Integrating fractional amplitude of low-frequency fluctuation and functional connectivity to investigate the mechanism and prognosis of severe traumatic brain injury.

Objective: Functional magnetic resonance imaging (fMRI) has been used for evaluating residual brain function and predicting the prognosis of patients with severe traumatic brain injury (sTBI). This study aimed to integrate the fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) to investigate the mechanism and prognosis of patients with sTBI. Methods: Sixty-five patients with sTBI were included and underwent fMRI scanning within 14 days after brain injury. The patient's outcome was assessed using the Glasgow Outcome Scale-Extended (GOSE) at 6 months post-injury. Of the 63 patients who met fMRI data analysis standards, the prognosis of 18 patients was good (GOSE scores ≥ 5), and the prognosis of 45 patients was poor (GOSE scores ≤ 4). First, we apply fALFF to identify residual brain functional differences in patients who present different prognoses and conjoined it in regions of interest (ROI)-based FC analysis to investigate the residual brain function of sTBI at the acute phase of sTBI. Then, the area under the curve (AUC) was used to evaluate the predictive ability of the brain regions with the difference of fALFF and FC values. Results: Patients who present good outcomes at 6 months post-injury have increased fALFF values in the Brodmann area (7, 18, 31, 13, 39 40, 42, 19, 23) and decreased FC values in the Brodmann area (28, 34, 35, 36, 20, 28, 34, 35, 36, 38, 1, 2, 3, 4, 6, 13, 40, 41, 43, 44, 20, 28 35, 36, 38) at the acute phase of sTBI. The parameters of these alterations can be used for predicting the long-term outcomes of patients with sTBI, of which the fALFF increase in the temporal lobe, occipital lobe, precuneus, and middle temporal gyrus showed the highest predictive ability (AUC = 0.883). Conclusion: We provide a compensatory mechanism that several regions of the brain can be spontaneously activated at the acute phase of sTBI in those who present with a good prognosis in the 6-month follow-up, that is, a destructive mode that increases its fALFF in the local regions and weakens its FC to the whole brain. These findings provide a theoretical basis for developing early intervention targets for sTBI patients.

Printing, Debinding and Sintering of 15-5PH Stainless Steel Components by Fused Deposition Modeling Additive Manufacturing.

Metal FDM technology overcomes the problems of high cost, high energy consumption and high material requirements of traditional metal additive manufacturing by combining FDM and powder metallurgy and realizes the low-cost manufacturing of complex metal parts. In this work, 15-5PH stainless steel granules with a powder content of 90% and suitable for metal FDM were developed. The flowability and formability of the feedstock were investigated and the parts were printed. A two-step (solvent and thermal) debinding process is used to remove the binder from the green part. After being kept at 75 °C in cyclohexane for 24 h, the solvent debinding rate reached 98.7%. Following thermal debinding, the material's weight decreased by slightly more than 10%. Sintering was conducted at 1300 °C, 1375 °C and 1390 °C in a hydrogen atmosphere. The results show that the shrinkage of the sintered components in the X-Y-Z direction remains quite consistent, with values ranging from 13.26% to 19.58% between 1300 °C and 1390 °C. After sintering at 1390 °C, the material exhibited a relative density of 95.83%, a hardness of 101.63 HRBW and a remarkable tensile strength of 770 MPa. This work realizes the production of metal parts using 15-5PH granules' extrusion additive manufacturing, providing a method for the low-cost preparation of metal parts. And it provides a useful reference for the debinding and sintering process settings of metal FDM. In addition, it also enriches the selection range of materials for metal FDM.

Optimization for Pipeline Corrosion Sensor Placement in Oil-Water Two-Phase Flow Using CFD Simulations and Genetic Algorithm.

Internal corrosion is a major concern in ensuring the safety of transmission and gathering pipelines in Structural Health Monitoring (SHM). It usually requires numerous sensors deployed inside the piping system to comprehensively cover the locations with high corrosion rates. This study presents a hybrid modeling strategy using Computational Fluid Dynamics (CFD) and Genetic Algorithm (GA) to improve the sensor placement scheme for corrosion detection and monitoring. The essence of the proposed strategy harnesses the well-validated physical modeling capability of the CFD to simulate the oil-water two-phase flow and the stochastic searching ability of the GA to explore better solutions on a global level. The CFD-based corrosion rate prediction was validated through experimental results and further used to form the initial population for GA optimization. Importantly, fitness was defined by considering both sensing effectiveness and cost of sensor coverage. The hybrid modeling strategy was implemented through case studies, where three typical pipe fittings were used to demonstrate the applicability of the sensor layout design for corrosion detection in pipelines. The GA optimization results show high accuracy for sensor placement inside the pipelines. The best fitness of the U-shaped, upward-inclined, and downward-inclined pipes were 0.9415, 0.9064, and 0.9183, respectively. Upon this, the hybrid modeling strategy can provide a promising tool for the pipeline industry to design the practical placement.

Characterization of a novel galectin in Sarcoptes scabiei and its role in regulating macrophage functions.

Sarcoptes scabiei (S. scabiei) endangers human and other mammalian health. There has been limited research into S. scabiei pathogenic mechanisms and the immunological interaction between S. scabiei and hosts. Galectins have critical roles in biological processes such as cell adhesion, signal transduction, and immune response mediation. Galectins of S. scabiei (SsGalectins) were cloned, expressed, and identified, and their transcriptional levels in S. scabiei were measured at various developmental stages. Fluorescent tissue localization was performed on SsGalectins of S. scabiei and scabies skin. A mouse AD model was constructed to evaluate the effect of rSsGalectins on skin pathogenic changes. Quantitative polymerase chain reaction and enzyme-linked immunoassay were used to identify macrophage polarization-related components and investigate the immunoregulatory effect of rSsGalectins on mouse macrophages. The results demonstrated that the S. scabiei infection causes macrophage infiltration in the scabies skin. The rSsGalectins displayed strong reactogenicity, and distinct genes of the SsGalectins were differently expressed in different developmental stages of S. scabiei. Fluorescence tissue localization revealed that the SsGalectins were mainly in the mouthparts, intestines, and body surface. Additionally, S. scabiei could secrete SsGalectins into the infected skin, proving that SsGalectins were excretion and secretion proteins of S. scabiei. In the mouse atopic dermatitis model, cutaneous macrophage infiltration and inflammation increase after rSsGalectins injection. Simultaneously, when rSsGalectins acted on bone marrow-derived macrophages, M1 macrophage-related polarization factors IL-1ß, IL-6, and inducible nitric oxide synthase all increased, demonstrating that rSsGalectins can induce M1 polarization and produce pro-inflammatory cytokines. In conclusion, the SsGalectins are involved in the pathogenic process of S. scabiei by regulating the polarization of host macrophages to the M1 type when S. scabiei invade the host and promoting the incidence and development of the host's inflammatory response. This study offers fresh light on the pathogenic process of scabies mites, investigates the immunological interaction mechanism between S. scabiei and the host, and offers new insights into S. scabiei prevention and therapy.

TransMUSE: Transferable Traffic Prediction in MUlti-Service Edge Networks.

The Covid-19 pandemic has forced the workforce to switch to working from home, which has put significant burdens on the management of broadband networks and called for intelligent service-by-service resource optimization at the network edge. In this context, network traffic prediction is crucial for operators to provide reliable connectivity across large geographic regions. Although recent advances in neural network design have demonstrated potential to effectively tackle forecasting, in this work we reveal based on real-world measurements that network traffic across different regions differs widely. As a result, models trained on historical traffic data observed in one region can hardly serve in making accurate predictions in other areas. Training bespoke models for different regions is tempting, but that approach bears significant measurement overhead, is computationally expensive, and does not scale. Therefore, in this paper we propose TransMUSE (Transferable Traffic Prediction in MUlti-Service Edge Networks), a novel deep learning framework that clusters similar services, groups edge-nodes into cohorts by traffic feature similarity, and employs a Transformer-based Multi-service Traffic Prediction Network (TMTPN), which can be directly transferred within a cohort without any customization. We demonstrate that TransMUSE exhibits imperceptible performance degradation in terms of mean absolute error (MAE) when forecasting traffic, compared with settings where a model is trained for each individual edge node. Moreover, our proposed TMTPN architecture outperforms the state-of-the-art, achieving up to 43.21% lower MAE in the multi-service traffic prediction task. To the best of our knowledge, this is the first work that jointly employs model transfer and multi-service traffic prediction to reduce measurement overhead, while providing fine-grained accurate demand forecasts for edge services provisioning.

Applying machine learning to the pharmacokinetic modeling of cyclosporine in adult renal transplant recipients: a multi-method comparison.

Objective: The aim of this study was to identify the important factors affecting cyclosporine (CsA) blood concentration and estimate CsA concentration using seven different machine learning (ML) algorithms. We also assessed the predictability of established ML models and previously built population pharmacokinetic (popPK) model. Finally, the most suitable ML model and popPK model to guide precision dosing were determined. Methods: In total, 3,407 whole-blood trough and peak concentrations of CsA were obtained from 183 patients who underwent initial renal transplantation. These samples were divided into model-building and evaluation sets. The model-building set was analyzed using seven different ML algorithms. The effects of potential covariates were evaluated using the least absolute shrinkage and selection operator algorithms. A separate evaluation set was used to assess the ability of all models to predict CsA blood concentration. R squared (R 2) scores, median prediction error (MDPE), median absolute prediction error (MAPE), and the percentages of PE within 20% (F20) and 30% (F30) were calculated to assess the predictive performance of these models. In addition, previously built popPK model was included for comparison. Results: Sixteen variables were selected as important covariates. Among ML models, the predictive performance of nonlinear-based ML models was superior to that of linear regression (MDPE: 3.27%, MAPE: 34.21%, F20: 30.63%, F30: 45.03%, R 2 score: 0.68). The ML model built with the artificial neural network algorithm was considered the most suitable (MDPE: -0.039%, MAPE: 25.60%, F20: 39.35%, F30: 56.46%, R 2 score: 0.75). Its performance was superior to that of the previously built popPK model (MDPE: 5.26%, MAPE: 29.22%, F20: 33.94%, F30: 51.22%, R 2 score: 0.68). Furthermore, the application of the most suitable model and the popPK model in clinic showed that most dose regimen recommendations were reasonable. Conclusion: The performance of these ML models indicate that a nonlinear relationship for covariates may help to improve model predictability. These results might facilitate the application of ML models in clinic, especially for patients with unstable status or during initial dose optimization.

Monitoring Epoxy Coated Steel under Combined Mechanical Loads and Corrosion Using Fiber Bragg Grating Sensors.

Fiber Bragg grating (FBG) sensors have been applied to assess strains, stresses, loads, corrosion, and temperature for structural health monitoring (SHM) of steel infrastructure, such as buildings, bridges, and pipelines. Since a single FBG sensor measures a particular parameter at a local spot, it is challenging to detect different types of anomalies and interactions of anomalies. This paper presents an approach to assess interactive anomalies caused by mechanical loading and corrosion on epoxy coated steel substrates using FBG sensors in real time. Experiments were performed by comparing the monitored center wavelength changes in the conditions with loading only, corrosion only, and simultaneous loading and corrosion. The theoretical and experimental results indicated that there were significant interactive influences between loading and corrosion for steel substrates. Loading accelerated the progress of corrosion for the epoxy coated steel substrate, especially when delamination in the epoxy coating was noticed. Through the real-time monitoring from the FBG sensors, the interactions between the anomalies induced by the loading and corrosion can be quantitatively evaluated through the corrosion depth and the loading contact length. These fundamental understandings of the interactions of different anomalies on steel structures can provide valuable information to engineers for better management of steel structures.

Factors Affecting Time-Varying Clearance of Cyclosporine in Adult Renal Transplant Recipients: A Population Pharmacokinetic Perspective.

AIM: The pharmacokinetic (PK) properties of cyclosporine (CsA) in renal transplant recipients are patient- and time-dependent. Knowledge of this time-related variability is necessary to maintain or achieve CsA target exposure. Here, we aimed to identify factors explaining variabilities in CsA PK properties and characterize time-varying clearance (CL/F) by performing a comprehensive analysis of CsA PK factors using population PK (popPK) modeling of long-term follow-up data from our institution. METHODS: In total, 3674 whole-blood CsA concentrations from 183 patients who underwent initial renal transplantation were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were selected according to a previous study and well-accepted theoretical mechanisms. Model-informed individualized therapeutic regimens were also evaluated. RESULTS: A two-compartment model adequately described the data and the estimated mean CsA CL/F was 32.6 L h-1 (relative standard error: 5%). Allometrically scaled body size, hematocrit (HCT) level, CGC haplotype carrier status, and postoperative time may contribute to CsA PK variability. The CsA bioavailability in patients receiving a prednisolone dose (PD) of 80 mg was 20.6% lower than that in patients receiving 20 mg. A significant decrease (52.6%) in CL/F was observed as the HCT increased from 10.5% to 60.5%. The CL/F of the non-CGC haplotype carrier was 14.4% lower than that of the CGC haplotype carrier at 3 months post operation. CONCLUSIONS: By monitoring body size, HCT, PD, and CGC haplotype, changes in CsA CL/F over time could be predicted. Such information could be used to optimize CsA therapy. CsA dose adjustments should be considered in different postoperative periods.

Protective effect of electrical stimulation of the vagus nerve in lipopolysaccharide­induced acute lung injury in rats.

The present study investigated the role of electrical stimulation of the vagus nerve in the acute lung injury (ALI) inflammatory response induced by lipopolysaccharide (LPS) in rats. A rat model of ALI was established using LPS and by connecting an electrode to the left vagus nerve proximal to the heart in order to provide continuous electrical stimulation (1 mA; 1 msec; 10 Hz). After 120 min, the rat lung tissue was stained with hematoxylin and eosin and the expression of inflammatory factors was evaluated by reverse transcription­quantitative PCR and western blot analysis. The change in apoptosis rate in cells from bronchoalveolar lavage fluid (BALF) was analyzed using flow cytometry. The results of the present study demonstrated that inflammatory cell infiltration, alveolar wall and interstitial thickening, and lung hyperemia in rats with LPS­induced ALI were decreased following electrical stimulation of the vagus nerve. Electrical stimulation inhibited the expression levels of IL­1, IL­6, IL­10, IL-8 and TNF­α at both the mRNA and protein levels and decreased early and late apoptosis rates in inflammatory cells from BALF. The results indicated that vagus nerve stimulation can reverse the inflammatory response in lung injury, thereby exerting a pulmonary protective effect.

FKBP-CaN-NFAT pathway polymorphisms selected by in silico biological function prediction are associated with tacrolimus efficacy in renal transplant patients.

AIM: The aim of the present study was to investigate the potential effects of genetic variations in the FKBP-CaN-NFAT pathway on clinical events associated with tacrolimus efficacy in Chinese renal transplant patients. METHODS: One hundred and forty Chinese renal transplant patients of Han ethnicity with over five years of follow-up were enrolled in our study. A pool of single nucleotide polymorphisms (SNPs) (1284 SNPs) was extracted from the Ensembl database according to chromosomal regions of the candidate genes. Next, 109 SNPs were screened out from this pool using multiple bioinformatics tools for subsequent genotyping using the MALDI-TOF-MS method. The associations of these candidate SNPs with acute rejection, nephrotoxicity, pneumonia and post-transplant estimated glomerular filtration rate (eGFR) were explored. RESULTS: Fourty-four SNPs were found to be associated with tacrolimus-related clinical drug response. Specifically, eight SNPs were associated with the incidence of biopsy-proven acute rejection, four SNPs were associated with the rate of nephrotoxicity, 16 SNPs were correlated with the onset of pneumonia, and 26 SNPs were found to significantly influence post-transplant eGFR trend. An elaborate scoring system was implemented to prioritize the validation of these potentially causal SNPs. In particular, NFATC2 rs150348438 (G>T) performed well during integrative scoring (Ptotal=23.8) and was significantly associated with the occurrence of pneumonia (P = 0.0035, HR=0.91, 95% CI=0.85-0.97) and post-transplant eGFR levels (P = 0.000003). CONCLUSIONS: NFATC2 rs150348438, rs6013219, rs1052653, and NFATC1 rs754093, ranking high in scoring, significantly affected the post-transplant eGFR and the incidence of pneumonia, acute rejection, and nephrotoxicity in renal transplant patients taking tacrolimus. Those SNPs may alter the expression and regulation of FKBP-CaN-NFAT pathway by influencing transcription regulation, mature mRNA degradation and RNA splicing, or protein coding. Critical SNPs of high ranking may serve as PD-associated pharmacogenetic biomarkers indicating individual response variability of TAC, and thus aid the clinical management of renal transplant patients.

[Effectiveness of convalescent plasma for treatment of coronavirus disease 2019 patients].

OBJECTIVE: To evaluate the effectiveness and safety of convalescent plasma therapy in patients with severe and critical coronavirus disease 2019 (COVID-19). METHODS: Plasma of 200-400 mL was collected from convalescent patients 2 weeks after being discharged from the hospital. After viral nucleic acid testing and antibody testing, the plasma was infused into 16 severe or critical COVID-19 patients. Time for viral nucleic acid amplification (NAA) test turning negative, total volume of plasma transfusion, average antibody concentration, and total antibody amount were recorded. White blood cell (WBC) counts, lymphocyte (LYM) counts, neutrophil (NEU) counts, alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), hypersensitive cardiac troponin T (hs-cTnT), and lactic acid (Lac) levels were measured and the rate of change was calculated at the baseline (d0) before plasma transfusion, and day 1 (d1), day 3 (d3) after transfusion. RESULTS: (1) Patient characteristics: among the 16 patients, 5 cases (31.25%) were severe COVID-19, and 11 cases (68.75%) were critical COVID-19; 62.50% (10/16) of the patients had primary disease; the percentage of invasive ventilation and use of extracorporeal membrane pulmonary oxygenation (ECMO) in critical patients were 90.91% (10/11) and 45.46% (5/11) respectively. (2) Antibody concentration of convalescent plasma and time for NAA test turning negative: the convalescent plasma antibody concentration in this study was ranged from 10.93 kAU/L to 114.7 kAU/L, with an average value of (56.44±39.40) kAU/L. NAA test was continuously positive before plasma transfusion in 10 patients, and the time for NAA test turning negative could be counted. Eight patients turned negative from day 2 to day 8 after transfusion. Severe patients showed a shorter time for NAA test turning negative than critical patients after transfusion [2 (2-3) vs. 5 (3-8), P = 0.036]. Two critical patients transfused plasma with lower antibody concentration remained a positive result of NAA test, and died on the 3rd and 6th day respectively. (3) Laboratory results: the change rates of WBC (0.81±0.28 vs. 1.00) and NEU (0.75±0.33 vs. 1.00) were significantly decreased at d1 after convalescent plasma treatment (both P < 0.05), and the CRP level decreased to about 63% of that before transfusion (P = 0.017). No adverse events were observed during convalescent plasma transfusion. CONCLUSIONS: Viral NAA test of most patients with COVID-19 who received convalescent plasma transfusion turned negative from day 2 to day 8 after transfusion, and the turning time of severe patients was shorter than that of critical patients. Convalescent plasma therapy can reduce the patients' CRP level, and no adverse events were found during the treatment. The antibody concentration in the convalescent plasma may be one of the factors that affect the time for the nucleic acid turning negative after transfusion. Detection and screening convalescent plasma of high-titer antibody and early application to severe and critical patients are expected to improve the efficacy of convalescent plasma.

EGFR drives the progression of AKI to CKD through HIPK2 overexpression.

The molecular mechanism underlying the transition of acute kidney injury (AKI) to chronic kidney disease (CKD) induced by vancomycin (VAN) remains largely unknown. Methods: The mice model of VAN drives AKI to CKD was developed to investigate the role and molecular mechanism of epidermal growth factor receptor (EGFR). The EGF receptor mutant (Wa-2) mice and gefitinib were used to inactivation of EGFR. The homeodomain interacting protein kinase 2 (HIPK2) siRNA was applied to silence of HIPK2. Human proximal tubular epithelial cells (HK-2) were used to explore the molecular regulation methanism of EGFR. ChIp analysis was used to investigate if STAT3 interaction with the promoter of HIPK2. Results: A novel VAN-induced AKI mouse model was established for the first time. Moreover, the expression levels collagen I&IV, α-SMA, p-EGFR and the expression of HIPK2 proteins were upregulated in this model. Interestingly, AKI caused by VAN was markedly attenuated in waved-2 mice at the early stage, as evidenced by the suppression of renal dysfunction, renal cell apoptosis and caspase3 activation. In the latter stage, renal fibrosis and inflammation were significantly ameliorated in Wa-2 mice, accompanied by the downregulation of profibrotic molecules and F4/80. Besides, the expression levels of HIPK2 and p-STAT3 were suppressed in Wa-2 mice during VAN-induced transition of AKI to CKD. In addition, renal fibrosis and inflammation, profibrotic molecules, and EGFR/STAT3/HIPK2 signaling were ameliorated by gefitinib treatment after VAN-induced AKI. These results were consistent with the findings of Wa-2 mice. EGFR/STAT3 signaling mediated VAN-induced HIPK2 expression in HK-2 cells. ChIp analysis revealed that STAT3 directly bound to the promoter region of HIPK2. Finally, inhibition of HIPK2 attenuated the VAN drove the progression of AKI to CKD. Conclusion: These data suggest that EGFR plays an important role in VAN-driven progression of AKI to CKD.

Highly coke resistant Mg-Ni/Al2O3 catalyst prepared via a novel magnesiothermic reduction for methane reforming catalysis with CO2: the unique role of Al-Ni intermetallics.

Addition of alkaline promoters is considered to be an effective way to improve the coking resistance of the metal/support composite catalysts for dry reforming of methane (DRM). The traditional metal/promoter/support composites for DRM catalysis are generally obtained from alkaline species impregnation and then high temperature H2 reduction. This two-step process leads to a random distribution of metal-promoter interaction. We herein report a novel magnesiothermic method to reduce Ni from spinel precursor and introduce alkaline Mg(ii) into the composite at the same time, which also gratifies the interaction between the promoter and metal nanoparticles (NPs). The reaction paths to Mg reduction are proposed. The as prepared catalysts show good activity and outstanding coking resistance in DRM. The Ni-Al intermetallics in the catalyst were found for the first time to play an important role in coking resistance as they can be in situ transformed into Ni nanoparticles and MgAl2O4 with strong metal-support interaction during the DRM.

FKBP1A rs6041749 polymorphism is associated with allograft function in renal transplant patients.

AIM: To investigate the potential impact of single-nucleotide polymorphisms (SNPs) in the FK506-binding protein (FKBP)-calcineurin (CaN)-nuclear factor of activated T cells (NFAT) signaling pathway on the efficacy and safety of tacrolimus (TAC) in Chinese renal transplant patients. METHODS: Seventy-seven tag SNPs were detected in 146 patients who were on TAC-based maintenance immunosuppression and who followed up for at least 2 years. The relationships of these polymorphisms with clinical outcomes such as acute rejection, acute nephrotoxicity, pneumonia, and estimated glomerular filtration rate (eGFR) were explored. For the FKBP1A rs6041749 polymorphism, which has a significant association with renal function over time, a preliminary functional analysis was performed using a dual-luciferase reporter gene system. RESULTS: The patients with FKBP1A rs6041749 TT genotype had a more stable eGFR level than CC and CT carriers (P = 2.08 × 10-8) during the 2 years following transplantation. Dual-luciferase reporter assay results showed that the rs6041749 C variant could enhance the relative luciferase activity compared with the T variant, which indicated that the rs6041749 C allele may increase the FKBP1A gene transcription. In addition, we did not find any association between these genetic variants and the risk of acute rejection, acute nephrotoxicity, and pneumonia in renal transplant patients receiving TAC-based immunosuppression. CONCLUSIONS: FKBP1A rs6041749 C allele carriers are at higher risk for eGFR deterioration. The variant might serve as a biomarker to predict allograft function in renal transplant patients.

Optimization and application of an HPLC method for quantification of inosine-5'-monophosphate dehydrogenase activity as a pharmacodynamic biomarker of mycophenolic acid in Chinese renal transplant patients.

BACKGROUND: The immunosuppressive agent mycophenolic acid (MPA) is a non-competitive, reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH). Thus, IMPDH activity can serve as a potential pharmacodynamic biomarker to optimize dosing of MPA. METHODS: Peripheral blood mononuclear cells were isolated from 2 mL blood samples and an in vitro enzymatic reaction was subsequently performed for 120 min. To determine IMPDH activity in Chinese healthy volunteers and renal transplant patients, a high performance liquid chromatography assay was established and validated by subtracting adenosine monophosphate (AMP) from blank samples for eliminating exogenous AMP interference. RESULTS: The accuracy of our method ranged between -0.8% and 12.5%, and the precision ranged between 0.7% and 6.3%. The mean value of IMPDH activity across 11 healthy volunteers was 46.60 ±â€¯14.28 µmol/s/mol AMP. A negative relationship between MPA concentration and IMPDH activity was observed in four renal transplant patients treated with MPA 13 days post-transplantation, while the inhibitory rate of IMPDH activity ranged from 24% to 42%. CONCLUSION: A bioanalytical assay for IMPDH quantification was optimized and evaluated. The differences in the pharmacodynamics of MPA between Asians and Caucasians may provide some evidence for dosing differences among ethnicities.

Pharmacokinetics Evaluation of Mycophenolic Acid and Its Glucuronide Metabolite in Chinese Renal Transplant Recipients Receiving Enteric-Coated Mycophenolate Sodium and Tacrolimus.

BACKGROUND: The aim of this study was to characterize the pharmacokinetics of mycophenolic acid (MPA) and MPA glucuronide (MPAG) in Chinese renal transplant patients taking enteric-coated mycophenolate sodium (EC-MPS). Limited sampling strategies (LSSs) were developed to estimate the area under the concentration curve from 0 to 12 hours (AUC0-12h) of total and free MPA. Another objective was to investigate the correlation between high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay technology (EMIT) for total MPA determination. METHODS: Serial blood samples were collected over 12 hours from 15 patients who were administered multiple doses of EC-MPS. LSS was developed by multiple stepwise regression analysis. Measurement by HPLC and EMIT was compared using Passing-Bablok regression and Bland-Altman analysis. RESULTS: Normalized to 720 mg twice daily, the AUC0-12h of total MPA and MPAG was 43.0 ± 17.4 and 653 ± 329 mg·h/L, respectively, whereas the free MPA AUC0-12h was 1.368 ± 0.988 mg·h/L. The free fraction of MPA was 3.01% ± 3.15%. The combination of C2h-C4h-C6h and C2h-C4h-C6h-C8h was found to be superior to estimate total and free MPA simultaneously. The EMIT showed an acceptable correlation with HPLC, with an AUC0-12h overestimation of 11.32% ± 15.77%. CONCLUSIONS: The pharmacokinetic profile of total and free MPA and its main metabolite MPAG was examined in Chinese adult renal transplant patients receiving EC-MPS. The use of LSS to estimate individual free and total MPA exposure could be useful in optimizing patient care.