A hidden problem: peripheral artery disease in women.

Peripheral artery disease (PAD) has a huge social and economic burden and is an important contributor to the global health burden. Sex differences in PAD are apparent, with recent data suggesting equal if not greater prevalence in women, and women having worse clinical outcomes. Why this occurs is not clear. To identify underlying reasons for gender inequalities in PAD, we executed a deeper exploration through a social constructive perspective. A scoping review was conducted using the World Health Organization model for analysis of gender-related needs in healthcare. Complex interacting factors, including biological, clinical, and societal variables, were reviewed to highlight gender-related inequities in the diagnosis, treatment, and management of PAD. Current gaps in knowledge were identified and insights into future directions aimed at improving these inequalities were discussed. Our findings highlight the multi-level complexities that need to be considered for strategies to improve gender-related needs in PAD healthcare.

Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.

OBJECTIVE: The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. METHODS: Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. RESULTS: The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. INTERPRETATION: A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.

Genetic analysis of PHOX2B in sudden unexpected death in epilepsy cases.

OBJECTIVE: To determine the contribution of sequence variations in PHOX2B to sudden unexpected death in epilepsy (SUDEP). METHODS: Patients who died of SUDEP were identified in 2 major Australian cohorts, the Epilepsy Genetics research program in Melbourne and postmortem cases at the Department of Forensic Medicine in Sydney. Coding exons of the PHOX2B gene were sequenced and a fluorescent sizing assay was used to measure the PHOX2B polyalanine repeat sequence. RESULTS: Sequencing of 68 cases of SUDEP identified a 15-nucleotide deletion in the PHOX2B polyalanine repeat region in one case, a 16-year-old adolescent with focal dyscognitive seizures from age 5 years. This deletion was verified using a fluorescent sizing assay. Two synonymous variants were identified in 4 cases, but no PHOX2B polyalanine repeat expansion alleles or point mutations were found. CONCLUSIONS: The absence of PHOX2B polyalanine repeat expansion alleles or point mutations in 68 Australian cases of SUDEP, with one deletion of uncertain significance, shows that PHOX2B mutations are not a common risk factor for SUDEP.