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Familial adult myoclonus epilepsy (FAME) management relies on antiseizure medications (ASMs), which inadequately address myoclonus and cortical tremor. This study evaluates Perampanel (PER), an AMPA-receptor antagonist, for treating FAME symptoms. Fifteen FAME2 patients participated in an observational prospective study. They received up to 6 mg daily of PER and underwent Unified-Myoclonus-Rating-Scale (UMRS) before and after treatment. Neurophysiological evaluations, including somatosensory evoked potentials (SEPs) and transcranial magnetic stimulation (TMS), assessed PER's impact on cortical glutamatergic excitatory and GABAergic inhibitory circuits. PER treatment significantly reduced UMRS total scores (p = 0.001) and action-myoclonus subscores (p = 0.002), irrespective of disease duration, age at onset, or testing time (p >0.05). Patients with more severe baseline myoclonus demonstrated significant improvements. Neurophysiological assessments revealed a PER-induced decrease in sensorimotor hyperexcitability, characterized by diminished N33 amplitudes, attenuated glutamatergic facilitation, and enhanced GABAergic inhibition in the motor cortex. In conclusion, low-dose PER is well tolerated and effective in alleviating myoclonus in FAME2 patients, supported by its modulatory effects on glutamatergic and GABAergic neuronal circuits. Plain Language Summary: This study investigated the effects of low-dose perampanel in individuals with Familial Adult Myoclonus Epilepsy2 (FAME2), a hereditary condition characterized by epilepsy and tremors. Perampanel, an antiepileptic drug, blocks AMPA receptors in the brain, reducing excessive neural activity that causes seizures and abnormal movements. The results showed significant symptom improvement, which correlated with changes in brain activity as measured by neurophysiological tests. This study suggests that perampanel helps regulate abnormal brain signals and may help managing FAME2 symptoms., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known., Methods: We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45 + cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks., Results: ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout-Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibition in this model., Conclusions: Using single-cell RNA sequencing in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF., Competing Interests: None.

This study aimed to evaluate the impact of Fabry disease (FD) on retinal microvasculature using optical coherence tomography angiography (OCTA), arterial stiffness, and the resistive index (RI) of the central retinal artery (CRA) in early disease stages. Twenty-nine genetically confirmed FD patients and twenty-six healthy controls were enrolled. Vessel density (VD) values of the superficial, deep, and choriocapillaris plexuses (SCP, DCP, and CC) were measured via OCTA. CRA RI was studied using color Doppler and grayscale sonography, and aortic pulse wave velocity (PWV) was assessed with the Complior method. CRA RI was significantly lower in the control group compared to the Fabry group (p < 0.001). Central VD was found to be significantly higher in the control group compared to the Fabry group in all the retinal layers (SCP (p < 0.001), DCP (p < 0.005), CC (p < 0.001)). PWV was significantly higher in the Fabry group than in the control group (p = 0.03). Fabry disease patients demonstrate elevated arterial stiffness, increased CRA RI, and diminished retinal microvascular density compared to healthy controls, indicating early ocular damage. Continuous monitoring and targeted screening for organ impairment are crucial in FD management. Identifying biomarkers for assessing ocular vascular involvement and treatment response is imperative. Further research is needed., (© 2024. The Author(s).)

Introduction: Surgery is still the main line of treatment for papillary thyroid cancer (PTC) with a current trend for de-intensified treatment based on an excellent prognosis. The role of a routine prophylactic central neck dissection (PCND) is still debated as its impact on oncologic outcomes has never been cleared by a randomized clinical trial. In this study, we aimed to report our long-standing experience in PCND and its potential contemporary role in the treatment of PTC., Methods: A retrospective institutional review was performed on all patients who underwent operation for PTC including PCND between 1998 and 2021. The primary outcomes were the rate of central lymph node metastases (CLNMs), cancer recurrence and incidence of complications. Survivals were analyzed using the Kaplan-Meier estimator and Cox proportional hazard models., Results: A total of 657 patients were included in this study with a median follow-up of 78 months (48-114 months). Two hundred and one patients presented occult CLNMs (30.6%). The presence of a pathological node represented the unique reason for a completion thyroidectomy and I 131 therapy in 12.5% of the population. Age lower than 55 years, microscopic or macroscopic extra-thyroid extension (ETE) and multifocality were independent factors predicting CLNMs. The rate of recurrence in the whole population was 2.7% (18 patients). Five-year and ten-year disease-free survival (DFS) was 96.5% (94.7-97.7) and 93.3% (90.3-95.5), respectively. Two patients relapsed in the central neck compartment (0.3%). Age (>55 years), pathological staging (pT) and extranodal extension (ENE) were independent factors associated with a worse DFS. The rate of temporary and permanent vocal fold palsy was 12.8% and 1.8%, respectively, and did not depend on the type of surgical procedure performed. Hypoparathyroidism was temporary in 42.2% and permanent in 11.9% of the patients. A sub-analysis upon cT1b-T2 patients treated primarily with thyroid lobectomy and ipsilateral PCND demonstrated a 2.6% rate of permanent hypoparathyroidism., Conclusions: PCND allows for a high disease-free survival and a proper selection of patients needing adjuvant treatment, in particular, those treated with a unilateral procedure. On the other hand, bilateral approach is burdened by a not-neglectable rate of permanent hypoparathyroidism.

Aims: The Italian Fabry Disease Cardiovascular Registry (IFDCR) comprises 50 Italian centres with specific expertise in managing cardiovascular manifestations and complications of patients with Fabry disease (FD). The primary aim of the IFDCR is to examine and improve the clinical care and outcomes of patients with FD by addressing several knowledge gaps in the epidemiology, natural history, genotype-phenotype correlations, diagnosis, and management of this condition, with particular focus on cardiovascular manifestations and complications., Methods and Results: The IFDCR is an international, longitudinal, multicentre, non-interventional, observational study. Consecutive patients aged ≥2 years with a diagnosis of FD will be included in the study. The recruitment period consists of two parts: the retrospective enrolment period, from January 1981 to December 2023, and the prospective enrolment period, spanning from January 2024 to December 2031. The registry collects baseline and follow-up data, including the enrolment setting, patient demographics, family history, symptoms, clinical manifestations, electrocardiogram, cardiovascular imaging, laboratory assessment, medical therapy, genetic testing results, and outcomes., Conclusions: The IFDCR is a national, multicentre, registry that includes patients with FD. It holds detailed and multiparametric data across the patient pathway and clinical manifestations, acting as a powerful tool for improving the quality of care and conducting high-impact research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: A compromised cardiac autonomic function has been found in subjects with insulin resistance related disorders such as obesity, impaired glucose tolerance (IGT) and type 2 diabetes and confers an increased risk of adverse cardiovascular outcomes. Growing evidence indicate that 1 h plasma glucose levels (1hPG) during an oral glucose tolerance test (OGTT) ≥ 155 mg/dl identify amongst subjects with normal glucose tolerance (NGT) a new category of prediabetes (NGT 1 h-high), harboring an increased risk of cardiovascular organ damage. In this study we explored the relationship between 1 h post-load hyperglycemia and cardiac autonomic dysfunction., Methods: Presence of cardiac autonomic neuropathy (CAN) defined by cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV), assessed by 24-h electrocardiography were evaluated in 88 non-diabetic subjects subdivided on the basis of OGTT data in: NGT with 1 h PG < 155 mg/dl (NGT 1 h-low), NGT 1 h-high and IGT., Results: As compared to subjects with NGT 1 h-low, those with NGT 1 h-high and IGT were more likely to have CARTs defined CAN and reduced values of the 24 h time domain HVR parameters including standard deviation of all normal heart cycles (SDNN), standard deviation of the average RR interval for each 5 min segment (SDANN), square root of the differences between adjacent RR intervals (RMSSD), percentage of beats with a consecutive RR interval difference > 50 ms (PNN50) and Triangular index. Univariate analyses showed that 1hPG, but not fasting and 2hPG, was inversely associated with all the explored HVR parameters and positively with CARTs determined presence of CAN. In multivariate regression analysis models including several confounders we found that 1hPG was an independent contributor of HRV and presence of CAN., Conclusion: Subjects with 1hPG ≥ 155 mg/dl have an impaired cardiac autonomic function., (© 2024. The Author(s).)

Aims: The aim of this study is to evaluate the effect of beta-blockers and angiotensin receptor blockers in reducing the aortic growth rate in children with bicuspid aortic valve (BAV)-related aortopathy and ascending phenotype., Methods: Consecutive paediatric patients (≤16 years) with BAV and ascending aorta (AsAo) dilation (z-score > 3) were enrolled in this observational retrospective cohort study. Patients receiving prophylactic treatment with either atenolol (0.5 to 1.0 mg/kg/daily) or losartan (0.7 to 1.4 mg/kg/daily) were compared with those who did not receive medical prophylaxis (control group). The primary outcome of interest was the annual rate of change in maximal AsAo diameter z-score in the treatment and control groups., Results: From a cohort of 1005 patients, 120 (mean age 11.3 ± 4.5 years, 82% males) fulfilled the inclusion criteria and were included in the study. Patients in the treatment and control group had similar age, sex, family history of BAV, BAV morphology, and baseline AsAo diameter. During a median follow-up of 7.1 years (interquartile range 3.8-10.2), no differences were observed in the annual growth rate of aortic diameter z-score between patients on treatment and controls. The prevalence of aortic diameter progression was similar in the treatment and control groups, and treatment with atenolol or losartan was not associated with a lower rate of aortic disease progression., Conclusions: The findings revealed no significant difference in the annual aortic growth rate between treated and untreated patients. Larger cohort studies or, ideally, randomized clinical controlled trials are needed to validate these findings., (Copyright © 2024. Published by Elsevier B.V.)

Aims: To utilize the estimated glucose disposal rate (eGDR) index of insulin sensitivity, which is based on readily available clinical variables, namely, waist circumference, hypertension and glycated haemoglobin, to discriminate between metabolically healthy and unhealthy phenotypes, and to determine the prevalence of prediabetic conditions., Methods: Non-diabetic individuals (n = 2201) were stratified into quartiles of insulin sensitivity based on eGDR index. Individuals in the upper quartiles of eGDR were defined as having metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW) or metabolically healthy obesity (MHO) according to their body mass index, while those in the lower quartiles were classified as having metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW) and metabolically unhealthy obesity (MUO), respectively., Results: The frequency of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and IFG + IGT status was comparable among the MHNW, MHOW and MHO groups, while it increased from those with MUNW status towards those with MUOW and MUO status. As compared with participants with MHNW, the odds ratio of having IFG, IGT, or IFG + IGT was significantly higher in participants with MUOW and MUO but not in those with MUNW, MHOW and MHO, respectively., Conclusions: A metabolically healthy phenotype is associated with lower frequency of IFG, IGT, and IFG + IGT status across all body weight categories., (© 2024 John Wiley & Sons Ltd.)

Introduction : The aim of this study was to evaluate the age at onset, clinical course, and patterns of left ventricular (LV) remodelling during follow-up in children and young patients with hypertrophic cardiomyopathy (HCM). Methods : We included consecutive patients with sarcomeric or non-syndromic HCM below 18 years old. Three pre-specified patterns of LV remodelling were assessed: maximal LV wall thickness (MLVWT) thickening; MLVWT thinning with preserved LV ejection fraction; and MLVWT thinning with progressive reduction in LV ejection fraction (hypokinetic end-stage evolution). Results : Fifty-three patients with sarcomeric/non-syndromic HCM (mean age 9.4 ± 5.5 years, 68% male) fulfilled the inclusion criteria. In total, 32 patients (60%) showed LV remodelling: 3 patients (6%) exhibited MLVWT thinning; 16 patients (30%) showed MLVWT thickening; and 13 patients (24%) progressed to hypokinetic end-stage HCM. Twenty-one patients (40%) had no LV remodelling during follow-up. In multivariate analysis, MLVWT was a predictor of the hypokinetic end-stage remodelling pattern during follow-up (OR 1.17 [95%CI 1.01-1.36] per 1 mm increase, p -value 0.043), regardless of sarcomeric variants and New York Heart Association class. Two patients with sarcomeric HCM, showing a pattern of MLVWT regression during childhood, experienced progression during adolescence. Conclusions : Different patterns of LV remodelling were observed in a cohort of children with sarcomeric/non-syndromic HCM. Interestingly, a pattern of progressive MLVWT thinning during childhood, with new progression of MLVWT during adolescence, was noted. A better understanding of the remodelling mechanisms in children with sarcomeric HCM may be relevant to defining the timing and possible efficacy of new targeted therapies in the preclinical stage of the disease.

Previous published studies have shown an improvement of penile hemodynamic parameters after low-intensity extracorporeal shockwave therapy (Li-ESWT). However, the clinical significance of these findings remains unclear, and definitive selection criteria for Li-ESWT based on preexisting comorbidities have yet to be established. This was an observational study of 113 patients with ED, evaluated between January 2019 and December 2021 in Andrology Unit at the Department of Urology and Renal Transplantation, University of Foggia (Foggia, Italy). Penile dynamic Doppler was performed to evaluate vascular parameters and 5-item version of the International Index of Erectile Dysfunction (IIEF-5) questionnaire was administered to assess the severity of ED. This was repeated 1 month after treatment. Patients with a peak systolic velocity (PSV) <30 cm s -1 were considered eligible for Li-ESWT. Our protocol consisted of 8 weekly sessions with 1500 strokes distributed in 5 different locations along the penis. After treatment, a significant mean (±standard deviation [s.d.]) PSV increase of 5.0 (±3.4) cm s -1 was recorded and 52/113 (46.0%) patients reached a PSV >30 cm s -1 at posttherapeutic penile dynamic Doppler. A clinically significant IIEF-5 score improvement was observed in 7 patients, 21 patients, and 2 patients with mild-to-moderate, moderate, and severe pretreatment ED, respectively. No different outcomes were assessed based on smoking habits, previous pelvic surgery, or use of oral phosphodiesterase-5 inhibitor (PDE5i). On the other side, only 1 (6.7%) in 15 patients with diabetes mellitus showed an IIEF-5 score improvement after Li-ESWT. Shockwave treatment determined a significant increase in PSV and correlated IIEF-5 improvement in ED patients. This advantage seemed particularly evident for moderate ED and was not affected by smoking habits, previous pelvic surgery, and use of PDE5i. Conversely, diabetic patients did not benefit from the treatment., (Copyright © 2024 Copyright: ©The Author(s)(2024).)

Background : This study aimed to evaluate the effect of treatment with tafamidis on clinical, laboratory, functional, and structural cardiovascular imaging parameters at the 12-month follow-up timepoint in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) and to assess the response to treatment in terms of disease progression. Methods : Patients with ATTRwt-CM undergoing treatment with tafamidis for >12 months were included. The patients underwent a comprehensive evaluation (including echocardiography, cardiac magnetic resonance imaging, six-minute walking test, assessment of quality of life, and laboratory tests) at baseline and the 12-month follow-up timepoint. Disease progression was assessed using a set of tools proposed by an international panel of experts, evaluating three main domains (clinical, biochemical, and structural). Results : The study cohort consisted of 25 patients (mean age of 75.9 ± 6.1 years, with 92% males). At the 12-month follow-up timepoint, an improvement in quality of life calculated with the KCCQ overall score (64 ± 20 vs. 75 ± 20, p = 0.002) and a reduction in pulmonary artery pressure (34 ± 10 mmHg vs. 30 ± 5 mmHg, p -value = 0.008) and in native T1 time were observed (1162 ± 66 ms vs. 1116 ± 52 ms, p -value = 0.001). Clinical, biochemical, and structural disease progression was observed in 6 (24%), 13 (52%), and 7 (28%) patients, respectively. Overall disease progression was observed in two patients (8%). Conclusions : This study described the impact of tafamidis treatment on clinical, laboratory, and functional parameters. Disease progression, assessed using a multiparametric tool recommended by a recent position paper of experts, was observed in a minority of patients.

Background: Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare tumors and available systemic therapies are limited., Aim: To explore the role of peptide receptor radionuclide therapy (PRRT) with Yttrium-90 ( 90 Y) and Lutetium-177 ( 177 Lu) peptides in pheochromocytomas (PCCs) and paragangliomas (PGLs)., Methods: We retrospectively analyzed more than 1500 patients with histologically proven neuroendocrine tumors treated with 177 Lu- or 90 Y-DOTA-TATE or -TOC between 1999 to 2017 at our Institute. Overall, 30 patients with confirmed malignant PCCs and PGLs matched inclusion/exclusion criteria and were considered eligible for this analysis., Results: Thirty (n = 30) patients were treated: 22 with PGLs and 8 with PCCs (12 M and 18 F, median age 47 [IQR: 35-60 years]). Eighteen patients (n = 18) had head and neck PGLs, 3 patients thoracic PGLs and 1 patient abdominal PGL. Sixteen patients (53%) had locally advanced and fourteen (47%) had metastatic disease. Twenty-seven (90%) patients had disease progression at baseline. Four (13%) patients were treated with 90 Y, sixteen (53%) with 177 Lu and ten (33%) with 90 Y +  177 Lu respectively. The median total cumulative activity from treatment with 90 Y- alone was 9.45 GBq (range 5.11-14.02 GBq), from 177 Lu- alone was 21.9 GBq (7.55-32.12 GBq) and from the combination treatment was 4.94 GBq from 90 Y- and 6.83 GBq from 177 Lu- (ranges 1.04-10.1 and 2.66-20.13 GBq, respectively). Seven out of 30 (23%) patients had partial response and 19 (63%) stable disease. Median follow up was 8.9 years (IQR: 2.9-12). The 5-y and 10-y PFS was 68% (95% CI: 48-82) and 53% (95% CI: 33-69), respectively, whereas 5-y and 10-y OS was 75% (95% CI: 54-87) and 59% (95% CI: 38-75), respectively. Grade 3 or 4 acute hematological toxicity occurred in three patients, two with leucopenia and one with thrombocytopenia, respectively., Conclusion: PRRT with 177 Lu- or 90 Y-DOTA-TATE or -TOC is feasible and well tolerated in advanced PGLs and PCCs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Data on the prevalence and clinical significance of interventricular conduction disturbances (IVCDs) in children are scarce. While incomplete right bundle branch blocks (IRBBBs) seem to be the most frequent and benign findings, complete bundle blocks and fascicular blocks are often seen in children with congenital/acquired cardiac conditions. This study aims to delineate the prevalence and the diagnostic accuracy of IVCD in children admitted to a paediatric cardiology unit. Methods: Children admitted to the paediatric cardiology unit between January 2010 and December 2020 who had an ECG were included in the study. IVCDs were diagnosed according to standard criteria adjusted for age. Results: Three thousand nine hundred and ninety-three patients were enrolled. The median age was 3.1 years (IQR: 0.0-9.2 years), and 52.7% were males. IVCDs were present in 22.5% of the population: 17.4% of the population presented with IRBBBs, 4.8% with a complete right bundle branch block (CRBBB), 0.1% with a complete left bundle branch block (CLBBB), 0.2% with a left anterior fascicular block (LAFB) and 0.2% with a combination of CRBBB and LAFB. Also, 26% of children with congenital heart disease had an IVCD, and 18% of children with an IVCD had previous cardiac surgery. The overall sensitivity of IVCD in detecting a cardiac abnormality was 22.2%, with a specificity of 75.5%, a PPV of 83.1% and an NPV of 15.1%, but the values were higher for CLBBB and LAFB. Conclusions : IVCDs were present in one-fifth of children admitted to the cardiology unit. IRBBB was the most frequent disturbance, while CRBBB, CLBBB and fascicular blocks were much rarer, though they had a higher predictive value for cardiac abnormalities.

Background/objectives: Glucagon is important in the maintenance of glucose homeostasis, with also effects on lipids. In this study, we aimed to apply a recently developed model of glucagon kinetics to determine the sensitivity of glucagon variations (especially, glucagon inhibition) to insulin levels ("alpha-cell insulin sensitivity"), during oral glucose administration., Subjects/methods: We studied 50 participants (spanning from normal glucose tolerance to type 2 diabetes) undergoing frequently sampled 5-hr oral glucose tolerance test (OGTT). The alpha-cell insulin sensitivity and the glucagon kinetics were assessed by a mathematical model that we developed previously., Results: The alpha-cell insulin sensitivity parameter (named S GLUCA ; "GLUCA": "glucagon") was remarkably variable among participants (CV=221%). S GLUCA was found inversely correlated with the mean glycemic values, as well as with 2-hr glycemia of the OGTT. When stratifying participants into two groups (normal glucose tolerance, NGT, N =28, and impaired glucose regulation/type 2 diabetes, IGR&#95;T2D, N =22), we found that S GLUCA was lower in the latter (1.50 ± 0.50·10 -2 vs . 0.26 ± 0.14·10 -2 ng·L -1 GLUCA /pmol·L -1 INS , in NGT and IGR&#95;T2D, respectively, p=0.009; "INS": "insulin")., Conclusions: The alpha-cell insulin sensitivity is highly variable among subjects, and it is different in groups at different glucose tolerance. This may be relevant for defining personalized treatment schemes, in terms of dietary prescriptions but also for treatments with glucagon-related agents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Andreozzi, Mancuso, Rubino, Salvatori, Morettini, Monea, Göbl, Mannino and Tura.)

X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date ( PCDH19 -related DEE, CDKL5 -related DEE, MECP2 -related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX , DCX , FLNA ) and DEEs associated with recently recognized genes (e.g., SLC9A6 , SLC35A2 , SYN1 , ARHGEF9 , ATP6AP2 , IQSEC2 , NEXMIF , PIGA , ALG13 , FGF13 , GRIA3 , SMC1A ). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype-phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

Background: A minority of patients with hypertrophic cardiomyopathy (HCM) presents advanced heart failure (HF) during their clinical course, in the context of left ventricular (LV) remodeling with reduced LV ejection fraction (LVEF), or of severe diastolic dysfunction without impaired LVEF. Aim of this study was to describe a multicentric end stage (ES) HCM population and analyze clinical course and outcome among its different phenotypes., Methods: Data of all HCM patients from 7 Italian referral centres were retrospectively evaluated. ES was diagnosed in presence of: LVEF <50% (ES-rEF) or NYHA functional class ≥II with severe diastolic dysfunction (ES-pEF). Outcomes were: HCM-related and all-cause mortality; combined arrhythmic events; advanced HF treatments., Results: Study population included 331 ES patients; 87% presented ES-rEF and 13% ES-pEF. At ES recognition, patients with ES-pEF were more commonly females, had more frequently NYHA III/IV, atrial fibrillation and greater maximal LV wall thickness. Over a median follow-up of 5.6 years, 83 (25%) patients died, 46 (15%) experienced arrhythmic events and (26%) 85 received advanced HF treatments. Incidence of HCM-related and all-cause mortality, and of combined arrhythmic events did not differ in ES-pEF and ES-rEF patients, but ES-pEF patients were less likely to receive advanced HF treatments. Older age at ES recognition was an independent predictor of increased HCM-related mortality (p = 0.01) and reduced access to advanced HF treatments (p < 0.0001)., Conclusions: Two different HCM-ES phenotypes can be recognized, with ES-pEF showing distinctive features at ES recognition and receiving less frequently advanced HF treatments. Older age at ES recognition has a major impact on outcomes., Competing Interests: Declaration of competing interest All Authors report no conflicts of interest related to the present work. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The purpose of this scoping review was to summarize key findings in the voice therapy adherence literature for individuals with phonotraumatic lesions. The particular focus was to identify how adherence has been defined and measured (operationalization and criteria for successful adherence) and to describe variables which were found to have a positive, neutral, or negative relationship with adherence to voice therapy., Methods: Data were identified and charted using the PRISMA-ScR protocol via searches of CINAHL, PsycINFO, Pubmed, SCOPUS, and Web of Science., Results: Literature mining revealed that adherence is rarely defined but is usually operationalized. "Successful completion of therapy" was the most common operationalization. Most variables studied in this field have been found to have no relationship with adherence. An incidental finding was that, most frequently, researchers have repeatedly studied variables which have already been documented to have no relationship with adherence., Conclusion: Research into voice therapy adherence is still emerging, and few if any variables have been identified which are strongly associated with adherence to voice therapy for people with phonotraumatic lesions. Inspiration for future research may be drawn from other disciplines, which point to relationship variables as central to the adherence process. Examination of such variables is currently underrepresented in the voice therapy literature; we suggest this and other gaps for pursuit in future research., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

A 59-year-old treatment-naive patient with advanced HIV infection presented with a severe and protracted course of mpox (formerly known as monkeypox) that did not respond to the current mpox treatment options. The patient worsened clinically, and developed new mucocutaneous lesions and necrotic evolution of pre-existing ones, along with multiple bilateral lung nodules and the appearance of a tracheal necrotic lesion. Although severe forms of mpox have been observed in people with severe immune system deficiency, including those with advanced HIV presentation, the immunological mechanisms underlying this observation have not yet been fully explained. To our knowledge, this is the first account of a necrotising mpox in a person living with HIV, with viral shedding for more than 11 months and a comprehensive immunological description. Moreover, we documented the virus' persistence by detecting mpox virus DNA from multiple sites and quantified anti-monkeypox virus IgA, IgM, IgG, and neutralising antibodies in serum samples. The severe HIV-driven immune depression and the presence of other co-infections might skew and impair immune responses, thus contributing to the persistence of monkeypox virus infection. Further investigations of immune responses to monkeypox virus infection in people with severe immunosuppression are required to improve management and prevention., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Left ventricular non-compaction (LVNC) is a myocardial disease characterized by a two-layered structure typically seen at the apical and lateral left portions of the ventricular myocardium, distal to the papillary muscles. While considered a rare disease, its prevalence in children is increasing due to the increased awareness of this condition and improved resolution of imaging techniques. The etiology is heterogeneous, ranging from inherited conditions to acquired diseases. Although many patients are asymptomatic, some patients may experience adverse events, including heart failure, arrhythmias, or thromboembolic events. Several echocardiographic or cardiac magnetic resonance imaging diagnostic criteria have been proposed for diagnosing LVNC. However, their application in children is significantly limited. This review aims to describe the clinical and genetic characteristics of children with LVNC and discuss the role of the proposed diagnostic criteria.

Introduction: COVID-19 is associated with higher morbimortality in pregnant people compared with non-pregnant people. At present, the benefits of maternal immunisation are considered to outweigh the risks, and therefore, vaccination is recommended during pregnancy. However, additional information is needed on the safety of the vaccines in this population., Methods and Analysis: This a retrospective cohort nested case-control study in pregnant people who attended maternity hospitals from eight Latin American and Caribbean countries. A perinatal electronic clinical history database with neonatal and obstetric information will be used. The proportion of pregnant people immunised with COVID-19 vaccines of the following maternal and neonatal events will be described: preterm infant, small for gestational age, low birth weight, stillbirth, neonatal death, congenital malformations, maternal near miss and maternal death. Moreover, the risk of prematurity, small for gestational age and low birth weight associated with exposure to COVID-19 vaccines will be estimated. Each case will be matched with two groups of three randomly selected controls. Controls will be matched by hospital and mother's age (±3 years) with an additional matching by delivery date and conception time in the first and second control groups, respectively. The estimated required sample size for the main analysis (exposure to any vaccine) concerning 'non-use' is at least 1009 cases (3027 controls) to detect an increased probability of vaccine-associated event risk of 30% and at least 650 cases (1950 controls) to detect 30% protection. Sensitivity and secondary analyses considering country, type of vaccine, exposure windows and completeness of immunisation will be reported., Ethics: The study protocol was reviewed by the Ethical Review Committee on Research of the Pan American Health Organization. Patient informed consent was waived due to the retrospective design and the utilisation of anonymised data (Ref. No: PAHOERC.0546.01). Results will be disseminated in open access journals., Competing Interests: Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© World Health Organization 2024. Licensee BMJ.)

Background and Aim: Atrial fibrillation (AF) is the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM) with significant effects on outcome. We aim to compare the left atrial (LA) diameter measurement with HCM-AF Score in predicting atrial fibrillation (AF) development in HCM., Methods: From the regional cohort of the Campania Region, Italy, 519 HCM patients (38% women, age45 ± 17 years) without history of AF, were enrolled in the study. The primary clinical endpoint was the development of AF, defined as at least 1 episode documented by ECG., Results: During the follow-up (mean 8 ± 6, IQ range 2.5-11.2 years), 99 patients (19%) developed AF. Patients who developed AF were more symptomatic, had higher prevalence of ICD implantation, had larger LA diameter, greater left ventricular (LV) maximal wall thickness and LV outflow tract obstruction (p < 0.01). Both LA diameter and HCM-AF score were higher in patients who developed AF versus those who did not (LA diameter 49 ± 7 versus 43 ± 6 mm; HCM-AF score 22 ± 4 versus 19 ± 4; p < 0.0001); however, ROC curve analysis demonstrated that LA diameter had a significant greater area under the curve than HCM-AF Score (p < 0.0001). At 5 years follow-up, a LA diameter > 46 mm, showed a similar accuracy in predicting AF development of HCM-AF score ≥ 22, which identifies patients at high risk to develop AF., Conclusion: Our analysis shows that LA diameter, a worldwide and simple echocardiographic measure, is capable alone to predict AF development in HCM patients., (Copyright © 2023 Elsevier Ireland Ltd. All rights reserved.)

Left ventricular non-compaction (LVNC) is a heterogeneous myocardial disorder characterized by prominent trabeculae protruding into the left ventricular lumen and deep intertrabecular recesses. LVNC can manifest in isolation or alongside other heart muscle diseases. Its occurrence among children is rising due to advancements in imaging techniques. The origins of LVNC are diverse, involving both genetic and acquired forms. The clinical manifestation varies greatly, with some cases presenting no symptoms, while others typically manifesting with heart failure, systemic embolism, and arrhythmias. Diagnosis mainly relies on assessing heart structure using imaging tools like echocardiography and cardiac magnetic resonance. However, the absence of a universally agreed-upon standard and limitations in diagnostic criteria have led to ongoing debates in the scientific community regarding the most reliable methods. Further research is crucial to enhance the diagnosis of LVNC, particularly in early life stages.

In vitro cultures of primary cardiac fibroblasts (CFs), the major extracellular matrix (ECM)-producing cells of the heart, are used to determine molecular mechanisms of cardiac fibrosis. However, the supraphysiologic stiffness of tissue culture polystyrene (TCPS) triggers the conversion of CFs into an activated myofibroblast-like state, and serial passage of the cells results in the induction of replicative senescence. These phenotypic switches confound the interpretation of experimental data obtained with cultured CFs. In an attempt to circumvent TCPS-induced activation and senescence of CFs, we used poly(ethylene glycol) (PEG) hydrogels as cell culture platforms with low and high stiffness formulations to mimic healthy and fibrotic hearts, respectively. Low hydrogel stiffness converted activated CFs into a quiescent state with a reduced abundance of α-smooth muscle actin (α-SMA)-containing stress fibers. Unexpectedly, lower substrate stiffness concomitantly augmented CF senescence, marked by elevated senescence-associated β-galactosidase (SA-β-Gal) activity and increased expression of p16 and p21, which are antiproliferative markers of senescence. Using dynamically stiffening hydrogels with phototunable cross-linking capabilities, we demonstrate that premature, substrate-induced CF senescence is partially reversible. RNA-sequencing analysis revealed widespread transcriptional reprogramming of CFs cultured on low-stiffness hydrogels, with a reduction in the expression of profibrotic genes encoding ECM proteins, and an attendant increase in expression of NF-κB-responsive inflammatory genes that typify the senescence-associated secretory phenotype (SASP). Our findings demonstrate that alterations in matrix stiffness profoundly impact CF cell state transitions, and suggest mechanisms by which CFs change phenotype in vivo depending on the stiffness of the myocardial microenvironment in which they reside. NEW & NOTEWORTHY Our findings highlight the advantages and pitfalls associated with culturing cardiac fibroblasts on hydrogels of varying stiffness. The findings also define stiffness-dependent signaling and transcriptional networks in cardiac fibroblasts.