SCN5A mutation is associated with a higher Shanghai Score in patients with type 1 Brugada ECG pattern.

AIMS: Brugada syndrome (BrS) is an inherited arrhythmic disease characterized by a coved ST-segment elevation in the right precordial electrocardiogram leads (type 1 ECG pattern) and is associated with a risk of malignant ventricular arrhythmias and sudden cardiac death. In order to assess the predictive value of the Shanghai Score System for the presence of a SCN5A mutation in clinical practice, we studied a cohort of 125 patients with spontaneous or fever/drug-induced BrS type 1 ECG pattern, variably associated with symptoms and a positive family history. METHODS: The Shanghai Score System items were collected for each patient and PR and QRS complex intervals were measured. Patients were genotyped through a next-generation sequencing (NGS) custom panel for the presence of SCN5A mutations and the common SCN5A polymorphism (H558R). RESULTS: The total Shanghai Score was higher in SCN5A+ patients than in SCN5A- patients. The 81% of SCN5A+ patients and the 100% of patients with a SCN5A truncating variant exhibit a spontaneous type 1 ECG pattern. A significant increase in PR (P = 0.006) and QRS (P = 0.02) was detected in the SCN5A+ group. The presence of the common H558R polymorphism did not significantly correlate with any of the items of the Shanghai Score, nor with the total score of the system. CONCLUSION: Data from our study suggest the usefulness of Shanghai Score collection in clinical practice in order to maximize genetic test appropriateness. Our data further highlight SCN5A mutations as a cause of conduction impairment in BrS patients.

IRF2BPL: A new genotype for progressive myoclonus epilepsies.

The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome-wide molecular studies on remaining, well-selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole-exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype-phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.

DMD deletions underlining mild dystrophinopathies: literature review highlights phenotype-related mutation clusters and provides insights about genetic mechanisms and prognosis.

DMD gene pathogenic variations cause a spectrum of phenotypes, ranging from severe Duchenne muscular dystrophy, the Becker milder cases, the intermediate or very mild muscle phenotypes invariably characterized by high CK, and the ultrarare fully-asymptomatic cases. Besides these phenotypes, X-linked dilated cardiomyopathy is also caused by DMD mutations. Males carrying DMD deletions with absent or very mild phenotypes have been sparsely described. We performed a horizon scan on public datasets to enroll males with the above phenotypes and carrying DMD deletions to delineate myopathic genotype-phenotype relationships. We inventoried 81 males, who were divided into the following clinical categorization: fully-asymptomatic males aged >43 years (A, N = 22); isolated hyperCKemia (CK, N = 35); and mild weakness (any age) with or without high CK (WCK, N = 24). In all cases, deleted intervals were exons 2 to 55, and no downstream exons were ever involved, apart from an exon 78 deletion in a WCK patient. All deletions were in-frame apart from the known exception to the rule of exon 2 and exon 78. We correlated the mild phenotypes (A and CK) to deleted exons, intronic breakpoints, exon-exon junctions, 3' isoforms rule, and protein epitopes, and we found that some genetic profiles are exclusively/mainly occurring in A/CK phenotypes, suggesting they are compatible with a quasi-normal muscular performance. We discussed diverse pathogenic mechanisms that may contribute to mild dystrophinopathic phenotypes, and we tried to address some "critical" genetic configurations or exon content needed to preserve a semi-functional DMD gene.

Cardiac Arrest in a Young Woman: A Near Miss Diagnosis.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare channelopathy involving cardiac calcium metabolism that often shows up at an early age with misleading clinical symptoms such as emotion or exercise-related syncope with a normal resting ECG, however, if misdiagnosed, CPVT can lead to cardiac arrest in children or young adults. We describe the case of a 27-year-old woman with several misdiagnosed syncopal episodes leading to out-of-hospital cardiac arrest (OHCA). Her previous medical history, combined with automatic external defibrillator records (AED) and clinical data, strongly suggested the diagnosis of CPVT. Thus beta blocker therapy was immediately started and targeted genetic test undertaken, revealing a previously unreported heterozygous variant in the ryanodine receptor-2 (RYR2) gene.

Reactogenicity of COVID-19 vaccine in hemodialysis patients: a single-center retrospective study.

Introduction: Some hemodialysis patients are reluctant to undergo COVID-19 vaccination for the fear of developing adverse events (AEs). The aim of this study was to verify the safety of the mRNA-1273 vaccine in hemodialysis patients. Methods: We conducted a retrospective analysis of in-center hemodialysis patients who underwent mRNA-1273 vaccine from March 1st to April 30th, 2021. All AEs occurring after the first and the second doses were collected and classified as local or systemic. Results: Overall, 126 patients on chronic maintenance dialysis without a prior COVID-19 diagnosis were vaccinated with two doses of mRNA-1273 vaccine. Mean age was 68 (IQR, 54,7-76) years and 53.6% of patients were aged ≥65 years. During the observational period of 68 (IQR, 66-70) days, AEs occurred in 57.9% and 61.9% of patients after the first dose and second dose, respectively. The most common AEs were: injection-site pain (61.9%), erythema (4.8%), itching (4.8%), swelling (16.7%), axillary swelling/tenderness (2.4%), fever (17.5%) headache (7.9%), fatigue (23.8%), myalgia (17.5%), arthralgia (12.7%), dyspnoea (2.4%), nausea/vomiting (7.1%), diarrhoea (5.6%), shivers (4%) and vertigo (1.6%). The rates of local AEs were similar after the first and second doses (P=0.8), whereas systemic AEs occurred more frequently after the second dose (P=0.001). Fever (P=0.03), fatigue (P=0.02) and nausea/vomiting (P=0.03) were significantly more frequent after the second dose of the vaccine. There were no age-related differences in the rate of AEs. Overall, vaccine-related AEs in hemodialysis patients seem to be lower than in the general population. Conclusion: The RNA-1273 vaccine was associated with the development of transient AEs after the first and second doses in patients on chronic maintenance hemodialysis. They were mostly local, whereas systemic AEs were more prevalent after the second dose. Overall, all AEs lasted for a few days, without any apparent sequelae.

Brugada ECG pattern in hypertrophic cardiomyopathy: Brugada phenocopy or overlapping syndrome?

The term phenocopy indicates a condition that imitates one produced by a gene and is also used for acquired Brugada-like ECG manifestations. Cases of Brugada phenocopies are increasingly reported in literature and an international registry is ongoing. We describe two patients with Hypertrophic Cardiomyopathy (HCM) and Brugada ECG pattern. Both patients carried the same pathogenic splicing mutation in MYBPC3 gene (responsible for HCM) while no genetic mutation associated with Brugada Syndrome was identified. To the best of our knowledge, Brugada ECG pattern has been rarely reported in patients with HCM.

Comparison Between Kidney Transplantation After Circulatory Death and After Brain Death: A Monocentric Retrospective Study After 1 Year of Follow-up.

BACKGROUND: Donation after circulatory death (DCD) is a solid resource to widen the kidney donor pool. Italian activity has grown in the last years with encouraging results. Our center has been active in DCD kidney transplantation (KTX) since November 2017, providing 22.5% of Italian DCD donations in 2018. We present a single-center retrospective analysis after a 1-year follow-up comparing DCD and donation after brain death (DBD) KTX outcomes. METHODS: DCD (controlled only) and DBD KTX performed in our center from November 2017 to December 2018 were considered. All DCDs underwent in situ normothermic perfusion with extracorporeal membrane oxygenation, ex situ hypothermic oxygenated perfusion, and renal biopsy prior to allocation. We considered features of donors and recipients, immunosuppressive regimen, delayed graft function (DGF), primary nonfunction (PNF), graft and patient survival (Kaplan-Meier), creatinine, and estimated glomerular filtration rate at 1 year. Mean comparison with a Student t test and with χ2 test for frequencies were elaborated. RESULTS: Twenty-eight DBD, 18 double (64.3%) and 10 single (35.7%), were performed; 7 DCD, 3 double (42.8%) and 4 single (57.2%), were performed. By comparing single and double KTX, no statistically significant difference was found. We recorded 7 DGFs (25%) in DBD and 1 (14.3%) in the DCD group (P > .99) and no PNF. No graft was lost during the first year. One-year estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration) was, respectively, 62.7 ± 25.3 and 54.71 ± 14.66 mL/min (P = .25). DBD patient survival rate was 92.8%, DCD was 100%, and Kaplan-Meier was not statistically significant (P = .72). CONCLUSIONS: Controlled DCD is a valid resource for KTX, with similar outcomes to DBD. A multidisciplinary donor evaluation, combining clinical, perfusion, and histologic data in the allocation process, allows excellent results.

Early prognostic value of nocturnal blood pressure: a single-centre experience.

Ambulatory blood pressure monitoring (ABPM) is now considered by current guidelines to be a reliable method of measurement for the diagnosis and assessment of hypertension. The aim of this study was to relate the short-term outcomes, comorbidity and ABPM findings determined from evaluating an everyday clinical cohort of hypertensive patients. A prospective study was carried out that included hypertensive patients who had undergone 24-h ABPM from January 2016 to November 2017. The following parameters were recorded in the database: age, sex, current antihypertensive treatment and documented history of comorbidities. New episodes of myocardial infarction and stroke requiring hospitalization during follow-up obtained from electronic medical records were considered to be major adverse cardiovascular events (MACE) and were our main outcome measures. To estimate the risk of MACE, a Cox multivariate analysis was carried out. We analysed 1521 ABPM values and recorded 33 MACE during a follow-up of 518±120 days; 15 patients suffered a myocardial infarction and 18 patients had a stroke. The mean age of the patients was 59.9±14.2 years, and 49.4% were men. Night-time systolic blood pressure (BP), mean BP and pulse pressure were higher in patients who suffered a MACE. Age [hazard ratio (HR): 1.031, 95% confidence interval (CI): 1.002-1.060; P=0.036], night-time BP (HR: 1.018, 95% CI: 1.001-1.037; P=0.044) and diabetes mellitus (HR: 2.393, 95% CI: 1.053-5.436; P=0.037) were associated independently with MACE. We conclude that night-time BP is an important parameter to evaluate in aged patients with diabetes as a predictor of MACE.

Spatial dynamics of DNA damage response protein foci along the ion trajectory of high-LET particles.

High-linear energy transfer (LET) ion irradiation of cell nuclei induces complex and severe DNA lesions, and foci of repair proteins are formed densely along the ion trajectory. To efficiently discriminate the densely distributed/overlapping foci along the ion trajectory, a focus recognition algorithm called FociPicker3D based on a local fraction thresholding technique was developed. We analyzed high-resolution 3D immunofluorescence microscopic focus images and obtained the kinetics and spatial development of γ-H2AX, 53BP1 and phospho-NBS1 foci in BJ1-hTERT cells irradiated with 55 MeV carbon ions and compared the results with the dynamics of double-strand break (DSB) distributions simulated using the PARTRAC model. Clusters consisting of several foci were observed along the ion trajectory after irradiation. The spatial dynamics of the protein foci supports that the foci clusters are not formed by neighboring foci but instead originate from the DSB cluster damage induced by high-LET radiations.