Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Outcomes of Hindfoot Joint-Sparing Reconstructive Procedures for Flexible Progressive Collapsing Foot Deformity: A Prospective Cohort Study

Category: Hindfoot; Other Introduction/Purpose: Treatment of Progressive Collapsing Foot Deformity (PCFD) is controversial and surgical procedures utilized usually depend on the type and rigidity of deformities present (PCFD classes and stages), degree of soft tissue involvement, and surgeon’s preference. Multiple surgical procedures are usually performed concomitantly to achieve adequate correction. Prospective data regarding the utilization of hindfoot joint-sparing reconstructive procedures in the treatment of flexible PCFD is scarce, and little is known about the influence of the different procedures utilized to treat PCFD in deformity correction and patient-reported outcomes (PROs). The objective of this prospective study was to evaluate the most used hindfoot joint-sparing procedures utilized by a single-surgeon to treat flexible PCFD, and the influence of the utilized procedures in deformity pattern corrections, and PROs. Methods: IRB-approved, prospective, and comparative cohort study. Adult PCFD patients with flexible deformity (stage 1), no history of surgical treatment, and that failed conservative treatment for >3-months were enrolled. Patients underwent surgical treatment by a single-surgeon. Patients were excluded if a hindfoot fusion procedure was needed intra-operatively to achieve correction. Types, numbers, and sizes of surgical procedures utilized were recorded. Weight-bearing CT (WBCT) measurements of overall 3D deformity, Classes A (hindfoot valgus), B (abduction), C (medial column instability), D (peritalar subluxation), and E (ankle valgus tilt) were assessed preoperatively, and at first 3-months WBCT. PROs were recorded preoperatively and at the most recent follow-up. Descriptive statistics were used to report the frequency of deformity and procedures utilized. Pre and postoperative measurements and PROs were compared with paired T-tests/Wilcoxon. Multivariate regression analysis was used to correlate procedures utilized with deformity correction and PROs. P-values of >0.05 were considered significant. Results: A total of 29 patients included (28 feet, 79%F, 21%M), mean age and BMI of respectively 47.6-years and 34kg/m 2 . Average number of procedures performed was five and mean follow-up was 19.1 months (range, 3 to 40). Frequency and sizes of medial displacement calcaneal osteotomy (MDCO), first ray plantarflexion procedure (Cotton/LapiCoton), and lateral column lengthening (LCL) procedures were, respectively: 100% (8.9mm displacement), 100% (66% Lapicotton/34% Cotton, 8.3mm wedge-opening) and 39% (6.8mm wedge-opening). Soft-tissue procedures performed: 83% Posterior tibial tendon (re-tensioning/FDL transfer/allograft reconstruction), 34% peroneal tendon (brevis-to-longus and brevis lengthening), 76% gastrocnemius-recession, 38% spring ligament (re-tensioning/reconstruction/augmentation) and 31% deltoid ligament (re- tensioning/reconstruction/augmentation). Significant improvement postoperatively was observed in all PCFD measurements performed and PROs (Figure). However, no direct correlation was found between procedures performed/measurement improvements and PROs. Conclusion: In this prospective comparative cohort study of flexible PCFD patients undergoing surgical treatment with hindfoot joint sparing surgical procedures, we observed significant postoperative improvement in all deformity patterns assessed (Classes A, B, C, and D) as well as PROs. MDCO and first ray plantarflexion procedures (Cotton or LapiCotton) were the most commonly utilized procedures and were performed in all cases. Even though deformity correction and PRO improvements were observed postoperatively, no direct correlation was observed between PROs and specific surgical procedures performed or deformity pattern corrections (PCFD classes)

Prevalence of Progressive Collapsing Foot Deformity in Hallux Valgus Patients

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: Hallux valgus (HV) and progressive collapsing foot deformity (PCFD) are very common foot and ankle conditions in the adult population. Both could potentially disrupt the tripod construct of the foot which leads to chronic pain and arthritis. Several procedures were described to address HV deformity depending on deformity characteristics. PCFD could alter the management plan for HV if they occur simultaneously. The aim of this study was to detect the prevalence of PCFD in HV patients and study the frequency of individual PCFD classes. Methods: In this retrospective IRB approved study, patients > 18 years old who were evaluated for symptomatic hallux valgus and had a weight bearing computed tomography (WBCT) imaging were included. Patients were considered for further analysis if they have a hallux valgus angle (HVA) > 15° or inter-metatarsal angle (IMA) > 9°. All relevant demographic data were extracted. Two fellowship trained foot and ankle orthopaedic surgeon measured the following parameters: foot and ankle offset (FAO%) (Class A), talo-navicular coverage angle (TNCA) (Class B), Meary’s angle (Class C) and middle facet subluxation (MFS%) (Class D). Cases that showed FAO% > 4.6% and MFS% > 28.7% were diagnosed as PCFD. The prevalence of PCFD classes (A,B,C and D) was calculated using threshold values for its respective radiographic marker. Descriptive statistics were performed. Results: Thirty-four cases were included. 16 cases were females (46.06%) and 16 (46.06%) were right side. The average age was 52.51 years (SD ± 17.75), the average BMI was 30.14 (SD ± 7.15). The average HVA was 26.82 (SD ± 9.98) and the average IMA was 15.41 (SD ± 3.53). 13 patients (38.24%) had MFS% and FAO% above the threshold values. The average FAO was 4.75% (SD ± 4.92) and the average MFS was 29.17% (SD ± 15.89). Prevalence of Class A (FAO%) was 20 (58.82%), Class B (TNCA) was 12 (35.29%), Class C (Meary’s angle) was 15 (44.12%) and Class D (MFS%) was 16 (47.06%). Conclusion: Progressive collapsing foot deformity is prevalent in the hallux valgus population (38.24%). Class C which indicates medial column instability was prevalent in 44.12% of the cases. Given this high prevalence of PCFD, we believe that in addition to the classic hallux valgus parameters, PCFD classes evaluation could favor a surgical approach over another such as first tarsometatarsal joint procedures over isolated distal first metatarsal procedures to correct the HV deformity and simultaneously halt PCFD progression