Haemodynamic support with percutaneous devices in patients with cardiogenic shock: the current evidence of mechanical circulatory support.

INTRODUCTION: Cardiogenic shock (CS) is a complex life-threatening condition that results from primary cardiac dysfunction, leading to persistent hypotension and systemic hypoperfusion. Among the therapeutic options for CS are various percutaneous mechanical circulatory support (MCS) devices that have emerged as an increasingly effective hemodynamic support option. Percutaneous therapies can act as short-term mechanical circulatory assistance and can be split into intra-aortic balloon pump (IABP) and non-IABP percutaneous mechanical devices. AREAS COVERED: This review will evaluate the MCS value while considering the mortality rate improvements. We also aim to outline the function of pharmacotherapies and percutaneous hemodynamic MCS devices in managing CS patients to avoid the onset of end-organ dysfunction and improve both early and late outcomes. EXPERT OPINION: Given the complexity, acuity and high mortality associated with CS, and despite the availability and efficacy of pharmacological management, MCS is required to achieve hemodynamic stability and improve survival. Various percutaneous MCS devices are available with varying indications and clinical outcomes. The rates of early mortality and complications were found to be comparable between the four devices, yet, IABP seemed to show the most optimal clinical profile whilst ECMO demonstrated its more long-term efficacy.

Long-Term Survival and Reintervention Following Thoracic Endovascular Aortic Repair in Blunt Traumatic Thoracic Aortic Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Blunt thoracic aortic injury (BTAI) represents one of the most devastating scenarios of vascular trauma. Different management strategies are available with varying clinical outcomes. However, thoracic endovascular aortic repair (TEVAR) has become the first-line option for most BTAI patients, mainly owing to its minimally invasive nature, yielding improved immediate results. This meta-analysis aims to investigate mortality, long-term survival, and reintervention following TEVAR in BTAI. MATERIAL AND METHODS: A systematic review conducted a comprehensive literature search on multiple electronic databases using strict search terms. Twenty-seven studies met the set inclusion/exclusion criteria. A proportional meta-analysis of extracted data was conducted using the Comprehensive Meta-Analysis Software, v.4. RESULTS: 1498 BTAI patients who underwent TEVAR were included. Using the SVS grading system, 2.6% of the population had Grade 1 injuries, 13.6% Grade 2, 62.2% Grade 3, 19.6% Grade 4, and 1.9% unspecific. All-cause mortality did not exceed 20% in all studies except one outlier with a 37% mortality rate. Using the random effects model, the pooled estimate of overall mortality was 12% (95% confidence interval [CI], 5.35-8.55%; I2 = 70.6%). This was 91% (95% CI, 88.6-93.2; I2 = 30.2%) at 6 months, 90.1% (95% CI, 86.7-92.3; I2 = 53.6%) at 1 year, 89.2% (95% CI, 85.2-91.8; I2 = 62.3%) at 2 years, and 88.1% (95% CI, 83.3-90.9; I2 = 69.6%) at 5 years. Moreover, the pooled estimate of reintervention was 6.4% (95% CI, 0.1-0.49%; I2 = 81.7%). CONCLUSIONS: Despite the high morbidity and mortality associated with BTAI, TEVAR has proven to be a safe and effective management strategy with favorable long-term survival and minimal need for reintervention. Nevertheless, diagnosis of BTAI requires a high index of suspicion with appropriate grading and prompt transfer to trauma centers with appropriate TEVAR facilities.

Outcomes of Patients Presenting With Non-ST Elevation Myocardial Infarction Who Underwent Surgical Revascularization.

Non-ST-segment elevation myocardial infarction (NSTEMI) is a leading cause of emergency hospitalization across Europe. This study evaluates the in-hospital and mid-term outcomes of patients who underwent coronary artery bypass graft (CABG) after NSTEMI. A retrospective analysis of all cases who underwent isolated CABG after NSTEMI from September 2017 to September 2022 at our center. Patients were stratified according to in-hospital survival. Patient characteristics, operative details, and procedural complications were compared between those who survived and those who did not. Predictors of in-hospital and mid-term mortality were evaluated using logistic and Cox regression modeling. Kaplan-Meier analysis was used to generate a survival curve for all alive patients at the time of discharge. Among 1,011 patients (median age 64 [56 to 72] years, 852 [84.3%] male), 735 (72.7%) underwent urgent, 239 (23.6%) elective, and 37 (3.7%) emergency CABG. The in-hospital mortality was 1.5% (15/1,011 patients). Those who died were more likely to be New York Heart Association class III/IV, have left ventricular ejection fraction <21%, severe renal impairment, peripheral vascular disease (PVD), or poor mobility. Emergency procedures, preoperative ventilation, inotropic support, and intra-aortic balloon pump (IABP) use were also more prevalent among those who died. Logistic regression modeling revealed new postoperative stroke (odds ratio 22.0, 95% confidence interval 3.6 to 135.5, p = 0.001), preoperative IABP use (11.4; 2.4 to 53.7, p = 0.002), new hemodialysis (9.6; 2.7 to 34.7, p <0.001), PVD (5.6; 1.6 to 20.0, p = 0.008), and poor mobility (odds ratio 4.8, 95% confidence interval 1.3 to 18.2, p = 0.022) as independent predictors of in-hospital mortality. In conclusion, new postoperative stroke, preoperative IABP use, new hemodialysis, PVD, and poor mobility are independent predictors of mortality in patients with NSTEMI who underwent isolated CABG.

Mouse mucosal-associated invariant T cell receptor recognition of MR1 presenting the vitamin B metabolite, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil.

Mucosal-associated invariant T (MAIT) cells can elicit immune responses against riboflavin-based antigens presented by the evolutionary conserved MHC class I related protein, MR1. While we have an understanding of the structural basis of human MAIT cell receptor (TCR) recognition of human MR1 presenting a variety of ligands, how the semi-invariant mouse MAIT TCR binds mouse MR1-ligand remains unknown. Here, we determine the crystal structures of 2 mouse TRAV1-TRBV13-2+ MAIT TCR-MR1-5-OP-RU ternary complexes, whose TCRs differ only in the composition of their CDR3ß loops. These mouse MAIT TCRs mediate high affinity interactions with mouse MR1-5-OP-RU and cross-recognize human MR1-5-OP-RU. Similarly, a human MAIT TCR could bind mouse MR1-5-OP-RU with high affinity. This cross-species recognition indicates the evolutionary conserved nature of this MAIT TCR-MR1 axis. Comparing crystal structures of the mouse versus human MAIT TCR-MR1-5-OP-RU complexes provides structural insight into the conserved nature of this MAIT TCR-MR1 interaction and conserved specificity for the microbial antigens, whereby key germline-encoded interactions required for MAIT activation are maintained. This is an important consideration for the development of MAIT cell-based therapeutics that will rely on preclinical mouse models of disease.

Sulfated bile acid is a host-derived ligand for MAIT cells.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin-based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue-derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes (Sult2a1-8) responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function.

Surgical management of atrial fibrillation in patients undergoing cardiac surgery: a systematic review of clinical practice guidelines and recommendations.

AIMS: Surgical ablation of atrial fibrillation (AF) has been demonstrated to be a safe procedure conducted concomitantly alongside cardiac surgery. However, there are conflicting guideline recommendations surrounding indications for surgical ablation. We conducted a systematic review of current recommendations on concomitant surgical AF ablation. METHODS AND RESULTS: We identified publications from MEDLINE and EMBASE between January 2011 and December 2022 and additionally searched Guideline libraries and websites of relevant organizations in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 895 studies screened, 4 were rigorously developed (AGREE-II > 50%) and included. All guidelines agreed on the definitions of paroxysmal, persistent, and longstanding AF based on duration and refraction to current treatment modalities. In the Australia-New Zealand (CSANZ) and European (EACTS) guidelines, opportunistic screening for patients >65 years is recommended. The EACTS recommends systematic screening for those aged >75 or at high stroke risk (Class IIa, Level B). However, this was not recommended by American Heart Association or Society of Thoracic Surgeons guidelines. All guidelines identified surgical AF ablation during concomitant cardiac surgery as safe and recommended for consideration by a Heart Team with notable variation in recommendation strength and the specific indication (three guidelines fail to specify any indication for surgery). Only the STS recommended left atrial appendage occlusion (LAAO) alongside surgical ablation (Class IIa, Level C). CONCLUSION: Disagreements exist in recommendations for specific indications for concomitant AF ablation and LAAO, with the decision subject to Heart Team assessment. Further evidence is needed to develop recommendations for specific indications for concomitant AF procedures and guidelines need to be made congruent.

Aortic Arch Debranching and Thoracic Endovascular Aortic Repair (TEVAR) for Type B Aortic Dissection.

BACKGROUND: Since its introduction, thoracic endovascular aortic repair (TEVAR) has revolutionized the treatment of type B aortic dissections (TBADs). However, the proximal aspect of the aortic pathology treated may infringe on the origin of the left subclavian artery or even more proximally. Hence, to ensure durable outcomes, the origin of these vessels needs to be covered, but an extra-anatomical bypass is required to perfuse vital branches, known as aortic arch debranching. This series aims to describe and delineate the disparities of aortic arch debranching during TEVAR for TBAD. METHODS: A retrospective review and analysis of a multicenter international database was conducted to identify patients with TBAD treated with TEVAR between 2005 and 2021. Data analyzed included patient demographics, disease characteristics, operative characteristics, and postoperative outcomes with follow-up on mortality and reintervention. All statistical analyses were carried out using IBM SPSS 26. Patient survival was calculated using a Kaplan-Meier survival analysis, and a P value of less than 0.05 was considered statistically significant. RESULTS: A total of 58 patients were included in the analysis, of which 27 (46.6%) presented with complicated disease and 31 were uncomplicated, of which 10 (17.2%) were classed as high risk and 21 (36.2%) low risk. Zone 2 was the most common proximal landing zone for the stent graft. Left subclavian artery bypass was performed selectively (26%), with 1 stroke occurring, likely due to embolic reasons. A further 6 underwent more proximal aortic debranching before TEVAR (10%) and was a significant risk factor for mortality and the number of stents deployed. The overall rates of reintervention and mortality were 17.2% (n = 10) and 29.3% (n = 17). CONCLUSIONS: Aortic arch debranching and TEVAR for TBAD is associated with significant mortality. Future developments to treat aortic arch pathology could incorporate branched graft devices, eliminating the need for debranching, improving stroke rates, and reducing future reinterventions.

Predictors of outcome in patients with moderate mixed aortic valve disease.

OBJECTIVES: Grading the severity of moderate mixed aortic stenosis and regurgitation (MAVD) is challenging and the disease poorly understood. Identifying markers of haemodynamic severity will improve risk stratification and potentially guide timely treatment. This study aims to identify prognostic haemodynamic markers in patients with moderate MAVD. METHODS: Moderate MAVD was defined as coexisting moderate aortic stenosis (aortic valve area (AVA) 1.0-1.5 cm2) and moderate aortic regurgitation (vena contracta (VC) 0.3-0.6 cm). Consecutive patients diagnosed between 2015 and 2019 were included from a multicentre registry. The primary composite outcome of death or heart failure hospitalisation was evaluated among these patients. Demographics, comorbidities, echocardiography and treatment data were assessed for their prognostic significance. RESULTS: 207 patients with moderate MAVD were included, aged 78 (66-84) years, 56% male sex, AVA 1.2 (1.1-1.4) cm2 and VC 0.4 (0.4-0.5) cm. Over a follow-up of 3.5 (2.5-4.7) years, the composite outcome was met in 89 patients (43%). Univariable associations with the primary outcome included older age, previous myocardial infarction, previous cerebrovascular event, atrial fibrillation, New York Heart Association >2, worse renal function, tricuspid regurgitation ≥2 and mitral regurgitation ≥2. Markers of biventricular systolic function, cardiac remodelling and transaortic valve haemodynamics demonstrated an inverse association with the primary composite outcome. In multivariable analysis, peak aortic jet velocity (Vmax) was independently and inversely associated with the composite outcome (HR: 0.63, 95% CI 0.43 to 0.93; p=0.021) in an adjusted model along with age (HR: 1.05, 95% CI 1.03 to 1.08; p<0.001), creatinine (HR: 1.002, 95% CI 1.001 to 1.003; p=0.005), previous cerebrovascular event (85% vs 42%; HR: 3.04, 95% CI 1.54 to 5.99; p=0.001) and left ventricular ejection fraction (LVEF) (HR: 0.97, 95% CI 0.95 to 0.99; p=0.007). Patients with Vmax ≤2.8 m/s and LVEF ≤50% (n=27) had the worst outcome compared with the rest of the population (72% vs 41%; HR: 3.87, 95% CI 2.20 to 6.80; p<0.001). CONCLUSIONS: Patients with truly moderate MAVD have a high incidence of death and heart failure hospitalisation (43% at 3.5 (2.5-4.7) years). Within this group, a high-risk group characterised by disproportionately low aortic Vmax (≤2.8 m/s) and adverse remodelling (LVEF ≤50%) have the worst outcomes.

Adapting the pre-trained convolutional neural networks to improve the anomaly detection and classification in mammographic images.

Mortality from breast cancer (BC) is among the top causes of cancer death in women. BC can be effectively treated when diagnosed early, improving the likelihood that a patient will survive. BC masses and calcification clusters must be identified by mammography in order to prevent disease effects and commence therapy at an early stage. A mammography misinterpretation may result in an unnecessary biopsy of the false-positive results, lowering the patient's odds of survival. This study intends to improve breast mass detection and identification in order to provide better therapy and reduce mortality risk. A new deep-learning (DL) model based on a combination of transfer-learning (TL) and long short-term memory (LSTM) is proposed in this study to adequately facilitate the automatic detection and diagnosis of the BC suspicious region using the 80-20 method. Since DL designs are modelled to be problem-specific, TL applies the knowledge gained during the solution of one problem to another relevant problem. In the presented model, the learning features from the pre-trained networks such as the squeezeNet and DenseNet are extracted and transferred with the features that have been extracted from the INbreast dataset. To measure the proposed model performance, we selected accuracy, sensitivity, specificity, precision, and area under the ROC curve (AUC) as our metrics of choice. The classification of mammographic data using the suggested model yielded overall accuracy, sensitivity, specificity, precision, and AUC values of 99.236%, 98.8%, 99.1%, 96%, and 0.998, respectively, demonstrating the model's efficacy in detecting breast tumors.

Molecular insights into metabolite antigen recognition by mucosal-associated invariant T cells.

Metabolite-based T-cell immunity is emerging as a major player in antimicrobial immunity, autoimmunity, and cancer. Here, small-molecule metabolites were identified to be captured and presented by the major histocompatibility complex class-I-related molecule (MR1) to T cells, namely mucosal-associated invariant T cells (MAIT) and diverse MR1-restricted T cells. Both MR1 and MAIT are evolutionarily conserved in many mammals, suggesting important roles in host immunity. Rational chemical modifications of these naturally occurring metabolites, termed altered metabolite ligands (AMLs), have advanced our understanding of the molecular correlates of MAIT T cell receptor (TCR)-MR1 recognition. This review provides a generalized framework for metabolite recognition and modulation of MAIT cells.

Myths and methodologies: Cardiopulmonary exercise testing for surgical risk stratification in patients with an abdominal aortic aneurysm; balancing risk over benefit.

The extent to which patients with an abdominal aortic aneurysm (AAA) should exercise remains unclear, given theoretical concerns over the perceived risk of blood pressure-induced rupture, which is often catastrophic. This is especially pertinent during cardiopulmonary exercise testing, when patients are required to perform incremental exercise to symptom-limited exhaustion for the determination of cardiorespiratory fitness. This multimodal metric is being used increasingly as a complementary diagnostic tool to inform risk stratification and subsequent management of patients undergoing AAA surgery. In this review, we bring together a multidisciplinary group of physiologists, exercise scientists, anaesthetists, radiologists and surgeons to challenge the enduring 'myth' that AAA patients should be fearful of and avoid rigorous exercise. On the contrary, by appraising fundamental vascular mechanobiological forces associated with exercise, in conjunction with 'methodological' recommendations for risk mitigation specific to this patient population, we highlight that the benefits conferred by cardiopulmonary exercise testing and exercise training across the continuum of intensity far outweigh the short-term risks posed by potential AAA rupture.

Uncomplicated Type B Aortic Dissection: Challenges in Diagnosis and Categorization.

BACKGROUND: Acute type B aortic dissection (TBAD) is a rare disease that is likely under-diagnosed in the UK. As a progressive, dynamic clinical entity, many patients initially diagnosed with uncomplicated TBAD deteriorate, developing end-organ malperfusion and aortic rupture (complicated TBAD). An evaluation of the binary approach to the diagnosis and categorisation of TBAD is needed. METHODS: A narrative review of the risk factors predisposing patients to progression from unTBAD to coTBAD was undertaken. RESULTS: Key high-risk features predispose the development of complicated TBAD, such as maximal aortic diameter > 40 mm and partial false lumen thrombosis. CONCLUSION: An appreciation of the factors that predispose to complicated TBAD would aid clinical decision-making surrounding TBAD.

Comparing Outcomes Between Surgical and Transcatheter Aortic Valve Replacement in Classical Low-Flow Low-Gradient Aortic Stenosis.

Patients with classic low-flow low-gradient (cLFLG) aortic stenosis (AS) have a poor prognosis but still benefit from aortic valve replacement. There is a paucity of evidence to guide the choice between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR). This study compared procedural and midterm outcomes in patients with cLFLG AS between TAVR and SAVR. Patients with cLFLG AS, defined as an aortic valve area ≤1 cm2, mean gradient <40 mm Hg, and left ventricular ejection fraction <50%, were selected from a single center between 2015 and 2020. Inverse probability weighting and regression were used to adjust for differences in baseline characteristics, the nonrandom assignment of treatment modalities, and procedural differences. The primary end point was all-cause mortality. A total of 322 patients (220 TAVR and 102 SAVR) were included. At a follow-up of 4.4 ± 1.5 years, the adjusted hazard ratio (HR) for mortality after inverse probability weighting with SAVR was 0.66, 95% confidence interval (CI) 0.31 to 1.35; p = 0.24. Worse renal function at baseline (per 10 ml/min/m2 increase HR 0.92, 95% CI 0.84 to 1.00, p = 0.04) and multiple valve interventions (HR 5.39, 95% CI 2.62 to 11.12, p <0.001) independently predicted mortality. There was no difference in stroke and permanent pacemaker implantation, but the rates of renal replacement therapy were higher among the SAVR cohort: 13.7% versus 0%; p <0.001. In conclusion, among patients with cLFLG AS, there was no difference in midterm mortality between TAVR and SAVR, supporting the use of either treatment. However, in patients with poor renal function or at risk of renal failure, TAVR may be the preferred option.

An Optimized Ensemble Deep Learning Model for Predicting Plant miRNA-IncRNA Based on Artificial Gorilla Troops Algorithm.

MicroRNAs (miRNA) are small, non-coding regulatory molecules whose effective alteration might result in abnormal gene manifestation in the downstream pathway of their target. miRNA gene variants can impact miRNA transcription, maturation, or target selectivity, impairing their usefulness in plant growth and stress responses. Simple Sequence Repeat (SSR) based on miRNA is a newly introduced functional marker that has recently been used in plant breeding. MicroRNA and long non-coding RNA (lncRNA) are two examples of non-coding RNA (ncRNA) that play a vital role in controlling the biological processes of animals and plants. According to recent studies, the major objective for decoding their functional activities is predicting the relationship between lncRNA and miRNA. Traditional feature-based classification systems' prediction accuracy and reliability are frequently harmed because of the small data size, human factors' limits, and huge quantity of noise. This paper proposes an optimized deep learning model built with Independently Recurrent Neural Networks (IndRNNs) and Convolutional Neural Networks (CNNs) to predict the interaction in plants between lncRNA and miRNA. The deep learning ensemble model automatically investigates the function characteristics of genetic sequences. The proposed model's main advantage is the enhanced accuracy in plant miRNA-IncRNA prediction due to optimal hyperparameter tuning, which is performed by the artificial Gorilla Troops Algorithm and the proposed intelligent preying algorithm. IndRNN is adapted to derive the representation of learned sequence dependencies and sequence features by overcoming the inaccuracies of natural factors in traditional feature architecture. Working with large-scale data, the suggested model outperforms the current deep learning model and shallow machine learning, notably for extended sequences, according to the findings of the experiments, where we obtained an accuracy of 97.7% in the proposed method.

Acute Decompensated Aortic Stenosis: State of the Art Review.

Aortic stenosis (AS) is a progressive disease that carries a poor prognosis. Patients are managed conservatively until satisfying an indication for transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) based on AS severity and the presence of symptoms or adverse impact on the myocardium. Up to 1 in 3 TAVIs are performed for patients with acute symptoms of dyspnea at rest, angina, and/or syncope - termed acute decompensated aortic stenosis (ADAS) and require urgent aortic valve replacement. These patients have longer hospital length of stay, undergo physical deconditioning, and have a higher rate of acute kidney injury and mortality compared to stable patients with less severe symptoms. There is an urgent need to prevent ADAS and to deliver pathways to manage and improve ADAS-related outcomes. We provide here a contemporary review on epidemiological and pathophysiological aspects of ADAS, with a focus on the impact of ADAS from clinical and economic perspectives. We offer a global overview of the available evidence for treatment of ADAS and with priorities suggested for addressing current gaps in the literature and unmet clinical needs to improve outcomes for AS patients.

Risk Prediction Models for Management of Patients following Acute Aortic Dissection.

Risk prediction of adverse outcomes post aortic dissection is dependet not only on the postdissection-associated clinical factors but on the very foundation of the risk factors that lead up to the dissection itself. There are various such risk factors existing prior to the dissection which impact the postdissection outcomes. In this paper, we review the literature to critically analyze various risk models, burdened by their significant limitations, that attempt to stratify risk prediction based on postdissection patient characteristics. We further review several studies across the literature that investigate the diverse set of predissection risk factors impacting postdissection outcomes. We have discussed and appraised numerous studies which attempt to develop a tool to stratify risk prediction by incorporating the impacts of different factors: malperfusion, blood biochemistry, and perioperative outcomes. The well-validated Penn classification has clearly demonstrated in the literature the significant impact that malperfusion has on adverse outcomes postdissection. Other risk models, already severely hindered by their limitations, lack such validation. We further discuss additional alluded risk factors, including the impact of predissection aortic size, the syndromic and nonsyndromic natures of dissection, and the effects of family history and genetics, which collectively contribute to the risk of adverse outcomes postdissection and prognosis. To achieve the goal of a true risk model, there remains the vital need for appreciation and appropriate consideration for all such aforementioned factors, from before and after the dissection, as discussed in this paper. By being able to incorporate the value of true risk prediction for a patient into the decision-making framework, it will allow a new page of precision medical decision-making to be written.

Cardiothoracic surgery leadership and learning are indispensable to each other.

Cardiothoracic surgery is facing a multitude of challenges in leadership and training on the global scale, these being a complex and aging patient population, shortage of cardiac surgeons, diminishing student interest and trainee enthusiasm, increasingly challenging training obstacles and work-life imbalances, suboptimal job prospects, reports of discrimination and bullying and lack of diversity as well as gap between innovation and technology, clinical application, and training of future surgeons. The survival of cardiac surgery hinges on the leadership attracting and retaining young surgeons into the specialty. Mentoring, leading through example, recognizing the work-life imbalances, adapting to diverse and modern training models and embracing diversity with respect to gender and race, will ultimately be required to create and cultivate a nurturing environment of training and preparing future leaders. The vision for training future generations of cardiothoracic surgeons must rely heavily on strengthening the unity of the heart team. In doing so we can provide the best possible care for our patients and a most fulfilling career for the future generation of cardiac surgeons.

Quantitative affinity measurement of small molecule ligand binding to major histocompatibility complex class-I-related protein 1 MR1.

The Major Histocompatibility Complex class I-related protein 1 (MR1) presents small molecule metabolites, drugs, and drug-like molecules that are recognized by MR1-reactive T cells. While we have an understanding of how antigens bind to MR1 and upregulate MR1 cell surface expression, a quantitative, cell-free, assessment of MR1 ligand-binding affinity was lacking. Here, we developed a fluorescence polarization-based assay in which fluorescent MR1 ligand was loaded into MR1 protein in vitro and competitively displaced by candidate ligands over a range of concentrations. Using this assay, ligand affinity for MR1 could be differentiated as strong (IC50 < 1 µM), moderate (1 µM < IC50 < 100 µM), and weak (IC50 > 100 µM). We demonstrated a clear correlation between ligand-binding affinity for MR1, the presence of a covalent bond between MR1 and ligand, and the number of salt bridge and hydrogen bonds formed between MR1 and ligand. Using this newly developed fluorescence polarization-based assay to screen for candidate ligands, we identified the dietary molecules vanillin and ethylvanillin as weak bona fide MR1 ligands. Both upregulated MR1 on the surface of C1R.MR1 cells and the crystal structure of a MAIT cell T cell receptor-MR1-ethylvanillin complex revealed that ethylvanillin formed a Schiff base with K43 of MR1 and was buried within the A'-pocket. Collectively, we developed and validated a method to quantitate the binding affinities of ligands for MR1 that will enable an efficient and rapid screening of candidate MR1 ligands.

CD8 coreceptor engagement of MR1 enhances antigen responsiveness by human MAIT and other MR1-reactive T cells.

Mucosal-associated invariant T (MAIT) cells detect microbial infection via recognition of riboflavin-based antigens presented by the major histocompatibility complex class I (MHC-I)-related protein 1 (MR1). Most MAIT cells in human peripheral blood express CD8αα or CD8αß coreceptors, and the binding site for CD8 on MHC-I molecules is relatively conserved in MR1. Yet, there is no direct evidence of CD8 interacting with MR1 or the functional consequences thereof. Similarly, the role of CD8αα in lymphocyte function remains ill-defined. Here, using newly developed MR1 tetramers, mutated at the CD8 binding site, and by determining the crystal structure of MR1-CD8αα, we show that CD8 engaged MR1, analogous to how it engages MHC-I molecules. CD8αα and CD8αß enhanced MR1 binding and cytokine production by MAIT cells. Moreover, the CD8-MR1 interaction was critical for the recognition of folate-derived antigens by other MR1-reactive T cells. Together, our findings suggest that both CD8αα and CD8αß act as functional coreceptors for MAIT and other MR1-reactive T cells.

Effect of Transcatheter Aortic Valve Implantation vs Surgical Aortic Valve Replacement on All-Cause Mortality in Patients With Aortic Stenosis: A Randomized Clinical Trial.

Importance: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear. Objective: To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk. Design, Setting, and Participants: In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019. Interventions: TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455). Main Outcomes and Measures: The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation. Results: Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of -2.0% (1-sided 97.5% CI, -∞ to 1.2%; P < .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75]). Conclusions and Relevance: Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year. Trial Registration: isrctn.com Identifier: ISRCTN57819173.