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We study a class of variational problems involving both bulk and interface energies. The bulk energy is of Dirichlet type albeit of very general form allowing the dependence from the unknown variable u and the position x. We employ the regularity theory of $$\Lambda $$ Λ -minimizers to study the regularity of the free interface. The hallmark of the paper is the mild regularity assumption concerning the dependence of the coefficients with respect to x and u that is of Hölder type.

In the present work, the response of composite hybrid laminates made of carbon and glass fibers in different stacking configurations was tested under low-velocity impact loads. Experimental drop impact tests were conducted on three different stacking sequences and three rising impact energy levels. The results from the tests were assumed for the development and validation of a numerical impact model reproducing for each stacking sequence and all the impact energy levels, the laminates impact response. The validated model investigated the occurred damage mechanisms, their distribution in the panel thickness and their extension on the plane of the laminate. Depending on the stacking sequence and the impact energy level, the energy absorption capacity was related to the dominant damage mechanism. The percentage contribution of interlaminar and intralaminar damages was presented and conclusions were drawn about the influence of stacking sequences on energy absorption and damage characteristics.

The impact of COVID-19 changed the use and delivery of health care services, requiring an abrupt shift in treatment and staffing models 1,2. This is particularly salient in youth acute and intensive treatment services (AITS), including inpatient psychiatric hospitals (IPH), intensive outpatient programs (IOP), and partial hospitalization programs (PHP), because of challenging issues of maintaining high-quality care and a safe therapeutic milieu during increased demand for acute services,3 all while limiting transmission of COVID-19 on locked units, in close quarters, and for youths traveling back and forth to day-programs. Over the past year, AITS adapted and evolved without the ability to pause services and plan, increase staffing, or allocate additional resources. This article discusses themes of changes made based on more than 20 facilities across the United States through the American Psychological Association Child and Adolescent Psychology Division’s Acute, Intensive, and Residential Service Special Interest Group.4 These facilities include psychiatric inpatient units and day-treatment programs. We discuss lessons learned from these changes, the need for evaluating these changes, and application of these lessons in future crises.

Background There is a positive continuous association between Lipoprotein(a) (Lp[a]) levels and the risk of recurrent ischemic events in patients with recent myocardial infarction (MI). However, the prognostic significance of the association between high Lp(a) levels and diabetes has been poorly investigated after MI. Purpose The aim of this study was to evaluate the association of Lp(a) levels with the long-term risk of adverse events in post-MI patients, and to investigate whether diabetes may influence this association. Methods Consecutive MI patients who underwent urgent/emergent coronary angiography at our Institution from February 2013 to June 2019 were prospectively collected. Lp(a) serum concentrations was expressed for increasing range values (≤10, >10–30, >30–50, >50–70, and ≥70 mg/dL). The primary outcome was the recurrence of MI; the secondary outcome was all-cause death. The propensity score weighting technique was used to account for potential confounding between patients with and without diabetes. Results The study population consisted of 1018 post-MI patients (median age: 63 years; 76% males). Diabetes was reported in 280 patients (27.5%). The median value of Lp(a) was 10 mg/dL, and patients with diabetes showed significantly lower Lp(a) levels than patients without diabetes (p=0.025). At a median follow-up of 1121 days, the primary outcome was reported in 109 patients (10.7%), and the secondary outcome in 100 (9.8%). After propensity score weighting, there was a significant association between increasing Lp(a) range values and the primary outcome both in the overall population (p trend = 0.030) and in non-diabetic patients (p trend = 0.009), but not in diabetics. Conversely, no significant association with the risk of all-cause mortality across increasing Lp(a) categories both in the overall population and in the study groups according to the presence or not of diabetes was found. Compared with the lowest Lp(a) category, Lp(a) plasma levels >70 mg/dL were independently associated with the risk of recurrent MI (HR: 3.222; 95% CI, 1.225–8.478, p=0.018) and all-cause death (HR: 2.656; 95% CI, 1.009–6.991, p=0.048) in non-diabetic patients, but not in diabetics. Conclusions In this real-world post-MI population, Lp(a) serum levels were lower in diabetic than in non-diabetic patients. Increasing Lp(a) levels were significantly associated with the risk of recurrent MI, and very high Lp(a) serum concentration (>70 mg/dL) independently predicted recurrent MI and death in non-diabetic patients, but not in diabetics. These results reinforce the importance of routine assessment of Lp(a) levels after MI, particularly in patients without diabetes. Funding Acknowledgement Type of funding sources: None.

Background The Academic Research Consortium for High Bleeding Risk (ARC–HBR) has recently proposed, by consensus, twenty clinical criteria for the assessment of the bleeding risk after percutaneous coronary intervention (PCI). A major criterion was defined as any individual clinical condition conferring in isolation a risk for major bleeding ≥4% up to 1 year after PCI; instead, a minor criterion was considered to confer a bleeding risk of Methods MEDLINE, COCHRANE, Web of Sciences, and SCOPUS were searched for studies aimed at validating the ARC–HBR criteria in patients treated with PCI. The primary outcome measure of this meta–analysis was major bleeding. Results The analysis included 10 studies encompassing 67,862 patients undergoing PCI; the HBR definition was fulfilled in 44.7% of the cases. The risk of major bleeding was significantly higher in HBR vs. Non–HBR group (RR, 2.56, 95% CI 2.28–2.89). The average C–statistic was 0.64 (95% CI 0.60–0.68), indicating modest discrimination. The risk of intracranial hemorrhage, gastrointestinal bleeding, fatal bleeding, ischaemic stroke, cardiac death and all–cause death was higher in HBR vs. Non–HBR group. Despite a higher incidence of myocardial infarction and stent thrombosis in patients deemed at HBR, the rate of target lesion revascularization was comparable between groups (RR, 1.01, 95% CI 0.88–1.16). When assessed in isolation, the mean cumulative incidence of major bleeding at 1 year exceeded the cut–off value of 4% for all the major criteria and for two out of six minor criteria, including age ≥75 years and moderate chronic kidney disease (CKD) (Figure). Conclusion The ARC–HBR definition identifies patients at higher risk of major bleeding and other adverse cardiovascular events after PCI. Almost all major criteria, but also two of the minor criteria, were individually associated with rates of major bleeding above 4% thus fulfilling the definition of major HBR criteria. These findings corroborate the ability of ARC–HBR major criteria in identifying PCI patients who are more likely to develop adverse events, but also suggest caution in the decision making of patients with isolated minor criteria, including age≥75 years and moderate CKD.

Aims To describe the baseline clinical, laboratory and angiographic characteristics of patients with acute myocardial infarction (MI) according to the presence or not of diabetes mellitus (DM), and to evaluate if DM may influence the effect of lipoprotein(a) [Lp(a)] serum level on long–term outcome in this very high–risk population. Methods This was a retrospective, single–center, study including consecutive patients admitted with MI diagnosis between January 1, 2017, and December 31, 2020. The availability of data on baseline Lp(a) serum level was considered as an inclusion criterion. The study population was divided into two groups according to the presence or not of DM. The Lp(a) value of 50 mg/dL was used to test the hypothesis of a different effect of Lp(a) on the clinical outcome of patients with or without DM. The primary study outcome was all–cause death at 3–year follow–up. Results The study population included 997 patients (mean age 63.7±13.5 years; 75.7% were males). Diabetes was reported in 280 (28.1%) patients. DM patients were older than those without DM (67.8±12.1 vs. 62.0±13.7 years, p Conclusion In this MI population, Lp(a) was independently associated with long–term mortality in patients without DM, but not in patients with DM. Whether DM can modify the effect of Lp(a) on clinical outcome after MI requires confirmation by larger prospective studies.

American Indian (AI) and Indigenous peoples utilize traditional medicine/healing (TM/H) for health and well-being. Allopathic health care practitioners (HCPs) receive minimal training and education on TM/H and its application and integration into health care settings. Lack of knowledge and practice guidelines on how to navigate these 2 health care perspectives (allopathic and traditional) creates uncertainties in the treatment of AI and Indigenous peoples. Such conflicts can undermine patient autonomy and result in culturally incongruent practice. This article presents a case study showcasing suggestions for how HCPs can direct clinical decision making when working with AI/Indigenous patients who utilize TM/H. The article argues that health professions education institutions and HCPs must dedicate effort to expanding awareness of and education about TM/H to enhance the delivery of evidence-based and integrated clinical treatment for AI/Indigenous patients.

Background Two prospective studies that were performed before the era of highly sensitive solid-phase assays have shown a lower incidence of acute rejection in highly sensitized kidney-transplant patients given polyclonal antibodies compared with those given anti-CD25 monoclonal antibodies. Methods This prospective pilot randomized French multicenter study aimed to compare anti–T-lymphocyte Ig (ATLG) (n = 32) and basiliximab (n = 27) in highly sensitized kidney-transplant patients without preformed donor-specific antibodies (pDSAs) as assessed by a Luminex Single-Antigen flow bead assay. Only patients with a calculated panel reactive antibody ≥50%, with at least 1 antibody with a mean fluorescence intensity ≥5000 and without a historical pDSA and without a pDSA on the day of transplantation were included. Results Treatment failure as defined by biopsy-proven acute rejection, patient lost to follow-up, graft loss, and death was observed in 18.8% (95% confidence interval [CI], 8.9%–37.1%) and 18.8% (95% CI, 8.9%–37.1%) in patients who received ATLG and 14.8% (95% CI, 5.8%–34.8%) and 28.2% (95% CI, 14.2%–51.2%) of patients who received basiliximab, respectively at 6 (P = 0.66) and 12 (P = 0.62) months post-transplantation. One T cell–mediated rejection was observed in ATLG-treated patients (3.1%). One antibody-mediated rejection due to a de novo donor-specific antibody (DSA) occurred in basiliximab-treated patients (3.7%). Patient survival, graft survival, kidney parameters, and infection rate were similar in the 2 groups. Conclusion This pilot study indicates that in highly sensitized kidney-transplant patients without pDSAs, both ATLG and basiliximab can be used efficiently and safely. However, because of the lack of power, these results should be interpreted with caution., Graphical abstract

Funding Acknowledgements Type of funding sources: None. Backgrounds although right ventricular (RV) systolic dysfunction seems to be associated with adverse outcome after transcatheter edge-to-edge mitral valve repair (TEER) with the MitraClip system, the prognostic value of RV free wall strain in this setting has not been yet investigated. Purpose aim of this study is to evaluate RV free wall strain as predictor of outcome in patients with severe or moderate-to-severe functional MR undergoing TEER and its prognostic role compared with tricuspid annular plane systolic excursion (TAPSE). Methods 102 patients [73 (IQR 66.8-77.0) years, 73 males (71.6%)] were retrospectively selected from March 2012 to February 2021. Echocardiograms were performed by using General Electric machines. RV free wall strain was assessed through RV modified apical 4-chamber view, setting the region of interest to minimum size (Figure 1). Values of RV free wall strain >-20% were recognized as abnormal. We considered a composite endpoint including rehospitalization for heart failure (HF) and overall death as primary outcome. Secondary outcomes were overall death, cardiac death and rehospitalization for HF. All patients were assessed at the longest available follow-up [median 22.1 (IQR 9.7-49.3) months]. Results primary outcome was found in 60 (58.8%) patients, while secondary outcomes, i.e. overall death, cardiac death and rehospitalization for HF, were found respectively in 50 (50.0%), 31 (30.4%) and 36 (35.3%) patients. Mean TAPSE was 16.7 ± 4.0 mm and mean RV free wall strain was -16.9 ± 6.0%. At univariable analysis both TAPSE (HR 0.907, CI 0.848-0.970, p value 0.004) and RV free wall strain (HR 0.937, CI 0.897-0.979, p value 0.004) were significantly associated with the primary outcome. Kaplan-Meier survival curves showed that patients with TAPSE -20% also showed a lower survival free from the composite outcome compared with patients with RV free wall strain ≤-20% (Log Rank 0.004). Among patients with preserved RV systolic longitudinal function as indicated by TAPSE ≥17 mm, subjects with RV free wall strain >-20% had a significantly higher incidence of the composite outcome compare with those with RV free wall strain ≤-20% (Log-Rank = 0.008, Figure 2). Conversely, no difference was found among patients with TAPSE Conclusions RV dysfunction assessed either by TAPSE and RV free wall strain is associated with poorer outcome in patients with severe or moderate-to-severe functional MR undergoing TEER. Compared with TAPSE, RV free wall strain seems to be superior in identifying patients at higher risk of adverse events during follow-up. Our data encourage the use of this speckle tracking-derived echocardiographic parameter in routinely evaluation of patients with functional MR candidate for TEER. Abstract Figure. Abstract Figure 2

International audience; Recently, Akalin et al.1 reported a 28% mortality among kidney‐transplant patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2). Two of the 10 patients who died had been transplanted within the previous 5 weeks. During the coronavirus disease (COVID)‐19 outbreak, kidney transplant programs were suspended in several countries2. Although the pandemic is still ongoing, the stop of lockdown has prompted several transplant centers to restart kidney transplantation programs. It is recommended to consider that donors and recipients are screened for SARS‐CoV‐2 before transplantation by means of nuclear acid tests with or without chest CT scans.

1,3:2,4-Dibenzylidene-D-sorbitol (DBS) and 12-hydroxystearic acid (12-HSA) are well-known as low-molecular-weight organogelators (LMOGs) capable of gelling an organic liquid phase. Considering their unique chemical and physical properties, we assessed their potential effects in new lipstick formulations by discrimination testing, in vitro measurements of the sun protection factor (SPF), and thermal, mechanical and texture analyzes. DBS and 12-HSA were used to formulate four types of lipsticks: L1 (1% DBS), L2 (10% 12-HSA), L3 (1.5% DBS) and L4 (control, no LMOGs). The lipsticks were tested for sensory perception with an untrained panel of 16 consumers. LMOG formulations exhibited higher UVA protection factor (UVA-PF) and in vitro SPF, particularly in the 12-HSA-based lipstick. Regarding thermal properties, the 12-HSA-based lipstick and those without LMOGs were more heat-amenable compared to thermoresistant DBS-based lipsticks. The results also showed the viscoelastic and thermally reversible properties of LMOGs and their effect of increasing pay-off values. In general, the texture analysis indicated that 12-HSA-based lipstick was significantly harder to bend compared to control, while the other formulations became softer and easier to bend throughout the stability study. This work suggests the potential use of LMOGs as a structuring agent for lipsticks, paving the way towards more photoprotective and sustainable alternatives.

Autobiographical memory studies conducted with narrative methods are onerous, requiring significant resources in time and labor. We have created a semi-automated process that allows autobiographical transcribing and scoring methods to be streamlined. Our paper focuses on the Autobiographical Interview (AI; Levine, Svoboda, Hay, Winocur, & Moscovitch, Psychology and Aging, 17, 677-89, 2002), but this method can be adapted for other narrative protocols. Specifically, here we lay out a procedure that guides researchers through the four main phases of the autobiographical narrative pipeline: (1) data collection, (2) transcribing, (3) scoring, and (4) analysis. First, we provide recommendations for incorporating transcription software to augment human transcribing. We then introduce an electronic scoring procedure for tagging narratives for scoring that incorporates the traditional AI scoring method with basic keyboard shortcuts in Microsoft Word. Finally, we provide a Python script that can be used to automate counting of scored transcripts. This method accelerates the time it takes to conduct a narrative study and reduces the opportunity for error in narrative quantification. Available open access on GitHub ( https://github.com/cMadan/scoreAI ), our pipeline makes narrative methods more accessible for future research.

Growth hormone-releasing peptide-6 (GHRP-6) is part of a group of small synthetic peptides with potent GH-releasing activity that have gained attention in the last two decades by virtue of their cyto- and cardioprotective effects. Despite numerous preclinical studies highlighting the potential cardiovascular benefits of GHRP-6, confirmation of clinical efficacy is still awaited. Recent advances in transdermal drug delivery systems have been made to address challenges related to the poor skin permeation rate of peptides by using pain-free microneedle (MN) devices. Accordingly, highly sensitive and validated analytical methods are required for the potential clinical translation of MN-based peptides. The ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) methods developed in this study aimed to quantify GHRP-6 in biological matrices (plasma, skin) and dissolving polymeric MNs. UHPLC/MS-MS method detection limits of 0.1, 1.1, 0.9 and 1.5 ng/mL were achieved in neat solution, plasma, MN polymer solution, and skin matrices, respectively. Method validation also involved assessment of precision, accuracy, limits of quantification, linearity of matched calibration curves (R2 > 0.990), extraction recovery, matrix effect, stability studies, selectivity, and carry-over effect. Additionally, quality control samples were analyzed at three concentration levels to determine recovery (85–109%) and accuracy/bias (3.2–14.7%). Intra- and inter-day precision were within the range of acceptance (RSDs of 3.0–13.9% and 0.4–14.5%, respectively). The validity and applicability of such methods were successfully demonstrated for transdermal GHRP-6 delivery using GHRP-6-loaded MN patches applied to pig skin.

Introduction Une faible immunogenicite des vaccins a ARN messager a ete rapportee chez les patients transplantes d’organes solides apres deux doses vaccinales. Description L’objectif de cette etude retrospective monocentrique etait d’identifier les facteurs predictifs de reponse vaccinale apres l’administration de deux doses de vaccin a ARN messager. Methodes Au total, 393 patients ont beneficie de deux doses de vaccins a ARN messager a 1 mois d’intervalle (vaccin BNT162b2, Pfizer-BioNTech, n = 391 ; vaccin mRNA 1273, Moderna, n = 2). Resultats A 1 mois de la seconde dose de vaccin a ARN messager, 97 des 288 transplantes renaux ont developpes des anticorps anti-SARS-CoV2 (33,7 %), contre 31 des 65 patients transplantes hepatiques (47,7 %), 5 des 35 patients transplantes thoraciques (14,3 %), et 1 des 5 transplantes du pancreas (20,0 %) (p = 0,005). Les patients ayant developpes une reponse vaccinale etaient plus jeunes, plus souvent des hommes et transplantes depuis plus longtemps que les patients non-repondeurs. Les patients ayant recu un traitement d’induction developpaient moins souvent des anticorps anti-SARS-CoV2 que les patients n’ayant pas recu de traitement d’induction. Les patients recevant de l’acide mycophenolique, des corticoides ou du belatacept developpaient moins souvent une reponse vaccinale. Inversement, les patients recevant des inhibiteurs des mTOR developpaient plus souvent des anticorps anti-SARS-CoV2. Finalement, quel que soit le type d’organe greffe, les patients ayant une reponse vaccinale avaient un DFG estime superieur a celui des patients n’ayant pas developpes d’anticorps. En analyse multivariee, etre un homme, a distance de la greffe et avoir un DFG eleve etaient associes a une reponse vaccinale positive. A l’inverse, etre jeune, receveur d’organe thoracique, sous traitement par acide mycophenolique, corticoides ou belatacept etaient associes a une reponse vaccinale negative. Conclusion La vaccination anti-SARS-CoV2 a ARN messager a deux doses possede une faible immunogenicite chez les receveurs d’organes solides. Le traitement immunosuppresseur serait le seul parametre modifiable permettant d’ameliorer la reponse vaccinale.

Additive manufacture (AM) technologies allow innovative structural design, including complex lattice structures. Selective laser melting (SLM) is an AM process that enables the manufacture of space filling lattice structures. Lattice structures are topologically ordered, three-dimensional open-celled structures composed of one or more repeating unit cells. From a mechanical designer viewpoint, a great advantage offered by cellular materials is high strength accompanied by a relatively low mass. Due to their complex structure, fine geometry and the absence of supports structures, the setting of the best parameters to print lattice structures is difficult and could negative influence their mechanical response. This study investigated how different parameters settings influence the compression behaviour of lattice structures in stainless steel 17-4PH (AISI-630) printed by SLM. A comparison between compressive response of structures printed with different parameters is presented and considerations about their behaviour exposed.

Composites are experiencing a new era. The spatial resolution at which is to date possible to build up complex architectured microstructures through additive manufacturing-based and sintering of powder metals 3D printing techniques, as well as the recent improvements in both filament winding and automated fiber deposition processes, are opening new unforeseeable scenarios for applying optimization strategies to the design of high-performance structures and metamaterials that could previously be only theoretically conceived. Motivated by these new possibilities, the present work, by combining computational methods, analytical approaches and experimental analysis, shows how finite element Design Optimization algorithms can be ad hoc rewritten by identifying as design variables the orientation of the reinforcing fibers in each ply of a layered structure for redesigning fiber-reinforced composites exhibiting at the same time high stiffness and toughening, two features generally in competition each other. To highlight the flexibility and the effectiveness of the proposed strategy, after a brief recalling of the essential theoretical remarks and the implemented procedure, selected example applications are finally illustrated on laminated plates under different boundary conditions, cylindrical layered shells with varying curvature subjected to point loads and composite tubes made of carbon fiber-reinforced polymers, recently employed as structural components in advanced aerospace engineering applications.

Objectives: To evaluate the maternal and perinatal outcomes of pregnancies affected by SARS-CoV-2 infection. Methods: This was a multinational retrospective cohort study including women with a singleton pregnancy and laboratory-confirmed SARS-CoV-2 infection, conducted in 72 centers in 22 different countries in Europe, the USA, South America, Asia and Australia, between 1 February 2020 and 30 April 2020. Confirmed SARS-CoV-2 infection was defined as a positive result on real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab specimens. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit (ICU), use of mechanical ventilation and death. Results: In total, 388 women with a singleton pregnancy tested positive for SARS-CoV-2 on RT-PCR of a nasopharyngeal swab and were included in the study. Composite adverse maternal outcome was observed in 47/388 (12.1%) women; 43 (11.1%) women were admitted to the ICU, 36 (9.3%) required mechanical ventilation and three (0.8%) died. Of the 388 women included in the study, 122 (31.4%) were still pregnant at the time of data analysis. Among the other 266 women, six (19.4% of the 31 women with first-trimester infection) had miscarriage, three (1.1%) had termination of pregnancy, six (2.3%) had stillbirth and 251 (94.4%) delivered a liveborn infant. The rate of preterm birth before 37 weeks' gestation was 26.3% (70/266). Of the 251 liveborn infants, 69/251 (27.5%) were admitted to the neonatal ICU, and there were five (2.0%) neonatal deaths. The overall rate of perinatal death was 4.1% (11/266). Only one (1/251, 0.4%) infant, born to a mother who tested positive during the third trimester, was found to be positive for SARS-CoV-2 on RT-PCR. Conclusions: SARS-CoV-2 infection in pregnant women is associated with a 0.8% rate of maternal mortality, but an 11.1% rate of admission to the ICU. The risk of vertical transmission seems to be negligible. © 2020 International Society of Ultrasound in Obstetrics and Gynecology. © 2020 International Society of Ultrasound in Obstetrics and Gynecology

Due to a technical error, the author list at the end of this article is unfortunately incorrect. Elif Gül Yapar Eyi is not a co-author, and therefore, his name and affiliation should not appear in the list. The correct author list and affiliations read as follows: Daniele Di Mascio, Cihat Sen, Gabriele Saccone, Alberto Galindo, Amos Grünebaum, Jun Yoshimatsu, Milan Stanojevic, AsimKurjak, Frank Chervenak, María Jos´e Rodríguez Suárez, Zita Maria Gambacorti-Passerini, María de los Angeles Anaya Baz, Esther Vanessa Aguilar Galán, Yolanda Cuñarro López, Juan Antonio De León Luis, Ignacio Cueto Hernández, Ignacio Herraiz, Cecilia Villalain, Roberta Venturella, Giuseppe Rizzo, Ilenia Mappa, Giovanni Gerosolima, Lars Hellmeyer, Josefine Königbauer, Giada Ameli, Tiziana Frusca, Nicola Volpe, Giovanni Battista Luca Schera, Stefania Fieni, Eutalia Esposito, Giuliana Simonazzi, Gaetana Di Donna, Aly Youssef, Anna Nunzia Della Gatta, Mariano Catello Di Donna, Vito Chiantera, Natalina Buono, Giulio Sozzi, Pantaleo Greco, Danila Morano, Beatrice Bianchi, Maria Giulia Lombana Marino, Federica Laraud, Arianna Ramone, Angelo Cagnacci, Fabio Barra, Claudio Gustavino, Simone Ferrero, Fabio Ghezzi, Antonella Cromi, Antonio Simone Laganá, Valentina Laurita Longo, Francesca Stollagli, Angelo Sirico, Antonio Lanzone, Lorenza Driul, Fabiana Cecchini D, Serena Xodo, Brian Rodriguez, Felipe Mercado-Olivares, Deena Elkafrawi, Giovanni Sisti, Rosanna Esposito, Antonio Coviello, Marco Cerbone, Maddalena Morlando, Antonio Schiattarella, Nicola Colacurci, Pasquale De Franciscis, Ilaria Cataneo, Marinella Lenzi, Fabrizio Sandri, Riccardo Buscemi, Giorgia Gattei, Francesca della Sala, Eleonora Valori, Maria Cristina Rovellotti, Elisa Done, Gilles Faron, Leonardo Gucciardo, Valentina Esposito, Flaminia Vena, Antonella Giancotti, Roberto Brunelli, Ludovico Muzii, Luigi Nappi, Felice Sorrentino, Lorenzo Vasciaveo, Marco Liberati, Danilo Buca, Martina Leombroni, Francesca Di Sebastiano, Luciano Di Tizio, Diego Gazzolo, Massimo Franchi, Quintino Cesare Ianniciello, Simone Garzon, Giuliano Petriglia, Leonardo Borrello, Albaro Jos´e Nieto-Calvache, Juan Manuel Burgos-Luna, Caroline Kadji, Andrew Carlin, Elisa Bevilacqua, Marina Moucho, Pedro Viana Pinto, Rita Figueiredo, Jos´e Morales Roselló, Gabriela Loscalzo, Alicia Martinez-Varea, Vincente Diago, Jesús S Jimenez Lopez, Alicia Yeliz Aykanat, Stefano Cosma, Andrea Carosso, Chiara Benedetto, Amanda Bermejo, Otto Henrique May Feuerschuette, Ozlem Uyaniklar, Sakine Rahimli Ocakouglu, Zeliha Atak, Reyhan Gündüz, Esra Tustas Haberal, Bernd Froessler, Anupam Parange, Peter Palm, Igor Samardjiski, Chiara Taccaliti, Erhan Okuyan, George Daskalakis, Renato Augusto Moreira de Sa, Alejandro Pittaro, Maria Luisa Gonzalez-Duran, Ana Concheiro Guisan, Serife Özlem Genç, Blanka Zlatohlávková, Anna Luengo Piqueras, Dolores Esteban Oliva, Aylin Pelin Cil, Olus Api, Panos Antsaklis, Liana Ples, Ioannis Kyvernitakis, Holger Maul, Marcel Malan, Albert Lila, Roberta Granese, Alfredo Ercoli, Giuseppe Zoccali, Andrea Villasco, Nicoletta Biglia, Ciuhodaru Madalina, Elena Costa, Caroline Daelemans, Axelle Pintiaux, Elisa Cueto, Eran Hadar, Sarah Dollinger, Noa A. Brzezinski Sinai, Erasmo Huertas, Pedro Arango, Amadeo Sanchez, Javier Alfonso Schvartzman, Liviu Cojocaru, Sifa Turan, Ozhan Turan, Maria Carmela Di Dedda, Rebeca Garrote Molpeceres, Snezana Zdjelar, Tanja Premru-Srsen, Lilijana Kornhauser Cerar, Mirjam Druškovic, Valentina De Robertis, Vedran Stefanovic, Irmeli Nupponen, Kaisa Nelskylä, Zulfiya Khodjaeva, Ksenia A. Gorina, Gennady T. Sukhikh, Giuseppe Maria Maruotti, Silvia Visentin, Erich Cosmi, Jacopo Ferrari, Alessandra Gatti, Daniela Luvero, Roberto Angioli, Ludovica Puri, Marco Palumbo, Giusella D’Urso, Francesco Colaleo, Agnese Maria Chiara Rapisarda, Ilma Floriana Carbone, Antonio Mollo, Giovanni Nazzaro, Mariavittoria Locci, Maurizio Guida, Attilio Di Spiezio Sardo, Pierluigi Benedetti Panici, Vincenzo Berghella, Maria Elena Flacco, Lamberto Manzoli, Giuseppe Bifulco, Giovanni Scambia, Fulvio Zullo and Francesco D’Antonio Flaminia Vena, Antonella Giancotti, Roberto Brunelli, Ludovico Muzii and Pierluigi Benedetti Panici, Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Rome, Italy Rosanna Esposito, Antonio Coviello, Marco Cerbone, Giuseppe Maria Maruotti, Giovanni Nazzaro, Mariavittoria Locci, Maurizio Guida, Attilio Di Spiezio Sardo, Giuseppe Bifulco and Fulvio Zullo, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy Ignacio Herraiz and Cecilia Villalain, Department of Obstetrics and Gynaecology, Fetal Medicine Unit, Maternal and Child Health and Development Network, University Hospital 12 de Octubre, Complutense University of Madrid, Madrid, Spain María Jos´e Rodríguez Suárez, Hospital Universitario Central de Asturias, Asturias, Spain Zita Maria Gambacorti-Passerini, Department of Obstetrics and Gynaecology, Ciudad Real University General Hospital, Ciudad Real, Spain María de los Angeles Anaya Baz and Esther Vanessa Aguilar Galán, Department of Obstetrics and Gynaecology, Ciudad Real University General Hospital, Ciudad Real, Spain; University of Castilla-La Mancha, Ciudad Real, Spain Yolanda Cuñarro López, Juan Antonio De León Luis and Ignacio Cueto Hernández, Department of Obstetrics and Gynaecology, Fetal Medicine Unit, Maternal and Child Health and Development Network, Gregorio Marañón Hospital, Complutense University of Madrid, Madrid, Spain Roberta Venturella, Department of Obstetrics and Gynaecology, School of Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy Giuseppe Rizzo, University of Roma Tor Vergata, Division of Maternal Fetal Medicine, Ospedale Cristo Re Roma, Rome, Italy; Department of Obstetrics and Gynaecology, The First I.M. Sechenov Moscow State Medical University, Moscow, Russia Ilenia Mappa, University of Roma Tor Vergata, Division of Maternal Fetal Medicine, Ospedale Cristo Re Roma, Rome, Italy Giovanni Gerosolima, Department of Obstetrics and Gynaecology, Ospedale AOSG Moscati, Avellino, Italy Lars Hellmeyer, Josefine Königbauer and Giada Ameli, Department of Gynaecology and Obstetrics, Vivantes Klinikum im Friedrichshain, Berlin, Germany Tiziana Frusca, Nicola Volpe, Giovanni Battista Luca Schera and Stefania Fieni, Department of Obstetrics and Gynaecology, University of Parma, Parma, Italy Eutalia Esposito, Department of Obstetrics and Gynaecology, Ospedale di San Leonardo, Castellammare di Stabia, Italy Giuliana Simonazzi, Gaetana Di Donna, Aly Youssef and Anna Nunzia Della Gatta, Department of Obstetrics and Gynaecology, University of Bologna, Sant’Orsola- Malpighi University Hospital, Bologna, Italy Mariano Catello Di Donna, Vito Chiantera, Natalina Buono and Giulio Sozzi, Department of Gynaecologic Oncology, University of Palermo, Palermo, Sicilia, Italy Pantaleo Greco, Danila Morano, Beatrice Bianchi and Maria Giulia Lombana Marino, Department ofMedical Sciences, Section of Obstetrics and Gynaecology, Azienda Ospedaliera-Universitaria Sant’Anna, University of Ferrara, Ferrara, Italy Federica Laraud, Arianna Ramone, Angelo Cagnacci, Fabio Barra, Claudio Gustavino and Simone Ferrero, Academic Unit of Obstetrics and Gynaecology, IRCCS Ospedale Policlinico, San Martino, Genova, Italy Fabio Ghezzi, Antonella Cromi and Antonio Simone Laganà, Department of Obstetrics and Gynaecology, “Filippo Del Ponte” Hospita University of Insubria, Varese, Italy Valentina Laurita Longo, Department of Obstetrics and Gynaecology, Fondazione Policlinico Universitario A Gemelli IRCCS – Università Cattolica del Sacro Cuore, Rome, Italy; Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italy; and Queen Margaret University, Institute for Global Health and Development, Edinburgh, UK Francesca Stollagli and Ludovica Puri, Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italy Angelo Sirico and Giovanni Scambia, Department of Obstetrics and Gynaecology, Fondazione Policlinico Universitario A Gemelli IRCCS – Università Cattolica del Sacro Cuore, Rome, Italy Antonio Lanzone, Department of Obstetrics and Gynaecology, Fondazione Policlinico Universitario A Gemelli IRCCS – Università Cattolica del Sacro Cuore, Rome, Italy; Istituto di Clinica Ostetrica e Ginecologica, Università Cattolica del Sacro Cuore, Rome, Italy Lorenza Driul, Fabiana Cecchini D and Serena Xodo, Clinic of Obstetrics and Gynaecology, University of Udine, Udine, Italy Brian Rodriguez, Felipe Mercado-Olivares, Deena Elkafrawi and Giovanni Sisti, Department of Obstetrics and Gynaecology, New York Health and Hospitals/Lincoln Bronx, The Bronx, NY, USA Maddalena Morlando, Antonio Schiattarella, Nicola Colacurci and Pasquale De Franciscis, Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy Ilaria Cataneo, Marinella Lenzi and Fabrizio Sandri, Unit of Obstetrics and Gynaecology, Ospedale Maggiore, Bologna, Italy Riccardo Buscemi, Giorgia Gattei, Francesca della Sala and Maria Cristina Rovellotti, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy Eleonora Valori, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy; Hospital Castelli, Verbania, Italy Elisa Done, Gilles Faron and Leonardo Gucciardo, UZ Brussel, Universitair Ziekenhuis, Brussel, Belgium Valentina Esposito, University of Milan, Milan, Italy Luigi Nappi, Felice Sorrentino and Lorenzo Vasciaveo, Department of Obstetrics and Gynaecology, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. © 2021 De Gruyter. All rights reserved.

Background In cardiac amyloidosis the application of Speckle Tracking Echocardiography allows to identify a specific left ventricular (LV) longitudinal strain (LS) pattern characterized by “apical sparing”, with a prominent involvement of basal and middle segments and normal LS of apical cap. The pattern of regional LS has been never investigated in monoclonal gammopathy of undetermined significance (MGUS), a condition which can predispose to cardiac amyloidosis. Purpose To compare LV regional LS patterns and LS base-to-apex behaviour of patients affected by MGUS in comparison with healthy subjects. Methods We enrolled 40 patients affected by MGUS (M/F=20/20; age 62.6±13.8 years), asymptomatic for cardiac symptoms, and a control group of 40 healthy subjects, matched for sex and age. Nineteen (47%) MGUS patients showed prevalent free K light chain and 21 (53%) had prevalent free λ light chain. Participants underwent standard echo-Doppler exam, including Speckle Tracking of the three apical views. Global longitudinal strain (GLS), the average LS of six basal (BLS), six middle (MLS), and six apical (ALS) segments (considered in absolute values) and relative regional strain ratio RRSR [=ALS/(BLS+MLS)] were computed. Exclusion criteria were overt heart failure, LV ejection fraction Results The two groups were comparable for body mass index, blood pressure and heart rate. LV mass index, relative wall thickness, left atrial volume index and Doppler-derived LV diastolic parameters did not differ significantly between the two groups. LV ejection fraction was also similar in MGUS and healthy controls. GLS resulted significantly lower in MGUS group than in controls (20.5±3.0 vs. 22.4±2.0%, p1. The figure depicts a LS bull'eye of a MGUS patient showing the prominent involvement of LV basal segments. Conclusions In presence of a normal LV ejection fraction, MGUS patients show a subclinical LV longitudinal systolic dysfunction. This is testified by a reduction of GLS and of regional LS which involves mainly LV basal segments, without substantial changes of relative regional strain ratio. LV regional longitudinal dysfunction could be useful to monitor LV myocardial mechanics during follow-up of MGUS patients. LS bull's eye in a MGUS patient Funding Acknowledgement Type of funding source: None

DNA methylation is a fundamental epigenetic modification regulating gene expression. Aberrant DNA methylation is the most common molecular lesion in cancer cells. However, medical intervention has been limited to the use of broadly acting, small molecule-based demethylating drugs with significant side-effects and toxicities. To allow for targeted DNA demethylation, we integrated two nucleic acid-based approaches: DNMT1 interacting RNA (DiR) and RNA aptamer strategy. By combining the RNA inherent capabilities of inhibiting DNMT1 with an aptamer platform, we generated a first-in-class DNMT1-targeted approach – aptaDiR. Molecular modelling of RNA-DNMT1 complexes coupled with biochemical and cellular assays enabled the identification and characterization of aptaDiR. This RNA bio-drug is able to block DNA methylation, impair cancer cell viability and inhibit tumour growth in vivo. Collectively, we present an innovative RNA-based approach to modulate DNMT1 activity in cancer or diseases characterized by aberrant DNA methylation and suggest the first alternative strategy to overcome the limitations of currently approved non-specific hypomethylating protocols, which will greatly improve clinical intervention on DNA methylation.

Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts. We comparatively investigated these unique complementary materials using morphofunctional, ultrastructural and flow cytometric assays accompanied by microRNA studies. We found that paragangliomas contain stem-like cells with hybrid mesenchymal/vasculoneural phenotype, stabilized and expanded in the derived cultures. The viability and growth of such cultures depended on the downregulation of the miR-200 and miR-34 families, which allowed high PDGFRA and ZEB1 protein expression levels. Both tumour tissue- and cell culture-derived xenografts recapitulated the vasculoneural paraganglioma structure and arose from mesenchymal-like cells through a fixed developmental sequence. First, vasculoangiogenesis organized the microenvironment, building a perivascular niche which in turn supported neurogenesis. Neuroepithelial differentiation was associated with severe mitochondrial dysfunction, not present in cultured paraganglioma cells, but acquired in vivo during xenograft formation. Vasculogenesis was the Achilles’ heel of xenograft development. In fact, imatinib, that targets endothelial-mural signalling, blocked paraganglioma xenograft formation (11 xenografts from 12 cell transplants in the control group versus 2 out of 10 in the treated group, P = 0.0015). Overall our key results were unaffected by the SDHx gene carrier status of the patient, characterized for 70 out of 77 cases. In conclusion, we explain the biphasic vasculoneural structure of paragangliomas and identify an early and pharmacologically actionable phase of paraganglioma organization. Electronic supplementary material The online version of this article (10.1007/s00401-017-1799-2) contains supplementary material, which is available to authorized users.

Background In non-valvular atrial fibrillation (AF) patients, risk stratification scores such as CHA2DS2VASc and HASBLED allow the prediction of thromboembolic and bleeding risks, respectively. However, no risk score for the prediction of AF recurrence has been yet validated. Purpose To evaluate the mayor anthropometric and echocardiographic determinants of AF recurrence in non-valvular paroxysmal AF patients at 1 year follow-up. Methods Among 395 consecutive adult patients with non valvular AF enrolled in the Neapolitan Atrial Fibrillation (NeAfi) Echo registry, 177 (F/M = 87/90, age = 66.5± 11.9 years) had paroxismal AF and underwent 1-year follow-up. Fifteen patients had AF recurrence. Anthropometric parameters and blood pressure (BP) were recorded and CHA2DS2VASc and HASBLED scores were calculated. At baseline, patients underwent a comprehensive echo-Doppler exam, including quantification of left atrial (LA) size measurements, peak atrial longitudinal strain (PALS) and left ventricular (LV) global longitudinal strain (GLS). Binary logistic regression analysis was used to establish a mathematical model of the relationship between the variables and AF recurrence. The covariates for regression analysis were chosen as potential confounding factors based on their significance in independent T test analyses for continuous variables of chi-square for dichotomous variables, or on their biological plausibility. Results AF recurrence was higher in male than in female patients (14.4 vs 2.3%, p = 0.008). Patients with AF recurrence had similar body mass index, systolic and diastolic BP and heart rate compared to those without. The two groups were similar for LV end-systolic and end-diastolic volumes, ejection fraction, LV mass index, diastolic indexes, pulmonary artery systolic pressure and GLS. LA diameter (p = 0.235) and PALS (p = 0.375) were also similar between the two groups, whereas LA volume index (LAVi) was greater in patients experiencing AF recurrence (45.5 ± 15.7 vs. 36.7 ± 10.4 ml/m², p = 0.003). Binomial multiple regression analysis model explained 25% (Nagelkerke R²) of the variance in AF recurrence and correctly classified 95.0% of cases. Males were 8.9 times more likely to exhibit AF recurrence than females (p = 0.04). Greater LAVi was associated with an increased likelihood of exhibiting AF recurrence (OR = 1.07, p = 0.03), whereas CHA2DS2VASc >1 in men and >2 in women, HASBLED >3 and greater LA diameter or lower PALS did not add significant information to the model. Conclusions Male gender and, with a lower extent, LAVi appear to be major determinants of AF recurrence in non-valvular paroxysmal AF. The quantification of PALS does not seem to add valuable information in the prediction of recurrent AF.

Background Hyperuricemia has been reported to accelerate the occurrence and worsening of cardiovascular disease, being a risk factor for coronary heart disease and cardiac mortality. Elevated uric acid (UA) is also associated with left ventricular (LV) hypertrophy and with LV diastolic dysfunction. The effect of hyperuricemia (HU) on LV systolic function is still unclear. Purpose Aim of our study was to evaluate the impact of elevated UA serum levels on LV systolic function, also evaluating longitudinal deformation, in a population of hypertensive patients. Methods We enrolled 160 treated hypertensive patients (M/F = 104/56, age 58.2 ± 13.3 years, blood pressure = 136.7 ± 16.8/81.3 ± 10.9 mmHg), who underwent standard echo-Doppler exam, including speckle tracking quantification of global longitudinal strain (GLS, considered in absolute value). HU was defined as UA≥7 mg/dL and the study population was divided in two groups: patients with (n = 63) and without (n = 97) HU. Exclusion criteria were coronary artery disease, overt heart failure, hemodynamically significant valve heart disease, primary cardiomyopathies, permanent atrial fibrillation and inadequate echo imaging. Results The two groups were comparable for sex prevalence, blood pressure and heart rate. Patients with HU were older and had higher body mass index (BMI) (both p Conclusions In hypertensive patients with multiple cardiovascular risk factors, the presence of HU is associated with LV diastolic and systolic dysfunction. Serum UA levels and GLS resulted independently associated even after adjusting for several clinical and echo confounders. Acid uric might be considered as an independent marker of early LV dysfunction, able to identify hypertensive patients at increased risk for heart failure. Abstract P658 Figure. Relation between uric acid and GLS

Background Overweight and obesity are related to the risk of new-onset atrial fibrillation (AF). Peak atrial longitudinal strain (PALS) is an advanced echocardiographic parameter of left atrial (LA) function with a recognized diagnostic and prognostic role in both the general population and AF. Purpose To investigate the impact of body mass index (BMI) on LA function by utilizing standard and advanced echocardiography in patients with non-valvular AF. Methods In the NeAfib-Echo registry, 395 consecutive adult patients with non-valvular AF (F/M: 175/220; mean age 70.6 ± 11 years, BMI: 27.8 ± 5.6 kg/m²) were enrolled. 215 patients (54.1%) had permanent/persistent AF (prAF) and 178 (45.9%) had paroxysmal AF (pxAF). Anthropometric parameters and blood pressure (BP) were recorded and CHA2DS2VASc score was calculated. Patients underwent a complete echo-Doppler exam, including determination of PALS and left ventricular (LV) global longitudinal strain (GLS) (both reported in absolute values). The overall population was divided according to BMI tertiles: first tertile 29.3 Kg/m² (n = 130). Results No significant difference of sex prevalence, age, systolic BP and heart rate was found among the three BMI tertiles, whereas diastolic BP was higher in the third tertile (p Conclusions In patients with non valvular AF, overweight and obesity exert a detrimental effect on LA function as testified by the gradual PALS reduction with the increase of BMI tertiles. BMI is associated with PALS independently of several confounders including CHA2DS2VASc. Besides CHA2DS2VASc score, BMI could be considered as an additional factor for evaluating cardiovascular risk in non valvular AF. Abstract P814 Figure. Relation between BMI and PALS

Background and aims Scavenger receptor class B member 3, also known as cluster of differentiation-36 (CD36) receptor, is involved in the uptake and accumulation of modified lipoprotein in macrophages, driving atherosclerosis progression. Azapeptide analogs of growth hormone-releasing peptide-6 (GHRP-6) have been developed as selective CD36 ligands and evaluated for their anti-atherosclerotic properties in apoe−/− mice. Methods From 4 to 19 weeks of age, male apoe−/− mice were fed a high fat high cholesterol (HFHC) diet, then switched to normal chow and treated daily with 300 nmol/kg of MPE-001 ([aza-Tyr4]-GHRP-6) or MPE-003 ([aza-(N,N-diallylaminobut-2-ynyl)Gly4]-GHRP-6) for 9 weeks. In another protocol, mice were fed a HFHC diet throughout the study. Results Azapeptides decreased lesion progression in the aortic arch and reduced aortic sinus lesion areas below pre-existing lesions levels in apoe−/− mice which were switched to chow diet. In mice fed a HFHC throughout the study, azapeptides reduced lesion progression in the aortic vessel and sinus. The anti-atherosclerotic effect of azapeptides was associated with a reduced ratio of iNOS+/CD206+ macrophages within lesions, and lowered plasma inflammatory cytokine levels. Monocytes from azapeptide-treated mice showed altered mitochondrial oxygen consumption rates, consistent with an M2-like phenotype. These effects were dependent on CD36, and not observed in apoe−/−cd36−/− mice. Conclusions Azapeptides MPE-001 and MPE-003 diminished aortic lesion progression and reduced, below pre-existing levels, lesions in the aortic sinus of atherosclerotic mice. A relative increase of M2-like macrophages was observed in lesions, associated with reduced systemic inflammation. Development of CD36-selective azapeptide ligands merits consideration for treating atherosclerotic disease.

International audience; Little is known about the impact of posttransplant blood transfusion on the sensitization of anti-HLA antibodies and the formation of donor-specific antibodies (DSAs). The aims of our study were to determine the 1-year incidence of DSAs (assessed using a solid-phase assay) and antibody-mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non– HLA-sensitized patients who had received an ABOcompatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1-year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p < 0.0001). AMR occurred more often in the transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation butnot for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.

In this review, we propose that paraganglioma is a fundamentally organized, albeit aberrant, tissue composed of neoplastic vascular and neural cell types that share a common origin from a multipotent mesenchymal-like stem/progenitor cell. This view is consistent with the pseudohypoxic footprint implicated in the molecular pathogenesis of the disease, is in harmony with the neural crest origin of the paraganglia, and is strongly supported by the physiological model of carotid body hyperplasia. Our immunomorphological and molecular studies of head and neck paragangliomas demonstrate in all cases relationships between the vascular and the neural tumor compartments, that share mesenchymal and immature vasculo-neural markers, conserved in derived cell cultures. This immature, multipotent phenotype is supported by constitutive amplification of NOTCH signaling genes and by loss of the microRNA-200s and -34s, which control NOTCH1, ZEB1, and PDGFRA in head and neck paraganglioma cells. Importantly, the neuroepithelial component is distinguished by extreme mitochondrial alterations, associated with collapse of the ΔΨm. Finally, our xenograft models of head and neck paraganglioma demonstrate that mesenchymal-like cells first give rise to a vasculo-angiogenic network, and then self-organize into neuroepithelial-like clusters, a process inhibited by treatment with imatinib.