Esketamine Combined with Dexmedetomidine to reduce Visceral Pain During elective Cesarean Section Under Combined Spinal-Epidural Anesthesia: A double-Blind Randomized Controlled Study.

Purpose: We aimed to evaluate the effect of intravenous esketamine combined with dexmedetomidine as supplemental analgesia in reducing intraoperative visceral pain during elective cesarean section under combined spinal-epidural anesthesia (CSEA). Patients and Methods: A total of 269 parturients scheduled for elective cesarean section under CSEA between May 2023 and August 2023 were assessed. The parturients were randomly allocated to receiving either intravenous infusion of 0.3-mg/kg esketamine combined with 0.5-µg/kg dexmedetomidine (group ED, n=76), 0.5-µg/kg dexmedetomidine (group D, n=76), or normal saline (group C, n=76) after umbilical cord clamping. The primary outcome was intraoperative visceral pain. Secondary outcomes included the visual analog scale (VAS) score for pain evaluation and other intraoperative complications. Results: The incidence of visceral pain was lower in group ED [9 (12.7%)] than in group D [32 (43.8%)] and group C [36 (48.6%), P <0.0001]. The VAS score was also lower in group ED when exploring abdominal cavity [0 (0), P <0.0001] and suturing the muscle layer [0 (0), P =0.036]. The mean arterial pressure was higher in group D [83 (9) mmHg] and group ED [81 (11) mmHg] than in group C [75 (10) mmHg, P <0.0001] after solution infusion. The heart rate after infusion of the solution was lower in group D [80 (12) bpm] than in group C [86 (14) bpm] and group ED [85 (12) bpm, P = 0.016]. The incidence of transient neurologic or mental symptoms was higher in group ED compared to group C and group D (76.1% vs 18.9% vs 23.3%, P<0.0001). Conclusion: During cesarean section, 0.3-mg/kg esketamine combined with 0.5-µg/kg dexmedetomidine can alleviate visceral traction pain and provide stable hemodynamics. Parturients receiving this regimen may experience transient neurologic or mental symptoms that can spontaneously resolve at the end of the surgery.

Some parturients endure experience indescribable pain and discomfort during fetal delivery. Esketamine combined with dexmedetomidine can alleviate this pain during cesarean section under combined spinal-epidural anesthesia. However, after intravenous injection of esketamine and dexmedetomidine, the parturients may experience nightmares, dizziness, hallucinations, and drowsiness, etc.

Structure driven bio-responsive ability of injectable nanocomposite hydrogels for efficient bone regeneration.

Injectable hydrogels are promising for treatment of bone defects in clinic owing to their minimally invasive procedure. Currently, there is limited emphasis on how to utilize injectable hydrogels to mobilize body's regenerative potential for enhancing bone regeneration. Herein, an injectable bone-mimicking hydrogel (BMH) scaffold assembled from nanocomposite microgel building blocks was developed, in which a highly interconnected microporous structure and an inorganic/organic (methacrylated hydroxyapatite and methacrylated gelatin) interweaved nano structure were well-designed. Compared with hydrogels lacking micro-nano structures or only showing microporous structure, the BMH scaffold enhanced the ingrowth of vessels and promoted the formation of dense cellular networks (including stem cells and M2 macrophages), across the entire scaffold at early stage after subcutaneous implantation. Moreover, the BMH scaffold could not only directly trigger osteogenic differentiation of the infiltrated stem cells, but also provided an instructive osteo-immune microenvironment by inducing macrophages into M2 phenotype. Mechanistically, our results reveal that the nano-rough structure of the BMH plays an essential role in inducing macrophage M2 polarization through activating mechanotransduction related RhoA/ROCK2 pathway. Overall, this work offers an injectable hydrogel with micro-nano structure driven bio-responsive abilities, highlighting harnessing body's inherent regenerative potential to realize bone regeneration.

A mechanical-assisted post-bioprinting strategy for challenging bone defects repair.

Bioprinting that can synchronously deposit cells and biomaterials has lent fresh impetus to the field of tissue regeneration. However, the unavoidable occurrence of cell damage during fabrication process and intrinsically poor mechanical stability of bioprinted cell-laden scaffolds severely restrict their utilization. As such, on basis of heart-inspired hollow hydrogel-based scaffolds (HHSs), a mechanical-assisted post-bioprinting strategy is proposed to load cells into HHSs in a rapid, uniform, precise and friendly manner. HHSs show mechanical responsiveness to load cells within 4 s, a 13-fold increase in cell number, and partitioned loading of two types of cells compared with those under static conditions. As a proof of concept, HHSs with the loading cells show an enhanced regenerative capability in repair of the critical-sized segmental and osteoporotic bone defects in vivo. We expect that this post-bioprinting strategy can provide a universal, efficient, and promising way to promote cell-based regenerative therapy.

Association between preoperative systemic immune inflammation index and postoperative sepsis in patients with intestinal obstruction: A retrospective observational cohort study.

BACKGROUND: Sepsis is a severe complication that results in increased morbidity and mortality after intestinal obstruction surgery. This study examined the role of preoperative systemic immune inflammation index (SII) for postoperative sepsis in intestinal obstruction patients. METHODS: Data on patients who underwent intestinal obstruction surgery were collected. SII was determined and separated into two groups (≤1792.19 and >1792.19) according to the optimal cut-off value of SII for postoperative sepsis. The odds ratio (OR) is calculated for the correlation between SII and postoperative sepsis. Additional analyses were used to estimate the robustness of SII. RESULTS: A total of 371 intestinal obstruction patients undergoing surgery were included in the final cohort, and 60 (16.17%) patients developed postoperative sepsis. Patients with an SII ＞1792.19 had a significantly higher risk for developing postoperative sepsis after multivariable adjustment [adjusted odds ratio = 2.12, 95% confidence interval: [1.02-4.40]]. The analysis of interaction showed no correlation between the preoperative SII and postoperative sepsis regarding age, hypertension, American Society of Anesthesiologists classification, blood loss, albumin, hemoglobin, creatinine, and leukocyte (all interactions p > .05). In subgroup analysis, all statistically significant subgroups showed that SII was a risk factor for postoperative sepsis (all p < .05). The analyses of subgroups and interactions revealed that the interaction effect of a preoperative SII ＞1792.19 and postoperative sepsis remained significant. A sensitivity analysis confirmed the robustness of the results. CONCLUSIONS: A preoperative SII ＞ 1792.19 was a risk factor for postoperative sepsis in patients undergoing intestinal obstruction surgery.

Label-free and highly sensitive detection of microRNA from cancer cells via target-induced cascade amplification generation of lighting-up RNA aptamers.

The abnormal expression levels of miRNAs have been proven to be highly related to the generation of various diseases and are also closely associated with the stages and types of disease development. The novel RNA aptamers-based homogenous fluorescent methods were simple, with low background signal and high signal-to-noise ratio, but lacked effective signal amplification technology to achieve sensitive detection of trace miRNA markers. There is an urgent need for combining effective nucleic acid amplification technology with RNA aptamer to achieve highly sensitive and accurate detection of miRNA. For this purpose, a new DNA multi-arm nanostructure-based dual rolling circle transcription machinery for the generation of lighting-up MG RNA aptamers is constructed for label-free and highly sensitive sensing of miRNA-21. In this system, the target miRNA-21 induces a structural transformation of the DNA multi-arm nanostructure probe to recycle miRNA-21 and trigger two independent rolling circle transcription reactions to generate two long RNAs, which can partially hybridize with each other to generate large amounts of complete MG RNA aptamers. These RNA aptamers can associate with organic MG dye to produce significantly enhanced fluorescence signals to accomplish ultrasensitive miRNA-21 detection down to 0.9 fM. In addition, this method exhibits high selectivity to distinguish miRNA-21 even with single nucleotide mismatch, and also has potential application capability to monitor different expression levels of miRNA-21 from different cancer cells. The effective collaboration between MG RNA aptamer and rolling circle transcription reaction makes this fluorescent method show the significant advantages of low background signal, high signal-to-noise ratio and high detection sensitivity. It has great potential to be a promising means to achieve label-free and highly sensitive monitoring of other trace biological markers via a simple change of target sequence.

Digital light processing-bioprinted poly-NAGA-GelMA-based hydrogel lenticule for precise refractive errors correction.

Refractive disorder is the most prevalent cause of visual impairment worldwide. While treatment of refractive errors can bring improvement to quality of life and socio-economic benefits, there is a need for individualization, precision, convenience, and safety with the chosen method. Herein, we propose using pre-designed refractive lenticules based on poly-NAGA-GelMA (PNG) bio-inks photo-initiated by digital light processing (DLP)-bioprinting for correcting refractive errors. DLP-bioprinting allows PNG lenticules to have individualized physical dimensions with precision achievable to 10µm (µm). Material characteristics of PNG lenticules in tests included optical and biomechanical stability, biomimetical swelling and hydrophilic capability, nutritional and visual functionality, supporting its suitability as stromal implants. Cytocompatibility distinguished by morphology and function of corneal epithelial, stromal, and endothelial cells on PNG lenticules suggested firm adhesion, over 90% viability, phenotypic maintenance instead of excessive keratocyte-myofibroblast transformation.In-vitroimmune response analyzed by illumina RNA sequencing in human peripheral blood mononuclear cells indicated that PNG lenticules activated type-2 immunity, facilitating tissue regeneration and suppressing inflammation.In-vivoperformance assessed using intrastromal keratoplasty models in New Zealand white rabbits illustrated that implantation of PNG lenticules maintained stable optical pathway, induced controlled stromal bio-integration and regeneration, avoided complications such as stromal melt, interface scarring, etc, but exerted no adverse effects on the host. Postoperative follow-up examination on intraocular pressure, corneal sensitivity, and tear production remained unaffected by surgery up to 1-month post-implantation of PNG lenticules. DLP-bioprinted PNG lenticule is a bio-safe and functionally effective stromal implants with customizable physical dimensions, providing potential therapeutic strategies in correction of refractive errors.

Comparison of chondro-inductivity between collagen and hyaluronic acid hydrogel based on chemical/physical microenvironment.

Achieving chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) successfully is crucial for cartilage regeneration. To date, various hydrogels with different chemical microenvironment have been used to modulate chondrogenic differentiation of BMSCs, especially collagen and hyaluronic acid hydrogel. However, the chondro-inductive ability of collagen and hyaluronic acid hydrogel has not been evaluated yet and the different chemical and physical microenvironment of these two hydrogels increase the difficulty of comparison. In this study, three different hydrogels based on collagen and hyaluronic acid (self-assembled collagen hydrogel (Col), self-assembled collagen hydrogel cross-linked with genipin (Cgp), and methacrylated hyaluronic acid hydrogel (HA)) were prepared and their chondro-inductive ability on the encapsulated BMSCs was evaluated. Col and Cgp have the same chemical composition and similar microstructure, but are different from HA, while Cgp and HA hydrogels have the same mechanical strength. It was found that chemical and physical microenvironments of the hydrogels combined to influence cell condensation. Thanks to cell condensation was more likely to occur in collagen hydrogels in the early stage, the cartilage-induced ability was in the order of Col > Cgp > HA. However, the severe shrinkage of Col and Cgp resulted in no enough space for cell proliferation within hydrogels in the later stage. In contrast, relatively stable physical microenvironment of HA helped to maintain continuous production of cartilage-related matrix in the later stage. Overall, these results revealed that the chondro-inductive ability of collagen and hyaluronic acid hydrogel with different chemical and physical microenvironment cannot be evaluated by a particular time period. However, it provided important information for optimization and design of the future hydrogels towards successful repair of articular cartilage.

Temperature-programmable and enzymatically solidifiable gelatin-based bioinks enable facile extrusion bioprinting.

The development of exceptional bioinks with excellent printability, high fidelity, and excellent cell viability maintenance for extrusion bioprinting remains a major challenge. Gelatin is an ideal candidate bioink due to its biocompatibility, biodegradability, and non-immunogenicity. However, its inherently low viscosity and unstable physical gelation under physiological conditions make it unsuitable for direct extrusion bioprinting of tissue-like gelatin constructs with high fidelity. Herein, sequential chemical modification using reversible quadruple-hydrogen-bonded ureido-pyrimidinone (UPy) and enzyme-responsive tyramine moieties (Tyr) were devloped to endow the gelatin with a temperature-programmable viscosity and enzyme-controlled solidification, thus realizing enhanced printability and superior fidelity. As demonstrated in a proof-of-concept study, various cell-laden constructs were built based on our modified gelatin, including two-dimensional human bone marrow mesenchymal stem cell (hBMSC)-laden patterns, three-dimensional interconnected hBMSC-laden scaffolds, a reversible twisting-tension human-scale hBMSC-laden ear, a bicellular tibia-like construct containing hBMSCs and endothelial cells and a hexagonal prism-shaped hepatocyte-laden scaffold. The loaded cells in the construct have high viability of over 90% at 24 h, and show proliferation and protein secretion over one week, suggesting that Gel-UPy-Tyr-based constructs under physiological temperature not only can keep high fidelity, but also can support the growth and functions of the loaded cells.

The negatively charged microenvironment of collagen hydrogels regulates the chondrogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo.

The differentiation of bone marrow mesenchymal stem cells (BMSCs) into functional chondrocytes is crucial for successful cartilage tissue engineering. Since the extracellular matrix (ECM) microenvironment can regulate the behaviours of BMSCs and guide their differentiation, it is important to simulate the natural cartilage ECM to induce the chondrogenesis of BMSCs. As the most abundant protein in the ECM, collagen hydrogels were found to provide a structural and chemical microenvironment for natural cartilage, and regulate the chondrogenic differentiation of BMSCs. However, as the negatively charged ECM microenvironment is crucial for chondrogenesis and homeostasis within cells in cartilage tissue, the electrical properties of collagen hydrogels need to be further optimized. In this study, three collagen hydrogels with different electrical properties were fabricated using methacrylic anhydride (MA) and succinic anhydride (SA) modification. The collagen hydrogels had a similar composition, storage modulus and integral triple helix structure of collagen, but their different negatively charged microenvironments significantly impacted the hydrophilicity, protein diffusion and binding, and consequently influenced BMSC adhesion and spreading on the surface of the hydrogels. Moreover, the BMSCs encapsulated in the collagen hydrogels also demonstrated improved sGAG secretion and chondrogenic and integrin gene expression with the increased negative charge in vitro. Similar results were also observed in subcutaneous implantation in vivo, where higher secretions of sGAG, SOX9 and collagen type II proteins were found in the collagen hydrogels with higher negative charge. Together, our results demonstrated that more negative charges introduced into the collagen hydrogel microenvironment would enhance the chondrogenic differentiation of BMSCs in vitro and in vivo. This revealed that the electrical properties are an important consideration in designing future collagen hydrogels for cartilage regeneration.

Influence of hydrogel network microstructures on mesenchymal stem cell chondrogenesis in vitro and in vivo.

Hydrogels, which provide three-dimensional (3D) niches for encapsulating bone marrow mesenchymal stem cells (BMSCs), are becoming a promising tissue engineering solution for chondrogenic differentiation of BMSCs. However, it remains a challenge to design a hydrogel material for effective chondrogenesis of BMSCs because of the complexity of cartilage ECM and cell-matrix interactions. Thus far, various studies have shown the physical-chemical cues of hydrogel materials to impact BMSCs chondrogenesis, but the design of the 3D network microstructure of the hydrogel to induce BMSCs chondrogenesis is still far from optimized. In this study, we successfully prepared two types of collagen hydrogels, namely, the fibrous network and porous network, with the same chemical composition and similar mechanical strength but with two distinct network microstructures. The two different network microstructures significantly influenced mass transfer, protein adsorption, degradability, and contraction of the collagen hydrogels. Moreover, the cells presented distinct proliferation and morphology in the two hydrogels, which consequently modulated chondrogenic differentiation of BMSCs derived from rat. Collagen hydrogels with a fibrous network promoted more chondrogenic differentiation of BMSCs without additional growth factors in vitro and subcutaneous implantation in vivo than those with a porous network. Moreover, fibrous network resulted in less ECM calcification than porous network. However, the fibrous network could not prevent hypertrophy of the chondrogenic cells induced by BMSCs. Overall, these results revealed that the 3D network microstructure of a hydrogel was a key design parameter for the chondrogenic differentiation of BMSCs. STATEMENT OF SIGNIFICANCE: Hydrogels had been used to induce the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in cartilage tissue engineering, but the key design parameters remain unoptimized. This was mainly due to the different material properties including composition, strength, and microstructure, which would interplay with each other and result in difficulties to investigate the effects for one factor. In this study, we fabricated two collagen hydrogels with the same chemical composition and mechanical strength, but two distinct network microstructures. The effects of the two network microstructures on the chondrogenic differentiation of BMSCs were investigated by in vitro and in vivo assays. The results highlight the effects of network microstructures and provide important information about optimizing the design of future hydrogels in cartilage tissue engineering.

Icariin conjugated hyaluronic acid/collagen hydrogel for osteochondral interface restoration.

Over the past decades, numerous tissue-engineered constructs have been investigated for the osteochondral repair. However, it still remains a challenge to regenerate the functionalized calcified layer. In this study, the potential of icariin (Ica) conjugated hyaluronic acid/collagen (Ica-HA/Col) hydrogel to promote the osteochondral interface restoration was investigated. Compared with HA/Col hydrogel, Ica-HA/Col hydrogel simultaneously facilitated chondrogenesis and osteogenesis in vitro. The cells encapsulated in Ica-HA/Col hydrogel tended to aggregate into bigger clusters. The chondrogenic genes' expression level was remarkably up-regulated, and the matrix synthesis of sGAG and type II collagen was significantly enhanced. Similarly, the osteogenic genes, including RUNX2, ALP, and OCN were also up-regulated at early stage. Consequently, more calcium deposition was observed in the Ica-HA/Col hydrogel construct. Moreover, the gene expression and matrix synthesis of type X collagen, an important marker for the formation of calcified layer; were significantly higher in the Ica-HA/Col hydrogel. Furthermore, the in vivo study showed that Ica-HA/Col constructs facilitated the reconstruction of osteochondral interface in rabbit subchondral defects. In the Ica-HA/Col group, the neo-cartilage layer contained more type II collagen and the newly formed subchondral bone deposited more abundant type I collagen. Overall, the results indicated that Ica-HA/Col hydrogel might be a promising scaffold to reconstruct an osteochondral interface, therefore promoting restoring of osteochondral defect. STATEMENT OF SIGNIFICANCE: The osteochondral defect restoration not only involves the repair of damaged cartilage and the subchondral bone, but also the reconstruction of osteochondral interface (the functional calcified layer). The calcified layer regeneration is essential for integrative and functional osteochondral repair. Over the past decade, numerous tissue engineered constructs have been investigated for the osteochondral repair. However, it still remains a challenge to regenerate a functionalized calcified layer. The present study demonstrates that Ica-HA/Col hydrogel facilitates deposition of matrix related to calcified layer in mixed chondrogenic/osteogenic inductive media and restoration of osteochondral defect in vivo. Since, Ica-HA/Col hydrogel as is cheaper, easier and more efficient, it might be a desired scaffold for the osteochondral defects restoration.

Medical Image Retrieval Using Multi-Texton Assignment.

In this paper, we present a multi-texton representation method for medical image retrieval, which utilizes the locality constraint to encode each filter bank response within its local-coordinate system consisting of the k nearest neighbors in texton dictionary and subsequently employs spatial pyramid matching technique to implement feature vector representation. Comparison with the traditional nearest neighbor assignment followed by texton histogram statistics method, our strategies reduce the quantization errors in mapping process and add information about the spatial layout of texton distributions and, thus, increase the descriptive power of the image representation. We investigate the effects of different parameters on system performance in order to choose the appropriate ones for our datasets and carry out experiments on the IRMA-2009 medical collection and the mammographic patch dataset. The extensive experimental results demonstrate that the proposed method has superior performance.

Photo-crosslinked mono-component type II collagen hydrogel as a matrix to induce chondrogenic differentiation of bone marrow mesenchymal stem cells.

Type II collagen is a prospective chondro-inductive matrix for bone marrow mesenchymal stem cells (BMSCs), a key component of the extracellular matrix of cartilage; however, its application is limited by deficient fibrillogenesis and gelation. Herein, type II collagen methacrylamide (Col-II-MA) was synthesized by an amidation reaction between the ε-amino groups on collagen lysine and methacrylic anhydride to enable photo-crosslinking of the collagen, thus accomplishing a one-step preparation of mono-component type II collagen hydrogel for the first time. BMSCs encapsulated within the Col-II-MA hydrogel exhibited accelerated proliferation and morphological changes that are similar to chondrogenesis, as well as up-regulated expression of chondrogenic genes and remarkable secretion of the cartilaginous matrix. These results demonstrated that this effective synthetic approach facilitated the formation of photo-active type II collagen hydrogel with a well-preserved triple helical conformation, which provides BMSCs with a favorable microenvironment for growth and the essential chondro-inductive matrix for differentiation. Furthermore, the hydrogel is applicable to microfabrication techniques and displays promise for future applications in microscale tissue engineering.

FOXM1 expression correlates with tumor invasion and a poor prognosis of colorectal cancer.

FOXM1, a member of the Forkhead Box (Fox) family of transcription factors, plays a critical role in tumor development and metastasis. The aim of this study was to elucidate its role in colorectal cancer (CRC), particularly prognosis and metastasis. Semi-quantitative RT-PCR and Western blot assays were used to measure the expression levels of FOXM1 mRNA and protein in 15 CRC and adjacent normal mucosa tissues. Immunohistochemical assay was performed to detect FOXM1 protein expression in 112 CRC tissues and further determine its clinicopathological and prognostic significance. RNA interference (RNAi) was used to knockdown endogenous FOXM1 expression in CRC cell lines and to analyze the effects of FOXM1 knockdown on migration and invasion of CRC cells. The relative expression levels of FOXM1 mRNA and protein were significantly higher in CRC tissues than in adjacent normal mucosa tissues (P<0.01). In addition, the immunostaining of FOXM1 protein was stronger in CRC tissues than in adjacent normal mucosa tissues. By statistical analysis, we showed that high FOXM1 expression was closely correlated with the presence of lymph node metastasis, incidence of liver metastasis, and advanced TNM stage. Moreover, the cumulative 5-year survival rate of CRC patients with high FOXM1 expression was lower than that of those with low FOXM1 expression (P=0.0047). Multivariate analysis showed that the status of FOXM1 expression was an independent prognostic factor for CRC patients (P=0.025). Furthermore, RNAi-mediated FOXM1 knockdown could significantly inhibit growth, migration and invasion of CRC cells. Our results showed that FOXM1 over-expression is a molecular marker predicting increased invasive/metastatic potential of CRC and a poorer prognosis.

Overexpression of survivin is correlated with increased invasion and metastasis of colorectal cancer.

BACKGROUND: The aim of this study was to investigate the association of survivin expression with metastasis of colorectal cancer (CRC). METHODS: RT-PCR and Western blot assays were performed to detect survivin expression in CRC cells and normal intestinal epithelial cell. The expression of survivin gene was also detected in 15 CRC tissues, surrounding and adjacent colon tissues. Moreover, survivin expression in 48 CRC tissues with or without lymph node metastasis was analyzed. Multivariate analysis for lymph node metastasis was performed using logistic regression model. RNA interference was used to inhibit survivin expression in CRC cells and analyze its effect on invasion and metastasis of CRC cells. RESULTS: The expression levels of survivin mRNA and protein were higher in CRC cells than in normal intestinal epithelial cell line. The average levels of survivin mRNA and protein were higher in CRC tissues than surrounding or adjacent colon tissues (P < 0.05). High survivin expression was an independent factor for predicting lymph node metastasis of CRC (P = 0.043). RNAi-mediated survivin knockdown could significantly inhibit in vitro invasion and in vivo metastasis of CRC cells, which might be inactivation of matrix metalloproteinases. CONCLUSION: Targeting survivin will be a potential strategy to suppress metastasis of CRC.