Plasma metabolomic and lipidomic profiles accurately classify mothers of children with congenital heart disease: an observational study.

INTRODUCTION: Congenital heart disease (CHD) is the most common congenital anomaly, representing a significant global disease burden. Limitations exist in our understanding of aetiology, diagnostic methodology and screening, with metabolomics offering promise in addressing these. OBJECTIVE: To evaluate maternal metabolomics and lipidomics in prediction and risk factor identification for childhood CHD. METHODS: We performed an observational study in mothers of children with CHD following pregnancy, using untargeted plasma metabolomics and lipidomics by ultrahigh performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). 190 cases (157 mothers of children with structural CHD (sCHD); 33 mothers of children with genetic CHD (gCHD)) from the children OMACp cohort and 162 controls from the ALSPAC cohort were analysed. CHD diagnoses were stratified by severity and clinical classifications. Univariate, exploratory and supervised chemometric methods were used to identify metabolites and lipids distinguishing cases and controls, alongside predictive modelling. RESULTS: 499 metabolites and lipids were annotated and used to build PLS-DA and SO-CovSel-LDA predictive models to accurately distinguish sCHD and control groups. The best performing model had an sCHD test set mean accuracy of 94.74% (sCHD test group sensitivity 93.33%; specificity 96.00%) utilising only 11 analytes. Similar test performances were seen for gCHD. Across best performing models, 37 analytes contributed to performance including amino acids, lipids, and nucleotides. CONCLUSIONS: Here, maternal metabolomic and lipidomic analysis has facilitated the development of sensitive risk prediction models classifying mothers of children with CHD. Metabolites and lipids identified offer promise for maternal risk factor profiling, and understanding of CHD pathogenesis in the future.

Performance Drift in Machine Learning Models for Cardiac Surgery Risk Prediction: Retrospective Analysis.

Background: The Society of Thoracic Surgeons and European System for Cardiac Operative Risk Evaluation (EuroSCORE) II risk scores are the most commonly used risk prediction models for in-hospital mortality after adult cardiac surgery. However, they are prone to miscalibration over time and poor generalization across data sets; thus, their use remains controversial. Despite increased interest, a gap in understanding the effect of data set drift on the performance of machine learning (ML) over time remains a barrier to its wider use in clinical practice. Data set drift occurs when an ML system underperforms because of a mismatch between the data it was developed from and the data on which it is deployed. Objective: In this study, we analyzed the extent of performance drift using models built on a large UK cardiac surgery database. The objectives were to (1) rank and assess the extent of performance drift in cardiac surgery risk ML models over time and (2) investigate any potential influence of data set drift and variable importance drift on performance drift. Methods: We conducted a retrospective analysis of prospectively, routinely gathered data on adult patients undergoing cardiac surgery in the United Kingdom between 2012 and 2019. We temporally split the data 70:30 into a training and validation set and a holdout set. Five novel ML mortality prediction models were developed and assessed, along with EuroSCORE II, for relationships between and within variable importance drift, performance drift, and actual data set drift. Performance was assessed using a consensus metric. Results: A total of 227,087 adults underwent cardiac surgery during the study period, with a mortality rate of 2.76% (n=6258). There was strong evidence of a decrease in overall performance across all models (P<.0001). Extreme gradient boosting (clinical effectiveness metric [CEM] 0.728, 95% CI 0.728-0.729) and random forest (CEM 0.727, 95% CI 0.727-0.728) were the overall best-performing models, both temporally and nontemporally. EuroSCORE II performed the worst across all comparisons. Sharp changes in variable importance and data set drift from October to December 2017, from June to July 2018, and from December 2018 to February 2019 mirrored the effects of performance decrease across models. Conclusions: All models show a decrease in at least 3 of the 5 individual metrics. CEM and variable importance drift detection demonstrate the limitation of logistic regression methods used for cardiac surgery risk prediction and the effects of data set drift. Future work will be required to determine the interplay between ML models and whether ensemble models could improve on their respective performance advantages.

Coronary Stenosis and Cardiogenic Shock Secondary to Aortitis Following Aortic Root Support Procedure.

A woman with recent personalized external aortic root support implant presented in cardiogenic shock with bilateral coronary ostial occlusion and aortic inflammation requiring emergency coronary angioplasty. Subsequent computed tomography with positron emission tomography scanning demonstrated aortitis with extensive inflammation adjacent to the personalized external aortic root support mesh, the first report of this important complication.

Growth capacity of a Wharton's Jelly derived mesenchymal stromal cells tissue engineered vascular graft used for main pulmonary artery reconstruction in piglets.

Background: Surgical treatment of congenital heart defects affecting the right ventricular outflow tract (RVOT) often requires complex reconstruction and multiple reoperations due to structural degeneration and lack of growth of currently available materials. Hence, alternative approaches for RVOT reconstruction, which meet the requirements of biocompatibility and long-term durability of an ideal scaffold, are needed. Through this full scale pre-clinical study, we demonstrated the growth capacity of a Wharton's Jelly derived mesenchymal stromal cells (WJ-MSC) tissue engineered vascular graft used in reconstructing the main pulmonary artery in piglets, providing proof of biocompatibility and efficacy. Methods: Sixteen four-week-old Landrace pigs were randomized to undergo supravalvar Main Pulmonary Artery (MPA) replacement with either unseeded or WJ-MSCs-seeded Small Intestinal Submucosa-derived grafts. Animals were followed up for 6 months by clinical examinations and cardiac imaging. At termination, sections of MPAs were assessed by macroscopic inspection, histology and fluorescent immunohistochemistry. Results: Data collected at 6 months follow up showed no sign of graft thrombosis or calcification. The explanted main pulmonary arteries demonstrated a significantly higher degree of cellular organization and elastin content in the WJ-MSCs seeded grafts compared to the acellular counterparts. Transthoracic echocardiography and cardiovascular magnetic resonance confirmed the superior growth and remodelling of the WJ-MSCs seeded conduit compared to the unseeded. Conclusion: Our findings indicate that the addition of WJ-MSCs to the acellular scaffold can upgrade the material, converting it into a biologically active tissue, with the potential to grow, repair and remodel the RVOT.

Protocol to decellularize porcine right ventricular outflow tracts using a 3D printed flow chamber.

Surgical treatment of pediatric congenital heart disease with tissue grafts is a lifesaving intervention. Decellularization to reduce immunogenicity of tissue grafts is an increasingly popular alternative to glutaraldehyde fixation. Here, we present a protocol to decellularize porcine right ventricular outflow tracts using a 3D printed flow chamber. We describe steps for 3D printing the flow rig, preparing porcine tissue, and using the flow rig to utilize shear forces for decellularization. We then detail procedures for characterizing the acellular scaffold. For complete details on the use and execution of this protocol, please refer to Vafaee et al.1.

Medium-Term Outcomes of Stent Therapy for Aortic Coarctation in Children Under 30 kg with New Generation Low-Profile Stents: A Follow-Up Study of a Single Centre Experience.

We previously reported short-term outcomes for stenting of aortic coarctation (CoA) (native or re-coarctation) with newer generation low-profile stents (Valeo, Formula, and Begraft stents) in children under 30 kg. We present here the medium-term outcomes of this procedure. Retrospective review of patients weighing under 30 kg who had percutaneous stent treatments for coarctation between 2012 and 2021 was performed. Clinical and procedural data were collected; 19 patients were included. The median age at the time of procedure was 5.1 [4.1-6.4] years and median weight 21.0 [17.3-22.3] kg. One patient had a history of re-coarctation. Thirteen (68%) patients were on anti-hypertensives pre-procedure. Different types of stents were used (14 Valeo™, 4 Formula® 535, 1 BeGraft), which can all be dilated to 18 mm or larger. One patient required a 9 F sheath, all others required a 7 F sheath. The narrowest diameter in the aorta increased from a median of 3.5 [3.0-4.5] to 9.4 [8.9-9.8] mm, p < 0.001; there was a reduction in the median pressure gradient across the coarctation from 35.0 [30.0-43.0] to 5.0 [0-10.0] mmHg, p < 0.001. There were no intra-procedural complications. Follow-up was for a median of 56.0 [13.0-65.0] months. Five (26%) of patients underwent re-intervention after a median time frame of 40.0 [39.5-52.0] months; four had balloon dilation, one had repeat stent implantation. Five (26%) patients were on anti-hypertensive agent(s) post-intervention. Our single centre experience demonstrates that percutaneous stenting for coarctation of aorta in children under 30 kg, with low-profile stents, had no significant complications during the median follow-up time of 56 months. This study demonstrated that the procedure is safe and effective for short and medium-term therapy in this group of patients with a 26% re-intervention rate. A quarter of patients remained on anti-hypertensive medication post stenting, emphasizing the importance of long-term follow-up.

Effect of on-pump vs. off-pump coronary artery bypass grafting in patients with non-dialysis-dependent severe renal impairment: propensity-matched analysis from the UK registry dataset.

Introduction: On-pump coronary artery bypass (ONCABG) grafting in patients with a pre-existing poor renal reserve is known to carry significant morbidity and mortality. There is limited controversial evidence on the benefit of off-pump coronary artery bypass (OPCABG) grafting in these high-risk groups of patients. We compared early clinical outcomes in propensity-matched cohorts of patients with non-dialysis-dependent pre-operative severe renal impairment undergoing OPCABG vs. ONCABG, captured in a large national registry dataset. Methods: All data for patients with a pre-operative creatinine clearance of less than 50 mL/min who underwent elective or urgent isolated OPCABG or ONCABG from 1996 to 2019 were extracted from the UK National Adult Cardiac Surgery Audit (NACSA) database. Propensity score matching was performed using 1:1 nearest neighbor matching without replacement using several baseline characteristics. We investigated the effect of ONCABG vs. OPCABG in the matched cohort using cluster-robust standard error regression. Results: We identified 8,628 patients with severe renal impairment undergoing isolated CABG, of whom 1,142 (13.23%) underwent OPCABG during the study period. We compared 1,141 propensity-matched pairs of patients undergoing OPCABG vs. ONCABG. The median age of the matched population was 78 years in both groups, with no significant imbalance post-matching in the rest of the variables. There was no difference between OPCABG and ONCABG in in-hospital mortality rates, post-operative dialysis, and stroke rates. However, the return to theatre for bleeding or tamponade was higher in ONCABG vs. OPCABG (P > 0.02); however, OPCABG reduced the total length of stay in the hospital by 1 day (P = 0.008). After double adjustment in the matched population using cluster-robust standard regression, ONCABG did not increase mortality compared to OPCABG (OR, 1.05, P = 0.78), postoperative stroke (OR, 1.7, P = 0.12), and dialysis (OR, 0.7, P = 0.09); however, ONCABG was associated with an increased risk of bleeding (OR, 1.53, P = 0.03). Discussion: In this propensity analysis of a large national registry dataset, we found no difference in early mortality and stroke in patients with pre-operative severe renal impairment undergoing OPCABG or ONCABG surgery; however, ONCABG was associated with an increased risk of return to theatre for bleeding and an increased length of hospital stay.

Use of the Occlutech pmVSD Device for Hybrid Closure of a Large Mid-Muscular Ventricular Septal Defect in a Small Infant Born With Hypoplastic Aortic Arch.

We describe the perventricular device closure of a large mid-muscular ventricular septal defect (VSD) in a 2.9 kg infant born with hypoplastic aortic arch and VSD using an Occlutech perimembranous occluder. In this case, the anatomy required a short low-profile device and hence a perimembranous occluder was used. To our knowledge, this is the first described use of this device for hybrid closure of a muscular VSD and the application of this technique in a patient <3 kg.

Influence of improved antenatal detection on the outcomes of complete atrioventricular block diagnosed in fetal-neonatal life and childhood periods - a single-centre experience in South Wales for 55 years.

OBJECTIVE: This study aimed to analyse the influence of improved antenatal detection on the course, contemporary outcomes, and mortality risk factors of the complete atrioventricular block during fetal-neonatal and childhood periods in South Wales. METHODS: The clinical characteristics and outcomes of complete atrioventricular block in patients without structural heart disease at the University Hospital of Wales from January 1966 to April 2021 were studied. Patients were divided into two groups according to their age at diagnosis: I-fetal-neonatal and II-childhood. Contemporary outcomes during the post-2001 era were compared with historical data preceding fetal service development and hence earlier detection. RESULTS: There were 64 patients: 26 were identified in the fetal-neonatal period and the remaining 38 in the childhood period. Maternal antibodies/systemic lupus erythematosus disease (anti-Ro/Sjögren's-syndrome-related Antigen A and/or anti-La/Sjögren's-syndrome-related Antigen B) were present in 15 (57.7%) of the fetal-neonatal. Fetal/neonatal and early diagnosis increased after 2001 with an incidence of 1:25000 pregnancies. Pacemaker implantation was required in 34 patients, of whom 13 were diagnosed in the fetal-neonatal group. Survival rates in cases identified before 2001 were at 96.3% (26/27), whereas it was 83.8% (31/37) in patients diagnosed after 2001 (P > 0.05). Other mortality risk factors comprised a lower gestational week at birth, maternal antibodies, and an average ventricular heart rate of < 55 bpm. CONCLUSIONS: Fetal diagnosis of complete atrioventricular block is still portends high fetal and neonatal mortality and morbidity despite significantly improved antenatal detection after 2001. Pacemaker intervention is needed earlier in the fetal-neonatal group. Whether routine antenatal medical treatment might alter this outcome calls for further prospective multicentre studies.

Surgical Patching in Congenital Heart Disease: The Role of Imaging and Modelling.

In congenital heart disease, patches are not tailored to patient-specific anatomies, leading to shape mismatch with likely functional implications. The design of patches through imaging and modelling may be beneficial, as it could improve clinical outcomes and reduce the costs associated with redo procedures. Whilst attention has been paid to the material of the patches used in congenital surgery, this review outlines the current knowledge on this subject and isolated experimental work that uses modelling and imaging-derived information (including 3D printing) to inform the design of the surgical patch.

Development and Evaluation of a Natural Language Processing System for Curating a Trans-Thoracic Echocardiogram (TTE) Database.

BACKGROUND: Although electronic health records (EHR) provide useful insights into disease patterns and patient treatment optimisation, their reliance on unstructured data presents a difficulty. Echocardiography reports, which provide extensive pathology information for cardiovascular patients, are particularly challenging to extract and analyse, because of their narrative structure. Although natural language processing (NLP) has been utilised successfully in a variety of medical fields, it is not commonly used in echocardiography analysis. OBJECTIVES: To develop an NLP-based approach for extracting and categorising data from echocardiography reports by accurately converting continuous (e.g., LVOT VTI, AV VTI and TR Vmax) and discrete (e.g., regurgitation severity) outcomes in a semi-structured narrative format into a structured and categorised format, allowing for future research or clinical use. METHODS: 135,062 Trans-Thoracic Echocardiogram (TTE) reports were derived from 146967 baseline echocardiogram reports and split into three cohorts: Training and Validation (n = 1075), Test Dataset (n = 98) and Application Dataset (n = 133,889). The NLP system was developed and was iteratively refined using medical expert knowledge. The system was used to curate a moderate-fidelity database from extractions of 133,889 reports. A hold-out validation set of 98 reports was blindly annotated and extracted by two clinicians for comparison with the NLP extraction. Agreement, discrimination, accuracy and calibration of outcome measure extractions were evaluated. RESULTS: Continuous outcomes including LVOT VTI, AV VTI and TR Vmax exhibited perfect inter-rater reliability using intra-class correlation scores (ICC = 1.00, p < 0.05) alongside high R2 values, demonstrating an ideal alignment between the NLP system and clinicians. A good level (ICC = 0.75-0.9, p < 0.05) of inter-rater reliability was observed for outcomes such as LVOT Diam, Lateral MAPSE, Peak E Velocity, Lateral E' Velocity, PV Vmax, Sinuses of Valsalva and Ascending Aorta diameters. Furthermore, the accuracy rate for discrete outcome measures was 91.38% in the confusion matrix analysis, indicating effective performance. CONCLUSIONS: The NLP-based technique yielded good results when it came to extracting and categorising data from echocardiography reports. The system demonstrated a high degree of agreement and concordance with clinician extractions. This study contributes to the effective use of semi-structured data by providing a useful tool for converting semi-structured text to a structured echo report that can be used for data management. Additional validation and implementation in healthcare settings can improve data availability and support research and clinical decision-making.

An incidental finding of a right atrial myxoma with undiagnosed Ebstein anomaly: a case report.

Background: Ebstein anomaly (EA) is a rare congenital abnormality of the tricuspid valve which can lead to progressive right heart dilatation and arrhythmias. While often seen in conjunction with other congenital cardiac lesions, such as atrial septal defects, it is not normally associated with atrial myxomas. Case summary: We present a case report of an incidental finding of a right atrial myxoma in the context of undiagnosed EA, in a 16-year-old male who presented with appendicitis. Subtle cardiomegaly on routine chest X-ray prompted further investigation, which demonstrated characteristic findings of both conditions and culminated in surgical repair using the Cone procedure. At 4-month follow-up, the patient was asymptomatic, and transthoracic echocardiography demonstrated a mean gradient of 4.5 mmHg across the tricuspid valve with mild regurgitation. Discussion: The combination of EA with right-sided myxoma is exceedingly rare, and, in this case, it may be that the apical displacement of the tricuspid valve was protective against right atrioventricular obstruction. We are reminded that although subtle abnormalities on routine investigations can be of limited significance, they can also indicate more serious underlying pathology and so consideration should be given to an appropriate cascade of further investigations to yield a timely diagnosis and enable prompt treatment.

Exaggerated elastin turnover in young individuals with Marfan syndrome: new insights from the AIMS trial.

Aims: The fragmentation and loss of elastic fibre in the tunica media of the aorta are pathological hallmarks of Marfan syndrome (MFS) but the dynamics of elastin degradation and its relationship to aortic size and physiological growth remain poorly understood. Methods and results: In this post hoc analysis of the AIMS randomized controlled trial, the association of plasma desmosine (pDES)-a specific biomarker of mature elastin degradation-with age and aortic size was analysed in 113 patients with MFS and compared to 109 healthy controls. There was a strong association between age and pDES in both groups, with higher pDES levels in the lower age groups compared to adults. During childhood, pDES increased and peaked during early adolescence, and thereafter decreased to lower adult levels. This trend was exaggerated in young individuals with MFS but in those above 25 years of age, pDES levels were comparable to controls despite the presence of aortic root dilation. In MFS children, increased aortic diameter relative to controls was seen at an early age and although the increase in diameter was less after adolescence, aortic root size continued to increase steadily with age. In MFS participants, there was an indication of a positive association between baseline pDES levels and aortic root dilatation during up to 5 years of follow-up. Conclusion: This study has shown that developmental age has a significant effect on levels of elastin turnover as measured by pDES in MFS individuals as well as healthy controls. This effect is exaggerated in those with MFS with increased levels seen during the period of physiologic development that plateaus towards adulthood. This suggests an early onset of pathophysiology that may present an important opportunity for disease-modifying intervention.

Graft rejection in paediatric congenital heart disease.

Congenital heart disease (CHD) affects around 1.35 million neonates worldwide per annum, and surgical repair is necessary in approximately 25% of cases. Xenografts, usually of bovine or porcine origin, are often used for the surgical reconstruction. These xenografts elicit an immune response due to significant immunological incompatibilities between host and donor. Current techniques to dampen the initial hyperacute rejection response involve aldehyde fixation to crosslink xenoantigens, such as galactose-α1,3-galactose and N-glycolylneuraminic acid. While this temporarily masks the epitopes, aldehyde fixation is a suboptimal solution, degrading over time, resulting in cytotoxicity and rejection. The immune response to foreign tissue eventually leads to chronic inflammation and subsequent graft failure, necessitating reintervention to replace the defective bioprosthetic. Decellularisation to remove immunoincompatible material has been suggested as an alternative to fixation and may prove a superior solution. However, incomplete decellularisation poses a significant challenge, causing a substantial immune rejection response and subsequent graft rejection. This review discusses commercially available grafts used in surgical paediatric CHD intervention, looking specifically at bovine jugular vein conduits as a substitute to cryopreserved homografts, as well as decellularised alternatives to the aldehyde-fixed graft. Mechanisms of biological prosthesis rejection are explored, including the signalling cascades of the innate and adaptive immune response. Lastly, emerging strategies of intervention are examined, including the use of tissue from genetically modified pigs, enhanced crosslinking and decellularisation techniques, and augmentation of grafts through in vitro recellularisation or functionalisation with human surface proteins.

Outcome monitoring and risk stratification after cardiac procedure in neonates, infants, children and young adults born with congenital heart disease: protocol for a multicentre prospective cohort study (Children OMACp).

INTRODUCTION: Congenital heart disease (CHD) represents the most common birth defect, affecting from 0.4% to 1.2% of children born in developed countries. The survival of these patients has increased significantly, but CHD remains one of the major causes of neonatal and childhood death. The aetiology of CHD is complex, with some evidence of both genetic and environmental causes. However, there is still lack of knowledge regarding modifiable risk factors and molecular and genetic mechanisms underlying the development of CHD. This study aims to develop a prospective cohort of patients undergoing cardiac procedures that will bring together routinely collected clinical data and biological samples from patients and their biological mothers, in order to investigate risk factors and predictors of postoperative-outcomes, as well as better understanding the effect of the surgical intervention on the early and long-term outcomes. METHODS AND ANALYSIS: Children OMACp (OMACp, outcome monitoring after cardiac procedure in congenital heart disease) is a multicentre, prospective cohort study recruiting children with CHD undergoing a cardiac procedure. The study aims to recruit 3000 participants over 5 years (2019-2024) across multiple UK sites. Routine clinical data will be collected, as well as participant questionnaires collecting sociodemographic, NHS resource use and quality of life data. Biological samples (blood, urine and surgical waste tissue from patients, and blood and urine samples from biological mothers) will be collected where consent has been obtained. Follow-up outcome and questionnaire data will be collected for 5 years. ETHICS AND DISSEMINATION: The study was approved by the London-Brent Research Ethics Committee on 30 July 2019 (19/SW/0113). Participants (or their parent/guardian if under 16 years of age) must provide informed consent prior to being recruited into the study. Mothers who wish to take part must also provide informed consent prior to being recruited. The study is sponsored by University Hospitals Bristol and Weston Foundation Trust and is managed by the University of Bristol. Children OMACp is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated through peer-reviewed publications, presentation at conference, meetings and through patient organisations and newsletters. TRIAL REGISTRATION NUMBER: ISRCTN17650644.

Zebrafish as a model for cardiac disease; Cryo-EM structure of native cardiac thin filaments from Danio Rerio.

Actin, tropomyosin and troponin, the proteins that comprise the contractile apparatus of the cardiac thin filament, are highly conserved across species. We have used cryo-EM to study the three-dimensional structure of the zebrafish cardiac thin and actin filaments. With 70% of human genes having an obvious zebrafish orthologue, and conservation of 85% of disease-causing genes, zebrafish are a good animal model for the study of human disease. Our structure of the zebrafish thin filament reveals the molecular interactions between the constituent proteins, showing that the fundamental organisation of the complex is the same as that reported in the human reconstituted thin filament. A reconstruction of zebrafish cardiac F-actin demonstrates no deviations from human cardiac actin over an extended length of 14 actin subunits. Modelling zebrafish homology models into our maps enabled us to compare, in detail, the similarity with human models. The structural similarities of troponin-T in particular, a region known to contain a hypertrophic cardiomyopathy 'hotspot', confirm the suitability of zebrafish to study these disease-causing mutations.

Single-cell T cell receptor sequencing of paired tissue and blood samples reveals clonal expansion of CD8+ effector T cells in patients with calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is a complex cardiovascular pathology, culminating in aortic stenosis, heart failure and premature mortality, with no comprehensive treatment strategy, except valve replacement. While T cells have been identified within the valve, their contribution to pathogenesis remains unclear. To elucidate the heterogenous phenotype of the immune populations present within patients with CAVD, deep phenotypic screens of paired valve and peripheral blood cells were conducted via flow cytometry (n=20) and immunohistochemistry (n=10). Following identification of a significant population of memory T cells; specifically, CD8+ T cells within the valve, single cell RNA sequencing and paired single T cell receptor sequencing was conducted on a further 4 patients on CD45+ CD3+, CD4+ or CD8+ T cells. Through unsupervised clustering, 7 T cell populations were identified within the blood and 10 identified within the valve. Tissue resident memory (T RM ) T cells were detected for the first time within the valve, exhibiting a highly cytotoxic, activated, and terminally differentiated phenotype. This pan-pro-inflammatory signal was differentially identified in T cells originating from the valve, and not observed in the blood, indicative of an adaptive, local not-systemic inflammatory signature in CAVD patients. T cell receptor analysis identified hyperexpanded clones within the CD8+ T cell central memory (T CM ) population, with T RM cells comprising the majority of large and medium clonal expansion within the entire T cell population. Clonal interaction network analysis demonstrated the greatest proportion of clones originating from CD8+ T cell effector memory (T EM ) and CD4+ naïve / T CM populations and ending in the CD8+ T RM and CD8+ T CM clusters, suggesting a clonal expansion and predicted trajectory of T cells towards a tissue resident, cytotoxic environment within the valve. CDR3 epitope predictive analysis identified 7 potential epitope targets, of which GALNT4 and CR1L have previously been implicated in a cardiovascular context as mediators of inflammation. Taken together, the data identified T cell sub-populations within the context of CAVD and further predicted possible epitopes responsible for the clonal expansion of the valvular T cells, which may be important for propagating inflammation in CAVD.

Cardiac surgery risk prediction using ensemble machine learning to incorporate legacy risk scores: A benchmarking study.

Objective: The introduction of new clinical risk scores (e.g. European System for Cardiac Operative Risk Evaluation (EuroSCORE) II) superseding original scores (e.g. EuroSCORE I) with different variable sets typically result in disparate datasets due to high levels of missingness for new score variables prior to time of adoption. Little is known about the use of ensemble learning to incorporate disparate data from legacy scores. We tested the hypothesised that Homogenenous and Heterogeneous Machine Learning (ML) ensembles will have better performance than ensembles of Dynamic Model Averaging (DMA) for combining knowledge from EuroSCORE I legacy data with EuroSCORE II data to predict cardiac surgery risk. Methods: Using the National Adult Cardiac Surgery Audit dataset, we trained 12 different base learner models, based on two different variable sets from either EuroSCORE I (LogES) or EuroScore II (ES II), partitioned by the time of score adoption (1996-2016 or 2012-2016) and evaluated on holdout set (2017-2019). These base learner models were ensembled using nine different combinations of six ML algorithms to produce homogeneous or heterogeneous ensembles. Performance was assessed using a consensus metric. Results: Xgboost homogenous ensemble (HE) was the highest performing model (clinical effectiveness metric (CEM) 0.725) with area under the curve (AUC) (0.8327; 95% confidence interval (CI) 0.8323-0.8329) followed by Random Forest HE (CEM 0.723; AUC 0.8325; 95%CI 0.8320-0.8326). Across different heterogenous ensembles, significantly better performance was obtained by combining siloed datasets across time (CEM 0.720) than building ensembles of either 1996-2011 (t-test adjusted, p = 1.67×10-6) or 2012-2019 (t-test adjusted, p = 1.35×10-193) datasets alone. Conclusions: Both homogenous and heterogenous ML ensembles performed significantly better than DMA ensemble of Bayesian Update models. Time-dependent ensemble combination of variables, having differing qualities according to time of score adoption, enabled previously siloed data to be combined, leading to increased power, clinical interpretability of variables and usage of data.

The Role of Immersive Virtual Reality and Augmented Reality in Medical Communication: A Scoping Review.

Communication between clinicians and patients and communication within clinical teams is widely recognized as a tool through which improved patient outcomes can be achieved. As emerging technologies, there is a notable lack of commentary on the role of immersive virtual reality (VR) and augmented reality (AR) in enhancing medical communication. This scoping review aims to map the current landscape of literature on this topic and highlights gaps in the evidence to inform future endeavors. A comprehensive search strategy was conducted across 3 databases (PubMed, Web of Science, and Embase), yielding 1000 articles, of which 623 were individually screened for relevance. Ultimately, 22 articles were selected for inclusion and review. Similarities across the cohort of studies included small sample sizes, observational study design, use of questionnaires, and more VR studies than AR. The majority of studies found these technologies to improve medical communication, although user tolerability limitations were identified. More studies are required, presenting more robust findings, in order to draw more definitive conclusions and stronger recommendations for use of immersive VR/AR in clinical environments.

Off-pump injectable versus on-pump conventional tissue valves for pulmonary valve replacement: the injectable valve implantation randomised trial (INVITE).

OBJECTIVES: To assess the effectiveness of injectable tissue pulmonary valve compared with standard pulmonary valve in patients requiring pulmonary valve replacement surgery. DESIGN: A multicentre, single-blind, parallel two-group randomised controlled trial. Participants were blind to their allocation. Follow-up continued for 6 months. Randomised allocations were generated by a computer using block randomisation, stratified by centre. SETTING: Two National Health Service secondary care centres in the UK. PARTICIPANTS: People aged 12-80 years requiring pulmonary valve replacement. INTERVENTIONS: Participants were randomly allocated (1:1 ratio) to injectable pulmonary valve replacement (IPVR) without cardiopulmonary bypass (CPB) or standard pulmonary valve replacement (SPVR) with CPB. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was chest drainage volume over the first 24 hours after surgery. Secondary outcomes included in-hospital clinical outcomes; valve and heart function 6 months postsurgery and health-related quality of life 6 weeks and 6 months postsurgery. RESULTS: Nineteen participants agreed to take part. Eleven were allocated to IPVR and eight to SPVR. The trial was stopped before the target sample size of 60 participants was reached due to challenges in recruitment. The primary analysis includes all randomised participants; there were no withdrawals. Chest drain volume 24 hours after surgery was on average 277.6 mL lower with IPVR (IPVR mean 340.0 mL; SPVR mean 633.8 mL; mean difference, -277.6; 95% CI, -484.0 to -71.2; p=0.005). There were no statistically significant differences in time to readiness for extubation (p=0.476), time to fitness for discharge (p=0.577) and time to first discharge from the intensive care unit (p=0.209). Six participants with IPVR required CPB. Safety profiles and quality of life scores were similar. CONCLUSIONS: IPVR reduced chest drain volume despite >50% of participants requiring CPB. There was no evidence of any other benefit of IPVR. TRIAL REGISTRATION NUMBER: ISRCTN23538073.