Although cancer immunotherapy has made great strides in the clinic, it is still hindered by the tumor immunosuppressive microenvironment (TIME). The stimulator of interferon genes (STING) pathway which can modulate TIME effectively has emerged as a promising therapeutic recently. However, the delivery of most STING agonists, specifically cyclic dinucleotides (CDNs), is performed intratumorally due to their insufficient pharmacological properties, such as weak permeability across cell membranes and vulnerability to nuclease degradation. To expand the clinical applicability of CDNs, a novel pH-sensitive polycationic polymer-modified lipid nanoparticle (LNP-B) system was developed for intravenous delivery of CDNs. LNP-B significantly extended the circulation of CDNs and enhanced the accumulation of CDNs within the tumor, spleen, and tumor-draining lymph nodes compared with free CDNs thereby triggering the STING pathway of dendritic cells and repolarizing pro-tumor macrophages. These events subsequently gave rise to potent anti-tumor immune reactions and substantial inhibition of tumors in CT26 colon cancer-bearing mouse models. In addition, due to the acid-sensitive property of the polycationic polymer, the delivery system of LNP-B was more biocompatible and safer compared with lipid nanoparticles formulated with an indissociable cationic DOTAP (LNP-D). These findings suggest that LNP-B has great potential in the intravenous delivery of CDNs for tumor immunotherapy.

Background The benchmark dose (BMD) method calculates the dose associated with a specific change in response based on a specific dose-response relationship. Compared with the traditional no observed adverse effect level (NOAEL) method, the BMD method has many advantages, and the 95% lower confidence limit of benchmark dose lower limit (BMDL) is recommended to replace NOAEL in deriving biological exposure limits. No authority has yet published any health-based guideline for rare earth elements. Objective To evaluate genotoxicity threshold induced by acute exposure to neodymium nitrate in mice using BMD modeling through micronucleus test and comet assay. Methods SPF grade mice (n=90) were randomly divided into nine groups, including seven neodymium nitrate exposure groups, one control group (distilled water), and one positive control group (200 mg·kg⁻¹ ethyl methanesulfonate), 10 mice in each group, half male and half female. The seven dose groups were fed by gavage with different concentrations of neodymium nitrate solution (male: 14, 27, 39, 55, 77, 109, and 219 mg·kg⁻¹; female: 24, 49, 69, 97, 138, 195, and 389 mg·kg⁻¹) twice at an interval of 21 h. Three hours after the last exposure, the animals were neutralized by cervical dislocation. The bone marrow of mice femur was taken to calculate the micronucleus rate of bone marrow cells, and the liver and stomach were taken for comet test. Results The best fitting models for the increase of polychromatophil micronucleus rate in bone marrow of female and male mice induced by neodymium nitrate were the exponential 4 model and the hill model, respectively. The BMD and the BMDL of female mice were calculated to be 31.37 mg·kg⁻¹ and 21.90 mg·kg⁻¹, and those of male mice were calculated to be 58.62 mg·kg⁻¹ and 54.31 mg·kg⁻¹, respectively. The best fitting models for DNA damage induced by neodymium nitrate in female and male mouse hepatocytes were the exponential 5 model and the exponential 4 model, respectively, and the calculated BMD and BMDL were 27.15 mg·kg⁻¹ and 11.99 mg·kg⁻¹ for female mice, and 16.28 mg·kg⁻¹ and 10.47 mg·kg⁻¹ for male mice, respectively. The hill model was the best fitting model for DNA damage of gastric adenocytes in both female and male mice, and the calculated BMD and BMDL were 36.73 mg·kg⁻¹ and 19.92 mg·kg⁻¹ for female mice, and 24.74 mg·kg⁻¹ and 14.08 mg·kg⁻¹ for male mice, respectively. Conclusion Taken the micronucleus rate of bone marrow cells, DNA damage of liver cells and gastric gland cells as the end points of genotoxicity, the BMDL of neodymium nitrate is 10.47 mg·kg⁻¹, which can be used as the threshold of genotoxic effects induced by acute exposure to neodymium nitrate in mice.

Objective:To evaluate the efficacy and safety of heating physiotherapy goggles in the treatment of meibomian gland dysfunction (MGD).Methods:A randomized controlled study was performed.Forty-four MGD patients were recruited in Wenzhou Medical University Eye Hospital from July 2021 to January 2022.Two patients were lost to follow-up.The patients were randomly divided into experimental group treated with heating physiotherapy goggles and control group treated with hot towels according to the random envelope method, with 21 patients (21 eyes) in each group.Throughout the study, the examiner was blinded.The data of the worse eye were analyzed.At baseline, 2 weeks and 4 weeks after treatment, the Ocular Surface Disease Index (OSDI), tear meniscus height (TMH), fluorescein breakup time (FBUT), corneal fluorescein staining score (CFS), lid margin hyperemia score and meibomian gland function scores were measured to evaluate the efficacy; visual acuity, intraocular pressure and slit lamp microscopy were examined to assess the safety.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Wenzhou Medical University Eye Hospital (No.2021-177-K-153-01).Results:There were significant differences in OSDI scores between before and after treatment ( Ftime=16.528, P<0.001). No significant difference was found in OSDI scores between 30.46±17.31 at 2 weeks after treatment and 35.43±18.22 before treatment in control group ( P=0.405). The OSDI score at 2 weeks after treatment was 26.27±16.47, which was significantly lower than 39.24±17.96 before treatment in experimental group ( P=0.001). The eyelid margin hyperemia score was 0.0(1.0, 2.0) at 4 weeks after treatment in experimental group, which was significantly lower than 2.0(1.0, 3.0) in control group (Wald χ2=11.444, P=0.001). The morphologic scores of meibomian gland orifices at 2 and 4 weeks after treatment were both 1.0(0.0, 1.0) in experimental group, which were significantly lower than 2.0(1.0, 3.0) and 2.0(1.0, 2.5) in control group (Wald χ2=15.082, 23.172; both at P<0.001). The scores of meibum quality at 2 and 4 weeks after treatment were 1.0(0.5, 2.0) and 1.0(0.0, 1.5) in experimental group, which were significantly lower than 2.0(1.0, 2.0) and 2.0(1.0, 2.5) in control group (Wald χ2=4.638, 9.395; both at P<0.05). The scores of upper meibomian gland expressibility at 2 and 4 weeks after treatment were both 2.0(1.0, 2.0) in experimental group, which were significantly lower than 3.0(2.0, 3.0) and 2.0(2.0, 2.5) in control group (Wald χ2=6.489, 11.562; both at P<0.05). The score of lower meibomian gland expressibility at 4 weeks after treatment in experimental group was 1.0(0.5, 2.0), which was significantly lower than 2.0(2.0, 3.0) in control group (Wald χ2=24.085, P<0.001). The FBUT at 2 and 4 weeks after treatment were 3.00(1.75, 3.50) and 3.00(2.00, 4.00) seconds in experimental group, which were significantly longer than 1.00(0.75, 2.00) and 2.00(1.00, 3.00) seconds in control group (Wald χ2=8.576, 8.539; both at P<0.05). There were significant differences in TMH among different time points ( Ftime=8.874, P<0.001). In control group, the TMH at 4 weeks after treatment was (0.24±0.09) mm, which was significantly higher than (0.18±0.05) mm before treatment ( P<0.05). In experimental group, the TMH at 4 weeks after treatment was (0.23±0.09) mm, which was significantly higher than (0.17±0.05) mm before treatment ( P<0.05). Significant differences were found in CFS score among different time points (Wald χ2time=10.116, P=0.006). There was no statistically significant differences in CFS score between before and after treatment in control group (Wald χ2=1.781, P=0.410). In experimental group, the CFS scores at 2 and 4 weeks after treatment were 0.0(0.0, 1.5) and 0.0(0.0, 0.0), which were significantly decreased in comparison with 0.00(0.00, 4.00) before treatment (both at P<0.05). In experimental group, the visual acuity converted to the logarithm of the minimum angle of resolution at 2 and 4 weeks after treatment were 0.10(0.00, 0.22) and 0.10(0.00, 0.22), which was significantly better than 0.10(0.00, 0.40) before treatment (both at P<0.05). There was no significant change in intraocular pressure at different time points between the two groups ( Fgroup=0.432, P=0.515; Ftime=0.329, P=0.721). No serious adverse effects occurred in both groups during the follow-up period. Conclusions:Compared with hot towel therapy, the use of heating physiotherapy goggles can relieve ocular discomfort of MGD patients more rapidly and improve the function and status of the meibomian gland more significantly.Heating physiotherapy goggles can treat MGD safely and effectively.

Depressive disorder ranks as a major bur-den of disease worldwide,yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects.The lateral septum(LS)is thought to control of depression,however,the cellular and circuit substrates are largely unknown.Here,we identified a subpopulation of LS GABAergic adenosine A2A receptors(A2AR)-positive neurons mediating depres-sive symptoms via direct projects to the lateral habenula(LHb)and the dorsomedial hypothalamus(DMH).Activa-tion of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipula-tion of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive pheno-types.Thus,the optogenetic modulation(stimulation or inhibition)of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH,phenocopied depressive behaviors.Moreover,A2AR are upregulated in the LS in two male mouse mod-els of repeated stress-induced depression.This identifica-tion that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant poten-tial of A2AR antagonists,prompting their clinical transla-tion.

Objective:To investigate the therapeutic effect of robot-assisted percutaneous screw fixation in LC-II pelvic fractures.Methods:A total of 46 patients with Young-Burgess LC-II pelvic fractures, who underwent surgical treatment at Shanghai Tenth People's Hospital from December 2019 to June 2022, were retrospectively analyzed. Among them, 27 were male and 19 were female, with an average age of 39.78±15.11 years (range, 19-68 years). The causes of injury were traffic accidents (28 cases) and fall from height (18 cases); all the cases were Type B pelvic fractures according to the Tile classification. The patients were divided into two groups based on the surgical approach: the robot group (26 cases) treated by Tianji robot-assisted percutaneous screw fixation, and the actual screw group (20 cases) treated by minimally invasive internal fixation under fluoroscopic guidance. The surgical time, blood loss, number of guide wire adjustments, the success rate of initial screw placement, postoperative vertical and horizontal displacement, and postoperative pelvic fracture reduction quality (Matta score) were compared between the two groups. Visual analogue scale (VAS) was used to assess patients' pain levels before and one week after surgery, and the clinical efficacy was evaluated using the Majeed score at the final follow-up. The occurrence of complications such as infection, vascular and nerve injury, and screw breakage was all recorded during the follow-up.Results:All patients successfully underwent the surgery and were followed up for an average of 11.93±3.09 months (range, 5-15 months). A total of 84 percutaneous screws were applied in the 46 cases, with 47 screws in the robot group and 37 screws in the actual screw group. The surgical time and number of guide wire adjustments were 81.27±4.90 minutes and 0.58±0.76 times in the robot group, 102.95±8.73 minutes and 5.80±2.24 times in the actual screw group, with significant differences ( t=-10.68, P<0.001; t=-11.13, P<0.001). There was no significant difference between the two groups in terms of intraoperative blood loss and postoperative vertical and horizontal displacement ( P>0.05). The success rate of initial screw placement in the robot group was 98% (46/47, 44 excellent, 2 good, 1 poor), while in the actual screw group, it was 86% (32/37, 27 excellent, 5 good, 5 poor), with a significant difference (χ 2=4.05, P=0.044). The VAS scores at one week postoperatively were 3.38±1.20 in the robot group and 6.80±1.61 in the actual screw group, with a significant difference ( t=-8.25, P<0.001). The excellent rate of Matta score after surgery was 92% in the robot group and 85% in the actual screw group, and the Majeed scores at the final follow-up were 86.54±3.10 and 85.7±2.20 respectively, with no significant difference between the two groups ( P>0.05). All patients achieved primary healing; no complications such as infection or screw breakage occurred during the follow-up period. Conclusion:Robot-assisted percutaneous access screw fixation for LC-II pelvic fracture can achieve accurate reduction of pelvic fracture, and is characterized by short operative time, low radiation exposure, and high safety and accuracy.

Objective:To build a small-sample ultra-widefield fundus images (UWFI) multi-disease classification artificial intelligence model, and initially explore the ability of artificial intelligence to classify UWFI multi-disease tasks.Methods:A retrospective study. From 2016 to 2021, 1 608 images from 1 123 patients who attended the Eye Center of the Renmin Hospital of Wuhan University and underwent UWFI examination were used for UWFI multi-disease classification artificial intelligence model construction. Among them, 320, 330, 319, 268, and 371 images were used for diabetic retinopathy (DR), retinal vein occlusion (RVO), pathological myopia (PM), retinal detachment (RD), and normal fundus images, respectively. 135 images from 106 patients at the Tianjin Medical University Eye Hospital were used as the external test set. EfficientNet-B7 was selected as the backbone network for classification analysis of the included UWFI images. The performance of the UWFI multi-task classification model was assessed using the receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity, and accuracy. All data were expressed using numerical values and 95% confidence intervals ( CI). The datasets were trained on the network models ResNet50 and ResNet101 and tested on an external test set to compare and observe the performance of EfficientNet with the 2 models mentioned above. Results:The overall classification accuracy of the UWFI multi-disease classification artificial intelligence model on the internal and external test sets was 92.57% (95% CI 91.13%-92.92%) and 88.89% (95% CI 88.11%-90.02%), respectively. These were 96.62% and 92.59% for normal fundus, 95.95% and 95.56% for DR, 96.62% and 98.52% for RVO, 98.65% and 97.04% for PM, and 97.30% and 94.07% for RD, respectively. The mean AUC on the internal and external test sets was 0.993 and 0.983, respectively, with 0.994 and 0.939 for normal fundus, 0.999 and 0.995 for DR, 0.985 and 1.000 for RVO, 0.991 and 0.993 for PM and 0.995 and 0.990 for RD, respectively. EfficientNet performed better than the ResNet50 and ResNet101 models on both the internal and external test sets. Conclusion:The preliminary UWFI multi-disease classification artificial intelligence model using small samples constructed in this study is able to achieve a high accuracy rate, and the model may have some value in assisting clinical screening and diagnosis.

Tumor-targeted immunotherapy is a remarkable breakthrough, offering the inimitable advantage of specific tumoricidal effects with reduced immune-associated cytotoxicity. However, existing platforms suffer from low efficacy, inability to induce strong immunogenic cell death (ICD), and restrained capacity of transforming immune-deserted tumors into immune-cultivated ones. Here, an innovative platform, perfluorooctyl bromide (PFOB) nanoemulsions holding MnO₂ nanoparticles (MBP), was developed to orchestrate cancer immunotherapy, serving as a theranostic nanoagent for MRI/CT dual-modality imaging and advanced ICD. By simultaneously depleting the GSH and eliciting the ICD effect via high-intensity focused ultrasound (HIFU) therapy, the MBP nanomedicine can regulate the tumor immune microenvironment by inducing maturation of dendritic cells (DCs) and facilitating the activation of CD8⁺ and CD4⁺ T cells. The synergistic GSH depletion and HIFU ablation also amplify the inhibition of tumor growth and lung metastasis. Together, these findings inaugurate a new strategy of tumor-targeted immunotherapy, realizing a novel therapeutics paradigm with great clinical significance.

At present, there are some problems in doctor-patient communication in standardized residency training in department of burns, such as insufficient understanding, lack of communication skills and short of teachers' guidance. Therefore, during the rotation of burns department, we should strengthen the cultivation of communication ability by improving humanistic care, professional level and communication training. At the same time, clinical teachers should strengthen their own quality and the assessment system should be improved. Through comprehensive efforts in many aspects, we will improve doctor-patient communication ability and build a harmonious doctor-patient relationship.

Cancer immunotherapy has veered the paradigm of cancer treatment. Despite recent advances in immunotherapy for improved antitumor efficacy, the complicated tumor microenvironment (TME) is highly immunosuppressive, yielding both astounding and unsatisfactory clinical successes. In this regard, clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME. Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME. The immunosuppressive TME may even dampen the efficacy of antitumor immunity. Recently, some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment (TIME) for robust immunotherapeutic responses. In this review, we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy, especially those unique classes associated with the immunosuppressive effect. The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation. After introducing the various strategies, we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.

The outbreak of corona virus disease (COVID-19) has raised concerns among dentists to develop strategies to prevent infection of dental equipment, materials, and patients during an epidemic period. Strategies following the National Laws and Standards of China and local standards of several provinces for controlling cross-infection and instituting protective measures for medical staff in dental clinics during an epidemic period are discussed. A proposal is put forth for dental clinics that will face similar situations in the future. Further research is warranted to address potential problems that will be encountered under such dire circumstances.