Genetically predicted waist circumference and risk of atrial fibrillation.

INTRODUCTION: Observational studies have revealed an association between waist circumference (WC) and atrial fibrillation (AF). However, it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors. Therefore, the causal role of WC in AF is unclear. This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization (MR) analysis. METHODS: In our two-sample MR analysis, the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study (GWAS) of WC (42 single nucleotide polymorphisms with a genetic significance of P <5 × 10 -8 ). The data of WC (from the Genetic Investigation of ANthropometric Traits consortium, containing 232,101 participants) and the data of AF (from the European Bioinformatics Institute database, containing 55,114 AF cases and 482,295 controls) were used to assess the causal role of WC on AF. Three different approaches (inverse variance weighted [IVW], MR-Egger, and weighted median regression) were used to ensure that our results more reliable. RESULTS: All three MR analyses provided evidence of a positive causal association between high WC and AF. High WC was suggested to increase the risk of AF based on the IVW method (odds ratio [OR] = 1.43, 95% confidence interval [CI], 1.30-1.58, P = 2.51 × 10 -13 ). The results of MR-Egger and weighted median regression exhibited similar trends (MR-Egger OR = 1.40 [95% CI, 1.08-1.81], P = 1.61 × 10 -2 ; weighted median OR = 1.39 [95% CI, 1.21-1.61], P = 1.62 × 10 -6 ). MR-Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF. CONCLUSIONS: Our findings suggest that greater WC is associated with an increased risk of AF. Taking measures to reduce WC may help prevent the occurrence of AF.

CIRP attenuates acute kidney injury after hypothermic cardiovascular surgery by inhibiting PHD3/HIF-1α-mediated ROS-TGF-ß1/p38 MAPK activation and mitochondrial apoptotic pathways.

BACKGROUND: The ischemia-reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms. METHODS: Utilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen-glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments. RESULTS: We discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-ß1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-ß1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo. CONCLUSION: Our findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.

Goal-directed perfusion for reducing acute kidney injury in cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Acute kidney injury (AKI) is a common complication following cardiopulmonary bypass (CPB) which can affect morbidity and mortality. Goal-directed perfusion (GDP) intended to avoid the nadir oxygen delivery index below the critical value is associated with reduced postoperative AKI. However, current studies suggested that GDP can only decrease the incidence of AKI stage 1 but showed no effects on AKI stages 2-3 and mortality. The objective of the present meta-analysis is to deter the effects of GDP on postoperative AKI in any stage and mortality following cardiac surgery. METHODS: MEDLINE, Embase, and the Cochrane Library were searched to identify all clinical trials comparing GDP with control (standard care) during cardiopulmonary bypass conducting in adults undergoing cardiac surgery. The primary outcome was postoperative acute kidney injury. Secondary outcomes included postoperative mortality and length of ICU stay. Data synthesis was obtained by using risk ratio with 95% confidence interval by a random-effects model. RESULT: From 1094 potential studies, 3 trials enrolling 777 patients were included. Meta-analysis suggested the GDP strategy based on DO2i reduced postoperative AKI compared with standard CPB management (RR = 0.52; 95% CI: 0.38-0.70; p < .0001), especially in AKI stage I (RR = 0.47; 95% CI: 0.33-0.66; p < .0001). But the GDP strategy did not reduce the incidence of severe AKI (stages 2-3) and postoperative mortality. CONCLUSION: The GDP strategy based on DO2i during CPB obviously reduces AKI stage 1 and thus reduces overall AKI incidence. But it shows no effects on severe AKI (stages 2-3) and mortality.

Association of high-sensitivity C-reactive protein and anemia with acute kidney injury in neonates.

Background: The association of high-sensitivity C-reactive protein (hsCRP) and anemia with postoperative acute kidney injury (AKI) in neonates with congenital heart disease (CHD) is still unclear. The purpose of this study was to examine whether anemia-associated AKI is modulated by hsCRP in neonates. Methods: This study included 253 consecutive neonatal patients who underwent CHD surgery in a national tertiary hospital. We investigated the association between postoperative AKI with baseline hsCRP, anemia, and their interaction by multivariable logistic regression analyses. Results: The incidence of AKI was 24.1% in the entire cohort. After being adjusted for covariates, hsCRP level was negatively correlated with AKI (P < 0.01 for 1 mg/L threshold), whereas anemia emerged as an independent risk factor of AKI (P = 0.02). In addition, there was a significant interaction between anemia and hsCRP level (P = 0.01). In neonates with hsCRP < 1 mg/L, anemia was positively associated with AKI (P = 0.03). However, no significant association was found between anemia and AKI in the context of hsCRP ≥ 1 mg/L. Combination of anemia and hsCRP < 1 mg/L was independently correlated with the risk of AKI (P < 0.01), while concomitant anemia and hsCRP ≥ 1 mg/L or hsCRP < 1 mg/L combined with non-anemia was not. Conclusions: In neonates with CHD, the risk of anemia-associated AKI may be modulated by hsCRP level. Attention should be paid to neonates with preoperative anemia and baseline hsCRP < 1 mg/L to reduce the risk of postoperative AKI.

Hemostatic complications and systemic heparinization in pediatric post-cardiotomy veno-arterial extracorporeal membrane oxygenation failed to wean from cardiopulmonary bypass.

Background: Hemostatic complications and the need for large amounts of blood products are major obstacles during veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Additionally, the occurrence of coagulopathy after cardiopulmonary bypass (CPB) affects systemic heparinization in pediatric post-cardiotomy patients. This study compares hemostatic complications in pediatric post-cardiotomy VA-ECMO patients for failure to wean from CPB with those who received post-cardiotomy VA-ECMO for other indications, while also exploring the relationship between different stages-hemostatic complications and the timing of systemic heparinization. Methods: We retrospectively analyzed 146 pediatric patients who received post-cardiotomy VA-ECMO support (CPB-ECMO, n=96 vs. non-CPB-ECMO, n=50) from January 2005 to June 2020. Patients were divided into survivors (n=46) and non-survivors (n=50) according to in-hospital mortality in the CPB-ECMO group. We compared clinical outcomes between the groups, then examined the associations between the timing of systemic heparinization after ECMO implantation and different stages-hemostatic complications, in the CPB-ECMO group. Results: We found that the risk of early bleeding was significantly increased in patients who failed to wean from CPB. The presence of early bleeding was accompanied by the higher demand for blood products transfusion in the CPB-ECMO group, and for treatment the patients received a longer delayed continuous heparin infusion. As a result of using delayed systemic heparinization to avoid early bleeding, early hemolysis increased in the CPB-ECMO group. A delayed systemic heparinization of 9.5 hours showed the best Youden index results and the overall greatest accuracy in predicting early hemolysis. Conclusions: A direct transition from CPB to ECMO in pediatric post-cardiotomy patients significantly increases early bleeding. Delayed systemic heparinization to reduce early bleeding has good discrimination for predicting early hemolysis in the CPB-ECMO group. Coagulopathy is complex in pediatric post-cardiotomy VA-ECMO patients who failed to wean from CPB, and, as such, it is extremely important to monitor coagulation-related indicators in multiple dimensions to determine the timing of systemic heparinization.

Mortality prediction in pediatric postcardiotomy veno-arterial extracorporeal membrane oxygenation: A comparison of scoring systems.

Background: Pediatric postcardiotomy veno-arterial extracorporeal membrane oxygenation (VA-ECMO) patients have high mortality and morbidity. There are currently three scoring systems available to predict mortality: the Pediatric Extracorporeal Membrane Oxygenation Prediction (PEP) model, Precannulation Pediatric Survival After VA-ECMO (Pedi-SAVE) score, and Postcannulation Pedi-SAVE score. These methods provide risk stratification scores for pediatric patients requiring ECMO for cardiac support. However, comparative validation of these scoring systems remains scarce. We aim to assess the ability of these models to predict outcomes in a cohort of pediatric patients undergoing VA-ECMO after cardiac surgery, and identify predictors of in-hospital mortality. Methods: A retrospective analysis of 101 children admitted to Fuwai Hospital who received VA-ECMO from January 1, 2010 to December 31, 2020 was performed. Patients were divided into two groups, survivors (n = 49) and non-survivors (n = 52) according to in-hospital mortality. PEP model and Pedi-SAVE scores were calculated. The primary outcomes were the risk factors of in-hospital mortality, and the ability of the PEP model, Precannulation Pedi-SAVE and Postcannulation Pedi-SAVE scores to predict in-hospital mortality. Results: Postcannulation Pedi-SAVE score accessing the entire ECMO process had the greatest area under receiver operator curve (AUROC), 0.816 [95% confidence interval (CI): 0.733-0.899]. Pre-ECMO PEP model could predict in-hospital mortality [AUROC = 0.691 (95% CI: 0.565-0.817)], and Precannulation Pedi-SAVE score had the poorest prediction [AUROC = 0.582(95% CI: 0.471-0.694)]. Lactate value at ECMO implantation [OR = 1.199 (1.064-1.351), P = 0.003] and infectious complications [OR = 5.169 (1.652-16.172), P = 0.005] were independent risk factors for in-hospital mortality. Conclusion: Pediatric cardiac ECMO scoring systems, including multiple risk factors before and during ECMO, were found to be useful in this cohort. Both the pre-ECMO PEP model and the Postcannulation Pedi-SAVE score were found to have high predictive value for in-hospital mortality in pediatric postcardiotomy VA-ECMO.

Risk factors and outcomes associated with acute kidney injury following extracardiac total cavopulmonary connection: a retrospective observational study.

Background: Total cavopulmonary connection (TCPC) is an important operation for the treatment of complex congenital heart disease. Epidemiology and outcomes for pediatric patients with acute kidney injury (AKI) following extracardiac TCPC have not been well documented. This study investigates the prevalence, risk factors, and outcomes of AKI in children after extracardiac TCPC surgery. Methods: We retrospectively evaluated patients (age at surgery <18 years) who underwent extracardiac TCPC surgery between January 2008 and January 2020 in the Pediatric Cardiac Surgical Center of Fuwai Hospital, Beijing, China. AKI was defined according to the pediatric-modified risk, injury, failure, loss of function, and end-stage renal disease criteria. Results: A total of 377 pediatric patients were included in this study; 123 patients (32.6%) had some degree of AKI. Among the patients with AKI, 101 (82.1%) were diagnosed with AKI-risk (AKI-R), while 22 (17.9%) were diagnosed with acute kidney injury/failure (AKI/F) (16 with AKI, and 6 with AKF). Preoperative estimated creatinine clearance (OR: 1.039, 95% CI: 1.024-1.055, P<0.001), neutrophil-to-lymphocyte ratio (OR: 1.208, 95% CI: 1.128-1.294, P<0.001), and renal perfusion pressure (OR: 0.962, 95% CI: 0.938-0.986, P=0.002) on postoperative day (POD) 0 were significantly associated with AKI after TCPC. Having previously undergone a bidirectional Glenn was significantly associated with the severity of postoperative AKI (OR: 0.253, 95% CI: 0.088-0.731, P=0.011). Furthermore, AKI was associated with prolonged mechanical ventilation time, prolonged intensive care unit stay, and composite adverse outcome. Compared with non-AKI patients, the 10-year survival rate of patients with severe AKI was significantly lower (95.5% vs. 65.9%, P=0.009). Conclusions: Although the incidence of AKI was high in patients undergoing TCPC surgery, most cases were AKI-R. Severe AKI was significantly associated with early adverse outcomes and poor long-term survival.

Preoperative Iron Deficiency Is Associated With Increased Blood Transfusion in Infants Undergoing Cardiac Surgery.

Background: Iron deficiency (ID) is common in patients undergoing cardiac surgery, which is associated with adverse outcomes. However, the relevance of ID in congenital heart disease is still unclear. This study aimed to investigate the characteristics of preoperative ID and its association with clinical outcomes in infants undergoing cardiac surgery with cardiopulmonary bypass. Methods: In this retrospective study, 314 patients undergoing cardiac surgery were assigned into three groups according to their preoperative ID status. Absolute ID was defined by serum ferritin <12 µg/L, and functional ID was defined by serum ferritin level at 12-30 µg/L and transferrin saturation <20%. Baseline characteristics were compared between groups and multiple logistic regression was used to identify predictors for ID. The association between ID and clinical outcomes, including allogenic blood transfusion requirements, was also evaluated. Results: Among the 314 patients included, 32.5% were absolute ID and 28.7% were functional ID. Patients with absolute ID were more often of higher weight, cyanotic heart disease, and anemia. The presence of absolute ID was associated with an increase in postoperative blood transfusion (OR 1.837, 95% CI 1.016-3.321, p = 0.044). There was no significant difference in postoperative morbidity, mortality, and the length of hospital stay. Conclusions: Absolute ID was associated with preoperative anemia and cyanotic heart disease, and was an independent risk factor for postoperative blood transfusion. Further research should better explore the definition of ID and its impact on outcomes in pediatric cardiac surgery.

Investigation of myocardial protection during pediatric CPB: Practical experience in 100 Chinese hospitals.

Many measures have been proposed for myocardial protection in pediatric congenital heart surgeries, but little data is available for China. This study investigates myocardial protection strategies in pediatric cardiopulmonary bypass (CPB) throughout China. Online questionnaires were delivered to 100 hospitals in 27 provinces. The number of yearly on-pump pediatric cardiovascular surgeries in these hospitals varied greatly. About 91.0% of respondents believe that each surgery should have at least two perfusionists, while only 64.0% of hospitals actually met this requirement. For pediatric patients, crystalloid cardioplegia was more prevalent than blood-based cardioplegia. Histidine-tryptophan-ketoglutarate solution and St. Thomas crystalloid solution were dominant among crystalloid cardioplegia. Del Nido cardioplegia and St. Thomas blood-based cardioplegia ranked the top two in the popularity of blood-based cardioplegia. Dosages varied among different kinds of cardioplegia. In the choice of different cardioplegia, perfusionists mainly focused on myocardial protective effect and cost. Hypothermia of cardioplegia solution was maintained by ice buckets in 3/4 of the hospitals in this survey. In conclusion, the essence of myocardial protection management during pediatric CPB was cardiac arrest induced by cardioplegia under systemic hypothermia. However, there is no uniform standard for the type of cardioplegia, or dosages. Therefore, well-designed multicenter randomized controlled trials are warranted to provide tangible evidence for myocardial protection of cardioplegia in pediatric CPB.

The lower threshold of hypothermic oxygen delivery to prevent neonatal acute kidney injury.

BACKGROUND: Oxygen delivery during cardiopulmonary bypass (CPB) is closely related to postoperative acute kidney injury (AKI). The value of critical indexed oxygen delivery (DO2i) is a key indicator to reflect oxygen supply in cardiovascular surgery. However, the target DO2i value for neonates undergoing hypothermic CPB remains unclear. METHODS: One hundred and twenty-six consecutive newborns (≤28 days) undergoing arterial switch operations were retrospectively divided into two groups according to AKI occurrence. Baseline characteristics, intraoperative variables, and clinical outcomes were collected. Multivariate logistic regression analysis and receiver-operating characteristic curve were performed to investigate the association between DO2i and AKI. RESULTS: Neonates in the no-AKI group (n = 67) had significantly higher nadir bypass flow and DO2i during the hypothermic phase compared with the AKI group (n = 59). AKI group had remarkably higher incidences of hepatic dysfunction and peritoneal dialysis requirement compared with newborns without AKI. Mixed venous oxygen saturation (SvO2) was comparable between the two groups. Base excess (BE)(P = 0.011) value during the hypothermic phase of the AKI group was higher than the no-AKI group. Multivariate analysis showed that hypothermic DO2i was negatively associated with AKI. The cut-off value of hypothermic DO2i was 269 mL min-1 m-2. CONCLUSIONS: The importance of hypothermic DO2i should be highlighted, even when SvO2 was satisfactory. A lower threshold of DO2i > 269 mL min-1 m-2 may help protect neonates from the risk of postoperative AKI. IMPACT: The key message of our article is that the lower threshold of DO2i > 269 mL min-1 m-2 may help protect neonates from the risk of AKI after on-pump hypothermic cardiovascular surgery. The critical DO2i value for neonates undergoing hypothermic CPB remains unclear, and our study may add new evidence for this matter based on the 6-year experience of our center. In this study, the lowest critical value of DO2i in neonatal hypothermic CPB is determined for the first time, which provides a reference for intra-CPB management strategy to improve the postoperative outcomes of newborns.

Risk Factors and Long-Term Prognosis for Chylothorax After Total Cavopulmonary Connection in Children: A Retrospective Study From a Single Center.

Background: Chylothorax is a severe complication after total cavopulmonary connection (TCPC) in children. This study was performed to evaluate the incidence, risk factors, and short- and long-term prognosis for chylothorax. Methods: We retrospectively reviewed the electronic records of patients who underwent TCPC between January 2008 and December 2020 in Fuwai Hospital. Patients were divided into two groups based on the occurrence of post-operative chylothorax. Univariate and multivariate analyses were performed to identify risk factors, and long-term survival was estimated by the Kaplan-Meier method. Results: Of 386 patients included in our study, chylothorax occurred in 60 patients (15.5%). Compared with the non-chylothorax group, the prevalence of prolonged intensive care unit (ICU) stay (p = 0.000) and post-operative hospital stay (p = 0.000) were greater in patients with chylothorax. Post-operative adverse events in terms of infection (p = 0.002), ascites (p = 0.001), prolonged pleural effusion (p = 0.000), and diaphragmatic paralysis (p = 0.026) were more frequent in chylothorax patients. The median follow-up duration was 4.0 (2.0, 6.8) years. The chylothorax group had significantly lower survival rates at 1 year (92.4 vs. 99.3%, p < 0.001) and 10 years (84.6 vs. 91.6%, p < 0.001), respectively. Having a right dominant ventricle [odds ratio (OR) = 2.711, 95% confidence interval (CI) = 1.285-5.721, p = 0.009] and a higher peak central venous pressure (CVP) on post-operative day (POD) 0 (OR = 1.116, 95% CI = 1.011-1.233, p = 0.030) were the risk factors for the development of chylothorax after TCPC operation. Conclusion: The incidence of chylothorax in patients undergoing TCPC is lower than previously reported but is associated with poor early- and long-term survival. Having a right dominant ventricle and a higher peak CVP on POD 0 are the risk factors for chylothorax after TCPC operation.

The association between neutrophil-lymphocyte ratio and poor outcomes following infant cardiac surgery.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) is a valuable indicator for evaluating inflammation and adverse outcomes after cardiac surgery. The objective of this study was to evaluate the association of perioperative NLR with clinical outcomes in infants undergoing congenital heart surgery with cardiopulmonary bypass. METHODS: We performed a retrospective review of 424 consecutive infants (≤ 1 year) undergoing cardiac surgery between January 2019 and September 2019. Neonates (≤ 28 days) and patients with incomplete NLR data were excluded. The study endpoint was a composite of poor outcomes after surgery. We assess the correlation between perioperative NLR and clinical outcomes. A receiver operating characteristic curve and multivariable logistic regression were applied to identify the prognosis performance of postoperative NLR for poor outcomes. RESULTS: A total of 68 (16%) infants experienced at least one of the poor outcomes. Postoperative NLR on the third day after the surgery showed the best prognostic significance (AUC = 0.763, 95%CI 0.700-0.826) among perioperative period, with a cut-off value of 2.05. Postoperative NLR was also strongly correlated with mechanical ventilation time, length of ICU and hospital stay (p < 0.001). Multivariable logistic regression revealed that elevated postoperative NLR (OR 3.722, 95%CI 1.895-7.309, p < 0.001) was an independent risk factor for poor outcomes in infants after cardiac surgery. CONCLUSIONS: Postoperative NLR was correlated with increased mechanical ventilation time, length of ICU and hospital stay. Elevated postoperative NLR was an independent predictor for poor outcomes after cardiac surgery in infants.

Comparable prognosis in different neonatal histidine-tryptophan-ketoglutarate dosage management.

BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) is a solution commonly used for organ transplantation. However, there is no certified fixed regimen for on-pump heart surgery in neonates. We aimed to retrospectively evaluate the outcomes related to different HTK dosages and to analyze the safety of high-dosage perfusion. METHODS: A total of 146 neonates who underwent on-pump heart surgery with single-shot HTK perfusion were divided into two groups according to HTK dosages: a standard-dose (SD) group (n = 63, 40 mL/kg < HTK ≤ 60 mL/kg) and a high-dose (HD) group (n = 83, HTK >60 mL/kg). Propensity score matching (PSM) was performed to control confounding bias. RESULTS: The SD group had a higher weight (3.7 ±â€Š0.4 vs. 3.4 ±â€Š0.4 kg, P < 0.0001), a lower proportion of complete transposition of the great artery (69.8% vs. 85.5%, P = 0.022), a lower cardiopulmonary bypass (CPB) time (123.5 [108.0, 136.0] vs. 132.5 [114.8, 152.5] min, P = 0.034), and a lower aortic x-clamp time (82.9 ±â€Š27.1 vs. 95.5 ±â€Š26.0 min, P = 0.005). After PSM, 44 patients were assigned to each group; baseline characteristics and CPB parameters between the two groups were comparable. There were no significant differences in peri-CPB blood product consumption after PSM (P > 0.05). The incidences of post-operative complications were not significantly different between the two groups. There were no significant differences in ventilation time, intensive care unit stay, and post-operative hospital stay (P > 0.05). Follow-up echocardiography outcomes at 1 month, 3 to 6 months, and 1 year showed that left ventricular ejection fraction and end-diastolic dimension were comparable between the two groups. CONCLUSIONS: In neonatal on-pump cardiac surgery patients, single-shot HD (>60 mL/kg) HTK perfusion had a comparable heart protection effect and short-term post-operative prognosis as standard dosage perfusion of 40 to 60 mL/kg. Thus, this study provides supporting evidence of the safety of HD HTK perfusion.

Contrast media exposure in the perioperative period confers no additional risk of acute kidney injury in infants and young children undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Recently, there has been an interest in the temporal relationship between contrast exposure (CM) and cardiac surgery suggesting that a "double hit" on the kidney function in close succession increases the risk of acute kidney injury (AKI) after cardiac surgery. However, data from young children is limited. The purpose of this study was to retrospectively evaluate the effects of preoperative CM exposure on postoperative AKI in infant and young children patients and to further analyze the influence of exposure time interval. METHODS: Patients (age ≤ 3 years) who underwent diagnostic imaging within 14 days before on-pump cardiac surgery between 1 May 2017 and 31 May 2018 in Fuwai Hospital, Beijing, were analyzed. Kidney outcome was assessed according to Kidney Disease: Improving Global Outcomes creatinine-based criteria. RESULTS: One thousand four hundred pediatric patients (192 CM and 1,248 non-CM) were identified. Postoperative AKI occurred in 57 (29.7%) of the 192 patients who were exposed to CM. Following propensity score adjustment, no difference in risk for AKI was observed between the CM and non-CM groups (RR 1.142, 95% CI 0.916-1.424; P = 0.264). Multivariable logistic regression of the CM group indicated that independent predictors of postoperative AKI were lower weight, lower preoperative creatinine level, and longer CPB duration. Time interval between CM exposure and on-pump cardiac surgery was not significantly associated with increased risk of AKI (OR 0.853, 95% CI 0.265~2.747; P = 0.790). CONCLUSIONS: For pediatric patients who are soon to undergo on-pump cardiac procedures, there appears to be no need to hesitate in performing the diagnostic imaging investigations requiring CM, or delay CPB after CM exposure. These patients may benefit from increased diagnostic utility without increasing their risk of postoperative AKI.

Outcomes and factors associated with early mortality in pediatric postcardiotomy veno-arterial extracorporeal membrane oxygenation.

Mortality and morbidity of children received veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support after cardiac surgery remain high despite remarkable advances in medical management and devices. The purpose of this study was to describe outcomes and risk factors of applying VA-ECMO in the surgical pediatric population. We retrospectively analyzed 85 consecutive pediatric patients (aged <18 years) who received postcardiotomy VA-ECMO from January 2010 to December 2018. Median (IQR) age at ECMO implantation in this cohort was 12.7 (6.4, 43.2) months, median weight was 8.5 (6.0, 12.8) kg, mean ECMO duration was 143.2 ± 81.6 hours and mean hospital length of stay was 48.4 ± 32.4 days. Seventy-five patients (88.2%) were indicated for postcardiotomy cardiogenic shock. The successful ECMO weaning rate was 70.6% and in-hospital mortality was 52.9%. The most common diagnosis was transposition of great arteries (n = 18, 21.2%), while acute kidney injury occurred most often (n = 64, 75.3%). Multivariate logistic regression analysis showed that thrombocytopenia, hemolysis, and nosocomial infection were positively correlated with in-hospital mortality. Multivariate Cox proportional hazard regression analysis presented that thrombocytopenia significantly increased the 180-day mortality in patients with successful weaning. Therefore, multiple factors had adverse effects on prognosis. Patient selection and procedures from ECMO implantation to weaning need to be closely monitored and performed in a timely manner to improve outcome.

Protein targeting chimeric molecules specific for dual bromodomain 4 (BRD4) and Polo-like kinase 1 (PLK1) proteins in acute myeloid leukemia cells.

Proteolysis targeting chimeras (PROTACs) are hetero-bifunctional molecules that could simultaneously bind to the target protein and the E3 ubiquitin ligase, thereby leading to selective degradation of the target protein. Polo-like kinase 1 (PLK1) and bromodomain 4 (BRD4) are both attractive therapeutic targets in acute myeloid leukemia (AML). Here, we developed a small-molecule BRD4 and PLK1 degrader HBL-4 based on PROTAC technology, which leads to fast, efficient, and prolonged degradation of BRD4 and PLK1 in MV4-11 cells tested in vitro and vivo, and potent anti-proliferation and BRD4 and PLK1 degradation ability in human acute leukemia MOLM-13 and KG1 cells. Meanwhile, HBL-4 more effectively suppresses c-Myc levels than inhibitor BI2536, resulting in more effective inducing apoptosis activity in MV4-11 cells. At the same time, HBL-4 induced dramatically improved efficacy in the MV4-11 tumor xenograft model as compared with BI2536. This study is, to our knowledge, the first reports about dual PLK1 and BRD4 degraders, which potentially represents an important therapeutic advance in the treatment of cancer.