To report diagnosis and treatment of a patient with rectal cancer and synchronous liver metastases, accompanied by severe coronary artery stenosis and cardiac insufficiency, and to provide a reference for clinical decision-making in such cases through introducing the treatment contradiction, the choice of systemic treatment plan and the timing of operation, and the final outcome. After definitive diagnosis, the patient received systemic therapy with cetuximab＋irinotecan＋oxaliplatin＋raltitrexed, and along with oral medication to improve cardiac function, followed by elective coronary revascularization. After revascularization, the cardiac function of patient was fully improved. And the tumor lesion was effectively controlled after antitumor therapy. Once the cardiac condition of patient stabilized, two-stage surgical resection of the primary rectal cancer and liver metastases was performed, ultimately achieving tumor-free status, and discharged.

ObjectiveTo investigate the effects of Huanglian Jiedutang （HLJDT） on cognitive function in mice with ischemic stroke （IS） and to elucidate whether its neuroprotective effects are mediated by inhibition of the nuclear factor-κB （NF-κB） signaling pathway and subsequent suppression of NF-κB-regulated neuronal apoptosis. MethodsAn IS model was established using middle cerebral artery occlusion （MCAO）. Sixty C57BL/6J mice were randomly assigned to five groups （n =12 per group）， i.e.， sham operation， model， HLJDT low-dose （3.9 g·kg^-1·d^-1）， HLJDT high-dose （7.8 g·kg^-1·d^-1）， and Ginkgo biloba extract （GBE， 31.2 mg·kg^-1·d^-1）. Post-operatively， neurological deficit scores （Longa score）， cerebral infarct volume assessed by 2，3，5-triphenyltetrazolium chloride （TTC） staining， and brain water content were evaluated. Learning and memory were assessed using new object recognition （NOR） and fear conditioning （FC） tests. Hippocampal pathology was examined via hematoxylin and eosin （HE） staining. Immunofluorescence detected expression of glial fibrillary acidic protein （GFAP， astrocyte marker）， cellular oncogene Fos （c-Fos， neuronal activation marker）， and glutamate decarboxylase 65 （GAD65）. Western blot measured nuclear factor-κB inhibitor protein α （IκBα）， phosphorylated IκBα （p-IκBα）， NF-κB p65， phosphorylated NF-κB p65 （p-NF-κB p65）， ionic calcium binding adapter molecule 1 （Iba-1）， tumor necrosis factor （TNF）-α， interleukin （IL）-1β， and apoptosis-related proteins， such as cleaved cysteinyl aspartate-specific protease 3 （Caspase-3）， B-cell lymphoma 2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. Real-time quantitative PCR （Real-time PCR） was used to assess mRNA levels of Iba-1， TNF-α， IL-1β， NF-κB p65， cleaved Caspase-3， Bax， and Bcl-2. ResultsCompared with the sham group， the model group exhibited significantly increased neurological deficit scores， brain water content， and cerebral infarct volume （P<0.01）. Hippocampal CA1 neurons were disorganized， showing nuclear pyknosis and karyolysis. NOR exploration time and FC freezing time were significantly reduced （P<0.01）. GFAP and c-Fos expression were increased， while GAD65 expression was decreased （P<0.01）. Cleaved Caspase-3 and Bax were upregulated， Bcl-2 was downregulated， and the Bax/Bcl-2 ratio was elevated （P<0.01）. Expression levels of p-IκBα， p-NF-κB p65， IL-1β， TNF-α， and Iba-1 were significantly increased （P<0.01）. Compared with the model group， HLJDT high-dose， low-dose， and GBE groups showed significant improvements in all parameters （P<0.01）. Among them， the HLJDT high-dose group showed the most pronounced neuronal structural recovery and superior performance in NOR and FC tests （P<0.01）. In this group， GFAP and c-Fos decreased， GAD65 increased （P<0.01）， apoptosis-related protein expression was reversed， and NF-κB signaling and related inflammatory factor expression were suppressed （P<0.01）. ConclusionHLJDT ameliorates cognitive dysfunction in mice after IS， potentially by inhibiting the NF-κB signaling pathway， thereby reducing neuroinflammation and hippocampal neuronal apoptosis.

ObjectiveTo explore the mechanisms of Qingchang Wenzhong Decoction （清肠温中方， QWD） in treating ulcerative colitis （UC）. MethodsA total of 100 male C57BL/6J mice were assigned to a pseudo-germ-free group （n=45） and a conventional group （n=55） using a random number table. Pseudo-germ-free model was established by giving antibiotic treatment and subsequently subjected to acute UC induction. After the model was successfully established， the 45 pseudo-germ-free acute UC mice were randomly allocated to a pseudo-germ-free model group， a pseudo-germ-free QWD group， and a pseudo-germ-free mesalazine group， with 15 mice in each group. The 55 conventional mice were randomly divided into a normal control group （n=10）， as well as a conventional model group， a conventional QWD group， and a conventional mesalazine group， with 15 mice in each group. Except for the normal control group， acute UC models were established in all other groups. Mice in the control group received no intervention. From day 32 of the experiment， mice in the pseudo-germ-free QWD group and the conventional QWD group were administered with QWD granules at a dose of 9.71 g/（kg·d） by gavage with deionized water， while those in the pseudo-germ-free mesalazine group and the conventional mesalazine group were given mesalazine enteric-coated tablets at a dose of 151.67 mg/（kg·d） by gavage. Mice in the remaining groups received an equal volume of deionized water once daily for 7 consecutive days. On day 25 of the experiment， six mice were randomly selected from both the pseudo-germ-free group and the conventional group to measure body weight， and fecal samples were collected for 16S rDNA sequencing to compare differences in gut microbiota， including operational taxonomic units （OTUs）， Shannon index， Observed_species index， and phylogenetic diversity （PD whole tree）. On day 39， body weight was measured in all groups， and the disease activity index （DAI） was evaluated. Colon length and colon wet weight were recorded. Histopathological changes in colonic tissues were assessed by hematoxylin and eosin （HE） staining， and histological injury scores were determined. In addition， the expression levels of mucopolysaccharides and mucin 2 （MUC2） in colonic tissues were measured. ResultsOn day 25， there was no significant difference in body weight between the pseudo-germ-free group and the conventional microbiota group （P＞0.05）. Compared to the conventional microbiota group， the pseudo-germ-free group showed significantly reduced OTUs， Shannon index， Observed_species index， and PD whole tree （P＜0.01）. On day 39， compared to the normal control group， mice in the conventional model group showed a significant decrease in the body weight and an increase in DAI， along with increased colon wet weight， shortened colon length， markedly elevated histopathological scores， and reduced expression of mucopolysaccharides and MUC2 （P＜0.01）. In contrast， no significant differences were observed in these parameters in the pseudo-germ-free model group （P＞0.05）. Compared to the conventional model group， the conventional QWD group showed significant improvement in all measured parameters， whereas the conventional mesalazine group showed reductions only in DAI scores and colon wet weight （P＜0.01）. No statistically significant differences were observed among the pseudo-germ-free model group， the pseudo-germ-free QWD group， and the pseudo-germ-free mesalazine group （P＞0.05）. ConclusionQWD may promote the reconstruction of the intestinal mucus barrier by regulating the intestinal flora， thereby exerting a therapeutic effect on acute UC.

ObjectiveTo explore the mechanisms of Qingchang Wenzhong Decoction （清肠温中方， QWD） in treating ulcerative colitis （UC）. MethodsA total of 100 male C57BL/6J mice were assigned to a pseudo-germ-free group （n=45） and a conventional group （n=55） using a random number table. Pseudo-germ-free model was established by giving antibiotic treatment and subsequently subjected to acute UC induction. After the model was successfully established， the 45 pseudo-germ-free acute UC mice were randomly allocated to a pseudo-germ-free model group， a pseudo-germ-free QWD group， and a pseudo-germ-free mesalazine group， with 15 mice in each group. The 55 conventional mice were randomly divided into a normal control group （n=10）， as well as a conventional model group， a conventional QWD group， and a conventional mesalazine group， with 15 mice in each group. Except for the normal control group， acute UC models were established in all other groups. Mice in the control group received no intervention. From day 32 of the experiment， mice in the pseudo-germ-free QWD group and the conventional QWD group were administered with QWD granules at a dose of 9.71 g/（kg·d） by gavage with deionized water， while those in the pseudo-germ-free mesalazine group and the conventional mesalazine group were given mesalazine enteric-coated tablets at a dose of 151.67 mg/（kg·d） by gavage. Mice in the remaining groups received an equal volume of deionized water once daily for 7 consecutive days. On day 25 of the experiment， six mice were randomly selected from both the pseudo-germ-free group and the conventional group to measure body weight， and fecal samples were collected for 16S rDNA sequencing to compare differences in gut microbiota， including operational taxonomic units （OTUs）， Shannon index， Observed_species index， and phylogenetic diversity （PD whole tree）. On day 39， body weight was measured in all groups， and the disease activity index （DAI） was evaluated. Colon length and colon wet weight were recorded. Histopathological changes in colonic tissues were assessed by hematoxylin and eosin （HE） staining， and histological injury scores were determined. In addition， the expression levels of mucopolysaccharides and mucin 2 （MUC2） in colonic tissues were measured. ResultsOn day 25， there was no significant difference in body weight between the pseudo-germ-free group and the conventional microbiota group （P＞0.05）. Compared to the conventional microbiota group， the pseudo-germ-free group showed significantly reduced OTUs， Shannon index， Observed_species index， and PD whole tree （P＜0.01）. On day 39， compared to the normal control group， mice in the conventional model group showed a significant decrease in the body weight and an increase in DAI， along with increased colon wet weight， shortened colon length， markedly elevated histopathological scores， and reduced expression of mucopolysaccharides and MUC2 （P＜0.01）. In contrast， no significant differences were observed in these parameters in the pseudo-germ-free model group （P＞0.05）. Compared to the conventional model group， the conventional QWD group showed significant improvement in all measured parameters， whereas the conventional mesalazine group showed reductions only in DAI scores and colon wet weight （P＜0.01）. No statistically significant differences were observed among the pseudo-germ-free model group， the pseudo-germ-free QWD group， and the pseudo-germ-free mesalazine group （P＞0.05）. ConclusionQWD may promote the reconstruction of the intestinal mucus barrier by regulating the intestinal flora， thereby exerting a therapeutic effect on acute UC.

Objective To investigate predictive value of soluble growth stimulation-expressed gene 2 protein (sST2), cardiac troponin T (cTnT), and creatine kinase-myocardial band (CK-MB) for steroid resistance and prognosis in patients with immune checkpoint inhibitor-associated myocarditis (ICIAM). Methods A total of 28 patients with ICIAM were prospectively enrolled from March 2023 to February 2024 at Zhongshan Hospital, Fudan University. All participants were divided into the steroid-resistant ICIAM (srICIAM) group and the non-srICIAM group. Baseline serum levels of sST2, cTnT and CK-MB were detected prior to treatment initiation. ROC curve analysis was applied to evaluate the predictive value of these biomarkers, and Kaplan-Meier survival analysis was performed to explore the relationship between sST2 and all-cause mortality. Results Baseline sST2, cTnT, and CK-MB levels were significantly higher in the srICIAM group (n＝15) than in the non-srICIAM group (n＝13, P＜0.05). Combination of cTnT and sST2 improved predictive performance for srICIAM (AUC＝0.857, sensitivity 0.714, specificity 1.000). After 6 months of follow-up, the high sST2 group had a significantly higher all-cause mortality than the low sST2 group (P＝0.016). Conclusions The combination of sST2 and cTnT could effectively predict srICIAM, and elevated sST2 is associated with increased higher all-cause mortality in ICIAM patients, providing a basis for early risk stratification and treatment optimization.

AIM: To analyze the changes of retinal structure and function before and after panretinal photocoagulation(PRP)in patients with proliferative diabetic retinopathy(PDR).METHODS: Prospective study. Totally 98 cases(98 eyes)of PDR patients who underwent PRP in Eye Hospital of Wenzhou Medical University from January 2022 to May 2023 were included. Optical coherence tomography angiography(OCTA)was used to detect central retinal thickness(CRT), central macular thickness(CMT), subfoveal choroidal thickness(SFCT), foveal avascular zone(FAZ), deep vascular complex(DVC)blood flow density, superficial vascular complex(SVC)blood flow density before and at 1 wk, 1 and 3 mo after PRP. During the follow-up, 1 eye underwent vitrectomy, 2 eyes were lost to follow-up, and finally 95 eyes completed 1 a follow-up, with a loss rate of 3%. According to the visual prognosis at 1 a after treatment, the patients were divided into two groups: 73 eyes in good prognosis group and 22 eyes in poor prognosis group(including 9 eyes of visual disability and 13 eyes of visual regression). The changes in retinal structure and function before and after PRP treatment were compared between the two groups of patients, and the receiver operating characteristic(ROC)curve and decision curve were used to analyze the predictive value of retinal structure and function for PDR treatment.RESULTS: There were statistical significant differences in PDR staging, CRT, CMT, SFCT, DVC blood flow density, and SVC blood flow density between the two groups of patients before treatment(all P<0.05). At 1 wk, 1 and 3 mo after treatment, the FAZ area of both groups decreased compared to before treatment, while the blood flow density of DVC and SVC increased compared to before treatment(both P<0.05). However, there was no significant difference in the blood flow density of FAZ, DVC, and SVC between the two groups at 1 wk, 1 and 3 mo after treatment(all P>0.05). The CRT, CMT and SFCT of the two groups at 1 wk after treatment were higher than those before treatment(all P<0.05), but there were no significant differences between the two groups(all P>0.05). The CRT, CMT and SFCT at 1 and 3 mo after treatment were lower than those at 1 wk after treatment and before treatment in both groups. The CRT, CMT and SFCT in the poor prognosis group at 3 mo after treatment were higher than those at 1 mo after treatment, and were higher than those in the good prognosis group(all P<0.05). ROC analysis showed that, at 3 mo after laser treatment in PDR patients, the area under the curve of the CRT, CMT, and SFCT alone or in combination after treatment for 1 a was 0.788, 0.781, 0.783, and 0.902, respectively, and the combined prediction value was better(P<0.05). Decision curve analysis showed that the combined detection of CRT, CMT, and SFCT in PDR patients at 3 mo after treatment can improve the predictive value of visual prognosis.CONCLUSION: The optimal time for retinal structure and function recovery in PDR patients after PRP treatment is between 1 wk and 1 mo. OCTA measurement of CRT, CMT, and SFCT at 3 mo after treatment can predict the visual prognosis during the 1 a treatment period.

Objective:To evaluate the effectiveness and safety of minimally invasive anchoring hook intraocular lens (IOL) interscleral suture fixation surgery.Methods:A cohort study was conducted.A total of 74 patients (74 eyes) with aphakia, artificial lens dislocation, or lens dislocation were included at Tengzhou Central People's Hospital from 2021 to 2022.According to the surgical method, the patients were divided into conventional fixation group (39 cases, 39 eyes) undergoing conventional intraocular lens suspension surgery and anchoring hook fixation group (35 cases, 35 eyes) undergoing minimally invasive anchoring hook type IOL interscleral suture fixation surgery.Surgical time, preoperative best corrected visual acuity (BCVA) before surgery and at 1 day and 1 month after surgery, corneal endothelial cell density before and at 1 month after surgery, mislocation of the artificial IOL and the incidence of complications were recorded.This study was reviewed and approved by the Ethics Committee of Tengzhou Central People's Hospital (No.2019-20), and all patients signed the informed consent form.Results:One day and 1 month after surgery, the BCVA of the anchoring hook fixation group was better than that of the conventional fixation group, and the differences were statistically significant (both P<0.05). The preoperative corneal endothelial cell densities of the anchor hook fixation group and conventional fixation group were (2 431±556) and (2 406±625)cells/mm 2, and the postoperative 1-month corneal endothelial cell densities were (2 012±703) and (2 004±759)cells/mm 2, respectively, without statistically significant difference (both P>0.05). The average surgical time of the anchoring hook fixation group was (67.1±7.2) minutes, which was significantly shorter than (93.1±17.9) minutes of the conventional fixation group, and the difference was statistically significant ( t=13.654, P<0.001). During the 1-month follow up, no IOL mislocation occurred in the two groups, and two eyes in the routine fixation group developed anterior chamber hemorrhage, accounting for 5.1%, no anterior chamber bleeding occurred in the anchoring hook fixation group.Corneal edema was observed in 6 eyes and 1 eye of the conventional fixation group and anchor hook fixation group, accounting for 15.4% and 2.9%, respectively.Macular edema was observed in 2 eyes of the conventional fixation group, accounting for 5.1%, and no macular edema occurred in the anchoring hook fixation group.Throughout the entire follow-up, there was no case of low intraocular pressure, ciliary detachment, exposed sutures, or requiring secondary surgical intervention in either group. Conclusions:Both minimally invasive anchoring hook IOL intrascleral suture fixation and conventional IOL suspension are safe and effective.Compared with conventional IOL suspension surgery, anchoring hook IOL intrascleral suture fixation surgery has more advantages in postoperative visual recovery, shorter surgical operation time and a lower incidence of postoperative complications.

Objective:To explore the human epidermal growth factor receptor 2 gene(HER2) expression amplification in endometrial cancer (EC) with different p53 expression patterns based on molecular typing, as well as their correlation and impact on prognosis.Methods:A retrospective analysis was conducted on 282 patients with EC who underwent surgical treatment at Dalian Women and Children′s Medical Center (Group) from January 2016 to December 2018 with complete clinical and pathological data. Immunohistochemistry and fluorescence in situ hybridization were used to detect the amplification of HER2 gene expression in paraffin- embedded tumor tissue of patients after surgery and confirmed the expression of p53. The clinical data were collected and tracked follow-up.Results:There were significant differences between HER2-positive patients and HER2-negative patients in the age of onset, pathological types of tumor tissue, depth of muscle infiltration, and tumor differentiation ( P< 0.05). The 5-year survival rate and 5-year progression-free survival rate of HER2-positive patients were lower than those of HER2-negative patients (45.45% vs. 95.16%, 45.45% vs. 95.11%), and there were statistical differences ( P<0.01). The positive expression of HER2 in EC tissues was positively correlated with p53 mutant expression ( r = 0.409, P<0.01). Among p53 wild-type EC patients, the 5-year survival rate was 98.4% for HER2-negative patients and 100.00% for HER2-positive patients. In the patients with p53 mutant EC, 58.05% and 37.50%, respectively, there was a statistical difference ( P<0.01). The 5-year progression-free survival rates were 97.50%, 100.00%, 60.20%, and 37.50%, respectively, and there was a statistical difference ( P<0.01). Conclusions:There is a significant positive correlation between HER2 positive overexpression and p53 mutant expression in EC tissue, and there is an inherent synergy between the two expressions. HER2 positive over expression is a key factor for poor prognosis in EC patients. Patients with HER2- positive over expression and p53 mutant expression have poorer 5-year overall survival and progression- free survival compared to other groups.

Objective:To evaluate the effectiveness and safety of minimally invasive anchoring hook intraocular lens (IOL) interscleral suture fixation surgery.Methods:A cohort study was conducted.A total of 74 patients (74 eyes) with aphakia, artificial lens dislocation, or lens dislocation were included at Tengzhou Central People's Hospital from 2021 to 2022.According to the surgical method, the patients were divided into conventional fixation group (39 cases, 39 eyes) undergoing conventional intraocular lens suspension surgery and anchoring hook fixation group (35 cases, 35 eyes) undergoing minimally invasive anchoring hook type IOL interscleral suture fixation surgery.Surgical time, preoperative best corrected visual acuity (BCVA) before surgery and at 1 day and 1 month after surgery, corneal endothelial cell density before and at 1 month after surgery, mislocation of the artificial IOL and the incidence of complications were recorded.This study was reviewed and approved by the Ethics Committee of Tengzhou Central People's Hospital (No.2019-20), and all patients signed the informed consent form.Results:One day and 1 month after surgery, the BCVA of the anchoring hook fixation group was better than that of the conventional fixation group, and the differences were statistically significant (both P<0.05). The preoperative corneal endothelial cell densities of the anchor hook fixation group and conventional fixation group were (2 431±556) and (2 406±625)cells/mm 2, and the postoperative 1-month corneal endothelial cell densities were (2 012±703) and (2 004±759)cells/mm 2, respectively, without statistically significant difference (both P>0.05). The average surgical time of the anchoring hook fixation group was (67.1±7.2) minutes, which was significantly shorter than (93.1±17.9) minutes of the conventional fixation group, and the difference was statistically significant ( t=13.654, P<0.001). During the 1-month follow up, no IOL mislocation occurred in the two groups, and two eyes in the routine fixation group developed anterior chamber hemorrhage, accounting for 5.1%, no anterior chamber bleeding occurred in the anchoring hook fixation group.Corneal edema was observed in 6 eyes and 1 eye of the conventional fixation group and anchor hook fixation group, accounting for 15.4% and 2.9%, respectively.Macular edema was observed in 2 eyes of the conventional fixation group, accounting for 5.1%, and no macular edema occurred in the anchoring hook fixation group.Throughout the entire follow-up, there was no case of low intraocular pressure, ciliary detachment, exposed sutures, or requiring secondary surgical intervention in either group. Conclusions:Both minimally invasive anchoring hook IOL intrascleral suture fixation and conventional IOL suspension are safe and effective.Compared with conventional IOL suspension surgery, anchoring hook IOL intrascleral suture fixation surgery has more advantages in postoperative visual recovery, shorter surgical operation time and a lower incidence of postoperative complications.

Objective:To explore the changes of atlantoaxial joint spaces and pharyngeal airway after combined orthodontic-orthognathic treatment in skeletal class Ⅲ patients with mandibular deviation.Methods:A total of 34 adult skeletal class Ⅲ patients (10 males and 24 females) with mandibular deviation who received combined orthodontic-orthognathic treatment at the Department of Orthodontics and the Department of Orthognathic Surgery in the Stomatological Hospital of Chongqing Medical University from August 2014 to October 2021 were retrospectively selected. The patients were 22 (5) years old (18-33 years). Cone-beam CT data of patients taken before treatment (T0), after preoperative orthodontics (T1), and 6 to 12 months after orthognathic surgery (T2) were collected. The anterior atlanto-dental interval (ADI), variance of bilateral lateral atlanto-dental interval (VBLADI), the anterior posterior length (APL), maximum transverse width (LTW), aspect ratio (L/W), cross-sectional area (CSA) of each airway cross-section, the airway volumes, as well as the positions of the maxillofacial landmark points [subspinale (point A), supramental (point B), posterior nasal spine (point PNS), the most anterior and superior point of the hyoid bone (point H)] were measured at different time points. The correlations between airway changes, maxillofacial movements as well as the changes in the atlantoaxial joint spaces were also analyzed.Results:During the combined orthodontic-orthognathic treatment, no statistically significant differences were found in the ADI and VBLADI among different treatment time points (all P>0.05). After preoperative orthodontics, the volume of total airway increased from 20 868 (6 669) mm 3 to 21 302 (8 911) mm 3 ( P<0.05). After orthognathic surgery, there were no statistically significant differences in the APL, CSA of the PNS plane, the L/W of the uvula plane, and the nasopharyngeal airway volume compared with those after preoperative orthodontics (all P>0.05). The L/W of the PNS plane after surgery was significantly increased compared with that after preoperative orthodontics ( P<0.05), while other airway parameters were all significantly decreased compared with those after preoperative orthodontics (all P<0.05). Compared with before treatment, the nasopharyngeal airway volume after surgery [6 186 (1 707) mm3] increased significantly ( P<0.05) and the palatopharyngeal airway volume [8 145 (2 594) mm3] and the glossopharyngeal airway volume [5 605 (4 395) mm3] decreased significantly (all P<0.05). There was no statistically significant difference in the total airway volume between after surgery and before treatment ( P>0.05). Correlation analysis showed that after preoperative orthodontics, the amount of the sagittal movement of point B was moderately positively correlated with the total airway volume change ( r=0.40, P=0.022). Before and after orthognathic surgery, the amount of the sagittal movement of point PNS was moderately positively correlated with the changes in the palatopharyngeal airway volume and the total airway volume ( r=0.43, P=0.015; r=0.46, P=0.008). In addition, the change in VBLADI before and after orthognathic surgery was weakly positively correlated with the changes in the CSA of the PNS plane and the APL of the uvula plane ( r=0.35, P=0.029; r=0.38, P=0.016). Conclusions:During the combined orthodontic-orthognathic treatment, the anterior atlanto-dental interval in skeletal class Ⅲ patients with mandibular deviation remained stable among different treatment time points. The total airway volume increased after preoperative orthodontics. After orthognathic surgery, the backward movement of the mandible tended to reduce the size of the pharyngeal airway, and the morphology of the glossopharyngeal airway tended to become more flattened. The changes in the pharyngeal airway dimensions were correlated with the maxillomandibular movements and the atlantoaxial joint space changes.