Explore the vast range of titles available.

Basal progenitors (BPs), including intermediate progenitors and basal radial glia, are generated from apical radial glia and are enriched in gyrencephalic species like humans, contributing to neuronal expansion. Shortly after generation, BPs delaminate towards the subventricular zone, where they further proliferate before differentiation. Gene expression alterations involved in BP delamination and function in humans are poorly understood. Here, we study the role of LGALS3BP, so far known as a cancer biomarker, which is a secreted protein enriched in human neural progenitors (NPCs). We show that individuals with LGALS3BP de novo variants exhibit altered local gyrification, sulcal depth, surface area and thickness in their cortex. Additionally, using cerebral organoids, human fetal tissues and mice, we show that LGALS3BP regulates the position of NPCs. Single-cell RNA-sequencing and proteomics reveal that LGALS3BP-mediated mechanisms involve the extracellular matrix in NPCs’ anchoring and migration within the human brain. We propose that its temporal expression influences NPCs’ delamination, corticogenesis and gyrification extrinsically. Basal progenitors are enriched in gyrencephalic species like humans contributing to neuronal expansion. Here the authors show that LGALS3BP de novo variants are related to reduced cortical complexity and area in humans and that LGALS3BP regulates neural progenitor position in organoids, human fetal tissue and mice.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7 . The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved. Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al . identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”

Background Clinical complexity, as the interaction between ageing, frailty, multimorbidity and polypharmacy, is an increasing concern in patients with AF. There remains uncertainty regarding how combinations of comorbidities influence management and prognosis of patients with atrial fibrillation (AF). We aimed to identify phenotypes of AF patients according to comorbidities and to assess associations between comorbidity patterns, drug use and risk of major outcomes. Methods From the prospective GLORIA-AF Registry, we performed a latent class analysis based on 18 diseases, encompassing cardiovascular, metabolic, respiratory and other conditions; we then analysed the association between phenotypes of patients and (i) treatments received and (ii) the risk of major outcomes. Primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). Secondary exploratory outcomes were also analysed. Results 32,560 AF patients (mean age 70.0 ± 10.5 years, 45.4% females) were included. We identified 6 phenotypes: (i) low complexity (39.2% of patients); (ii) cardiovascular (CV) risk factors (28.2%); (iii) atherosclerotic (10.2%); (iv) thromboembolic (8.1%); (v) cardiometabolic (7.6%) and (vi) high complexity (6.6%). Higher use of oral anticoagulants was found in more complex groups, with highest magnitude observed for the cardiometabolic and high complexity phenotypes (odds ratio and 95% confidence interval CI): 1.76 [1.49–2.09] and 1.57 [1.35–1.81], respectively); similar results were observed for beta-blockers and verapamil or diltiazem. We found higher risk of the primary outcome in all phenotypes, except the CV risk factor one, with highest risk observed for the cardiometabolic and high complexity groups (hazard ratio and 95%CI: 1.37 [1.13–1.67] and 1.47 [1.24–1.75], respectively). Conclusions Comorbidities influence management and long-term prognosis of patients with AF. Patients with complex phenotypes may require comprehensive and holistic approaches to improve their prognosis.

We developed a survey to describe current practice on the detection and management of new-onset postoperative atrial fibrillation (POAF) occurring after coronary artery bypass grafting (CABG) or non-cardiac surgery. We e-mailed an online anonymous questionnaire of 17 multiple choice or rank questions to an international network of healthcare professionals. Between June 2023 and June 2024, 158 participants from 25 countries completed the survey. For CABG patients, 62.7% of respondents reported use of telemetry to detect POAF on the ward until discharge, and 40% reported no dedicated methods for monitoring AF recurrences during follow-up. The largest number (46%) reported prescribing oral anticoagulants (OACs) at discharge if patients were at risk according to CHA 2 DS 2 -VASc/CHA 2 DS 2 -VA scores, and the most common duration of OAC therapy was 3 months to 1 year (43%). For non-cardiac surgery patients, POAF detection methods varied, with 29% using periodic 12-lead ECG and 27% using telemetry followed by periodic ECGs. For monitoring AF recurrence, 33% reported planned cardiology visits with ECG. Regarding OAC prescription during follow-up, 51% reported they prescribe OACs only for patients who are at risk of stroke, and 42% prescribe OACs for an interval of 3 months to 1 year. The most commonly reported barrier to OAC prescription was the lack of randomized controlled trial data. For both CABG and non-cardiac surgery, the reported methods for POAF detection and recurrences monitoring were heterogeneous and prescription patterns for OACs varied greatly. The most frequently reported concern about long-term anticoagulation was lack of randomized data, indicating the urgent need for sound studies that inform daily clinical practice.

The aim of this study was to describe changes in estimated glomerular filtration rate (eGFR), left ventricular ejection fraction (LVEF) and clinical outcomes in a real-world cohort of patients with heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation (AF). A total of 321 patients (67 [58–74] years old, 19.3% females) were included; 134 (41.7%) had AF. AF patients were less frequently prescribed angiotensin receptor–neprilysin inhibitor (ARNi), with no differences concerning sodium–glucose transport protein 2 inhibitors (SGLT2is) and had lower median baseline eGFR values. At 6- and 12-month follow-ups, renal function declined similarly in both groups, with no difference in the proportion of patients experiencing an eGFR decrease of ≥30% from baseline. Regarding cardiac remodeling, patients without AF showed a higher proportion of individuals with an LVEF improvement of ≥10% from baseline, however with no differences between groups in LVEF final recovery. During a median follow-up of 582 (339–1481) days, AF patients showed a higher risk of composite outcome (aHR, 95% CI: 2.12, 1.16–3.86) and of hospitalization for heart failure (hHF) (2.80, 1.44–5.46), without differences in all-cause death. Delta eGFR changes with at least a 30% decline in eGFR were associated with a higher risk of the primary endpoint. Despite lower baseline renal function, AF patients exhibited similar LVEF improvement and renal decline, which emphasizes the importance of guideline-directed medical therapy. AF was associated with a higher risk of adverse events, primarily driven by hHF.

This study investigates the genetic background of pediatric-onset cardiac channelopathies, a rare group of genetic disorders causing arrhythmias and sometimes sudden death, whose genetic background remains partially unknown. The research analyzed 59 pediatric patients (<18 years of age) diagnosed with different channelopathies (LQTS, BrS, CPVT, SQTS, and conduction disorders), along with 40 of their family members, using Next-Generation Sequencing (NGS) after genetic counseling. A causative genetic variant was found in 47% of cases, mainly in the KCNQ1 (42%), RYR2 (16%), CACNA1C (10%), and SCN5A (10%) genes. Notably, a de novo large deletion in KCNH2 was detected in an LQTS patient, and a pathogenic CALM1 variant was identified in a child. A compound heterozygous KCNQ1 was consistent with Jervell and Lange-Nielsen syndrome. In light of these data, genetic testing is crucial for diagnosis, prognosis, and treatment planning; cascade screening allowed early risk identification and preventive interventions for family members. Expanding NGS technologies and research on new candidate genes may enhance personalized therapies in the future.

The exome contains many obscure regions difficult to explore with current short-read sequencing methods. Repetitious genomic regions prevent the unique alignment of reads, which is essential for the identification of clinically-relevant genetic variants. Long-read technologies attempt to resolve multiple-mapping regions, but they still produce many sequencing errors. Thus, a new approach is required to enlighten the obscure regions of the genome and rescue variants that would be otherwise neglected. This work aims to improve the alignment of multiple-mapping reads through the extension of the standard DNA fragment size. As Illumina can sequence fragments up to 550 bp, we tested different DNA fragment lengths using four major commercial WES platforms and found that longer DNA fragments achieved a higher genotypability. This metric, which indicates base calling calculated by combining depth of coverage with the confidence of read alignment, increased from hundreds to thousands of genes, including several associated with clinical phenotypes. While depth of coverage has been considered crucial for the assessment of WES performance, we demonstrated that genotypability has a greater impact in revealing obscure regions, with ~1% increase in variant calling in respect to shorter DNA fragments. Results confirmed that this approach enlightened many regions previously not explored.

Protocadherin-19 ( PCDH19 ) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this study, we adopted morphometric, network-based and multivariate statistical methods to examine the cortex and substructure of the hippocampus and amygdala in a cohort of 20 PCDH19 -mutated patients and evaluated the relation between structural patterns and clinical variables at individual level. We also correlated morphometric alterations with known patterns of PCDH19 expression levels. We found patients to exhibit high-significant reductions of cortical surface area at a whole-brain level (left/right p value  = 0.045/0.084), and particularly in the regions of the limbic network (left/right parahippocampal gyri p value  = 0.230/0.016; left/right entorhinal gyri p value  = 0.002/0.327), and bilateral atrophy of several subunits of the amygdala and hippocampus, particularly in the CA regions (head of the left CA3 p value  = 0.002; body of the right CA3 p value  = 0.004), and differences in the shape of hippocampal structures. More severe psychiatric comorbidities correlated with more significant altered patterns, with the entorhinal gyrus ( p value  = 0.013) and body of hippocampus ( p value  = 0.048) being more severely affected. Morphometric alterations correlated significantly with the known expression patterns of PCDH19 ( r value  = -0.26, p spin  = 0.092). PCDH19 encephalopathy represents a model of genetically determined neural network based neuropsychiatric disease in which quantitative MRI-based findings correlate with the severity of clinical manifestations and had have a potential predictive value if analyzed early.

Background: Paroxysmal atrial fibrillation (AF) may often progress towards more sustained forms of the arrhythmia, but further research is needed on the factors associated with this clinical course. Methods: We analyzed patients enrolled in a prospective cohort study of AF patients. Patients with paroxysmal AF at baseline or first-detected AF (with successful cardioversion) were included. According to rhythm status at 1 year, patients were stratified into: (i) No AF progression and (ii) AF progression. All-cause death was the primary outcome. Results: A total of 2688 patients were included (median age 67 years, interquartile range 60–75, females 44.7%). At 1-year of follow-up, 2094 (77.9%) patients showed no AF progression, while 594 (22.1%) developed persistent or permanent AF. On multivariable logistic regression analysis, no physical activity (odds ratio [OR] 1.35, 95% CI 1.02–1.78), valvular heart disease (OR 1.63, 95% CI 1.23–2.15), left atrial diameter (OR 1.03, 95% CI 1.01–1.05), or left ventricular ejection fraction (OR 0.98, 95% CI 0.97–1.00) were independently associated with AF progression at 1 year. After the assessment at 1 year, the patients were followed for an extended follow-up of 371 days, and those with AF progression were independently associated with a higher risk for all-cause death (adjusted hazard ratio 1.77, 95% CI 1.09–2.89) compared to no-AF-progression patients. Conclusions: In a contemporary cohort of AF patients, a substantial proportion of patients presenting with paroxysmal or first-detected AF showed progression of the AF pattern within 1 year, and clinical factors related to cardiac remodeling were associated with progression. AF progression was associated with an increased risk of all-cause mortality.

Background In patients with atrial fibrillation (AF), the impact of peripheral artery disease (PAD) on oral anticoagulant (OAC) therapy use and the risk of outcomes remains unclear. Objective To analyse the epidemiology of PAD in a large cohort of European and Asian AF patients, and the impact on treatment patterns and risks of adverse outcomes. Methods We analysed AF patients from two large prospective observational registries. OAC prescription and risk of outcomes were analysed according to the presence of PAD, using adjusted Logistic and Cox regression analyses. The primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). Interaction analyses were also performed. Results Fifteen-thousand-four-hundred-ninety-seven patients with AF (mean age 68.9, SD 11.6 years; 38.6% female, 30% from Asia) were included in the analysis. PAD was found in 941 patients (6.1%), with a higher prevalence among European individuals compared to Asian (8.1% vs 1.2%, p  < 0.001). On logistic regression analysis, European patients had sixfold higher odds of presenting with PAD compared with Asians (OR 6.23, 95% CI 4.75–8.35). After adjustments, PAD was associated with lower use of OAC (OR: 0.59, 95% CI: 0.50–0.69). On Cox regression analysis, PAD was associated with a higher risk of the primary composite outcome (HR 1.28, 95% CI: 1.08–1.52) and all-cause death (HR 1.40, 95% CI: 1.16–1.69). A significant interaction was observed between PAD and age, with higher effects of PAD found in younger patients (< 65 years) for the risk of the primary outcome ( p int  = 0.014). Conclusions In patients with AF, PAD is associated with lower use of OAC and a higher risk of adverse outcomes, with a greater risk seen in younger patients.