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Introduction: Non-ischemic dilated cardiomyopathy (NIDCM) is characterized by a reduced left ventricular (LV) ejection fraction (LVEF, Aim: To explore the features of echocardiography-derived HDFs in NIDCM and their association with clinical endpoints. Methods: Asymptomatic, non-hospitalized NIDCM patients free from coronary artery disease and moderate or severe valvular heart disease were included in this single-center observational retrospective longitudinal study. Those with atrial fibrillation and a follow-up Results: Ninety-seven patients were included, sixty-seven (69%) were males, mean age was 62 ± 14 years, and mean LVEF was 39.2 ± 8.6%. During a median follow-up of 4.2 (3.1–5.1) years, 19 (20%) patients experienced MACE. These patients had a higher HDFs-angle (71.0 (67.0–75.0) vs. 68.0 (63.0–71.0)°, p = 0.005), lower HDFs-ls (1.36 (1.01–1.85) vs. 1.66 ([1.28–2.04])%, p = 0.015), but similar HDFs-ab (5.02 (4.39–6.34) vs. 5.66 (4.53–6.78)%, p = 0.375) compared to those without MACE. in a Cox regression analysis, HDFs-angle (HR 1.16 (95%-CI 1.04–1.30), p = 0.007) was associated with MACE, while other conventional echocardiography parameters, including LVEF and LV longitudinal strain, were not. Conclusions: HDFs-angle is associated with clinical endpoints in NIDCM. A higher HDFs-angle may be a marker of impaired myocardial performance in patients with reduced LVEF.

Abstract The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function. Mechanistically, p140Cap inhibition of β-Catenin depends on its ability to localize in and stabilize the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Clinical studies in women show that low p140Cap expression correlates with reduced presence of tumor-infiltrating lymphocytes and more aggressive tumor types in a large cohort of real-life female breast cancer patients, highlighting the potential of p140Cap as a biomarker for therapeutic intervention targeting the β-Catenin/ Tumor-initiating cells /G-CSF/ polymorphonuclear myeloid-derived suppressor cell axis to restore an efficient anti-tumor immune response.

Background: The measurement of aortic dimensions and their evolution are key in the management of patients with aortic diseases. Manual assessment, the current guideline-recommended method and clinical standard, is subjective, poorly reproducible, and time-consuming, limiting the capacity to track aortic growth in everyday practice. Aortic geometry mapping (AGM) via image registration of serial computed tomography angiograms outperforms manual assessment, providing accurate and reproducible 3D maps of aortic diameter and growth rate. This observational study aimed to evaluate the accuracy and reproducibility of AGM on non-gated contrast-enhanced (CE-) and cardiac- and respiratory-gated (GN-) magnetic resonance angiographies (MRA). Methods: Patients with thoracic aortic disease followed with serial CE-MRA (n = 30) or GN-MRA (n = 15) acquired at least 1 year apart were retrospectively and consecutively identified. Two independent observers measured aortic diameters and growth rates (GR) manually at several thoracic aorta reference levels and with AGM. Agreement between manual and AGM measurements and their inter-observer reproducibility were compared. Reproducibility for aortic diameter and GR maps assessed with AGM was obtained. Results: Mean follow-up was 3.8 ± 2.3 years for CE- and 2.7 ± 1.6 years for GN-MRA. AGM was feasible in the 93% of CE-MRA pairs and in the 100% of GN-MRA pairs. Manual and AGM diameters showed excellent agreement and inter-observer reproducibility (ICC>0.9) at all anatomical levels. Agreement between manual and AGM GR was more limited, both in the aortic root by GN-MRA (ICC=0.47) and in the thoracic aorta, where higher accuracy was obtained with GN- than with CE-MRA (ICC=0.55 vs 0.43). The inter-observer reproducibility of GR by AGM was superior compared to manual assessment, both with CE- (thoracic: ICC= 0.91 vs 0.51) and GN-MRA (root: ICC=0.84 vs 0.52; thoracic: ICC=0.93 vs 0.60). AGM-based 3D aortic size and growth maps were highly reproducible (median ICC >0.9 for diameters and >0.80 for GR). Conclusion: Mapping aortic diameter and growth on MRA via 3D image registration is feasible, accurate and outperforms the current manual clinical standard. This technique could broaden the possibilities of clinical and research evaluation of patients with aortic thoracic diseases.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with adverse CV outcomes. Vascular aging (VA), which is defined as the progressive deterioration of arterial function and structure over a lifetime, is an independent predictor of both AF development and CV events. A timing identification and treatment of early VA has therefore the potential to reduce the risk of AF incidence and related CV events. A network of scientists and clinicians from the COST Action VascAgeNet identified five clinically and methodologically relevant questions regarding the relationship between AF and VA and conducted a narrative review of the literature to find potential answers. These are: (1) Are VA biomarkers associated with AF? (2) Does early VA predict AF occurrence better than chronological aging? (3) Is early VA a risk enhancer for the occurrence of CV events in AF patients? (4) Are devices measuring VA suitable to perform subclinical AF detection? (5) Does atrial-fibrillation-related rhythm irregularity have a negative impact on the measurement of vascular age? Results showed that VA is a powerful and independent predictor of AF incidence, however, its role as risk modifier for the occurrence of CV events in patients with AF is debatable. Limited and inconclusive data exist regarding the reliability of VA measurement in the presence of rhythm irregularities associated with AF. To date, no device is equipped with tools capable of detecting AF during VA measurements. This represents a missed opportunity to effectively perform CV prevention in people at high risk. Further advances are needed to fill knowledge gaps in this field.

Magnetic resonance imaging and computed tomography allow the characterization of arterial state and function with high confidence and thus play a key role in the understanding of arterial aging and its translation into the clinic. Decades of research into the development of innovative imaging sequences and image analysis techniques have led to the identification of a large number of potential biomarkers, some bringing improvement in basic science, others in clinical practice. Nonetheless, the complexity of some of these biomarkers and the image analysis techniques required for their computation hamper their widespread use. In this narrative review, current biomarkers related to aging of the aorta, their founding principles, the sequence, and postprocessing required, and their predictive values for cardiovascular events are summarized. For each biomarker a summary of reference values and reproducibility studies and limitations is provided. The present review, developed in the COST Action VascAgeNet, aims to guide clinicians and technical researchers in the critical understanding of the possibilities offered by these advanced imaging modalities for studying the state and function of the aorta, and their possible clinically relevant relationships with aging.

Background: In Cri du Chat (CdC), cancer as comorbidity is extremely rare. In databases from Denmark, Spain, Australia, New Zealand, and Japan, no cancer was reported; in Italy and Germany, four cancers were identified out of 321 CdCs. Methods: In a 29-year-old CdC patient, clinical investigations following hematemesis led to the diagnosis of esophageal adenocarcinoma (EAC). A high pain threshold was also observed. Conventional and molecular cytogenetic defined the size of the deletion, and exome analysis on the trio completed the molecular work. Results: Cytogenetic analysis showed a de novo chromosomal alteration: 46,XY,ishdel(5)(p14.3)(D5S28-) and arr[GRCh37] 5p15.33p14.3(1498180_19955760)x1. A quantitative sensory test demonstrated a high heat threshold. A 18f-fluorodeoxyglucose PET/TC scan of the brain failed to detect reduction of metabolism in the somatosensory area or insular cortex. Exome analysis in the trio (patient and parents) failed to identify variants to be interpreted as a likely risk factor for EAC. Conclusion: We conclude that the presence of well-known risk factors (maleness, obesity, gastroesophageal reflux, and Barrett’s metaplasia) in a patient with very limited capability of expressing discomfort or referring clinical symptoms have been the main risk factors for developing EAC. At present, based on the available data, there is no evidence of any increased risk of developing cancer in CdC patients.

Abstract Radiomics is an emerging technique for the quantification of imaging data that has recently shown great promise for deeper phenotyping of cardiovascular disease. Thus far, the technique has been mostly applied in single-centre studies. However, one of the main difficulties in multi-centre imaging studies is the inherent variability of image characteristics due to centre differences. In this paper, a comprehensive analysis of radiomics variability under several image- and feature-based normalisation techniques was conducted using a multi-centre cardiovascular magnetic resonance dataset. 218 subjects divided into healthy (n = 112) and hypertrophic cardiomyopathy (n = 106, HCM) groups from five different centres were considered. First and second order texture radiomic features were extracted from three regions of interest, namely the left and right ventricular cavities and the left ventricular myocardium. Two methods were used to assess features’ variability. First, feature distributions were compared across centres to obtain a distribution similarity index. Second, two classification tasks were proposed to assess: (1) the amount of centre-related information encoded in normalised features (centre identification) and (2) the generalisation ability for a classification model when trained on these features (healthy versus HCM classification). The results showed that the feature-based harmonisation technique ComBat is able to remove the variability introduced by centre information from radiomic features, at the expense of slightly degrading classification performance. Piecewise linear histogram matching normalisation gave features with greater generalisation ability for classification ( balanced accuracy in between 0.78 ± 0.08 and 0.79 ± 0.09). Models trained with features from images without normalisation showed the worst performance overall ( balanced accuracy in between 0.45 ± 0.28 and 0.60 ± 0.22). In conclusion, centre-related information removal did not imply good generalisation ability for classification.

Abstract Background Patency of the false lumen in chronic aortic dissection (AD) is associated with aortic dilation and long-term aortic events. However, predictors of adverse outcomes in this population are limited. The aim of this study was to evaluate the relationship between aortic growth rate and false lumen flow dynamics and biomechanics in patients with chronic, patent AD. Methods Patients with a chronic AD with patent false lumen in the descending aorta and no genetic connective tissue disorder underwent an imaging follow-up including a contrast-enhanced 4D flow cardiovascular magnetic resonance (CMR) protocol and two consecutive computed tomography angiograms (CTA) acquired at least 1 year apart. A comprehensive analysis of anatomical features (including thrombus quantification), and false lumen flow dynamics and biomechanics (pulse wave velocity) was performed. Results Fifty-four consecutive patients with a chronic, patent false lumen in the descending aorta were included (35 surgically-treated type A AD with residual tear and 19 medically-treated type B AD). Median follow-up was 40 months. The in-plane rotational flow, pulse wave velocity and the percentage of thrombus in the false lumen were positively related to aortic growth rate (p = 0.006, 0.017, and 0.037, respectively), whereas wall shear stress showed a trend for a positive association (p = 0.060). These results were found irrespectively of the type of AD. Conclusions In patients with chronic AD and patent false lumen of the descending aorta, rotational flow, pulse wave velocity and wall shear stress are positively related to aortic growth rate, and should be implemented in the follow-up algorithm of these patients. Further prospective studies are needed to confirm if the assessment of these parameters helps to identify patients at higher risk of adverse clinical events.

Introduction: SARS-CoV-2 infection is associated with different cutaneous manifestations, including chilblain-like lesions (“COVID-19 toes”), more frequently observed in younger patients. During the current COVID-19 pandemic, pediatric teledermatology has increased considerably since it allows to assist even children quarantined or living in distant geographic locations, also reducing long waiting times. Nonetheless, the correct clinical interpretation of skin lesions suspicious for being related to COVID19 represent a challenge for the dermatologist; in fact, many cutaneous diseases of both infectious and non-infectious origin, like pool palms (also known as “juvenile palmar dermatitis of swimming pools”), can simulate COVID-19 toes. Objectives: to report a telemedicine-assisted experience on outpatient pediatric cases affected by acral dermatitis during the current COVID-19 outbreak, highlighting a possible underdiagnosed differential diagnosis. Methods: We included 6pediatric cases, affected by acral acute dermatitis, for which, due to the ongoing pandemic, it was impracticable to conduct a face-to-face visit. We collected clinical data and high resolution images of skin lesions, which were independently examined by three different dermatologists. Results: We described the first three pediatric cases of pool palms reported in the COVID-era, comparing the clinical characteristics of three other pediatric patients affected by COVID-19 toes. We also performed a literature review of all pool palms cases published to date. Conclusions: Our real-life experience highlights the crucial rule of teledermatology during the ongoing pandemic. Furthermore, the paper emphasizes its criticalities, mainly related to the difficult collection of anamnestic data.

Background and PurposePrognostic models based on cardiovascular hemodynamic parameters may bring new information for an early assessment of patients with bicuspid aortic valve (BAV), playing a key role in reducing the long-term risk of cardiovascular events. This work quantifies several three-dimensional hemodynamic parameters in different patients with BAV and ranks their relationships with aortic diameter.Materials and MethodsUsing 4D-flow CMR data of 74 patients with BAV (49 right-left and 25 right-non-coronary) and 48 healthy volunteers, aortic 3D maps of seventeen 17 different hemodynamic parameters were quantified along the thoracic aorta. Patients with BAV were divided into two morphotype categories, BAV-Non-AAoD (where we include 18 non-dilated patients and 7 root-dilated patients) and BAV-AAoD (where we include the 49 patients with dilatation of the ascending aorta). Differences between volunteers and patients were evaluated using MANOVA with Pillai's trace statistic, Mann–Whitney U test, ROC curves, and minimum redundancy maximum relevance algorithm. Spearman's correlation was used to correlate the dilation with each hemodynamic parameter.ResultsThe flow eccentricity, backward velocity, velocity angle, regurgitation fraction, circumferential wall shear stress, axial vorticity, and axial circulation allowed to discriminate between volunteers and patients with BAV, even in the absence of dilation. In patients with BAV, the diameter presented a strong correlation (> |+/−0.7|) with the forward velocity and velocity angle, and a good correlation (> |+/−0.5|) with regurgitation fraction, wall shear stress, wall shear stress axial, and vorticity, also for morphotypes and phenotypes, some of them are correlated with the diameter. The velocity angle proved to be an excellent biomarker in the differentiation between volunteers and patients with BAV, BAV morphotypes, and BAV phenotypes, with an area under the curve bigger than 0.90, and higher predictor important scores.ConclusionsThrough the application of a novel 3D quantification method, hemodynamic parameters related to flow direction, such as flow eccentricity, velocity angle, and regurgitation fraction, presented the best relationships with a local diameter and effectively differentiated patients with BAV from healthy volunteers.

ObjectivesTo determine the risk of mortality and need for aortic valve replacement (AVR) in patients with low-flow low-gradient (LFLG) aortic stenosis (AS).MethodsA longitudinal multicentre study including consecutive patients with severe AS (aortic valve area [AVA] < 1.0 cm2) and normal left ventricular ejection fraction (LVEF). Patients were classified as: high-gradient (HG, mean gradient ≥ 40 mmHg), normal-flow low-gradient (NFLG, mean gradient < 40 mmHg, indexed systolic volume (SVi) > 35 ml/m2) and LFLG (mean gradient < 40 mmHg, SVi ≤ 35 ml/m2).ResultsOf 1,391 patients, 147 (10.5%) had LFLG, 752 (54.1%) HG, and 492 (35.4%) NFLG. Echocardiographic parameters of the LFLG group showed similar AVA to the HG group but with less severity in the dimensionless index, calcification, and hypertrophy. The HG group required AVR earlier than NFLG (p < 0.001) and LFLG (p < 0.001), with no differences between LFLG and NFLG groups (p = 0.358). Overall mortality was 27.7% (CI 95% 25.3–30.1) with no differences among groups (p = 0.319). The impact of AVR in terms of overall mortality reduction was observed the most in patients with HG (hazard ratio [HR]: 0.17; 95% CI: 0.12–0.23; p < 0.001), followed by patients with LFLG (HR: 0.25; 95% CI: 0.13–0.49; p < 0.001), and finally patients with NFLG (HR: 0.29; 95% CI: 0.20–0.44; p < 0.001), with a risk reduction of 84, 75, and 71%, respectively.ConclusionsParadoxical LFLG AS affects 10.5% of severe AS, and has a lower need for AVR than the HG group and similar to the NFLG group, with no differences in mortality. AVR had a lower impact on LFLG AS compared with HG AS. Therefore, the findings of the present study showed LFLG AS to have an intermediate clinical risk profile between the HG and NFHG groups.

Abstract Background Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children. Results In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.

Vitamin B6 is a micronutrient required by the body. It acts as a coenzyme in biochemical reactions. Vitamin B6 toxicity is not caused by the intake of food-based sources. The few reported cases of vitamin B6 toxicity are always caused by overdosing of nutritional supplements. Chronic toxicity typically occurs with peripheral neuropathy such as paraesthesia, ataxia, and imbalance, paradoxically mimicking vitamin B6 deficiency. However, the prognosis is favorable, and symptoms usually show improvement once excessive vitamin B6 levels return to the physiological range. We report a newborn presenting with diffuse tremor at birth, interpreted as secondary to the mother's intake of high doses of a supplement containing vitamin B6 during pregnancy and breastfeeding. As expected, the newborn’s serum levels of vitamin B6 were high. The tremors disappeared when the maternal supplement was stopped.

Left Ventricular (LV) Non-compaction (LVNC), Hypertrophic Cardiomyopathy (HCM), and Dilated Cardiomyopathy (DCM) share morphological and functional traits that increase the diagnosis complexity. Additional clinical information, besides imaging data such as cardiovascular magnetic resonance (CMR), is usually required to reach a definitive diagnosis, including electrocardiography (ECG), family history, and genetics. Alternatively, indices of hypertrabeculation have been introduced, but they require tedious and time-consuming delineations of the trabeculae on the CMR images. In this paper, we propose a radiomics approach to automatically encode differences in the underlying shape, gray-scale and textural information in the myocardium and its trabeculae, which may enhance the capacity to differentiate between these overlapping conditions. A total of 118 subjects, including 35 patients with LVNC, 25 with HCM, 37 with DCM, as well as 21 healthy volunteers (NOR), underwent CMR imaging. A comprehensive radiomics characterization was applied to LV short-axis images to quantify shape, first-order, co-occurrence matrix, run-length matrix, and local binary patterns. Conventional CMR indices (LV volumes, mass, wall thickness, LV ejection fraction—LVEF—), as well as hypertrabeculation indices by Petersen and Jacquier, were also analyzed. State-of-the-art Machine Learning (ML) models (one-vs.-rest Support Vector Machine—SVM—, Logistic Regression—LR—, and Random Forest Classifier—RF—) were used for one-vs.-rest classification tasks. The use of radiomics models for the automated diagnosis of LVNC, HCM, and DCM resulted in excellent one-vs.-rest ROC-AUC values of 0.95 while generating these results without the need for the delineation of the trabeculae. First-order and texture features resulted to be among the most discriminative features in the obtained radiomics signatures, indicating their added value for quantifying relevant tissue patterns in cardiomyopathy differential diagnosis.

Abstract Background Sudden unexpected postnatal collapse of presumably healthy neonates during early skin-to-skin contact is a rare, yet recognized occurrence, associated with a high risk of mortality and morbidity. A survey was conducted in 2012 in 30 delivery wards throughout Piedmont and the Aosta Valley to evaluate the environmental and logistical aspects that could be linked to SUPC. The survey was again conducted in 2016 in 28 delivery wards in Piedmont and the Aosta Valley in order to evaluate organizational improvements introduced after ministerial indications and recommendations by the Italian Society of Neonatology were published in 2014, in light of new findings regarding the phenomenon. Methods A questionnaire specifically asking about the organization of delivery wards, and surveillance or supervision during early skin-to-skin contact, was sent to all of the hospitals taking part in the survey in both 2012 and 2016. The collected data were elaborated anonymously and the statistical analysis was performed by using the two by two table. Results In 2012, 28 out of 30 delivery wards in Piedmont and Aosta, with a total of 31,074 newborns out of 35,435, were evaluated in all of the environmental and logistical aspects that might be cause for SUPC to occur. An identical survey was taken again in 2016; 26 out of 28 wards participated with a total of 27,484 newborns out of 30,339. In 2012, early skin-to-skin contact took place immediately in all the delivery rooms in 27 wards, and soon after in the post-partum room in one; in 11 out of 28 wards there was early skin-to-skin contact in the operating theater itself, following caesarean sections (11/26 in 2016). Routine newborn care was given after 3 h in 8 delivery wards (7/26 in 2016); after 2 h in 12 (7/26 in 2016); after 1 h in 2 (4/26 in 2016); after 30 min in 3 (2/26 in 2016); after 10 min in 1 (0/26 in 2016); after 1 or 2 min in 1 (0/26 in 2016) and at any time in one ward (6/26 in 2016). Conclusion Periodic surveys of delivery wards are useful for the assessment of all the aspects and risk factors that need to be changed in order to implement safe early skin-to-skin contact.

Background: Many aspects of SARS-CoV-2 infection in children and adolescents remain unclear and optimal treatment is debated. The objective of our study was to investigate epidemiological, clinical and therapeutic characteristics of pediatric SARS-CoV-2 infection, focusing on risk factors for complicated and critical disease.Methods: The present multicenter Italian study was promoted by the Italian Society of Pediatric Infectious Diseases, involving both pediatric hospitals and general pediatricians/family doctors. All subjects under 18 years of age with documented SARS-CoV-2 infection and referred to the coordinating center were enrolled from March 2020.Results: As of 15 September 2020, 759 children were enrolled (median age 7.2 years, IQR 1.4; 12.4). Among the 688 symptomatic children, fever was the most common symptom (81.9%). Barely 47% of children were hospitalized for COVID-19. Age was inversely related to hospital admission (p < 0.01) and linearly to length of stay (p = 0.014). One hundred forty-nine children (19.6%) developed complications. Comorbidities were risk factors for complications (p < 0.001). Viral coinfections, underlying clinical conditions, age 5–9 years and lymphopenia were statistically related to ICU admission (p < 0.05).Conclusions: Complications of COVID-19 in children are related to comorbidities and increase with age. Viral co-infections are additional risk factors for disease progression and multisystem inflammatory syndrome temporarily related to COVID-19 (MIS-C) for ICU admission.

Purpose: To compare performance of visual and quantitative analyses for detecting myocardial ischaemia from single- and dual-energy computed tomography (CT) in patients with suspected coronary artery disease (CAD). Methods: Eighty-four patients with suspected CAD were scheduled for dual-energy cardiac CT at rest (CTA) and pharmacological stress (CTP). Myocardial CT perfusion was analysed visually and using three parameters: mean attenuation density (MA), transmural perfusion ratio (TPR) and myocardial perfusion reserve index (MPRI), on both single-energy CT and CT-based iodine images. Significant CAD was defined in AHA-segments by concomitant myocardial hypoperfusion identified visually or quantitatively (parameter

Background: Low longitudinal strain of the ascending aorta (AAo) by cardiac magnetic resonance (CMR) predicts dilation and aortic events in Marfan syndrome (MFS) [1], possibly reflecting aortic stiffness [2]. Speckle-tracking is established for cardiac deformation, but proximal aorta applications are challenging due to wall thickness and substantial motion. We aimed to validate a purpose-specific speckle-tracking tool for root longitudinal strain analysis by comparison with CMR-derived AAo longitudinal strain and as predictor of dilation in MFS patients. Methods: CMR feature-tracking [1] and echocardiography speckle-tracking where applied to 25 MFS patients free from previous aortic surgery by a single observer blind to clinical data. For echocardiography, two regions of interests were manually created covering both walls in a parasternal long-axis view and tracked along the cardiac cycle. Longitudinal strain was computed as the average of maximum increase in relative distance of several sub-regions covering both walls. Aortic diameter was measured on CMR images. Results: Both techniques were successfully applied to all patients. Aortic root longitudinal strain by echocardiography was linearly related to CMR-derived AAo longitudinal strain (R = 0.573, p = 0.003, Figure A) and was higher (20.4 ± 8.4 vs 10.5 ± 3.8), especially at higher absolute values (Figure B). After a mean follow up of 45 ± 13 months, aortic root diameter growth rate was 0.27 ± 0.3 mm/year. In multivariable analysis corrected for root diameter and heart rate (p = 0.083 and 0.005, respectively), baseline longitudinal strain by echocardiography was independently related to progressive dilation (B = −0.017, p = 0.005). Conclusion: Aortic root longitudinal strain by echocardiography is related to CMR-derived AAo longitudinal strain and is an independent predictor of progressive dilation in MFS patients.

Background: Thoracic endovascular aortic repair (TEVAR) is becoming the preferred treatment option to repair the proximal descending aorta after rupture following blunt traumatic injury. However, hemodynamic and mechanic implications of this intervention are poorly understood. Exploiting the possibilities of 4D flow magnetic resonance imaging, hemodynamics, stiffness and local dilation in the ascending aorta in patients following aortic repair by TEVAR are studied. Methods: Fifteen apparently healthy individuals who underwent TEVAR implantation after traumatic descending aortic injury and 44 healthy volunteers (HV) underwent 4D flow-MRI. Ascending aorta pulse wave velocity was computed [1]. Moreover, at eight planes equally distributed in the ascending aorta systolic flow reversal ratio, i.e. relative amount of backward flow during systole, and in-plane rotational flow, measuring the strength of helical flow, were computed [2,3]. Results: TEVAR patients and HV did not differ in terms of age, sex, BSA and blood pressure (Table). However, compared to HV, TEVAR patients showed reduced in-plane rotational flow in the distal ascending aorta in patients with TEVAR and increased backward systolic flow in the whole ascending aorta (Figure). Patients with TEVAR had a stiffer ascending aorta, with pulse wave velocity higher compared control (7.8 ± 4.2 vs 5.3 ± 1.9, p = 0.004). Finally, aortic root and ascending aorta diameters were larger in TEVAR patients compared to HV (Table). Healthy volunteers TEVAR patients p N 44 15 Age [years] 40 ± 12 43 ± 10 0.392 Sex [% male] 66 80 0.075 Years from intervention [years] N/A 10.3 ± 6.4 N/A Body surface area [m2] 1.87 ± 0.15 1.96 ± 0.23 0.088 Systolic blood pressure [mmHg] 127 ± 19 131 ± 15 0.389 Diastolic blood pressure [mmHg] 70 ± 11 74 ± 9 0.198 Aortic root diameter [mm] 31 ± 4 34 ± 4 0.026 Ascending aorta diameter [mm] 28 ± 4 32 ± 3 0.003 Ascending aorta PWV [m/s] 5.3 ± 1.9 7.8 ± 4.2 0.004 FigureIn-plane rotational flow (IRF, left) and systolic flow reversal ratio (SFRR, right) in healthy volunteers (black) and TEVAR patients (yellow) in the proximal (planes 1 to 4) and distal (planes 5 to 8) ascending aorta. Stars show statistically-significant differences (p < 0.05). Conclusions: The implantation of TEVAR in apparently healthy individuals after traumatic rupture of the proximal descending aorta is associated with altered hemodynamics, higher stiffness and larger aortic diameter in the region proximal to the TEVAR.

Background: Strain analysis with speckle-tracking echocardiography (STE) is considered superior to ejection fraction for ventricular function assessment in different clinical scenarios. Feature tracking (FT) permits cardiac magnetic resonance (CMR) strain analysis in routinely acquired cine images. This study evaluated the feasibility of CMR-FT and its agreement with STE in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods: An echocardiogram and CMR were performed in 128 patients who underwent primary percutaneous revascularisation after a STEMI. Adequate strain analysis was obtained by both techniques in 98 patients and peak systolic longitudinal strain (LS) was assessed with STE and CMR-FT. Results: Of 1568 myocardial segments, 97.2% were correctly tracked with STE and 97.7% with CMR-FT. For global LS, STE showed a mean of −14.8 ± 3.3% and CMR-FT −13.7 ± 3.0%, with good agreement between modalities [intraclass correlation coefficient (ICC) 0.826; bias −1.09%; limits of agreement (LOA) ± 4.2%]. On the other hand, segmental LS agreement was only moderate, with an ICC of 0.678 (bias −1.14%; LOA ± 11.76%) and the ICC ranged from 0.538 at the basal antero-lateral segment to 0.815 at the apical lateral segment. Finally, both STE and CMR-FT showed excellent intra- and inter-observer reproducibility (ICC > 0.9). Conclusions: CMR-FT provides LS with similar feasibility to STE and both techniques showed good agreement for global LS, although agreement at segmental level was only moderate. CMR-FT showed excellent reproducibility, strengthening its robustness and potential for both research and clinical applications.

Thoracic aortic aneurysm is a common cardiovascular disease consisting of marked dilation of the aorta. Aortic aneurysms carry a high risk of life-threatening complications such as aortic dissection or rupture. Classically, maximum aortic diameter has been used as the sole descriptor of aneurysm severity and is considered the main predictor of complications. However, maximum aortic diameter measurement is often poorly reproducible and about 60% of type A and 80% of type B aortic dissections occurred in patients with an aortic diameter inferior to that recommended for the indication of elective surgical treatment. Therefore, new biomarkers for risk stratification in thoracic aortic aneurysm are needed. Cardiovascular magnetic resonance (CMR) imaging is a non-invasive imaging technique widely used for diagnosis, clinical follow-up and research in thoracic aortic aneurysms. CMR applications to thoracic aortic aneurysms are generally based on either cine CMR images, which are time-resolved images providing dynamic structural visualization, or phase-contrast images, which utilise a flow-encoding gradient to assess timeresolved velocity data. Particularly with 3D velocity encoding (4D flow MRI), phase-contrast imaging permits detailed study of haemodynamic in thoracic aortic aneurysms while cine CMR is often used to assess aortic geometry and its changes through the cardiac cycle or during follow-up. The possibilities offered by CMR for studying thoracic aortic aneurysms and a description of their applications in Bicuspid Aortic Valve (BAV) and Marfan patients are here reviewed.

Background: Aortic type B dissection is a life-threating condition in which blood flows between aortic wall layers. Despite a role for morphological variables, such as entry tear location and dimension, in the prediction of progressive false lumen (FL) dilation has been suggested, the role of flow characteristics has not been studied due to the unavailability of proper flow descriptions. Now that 4D phase-contrast magnetic resonance imaging (4D-flow MRI) allows for the evaluation of flow field with unprecedented detail, we tested whether flow deceleration in the FL, being a marker of occluded flow exit, is related to FL dilation. Methods: In 29 patients with a patent FL and with a retrospective CT-based follow-up >3 years underwent 4D-flow MRI. Flow acceleration in the FL was calculated in a standardized sub-volume of the descending aorta. The maximum systolic flow deceleration rate (MSDR) was quantified as maximum minus minimum acceleration during systole divided by the corresponding time interval (Figure 1a). Results: Demographic and clinical variables were similar among growth-rate (GR) tertiles. MSDR was statistically different in patients with a GR

Background: Impaired ascending aorta (AAo) longitudinal strain, a marker of AAo deformation due to aorto-ventricular mechanical interaction, is related to progressive dilation and aortic events in Marfan syndrome [1]. Whether the high prevalence of dilation in bicuspid aortic valve (BAV) is due to intrinsically-altered aortic wall properties [2] or hemodynamic [3] is widely-discussed [4]. Whether AAo longitudinal strain is altered in BAV patients has never been assessed. Methods: One-hundred five BAV patients, 47 patients with AAo dilation and tricuspid aortic valve (TAV) and 31 healthy volunteers, free from previous cardiac/aortic surgery, dissection and moderate/severe valvular disease had cine MR images to compute AAo longitudinal strain [1]. Results: Compared to healthy volunteers, the 25 non-dilated (z-score < 2) BAV patients were older (p < 0.001), had higher systolic blood pressure (SBP, p = 0.001), clinically-meaningless (BAV z-score = 0.74 ± 1.1) larger AAo diameter (p < 0.001) and similar diastolic blood pressure (DBP), BSA, stroke volume and heart rate. AAo longitudinal strain was lower in non-dilated BAV compared to healthy volunteers (13.7 vs 10.3%, p = 0.008) but this difference was not significant after correction for age. Compared to dilated TAV, dilated BAV patients were younger (p < 0.001), had lower BSA (p = 0.010) and AAo diameter (p = 0.003), higher DBP (p = 0.032) and similar SBP, stroke volume and heart rate. AAo longitudinal strain was higher in dilated BAV compared to dilated TAV (10 vs 7.2%, p < 0.001) but this difference was not significant after correction for age, BSA and DBP. Conclusion: AAo longitudinal strain is similar in BAV and TAV matched for aortic dilation.

Multimodality imaging is the basis of the diagnosis, follow-up, and surgical management of bicuspid aortic valve (BAV) patients. Transthoracic echocardiography (TTE) is used in our clinical routine practice as a first line imaging for BAV diagnosis, valvular phenotyping and function, measurement of thoracic aorta, exclusion of other aortic malformations, and for the assessment of complications such are infective endocarditis and aortic. Nevertheless, TTE is less useful if we want to assess accurately other aortic segments such as mid-distal ascending aorta, where computed tomography (CT) and magnetic resonance (CMR) could improve the precision of aorta size measurement by multiplanar reconstructions. A major advantage of CT is its superior spatial resolution, which affords a better definition of valve morphology and calcification, accuracy, and reproducibility of ascending aorta size, and allows for coronary artery assessment. Moreover, CMR offers the opportunity of being able to evaluate aortic functional properties and blood flow patterns. In this setting, new developed sequences such as 4D-flow may provide new parameters to predict events during follow up. The integration of all multimodality information facilitates a comprehensive evaluation of morphologic and dynamic features, stratification of the risk, and therapy guidance of this cohort of patients.

Structural and functional dysfunction in both the macro- and microvasculature are a feature of essential hypertension. In a healthy cardiovascular system, the elastic properties of the large arteries ensure that pulsations in pressure and flow generated by cyclic left ventricular contraction are dampened, so that less pulsatile pressure and flow are delivered at the microvascular level. However, in response to aging, hypertension, and other disease states, arterial stiffening limits the buffering capacity of the elastic arteries, thus exposing the microvasculature to increased pulsatile stress. This is thought to be particularly pertinent to high flow/low resistance organs such as the brain and kidney, which may be sensitive to excess pressure and flow pulsatility, damaging capillary networks, and resulting in target organ damage. In this review, we describe the clinical relevance of the pulsatile interaction between the macro- and microvasculature and summarize current methods for measuring the transmission of pulsatility between the two sites.

Abstract Background In patients with bicuspid valve (BAV), ascending aorta (AAo) dilatation may be caused by altered flow patterns and wall shear stress (WSS). These differences may explain different aortic dilatation morphotypes. Using 4D-flow cardiovascular magnetic resonance (CMR), we aimed to analyze differences in flow patterns and regional axial and circumferential WSS maps between BAV phenotypes and their correlation with ascending aorta dilatation morphotype. Methods One hundred and one BAV patients (aortic diameter ≤ 45 mm, no severe valvular disease) and 20 healthy subjects were studied by 4D-flow CMR. Peak velocity, flow jet angle, flow displacement, in-plane rotational flow (IRF) and systolic flow reversal ratio (SFRR) were assessed at different levels of the AAo. Peak-systolic axial and circumferential regional WSS maps were also estimated. Unadjusted and multivariable adjusted linear regression analyses were used to identify independent correlates of aortic root or ascending dilatation. Age, sex, valve morphotype, body surface area, flow derived variables and WSS components were included in the multivariable models. Results The AAo was non-dilated in 24 BAV patients and dilated in 77 (root morphotype in 11 and ascending in 66). BAV phenotype was right-left (RL-) in 78 patients and right-non-coronary (RN-) in 23. Both BAV phenotypes presented different outflow jet direction and velocity profiles that matched the location of maximum systolic axial WSS. RL-BAV velocity profiles and maximum axial WSS were homogeneously distributed right-anteriorly, however, RN-BAV showed higher variable profiles with a main proximal-posterior distribution shifting anteriorly at mid-distal AAo. Compared to controls, BAV patients presented similar WSS magnitude at proximal, mid and distal AAo (p = 0.764, 0.516 and 0.053, respectively) but lower axial and higher circumferential WSS components (p

Our objective is to collect data and information for a better care and follow up in Cri du Chat patients. We conducted a literature review in August 2017 and then discuss the outcomes within the ABC (Associazione Bambini Cri du Chat, Italian CdC families support group). A proposal for clinical, laboratory and imaging work up should be performed at various ages in CdC patients. Follow up and rehabilitation should continue lifelong as some improvements can be obtained also in older ages and not to lose acquired skills.

Background: Hypertension clinical treatment largely relies on different drugs. Some of these drugs are thought to exhibit specific protective functions in addition to those resulting from blood pressure reduction per se. Through a validated multiscale mathematical model of the cardiovascular system, we studied the impact of commonly-used antihypertensive drugs on myocardial oxygen supply–consumption balance, which plays a crucial role in type 2 myocardial infarction. Methods: Forty-two wash-out hypertensive patients were included in this study. Patients’ demographics, heart rate, brachial pressure, Left Ventricular (LV) volumes and carotid-femoral pulse wave velocity were used to set to patient specific condition a largely accepted benchmark data set describing generic healthy subjects. Starting from literature data, drugs effects were modeled by means of six coefficients, describing LV function, heart rate, peripheral resistances and arterial stiffness. These drug-specific sextuplets were used to multiply some parameters of each patient model to simulate drugs impact. Results: Our results ascribed the well-known major cardioprotective efficiency of β blockers to a positive change of myocardial oxygen balance. This was due to the concomitant reduction in LV work and increase in coronary flow. Similarly, RAAS blockers induced several positive changes, but to a reduced extent. In contrast, calcium channel blockers seem to induce some potentially negative effects on myocardial oxygen balance. Conclusions: Patient specific multiscale mathematical model is able to reproduce clinically-relevant changes in coronary hemodynamics and ventricular function driven by anti-hypertensive drugs. Further studies are needed to evaluate eventual clinical usefulness of in-silico modeling of anti-hypertensive drugs.

Background: Aortic root dilation and type A aortic dissection are the most common cardiovascular complications of Marfan syndrome (MFS). Current clinical management of MFS patients relies on a close follow-up of aortic root diameter and preventive aortic root surgery in case of severe or fast-progressing dilation. However, as the capacity of aortic diameter to predict type A aortic dissection is limited, new non-invasive biomarkers to improve risk stratification are needed. We investigated the capacity of proximal aorta circumferential and longitudinal strain and ascending aorta distensibility to predict aortic root diameter dilation and occurrence of major cardiovascular events in Marfan patients. Methods: Eighty-seven Marfan patients without previous cardiac/aortic surgery or dissection were prospectively included in a multicenter follow-up. Proximal aorta longitudinal and circumferential strain and distensibility were computed from baseline CMR. Results: During a follow-up of 81.6 ± 17 months, 11 patients underwent elective aortic root replacement, and 2 experienced type A aortic dissections. Mean dilation rate was 0.65 ± 0.67 mm/year and z-score growth rate 0.07 ± 0.13 1/year. In multivariable analysis, proximal aorta longitudinal strain but not circumferential strain and distensibility were independent predictors of diameter growth-rate (p = 0.001, p = 0.385 and p = 0.381, respectively), z-score growth-rate (p = 0.018, p = 0.515 and p = 0.484, respectively) and major cardiovascular events (p = 0.018, p = 0.064 and p = 0.205, respectively) corrected for demographic and clinical characteristics and baseline aortic root diameter. Conclusions: In Marfan syndrome, proximal aorta longitudinal strain is an independent predictor of aortic root dilation and major cardiovascular events beyond aortic root diameter and established risk factors.

Introduction: Ascending aorta aneurysm and dissection are the most common cardiovascular complications affecting Marfan syndrome patients (MFS). Recent large increase in life expectancy of MFS driven the growing prevalence of descending aorta (DAo) dilation and dissection. Despite local abnormal vortices in the proximal Dao were related to local dilation, their origins have never been explored. We investigated the link between aortic geometrical characteristics and abnormal flow pattern in the thoracic aorta of MFS. Methods: Fifty-tree MFS without significant aortic valve disease and forty age-matched healthy volunteers (HV) were prospectively included in 4D flow-MRI study, obtaining flow field and angiography. Spatial distribution of flow (in-plane rotational flow (IRF) and systolic flow reversal ratio (SFRR)) and geometric (diameter, ellipticity and curvature) parameters were investigated. Results: Compared to HV, MFS presented larger aortic diameters only in the proximal AAo (p < 0.001) and DAo (p = 0.028). Increased ellipticity and a more distal location for the peak of aortic curvature were evident, even in the absence of dilation. Through most of the thoracic aorta, IRF was substantially lower in MFS, while SFRR was larger. Interestingly, non-dilated MFS had decreased IRF in the thoracic aorta compared to HV, although SFRR was not increased. Statistically-significant bivariate relations were found between arch IRF and arch ellipticity (R = -0.34) and proximal DAo peak curvature (R = -0.35). Local diameter was negatively correlated with local IRF (R = -0.3) and positively correlated to local SFRR (R = 0.605). Conclusions: MFS presented altered ellipticity and curvature distribution, which are related to abnormal flow patterns even in the absence of dilation.

Background: Aortic root dilation is an established risk factor for aortic dissection. Despite the relations between aortic root remodeling, carotid-femoral pulse wave velocity (cfPWV) and aortic blood pressure have been advocated by several clinical studies and is supported by physical law, invasive data are lacking. We aimed to investigate the relationship between aortic root remodeling, invasively-measured central blood pressure and cfPWV in patients referred for invasive hemodynamic evaluation for suspected coronary disease. Methods: In 71 patients aortic pulse pressure (aoPP) was measured in the proximal aorta with a calibrated fluid-filled pressure catheter. Before entering the hemodynamic room all patients underwent 2D echocardiographic quantification of aortic root diameter and measurement of cfPWV. Aortic root diameter was then expressed into z-score following age, sex and height adjusted reference values (1). Results: Mean age was 67 ± 10 years and 76.1% of patients were men. Invasive aortic systolic pressure was 146 ± 23 mmHg, diastolic pressure was 78 ± 13 mmHg, and aoPP was 68 ± 21 mmHg. Aortic Z-score was −0.32 ± 1.7, while CfPWV was 9.8±3 m/s. While Log10cfPWV and aoPP showed a positive relation (r=0.426, p

Rapunzel syndrome is a rare form of tricobezoar with a tail extending from the stomach into the small bowel; surgical removal is generally required. About 60 cases have been reported and described in the literature since 1968. We present the case of an 8-year-old girl who, during the course of a genetic consultation, was initially assigned with a clinical suspicion of ectodermal dysplasia. Surgical intervention, which resulted in the extraction of a tricobezoar of enormous size and extension, led us to the diagnosis of Rapunzel syndrome. The possibility of a tricobezoar should be considered in all cases of adolescent patients who present signs of intestinal occlusion or sub-occlusion, suffer from psychiatric disorders, and have a history of trichotillomania. Endoscopic methodology, medical imaging and clinical diagnostics are fundamental for a differential diagnosis. Psychiatric follow-up is advised to prevent recurrence.

Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and characterized by typical clinical features. The congenital malformations typical of this syndrome call for early diagnostic and surgical procedures requiring general anesthesia, but few information about the anesthesiology management of such patients is available. We enrolled 11 families of patients with Mowat-Wilson syndrome who had undergone surgical or diagnostic procedures requiring general anesthesia, and sent them a retrospective questionnaire including 16 open questions about the procedures. They were further contacted by phone for a semi-structured interview. A total of 37 procedures requiring general anesthesia was reported in 11 patients. Only two patients reported anesthesia-related complications during the procedure. No true additional anesthesia-related risk was present for the patients with MW syndrome, besides difficult intubation, weaning and lower respiratory tract infection. Perception of risk, however, is derived by non-medical observation on the part of the parents.

Purpose: Aortic blood pressure has a superior prognostic value with respect to the brachial pressure [ 1]. Nonetheless, the low efficacy of the most used non-invasive methods (i.e., approaches based on the generalized transfer function (GTF)) may hamper the detection of this superiority in population studies [2]. In this sense, low-order, patient-specific whole-body mathematical models might help to bridge brachial to aortic pressure waveforms. We aimed to compare (i) GTF, (ii) a patient-specific 1D-0D mathematical model, and (iii) brachial blood pressure in the estimation of invasive aortic pressure measured through catheter. Method: One-hundred patients referred to diagnostic coronary angiography were included in this study. Brachial pressure was measured with a validated automatic oscillometric device simultaneously to invasive aortic pressure, which was measured with a calibrated fluid-filled catheter. End-systolic and end-diastolic left ventricular volumes, carotid-femoral pulse wave velocity and tonometric radial waveform were measured immediately prior to the invasive procedure and were used to set GTF and the mathematical model. Results: Oscillometric brachial pressure overestimated both systolic (2.4 ± 12.6 mmHg, R2 = 0.71) and diastolic (3.7 ± 9.8 mmHg, R2 = 0.48) aortic pressure. GTF method underestimated systolic (9.4 ± 11 mmHg, R2 = 0.71) and overestimated diastolic (4.5 ± 10.2 mmHg, R2 = 0.4) aortic pressure. Mathematical model underestimated both systolic (4 ± 16.5 mmHg, R2 = 0.47) and diastolic (3.9 ± 10.4 mmHg, R2 = 0.62) aortic pressure. Brachial pressure and GTF methods presented trends toward systolic and diastolic pressure overestimation for higher aortic pressure, while mathematical modeling not. Conclusions: Systolic and diastolic oscillometric brachial pressures give a better predictor of aortic pressure extremes with respect to both GTF- and mathematical model-based methods.

Purpose: Different altered flow dynamics may influence ascending aorta (AAo) dilation morphotypes in bicuspid aortic valve (BAV) (1). Using 4D-flow CMR, we aimed to identify flow variables related to root or ascending dilation in BAV. Methods: One-hundred and one BAV patients (no severe valvular disease, aortic diameters 2. Univariate and multivariate linear regression were used to identify factors related to dilation. ROC curves were performed to assess the relationship between variables obtained in the multivariate analysis and dilation morphotypes. Results: Fusion phenotype was right-left (RL) in 78 patients, and right-non coronary (RN) in 23. Dilation morphotype was non-dilated in 24 patients, root in 11 and ascending in 66. On univariate analysis, BAV phenotype (RN), displacement and circumferential WSS presented the highest odds ratios (Table). On multivariate analysis, sex (male), proximal velocity and axial WSS were related to root morphotype (AUC 0.91, P < 0.001), while RN-BAV, distal IRF, and mid-AAo SFRR and circumferential WSS were related to ascending morphotype (AUC 0.81, P < 0.001) (Table and Figure). Univariate analysis of aortic dilation Multivariate analysis of aortic dilation Root morphotype Ascending morphotype Odds Ratio P-value Odds Ratio P-value Odds Ratio P-value BAV phenotype (RL/RN) 3.23 0.02 1.33 0.008 Sex (Male) 1.10 0.02 4.67 0.005 Prox Peak velocity 1.02 0.028 1.10 0.043 Jet angle 1.05 0.037 Displacement 3.56 0.001 1.11 0.021 IRF 1.01 0.002 WSSaxial 1.20 0.003 7.64 0.008 WSSCireumf 1.65 0.05 Mid Jet angle 1.07 0.006 Displacement 2.46 0.002 IRF 1.01 0.007 SFRR (%) 1.20 0.001 1.2

Purpose: Bicuspid aortic valve (BAV) is a cardiac congenital disease associated with ascending aorta (AAo) dilation. The study of the impact of aortic biomechanics in this population has been limited by technical difficulties. Contrasting results have been reported for distensibility while studies including regional pulse wave velocity (PWV) are still lacking. Using 4D-flow MRI, we assessed AAo and descending aortic (DAo) biomechanical properties and determined their association in BAV aortopathy. Methods: One-hundred thirty-six BAV patients with no severe valvular disease and 40 healthy volunteers were recruited. The protocol included a 4D-flow acquisition and a set of 2D CINE PC-MRI at 1.5 T. Aortic 3D geometry was reconstructed from 4D-flow-derived angiography and at least 100 analysis planes were identified in the thoracic aorta. Transit time was calculated on the velocity upslope through wavelet analysis [1]. CINE PC-MRI were used to compute distensibility. Statistical significance is reported corrected for confounding factors. Results: Non-dilated BAV and controls have similar AAo and DAo PWV and distensibility. Dilated patients presented lower AAo PWV and higher DAo PWV compared to non-dilated (p < 0.001 and p = 0.017, respectively). Distensibility did not differentiate dilated from non-dilated patients and presented lower association with dilation severity (see Figure). Conclusions: Confirming for the first time previous findings in abdominal aorta aneurysm and fluid-mechanics theory, AAo PWV is reduced in aneurysmatic BAV patients. BAV aortopathy is related to a stiffer DAo. Regional PWV outperforms distensibility as a marker of local aortic biomechanics. These data exclude congenital aortic wall pathology related to BAV

Dyskeratosis congenita (DC) is an inherited bone marrow failure disorder characterized by mucocutaneous features (skin pigmentation, nail dystrophy and oral leukoplakia), pulmonary fibrosis, hematologic and solid malignancies. Its severe form, recognized as Hoyeraal-Hreidarsson syndrome (HHS), also includes cerebellar hypoplasia, microcephaly, developmental delay and prenatal growth retardation. In literature phenotypic variability among DC patients sharing the same mutation is wellknown. To our knowledge this report describes for the first time a family of DC patients, characterized by a member with features of classic DC and another one with some features of HHS, both with the same mutation in DKC1. Our family confirms again that one mutation can be associated with different phenotypes and different hematological manifestations. It’s possible to speculate that there are likely to be patients who do not clinically fit neatly into either classical DC or HHS, but whose clinical features are due to mutations in DKC1 or in genes responsible for autosomal DC/HHS.

Cri du Chat syndrome (CdC) is a chromosomal abnormality (deletion of short arm of chromosome 5) associated with intellectual disability and typical anatomical abnormalities. Research up to now focuses on the management of the disease during childhood. The longer lifespan of these patients warrants deeper investigations of how and if aging could be affected by the syndrome. We decided to focus on the association of the disease with proliferative disorders. Data on proliferative disorders in a cohort of 321 patients from Italian and German Cri du Chat databases were collected. A neoplasia was present in four patients (age 10–50 yrs), and a fifth patient developed a cholesteatoma during childhood. It is of interest that two cases had an early onset of the neoplasia as compared to the expected age of development in the general population. The chromosome region deleted in 5p does not contain genes whose haploinsufficiency is a well-known main cause of the proliferative disorders observed. We nonetheless believe that reporting even sporadic cases of proliferative disorders in CdC patients may increase our knowledge as to the natural history of the disease. In conclusion, available information suggests that surveillance for cancer development in CdC can follow the guidelines for the general population.

Early skin-to-skin contact (SSC) after birth is a physiological practice that is internationally recommended and has well-documented importance for the baby and for the mother. This study aims to examine SSC with a cohort of mothers or fathers in the operating room after a Cesarean section (C-section) and its relationship with duration of breastfeeding. From January 1, 2012, to December 31, 2012, at the Castelli Hospital in Verbania, Italy, a Baby Friendly designated hospital, 252 consecutive women who had a C-section were enrolled in the study and followed for 6 months. The sample was later divided into three groups depending on the real outcomes in the operating room: SSC with the mother (57.5%), SSC with the father (17.5%), and no SSC (25%). Our study showed a statistical association between skin-to-skin contact with the mother and the exclusive breastfeeding rates on discharge. This effect is maintained and statistically significant at three and six months, as compared to the groups that had paternal SSC or no SSC. After a C-section, skin-to-skin contact with the mother can be an important practice for support, promotion, and duration of breastfeeding.

Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the neurocristopathies, a group of congenital multisystem disorders caused by an altered development of the neural crest cells, multipotent progenitors of a wide variety of different lineages, including those differentiating into peripheral nervous system glial cells and melanocytes. We report on clinical and genetic findings of two monozygotic twins from a large Albanian family who showed a complex phenotype featured by sensorineural congenital deafness, severe neuropsychiatric impairment, and inborn pigmentary defects of hair and skin. The genetic analyzes identified, in both probands, an unreported co-occurrence of a new heterozygous germline pathogenic variant (c.2484 + 5G > T splicing mutation) in the KIT gene, consistent with the diagnosis of piebaldism, and a heterozygous deletion at chromosome 15q13.3, responsible for the neuropsychiatric impairment. This case represents the first worldwide report of dual locus inherited syndrome in piebald patients affected by a complex auditory-pigmentary multisystem phenotype. Here we also synthesize the clinical and genetic findings of all known neurocristopathies characterized by a hypopigmentary congenital disorder.

[This corrects the article DOI: 10.1371/journal.pone.0151523.].

The Cri du Chat syndrome (CdC) is a rare genetic disorder caused by variable size deletions of the short arm of chromosome 5 (5p−). It is well known that home-reared patients show better performances as compared to institutionalised cases, and it was reported that continuous educational intervention can ameliorate their performances. To assess the efficacy of educational intervention and to develop new CdC oriented programs of rehabilitation, we compare the results obtained for many developmental skills in two groups of CdC patients undergoing two different rehabilitation programs. Using data on the development of a group of CdC patients obtained by validated Italian translation for the Denver Developmental Screening Test II, we compared a group of 13 patients undergoing an educational program developed for CdC patients, the Mayer Project (MP), with a second group of 15 cases in whom caring was not specifically oriented. A positive impact of the MP was reported by parents, observing an improvement in social skills obtained, even if no significant differences were observed when the items of the Denver Test are studied. The need for personalized care in CdC patients and the choice of different methods to compare the results are also discussed.

The use of antiemetics for vomiting in acute gastroenteritis in children is still a matter of debate. We conducted a double-blind randomized trial to evaluate whether a single oral dose of ondansetron vs domperidone or placebo improves outcomes in children with gastroenteritis. After failure of initial oral rehydration administration, children aged 1-6 years admitted for gastroenteritis to the pediatric emergency departments of 15 hospitals in Italy were randomized to receive one oral dose of ondansetron (0.15 mg/kg) or domperidone (0.5 mg/kg) or placebo. The primary outcome was the percentage of children receiving nasogastric or intravenous rehydration. A p value of 0.014 was used to indicate statistical significance (and 98.6% CI were calculated) as a result of having carried out two interim analyses. 1,313 children were eligible for the first attempt with oral rehydration solution, which was successful for 832 (63.4%); 356 underwent randomization (the parents of 125 children did not give consent): 118 to placebo, 119 to domperidone, and 119 to ondansetron. Fourteen (11.8%) needed intravenous rehydration in the ondansetron group vs 30 (25.2%) and 34 (28.8%) in the domperidone and placebo groups, respectively. Ondansetron reduced the risk of intravenous rehydration by over 50%, both vs placebo (RR 0.41, 98.6% CI 0.20-0.83) and domperidone (RR 0.47, 98.6% CI 0.23-0.97). No differences for adverse events were seen among groups. In a context of emergency care, 6 out of 10 children aged 1-6 years with vomiting due to gastroenteritis and without severe dehydration can be managed effectively with administration of oral rehydration solution alone. In children who fail oral rehydration, a single oral dose of ondansetron reduces the need for intravenous rehydration and the percentage of children who continue to vomit, thereby facilitating the success of oral rehydration. Domperidone was not effective for the symptomatic treatment of vomiting during acute gastroenteritis.

INTRODUCTION:Current evidence suggests that aortic blood pressure has a superior prognostic value with respect to brachial pressure for cardiovascular events, but direct measurement is not feasible in daily clinical practice. AIM:The aim of the present study is the clinical validation of a multiscale mathematical model for non-invasive appraisal of central blood pressure from subject-specific characteristics. METHODS:A total of 51 young male were selected for the present study. Aortic systolic and diastolic pressure were estimated with a mathematical model and were compared to the most-used non-invasive validated technique (SphygmoCor device, AtCor Medical, Australia). SphygmoCor was calibrated through diastolic and systolic brachial pressure obtained with a sphygmomanometer, while model inputs consist of brachial pressure, height, weight, age, left-ventricular end-systolic and end-diastolic volumes, and data from a pulse wave velocity study. RESULTS:Model-estimated systolic and diastolic central blood pressures resulted to be significantly related to SphygmoCor-assessed central systolic (r = 0.65 p

Coronary artery diseases are the most common type of cardiovascular diseases and have an increasing prevalence with age. Epidemiological studies demonstrated that coronary failure is associated with several pathologies (as atherosclerosis, hypertension, diabetes, endothelial dysfunction, renal insufficiency). Since the majority of these pathologies has an increasing prevalence with age, little is known about the effect of ageing alone on the coronary circulation. In this context, the aim of the present work is to isolate the impact of ageing on the coronary flow. A fluid mechanics-based approach is adopted, based on the coupling of the mathematical model of the systemic circulation we proposed and validated with a model of the coronary circulation proposed and validated by Mynard et al (Am J Physiol, 2014). The resulting evolution of coronary pressure/flow waveforms and their coupling with the left-ventricular condition are analysed using impedance analysis and wave intensity analysis. Confirming results from several clinical studies, we highlight a complex spatiotemporal coronary wave pattern, where intense waves originate from the aorta and from the deep myocardium, during both isovolumic compression and diastolic phase. The subendocardial viability ratio decreases with age, total coronary flow is slightly reduced, and left-ventricular work increases. Consequently, the left-ventricular work per unit of blood flow increases, thus limiting cell oxygen availability abundance, therefore increasing the risk of myocardial infraction. Our results highlight a physiological age-induced supply/demand unbalance in the coronary arteries, which can augment the risk of myocardial ischemia and can contribute to pave the way to other coronary pathologies.

The arterial tree exhibits a complex spatio-temporal wave pattern, whose healthy behaviour depends on a balance between mechanical and geometrical properties. Several clinical studies demonstrated that this balance progressively breaks down during ageing, when the aorta stiffens and remodels. This dual mechanism is investigated by a validated multi-scale model aiming to elucidate how aortic stiffening and remodelling quantitatively impact the waves pattern in the aorta. The detrimental increase of maximum pressure and left-ventricular work during ageing is here shown to results from the impairment of fluid dynamic balance between generation-propagation of forward waves and reflections- damping of backward waves. Our quantitative outcomes confirm several clinical studies results. Our results shed light on how ageing-induced aortic stiffening and remodelling affect this balance: the former enhances first pressure pulse at ventricular-aortic interface during ejection, while the latter damps it; although stiffening tends to decrease reflection coefficients at bifurcations, their remodelling-induced growth prevails; aortic remodelling undermines the protective wave-trapping mechanism while stiffening enhances it; aortic stiffening reduces pulse pressure amplification while remodelling augments it; by contrast, both stiffening and remodelling contribute to limit the growth of left-ventricle work with age. These results suggest that an excessive imbalance between aortic stiffness and geometric remodelling during clinical treatment of elderly subjects should be avoided. Our results show how a dramatic reduction of the pulse wave velocity in a dilated aorta can lead to an increase of pulse pressure amplification, with potential detrimental effects on organs such as the kidneys.

Although many epidemiological studies defining child sexual abuse prevalence rates in many countries of the world are now available, Italy presents a lack of data regarding this specific issue. Only recently some attempts to define the epidemiology of this public health problem have been tried. Between 2003 and 2010, the Department of Public Health at University of Milan was in charge of one of the more important study of this kind in Italy, involving almost 3000 students aged 18 attending secondary schools in the City of Milan who filled out an anonymous questionnaire aiming at detecting their previous experiences of sexual victimization during childhood and adolescence. After this first edition, the study was replicated among students attending secondary schools in the city of Varese, in the area of Piedmont and in Basilicata (area of Lauria), using the same investigational model and questionnaire. This paper presents the main data collected through four different epidemiological studies using the same methodology and survey tool. Considering at least one of the five different forms of child sexual abuse surveyed (being exposed to pornography, being touched on private parts, being forced to masturbate an older person, being forced to perform oral sex, or being penetrated), the prevalence rate among our samples ranges between a minimum of 12.5% (Varese) and a maximum of 34.1% (Lauria). In Lauria the research reveals a higher prevalence rate of child sexual abuse, especially among the male population, for all typologies of abuse but being touched in their private parts. In all other geographical areas and for all typologies of abuse, there is always a higher prevalence among girls, with the only exception of abuse such as being exposed to pornographic materials.