Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Immunotherapy has recently shown significant potential in treating malignant tumors.However,the immunosuppressive nature of the tumor microenvironment(TME)limits the number of patients who benefit from this approach.Combining ultrasound with drug-loaded microbubble technology can directly induce tumor cell death through cavitation and pore-forming effects;this promotes tumor anti-gen presentation and enhances immune recognition of these antigens.This strategy also modulates the immunosuppressive state of the tu-mor microenvironment,making it more conducive to an effective immune response.It also normalizes blood vessels and reduces interstitial fluid pressure within the tumor,as well as helps therapeutic agents or genes to penetrate tumor tissues,thereby enhancing overall immune efficacy.This review examines the use of low-intensity ultrasound combined with drug-loaded microbubbles to improve the tumor microen-vironment and boost tumor immune responses.

Arthroscopic surgery currently faces challenges such as limited intraoperative visibility and high technical demands, resulting in a particularly steep learning curve. However, traditional teaching methods at present also present problems including significant operational risks, high learning costs, and ethical dilemmas associated. This has created an urgent need among surgeons for a more efficient and economical training approach. Recent advancements in virtual reality technology have created high-fidelity virtual environments which allow surgeon users to undergo immersive surgical training within simulated settings, offering novel perspectives for standardised arthroscopic skills training. This review systematically summarises the current application progress, technical challenges, and potential future directions of virtual reality arthroscopy simulators, focusing on their technical architecture, characteristics, and advantages. We aim to provide a theoretical basis for the technical standardisation and clinical translation of virtual reality technology in the field of arthroscopic surgical training.

Immunotherapy has recently shown significant potential in treating malignant tumors.However,the immunosuppressive nature of the tumor microenvironment(TME)limits the number of patients who benefit from this approach.Combining ultrasound with drug-loaded microbubble technology can directly induce tumor cell death through cavitation and pore-forming effects;this promotes tumor anti-gen presentation and enhances immune recognition of these antigens.This strategy also modulates the immunosuppressive state of the tu-mor microenvironment,making it more conducive to an effective immune response.It also normalizes blood vessels and reduces interstitial fluid pressure within the tumor,as well as helps therapeutic agents or genes to penetrate tumor tissues,thereby enhancing overall immune efficacy.This review examines the use of low-intensity ultrasound combined with drug-loaded microbubbles to improve the tumor microen-vironment and boost tumor immune responses.

Arthroscopic surgery currently faces challenges such as limited intraoperative visibility and high technical demands, resulting in a particularly steep learning curve. However, traditional teaching methods at present also present problems including significant operational risks, high learning costs, and ethical dilemmas associated. This has created an urgent need among surgeons for a more efficient and economical training approach. Recent advancements in virtual reality technology have created high-fidelity virtual environments which allow surgeon users to undergo immersive surgical training within simulated settings, offering novel perspectives for standardised arthroscopic skills training. This review systematically summarises the current application progress, technical challenges, and potential future directions of virtual reality arthroscopy simulators, focusing on their technical architecture, characteristics, and advantages. We aim to provide a theoretical basis for the technical standardisation and clinical translation of virtual reality technology in the field of arthroscopic surgical training.

Objective:To evaluate the role of spinal cord microglia in chronic pain after chronic heart failure (CHF) in mice.Methods:Eighteen SPF healthy male C57BL/6 mice, aged 8-12 weeks, weighing 20-25 g, were divided into 3 groups ( n=6 each) using a random number table method: sham operation group (Sham group), CHF group, and CHF+ microglia inhibitor PLX3397 group (CHF+ PLX group). The model of chronic heart failure was prepared by ligating the anterior descending branch of the left coronary artery in anesthetized mice. Mice were continuously fed a PLX3397-containing diet from 7 days before preparing the model to 28 days after preparing the model in CHF + PLX group. The cardiac function was evaluated using echocardiography at 28 days after surgery. The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured on 1 day before developing the model (T 0) and 1, 3, 7, 14 and 28 days after developing the model (T 1-5). The mice were sacrificed under deep anesthesia after the pain threshold was measured at T 5, and the spinal cord tissues of the lumbar segment (T 2-6 and L 4-6) were removed for determination of the expression of microglial marker Iba1 in the spinal dorsal horn (by immunofluorescence method). Results:Compared with Sham group, the left ventricular ejection fraction and left ventricular short axis shortening rate were significantly decreased, and the left ventricular internal diameter at end-diastole and the left ventricular internal diameter at end-systole were increased, the TWL was shortened and MWT was decreased at T 4-5, and the expression of Iba1 in the spinal dorsal horn was up-regulated in CHF group ( P<0.05). Compared with CHF group, the left ventricular ejection fraction and left ventricular short axis shortening rate were significantly increased, and the left ventricular internal diameter at end-diastole and the left ventricular internal diameter at end-systole were decreased, the TWL was prolong and MWT was increased at T 2-5, and the expression of Iba1 in the spinal dorsal horn was down-regulated in CHF+ PLX group ( P<0.05). Conclusions:The chronic pain after CHF may be related to microglial activation in the spinal cord of mice.

With the number of cases of coronavirus disease-2019 (COVID-19) increasing rapidly, the World Health Organization (WHO) has recommended that patients with mild or moderate symptoms could be released from quarantine without nucleic acid retesting, and self-isolate in the community. This may pose a potential virus transmission risk. We aimed to develop a nomogram to predict the duration of viral shedding for individual COVID-19 patients. This retrospective multicentric study enrolled 135 patients as a training cohort and 102 patients as a validation cohort. Significant factors associated with the duration of viral shedding were identified by multivariate Cox modeling in the training cohort and combined to develop a nomogram to predict the probability of viral shedding at 9, 13, 17, and 21 d after admission. The nomogram was validated in the validation cohort and evaluated by concordance index (C-index), area under the curve (AUC), and calibration curve. A higher absolute lymphocyte count (
Aged ; Aged, 80 and over ; Antibodies, Viral/blood* ; Area Under Curve ; COVID-19/virology* ; Female ; Humans ; Lymphocyte Count ; Male ; Middle Aged ; Nomograms ; Proportional Hazards Models ; Retrospective Studies ; Viral Load ; Virus Shedding

Objective:To investigate the value of programmed death-1（PD-1） expression on the T lymphocytes for the prognosis of septic patients.Methods:From September 2017 to May 2019, septic patients were included in Department of Intensive Care Unit at 6 hospitals. The PD-1 expression on T cells were measured by flow cytometry. Logistic regression was conducted to analyze independent risk factors related to death within 28 days，and receiver operating characteristic curve(ROC) was conducted to evaluate the prognostic value of PD-1 expression on T cells in septic patients.Results:A total of 64 septic patients were enrolled to this study，including 32 survivors and 32 deaths. The PD-1 expression on T cells in the death group was significantly higher than that in the surviving group ( P<0.05). Correlation analysis showed that the percentages of PD-1 +/CD3 +T cells and PD-1 +/CD8 +T cells were positively correlated with procalciton in ( r=0.313, P =0.015； r=0.375, P=0.003), logistic regression analysis showed that the percentages of PD-1 +/CD3 +，PD-1 +/CD4 +，PD-1 +/CD8 +T cells were independent risk factors for the death of sepsis patients. The percentage of PD-1 +/CD3 +T cell was 3.63%, with AUC 0.842, sensitivity to predict the mortality 96.43% and specificity 59.38%, ( P<0.000 1). The percentage of PD-1 +/CD4 +T cell was 4.65%, with AUC 0.847, sensitivity 96.43%, specificity 62.50%，( P<0.000 1). The percentage of PD-1 +/CD8 +T cell was 3.91%, with AUC 0.771, sensitivity 64.29%, specificity 81.25%，( P=0.000 3). Conclusions:The T cell PD-1 expression is an independent risk factor to predict the 28-day mortality in septic patients. Combining the proportions of PD-1 +/CD3 +, PD-1 +/CD4 +and PD-1 +/CD8 +T cells may further enhance the predictive value for death.

Objective To investigate the effect of levosimendan on cardiac function and prognosis in elderly patients with septic myocardial contractility impairment.Methods A prospective,randomized,controlled study was conducted.The elderly patients with septic myocardial contractility impairment who were admitted to Intensive Care Unit in Zhejiang Hospital were consecutively enrolled from January 2017 to September 2017.The key inclusive criterion was left ventricular ejection fraction (LVEF) ≤ 50％ after fluid resuscitation.A total of 30 patients were randomly assigned to levosimendan group (n=15) and dobutamine group (n=15).Based onconventional treatment,intravenous dobutamine (5 μg per kilogram of body weight per minute) or levosimendan (0.2 μg per kilogram of body weight per minute)were continuously administrated for 24 hours in two groups.At 0 h,24 h,48 h,72 h after injection,the following parameters or values were recorded including serum lactic acid (Lac),and echocardiographic parameters such as LVEF,stroke volume (SV).The time of mechanical ventilation,length of stay in ICU and 28-day mortality were compared in two groups.Results Compared with dobutamine group,blood Lac at 24 h [(1.97±1.10)mmol/L vs.(2.73 ± 2.06) mmol/L,P=0.002] decreased significantlyin levosimendan group.LVEF and SV were significantly higher in levosimendan group at 24 h [LVEF:(47.93±5.01)％ vs.(45.60±5.47)％,P=0.004;SV:(47.73 ± 14.01) ml vs.(44.80±16.89) ml,P=0.035;respectively],48 h [LVEF:(51.07 ± 5.05)％ vs.(46.73 ± 6.34)％,P=0.004;SV:(49.87 ± 14.15) ml vs.(45.07± 16.94) ml,P=0.005;respectively] and 72 h [LVEF:(53.20±5.92)％ vs.(47.70±6.71)％,P=0.002;SV:(51.27±14.98) ml vs.(45.73±17.34) ml,P=0.010].The time of mechanical ventilation,length of stay in ICU and 28-day mortality were comparable between two groups (P＞0.05).Conclusions Levosimendan improves cardiac systolic function and tissue perfusion in elderly patients with septic myocardial contractility impairment.However,cardiac diastolic function,liver and kidney function are not further improved by levosimendan compare with dubutamine.Time of mechanical ventilation,length of stay in ICU and 28-day mortality in two groups are similar.

To analyze the correlation between transcutaneous oxygen pressure (PtcO2) and blood lactate in patients with septic shock. Fifty-sixpatients with septic shock were prospectively investigated. PtcO2 was monitored continuously for 6 hours, and arterial blood gas was measured at baseline (T0) and 6 hours (T6). Records of PtcO2, were analyzed for the correlation with lactate level and lactate clearance rate. PtcO2 valuesin the high lactate clearance group and the low one were compared.The lowest value of PtcO2 at T6 and duration of PtcO2<40 mmHg (1 mmHg=0.133 kPa) were both correlated with lactate level and lactate clearance rateat T6. The low predictive value of PtcO2 was 29 mmHg of lactate clearance under 20％with a sensitivity 85.2％and a specificity 65.5％. The low predictive value of PtcO2 in high lactate clearance group was significantly higher than that in low lactate clearance group, while the duration of PtcO2<40 mmHg was shorter than the latter. During 6 h continuous monitoring, patients with a significant low PtcO2 or prolonged duration of low PtcO2 have relatively high lactate or low lactate clearance after resuscitation.