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BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been widely used in patients with COVID-19, but uncertainty remains about the determinants of in-hospital mortality and data on post-discharge outcomes are scarce. The aims of this study were to investigate the variables associated with in-hospital outcomes in patients who received ECMO during the first wave of COVID-19 and to describe the status of patients 6 months after ECMO initiation.METHODS: EuroECMO-COVID is a prospective, multicentre, observational study developed by the European Extracorporeal Life Support Organization. This study was based on data from patients aged 16 years or older who received ECMO support for refractory COVID-19 during the first wave of the pandemic-from March 1 to Sept 13, 2020-at 133 centres in 21 countries. In-hospital mortality and mortality 6 months after ECMO initiation were the primary outcomes. Mixed-Cox proportional hazards models were used to investigate associations between patient and management-related variables (eg, patient demographics, comorbidities, pre-ECMO status, and ECMO characteristics and complications) and in-hospital deaths. Survival status at 6 months was established through patient contact or institutional charts review. This study is registered with ClinicalTrials.gov, NCT04366921, and is ongoing.FINDINGS: Between March 1 and Sept 13, 2020, 1215 patients (942 [78%] men and 267 [22%] women; median age 53 years [IQR 46-60]) were included in the study. Median ECMO duration was 15 days (IQR 8-27). 602 (50%) of 1215 patients died in hospital, and 852 (74%) patients had at least one complication. Multiorgan failure was the leading cause of death (192 [36%] of 528 patients who died with available data). In mixed-Cox analyses, age of 60 years or older, use of inotropes and vasopressors before ECMO initiation, chronic renal failure, and time from intubation to ECMO initiation of 4 days or more were associated with higher in-hospital mortality. 613 patients did not die in hospital, and 547 (95%) of 577 patients for whom data were available were alive at 6 months. 102 (24%) of 431 patients had returned to full-time work at 6 months, and 57 (13%) of 428 patients had returned to part-time work. At 6 months, respiratory rehabilitation was required in 88 (17%) of 522 patients with available data, and the most common residual symptoms included dyspnoea (185 [35%] of 523 patients) and cardiac (52 [10%] of 514 patients) or neurocognitive (66 [13%] of 512 patients) symptoms.INTERPRETATION: Patient's age, timing of cannulation (FUNDING: None.

BACKGROUND AND PURPOSE: Congenital diaphragmatic hernia is associated with high mortality and morbidity, including evidence suggesting neurodevelopmental comorbidities after birth. The aim of this study was to document longitudinal changes in brain biometry and the cortical folding pattern in fetuses with congenital diaphragmatic hernia compared with healthy fetuses. MATERIALS AND METHODS: This is a retrospective cohort study including fetuses with isolated congenital diaphragmatic hernia between January 2007 and May 2019, with at least 2 MR imaging examinations. For controls, we used images from fetuses who underwent MR imaging for an unrelated condition that did not compromise fetal brain development and fetuses from healthy pregnant women. Biometric measurements and 3D segmentations of brain structures were used as well as qualitative and quantitative grading of the supratentorial brain. Brain development was correlated with disease-severity markers. RESULTS: Forty-two fetuses were included, with a mean gestational age at first MR imaging of 28.0 (SD, 2.1) weeks and 33.2 (SD, 1.3) weeks at the second imaging. The mean gestational age in controls was 30.7 (SD, 4.2) weeks. At 28 weeks, fetuses with congenital diaphragmatic hernia had abnormal qualitative and quantitative maturation, more extra-axial fluid, and larger total skull volume. By 33 weeks, qualitative grading scores were still abnormal, but quantitative scoring was in the normal range. In contrast, the extra-axial fluid volume remained abnormal with increased ventricular volume. Normal brain parenchymal volumes were found. CONCLUSIONS: Brain development in fetuses with congenital diaphragmatic hernia around 28 weeks appears to be delayed. This feature is less prominent at 33 weeks. At this stage, there was also an increase in ventricular and extra-axial space volume. ispartof: AMERICAN JOURNAL OF NEURORADIOLOGY vol:44 issue:2 pages:205-211 ispartof: location:United States status: published

Funding Acknowledgements Type of funding sources: None. Background Brugada syndrome (BrS) is an inherited disease characterized by an increased risk of sudden cardiac death (SCD). According to the latest ESC guidelines, provocation with sodium channel blocker test is less specific than previously thought, especially in asymptomatic patients(1). In these cases, in which the diagnosis of BrS itself can be controversial, management currently consists in clinical follow-up only. However, we still observe a big gap between the patient’s perception and medical recommendations of living a normal life. Objective The goal of this study was to analyze exercise habits before and after positive ajmaline testing (AT), focusing on its psychological impact on a population of low-risk young patients. Methods We enrolled all-comers patients with ajmaline-induced Brugada type 1 pattern who came to our department between 2015 and 2022. Patients were asked to rate their heart-focused anxiety using the German version of the Cardiac Anxiety Questionnaire (CAQ) (2) at last medical contact after ajmaline challenge. The intensity of habitual physical exercise was estimated in METs and divided in 3 categories: mild (6 METs). Different groups were compared using Student’s t-test for continuous variables. Significance level was set to p Results A total of 87 patients resulted positive to ajmaline challenge; among these, 16 (18.4%) underwent EPS and 4 (4.6%) of them underwent ICD implantation. Therefore, our population included 83 patients. Mean age was 45.1±13.5 years; M/F ratio was 1.4/1. 12 patients (14.5%) had family history of SCD. Mean follow-up duration was 31.6±25.3 months. After positive AT, 5 patients (5.7%) did intense physical activity (PA), 27 (31.0%) did moderate PA, 51 (58.6%) were sedentary or practiced low-intensity PA. Mean CAQ score in the overall population was 19.1±6.6 points (fig. 1A), noticeably higher than the general population (2). As shown in fig. 1B, anxiety levels were significantly lower in patients who did almost moderate PA (p=0.03), independently from previous sport habits. This suggests sport to be a protective factor against anxiety. A total of 23 people (27.7%) reduced PA (fig. 2). We compared this population to the two groups of patients whose habits were not affected by the test: respectively high-high (n=22; 25.3%) and low-low groups (n=34; 39.1%). Anxiety in high-low group patients was not significantly different from the other two (fig. 1C), although it was higher than the general population. Conclusions After positive AT, many patients lead a sedentary lifestyle. Regardless of this, anxiety after the test is higher than the normal population. Anxiety levels do not change significantly between patients who reduced PA and those who did not change their habits. Further investigation is needed to assess the trade-offs between individual arrhythmic risk and global cardiovascular risk due to sedentary lifestyle in these patients.

The neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as mediators of migraine pathogenesis. Both are vasodilatory peptides that can cause migraine-like attacks when infused into people and migraine-like symptoms when injected into rodents. In this narrative review, we compare the similarities and differences between the peptides in both their clinical and preclinical migraine actions. A notable clinical difference is that PACAP, but not CGRP, causes premonitory-like symptoms in patients. Both peptides are found in distinct, but overlapping areas relevant to migraine, most notably with the prevalence of CGRP in trigeminal ganglia and PACAP in sphenopalatine ganglia. In rodents, the two peptides share activities, including vasodilation, neurogenic inflammation, and nociception. Most strikingly, CGRP and PACAP cause similar migraine-like symptoms in rodents that are manifested as light aversion and tactile allodynia. Yet, the peptides appear to act by independent mechanisms possibly by distinct intracellular signaling pathways. The complexity of these signaling pathways is magnified by the existence of multiple CGRP and PACAP receptors that may contribute to migraine pathogenesis. Based on these differences, we suggest PACAP and its receptors provide a rich set of targets to complement and augment the current CGRP-based migraine therapeutics.

We studied the incidence of primary graft dysfunction (PGD), its impact on in-hospital and follow-up outcomes and searched for independent risk factors.During an 18-year period, 508 individuals underwent heart transplantation at our institution. Patients were diagnosed with none, mild, moderate or severe PGD according to ISHLT criteria.Thirty-eight patients (7.5%) met the ISHLT criteria for mild PGD, 92 (18.1%) for moderate PGD and 23 (4.5%) for severe PGD. Patients were classified into none/mild PGD (77.4%) and moderate/severe PGD (22.6%) groups. In-hospital mortality was 12.4% (7.8% for none/mild PGD and 28.7% for moderate/severe PGD; p .001). Survival at 1, 5, and 15 years was 85.5 ± 1.9% versus 67.2 ± 4.5%, 80 ± 2.2% versus 63.5 ± 4.7%, and 60.4 ± 3.6% versus 45.9 ± 8.4%, respectively (p .001). Excluding the events occurring during the first month of follow-up, survival was comparable between the two groups (93.1 ± 1.4% vs. 94.7 ± 2.6 at 1 year and 65.6 ± 3.8% vs. 70.4 ± 10.4% at 15 years, respectively; p = .88). Upon multivariate logistic regression analysis preoperative mechanical circulatory support (odds ratio [OR] = 5.86) and preoperative intra-aortic balloon pump (IABP) (OR = 9.58) were independently associated with moderate/severe PGD.Our results confirm that PGD is associated with poor in-hospital outcome. The poor outcome does not extend beyond the first month of follow-up, with comparable survival between patients with none/mild PGD and moderate/severe PGD in the short and long-term. Mechanical circulatory support and preoperative IABP were found to be independent risk factors for moderate/severe PGD.

A 63–year–old woman presented to our Center for a longstanding history of typically radiating oppressive chest pain, with both resting and exertional episodes,mostly occurring early in the morning and exacerbated by cold.Two years before for a treadmill test positive for electrocardiographic (EKG) criteria of exercise–induced ischemia, she underwent coronary angiography which was found negative for epicardial obstructive coronary artery disease.Given the suspicion of coronary microvascular disease,empirical antianginal therapy with Ranolazine was started at that time,with transient improvement of symptoms. She presented to our Center for a 6 month history of recurrence of symptoms. Her antianginal therapy with Ranolazine was up titrated to 750 mg BID and Verapamil (40 mg TID) was added to her usual therapy given the suspicion of coronary vasospasm as additional component in the pathogenesis of her symptoms,as suggested by the anamnestic recall.Moreover a 24–hour–Holter monitoring was performed with subsequent finding of several episodes of horizontal ST–segment depression(up to 3 mm),mainly on awakening,in the absence of significant arrhythmias.The patient underwent coronary angiography for the assessment of coronary physiology. On angiography, the absence of epicardial obstructive coronary artery disease was confirmed, with the finding of extensive coronary fistulas originating from the left coronary system and communicating with the left ventricular cavity.After induction of maximal hyperemia, the clinical suspicion of coronary microvascular disease was confirmed (CFR 1.9).In addition, reduced coronary flow reserve in the left anterior descending (LAD) territory compatible with both microvascular dysfunction and coronary steal was documented (RFR 0.91;baseline FFR:0.94,after systemic adenosine:0.79).Given the clinical suspicion, vasoreactivity test with intracoronary acetylcholine (2–20–100–200 mcg) was also performed,which was positive for epicardial spasm at mid–distal LAD and concomitant onset of chest pain and ischemic EKG changes(diffuse ST–segment depression) with prompt regression after intracoronary nitrate administration.Taken together,clinical and instrumental findings suggested the diagnosis of mixed angina by combination of three mechanisms:microvascular disease,epicardial spasm and coronary steal due to extensive coronary artery fistulas.The patient was discharged with Ranolazine and Diltiazem at maximum tolerated dose with clinical benefit.

We developed an automated squint assay using both black C57BL/6J and white CD1 mice to measure the interpalpebral fissure area between the upper and lower eyelids as an objective quantification of pain. The automated software detected a squint response to the commonly used nociceptive stimulus formalin in C57BL/6J mice. After this validation, we used the automated assay to detect a dose-dependent squint response to a migraine trigger, the neuropeptide calcitonin gene-related peptide, including a response in female mice at a dose below detection by the manual grimace scale. Finally, we found that the calcitonin gene-related peptide amylin induced squinting behavior in female mice, but not males. These data demonstrate that an automated squint assay can be used as an objective, real-time, continuous-scale measure of pain that provides higher precision and real-time analysis compared with manual grimace assessments.

Objectives The aim of this study was to evaluate clinical characteristics, mechanisms of failure, and outcomes of transcatheter aortic valve replacement (TAVR) explantation. Background Surgical explantation following TAVR may be required for structural valve degeneration, paravalvular leak, infection, or other reasons. However, in-depth data on indications and outcomes are lacking. Methods Data from a multicenter, international registry (EXPLANT-TAVR) of patients who underwent TAVR explantation were reviewed retrospectively. Explantations performed during the same admission as initial TAVR were excluded. Clinical and echocardiographic outcomes were evaluated. Median follow-up duration was 6.7 months (interquartile range [IQR]: 1.0-18.8 months) after TAVR explantation and was 97.7% complete at 30 days and 86.1% complete at 1 year. Results From November 2009 to September 2020, 269 patients across 42 centers with a mean age of 72.7 ± 10.4 years underwent TAVR explantation. About one quarter (25.9%) were deemed low surgical risk at index TAVR, and median Society of Thoracic Surgeons risk at TAVR explantation was 5.6% (IQR: 3.2%-9.6%). The median time to explantation was 11.5 months (IQR: 4.0-32.4 months). Balloon-expandable and self-expanding or mechanically expandable valves accounted for 50.9% and 49.1%, respectively. Indications for explantation included endocarditis (43.1%), structural valve degeneration (20.1%), paravalvular leak (18.2%), and prosthesis-patient mismatch (10.8%). Redo TAVR was not feasible because of unfavorable anatomy in 26.8% of patients. Urgent or emergency cases were performed in 53.1% of patients, aortic root replacement in 13.4%, and 54.6% had concomitant cardiac procedures. Overall survival at last follow-up was 76.1%. In-hospital, 30-day, and 1-year mortality rates were 11.9%, 13.1%, and 28.5%, respectively, and stroke rates were 5.9%, 8.6%, and 18.7%, respectively. Conclusions The EXPLANT-TAVR registry reveals that surgical risks associated with TAVR explantation are not negligible and should be taken into consideration in the lifetime management of aortic stenosis.

Migraine is a disabling neurological disease characterized by moderate or severe headaches and accompanied by sensory abnormalities, e.g., photophobia, allodynia, and vertigo. It affects approximately 15% of people worldwide. Despite advancements in current migraine therapeutics, mechanisms underlying migraine remain elusive. Within the central nervous system, studies have hinted that the cerebellum may play an important sensory integrative role in migraine. More specifically, the cerebellum has been proposed to modulate pain processing, and imaging studies have revealed cerebellar alterations in migraine patients. This review aims to summarize the clinical and preclinical studies that link the cerebellum to migraine. We will first discuss cerebellar roles in pain modulation, including cerebellar neuronal connections with pain-related brain regions. Next, we will review cerebellar symptoms and cerebellar imaging data in migraine patients. Lastly, we will highlight the possible roles of the neuropeptide calcitonin gene-related peptide (CGRP) in migraine symptoms, including preclinical cerebellar studies in animal models of migraine.

Calcitonin gene-related peptide (CGRP) is involved in several of the pathophysiological processes underpinning migraine attacks. Therapies that target CGRP or its receptor have shown efficacy as preventive or acute treatments for migraine. Two small-molecule CGRP receptor antagonists (rimegepant and ubrogepant) are approved for the acute treatment of migraine, and four monoclonal antibodies (eptinezumab, erenumab, fremanezumab, and galcanezumab) are approved for migraine prevention; erenumab targets the canonical CGRP receptor, the others CGRP ligand. CGRP plays a role in gastrointestinal nociception, inflammation, gastric acid secretion, and motility. Nausea and vomiting are among the gastrointestinal symptoms associated with migraine, but individuals with migraine may also experience functional upper and lower gastrointestinal comorbidities, such as gastroesophageal reflux disease, gastroparesis, functional diarrhea or constipation, and irritable bowel syndrome. Although gastrointestinal symptoms in migraine can be treatment-related, they may also be attributable to increased CGRP. In this review, we summarize the epidemiological evidence for associations between migraine and gastrointestinal disorders, consider the possible physiological role of CGRP in these associations, and review the clinical occurrence of gastrointestinal events in patients with migraine receiving CGRP-based therapies and other migraine treatments. Because patients with migraine are at an increased risk of comorbid and treatment-related gastrointestinal effects, we also propose a patient-management strategy to mitigate these effects.

Migraine involves brain hypersensitivity with episodic dysfunction triggered by behavioral or physiological stressors. During an acute migraine attack the trigeminal nerve is activated (peripheral sensitization). This leads to central sensitization with activation of the central pathways including the trigeminal nucleus caudalis, the trigemino-thalamic tract, and the thalamus. In episodic migraine the sensitization process ends with the individual act, but with chronic migraine central sensitization may continue interictally. Increased allostatic load, the consequence of chronic, repeated exposure to stressors, leads to central sensitization, lowering the threshold for future neuronal activation (hypervigilance). Ostensibly innocuous stressors are then sufficient to trigger an attack. Medications that reduce sensitization may help patients who are hypervigilant and help to balance allostatic load. Acute treatments and drugs for migraine prevention have traditionally been used to reduce attack duration and frequency. However, since many patients do not fully respond, an unmet treatment need remains. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in nociception and in the sensitization of peripheral and central neurons of the trigeminovascular system, which is implicated in migraine pathophysiology. Elevated CGRP levels are associated with dysregulated signaling in the trigeminovascular system, leading to maladaptive responses to behavioral or physiological stressors. CGRP may, therefore, play a key role in the underlying pathophysiology of migraine. Increased understanding of the role of CGRP in migraine led to the development of small-molecule antagonists (gepants) and monoclonal antibodies (mAbs) that target either CGRP or the receptor (CGRP-R) to restore homeostasis, reducing the frequency, duration, and severity of attacks. In clinical trials, US Food and Drug Administration-approved anti-CGRP-R/CGRP mAbs were well tolerated and effective as preventive migraine treatments. Here, we explore the role of CGRP in migraine pathophysiology and the use of gepants or mAbs to suppress CGRP-R signaling via inhibition of the CGRP ligand or receptor. Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00250-7., Plain Language Summary Migraine is a neurological disease affecting one in eight people. Symptoms include nausea and/or sensitivity to light and sound, and a throbbing headache. Although certain genes may increase the likelihood of migraine, environmental stimuli and molecules that increase the sensitivity of brain blood vessels and their innervations also play a role. During a migraine attack, nerves in the brain are activated, leading to increased sensitivity to stimuli, lowering the future threshold for activation, and making patients hypervigilant. Chronic, repeated exposure to certain stimuli can also lower this activation threshold, such that relatively innocuous stimuli can trigger an attack. Excessive use of certain migraine treatments can increase headache frequency over time and produce unwanted side effects; thus, selective agents are needed that specifically target the systems and pathways affected in migraine pathophysiology. Calcitonin gene-related peptide (CGRP), produced and released by nerve cells, is important in migraine pathophysiology. CGRP binds smooth muscle cell receptors, dilating blood vessels supplying the brain, and also binds to peripheral nerve cells that transmit pain signals to the spinal cord and brain. CGRP levels are elevated during a migraine attack. Medications targeting the CGRP pathway may decrease sensitivity and potentially normalize responses in hypervigilant patients. Two commercially available oral drugs that block CGRP receptors (‘gepants’) have reduced symptoms during migraine attacks in clinical trials. Four monoclonal antibodies (proteins that bind a specific molecule) have also been developed that target CGRP or the receptor and have been shown to significantly reduce the number of migraine days per month. Role of CGRP in Migraine Supplementary Information The online version contains supplementary material available at 10.1007/s40120-021-00250-7.

Introduction Recent guidelines suggest a limited duration of triple antithrombotic therapy (TAT) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) at elevated bleeding risk. Indeed, in patients who are also at elevated thrombotic risk and with indication to prolonged dual antiplatelet therapy, percutaneous left atrial appendage closure (LAAC) could be a possible safe and effective option to prevent both bleeding and thrombotic events. Methods retrospective single–center study enrolling all consecutive patients between September 2012 and February 2020, comparing patients deemed at increased thrombotic and bleeding risk who received LAA percutaneous closure to avoid TAT before or after PCI with patients who received TAT after PCI. The aim of the study was to establish the safety and efficacy of LAAC in comparison to TAT. Results A total of 168 patients were included in the study: 56 underwent percutaneous LAAC while 112 were discharged in TAT. Median age was 75 (69–79). TAT patients had a CHA2DS2–VASc score of 4 (3–5) and a mean HAS–BLED score of 3 (2–3), whereas in LAAC patients the mean CHA2DS2–VASc was 4.9 (±1.5) and the mean HAS–BLED was 3.9 (±0.9); the difference in Score Points was statistically significant (p=0.001). The population who underwent LAAC was characterized by a remarkable procedural PCI complexity with a mean DAPT score of 1.4 (±1.3), with respect to the population discharged in TAT which was 0 (0–2). At follow–up (mean follow–up period in days: 727 [489–1000]), four bleeding episodes were recorded in LAAC population in comparison to 16 bleeding episodes observed in TAT population (12.6% vs. 15.4%; p–value=0.142): two bleeding episodes were major in LAAC group and five in TAT group (3.6% vs. 4.8%; p–value=1). One case of stroke (1.8%) occurred in LAAC population and two cases (1.8%) in TAT population (p=1.000). Conclusions In a single–centre retrospective study no significant difference was observed in terms of bleeding between TAT and LAAC, in patients at high ischemic and thrombotic risk with indication to prolonged dual antiplatelet therapy after PCI and anticoagulation for AF. Nevertheless, the non statistical trend to reduction of bleeding events in LAAC group might be explored in a larger study population.

Introduction Mid Ventricular (MVO) and Left Ventricular Outflow Tract Obstruction (LVOTO) after Trans–catheter Aortic Valve Implantation (TAVI) have been previously described and are associated with adverse outcome. Pre–procedural identification of patient at risk of MVO and LVOTO after TAVI may help pre–operative risk stratification and patient selection and facilitate intra–operative management, finally improving clinical outcomes. This study aims to identify CT–scan and Echocardiographic predictors of Left Ventricular Obstruction (LVO), defined as the composite of MVO and LVOTO. Methods We retrospectively reviewed pre–operative CT scans and Trans–Thoracic Echocardiography of 349 patients treated with TAVI at our Centre between January 2019 and December 2021. Correlations between post–operative development of MVO and LVOTO and pre–operative Echocardiographic and CT scan measurements were tested. Results LVO occurred in 16.3% of patients after TAVI. At univariate analysis clinical factors associated to LVO were female gender (OR=2.2, p=0.006) and body surface area (OR=0.19, p=0.006); pre–procedural echocardiographic parameters identified were end–diastolic–diameter (OR=0.89, p Conclusions Left ventricle obstruction (LVOTO + MVO) after TAVI can be predicted by CT scan derived parameters. Pre–procedural identification of patients at risk may help intraprocedural and postprocedural management, thus improving clinical outcomes.

[EN]: Introduction: The COVID-19 pandemic outbreak introduced dramatic changes in all our lives, daily practice, and medical conferences. In search of a tool to spread dermatologic knowledge during confinement, an online medical meeting was held on April 25th to 26th, 2020. In this study, we aimed to assess the characteristics, opinion and satisfaction of the attendees to a free-of-charge online congress. Secondarily, we intended to explain how this meeting was prepared. Material and Methods: Online survey administered to the attendees to an online congress organised via the Telegram® Messenger App. Its organisation and planning, which needed no financial support and was done by volunteer organisers, moderators and speakers, is described step by step. Results: The satisfaction of both speakers and attendees was very high. All participants considered that this format had a great present and future, and most of them rated it as superior to regular face-to-face meetings. Female gender and predominantly private practice favoured this opinion. Discussion: The COVID-19 pandemic has forced the cancellation of most scientific gatherings. This has been seen by some authors as an excellent opportunity, encouraging medical societies and organisations to lead the change to virtual meetings. Although confinement did not allow real contact, our online meeting showed it was possible to ensure interaction and participation between attendees, moderators and speakers. Dermatologists enjoyed some dermatologic science, even despite the extraordinary circumstances disrupting their daily clinical practice. Most of them felt they were participating in something new and compelling that many felt superior to traditional meetings., [ES]: Introducción: La pandemia de COVID-19 introdujo cambios drásticos en nuestras vidas. Tratando de encontrar una herramienta adecuada para la formación y el debate dermatológico durante el confinamiento, se celebró un congreso médico on-line durante los días 25 y 26 de abril del 2020. El objetivo del presente estudio fue evaluar las características, la opinión y el grado de satisfacción de los asistentes a dicho congreso. En segundo lugar, se buscó explicar cómo se organizó este formato de reunión. Material y métodos: Se entregó un cuestionario a los asistentes a un congreso on-line realizado a través de la aplicación Telegram® Messenger App. Se describió paso a paso su organización y planificación. No se necesitó apoyo financiero, ya que fue realizado de manera voluntaria. Resultados: El grado de satisfacción tanto de los ponentes como de los asistentes fue muy elevado. Todos los participantes consideraron que este formato tenía un gran presente y futuro. La mayoría lo calificó como superior a las reuniones presenciales tradicionales. Ser del sexo femenino y tener una práctica clínica predominantemente privada favorecieron esta opinión. Discusión: La pandemia obligó a cancelar la mayoría de las reuniones científicas presenciales. Esto fue visto por algunos autores como una excelente oportunidad para mejorar y liderar el cambio a las reuniones virtuales. Aunque el confinamiento no permitió un contacto real, nuestra reunión demostró que era posible asegurar la interacción entre los participantes. Los dermatólogos pudieron participar en una actividad formativa a pesar de que debido a las circunstancias se interrumpiera su actividad práctica diaria. La mayoría de los asistentes tuvieron la sensación de que esta era una actividad nueva y atractiva, que superaba incluso a las reuniones presenciales tradicionales.

Introduction: The COVID-19 pandemic outbreak introduced dramatic changes in all our lives, daily practice, and medical conferences. In search of a tool to spread dermatologic knowledge during confinement, an online medical meeting was held on April 25th to 26th, 2020. In this study, we aimed to assess the characteristics, opinion and satisfaction of the attendees to a free-of-charge online congress. Secondarily, we intended to explain how this meeting was prepared. Material and Methods: Online survey administered to the attendees to an online congress organised via the Telegram® Messenger App. Its organisation and planning, which needed no financial support and was done by volunteer organisers, moderators and speakers, is described step by step. Results: The satisfaction of both speakers and attendees was very high. All participants considered that this format had a great present and future, and most of them rated it as superior to regular face-to-face meetings. Female gender and predominantly private practice favoured this opinion. Discussion: The COVID-19 pandemic has forced the cancellation of most scientific gatherings. This has been seen by some authors as an excellent opportunity, encouraging medical societies and organisations to lead the change to virtual meetings. Although confinement did not allow real contact, our online meeting showed it was possible to ensure interaction and participation between attendees, moderators and speakers. Dermatologists enjoyed some dermatologic science, even despite the extraordinary circumstances disrupting their daily clinical practice. Most of them felt they were participating in something new and compelling that many felt superior to traditional meetings. Yes Introducción: La pandemia de COVID-19 introdujo cambios drásticos en nuestras vidas. Tratando de encontrar una herramienta adecuada para la formación y el debate dermatológico durante el confinamiento, se celebró un congreso médico on-line durante los días 25 y 26 de abril del 2020. El objetivo del presente estudio fue evaluar las características, la opinión y el grado de satisfacción de los asistentes a dicho congreso. En segundo lugar, se buscó explicar cómo se organizó este formato de reunión. Material y métodos: Se entregó un cuestionario a los asistentes a un congreso on-line realizado a través de la aplicación Telegram® Messenger App. Se describió paso a paso su organización y planificación. No se necesitó apoyo financiero, ya que fue realizado de manera voluntaria. Resultados: El grado de satisfacción tanto de los ponentes como de los asistentes fue muy elevado. Todos los participantes consideraron que este formato tenía un gran presente y futuro. La mayoría lo calificó como superior a las reuniones presenciales tradicionales. Ser del sexo femenino y tener una práctica clínica predominantemente privada favorecieron esta opinión. Discusión: La pandemia obligó a cancelar la mayoría de las reuniones científicas presenciales. Esto fue visto por algunos autores como una excelente oportunidad para mejorar y liderar el cambio a las reuniones virtuales. Aunque el confinamiento no permitió un contacto real, nuestra reunión demostró que era posible asegurar la interacción entre los participantes. Los dermatólogos pudieron participar en una actividad formativa a pesar de que debido a las circunstancias se interrumpiera su actividad práctica diaria. La mayoría de los asistentes tuvieron la sensación de que esta era una actividad nueva y atractiva, que superaba incluso a las reuniones presenciales tradicionales.

The neuropeptide calcitonin gene-related peptide (CGRP) is expressed in the trigeminal ganglia, a key site in craniofacial pain and migraine. CGRP potently activates two receptors: the CGRP receptor and the AMY1 receptor. These receptors are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with either the calcitonin receptor-like receptor (CLR) to form the CGRP receptor or the calcitonin receptor (CTR) to form the AMY1 receptor. The expression of the CGRP receptor in trigeminal ganglia has been described in several studies; however, there is comparatively limited data available describing AMY1 receptor expression and in which cellular subtypes it is found. This research aimed to determine the relative distributions of the AMY1 receptor subunit, CTR, and CGRP in neurons or glia in rat, mouse and human trigeminal ganglia. Antibodies against CTR, CGRP and neuronal/glial cell markers were applied to trigeminal ganglia sections to investigate their distribution. CTR-like and CGRP-like immunoreactivity were observed in both discrete and overlapping populations of neurons. In rats and mice, 30–40% of trigeminal ganglia neurons displayed CTR-like immunoreactivity in their cell bodies, with approximately 78–80% of these also containing CGRP-like immunoreactivity. Although human cases were more variable, a similar overall pattern of CTR-like immunoreactivity to rodents was observed in the human trigeminal ganglia. CTR and CGRP appeared to be primarily colocalized in small to medium sized neurons, suggesting that colocalization of CTR and CGRP may occur in C-fiber neurons. CGRP-like or CTR-like immunoreactivity were not typically observed in glial cells. Western blotting confirmed that CTR was expressed in the trigeminal ganglia of all three species. These results confirm that CTR is expressed in trigeminal ganglia neurons. The identification of populations of neurons that express both CGRP and CTR suggests that CGRP could act in an autocrine manner through a CTR-based receptor, such as the AMY1 receptor. Overall, this suggests that a trigeminal ganglia CTR-based receptor may be activated during migraine and could therefore represent a potential target to develop treatments for craniofacial pain and migraine.

Aims Recent evidences have shown that transcatheter heart valve (THV) anchoring in BAV patients might occur at the raphe–level, known as the LIRA (Level of Implantation at the RAphe) plane. A novel supra–annular sizing method based on the measurement of the perimeter at the raphe–level (LIRA–method) was shown to be safe and effective in 20 consecutive BAV patients with severe aortic stenosis. The purpose of this study was to confirm the safety and the efficacy of the LIRA method in a larger study population. Methods the LIRA plane method was applied to all consecutive patients with raphe–type BAV disease between November 2018 to October 2021 in our centre. We prospectively sized TAVI prosthesis according to the manufacture recommendations on the basis of baseline CT scan perimeters at the LIRA plane. Post–procedural device success, defined according to Valve Academic Research Consortium–2 (VARC–2) criteria, was evaluated in the overall cohort. Results 50 patients were identified as having a raphe–type BAV disease at pre–TAVI CT scans. Mean patient age was 80 ± 6.2 years. Three different BAV anatomies (47 patients with BAV type 1 and 3 patients with BAV type 2) were implanted with different types of TAVI prostheses (28 Acurate Neo/Neo 2, 21 Core Valve Evolut R/Pro,1 Lotus) sized prospectively according to the LIRA plane method. In all patients, there was a significant discrepancy between LIRA and virtual basal ring (VBR) (mean perimeter LIRA 73.1 ± 8.3 mm vs mean perimeter VBR 81.5 ± 6.6 mm; p 20 mmHg pre–discharge. The rate of new pacemaker implantation was 10%. Conclusions Supra–annular sizing according to the LIRA plane method confirmed to be safe with a high device success in a larger study population. The application of the LIRA plane method might optimize TAVI prosthesis sizing in patients with raphe–type BAV disease.

Background Calcitonin gene-related peptide is recognized as a key player in migraine, yet the mechanisms and sites of calcitonin gene-related peptide action remain unknown. The efficacy of calcitonin gene-related peptide-blocking antibodies as preventative migraine drugs supports a peripheral site of action, such as the trigeminovasculature. Given the apparent disconnect between the importance of vasodilatory peptides in migraine and the prevailing opinion that vasodilation is an epiphenomenon, the goal of this study was to test whether vasodilation plays a role in calcitonin gene-related peptide-induced light aversive behavior in mice. Methods Systemic mean arterial pressure and light aversive behavior were measured after intraperitoneal administration of calcitonin gene-related peptide and vasoactive intestinal peptide in wild-type CD1 mice. The functional significance of vasodilation was tested by co-administration of a vasoconstrictor (phenylephrine, endothelin-1, or caffeine) with calcitonin gene-related peptide to normalize blood pressure during the light aversion assay. Results Both calcitonin gene-related peptide and vasoactive intestinal peptide induced light aversion that was associated with their effect on mean arterial pressure. Notably, vasoactive intestinal peptide caused relatively transient vasodilation and light aversion. Calcitonin gene-related peptide-induced light aversion was still observed even with normalized blood pressure. However, two of the agents, endothelin-1 and caffeine, did reduce the magnitude of light aversion. Conclusion We propose that perivascular calcitonin gene-related peptide causes light-aversive behavior in mice by both vasomotor and non-vasomotor mechanisms.

Migraine is the most common neurological disorder in the world, affecting 12% of the population. Migraine involves the central nervous system, trigeminal nerves and meninges. Recent advances have shown that targeting calcitonin gene-related peptide (CGRP) through either antibodies or small molecule receptor antagonists is effective at reducing episodic and chronic migraine episodes, but these therapeutics are not effective in all patients. This suggests that migraine does not have a singular molecular cause but is likely due to dysregulated physiology of multiple mechanisms. An often-overlooked part of migraine is the potential involvement of the immune system. Clinical studies have shown that migraine patients may have dysregulation in their immune system, with abnormal plasma cytokine levels either during the attack or at baseline. In addition, those who are immunocompromised appear to be at a higher risk of migraine-like disorders. A recent study showed that migraine caused changes to transcription of immune genes in the blood, even following treatment with sumatriptan. The dura mater is densely packed with macrophages, mast and dendritic cells, and they have been found to associate with meningeal blood vessels and trigeminal afferent endings. Recent work in mice shows activation and morphological changes of these cells in rodents following the migraine trigger cortical spreading depression. Importantly, each of these immune cell types can respond directly to CGRP. Since immune cells make up a large portion of the dura, have functional responses to CGRP, and interact with trigeminal afferents, CGRP actions on the dural immune system are likely to play key roles in migraine.

The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. Previous preclinical studies demonstrated that intracerebroventricular administration of CGRP caused migraine-like behaviors in mice, but the sites of action in the brain remain unidentified. The cerebellum has the most CGRP binding sites in the central nervous system and is increasingly recognized as both a sensory and motor integration center. The objective of this study was to test whether the cerebellum, particularly the medial cerebellar nuclei (MN), might be a site of CGRP action. In this study, CGRP was directly injected into the right MN of C57BL/6J mice via a cannula. A battery of behavioral tests was done to assess migraine-like behaviors. CGRP caused light aversion measured as decreased time in the light zone even with dim light. The mice also spent more time resting in the dark zone, but not the light, along with decreased rearing and transitions between zones. These behaviors were similar for both sexes. In contrast, significant responses to CGRP were seen only with female mice in the open field assay, von Frey test, and automated squint assay, indicating anxiety, tactile hypersensitivity, and spontaneous pain, respectively. In male mice, the responses had the same trend as females but did not reach statistical significance. No detectable effect of CGRP on gait was observed in either sex. These results suggest that CGRP in the MN causes light aversion in males, while in females, light aversion is accompanied by increased anxiety, tactile hypersensitivity, and spontaneous pain. A caveat is that we cannot exclude contributions from other cerebellar regions in addition to the MN due to diffusion of the injected peptide. These results reveal the cerebellum as a new site of CGRP actions that may contribute to migraine pathophysiology and possibly its prevalence in females.

The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. Previous preclinical studies demonstrated that intracerebroventricular administration of CGRP caused migraine-like behaviors in mice, but the sites of action in the brain remain unidentified. The cerebellum has the most CGRP binding sites in the central nervous system and is increasingly recognized as both a sensory and motor integration center. The objective of this study was to test whether the cerebellum, particularly the medial cerebellar nuclei (MN), might be a site of CGRP action. In this study, CGRP was directly injected into the right MN of C57BL/6J mice via a cannula. A battery of tests was done to assess preclinical behaviors that are surrogates of migraine-like symptoms. CGRP caused light aversion measured as decreased time in the light zone even with dim light. The mice also spent more time resting in the dark zone, but not the light, along with decreased rearing and transitions between zones. These behaviors were similar for both sexes. Moreover, significant responses to CGRP were seen in the open field assay, von Frey test, and automated squint assay, indicating anxiety, tactile hypersensitivity, and spontaneous pain, respectively. Interestingly, CGRP injection caused significant anxiety and spontaneous pain responses only in female mice, and a more robust tactile hypersensitivity in female mice. No detectable effect of CGRP on gait was observed in either sex. These results suggest that CGRP injection in the MN causes light aversion accompanied by increased anxiety, tactile hypersensitivity, and spontaneous pain. A caveat is that we cannot exclude contributions from other cerebellar regions in addition to the MN due to diffusion of the injected peptide. These results reveal the cerebellum as a new site of CGRP actions that may contribute to migraine-like hypersensitivity.

Voltage-gated Cav Ca2+ channels are critical for the development and mature function of the nervous system. Variants in the CACNA2D4 gene encoding the α2δ-4 auxiliary subunit of these channels are associated with neuropsychiatric and neurodevelopmental disorders. α2δ-4 is prominently expressed in the retina and is crucial for vision, but extra-retinal functions of α2δ-4 have not been investigated. Here, we sought to fill this gap by analyzing the behavioral phenotypes of α2δ-4 knockout (KO) mice. α2δ-4 KO mice (both males and females) exhibited significant impairments in prepulse inhibition that were unlikely to result from the modestly elevated auditory brainstem response thresholds. Whereas α2δ-4 KO mice of both sexes were hyperactive in various assays, only females showed impaired motor learning/coordination in the rotarod assay. Female but not male α2δ-4 KO mice exhibited anxiolytic and anti-depressive behaviors in the elevated plus maze and tail suspension tests, respectively. Our results reveal an unexpected role for α2δ-4 in cognitive and motor function and identify α2δ-4 KO mice as a novel model for studying the pathophysiology associated with CACNA2D4 variants.

We bound EFT coefficients appearing in $2 \to 2$ photon scattering amplitudes in four dimensions. After reviewing unitarity and positivity conditions in this context, we use dispersion relations and crossing symmetry to compute sum rules and null constraints. This allows us to derive new rigorous bounds on operators with four, six, and eight derivatives, including two-sided bounds on their ratios. Comparing with a number of partial UV completions, we find that some of our bounds are saturated by the amplitudes that arise from integrating out a massive scalar or axion, while others suggest the existence of unknown amplitudes., 39 pages, 6 figures

The ASTRI Mini-Array (MA) is an INAF project to build and operate a facility to study astronomical sources emitting at very high-energy in the TeV spectral band. The ASTRI MA consists of a group of nine innovative Imaging Atmospheric Cherenkov telescopes. The telescopes will be installed at the Teide Astronomical Observatory of the Instituto de Astrofisica de Canarias (IAC) in Tenerife (Canary Islands, Spain) on the basis of a host agreement with INAF. Thanks to its expected overall performance, better than those of current Cherenkov telescopes' arrays for energies above \sim 5 TeV and up to 100 TeV and beyond, the ASTRI MA will represent an important instrument to perform deep observations of the Galactic and extra-Galactic sky at these energies., 19 pages, 22 figures

Calcitonin gene-related peptide (CGRP) is a key component of migraine pathophysiology, yielding effective migraine therapeutics. CGRP receptors contain a core accessory protein subunit: receptor activity-modifying protein 1 (RAMP1). Understanding of RAMP1 expression is incomplete, partly due to the challenges in identifying specific and validated antibody tools. We profiled antibodies for immunodetection of RAMP1 using Western blotting, immunocytochemistry and immunohistochemistry, including using RAMP1 knockout mouse tissue. Most antibodies could detect RAMP1 in Western blotting and immunocytochemistry using transfected cells. Two antibodies (844, ab256575) could detect a RAMP1-like band in Western blots of rodent brain but not RAMP1 knockout mice. However, cross-reactivity with other proteins was evident for all antibodies. This cross-reactivity prevented clear conclusions about RAMP1 anatomical localization, as each antibody detected a distinct pattern of immunoreactivity in rodent brain. We cannot confidently attribute immunoreactivity produced by RAMP1 antibodies (including 844) to the presence of RAMP1 protein in immunohistochemical applications in brain tissue. RAMP1 expression in brain and other tissues therefore needs to be revisited using RAMP1 antibodies that have been comprehensively validated using multiple strategies to establish multiple lines of convincing evidence. As RAMP1 is important for other GPCR/ligand pairings, our results have broader significance beyond the CGRP field.

A membrane can be defined as a selective barrier which separates two phases, regulating the transport of various chemical species between the two compartments. Specifically, it is possible to distinguish homogeneous or heterogeneous membranes, with symmetric or asymmetric structure or again they may be positive or negative superficial charges, etc. Therefore the term "membrane" includes several types of membrane materials and membrane morphologies. Today, membrane processes are employed in a wide range of applications thanks to their advantageous separation/concentration/fractionation properties, and to the possibility of exploiting the synergy between different membrane operations in an integrated system. Recently, much research has been devoted to biorefinery, defined as the sustainable transformation of biomass into a spectrum of bio-based products (food, feed, materials, and chemicals) and bioenergy (biofuels, energy, and heat). In this context, membrane technology represents an optimal solution thanks to its important advantages as low energy consumption, low processing operations, and high separation efficiency. Indeed, membranes can be successfully applied in biorefinery for several separation processes such as microfiltration, ultrafiltration, nanofiltration, pervaporation (PV), and membrane distillation (MD). In this chapter the attention will be focused on PV and MD processes. In particular, a general overview of PV and MD processes will be treated and their applications in biorefinery will be discussed in detail.

A multiscale mathematical model is presented to describe the de novo granulation and the evolution of multispecies granular biofilms within a continuous reactor. The granule is modelled as a spherical free boundary domain with radial symmetry. The equation which governs the free boundary is derived from global mass balance considerations and takes into account the growth of sessile biomass and the exchange fluxes with the bulk liquid. Starting from a vanishing initial value, the expansion of the free boundary is initiated by the attachment process, which depends on the microbial species concentrations within the bulk liquid and their specific attachment velocity. Nonlinear hyperbolic PDEs model the growth of the sessile microbial species, while quasi-linear parabolic PDEs govern the dynamics of substrates and invading species within the granular biofilm. Nonlinear ODEs govern the evolution of soluble substrates and planktonic biomass within the bulk liquid. The model is applied to an anaerobic granular-based system and solved numerically to test its qualitative behaviour and explore the main aspects of de novo anaerobic granulation: ecology, biomass distribution, relative abundance, dimensional evolution of the granules and soluble substrates and planktonic biomass dynamics within the reactor. The numerical results confirm that the model accurately describes the ecology and the concentrically-layered structure of anaerobic granules observed experimentally, and is able to predict the effects of some significant factors, such as influent wastewater composition, granulation properties of planktonic biomass, biomass density and hydrodynamic and shear stress conditions, on the process performance., Comment: 41 pages, 21 figures, preprint version

The 87Sr/86Sr isotope ratio can, in principle, be used for provenancing of cement. However, while commercial cements consist of multiple components, no detailed investigation into their individual 87Sr/86Sr isotope ratios or their influence on the integral 87Sr/86Sr isotope ratio of the resulting cement was conducted previously. Therefore, the present study aimed at determining and comparing the conventional 87Sr/86Sr isotope ratios of a diverse set of Portland cements and their corresponding Portland clinkers, the major component of these cements. Two approaches to remove the additives from the cements, i.e. to measure the conventional 87Sr/86Sr isotopic fingerprint of the clinker only, were tested, namely, treatment with a potassium hydroxide/sucrose solution and sieving on a 11-µm sieve. Dissolution in concentrated hydrochloric acid/nitric acid and in diluted nitric acid was employed to determine the 87Sr/86Sr isotope ratios of the cements and the individual clinkers. The aim was to find the most appropriate sample preparation procedure for cement provenancing, and the selection was realised by comparing the 87Sr/86Sr isotope ratios of differently treated cements with those of the corresponding clinkers. None of the methods to separate the clinkers from the cements proved to be satisfactory. However, it was found that the 87Sr/86Sr isotope ratios of clinker and cement generally corresponded, meaning that the latter can be used as a proxy for the clinker 87Sr/86Sr isotope ratio. Finally, the concentrated hydrochloric acid/nitric acid dissolution method was found to be the most suitable sample preparation method for the cements; it is thus recommended for 87Sr/86Sr isotope analyses for cement provenancing. Graphical abstract