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Software bug repair is a problem that cannot be ignored in the process of software life.How to efficiently assign software bugs automatically is a very important research direction.Now,the existing research methods mainly focus on the bugreport’s text content or the low-level information of the developers’ tossing network,while ignoring the high-level topology information in the tossing network.Therefore,this paper proposes a software bug automatic assignment model MFD-GCN based on the developers’ multivariate features.Model fully considers the high-level topological features in the developers’ tossing network,and uses the powerful network feature extraction capabilities of graph convolution network to fully mine the multivariate features that represent developers’ deep cooperation relationship and fixing preferences,and train the classifier together with the bug text features.The proposed method is evaluated on two large open-source software projects,i.e.,Eclipse and Mozilla.Expe-rimental results show that compared with the mainstream bug-assignment methods proposed in recent years,the MFD-GCN mo-del has achieved state-of-art results in recommending the top K developers.The accuracy rate of top-1 recommendation on the Eclipse and Mozilla project reaches 69.8% and 59.7%,respectively.

In order to improve the friction and wear properties of 20CrNiMo carburized steel, the cryogenic treatment was carried out on it for different durations and different cycles. The changes of microstructure, hardness and impact toughness before and after cryogenic treatment were analyzed by means of scanning electron microscope and Rockwell hardness tester. The friction and wear properties of samples before and after cryogenic treatment were compared and investigated by friction and wear testing machine. Results showed that the cryogenic treatment had a limited effect on the surface hardness of 20CrNiMo carburized steel. The impact toughnesses of the samples were significantly improved after cryogenic treatment, and the impact toughness was the highest when the sample was treated with a single cycle of 6 h cryogenic treatment, which was increased by 10.9% compared with the un - cryogenic sample (QT). The average friction coefficient and relative wear rate of cryogenic samples were significantly reduced. The samples treated with a single cycle of 6 h cryogenic treatment and 3 cycles of 3 h cryogenic treatment had better friction and wear properties, and the average friction coefficient were 0.50 and 0.52 respectively. Compared with the QT samples, the wear rates were reduced by 25.9% and 23.3% respectively.

In order to enhance the UV absorption characteristic of epicatechin derivatives and improve their solubility in non-polar solvents such as oils and fats, 2,2'-di(p-hydroxybenzocarbonyl)-epicatechin was synthesized from epicatechin and p-hydroxybenzoic acid using methane sulfonic acid as solvent and catalyst. The target products were separated by column chromatography, and the purity was verified by high performance liquid chromatography (HPLC), and the structure of the target products were verified by UV-vis, FT-IR, ¹H NMR, 13C NMR, LC-MS spectroscopy. The UV absorption characteristic of 2,2'-di(p-hydroxybenzocarbonyl)-epicatechin and its ability to scavenge ABTS+·, DPPH· and O2-· were evaluated. The results show that the synthesized 2,2'-di(p-hydroxybenzocarbonyl)-epicatechin had similar UV absorption and comparable molar absorptivity to OMC, the commonly used UV absorber, and is expected to be an excellent UV absorber in the UVB band. 2,2'-di(p-hydroxybenzocarbonyl)-epicatechin had good antioxidant activity in vitro, and its antioxidant capacity in vitro was higher than that of VC and slightly lower than that of epicatechin, which is expected to be used for cosmetic applications. [ABSTRACT FROM AUTHOR]

In order to study the marginal effect of Lycopersicon esculentum var. cerasiforme in the greenhouse cultivation, by using the cherry tomato Huangfei inbred line as the material, the main agronomic traits such as the plant height, leaf size, stem diameter, internode length and fruit size were investigated and analyzed. The results showed that the plants planted in the east and middle of the greenhouse were generally higher, and the plant height in the south was higher than that in the north. The plant leaves planted in the east and middle of the greenhouse were generally larger, while the stem diameter of plants planted in the east was larger than that in the west, and similar in the north and south. The plant internodes planted in the west of the greenhouse was longer than those in the east, and the plant internodes in the north and south of the greenhouse were shorter than those in the middle. The fruit was slightly longer overall, but rounder in the middle than at the edges. The results showed that the tomato plants grew better in the east, south and middle areas of the greenhouse, and the marginal effect of cherry tomato in the north and south of the greenhouse was significantly greater than that in the east and west, while the internode length of the plants growing in the west and middle areas was greater than that in the east. [ABSTRACT FROM AUTHOR]

Background Brain-derived neurotrophic factor (BDNF) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). MicroRNA (miRNA)-132, which is widely expressed in neurons, is involved in BDNF-mediated neural development by regulating the expression of target gene. This study aims to investigate the effect of miRNA-132 on BDNF and its neuroprotective effect. Methods The hippocampal neurons were transfected by miRNA-132 after 72 h in vitro, then exposed to amyloid β-protein (Aβ) on the 7th day to build AD models. The difference of miRNA-132 expression between AD group and control group was detected by real-time fluorescent quantitative polymerase chain reaction (PCR). The alterations of BDNF mRNA were observed in the neurons of different groups. Finally, the cell viability was observed by methyl thiazolyl tetrazolium (MTT) assay in AD neurons transfected with miRNA-132 or incubated with BDNF. Results 1) MiRNA-132 was significantly decreased (t = 13.888, P = 0.000), and the expression of BDNF mRNA was also reduced in AD group (t = -12.274, P = 0.000). 2) Green fluorescence was clearly visible by inverted phase-contrast fluorescence microscopy after transfected with miRNA-132. BDNF mRNA was upregulated when miRNA-132 overexpression both in control group (t = 16.135, P = 0.000) and AD group (t = 8.656, P = 0.000). 3) Cell viability was obviously decreased in neurons exposed to Aβ (t = -6.023, P = 0.000), which was improved when transfected with miRNA-132 (t = 3.385, P = 0.007) or incubated with BDNF (t = 3.672, P = 0.004). Conclusions The expression of miRNA-132 and BDNF was reduced in neuronal AD model. MiRNA-132 played an important role on neuroprotection against A β-induced neuronal damage via upregulation of BDNF. It could be expected to provide new perspective for the diagnosis and treatment of AD. DOI: 10.3969/j.issn.1672-6731.2016.07.009

Mammalian genomes encode numerous natural antisense transcripts (NATs). These antisense transcripts are now recognized as an important component of molecular mechanisms involved in the regulation of gene expression. NATs are particularly prevalent in the mammalian nervous system. The importance of NATs in the normal functioning of nervous system is becoming increasingly evident. They are not only involved in neuronal differentiation, myelination and ion channel regulation, but also in advanced cognitive processes, such as synapse plasticity and memory formation. This paper focuses on the potential involvement of NATs in various neurodegenerative disorders. DOI: 10.3969/j.issn.1672-6731.2015.03.014

Background Catechol-O-methyltransferase (COMT) has a key function in the degradation of catecholamines and inactivating estrogen. A common polymorphism in the COMT gene is guanine-adenine (G-A) point mutation on rs4680, which causes a valine (Val) substitution to methionine (Met) in 108 and (or) 158 amino acid by this gene and is responsible for lowered activity of the enzyme. The Val/Met polymorphism has been recognized to be associated with psychiatric disorders, alcohol dependence and drug side effects, but few study has been done to examine the relationship with cerebral infarction (CI). The objective of this study is to investigate the relationship between the polymorphisms of COMT gene and CI. Methods The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect COMT Val158Met genotype in 181 CI patients and 148 cases of controls. Meanwhile the serum levels of glucose, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB) and ApoA in CI group were detected. Results The frequency of Val allele (78.45%) and Val/Val genotype (61.33%) in CI was significantly higher than that in the control group (68.24% and 45.95%, P < 0.05). Further analysis showed the frequency of Val allele in CI was significant higher in men (82.52% vs 66.67%, P < 0.01), but not in women (69.83% vs 69.07%, P > 0.05) than that in the control group. The serum levels of glucose, TC, TG, LDL-C, HDL-C, ApoB, ApoA and the frequency of hypertension had no difference between Val/Val genotype and Val/Met + Met/Met genotypes (P > 0.05, for all). Conclusion The frequencies of Val allele and Val/Val genotype can be considered as genetic risk factors of male CI patients. The effect of COMT on CI is not related to blood pressure, serum lipid and glucose.

Heterogeneous information network based recommendation methods have been a research focus in current data mining field. However, most of the traditional HIN-based recommendation methods exist sparse inconsistency and lack of interpretability, which cannot adequately explore the user's potential preference features and effectively integrate features. Therefore, the paper proposes an attention preference recommendation method with Fusing Heterogeneous Information Network Embedding (named as MFFHINE). Symmetric meta path is apt at characterizing the semantic relationships between objects, hence the network embedding method based on random walks on each symmetric meta path is designed to learn preference features of users. Then the preference weights fusion strategy based on attention mechanism is considered to fuse these learned preference features and then integrate them into the extended matrix factorization model. In this way, the matrix factorization model and the fusion function are jointly optimized to perform the score prediction task. Finally, compared with other benchmark algorithms on Douban and Yelp real large- scale datasets, the algorithm experiments analyze on the training set ratio, meta path settings, latent factor dimensions. Experimental results show that the proposed MFFHINE has been improved more significantly than the state of art algorithms. [ABSTRACT FROM AUTHOR]

Interictal regional positron emission tomography (PET) hypermetabolism often causes confusion in the localization of epileptogenic zone. It is of practical importance to make right interpretation. This article reviews previous literatures and analyzes possible mechanisms of interictal PET hypermetabolism, such as frequent epileptiform discharges, compensatory activities, excitotoxicity, etc. Besides, the prevalence and possible mechanisms of interictal regional PET hypermetabolism in some specific epileptic syndromes or diseases are also reviewed. This helps to summarize the value of interictal PET hypermetabolism in presurgical evaluation under different clinical backgrounds, and also implies comprehensive analysis with underlying etiology and other clinical information is necessary to aid the clinical practice. [ABSTRACT FROM AUTHOR]

Taking Quercus mongolica population in the secondary forest of Q. mongolica as the research object, two plots in different stages of succession (A and B) were set up in Tazigou Forest Farm of Wangqing Forestry Bureau, Jilin Province. By applying the method of adjacent grid survey, each plot was divided into 100 units of 10 mx10 m and the spatial coordinates of each tree in the unit were accurately located to survey all the basic information of trees with diameter at breast height (DBH) ≽ 1 cm. The degree, composition, scale and pattern of spatial heterogeneity of individual tree of Q. mongolica were analyzed by means of semi-variance function and fractal dimension of geostatistics. By using Kriging interpolation method, unbiased estimation of tree attribute with spatial autocorrelation was carried out, distribution map was drawn and spatial distribution pattern was analyzed. The results showed that the best semi-variance function of tree attributes in two plots was mainly distributed in an exponential model and a spherical model with an aggregated distribution. The degree of spatial autocorrelation and continuity of plot A were higher than that of plot B. The DBH and the east-west crown (CEW) had strong spatial heterogeneity and autocorrelation in the two plots. The tree attributes of both plots showed strong spatial heterogeneity in the north-south direction. In addition, there was strong spatial heterogeneity in the northwest-southeast direction of plot A and in the northeast-southwest of plot B. The strength of the spatial heterogeneity was higher and the scale being larger in plot A. The variations of DBH and CEW were obvious in plot A, while the variations of CEW and south-north crown (CSN) were obvious in plot B. The fractal dimension and semi- variogram function showed the same result. The tree attributes of plot A were mainly patchy and stripe, and the variation trend of spatial distribution pattern was obvious. The tree attributes of plot B was broken, with complex pattern. Those results indicated that the characteristics of population, community development, spatial scale and spatial horizontal direction might affect the spatial pattern of populations. The geostatistical analysis method is helpful to quantitatively and directly describe population growth and development trend, which can provide a theoretical basis for the sustainable management of Q. mongolica secondary forests in Northeast China. [ABSTRACT FROM AUTHOR]

Objective: To explore the clinical characteristics of a child with early-onset infantile epileptic encephalopathy type 8 associated with synonymous variant of ARHGEF9 gene., Methods: Clinical data of the patient was summarized. The child and his parents were subjected to trio-whole exome sequencing., Results: The child has presented with global developmental delay, epilepsy, impulsive behavior, hypersensitivity to sound, and mental retardation. He was found to harbor a de novo synonymous variant c.741C>T (p.Cys247Cys) of the ARHGEF9 gene. RNA splicing analysis confirmed that the variant has led to abnormal splicing of exon 5, resulting in a 55-bp deletion., Conclusion: The clinical features of ARHGEF9 gene-related early-onset infantile epileptic encephalopathy type 8 includes mental and motor developmental delay, epilepsy, auditory allergy, and hyperactivity impulsivity. For synonymous variant, in vitro study and transcriptional experiment may be carried out to evaluate its functional and splicing effect. Above finding has enriched the phenotypic and genotypic spectrum of the ARHGEF9 gene.

It was pointed out in Opinions on Promoting the Inheritance, Innovation and Development of Traditional Chinese Medicine issued by the State Council in 2019 that 100 varieties of traditional Chinese medicine(TCM) with unique curative effects should be screened out within about three years. Due to the multi-component and multi-target mechanisms of TCM varieties, it is difficult to directly and simply evaluate their multi-dimensional clinical value using methods applicable to chemical or biological agents. The heterogeneity of outcomes for similar TCM makes it difficult to determine the advantages of similar products. The fuzzy comprehensive evaluation method that is developed on the basis of core outcome set and fuzzy mathematics for clinical efficacy evaluation of TCM may solve these problems. This study developed a fuzzy comprehensive evaluation model for the clinical efficacy evaluation of Chinese patent me-dicines for coronary heart disease and angina pectoris, and selected the previous normative studies with complete or incomplete data for verifying the model application. The results showed that original studies with complete data failed to evaluate and compare the comprehensive efficacy of different interventions. The original research only mentioned the advantages and disadvantages of different interventions in different aspects. The comprehensive clinical efficacy of three different interventions obtained through fuzzy comprehensive evaluation was all graded as level Ⅱ. The original research with incomplete data drew the same conclusions as the fuzzy comprehensive evaluation, and the results of fuzzy comprehensive evaluation can provide more comprehensive information. Therefore, the fuzzy comprehensive evaluation shows the products with overall advantages of clinical efficacy, which may become a feasible method for the screening of TCM.

Extreme weather/climate events increased significantly because of global warming. Based on daily records from 16 meteorological stations in the Poyang Lake Basin (PLB) from 1959 to 2019, we comprehensively investigated the temporal-spatial and non-stationarity characteristics of extreme precipitation from three dimensions (intensity, frequency and duration) using PreWhite-ning Mann-Kendall (PWMK), extreme-point symmetric mode decomposition method (ESMD) and the generalized additive models for location, scale and shape (GAMLSS). The results showed that the intensity and frequency of extreme precipitation increased significantly in the PLB, while the duration of extreme precipitation decreased from 1959 to 2019. The extreme precipitation had features of high intensity, high frequency, and short duration in the PLB. There was a clear distinction between flood season and non-flood season for extreme precipitation. Extreme precipitation was concentrated in the northern and central PLB during the flood season and in the central PLB during the non-flood season. The increasing trend of extreme precipitation amount was 2.10 mm·a -1 in the Xinjiang basin, which had the largest increment over the PLB. In the flood season, the extreme precipitation had longer duration but weaker intensity and smaller range, contrasting with the status during the non-flood season. The intensity and frequency of extreme precipitation showed stationarity characteristics in the PLB. However, the duration of extreme precipitation showed non-stationarity characteristics. With the continuous increase of extreme precipitation amount, the risk of related disasters would increase.

Biomass conversion and expansion factors (BCEFs) are important parameters for estimating carbon storage in forest biomass. Clarifying the source of differences in estimating BCEFs could reduce uncertainties in forest biomass carbon estimation. The decision tree models of ensemble learning can be used to properly figure out the source of differences in estimating BCEFs. However, the comparison of different decision tree models for analyzing differences in estimating BCEFs has never been reported. In this study, three models [the boosted regression trees (BRT), random forest(RF), and Cubist] and data of 331 masson pine plots from the 8 th Chinese National Forest Inventory for Fujian Province were used to analyze the differences in estimating BCEFs (including above- and below-ground). The results showed that BCEFs were following right-skewed distribution, with the mean, minimum and maximum value being 0.69 t·m -3 , 0.67 t·m -3 and 0.71 t·m -3 , respectively. All three models performed well in BCEFs prediction and fitting, and could explain more than 92.8% variations of BCEFs. All three models showed that average DBH and volume were the top two highest relative importance predictors. BCEFs decreased with the increases of average DBH and volume. Stand characteristics factors, such as average DBH, volume, average age and average height, had great influence on BCEFs. Both soil factors and topographic factors had little influence on BCEFs. Using a few variables (such as average DBH, volume, average age and avera-ge height) which contained more BCEFs prediction information could have preferable forecasting precision when building BCEFs models. Moreover, widely representative samples with different average tree ages, average DBH and volume should be chosen to calculate BCEFs when applying constant BCEFs.

Model based on vegetation ecophysiological process contains many parameters, and reasonable parameter values will greatly improve simulation ability. Sensitivity analysis, as an important method to screen out the sensitive parameters, can comprehensively analyze how model parameters affect the simulation results. In this paper, we conducted parameter sensitivity analysis of BIOME-BGC model with a case study of simulating net primary productivity (NPP) of Larix olgensis forest in Wangqing, Jilin Province. First, with the contrastive analysis between field measurement data and the simulation results, we tested the BIOME-BGC model' s capability of simulating the NPP of L. olgensis forest. Then, Morris and EFAST sensitivity methods were used to screen the sensitive parameters that had strong influence on NPP. On this basis, we also quantitatively estimated the sensitivity of the screened parameters, and calculated the global, the first-order and the second-order sensitivity indices. The results showed that the BIOME-BGC model could well simulate the NPP of L. olgensis forest in the sample plot. The Morris sensitivity method provided a reliable parameter sensitivity analysis result under the condition of a relatively small sample size. The EFAST sensitivity method could quantitatively measure the impact of simulation result of a single parameter as well as the interaction between the parameters in BIOME-BGC model. The influential sensitive parameters for L. olgensis forest NPP were new stem carbon to new leaf carbon allocation and leaf carbon to nitrogen ratio, the effect of their interaction was significantly greater than the other parameter' teraction effect.

The safety of Chinese patent medicine has become a focus of social. It is necessary to carry out work on post-marketing clinical safety evaluation for Chinese patent medicine. However, there have no criterions to guide the related research, it is urgent to set up a model and method to guide the practice for related research. According to a series of clinical research, we put forward some views, which contained clear and definite the objective and content of clinical safety evaluation, the work flow should be determined, make a list of items for safety evaluation project, and put forward the three level classification of risk control. We set up a model of post-marketing clinical safety evaluation for Chinese patent medicine. Based this model, the list of items can be used for ranking medicine risks, and then take steps for different risks, aims to lower the app:ds:risksrisk level. At last, the medicine can be managed by five steps in sequence. The five steps are, collect risk signal, risk recognition, risk assessment, risk management, and aftereffect assessment. We hope to provide new ideas for the future research.

Objective: To assess the efficacy and safety of Xuebijing injection for the treatment of severe acute pancreatitis ( SAP )., Methods: An extensive search of related literatures from the Cochrane Library, EMBASE, China Biology Medicine ( CBM ), CNKI, VIP and Wanfang data up to March 2014 was performed. Randomized controlled trials ( RCTs ) regarding Xuebijing injection for the treatment of SAP were collected regardless of languages. Jadad scale was taken for quality evaluation of the included studies by two researchers. The patients in control group were given conventional treatment, and those of the Xuebijing group were given Xuebijing injection on the top of conventional treatment. The Cochrane Collaboration RevMan 5.2 software was used for data analysis regarding the effect of Xuebijing injection on the mortality, incidence of complication, effective rate, the length of stay in hospital, and the safety of the drug in patients with SAP., Results: A total of 15 published reports meeting the inclusion criteria were enrolled. The methodological quality of the trials was low. Meta analysis showed that the mortality in Xuebijing group was significantly lower [ odds ratio ( OR ) = 0.37, 95% confidence interval ( 95%CI ) = 0.17 - 0.77, P = 0.008 ], and the incidence of complication was also significantly decreased ( OR = 0.26, 95%CI = 0.14 - 0.45, P < 0.000 01 ) as compared with those of control group. The effective rate in Xuebijing group was significantly higher than that of the control group [ relative risk ( RR ) = 0.85, 95%CI = 0.80-0.91, P < 0.000 01 ]. The length of stay in hospital in Xuebijing group was significantly shorter than that of the control group [ mean difference ( MD ) = -5.28, 95%CI = -6.69 to -3.86, P < 0.000 01 ]. Adverse reactions of Xuebijing injection were reported in 2 studies. The adverse reaction in one study was headache and nausea, which were relieved by adjusting the speed of intravenous infusion, and mild rash was reported in another case, and it disappeared after the withdrawal of Xuebijing., Conclusions: The currently available evidence shows that Xuebijing injection may have some therapeutic effect on SAP. Because of the low methodological quality of the included trials, multi-center and high-quality RCTs with large sample sizes are needed to provide stronger evidence.

Objective: To develop a detection method of the third-stage larvae of Angiostrongylus cantonensis by real-time PCR and high-resolution melt curve analysis., Methods: A pair of specific primers was designed based on the internal transcribed spacer 1 (ITS1) region of the nuclear ribosomal DNA of A. cantonensis. The third-stage larvae of A. cantonensis were detected by real-time PCR and high-resolution melt curve analysis. The specificity of the method was analyzed by testing DNAs of A. cantonensis, Clonorchis sinensis, and Gnathostoma spinigerum. The genomic DNA were extracted from 1 to 10 third-stage larvae of A. cantonensis, respectively, and used to identify the sensitivity of the method., Results: This method could specifically detect A. cantonensis and the detection limit reached to one larva. No amplification curve and melt curve were found in C. sinensis and G. spinigerum., Conclusion: Real-time PCR and high-resolution melt curve analysis show good specificity and sensitivity for detecting the third-stage larvae of A. cantonensis.

The sodium tetraphenylboron has the fluorescence quenching effect on rhodamine B, making the fluorescence signal intensity weaken or even disappear. But cetirizine dihydrochloride has the anti-quenching effect on rhodamine B--the fluorescence signal is enhanced, and there was a linear relationship between the fluorescence signal enhancement degree and drug concentration. In the present paper, 491 and 610 nm were chosen as the excitation and emission wavelength for measurement of the fluorescence intensity difference deltaF = F1 - F0 of blank solution and test solution, and according to positive correlation between the value of deltaF and cetirizine hydrochloride concentration of test solution, a new method of anti-fluorescence quenching for the determination of cetirizine hydrochloride was established. The linear regression equation was deltaF = 0.727 5m - 2.357, correlation coefficient was 0.997 2, linear range was 3.50-129.3 mg x L(-1), the detection limit was 1.05 mg x L(-1) and RSD was 1.2%. The cetirizine hydrochloride tablets and cetirizine hydrochloride capsules from different manufacturers were determined by this method, the measured values were basically in line with the labeled amount of drugs, and the recovery rate was between 92% and 106%.

Objective: To study the cell surface antigen expression of orbital preadipocytes between patients with thyroid-associated ophthalmopathy (TAO) and healthy adults., Methods: Tissue culture Methods were used in the cell culture of orbital preadipocytes in patients with TAO and healthy adults. Flow cytometry was used to analyze the expression of CD29, CD44, CD49d, and HLA-DR in these 2 cells., Results: Positive expressions were examined in orbital preadipocytes of patients with TAO and healthy adults. The orbital preadipocytes of patients with TAO had a higher expression of HLA-DR than that of healthy adults., Conclusion: The orbital preadipocytes of patients with TAO and healthy adults cultured by tissue cultured Methods both belong to mesenchymal stem cells, and the former may participate in the orbital inflammation.

Objective: Pigmented villonodular synovitis(PVS) is a synovial proliferative disorder that remains a diagnostic difficulty. In this retrospective study we evaluated the diagnostic procedures, clinical symptoms and surgical treatment of PVS., Methods: Six surgically treated cases of PVS were evaluated: five of the lesions were located in the knee joint and one in the hip joint. Diagnosis of PVS was confirmed by histological examination. Operation showed characteristic findings of a joint effusion, and synovial proliferation., Results: Five cases were treated with complete open total synovectomy, and one case received arthoplasty. The followed-up period averaged 3 years and six months (rangeing from 6 months to 6 years). Excellent and good function was seen in all and there was no recurrence., Conclusion: PVS diagnosis is frequently delayed due to nonspecific symptoms. Proper treatment includes surgery: extension synovectomy for the diffuse form, and arthoplasty and total joint replacement for the severe bone involvement.