Direct reprogramming of fibroblasts into functional hepatocytes via CRISPRa activation of endogenous Gata4 and Foxa3.

BACKGROUND: The ability to generate functional hepatocytes without relying on donor liver organs holds significant therapeutic promise in the fields of regenerative medicine and potential liver disease treatments. Clustered regularly interspaced short palindromic repeats (CRISPR) activator (CRISPRa) is a powerful tool that can conveniently and efficiently activate the expression of multiple endogenous genes simultaneously, providing a new strategy for cell fate determination. The main purpose of this study is to explore the feasibility of applying CRISPRa for hepatocyte reprogramming and its application in the treatment of mouse liver fibrosis. METHOD: The differentiation of mouse embryonic fibroblasts (MEFs) into functional induced hepatocyte-like cells (iHeps) was achieved by utilizing the CRISPRa synergistic activation mediator (SAM) system, which drove the combined expression of three endogenous transcription factors-Gata4, Foxa3, and Hnf1a-or alternatively, the expression of two transcription factors, Gata4 and Foxa3. In vivo, we injected adeno-associated virus serotype 6 (AAV6) carrying the CRISPRa SAM system into liver fibrotic Col1a1-CreER; Cas9fl/fl mice, effectively activating the expression of endogenous Gata4 and Foxa3 in fibroblasts. The endogenous transcriptional activation of genes was confirmed using real-time quantitative polymerase chain reaction (RT-qPCR) and RNA-seq, and the morphology and characteristics of the induced hepatocytes were observed through microscopy. The level of hepatocyte reprogramming in vivo is detected by immunofluorescence staining, while the improvement of liver fibrosis is evaluated through Sirius red staining, alpha-smooth muscle actin (α-SMA) immunofluorescence staining, and blood alanine aminotransferase (ALT) examination. RESULTS: Activation of only two factors, Gata4 and Foxa3, via CRISPRa was sufficient to successfully induce the transformation of MEFs into iHeps. These iHeps could be expanded in vitro and displayed functional characteristics similar to those of mature hepatocytes, such as drug metabolism and glycogen storage. Additionally, AAV6-based delivery of the CRISPRa SAM system effectively induced the hepatic reprogramming from fibroblasts in mice with live fibrosis. After 8 weeks of induction, the reprogrammed hepatocytes comprised 0.87% of the total hepatocyte population in the mice, significantly reducing liver fibrosis. CONCLUSION: CRISPRa-induced hepatocyte reprogramming may be a promising strategy for generating functional hepatocytes and treating liver fibrosis caused by hepatic diseases.

Community-based prevention and treatment of cardiovascular diseases.

The Annual Report on Cardiovascular Health and Diseases in China (2022) intricate landscape of cardiovascular health in China. This is the third section of the report with a specific focus on community-based prevention and treatment of cardiovascular diseases (CVD). This section of the report underscores the importance of initiatives outlined in the "Healthy China 2030 Plan," emphasizing the comprehensive prevention and control strategy for chronic diseases. A key aspect of this plan involves the establishment of national demonstration areas aimed at comprehensive prevention and control of chronic diseases. By 2020, 488 such areas had been set up across China, surpassing the initial target and covering a significant proportion of counties and districts. The report highlights the successful implementation of these strategies in Lishan district, Anshan city, where demonstration areas for comprehensive prevention and control of chronic diseases were launched in 2013. Over the course of seven years, the number of healthy units increased substantially, leading to improvements in managing risk factors for CVD among residents. Significant reductions in prevalence rates of overweight, obesity, smoking, passive smoking, and drinking were observed, along with the development of healthier behaviors among residents. Similarly, Qiaokou district in Wuhan City, designated as a national demonstration area in 2014, implemented comprehensive public health promotion initiatives. Notably, special clinics for hypertension intervention were established, contributing to an increase in self-reported rates of hypertension, a slight decrease in prevalence, and a remarkable improvement in the control rate among treated patients. Overall, these efforts underscore the effectiveness of community-based approaches in driving positive health outcomes and advancing the comprehensive prevention and control of chronic diseases, particularly cardiovascular diseases, in China.

PBX/Knotted 1 homeobox-2 (PKNOX2) is a novel regulator of myocardial fibrosis.

Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing. However, the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription factors. In this study, we optimized a pipeline for isolating nuclei and conducting single-nucleus RNA sequencing targeted to detect a higher number of cell signal genes and an optimal number of transcription factors. With this unbiased protocol, we characterized the cellular composition of healthy human hearts and investigated the transcriptional regulation networks involved in determining the cellular identities and functions of the main cardiac cell subtypes. Particularly in fibroblasts, a novel regulator, PKNOX2, was identified as being associated with physiological fibroblast activation in healthy hearts. To validate the roles of these transcription factors in maintaining homeostasis, we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast remodelling. The trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast formation. Both gain- and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis remodelling. Moreover, fibroblast-specific overexpression and knockout of PKNOX2 in a heart failure mouse model induced by transverse aortic constriction surgery significantly improved and aggravated myocardial fibrosis, respectively. In summary, this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart muscle. With this optimized protocol, we described the transcriptional regulation networks of the main cardiac cell subtypes and identified PKNOX2 as a novel regulator in suppressing fibrosis and a potential therapeutic target for future translational studies.

A multi-constituent model for assessing the effect of impeller shroud on the thrombosis potential of a centrifugal blood pump.

Centrifugal blood pumps can be used for treating heart failure patients. However, pump thrombosis has remained one of the complications that trouble clinical treatment. This study analyzed the effect of impeller shroud on the thrombosis risk of the blood pump, and predicted areas prone to thrombosis. Multi-constituent transport equations were presented, considering mechanical activation and biochemical activation. It was found that activated platelets concentration can increase with shear stress and adenosine diphosphate(ADP) concentration increasing, and the highest risk of thrombosis inside the blood pump was under extracorporeal membrane oxygenation (ECMO) mode. Under the same condition, ADP concentration and thrombosis index of semi-shroud impeller can increase by 7.3% and 7.2% compared to the closed-shroud impeller. The main reason for the increase in thrombosis risk was owing to elevated scalar shear stress and more coagulation promoting factor-ADP released. The regions with higher thrombosis potential were in the center hole, top and bottom clearance. As a novelty, the findings revealed that impeller shroud can influence mechanical and biochemical activation factors. It is useful for identifying potential risk regions of thrombus formation based on relative comparisons.

Influencing Factors on Cardiovascular Health in China.

The Annual Report on Cardiovascular Health and Diseases in China (2022) intricate landscape of cardiovascular health in China. This is the first section of the report, which dissects influential factors across diverse domains. The investigation identifies tobacco use as a paramount concern, portraying China as the global epicenter of tobacco consumption. Cigarette smoking, exacerbated by second-hand smoke exposure, emerges as a critical and preventable risk factor, contributing to a surge in attributable deaths over the past three decades. In the realm of dietary nutrition, the study discerns an overall improvement, yet discerns worrisome deviations, notably an escalating fat intake surpassing recommended guidelines. The shifting dietary structure reveals diminished consumption of cereals and vegetables juxtaposed with an uptick in animal foods, while excessive intake of cooking oil and salt persists, straying substantially from endorsed levels. The exploration of physical activity patterns unfolds a nuanced narrative. Varied trends are observed among students, with concerns arising from sedentary behaviors and inadequate adherence to recommended guidelines. The analysis spans a trajectory of declining physical activity in Chinese adults, coupled with an alarming surge in sedentary leisure time, ultimately linking these factors to heightened risks of cardiovascular diseases and increased adiposity. An examination of overweight and obesity trends uncovers a relentless upward trajectory, projecting substantial prevalence by 2030. Noteworthy prevalence rates underscore the imperative for targeted interventions to curtail this burgeoning health crisis, with the anticipated prevalence extending to nearly two-thirds of the adult population. Psychological factors, notably depression, constitute an integral facet of cardiovascular health. Prevalence rates among patients with coronary artery disease and acute myocardial infarction underscore the intricate interplay between mental health and cardiovascular outcomes. Additionally, persistent depressive symptoms are shown to significantly elevate the risk of cardiovascular diseases and mortality. This first section underscores the multifaceted challenges facing cardiovascular health in China, emphasizing the imperative for tailored interventions across tobacco control, dietary habits, physical activity, obesity management, and psychological well-being to mitigate the escalating burden of cardiovascular diseases in the population.

Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Dilation may be the first right ventricular change and accelerates the progression of threatening ventricular tachyarrhythmias and heart failure for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but the treatment for right ventricular dilation remains limited. METHODS: Single-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2)mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster. RESULTS: Right ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and TNMD+ fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2mut/mut mice (an ARVC mouse model). CONCLUSIONS: This study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC.

Profiling cardiomyocytes at single cell resolution reveals COX7B could be a potential target for attenuating heart failure in cardiac hypertrophy.

Cardiac hypertrophy can develop to end-stage heart failure (HF), which inevitably leading to heart transplantation or death. Preserving cardiac function in cardiomyocytes (CMs) is essential for improving prognosis in hypertrophic cardiomyopathy (HCM) patients. Therefore, understanding transcriptomic heterogeneity of CMs in HCM would be indispensable to aid potential therapeutic targets investigation. We isolated primary CM from HCM patients who had extended septal myectomy, and obtained transcriptomes in 338 human primary CM with single-cell tagged reverse transcription (STRT-seq) approach. Our results revealed that CMs could be categorized into three subsets in nonfailing HCM heart: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (COX7B), a subunit of Complex IV in ETC had trends of positively correlation with CMs size. Further, by assessing COX7B expression in HCM patients, we speculated that COX7B was compensatory up-regulated at early-stage but down-regulated in failing HCM heart. To test the hypothesis that COX7B might participate both in hypertrophy and HF progression, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7b in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7b would accelerate HF and Cox7b overexpression could restore partial cardiac function in hypertrophy. Our result highlights targeting COX7B and preserving energy synthesis in hypertrophic CMs could be a promising translational direction for HF therapeutic strategy.

Summary of the 2022 Report on Cardiovascular Health and Diseases in China.

ABSTRACT: Recent decades have seen the remarkable development of China in medical accessibility and quality index, and the application of a number of new advanced cardiovascular technologies benefits more patients. However, according to the Annual Report on Cardiovascular Health and Diseases in China published in this article, which was organized and summarized by National Center for Cardiovascular Diseases, there is still a huge population living with risk factors of cardiovascular diseases (CVD), and the morbidity and mortality of CVD are increasing. It is estimated that there are around 330 million patients suffering from CVD currently, including 245 million of hypertension, 13 million of stroke, 45.3 million of peripheral artery disease, 11.39 million of coronary heart disease (CHD), 8.9 million of heart failure, 5 million of pulmonary heart disease, 4.87 million of atrial fibrillation, 2.5 million of rheumatic heart disease, and 2 million of congenital heart disease. Tobacco use, diet and nutrition factors, physical activity, overweight and obesity, and psychological factors are what affect cardiovascular health, while hypertension, dyslipidemia, diabetes, chronic kidney disease, metabolic syndrome, and air pollution are the risk factors for CVD. In this article, in addition to risk factors for CVD, we also report the epidemiological trends of CVD, including CHD, cerebrovascular disease, arrhythmias, valvular heart disease, congenital heart disease, cardiomyopathy, heart failure, pulmonary vascular disease and venous thromboembolism, and aortic and peripheral artery diseases, as well as the basic research and medical device development in CVD. In a word, China has entered a new stage of transforming from high-speed development focusing on scale growth to high-quality development emphasizing on strategic and key technological development to curb the trend of increasing incidence and mortality of CVD.

Report on cardiovascular health and diseases in China 2021: an updated summary.

In 2019, cardiovascular disease (CVD) accounted for 46.74% and 44.26% of all deaths in rural and urban areas, respectively. Two out of every five deaths were attributed to CVD. It is estimated that approximately 330 million individuals in China are affected by CVD. Among them, there are 13 million cases of stroke, 11.4 million cases of coronary heart disease, 5 million cases of pulmonary heart disease, 8.9 million cases of heart failure, 4.9 million cases of atrial fibrillation, 2.5 million cases of rheumatic heart disease, 2 million cases of congenital heart disease, 45.3 million cases of lower extremity artery disease, and 245 million cases of hypertension. With the dual challenges of population aging and a steady increase in the prevalence of metabolic risk factors, the burden of CVD in China is expected to continue rising. Consequently, new demands arise for CVD prevention, treatment, and the allocation of medical resources. Emphasizing primary prevention to reduce disease prevalence, increasing the allocation of medical resources for CVD emergency and critical care, and providing rehabilitation services and secondary prevention to reduce the risk of recurrence, rehospitalization, and disability among CVD survivors are of paramount importance. Hypertension, dyslipidemia, and diabetes affect millions of individuals in China. Since blood pressure, blood lipids, and blood sugar levels often rise insidiously, vascular disease and serious events such as myocardial infarction and stroke occur by the time they are detected in this population. Therefore, it is crucial to implement strategies and measures to prevent risk factors such as hypertension, dyslipidemia, diabetes, obesity, and smoking. Furthermore, greater efforts should be directed towards assessing cardiovascular health status and conducting research on early pathological changes to enhance prevention, treatment, and understanding of CVD.

Fate of transposition of the great arteries with pulmonary stenosis after double-root translocation, Rastelli, and Réparation à l'Etage Ventriculaire.

OBJECTIVES: For transposition of the great arteries with unrestricted ventricular septal defect and pulmonary stenosis, double-root translocation is reported to reconstruct ideal double artery roots with growth potential. However, prospective long-term studies describing the long-term outcomes are still scarce. Therefore, the aim was to assess development of double artery roots, hemodynamics, and freedom from death and heart failure 17 years after double-root translocation, Rastelli, and Réparation à l'Etage Ventriculaire procedures. METHODS: In this prospective population-based study, 266 patients with transposition of the great arteries/ventricular septal defect/pulmonary stenosis (from July 2004 to August 2021) were consecutively included before surgery. All patients were divided into 3 groups based on the type of operation: double-root translocation (174), Rastelli (68), and Réparation à l'Etage Ventriculaire (24), who accepted postoperative evaluations annually. Generalized linear mixed model analysis was performed to determine growth potential of artery roots. RESULTS: Longitudinal repeated computed tomography measurements show the pulmonary root has significantly increased diameter (0.62 [0.03] mm/y, P < .001) over time and an adequate Z-score (-0.18) at the last follow-up only in the double-root translocation group. The pressure gradients of double outflow tracts in the double-root translocation group were the least among 3 groups. The probabilities of freedom from death/heart failure at the 15th year were 73.1%, 59.3%, and 60.9% in the double-root translocation, Rastelli, and Réparation à l'Etage Ventriculaire groups, respectively (double-root translocation vs Rastelli, P = .026; double-root translocation vs Réparation à l'Etage Ventriculaire, P = .009; Rastelli vs Réparation à l'Etage Ventriculaire, P = .449). CONCLUSIONS: By reconstructing ideal double artery roots, double-root translocation can provide postoperative long-term excellent hemodynamics and minimal death and heart failure for patients with transposition of the great arteries/ventricular septal defect/pulmonary stenosis.

Multicentre, randomised, double-blind, parallel controlled trial to investigate timing of platelet inhibition after coronary artery bypass grafting: TOP-CABG trial study.

INTRODUCTION: Dual antiplatelet therapy (DAPT), referred to as the combination of aspirin and P2Y12 receptor antagonist (clopidogrel or ticagrelor), potentially improves patency of saphenous vein grafts (SVG) after coronary artery bypass grafting (CABG), while it is further proposed that DAPT potentially increases bleeding risk. Compared with DAPT, de-escalated DAPT (De-DAPT) is an effective antiplatelet strategy for acute coronary syndrome treatment, which significantly reduces the risk of bleeding without increasing the incidence of major adverse cardiovascular events. However, insufficient evidence is available to determine the timing of DAPT after CABG. METHODS AND ANALYSIS: ETHICS AND DISSEMINATION: The Ethics Committee in Fuwai hospital approved this study (2022-1774). Fifteen centres agreed to participate the TOP-CABG trial, and the study has been approved in these 15 centres by whose ethics committee. The results of the trial will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05380063.

Outcomes of quantitative flow ratio-based functional incomplete revascularization after coronary artery bypass grafting surgery.

OBJECTIVE: Quantitative flow ratio is a novel functional assessment tool of coronary diseases. Whether quantitative flow ratio could improve the outcomes of coronary artery bypass grafting is undetermined. This study aimed to investigate the association between the quantitative flow ratio based functional incomplete revascularization and the outcomes after coronary artery bypass grafting surgery. METHODS: The quantitative flow ratio assessment was retrospectively performed in patients undergoing coronary artery bypass grafting surgery in the PATENCY trial. The anatomic complete revascularization denoted revascularizing each territory with stenosis greater than 50% evaluated by angiography. The functional complete revascularization was defined as grafting all vessels with a quantitative flow ratio 0.80 or less. The primary end point was the 12-month composite major adverse cardiac or cerebral vascular events. RESULTS: A total of 2024 patients with available quantitative flow ratio values were included. Functional complete revascularization was achieved in 1846 patients (91.2%), and 1600 received anatomic complete revascularization (79.1%). Both the functional incomplete revascularization and anatomic incomplete revascularization groups were associated with significantly increased risks of 12-month major adverse cardiac or cerebral vascular events (functional: hazard ratio, 2.91; 95% confidence interval, 1.56 to 5.43; P = .001; anatomic: hazard ratio, 2.82; 95% confidence interval, 1.54 to 5.16; P = .001). Additionally, for the subgroup of patients (n = 246) receiving anatomic incomplete revascularization but judged as functional complete revascularization by quantitative flow ratio, the risk of the 12-month major adverse cardiac or cerebral vascular events was not significantly increased (adjusted hazard ratio, 1.36; 95% confidence interval, 0.71-2.60; P = .35). CONCLUSIONS: Both the functional incomplete revascularization and anatomic incomplete revascularization were associated with increased risks of 12-month major adverse cardiac or cerebral vascular events after coronary artery bypass grafting surgery. The quantitative flow ratio can serve as a supplementary tool for the decision-making of surgical revascularization.

The relationship between false-lumen area ratio and renal replacement therapy after acute aortic dissection repair on bilateral artery cannulation: a cross-sectional study.

Background: Malperfusion poses a serious challenge to organ function in the repair of acute aortic dissection (AAD). The purpose of this study was to explore the segment change of false-lumen area ratio (FLAR; the ratio of the maximal false-lumen area to the total lumen area) in the descending aorta and its relationship with renal replacement therapy (RRT) after total aortic arch (TAA) surgery. Methods: A total of 228 patients with AAD who received TAA using perfusion mode right axillary and femur artery cannulation between March 2013 and March 2022 were included in a cross-sectional study. The descending aorta was divided into 3 segments: the descending thoracic aorta (S1), the abdominal aorta above the ostium of the renal artery (S2), and the abdominal aorta between the ostium of the renal artery and the iliac bifurcation (S3). The primary outcomes were postoperative segmental FLAR changes in the descending aorta, which were observed using computed tomography angiography before the patients were discharged from the hospital. The secondary outcomes were RRT and 30-day mortality. Results: The total potencies in the false lumen were 71.1%, 95.2%, and 88.2% in S1, S2, and S3. The postoperative/preoperative ratio of the FLAR was higher in S2 than that in S1 and S3 (S1: 67%±14%; S2: 80%±8%; S3: 57%±12%; all P values <0.001). For the patients undergoing RRT, there was a higher postoperative/preoperative ratio of the FLAR for the S2 segment (85%±7% vs. 79%±8%; P<0.001) and higher mortality (28.9% vs. 7.7%; P<0.001) after AAD repair compared with patients in the no-RRT group. Conclusions: This study demonstrated there was less attenuation of the FLAR on the abdominal aorta above the ostium of the renal artery in the whole descending aorta after AAD repair with intraoperative right axillary and femur artery perfusion mode. The patients needing RRT were associated with less postoperative/preoperative change of the FLAR and worse clinical outcomes.

Quantitative flow ratio and graft outcomes of coronary artery bypass grafting surgery: A retrospective study.

OBJECTIVE: Quantitative flow ratio (QFR) is a novel noninvasive tool for the functional assessment of coronary stenosis. Whether or not QFR could predict graft outcomes after coronary artery bypass grafting procedure is unknown. This study aimed to investigate the association of QFR value with graft outcomes after coronary artery bypass grafting surgery. METHODS: The QFR values were retrospectively obtained from patients receiving coronary artery bypass grafting surgery from 2017 to 2019 in the Graft Patency Between No-Touch Vein Harvesting Technique and Conventional Approach in Coronary Artery Bypass Graft Surgery (PATENCY) trial. QFR calculation was conducted in eligible coronary arteries, defined as those with ≥50% stenosis and a diameter ≥1.5 mm. A threshold of QFR ≤0.80 was considered functionally significant stenosis. The primary outcome was graft occlusion at 12 months evaluated by computed tomography angiography. RESULTS: Two thousand twenty-four patients with 7432 grafts (2307 arterial grafts and 5125 vein grafts) were included. For the arterial grafts, the risk of 12-month occlusion was significantly increased in the QFR >0.80 group than in the QFR ≤0.80 group (7.1% vs 2.6%; P = .001; unadjusted model: odds ratio, 3.08; 95% CI, 1.65-5.75; fully adjusted model: odds ratio, 2.67; 95% CI, 1.44-4.97). No significant association was observed in the vein grafts (4.6% vs 4.3%; P = .67; unadjusted model: odds ratio, 1.10; 95% CI, 0.82-1.47; fully adjusted model: odds ratio, 1.12; 95% CI, 0.83-1.51). Results were stable across sensitivity analyses with a QFR threshold of 0.78 and 0.75. CONCLUSIONS: Target vessel QFR >0.80 was associated with a significantly higher risk of arterial graft occlusion at 12 months after coronary artery bypass grafting surgery. No significant association was found between target lesion QFR and vein graft occlusion.

Tranexamic acid is associated with improved hemostasis in elderly patients undergoing coronary-artery surgeries in a retrospective cohort study.

Background: More elderly patients undergo coronary artery bypass surgery (CABG) than younger patients. Whether tranexamic acid (TA) is still effective and safe in elderly patients undergoing CABG surgeries is still unclear. Methods: In this study, a cohort of 7,224 patients ≥70 years undergoing CABG surgery were included. Patients were categorized into the no TA group, TA group, high-dose group, and low-dose group according whether TA was administered and the dose administered. The primary endpoint was blood loss and blood transfusion after CABG. The secondary endpoints were thromboembolic events and in-hospital death. Results: The blood loss at 24 and 48 h and the total blood loss after surgery in patients in the TA group were 90, 90, and 190 ml less than those in the no-TA group, respectively (p < 0.0001). The total blood transfusion was reduced 0.38-fold with TA administration compared to that without TA (OR = 0.62, 95% CI 0.56-0.68, p < 0.0001). Blood component transfusion was also reduced. High-dose TA administration reduced the blood loss by 20 ml 24 h after surgery (p = 0.032) but had no relationship with the blood transfusion. TA increased the risk of perioperative myocardial infarction (PMI) by 1.62-fold [p = 0.003, OR = 1.62, 95% CI (1.18-2.22)] but reduced the hospital stay time in patients who were administered TA compared to that of patients who did not receive TA (p = 0.026). Conclusion: We revealed that elderly patients undergoing CABG surgeries had better hemostasis after TA administration but increased the risk of PMI. High-dose TA was effective and safe compared with low-dose TA administration in elderly patients undergoing CABG surgery.

Evaluation of the effectiveness and safety of a multi-faceted computerized antimicrobial stewardship intervention in surgical settings: A single-centre cluster-randomized controlled trial.

BACKGROUND: Inappropriate antimicrobial use is common among patients undergoing surgery. It remains unclear whether a multi-faceted computerized antimicrobial stewardship programme is effective and safe in reducing inappropriate antimicrobial use in surgical settings. METHODS: A multi-faceted computerized antimicrobial stewardship intervention system was developed, and an open-label, cluster-randomized, controlled trial was conducted among 18 surgical teams that enrolled 2470 patients for open chest cardiovascular surgery. The surgical teams were divided at random into intervention and control groups at a ratio of 1:1. The primary endpoints were days of therapy (DOT)/1000 patient-days, defined daily dose (DDD)/1000 patient-days and length of therapy (LOT)/1000 patient-days. RESULTS: Mean DOT, DDD and LOT per 1000 patient-days were significantly lower in the intervention group compared with the control group (472.2 vs 539.8, 459.5 vs 553.8, and 438.4 vs 488.7; P<0.05), with reductions of 14.2% [95% confidence interval (CI) 11.8-16.7%], 18.7% (95% CI 15.9-21.4%) and 11.9% (95% CI 9.6-14.1%), respectively. The daily risk of inappropriate antimicrobial use after discharge from the intensive care unit decreased by 23.9% [95% CI 15.5-31.5% (incidence risk ratio 0.76, 95% CI 0.69-0.85)] in the intervention group. There was no significant difference in rates of infection or surgical-related complications between the groups. Median antimicrobial costs were significantly lower in the intervention group {873.4 [interquartile range (IQR) 684.5-1255.4] RMB vs 1178.7 (IQR 869.1-1814.5) RMB; P<0.001} (1 RMB approximately equivalent to 0.16 US$ in 2022). CONCLUSIONS: The multi-faceted computerized antimicrobial stewardship interventions reduced inappropriate antimicrobial use safely. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT04328090.

A comparison of bilateral and unilateral cerebral perfusion for total arch replacement surgery for non-marfan, type A aortic dissection.

OBJECTIVES: Acknowledging lacking of consensus exist in total aortic arch (TAA) surgery for acute type A aortic dissection (AAD), this study aimed to investigate the neurologic injury rate between bilateral and unilateral cerebrum perfusion on the specific population. METHODS: A total of 595 AAD patients other than Marfan syndrome receiving TAA surgery since March 2013 to March 2022 were included. Among them, 276 received unilateral cerebral perfusion (via right axillary artery, RCP) and 319 for bilateral cerebral perfusion (BCP). The primary outcome was neurologic injury rate. Secondary outcomes were 30-day mortality, serum inflammation response (high sensitivity C reaction protein, hs-CRP; Interleukin-6, IL-6; cold-inducible RNA binding protein, CIRBP) and neuroprotection (RNA-binding motif 3, RBM3) indexes. RESULTS: The BCP group reported a significantly lower permanent neurologic deficits [odds ratio: 0.481, Confidence interval (CI): 0.296-0.782, p = 0.003] and 30-day mortality (odds ratio: 0.353, CI: 0.194-0.640, p < 0.001) than those received RCP treatment. There were also lower inflammation cytokines (hr-CRP: 114 ± 17 vs. 101 ± 16 mg/L; IL-6: 130 [103,170] vs. 81 [69,99] pg/ml; CIRBP: 1076 [889, 1296] vs. 854 [774, 991] pg/ml, all p < 0.001), but a higher neuroprotective cytokine (RBM3: 4381 ± 1362 vs 2445 ± 1008 pg/mL, p < 0.001) at 24 h after procedure in BCP group. Meanwhile, BCP resulted in a significantly lower Acute Physiology, Age and Chronic Health Evaluation (APACHE) Ⅱscore (18 ± 6 vs 17 ± 6, p < 0.001) and short stay in intensive care unit (4 [3,5] vs. 3 [2,3] days, p < 0.001) and hospital (16 ± 4 vs 14 ± 3 days, p < 0.001). CONCLUSIONS: This present study indicated that BCP compared with RCP was associated with lower permanent neurologic deficits and 30-day mortality in AAD patients other than Marfan syndrome receiving TAA surgery.

Simultaneous Hybrid Coronary Revascularization vs Conventional Strategies for Multivessel Coronary Artery Disease: A 10-Year Follow-Up.

BACKGROUND: Although evidence is sufficient to confirm that hybrid coronary revascularization (HCR) is safe and effective in the short term, its value in the long run is debatable. OBJECTIVES: This study sought to compare the long-term outcomes of HCR with coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for multivessel disease. METHODS: Three groups of patients, 540 each, receiving HCR, CABG, or PCI between June 2007 to September 2018, were matched using propensity score matching. Patients were stratified by EuroSCORE (European System for Cardiac Operative Risk Evaluation) II (low ≤0.9; 0.9 < medium <1.5; high ≥1.5) and SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (low ≤22; 22 < medium <33; high ≥33). Major adverse cardiac and cerebrovascular events (MACCE) and Seattle Angina Questionnaire (SAQ) scores were compared among the 3 groups. RESULTS: In terms of MACCE and SAQ, HCR performed similarly to off-pump CABG but significantly outperformed PCI (P < 0.001). In the low-to-medium EuroSCORE II and medium-to-high SYNTAX score tertiles, MACCE rates in the HCR group were significantly lower than those in the PCI (EuroSCORE II: low, 30.7% vs 41.2%; P = 0.006; medium, 31.3% vs 41.7%; P = 0.013; SYNTAX score: medium, 27.6% vs 41.2%; P = 0.018; high, 32.4% vs 52.7%; P = 0.011) but were similar to those in the CABG group. In the high EuroSCORE II stratum, HCR had a lower MACCE rate than CABG (31.9% vs 47.0%; P = 0.041) and PCI (31.9% vs 53.7%; P = 0.015). CONCLUSIONS: Compared with conventional strategies, HCR provided satisfactory long-term outcomes in MACCE and functional status for multivessel disease.

Evaluation of the effect of simultaneous hybrid coronary revascularization on postoperative bleeding and renal function: A comparison study with minimally invasive direct off-pump coronary artery bypass grafting in patients with multivessel coronary artery disease.

OBJECTIVES: The present study sought to compare postoperative bleeding and renal function in patients with multivessel coronary artery disease undergoing simultaneous hybrid coronary revascularization (HCR) and minimally invasive direct off-pump coronary artery bypass grafting (MIDCABG). METHODS: The study retrospectively collected the data of 594 consecutive patients who underwent simultaneous HCR and 351 patients who underwent MIDCABG with planned staged HCR (MIDCABG first, then elective percutaneous coronary intervention) in Fuwai Hospital from June 2007 to December 2020. A total of 317 pairs of patients who were matched in a 1:1 ratio with propensity score matching were enrolled in this study. Bleeding and changes in renal function were compared between the 2 groups. RESULTS: Compared with patients who underwent MIDCABG, patients who underwent simultaneous HCR had significantly greater chest tube drainage on the day of the operation (492.7 ± 282.4 mL vs 441.0 ± 261.9 mL; P = .023), but no significant difference was detected in the total amount during the postoperative period (788.8 ± 458.9 mL vs 753.3 ± 409.8 mL; P = .74). The differences in re-exploration for bleeding (0.3% vs 1.6%; P = .13), blood transfusion (18.9% vs 16.4%; P = .13), acute kidney injury (23.3% vs 18.6%; P = .53), and in-hospital major adverse cardiovascular and cerebrovascular events (including all-cause death, myocardial infarction, stroke, and repeated revascularization) (2.5% vs 1.9%; P = .67) between the 2 groups did not reach statistical significance. CONCLUSIONS: Compared with MIDCABG, simultaneous HCR (MIDCABG first, instant percutaneous coronary intervention) did not increase postoperative bleeding or the incidence of acute kidney injury.

Urine metabolites for preoperative prediction of acute kidney injury after coronary artery bypass graft surgery.

OBJECTIVE: Acute kidney injury is a common complication after on-pump coronary artery bypass grafting. Prediction of acute kidney injury remains a challenge. Our study aims to identify a panel of urine metabolites for preoperative warning of acute kidney injury after on-pump coronary artery bypass grafting. METHODS: A total of 159 patients undergoing isolated on-pump coronary artery bypass grafting were enrolled from July 7, 2017, to May 17, 2019. Preoperative urine samples were analyzed with the approach of liquid chromatography-mass spectrometry-based urine metabolomics. The study end point was the episode of acute kidney injury within 48 hours postoperatively. The predictive performance was determined by the area under the curve and calibration curve. The results were validated using bootstrap resampling. RESULTS: The acute kidney injury (n = 55) and nonacute kidney injury (n = 104) groups showed significant different metabolic profiling. A total of 28 metabolites showed significant differences between the acute kidney injury and nonacute kidney injury groups. A metabolite panel of 5 metabolites (tyrosyl-gamma-glutamate, deoxycholic acid glycine conjugate, 5-acetylamino-6-amino-3-methyluracil, arginyl-arginine, and L-methionine) was discovered to have a good predicting performance (area under the curve, 0.89; 95% confidence interval, 0.82-0.93), which is higher than the clinical factor-based model (area under the curve, 0.63; 95% confidence interval, 0.53-0.72). Internal validation by bootstrap resampling showed an adjusted area under the curve of 0.88, and the calibration curve demonstrated good agreement between prediction and observation in the probability of postoperative acute kidney injury. Decision curve analysis revealed a superior net benefit of the metabolite model over the traditional clinical factor-based model. CONCLUSIONS: We present 5 urine metabolites related to acute kidney injury after coronary artery bypass grafting. This metabolite model may serve as a preoperative warning of acute kidney injury after on-pump coronary artery bypass grafting.