological function or disease. Approaches to select variants (often out of thousands of candidates) that are responsible for a particular phenomenon have many clinical applications and can help illuminate differences between individuals. Selecting meaningful variants is greatly aided by integration with information about molecular mechanism, whether known from protein structures or interactions or biological pathways. In this review we discuss the nature of genetic variants, and recent studies highlighting what is currently known about the relationship between genetic variation, biomolecular function, and disease., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2018
- Full Text
- View/download PDF
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