Scientific document processing: challenges for modern learning methods.

Neural network models enjoy success on language tasks related to Web documents, including news and Wikipedia articles. However, the characteristics of scientific publications pose specific challenges that have yet to be satisfactorily addressed: the discourse structure of scientific documents crucial in scholarly document processing (SDP) tasks, the interconnected nature of scientific documents, and their multimodal nature. We survey modern neural network learning methods that tackle these challenges: those that can model discourse structure and their interconnectivity and use their multimodal nature. We also highlight efforts to collect large-scale datasets and tools developed to enable effective deep learning deployment for SDP. We conclude with a discussion on upcoming trends and recommend future directions for pursuing neural natural language processing approaches for SDP.

Controlled Adhesion of Ice-Toward Ultraclean 2D Materials.

The scalable 2D device fabrication and integration demand either the large-area synthesis or the post-synthesis transfer of 2D layers. While the direct synthesis of 2D materials on most targeted surfaces remains challenging, the transfer approach from the growth substrate onto the targeted surfaces offers an alternative pathway for applications and integrations. However, the current transfer techniques for 2D materials predominantly involve polymers and organic solvents, which are liable to contaminate or deform the ultrasensitive atomic layers. Here, novel ice-aided transfer and ice-stamp transfer methods are developed, in which water (ice) is the only medium in the entire process. In practice, the adhesion between various 2D materials and ice can be well controlled by temperature. Through such controlled adhesion of ice, it is shown that the new transfer methods can yield ultrahigh quality and exceptional cleanliness in transferred 2D flakes and continuous 2D films, and are applicable for a wide range of substrates. Furthermore, beyond transfer, ice can also be used for cleaning the surfaces of 2D materials at higher temperatures. These novel techniques can enable unprecedented ultraclean 2D materials surfaces and performances, and will contribute to the upcoming technological revolutions associated with 2D materials.

Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Critical Overview of Hepatic Factors That Link Non-Alcoholic Fatty Liver Disease and Acute Kidney Injury: Physiology and Therapeutic Implications.

Non-alcoholic fatty liver disease (NAFLD) is defined as a combination of a group of progressive diseases, presenting different structural features of the liver at different stages of the disease. According to epidemiological surveys, as living standards improve, the global prevalence of NAFLD increases. Acute kidney injury (AKI) is a class of clinical conditions characterized by a rapid decline in kidney function. NAFLD and AKI, as major public health diseases with high prevalence and mortality, respectively, worldwide, place a heavy burden on societal healthcare systems. Clinical observations of patients with NAFLD with AKI suggest a possible association between the two diseases. However, little is known about the pathogenic mechanisms linking NAFLD and AKI, and the combination of the diseases is poorly treated. Previous studies have revealed that liver-derived factors are transported to distal organs via circulation, such as the kidney, where they elicit specific effects. Of note, while NAFLD affects the expression of many hepatic factors, studies on the mechanisms whereby NAFLD mediates the generation of hepatic factors that lead to AKI are lacking. Considering the unique positioning of hepatic factors in coordinating systemic energy metabolism and maintaining energy homeostasis, we hypothesize that the effects of NAFLD are not only limited to the structural and functional changes in the liver but may also involve the entire body via the hepatic factors, e.g., playing an important role in the development of AKI. This raises the question of whether analogs of beneficial hepatic factors or inhibitors of detrimental hepatic factors could be used as a treatment for NAFLD-mediated and hepatic factor-driven AKI or other metabolic disorders. Accordingly, in this review, we describe the systemic effects of several types of hepatic factors, with a particular focus on the possible link between hepatic factors whose expression is altered under NAFLD and AKI. We also summarize the role of some key hepatic factors in metabolic control mechanisms and discuss their possible use as a preventive treatment for the progression of metabolic diseases.

Eleutheroside B-loaded poly (lactic-co-glycolic acid) nanoparticles protect against renal fibrosis via Smad3-dependent mechanism.

Although renal fibrosis is a common complication of chronic kidney disease (CKD), effective options for its treatment are currently limited. In this study, we evaluated the renal protective effect and possible mechanism of eleutheroside B. In order to solve the allergic reactions, side effects, and low oral bioavailability of eleutheroside B, we successfully prepared PLGA (poly [lactic-co-glycolic acid])-eleutheroside B nanoparticles (NPs) with the diameter of about 128 nm. In vitro and in vivo results showed that eleutheroside B could inhibit expression levels of α-smooth muscle actin (α-SMA) and collagen I. Molecular docking results showed that eleutheroside B bound to Smad3 and significantly decreased the expression of phospho-Smad3 (p-Smad3). Silencing Smad3 reversed the fibrotic protective effect of eleutheroside B in HK2 cells. Furthermore, small animal imaging showed that NPs can selectively accumulate in the UUO kidneys of mice, and retention time reached as long as 7 days. In conclusion, our results suggested that eleutheroside B is a potential drug to protect renal fibrosis and PLGA-eleutheroside B NPs could facilitate specific targeted therapy for renal fibrosis.

Gypenoside XLIX loaded nanoparticles targeting therapy for renal fibrosis and its mechanism.

Renal fibrosis is the main pathological feature of the occurrence and development of chronic nephropathy. At present, there is no effective treatment, except for renal transplantation and dialysis. Previous studies have shown that nano-preparations can be used as a therapeutic tool to target organs. In this study, we studied the therapeutic effect and mechanism of Chinese medicine monomer Gypenoside (Gyp) XLIX on renal fibrosis and explored the targeting and therapeutic effects of polylactic acid-co-glycoside (PLGA)-Gyp XLIX nanoparticles in unilateral ureteral occlusion (UUO) kidney. Gyp XLIX and PLGA-Gyp XLIX nanoparticles were used to treat UUO mice and Human renal tubular epithelial (HK2) cells stimulated by transforming growth factor-ß (TGF-ß). Histopathological and molecular biological techniques were used to detect the expression of type I collagen and alpha-smooth muscle actin (α-SMA). To investigate the in vivo targeting of PLGA nanoparticles, they were loaded with 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide and injected into UUO mice. We evaluated the effect of Gyp XLIX nanoparticles on TGF-ß/Smad3 pathway, a central driver for renal fibrosis in Smad-deficient HK2 cells. Fluorescence imaging showed that the PLGA nanoparticles around 120 nm could be targeted to the UUO kidney. Compared with Gyp XLIX, PLGA-Gyp XLIX nanoparticles could effectively inhibit renal fibrosis and reduce collagen deposition and reduce renal tubular necrosis. Gyp XLIX decreased the phosphorylation of Smad3, but could not further reduce the levels of type I collagen and α-SMA in Smad-deficient cells. This study opens a promising way for targeted drug treatment of renal fibrosis.

LPS-Induced Inflammation Affects Midazolam Clearance in Juvenile Mice in an Age-Dependent Manner.

PURPOSE: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis. METHODS: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9-42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2. RESULTS: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age. CONCLUSION: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.

Off-label use of letrozole in Chinese short pubertal boys: Effectiveness, safety, and exposure-response analysis.

AIMS: Recently, letrozole has been used off-label to treat short pubertal boys. The experience on letrozole effectiveness and safety has been obtained primarily from Caucasian children. A simple extrapolation of the data to Chinese paediatric populations is questionable because of the substantial ethnic differences between the two populations. Therefore, the present study aimed to determine the effectiveness and safety of letrozole use in Chinese short pubertal boys as well as to establish an exposure-response relationship. METHODS: Forty-one Chinese boys were included in the study. Patients were given letrozole tablets (2.5 mg) once daily in combination with growth hormone, and follow-up visits were made after 1, 3, 6 and 12 months of treatment. Plasma samples were taken from clinical examinations and analysed using high performance liquid chromatography with fluorescence detection. RESULTS: After 1 year of treatment, 35 (88%) boys showed increased predicted adult heights. However, possible adverse drug reactions were seen in nine boys (22%). Predicted adult heights increased significantly from 168.4 ± 3.7 to 173.0 ± 4.2 cm, while oestrogen levels dropped from 33.2 ± 7.4 to 21.6 ± 7.3 pg/mL. Increments in predicted adult height were significantly correlated with trough letrozole concentrations (r = 0.39, P = .01). CONCLUSION: Letrozole treatment in Chinese pubertal populations should be further optimized, and more personalized therapies should be developed.

Naringin Targets NFKB1 to Alleviate Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury in PC12 Cells Via Modulating HIF-1α/AKT/mTOR-Signaling Pathway.

This study was designed to investigate the effect of naringin in oxygen-glucose deprivation/reoxygenation (OGD/R) model and its mechanism. The target gene of naringin and the enriched pathways of the gene were searched and identified using bioinformatics analysis. Then OGD/R model was built using PC12 cells, after which the cells were treated with different concentrations of naringin. Subsequently, cell proliferation and apoptosis were evaluated by cell counting kit-8 (CCK-8) and flow cytometry assays, respectively. Meanwhile, the expression of NFKB1 in PC12 cells underwent OGD/R-induced injury was detected by qRT-PCR, while apoptosis-related and pathway-related proteins were checked by Western blot. DCF-DA kit was utilized to measure the level of ROS. Our results revealed that NFKB1, which was upregulated in MACO rats and OGD/R-treated PC12 cells, was a target gene of naringin. Naringin could alleviate OGD/R-induced injury via promoting the proliferation, and repressing the apoptosis of PC12 cells through regulating the expression of NFKB1 and apoptosis-associated proteins and ROS level. Besides, the depletion of NFKB1 was positive to cell proliferation but negative to cell apoptosis. Moreover, the depletion of NFKB1 enhanced the influences of naringin on cell proliferation and apoptosis as well as the expression of apoptosis-related proteins and ROS level. Western blotting indicated that both naringin treatment and depletion of NFKB1 could increase the expression of HIF-1α, p-AKT, and p-mTOR compared with OGD/R group. What's more, treatment by naringin and si-NFKB1 together could significantly increase these effects. Nevertheless, the expression of AKT and mTOR among each group was almost not changed. In conclusion, naringin could prevent the OGD/R-induced injury in PC12 cells in vitro by targeting NFKB1 and regulating HIF-1α/AKT/mTOR-signaling pathway, which might provide novel ideas for the therapy of cerebral ischemia-reperfusion (I/R) injury.

Prediction of Unbound Ceftriaxone Concentration in Children: Simple Bioanalysis Method and Basic Mathematical Equation.

The pharmacological activity of ceftriaxone depends on the unbound concentration. However, direct measurement of unbound concentrations is obstructive, and high individual variability of the unbound fraction of ceftriaxone was shown in children. We aim to evaluate and validate a method to predict unbound ceftriaxone concentrations in pediatric patients. Ninety-five pairs of concentrations (total and unbound) from 92 patients were measured by the bioanalysis method that we developed. The predictive performance of the three equations (empirical in vivo equation, disease-adapted equation, and multiple linear regression equation) was assessed by the mean absolute prediction error (MAPE), the mean prediction error (MPE), the proportions of the prediction error within ±30% (P30) and ±50% (P50), and linear regression of predicted versus actual unbound levels (R2). The average total and unbound ceftriaxone concentrations were 126.18 ± 81.46 µg/ml and 18.82 ± 21.75 µg/ml, and the unbound fraction varied greatly from 4.75% to 39.97%. The MPE, MAPE, P30, P50, and R2 of the empirical in vivo equation, disease equation, and multiple linear equation were 0.17 versus 0.00 versus 0.06, 0.24 versus 0.15 versus 0.27, 63.2% versus 89.5% versus 74.7%, 96.8% versus 97.9% versus 86.3%, and 0.8730 versus 0.9342 versus 0.9315, respectively. The disease-adapted equation showed the best predictive performance. We have developed and validated a bioanalysis method with one-step extraction pretreatment for the determination of total ceftriaxone concentrations, and a prediction equation of the unbound concentration is recommended. The proposed method can facilitate clinical practice and research on unbound ceftriaxone in children. (This study has been registered at ClinicalTrials.gov under identifier NCT03113344.).

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

PURPOSE: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. METHODS: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. CONCLUSIONS: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Neural side effect discovery from user credibility and experience-assessed online health discussions.

BACKGROUND: Health 2.0 allows patients and caregivers to conveniently seek medical information and advice via e-portals and online discussion forums, especially regarding potential drug side effects. Although online health communities are helpful platforms for obtaining non-professional opinions, they pose risks in communicating unreliable and insufficient information in terms of quality and quantity. Existing methods in extracting user-reported adverse drug reactions (ADRs) in online health forums are not only insufficiently accurate as they disregard user credibility and drug experience, but are also expensive as they rely on supervised ground truth annotation of individual statement. We propose a NEural ArchiTecture for Drug side effect prediction (NEAT), which is optimized on the task of drug side effect discovery based on a complete discussion while being attentive to user credibility and experience, thus, addressing the mentioned shortcomings. We train our neural model in a self-supervised fashion using ground truth drug side effects from mayoclinic.org. NEAT learns to assign each user a score that is descriptive of their credibility and highlights the critical textual segments of their post. RESULTS: Experiments show that NEAT improves drug side effect discovery from online health discussion by 3.04% from user-credibility agnostic baselines, and by 9.94% from non-neural baselines in term of F1. Additionally, the latent credibility scores learned by the model correlate well with trustworthiness signals, such as the number of "thanks" received by other forum members, and improve credibility heuristics such as number of posts by 0.113 in term of Spearman's rank correlation coefficient. Experience-based self-supervised attention highlights critical phrases such as mentioned side effects, and enhances fully supervised ADR extraction models based on sequence labelling by 5.502% in terms of precision. CONCLUSIONS: NEAT considers both user credibility and experience in online health forums, making feasible a self-supervised approach to side effect prediction for mentioned drugs. The derived user credibility and attention mechanism are transferable and improve downstream ADR extraction models. Our approach enhances automatic drug side effect discovery and fosters research in several domains including pharmacovigilance and clinical studies.

Population pharmacokinetics and dose optimization of ceftriaxone for children with community-acquired pneumonia.

PURPOSE: To assess ceftriaxone population pharmacokinetics in a large pediatric population and describe the proper dose for establishing an optimized antibiotic regimen. METHODS: From pediatric patients using ceftriaxone, blood samples were obtained and the concentration was measured using high-performance liquid chromatography ultraviolet detection. The NONMEM software program was used for population pharmacokinetic analysis, for which data from 99 pediatric patients (2 to 12 years old) was collected and 175 blood concentrations were obtained. RESULTS: The best fit with the data was shown by the one-compartment model with first-order elimination. According to covariate analysis, weight had a significant impact on the clearance of ceftriaxone. Using Monte Carlo simulation, in a pediatric population with community-acquired pneumonia, a dose regimen of 100 mg/kg every 24 h produced satisfactory target attainment rates while remaining within the required minimum inhibitory concentration (2 mg/L). CONCLUSION: Population pharmacokinetics of ceftriaxone was evaluated in children and an optimum dosing regimen was constructed on the basis of the pharmacokinetics-pharmacodynamics model-based approach.

First dose in neonates: pharmacokinetic bridging study from juvenile mice to neonates for drugs metabolized by CYP3A.

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (Vd), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

An adapted LC-MS/MS method for the determination of free plasma concentration of cefoperazone in children: Age-dependent protein binding.

Antimicrobial activity of cefoperazone, a high protein bound cephalosporin, depends on its unbound concentration. However, the protein binding data of cefoperazone in children is limited, making it challenging to optimize antimicrobial therapy in pediatric clinical practice. Furthermore, a validated method to measure the free part in children is unavailable with the small volume of samples that can be obtained. Therefore, in the present study, we developed and validated an LC-MS/MS method for the determination of free cefoperazone in children. In this study, 70 µL of plasma was used to prepare the ultrafiltrate (only containing the free drug). Chromatographic separation of the analyte was achieved on a C18 column using gradient elution with a mobile phase of acetonitrile and water (0.1% formic acid). Negative electrospray ionisation in the multiple reaction monitoring mode was applied for the detection of cefoperazone and ceftiofur (internal standard). The calibration curve was prepared in the range of 5-5000 ng/mL with excellent linearity. For each level of quality control samples, the intra- and inter-day precision (CV) was below 9.0%, and the accuracy ranged from 91.5% to 105.0%. The matrix effect was less than 11.7%, and the recovery was between 92.9% and 95.9% of cefoperazone. The validated method has been successfully applied to the determination of free plasma concentration of cefoperazone in pediatric patients. The results of the unbound fraction showed considerable individual variability (range: 8.1-48.0%). The correlation analysis showed that age and albumin had significant effects on the protein binding of cefoperazone.

Cefotiam Treatment in Children: Evidence of Subtherapeutic Levels.

BACKGROUND: Cefotiam, a second-generation cephalosporin, is a broad-spectrum antibiotic with good antibacterial action against both gram-negative and gram-positive bacteria. It is used widely in clinical practice, although bacterial drug resistance makes its clinical use problematic. The authors hypothesized that subtherapeutic concentrations of cefotiam leads to bacterial resistance. The present study was conducted to evaluate whether the standard cefotiam dosing regimen resulted in a subtherapeutic concentrations in children. METHOD: Data were prospectively collected from pediatric patients with suspected or confirmed community-acquired pneumonia who were receiving cefotiam at the standard dosing regimen (40-80 mg/kg, 2 or 3 times daily). A blood sample was collected after 70%-100% of the dosing interval, and plasma concentrations were determined by high-performance liquid chromatography using an ultraviolet detector. RESULTS: The data from 88 patients (age, 3.0 ± 2.8 years; weight, 15.4 ± 8.3 kg) were used for analysis. The average of cefotiam concentrations was 0.06 mcg/mL (range: <0.05-0.79 mcg/mL). Most patients (n = 72, 81.8%) had concentrations below 0.1 mcg/mL; only 2 patients had concentrations higher than 0.4 mcg/mL. CONCLUSIONS: The standard dosing regimen for cefotiam resulted in extremely low plasma concentrations in children; such low concentrations may lead to antimicrobial drug resistance. Thus, an increase in cefotiam dosage in children to 80 mg/kg 4 times daily is recommended (maximum dose on the label).

Developmental population pharmacokinetics-pharmacodynamics and dosing optimization of cefoperazone in children.

OBJECTIVES: To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic-pharmacodynamic approach in order to optimize cefoperazone treatment. METHODS: A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic-pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). RESULTS: A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with '40 mg/kg/day, q8h, IV drip 3 h' would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. CONCLUSIONS: For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics-pharmacodynamics. The dose indicated in the instructions (20-160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.

Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.

BACKGROUND: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients. METHODS: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped. RESULTS: Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001). CONCLUSION: The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.

Pyrrolidine Dithiocarbamate Prevents Neuroinflammation and Cognitive Dysfunction after Endotoxemia in Rats.

Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood. Using a model of peripheral endotoxemia with lipopolysaccharide (LPS) we investigated the role of nuclear factor-κB (NF-κB) activity in mediating long-term neuroinflammation and cognitive dysfunction in aged rats. Herein we describe the anti-inflammatory effects of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, in modulating systemic cytokines including tumor necrosis factor (TNF)-α and interleukin-1ß (IL-1ß) and CNS markers after LPS exposure in aged rats. In the hippocampus, PDTC not only reduced neuroinflammation by modulating canonical NF-κB activity but also affected IL-1ß expression in astrocytes. Parallel effects were observed on behavior and postsynaptic density-95 (PSD95), a marker of synaptic function. Taken together these changes improved acute and long-term cognitive function in aged rats after LPS exposure.

Structure and Properties of Egyptian Blue Monolayer Family: XCuSi4O10 (X = Ca, Sr, and Ba).

Motivated by the recent experimental advances in exfoliating Egyptian blue monolayers, we have carried out extensive calculations using density functional theory to understand their geometry, stability, mechanical properties, electronic structures, and magnetism. Upon exfoliation from the bulk, XCuSi4O10 (X = Ca, Sr, and Ba) monolayers are found to change symmetry from tetragonal to orthorhombic. They all satisfy Born criteria and are mechanically stable. Each Cu site carries a magnetic moment of 1.0 µB but with degenerate ferromagnetic and antiferromagnetic coupling states. From Ca to Sr and Ba, as the atomic number increases, the thickness, elastic constants, Young's moduli, and Poisson's ratios of the monolayers increase, while the band gaps decrease. Applying strain can tune the magnitude of energy band gaps, but the direct gap feature remains. Complementing the widely studied graphene, MXenes, black phosphorus, and dichalcogenide sheets, the Egyptian blue monolayers add additional features to the family of two-dimensional materials.