Temperature effect on coagulation function in mild hypothermic patients undergoing thoracic surgeries: thromboelastography (TEG) versus standard tests.

PURPOSE: Our previous research has revealed that mild hypothermia leads to excessive bleeding in thoracic surgeries, while the underlying mechanism stayed unrevealed by the standard coagulation tests. The research question in this study was as follows: "How does mild hypothermia impair the hemostatic function in patients receiving thoracic surgeries?". The purpose was to detect the disturbed coagulation processes by comparing the TEG parameters in patients receiving active vs. passive warming during thoracic surgeries. METHODS: Standard coagulation tests and thromboelastography (TEG) were adopted to compare the hemostatic functions in patients receiving active vs. passive warming during thoracic surgeries. Furthermore, blood samples from passive warming group were retested for TEG at actual core body temperatures. RESULTS: Sixty-four eligible patients were included in this study. TEG revealed that mild hypothermia significantly disturbed coagulation by decreasing MA (59.4 ± 4.5 mm vs. 64.2 ± 5.7 mm, p = 0.04) and α angle (70.4 ± 5.2° vs. 74.9 ± 4.4°, p = 0.05) and prolonging ACT (122.2 ± 19.3 s vs. 117.3 ± 15.2 s, p = 0.01) and K time (1.9 ± 1.0 s vs. 1.3 ± 0.4 min, p = 0.02). TEGs conducted under core body temperatures revealed more impaired coagulation than those incubated at 37 °C. Furthermore, postoperative shivering and waking time were significantly increased in mild hypothermic patients. CONCLUSION: Mild hypothermia significantly impaired coagulation function in patients receiving thoracic surgeries, which could be detected by TEGs other than the standard coagulation tests. Temperature-adjusted TEGs may provide a preferable method of hemostatic monitoring and transfusion guidance in thoracic surgeries, which warrants further clinical investigations.

Tranexamic acid given into wound reduces postoperative drainage, blood loss, and hospital stay in spinal surgeries: a meta-analysis.

BACKGROUND: Although intravenous tranexamic acid administration (ivTXA) has prevailed in clinical antifibrinolytic treatment, whether it increases thromboembolic risks has remained controversial. As a potent alternative to ivTXA, topical use of TXA (tTXA) has been successfully applied to attenuate blood loss in various surgical fields while minimizing systemic exposure to TXA. This meta-analysis was conducted to gather scientific evidence for tTXA efficacy on reducing postoperative drainage, blood loss, and the length of hospital stay in spine surgeries. OBJECTIVES: To examine whether topical use of TXA (tTXA) reduces postoperative drainage output and duration, hidden blood loss, hemoglobin level drop, hospital stay, and adverse event rate, we reviewed both randomized and non-randomized controlled trials that assessed the aforementioned efficacies of tTXA compared with placebo in patients undergoing cervical, thoracic, or lumbar spinal surgeries. METHODS: An exhaustive literature search was conducted in MEDLINE and EMBASE databases from January 2000 through March 2020. Measurable outcomes were pooled using Review Manager (RevMan) version 5.0 in a meta-analysis. RESULTS: Significantly reduced postoperative drainage output (weighted mean difference [WMD]= - 160.62 ml, 95% confidence interval (95% CI) [- 203.41, - 117.83]; p < .00001) and duration (WMD= - 0.75 days, 95% CI [- 1.09, - 0.40]; p < .0001), perioperative hidden blood loss (WMD= - 91.18ml, 95% CI [- 121.42, - 60.94]; p < .00001), and length of hospital stay (WMD= - 1.32 days, 95% CI [- 1.90, - 0.74]; p < .00001) were observed in tTXA group. Pooled effect for Hb level drop with tTXA vs placebo crossed the equivalent line by a mere 0.05 g/dL, with the predominant distribution of 95% confidence interval (CI) favoring tTXA use. CONCLUSIONS: With the most comprehensive literature inclusion up to the present, this meta-analysis suggests that tTXA use in spinal surgeries significantly reduces postoperative drainage, hidden blood loss, and hospital stay duration. The pooled effect also suggests that tTXA appears more effective than placebo in preserving postoperative Hb level, which needs further validation by future studies.

SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells.

Adolescent idiopathic scoliosis (AIS) is a complex, three-dimensional deformity of the spine that commonly occurs in pubescent girls. Decreased osteogenic differentiation and aberrant melatonin signalling have been demonstrated in mesenchymal stem cells (MSCs) from AIS patients and are implicated in the pathogenesis of AIS. However, the molecular mechanisms underlying these abnormal cellular features remain largely unknown. Our previous work comparing gene expression profiles between MSCs from AIS patients and healthy controls identified 1027 differentially expressed genes. In the present study, we focused on one of the most downregulated genes, SPRY4, in the MAPK signalling pathway and examined its role in osteogenic differentiation. We found that SPRY4 is markedly downregulated in AIS MSCs. Knockdown of SPRY4 impaired differentiation of healthy MSCs to osteoblasts, while SPRY4 overexpression in AIS MSCs enhanced osteogenic differentiation. Furthermore, melatonin treatment boosted osteogenic differentiation, whereas SPRY4 ablation ablated the promotional effects of melatonin. Moreover, SPRY4 was upregulated by melatonin exposure and contributed to osteogenic differentiation and melatonin response in a MEK-ERK1/2 dependent manner. Thus, loss of SPRY4 in bone marrow derived-MSCs results in reduced osteogenic differentiation, and these defects are further aggravated under the influence of melatonin. Our findings provide new insights for understanding the role of melatonin in AIS aetiology and highlight the importance of MSCs in AIS pathogenesis.

Differential miRNAs profile and bioinformatics analyses in bone marrow mesenchymal stem cells from adolescent idiopathic scoliosis patients.

BACKGROUND CONTEXT: Coexistence of abnormal skeletal growth and reduced bone mineral density in the context of adolescent idiopathic scoliosis (AIS) suggests disturbed bone metabolism existing in such patients. Our previous study suggested increased proliferation ability and decreased osteogenic differentiation ability of bone marrow mesenchymal stem cells (BM-MSCs) of AIS. PURPOSE: To explore the differential miRNA expression profile, Go (gene ontology) terms and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways in BM-MSCs of AIS and non-AIS controls were conducted using microarray approach and bioinformatics analyses. STUDY DESIGN: miRNA microarray approach and bioinformatics analysis. METHODS: The differentially expressed miRNAs (DEMs) of BM-MSCs from AIS patients compared with those from healthy individuals were analyzed using a microarray analysis. Comprehensive bioinformatics analyses were then used to enrich datasets for gene ontology and pathway. Based on the interaction network analysis of DEMs contained in significant pathways, 12 potential crucial miRNAs were selected for validation by RT-PCR. RESULTS: The study identified 54 previously unrecognized DEMs (12 upregulated, 42 downregulated) in BM-MSCs from AIS patients. These miRNAs are involved in multiple biological processes, including small GTPase-mediated signal transduction, DNA-dependent transcription, cytokinesis, cell adhesion, transmembrane transport, response to hypoxia, etc. Pathway analysis of these new identified miRNAs revealed dysregulated MAPK signaling pathway, PI3K-Akt signaling pathway, calcium signaling pathway, Notch signaling pathway, and ubiquitin-mediated proteolysis pathway, all of which have been reported to play important role in regulating the osteogenic or adipogenic differentiation of MSCs. Furthermore, interaction networks analysis indicated that seven most significant central miRNAs, including miR-17-5p, miR-106a-5p, miR-106b-5p, miR-16-5p, miR-93-5p, miR-15a-5p, and miR-181b-5p may play essential roles in AIS pathogenesis and accompanied osteopenia. CONCLUSION: The current study reports the differential miRNAs expression profiles of BM-MSCs from AIS patients and related pathways for the first time. The identification of these candidate miRNAs provides a deep insight into the pathogenesis of AIS and the accompanying generalized osteopenia.

Tranexamic Acid in Reducing Gross Hemorrhage and Transfusions of Spine Surgeries (TARGETS): study protocol for a prospective, randomized, double-blind, non-inferiority trial.

BACKGROUND: Tranexamic acid (TXA) has been routinely delivered in multisegmental spinal decompression and bone graft fusion surgeries with satisfactory outcomes in minimizing gross blood loss and transfusion demands. However, concerns remain that intravenously delivered TXA (ivTXA) may increase risks of postoperative convulsive seizures and systemic thrombogenicity. Topical use of TXA (tTXA), being more targeted to the surgical bleeding site while minimizing patient systemic exposure to ivTXA, has been successfully applied to attenuate blood losses and transfusion requirements in hip and knee arthroplasty. Yet, randomized controlled trials on tTXA efficacy and safety are still lacking in spinal surgeries. With this knowledge gap, we hypothesize that tTXA exhibits non-inferiority to ivTXA in blood conservation and clinical safety in multisegmental spinal decompression and bone graft fusion surgeries. METHODS: A prospective, randomized, double-blind, non-inferiority study design will be adopted. The target sample size is 176. Eligible patients will be randomly allocated to receive either ivTXA or tTXA treatment. The primary end point is the perioperative total blood loss. Secondary end points consist of visible blood losses (intraoperative, postoperative 0-24 h, postoperative 0-48 h, combined perioperative blood loss, total postoperative blood loss), postoperative hidden blood loss, plasma TXA levels, postoperative conventional coagulation monitoring (prothrombin time, activated partial thromboplastin time, fiber Bragg grating, international normalized ratio), postoperative thromboelastography monitoring (reaction time, clot formation time, clot strength, fibrinolysis), postoperative hemoglobin nadir (within postoperative 48 h), perioperative transfusion amounts and rates, and length of hospital stay. Safety end points will be monitored too. DISCUSSION: This proposed study will contribute to expanding clinical evidences of tTXA for bleeding management in major spinal surgeries. This will be a high-quality prospective randomized trial with sufficient sample size, strict methodology, and few design deficits. It will investigate the potentiality of tTXA as an alternative to ivTXA in improving the current standard of care in multisegmental spinal surgeries, thereby optimizing the enhanced recovery after surgery scheme in spinal surgeries. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03011866 . Registered on 5 January 2017.

Long noncoding RNA lncAIS downregulation in mesenchymal stem cells is implicated in the pathogenesis of adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a complex, three dimensional deformity of the spine that commonly occurs in pubescent girls. Abnormal osteogenic differentiation of mesenchymal stem cells (MSCs) is implicated in the pathogenesis of AIS. However, the biological roles of long noncoding RNAs (lncRNAs) in the regulation of osteogenic differentiation of MSCs are unknown. Through microarray analyses of bone marrow (BM) MSCs from healthy donors and AIS patients, we identified 1483 differentially expressed lncRNAs in AIS BM-MSCs. We defined a novel lncAIS (gene symbol: ENST00000453347) is dramatically downregulated in AIS BM-MSCs. In normal BM-MSCs, lncAIS interacts with NF90 to promote HOXD8 mRNA stability that enhances RUNX2 transcription in BM-MSCs, leading to osteogenic differentiation of normal BM-MSCs. By contrast, lncAIS downregualtion in AIS BM-MSCs cannot recruit NF90 and abrogates HOXD8 mRNA stability, which impedes RUNX2 transcription for osteogenic differentiation. Thereby lncAIS downregualtion in BM-MSCs suppresses osteogenic differentiation that is implicated in the pathogenesis of AIS.

Can tranexamic acid conserve blood and save operative time in spinal surgeries? A meta-analysis.

BACKGROUND CONTEXT: It is widely accepted that tranexamic acid (TXA) effectively reduces blood losses and transfusions in major surgeries. However, limited studies investigated the role of TXA in conserving blood and saving operative time in spine surgeries. PURPOSE: This meta-analysis was conducted to gather scientific evidence for TXA efficacy on conserving blood and saving operative time in spine surgeries. STUDY DESIGN: A meta-analysis was performed. PATIENT SAMPLE: Eighteen RCTs and 18 non-RCT studies involving 2,572 patients were included in the final analyses, comparing the effectiveness of intravenous TXA with a placebo/no treatment group. OUTCOME MEASURES: Outcomes of interest included intraoperative, postoperative, and perioperative blood losses, allogeneic blood transfusion rates, cell salvage transfusion amounts, operative time, and the number of postoperative thrombosis events. METHODS: An exhaustive literature search was conducted in the MEDLINE and EMBASE databases from January 2000 through March 2017. Meta-analysis was performed using Review Manager (RevMan) version 5.0. For continuous outcomes, the means and standard deviations were pooled to a mean difference and 95% confidence interval (CI). Odds ratios (OR) and 95% CI were calculated for dichotomous outcomes. The quantity of heterogeneity was assessed using I2 statistics. When there was no statistical evidence of substantial heterogeneity (I2≤50%), a fixed-effect model was adopted; otherwise, a random-effect model was chosen. Subgroup analysis was performed when more than three studies were included on one issue, based on low or high the dose of TXA. Beijing Talent Fund (2016) was received to support this work. RESULTS: Significantly reduced intraoperative (weighted mean difference [WMD]=-280.09.00, p<.00001), postoperative (WMD=-120.15, p<.00001), perioperative (WMD=-310.86, p<.00001) blood losses, cell salvage transfusion amount (WMD=-471.79, p=.01), perioperative transfusion rate (odds ratio [OR], 0.33 [0.17, 0.65], p=.001), and operative time (WMD=-4.69, p=.003) were observed in TXA group. Furthermore, subgroup analysis revealed that high-dose TXA could reduce both intraoperative-perioperative allogeneic transfusion rates and operative time, whereas low dose of the drug does not convey such effects. CONCLUSIONS: With the most comprehensive literature inclusion up to the present, this meta-analysis suggests that intravenous TXA use constitutes an important measure for conserving blood and saving operative time in spinal surgeries. High-dose TXA significantly reduces intraoperative-perioperative allogeneic transfusion rates and operative time, whereas low-dose TXA does not convey such efficacies. Larger prospective trials are still required to define the optimal regimen and to confirm the safety of TXA use in such surgeries.

STAT3 inhibitor WP1066 as a novel therapeutic agent for bCCI neuropathic pain rats.

Activation of signal transducer and activator of transcription-3 (STAT3) is suggested to be critically involved in the development of chronic pain, but the complex regulation of STAT3-dependent pathway and the functional significance of inhibiting this pathway during the development of neuropathic pain remain elusive. To evaluate the contribution of the JAK2/STAT3 pathway to neuropathic pain and the potentiality of this pathway as a novel therapeutic target, we examined the effects of the STAT3 inhibitor WP1066 by intrathecal administration in a rat model of bilateral chronic constriction injury (bCCI). The pain behavior tests were performed before the surgery and on postoperative day 3, 7, 14 and 21. L4-L6 dorsal spinal cord were harvested at each time point. Both RT-PCR and Western blot were performed to evaluate the activation of JAK2/STAT3 pathway. To observe the influence of WP1066 on neuropathic pain and its molecular mechanism, WP1066 (10 µl, 10 mmol/L in DMSO) or the same capacity of DMSO as the control were applied through the intrathecal tube on the day before bCCI surgery, and on the postoperative day 3 and 5. Behavioral tests were performed to observe the therapeutic effect on mechanical, thermal and cold hyperalgesia. L4-L6 dorsal spinal cord was harvested on postoperative day fourteen, followed by RT-PCR and Western blot evaluation of the JAK2/STAT3 pathway activation. The mechanical, thermal and cold hyperalgesia of the bCCI rats were significantly decreased when compared with the Sham or the Naïve group at each postoperative time point (P<0.05). JAK2 mRNA and STAT3 mRNA were significantly increased in the bCCI rats, accompanied by SOCS3 mRNA with a similar tendency. Western blot analysis showed that JAK2 and phosphorylated STAT3 increased significantly since 3 days after bCCI. JAK2 peaked on postoperative day 14 while phosphorylated STAT3 peaked on postoperative day 7 and gradually decreased thereafter and SOCS3׳s peak level on postoperative day 3. When WP1066 were administered intrathecally, the pain behaviors of the bCCI rats were significantly improved (P<0.05). WP1066 also inhibited the mRNA level of JAK2, STAT3 and SOCS3 in bCCI rats significantly, together with the protein level of JAK2, phosphorylated STAT3 and SOCS3 on postoperative day 14 as well. Our results found that the JAK2/STAT3 pathway in the spinal cord dorsal horn was significantly activated in the bCCI neuropathic pain rats. WP1066, which inhibited the STAT3 pathway specifically, could partially alleviate the pain behavior of the bCCI rats. So it may serve as a novel therapeutic strategy against neuropathic pain.