Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases.

N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.

Quality of childcare and delayed child development in left-behind children in China.

BACKGROUND: Inequalities in job opportunities and income prompts many Chinese parents to leave rural regions to work in urban regions. Their children are left behind in rural regions, subjected to worse quality of childcare that jeopardizes their development. This study aimed to examine the association between quality of childcare and delayed child development in under-three years children left behind in China. METHODS: Cross-sectional national survey was conducted in children left behind in rural China in 2017. Exploratory and confirmatory factor analysis was used to develop a quality of childcare index. Mutlilevel analyses determined factors associated with quality of childcare and child development on a province and individual level. RESULT: The largest population of at-risk children left behind were found in higher-GDP provinces. Children left behind had the lowest mean quality of childcare score. Multilevel analysis found that province level accounted for a great proportion of variance observed. CONCLUSIONS: While migration to urban regions for work may improve household income, a trade-off in worse quality of childcare and developmental delays exists. With improving household income often being the greatest contributing factor for parental migration, policies to reduce inequalities in job opportunities and wealth between rural and urban regions are required. IMPACT: Previous studies identified higher prevalence of developmental delays in children left behind in China. However, quality of childcare has not been examined. Based on WHO's Nurturing Care Framework, we developed a quality of childcare index to assess its association with child development in children left behind. Greatest proportion of children left behind at-risk of developmental delays resided in higher-GDP states, indicating a trade-off in worse quality of childcare and developmental delays. Since improving household income is the main factor for parental migration, policies to close inequalities in job opportunities and wealth between rural and urban regions are required.

Sevoflurane postconditioning attenuates cardiomyocytes hypoxia/reoxygenation injury via PI3K/AKT pathway mediated HIF-1α to regulate the mitochondrial dynamic balance.

BACKGROUND: Myocardial ischemia-reperfusion injury (I/RI) is a major cause of perioperative cardiac-related adverse events and death. Studies have shown that sevoflurane postconditioning (SpostC), which attenuates I/R injury and exerts cardioprotective effects, regulates mitochondrial dynamic balance via HIF-1α, but the exact mechanism is unknown. This study investigates whether the PI3K/AKT pathway in SpostC regulates mitochondrial dynamic balance by mediating HIF-1α, thereby exerting myocardial protective effects. METHODS: The H9C2 cardiomyocytes were cultured to establish the hypoxia-reoxygenation (H/R) model and randomly divided into 4 groups: Control group, H/R group, sevoflurane postconditioning (H/R + SpostC) group and PI3K/AKT blocker (H/R + SpostC + LY) group. Cell survival rate was determined by CCK-8; Apoptosis rate was determined by flow cytometry; mitochondrial membrane potential was evaluated by Mito Tracker™ Red; mRNA expression levels of AKT, HIF-1α, Opa1and Drp1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR); Western Blot assay was used to detect the protein expression levels of AKT, phosphorylated AKT (p-AKT), HIF-1α, Opa1 and Drp1. RESULTS: Compared with the H/R group, the survival rate of cardiomyocytes in the H/R + SpostC group increased, the apoptosis rate decreased and the mitochondrial membrane potential increased. qRT-PCR showed that the mRNA expression of HIF-1α and Opa1 were higher in the H/R + SpostC group compared with the H/R group, whereas the transcription level of Drp1 was lower in the H/R + SpostC group. In the H/R + SpostC + LY group, the mRNA expression of HIF-1α was lower than the H/R + SpostC group. There was no difference in the expression of Opa1 mRNA between the H/R group and the H/R + SpostC + LY group. WB assay results showed that compared with the H/R group, the protein expression levels of HIF-1α, Opa1, P-AKT were increased and Drp1 protein expression levels were decreased in the H/R + SpostC group. HIF-1α, P-AKT protein expression levels were decreased in the H/R + SpostC + LY group compared to the H/R + SpostC group. CONCLUSION: SpostC mediates HIF-1α-regulated mitochondrial fission and fusion-related protein expression to maintain mitochondrial dynamic balance by activating the PI3K/AKT pathway and increasing AKT phosphorylation, thereby attenuating myocardial I/R injury.

Phase I clinical trial of HC-1119 soft capsule in Chinese healthy adult male subjects: Pharmacokinetics and safety of single-dose proportionality and effects of food.

BACKGROUND: Preclinical studies showed that HC-1119, a deuterated version of enzalutamide, could competitively inhibit androgen binding to androgen receptor by blocking the transmission of androgen receptor signaling pathway as enzalutamide, inducing apoptosis of prostate cancer cells and reducing the proliferation of prostate cancer cells. Animal pharmacokinetic studies also show that deuterization of enzalutamide as HC-1119 could retain the basic properties of mother drug, increases the stability of compounds to metabolic enzymes and the drug exposure in vivo, prolong the half-life and reduce the production of metabolites, which may lead to a better efficacy and safety of HC-1119 compared with enzalutamide. METHODS: To evaluate the pharmacokinetics and safety of HC-1119 and the effects of food on pharmacokinetics in healthy adult Chinese men after single-dose administration of HC-1119. A total of 47 Chinese healthy adult male subjects received HC-1119 soft capsule at a single oral dose of 40, 80, or 160 mg followed on fasting or 160 mg after high-fat meal respectively. HC-1119 prototype and its metabolites M1 and M2 in plasma were collected individually in a total 23 time points. Pharmacokinetics were determined by sensitive LC/MS/MS for dose-proportionality study. RESULTS: In subjects taking HC-1119 soft capsules on fasting, Cmax of HC-1119 prototype increased dose-dependently. Either Cmax and AUC0-∞ of M1 or Cmax of M2 showed statistically significant difference. Dose-proportionality evaluation showed linear pharmacokinetic characteristics in Cmax of HC-1119 prototype, Cmax and AUC0-∞ of M2 in dose range of 40-160 mg. Cmax of HC-1119 was significantly different between the two groups as 160 mg HC-1119 on fasting or after a high-fat diet respectively, while the other parameter were not. HC-1119 and its metabolites M1 and M2 showed a linear dynamic trend. CONCLUSIONS: HC-1119 is expected to have lower clinical dose than the similar drug enzalutamide. The absorption of HC-1119 and the main pharmacokinetic parameters of HC-1119 and its metabolites M1 and M2 were not affected by high-fat diet. The clinical application of HC-1119 soft capsule in the later stage can be recommended for both fasting and postprandial. The safety and tolerance were good in this population.

Bone marrow mesenchymal stem cells-derived exosomes mediate nuclear receptor coactivator-3 expression in osteoblasts by delivering miR-532-5p to influence osteonecrosis of the femoral head development.

Exosomes (Exo) originated from bone marrow mesenchymal stem cells (BMSCs) have therapeutic impacts on osteonecrosis of the femoral head (ONFH), and microRNA (miR)-532-5p has been confirmed to participate in ONFH progression. In the research, it was figured out whether BMSCs-Exo could relieve ONFH by delivering miR-532-5p. MG-63 cells were treated with DEX to construct an ONFH cell model in vitro. The effects of Exo and miR-532-5p on the cell viability, lactate dehydrogenase (LDH) content, and apoptosis of BMSCs were detected. The ONFH rat model was established, and the effect of BMSCs-Exo delivering miR-532-5p on the pathological damage of ONFH rats was evaluated. Changes in nuclear receptor coactivator-3 (NCOA3) and apoptotic proteins were assessed by western blot. The relationship between miR-532-5p and NCOA3 was verified by dual luciferase reporter experiments. miR-532-5p was elevated in vivo and in vitro ONFH-models, while NCOA3 expression was reduced. Overexpression of miR-532-5p aggravated DEX toxicity in osteoblasts, decreased cell viability, and promoted apoptosis. Knockdown of miR-532-5p made Exo further attenuate the toxic effect of DEX on osteoblasts and inhibited apoptosis. The protective effect of miR-532-5p-delivering Exo on osteoblasts was reversed by NCOA3 silencing. In addition, in vivo experiments also confirmed that knockdown of miR-532-5p enhanced the therapeutic effect of Exo on ONFH rats. This study demonstrates that miR-532-5p-delivering BMSCs-Exo inhibits osteoblast viability and promote apoptosis by targeting NCOA3, thereby aggravating ONFH development.

SIRT1/Notch1 signal axis involves in the promoting effect of Segetalin B on bone formation.

Phytoestrogens are a class of potential natural medicines for treating postmenopausal osteoporosis (PMOP). Segetalin B (SB) is a cyclic peptide compound showing estrogenic activity. This study reports the effect of SB on bone formation among ovariectomized (OVX) rats. The bone marrow mesenchymal stem cells (BMSCs) from OVX rats were cultured in vitro. Alizarin Red staining was utilized to observe the effect of SB on the mineralization of BMSCs. The levels of alkaline phosphatase (ALP), osteocalcin, bone morphogenetic protein (BMP-2), and Sirtuin 1 (SIRT1) activities were detected. The OVX rats were treated with SB in vivo. Micro-CT was utilized for imaging analysis. Urine calcium and phosphorus, and ALP activity in bone marrow were assayed. Western blot analysis and immunofluorescence were incorporated to detect protein expressions in vitro and in vivo. The results showed that SB dose-dependently promoted mineralization of OVX rat-derived BMSCs in vitro increased the level of Osteocalcin, BMP-2, ALP, and SIRT1 activity. Moreover, it upregulated expressions of Runx2, Osterix, and SIRT1, downregulated expressions of Notch intracellular domain (NICD), acetyl-NICD, and hairy and enhancer of split 1 (Hes1). In addition, SB treatment significantly decreased bone loss, inhibited calcium and phosphorus loss, elevated ALP activity, upregulated Runx2, Osterix, and SIRT1, and downregulated NICD and Hes1 in OVX rats in vivo. However, EX527, a SIRT1-selective inhibitor, could reverse the above effects of SB in vitro or in vivo. These results indicate that SB is a potential natural medicine to improve PMOP. Thus, its mechanism of promoting bone formation involves the SIRT1/Notch1 signaling axis.

Evaluation of a novel Cardiac Peri-Operative Transfusion Trigger Scoring system in patients with coronary artery disease.

BACKGROUND: A simple and accurate scoring system to guide perioperative blood transfusion in patients with coronary artery disease (CAD) undergoing cardiac surgery is lacking. The trigger point for blood transfusions for these patients may be different from existing transfusion guidelines. This study aimed to evaluate the safety and efficacy of a new scoring strategy for use in guiding transfusion decisions in patients with CAD. METHODS: A multicenter randomized controlled trial was conducted at three third-level grade-A hospitals from January 2015 to May 2018. Data of 254 patients in a Cardiac Peri-Operative Transfusion Trigger Score (cPOTTS) group and 246 patients in a group receiving conventional evaluation of the need for transfusion (conventional group) were analysed. The requirements for transfusion and the per capita consumption of red blood cells (RBCs) were compared between groups. RESULTS: Baseline characteristics of the two groups were comparable. Logistic regression analyses revealed no significant differences between the two groups in primary outcomes (1-year mortality and perioperative ischemic cardiac events), secondary outcomes (shock, infections, and renal impairment), ICU admission, and ICU stay duration. However, patients in the cPOTTS group had significantly shorter hospital stays, lower hospital costs, lower utilization rate and lower per capita consumption of transfused RBCs than controls. Stratified analyses revealed no significant differences between groups in associations between baseline characteristics and perioperative ischemic cardiac events, except for hemofiltration or dialysis and NYHA class in I. CONCLUSIONS: This novel scoring system offered a practical and straightforward guideline of perioperative blood transfusion in patients with CAD. Trial registration chiCTR1800016561(2017/7/19).

The risk factors of postoperative delirium in patients with hip fracture: implication for clinical management.

BACKGROUND: Delirium is a common complication of hip surgery patients. It is necessary to investigate the epidemiological characteristics and related risk factors of delirium after hip fracture surgery, to provide evidence supports for the prevention and management of delirium. METHODS: Hip fracture patients admitted to our hospital for surgical treatment from March 2018 to March 2020 were identified as participants. The characteristics and laboratory examinations in patients with and without postoperative delirium were compared and analyzed. Logistic regression analyses were conducted to ascertain the independent risk factors, and the area under the curve (AUC) were calculated to analyze the predictive value. RESULTS: A total of 568 postoperative patients with hip fracture were included, the incidence of delirium in postoperative patients with hip fracture was 14.44 %. The preoperative albumin (OR 4.382, 2.501 ~ 5.538), history of delirium (OR 2.197, 1.094 ~ 3.253), TSH (OR1.245, 1.077 ~ 1.638), the resting score on the first postoperative day (OR1.235, 0.944 ~ 1.506) and age(OR1.185, 0.065 ~ 1.814) were the independent risk factors for the postoperative delirium in patients with hip fracture(all p < 0.05). The AUC of albumin, history of delirium, TSH, the resting score on the first postoperative day and age were 0.794, 0.754, 0.746, 0.721 and 0.689 respectively. CONCLUSIONS: The incidence of delirium in postoperative patients with hip fracture is rather high, especially for patients with old age and history of delirium. Monitoring albumin, TSH and resting score may be beneficial to the management of postoperative delirium.

Heparin sensitivity and postoperative blood loss in patients undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Heparin-associated coagulation disorder is an important factor related to postoperative bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass. Currently, the relationship between heparin sensitivity and postoperative bleeding is unknown. OBJECTIVE: To investigate the relationship between individual heparin sensitivity and postoperative blood loss in patients undergoing cardiac surgery. DESIGN: Prospective controlled study. SETTING: Tertiary teaching hospital, Urumqi, Xinjiang, PR China. The study was conducted from January 2016 to August 2018. PATIENTS: A total of 195 adult patients undergoing cardiac valve replacement surgery were included. INTERVENTION: After initial heparin dosing (2.5 mg kg), patients were divided into three groups according to the whole blood activated clotting time (ACT): group A, insensitive group (ACT < 480 s); group B, sensitive group (480 s < ACT < 750 s); group C, hypersensitive group (ACT > 750 s). MAIN OUTCOME MEASURES: First, intra-operative and 24-h postoperative blood loss. Second, antithrombin (AT) and factor X mRNA levels. Third, the plasma levels of AT-III and factor X. Fourth, heparin sensitivity index. RESULTS: Blood loss was approximately 20 to 25% lower in group B than in groups A and C, which was statistically significant (P < 0.01). The AT-III mRNA levels increased from groups A to C and was positively associated with heparin sensitivity; the factor X mRNA levels changed in the opposite direction; a significant difference was observed between groups A and C (P < 0.05). The factor X plasma level showed the same trend as its mRNA. The AT-III plasma level was significantly lower in group B than in groups A and C (P < 0.05). CONCLUSION: Postoperative blood loss is related to heparin sensitivity in patients undergoing cardiac surgery, and the moderately sensitive patients have the least postoperative bleeding. Individual variation in heparin sensitivity is related to the mRNA and plasma levels of AT-III and factor X. TRIAL REGISTRATION: Registration number ChiCTR-RPC-17012259.

Statistical Mechanics Approximation of Biogeography-Based Optimization.

Biogeography-based optimization (BBO) is an evolutionary algorithm inspired by biogeography, which is the study of the migration of species between habitats. This paper derives a mathematical description of the dynamics of BBO based on ideas from statistical mechanics. Rather than trying to exactly predict the evolution of the population, statistical mechanics methods describe the evolution of statistical properties of the population fitness. This paper uses the one-max problem, which has only one optimum and whose fitness function is the number of 1s in a binary string, to derive equations that predict the statistical properties of BBO each generation in terms of those of the previous generation. These equations reveal the effect of migration and mutation on the population fitness dynamics of BBO. The results obtained in this paper are similar to those for the simple genetic algorithm with selection and mutation. The paper also derives equations for the population fitness dynamics of general separable functions, and we find that the results obtained for separable functions are the same as those for the one-max problem. The statistical mechanics theory of BBO is shown to be in good agreement with simulation.

Constrained multiobjective biogeography optimization algorithm.

Multiobjective optimization involves minimizing or maximizing multiple objective functions subject to a set of constraints. In this study, a novel constrained multiobjective biogeography optimization algorithm (CMBOA) is proposed. It is the first biogeography optimization algorithm for constrained multiobjective optimization. In CMBOA, a disturbance migration operator is designed to generate diverse feasible individuals in order to promote the diversity of individuals on Pareto front. Infeasible individuals nearby feasible region are evolved to feasibility by recombining with their nearest nondominated feasible individuals. The convergence of CMBOA is proved by using probability theory. The performance of CMBOA is evaluated on a set of 6 benchmark problems and experimental results show that the CMBOA performs better than or similar to the classical NSGA-II and IS-MOEA.

Multigranularity Surrogate Modeling for Evolutionary Multiobjective Optimization With Expensive Constraints.

Multiobjective optimization problems (MOPs) with expensive constraints pose stiff challenges to existing surrogate-assisted evolutionary algorithms (SAEAs) in a very limited computational cost, due to the fact that the number of expensive constraints for an MOP is often large. For existing SAEAs, they always approximate constraint functions in a single granularity, namely, approximating the constraint violation (CV, coarse-grained) or each constraint (fine-grained). However, the landscape of CV is often too complex to be accurately approximated by a surrogate model. Although the modeling of each constraint function may be simpler than that of CV, approximating all the constraint functions independently may result in tremendous cumulative errors and high computational costs. To address this issue, in this article, we develop a multigranularity surrogate modeling framework for evolutionary algorithms (EAs), where the approximation granularity of constraint surrogates is adaptively determined by the position of the population in the fitness landscape. Moreover, a dedicated model management strategy is also developed to reduce the impact resulting from the errors introduced by constraint surrogates and prevent the population from trapping into local optima. To evaluate the performance of the proposed framework, an implementation called K-MGSAEA is proposed, and the experimental results on a large number of test problems show that the proposed framework is superior to seven state-of-the-art competitors.

Goal-directed fluid therapy in gastrointestinal surgery in older coronary heart disease patients: randomized trial.

BACKGROUND: Our aim was to determine whether substitution of goal-directed fluid therapy (GDT) (perioperative fluid administration) for traditional therapy to manage elderly patients with coronary heart disease scheduled for gastrointestinal (GI) surgery was advantageous. We determined if it would reduce cardiac complications and shorten time to recovery and discharge. METHODS: Altogether, 60 of these elderly patients were randomized into GDT (n = 30) and control (n = 30) groups. In the GDT group, fluid management was carried out under guidance of hemodynamic status indicators. Types and quantities of fluids administered, blood loss, intraoperative urine output, time of extubation, intensive care unit (ICU) stay, hospital stay, postoperative adverse cardiac events, and GI complications were recorded. RESULTS: Total fluids infused were 2,910 ± 645 ml (GDT group) and 3,640 ± 771 ml (control group) (p < 0.05). Numbers of adverse cardiac events in the two groups were not significantly different (p = 0.121). Return of GI function was significantly faster in the GDT group (p < 0.001). Median ICU stay was 32.5 h in the GDT group and 47.5 h in the control group (p < 0.001). Median hospital stay was 18 days in the GDT group and 22 days in the control group (p < 0.001). CONCLUSIONS: GDT was associated with shorter ICU stay and time to discharge and faster return of GI function compared to traditional fluid therapy. The number of adverse cardiac events was similar in the two groups.

[Perioperative change in serum neutrophil gelatinase-associated lipocalin level among children with congenital heart disease and pulmonary hypertension].

OBJECTIVE: To study the perioperative change in serum neutrophil gelatinase-associated lipocalin (NGAL) level among children with congenital heart disease (CHD) and pulmonary hypertension (PH) and its significance. METHODS: Eighty children with CHD were divided into four groups according to pulmonary artery systolic pressure: non-PH, mild PH, moderate PH and severe PH groups. Serum NGAL levels were measured before operation, immediately after operation and 24 hours after operation. The relationship of serum NGAL level with PH and early prognosis was analyzed. RESULTS: The mild, moderate and severe PH groups had significantly higher serum NGAL levels than the non-PH group, and the severer the PH, the higher the serum NGAL level (P<0.01). All groups showed significant decreases in serum NGAL levels after operation (P<0.01). Serum NGAL level was positively correlated with the degree of PH and length of stay in the intensive care unit (P<0.01). CONCLUSIONS: Serum NGAL level increases in children with CHD and PH, and it gradually decreases after operation for closing the abnormal shunt. Serum NGAL level may be used as a serological indicator for evaluating the degree of PH and surgical outcome.

SegT: Separated edge-guidance transformer network for polyp segmentation.

Accurate segmentation of colonoscopic polyps is considered a fundamental step in medical image analysis and surgical interventions. Many recent studies have made improvements based on the encoder-decoder framework, which can effectively segment diverse polyps. Such improvements mainly aim to enhance local features by using global features and applying attention methods. However, relying only on the global information of the final encoder block can result in losing local regional features in the intermediate layer. In addition, determining the edges between benign regions and polyps could be a challenging task. To address the aforementioned issues, we propose a novel separated edge-guidance transformer (SegT) network that aims to build an effective polyp segmentation model. A transformer encoder that learns a more robust representation than existing convolutional neural network-based approaches was specifically applied. To determine the precise segmentation of polyps, we utilize a separated edge-guidance module consisting of separator and edge-guidance blocks. The separator block is a two-stream operator to highlight edges between the background and foreground, whereas the edge-guidance block lies behind both streams to strengthen the understanding of the edge. Lastly, an innovative cascade fusion module was used and fused the refined multi-level features. To evaluate the effectiveness of SegT, we conducted experiments with five challenging public datasets, and the proposed model achieved state-of-the-art performance.

Pharmacokinetic and bioequivalence study of two capecitabine tablets in Chinese patients with breast, colorectal or gastric cancer under fed condition: A multicentric, randomized, open-label, single-dose, two-period, two-way crossover clinical trial.

OBJECTIVE: The aim of this study was to examine the pharmacokinetics, bioequivalence, and safety of two tablet formulations of capecitabine 500 mg in Chinese patients with breast, colorectal or gastric cancer under fed condition. METHODS: A multicentric, randomized, open-label, single-dose, two-period, two-way crossover trial was conducted by randomizing a single oral dose of test (T) or reference (R, Xeloda®) capecitabine (500 mg) to patients of either sex with colon, colorectal or breast cancer under fed condition (high-fat and high-calorie diet). Pharmacokinetic parameters were calculated using non-compartmental methods. Patients were monitored for safety and tolerability throughout the study. RESULTS: 74 subjects were randomly enrolled. The T/R geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for Cmax, AUC0-t and AUC0-∞ of capecitabine were 96.60% (85.87-108.67%), 99.07% (95.40-102.89%), 99.17% (95.29-103.21%), respectively. All 90% CIs fell within the bioequivalence acceptance range of 80.00-125.00%. The common adverse events (AEs) included clinically significant laboratory abnormalities and gastrointestinal diseases. There were no serious adverse events (SAEs) or deaths during the study. No subject withdrew from the study due to AEs. CONCLUSION: Single oral intake of test and the reference capecitabine tablets were bioequivalent under fed condition and had similar favourable safety profiles in Chinese patients with breast, colorectal or gastric cancer. TRIAL REGISTRATION: chinadrugtrials.org.cn (CTR20182110).

Long Noncoding RNA Zinc Finger Antisense 1 Affects Glucocorticoid-Induced Osteonecrosis of the Femoral Head by Performing as a ceRNA for MicroRNA-124-3p and Accelerating Transforming Growth Factor Type III Receptor.

In recent years, plentiful studies have uncovered the long noncoding RNA's (lncRNA's) momentous functions in osteonecrosis of the femoral head (ONFH), but the specific mechanism has not been fully illustrated. The study was to figure out lncRNA Zinc finger antisense 1 (LncZFAS1)'s biological function and its latent downstream molecular mechanism in glucocorticoid- (GC-) induced ONFH. The results manifested LncZFAS1 and transforming growth factor type III receptor (TGFBR3) were elevated, while microRNA- (miR-) 124-3p was reduced in ONFH tissues and cells. Knockdown LncZFA1 reduced rat femoral cell apoptosis, perfected bone microstructure and bone density, and accelerated osteogenic proteins bone morphogenetic protein- (BMP-) 9, BMP-3, and osteocalcin. In vitro studies manifested knockdown LncZFAS1 prevented GC-induced reduction in osteoblast advancement with facilitating osteoblast calcification capacity, ALP activity, and osteogenic proteins. Elevation of LncZFAS1 further aggravated GC-induced osteoblast injury, but this effect was turned around by enhancement of miR-124-3p or knockdown of TGFBR3. Mechanistically, LncZFAS1 performed as a sponge for miR-124-3p to mediate TGFBR3 expression to motivate GC-induced ONFH. All in all, the results of this study indicate the LncZFAS1/miR-124-3p/TGFBR3 axis is supposed to be a latent therapeutic molecular target for GC-induced ONFH.

miR-3064-5p and miR-4745-5p affect heparin sensitivity in patients undergoing cardiac surgery by regulating AT-III and factor X mRNA levels.

Subject: Perioperative regulation of coagulation function through heparin in patients undergoing cardiac surgery with cardiopulmonary bypass is an important part of performing cardiac surgery, and postoperative bleeding due to abnormal coagulation function caused by differences in heparin sensitivity in different individuals is an independent risk factor for postoperative complications and death. Method: Using an online database, 10 miRNAs interacting with AT-III and FX genes were predicted. Patients were divided into three groups according to the difference in activated clotting time (ACT) after the first dose of heparin (2.5 mg kg-1): group A: hyposensitive group (ACT < 480 s); group B: sensitive group (480 s ≤ ACT ≤ 760 s); and group C: hypersensitive group (ACT > 760 s). Perioperative and 24 h postoperative blood loss and other clinical data of patients in the three groups were recorded. Blood samples were collected before surgery, and RT-PCR was used to detect the levels of AT-III and FX gene mRNA and the levels of predicted 10 miRNAs. Result: Heparin sensitivity was positively correlated with AT-III mRNA levels and negatively correlated with FX gene mRNA levels in the three groups, and the blood loss in group B was significantly lower than that in groups A and C, which was statistically significant (p < 0.05). miR-3064-5p and miR-4745-5p expression levels were significantly different among group A, group B, and group C (p < 0.05) and were closely correlated with AT-III and FX gene mRNA expression levels, respectively. Conclusion: Differences in heparin sensitivity in patients undergoing cardiac surgery were associated with the mRNA expression of AT-III and FX genes, and the expression levels of miR-3064-5p and miR-4745-5p were found to be closely related to the AT-III and FX gene mRNA, respectively, indicating that miR-3064-5p and miR-4745-5p affect the differences in heparin sensitivity among different individuals by regulating the mRNA expression levels of AT-III and FX genes. Clinical Trial Registration: http://www.chictr.org.cn/abouten.aspx, identifier registration number: ChiCTR-2100047348.

Effect of Etomidate vs Propofol for Total Intravenous Anesthesia on Major Postoperative Complications in Older Patients: A Randomized Clinical Trial.

Importance: Older patients may benefit from the hemodynamic stability of etomidate for general anesthesia. However, it remains uncertain whether the potential for adrenocortical suppression with etomidate may increase morbidity. Objective: To test the primary hypothesis that etomidate vs propofol for anesthesia does not increase in-hospital morbidity after abdominal surgery in older patients. Design, Setting, and Participants: This multicenter, parallel-group, noninferiority randomized clinical trial (Etomidate vs Propofol for In-hospital Complications [EPIC]) was conducted between August 15, 2017, and November 20, 2020, at 22 tertiary hospitals in China. Participants were aged 65 to 80 years and were scheduled for elective abdominal surgery. Patients and outcome assessors were blinded to group allocation. Data analysis followed a modified intention-to-treat principle. Interventions: Patients were randomized 1:1 to receive either etomidate or propofol for general anesthesia by target-controlled infusion. Main Outcomes and Measures: Primary outcome was a composite of major in-hospital postoperative complications (with a noninferiority margin of 3%). Secondary outcomes included intraoperative hemodynamic measurements; postoperative adrenocortical hormone levels; self-reported postoperative pain, nausea, and vomiting; and mortality at postoperative months 6 and 12. Results: A total of 1944 participants were randomized, of whom 1917 (98.6%) completed the trial. Patients were randomized to the etomidate group (n = 967; mean [SD] age, 70.3 [4.0] years; 578 men [59.8%]) or propofol group (n = 950; mean [SD] age, 70.6 [4.2] years; 533 men [56.1%]). The primary end point occurred in 90 of 967 patients (9.3%) in the etomidate group and 83 of 950 patients (8.7%) in the propofol group, which met the noninferiority criterion (risk difference [RD], 0.6%; 95% CI, -1.6% to 2.7%; P = .66). In the etomidate group, mean (SD) cortisol levels were lower at the end of surgery (4.8 [2.7] µg/dL vs 6.1 [3.4] µg/dL; P < .001), and mean (SD) aldosterone levels were lower at the end of surgery (0.13 [0.05] ng/dL vs 0.15 [0.07] ng/dL; P = .02) and on postoperative day 1 (0.14 [0.04] ng/dL vs 0.16 [0.06] ng/dL; P = .001) compared with the propofol group. No difference in mortality was observed between the etomidate and propofol groups at postoperative month 6 (2.2% vs 3.0%; RD, -0.8%; 95% CI, -2.2% to 0.7%) and 12 (3.3% vs 3.9%; RD, -0.6%; 95% CI, -2.3% to 1.0%). More patients had pneumonia in the etomidate group than in the propofol group (2.0% vs 0.3%; RD, 1.7%; 95% CI, 0.7% to 2.8%; P = .001). Results were consistent in the per-protocol population. Conclusions and Relevance: Results of this trial showed that, compared with propofol, etomidate anesthesia did not increase overall major in-hospital morbidity after abdominal surgery in older patients, although it induced transient adrenocortical suppression. Trial Registration: ClinicalTrials.gov Identifier: NCT02910206.

[A meta-analysis on efficacy of antifibrinolytic agents during perioperative period in patients undergoing coronary artery bypass grafting treated with antiplatelet agents].

OBJECTIVE: To evaluate the efficacy of antifibrinolytic agents in coronary artery bypass grafting (CABG) patients receiving antiplatelet. METHODS: We searched PubMed, EMbase, Highwire, CENTREN and its affiliated clinical trial registration data center, CBMdisc and CNKI databases from 2000 to 2010. Randomized controlled trials investigating the efficacy of anti-fibrinolytic agents (aprotinin and tranexamic acid) in CABG patients were identified. Study selection and meta-analysis were conducted according to the Cochrane Handbook for systematic reviews. Date were extracted from these trials by 2 reviewers independently and analyzed by RevMan 5.0 software. RESULT: Eleven RCT trials (n = 725) were included and data confirmed the efficacy of antifibrinolytic therapy in terms of reducing bleeding within 24 hours after operation (MD = -306.5 ml, 95%CI: -351.52 to -261.52, P < 0.01), number of patients who need blood transfusion (OR = 0.37, 95%CI: 0.26 to 0.51, P < 0.01), amount of blood transfusion (MD = -0.59 U, 95%CI: -0.69 to -0.50, P < 0.01), surgical re-exploration(OR = 0.27, 95%CI: 0.09 to 0.78, P = 0.02), and thrombotic events (OR = 0.49, 95%CI: 0.25 to 0.97, P = 0.04) in CABG patients receiving antiplatelet, while compared with blank treatment. CONCLUSION: This analysis showed that antifibrinolytic agents are effective for reducing bleeding within 24 hours after operation, amount of blood transfusion, surgical re-exploration and do not increase the incidence of thrombotic events in CABG patients receiving antiplatelet before operation.