Precision Identification of Locally Advanced Rectal Cancer in Denoised CT Scans Using EfficientNet and Voting System Algorithms.

BACKGROUND AND OBJECTIVE: Local advanced rectal cancer (LARC) poses significant treatment challenges due to its location and high recurrence rates. Accurate early detection is vital for treatment planning. With magnetic resonance imaging (MRI) being resource-intensive, this study explores using artificial intelligence (AI) to interpret computed tomography (CT) scans as an alternative, providing a quicker, more accessible diagnostic tool for LARC. METHODS: In this retrospective study, CT images of 1070 T3-4 rectal cancer patients from 2010 to 2022 were analyzed. AI models, trained on 739 cases, were validated using two test sets of 134 and 197 cases. By utilizing techniques such as nonlocal mean filtering, dynamic histogram equalization, and the EfficientNetB0 algorithm, we identified images featuring characteristics of a positive circumferential resection margin (CRM) for the diagnosis of locally advanced rectal cancer (LARC). Importantly, this study employs an innovative approach by using both hard and soft voting systems in the second stage to ascertain the LARC status of cases, thus emphasizing the novelty of the soft voting system for improved case identification accuracy. The local recurrence rates and overall survival of the cases predicted by our model were assessed to underscore its clinical value. RESULTS: The AI model exhibited high accuracy in identifying CRM-positive images, achieving an area under the curve (AUC) of 0.89 in the first test set and 0.86 in the second. In a patient-based analysis, the model reached AUCs of 0.84 and 0.79 using a hard voting system. Employing a soft voting system, the model attained AUCs of 0.93 and 0.88, respectively. Notably, AI-identified LARC cases exhibited a significantly higher five-year local recurrence rate and displayed a trend towards increased mortality across various thresholds. Furthermore, the model's capability to predict adverse clinical outcomes was superior to those of traditional assessments. CONCLUSION: AI can precisely identify CRM-positive LARC cases from CT images, signaling an increased local recurrence and mortality rate. Our study presents a swifter and more reliable method for detecting LARC compared to traditional CT or MRI techniques.

Single-cell transcriptome analysis reveals the effectiveness of cytokine priming irrespective of heterogeneity in mesenchymal stromal cells.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are recognized as a potential cell-based therapy for regenerative medicine. Short-term inflammatory cytokine pre-stimulation (cytokine priming) is a promising approach to enhance regenerative efficacy of MSCs. However, it is unclear whether their intrinsic heterogenic nature causes an unequal response to cytokine priming, which might blunt the accessibility of clinical applications. METHODS: In this study, by analyzing the single-cell transcriptomic landscape of human bone marrow MSCs from a naïve to cytokine-primed state, we elucidated the potential mechanism of superior therapeutic potential in cytokine-primed MSCs. RESULTS: We found that cytokine-primed MSCs had a distinct transcriptome landscape. Although substantial heterogeneity was identified within the population in both naïve and primed states, cytokine priming enhanced the several characteristics of MSCs associated with therapeutic efficacy irrespective of heterogeneity. After cytokine-priming, all sub-clusters of MSCs possessed high levels of immunoregulatory molecules, trophic factors, stemness-related genes, anti-apoptosis markers and low levels of multi-lineage and senescence signatures, which are critical for their therapeutic potency. CONCLUSIONS: In conclusion, our results provide new insights into MSC heterogeneity under cytokine stimulation and suggest that cytokine priming reprogrammed MSCs independent of heterogeneity.

Mesenchymal stem cells alleviate dexamethasone-induced muscle atrophy in mice and the involvement of ERK1/2 signalling pathway.

BACKGROUND: High dosage of dexamethasone (Dex) is an effective treatment for multiple diseases; however, it is often associated with severe side effects including muscle atrophy, resulting in higher risk of falls and poorer life quality of patients. Cell therapy with mesenchymal stem cells (MSCs) holds promise for regenerative medicine. In this study, we aimed to investigate the therapeutic efficacy of systemic administration of adipose-derived mesenchymal stem cells (ADSCs) in mitigating the loss of muscle mass and strength in mouse model of DEX-induced muscle atrophy. METHODS: 3-month-old female C57BL/6 mice were treated with Dex (20 mg/kg body weight, i.p.) for 10 days to induce muscle atrophy, then subjected to intravenous injection of a single dose of ADSCs ([Formula: see text] cells/kg body weight) or vehicle control. The mice were killed 7 days after ADSCs treatment. Body compositions were measured by animal DXA, gastrocnemius muscle was isolated for ex vivo muscle functional test, histological assessment and Western blot, while tibialis anterior muscles were isolated for RNA-sequencing and qPCR. For in vitro study, C2C12 myoblast cells were cultured under myogenic differentiation medium for 5 days following 100 [Formula: see text]M Dex treatment with or without ADSC-conditioned medium for another 4 days. Samples were collected for qPCR analysis and Western blot analysis. Myotube morphology was measured by myosin heavy chain immunofluorescence staining. RESULTS: ADSC treatment significantly increased body lean mass (10-20%), muscle wet weight (15-30%) and cross-sectional area (CSA) (~ 33%) in DEX-induced muscle atrophy mice model and down-regulated muscle atrophy-associated genes expression (45-65%). Hindlimb grip strength (~ 37%) and forelimb ex vivo muscle contraction property were significantly improved (~ 57%) in the treatment group. Significant increase in type I fibres (~ 77%) was found after ADSC injection. RNA-sequencing results suggested that ERK1/2 signalling pathway might be playing important role underlying the beneficial effect of ADSC treatment, which was confirmed by ERK1/2 inhibitor both in vitro and in vivo. CONCLUSIONS: ADSCs restore the pathogenesis of Dex-induced muscle atrophy with an increased number of type I fibres, stronger muscle strength, faster recovery rate and more anti-fatigue ability via ERK1/2 signalling pathway. The inhibition of muscle atrophy-associated genes by ADSCs offered this treatment as an intervention option for muscle-associated diseases. Taken together, our findings suggested that adipose-derived mesenchymal stem cell therapy could be a new treatment option for patient with Dex-induced muscle atrophy.

Mechanotransduction of mesenchymal stem cells and hemodynamic implications.

Mesenchymal stem cells (MSCs) possess the capacity for self-renewal and multipotency. The traditional approach to manipulating MSC's fate choice predominantly relies on biochemical stimulation. Accumulating evidence also suggests the role of physical input in MSCs differentiation. Therefore, investigating mechanotransduction at the molecular level and related to tissue-specific cell functions sheds light on the responses secondary to mechanical forces. In this review, a new frontier aiming to optimize the cultural parameters was illustrated, i.e. spatial boundary condition, which recapitulates in vivo physiology and facilitates the investigations of cellular behavior. The concept of mechanical memory was additionally addressed to appreciate how MSCs store imprints from previous culture niches. Besides, different types of forces as physical stimuli were of interest based on the association with the respective signaling pathways and the differentiation outcome. The downstream mechanoreceptors and their corresponding effects were further pinpointed. The cardiovascular system or immune system may share similar mechanisms of mechanosensing and mechanotransduction; for example, resident stem cells in a vascular wall and recruited MSCs in the bloodstream experience mechanical forces such as stretch and fluid shear stress. In addition, baroreceptors or mechanosensors of endothelial cells detect changes in blood flow, pass over signals induced by mechanical stimuli and eventually maintain arterial pressure at the physiological level. These mechanosensitive receptors transduce pressure variation and regulate endothelial barrier functions. The exact signal transduction is considered context dependent but still elusive. In this review, we summarized the current evidence of how mechanical stimuli impact MSCs commitment and the underlying mechanisms. Future perspectives are anticipated to focus on the application of cardiovascular bioengineering and regenerative medicine.

Ginkgolide B facilitates muscle regeneration via rejuvenating osteocalcin-mediated bone-to-muscle modulation in aged mice.

BACKGROUND: The progressive deterioration of tissue-tissue crosstalk with aging causes a striking impairment of tissue homeostasis and functionality, particularly in the musculoskeletal system. Rejuvenation of the systemic and local milieu via interventions such as heterochronic parabiosis and exercise has been reported to improve musculoskeletal homeostasis in aged organisms. We have shown that Ginkgolide B (GB), a small molecule from Ginkgo biloba, improves bone homeostasis in aged mice by restoring local and systemic communication, implying a potential for maintaining skeletal muscle homeostasis and enhancing regeneration. In this study, we investigated the therapeutic efficacy of GB on skeletal muscle regeneration in aged mice. METHODS: Muscle injury models were established by barium chloride induction into the hind limb of 20-month-old mice (aged mice) and into C2C12-derived myotubes. Therapeutic efficacy of daily administrated GB (12 mg/kg body weight) and osteocalcin (50 µg/kg body weight) on muscle regeneration was assessed by histochemical staining, gene expression, flow cytometry, ex vivo muscle function test and rotarod test. RNA sequencing was used to explore the mechanism of GB on muscle regeneration, with subsequent in vitro and in vivo experiments validating these findings. RESULTS: GB administration in aged mice improved muscle regeneration (muscle mass, P = 0.0374; myofiber number/field, P = 0.0001; centre nucleus, embryonic myosin heavy chain-positive myofiber area, P = 0.0144), facilitated the recovery of muscle contractile properties (tetanic force, P = 0.0002; twitch force, P = 0.0005) and exercise performance (rotarod performance, P = 0.002), and reduced muscular fibrosis (collagen deposition, P < 0.0001) and inflammation (macrophage infiltration, P = 0.03). GB reversed the aging-related decrease in the expression of osteocalcin (P < 0.0001), an osteoblast-specific hormone, to promote muscle regeneration. Exogenous osteocalcin supplementation was sufficient to improve muscle regeneration (muscle mass, P = 0.0029; myofiber number/field, P < 0.0001), functional recovery (tetanic force, P = 0.0059; twitch force, P = 0.07; rotarod performance, P < 0.0001) and fibrosis (collagen deposition, P = 0.0316) in aged mice, without an increased risk of heterotopic ossification. CONCLUSIONS: GB treatment restored the bone-to-muscle endocrine axis to reverse aging-related declines in muscle regeneration and thus represents an innovative and practicable approach to managing muscle injuries. Our results revealed the critical and novel role of osteocalcin-GPRC6A-mediated bone-to-muscle communication in muscle regeneration, which provides a promising therapeutic avenue in functional muscle regeneration.

Functioning tailor-made 3D-printed vascular graft for hemodialysis.

BACKGROUND: The two ends of arteriovenous graft (AVG) are anastomosed to the upper limb vessels by surgery for hemodialysis therapy. However, the size of upper limb vessels varies to a large extent among different individuals. METHODS: According to the shape and size of neck vessels quantified from the preoperative computed tomography angiographic scan, the ethylene-vinyl acetate (EVA)-based AVG was produced in H-shape by the three-dimensional (3D) printer and then sterilized. This study investigated the function of this novel 3D-printed AVG in vitro and in vivo. RESULTS: This 3D-printed AVG can be implanted in the rabbit's common carotid artery and common jugular vein with ease and functions in vivo. The surgical procedure was quick, and no suture was required. The blood loss was minimal, and no hematoma was noted at least 1 week after the surgery. The blood flow velocity within the implanted AVG was 14.9 ± 3.7 cm/s. Additionally, the in vitro characterization experiments demonstrated that this EVA-based biomaterial is biocompatible and possesses a superior recovery property than ePTFE after hemodialysis needle cannulation. CONCLUSIONS: Through the 3D printing technology, the EVA-based AVG can be tailor-made to fit the specific vessel size. This kind of 3D-printed AVG is functioning in vivo, and our results realize personalized vascular implants. Further large-animal studies are warranted to examine the long-term patency.

Demystifying the long noncoding RNA landscape of small EVs derived from human mesenchymal stromal cells.

INTRODUCTION: The regenerative capacity of mesenchymal stromal cells or medicinal signaling cells (MSCs) is largely mediated by their secreted small extracellular vesicles (sEVs), and the therapeutic efficacy of sEVs can be enhanced by licensing approaches (e.g., cytokines, hypoxia, chemicals, and genetic modification). Noncoding RNAs within MSC-derived sEVs (MSC-sEVs) have been demonstrated to be responsible for tissue regeneration. However, unlike miRNA fingerprints, which have been explored, the landscape of long noncoding RNAs (lncRNAs) in MSC-sEVs remains to be described. OBJECTIVES: To characterize lncRNA signatures in sEVs of human adipose-derived MSCs with or without inflammatory cytokine licensing and depict MSC-sEV-specific and MSC-enriched lncRNA repertoires. METHODS: sEVs were isolated from MSCs with or without TNF-α and IFN-γ (20 ng/mL) stimulation. High-throughput lncRNA sequencing and an in silico approach were employed to analyze the profile of lncRNAs in sEVs and predict lncRNA-protein interactomes. RESULTS: sEVs derived from human MSCs and fibroblasts carried a unique landscape of lncRNAs distinct from the lncRNAs inside these cells. Compared with fibroblast-derived sEVs (F-sEVs), 194 MSC-sEV-specific and 8 upregulated lncRNAs in MSC-sEVs were considered "medicinal signaling lncRNAs"; inflammatory cytokines upregulated 27 lncRNAs in MSC-sEVs, which were considered "licensing-responsive lncRNAs". Based on lncRNA-protein interactome prediction and enrichment analysis, we found that the proteins interacting with medicinal signaling lncRNAs or licensing-responsive lncRNAs have a tight interaction network involved in chromatin remodeling, SWI/SNF superfamily type complexes, and histone binding. CONCLUSION: In summary, our study depicts the landscape of lncRNAs in MSC-sEVs and predicts their potential functions via the lncRNA-protein interactome. Elucidation of the lncRNA landscape of MSC-sEVs will facilitate defining the therapeutic potency of MSC-sEVs and the development of sEV-based therapeutics.

Mechanical and chemical cues synergistically promote human venous smooth muscle cell osteogenesis through integrin ß1-ERK1/2 signaling: A cell model of hemodialysis fistula calcification.

Arteriovenous fistula (AVF) is the vascular access of choice for renal replacement therapy. However, AVF is susceptible to calcification with a high prevalence of 40%-65% in chronic hemodialysis patients. Repeated needle puncture for hemodialysis cannulation results in intimal denudation of AVF. We hypothesized that exposure to blood shear stress in the medial layer promotes venous smooth muscle cell (SMC) osteogenesis. While previous studies of shear stress focused on arterial-type SMCs, SMCs isolated from the vein had not been investigated. This study established a venous cell model of AVF using the fluid shear device, combined with a high phosphate medium to mimic the uremic milieu. Osteogenic gene expression of venous SMCs upon mechanical and chemical cues was analyzed in addition to the activated cell signaling pathways. Our findings indicated that upon shear stress and high phosphate environment, mechanical stimulation (shear stress) had an additive effect in up-regulation of an early osteogenic marker, Runx2. We further identified that the integrin ß1-ERK1/2 signaling pathway was responsible for the molecular basis of venous SMC osteogenesis upon shear stress exposure. Mitochondrial biogenesis also took part in the early stage of this venopathy pathogenesis, evident by the up-regulated mitochondrial transcription factor A and mitochondrial DNA polymerase γ in venous SMCs. In conclusion, synergistic effects of fluid shear stress and high phosphate induce venous SMC osteogenesis via the ERK1/2 pathway through activating the mechanosensing integrin ß1 signaling. The present study identified a promising druggable target for reducing AVF calcification, which deserves further in vivo investigations.

Molecular Mechanisms of Mesenchymal Stem Cell-Based Therapy in Acute Kidney Injury.

Acute kidney injury (AKI) causes a lot of harm to human health but is treated by only supportive therapy in most cases. Recent evidence shows that mesenchymal stem cells (MSCs) benefit kidney regeneration through releasing paracrine factors and extracellular vesicles (EVs) to the recipient kidney cells and are considered to be promising cellular therapy for AKI. To develop more efficient, precise therapies for AKI, we review the therapeutic mechanism of MSCs and MSC-derived EVs in AKI and look for a better understanding of molecular signaling and cellular communication between donor MSCs and recipient kidney cells. We also review recent clinical trials of MSC-EVs in AKI. This review summarizes the molecular mechanisms of MSCs' therapeutic effects on kidney regeneration, expecting to comprehensively facilitate future clinical application for treating AKI.

The Crosstalk between Mesenchymal Stem Cells and Macrophages in Bone Regeneration: A Systematic Review.

Bone regeneration is a complex and well-coordinated process that involves crosstalk between immune cells and resident cells in the injury site. Transplantation of mesenchymal stem cells (MSCs) is a promising strategy to enhance bone regeneration. Growing evidence suggests that macrophages have a significant impact on osteogenesis during bone regeneration. However, the precise mechanisms by which macrophage subtypes influence bone regeneration and how MSCs communicate with macrophages have not yet been fully elucidated. In this systematic literature review, we gathered evidence regarding the crosstalk between MSCs and macrophages during bone regeneration. According to the PRISMA protocol, we extracted literature from PubMed and Embase databases by using "mesenchymal stem cells" and "macrophages" and "bone regeneration" as keywords. Thirty-three studies were selected for this review. MSCs isolated from both bone marrow and adipose tissue and both primary macrophages and macrophage cell lines were used in the selected studies. In conclusion, anti-inflammatory macrophages (M2) have significantly more potential to strengthen bone regeneration compared with naïve (M0) and classically activated macrophages (M1). Transplantation of MSCs induced M1-to-M2 transition and transformed the skeletal microenvironment to facilitate bone regeneration in bone fracture and bone defect models. This review highlights the complexity between MSCs and macrophages, providing more insight into the polarized macrophage behavior in this evolving field of osteoimmunology. The results may serve as a useful reference for definite success in MSC-based therapy based on the critical interaction with macrophages.

Ginkgolide B monotherapy reverses osteoporosis by regulating oxidative stress-mediated bone homeostasis.

Osteoporosis is characterized by reductions in bone mass, which could be attributed to the dysregulation of bone homeostasis, such as the loss of balance between bone-resorbing osteoclasts and bone-forming osteoblasts. Elevated levels of oxidative stress increase bone resorption by promoting osteoclastogenesis and inhibiting the osteogenesis. Ginkgolide B (GB), a small natural molecule from Ginkgo biloba, has been reported to possess pharmacological activities by regulating reactive oxygen species (ROS) in aging-related degenerative diseases. Herein, we assessed the therapeutic effects of GB on the bone phenotypes of mice with osteoporosis induced by (I) aging, (II) ovariectomy, and (III) glucocorticoids. In all three animal models, oral gavage of GB significantly improved bone mass consistent with the increase in the OPG-to-RANKL ratio. In the in vitro experiments, GB promoted osteogenesis in aged mesenchymal stem cells (MSCs) and repressed osteoclastogenesis in aged macrophages by reducing ROS. The serum protein profile in GB-treated aged mice revealed moderate rejuvenating effects; signaling pathways associated with ROS were also regulated. The anabolic and anti-catabolic effects of GB were illustrated by the reduction in ROS. Our results indicate that GB is effective in treating osteoporosis. The use of GB in patients with osteoporosis is worthy of further clinical investigation.

Alteration of 3D Matrix Stiffness Regulates Viscoelasticity of Human Mesenchymal Stem Cells.

Human mesenchymal stem cells (hMSCs) possess potential of bone formation and were proposed as ideal material against osteoporosis. Although interrogation of directing effect on lineage specification by physical cues has been proposed, how mechanical stimulation impacts intracellular viscoelasticity during osteogenesis remained enigmatic. Cyto-friendly 3D matrix was prepared with polyacrylamide and conjugated fibronectin. The hMSCs were injected with fluorescent beads and chemically-induced toward osteogenesis. The mechanical properties were assessed using video particle tracking microrheology. Inverted epifluorescence microscope was exploited to capture the Brownian trajectory of hMSCs. Mean square displacement was calculated and transformed into intracellular viscoelasticity. Two different stiffness of microspheres (12 kPa, 1 kPa) were established. A total of 45 cells were assessed. hMSCs possessed equivalent mechanical traits initially in the first week, while cells cultured in rigid matrix displayed significant elevation over elastic (G') and viscous moduli (G") on day 7 (p < 0.01) and 14 (p < 0.01). However, after two weeks, soft niches no longer stiffened hMSCs, whereas the effect by rigid substrates was consistently during the entire differentiation course. Stiffness of matrix impacted the viscoelasticity of hMSCs. Detailed recognition of how microenvironment impacts mechanical properties and differentiation of hMSCs will facilitate the advancement of tissue engineering and regenerative medicine.

Adipose-derived mesenchymal stem cells attenuate dialysis-induced peritoneal fibrosis by modulating macrophage polarization via interleukin-6.

BACKGROUND: Life-long peritoneal dialysis (PD) as a renal replacement therapy is limited by peritoneal fibrosis. Previous studies showed immunomodulatory and antifibrotic effects of adipose-derived mesenchymal stem cells (ADSCs) on peritoneal fibrosis. However, the role of the peritoneal macrophage in this process remains uninvestigated. METHODS: We examined the therapeutic effects of ADSC and bone marrow-derived mesenchymal stem cells (BM-MSC) in the rat model of dialysis-induced peritoneal fibrosis using methylglyoxal. In addition, treatment of macrophages with the conditioned medium of ADSC and BM-MSC was performed individually to identify the beneficial component of the stem cell secretome. RESULTS: In the in vivo experiments, we found dialysis-induced rat peritoneal fibrosis was attenuated by both ADSC and BM-MSC. Interestingly, ADSC possessed a more prominent therapeutic effect than BM-MSC in ameliorating peritoneal membrane thickening while also upregulating epithelial cell markers in rat peritoneal tissues. The therapeutic effects of ADSC were positively associated with M2 macrophage polarization. In the in vitro experiments, we confirmed that interleukin-6 (IL-6) secreted by MSCs upon transforming growth factor-ß1 stimulation promotes M2 macrophage polarization. CONCLUSIONS: In dialysis-induced peritoneal fibrosis, MSCs are situated in an inflammatory environment of TGF-ß1 and secrete IL-6 to polarize macrophages into the M2 phenotype. Our findings reveal a previously unidentified role of tissue macrophage in this antifibrotic process. ADSC has the advantage of abundance and accessibility, making the application values extremely promising. In dialysis-induced peritoneal fibrosis, peritoneal mesothelial cells secrete transforming growth factor-ß1 (TGF-ß1) when exposed to methylglyoxal (MGO)-containing peritoneal dialysate. When situated in TGF-ß1, the inflammatory environment induces mesenchymal stem cells to secrete interleukin-6 (IL-6), IL-6 polarizes macrophages into the M2 phenotype. The dominant peritoneal tissue M2 macrophages, marked by upregulated Arg-1 expression, account for the attenuation of MGO-induced dedifferentiation of peritoneal mesothelial cells to maintain epithelial integrity.

Revisit incidence of complications after impacted mandibular third molar extraction: A nationwide population-based cohort study.

Most of complications after impacted mandibular third molar (iLM3) extraction surgeries are transient and resolved spontaneously within one or two weeks, but some of them are more complicated and required further treatments to alleviate the symptoms. The aim of study is to revisit incidence and predictors of complications after iLM3 surgery by reviewing previous literature and investigating a population-based data. From Taiwan National Health Insurance Research Database, records of 16,609 patients who had received iLM3 extraction under ambulatory settings were retrieved for analysis. Outcomes of interest included dry socket (DS), prolonged temporomandibular joint symptoms (TMD), and surgical site infection (SSI), which necessitated additional appointments to manage. Odds ratios of having those complications between different variables were analyzed. The incidence rates of DS, TMD, and SSI were 3.6%, 0.41%, 0.17%, respectively; while they ranged from 0.33-19.14% (DS), 0-4.17% (TMD), and 0.2-5.17% (SSI) in previous studies. Logistic regression revealed DS significantly correlated with complexity of odontectomy (2.5-fold of risk) and history of gingivitis or pericoronitis (1.3-fold of risk). More TMD was found in female than male patients (0.5% versus 0.3%). However, no factors associated with SSI was found; neither did we find aging as a risk in association with any of above complications. Compared to previous studies, our data supports that surgical intervention should be considered in iLM3 with risk of gingivitis or pericoronitis to reduce the occurrence of DS. The original information in this article, which provides a "real-world" evidence, along with the organizing data we summarized from previous article, can serve as a reference for clinicians in assessing the complication risks before treatment of iLM3.

The Anastomotic Angle of Hemodialysis Arteriovenous Fistula Is Associated With Flow Disturbance at the Venous Stenosis Location on Angiography.

The juxta-anastomotic stenosis of an arteriovenous fistula (AVF) is a significant clinical problem in hemodialysis patients with no effective treatment. Previous studies of AV anastomotic angles on hemodynamics and vascular wall injury were based on computational fluid dynamics (CFD) simulations using standardized AVF geometry, not the real-world patient images. The present study is the first CFD study to use angiographic images with patient-specific outcome information, i.e., the exact location of the AVF stenotic lesion. We conducted the CFD analysis utilizing patient-specific AVF geometric models to investigate hemodynamic parameters at different locations of an AVF, and the association between hemodynamic parameters and the anastomotic angle, particularly at the stenotic location. We analyzed 27 patients who used radio-cephalic AVF for hemodialysis and received an angiographic examination for juxta-anastomotic stenosis. The three-dimensional geometrical model of each patient's AVF was built using the angiographic images, in which the shape and the anastomotic angle of the AVF were depicted. CFD simulations of AVF hemodynamics were conducted to obtain blood flow parameters at different locations of an AVF. We found that at the location of the stenotic lesion, the AV angle was significantly correlated with access flow disturbance (r = 0.739; p < 0.001) and flow velocity (r = 0.563; p = 0.002). Furthermore, the receiver operating characteristic (ROC) curve analysis revealed that the AV angle determines the lesion's flow disturbance with a high area under the curve value of 0.878. The ROC analysis also identified a cut-off value of the AV angle as 46.5°, above or below which the access flow disturbance was significantly different. By applying CFD analysis to real-world patient images, the present study provides evidence that an anastomotic angle wider than 46.5° might lead to disturbed flow generation, demonstrating a reference angle to adopt during the anastomosis surgery.

Prediction of the development of acute kidney injury following cardiac surgery by machine learning.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major complication that results in increased morbidity and mortality after cardiac surgery. Most established prediction models are limited to the analysis of nonlinear relationships and fail to fully consider intraoperative variables, which represent the acute response to surgery. Therefore, this study utilized an artificial intelligence-based machine learning approach thorough perioperative data-driven learning to predict CSA-AKI. METHODS: A total of 671 patients undergoing cardiac surgery from August 2016 to August 2018 were enrolled. AKI following cardiac surgery was defined according to criteria from Kidney Disease: Improving Global Outcomes (KDIGO). The variables used for analysis included demographic characteristics, clinical condition, preoperative biochemistry data, preoperative medication, and intraoperative variables such as time-series hemodynamic changes. The machine learning methods used included logistic regression, support vector machine (SVM), random forest (RF), extreme gradient boosting (XGboost), and ensemble (RF + XGboost). The performance of these models was evaluated using the area under the receiver operating characteristic curve (AUC). We also utilized SHapley Additive exPlanation (SHAP) values to explain the prediction model. RESULTS: Development of CSA-AKI was noted in 163 patients (24.3%) during the first postoperative week. Regarding the efficacy of the single model that most accurately predicted the outcome, RF exhibited the greatest AUC (0.839, 95% confidence interval [CI] 0.772-0.898), whereas the AUC (0.843, 95% CI 0.778-0.899) of ensemble model (RF + XGboost) was even greater than that of the RF model alone. The top 3 most influential features in the RF importance matrix plot were intraoperative urine output, units of packed red blood cells (pRBCs) transfused during surgery, and preoperative hemoglobin level. The SHAP summary plot was used to illustrate the positive or negative effects of the top 20 features attributed to the RF. We also used the SHAP dependence plot to explain how a single feature affects the output of the RF prediction model. CONCLUSIONS: In this study, machine learning methods were successfully established to predict CSA-AKI, which determines risks following cardiac surgery, enabling the optimization of postoperative treatment strategies to minimize the postoperative complications following cardiac surgeries.

Alteration of Young's modulus in mesenchymal stromal cells during osteogenesis measured by atomic force microscopy.

Mechanical properties of biological tissues are increasingly recognized as an important parameter for the indication of disease states as well as tissue homeostasis and regeneration. Multipotent mesenchymal stromal/stem cells (MSCs), which play important roles in bone formation and remodeling, are potential cell sources for regenerative medicine. However, the cellular mechanical properties of differentiating MSCs corresponding to the substrate stiffness has not been sufficiently studied. In this study, we used Atomic Force Microscopy (AFM) to measure changes of stiffness of human MSCs cultured in rigid Petri dish and on polyacrylamide (PA) substrates during osteogenic differentiation. The results showed that the Young's modulus of MSC cytoplasmic outer region increased over time during osteogenesis. There is a strong linear correlation between the osteogenic induction time and the Young's modulus of the cells cultured in rigid Petri dishes in the first 15 days after the induction; the Young's modulus approaches to a plateau after day 15. On the other hand, the Young's moduli of MSCs cultured on PA gels with stiffness of 7 kPa and 42 kPa also increase over time during osteogenic differentiation, but the inclination of such increase is much smaller than that of MSCs differentiating in rigid dishes. Herein, we established a protocol of AFM measurement to evaluate the maturation of stem cell osteogenic differentiation at the single cell level and could encourage further AFM applications in tissue engineering related to mechanobiology.

Real-Time Streaming of Surgery Performance and Intraoperative Imaging Data in the Hybrid Operating Room: Development and Usability Study.

BACKGROUND: The trend of quick evolution and increased digital data in today's operating rooms (ORs) has led to the construction of hybrid ORs. There is often a main control room with monitors for integrating intraoperative data from multiple devices in the hybrid OR. However, there is no adequate solution for communicating the data with people outside the OR. OBJECTIVE: The objective of this study was to design an intelligent operating room (iOR) system, augmented onto the existing information technology (IT) infrastructure of hybrid ORs, to stream surgery performance and intraoperative imaging data. METHODS: In this study, an all-in-one device with synergetic encoder and decoder was used. The device was able to stream multiple sources to one display. The lossless video and images from specific surgical workflows were streamed outside the hybrid OR through network protocols and were further managed by a streaming server and wireless control system. The steps of this study included the following: (1) defining the requirements and feasibility of an iOR system in the hybrid OR, (2) connecting multiple sources, (3) setting up equipment across the hybrid OR and a conference room, (4) designing a video management system, and (5) real-time streaming under specific surgical workflows. RESULTS: The wired streamed video was shown simultaneously on the display in the hybrid OR and the display in the conference room with near-zero latency. Additionally, an interactive video between the hybrid OR and the conference room was achieved through the bidirectional wireless control system. The functions of recording, archiving, and playback were successfully provided by the streaming server. The readily available hardware components and open-access programming reduced the cost required to construct this streaming system. CONCLUSIONS: This flexible and cost-effective iOR system not only provided educational benefits, but also contributed to surgical telementoring.

The shift in macrophages polarisation after tendon injury: A systematic review.

BACKGROUND: The role of macrophages (Mφs) in tendon injury healing is controversy. The aims of this study were to determine whether there is a shift in Mφs polarisation after an acute and chronic tendon injury â€‹and to assess whether the Mφs polarisation between the partial and complete rupture is different. METHODS: This systematic review of the scientific literature was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane guidelines. PubMed database and Excerpta Medica Database (EMBASE) were used for specific search criteria. Only studies measuring Mφs using specific cell markers in Achilles tendon tissue and rotator cuff tendon tissue were included, respectively. RESULTS: Five Achilles tendon injury studies and four rotator cuff injury studies were included. Expression of the pan Mϕs marker Cluster of Differentiation (CD) 68 was significantly upregulated in acute Achilles tendon ruptures compared to intact tendons, while no significant changes were found in Mφs polarisation markers CD80 (M1 Mφs) and CD206 (M2 Mφs). High levels of CD86 (M1 Mφs) and CD206 were observed in acute partial rupture. Expression of CD68 and CD206 were significantly upregulated in chronic rotator cuff tendinopathy and downregulated as structural failure increases. A low level of CD206 was observed in complete tendon rupture regardless of acute or chronic injury. DISCUSSION AND CONCLUSION: In spite of the limited number of articles included, findings from this study suggested that the process of inflammation plays an important role in acute Achilles tendon injuries, indicated by the increased expression of CD68+ Mφs. Low levels of CD206+ Mφs were constantly observed in complete Achilles tendon rupture, while high levels of CD80+ Mφs and CD206+ Mφs were observed in partial Achilles tendon rupture, which suggested the potential correlation between M2 Mφs and tendon structure. For chronic rotator cuff injury, CD68+ Mφs and CD206+ Mφs were higher in tendinopathic tissues in comparison to the intact control tissues. Both CD68+ Mφs and CD206+ Mφs has an inverse relation to the structural failure in the torn rotator cuff tendon. After tendon rupture, the time point of biopsy specimen collection is an important factor, which could occur in the acute phase or chronic phase. Collectively, the understanding of the roles in Mφs after tendon injury is inadequate, and more research efforts should be devoted to this direction. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This article provided a potential implication on how pan Mφs or M2 Mφs might be associated with ruptured or torn tendon structure. Managing Mφs numbers and phenotypes may lead to possible novel therapeutic approaches to the management of early tendinopathy, early acute tendon rupture, hence, promote healing after restoration surgery.

Mesenchymal stem cells prolong survival and prevent lethal complications in a porcine model of fulminant liver failure.

BACKGROUND: Fulminant liver failure (FLF) is a life-threatening disease. METHODS: Lethal FLF was induced by ischemia-reperfusion (I-R) injury in mini-pigs, and MSCs were infused via splenic vein after reperfusion. RESULTS: Accumulated survival within 28 days was significantly improved by MSCs (P = 0.0348). Notably, MSCs maintained blood-gas homeostasis in the first 24 hours and prevented FLF-induced elevation of prothrombin time, international normalized ratio, and creatinine and ammonia levels in the first 3 days. With MSCs, serum levels of liver enzymes gradually decreased after 3 days, and platelet count was back to normal at 1 week of FLF. MSCs promoted liver regeneration within 2 weeks and differentiated into functional hepatocytes at 2-4 weeks after transplantation, evidenced by increase in Ki67-positive cells, detectable human hepatocyte growth factor, human vascular endothelial growth factor, human hepatocyte-specific antigen, and human albumin-expressing cells in the liver at different time points. Reactive oxidative species (ROS) were accumulated after FLF and eliminated at 4 weeks after MSC transplantation. CONCLUSIONS: Together, MSCs prolong the survival and prevent lethal sequelae of I-R injury-induced FLF by maintenance of liver-function homeostasis and rescue of ROS in the acute stage and by homing and differentiation into hepatocytes in the subacute stage.