Publications by authors named "Fabrizio Drago"

126 Publications

Deciphering Genetic Variants of Warfarin Metabolism in Children With Ventricular Assist Devices.

Pediatr Cardiol 2021 Apr 10. Epub 2021 Apr 10.

Heart Failure, Transplant and Mechanical Assistance Program Unit, Bambino Gesù Children Hospital, Rome, Italy.

Warfarin is prescribed in patients with ventricular assist devices (VADs). Dosage depends on several factors including the underlying genotype. These include polymorphisms of genes encoding cytochrome P450 enzymes, the main ones being CYP2C9, VKORC1, and CYP4F2. The objectives of this study were to evaluate the prevalence of CY2CP9 1*2*3*, VKORC1, and CYP4F2 in children with VADs and the time to reach the target international normalized ratio. We performed a retrospective/prospective study in children with VADs. We recorded polymorphisms, disease, type of VAD, ethnicity, age, gender, height, weight, INR values, bleeding, and thromboembolic episodes. Informed consent was obtained. We enrolled 34 children (19 male, 15 female), with a median age of 2 years (range 0.3-17 years) and median weight of 6.9Kg. The Berlin Heart was the most commonly implanted VAD (22/34; 64%), and the most common diagnosis was dilated cardiomyopathy. Statistical analysis confirmed a significant partial correlation with VKORC1 CC (p = 0.019). The CYP2C9*2 CT genotype showed a late rise in target INR values (p = 0.06), while the CYP2C9*2 CC showed a tendency toward an early INR rise (p = 0.024). We provide new information on the contribution of the warfarin polymorphisms in children with VAD implantation. Pharmacogenomic dosing for children using warfarin has the potential to improve clinical care in VAD patients. Patients with the CYP2C9*2 CT genotype may need more time or higher doses to reach target INR, while clinicians may need to be aware of the potential for a rapid rise in INR in patients with the CYP2C9*2 CC genotype.
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http://dx.doi.org/10.1007/s00246-021-02585-2DOI Listing
April 2021

Remember friedreich ataxia even in a toddler with apparently isolated dilated (not hypertrophic!) cardiomyopathy: revisited.

Minerva Pediatr (Torino) 2021 Apr 2. Epub 2021 Apr 2.

European Reference Network for rare, low prevalence and complex diseases of the heart - ERN GUARD-Heart HCP, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, Rome, Italy -

Background: Friedreich Ataxia (FRDA) is the most common form of ataxia in late childhood. Neurological manifestations often precede cardiac involvement, presenting mainly as hypertrophic cardiomyopathy.

Methods: We describe a toddler with apparently isolated severe heart failure, successfully managed with heart transplant (HT). Although well described in adolescents and adults, onset of FRDA is very uncommon in toddlers and neurological ataxic features are predominant. The presenting symptom of cardiomyopathy is very rare. Similar history is rarely reported in literature, that we described, including an aggressive cardiomyopathy in children younger than 5years-old.

Results: Our patient was diagnosed with FRDA at a postoperative stage due to minimal neurological manifestations. Moreover, the novelty of this study lies in demonstrating a major DNA triplet repeat expansion in skeletal muscle compared to DNA from peripheral blood leukocytes. These results support the concept that triplet repeat expansion is variable among different tissues in FRDA, and in our case it was more expanded in the post mitotic muscular tissue than in blood cells.

Conclusions: We believe on the importance of taking in consideration this rare condition even in a toddler with apparently isolated cardiomyopathy and especially when conventional investigations give negative results. We discuss potential trigger effect of heart transplant as a precipitating factor in manifesting neurological symptoms. This observation corresponds to our experience and relates to three patients described so far (the third patient died suddenly). Early onset cardiomyopathy with FRDA should increase awareness of this rare condition and we highlight HT successful outcome. Further reports are needed to delineate this rare condition in youngsters.
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http://dx.doi.org/10.23736/S2724-5276.21.05969-3DOI Listing
April 2021

The role of the electrocardiographic phenotype in risk stratification for sudden cardiac death in childhood hypertrophic cardiomyopathy.

Eur J Prev Cardiol 2021 Mar 27. Epub 2021 Mar 27.

Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK.

Aims: The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events.

Methods And Results: Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484-0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7.

Conclusion: In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.
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http://dx.doi.org/10.1093/eurjpc/zwab046DOI Listing
March 2021

Identification of human immune cell subtypes most responsive to IL-1β-induced inflammatory signaling using mass cytometry.

Sci Signal 2021 03 9;14(673). Epub 2021 Mar 9.

Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA.

IL-1β is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1β blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4 T cells and CD4CD8CD161 T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1β. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16CD56CD161 and CD16CD56CD161), and lineage (Lin) cells expressing CD161 and CD25. IL-1β also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1β stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1β-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1β in CCR6 T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1β-neutralizing therapies.
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http://dx.doi.org/10.1126/scisignal.abc5763DOI Listing
March 2021

Chemokine Receptor-6 Promotes B-1 Cell Trafficking to Perivascular Adipose Tissue, Local IgM Production and Atheroprotection.

Front Immunol 2021 19;12:636013. Epub 2021 Feb 19.

Carter Immunology Center, University of Virginia, Charlottesville, VA, United States.

Chemokine receptor-6 (CCR6) mediates immune cell recruitment to inflammatory sites and has cell type-specific effects on diet-induced atherosclerosis in mice. Previously we showed that loss of CCR6 in B cells resulted in loss of B cell-mediated atheroprotection, although the B cell subtype mediating this effect was unknown. Perivascular adipose tissue (PVAT) harbors high numbers of B cells including atheroprotective IgM secreting B-1 cells. Production of IgM antibodies is a major mechanism whereby B-1 cells limit atherosclerosis development. Yet whether CCR6 regulates B-1 cell number and production of IgM in the PVAT is unknown. In this present study, flow cytometry experiments demonstrated that both B-1 and B-2 cells express CCR6, albeit at a higher frequency in B-2 cells in both humans and mice. Nevertheless, B-2 cell numbers in peritoneal cavity (PerC), spleen, bone marrow and PVAT were no different in compared to mice. In contrast, the numbers of atheroprotective IgM secreting B-1 cells were significantly lower in the PVAT of compared to mice. Surprisingly, adoptive transfer (AT) of CD43 splenic B cells into B cell-deficient μ mice repopulated the PerC with B-1 and B-2 cells and reduced atherosclerosis when transferred into mice only when those cells expressed both CCR6 and sIgM. CCR6 expression on circulating human B cells in subjects with a high level of atherosclerosis in their coronary arteries was lower only in the putative human B-1 cells. These results provide evidence that B-1 cell CCR6 expression enhances B-1 cell number and IgM secretion in PVAT to provide atheroprotection in mice and suggest potential human relevance to our murine findings.
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http://dx.doi.org/10.3389/fimmu.2021.636013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933012PMC
February 2021

Quantitative Measurement of IgG to Severe Acute Respiratory Syndrome Coronavirus-2 Proteins Using ImmunoCAP.

Int Arch Allergy Immunol 2021 Feb 23:1-8. Epub 2021 Feb 23.

Division of Allergy & Clinical Immunology, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA,

Background: Detailed understanding of the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of coronavirus disease 2019 (CO-VID-19) has been hampered by a lack of quantitative antibody assays.

Objective: The objective was to develop a quantitative assay for IgG to SARS-CoV-2 proteins that could be implemented in clinical and research laboratories.

Methods: The biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding domain (RBD) or nucleocapsid protein to the solid phase of the ImmunoCAP. Plasma and serum samples from patients hospitalized with COVID-19 (n = 60) and samples from donors banked before the emergence of COVID-19 (n = 109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform.

Results: At a cutoff of 2.5 μg/mL, the assay demonstrated sensitivity and specificity exceeding 95% for IgG to both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 μg/mL (IQR 18-52) and 24.5 μg/mL (IQR 9-59), respectively. Among 17 patients with longitudinal samples, there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 μg/mL, or 1% of total IgG.

Conclusions: We have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to mutated COVID-19 proteins, has good performance characteristics, and has a readout in standardized units.
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http://dx.doi.org/10.1159/000514203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018212PMC
February 2021

Progressive involvement of cardiac conduction system in paediatric patients with Kearns-Sayre syndrome: how to predict occurrence of complete heart block and sudden cardiac death?

Europace 2020 Dec 18. Epub 2020 Dec 18.

Department of Paediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital, IRCCS, Sant'Onofrio 4, 00165 Rome, Italy.

Aims: The aims of this study are to evaluate the progressive involvement of the cardiac conduction system in the Kearn-Sayre syndrome (KSS) and to establish criteria for the prevention of episodes of syncope or sudden cardiac death.

Methods And Results: This is a prospective monocentric study including KSS patients, with diagnosis based on clinical manifestations, muscle biopsy, and genetic tests, before the age of 18. All patients underwent cardiac screening examination with 12-lead electrocardiogram (ECG), 24-h Holter monitoring, and pacemaker (PM) interrogation twice a year. Fifteen patients (nine males, mean age 16.6 ± 3.9 years) with a sporadic KSS were recruited. All subjects manifested at least one of the intraventricular conduction defects (IVDs): 1 right bundle branch block (RBBB), 2 left anterior fascicular block (LAFB), 11 a bi-fascicular block (RBBB + LAFB), and 1 left posterior fascicular block. Most children with bi-fascicular block developed LAFB before the RBBB (P = 0.0049). In six patients, IVD degenerated into atrioventricular block (AVB). Endocavitary PM was implanted in 11 patients (6 with AVB and 5 with a bi-fascicular block), while an implantable cardioverter-defibrillator only in one patient with a non-sustained ventricular tachycardia. Four died at mean age of 14.7 ± 2.6 years, but none of them suddenly.

Conclusion: Even a 'simple' ECG can predict the arrhythmic risk and the occurrence of catastrophic events in young patients with KSS. Left anterior fascicular block precedes RBBB in determining the bi-fascicular block and this can predict an inexorable progression of the conduction defects even in a short time. Pacemaker implantation may be indicated in these patients since the first bi-fascicular block manifestation.
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http://dx.doi.org/10.1093/europace/euaa335DOI Listing
December 2020

Three-dimensional guided selective right ventricular septal pacing preserves ventricular systolic function and synchrony in pediatric patients.

Heart Rhythm 2021 Mar 8;18(3):434-442. Epub 2020 Dec 8.

Paediatric Cardiology and Cardiac Arrhythmia/Syncope Unit, Bambino Gesù Children's Hospital IRCCS, Rome, Italy; European Reference Network for Rare and Low Prevalence Complex Disease of the Heart (ERN GUARD-Heart).

Background: Nonfluoroscopic 3-dimensional (3D) electroanatomic mapping systems (EAMs) have been developed to guide cardiac catheter navigation and reduce fluoroscopy. Selective right ventricular (RV) septal pacing could prevent pacing-induced left ventricular (LV) dysfunction.

Objective: The purpose of this study was to determine whether EAM-guided selective RV septal pacing preserves LV contractility/synchrony in pediatric patients with complete atrioventricular block (CAVB) and no other congenital heart defects.

Methods: Prospective analysis of children/adolescents who underwent EAM-guided selective RV pacing was performed. A 3D pacing map guided ventricular lead implantation at septal sites with narrow paced QRS. Serial echocardiograms were obtained after pacemaker implantation to monitor for function (volumes, ejection fraction [EF], global longitudinal/circumferential strain) and synchrony (interventricular mechanical delay, septal to posterior wall motion delay, systolic dyssynchrony index). Data are reported as median (25th-75th percentile).

Results: Thirty-two CAVB patients (age 9.8 [7.0-14.0] years; 11 with a previous pacing system) underwent selective RV septal pacing (13 DDD, 19 VVIR pacemaker; midseptum 22, parahisian 7, RV outflow tract 3) with narrow paced QRS (110 [100-120] ms) and low radiation exposure. Follow-up over 24 (5-33) months showed preserved LV function and synchrony, without significant differences between pacing sites (midseptum-parahisian) and mode (VVIR-DDD). EF decreased after implantation in patients without previous pacing, although values were mainly within normal limits. Three parahisian patients underwent early lead repositioning.

Conclusion: EAM-guided selective RV septal pacing is a feasible technique associated with preserved LV systolic function and synchrony and low radiation exposure in pediatric patients with CAVB.
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http://dx.doi.org/10.1016/j.hrthm.2020.12.004DOI Listing
March 2021

Recommendations from the Association for European Paediatric and Congenital Cardiology for training in diagnostic and interventional electrophysiology.

Cardiol Young 2021 Jan 9;31(1):38-46. Epub 2020 Dec 9.

Gottsegen György Hungarian Institute of Cardiology, Hungarian Paediatric Heart Center, Budapest, Hungary.

The field of electrophysiology (EP) in paediatric cardiology patients and adults with congenital heart disease is complex and rapidly growing. The current recommendations for diagnostic and invasive electrophysiology of the working group for Cardiac Dysrhythmias and Electrophysiology of the Association for European Paediatric and Congenital Cardiology acknowledges the diveristy of European countries and centers. These training recommendations can be fulfilled in a manageable period of time, without compromising the quality of training required to become an expert in the field of paediatric and congenital EP and are for trainees undergoing or having completed accredited paediatric cardiologist fellowship. Three levels of expertise, the training for General paediatric cardiology EP, for non-invasive EP and invasive EP have been defined. This Association for European EP curriculum describes the theoretical and practicsal knowledge in clinical EP; catheter ablation, cardiac implantable electronic devices, inherited arrhythmias and arrhythmias in adults with congenital heart defects for the 3 levels of expertise.
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http://dx.doi.org/10.1017/S1047951120004096DOI Listing
January 2021

Quantitative measurement of IgG to SARS-CoV-2 proteins using ImmunoCAP.

medRxiv 2020 Nov 12. Epub 2020 Nov 12.

Background: Detailed understanding of the immune response to SARS-CoV-2, the cause of coronavirus disease 2019 (COVID-19), has been hampered by a lack of quantitative antibody assays.

Objective: To develop a quantitative assay for IgG to SARS-CoV-2 proteins that could readily be implemented in clinical and research laboratories.

Methods: The biotin-streptavidin technique was used to conjugate SARS-CoV-2 spike receptor-binding-domain (RBD) or nucleocapsid protein to the solid-phase of the ImmunoCAP resin. Plasma and serum samples from patients with COVID-19 (n=51) and samples from donors banked prior to the emergence of COVID-19 (n=109) were used in the assay. SARS-CoV-2 IgG levels were followed longitudinally in a subset of samples and were related to total IgG and IgG to reference antigens using an ImmunoCAP 250 platform.

Results: Performance characteristics demonstrated 100% sensitivity and 99% specificity at a cut-off level of 2.5 µg/mL for both SARS-CoV-2 proteins. Among 36 patients evaluated in a post-hospital follow-up clinic, median levels of IgG to spike-RBD and nucleocapsid were 34.7 µg/mL (IQR 18-52) and 24.5 µg/mL (IQR 9-59), respectively. Among 17 patients with longitudinal samples there was a wide variation in the magnitude of IgG responses, but generally the response to spike-RBD and to nucleocapsid occurred in parallel, with peak levels approaching 100 µg/mL, or 1% of total IgG.

Conclusions: We have described a quantitative assay to measure IgG to SARS-CoV-2 that could be used in clinical and research laboratories and implemented at scale. The assay can easily be adapted to measure IgG to novel antigens, has good performance characteristics and a read-out in standardized units.
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http://dx.doi.org/10.1101/2020.11.09.20228411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668760PMC
November 2020

Ablation in Pediatric Patients and in Association with Congenital Heart Disease.

Card Electrophysiol Clin 2020 12 24;12(4):583-590. Epub 2020 Sep 24.

Cardiology and Electrophysiology/Syncope Unit, Cardiology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Transcatheter ablation (TA) for treatment of pediatric tachyarrhythmias was first introduced in the early 1990s. Since then, its use as an alternative to antiarrhythmic drugs to treat supraventricular tachycardias caused by accessory pathway has been increasing. Nowadays, TA can be performed with high success rates and low complication rates even in very young children. Recently, the use of different types of energy (radiofrequency and cryoenergy), special ablation catheters, and 3D nonfluoroscopic mapping systems equipped with high technological tools has further improved safety and efficacy of TA, especially in difficult substrates and in patients with congenital heart disease.
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http://dx.doi.org/10.1016/j.ccep.2020.08.006DOI Listing
December 2020

Persistent myocardial atrophy despite LV reverse remodeling in Duchenne cardiomyopathy treated by LVAD.

Pediatr Transplant 2021 Mar 26;25(2):e13890. Epub 2020 Oct 26.

Pediatric Cardiology and Cardiac Arrhythmias/Syncope Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

DCM is the leading cause of death in Duchenne patients. LVADs are considered as therapeutic options as DT in advanced HF. The aim of our study was to evaluate LV remodeling of Duchenne after LVADs and chronic therapy. Demographic and echocardiographic data of 8 Duchenne patients implanted with LVADs were reviewed and analyzed. All measures were collected before LVAD implantation, after 1 month and 1 year. All patients were affected by end-stage DCM, and mean age at implantation was 16.9 ± 2.9 years. Patients were treated with maximal medical therapy. One-year post-implantation HR decreased from a mean of 110 ± 19 bpm to 82 ± 2 bpm (P = .002), and a significant decrease in LV volumes and diameters LVEDD P = .03, LVESD P = .02, EDV P = .01, and ESV P = .02) was noticed together with a significant increase in EF (P = .0036). However, RWT did not change over time, showing an eccentric remodeling pattern pre- and post-LVADs. Our data showed that cardiac atrophy is persistent in Duchenne cardiomyopathy despite the improvement of LV function secondary to a significant ventricular unloading due to LVADs coupled with chronic therapy.
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http://dx.doi.org/10.1111/petr.13890DOI Listing
March 2021

Low-voltage bridge strategy to guide cryoablation of typical and atypical atrioventricular nodal re-entry tachycardia in children: mid-term outcomes in a large cohort of patients.

Europace 2021 Feb;23(2):271-277

Paediatric Cardiology and Cardiac Arrhythmias Complex Unit, Department of Paediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Palidoro-Rome, Piazza Sant'Onofrio 4, 00165 Rome, Italy.

Aims: In the current literature, results of the low-voltage bridge (LVB) ablation strategy for the definitive treatment of atrioventricular nodal re-entry tachycardia (AVNRT) seem to be encouraging also in children. The aims of this study were (i) to prospectively evaluate the mid-term efficacy of LVB ablation in a very large cohort of children with AVNRT, and (ii) to identify electrophysiological factors associated with recurrence.

Methods And Results: One hundred and eighty-four children (42% male, mean age 13 ± 4 years) with AVNRT underwent transcatheter cryoablation guided by voltage mapping of the Koch's triangle. Acute procedural success was 99.2% in children showing AVNRT inducibility at the electrophysiological study. The overall recurrence rate was 2.7%. The presence of two LVBs, a longer fluoroscopy time and the presence of both typical and atypical AVNRT, were found to be significantly associated with an increased recurrence rate during mid-term follow-up. Conversely, there was no significant association between recurrences and patient's age, type of LVB, lesion length, number of cryolesions or catheter tip size.

Conclusion: The LVB ablation strategy is very effective in AVNRT treatment in children. Recurrences are related to the complexity of the arrhythmogenic substrate.
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http://dx.doi.org/10.1093/europace/euaa195DOI Listing
February 2021

Duchenne Dilated Cardiomyopathy: Cardiac Management from Prevention to Advanced Cardiovascular Therapies.

J Clin Med 2020 Oct 1;9(10). Epub 2020 Oct 1.

Heart Failure Clinic-Heart Failure, Heart Transplant, Mechanical Circulatory Support Unit, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplant, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

Duchenne muscular dystrophy (DMD) cardiomyopathy (DCM) is characterized by a hypokinetic, dilated phenotype progressively increasing with age. Regular cardiac care is crucial in DMD care. Early recognition and prophylactic use of angiotensin converting enzyme inhibitors (ACEi) are the main stay therapeutic strategy to delay incidence of DMD-DCM. Pharmacological treatment to improve symptoms and left ventricle (LV) systolic function, have been widely implemented in the past years. Because of lack of DMD specific drugs, actual indications for established DCM include current treatment for heart failure (HF). This review focuses on current HF strategies to identify, characterize, and treat DMD-DCM.
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http://dx.doi.org/10.3390/jcm9103186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600130PMC
October 2020

Atrial fibrillation, anticoagulation management and risk of stroke in the Cardiomyopathy/Myocarditis registry of the EURObservational Research Programme of the European Society of Cardiology.

ESC Heart Fail 2020 Sep 17. Epub 2020 Sep 17.

Department of Cardiology and Structural Heart Disease, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.

Aims: Cardiomyopathies are a heterogeneous group of disorders that increase the risk for atrial fibrillation (AF). The aim of the study is to assess the prevalence of AF, anticoagulation management, and risk of stroke/transient ischaemic attack (TIA) in patients with cardiomyopathy.

Methods And Results: Three thousand two hundred eight consecutive adult patients with cardiomyopathy (34.9% female; median age: 55.0 years) were prospectively enrolled as part of the EURObservational Research Programme Cardiomyopathy/Myocarditis Registry. At baseline, 903 (28.2%) patients had AF (29.4% dilated, 27.5% hypertrophic, 51.5% restrictive, and 14.7% arrhythmogenic right ventricular cardiomyopathy, P < 0.001). AF was associated with more advanced New York Heart Association class (P < 0.001), increased prevalence of cardiovascular risk factors and co-morbidities, and a history of stroke/TIA (P < 0.001). Oral anticoagulation was administered in 71.7% of patients with AF (vitamin K antagonist: 51.6%; direct oral anticoagulant: 20.1%). At 1 year follow-up, the incidence of cardiovascular endpoints was as follows: stroke/TIA 1.85% (AF vs. non-AF: 3.17% vs. 1.19%, P < 0.001), death from any cause 3.43% (AF vs. non-AF: 5.39% vs. 2.50%, P < 0.001), and death from heart failure 1.67% (AF vs. non-AF: 2.44% vs. 1.31%, P = 0.033). The independent predictors for stroke/TIA were as follows: AF [odds ratio (OR) 2.812, P = 0.005], history of stroke (OR 7.311, P = 0.010), and anaemia (OR 3.119, P = 0.006).

Conclusions: The study reveals a high prevalence and diverse distribution of AF in patients with cardiomyopathies, inadequate anticoagulation regimen, and high risk of stroke/TIA in this population.
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http://dx.doi.org/10.1002/ehf2.12854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754739PMC
September 2020

Cardiovascular Involvement in Pediatric Laminopathies. Report of Six Patients and Literature Revision.

Front Pediatr 2020 24;8:374. Epub 2020 Jul 24.

The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children Hospital and Research Institute, Rome, Italy.

Lamin A/C () encodes for two nuclear intermediate filament proteins. Mutations in cause a highly heterogeneous group of diseases predominantly leading to muscular or cardiac disease, lipodystrophy syndromes, peripheral neuropathy, and accelerated aging disorders. Cardiac involvement includes progressive arrhythmias (brady/tachyarrhythmias, sudden cardiac death). Furthermore, cardiomyocyte damage often progresses into dilated cardiomyopathy (DCM), rarely described in the pediatric age group. Neuromuscular manifestations are even rarer in children. We report on six pediatric patients with mutations: patient 1 was operated on for aortic coarctation, non-compact left ventricle, atrial fibrillation (AF) preceding the diagnosis of DCM; patient 2 was operated on for ventricular septal defect (VSD), developed after years malignant arrhythmias preceding the progression to DCM (left ventricular non-compaction with LV dysfunction); patient 3 had ectopic atrial tachycardia as first manifestation of a DCM; patients 4 and 5 had no major arrhythmic events but only dilated ascending aorta, mildly dilated LV with mild hypertrabeculation of the lateral wall and a normally functioning but dilated left ventricle, respectively; patient 6 showed aortic coarctation, supraventricular tachycardia. Paroxysmal AF occurred in patients 1, 2, and 3 (50% of cases). Our series highlight the coexistence of congenital heart defects (CHDs) and aortic involvement with laminopathies in four of our patients: consisting of aortic coarctation (two patients), aortic root dilatation (one patient), and VSD (one patient). Aortic changes in laminopathies have been reported only once in an adult patient. This is the first report in the pediatric setting, and no associations with CHD have been previously described.
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http://dx.doi.org/10.3389/fped.2020.00374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393225PMC
July 2020

Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study.

Birth Defects Res 2020 06;112(10):725-731

Pediatric Cardiology, Department of Pediatrics, Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy.

Background: RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies.

Methods: A retrospective, multicentric observational study (CArdiac Rasopathy NETwork-CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected.

Results: Forty-five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow-up was 20.1 years (range 6.9-47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019.

Conclusions: Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended.
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http://dx.doi.org/10.1002/bdr2.1670DOI Listing
June 2020

2019 American Heart Association and American Red Cross presyncope update.

Authors:
Fabrizio Drago

J Pediatr 2020 05;220:264-267

Bambino Gesù Pediatric Hospital, Rome, Italy.

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http://dx.doi.org/10.1016/j.jpeds.2020.02.066DOI Listing
May 2020

Differences in morbidity and mortality in Down syndrome are related to the type of congenital heart defect.

Am J Med Genet A 2020 06 22;182(6):1342-1350. Epub 2020 Apr 22.

Pediatric Cardiology and Cardiac Arrhythmias Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.
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http://dx.doi.org/10.1002/ajmg.a.61586DOI Listing
June 2020

Psychosocial and environmental determinants of child cognitive development in rural south africa and tanzania: findings from the mal-ed cohort.

BMC Public Health 2020 Apr 16;20(1):505. Epub 2020 Apr 16.

Department of Public Health Sciences and Division of Infectious Diseases & International Health, University of Virginia, Charlottesville, USA.

Background: Approximately 66% of children under the age of 5 in Sub-Saharan African countries do not reach their full cognitive potential, the highest percentage in the world. Because the majority of studies investigating child cognitive development have been conducted in high-income countries (HICs), there is limited knowledge regarding the determinants of child development in low- and middle-income countries (LMICs).

Methods: This analysis includes 401 mother-child dyads from the South Africa and Tanzania sites of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal birth cohort study. We investigated the effect of psychosocial and environmental determinants on child cognitive development measured by the Wechsler Preschool Primary Scales of Intelligence (WPPSI) at 5 years of age using multivariable linear regression.

Results: Socioeconomic status was most strongly associated with child cognitive development (WPSSI Score Difference (SD):14.27, 95% CI:1.96, 26.59). Modest associations between the organization of the home environment and its opportunities for cognitive stimulation and child cognitive development were also found (SD: 3.08, 95% CI: 0.65, 5.52 and SD: 3.18, 95% CI: 0.59, 5.76, respectively).

Conclusion: This study shows a stronger association with child cognitive development at 5 years of age for socioeconomic status compared to more proximal measures of psychosocial and environmental determinants. A better understanding of the role of these factors is needed to inform interventions aiming to alleviate the burden of compromised cognitive development for children in LMICs.
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http://dx.doi.org/10.1186/s12889-020-08598-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164138PMC
April 2020

Left ventricular (LV) pacing in newborns and infants: Echo assessment of LV systolic function and synchrony at 5-year follow-up.

Pacing Clin Electrophysiol 2020 06 22;43(6):535-541. Epub 2020 Apr 22.

Pediatric Cardiology and Cardiac Arrhythmias Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.

Background: Small retrospective studies reported that left ventricular (LV) pacing is likely to preserve LV function in children with isolated congenital complete atrioventricular block (CCAVB). The aim of this study was to prospectively evaluate LV contractility and synchrony in a cohort of neonates/infants at pacemaker implantation and follow-up.

Methods: Patients with CCAVB who underwent LV pacing were evaluated with electrocardiogram and echocardiogram in a single-center, prospective study. Data were collected at implantation, at 1-month and every year of follow-up, up to 5 years. LV ventricular dimensions (diameters and volumes), systolic function (ejection fraction [EF] and global longitudinal strain [GLS]), and synchrony were evaluated. Data are reported as median (25th-75th centiles).

Results: Twenty consecutive patients with CCAVB underwent pacemaker implantation (12 single-chamber pacemaker [VVIR] and eight dual-chamber pacemaker [DDD]) with epicardial leads: 17 on the LV apex and three on the free wall. Age at implantation was 0.3 months (1 day-4.5 months). Patients showed good clinical status, normal LV dimensions, preserved systolic function, and synchrony at 60 (30-60) months follow-up. EF increased to normal values in patients with preimplantation EF <50%. Presence of antibodies and pacing mode (DDD vs VVIR) had no impact on the outcome.

Conclusions: LV pacing preserved LV systolic function and synchrony in neonates and infants with CCAVB at 5-year follow-up. LV EF improved in patients with low preimplantation EF. Pacing mode or the presence of autoantibodies did not demonstrated an impact on LV contractility and synchrony.
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http://dx.doi.org/10.1111/pace.13908DOI Listing
June 2020

A Novel Mobile Phone App Intervention With Phone Coaching to Reduce Symptoms of Depression in Survivors of Women's Cancer: Pre-Post Pilot Study.

JMIR Cancer 2020 Feb 6;6(1):e15750. Epub 2020 Feb 6.

University of Virginia, Charlottesville, VA, United States.

Background: Psychological distress is a major issue among survivors of women's cancer who face numerous barriers to accessing in-person mental health treatments. Mobile phone app-based interventions are scalable and have the potential to increase access to mental health care among survivors of women's cancer worldwide.

Objective: This study aimed to evaluate the acceptability and preliminary efficacy of a novel app-based intervention with phone coaching in a sample of survivors of women's cancer.

Methods: In a single-group, pre-post, 6-week pilot study in the United States, 28 survivors of women's cancer used iCanThrive, a novel app intervention that teaches skills for coping with stress and enhancing well-being, with added phone coaching. The primary outcome was self-reported symptoms of depression (Center for Epidemiologic Studies Depression Scale). Emotional self-efficacy and sleep disruption were also assessed at baseline, 6-week postintervention, and 4 weeks after the intervention period. Feedback obtained at the end of the study focused on user experience of the intervention.

Results: There were significant decreases in symptoms of depression and sleep disruption from baseline to postintervention. Sleep disruption remained significantly lower at 4-week postintervention compared with baseline. The iCanThrive app was launched a median of 20.5 times over the intervention period. The median length of use was 2.1 min. Of the individuals who initiated the intervention, 87% (20/23) completed the 6-week intervention.

Conclusions: This pilot study provides support for the acceptability and preliminary efficacy of the iCanThrive intervention. Future work should validate the intervention in a larger randomized controlled study. It is important to develop scalable interventions that meet the psychosocial needs of different cancer populations. The modular structure of the iCanThrive app and phone coaching could impact a large population of survivors of women's cancer.
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http://dx.doi.org/10.2196/15750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055784PMC
February 2020

Mapping of low-voltage bridges with a high-density multipolar catheter in a child with atrioventricular nodal reentry tachycardia.

HeartRhythm Case Rep 2020 Jan 30;6(1):8-10. Epub 2019 Sep 30.

Paediatric Cardiology and Cardiac Arrhythmias/Syncope Unit, Bambino Gesu Children's Hospital and Research Institute, Rome, Italy.

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http://dx.doi.org/10.1016/j.hrcr.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962720PMC
January 2020

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Circulation 2020 02 16;141(6):429-439. Epub 2020 Jan 16.

Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (M.B., J.R.G., M.J.A.).

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare variants implicated in LQT5 was sought through an international multicenter collaboration.

Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.

Results: A total of 32 distinct rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], =0.590). The cumulative prevalence of the 32 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%).

Conclusions: The present study suggests that putative/confirmed loss-of-function variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035205PMC
February 2020

Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: A potential pitfall for the diagnosis.

Am J Med Genet A 2020 01 15;182(1):64-70. Epub 2019 Nov 15.

Metabolic Diseases Unit, Bambino Gesù Children Hospital and Research Institute, Rome, Italy.

Infantile onset cardiomyopathies are highly heterogeneous with several phenocopies compared with adult cardiomyopathies. Multidisciplinary management is essential in determining the underlying etiology in children's cardiomyopathy. Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) is a useful tool in identifying the etiology in some metabolic cardiomyopathy. Here, we report the delayed appearance of 3-MGA-uria, between 6 and 18 months in three patients (out of 100 childhood onset cardiomyopathy) with neonatal onset cardiomyopathy, secondary to TMEM70 mutations and TAZ mutations (Barth syndrome), in whom extensive metabolic investigations, performed in the first weeks of life, did not display 3-MGA-uria. Serial retrospective evaluations showed full characteristic features of TMEM70 and TAZ mutations (Barth syndrome) in these three patients, including a clearly abnormal monolysocardiolipin/cardiolipin ratio in the two Barth syndrome patients. Serially repeated metabolic investigations finally discovered the 3-MGA-uria biomarker in all three patients between the age of 6 and 18 months. Our observation provides novel insights into the temporal appearance of 3-MGA-uria in TMEM70 and TAZ mutations (Barth syndrome) and focus the importance of multidisciplinary management and careful evaluation of family history and red flag signs for phenocopies in infantile onset cardiomyopathies.
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http://dx.doi.org/10.1002/ajmg.a.61383DOI Listing
January 2020

SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review.

Am J Med Genet A 2019 10 1;179(10):2083-2090. Epub 2019 Aug 1.

Pediatric Cardiology and Cardiac Arrhythmias Unit, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.

Noonan syndrome (NS) is caused by mutations in more than 10 genes, mainly PTPN11, SOS1, RAF1, and RIT1. Congenital heart defects and cardiomyopathy (CMP) are associated with significant morbidity and mortality in NS. Although hypertrophic CMP has "classically" been reported in association to RAF1, RIT1, and PTPN11 variants, SOS1 appears to be poorly related to CMP. Patients with NS attending our Center from January 2013 to June 2018 were eligible for inclusion if they carried SOS1 variants and presented with-or developed-CMP. Literature review describing the co-existence of SOS1 mutation and CMP was also performed. We identified six patients with SOS1 variants and CMP (male to female ratio 2:1) including two novel variants. CMP spectrum encompassed: (a) dilated CMP, (b) nonobstructive hypertrophic CMPs, and (c) obstructive hypertrophic CMPs. Survival is 100%. Literature review included 16 SOS1 mutated in CMP. CMP, mainly hypertrophic, has been often reported in association to RAF1, RIT1, and PTPN11 variants. Differently from previous reports, due to the frequent association of SOS1 variants and CMP in our single center experience, we suggest potential underestimated proportion of SOS1 in pediatric CMPs.
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http://dx.doi.org/10.1002/ajmg.a.61312DOI Listing
October 2019

Examining the feasibility, acceptability, and potential utility of mobile distress screening in adult cancer patients.

Psychooncology 2019 09 18;28(9):1887-1893. Epub 2019 Jul 18.

University of Virginia School of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia.

Objective: A common method of distress monitoring in cancer patients relies on static and retrospective data collected in-person at the time of a health care provider appointment. Relatively little work has examined the potential usefulness of mobile distress monitoring using cancer patients' smartphones. The current study deployed longitudinal distress monitoring using secure text messaging.

Methods: In an observational study, a total of 52 cancer patients receiving active cancer treatment (M  = 58, 62% female) received a text message once a week for 4 weeks. Text messages contained a secure link to complete online the Patient Health Questionnaire-4 (PHQ-4), a commonly used distress screener.

Results: Cancer patients completed a distress screener 75% of the time they received a text message. On average, it took less than a minute to complete each mobile distress screener. Geolocation data indicated that cancer patients completed distress screeners across a range of locations. Analyses of model fit of distress scores indicated significant heterogeneity in variability of distress scores over time and across cancer patients (AIC = 630.5). Quantitative feedback from cancer patients at the end of the study indicated high ease of use, ease of learning, and satisfaction of completing mobile distress screeners.

Conclusions: These findings support the use of secure text messaging to monitor longitudinal, out of clinic, distress in cancer patients. Findings also highlight the importance of mobile-based approaches to distress screening in order to maximize opportunities to intervene.
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http://dx.doi.org/10.1002/pon.5168DOI Listing
September 2019

A heterozygous, intragenic deletion of CNOT2 recapitulates the phenotype of 12q15 deletion syndrome.

Am J Med Genet A 2019 08 30;179(8):1615-1621. Epub 2019 May 30.

Department of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Only a few individuals with 12q15 deletion have been described, presenting with a disorder characterized by learning disability, developmental delay, nasal speech, and hypothyroidism. The smallest region of overlap for this syndrome was included in a genomic segment spanning CNOT2, KCNMB4, and PTPRB genes. We report on an additional patient harboring a 12q15 microdeletion encompassing only part of CNOT2 gene, presenting with a spectrum of clinical features overlapping the 12q15 deletion syndrome phenotype. We propose CNOT2 as the phenocritical gene for 12q15 deletion syndrome and its haploinsufficiency being associated with an autosomal dominant disorder, presenting with developmental delay, hypotonia, feeding problems, learning difficulties, nasal speech, skeletal anomalies, and facial dysmorphisms.
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http://dx.doi.org/10.1002/ajmg.a.61217DOI Listing
August 2019