Objective:To screen the optimal machine learning model for predicting the recurrence condition of hepatocellular carcinoma (HCC) at different time points post-surgery, based on the cutoff value of the Ki67 positive proliferation index condition calculated from recurrence-free survival and combined with various clinical features.Methods:retrospective study included initially treated patients with solitary HCC who underwent radical surgery at the Fifth Medical Center of the PLA General Hospital from January 2013 to March 2023. Data included general clinical data, preoperative laboratory parameters, and surgical pathology information about the subjects. The postoperative recurrence status was assessed by querying the medical record system or by telephone follow-up. The Ki67 positive index cutoff value was determined by the X-tile software based on the patient's recurrence-free survival status and time analysis. Survival rates were calculated using the Kaplan-Meier method, and survival curves were plotted. The study population was randomly divided into training and testing groups in a 7:3 ratio using a computer-generated random number method. The minimum redundancy maximum relevance (mRMR) method was used for feature variable selection. Predictive models for postoperative HCC recurrence conditions in patients with HCC were constructed using random forest, support vector machine, logistic regression, and gradient boosting decision tree machine learning algorithms. Inter-group comparisons for continuous data were performed using the t-test or Mann-Whitney U test. Inter-group comparisons of enumeration data were performed using the Pearson χ2 test, continuity-corrected χ2 test, or Fisher's exact test. Results:The cutoff values for the Ki67 positivity index were 0.3 and 0.5 in 510 cases, with a follow-up time ranging from 1.2 to 11.4 years (median: 6.2 years). The recurrence-free survival time was between 1 and 135 months (median: 32 months), with recurrence-free survival rates post-surgery at 1, 2, 3, and 5 years were 87.5%, 77.1%, 61.2%, and 54.5%, respectively. The top five variables predicted HCC recurrence and non-recurrence conditions following surgical follow-up at 6 months, 1 year, 2 years, and beyond 2 years, in accordance with information obtained by the mRMR screen out. The Ki67 positivity index screened a successfully constructed machine learning model to predict HCC recurrence and non-recurrence conditions following surgical follow-up at 6 months, 1 year, 2 years, and beyond 2 years. The machine learning model based on the gradient boosting decision tree algorithm had the best prediction performance among them (areas under the receiver operating characteristic curves for predicting HCC recurrence within six months in the training and validation sets were 0.996 and 0.946, and accuracies were 0.972 and 0.935, respectively).Conclusion:A machine learning model was successfully constructed using the Ki67 positivity index combined with four readily available clinical features to predict HCC recurrence. The machine learning model based on the gradient boosting decision tree algorithm demonstrated the best performance in terms of predicting HCC recurrence within six months after surgery.

Objectives:To evaluate the feasibility and clinical efficacy of eccentric occluder for the treatment of ventricular septal defect(VSD)without distance from the aortic valve.Methods:This analysis included 16 patients(9 males and 7 females)with VSD without distance from the aortic valve,who were treated at Fuwai Central China Cardiovascular Hospital from February 2022 to June 2024.Ten cases had mild right coronary sinus prolapse,and 2 had mild aortic valve regurgitation.All patients were diagnosed with VSD located zero-distance from aortic valve through transthoracic echocardiography(TTE)and left ventricular angiography.Eccentric occluder was used for interventional closure.TTE and 12-lead electrocardiography(ECG)were performed at 1 month,3 months,and 6 months after surgery to observe the presence of residual shunt,aortic valve regurgitation,and cardiac electrical conduction abnormalities.Results:Transcatheter closure was successful in 15 patients,procedure failed in one patient due to the unstable fixation of the occluder.Average diameter of the defect is(4.37±1.53)mm,and the diameter of the occluder is 6.5(6.0,8.0)mm.Postoperative left ventricular angiography showed minimal residual shunt in 3 cases,and no complications such as pericardial tamponade,hemolysis,thromboembolism,or infection,were observed.At one month after occlusion,TTE results showed that residual shunt disappeared in 3 patients with residual shunt.During 3-month and 6-month follow-up,all the occluders were well-positioned with no new aortic valve regurgitation or worsening of the original regurgitation,and no atrioventricular block or bundle branch block and other electrocardiographic conduction abnormalities.Conclusions:The use of eccentric occluder for intervention of ventricular septal defect patients without distance from the aortic valve is safe and effective.

OBJECTIVE: To investigate the effect of moxibustion on central insulin resistance related proteins of the rats suffering from diabetic cognitive decline, and analyze the underlying mechanism of moxibustion for cognition improvement. METHODS: Using the intraperitoneal injection of STZ combined with a high-fat diet, the rat model of diabetic cognitive decline were prepared. Twenty successfully-modeled rats were assigned randomly into a model group and a moxibustion group, 10 rats in each one. Besides, a blank group was set up with 10 rats collected. In the moxibustion group, suspending moxibustion was applied to "Baihui" (GV20), "Shenting" (GV24) and "Dazhui" (GV14) at the same time, 20 min in each intervention, once a day, and 6 interventions were delivered weekly and the duration of treatment was consecutive 4 weeks. The random blood glucose was measured using glucometer, and the learning-memory ability was detected by water maze test. HE staining was used to observe the morphology of neurons in the hippocampal tissue, real-time PCR assay was to detect mRNA expression of insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in the hippocampal tissue. The Western blot method was employed to detect the protein expression of IRS1, PI3K, AKT, phosphorylated IRS1 (p-IRS1), phosphorylated PI3K (p-PI3K) and phosphorylated AKT (p-AKT) in the hippocampal tissue, and the ratio of p-IRS1/IRS1, p-PI3K/PI3K and p-AKT/AKT was calculated separately. The immunofluorescence intensity of p-IRS1, p-PI3K, and p-AKT was measured using immunofluorescence. RESULTS: Compared with the blank group, the rats of the model group exhibited higher random blood glucose (P<0.001), longer escape latency (P<0.001), severe pathological damage in the hippocampus, lower mRNA expression of IRS1, PI3K, and AKT (P<0.001), reduced ratio of p-IRS1/IRS1, p-PI3K/PI3K and p-AKT/AKT (P<0.001), and declined immunofluorescence intensity of p-IRS1, p-PI3K, and p-AKT in the hippocampal tissue (P<0.001). In comparison with the model group, for the rats of the moxibustion group, the random blood glucose decreased (P<0.05), the escape latency was shortened (P<0.01), the hippocampal pathological damage was attenuated, the mRNA expression of IRS1, PI3K and AKT increased (P<0.01), the ratio of p-IRS1/IRS1, p-PI3K/PI3K and p-AKT/AKT was elevated (P<0.01, P<0.05), and the immunofluorescence intensity of p-IRS1, p-PI3K, and p-AKT in the hippocampal tissue was strengthened (P<0.01, P<0.05). CONCLUSION In diabetic rats experiencing cognitive decline, moxibustion can enhance the learning-memory ability, which may be attributed to modulating the protein expression of IRS1, PI3K, and AKT, and their phosphorylation, activating insulin signal transduction, and reducing central insulin resistance.
Animals ; Moxibustion ; Insulin Resistance ; Rats ; Male ; Insulin Receptor Substrate Proteins/genetics* ; Rats, Sprague-Dawley ; Humans ; Proto-Oncogene Proteins c-akt/genetics* ; Cognitive Dysfunction/genetics* ; Diabetes Mellitus, Experimental/therapy* ; Hippocampus/metabolism* ; Acupuncture Points ; Phosphatidylinositol 3-Kinases/genetics*

Objectives:To evaluate the feasibility and clinical efficacy of eccentric occluder for the treatment of ventricular septal defect(VSD)without distance from the aortic valve.Methods:This analysis included 16 patients(9 males and 7 females)with VSD without distance from the aortic valve,who were treated at Fuwai Central China Cardiovascular Hospital from February 2022 to June 2024.Ten cases had mild right coronary sinus prolapse,and 2 had mild aortic valve regurgitation.All patients were diagnosed with VSD located zero-distance from aortic valve through transthoracic echocardiography(TTE)and left ventricular angiography.Eccentric occluder was used for interventional closure.TTE and 12-lead electrocardiography(ECG)were performed at 1 month,3 months,and 6 months after surgery to observe the presence of residual shunt,aortic valve regurgitation,and cardiac electrical conduction abnormalities.Results:Transcatheter closure was successful in 15 patients,procedure failed in one patient due to the unstable fixation of the occluder.Average diameter of the defect is(4.37±1.53)mm,and the diameter of the occluder is 6.5(6.0,8.0)mm.Postoperative left ventricular angiography showed minimal residual shunt in 3 cases,and no complications such as pericardial tamponade,hemolysis,thromboembolism,or infection,were observed.At one month after occlusion,TTE results showed that residual shunt disappeared in 3 patients with residual shunt.During 3-month and 6-month follow-up,all the occluders were well-positioned with no new aortic valve regurgitation or worsening of the original regurgitation,and no atrioventricular block or bundle branch block and other electrocardiographic conduction abnormalities.Conclusions:The use of eccentric occluder for intervention of ventricular septal defect patients without distance from the aortic valve is safe and effective.

Objective:To screen the optimal machine learning model for predicting the recurrence condition of hepatocellular carcinoma (HCC) at different time points post-surgery, based on the cutoff value of the Ki67 positive proliferation index condition calculated from recurrence-free survival and combined with various clinical features.Methods:retrospective study included initially treated patients with solitary HCC who underwent radical surgery at the Fifth Medical Center of the PLA General Hospital from January 2013 to March 2023. Data included general clinical data, preoperative laboratory parameters, and surgical pathology information about the subjects. The postoperative recurrence status was assessed by querying the medical record system or by telephone follow-up. The Ki67 positive index cutoff value was determined by the X-tile software based on the patient's recurrence-free survival status and time analysis. Survival rates were calculated using the Kaplan-Meier method, and survival curves were plotted. The study population was randomly divided into training and testing groups in a 7:3 ratio using a computer-generated random number method. The minimum redundancy maximum relevance (mRMR) method was used for feature variable selection. Predictive models for postoperative HCC recurrence conditions in patients with HCC were constructed using random forest, support vector machine, logistic regression, and gradient boosting decision tree machine learning algorithms. Inter-group comparisons for continuous data were performed using the t-test or Mann-Whitney U test. Inter-group comparisons of enumeration data were performed using the Pearson χ2 test, continuity-corrected χ2 test, or Fisher's exact test. Results:The cutoff values for the Ki67 positivity index were 0.3 and 0.5 in 510 cases, with a follow-up time ranging from 1.2 to 11.4 years (median: 6.2 years). The recurrence-free survival time was between 1 and 135 months (median: 32 months), with recurrence-free survival rates post-surgery at 1, 2, 3, and 5 years were 87.5%, 77.1%, 61.2%, and 54.5%, respectively. The top five variables predicted HCC recurrence and non-recurrence conditions following surgical follow-up at 6 months, 1 year, 2 years, and beyond 2 years, in accordance with information obtained by the mRMR screen out. The Ki67 positivity index screened a successfully constructed machine learning model to predict HCC recurrence and non-recurrence conditions following surgical follow-up at 6 months, 1 year, 2 years, and beyond 2 years. The machine learning model based on the gradient boosting decision tree algorithm had the best prediction performance among them (areas under the receiver operating characteristic curves for predicting HCC recurrence within six months in the training and validation sets were 0.996 and 0.946, and accuracies were 0.972 and 0.935, respectively).Conclusion:A machine learning model was successfully constructed using the Ki67 positivity index combined with four readily available clinical features to predict HCC recurrence. The machine learning model based on the gradient boosting decision tree algorithm demonstrated the best performance in terms of predicting HCC recurrence within six months after surgery.

Objective:To investigate the efficacy and safety of oral testosterone therapy in individuals diagnosed with androgen insensitivity syndrome (AIS).Methods:A self-controlled study design was utilized, focusing on individuals with AIS who were genetically diagnosed at the Department of Endocrinology, Genetics, and Metabolism of Beijing Children′s Hospital between 2009 and 2021. These patients underwent treatment involving the administration of testosterone. The primary observed indexes include the measurement of penis length, which should meet the minimal surgical standard (penis length≥2.5 cm) or greater than or equal to -2.5 s (lower limit of normal). Secondary observed indexes include penile length standard deviation score (PL-SDS), an increase in penis longitude (ΔPL), medication dosage, the course of therapy, and safety indicators, among others. There were 4 courses of treatment. After each course, patients were evaluated to determine whether termination of treatment was appropriate. Patients who exhibited inadequate post-treatment penile length growth were advised to continue with further treatment. The statistical methodology included t-test, and a Wilcoxon rank sum test to describe efficacy and safety. The patients were followed up until 2023. Results:The study comprised a total of 51 individuals with AIS, comprising 33 males and 18 females (gender of registered permanent residence). Among these patients, 10 were diagnosed with complete androgen insensitivity syndrome (CAIS) and 41 were diagnosed with partial androgen insensitive syndrome (PAIS). There were 2 children with CAIS were diagnosed by doctors and prescribed testosterone undecanoate, but the children did not really take medicine.The penile length of CAIS patients could not be measured (penile length<0.5 cm) before and after treatment. For PAIS patients, baseline penile length and PL-SDS were (2.3±0.6) cm and -3.7±1.3, respectively. The measurements for penile length and PL-SDS after each treatment course were recorded as follows: (2.7±0.8), (2.8±0.6), (2.6±0.4), (2.6±0.4) cm and -2.8±1.6, 2.5±1.6, 2.9±1.2, -3.2±0.9, respectively. Both penile length and PL-SDS interventions showed statistically significant gains when compared to the baseline performance of the 4 courses ( t=4.05、3.56、2.55、2.23 and 3.88、3.50、2.50、2.19, all P<0.05). Before treatment, 13 PAIS patients (32%) reached 2.5 cm and seven (17%) reached greater than or equal to -2.5 s. Following the initial, subsequent, third, and fourth therapeutic interventions, 18 cases (44%), 24 cases (59%), 25 cases (61%), and 26 cases (63%) reached 2.5 cm, respectively. Additionally, A total of 12 cases (29%), 15 cases (37%), 20 cases (49%), and 21 cases (51%), respectively, were found to reach greater than or equal to -2.5 s. The study involved the longitudinal monitoring of patients with the highest recorded age being 13.7 years. The weight, height, body mass index, bone age/age, cholesterol, hemoglobin and so on were all within the normal range and the difference were not statistically significant (all P>0.05). All 49 patients were no abnormalities in blood electrolyte, liver and kidney function and thyroid function and no changes in precocious puberty, pubic hair growth, aggressive behavior, vulvar skin darkening, diarrhea or other conditions. Conclusions:Testosterone undecanote in children with CAIS was no effective. The initial course of treatment for patients with PAIS demonstrates observable enhancements in penile length and PL-SDS. For patients with inadequate penile length growth, continued treatment in subsequent courses (such as the second, third, and fourth courses) is recommended toenhance outcomes gradually. Testosterone undecanoate was safe and effective for the majority of individuals with PAIS patients, with few adverse effects and good treatment tolerance.

Objective:To summarize long-term clinical follow-up results of segment instability between the upper instrumented vertebra (UIV) and the adjacent upper vertebra (UIV+1) and to establish the optimal timing for surgery for UIV+1.Methods:A retrospective analysis was conducted on 265 patients with lumbar degenerative diseases who underwent transforaminal lumbar interbody fusion (TLIF) surgery at the Department of Spinal Surgery, Zhongda Hospital, from January 2014 to December 2018. The cohort included 119 male and 146 female patients, with an average age of 64.93 years (range: 32-86 years). Preoperative dynamic imaging measured sagittal angulation (SA) and sagittal translation (ST) of the UIV+1/UIV segment. Patients with SA>10° or ST>2 mm were categorized into the unstable group, further divided into the unstable non-fusion group and the unstable fusion group based on whether UIV+1 expansion fusion was performed. The remaining patients were classified into the stable group. Imaging indicators, Visual Analogue Scale (VAS) scores, Oswestry disability index (ODI) scores, and Japanese Orthopaedic Association (JOA) scores were compared among the groups, with JOA improvement rates calculated to assess clinical efficacy. Pearson correlation coefficient analysis was employed to examine correlations between preoperative imaging indicators and final follow-up JOA improvement rates. Receiver Operating Characteristic (ROC) curves and the maximum Youden index were utilized to determine thresholds for preoperative SA and ST.Results:The follow-up duration for all patients was 73.53±12.92 months (range: 61-108 months). The stable group (124 cases) included 61 males and 63 females, aged 64.31±9.83 years (range: 44-82 years). The unstable non-fusion group (59 cases) included 22 males and 37 females, aged 65.76±11.01 years (range: 32-86 years). The unstable fusion group (82 cases) included 36 males and 46 females, aged 65.26±8.68 years (range: 47-80 years). At the last follow-up, the unstable non-fusion group exhibited ΔSA 0.90°±1.97° and ΔST 0.77±1.27 mm, both significantly higher than the stable group's ΔSA 0.25°±1.57° and ΔST 0.34±0.34 mm ( t=3.564, P<0.001; t=2.311, P=0.022). Clinical improvements were lower in the unstable non-fusion group compared to the other two groups: VAS (2.28±0.83), ODI (5.91%±3.46%), JOA (24.11±1.78), with a JOA improvement rate of 60%. The stable group showed VAS (1.51±0.69), ODI (3.71%±1.75%), JOA (27.33±1.91), with a JOA improvement rate of 83%. The unstable fusion group had VAS (1.46±0.83), ODI (3.46%±1.81%), JOA (26.48±1.66), with a JOA improvement rate of 78%. These differences were statistically significant ( F=32.117, P<0.001; F=24.827, P<0.001; F=92.658, P<0.001; F=93.341, P<0.001). The JOA improvement rate was negatively correlated with preoperative SA ( r=-0.363, P<0.001) to a low extent, and with preoperative ST ( r=-0.596, P<0.001) to a moderate extent. ROC curve analysis determined the preoperative SA threshold as 11.5° and the preoperative ST threshold as 1.85 mm. Conclusion:Pre-existing instability of the responsible segment UIV and UIV+1 (SA>10° or ST>2 mm) may worsen during long-term follow-up after TLIF. When preoperative SA exceeds 11.5° and ST exceeds 1.85 mm between UIV and UIV+1, performing an extended fusion involving UIV+1 can ensure surgical efficacy over long-term follow-up.

With an aging population, the incidence of osteoporotic vertebral fractures (OVFs) is on the rise, posing new challenges for developing personalized treatment strategies. For patients who do not respond to conservative treatment, percutaneous vertebroplasty or percutaneous kyphoplasty (PVP/PKP) remains the preferred surgical option due to its minimal invasiveness and rapid recovery time. However, progressive local kyphosis (PLK) is one of the most severe complications following PVP/PKP, with an incidence rate of 1.5%-25.8%. PLK often presents with recurring thoracic and lower back pain, and in severe cases, spinal stenosis, causing symptoms like numbness and pain in the lower limbs. The severity of PLK varies, and treatments can range from conservative management and bone cement reinforcement to internal fixation or osteotomy. Current studies suggest that re-fracture of the affected vertebra, intervertebral disc degeneration, and osteonecrosis may be underlying mechanisms. These conditions shift the axial load forward, promoting postoperative PLK, which tends to progress over time. Postoperative PLK is closely associated with patient characteristics, fracture details, surgical factors, and post-surgery osteoporosis management. 1) The severity of osteoporosis, as indicated by the T-score from bone mineral density testing, can help predict postoperative PLK. While factors like age and gender influence osteoporosis severity, no direct relationship has been established between these factors and PLK. 2) Thoracolumbar fractures, old nonunion fractures, endplate fractures, or severe preoperative compression changes with kyphosis can increase PLK risk. Surgical factors, including the use of balloons or implants and the distribution of bone cement, also play a role. Personalized treatment plans should be developed based on the patient's general condition and imaging results to ensure adequate bone cement diffusion, as enhanced integration can reduce PLK risk. 3) Postoperative anti-osteoporosis therapy is also crucial; long-term therapy, particularly with teriparatide, can prevent PLK. Recognizing the related risk factors and establishing predictive models can help clinicians tailor treatments. Machine learning models, utilizing big data, are particularly adept at handling complex interrelated risk factors and may provide a powerful tool for personalized treatment in the future.

Objective To investigate the mechanism of the preventive effect of alum-borneol nanoemulsion on hypertrophic scars by observing its effect on cAMP-response element-binding protein 3-like 1(CREB3L1)and inflammatory damage in hypertrophic scar tissues of rabbit ear.Methods Thirty New Zealand big-eared white rabbits were randomly divided into blank group,model group,alum-borneol nanoemulsion low-,medium-,and high-dose groups(8.15,16.3,and 32.6 mg·mL-1),and asiaticoside group.The animal model was established by thermal injury.Topical application of appropriate drugs was given on the 14th day after successful modeling of deep Ⅱ-degree burns.Equal amounts of saline were applied externally to the blank and model groups twice daily and administered continuously until the 35th day.Histopathological changes in rabbit ear scar tissue were observed by hematoxylin-eosin(HE)staining.Masson staining was used for collagen deposition in scar tissue.Coexpression of CREB3L1/alpha-smooth muscle actin(α-SMA)in rabbit ear scar tissue was detected by immunofluorescence double-labeling assay.Enzyme-linked immunosorbent assay(ELISA)was applied for the detection of interleukin-6(IL-6)and interleukin-10(IL-10)in scar tissue.Real-time fluorescence quantitative polymerase chain reaction(Real-time PCR)was applied for the detection of CREB3L1,Collagen Type I(COL-Ⅰ),Collagen Type Ⅲ(COL-Ⅲ),and α-SMA mRNA expression.Protein expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA was detected by protein immunoblotting analysis(Western Bolt).Results Compared with the blank group,the scar proliferation index of the model group was significantly increased(P<0.01).Pathologic changes including the thickening of the dermis,the formation of dense reticular fibers,and accompaniment of inflammatory cell infiltration were observed.Masson staining reveals thickening of the dermis,disordered arrangement and large deposits of blue-stained collagen fibers.Double-labeling immunofluorescence results showed that positive expression of CREB3L1 and α-SMA in scar tissue increased.IL-6 levels were significantly increased(P<0.01),while IL-10 levels were significantly decreased(P<0.01).The relative mRNA expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA in the scar tissue of rabbit ear was significantly increased(P<0.01).The protein expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA was significantly increased(P<0.01).Compared with the model group,the scar proliferation index was significantly decreased after the treatment of medium-,high-dose of alum-borneol nanoemulsion and asiaticoside(P<0.01,P<0.05,P<0.01).Pathologic changes including the thinning of the dermis,as well as varying degrees of reduction of inflammatory cells and blue-stained collagen fibers were found.Double-labeling immunofluorescence showed positive expression of CREB3L1 and α-SMA in scar tissue decreased.IL-6 levels significantly reduced(P<0.01),while IL-10 levels significantly raised(P<0.01).The alum-borneol nanoemulsion medium-,high-dose and asiaticoside groups could significantly down-regulate the mRNA expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA(all P<0.01),and reduce the protein expression of CREB3L1,COL-Ⅰ,COL-Ⅲ,and α-SMA(P<0.05,P<0.01).Conclusion Alum-borneol nanoemulsion may prevent hyperplastic scar formation by regulating the expression of CREB3L1 and related fibrotic proteins and reducing inflammatory level,which enriches the scientific connotation of"prevention of disease from exacerbating"and"treatment of the disease before its onset"in Chinese medicine.

Ex vivo culture-amplified mesenchymal stem cells (MSCs) have been studied because of their capacity for healing tissue injury. MSC transplantation is a valid approach for promoting the repair of damaged tissues and replacement of lost cells or to safeguard surviving cells, but currently the efficiency of MSC transplantation is constrained by the extensive loss of MSCs during the short post-transplantation period. Hence, strategies to increase the efficacy of MSC treatment are urgently needed. Iron overload, reactive oxygen species deposition, and decreased antioxidant capacity suppress the proliferation and regeneration of MSCs, thereby hastening cell death. Notably, oxidative stress (OS) and deficient antioxidant defense induced by iron overload can result in ferroptosis. Ferroptosis may inhibit cell survival after MSC transplantation, thereby reducing clinical efficacy. In this review, we explore the role of ferroptosis in MSC performance. Given that little research has focused on ferroptosis in transplanted MSCs, further study is urgently needed to enhance the in vivo implantation, function, and duration of MSCs.
Humans ; Antioxidants/metabolism* ; Ferroptosis ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells ; Iron Overload/metabolism*