Effect of PCI on Health Status in Ischemic Left Ventricular Dysfunction: Insights From REVIVED-BCIS2.

BACKGROUND: In the REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction) trial, percutaneous coronary intervention (PCI) did not reduce the incidence of death or hospitalization for heart failure (HHF). OBJECTIVES: This prespecified secondary analysis investigated the effect of PCI on health status measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) combined with the primary outcome in a win ratio. METHODS: Participants with severe ischemic left ventricular dysfunction were randomized to either PCI in addition to optimal medical therapy (OMT) (PCI) or OMT alone (OMT). The primary outcome was a hierarchical composite of all-cause death, HHF, and KCCQ-Overall Summary Score (OSS) at 24 months analyzed using the unmatched win ratio. The key secondary endpoint was a KCCQ-OSS responder analysis. RESULTS: A total of 347 participants were randomized to PCI and 353 to OMT. Median age was 70.0 years (Q1-Q3: 63.3-76.1 years). Mean left ventricular ejection fraction was 27.0 ± 6.7%. PCI did not improve the primary endpoint (win ratio for PCI vs OMT: 1.05; 95% CI: 0.88-1.26; P = 0.58). PCI resulted in more KCCQ-OSS responders than OMT at 6 months (54.1% vs 40.7%; OR: 1.96; 95% CI: 1.41-2.71; P < 0.001) and fewer deteriorators (25.2% vs 31.4%; OR: 0.69; 95% CI: 0.47-1.00; P = 0.048). PCI did not impact KCCQ-OSS responders or deteriorators at 12 or 24 months. CONCLUSIONS: PCI did not improve the hierarchical composite of death, HHF, and health status at 2 years. PCI improved KCCQ-OSS at 6 months, but this benefit was not sustained to 1- or 2-year follow-up. (Revacularization for Ischemic Ventricular Dysfunction [REVIVED-BCIS2]; NCT01920048).

Beyond the Human Genome Project: The Age of Complete Human Genome Sequences and Pangenome References.

The Human Genome Project was an enormous accomplishment, providing a foundation for countless explorations into the genetics and genomics of the human species. Yet for many years, the human genome reference sequence remained incomplete and lacked representation of human genetic diversity. Recently, two major advances have emerged to address these shortcomings: complete gap-free human genome sequences, such as the one developed by the Telomere-to-Telomere Consortium, and high-quality pangenomes, such as the one developed by the Human Pangenome Reference Consortium. Facilitated by advances in long-read DNA sequencing and genome assembly algorithms, complete human genome sequences resolve regions that have been historically difficult to sequence, including centromeres, telomeres, and segmental duplications. In parallel, pangenomes capture the extensive genetic diversity across populations worldwide. Together, these advances usher in a new era of genomics research, enhancing the accuracy of genomic analysis, paving the path for precision medicine, and contributing to deeper insights into human biology.

Device-related thrombosis after transcatheter closure of atrial septal defect using the Gore Cardioform ASD occluder.

A previously healthy 60-year-old female was diagnosed with a secundum atrial septal defect measuring 23 x 12 mm on transesophageal echocardiogram.

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis -regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our V al i dated S ystematic I ntegrati on (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Sources of gene expression variation in a globally diverse human cohort.

Genetic variation influencing gene expression and splicing is a key source of phenotypic diversity. Though invaluable, studies investigating these links in humans have been strongly biased toward participants of European ancestries, diminishing generalizability and hindering evolutionary research. To address these limitations, we developed MAGE, an open-access RNA-seq data set of lymphoblastoid cell lines from 731 individuals from the 1000 Genomes Project spread across 5 continental groups and 26 populations. Most variation in gene expression (92%) and splicing (95%) was distributed within versus between populations, mirroring variation in DNA sequence. We mapped associations between genetic variants and expression and splicing of nearby genes (cis-eQTLs and cis-sQTLs, respective), identifying >15,000 putatively causal eQTLs and >16,000 putatively causal sQTLs that are enriched for relevant epigenomic signatures. These include 1310 eQTLs and 1657 sQTLs that are largely private to previously underrepresented populations. Our data further indicate that the magnitude and direction of causal eQTL effects are highly consistent across populations and that apparent "population-specific" effects observed in previous studies were largely driven by low resolution or additional independent eQTLs of the same genes that were not detected. Together, our study expands understanding of gene expression diversity across human populations and provides an inclusive resource for studying the evolution and function of human genomes.

The complete sequence of a human Y chromosome.

The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure that includes long palindromes, tandem repeats and segmental duplications1-3. As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished4,5. Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference, showing the complete ampliconic structures of gene families TSPY, DAZ and RBMY; 41 additional protein-coding genes, mostly from the TSPY family; and an alternating pattern of human satellite 1 and 3 blocks in the heterochromatic Yq12 region. We have combined T2T-Y with a previous assembly of the CHM13 genome4 and mapped available population variation, clinical variants and functional genomics data to produce a complete and comprehensive reference sequence for all 24 human chromosomes.

Characterization of large-scale genomic differences in the first complete human genome.

BACKGROUND: The first telomere-to-telomere (T2T) human genome assembly (T2T-CHM13) release is a milestone in human genomics. The T2T-CHM13 genome assembly extends our understanding of telomeres, centromeres, segmental duplication, and other complex regions. The current human genome reference (GRCh38) has been widely used in various human genomic studies. However, the large-scale genomic differences between these two important genome assemblies are not characterized in detail yet. RESULTS: Here, in addition to the previously reported "non-syntenic" regions, we find 67 additional large-scale discrepant regions and precisely categorize them into four structural types with a newly developed website tool called SynPlotter. The discrepant regions (~ 21.6 Mbp) excluding telomeric and centromeric regions are highly structurally polymorphic in humans, where the deletions or duplications are likely associated with various human diseases, such as immune and neurodevelopmental disorders. The analyses of a newly identified discrepant region-the KLRC gene cluster-show that the depletion of KLRC2 by a single-deletion event is associated with natural killer cell differentiation in ~ 20% of humans. Meanwhile, the rapid amino acid replacements observed within KLRC3 are probably a result of natural selection in primate evolution. CONCLUSION: Our study provides a foundation for understanding the large-scale structural genomic differences between the two crucial human reference genomes, and is thereby important for future human genomics studies.

Identification of Clinically Insignificant Renal Calculi on Sonography.

OBJECTIVE: To determine factors predicting if a radiologists... report of a .. stone... on ultrasound (US) was not actually a clinically significant stone, based on subsequent computed tomogram (CT). US often overestimates stone size and various pathologic entities are also hyperechoic;.ßthus, a subsequent CT without a clinically significant stone may represent unnecessary radiation exposure. A decision-tree and nomogram were developed to predict when stones are unlikely on subsequent CT. METHODS: Retrospective analysis of patients, of any age, receiving CT within 24.ßhours of a sonographic report documenting a single renal stone, during 2019...2020, in any phase of care, at one institution. Novel stone-likelihood-systems for US and CT (US-SLS, CT-SLS) were devised and validated to classify stones as clinically significant or insignificant, with CT as the gold standard. Binomial logistic regression predicting clinically significant stones was performed with sonographic and patient characteristics. RESULTS: Eight hundred twenty patients had US followed by CT, 228 (27.8%) reported documented stones, 140 (17.1%) reported a single stone. Clinically significant stones were associated with larger stone size (P: .002), location (P: .002), hydronephrosis (P: .04), shadowing-artifact (P: .02) depth.ßto.ßstone (P: .008), and Body mass Index (BMI) (P: .01). US-SLS had higher sensitivity (95.4%) and negative-predictive-value (81.8%) compared to a multivariate model of significant variables. CONCLUSION: US-SLS appears to exclude clinically irrelevant .. stones... better than established criteria including twinkle or shadow in this retrospective analysis. A diagnostic algorithm and nomogram are presented. US-SLS and the associated decision tree can assist providers in avoiding unnecessary radiation when clinically significant stones are unlikely.

Transcatheter Aortic Valve Implantation in a Failed Perceval Sutureless Valve, Complicated by Aortic Annular Rupture.

As the use of surgically implanted sutureless aortic valves has increased over the past decade, we expect to encounter their failure increasingly in coming years. We describe a case of Perceval aortic valve failure with stent infolding and severe stenosis. This condition was treated with valve-in-valve transcatheter aortic valve implantation and complicated by aortic annular rupture at the site of infolding. This case is important because it outlines the limited experience with valve-in-valve transcatheter aortic valve implantation to treat failed sutureless valves and identifies sutureless valve infolding as a potential risk for annular rupture.

Puisque l'implantation valvulaire aortique sans suture s'est accrue au cours de la dernière décennie, nous nous attendons à rencontrer de plus en plus de défaillances de valves dans les années à venir. Nous décrivons un cas de défaillance de la valve aortique Perceval avec pliage de l'endoprothèse et sténose grave. Le traitement qui consistait en l'implantation valvulaire aortique de type valve-in-valve par cathéter a été compliqué par la rupture de l'anneau aortique au site du pliage. Il s'agit d'un cas important puisqu'il décrit le peu d'expérience en matière d'implantation valvulaire aortique de type valve-in-valve par cathéter dans le traitement des valves sans suture défectueuses et établit que le pliage d'une valve sans suture expose à un risque de rupture de l'anneau.

A Case of Electrical Right-Ventricular Infarction in the Absence of Clinical Right-Ventricular Failure.

In the setting of acute coronary syndrome, right-ventricular (RV) infarction, which has significant clinical implications, can occur in conjunction with inferior left-ventricular (LV) infarction. In rare cases, RV infarction is isolated. We describe a case of isolated RV infarction identified based on previously described electrocardiogram findings in the absence of hemodynamic or imaging evidence of RV dysfunction. This case highlights the fact that RV transmural ischemia can exist in the absence of the clinical syndrome associated with RV infarction, which we hypothesize is related to the proportion of RV myocardium involved in the infarct, or conversely, the amount of myocardium protected through various mechanisms.

Dans le cadre du syndrome coronarien aigu, l'infarctus du ventricule droit, qui a des répercussions cliniques importantes, peut survenir conjointement avec un infarctus inférieur du ventricule gauche. Dans de rares cas, l'infarctus du ventricule droit est isolé. Nous décrivons un cas d'infarctus du ventricule droit isolé décelé à l'aide des résultats précédemment décrits d'un électrocardiogramme faute de résultats hémodynamiques ou d'imagerie indiquant une dysfonction ventriculaire droite. Ce cas souligne le fait qu'une ischémie transmurale du ventricule droit peut survenir même sans syndrome clinique associé à l'infarctus du ventricule droit, ce qui s'explique, selon notre hypothèse, par la proportion de myocarde ventriculaire droit touché par l'infarctus ou, à l'inverse, la quantité de myocarde protégé par divers mécanismes.

A complete reference genome improves analysis of human genetic variation.

Compared to its predecessors, the Telomere-to-Telomere CHM13 genome adds nearly 200 million base pairs of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome for clinical and functional study. We show how this reference universally improves read mapping and variant calling for 3202 and 17 globally diverse samples sequenced with short and long reads, respectively. We identify hundreds of thousands of variants per sample in previously unresolved regions, showcasing the promise of the T2T-CHM13 reference for evolutionary and biomedical discovery. Simultaneously, this reference eliminates tens of thousands of spurious variants per sample, including reduction of false positives in 269 medically relevant genes by up to a factor of 12. Because of these improvements in variant discovery coupled with population and functional genomic resources, T2T-CHM13 is positioned to replace GRCh38 as the prevailing reference for human genetics.

Somatostatin venom analogs evolved by fish-hunting cone snails: From prey capture behavior to identifying drug leads.

Somatostatin (SS) is a peptide hormone with diverse physiological roles. By investigating a deep-water clade of fish-hunting cone snails, we show that predator-prey evolution has generated a diverse set of SS analogs, each optimized to elicit specific systemic physiological effects in prey. The increased metabolic stability, distinct SS receptor activation profiles, and chemical diversity of the venom analogs make them suitable leads for therapeutic application, including pain, cancer, and endocrine disorders. Our findings not only establish the existence of SS-like peptides in animal venoms but also serve as a model for the synergy gained from combining molecular phylogenetics and behavioral observations to optimize the discovery of natural products with biomedical potential.

Post-discharge after surgery Virtual Care with Remote Automated Monitoring-1 (PVC-RAM-1) technology versus standard care: randomised controlled trial.

OBJECTIVE: To determine if virtual care with remote automated monitoring (RAM) technology versus standard care increases days alive at home among adults discharged after non-elective surgery during the covid-19 pandemic. DESIGN: Multicentre randomised controlled trial. SETTING: 8 acute care hospitals in Canada. PARTICIPANTS: 905 adults (≥40 years) who resided in areas with mobile phone coverage and were to be discharged from hospital after non-elective surgery were randomised either to virtual care and RAM (n=451) or to standard care (n=454). 903 participants (99.8%) completed the 31 day follow-up. INTERVENTION: Participants in the experimental group received a tablet computer and RAM technology that measured blood pressure, heart rate, respiratory rate, oxygen saturation, temperature, and body weight. For 30 days the participants took daily biophysical measurements and photographs of their wound and interacted with nurses virtually. Participants in the standard care group received post-hospital discharge management according to the centre's usual care. Patients, healthcare providers, and data collectors were aware of patients' group allocations. Outcome adjudicators were blinded to group allocation. MAIN OUTCOME MEASURES: The primary outcome was days alive at home during 31 days of follow-up. The 12 secondary outcomes included acute hospital care, detection and correction of drug errors, and pain at 7, 15, and 30 days after randomisation. RESULTS: All 905 participants (mean age 63.1 years) were analysed in the groups to which they were randomised. Days alive at home during 31 days of follow-up were 29.7 in the virtual care group and 29.5 in the standard care group: relative risk 1.01 (95% confidence interval 0.99 to 1.02); absolute difference 0.2% (95% confidence interval -0.5% to 0.9%). 99 participants (22.0%) in the virtual care group and 124 (27.3%) in the standard care group required acute hospital care: relative risk 0.80 (0.64 to 1.01); absolute difference 5.3% (-0.3% to 10.9%). More participants in the virtual care group than standard care group had a drug error detected (134 (29.7%) v 25 (5.5%); absolute difference 24.2%, 19.5% to 28.9%) and a drug error corrected (absolute difference 24.4%, 19.9% to 28.9%). Fewer participants in the virtual care group than standard care group reported pain at 7, 15, and 30 days after randomisation: absolute differences 13.9% (7.4% to 20.4%), 11.9% (5.1% to 18.7%), and 9.6% (2.9% to 16.3%), respectively. Beneficial effects proved substantially larger in centres with a higher rate of care escalation. CONCLUSION: Virtual care with RAM shows promise in improving outcomes important to patients and to optimal health system function. TRIAL REGISTRATION: ClinicalTrials.gov NCT04344665.

Local adaptation and archaic introgression shape global diversity at human structural variant loci.

Large genomic insertions and deletions are a potent source of functional variation, but are challenging to resolve with short-read sequencing, limiting knowledge of the role of such structural variants (SVs) in human evolution. Here, we used a graph-based method to genotype long-read-discovered SVs in short-read data from diverse human genomes. We then applied an admixture-aware method to identify 220 SVs exhibiting extreme patterns of frequency differentiation - a signature of local adaptation. The top two variants traced to the immunoglobulin heavy chain locus, tagging a haplotype that swept to near fixation in certain southeast Asian populations, but is rare in other global populations. Further investigation revealed evidence that the haplotype traces to gene flow from Neanderthals, corroborating the role of immune-related genes as prominent targets of adaptive introgression. Our study demonstrates how recent technical advances can help resolve signatures of key evolutionary events that remained obscured within technically challenging regions of the genome.

Post Discharge after Surgery Virtual Care with Remote Automated Monitoring Technology (PVC-RAM): protocol for a randomized controlled trial.

BACKGROUND: After nonelective (i.e., semiurgent, urgent and emergent) surgeries, patients discharged from hospitals are at risk of readmissions, emergency department visits or death. During the coronavirus disease 2019 (COVID-19) pandemic, we are undertaking the Post Discharge after Surgery Virtual Care with Remote Automated Monitoring Technology (PVC-RAM) trial to determine if virtual care with remote automated monitoring (RAM) compared with standard care will increase the number of days adult patients remain alive at home after being discharged following nonelective surgery. METHODS: We are conducting a randomized controlled trial in which 900 adults who are being discharged after nonelective surgery from 8 Canadian hospitals are randomly assigned to receive virtual care with RAM or standard care. Outcome adjudicators are masked to group allocations. Patients in the experimental group learn how to use the study's tablet computer and RAM technology, which will measure their vital signs. For 30 days, patients take daily biophysical measurements and complete a recovery survey. Patients interact with nurses via the cellular modem-enabled tablet, who escalate care to preassigned and available physicians if RAM measurements exceed predetermined thresholds, patients report symptoms, a medication error is identified or the nurses have concerns they cannot resolve. The primary outcome is number of days alive at home during the 30 days after randomization. INTERPRETATION: This trial will inform management of patients after discharge following surgery in the COVID-19 pandemic and offer insights for management of patients who undergo nonelective surgery in a nonpandemic setting. Knowledge dissemination will be supported through an online multimedia resource centre, policy briefs, presentations, peer-reviewed journal publications and media engagement. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04344665.

Small-molecule mimicry hunting strategy in the imperial cone snail, Conus imperialis.

Venomous animals hunt using bioactive peptides, but relatively little is known about venom small molecules and the resulting complex hunting behaviors. Here, we explored the specialized metabolites from the venom of the worm-hunting cone snail, Conus imperialis Using the model polychaete worm Platynereis dumerilii, we demonstrate that C. imperialis venom contains small molecules that mimic natural polychaete mating pheromones, evoking the mating phenotype in worms. The specialized metabolites from different cone snails are species-specific and structurally diverse, suggesting that the cones may adopt many different prey-hunting strategies enabled by small molecules. Predators sometimes attract prey using the prey's own pheromones, in a strategy known as aggressive mimicry. Instead, C. imperialis uses metabolically stable mimics of those pheromones, indicating that, in biological mimicry, even the molecules themselves may be disguised, providing a twist on fake news in chemical ecology.

Mid-term outcomes with adult endovascular treatment of coarctation of the aorta.

BACKGROUND: This study examines the contemporary medium- and long-term outcomes of endovascular repair of aortic coarctation in the adult. METHODS: We reviewed the clinical and imaging data of 56 consecutive adult patients with aortic coarctation who underwent endovascular repair at the Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada, from 2003 to 2018. RESULTS: There were 20 (35.7%) female and 36 (64.3%) male patients (including 9 re-intervention cases) with a mean age of 33.6 ± 13.6 years. Thirty-seven (66.1%) were treated with balloon-expandable covered stent and 12 (21.4%) were treated with balloon-expandable bare-metal stent. Pressure gradients decreased from baseline level of 27.99 ± 12.75 (8-70) mm Hg to 5.33 ± 4.42 (0-17.5) mm Hg following the procedure. There were 2 (3.6%) procedure related complications (aortic dissection [n = 1] and stent malposition [n = 1]). During a median (Q1 - Q3) follow up of 5.36 (2.28-7.58) years, 2 deaths (4.2%) and 9 (19%) re-interventions occurred, and the overall survival was 95.8%. CONCLUSION: Percutaneous coarctoplasty, with either covered or bare metal stents, is a safe and durable option for aortic coarctation repair with excellent long-term survival.

Effects of Transcatheter Aortic Valve Implantation on Frailty and Quality of Life.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an effective alternative to surgical valve replacement in high-risk patients with severe aortic stenosis. Although measures of frailty have been used to attempt to predict outcomes in this population, few studies have demonstrated changes in these measures. METHODS: We performed a prospective, observational study of 171 patients undergoing TAVI, of whom 44 had maximal follow-up of 1 month and 50 had maximal follow-up of 1 year. Quality of life was assessed using the Minnesota Living With Heart Failure Questionnaire, Katz Index of Independence in Activities of Daily Living questionnaire, and patient perception of overall well-being. Frailty was measured using the 10-m walk test and handgrip strength testing. RESULTS: In the overall cohort, participants demonstrated improvements in quality of life metrics, but deterioration in 10-m walk test and handgrip at 1 month. These trends continued at 1 year. However, patients in the lowest quintile of handgrip and 10-m walk test demonstrated a trend of improvements in these metrics during follow-up. CONCLUSIONS: Despite improvements in quality of life after TAVI, no improvements in frailty were observed in patients at 1 year.

CONTEXTE: Le remplacement valvulaire aortique par cathéter (TAVI) est une solution de rechange efficace à la chirurgie de remplacement valvulaire chez les patients atteints de sténose aortique grave et présentant un risque élevé. Les mesures de la fragilité sont utilisées pour tenter de prévoir les résultats au sein de cette population. Néanmoins, peu d'études ont permis d'objectiver les variations de ces mesures. MÉTHODOLOGIE: Nous avons réalisé une étude observationnelle prospective portant sur 171 patients ayant subi un TAVI, dont 44 suivis pendant un mois ou moins, et 50 durant un an ou moins. La qualité de vie a été évaluée au moyen de questionnaires ­ Minnesota Living With Heart Failure Questionnaire et Katz Index of Independence in Activities of Daily Living Questionnaire ­ et en fonction de la perception du patient relativement à son bien-être général. La fragilité a été mesurée à l'aide d'un test de marche sur dix mètres et d'un test de force de préhension. RÉSULTATS: Dans l'ensemble de la cohorte, une amélioration des mesures de la qualité de vie a été observée parallèlement à une détérioration des résultats au test de marche sur dix mètres et au test de force de préhension après un mois. Les tendances à cet égard se sont poursuivies au bout d'un an. Cependant, les résultats des patients du quintile inférieur au test de marche sur 10 m et au test de force de préhension ont eu tendance à s'améliorer au cours de la période de suivi. CONCLUSIONS: Malgré une amélioration de la qualité de vie après le TAVI, la fragilité des patients ne s'est nullement améliorée après un an.

A Unique Intracardiac Shunt: Identifying Complex Anatomy in Reoperative Adult Congenital Heart Disease.

Adult patients with repaired congenital heart disease are presenting with previously unseen types of residual lesions and consequences of prior repair. Patients with d-transposition of the great arteries repaired with atrial switch operations are returning with dysrhythmias and atrioventricular valve disease requiring intervention. We present the challenging case of a young adult with a residual shunt identified on preoperative three-dimensional transthoracic echocardiography, the precise anatomy of which was only characterized intraoperatively.