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Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (hPSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon human endogenous retrovirus subfamily H (HERV-H) in creating topologically associating domains (TADs) in hPSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces the transcription of upstream genes, while de novo insertion of HERV-H elements can introduce new TAD boundaries. The ability of HERV-H to create TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents the formation of boundaries. This ability is not limited to hPSCs, as these actively transcribed HERV-H elements and their corresponding TAD boundaries also appear in pluripotent stem cells from other hominids but not in more distantly related species lacking HERV-H elements. Overall, our results provide direct evidence for retrotransposons in actively shaping cell type- and species-specific chromatin architecture. Genetic deletion or transcriptional silencing of HERV-H elements in human pluripotent stem cells (hPSCs) eliminates nearby topologically associating domain boundaries, while de novo insertion of HERV-H elements can introduce new ones. Mutations of specific HERV-H elements can impact hPSC differentiation.

A complex interplay involving Notch- and Erbb2-mediated signalling between cardiomyocytes guides the morphogenesis of the ventricular wall. Many organs are composed of complex tissue walls that are structurally organized to optimize organ function. In particular, the ventricular myocardial wall of the heart comprises an outer compact layer that concentrically encircles the ridge-like inner trabecular layer. Although disruption in the morphogenesis of this myocardial wall can lead to various forms of congenital heart disease 1 and non-compaction cardiomyopathies 2 , it remains unclear how embryonic cardiomyocytes assemble to form ventricular wall layers of appropriate spatial dimensions and myocardial mass. Here we use advanced genetic and imaging tools in zebrafish to reveal an interplay between myocardial Notch and Erbb2 signalling that directs the spatial allocation of myocardial cells to their proper morphological positions in the ventricular wall. Although previous studies have shown that endocardial Notch signalling non-cell-autonomously promotes myocardial trabeculation through Erbb2 and bone morphogenetic protein (BMP) signalling 3 , we discover that distinct ventricular cardiomyocyte clusters exhibit myocardial Notch activity that cell-autonomously inhibits Erbb2 signalling and prevents cardiomyocyte sprouting and trabeculation. Myocardial-specific Notch inactivation leads to ventricles of reduced size and increased wall thickness because of excessive trabeculae, whereas widespread myocardial Notch activity results in ventricles of increased size with a single-cell-thick wall but no trabeculae. Notably, this myocardial Notch signalling is activated non-cell-autonomously by neighbouring Erbb2-activated cardiomyocytes that sprout and form nascent trabeculae. Thus, these findings support an interactive cellular feedback process that guides the assembly of cardiomyocytes to morphologically create the ventricular myocardial wall and more broadly provide insight into the cellular dynamics of how diverse cell lineages organize to create form.

A critical step in the assembly of the neural circuits that control tetrapod locomotion is the specification of the lateral motor column (LMC), a diverse motor neuron population targeting limb musculature. Hox6 paralog group genes have been implicated as key determinants of LMC fate at forelimb levels of the spinal cord, through their ability to promote expression of the LMC-restricted genes Foxp1 and Raldh2 and to suppress thoracic fates through exclusion of Hoxc9. The specific roles and mechanisms of Hox6 gene function in LMC neurons, however, are not known. We show that Hox6 genes are critical for diverse facets of LMC identity and define motifs required for their in vivo specificities. Although Hox6 genes are necessary for generating the appropriate number of LMC neurons, they are not absolutely required for the induction of forelimb LMC molecular determinants. In the absence of Hox6 activity, LMC identity appears to be preserved through a diverse array of Hox5-Hox8 paralogs, which are sufficient to reprogram thoracic motor neurons to an LMC fate. In contrast to the apparently permissive Hox inputs to early LMC gene programs, individual Hox genes, such as Hoxc6, have specific roles in promoting motor neuron pool diversity within the LMC. Dissection of motifs required for Hox in vivo specificities reveals that either cross-repressive interactions or cooperativity with Pbx cofactors are sufficient to induce LMC identity, with the N-terminus capable of promoting columnar, but not pool, identity when transferred to a heterologous homeodomain. These results indicate that Hox proteins orchestrate diverse aspects of cell fate specification through both the convergent regulation of gene programs regulated by many paralogs and also more restricted actions encoded through specificity determinants in the N-terminus.

Background Tricuspid regurgitation(TR) following heart transplantation could adversely affect clinical outcomes. In an effort to reduce the incidence of TR, prophylactic donor heart tricuspid valve annuloplasty has been performed during heart transplantation in our institution. We assessed early and long-term outcomes. Methods Between August 2011 and August 2021, 349 patients who underwent prophylactic tricuspid valve annuloplasty were included. Tricuspid valve annuloplasty was performed using the DeVega annuloplasty technique. The clinical outcomes of the interests included complete atrioventricular block requiring pacemaker implantation, the occurrence of significant TR(defined as moderate or greater), and survival. Long-term survival was compared in patients with and without significant TR using the Kaplan-Meier method. The Cox proportional hazards regression with time-dependent covariate analysis was used to see if significant TR affected the long-term survival. Results There was one patient(0.3%) who required pacemaker implantation for complete atrioventricular block. No patients developed tricuspid valve stenosis that required intervention. Significant TR developed in 31 patients(8.9%) during the follow-up period. The survival rate of patients who developed significant TR was significantly lower than that of those who did not(log rank < 0.01). Significant TR was associated with the long-term mortality(HR2.92, 95%CI 1.47–5.82, p < 0.01). Conclusions Prophylactic donor heart tricuspid valve annuloplasty has the potential to reduce the occurrence of significant TR and can be performed safely. The significant TR that developed in patients with prophylactic annuloplasty negatively affected survival and was an independent predictor of long-term mortality.

Aims Aortic pulsatility index (API), calculated as (systolic–diastolic blood pressure)/pulmonary capillary wedge pressure (PCWP), is a novel haemodynamic measurement representing both cardiac filling pressures and contractility. We hypothesized that API would better predict clinical outcomes than traditional haemodynamic metrics of cardiac function. Methods and results The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial individual‐level data were used. Routine haemodynamic measurements, including Fick cardiac index (CI), and the advanced haemodynamic metrics of API, cardiac power output (CPO), and pulmonary artery pulsatility index (PAPI) were calculated after final haemodynamic‐monitored optimization. The primary outcome was a composite endpoint of death or need for orthotopic heart transplant (OHT) or left ventricular assist device (LVAD) at 6 months. A total of 433 participants were enrolled in the ESCAPE trial of which 145 had final haemodynamic data. Final API measurements predicted the primary outcome, OR 0.47 (95% CI 0.32–0.70, P < 0.001), while CI, CPO, and PAPI did not. Receiver operator characteristic analyses of final advanced haemodynamic measurements indicated API best predicted the primary outcome with a cutoff of 2.9 (sensitivity 76.2%, specificity 55.3%, correctly classified 61.4%, area‐under‐the‐curve 0.71), compared with CPO, CI, and PAPI. Kaplan–Meier analyses indicated API ≥ 2.9 was associated with greater freedom from the primary outcome (83.5%), compared with API < 2.9 (58.4%), P = 0.001. While PAPI was also significantly associated, CI and CPO were not. Conclusions The novel haemodynamic measurement API better predicted clinical outcomes in the ESCAPE trial when compared with traditional invasive haemodynamic metrics of cardiac function.

The heart, a vital organ which is first to develop, has adapted its size, structure and function in order to accommodate the circulatory demands for a broad range of animals. Although heart development is controlled by a relatively conserved network of transcriptional/chromatin regulators, how the human heart has evolved species-specific features to maintain adequate cardiac output and function remains to be defined. Here, we show through comparative epigenomic analysis the identification of enhancers and promoters that have gained activity in humans during cardiogenesis. These cis-regulatory elements (CREs) are associated with genes involved in heart development and function, and may account for species-specific differences between human and mouse hearts. Supporting these findings, genetic variants that are associated with human cardiac phenotypic/disease traits, particularly those differing between human and mouse, are enriched in human-gained CREs. During early stages of human cardiogenesis, these CREs are also gained within genomic loci of transcriptional regulators, potentially expanding their role in human heart development. In particular, we discovered that gained enhancers in the locus of the early human developmental regulator are selectively accessible within a subpopulation of mesoderm cells which exhibits cardiogenic potential, thus possibly extending the function of beyond its conserved left-right asymmetry role. Genetic deletion of these enhancers identified a human gained enhancer that was required for not only and early cardiac gene expression at the mesoderm stage but also cardiomyocyte differentiation. Overall, our results illuminate how human gained CREs may contribute to human-specific cardiac attributes, and provide insight into how transcriptional regulators may gain cardiac developmental roles through the evolutionary acquisition of enhancers.

Background A central goal among researchers and policy makers seeking to implement clinical interventions is to identify key facilitators and barriers that contribute to implementation success. Despite calls from a number of scholars, empirical insights into the complex structural and cultural predictors of why decision aids (DAs) become routinely embedded in health care settings remains limited and highly variable across implementation contexts. Methods We examined associations between “reach”, a widely used indicator (from the RE-AIM model) of implementation success, and multi-level site characteristics of nine LVAD clinics engaged over 18 months in implementation and dissemination of a decision aid for left ventricular assist device (LVAD) treatment. Based on data collected from nurse coordinators, we explored factors at the level of the organization (e.g. patient volume), patient population (e.g. health literacy; average sickness level), clinician characteristics (e.g. attitudes towards decision aid; readiness for change) and process (how the aid was administered). We generated descriptive statistics for each site and calculated zero-order correlations (Pearson’s  r ) between all multi-level site variables including cumulative reach at 12 months and 18 months for all sites. We used principal components analysis (PCA) to examine any latent factors governing relationships between and among all site characteristics, including reach. Results We observed strongest inclines in reach of our decision aid across the first year, with uptake fluctuating over the second year. Average reach across sites was 63% (s.d. = 19.56) at 12 months and 66% (s.d. = 19.39) at 18 months. Our PCA revealed that site characteristics positively associated with reach on two distinct dimensions, including a first dimension reflecting greater organizational infrastructure and standardization (characteristic of larger, more established clinics) and a second dimension reflecting positive attitudinal orientations, specifically, openness and capacity to give and receive decision support among coordinators and patients. Conclusions Successful implementation plans should incorporate specific efforts to promote supportive and mutually informative interactions between clinical staff members and to institute systematic and standardized protocols to enhance the availability, convenience and salience of intervention tool in routine practice. Further research is needed to understand whether “core predictors” of success vary across different intervention types.

Aims Heart transplantation involves many factors such as donor selection, recipient management, multidisciplinary assessment, coordination with other organ teams, and transportation. Because of some unpredictable factors, heart transplantation can be conducted at any time of day. The purpose of this study is to investigate if outcomes differ between heart transplants taking place inside or outside of normal working hours. Methods and results We reviewed patients who underwent heart transplantation at our institution from January 2010 to July 2020 (n = 329). Based on the documented start time of the recipient surgeries, the cohort was divided into two groups: working hours (Group A: 7:30 to 17:00; n = 92) and after hours (Group B: 17:00 to 7:30; n = 237). We compared these groups using propensity score matching analysis. After propensity score matching, 78 pairs of patients were successfully matched. We reviewed early and late clinical outcomes including survival. Long‐term survival was compared using the Kaplan–Meier method. In the propensity‐score matched patients, there were no significant differences in the baseline characteristics between two groups. In‐hospital mortality was not significantly different between the two groups (Group A: 6.4% vs. Group B: 2.6%, P = 0.44). Ischaemic time and cross‐clamp time did not differ between the groups. In terms of postoperative complications, there were no significant differences between two groups in stroke (6.4% vs. 3.9%, P = 0.72), primary graft dysfunction requiring extracorporeal membrane oxygenation (5.1% vs. 7.7%, P = 0.75), re‐exploration for bleeding (9.0% vs. 12.8%, P = 0.44), and newly required haemodialysis (7.7% vs. 6.4%, P = 0.75). The survival rate in Group A (88.1% at 1 year, 81.3% at 3 years) was not significantly different from Group B (90.5% at 1 year, 82.3% at 3 years, log rank = 0.96). Conclusion There was no significant difference in clinical outcomes between heart transplants taking place inside or outside of working hours. A high quality of care can be provided for heart transplant patients even during after hours.

Management of acute right ventricular failure, both with and without coexisting pulmonary hypertension, is a common challenge encountered in the intensive care setting. Both right ventricular dysfunction and pulmonary hypertension portend a poor prognosis, regardless of the underlying cause and are associated with significant morbidity and mortality. The right ventricle is embryologically distinct from the left ventricle and has unique morphologic and functional properties. Management of right ventricular failure and pulmonary hypertension in the intensive care setting requires tailored hemodynamic management, pharmacotherapy, and often mechanical circulatory support. Unfortunately, our understanding of the management of right ventricular failure lags behind that of the left ventricle. In this review, we will explore the underlying pathophysiology of the failing right ventricle and pulmonary vasculature in patients with and without pulmonary hypertension and discuss management strategies based on evidence-based studies as well as our current understanding of the underlying physiology.