The Ross Procedure in Adolescence and Beyond: Are There Still Contraindications?

The Ross procedure is an excellent operation to treat children and adults with aortic valve disease. Compared to prosthetic aortic valve replacement, it provides important clinical benefits in terms of survival, hemodynamics, freedom from valve-related complications, and durability, especially in women of childbearing age. However, the Ross procedure is a longer and technically more challenging operation. As a result, the choice of procedure should be driven by patient anatomy and clinical characteristics. This highlights the importance of concentrating care in Ross reference centers where surgical expertise and experience are present to ensure patient safety and long-term effectiveness of the operation. This manuscript reviews the major and relative contraindications to the Ross procedure.

Opening the "Black Box" for Canadian Cardiac Surgery Residency Applicants∗.

Background: This study reports on the main criteria used by Canadian cardiac surgery residency program committees (RPCs) to select applicants and the perceptions of Canadian medical students interested in cardiac surgery. Methods: A 50-question online survey was sent to all 12 Canadian cardiac surgery RPCs. A similar 52-question online survey targeted at Canadian medical students interested in applying to cardiac surgery residency programs was distributed. Data from both surveys were analyzed using descriptive statistics. Results: A total of 62% of all cardiac surgery RPC members (66 of 106) participated, including committee members from all 12 programs (range: 1-12 members per program; 9%-100% response rate per program) and 67% of program directors (8 of 12). Forty-one Canadian medical students (22 pre-clerks [54%], 2 MD/PhD students [5%], and 17 clinical clerks [41%]) participated. Committee members considered the following criteria to be most important when selecting candidates: on-service clinical performance, the interview, quality of reference letters from cardiac surgeons, and completing a rotation at the target program's institution. In contrast, the following criteria relating to the candidate were considered to be less important: wanting to practice in the city or province of training, having a connection to the program location, and personally knowing committee members. Medical students' perceptions were concordant regarding what factors are the most important but they overestimated the influence of non-clinical factors and research productivity in increasing their competitiveness. Conclusion: Canadian cardiac surgery residency programs seek applicants who demonstrate clinical excellence, as assessed by surgical rotations and reference letters from colleagues, and strong interview performance.

Contexte: Cette étude fait état des principaux critères utilisés par les comités des programmes de résidence (CPR) canadiens en chirurgie cardiaque pour sélectionner les candidats, ainsi que des perceptions des étudiants en médecine canadiens qui s'intéressent à la chirurgie cardiaque. Méthodologie: Un sondage en ligne comptant 50 questions a été envoyé aux 12 CPR canadiens en chirurgie cardiaque. Un sondage en ligne semblable (comptant 52 questions) a été distribué aux étudiants en médecine qui souhaitaient soumettre leur candidature à un programme de résidence en chirurgie cardiaque au Canada. Les données des deux sondages ont été analysées à l'aide de statistiques descriptives. Résultats: Au total, 62 % des membres de CPR en chirurgie cardiaque (66 sur 106) ont répondu au sondage, y compris des membres des comités des 12 programmes (plage : 1 à 12 membres par programme; taux de réponse de 9 à 100 % par programme) et 67 % des directeurs de programme (8 sur 12). Au total, 41 étudiants en médecine canadiens (22 en préexternat [54 %], 2 étudiants au M.D./Ph. D. [5 %] et 17 stagiaires en formation clinique [41 %]) ont répondu au sondage. Les membres du comité ont considéré les critères suivants comme étant les plus importants dans le choix de candidats : le rendement clinique en service, l'entrevue, la qualité des lettres de recommandation de chirurgiens cardiaques et la réalisation d'un stage dans l'établissement associé au programme. En revanche, les critères suivants étaient considérés comme moins importants : le désir de pratiquer dans la ville ou la province de formation, un lien avec le lieu du programme, et la connaissance personnelle de membres du co-mité. Les perceptions des étudiants en médecine concordaient quant aux facteurs les plus importants, mais les étudiants surestimaient l'influence de facteurs non cliniques et de la productivité en recherche dans l'aspect concurrentiel de leur candidature. Conclusion: Les programmes de résidence canadiens en chirurgie cardiaque recherchent des candidats forts d'une excellence clinique, évaluée par les stages en chirurgie et les lettres de recommandation de collègues, et offrant une bonne performance en entrevue.

Asymptomatic Left Ventricular Malignant Psammomatous Melanotic Schwannoma.

Malignant psammomatous melanotic schwannoma (MPMS) is a rare type of tumour, occasionally reported to occur with mediastinal involvement. Histopathologic similarities with melanoma may lead to a wrong diagnosis, but distinguishing between types of tumours is mandatory for adequate management and prognosis. MPMS may be aggressive and manifest unpredictable behavior, with a poor midterm prognosis despite benign histopathologic features. We discuss the challenges that come with a diagnosis of MPMS, and the rationale for our treatment strategy, in this first report regarding MPMS involving the left heart ventricle.

Le schwannome mélanotique psammomateux malin (SMPM) est un type de tumeur rare qui est à l'occasion observé au niveau du médiastin. Ses similitudes histologiques avec le mélanome peuvent conduire à un diagnostic erroné, mais il est impératif de savoir faire la distinction entre ces types de tumeur pour optimiser la prise en charge et le pronostic. Le SMPM peut être agressif et avoir une évolution imprévisible, avec un pronostic défavorable à moyen terme malgré des caractéristiques histopathologiques bénignes. Dans cette première étude de cas de SMPM présentant une atteinte du ventricule gauche, nous décrivons les défis posés par un diagnostic de SMPM et justifions notre stratégie de traitement.

Transthoracic aorto-axillary extra-anatomical bypass for difficult subclavian artery revascularization: a multicenter patency study.

In situ revascularization of the subclavian artery can be challenging in the context of emergency situations, a large aortic aneurysm with a posteriorly displaced left subclavian artery, a complex redo procedure or in the presence of an aberrant subclavian artery. A transthoracic aorto-axillary extra-anatomical bypass is a low risk alternative to in situ revascularization or carotid to subclavian bypass. We herein describe the surgical steps during a single-stage surgery complex aortic arch surgery. We report a 95.3% graft patency for 77 consecutive transthoracic aorto-axillary extra-anatomical bypass performed to 66 patients at the mean follow-up of 2.9 ± 2.4 years. We encountered 3 early (before 180 days postop) graft failures and no late graft failure. Graft failure had no clinical significance.

Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases.

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

Variability in opioid prescribing practices among cardiac surgeons and trainees.

BACKGROUND AND AIM: The opioid epidemic has become a major public health crisis in recent years. Discharge opioid prescription following cardiac surgery has been associated with opioid use disorder; however, ideal practices remain unclear. Our aim was to examine current practices in discharge opioid prescription among cardiac surgeons and trainees. METHODS: A survey instrument with open- and closed-ended questions, developed through a 3-round Delphi method, was circulated to cardiac surgeons and trainees via the Canadian Society of Cardiac Surgeons. Survey questions focused on routine prescription practices including type, dosage and duration. Respondents were also asked about their perceptions of current education and guidelines surrounding opioid medication. RESULTS: Eighty-one percent of respondents reported prescribing opioids at discharge following routine sternotomy-based procedures, however, there remained significant variability in the type and dose of medication prescribed. The median (interquartile range) number of pills prescribed was 30 (20-30) with a median total dose of 135 (113-200) Morphine Milligram Equivalents. Informal teaching was the most commonly reported primary influence on prescribing habits and a lack of formal education regarding opioid prescription was associated with a higher number of pills prescribed. A majority of respondents (91%) felt that there would be value in establishing practice guidelines for opioid prescription following cardiac surgery. CONCLUSIONS: Significant variability exists with respect to routine opioid prescription at discharge following cardiac surgery. Education has come predominantly from informal sources and there is a desire for guidelines. Standardization in this area may have a role in combatting the opioid epidemic.

More Than 25 Years of Experience With the Ross Procedure in Children: A Single-Center Experience.

BACKGROUND: Aortic valve replacement in children represents an important challenge. Concerns regarding pulmonary autograft and homograft longevity requiring reoperations are well recognized. Very long-term outcomes after the Ross procedure are still unknown. We reviewed our experience with the Ross procedure, aiming to define very long-term survival rate and freedom from reintervention. METHODS: This was a single-center retrospective cohort including 63 consecutive children who underwent the Ross procedure. Median follow-up duration was 20.5 years. Time-related events were assessed using Kaplan-Meier estimator. RESULTS: There were 51 (81%) boys, mean age 10.1 ± 5.8 years. Isolated aortic stenosis was the most common diagnosis (n = 29, 46%) and 34 (54%) patients previously underwent cardiac surgery. There was 1 (1.6%) in-hospital death. Overall survival at 5, 15, and 25 years was 96.7%, 94.4%, and 94.4%, respectively. Freedom from any autograft-related reintervention was 98.1%, 86.4%, and 61.2% at 5, 15, and 25 years, respectively. Fifteen (24%) patients underwent autograft reoperations. Among them, 10 (67%) patients underwent valve-sparing autograft reoperation. Freedom from any pulmonary conduit reintervention was 93.2%, 58.2%, and 28.3% at 5, 15, and 25 years, respectively. Thirty (46.6%) patients underwent conduit reintervention (8 percutaneous, 22 surgical replacements). CONCLUSIONS: The pediatric Ross procedure is associated with excellent long-term survival. Ross-related reinterventions are more than twice as common on the pulmonary homograft than on the autograft.

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans.

Genomic imprinting is an epigenetic mechanism leading to parent-of-origin silencing of alleles. So far, the precise number of imprinted regions in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at three time points (birth, childhood and adolescence) and genome-wide association studies (GWAS) data in 740 mother-child duos from the Avon Longitudinal Study of parents and children to identify candidate imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 82 loci, 34 novel and 48 regions previously implicated in imprinting (3.7-10

The MR-Base platform supports systematic causal inference across the human phenome.

Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.

Partitioning Phenotypic Variance Due to Parent-of-Origin Effects Using Genomic Relatedness Matrices.

We propose a new method, G-REMLadp, to estimate the phenotypic variance explained by parent-of-origin effects (POEs) across the genome. Our method uses restricted maximum likelihood analysis of genome-wide genetic relatedness matrices based on individuals' phased genotypes. Genome-wide SNP data from parent child duos or trios is required to obtain relatedness matrices indexing the parental origin of offspring alleles, as well as offspring phenotype data to partition the trait variation into variance components. To calibrate the power of G-REMLadp to detect non-null POEs when they are present, we provide an analytic approximation derived from Haseman-Elston regression. We also used simulated data to quantify the power and Type I Error rates of G-REMLadp, as well as the sensitivity of its variance component estimates to violations of underlying assumptions. We subsequently applied G-REMLadp to 36 phenotypes in a sample of individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We found that the method does not seem to be inherently biased in estimating variance due to POEs, and that substantial correlation between parental genotypes is necessary to generate biased estimates. Our empirical results, power calculations and simulations indicate that sample sizes over 10000 unrelated parent-offspring duos will be necessary to detect POEs explaining < 10% of the variance with moderate power. We conclude that POEs tagged by our genetic relationship matrices are unlikely to explain large proportions of the phenotypic variance (i.e. > 15%) for the 36 traits that we have examined.

LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis.

MOTIVATION: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously. RESULTS: In this manuscript, we describe LD Hub - a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies. AVAILABILITY AND IMPLEMENTATION: The web interface and instructions for using LD Hub are available at http://ldsc.broadinstitute.org/ CONTACT: jie.zheng@bristol.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.

HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics.

MOTIVATION: Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients ([Formula: see text]) of the variants. However, haplotypes rather than pairwise [Formula: see text], are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. RESULTS: Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N < 2000) while other methods become suboptimal. Moreover, HAPRAP's performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome meta-analyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization). AVAILABILITY AND IMPLEMENTATION: The HAPRAP package and documentation are available at http://apps.biocompute.org.uk/haprap/ CONTACT: : jie.zheng@bristol.ac.uk or tom.gaunt@bristol.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online.

Repair of Anterior Mitral Leaflet Prolapse: Comparison of Mid-Term Outcomes with Chordal Transposition and Chordal Replacement Techniques.

BACKGROUND: The repair of anterior mitral leaflet prolapse is known to be challenging. Hence, the study aim was to compare the mid-term results of anterior leaflet prolapse (ALP) using chordal transposition with results obtained using chordal replacement with expanded polytetrafluoroethylene (ePTFE) sutures. METHODS: Between 1999 and 2012, a total of 96 consecutive patients (mean age 62 years) with ALP underwent mitral valve repair at the authors' institution. Surgery involved either chordal transposition from the posterior to the anterior leaflet (n = 67), or chordal replacement using ePTFE sutures (n = 29). Clinical, operative and follow up data were recorded prospectively for each patient. The follow up was 100% complete (mean 3.4 years; range 0 to 12.9 years). RESULTS: Mitral valve repair was accomplished in all patients, with no operative mortality. The durations of cardiopulmonary bypass and aortic cross-clamp were significantly longer in the chordal replacement group. Actuarial overall survival at one, five and 10 years was 95 ± 3%, 87 ± 5% and 82 ± 7% versus 89 ± 6%, 89 ± 6% and 89 ± 6% in the chordal transposition and chordal replacement groups, respectively (p = 0.84). Freedom from reoperation in the two groups at five years was 95 ± 3% and 91 ± 7%, respectively (p = 0.24). The recurrence of moderate or severe mitral regurgitation (MR) (grade ≤2+) and of severe (grade ≤3+) MR was significantly higher in patients who underwent chordal replacement compared to chordal transposition (p = 0.04 and p = 0.01, respectively). CONCLUSIONS: Provided that chordal quality is preserved, chordal transposition is easier and quicker to achieve for ALP repair, and is also durable in the mid term. Chordal replacement offers a satisfying durability even if the recurrence of severe MR appears to be higher. Preferably, both surgical techniques should be mastered to allow valve repair when anatomic conditions prevent chordal transposition.