Objective To elucidate the molecular mechanism of sirtuin-3 (SIRT3) in regulating mitochondrial biogenesis in human renal tubular epithelial cells. Methods Cells were stimulated with different concentrations of H₂O₂ and divided into four groups: control (NC), 50 μmol/L H₂O₂, 110 μmol/L H₂O₂ and 150 μmol/L H₂O₂. SIRT3 protein expression was then measured. SIRT3 was knocked down with siRNA, and cells were further assigned to five groups: control (NC), negative-control siRNA (NCsi), SIRT3-siRNA (siSIRT3), NCsi+H₂O₂, and siSIRT3+H₂O₂. After 24 h, cellular adenosine triphosphate (ATP) and mitochondrial superoxide anion (O₂•⁻) levels were determined, together with mitochondrial expression of SIRT3, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), superoxide dismutase 2 (SOD2), acetylated-SOD2 and adenosine monophosphate activated protein kinase α1 (AMPKα1). Results The 110 and 150 μmol/L H₂O₂ decreased SIRT3 protein (both P<0.05). ATP and mitochondrial O₂•⁻ did not differ between NC and NCsi groups (both P>0.05). Compared to the NCsi group, the siSIRT3 group exhibited elevated O₂•⁻ level, decreased SIRT3 protein and increased expression levels of SOD2 and acetylated SOD2 protein (all P<0.05). Compared to the NCsi group, the NCsi+H₂O₂ group exhibited decreased cellular ATP levels, elevated mitochondrial O₂•⁻ levels, and reduced protein expression levels of SIRT3, SOD2, TFAM, AMPKα1, PGC-1α and NRF1 (all P<0.05). Compared with the siSIRT3 group, the siSIRT3+H₂O₂ group showed a decrease in cellular ATP levels, an increase in mitochondrial O₂•⁻ levels, a decrease in SIRT3, SOD2, TFAM, AMPKα1, PGC-1α and NRF1 protein expression levels and a decrease in acetylated SOD2 protein expression levels (all P<0.05). Compared with the NCsi+H₂O₂ group, the siSIRT3+H₂O₂ group showed a decrease in cellular ATP levels, an increase in mitochondrial O₂•⁻ levels, a decrease in SIRT3, AMPKα1, PGC-1α and NRF1, TFAM protein expression levels, and an increase in SOD2 and acetylated SOD2 protein expression levels (all P<0.05). Conclusions SIRT3 promotes mitochondrial biogenesis in tubular epithelial cells via the AMPK/PGC-1α/NRF1/TFAM axis, representing a key mechanism through which SIRT3 ameliorates oxidative stress-induced mitochondrial dysfunction.

Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood. Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort. Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.

OBJECTIVE To evaluate the influence of pharmaceutical quality control on the efficiency and outcomes of standardized medication therapy management （MTM） services for patients with coronary heart disease by using Economic， Clinical and Humanistic Outcomes （ECHO） model. METHODS This study collected case data of coronary heart disease patients who received MTM services during January-March 2023 （pre-quality control implementation group， n＝96） and June-August 2023 （post-quality control implementation group， n＝164）. Using propensity score matching analysis， 80 patients were selected from each group. The study subsequently compared the economic， clinical， and humanistic outcome indicators of pharmaceutical services between the two matched groups. RESULTS There were no statistically significant differences in baseline data between the two groups after matching （P＞0.05）. Compared with pre-quality control implementation group， the daily treatment cost （16.26 yuan vs. 24.40 yuan， P＜0.001）， cost-effectiveness ratio [23.12 yuan/quality-adjusted life year （QALY） vs. 32.32 yuan/QALY， P＜0.001]， and the incidence of general adverse drug reactions （2.50% vs. 10.00%， P＝0.049） of post-quality control implementation group were decreased significantly； the utility value of the EuroQol Five-Dimensional Questionnaire （0.74± 0.06 vs. 0.71±0.07， P＝0.003）， the reduction in the number of medication related problems （1.0 vs. 0.5， P＜0.001）， the medication adherence score （[ 6.32±0.48） points vs. （6.10±0.37） points， P＝0.001]， and the satisfaction score （[ 92.56±1.52） points vs. （91.95±1.56） points， P＝0.013] all showed significant improvements. Neither group experienced serious adverse drug reactions. There was no statistically significant difference in the incidence of new adverse reactions between the two groups （1.25% vs. 3.75%， P＝0.310）. CONCLUSIONS Pharmaceutical quality control can improve the quality of pharmaceutical care， and the ECHO model can quantitatively evaluate the effect of MTM services， making pharmaceutical care better priced and more adaptable to social needs， thus being worthy of promotion.

Objective: To explore the association between mental health and muscle strength among Chinese adolescents aged 13- 18, providing a theoretical foundation and intervention strategies for mental health promotion. Methods: Data were obtained from the 2019 Chinese National Survey on Students Constitution and Health, including 98 631 Chinese adolescents aged 13- 18. Psychological distress was assessed by using the Kessler Psychological Distress Scale (K10), and mental well being was measured with the Warwick-Edinburgh Mental Well being Scale (WEMWBS). Based on the gender and age specific Z scores of various test items [grip strength, standing long jump, pull ups (for males), and sit ups (for females)], muscle strength index (MSI) was constructed to evaluate the comprehensive level of muscle strength in adolescents. According to the Dual factor Model (DFM) of mental health, participants were categorized into four groups:troubled, symptomatic but content, vulnerable, and complete mental health. Gender differences were analyzed by using Chi-square tests, trends were tested with Cochran-Armitage tests, and multinomial Logistic regression models were applied to assess associations between muscle strength and mental health among adolescents. Results: In 2019, 37.4% of Chinese adolescents aged 13-18 were reported of high mental distress, and 59.9% were reported of low mental well being. Boys had significantly lower rates of high mental distress (35.3%) and low mental well being (55.6%) compared to girls (39.4%, 64.3%), and the differences were of statistical significance ( χ 2=176.13, 780.42, both P <0.05). In 2019, the rate of complete mental health among adolescents showed a downward trend with increasing age ( χ 2 trend = 258.47) and a gradual upward trend with increasing muscle strength levels ( χ 2 trend =123.14)，and both boys and girls exhibited similar trends ( χ 2 trend =103.83, 168.46; 57.00 , 67.34) (all P <0.05). The results of the unordered multiclass Logistic regression model showed that after controlling for confounding factors such as age and gender, when the completely pathological group as a reference, for every 1 unit increase in MSI in adolescents, the likelihood of being in a completely mental health state increased by 29% ( OR = 1.29); for every unit increase in the Z-score for pull ups, the likelihood of being in a completely mental health state increased by 6% ( OR =1.06) among boys; for every 1 unit increase in sit up Z score, the likelihood of being in a completely mental health state increased by 19% ( OR =1.19) among girls (all P <0.05). Conclusions The mental health status of Chinese adolescents is not good enough. Muscle strength is positively associated with mental health.

Objective:To compare the efficacy of robot system-assisted versus freehand screw revision for ankylosing spondylitis (AS) with lower cervical fractures.Methods:A multicenter retrospective cohort study was conducted to analyze the clinical data of 57 patients with AS combined with lower cervical fractures admitted to Honghui Hospital Affiliated to Xi'an Jiaotong University School of Medicine, Henan Provincial People's Hospital, Zhengzhou Orthopedic Hospital, and Qilu Hospital of Shandong University, including 46 males and 11 females, aged 38-77 years [(65.4±9.5)years]. Injury segments involved C 3 in 7 patients, C 4 in 13, C 5 in 25, C 6 in 10, and C 7 in 2. All the patients underwent revision surgery, among whom, 22 patients were treated with robot system-assisted cervical pedicle screw placement (robot nailing group, with 190 screws), and 35 with freehand cervical pedicle screw placement (freehand nailing group, with 300 screws). The operative duration, intraoperative bleeding volume, frequency of intraoperative fluoroscopy, incision length, and length of hospital stay of the two groups were compared; the time of single nscrew insertion, the number of single nail revisions, the distance between screws and the anterior cortex, the accuracy of screw placement of grade 0 and grade 0+1 were recorded in the two groups. The visual analogue scale (VAS), Japanese Orthopedic Society (JOA) score, neck dysfunction index (NDI), American Spine Injury Association (ASIA) classification before operation, at 3 days, 3 months after operation and at the last follow-up were compared between the two groups. The complication rate was also noted. Results:All the patients were followed up for 12-16 months [(14.3±2.1)months]. The operative duration, intraoperative bleeding volume, and frequency of intraoperative fluoroscopy were (186.4±12.9)minutes, (486.1±68.6)ml, and (3.4±1.3)times in the robot nailing group, which were shorter or less than (206.7±14.4)minutes, (660.3±45.2)ml, and (13.5±3.6)times in the freehand nailing group ( P<0.01). The incision length was (9.4±2.4)cm in the robot nailing group, longer than (5.6±1.2)cm in the freehand nailing group ( P<0.01), and the length of hospital stay was (3.7±0.4)days, shorter than (4.4±1.4)days in the freehand nailing group ( P<0.01). The length of single nail insertion, the number of single nail revision, and the distance between the screws and the front cortex were (6.5±0.4)minutes, (1.1±0.1)times, and (3.5±1.3)mm in the robot nailing group, which were shorter or less than (11.6±0.2)minutes, (1.5±0.2)times, and (12.4±4.7)mm in the freehand nailing group ( P<0.01). The accuracy of the screw placement in the robot nailing group was 90.0% (171/190) and 95.8% (182/190) with level 0 and 0+1 screws, better than 80.0% (240/300) and 89.0% (267/300) in the freehand nailing group ( P<0.05). There was no significant difference in VAS, JOA score, NDI, or ASIA grading between the two groups before operation ( P>0.05). The VAS, JOA, and NDI scores at 3 days after operation were (3.1±0.6)points, (12.1±1.2)points, and (15.6±2.9)points, respectively in the robot nailing group, which were better than (5.0±1.4)points, (11.3±1.1)points and (22.5±3.7)points, respectively in the freehand nailing group ( P<0.05). No statistically significant difference was observed in the ASIA grade between the two groups at 3 days after operation ( P>0.05). There were no significant differences in VAS, JOA, NDI scores, or ASIA grading between the two groups at 3 months after operation and at the last follow-up ( P>0.05). Compared with those before operation, the VAS, JOA, NDI scores, and ASIA grading were significantly improved at 3 days, 3 months after operation and at the last follow-up in the two groups, which were further improved with the passage of time. Two patients in the robot nailing group had pneumonia, with a complication rate of 9% (2/22), while 2 patients in the freehand nailing group had dural sac rupture and cerebrospinal fluid leakage and 3 had lung infection after operation, with a complication rate of 14% (5/35) ( P<0.05). Conclusion:Compared with freehand nailing, the robot system-assisted nailing revision for AS with lower cervical fracture has more advantages in terms of the operative duration, length of hospital stay, intraoperative bleeding volume, frequency of intraoperative fluoroscopy nailing speed and accuracy, screw holding force, early pain relief, function restoration, and complication rate, despite longer surgical incision.

Objective:To compare the efficacy of laminoplasty via the intermuscular approach or posterior midline approach for treating spinal cord injury without radiographic abnormality (SCIWORA).Methods:A multi-center retrospective cohort study was conducted to analyze the clinical data of 135 patients with SCIWORA admitted to Honghui Hospital Affiliated to Xi'an Jiaotong University School of Medicine, Xi'an No.5 Hospital, Henan Provincial People's Hospital, Zhengzhou Orthopedic Hospital, Xuanwu Hospital of Capital Medical University from February 2021 to June 2023, including 75 males and 60 females, aged 35-78 years [(55.3±8.1)years]. The injury segments involved C 3-C 6. All the patients underwent posterior cervical open-door laminoplasty, among whom 70 patients were treated via the intermuscular approach (intermuscular group) and 65 via the posterior midline approach (posterior midline group). The operation duration, intraoperative blood loss, postoperative drainage volume, and length of hospital stay were recorded. The visual analogue scale (VAS) score, Japanese Orthopedic Association (JOA) score, neck disability index (NDI), Barthel index, cervical Cobb angle, and cervical range of motion (ROM) were measured preoperatively, at 3, 6, 12 months postoperatively and at the final follow-up. The American Spinal Injury Association (ASIA) scale was evaluated preoperatively, at 3, 12 months postoperatively and at the final follow-up. The postoperative complication rate was recorded as well. Results:All the patients were followed up for 15-19 months [(16.3±1.6)months]. The operation duration, intraoperative blood loss, postoperative drainage and length of hospital stay were (125.0±23.0)minutes, (210.4±34.8)ml, and (165.3±23.7)ml, and (5.3±0.1)days in the intermuscular group, which were significantly shorter or less than (168.0±27.6)minutes, (260.2±45.3)ml, (196.4±31.6)ml, and (6.4±0.2)days in the posterior midline group ( P<0.01). The preoperative VAS score, JOA score, NDI and Barthel index showed no significant differences between the two groups ( P>0.05). The VAS score and JOA score also showed no significant differences between the two groups at 3, 6, 12 months postoperatively or at the final follow-up ( P>0.05). The NDI and Barthel index also showed no significant differences between the two groups at 3 months postoperatively ( P>0.05). At 6, 12 months postoperatively and at the final follow-up, the NDI were (15.4±2.5)points, (11.8±2.1)points and (8.6±1.5)points in the intermuscular group, significantly lower than (19.1±3.4)points, (14.3±2.4)points and (11.9±1.4)points in the posterior midline group ( P<0.01). At 6, 12 months postoperatively and at the final follow-up, the Barthel index were (71.4±6.2)points, (83.4±5.8)points and (89.2±7.1)points in the intermuscular group, significantly higher than (59.6±4.7)points, (74.2±3.9)points and (78.8±6.2)points in the posterior midline group ( P<0.01). Both groups showed significant improvements in VAS score, JOA score, NDI and Barthel index at 3, 6, 12 months postoperatively and at the final follow-up when compared to those preoperatively ( P<0.05). Among them, the VAS score, NDI and Barthel index were further improved over time ( P<0.05). Simultaneously, the JOA score was significantly improved at 6, 12 months postoperatively and at the last follow-up when compared to that at 3 months postoperatively ( P<0.05), with no significant difference at later time points between the two groups ( P>0.05). The preoperative cervical Cobb angle and ROM showed no significant differences between the two groups ( P>0.05). There was no significant difference in the Cobb angle between the two groups at 3, 6 or 12 months postoperatively ( P>0.05), while it was (13.6±2.4)° in the intermuscular group at the final follow-up, significantly larger than (10.4±2.8)° in the posterior midline group ( P<0.01). At 3, 6, 12 months postoperatively and at the final follow-up, the cervical ROM were (34.1±6.4)°, (32.6±7.3)°, (31.8±9.1)° and (29.6±8.7)° in the intermuscular group, significantly larger than (23.7±8.3)°, (22.3±7.8)°, (22.5±8.1)° and (20.6±9.3)° in the posterior midline group ( P<0.01). In the intermuscular group, the cervical Cobb angle showed no significant changes at 3, 6, 12 months postoperatively and at the final follow-up when compared to those preoperatively ( P>0.05). In the posterior midline group, the Cobb angles were significantly reduced at 3, 6, 12 months postoperatively and at the final follow-up when compared to those preoperatively ( P<0.05), showing significant decrease at 12 months postoperatively and at the final follow-up from those at 3, 6 months postoperatively ( P<0.05), no significant difference at 6 months postoperatively from that at 3 months postoperatively ( P>0.05), and significant decrease at the final follow-up from that at 12 months postoperatively ( P>0.05). In the intermuscular group, the cervical ROM were significantly improved at 3, 6, 12 months postoperatively and at the final follow-up when compared to those preoperatively and showed further improvement over time ( P<0.05). In the posterior midline group, the cervical ROM were significantly improved at 3, 6, 12 months postoperatively and at the final follow-up when compared to those preoperatively ( P<0.05), showing significant decreases at 6, 12 months postoperatively and at the final follow-up from that at 3 months postoperatively ( P<0.05), significant decreases at the final follow-up from those at 6, 12 months postoperatively ( P<0.05), and no significant difference at 12 months postoperatively from that at 6 months postoperatively ( P>0.05). The ASIA grades showed no significant difference between the two groups preoperatively, at 3, 12 months postoperatively and at the final follow-up ( P>0.05) , but were gradually improved over time in both groups ( P<0.05). The postoperative complication rate was 9%(6/70) in the intermuscular group, significantly lower than 48%(31/65) in the posterior midline group ( P<0.01). Conclusion:Compared to the posterior midline approach, the intermuscular approach for laminoplasty in patients with SCIWORA possesses advantages, including shorter operative time and length of hospital stay, reduced intraoperative blood loss and postoperative drainage, less postoperative neck disability, higher daily life quality, better long-term preservation of cervical lordosis and motion, and a lower complication rate.

Objective:To compare the clinical efficacy of navigation system and orthopedic robot-assisted nail placement in the treatment of lower cervical fracture and dislocation.Methods:A retrospective cohort study was conducted to analyze the clinical data of 49 patients with fracture and dislocation of the lower cervical spine who were admitted to Honghui Hospital, Xi′an Jiaotong University School of Medicine from May 2021 to October 2022, including 38 males and 11 females, aged 29-61 years [(39.3±7.3)years]. Injury segments involved C 3 in 12 patients, C 4 in 11, C 5 in 8, C 6 in 9 and C 7 in 9. Twenty-one patients were treated with S8 navigation system (navigation group, 84 screws), and 28 with TINAVI orthopedic robot (robot group, 112 screws). The two groups were compared in terms of the total surgical duration, single screw placement time, total screw placement time, distance between the screw and the anterior cortex, incision length, intraoperative radiation dose, intraoperative blood loss and length of hospital stay. The height of intervertebral space, Cobb angle, sliding distance between vertebral bodies and American Spinal Injury Association (ASIA) grade were assessed before surgery and at 3 days after surgery. Visual analogue scale (VAS), Japanese Orthopedic Association (JOA) score and neck dysfunction index (NDI) before surgery, at 3 days, 3 months after surgery and at the last follow-up were compared. The accuracy of screw placement, intraoperative invasion rate of adjacent facet joints and rate of postoperative complications (infection, screw loosening, etc.) were evaluated. Results:All the patients were followed up for 12-16 months [(13.6±1.9)months]. In the navigation group, the total surgical duration, distance from the screw to the anterior cortex and the intraoperative radiation dose were (236.2±30.6)minutes, (2.0±0.2)mm and (374.3±90.3)mGy respectively, which were significantly shorter or less than those in the robot group [(278.4±20.7)minutes, (10.6±2.9)mm and (448.4±77.9)mGy] ( P<0.01). The single screw placement time, total screw placement time, incision length and intraoperative blood loss were (3.5±0.4)minutes, (23.9±0.5)minutes, (9.1±2.4)cm and (422.2±30.4)ml respectively, which were significantly longer or more than those in the robot group [(2.6±0.2)minutes, (17.9±0.7)minutes, (6.6±2.6)cm and (360.3±56.3)ml] ( P<0.01). There was no significant difference in the length of hospital stay between the two groups ( P>0.05). No significant differences were observed in the height of the intervertebral space, Cobb angle, sliding distance between the vertebral bodies and ASIA grade between the two groups ( P>0.05). At 3 days after surgery, the height of intervertebral space, Cobb angle, sliding distance between vertebral bodies and ASIA grade in both groups were significantly improved when compared with those before surgery ( P<0.05 or 0.01). There were no significant differences in VAS, JOA scores or NDI between the two groups before surgery, at 3 days, 3 months after surgery and at the last follow-up ( P>0.05). The VAS, JOA scores and NDI in both groups were gradually improved at 3 days, 3 months and at the last follow-up after surgery when compared with those before surgery ( P<0.05). There was no significant difference in the accuracy of screw placement of levels 0 and 0+1 between the two groups ( P>0.05). No significant difference in the intraoperative invasion rate of adjacent facet joints between the two groups was found ( P>0.05). There were no serious complications such as infection or screw loosening after surgery in both groups. Conclusions:For lower cervical fracture and dislocation, although there are more advantages in total surgical duration, screw holding force and radiation control regarding the navigation system, and more outstanding performance in screw placement efficiency, incision length and intraoperative blood loss regarding the orthopedic robot, both of them can effectively rebuild the cervical structure, improve neurological function, relieve postoperative pain, improve screw placement accuracy and reduce facet joint injury and serious complications. Selection of the best auxiliary screw placement system should comprehensively consider patients′ conditions and the experience of the surgical team.

BACKGROUND:The regulation of intestinal flora by exercise is closely related to human health,but intestinal flora involves many factors.Existing studies have lacked consistent evidence on the effect of exercise on the intestinal flora of college students. OBJECTIVE:To explore the effects of exercise on intestinal flora diversity and species composition of college students. METHODS:Through systematic search of PubMed,Web of Science,Embase,Medline,Cochrane Library,CNKI,WanFang Database and VIP database,eight empirical studies were selected and included,and semi-quantitative analysis was performed on them. RESULTS AND CONCLUSION:In terms of the species diversity of the intestinal flora,both high-intensity interval training and Tai Chi exercise significantly enhance the species diversity of intestinal flora in college students,while aerobic exercise does not have a significant effect on the enhancement of intestinal flora diversity in college students.In terms of the species composition of the intestinal flora,all three exercise modalities significantly alter the compositional structure of the intestinal flora in college students,which can increase the abundance of beneficial bacteria such as Ruminalococcus,Faecalis prevotelli,Blautia,and decrease the abundance of harmful bacteria such as Escherichia spp.Compared with high-intensity interval training,aerobic and Tai Chi exercise causes more elevated abundance of beneficial bacteria.In addition to changes in intestinal flora characteristics,exercise improves body composition,cardiorespiratory function,and executive function in college students,and these health benefits are closely linked to exercise-induced changes in intestinal flora that can produce health benefits for the body through metabolic regulation,barrier function,and neuromodulation.Although studies have confirmed the association between exercise and intestinal flora,the mechanism by which exercise affects intestinal flora has not yet been clarified,and at the same time,localizing the flora related to the host health is the key to targeting intestinal flora as a therapeutic target in the future,all of which are worthy of further attention and investigation.

The polymerase 1 and transcript release factor (PTRF)-cytoplasmic phospholipase A2 (cPLA2) phospholipid remodeling pathway facilitates tumor proliferation in glioma. Nevertheless, blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance. Here, CD26/dipeptidyl peptidase 4 (DPP4) was identified through screening of CRISPR/Cas9 libraries. Suppressing PTRF-cPLA2 signaling resulted in the activation of the epidermal growth factor receptor (EGFR) pathway through phosphatidylcholine and lysophosphatidylcholine remodeling, which ultimately increased DPP4 transcription. In turn, DPP4 interacted with EGFR and prevented its ubiquitination. Linagliptin, a DPP4 inhibitor, facilitated the degradation of EGFR by blocking its interaction with DPP4. When combined with the cPLA2 inhibitor AACOCF3, it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells. Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide. DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR. Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4-EGFR interaction. This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.

Objective:To develop outcome indicators for the implementation of comprehensive inter-ventions targeting the multimorbidity of myopia and obesity in children and adolescents,providing a basis for the co-prevention of multimorbidity and the outcome measurement of implementation research in children and adolescents.Methods:Based on the RE-AIM framework,a preliminary set of indicators was constructed.The Delphi method was employed,with experts scoring and providing feedback on the proposed indicators via questionnaires.After each round of consultation,expert enthusiasm index,authority coefficient,coordination degree,and consensus level were calculated.Expert opinions were col-lected and analyzed to modify,delete,or add indicators based on consultation results and screening crite-ria.Two Delphi rounds were conducted until consensus was achieved.Results:A total of 28 experts par-ticipated actually in both rounds.The Kendall's W coefficients for the two rounds of expert consultation were0.352(x2=413.952,P＜0.001)and 0.499(x2=405.044,P＜0.001),both statistically sig-nificant.The final outcome indicators for implementation research on comprehensive interventions for myopia and obesity comorbidity in children and adolescents included five primary dimensions with 13 secondary and 20 tertiary indicators.The dimension of reach included the number of children and adoles-cents involved,participant representativeness,and full-course participation representativeness.The di-mension of effectiveness included multimorbidity incidence,myopia incidence,spherical equivalent,body mass index(BMI),overweight and obesity prevalence,waist-to-height ratio,comprehensive health knowledge score,and comprehensive health behavior score.The dimension of adoption covered school representativeness and representativeness of school nurses and teachers involved in implementation.The dimension of implementation included fidelity,content modification,and cost.The dimension of mainte-nance included individual health outcomes and organizational sustainment.Conclusion:This study developed implementation outcome indicators for comprehensive interventions targeting multimorbidity of myopia and obesity among the children and adolescents based on the RE-AIM framework.These indica-tors can serve as a reference for optimizing intervention research strategies related to common multimor-bidity among children and adolescents in China.