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Hematopoietic humanized (hu) mice are powerful tools for modeling the action of human immune system and are widely used for preclinical studies and drug discovery. However, generating a functional human T cell compartment in hu mice remains challenging, primarily due to the species-related differences between human and mouse thymus. While engrafting human fetal thymic tissues can support robust T cell development in hu mice, tissue scarcity and ethical concerns limit their wide use. Here, we describe the tissue engineering of human thymus organoids from inducible pluripotent stem cells (iPSC-thymus) that can support the de novo generation of a diverse population of functional human T cells. T cells of iPSC-thymus-engrafted hu mice could mediate both cellular and humoral immune responses, including mounting robust proinflammatory responses on T cell receptor engagement, inhibiting allogeneic tumor graft growth and facilitating efficient Ig class switching. Our findings indicate that hu mice engrafted with iPSC-thymus can serve as a new animal model to study human T cell-mediated immunity and accelerate the translation of findings from animal studies into the clinic.

During acute wound (AW) healing, a series of proper communications will occur between different epidermal cells at precise temporal stages to restore the integrity of the skin. However, it is still unclear what variation happened in epidermal cell interaction in the chronic wound environment. To provide new insights into chronic wound healing, we reconstructed the variations in the epidermal cell-cell communication network that occur in chronic wound healing via single-cell RNA-seq (scRNA-seq) data analysis. We found that the intricate cellular and molecular interactions increased in pressure ulcer (PU) compared to AW, especially the PARs signaling pathways were significantly upregulated. It shows that the PARs signaling pathways’ main source was melanocytes and the CTSG-F2RL1 ligand-receptor pairs were its main contributor. Cathepsin G (CatG or CTSG) is a serine protease mainly with trypsin- and chymotrypsin-like specificity. It is synthesized and secreted by some immune or non-immune cells. Whereas, it has not been reported that melanocytes can synthesize and secrete the CTSG. F2R Like Trypsin Receptor 1 (F2RL1) is a member of proteinase-activated receptors (PARs) that are irreversibly activated by proteolytic cleavage and its stimulation can promote inflammation and inflammatory cell infiltration. In this study, we found that melanocytes increased in pressure ulcers, melanocytes can synthesize and secrete the CTSG and may promote inflammation in chronic wounds through CTSG-F2RL1 pairs, which may be a novel potential target and a therapeutic strategy in the treatment of chronic wounds.

Objectives Treating chronic cutaneous wounds is challenging, and debridement is a central concept in treating them. Studies have shown that CO2 laser debridement can control local infection and promote the wound healing process. The present study aimed to investigate the efficacy and safety of fully ablative CO2 laser debridement compared to routine surgical debridement in the treatment of chronic wounds. Methods The retrospective cohort study was conducted on patients with chronic (>1 month) cutaneous wounds (≥1 cm2 ) between December 1, 2017, and December 1, 2020, in the Wound Healing Center at Shanghai Ruijin Hospital, China. Patients treated with CO2 laser debridement with a DEKA SmartXide2 C80 (DEKA) (the CO2 laser group) were compared with matched control patients with similar baseline characteristics who had undergone routine surgical debridement (the routine group). The primary outcome was time-to-heal (days) for chronic wounds in two groups, and secondary outcomes included the wound area and BWAT (Bates-Jensen wound assessment tool) score before treatment, and at 1, 2, 3, and 4 weeks after treatment. Results The study included 164 patients (82 in the CO2 laser group and 82 matched in the routine group). The time-to-heal for patients in the CO2 laser group (41.30 ± 17.11) was significantly shorter than that of the patients in the routine group (48.51 ± 24.32) (p = 0.015). At 3 and 4 weeks after treatment, the absolute wound area of the CO2 laser group was significantly smaller than that of the routine group. Also, the CO2 laser group exhibited a significantly lower relative area at 2, 3, and 4 weeks after treatment. The CO2 laser group yielded significantly lower BWAT scores at 2, 3, and 4 weeks after treatment. Additionally, the relative BWAT score was significantly lower in the CO2 laser group than the relative scores in the routine group at 2, 3, and 4 weeks after treatment. No adverse events related to the treatments were observed in either group during the study period. Conclusions The present study has shown that fully ablative CO2 laser debridement has several advantages over routine sharp surgical debridement. It is superior at ameliorating wound status and reducing wound area, and it also significantly reduces the time-to-heal for chronic wounds, without causing any adverse events.

The purpose of this study was to investigate the clinical efficacy of compound polymyxin B ointment for treating chronic refractory wounds. A retrospective analysis was performed on 111 patients who underwent chronic refractory wound treatment. Patients were divided into 2 groups, with 45 patients included in the experimental group (compound polymyxin B group) and 66 patients included in the control group (silver sulfadiazine group). After thorough debridement in both groups, either compound polymyxin B ointment or silver sulfadiazine cream was evenly applied to the patient’s wound and covered with sterile gauze. In both groups, dressing changes were dependent on the wound’s condition and secretions. Using the Bates-Jensen Wound Assessment Tool (BWAT), patients in both groups were scored, after which wound healing, infection, and healing time were compared. There was no significant difference in BWAT scores between the 2 groups on the 7th or 14th day; however, on the 21st day, the BWAT score in the experimental group was significantly lower than that of the control group. The difference was statistically significant ( P < .05). There was no significant difference in the BWAT-I scores between the 2 groups on the seventh day. The healing time in the experimental group was significantly shorter than that of the control group, and the difference was statistically significant ( P < .05). For the treatment of chronic refractory wounds, thorough debridement followed by compound polymyxin B ointment topical application can reduce and control wound infection effectively and accelerate the process of wound repair.

The purpose of our study is to predict the occurrence and prognosis of diabetic foot ulcers (DFUs) by clinical and lower extremity computed tomography angiography (CTA) data of patients using the artificial neural networks (ANN) model. DFU is a common complication of diabetes that severely affects the quality of life of patients, leading to amputation and even death. There are a lack of valid predictive techniques for the prognosis of DFU. In clinical practice, the use of scales alone has a large subjective component, leading to significant bias and heterogeneity. Currently, there is a lack of evidence-based support for patients to develop clinical strategies before reaching end-stage outcomes. The present study provides a novel technical tool for predicting the prognosis of DFU. After screening the data, 203 patients with diabetic foot ulcers (DFUs) were analyzed and divided into two subgroups based on their Wagner Score (138 patients in the low Wagner Score group and 65 patients in the high Wagner Score group). Based on clinical and lower extremity CTA data, 10 predictive factors were selected for inclusion in the model. The total dataset was randomly divided into the training sample, testing sample and holdout sample in ratio of 3:1:1. After the training sample and testing sample developing the ANN model, the holdout sample was utilized to assess the accuracy of the model. ANN model analysis shows that the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the curve (AUC) of the overall ANN model were 92.3%, 93.5%, 87.0%, 94.2% and 0.955, respectively. We observed that the proposed model performed superbly on the prediction of DFU with a 91.6% accuracy. Evaluated with the holdout sample, the model accuracy, sensitivity, specificity, PPV and NPV were 88.9%, 90.0%, 88.5%, 75.0% and 95.8%, respectively. By contrast, the logistic regression model was inferior to the ANN model. The ANN model can accurately and reliably predict the occurrence and prognosis of a DFU according to clinical and lower extremity CTA data. We provided clinicians with a novel technical tool to develop clinical strategies before end-stage outcomes.

BackgroundWound healing is a complex, highly regulated process that is critical for restoring the anatomic and functional integrity of the skin after injury, which requires the interaction of various cell types. During acute wound healing, epidermal cells will activate at precise temporal stages, and proper communication will occur between different cells and will restore the skin integrity eventually. However, why the chronic wounds stagnate in an undefined non-healing state and how the epidermal cells interact with each other in the chronic wound environment is still unclear. To provide new insights into chronic wound healing, we reconstructed the variations in the epidermal cell-cell communication network that occur in chronic wound healing via single-cell RNA-seq (scRNA-seq) data analysis. MethodsWe used the count matrix of scRNA-seq data to create a Seurat object with the R package “Seurat” which was analyzed using default parameters. GO analysis was performed for the differentially expressed genes with Enrichr by R package “Cluster Profiler”. Then we created a CellChat object with the R package “CellChat” from Seurat and reconstructed the cell-cell autocrine and paracrine signaling interactions through CellChatDB.ResultsSix cell types are annotated in each wound type and through comparing the acute and chronic wounds we found that cellular and molecular interactions of epidermal cells are enhanced in chronic wounds. Especially, the PTN and PAR signaling pathways were significantly changed in chronic wounds. Then we found the melanocyte cell population was the dominant sender of PTN and PAR signaling pathways and the most contributing ligand-receptor pairs of the PTN and PAR signaling pathways were PTN-SDC1 and CTSG-F2RL1 respectively. ConclusionsIn this study, we used CellChat to reconstruct the epidermal cell-cell autocrine and paracrine signaling networks and try to understand the underlying molecular and physiological perturbations in non-healing wounds. we speculate that melanocytes may play a key role in skin regeneration, and that the absence of the PTN pathway and increasing PAR signaling pathways may disrupt the healing in chronic wounds. In addition, we identified that CTSG and PTN may respectively be a novel potential target and a therapeutic strategy in the treatment of chronic wounds.

Nephrocutaneous fistula (NCF) is a rare and severe complication of renal disease and surgical procedures. Treatments for NCF are based on the renal function, and can include nephrectomy, heminephrectomy, nephroureterectomy, endourological maneuvers or antibiotic therapy alone. Here we report a case of a chronic NCF which occurred 5 years after partial nephrectomy. In this report, we describe a new surgical approach for the management of a patient with postoperative NCF. In the present case, in addition to removing the fistulous tract, we also performed an omental flap grafting to tightly cover the kidney. In addition to limiting and controlling the local inflammation, the omental flap prevents contact between the kidney and the flank muscle on its posterior rim. No recurrence or complications occurred throughout 10 months of follow-up. The NCF was successfully treated with completely removal of the sinus tract and omental flap grafting, without nephrectomy. This case adds new aspects to the treatment of NCF.

Transcranial direct current stimulation (tDCS) delivers weak current into the brain to modulate neural activities. Many methods have been proposed to determine electrode positions and stimulation intensities. Due to the trade-off between intensity and focality, it is actually a multi-objective optimization problem that has a set of optimal solutions. However, traditional methods can produce only one solution at each time, and many parameters need to be determined by experience. In this study, we proposed the nondominated sorting genetic algorithm II (NSGA-II) to solve the current optimization problem of multi-electrode tDCS. We also compared the representative solutions with LCMV solutions. The result shows that a group of solutions close to the optimal front can be obtained just in only one run without any prior knowledge.

Treating chronic cutaneous wounds is challenging, and debridement is a central concept in treating them. Studies have shown that COThe retrospective cohort study was conducted on patients with chronic (1 month) cutaneous wounds (≥1 cmThe study included 164 patients (82 in the COThe present study has shown that fully ablative CO

Objective: To explore the regulation relationship between miR-181a-3p and BMP10, and their mechanism of osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (MSCs).Methods: After osteogenic induction of MSCs, the ALP activity was detected by ELISA. The expression of miRNA-181a-3p and BMP10 was detected by RT-qPCR, and the protein levels of BMP10 and osteogenic differentiation marker proteins ALK and RUNX2 were detected by Western blot. The TargetScan online website was used to predict the putative target of miR-181a-3p, and dual luciferase reporter assay was performed to validate the targeting relationship between miR-181a-3p and BMP10.Results: In osteogenic differentiation of MSCs, ALP activity, the level of ALK and RUNX2 was evidently increased (p < .05), and the expression of miR-181a-3p was significantly downregulated (p < .05). Moreover, overexpression of miR-181a-3p obviously decreased the expression of BMP10 (p < .05), miR-181a-3p knockdown increased the expression of BMP10 prominently (p < .05). The transfection of miR-181a-3p mimics resulted in significantly downregulation of ALP activity and RUNX2 protein expression in MSCs (p < .05). In addition, overexpression of BMP10 could reverse the inhibitory effect of miR-181a-3p on osteogenic differentiation (p < .05).Conclusions: In conclusion, we found that miR-181a-3p inhibited osteogenic differentiation of MCSs by targeting BMP10.

Decoding movement-related cortical potential (MRCP) plays an important role in the Brain-computer interface (BCI) system. MRCP is not easy to be detected on sensors due to the volume conduction effect. This work combines the scout EEG source imaging (ESI) and Locality Preserving Projection (LPP) followed by a linear discriminant analysis (LDA) classifier to detect MRCP of motor imagery and execution. Seven healthy subjects participated in this study and performed cue-based ballistic dorsiflexion. Our results showed that the source domain-based method achieved a significantly higher true positive rate (TPR) than that obtained from the sensor domain in both motor imagery (MI) (76.65±4.26% vs. 70.3±5.4%) and motor execution (ME) (81.66±2.55% vs. 74.49±6.48%) tasks. The false-positive rate (FPR) calculated in the source or sensor space for MI and ME was (24.46±5.07% vs. 28.59±5.17%) and (22.52±3.35% vs. 25.99±7.37%), respectively. Therefore, we demonstrated that EEG signals obtained from the source domain could improve the MRCP detection rather than those in the sensor domain.

Methylglyoxal (MGO) is a highly reactive dicarbonyl compound formed during hyperglycaemia. MGO combines with proteins to form advanced glycation end products (AGEs), leading to cellular dysfunction and organ damage. In type 2 diabetes mellitus (T2DM), the higher the plasma MGO concentration, the higher the lower extremity amputation rate. Here, we aimed to identify the mechanisms of MGO‐induced dysfunction. We observed that the accumulation of MGO‐derived AGEs in human diabetic wounds increased, whereas the expression of glyoxalase 1 (GLO1), a key metabolic enzyme of MGO, decreased. We show for the first time that topical application of pyridoxamine (PM), a natural vitamin B6 analogue, reduced the accumulation of MGO‐derived AGEs in the wound tissue of type‐2 diabetic mice, promoted the influx of macrophages in the early stage of tissue repair, improved the dysfunctional inflammatory response, and accelerated wound healing. In vitro, MGO damaged the phagocytic functions of M1‐like macrophages induced by lipopolysaccharide (LPS), but not those of M0‐like macrophages induced by PMA or of M2‐like macrophages induced by interleukins 4 (IL‐4) and 13 (IL‐13); the impaired phagocytosis of M1‐like macrophages was rescued by PM administration. These findings suggest that the increase in MGO metabolism in vivo might contribute to macrophage dysfunction, thereby affecting wound healing. Our results indicate that PM may be a novel therapeutic approach for treating diabetic wounds. MGO forms protein adducts that cause macrophage dysfunction. These adducts cause cell and organ dysfunction that is common in diabetes. Pyridoxamine scavenges MGO to ameliorate this dysfunction, promoting wound healing. Pyridoxamine could be used therapeutically to treat non‐healing diabetic wounds.

Transcranial direct current stimulation (tDCS) is a promising brain modulation technique in clinical application. Computational models of brain current flow have been used to provide better insights into determining the stimulation parameters, but there are only a few studies to validate the numerical simulation model. The purpose of this study is to validate the simulation model of tDCS. A one-/three-layered spherical phantom model was constructed to mimic the human head. The tDCS-induced voltages were measured at different depth in the spherical phantom model with stereotactic-EEG (s-EEG) electrodes. Comparing the measured values with the simulation data from the computational models, we found that the computational and empirically measured electric field distributions on the brain surface is similar and that the deviation between the predicted and measured electric field value becomes larger near the electrode.

Background: The effect of enteral immunonutrition (EIN) in patients undergoing pancreaticoduodenectomy (PD) is still doubtful. This meta-analysis aimed to assess the impact of EIN on postoperative clinical outcomes for patients undergoing PD. Methods: A literature search was carried out to identify all of the randomized controlled trials (RCTs) concerning the use of EIN for PD. Data collection ended on April 1, 2018. Pooled risk ratios (RRs) and the mean difference (MD) with a 95% CI were calculated using fixed effects or random effects models. The analyses were performed with RevMan 5.3.5. Results: Four RCTs with a total of 299 patients were included. Immunonutrition reduced the incidence of postoperative infectious complications (RR 0.58, 95% CI 0.37–0.92; p = 0.02) and shortened the length of hospital stay (MD –1.79, 95% CI –3.40 to 0.18; p = 0.03). Conversely, there were no significant differences in the incidence of overall postoperative complications (RR 0.81, 95% CI 0.62–1.05; p = 0.11), non-infectious complications (RR 0.94, 95% CI 0.69–1.28; p = 0.70) and postoperative mortality (RR 2.43, 95% CI 0.37–16.10; p = 0.36). Conclusions: EIN reduced postoperative infectious complications and shortened the length of the hospital stay; immunonutrition should be encouraged in patients undergoing PD.