The Solomon four-group design， a critical method for improving internal validity in clinical research， can reduce bias and control the interference of Hawthorne effects and pretest sensitization on research results， which offers unique advantages in evaluating complex intervention outcomes. This paper systematically outlined the core framework and key points of statistical analysis of the Solomon four-group design， summarized its applications in clinical research at home and abroad， explored its advantages and limitations， and discussed the potential value in traditional Chinese medicine （TCM） clinical trials. It is believed that the Solomon four-group design can help distinguish between testing effects and intervention effects in TCM clinical studies， and reduce the bias in the evaluation of subjective indicators. Meanwhile， given the complexity of the Solomon four-group design and the particularity of TCM clinical research， it is proposed that future TCM clinical studies should focus on using psychological scales， know-ledge， attitude， and behavior measurements， and other similat evaluations as endpoints. It also advocates strengthening interdisciplinary collaboration to provide new methodological paths for TCM clinical research.

Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8⁺ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8⁺ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

Mesenchymal stem cells (MSCs) have been widely used in the treatment of various autoimmune and inflammation-related diseases due to their potent immunomodulatory properties. Several studies have demonstrated that MSC-mediated immunomodulation is complex and bidirectional, with the in vivo microenvironment influencing the direction of this modulation. Indoleamine-2,3-dioxygenase (IDO), an immunosuppressive factor, has been identified as a key "switch" in the immunomodulatory role of MSCs. In this review, we explore how IDO functions as a critical regulator of MSC immunoregulatory plasticity. We delve into the mechanisms by which changes in IDO expression affect the function of various immune cells, summarize relevant research and clinical advances regarding the role of IDO expression in MSC-based therapies for various diseases, and discuss potential therapeutic strategies that target IDO to enhance the stability of MSC therapeutic effects. This provides a theoretical foundation for optimizing MSCs as safer and more effective clinical therapeutic agents.

Inflammatory bowel disease (IBD) is a chronic immune-mediated gastrointestinal inflammatory disorder that includes ulcerative colitis (UC) and Crohn disease (CD). Currently, there is a lack of reliable diagnostic methods for IBD. Endoscopic biopsy is one of the common methods for detecting IBD, but it has limitations. In non-invasive assessment of IBD, ultrasound, CT, and MRI are less invasive and better tolerated than endoscopy, and can show the complete bowel condition, assess the thickness of the intestinal wall, and detect parenteral complications. Meanwhile, with the further study of IBD biomarkers, SPECT and PET are increasingly used in early diagnosis and efficacy monitoring of IBD, especially in patients who cannot tolerate invasive tests. The continuous developments of the above imaging techniques provide a more minimally invasive method than endoscopy for early non-invasive diagnosis and efficacy monitoring of IBD. This article reviews the latest research and application progress of the above imaging techniques in IBD.

Objective:To explore any effect of excitatory and inhibitory multi-focal transcranial direct current stimulation (m-tDCS) on cortical functioning in healthy adults.Methods:Fifteen healthy participants received 20-minute excitatory and inhibitory episodes of m-tDCS targeting C1-C2-FC1-FC2. Finite element analysis and functional near-infrared spectroscopy were then used to model the normal component of the electric field (En) applied and to monitor the oxygenated hemoglobin (HbO), deoxygenated hemoglobin (HbR), and total hemoglobin (THb) concentrations in the targeted regions during the stimulation.Results:The excitatory protocol induced En values of 0.057V/m and 0.058V/m in the left and right hemispheres, respectively, with an average of 0.058V/m, while the inhibitory one evoked corresponding En values of -0.057V/m and -0.058V/m with an average of -0.058V/m. During excitatory m-tDCS, HbO and THb concentrations in the target cortices were higher than in the inhibitory protocol, with significant differences at FC1, FC2, and C2 for HbO, and at FC2 and C2 for THb. However, no significant inter-group differences in HbR concentrations were observed. Moreover, either protocol induced severe adverse reactions including pain, though the pain decreased with prolonged stimulation.Conclusions:Both excitatory and inhibitory m-tDCS modulate cortical function among healthy individuals. Excitatory m-tDCS is the more effective in enhancing cortical excitability.

BACKGROUND:Facet joint osteoarthritis is acknowledged as a significant contributor to lower back pain in the geriatric population.The advent of an innovative spinal facet joint fusion device presents a therapeutic option for intervening during the initial stages of facet joint osteoarthritis,and significantly reduces the incidence of a series of complications caused by poor early conservative treatment and late surgical treatment.However,its effect on the biomechanics of the lumbar spine is unknown.OBJECTIVE:To investigate the biomechanical disparities between the novel lumbar zygapophyseal joint fusion device and traditional fusion devices.METHODS:A comprehensive three-dimensional finite element model of the L3-S1 lumbar spine was established and validated.Based on this intact model,three groups of surgical models were constructed:a bilateral pedicle screw fixation model,a bilateral novel facet joint fusion fixation model,and a bilateral facet screw fixation model,with the surgical segment designated as L4-5.Under a load of 500 N,a torque of 7.5 Nm was applied to all lumbar models to calculate the range of motion,displacement values,and intervertebral disc stress values at the L4-5 segment;stress values at the L3-4 and L5-S1 segments were also measured.RESULTS AND CONCLUSION:(1)Compared with the intact model,the range of motion at the L4-5 segment was reduced in all surgical models.(2)The novel device exhibited the smallest range of motion at the L4-5 segment under left and right rotational conditions;the greatest range of motion at the L4-5 segment under extension conditions;and a greater range of motion under other conditions than the bilateral pedicle screw fixation model.(3)The novel device demonstrated the smallest displacement values at the L4-5 segment under left and right rotational conditions;under other conditions,the displacement values at the L4-5 segment were greater than those in the bilateral pedicle screw fixation model.(4)In terms of stress distribution at the L4-5 segment,the novel device consistently exhibited the smallest values across all conditions.(5)For the L3-4 segment,the novel device showed the greatest stress values under extension and left and right rotational conditions,while under other conditions,the values were lower than those in the bilateral pedicle screw fixation model.(6)Compared with pedicle screw fixation,the novel device produced smaller stress values at the L5-S1 segment.(7)This study indicates that,compared with pedicle screw fixation,the novel device impacts the biomechanics of the lumbar spine by fusing the facet joints.It provides stability while preserving the range of motion at the surgical segment and reduces stress on the intervertebral discs of the surgical and adjacent segments,thereby potentially delaying disc degeneration.This suggests that the novel device can achieve biomechanical effects similar to those of pedicle screw fixation in theory.

Objective:To investigate the impact and potential mechanisms of Sorbin and SH3 domain-containing protein 2 (Sorbs2) on ventricular arrhythmias in mice.Methods:In the animal experiments, mating was performed using six 8-week-old Sorbs2 +/- mice (3 males and 3 females) weighing 20-22 g. Wild-type (Sorbs2 +/+, n=8) and homozygous (Sorbs2 -/-, n=6) offspring were selected as experimental subjects through genotyping. Echocardiography was performed at 16 weeks of age to record cardiac function parameters in both groups. Resting-state and caffeine-dobutamine-induced electrocardiograms were also conducted. Real-time quantitative reverse transcription polymerase chain reaction was used to detect Sorbs2 messenger RNA expression in the heart, liver, spleen, lung, kidney, brain, small intestine, and skeletal muscle tissues of wild-type mice. Western blotting was employed to measure the protein expression levels of Sorbs2 and voltage-dependent sodium channel alpha subunit 1.5 (Na v1.5) in myocardial tissues from both groups. In the cell experiments, H9C2 cells were transfected with Sorbs2 small interfering RNA as the si-Sorbs2 group, with a corresponding si-negative control group established. Western blot was performed to detect the protein expression levels of Sorbs2 and Na v1.5 in both groups. Results:Sorbs2 was abundantly expressed in cardiac tissue. Compared with wild-type mice, homozygous mice exhibited larger left ventricular end-systolic diameter, along with lower left ventricular ejection fraction and fractional shortening ( P all<0.05). Resting-state electrocardiograms revealed no spontaneous arrhythmias in either group; however, homozygous mice showed shorter RR intervals but longer QRS and QTc intervals versus wild-type mice ( P all<0.05). Following caffeine and dobutamine induction, homozygous mice demonstrated a higher incidence of ventricular arrhythmias, longer arrhythmia duration, and higher ventricular arrhythmia scores than wild-type mice ( P all<0.05). Western blot analysis revealed that Na v1.5 protein expression was markedly lower in myocardial tissues of homozygous mice compared to wild-type mice. Similarly, si-Sorbs2-transfected H9C2 cells exhibited lower Na v1.5 protein levels compared to the si-negative control group ( P<0.05). Conclusion:Sorbs2 plays a critical role in maintaining normal cardiac electrophysiological function. Deficiency of Sorbs2 may lead to impaired cardiac function and increased susceptibility to ventricular arrhythmias in mice, which could be associated with reduced expression of Na v1.5 protein.

Objectives:To explore whether short-course radiotherapy (SCRT)-based total neoadjuvant therapy (TNT) combined with PD-1 inhibitors could further promote tumor regression and improve the prognosis.Methods:This is a prospective, multicenter, two-arm randomized controlled, seamless phase Ⅱ/Ⅲ trial for proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). Eligible patients were randomly assigned to the iTNT (TNT+PD-1) group or the TNT group. Patients in the TNT group received SCRT (5 Gy×5) followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX chemotherapy, with the iTNT group receiving SCRT followed by the same regime in combination with 4 cycles of Sintilimab. Total mesorectal excision (TME) surgery or watch and wait (W&W) was performed after neoadjuvant therapy and then 2 cycles of same regimen as before were recommended. The primary endpoints are the complete response (CR) rate for phase Ⅱ trial and 3-year disease-free survival (DFS) for phase Ⅲ trial. A total of 588 patients will be enrolled for the phase Ⅱ/Ⅲ trial. Short-term efficacy and safety data from the initial 100 treated patients were analyzed as planned.Results:From 2022-8-31 to 2023-5-24 the initial 100 patients were enrolled from 10 hospitals in China, 76.0%(76/100) patients were male, and the median age was 61 years (21-74 years). More patients had tumors located in the lower rectum (78.0%, 78/100), staged T3-4 (97.0%, 97/100) and N1-2 (93.0%, 93/100), and about half of the tumors invaded the mesorectal fascia (52.0%, 52/100) and with extramural vascular invasion (51.0%, 51/100). Analyses were performed according to the per-protocal (PP) set. All patients in the iTNT group ( n=52) and the TNT group ( n=48) completed SCRT; The 4-cycle chemotherapy±Sintilimab completion rates were 86.5% and 100.0% in the iTNT and TNT groups, respectively. In the iTNT group, 82.7% (43/52), 11.5% (6/52), and 5.8% (3/52) of the patients received 4, 3, and 2 cycles of PD-1 inhibitor. After TNT, 68 patients underwent radical surgery and 15 patients achieved cCR and adopted W&W. The pathological complete response (pCR) rates were 48.5% (16/33) and 17.1% (6/35) in the iTNT and TNT groups, with CR rates of 50.0% (25/50) and 26.1% (12/46), respectively. The incidence of treatment-related grade 3-4 adverse events was 26.9% (14/52, iTNT group) and 18.8% (9/48, TNT group), with thrombocytopenia and leukopenia being the most common. Among patients receiving immunotherapy, grade 3 immunotherapy-related adverse events occurred in 2 (3.8%, 2/52) patients: one case was pancreatitis, another case was hepatitis combined with myositis and myocarditis. Conclusion:The preliminary results show that SCRT-based TNT combined with PD-1 inhibitors could further improve the CR rate for LARC without unexpected serious adverse events.

Objective:To evaluate the levels and source of cadmium exposure by dietary pathway among middle-aged and elderly people ≥40 in cadmium-contaminated areas of China.Methods:A total of 7 193 people aged 40-89 years from four typical cadmium-contaminated areas in China were selected as the study subjects. Food Frequency Questionnaire (FFQ), Total Diet Study (TDS) and a 3-day-24-hour dietary recall survey were conducted. Dietary cadmium intake and food sources through dietary pathways were assessed based on cadmium content in foods, consumption amounts and intake frequencies.Results:The mean age of the participants was 63.39±12.21 years, with 50.05% being males. The average monthly dietary cadmium intake was 7.39 μg/(kg·BW). Staple foods and vegetables were the primary sources of dietary cadmium intake, accounting for 57.51% and 32.48%, respectively. The monthly dietary cadmium intake in all surveyed regions did not exceed the Provisional Tolerable Monthly Intake (PTMI) recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).Conclusion:The monthly dietary cadmium intake among middle-aged and elderly people in cadmium-contaminated areas of China is relatively low, with the risk remaining at an acceptable level. Staple foods and vegetables are the most significant contributors to dietary cadmium intake.

Contralateral radiculopathy, a postoperative complication after transforaminal lumbar interbody fusion, refers to postoperative numbness, pain and other neurological symptoms of the lower limb on the side opposite to the symptomatic or the surgical decompression side. Its main causes include excessive restoration of lordosis, intervertebral space tilt caused by improper cage position, poor screw position, new protrusion of nucleus pulposus or bone graft, and hematoma. At present, attention to this complication is gradually increasing. This review summarizes its risk factors from the recent related reports of the condition and puts forward preventive measures in order to promote the preventive awareness of this complication.