ObjectiveTo systematically compare the differential regulation of the maternal-fetal interface cell lineages and communication networks in the CBA/J×DBA/2 mouse model of recurrent pregnancy loss （RPL） by the two classic therapeutic methods-tonifying the kidney to stabilize the fetus and invigorating the spleen to stabilize the fetus （Shoutai Wan， Juyuan Jian）-of traditional Chinese medicine （TCM） at the single-cell resolution and clarify their modern scientific connotations. MethodsFemale non-pregnant CBA/J mice were caged with male BALB/c （blank group） and DBA/2 （modeling group） mice separately. Pregnant mice in the modeling group were randomly grouped as follows： high/low-dose Shoutai Wan， high/low-dose Juyuan Jian， model （RPL）， and positive control （dydrogesterone）， with 10 mice in each group. Starting from the day after the detection of the vaginal plug， mice were administrated with drugs or an equal volume of normal saline by gavage for 10 consecutive days. After the intervention， the following indicators were measured. ① Macroscopic evaluation： general conditions， uterine wet weight， embryo loss rate， four coagulation parameters ［prothrombin time （PT）， activated partial thromboplastin time （APTT）， fibrinogen （FIB）， and thrombin time （TT）］， and peripheral blood estradiol （E₂） and progesterone （Pg） levels. The decidua with embryos was stained with hematoxylin-eosin （HE） and evaluated by transmission electron microscopy （TEM）. The expression of B-cell lymphoma-2 （Bcl-2）， vascular endothelial growth factor （VEGF）， angiotensin Ⅱ （AngⅡ）， matrix metalloproteinase-2 （MMP-2）， interleukin-6 （IL-6）， leukemia inhibitory factor （LIF）， CXC chemokine ligand 12 （CXCL12）， and microtubule-associated protein 1 light chain 3 homolog （LC3）Ⅰ/Ⅱ was quantified by Western blot. ② Mechanism analysis at the single-cell level： The decidua with embryos from the blank， model， high-dose Shoutai Wan， and high-dose Juyuan Jian groups （6 mice per group， with 3 single-cell samples per group， totaling 24 mice） were analyzed by the BD Rhapsody™ platform， and the whole-cell atlas was drawn by uniform manifold approximation and projection （UMAP） dimensionality reduction clustering combined with the single-cell mouse cell atlas （scMCA）. The differentially expressed genes （DEGs） and cell interaction networks were analyzed via Gene Ontology （GO）， Kyoto Encyclopedia of Genes and Genomes （KEGG）， and CellChat， and the protein-protein interaction （PPI） map of subtype cells was constructed. The CytoTRACE pseudo-temporal analysis was performed to explore the developmental trajectories of core immune cells （natural killer cells， NK cells） from maternal and fetal sources. Results① Pathological and Western blot results indicated that compared with the blank group， the RPL group showed an increase in the embryo loss rate （P<0.01）， down-regulated expression of Bcl-2， LIF， MMP-2， and Vegf in the decidua with embryos （P<0.05）， up-regulated protein levels of CXCL-12， AngⅡ， and IL-6 （P<0.05）， blocked angiogenesis， apoptosis-inflammation imbalance， and coagulation dysfunction. Both prescriptions dose-dependently reduced the abortion rate and restored the angiogenesis-inflammation balance， and Shoutai pill showed superior performance in restoring the E₂ level to the Pg level （P<0.05）. ② Single-cell transcriptome analysis indicated that compared with the blank group， the RPL group showed differences in multiple key cell populations such as decidual cells， trophoblast cells， endothelial cells， erythroblasts， NK cells， and macrophages at the maternal-fetal interface. Immunity and angiogenesis were the key links in RPL. Compared with the RPL group， high-dose Shoutai Wan reversed the changes of NK cells in the embryonic layer （upregulating the mRNA levels of 17 genes and downregulating the mRNA levels of 29 genes） and macrophages （upregulating the mRNA levels of 117 genes and downregulating the mRNA levels of 53 genes） through the regulation of gene expression. High-dose Shoutai pill regulated the immune cells to affect unfolded proteins， cell adhesion， and programmed cell death， thereby promoting decidualization and angiogenesis and modulating embryo-membrane development. High-dose Juyuan Jian regulated the key subgroups of NK cells （up-regulating the mRNA levels of 9 genes and down-regulating the mRNA levels of 17 genes） and macrophages （up-regulating the mRNA levels of 110 genes and down-regulating the mRNA levels of 81 genes）， which affected decidual inflammation and apoptosis and intervened in glycolysis. ③ The pseudo-temporal analysis and communication network indicated that the communication frequency of the RPL group decreased. High-dose Shoutai Wan restored maternal-fetal tolerance through pathways such as NKG2D， CDH5， GDF， and FASLG. High-dose Juyuan Jian enhanced the IL-6/LIFR/JAK/signal transducer and activator of transcription 3 （STAT3） and desmosome/SEMA6/tumor necrosis factor-like weak inducer of apoptosis （TWEAK） signaling to improve endometrial receptivity. The RPL group showed an increased proportion of toxic dNK7， a decreased proportion of reparative dNK4， and blocked embryo fNK1. High-dose Shoutai Wan down-regulated dNK7 and up-regulated dNK4. High-dose Juyuan Jian inhibited the terminal differentiation of dNK7 and up-regulated LILRB1， thus restoring the balance of cytotoxicity and repair. ConclusionBoth the kidney-tonifying and spleen-invigorating methods are effective in treating RPL. NK and macrophages are the key immune cells in the interaction between the embryo and the membrane. The kidney-tonifying method （Shoutai Wan） has an advantage in regulating the phenotypes of unfolded protein， cell adhesion， and programmed cell death， and shows expression characteristics closer to the physiological state in the regulation of NKG2D and CDH5 signals. The spleen-invigorating method （Juyuan Jian） has an advantage in regulating epithelial-mesenchymal transition （EMT）， angiogenesis， and glycolysis and shows higher communication intensity in the IL-6 and LIFR pathways.

Objective: To explore the core features of trait aggression in children and adolescents, so as to provide a theoretical basis for behavioral interventions targeting the central psychological characteristics of aggression in children and adolescents. Methods: From March to May 2020, a simple random convenience sampling method was employed to recruit 39 165 students from grades 4 to 12 in Sichuan, Chongqing, Guizhou, and Shandong. Data were collected via online questionnaires, with all participants completing the Chinese Version of the Aggression Questionnaire. Psychometric network analysis was utilized for data processing. Results: Trait aggression among Chinese children and adolescents was at a moderately low level. The core nodes of the network structure included physical aggression [if someone intentionally causes trouble for me, I will hit them severely (AGG6); if someone hits me, I will retaliate (AGG11)] and self aggression [When I am very irritable, I think of hurting myself (AGG5); when I am in a bad mood, I engage in behaviors that harm my health, such as overeating (AGG25)]. Across grade levels, core nodes primarily originated from the anger dimension [When I m angry, I feel like a powder magazine that could explode at any moment (AGG13); I can t control my temper (AGG18); I am prone to getting angry when I see things that are not pleasing to the eye (AGG23); I will get angry for no reason (AGG27)]. Except for grades 7 and 9, core nodes in other grades included the verbal aggression dimension [I am prone to arguments with people (AGG22)]. Before grade 8, core nodes incorporated the self aggression dimension (AGG 5, AGG 25); after grade 8, core nodes included the physical aggression dimension [AGG 6, AGG 11, I fight slightly more than others (AGG16), and if people around me make things difficult for me to a certain extent, I will fight with them (AGG26)]. No statistically significant differences were found in the trait aggression network structures across grades, genders, or within gender comparisons of different grades. Conclusion These findings broaden our understanding of aggression in children and adolescents, suggesting that behavioral interventions can effectively reduce aggressive behaviors in this population.

OBJECTIVE: To explore the construction of a canine model of vascularized allogeneic spinal cord transplantation (vASCT) and preliminarily evaluate its therapeutic efficacy for spinal cord injury (SCI). METHODS: Sixteen female Beagle dogs aged 8-12 months were randomly selected, with 8 dogs serving as donors for the harvesting of spinal cord tissue with a vascular pedicle [dorsal intercostal artery (DIA) at the T₁₀ level and accompanying vein]. The remaining 8 dogs underwent a 1.5-cm-length spinal cord defect at the T₁₀ level, followed by transplantation of the donor spinal cord tissue for repair. Polyethylene glycol (PEG) was applied to both ends to spinal cord graft; then, using a random number table method, the dogs were divided into an experimental group (n=4) and a control group (n=4). The experimental group received immunosuppressive intervention with oral tacrolimus [0.1 mg/(kg∙d)] postoperatively, while the control group received no treatment. The operation time and ischemia-reperfusion time of two groups were recorded. The recovery of hind limb function was estimated by Olby score within 2 months after operation; the motor evoked potentials (MEP) was measured through neuroelectrophysiological examination, and the spinal cord integrity was observed through MRI. RESULTS: There was no significant difference in the operation time and ischemia-reperfusion time between the two groups (P>0.05). All dogs survived until the completion of the experiment. Within 2 months after operation, all dogs in the control group failed to regain the movement function of hind limbs, and Olby scores were all 0. In the experimental group, the movement and weight-bearing, as well as walking abilities of the hind limbs gradually recovered, and the Olby scores also showed a gradually increasing trend. There was a significant difference between the two groups from 3 to 8 weeks after operation (P<0.05). Neuroelectrophysiological examination indicated that the electrical signals of the experimental group passed through the transplanted area, and the latency was shortened compared to that at 1 month after operation (P<0.05), showing continuous improvement, but the amplitude did not show significant improvement (P>0.05). The control group was unable to detect any MEP changes after operation. MRI examination showed that the transplanted spinal cord in the experimental group survived and had good continuity with normal spinal cord tissue, while no relevant change was observed in the control group. CONCLUSION The vASCT model of dogs was successfully constructed. This surgical procedure can restore the continuity of the spinal cord. The combination of tacrolimus anti-immunity is a key factor for the success of transplantation.
Animals ; Dogs ; Female ; Spinal Cord/blood supply* ; Spinal Cord Injuries/surgery* ; Transplantation, Homologous ; Disease Models, Animal ; Recovery of Function ; Plastic Surgery Procedures/methods* ; Tacrolimus ; Immunosuppressive Agents

BACKGROUND:Confirming the reliability and validity of the My jump 2 application for measuring lower limb vertical stiffness may offer the possibility of it as an alternative to the Kistler three-dimensional force platform for measuring lower limb stiffness. OBJECTIVE:To verify the reliability and validity of the My Jump 2 application in measuring lower limb vertical stiffness of college students. METHODS:The drop jump data of the participants were collected through the Kistler three-dimensional force platform and the My Jump 2 application,and the vertical stiffness of the participants'lower limb vertical stiffness was calculated.The intraclass correlation coefficient was used to analyze the data measured by the My Jump 2 application and the Kistler three-dimensional force platform,attempting to verify the reliability of the My Jump 2 application.The bias and average between the two devices were drawn into a Bland-Altman diagram to verify the consistency between the two test methods.Finally,the test-retest reliability of the My Jump 2 applications at 30 cm and 40 cm was analyzed using the Cronbach's alpha(α)and coefficient of variation.Pearson product-moment correlation was used to analyze the correlation of My Jump 2 applications. RESULTS AND CONCLUSION:My Jump 2 application has high reliability and validity when measuring the vertical stiffness of the lower limb.At the same time,due to its advantages of low cost,convenient portability and field testing for large samples,it can be used as an alternative to the Kistler three-dimensional force platform to test the vertical stiffness of the lower limb in college students and similar populations.

Objective:To explore the possible effects of Bushen Huoxue Formula (the kidney tonifying and blood activating prescription) on the proliferation and extracellular matrix synthesis of nucleus pulposus cells by regulating the circ_0036763/miR-583 axis.Methods:Real time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression levels of circ0036763 and miR-583 in normal and intervertebral disc degeneration (IDD) nucleus pulposus cells; IDD nucleus pulposus cells were divided into pcDNA group, pcDNA circ_0036763 group, pcDNA circ_0036763+ mimic NC group, and pcDNA circ_0036763+ miR-583 mimic group. qRT-PCR was used to detect the expression levels of circ_0036763 and miR-583 in nucleus pulposus cells in each group, methyl thiazolyl tetrazolium (MTT) was used to detect cell proliferation (A value), and Western blot was used to detect the expression of proliferating cell nuclear antigen (PCNA), collagen Ⅰ, and collagen Ⅱ proteins in nucleus pulposus cells, The dual luciferase assay reported experimental validation of the targeting relationship between circ_0036763 and miR-583. 27 mice were divided into sham surgery group, IDD group, and kidney tonifying and blood activating formula group. IDD models were established in all groups except for the sham surgery group. After successful modeling, the sham surgery group and IDD group were given physiological saline by gavage, while the kidney tonifying and blood activating formula group was given 1.5 g/ml of kidney tonifying and blood activating formula by gavage for 3 consecutive weeks. QRT-PCR was used to detect the expression levels of circ0036763 and miR-583 in the nucleus pulposus cells of mice in each group, MTT was used to detect cell proliferation, and Western blot was used to detect the expression of PCNA, collagen Ⅰ, and collagen Ⅱ proteins.Results:The expression level of circ_0036763 in IDD nucleus pulposus cells decreased, while the expression level of miR-583 increased (all P<0.05); Overexpression of circ_0036763 can promote proliferation and extracellular matrix synthesis of nucleus pulposus cells (all P<0.05); Circ_0036763 targets miR-583 and upregulates miR-583 reversible overexpression. Circ_0036763 enhances the proliferation and extracellular matrix synthesis ability of IDD nucleus pulposus cells. Compared with the sham surgery group, the IDD group showed an increase in collagen Ⅰ protein expression and miR-583 expression levels (all P<0.05), while the cell A value, PCNA and collagen Ⅱ protein expression, and circ_0036763 expression levels decreased (all P<0.05); Compared with the IDD group, the Kidney Tonifying and Blood Activating Formula group showed a decrease in collagen Ⅰ protein expression and miR-583 expression levels (all P<0.05), while the cell A value, PCNA and collagen Ⅱ protein expression, and circ_0036763 expression levels increased (all P<0.05). Conclusions:The kidney tonifying and blood activating formula (Bushen Huoxue) may induce proliferation and extracellular matrix synthesis of nucleus pulposus cells by regulating the circ_0036763/miR-583 axis.

Objective:To design and evaluate the application value of intracavitary-interstitial brachytherapy (IC-ISBT) applicator template for locally advanced cervical cancer.Methods:MRI data of 100 patients with ⅡB-ⅣA stage cervical cancer (International Federation of Gynecology and Obstetrics 2018 staging system) before and after external beam radiation therapy (EBRT) admitted to Sun Yat-sen University Cancer Center from March 2019 to September 2020 were collected. The range of primary cervical lesions was retrospectively analyzed and compared. Based on the residual mass of patients, the corresponding high-risk clinical target volume (HR-CTV) was delineated, and the IC-ISBT applicator template was designed and initially applied to cervical cancer patients. Dosimetry analysis and efficacy evaluation were compared between the applicator template-guided ( n=37) and free-hand implantation groups ( n=63). Chi-square test or Fisher exact test was performed for categorical variables, and t-test or U-test for continuous variables. Results:The median distance between the residual tumor margin (clockwise 3, 6, 9, 12 o'clock) and the center of 100 patients with ⅡB-ⅣA stage cervical cancer after EBRT was 16.5, 14.0, 17.0 and 13.0 mm, respectively. The corresponding HR-CTV was superimposed to reconstruct the three-dimensional diagram, and the cylindrical IC-ISBT applicator template with mushroom-like head was designed and manufactured: the longest and shortest diameter of the head was 35 and 20 mm, respectively; the central channel was adapted to the uterine tube, the C1-C12 channels was arranged in inner circle, and the peripheral B1-B5 and A1-A4 pin channels were expanded bilaterally. In terms of dose coverage, there was no significant difference between the HR-CTV D 90% [(635.12±22.65) vs. (635.80±25.84) cGy], bladder D 2 cm3 [(473.79±44.78) vs. (463.55±66.43) cGy)], rectum D 2 cm3 [(396.99±73.54) vs. (408.00±73.94) cGy] and sigmoid colon D 2 cm3 [(293.07±152.72) vs. (311.31±135.77) cGy] between the template-guided and free-hand implantation groups (all P>0.05), but the HR-CTV D 98% was significantly higher [(544.78±32.07) vs. (536.78±32.04) cGy, P=0.007] and the rectum D 1 cm3 and D 0.1 cm3 were significantly lower [(438.62±69.65) vs. (453.97±67.89) cGy, P=0.016; (519.46±70.67) vs. (543.82±81.24) cGy, P=0.001] in the template-guided implantation group. In addition, there was no significant difference in the complete response rate between two groups (86% vs. 83%, P>0.05). Conclusions:This IC-ISBT applicator template is reasonably designed, and the therapeutic efficacy of the template-guided implantation is equivalent to that of free-hand implantation. The dose coverage of the target area meets the clinical demand with a better protection of the organs at risk. The applicator template has the potential to be widely used as a conventional template in clinical practice as the applicator-guided implantation is convenient to operate and repeat.

Objective:To verify the predictive value of the Second Revision of the International Staging System (R2-ISS) in newly diagnosed patients with multiple myeloma (MM) who underwent first-line autologous hematopoietic stem cell transplantation (ASCT) in a new drug era in China.Methods:This multicenter retrospective cohort study enrolled patients with newly diagnosed MM from three centers in China (Beijing Chao-Yang Hospital, Capital Medical University; the First Affiliated Hospital, Sun Yat-Sen University, and the Second Affiliated Hospital of Naval Medical University) from June 2008 to June 2018. A total of 401 newly diagnosed patients with MM who were candidates for ASCT were enrolled in this cohort, all received proteasome inhibitor and/or immunomodulator-based induction chemotherapy followed by ASCT. Baseline and follow-up data were collected. The patients were regrouped using R2-ISS. Progression-free survival (PFS) and overall survival (OS) were analyzed. The Kaplan-Meier method was used to analyze the survival curve and two survival curves were compared using the log-rank test. Cox regression analysis were performed to analyze the relationship between risk factors and survival.Results:The median age of the patients was 53 years (range 25-69 years) and 59.5% (240 cases) were men. Newly diagnosed patients with renal impairment accounted for 11.5% (46 cases). According to Revised-International Staging System (R-ISS), 74 patients (18.5 %) were diagnosed with stage Ⅰ, 259 patients (64.6%) with stage Ⅱ, and 68 patients (17.0%) with stage Ⅲ. According to the R2-ISS, the distribution of patients in each group was as follows: 50 patients (12.5%) in stage Ⅰ, 95 patients (23.7%) in stage Ⅱ, 206 patients (51.4%) in stage Ⅲ, and 50 patients (12.5%) in stage Ⅳ. The median follow-up time was 35.9 months (range, 6-119 months). According to the R2-ISS stage, the median PFS in each group was: 75.3 months for stage Ⅰ; 62.0 months for stage Ⅱ, 39.2 months for stage Ⅲ, and 30.3 months for stage Ⅳ; and the median OS was not reached, 86.6 months, 71.6 months, and 38.5 months, respectively. There were statistically significant differences in PFS and OS between different groups (both P<0.001). Multivariate Cox regression analysis showed that stages Ⅲ and Ⅳ of the R2-ISS were independent prognostic factors for PFS ( HR=2.37, 95% CI 1.30-4.30; HR=4.50, 95% CI 2.35-9.01) and OS ( HR=4.20, 95% CI 1.50-11.80; HR=9.53, 95% CI 3.21-28.29). Conclusions:The R2-ISS has significant predictive value for PFS and OS for transplant-eligible patients with MM in the new drug era. However, the universality of the R2-ISS still needs to be further verified in different populations.

Objective:To correlate serum Nesfatin-1, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cystatin C (CysC) levels with myocardial enzymes and cardiac function in patients with acute ST-elevation myocardial infarction (STEMI).Methods:This is a case-control study. A total of 100 patients with acute STEMI who received treatment at Lishui People's Hospital from January 2020 to December 2022 were included in the STEMI group. An additional 80 healthy controls who concurrently received physical examinations in the same hospital were included in the control group. Serum levels of Nesfatin-1, NT-proBNP, CysC, creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) levels were determined in each group. Left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDD), and left ventricular end-systolic diameter (LVDS) were measured using color Doppler ultrasound. Correlation analysis was performed.Results:Serum Nesfatin-1 level in the STEMI group was (89.96 ± 15.25) ng/L, which was significantly lower than (226.36 ± 37.47) ng/L in the control group ( t = 33.15, P < 0.05). Serum levels of NT-proBNP and CysC in the STEMI group were (1 325.12 ± 378.48) ng/L and (1.37 ± 0.24) mg/L, which were significantly higher than (78.95 ± 13.42) ng/L and (0.79 ± 0.16) mg/L in the control group ( t = -29.42, -18.56, both P < 0.05). Serum CK-MB and cTnI levels in the STEMI group were (46.51 ± 12.14) U/L and (1.13 ± 0.25) U/L, respectively, which were significantly higher than (12.23 ± 4.01) U/L and (0.09 ± 0.02) U/L in the control group ( t = -24.06, -37.09, both P < 0.05). The LVEF in the STEMI group was (37.84 ± 5.45)%, which was significantly lower than (72.41 ± 4.26)% in the control group ( t = 46.49, P < 0.05). The LVDD and LVDS in the STEMI group were (40.92 ± 5.25) mm and (58.98 ± 6.25) mm, which were significantly higher than (19.86 ± 3.36) mm and (34.21 ± 4.38) mm in the control group ( t = -31.13, -30.03, both P < 0.05). Serum Nesfatin-1 level was positively correlated with LVEF ( r = 0.572), but it was negatively correlated with serum CK-MB and cTnI levels, LVDD, and LVDS ( r = -0.498, -0.617, -0.506, -0.534, all P < 0.05). Serum NT-proBNP and CysC levels were negatively correlated with LVEF ( r = -0.653, -0.607), but they were positively correlated with serum CK-MB and cTnI levels, LVDD, and LVDS ( r = 0.582, 0.526, 0.712, 0.565, 0.631, 0.578, 0.659, 0.635, all P < 0.05). Conclusion:Serum Nesfatin-1 levels decrease, while serum NT-proBNP and CysC levels increase in patients with acute STEMI. Serum Nesfatin-1, NT-proBNP, and CysC levels are closely related to myocardial enzymes and cardiac function.

In the past 20 years,the development of artificial intelligence has made rapid progress,and it is increasingly applied in the medical field,including medical image-assisted diagnosis and treatment,health management,disease risk prediction and so on.In this paper,the application status of artificial intelligence-assisted detection and diagnosis system based on deep learning in anorectal diseases is summarized,and the new methods related to the diagnosis and treatment of anorectal diseases at home and abroad are summarized.It mainly reviews the research progress of artificial intelligence technology in the diagnosis and treatment of anal fistula,perianal abscess,hemorrhoids and other anorectal diseases.

Objective To investigate the dosimetric difference between manual and inverse optimization in 3-dimensional (3D) brachytherapy for gynecologic tumors. Methods This retrospective study was conducted among a total of 110 patients with gynecologic tumors undergoing intracavitary combined with interstitial brachytherapy or interstitial brachytherapy. Based on the original images, the brachytherapy plans were optimized for each patient using Gro, IPSA1, IPSA2 (with increased volumetric dose limits on the basis of IPSA1) and HIPO algorithms. The dose-volume histogram (DVH) parameters of the clinical target volume (CTV) including V200, V150, V100, D90, D98 and CI, and the dosimetric parameters D2cc, D1cc, and D0.1cc for the bladder, rectum, and sigmoid colon were compared among the 4 plans. Results Among the 4 plans, Gro optimization took the longest time, followed by HIPO, IPSA2 and IPSA1 optimization. The mean D90, D98, and V100 of HIPO plans were significantly higher than those of Gro and IPSA plans, and D90 and V100 of IPSA1, IPSA2 and HIPO plans were higher than those of Gro plans (P<0.05), but the CI of the 4 plans were similar (P>0.05). For the organs at risk (OARs), the HIPO plan had the lowest D2cc of the bladder and rectum;the bladder absorbed dose of Gro plans were significantly greater than those of IPSA1 and HIPO (P<0.05). The D2cc and D1cc of the rectum in IPSA1, IPSA2 and HIPO plans were better than Gro (P<0.05). The D2cc and D1cc of the sigmoid colon did not differ significantly among the 4 plans. Conclusion Among the 4 algorithms, the HIPO algorithm can better improve dose coverage of the target and lower the radiation dose of the OARs, and is thus recommended for the initial plan optimization. Clinically, the combination of manual optimization can achieve more individualized dose distribution of the plan.