Model informed precision dosing for warfarin is to provide individualized dosing by integrating information related to patient characteristics, disease status and pharmacokinetics /pharmacodynamics of warfarin, through mathematical modeling and simulation techniques based on the quantitative pharmacology. Compared with empirical dosing, it can improve the safety, effectiveness, economy, and adherence of pharmacotherapy of warfarin. This consensus report describes the commonly used modeling and simulation techniques for warfarin, their application in developing and adjusting dosing regimens, medication adherence and economy. Moreover, this consensus also elaborates the detailed procedures for the implementation in the warfarin pharmacy service pathway to facilitate the development and application of model informed precision dosing for warfarin.

Objective:To identify the disease-causing mutation in a Chinese family with Stickler syndrome type 1.Methods:The pedigree investigation was conducted.A Chinese family with Stickler syndrome type 1 was enrolled in the Shantou International Eye Center in June 2012.Medical history collection and clinical examinations, such as vision, intraocular pressure, slit lamp microscopy and fundus, were carried out in all the included family members and the diagnosis was made by clinical experts.Total genomic DNAs were extracted from the peripheral blood samples (5 ml) obtained from 5 patients and 4 healthy members.The potential variant of the proband's father Ⅲ-5 were screened by whole exome sequencing (WES) and stepwise bioinformatic analysis.The segregation and mutation conformation of the variant was verified by Sanger sequencing.The pathogenicity of the variant was predicted by SIFT, Polyphen2, and MutationTaster.Conservation and three-dimensional structure of amino acid mutation were analyzed by multiple sequence alignment and UniProt.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Joint Shantou International Eye Center (No.EC20110310[2]-P02).Written informed consent was obtained from each subject or the guardian.Results:An autosomal dominant inherence in 39 members of 4 generations including 15 patients and 24 phenotypically normal members was found in the family.The proband (Ⅳ-4) showed high myopia, retinal detachment and strabismus in the right eye, and the left eye was blind.A patient (Ⅲ-5) showed high myopia and cataract in the right eye, atrophy in the left eye.A patient (Ⅳ-9) showed binocular high myopia.A heterozygous variation, c.1693C>T: p.Arg565Cys, within the exon 26 of COL2A1 gene was revealed in patient Ⅲ-5, which was only found in the patients and not in phenotypically normal members, indiacating co-separation in this family.The variant was predicted to be a severe damage by SIFT, Polyphen2 and MutationTaster.The amino acid mutation at position 565 was highly conservative among human, mouse, rat, bovine and Xenopus laevis, which caused the arginine to cysteine substitution at the X position in triple helix repeat region Gly-X-Y, affecting the function of fibrous protein and becoming pathogenic. Conclusions:Variant c.1693C>T: p.Arg565Cys in COL2A1 gene is disease-causing in this family and this is the first report about the variant in China.

Purpose: There is no optimal prognostic model for T-cell lymphoblastic lymphoma (T-LBL). Here, we discussed the predictive value of total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) measured on 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) in T-LBL. Materials and Methods: Thirty-seven treatment naïve T-LBL patients with PET-CT scans were enrolled. TMTV was obtained using the 41% maximum standardized uptake value (SUVmax) threshold method, and TLG was measured as metabolic tumor volume multiplied by the mean SUV. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier curves and compared by the log-rank test. Results: The optimal cutoff values for SUVmax, TMTV, and TLG were 12.7, 302 cm3, and 890, respectively. A high SUVmax, TMTV, and TLG indicated a shorten PFS and OS. On multivariable analysis, TMTV ≥ 302 cm3, and central nervous system (CNS) involvement predicted inferior PFS, while high SUVmax, TLG and CNS involvement were associated with worse OS. Subsequently, we generated a risk model comprising high SUVmax, TMTV or TLG and CNS involvement, which stratified the population into three risk groups, which had significantly different median PFS of not reached, 14 months, and 7 months for low-risk group, mediate-risk group, and high-risk group, respectively (p < 0.001). Median OS were not reached, 27 months, and 13 months, respectively (p < 0.001). Conclusion Baseline SUVmax, TMTV, and TLG measured on PET-CT are strong predictors of worse outcome in T-LBL. A risk model integrating these three parameters with CNS involvement identifies patients at high risk of disease progression.

Purpose: There is no optimal prognostic model for T-cell lymphoblastic lymphoma (T-LBL). Here, we discussed the predictive value of total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) measured on 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) in T-LBL. Materials and Methods: Thirty-seven treatment naïve T-LBL patients with PET-CT scans were enrolled. TMTV was obtained using the 41% maximum standardized uptake value (SUVmax) threshold method, and TLG was measured as metabolic tumor volume multiplied by the mean SUV. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier curves and compared by the log-rank test. Results: The optimal cutoff values for SUVmax, TMTV, and TLG were 12.7, 302 cm3, and 890, respectively. A high SUVmax, TMTV, and TLG indicated a shorten PFS and OS. On multivariable analysis, TMTV ≥ 302 cm3, and central nervous system (CNS) involvement predicted inferior PFS, while high SUVmax, TLG and CNS involvement were associated with worse OS. Subsequently, we generated a risk model comprising high SUVmax, TMTV or TLG and CNS involvement, which stratified the population into three risk groups, which had significantly different median PFS of not reached, 14 months, and 7 months for low-risk group, mediate-risk group, and high-risk group, respectively (p < 0.001). Median OS were not reached, 27 months, and 13 months, respectively (p < 0.001). Conclusion Baseline SUVmax, TMTV, and TLG measured on PET-CT are strong predictors of worse outcome in T-LBL. A risk model integrating these three parameters with CNS involvement identifies patients at high risk of disease progression.

BACKGROUND: Zinc, an inorganic antibacterial material, has a suitable degradation rate and good antibacterial property. Adding alloying elements can improve the mechanical properties and biocompatibility of the material, which is the development direction of novel medical biodegradable metal materials. There is still lack a comparable research on the antibacterial properties among zinc-based materials. OBJECTIVE: To investigate the antibacterial properties of pure zine and zinc-based alloys in vivo. METHODS: Eighty Sprague-Dawley rats, SPF grade, were randomized into two groups (n=40/group) , and all rats were injected with Staphylococcus aureus or Escherichia coli solution to prepare infection models. Different materials (Zn, ZnAl, ZnSr, Zn3 Mg, Zn3 Ag, Zn3 Ca and Zn4 Cu; five rats for each material) were implanted into the medullary cavity of femur. The control group without any material was set. At 1, 4, 7 and 14 days after implantation, the changes of body temperature, white blood cell count, serum tumor necrosis factor α and serum zinc content in rats were detected. The secretions and tissues of the surgical site were collected to identify the bacterial species. RESULTS AND CONCLUSION: (1) The body temperature in all the rats was increased to different extents after bacterial infection, but the temperature of the rats implanted with zinc and zinc alloys was always lower than that in the control group at 7 and 14 days (P < 0.05) . The temperature in the Zn3 Ag group was significantly lower than that in the other groups at 7 and 14 days (P < 0.05) . (2) The white blood cell count and tumor necrosis factor α level in the zinc and zinc alloys groups were significantly lower than those in the control group at 7 and 14 days after implantation (P < 0.05) . The white blood cell count and tumor necrosis factor α level in the Zn3 Ag group were significantly lower than those in the other groups (P < 0.05) . (3) The serum zinc content in all groups has no significant difference (P> 0.05) . (4) The bacterial culture results showed S.aureus (+) in the Staphylococcus aureus infection group and E.coli (+) in the Escherichia coli infection group. (5) To conclude, degradable zinc-based alloys exert marked antibacterial effects, and Zn3 Ag alloys have the best antibacterial activity.

Objective To develop a simple method of determination of sorafenib in serum by reversed-phase high performance liquid chromatography (RP-HPLC) and to explore its application in sorafenib therapeutic drug monitoring (TDM).Methods Sorafenib extracted by ethyl ether-petroleum (9∶1) with internal standard of erlotinib from serum was wiped off in 60 ℃ water bath.Sorafenib was redissolved by mobile buffer and analyzed by 40 μl.Chromatographic column was Symmetry Rp18 (5 μm,4.6 mm×250 mm,waters) column in normal temperature.The mobile buffer was 28 mmol/L acetate buffer (pH 5.8)-acetonitrile (37∶63).Sorafenib and erlotinib were detected in 249 nm and 335 nm,respectively.Results The concentration range of sorafenib was 0.50-20.00 μg/ml (r =0.9999).The within-day and between-day accuracies of sorafenib were less than 4.77 ％ and 8.79 ％,respectively.The average recovery rate was 98.48 ％.Sorafenib was stable in serum or after extraction.The concentrations of sorafenib in two patients were detected.Conclusion Detection of sorafenib in serum by RP-HPLC is simple and accurate,which is available to determine sorafenib in serum.The TDM of sorafenib has clinical significance.

Objective To study the diagnostic value of endoscopic retrograde cholangiopancreatography (ERCP) combined with intraductal ultrasonography (IDUS) for bile duct stricture diseases.Methods The results of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography,intraductal uhrasonography,bile duct brushing cytology,the liquid-based cytology and the histopathological examination were analyzed retrospectively.The final diagnosis was made based on clinical data,histopathology and follow-up results(≥4 months).Results Twenty-one patients were diagnosed as having malignant biliary diseases,including 9 biliary tract carcinoma,4 duodenal papilla carcinoma,4 pancreatic cancer infiltrated common bile duct,4 cancer of the liver infiltrated common bile duct ; 15 were diagnosed as having benign biliary diseases,including 9 bile duct stones,4 liver fluke disease,lbile duct inflammatory stenosis,1 bile duct stricture caused by external compression.The accuracy rate of the EUS,ERCP,IDUS and ERCP + IDUS in the differential diagnosis of the bile duct stricture disease were 77.8％,88.9％,91.7％ and 94.4％,respectively.The accuracy rates of IDUS,ERCP,ERCP combined with IDUS were significantly higher than that of EUS (P ＜ 0.05).The sensitivity,specificity,positive predictive value and negative predictive value of ERCP combined with IDUS were 95.2％,93.3％,95.2％ and 93.3％ respectively which were higher than those of EUS,ERCP and IDUS.After the bile duct brushing cytology and the liquid-based cytology or histopathological examination,19 patients were diagnosed as having malignant biliary diseases,17 were benign biliary diseases.The sensitivity,specificity and accuracy of the procedures for malignant bile duct stricture disease were 90.5％,100.0％,94.4％ respectively.Conclusion ERCP combined with IDUS can improve the diagnostic accuracy.The diagnostic positive rate will be higher with the help of ERCP,IDUS and targeted brush.

Objective To assess the variation of salivary gland function in differentiated thyroid carcinoma (DTC) patients receiving different doses of 131 I therapy in the first.Methods 40 DTC patients were divided into two groups according to the application 131I doses,salivary scintigraphy was performed with 99TcmO4-on DTC patients before and 3months after 131 I therapy.Quantitative analysis of salivary gland function were performed.Results In low dose group,only the uptake ratio of 30min (UR30) of bilateral parotid decreased ( P ＜ 0.05 ) ; but in high - dose group,the uptake ratio of 30min (UR30),excretion fraction ( EF ),excretion rate (ER) of bilateral parotid and submandibular glands were significantly decreased,excretion time(EP) significantly prolonged after 131 I therapy( all P ＜0.05) ;the parotid gland was more severely than the submandibular gland.Conclusion Salivary gland function was damaged of DTC patients receiving different doses of 131I therapy in the first,salivary gland dysfunction correlated well with the administered dose.

Aim To investigate the influence of intranasal delivery of calcitonin gene-related peptide(CGRP)on cerebral blood supply and expression of vascular endothelial growth factor(VEGF)following experimental subarachnoid hemorrhage(SAH).Methods Wistar rats were divided into normal control group,SAH group,intranasal normal saline(NS)+SAH group and intranasal CGRP+SAH group.SAH models were produced by double injection of autologous arterial blood into cisterna magna.CGRP and NS were given by intranasal perfusion.Dynamic observations of regional cerebral blood flow(rCBF)of cerebral cortex were made using a laser Doppler flowmeter probe.On the third day after the second cisternal injection,the expression of VEGF protein in cerebral cortex was observed by immunofluorescence method combined with laser confocal microscopic observation.Results Anatomic observation revealed that SAH models were successfully manufactured.In SAH and intranasal NS+SAH groups,a drastic and persistent drop in rCBF was noted during the observed periods.The decrease of rCBF in intranasal CGRP+SAH group was slighter as compared with that in SAH and intranasal NS+SAH groups.In SAH and intranasal NS+SAH groups,increased expression of VEGF protein in cerebral cortex was observed on the third day after second cisternal injection as compared with that in normal control group.The expression of VEGF in intranasal CGRP+SAH group was more obvious than that in intranasal NS+SAH group.Conclusion Intranasal delivery of CGRP improves cerebral blood supply and promotes angiogenesis by enhancing the expression of VEGF after SAH.

Tumors of the sacrum are rare.The valve of adjuvant is uncertain,and en bloc tumor resection remains the primary mode of treatment.But en bloc tumor resectiong often leads to unstability of the pelvic ring.Therefore,the most factor providing the successful outcome in the management of sacral tumor is how to establish stability in the lumbo-sacrai junction.The various spinopelvic reconstruction techniques are reported in the literature.This includes various methods triangular frame reconstruction,or lilac rod or iliac screw fixation,modified galveston,custom-made prosthesis and so on.The authors review the modes of reconstruction after sacral tumor resection and discuss the outcomes.