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Background: Trauma, including traumatic brain injury (TBI), is the leading cause of nonobstetric maternal mortality during pregnancy. Few data are available regarding the optimal management of pregnant patients with TBI, leading to a lack of dedicated guidelines. We performed an international survey to examine the management of severe TBI in pregnant patients, focusing on monitoring, therapy, and intensive care practices., Methods: This survey, endorsed by the World Society of Emergency Surgery, was composed of a questionnaire with 79 items divided into four sections: (1) general information (items 1-7), (2) management of the maternal-fetal unit (items 8-43), (3) management of intracranial hypertension (items 44-76), and (4) specific considerations (items 77-79)., Results: One hundred and twenty-two physicians from 110 centers in 35 countries responded. The main findings related to TBI care in pregnant patients included the following: (1) a lack of availability of a specific TBI protocol in pregnancy; (2) an increase in the utilization of magnetic resonance imaging as the primary neuroimaging tool; (3) higher hemoglobin thresholds for transfusion; and (4) a lower utilization of therapeutic hypothermia, neuromuscular blocking agents, and barbiturate coma. We also report large variability in the timing of cesarean section in pregnant patients with TBI (≥ 23 weeks of gestation) needing an emergency craniotomy (simultaneously 23% vs. later cesarean section 50.8%)., Conclusions: Great variability in the management of pregnant patients with severe TBI was identified worldwide from the results of our survey. These findings, highlighting the lack of robust evidence on this topic, will be helpful to stimulate future investigations and to promote educational efforts on this difficult scenario., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Pediatric patients with congenital heart disease (CHD) often undergo low dose ionizing radiation (LDIR) from cardiac catheterization (CC) for the diagnosis and/or treatment of their disease. Although radiation doses from a single CC are usually low, less is known about the long-term radiation associated cancer risks. We aimed to assess the risk of lympho-hematopoietic malignancies in pediatric CHD patients diagnosed or treated with CC. A French cohort of 17,104 children free of cancer who had undergone a first CC from 01/01/2000 to 31/12/2013, before the age of 16 was set up. The follow-up started at the date of the first recorded CC until the exit date, i.e., the date of death, the date of first cancer diagnosis, the date of the 18th birthday, or the 31/12/2015, whichever occurred first. Poisson regression was used to estimate the LDIR associated cancer risk. The median follow-up was 5.9 years, with 110,335 person-years. There were 22,227 CC procedures, yielding an individual active bone marrow (ABM) mean cumulative dose of 3.0 milligray (mGy). Thirty-eight incident lympho-hematopoietic malignancies were observed. When adjusting for attained age, gender and predisposing factors to cancer status, no increased risk was observed for lympho-hematopoietic malignancies RR /mGy = 1.00 (95% CI: 0.88; 1.10). In summary, the risk of lympho-hematopoietic malignancies and lymphoma was not associated to LDIR in pediatric patients with CHD who undergo CC. Further epidemiological studies with greater statistical power are needed to improve the assessment of the dose-risk relationship., (© 2023. Springer Nature B.V.)

Background: Ventricular arrhythmias and sudden death are recognized complications in tetralogy of Fallot. Electrophysiological studies (EPS) before pulmonary valve replacement (PVR), the most common reintervention in tetralogy of Fallot, could potentially inform therapy to improve arrhythmic outcomes., Methods: A prospective multicenter study was conducted to systematically assess EPS with programmed ventricular stimulation in patients with tetralogy of Fallot referred for PVR from January 2020 to December 2021. A standardized stimulation protocol was used across all centers., Results: A total of 120 patients were enrolled, mean age 39.2±14.5 years, 53.3% males. Sustained ventricular tachycardia was induced in 27 (22.5%) patients. When identifiable, the critical isthmus most commonly implicated (ie, in 90.0%) was between the ventricular septal defect patch and pulmonary annulus. Factors independently associated with inducible ventricular tachycardia were history of atrial arrhythmia (odds ratio, 8.56 [95% CI, 2.43-34.73]) and pulmonary annulus diameter >26 mm (odds ratio, 5.05 [95% CI, 1.47-21.69]). The EPS led to a substantial change in management in 23 (19.2%) cases: 18 (15.0%) had catheter ablation, 3 (2.5%) surgical cryoablation during PVR, and 9 (7.5%) defibrillator implantation. Repeat EPS 5.1 (4.8-6.2) months after PVR was negative in 8 of 9 (88.9%) patients. No patient experienced a sustained ventricular arrhythmia during 13 (6.1-20.1) months of follow-up., Conclusions: Systematically performing programmed ventricular stimulation in patients with tetralogy of Fallot referred for PVR yields a high rate of inducible ventricular tachycardia and carries the potential to alter management. It remains to be determined whether a standardized treatment approach based on the results of EPS will translate into improved outcomes., Registration: URL: https://clinicaltrials.gov/ct2/show/NCT04205461; Unique identifier: NCT04205461., Competing Interests: Disclosures None.

Moderate and severe traumatic brain injury (TBI) are major causes of disability and death. In addition, when TBI occurs during pregnancy, it can lead to miscarriage, premature birth, and maternal/fetal death, engendering clinical and ethical issues. Several recommendations have been proposed for the management of TBI patients; however, none of these have been specifically applied to pregnant women, which often have been excluded from major trials. Therefore, at present, evidence on TBI management in pregnant women is limited and mostly based on clinical experience. The aim of this manuscript is to provide the clinicians with practical suggestions, based on 10 rules, for the management of moderate to severe TBI during pregnancy. In particular, we firstly describe the pathophysiological changes occurring during pregnancy; then we explore the main strategies for the diagnosis of TBI taking in consideration the risks related to mother and fetus, and finally we discuss the most appropriate approaches for the management in this particular condition. Based on the available evidence, we suggest a stepwise approach consisting of different tiers of treatment and we describe the specific risks according to the severity of the neurological and systemic conditions of both fetus and mother in relation to each trimester of pregnancy. The innovative feature of this approach is the fact that it focuses on the vulnerability and specificity of this population, without forgetting the current knowledge on adult non-pregnant patients, which has to be applied to improve the quality of the care process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Di Filippo, Godoy, Manca, Paolessi, Bilotta, Meseguer, Severgnini, Pelosi, Badenes and Robba.)

Background: Although patients with systemic right ventricle (SRV) represent a significant proportion of patients with congenital heart disease (CHD) implanted with cardiac resynchronization therapy (CRT), there are limited and conflicting data in this specific patient group., Objective: We aimed to analyze outcomes of patients with SRV implanted with a CRT device., Methods: Data were analyzed from an observational, retrospective, multicenter cohort study including all patients with CHD implanted with a CRT device from 6 French centers from 2004 to 2020. Response to CRT was defined as an increase in systemic ventricular ejection fraction of ≥10% and/or an improvement in New York Heart Association functional class by at least 1 grade., Results: A total of 85 patients with CHD were enrolled (mean age 39.8 ± 20.0 years; 55 [64.7%] males; 25 defibrillators [29.4%]), including 31 patients with SRV (36.5%) (mean age 43.9 ± 19.8 years; 16 [51.6%] males). The mean change in QRS duration after implantation was similar as compared with patients with systemic left ventricle (-46 ± 26 ms vs -35 ± 32 ms; P = .16). During a mean follow-up of 5.1 ± 3.5 years, late complications included 2 lead dysfunctions (6.5%), 3 CRT-related infections (9.7%), and 1 inappropriate implantable cardioverter-defibrillator shock (3.2%). The proportion of CRT responders at 6, 12, and 24 months were 82.6%, 80.0%, and 77.8% in patients with SRV vs 66.7%, 64.3%, and 69.6% in patients with systemic left ventricle (P = NS)., Conclusion: In this multicenter cohort, one-third of patients with CHD implanted with a CRT device had SRV. CRT in patients with SRV was associated with a high rate of responders, comparable to that of patients with systemic left ventricle., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to assess the incidence, associated factors, and outcomes of atrial arrhythmias in adults with atrioventricular septal defect (AVSD)., Background: Data regarding atrial arrhythmias in adults with AVSD are particularly scarce., Methods: Data were analyzed from a multicentric cohort of adult patients with AVSD. Lifetime cumulative incidences of atrial arrhythmias were studied. Multiple logistic regression models were used to identify risk factors., Results: A total of 391 patients (61.6% women) were enrolled with a mean age of 36.3 ± 16.3 years and a mean follow-up of 17.3 ± 14.2 years after initial surgical repair. Overall, 98 patients (25.1%) developed at least 1 episode of atrial arrhythmia at a mean age of 39.2 ± 17.2 years. The mean ages of patients at first episode of intra-atrial re-entrant tachycardia (IART)/ focal atrial tachycardia (FAT) and atrial fibrillation were 33.7 ± 15.3 and 44.3 ± 16.5 years, respectively. The lifetime risks for developing atrial arrhythmia to ages 20, 40, and 60 years were 3.7%, 17.8%, and 55.3%, respectively. IART/FAT was the leading arrhythmia until the age of 45, then atrial fibrillation surpassed IART/FAT. Age (odds ratio [OR]: 1.4; 95% confidence interval [CI]: 1.2-1.6), number of cardiac surgeries (OR: 4.1; 95% CI: 2.5-6.9), left atrial dilatation (OR: 3.1; 95% CI: 1.4-6.8), right atrial dilatation (OR: 4.1; 95% CI: 1.7-10.3), and moderate or severe left atrioventricular valve regurgitation (OR: 3.7; 95% CI: 1.2-11.7) were independently associated with a higher risk of atrial arrhythmias, whereas the type of AVSD and the age at repair were not. The occurrence of atrial arrhythmias was associated with pacemaker implantation (41.8% vs. 8.5%; P < 0.001), heart failure (24.5% vs. 1.0%; P < 0.001), and cerebrovascular accidents (11.2% vs. 3.4%; P = 0.007)., Conclusions: The lifetime risk of atrial arrhythmias in patients with AVSD is considerable with more than half of patients developing ≥1 atrial arrhythmia by the age of 60 and is associated with a significant morbidity. The risk in partial/intermediate AVSD is as high as in complete AVSD and is not impacted by age at repair., Competing Interests: Funding Support and Author Disclosures The authors have received a research grant from the French Institute of Health and Medical Research and the Fédération Française de Cardiologie., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: This study aimed to assess the impact of pulmonary valve replacement (PVR) on ventricular arrhythmias burden in a population of tetralogy of Fallot (TOF) patients with continuous cardiac monitoring by implantable cardioverter-defibrillators (ICDs)., Background: Sudden cardiac death is a major cause of death in TOF, and right ventricular overload is commonly considered to be a potential trigger for ventricular arrhythmias., Methods: Data were analyzed from a nationwide French ongoing study (DAI-T4F) including all TOF patients with an ICD since 2000. Survival data with recurrent events were used to compare the burden of appropriate ICD therapies before and after PVR in patients who underwent PVR over the study period., Results: A total of 165 patients (mean age 42.2 ± 13.3 years, 70.1% male) were included from 40 centers. Over a median follow-up period of 6.8 (interquartile range: 2.5 to 11.4) years, 26 patients (15.8%) underwent PVR. Among those patients, 18 (69.2%) experienced at least 1 appropriate ICD therapy. When considering all ICD therapies delivered before (n = 62) and after (n = 16) PVR, the burden of appropriate ICD therapies was significantly lower after PVR (HR: 0.21; 95% confidence interval [CI]: 0.08 to 0.56; p = 0.002). Respective appropriate ICD therapies rates per 100 person-years were 44.0 (95% CI: 35.7 to 52.5) before and 13.2 (95% CI: 7.7 to 20.5) after PVR (p < 0.001). In the overall cohort, PVR before ICD implantation was also independently associated with a lower risk of appropriate ICD therapy in primary prevention patients (HR: 0.29 [95% CI: 0.10 to 0.89]; p = 0.031)., Conclusions: In this cohort of high-risk TOF patients implanted with an ICD, the burden of appropriate ICD therapies was significantly reduced after PVR. While optimal indications and timing for PVR are debated, these findings suggest the importance of considering ventricular arrhythmias in the overall decision-making process. (French National Registry of Patients With Tetralogy of Fallot and Implantable Cardioverter Defibrillator [DAI-T4F]; NCT03837574)., Competing Interests: Funding Support and Author Disclosures The Paris-Sudden Death Expertise Center activities are supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris, Assistance Publique-Hôpitaux de Paris, Fondation Coeur et Artères, Global Heart Watch, Fédération Française de Cardiologie, Société Française de Cardiologie, Fondation Recherche Medicale, as well as unrestricted grants from industrial partners (Abbott, Biotronik, Boston Scientific, Medtronic, MicroPort, Schiller and Zoll). SDEC Executive Committee is part of the ESCAPE-NET project (Horizon2020 programme). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Anomalous aortic origin of a coronary artery, particularly in the presence of inter-arterial course between the great arteries, has been found to be associated with sudden death in young people., Methods: This study reports a single-center experience in the management of anomalous aortic origin of a coronary artery, with or without inter-arterial course, by focusing specifically on presentation, diagnosis, and patient outcome., Results: From March 1993 to February 2018, 100 patients (70 males) were diagnosed with anomalous aortic origin of a coronary artery, including 27 left coronary artery from the right sinus, 60 right coronary artery from the left sinus, and 13 other anomalies. Patients with inter-arterial course between the great arteries presented more frequently with syncope and/or sudden death compared to patients without (23.4% vs. 0%, p = 0.026). Diagnosis was reached using first-line transthoracic echocardiography in 65% of cases. Surgical repair was performed in 61 patients (61%). All operated patients (60 direct implantations, 1 unroofing) had been diagnosed with inter-arterial course between the great arteries, and were asymptomatic at a mean (±SD) postoperative follow-up of 4.9 ± 5.3 years., Conclusions: An inter-arterial course of the anomalous right or left coronary arteries arising from the opposite sinus is associated with life-threatening events. Direct reimplantation of coronary artery is reliable, and should be discussed even in asymptomatic patients., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Advances in paediatric cardiology have improved the prognosis of children with inherited cardiac disorders. However, health-related quality of life (QoL) and physical activity have been scarcely analysed in children with inherited cardiac arrhythmia or inherited cardiomyopathy. Moreover, current guidelines on the eligibility of young athletes with inherited cardiac disorders for sports participation mainly rely on expert opinions and remain controversial., Methods: The QUALIMYORYTHM trial is a multicentre observational controlled study. The main objective is to compare the QoL of children aged 6 to 17 years old with inherited cardiac arrhythmia (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or arrhythmogenic right ventricular dysplasia), or inherited cardiomyopathy (hypertrophic, dilated, or restrictive cardiomyopathy), to that of age and gender-matched healthy subjects. The secondary objective is to assess their QoL according to the disease's clinical and genetic characteristics, the level of physical activity and motivation for sports, the exercise capacity, and the socio-demographic data. Participants will wear a fitness tracker (ActiGraph GT3X accelerometer) for 2 weeks. A total of 214 children are required to observe a significant difference of 7 ± 15 points in the PedsQL, with a power of 90% and an alpha risk of 5%., Discussion: After focusing on the survival in children with inherited cardiac disorders, current research is expanding to patient-reported outcomes and secondary prevention. The QUALIMYORYTHM trial intends to improve the level of evidence for future guidelines on sports eligibility in this population. Trial registration ClinicalTrials.gov Identifier: NCT04712136, registered on January 15th, 2021 ( https://clinicaltrials.gov/ct2/show/NCT04712136 )., (© 2021. The Author(s).)

Background: Abnormal coronary pattern may complicate coronary transfer during arterial switch operation., Objective: To evaluate the accuracy of echocardiography in assessing the anatomy of coronary arteries in neonates with transposition of the great arteries, and determine impact on outcomes., Methods: We conducted a retrospective analysis of data in neonates with transposition of the great arteries. Preoperative echocardiographic coronary artery pattern and surgical intraoperative reports were compared. Mismatch between transthoracic echocardiography and surgical intraoperative reports and the impact on perioperative outcome were assessed. Coronary patterns were classified into four groups: type 1 (normal); type 2 (risk of coronary with intramural course); type 3 (coronary loop); and type 2+3., Results: Overall, 108 neonates who underwent an arterial switch operation were included: 68 were classified as type 1; seven as type 2; 32 as type 3; and one as type 2+3. Overall, 10 adverse events occurred. Five patients died, three from coronary causes. Survival was 96% at 1 month. Transthoracic echocardiography and surgical intraoperative reports differed in 17.6% of cases. Mortality was 15.8% in case of inappropriate diagnosis and 2.2% for appropriate diagnosis (P=0.01). Mortality in type 2 was 66.7% in case of discordance versus 0% when concordant. Multivariable analysis found that inappropriate preoperative transthoracic echocardiography diagnosis of coronary pattern was the only significant risk factor for mortality (P=0.04)., Conclusions: Echocardiography can assess coronary artery anatomy in neonates with transposition of the great arteries. Intramural coronary course is often misdiagnosed. Preoperative misdiagnosis of coronary artery anomaly may impact perioperative mortality. However, this assessment will have to be confirmed by further larger studies., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: The aim of the study was to document cardiovascular clinical findings, cardiac imaging, and laboratory markers in children presenting with the novel multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) infection., Methods: This real-time internet-based survey has been endorsed by the Association for European Paediatric and Congenital Cardiologists Working Groups for Cardiac Imaging and Cardiovascular Intensive Care. Children 0 to 18 years of age admitted to a hospital between February 1 and June 6, 2020, with a diagnosis of an inflammatory syndrome and acute cardiovascular complications were included., Results: A total of 286 children from 55 centers in 17 European countries were included. The median age was 8.4 years (interquartile range, 3.8-12.4 years) and 67% were boys. The most common cardiovascular complications were shock, cardiac arrhythmias, pericardial effusion, and coronary artery dilatation. Reduced left ventricular ejection fraction was present in over half of the patients, and a vast majority of children had raised cardiac troponin when checked. The biochemical markers of inflammation were raised in most patients on admission: elevated C-reactive protein, serum ferritin, procalcitonin, N-terminal pro B-type natriuretic peptide, interleukin-6 level, and D-dimers. There was a statistically significant correlation between degree of elevation in cardiac and biochemical parameters and the need for intensive care support ( P <0.05). Polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 was positive in 33.6%, whereas immunoglobulin M and immunoglobulin G antibodies were positive in 15.7% cases and immunoglobulin G in 43.6% cases, respectively, when checked. One child in the study cohort died., Conclusions: Cardiac involvement is common in children with multisystem inflammatory syndrome associated with the Covid-19 pandemic. The majority of children have significantly raised levels of N-terminal pro B-type natriuretic peptide, ferritin, D-dimers, and cardiac troponin in addition to high C-reactive protein and procalcitonin levels. In comparison with adults with COVID-19, mortality in children with multisystem inflammatory syndrome associated with COVID-19 is uncommon despite multisystem involvement, very elevated inflammatory markers, and the need for intensive care support.

Background: Progress in the management of complex congenital heart disease (CHD) led to an improvement in survival rates of adults with a Fontan-like circulation. The objective of this study was to assess the subjective health status and quality of life of this population., Methods and Results: Patients aged more than 18 years at the time of the study, who underwent a Fontan-like procedure. Subjective health status was assessed by the SF-36 questionnaire and a linear analog scale was used to score patients' self-perception of their quality of life; cardiac and demographic parameters were collected., Results: Among 65 eligible patients, 60 (23 females; mean ± SD age: 25.7 ± 7.2 years) answered the SF-36 questionnaire and 46 of these were interviewed to evaluate their perceived quality of life. Among them, 20 (33.3%) were working full-time and 21 (35%) experienced arrhythmias. The physical SF-36 scores were lower in patients than in the general population (p ≤ 0.05). The New York Hear Association (NYHA) class and occupation were correlated with SF-36 scores of physical activity (respectively, p = 0.0001 and p = 0.025). SF-36 scores of psychological status were associated with the number of drugs and occupation (respectively, p = 0.0001 and p = 0.02). The mean ± SD quality of life score measured using a linear analog scale was 7.02 ± 1.6 and was linked to education and occupation (p ≤ 0.05) but not with cardiac parameters., Conclusion: Adult Fontan patients perceive an impaired physical health but report a good overall quality of life. Education and occupation impacts significantly on Fontan patients' quality of life.

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants., (© 2020 Wiley Periodicals LLC.)

Background: Our purpose was to determine the complication rate from intravascular ultrasound (IVUS) in a large, multicenter cohort of pediatric heart transplant (PHT) patients., Methods: We retrospectively reviewed all PHT who underwent IVUS at 5 institutions (2006-2014). Rates of major and minor complications were calculated. All adverse events (AE) were graded from 1 to 5 using a previously published AE severity scale., Results: There were 1380 catheterizations in 505 patients and 32 AE (2.3%); 9 major (0.6%) and 23 AE (1.7%). The major AE attributed to IVUS were all coronary artery vasospasm (7). Major and minor AE rates directly related to IVUS were 0.5% and 0.7%, respectively. Minor AE possibly attributable to IVUS included excessive fluoroscopy (3) and transient ST segment changes (7). Of AE related to IVUS, only 3 were of moderate severity. The rest were ≤ minor in severity. There were no reports of coronary artery dissection or death., Conclusion: Most AE during routine PHT coronary evaluation with IVUS were minor and not directly related to the use of IVUS. The number of coronary related AE was similar to a registry-based report of coronary angiography alone. Efforts to minimize IVUS-related complications should be focused on preventing coronary artery vasospasm., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: Cardiac injury and myocarditis have been described in adults with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the multisystem inflammatory syndrome in children as defined by the US Centers for Disease Control and Prevention., Methods: Over a 2-month period, contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state., Results: Thirty-five children were identified and included in the study. Median age at admission was 10 years (range, 2-16 years). Comorbidities were present in 28%, including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one-third; 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation. Inflammation markers were suggestive of cytokine storm (interleukin-6 median, 135 pg/mL) and macrophage activation (D-dimer median, 5284 ng/mL). Mean BNP (B-type natriuretic peptide) was elevated (5743 pg/mL). Thirty-one of 35 patients (88%) tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. All patients received intravenous immunoglobulin, with adjunctive steroid therapy used in one-third. Left ventricular function was restored in the 25 of 35 of those discharged from the intensive care unit. No patient died, and all patients treated with extracorporeal membrane oxygenation were successfully weaned., Conclusions: Children may experience an acute cardiac decompensation caused by severe inflammatory state after SARS-CoV-2 infection (multisystem inflammatory syndrome in children). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

The population of patients with congenital heart disease (CHD) is continuously increasing, and a significant proportion of these patients will experience arrhythmias because of the underlying congenital heart defect itself or as a consequence of interventional or surgical treatment. Arrhythmias are a leading cause of mortality, morbidity and impaired quality of life in adults with CHD. Arrhythmias may also occur in children with or without CHD. In light of the unique issues, challenges and considerations involved in managing arrhythmias in this growing, ageing and heterogeneous patient population and in children, it appears both timely and essential to critically appraise and synthesize optimal treatment strategies. The introduction of catheter ablation techniques has greatly improved the treatment of cardiac arrhythmias. However, catheter ablation in adults or children with CHD and in children without CHD is more technically demanding, potentially causing various complications, and thus requires a high level of expertise to maximize success rates and minimize complication rates. As French recommendations regarding required technical competence and equipment are lacking in this situation, the Working Group of Pacing and Electrophysiology of the French Society of Cardiology and the Affiliate Group of Paediatric and Adult Congenital Cardiology have decided to produce a common position paper compiled from expert opinions from cardiac electrophysiology and paediatric cardiology. The paper details the features of an interventional cardiac electrophysiology centre that are required for ablation procedures in adults with CHD and in children, the importance of being able to diagnose, monitor and manage complications associated with ablations in these patients and the supplemental hospital-based resources required, such as anaesthesia, surgical back-up, intensive care, haemodynamic assistance and imaging. Lastly, the need for quality evaluations and French registries of ablations in these populations is discussed. The purpose of this consensus statement is therefore to define optimal conditions for the delivery of invasive care regarding ablation of arrhythmias in adults with CHD and in children, and to provide expert and - when possible - evidence-based recommendations on best practice for catheter-based ablation procedures in these specific populations., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Introduction: Infective endocarditis (IE) is a life-threatening adverse event for patients with congenital heart disease (CHD). Its incidence has changed little over time despite progress in techniques for diagnosis and treatment, and guidelines for prophylaxis., Areas Covered: The review sought for key-words: 'congenital heart disease,' 'infective endocarditis,' 'microbial diagnosis,' 'imaging diagnosis,' 'surgical techniques,' 'prognosis,' 'prophylaxis.' Objectives were to investigate epidemiology, novel techniques for imaging and microbial diagnosis, therapeutic management and prognosis, and guidelines for prophylaxis in patients with CHD. The incidence of IE is increasing in adults with CHD. Morbidity caused by a broad clinical spectrum of cardiac and extracardiac episode-related complications is high. Surgical management is increasingly required in the early phase of the disease. Despite new techniques for diagnosis and microbiological therapy, mortality rate is still up to 10-20%., Expert Opinion: IE has increased in the growing cohort of adults with complex heart disease, living with residual cardiac lesions and prosthetic materials. Diagnosis is challenging for complex heart defects. Pet-scan technique can provide beneficial information to locate intracardiac lesions and embolic foci. Identification of the microbiological agents is improving. Innovative surgical techniques aim to avoid prosthetic material. Guidelines for prophylaxis currently emphasize oral and skin daily hygiene.

About 10-20% of patients with Kawasaki disease (KD) are unresponsive to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations. We investigated the accuracy of 3 Japanese scoring systems and studied factors associated with IVIg unresponsiveness in a large multiethnic French population of children with KD to build a new scoring system. Children admitted for KD between 2011-2014 in 65 centers were enrolled. Factors associated with second line-treatment; i.e. unresponsiveness to initial IVIg treatment, were analyzed by multivariate regression analysis. The performance of our score and the Kobayashi, Egami and Sano scores were compared in our population and in ethnic subgroups. Overall, 465 children were reported by 84 physicians; 425 were classified with KD (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 14-61%). On multivariate regression analysis, predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count <2400/mm 3 and time to treatment <5 days. The best sensitivity (77%) and specificity (60%) of this model was with 1 point per variable and cut-off ≥2 points. The sensitivity remained good in our 3 main ethnic subgroups (74-88%). We identified predictors of IVIg resistance and built a new score with good sensitivity and acceptable specificity in a non-Asian population.

The aims of this study were to translate and culturally adapt the Volitional Questionnaire (VQ) into Italian and to evaluate its psychometric properties in an Italian population of patients with psychiatric disorders. The translation process from English into Italian was carried out in agreement with the authors of the original scale. The study was carried out in three psychiatric facilities, with 33 patients with psychiatric diagnoses, who were older than 18 years, and two raters (6 total) for each facility in Rome, Italy. The psychometric properties were assessed via its internal consistency, test-retest and inter-rater reliability and construct validity through comparisons with the Barthel Index, Short Form-12, Beck Depression Inventory-II and Camberwell Assessment of Need (CAN). Results showed internal consistency, using Cronbach's alpha, was significant at 0.92. In the test-retest reliability evaluation, the intraclass correlation coefficient was 0.97 and the interclass correlation coefficient was 0.99. The Spearman correlation showed significant results in the comparison with the CAN (r = -0.45, p < 0.05). These results suggest that the IT-VQ may be a valid, standardized and reliable evaluation tool that can be used to detect volitional performance improvements in a population of Italian psychiatric patients.

Apparently, balanced chromosomal rearrangements usually have no phenotypic consequences for the carrier. However, in some cases, they may be associated with an abnormal phenotype. We report herein the case of a 4-year-old boy presenting with clinically isolated supravalvular aortic stenosis (SVAS). No chromosomal imbalance was detected by array CGH. The karyotype showed a balanced paracentric chromosome 7 inversion. Breakpoint characterization using paired-end whole-genome sequencing (WGS) revealed an ELN gene disruption in intron 1, accounting for the phenotype. Family study showed that the inversion was inherited, with incomplete penetrance. To our knowledge, this is the first case of a disruption of the ELN gene characterized by WGS. It contributes to refine the genotype-phenotype correlation in ELN disruption. Although this disruption is a rare etiology of SVAS, it cannot be detected by the diagnostic tests usually performed, such as array CGH or sequencing methods (Sanger, panel, or exome sequencing). With the future perspective of WGS as a diagnostic tool, it will be important to include a structural variation analysis in order to detect balanced rearrangements and gene disruption., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2019 by S. Karger AG, Basel.)

To assess the outcomes of neonates prenatally diagnosed with ventricular asymmetry and not operated on within the neonatal period and to determine the risk factors for left heart obstruction occurrence at follow-up. All neonates with prenatal asymmetry of the ventricles, diagnosed from August 1993 to July 2015, not operated on within the neonatal period, were retrospectively included in the study. Left heart echocardiographic measurements at birth and at last follow-up were collected and compared. Left heart anomaly included isthmus and/or aortic valve and/or mitral valve obstruction. There were a total of 34 newborns included in the study. The median follow-up was 2 years. There was no death. Eleven patients were operated on at a median age of three months; seven of them had an obstruction of the left heart (five coarctations of the aorta, one sub-aortic and aortic valve stenosis, and one mitral stenosis). Estimated freedom of left heart surgery was 80% at 6 months and 75% at 10 years. The main risk factor for progression to a left heart anomaly was a hypoplasia of the aortic isthmus (p = 0.0003), while the presence of a left superior vena cava was more frequent in these patients although the difference was not significant. Patients with an aortic isthmus z-score below - 2 at the closure of arterial duct are at risk of later coarctation and therefore follow-up should be extended to at least 3 months. Furthermore, the prenatal ventricular asymmetry does not only identify patients at risk of coarctation but also of other left heart anomalies. This last point should be a better approach with future parents to improve prenatal counseling on a more complex postnatal diagnostic than a simple isolated coarctation.

Introduction: A reliable method of intradialysis calcium mass balance quantification is far from been established. We herein investigated the use of a single-pool variable-volume Calcium kinetic model to assess calcium mass balance in chronic and stable dialysis patients., Methods: Thirty-four patients on thrice-weekly HD were studied during 240 dialysis sessions. All patients were dialyzed with a nominal total calcium concentration of 1.50 mmol/L. The main assumption of the model is that the calcium distribution volume is equal to the extracellular volume during dialysis. This hypothesis is assumed valid if measured and predicted end dialysis plasma water ionized calcium concentrations are equal. A difference between predicted and measured end-dialysis ionized plasma water calcium concentration is a deviation on our main hypothesis, meaning that a substantial amount of calcium is exchanged between the extracellular volume and a nonmodeled compartment., Findings: The difference between predicted and measured values was 0.02 mmol/L (range -0.08:0.16 mmol/L). With a mean ionized dialysate calcium concentration of 1.25 mmol/L, calcium mass balance was on average negative (mean ± SD -0.84 ± 1.33 mmol, range -5.42:2.75). Predialysis ionized plasma water concentration and total ultrafiltrate were the most important predictors of calcium mass balance. A significant mobilization of calcium from the extracellular pool to a nonmodeled pool was calculated in a group of patients., Discussion: The proposed single pool variable-volume Calcium kinetic model is adequate for prediction and quantification of intradialysis calcium mass balance, it can evaluate the eventual calcium transfer outside the extracellular pool in clinical practice., (© 2017 International Society for Hemodialysis.)

Evidence on everolimus in breast cancer has placed hyperglycemia among the most common high grade adverse events. Anthropometrics and biomarkers of glucose metabolism were investigated in a observational study of 102 postmenopausal, HR + HER2- metastatic breast cancer patients treated with everolimus-exemestane in first and subsequent lines. Best overall response (BR) and clinical benefit rate (CBR) were assessed across subgroups defined upon fasting glucose (FG) and body mass index (BMI). Survival was estimated by Kaplan-Meier method and log-rank test. Survival predictors were tested in Cox models. Median follow up was 12.4 months (1.0-41.0). The overall cohort showed increasing levels of FG and decreasing BMI (p < 0.001). Lower FG fasting glucose at BR was more commonly associated with C/PR or SD compared with PD (p < 0.001). We also observed a somewhat higher BMI associated with better response (p = 0.052). More patients in the lowest FG category achieved clinical benefit compared to the highest (p < 0.001), while no relevant differences emerged for BMI. Fasting glucose at re-assessment was also predictive of PFS (p = 0.037), as confirmed in models including BMI and line of therapy (p = 0.049). Treatment discontinuation was significantly associated with changes in FG (p = 0.014). Further research is warranted to corroborate these findings and clarify the underlying mechanisms.

The European Union has determined that from 2016 breast cancer patients should be treated in Specialist Breast Units that achieve the minimum standards for the mandatory quality indicators as defined by Eusoma. The existing standard for axillary lymph node staging in breast cancer is sentinel node biopsy (SNB), performed using Technetium-sulphur colloid ( 99m Tc) alone or with blue dye. The major limits of radioisotope consist in the problems linked to radioactivity, in the shortage of tracer and nuclear medicine units. Among existing alternative tracers, SentiMag ® , which uses superparamagnetic iron oxide particles, can represent a valid option for SNB. We conducted a paired, prospective, multicentre study to evaluate the non-inferiority of SentiMag ® vs. 99m Tc. The primary end point was the detection rate (DR) per patient. The study sample consists of 193 women affected by breast carcinoma with negative axillary assessment. The concordance rate per patients between 99m Tc and SentiMag ® was 97.9%. The DR per patient was 99.0% for 99m Tc and 97.9% for SentiMag ® . SentiMag ® appears to be non-inferior to the radiotracer and safe. While 99m Tc remains the standard, SentiMag ® DR appears adequate after a minimum learning curve. In health care settings where nuclear medicine units are not available, SentiMag/Sienna+ ® allows effective treatment of breast cancer patients., (© 2015 John Wiley & Sons Ltd.)

Infective endocarditis can negatively impact prognosis of congenital heart disease and has a 10-15% incidence of mortality. New guidelines recommend prophylaxis of infective endocarditis only for high-risk group (cyanotic congenital heart disease, valvular prosthesis, previous endocarditis) and for some specific invasive dental procedures. New guidelines are focused mainly on oral and cutaneous hygiene. Native shunts and valvular disease are no more targets for prophylaxis. More than half of the physicians do not follow the new guidelines. High-velocity shunts like ventricular septal defect should be included in the at-risk congenital disease for infective endocarditis where prophylaxis should be applied. The new guidelines for prophylaxis of infective endocarditis did not impact on the incidence of infective endocarditis., (Copyright © 2017. Published by Elsevier Masson SAS.)

Aortic pseudocoarctation is a rare congenital anomaly characterized by elongation and deformity of the aortic arch and is known to be associated with aneurysmal formation. Several studies unite to say it leads to a surgical sanction as soon as symptomatic or associated with aneurysms of the aortic arch. Our patient is a 12 years old boy, followed since birth for a little tight pseudocoarctation with a cervical aortic arch and transverse aortic arch hypoplasia. Close clinical and paraclinical monitoring including angioscans, showed the gradual enlargement of the superior mediastinum, in relation with the appearance of three aneurysms of the aortic arch. The intervention, performed by sternotomy, has consisted of the resection of the aneurysmal area and the interposition of a Dacron tube to repair the aortic arch and the reimplantation of the left subclavian artery into the left carotid artery. The postoperative course was uneventful. Management of pseudocoarctation associated with cervical aortic arch and aneurysms remains surgical. Close monitoring of patients with pseudocorctation, seems to be essential to avoid fatal complications such as aneurysmal rupture., Competing Interests: The authors declare no competing interest.

Background: Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM., Objectives: This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children., Methods: We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes., Results: We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3)., Conclusions: Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Since 2007, one-step nucleic acid amplification (OSNA) has been used as a diagnostic system for sentinel lymph node (SLN) examination in patients with breast cancer. This study aimed to define a new clinical cut-off of CK19 mRNA copy number based on the calculation of the risk that an axillary lymph node dissection (ALND) will be positive. We analyzed 1529 SLNs from 1140 patients with the OSNA assay and 318 patients with positive SLNs for micrometastasis (250 copies) and macrometastasis (5000 copies) underwent ALND. Axillary non-SLNs were routinely examined. ROC curves and Youden's index were performed in order to identify a new cut-off value. Logistic regression models were performed in order to compare OSNA categorical variables created on the basis of our and traditional cut-off to better identify patients who really need an axillary dissection. 69% and 31% of OSNA positive patients had a negative and positive ALND, respectively. ROC analysis identified a cut-off of 2150 CK19 mRNA copies with 95% sensitivity and 51% specificity. Positive and negative predictive values of this new cut-off were 47% and 96%, respectively. Logistic regression models indicated that the cut-off of 2150 copies better discriminates patients with node negative or positive in comparison with the conventional OSNA cut-off (p<0.0001). This cut-off identifies false positive and false negative cases and true-positive and true negative cases very efficiently, and therefore better identifies which patients really need an ALND and which patients can avoid one. This is why we suggest that the negative cut-off should be raised from 250 to 2150. Furthermore, we propose that for patients with a copy number that ranges between 2150 and 5000, there should be a multidisciplinary discussion concerning the clinical and bio-morphological features of primary breast cancer before any decision is taken on whether to perform an ALND or not., Competing Interests: The authors have declared that no competing interests exist.

Left ventricular noncompaction cardiomyopathy (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. A NGS workflow, based on a panel of 95 genes developed for sequencing most prevalent sudden cardiac death-causing genes, was used to make a rapid and costless molecular diagnosis in two siblings with a severe noncompaction cardiomyopathy starting prenatally and leading to rapid cardiac failure. For the first time, a total homozygous PKP2 deletion was identified. This molecular defect was further confirmed by MLPA and array-comparative genomic hybridization (CGH). Heterozygous PKP2 mutations are usually reported in a significant proportion of Arrhythmogenic Right Ventricular Cardiomyopathy cases. Our results show, for the first time, the involvement of PKP2 in severe cardiomyopathy with ventricular non compaction., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Tumor-positive sentinel lymph node (SLN) biopsy results in a risk of non sentinel node metastases in micro- and macro-metastases ranging from 20 to 50%, respectively. Therefore, most patients underwent unnecessary axillary lymph node dissections. We have previously developed a mathematical model for predicting patient-specific risk of non sentinel node (NSN) metastases based on 2460 patients. The study reports the results of the validation phase where a total of 1945 patients were enrolled, aimed at identifying a tool that gives the possibility to the surgeon to choose intraoperatively whether to perform or not axillary lymph node dissection (ALND)., Methods: The following parameters were recorded: Clinical: hospital, age, medical record number; Bio pathological: Tumor (T) size stratified in quartiles, grading (G), histologic type, lymphatic/vascular invasion (LVI), ER-PR status, Ki 67, molecular classification (Luminal A, Luminal B, HER-2 Like, Triple negative); Sentinel and non-sentinel node related: Number of NSNs removed, number of positive NSNs, cytokeratin 19 (CK19) mRNA copy number of positive sentinel nodes stratified in quartiles. A total of 1945 patients were included in the database. All patient data were provided by the authors of this paper., Results: The discrimination of the model quantified with the area under the receiver operating characteristics (ROC) curve (AUC), was 0.65 and 0.71 in the validation and retrospective phase, respectively. The calibration determines the distance between predicted outcome and actual outcome. The mean difference between predicted/observed was 2.3 and 6.3% in the retrospective and in the validation phase, respectively. The two values are quite similar and as a result we can conclude that the nomogram effectiveness was validated. Moreover, the ROC curve identified in the risk category of 31% of positive NSNs, the best compromise between false negative and positive rates i.e. when ALND is unnecessary (<31%) or recommended (>31%)., Conclusions: The results of the study confirm that OSNA nomogram may help surgeons make an intraoperative decision on whether to perform ALND or not in case of positive sentinel nodes, and the patient to accept this decision based on a reliable estimation on the true percentage of NSN involvement. The use of this nomogram achieves two main gools: 1) the choice of the right treatment during the operation, 2) to avoid for the patient a second surgery procedure.

To report the results of the DECT trial, a phase II study of locally advanced or operable HER2-positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA-IIIB HER2-positive BC, 18-75 years, normal organ functions, ECOG ≤1, and left ventricular ejection fraction (LVEF) ≥55%) received four cycles of neoadjuvant docetaxel, 100 mg/m(2) intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3-weekly cycles of epirubicin 120 mg/m(2) and cyclophosphamide, 600 mg/m(2) , plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI ≥25 and with hormone negative disease. The median follow up was 46 months (8-78). Four-year recurrence-free survival was 74.7% (95%CI, 58.2-91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient we observed a ≥10% asymptomatic LVEF decrease persisting after surgery. Notwithstanding their limited applicability due to the current guidelines, our findings support the efficacy of the regimen of interest in the neoadjuvant setting along with a fairly acceptable toxicity profile, including cardiotoxicity. Results on BMI may invite further assessment in future studies. J. Cell. Physiol. 231: 2541-2547, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc., (© 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.)

Human papillomavirus (HPV) is widely known as a cause of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN). HPVs related to cancer express two main oncogenes, i.e. E6 and E7, considered as tumorigenic genes; their integration into the host genome results in the abnormal regulation of cell cycle control. Due to their peculiarities, these oncogenes represent an excellent target for cancer immunotherapy. In this work the authors highlight the potential use of therapeutic vaccines as safe and effective pharmacological tools in cervical disease, focusing on vaccines that have reached the clinical trial phase. Many therapeutic HPV vaccines have been tested in clinical trials with promising results. Adoptive T-cell therapy showed clinical activity in a phase II trial involving advanced CC patients. A phase II randomized trial showed clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN. Several trials involving peptide-protein-based vaccines and live-vector based vaccines demonstrated that these approaches are effective in CIN as well as in advanced CC patients. HPV therapeutic vaccines must be regarded as a therapeutic option in cervical disease. The synergic combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, immunomodulators or immune checkpoint inhibitors opens a new and interesting scenario in this disease.

Sudden unexpected death in infancy occurs in apparently healthy infants and remains largely unexplained despite thorough investigation. The vast majority of cases are sporadic. Here we report seven individuals from three families affected by sudden and unexpected cardiac arrest between 4 and 20 months of age. Whole-exome sequencing revealed compound heterozygous missense mutations in PPA2 in affected infants of each family. PPA2 encodes the mitochondrial pyrophosphatase, which hydrolyzes inorganic pyrophosphate into two phosphates. This is an essential activity for many biosynthetic reactions and for energy metabolism of the cell. We show that deletion of the orthologous gene in yeast (ppa2Δ) compromises cell viability due to the loss of mitochondria. Expression of wild-type human PPA2, but not PPA2 containing the mutations identified in affected individuals, preserves mitochondrial function in ppa2Δ yeast. Using a regulatable (doxycycline-repressible) gene expression system, we found that the pathogenic PPA2 mutations rapidly inactivate the mitochondrial energy transducing system and prevent the maintenance of a sufficient electrical potential across the inner membrane, which explains the subsequent disappearance of mitochondria from the mutant yeast cells. Altogether these data demonstrate that PPA2 is an essential gene in yeast and that biallelic mutations in PPA2 cause a mitochondrial disease leading to sudden cardiac arrest in infants., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation. Here, we found that both apoptotic epitope-specific and hepatitis C virus (HCV)-specific CD8(+) T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA(+) cell subsets expressing a dysfunctional T-helper 1-like signature program in chronic HCV infection. However, apoptotic epitope-specific CD8(+) T cells produced tumor necrosis factor α and interleukin 2 at the intrahepatic level significantly more than HCV-specific CD8(+) T cells, despite both populations expressing high levels of programmed death 1 receptor. Contextually, only apoptotic epitope-specific CD8(+) T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Together, these data suggest that, compared with HCV-specific CD8(+) T cells, apoptotic epitope-specific CD8(+) T cells can better sustain chronic immune activation, owing to their capacity to produce tumor necrosis factor α, and exhibit greater resistance to inhibitory signals during chronic HCV infection., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

In recent years acetylated, propionylated and butyrylated starches have received special attention due to their capacity to deliver specific short chain fatty acids (SCFAs) to the colon in a sustained and predictable manner, and thus contribute to maintaining the normal physiologic function of the large bowel and preventing specific diseases. In the current contribution a non-conventional organocatalytic solventless route for the eco-friendly propionylation of corn starch is proposed. The catalyst used in the acylation is a naturally occurring α-hydroxy acid (l-tartaric acid). Propionylated starches with degree of substitution (DS) in the 0.05-1.59 interval were obtained and characterized in terms of chemical structure, morphology, crystallinity, thermal stability and hydrophilicity. Results showed that by the proposed methodology propionylated starch with the DS required for clinical use (i.e. 0.2-0.3) could be obtained within 2-3h of reaction. Characterization results evidenced the progressive loss of crystallinity of starch granules as higher substitution levels were conferred., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Acute viral myocarditis may impair prognosis in children of all ages. Its true incidence is underestimated because of heterogeneity of presentation and outcome. Patients may either recover or progress to chronic cardiomyopathy or death. Improving short-term and long-term prognosis is challenging but can probably be achieved by new diagnostic techniques and novel targeted therapies. The objectives of this review are: (1) to detail the current state of knowledge of the pathophysiological mechanisms of acute myocarditis; (2) to provide an update on diagnostic tools such as magnetic resonance imaging and endomyocardial biopsy; and (3) to present new insights in therapeutic strategies, targeted therapies and management of fulminant cases. Options for improving outcomes in acute myocarditis in the pediatric population are discussed.

Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates.

Survival and quality of life of dialysis patients are strictly dependent on the quality of the haemodialysis (HD) treatment. In this respect, dialysate composition, including water purity, plays a crucial role. A major aim of HD is to normalize predialysis plasma electrolyte and mineral concentrations, while minimizing wide swings in the patient's intradialytic plasma concentrations. Adequate sodium (Na) and water removal is critical for preventing intra- and interdialytic hypotension and pulmonary edema. Avoiding both hyper- and hypokalaemia prevents life-threatening cardiac arrhythmias. Optimal calcium (Ca) and magnesium (Mg) dialysate concentrations may protect the cardiovascular system and the bones, preventing extraskeletal calcifications, severe secondary hyperparathyroidism and adynamic bone disease. Adequate bicarbonate concentration [HCO3 (-)] maintains a stable pH in the body fluids for appropriate protein and membrane functioning and also protects the bones. An adequate dialysate glucose concentration prevents severe hyperglycaemia and life-threating hypoglycaemia, which can lead to severe cardiovascular complications and a worsening of diabetic comorbidities.

Background: Breast cancer is the most common cancer in women worldwide and is the second most common cause of cancer death in women. Electrochemotherapy (ECT) used in early-phase clinical trials for the treatment of primary breast cancer resulted in a not complete tumor necrosis in most cases. The present study was undertaken to analyze the feasibility to use ECT to treat patients with histologically proven unifocal ductal breast cancer. In particular, results of ECT treatment in a clinical case are compared with the ones of a simplified 3D dosimetric model., Methods: This clinical study was conducted with the pulse generator Cliniporator Vitae (IGEA, Carpi, Italy). ECT procedures were performed according to ESOPE standard operating procedures. Five single needle electrodes were used with one positioned in the center of the tumor, and the other four distributed around the nodule. Histological images of the resected tumor are compared with the maps of the electric field obtained with a simplified 3D model in Comsol Multiphysics v 4.3., Results: The results of the clinical case demonstrated a reduced efficacy of the ECT treatment described. The proposed simple numerical model of the breast tumor located in a low conductive tissue suggests that this is due to the reduced electric field induced inside the tumor with such 5 electrodes placement. However, where the electric field is predicted higher than the reversible electroporation threshold (E>400 V/cm), also the histological images confirm the necrosis of the target with a good agreement between the modeled and clinical results., Conclusions: The results suggest the dependence of the effectiveness of the treatment on the careful placement of the electrodes. A detailed planned procedure for the tumor analysis after the treatment is also needed in order to better correlate the single electrode positions and the histological images. Simulation models could be used to identify better electrodes configuration in planning the experimental protocol for ECT treatment of breast tumors.

Background: Over the past several years the incidence of cutaneous melanoma has rapidly increased. This tumor develops often in-transit metastases that significantly reduce patient survival at 5 years. To improve prognosis and quality of life in patients with melanoma metastases, a mini invasive procedure like electrochemotherapy (ECT) is adopted to remove superficial tissue lesions. To detect the melanoma metastases, high frequency (HF) ultrasound (US) is used. This technique, though, can be time-consuming and it needs an expert operator and a high performing machine. Therefore, we asked whether the US could be replaced or integrated with other less time-consuming techniques such as 18-FDG positron emission tomography/computed tomography (PET-CT) and telethermography (TT)., Methods: Fifteen patients (4 males and 11 females - age range: 63-91) affected whit advanced stage melanoma were enrolled. They presented 52 in-transit metastases as detected by the three techniques used, HF-US, PET/CT and TT within 30 days before ECT., Results: All the 52 lesions were detected by HF-US (100%), 24/52 were detected by PET-CT (42,6%) and 15/52 were detected by TT (27,7%). PET-CT reported 3.7% false positives, while no false positive were reported by TT., Conclusions: As US detected 100% lesions, compared to the other two techniques used, US, along with clinical examination, has still to be considered as gold standard in the diagnosis of metastatic lesions. US, associated with an exhaustive anamnesis and accurate clinical examination, cannot be replaced by either PET-CT or TT. When US performing devices and experienced operators are not available, though, it is highly recommended to integrate US with at least one of the other techniques. Under certain circumstances, as in the case of obese and non-collaborating patients or in patients with lymphatic stasis, these techniques should be integrated to obtain exact in-transit metastases evaluation.

Unlabelled: Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T-bethigh IFN-γ- "T-helper (Th)1-suppressing" phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon-gamma (IFN-γ; T-bet+IFN-γ+), thus becoming "Th1-like" cells. OX40-expressing and Th1-suppressing Tregs were enriched in the Helios-positive subset, carrying highly demethylated Treg cell-specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2-like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-γ, ultimately leading to complete, full Th1-like Treg differentiation., Conclusion: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ., (© 2014 by the American Association for the Study of Liver Diseases.)

Purpose: Chemotherapy regimens containing anthracyclines and taxanes represent the landmark of neoadjuvant systemic therapy of breast cancer. In advanced breast cancer patients liposomal anthracyclines (LA) have shown similar efficacy and less cardiac toxicity when compared to conventional anthracyclines. We performed this retrospective analysis in order to evaluate the efficacy and tolerability of neoadjuvant regimens including LA outside of clinical trials in routine clinical practice., Methods: Fifty operable or locally advanced, HER2 negative, breast cancer patients were retrospectively identified in 5 Italian cancer centres. Nineteen patients had received 4 cycles of non-pegylated liposomal doxorubicin (NPLD) and cyclophosphamide, followed by 4 cycles of docetaxel, every 3 weeks. In 25 patients the reverse sequence was employed, and a third subgroup of 6 patients received 4 cycles of NPLD/cyclophosphamide every 3 weeks followed by 4 cycles of weekly carboplatin and paclitaxel., Results: We observed 10 pathological complete responses (pCR) (20.0%, 95%CI, 9% to 31%), and 35 (70%, 95%CI, 57.3% to 82.7%) partial responses (pPR), whereas no patients progressed onto therapy. In the small subset of triple negative tumors the pCR rate was 37.5%, and in tumors expressing ER and/or PgR it was 16.7%. A pCR rate of 26.5% was observed in tumors with high Ki-67, whereas in tumors with low Ki-67 only one (6.2%) pCR was observed (p=0.14). Treatments were well tolerated. The most common toxicities were myelosuppression and palmar-plantar erytrodysesthesia; 4 asymptomatic and transient LVEF decrease have been recorded, without any case of clinical cardiotoxicity., Conclusions: NPLD-cyclophosphamide and taxanes sequential regimens were proven effective and well tolerated in breast cancer patients with contra-indication to conventional anthracyclines undergoing neoadjuvant chemotherapy, even outside of clinical trials in everyday clinical practice.

Background: Late presentation of abnormal origin of coronary artery from the pulmonary artery (ACAPA) is uncommon compared with early presentation, which usually induces extended myocardial necrosis and severe heart failure. The late presentation is characterized by abundant development of intercoronary collaterals resulting in mild and rare symptoms, but nevertheless can cause sudden cardiac death. Our objective was to describe presentation, cardiovascular imaging methods for diagnosis and outcomes of patients with late presentation of ACAP., Methods: The study is a retrospective review of a single-center database to identify all patients diagnosed with ACAPA beyond the first year of life., Results: From 1976 to 2011, 10 patients were identified with ACAPA at the age of 1.1-64 years: 6 with left coronary artery from the pulmonary artery (ALCAPA) and 4 with right coronary artery from the pulmonary artery (ARCAPA). Echocardiography and Doppler imaging evidenced: (1) direct signs: the abnormal coronary ostium arising from the pulmonary trunk with retrograde coronary artery flow and (2) indirect signs: abundant intercoronary septal collaterals with anterograde flow (ARCAPA) or retrograde flow (ALCAPA) and dilatation of the controlateral normally originated coronary artery. Nine patients underwent surgical implantation of the ACAPA into the ascending aorta. After 7.9 years mean follow-up, all were asymptomatic except one who required a second surgery., Conclusions: Noninvasive cardiovascular imaging, namely transthoracic echocardiography and Doppler specific parameters, can reach diagnosis of late presentation of ACAPA. Direct aortic implantation is a reliable and effective to establish dual coronary artery circulation and prevent risks due to myocardial ischemia., (© 2013, Wiley Periodicals, Inc.)