The precision dosing of antimicrobial agents serves as a key strategy to improve effectiveness while minimizing adverse drug effects, thereby enhancing therapeutic outcomes. It also aims to reduce the risk of antimicrobial resistance and optimize the utilization of healthcare resource. This article reviews the key technical elements of antimicrobial precision dosing, including novel therapeutic drug monitoring (TDM) methods, the concepts, modelling and stimulation approaches, and model evaluation of model-informed precision dosing (MIPD), and the implementation of MIPD with clinical decision support system (CDSS). Meanwhile, applications on how artificial intelligence (AI) techniques facilitate MIPD are discussed. We hope that the advances discussed and perspectives presented in this article will provide insights into the precision dosing and individualized therapy of antimicrobials in clinical practice.

The precision dosing of antimicrobial agents serves as a key strategy to improve effectiveness while minimizing adverse drug effects, thereby enhancing therapeutic outcomes. It also aims to reduce the risk of antimicrobial resistance and optimize the utilization of healthcare resource. This article reviews the key technical elements of antimicrobial precision dosing, including novel therapeutic drug monitoring (TDM) methods, the concepts, modelling and stimulation approaches, and model evaluation of model-informed precision dosing (MIPD), and the implementation of MIPD with clinical decision support system (CDSS). Meanwhile, applications on how artificial intelligence (AI) techniques facilitate MIPD are discussed. We hope that the advances discussed and perspectives presented in this article will provide insights into the precision dosing and individualized therapy of antimicrobials in clinical practice.

Objective:To investigate the distribution of fungal species and their sensitivity to antifungal drugs in children with invasive fungal infections.Methods:All the fungal strains primarily isolated from the sterile parts of children in Beijing Children′s Hospital, Capital Medical University from January 2010 to December 2016 were analyzed.The sensitivity of strains to 5-Fluorocytosine, Fluconazole, Amphotericin B, Itraconazole and Voriconazole was tested using ATB-FUNGUS 3 yeast drug sensitivity test strip in accordance with the standards of Clinical and Laboratory Standards Institute M27-A2.Statistical analysis of data was performed using WHONET 5.6 software.Results:Among 236 fungi isolated from aseptic samples, 64.0% (151 strains) were from blood, 22.9%(54 strains) from cerebrospinal fluid, 3.8%(9 strains) from bone marrow, 3.8%(9 strains) from ascites, 3.4%(8 strains) from pleural effusion and 2.1%(5 strains) from tissues.The top 3 dominant species detected in the 236 strains of fungi were Candida spp.(175 strains, 74.2%), Cryptococcus neoformans (31 strains, 13.1%), and Saccharomyces spp.(9 strains, 3.8%). Among the Candida spp., the main isolates were Candida albicans (107 strains, 61.1%), Candida parapsilosis (33 isolates, 18.9%), and Candida tropicalis (13 isolates, 7.4%). Rare fungi of Penicillium marneffei, Exophiala spp.and Rhizopys spp.were also detected. Candida spp.was 100% sensitive to Amphotericin B. Cryptococcus neoformans was 100% sensitive to Fluconazole, Voliconazole and Amphotericin B. Conclusions:The most common strain isolated from pediatric patients with invasive fungal infections is Candida spp., especially Candida albicans. Cryptococcus neoformans causes central nervous system and systemic disseminated infections that can′t be ignored.Amphotericin B has higher antibacterial activity against Candida spp.and Cryptococcus neoformans.Separation of species of invasive fungal infections and monitoring of drug resistance in children should be strengthened to effectively control invasive fungal infections and facilitate rational use of antifungal drugs.

Objective: To investigate the expression of B7H3 and B7H4 in T lymphoblastic lymphoma/leukemia (T-LBL/ALL) in correlation with clinicopathological parameters and patient prognosis. Methods: Immunohistochemistry (IHC) was used to detect the expression of B7H3 and B7H4 protein in 100 cases of T-LBL/ALL(test group) and 30 cases of lymph node reactive hyperplasia (LH) (control group), diagnosed at Shanxi Cancer Hospital from January 2001 to June 2017. Real-time RT-PCR was used to detect the mRNA expression of B7H3 and B7H4 in 50 cases of T-LBL/ALL and 30 cases of LH (control group). Results: There were 79 males,21 females. Immunohistochemical results showed that the expression rates of B7H3 and B7H4 were 23%(23/100) and 54%(54/100), respectively. By real-time RT-PCR, the relative expression of B7H3 mRNA in the T-LBL/ALL group was 2.5 times of that of the LH group. The expression levels of B7H4 mRNA in T-LBL/ALL group and LH group were extremely low.Single factor analysis showed that B7H3 protein expression in T-LBL/ALL group was associated with B symptoms and primary nodal disease (P<0.05). B7H4 protein expression was associated with mediastinal broadening and bone marrow involvement (P<0.05). B7H3 protein, B7H3 mRNA, B7H4 protein expression and IPI score were associated with prognosis (P<0.05), and the combined expression of B7H3 and B7H4 was associated with T-LBL/ALL prognosis (P<0.05). Multivariate Cox regression analysis showed that overexpression of B7H3 mRNA was an independent risk factor for the prognosis of patients with T-LBL/ALL (P<0.05). Conclusion Expression of B7H3 and B7H4 is closely corelated with clinicopathological parameters and prognosis of patients with T-LBL/ALL, suggesting that B7H3 and B7H4 expression play an important role in the development of T-LBL/ALL.

Objective To investigate the expression of B7H3 and B7H4 in T lymphoblastic lymphoma/leukemia (T?LBL/ALL) in correlation with clinicopathological parameters and patient prognosis. Methods Immunohistochemistry (IHC) was used to detect the expression of B7H3 and B7H4 protein in 100 cases of T?LBL/ALL(test group) and 30 cases of lymph node reactive hyperplasia (LH) (control group), diagnosed at Shanxi Cancer Hospital from January 2001 to June 2017. Real?time RT?PCR was used to detect the mRNA expression of B7H3 and B7H4 in 50 cases of T?LBL/ALL and 30 cases of LH (control group). Results There were 79 males,21 females. Immunohistochemical results showed that the expression rates of B7H3 and B7H4 were 23%(23/100) and 54%(54/100), respectively. By real?time RT?PCR, the relative expression of B7H3 mRNA in the T?LBL/ALL group was 2.5 times of that of the LH group. The expression levels of B7H4 mRNA in T?LBL/ALL group and LH group were extremely low.Single factor analysis showed that B7H3 protein expression in T?LBL/ALL group was associated with B symptoms and primary nodal disease (P<0.05). B7H4 protein expression was associated with mediastinal broadening and bone marrow involvement (P<0.05). B7H3 protein, B7H3 mRNA, B7H4 protein expression and IPI score were associated with prognosis (P<0.05), and the combined expression of B7H3 and B7H4 was associated with T?LBL/ALL prognosis (P<0.05). Multivariate Cox regression analysis showed that overexpression of B7H3 mRNA was an independent risk factor for the prognosis of patients with T?LBL/ALL (P<0.05). Conclusion Expression of B7H3 and B7H4 is closely corelated with clinicopathological parameters and prognosis of patients with T?LBL/ALL, suggesting that B7H3 and B7H4 expression play an important role in the development of T?LBL/ALL.

OBJECTIVE: To investigate the effect and mechanism of lead exposure on hypothalamic inflammatory factors in mice fed with high-fat diet. METHODS: Specific pathogen free healthy male Kunming mice were randomly divided into control group, high-fat diet group, lead exposure group, and combined exposure group, with 8 rats in each group. The control group and the lead exposure group were given regular diet, while high-fat diet group and combined exposure group were given high-fat diet. The lead exposure group and combined exposure group were given water with 250 mg/L lead acetate. The control group and high-fat diet group were given double distilled water. Continuous lead exposure was given for 9 weeks, 7 days per week. Body weights of the mice were measured every other week. After 9 weeks of exposure, the behavioral changes of mice were detected by open field test. The levels of triglyceride(TG), low density lipoprotein(LDL) and high density lipoprotein(HDL) in serum were detected by microplate reader. Western blotting was used to detect the relative protein expression of interleukin(IL)-1β, IL-6, IL-17 A, IL-22, tumor necrosis factor-α(TNF-α) and transforming growth factor-β(TGF-β) in the hypothalamus of mice. The relative expression of mRNA of IL-1β, IL-6, IL-17 A and TNF-α mRNA was detected by real-time fluorescence quantitative polymerase chain reaction. RESULTS: Beginning from the first week, the body weights of mice in the high-fat diet group and the combined exposure group were higher than that in the control group and the lead exposure group(P<0.05). The numbers of standing in the lead exposure group and the combined exposure group were lower than that in the control group and the high-fat diet group(P<0.05). The distances of central area activity in the high-fat diet group, the lead exposure group and the combined exposure group were lower than that in the control group(P<0.05). The total distances in the high-fat diet group and the combined exposure group were lower than that in the control group(P<0.05). The serum levels of TG and LDL in the combined exposure group increased(P<0.05), and the HDL level decreased(P<0.05), when compared with the control group and the lead exposure group. The relative protein expression of IL-1β, IL-6, IL-17 A and IL-22 in the hypothalamus of the high-fat diet group and lead exposure group was higher than those of the control group(P<0.05). The relative protein expression of TNF-α and TGF-β in the hypothalamus of the lead exposure group was higher than that in the control group(P<0.05). The relative protein expression of IL-1β, IL-6, IL-17 A, TGF-β in the hypothalamus of the combined exposure group was higher than the other 3 groups(P<0.05). The relative protein expression of IL-22 in the hypothalamus of the combined exposure group was higher than that of the control group(P<0.05), while the relative protein expression of TNF-α was higher than that of the control group and the high-fat diet group(P<0.05). The relative expression of IL-1β, IL-6, IL-17 A, and TNF-α mRNA in the hypothalamus of the high-fat diet group, the lead exposure group and the combined exposure group was higher than that in the control group(P<0.05). The above indicators of mice in the lead exposure group were higher than that in the high-fat diet group(P<0.05). The above indicators of mice in the combined exposure group were higher than those in the high-fat diet group and the lead exposure group(P<0.05). CONCLUSION: Lead exposure can promote neurobehavioral changes and hypothalamic inflammatory damage in high-fat diet mice. IL-1β, IL-6, IL-17 A, TGF-β and TNF-α might involve in the process of synergistic effect of lead and high-fat diet exposure on inflammatory hypothalamic injury.

Objective · To investigate antiemetic effect of aprepitant for moderately chemotherapy-induced nausea and vomiting in patients with gastrointestinal cancer. Methods · From 2014 July to 2015 August, 130 cases of gastrointestinal cancer patients were collected in Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, who received moderate emetogenic risk of chemotherapy for at least four courses. One hundred and nine patients were treated with aprepitant, palonosetron and dexamethasone on day 1, and aprepitant and dexamethasone on day 2 and 3. Twenty-one patients only received aprepitant and dexamethasone on day 1 and dexamethasone on day 2 and 3 in the first course of chemotherapy. During subsequent courses of chemotherapy they received aprepitant and treated in the same way as 109 patients. MASCC antiemetic tool (MAT) was used to evaluate the intensity of nausea. The primary endpoint was complete response (CR, no emesis and use of no rescue antiemetics) during the overall study phase (0-120 h after chemotherapy) at the second course. The secondary endpoint was complete protection (CP, CR plus no significant nausea) during the overall, acute (0-24 h), and delayed (24-120 h) phases at the second course. Results · The CR rates were 90.0%, 94.6% and 90.8% of patients in the overall, acute and delayed phases, respectively. The corresponding CP rates were 83.8%, 87.8% and 84.6 %, respectively. The CR rate increased from 42.9% to 57.1% during acute phase and increased from 9.5% to 90.5% during delayed phase for 21 patients after treatment with aprepitant. The main adverse reactions include constipation, anorexia and hiccups. Conclusion · Aprepitant combined with palonosetron and dexamethasone can effectively prevent moderately chemotherapy-induced nausea and vomiting in patients with gastrointestinal cancer. Aprepitant therapy can effectively maintain antiemetic effect in patients with many chemotherapy courses.

Purpose To investigate the mutation status of KRAS and PIK3CA gene in colorectal cancer (CRC) primary lesions and corresponding liver metastasis and its clinical significance.Methods The gene mutations of KRAS and PIK3CA were detected in 58 cases of primary lesions of CRC and corresponding liver metastasis tissue by real-time PCR.Results The mutation rates of KRAS were 31.03％ (18/58) and 25.86％ (15/58) in primary lesions of CRC and corresponding liver metastasis tissue,respectively,in which G12D was most commonly detected.The mutation rates of PIK3CA were 8.62％ (5/58) and 10.34％ (6/58) respectively,in which the most common mutation site was E545K.Only one case carried simultaneously both mutations of KRAS (G12D) and PIK3CA (E545K).The mutation of KRAS and PIK3CA had a good consistency between primary lesions and liver metastasis.Univariate analysis showed that the mutation of KRAS was related to the primary lesion of tumor location,the quantity of metastasis and the types of tumor (P ＜ O.05),PIK3 CA mutation was associated with the synchronous/metachronous liver metastasis and the quantity of metastasis (P ＜ 0.05).Multivariate Cox regression analysis showed that synchronous/metachronous liver metastasis and the mutation of KRAS were influencing factors for prognosis of CRC.The overall survival of patients with CRC who had simultaneous liver metastases was longer than those with heterotopic liver metastases;the overall survival of KRAS wild-type mutant patients was longer than those of mutant patients (P ＜ 0.05).Conclusion The G12D site of KRAS gene has the highest mutation frequency in CRC,KRAS/PIK3CA mutation has a good consistency of the primary lesions of CRC and corresponding liver metastasis.Primary lesions can be as the source of molecular detection.To achieve individualized treatment,we need to reassess the genetic status of metastasis based on the choice of targeted therapy for precision medicine.

Objective To investigate the significance of CXCL 12/CXCR4 expression in T lymphoblastic lymphoma/leukemia ( T-LBL/ALL ) and its prognostic significance . Methods Using immunohistochemical EnVision method , CXCL12, CXCR4 and Ki-67 expression were evaluated in 72 cases of T-LBL/ALL and 30 selected cases of lymph node reactive hyperplasia ( LH) as control.In addition, CXCL12 and CXCR4 mRNA expression levels were examined by real-time reverse transcription polymerase chain reaction ( real-time RT-PCR ) method.Results Immunohistochemical results showed that the expression rates of CXCL 12 and CXCR4 in T-LBL/ALL were 84.7%( 61/72 ) and 91.6%( 66/72 ) , respectively, and these were not different from the expression in the LH control group .The expression indexes of Ki-67 <80% and ≥80% were 25 cases (34.7%,25/72) and 47 cases (65.3%,47/72), respectively.Real-time quantitative PCR demonstrated that CXCL 12 and CXCR4 mRNA expression in T-LBL/ALL was 62.4%and 71.5%, respectively, and was statistically different (P<0.05) from that of the control group.Single factor analysis found that CXCL 12 mRNA expression in T-LBL/ALL was positively correlated with Ann Arbor staging and KPS score ( P<0.05 ); CXCL12 protein expression was positively correlated with splenomegaly ( P<0.05 ); CXCR4 mRNA expression was positively correlated with the IPI score, clinical symptoms, mediastinal widening and bone marrow involvement (P<0.05); CXCR4 protein expression was positively correlated with mediastinal widening ( P<0.05); CXCL12 mRNA expression was positively correlated with CXCL12 protein and CXCR4 protein expression (P<0.05), but not the CXCR4 mRNA and protein levels.There was no correlation between CXCL 12 and CXCR4 protein expression and CXCR4 mRNA expression.Multivariate COX regression analysis showed that high expression of CXCR 4 protein, hepatosplenomegaly and bone marrow involvement were risk factors for T-LBL/ALL outcome . Conclusions CXCL12/CXCR4 expression is associated with disease progress , mediastinal widening , bone marrow involvement and adverse outcome in T-LBL/ALL.CXCL12/CXCR4 axis plays an essential role in the occurrence and development of T-LBL/ALL.However , CXCL12 and CXCR4 protein expression are not entirely reflected by mRNA transcription levels , and there may be other molecules involved in CXCL 12/CXCR4 expression and regulation . With CXCR4 antagonists undergoing clinical trials , targeting the CXCL12/CXCR4 axis may be a promising treatment strategy for T-LBL/ALL.

Purpose To ana1yze the expression features of 5-F1uorouraci1(5-FU)metabo1ic enzyme thymidy1ate synthetase(TS),thy-midine phosphory1ase( TP),dihydropyrimidine dehydrogenase( DPD)and its re1ationship with c1inicopatho1ogica1 factors and progno-sis in co1orecta1 cancer,in order to further exp1ore its potentia1 significance in guiding co1orecta1 cancer chemotherapy. Methods Es-tab1ishment of a tissue microarray containing 72 patients with co1orecta1 cancer,and 56 norma1 tissue( dista1 cut edge tissue near carci-noma)was used to detect TS,TP,and DPD by immunohistochemistry,and to ana1yze its re1ationship with c1inicopatho1ogica1 factors and prognosis of co1orecta1 cancer through statistica1 method. Results The expression of TS in co1orecta1 cancer was 1ower than that in norma1 tissue(P=0. 876),which was associated with TNM(P=0. 043)and positive1y corre1ated with patients’overa11 surviva1(P=0. 027),the expression of TP in co1orecta1 cancer was higher than that in norma1 tissue(P=0. 315)that was associated with 1ymph node metastasis(P=0. 009)and negative1y corre1ated with the prognosis of patients(P=0. 040),DPD expression in co1orecta1 canc-er was higher than that in norma1 tissue(P=0. 071),which was re1ated to the histo1ogic type(P=0. 029). Overa11 surviva1 was sig-nificant1y shortened in co1orecta1 cancer with DPD high expression( P=0. 011). Conclusions TS,TP and DPD might be app1ied as important index of prognosis in co1orecta1 cancer patients using 5-FU adjuvant chemotherapy. The expression of TS re1ated c1ose1y with the c1inica1 stage is a bio1ogica1 marker of tumor progression. TP expression is c1ose1y re1ated to 1ymph nodes metastasis and recur-rence,which is an important factor of postoperative recurrence and metastasis.