Clinical utility of a model-based amoxicillin dosage regimen in neonates with early-onset sepsis.

Early-onset sepsis (EOS) is one of the most significant causes of morbidity and mortality in neonates. Currently, amoxicillin is empirically used to treat neonates with EOS. However, data on its effectiveness in neonates with EOS are still limited. Therefore, we aimed to evaluate the pharmacodynamics (PD) target attainment and effectiveness of a model-based amoxicillin dosage regimen in these neonates. We used a previously developed model and collected additional clinical data from the EOS neonates who used the model-based dosage regimen (25 mg/kg every 12 h). The primary outcomes were PD target attainment (free drug concentration above minimum inhibitory concentration during 70% of the dosing interval) and treatment failure rate. The secondary endpoints were length of amoxicillin treatment, duration of hospitalization etc. Seventy-five neonates (postmenstrual age 28.4-41.6 wk) were enrolled. A total of 70 (93.3%) neonates reached their PD target using 1 mg/L as the minimum inhibitory concentration breakpoint. The treatment failure rate was 10.7%.

Gold nanoparticle-assisted plasmonic enhancement for DNA detection on a graphene-based portable surface plasmon resonance sensor.

The impact of different gold nanoparticle (GNP) structures on plasmonic enhancement for DNA detection is investigated on a few-layer graphene (FLG) surface plasmon resonance (SPR) sensor. Two distinct structures of gold nano-urchins (GNu) and gold nanorods (GNr) were used to bind the uniquely designed single-stranded probe DNA (ssDNA) of Mycobacterium tuberculosis complex DNA. The two types of GNP-ssDNA mixture were adsorbed onto the FLG-coated SPR sensor through the π-π stacking force between the ssDNA and the graphene layer. In the presence of complementary single-stranded DNA, the hybridization process took place and gradually removed the probes from the graphene surface. From SPR sensor preparation, the annealing process of the Au layer of the SPR sensor effectively enhanced the FLG coverage leading to a higher load of the probe DNA onto the sensing interface. The FLG was shown to be effective in providing a larger surface area for biomolecular capture due to its roughness. Carried out in the DNA hybridization study with the SPR sensor, GNu, with its rough and spiky structures, significantly reinforced the overall DNA hybridization signal compared with GNr with smooth superficies, especially in capturing the probe DNA. The DNA hybridization detection assisted by GNu reached the femtomolar range limit of detection. An optical simulation validated the extreme plasmonic field enhancement at the tip of the GNu spicules. The overall integrated approach of the graphene-based SPR sensor and GNu-assisted DNA detection provided the proof-of-concept for the possibility of tuberculosis disease screening using a low-cost and portable system to be potentially applied in remote or third-world countries.

Surface plasmon-enhanced solution-processed phosphorescent organic light-emitting diodes by incorporating gold nanoparticles.

Organic light-emitting diodes (OLEDs) have attracted increasing attention due to their superiority as high quality displays and energy-saving lighting. However, improving the efficiency of solution-processed devices especially based on blue emitter remains a challenge. Excitation of surface plasmons on metallic nanoparticles has potential for increasing the absorption and emission from optoelectronic devices. We demonstrate here that the incorporation of gold nano particles (GNPs) in the hole injection layer of poly(3,4-ethylene dioxythiophene):polystyrene sulfonic acid with an appropriate size and doping concentration can greatly enhance the efficiency OLED device especially at higher voltage. Apparently, the spectral of the multiple plasmon resonances of the GNPs and the luminescence of the emitting materials significantly overlap with each other. At 1000 cd m-2 for example, the power efficiency of a studied green device is increased from 29.0 to 36.2 lm W-1, an increment of 24.8%, and the maximum brightness improved from 21 550 to 27 810  cd m-2, an increment of 29.1%, as 2 wt% of a 12 nm GNP is incorporated. Remarkably, designed blue OLED also exhibited an increment of 50% and 35% in power efficacy at 100 and 1000 cd m-2, respectively, for same device structure. The reason why the enhancement is marked may be attributed to a strong absorption of the short-wavelength emission from the device by the gold nano particles, which in turn initiates a strong surface plasmon resonance effect, leading to a high device efficiency.

Influence of prevention of caffeine citrate on cytokine profile and bronchopulmonary dysplasia in preterm infants with apnea.

BACKGROUND: This study aims to investigate the preventive effects of caffeine citrate on cytokine profile and bronchopulmonary dysplasia (BPD) in preterm infants with apnea. METHODS: Preterm infants with apnea who were born at less than 32 weeks of gestational age and birth weight ≤1500 g were randomly divided into caffeine citrate prevention group and caffeine citrate treatment group. Preterm infants in caffeine citrate prevention group who were at risk of developing recurrent apnea were given to caffeine citrate within 8 h after birth. Those in caffeine citrate treatment group experienced apnea after birth were given to caffeine citrate for treatment. Preterm infants in both groups were treated with the same respiratory management and other conventional therapy. After drug discontinuation, levels of cytokine profile, and incidence of BPD were compared between two groups. RESULTS: A total of 56 preterm infants were enrolled. Differences in gestational age (P=0.11) and birth weight (P=0.251) were not statistically significant. Differences in application time of caffeine citrate (P=0.356), hour of ventilator use (P=0.152), length of stay (P=0.416) and BPD morbidity (P=1.00) between two groups were not statistically significant. At birth, there were no statistically significant in levels of IL-6 (P=0.063) and IL-8 (P=0.125) between two groups. After conventional therapy, levels of IL-6 (P=0.001) and IL-8 (P=0.001) significantly decreased in caffeine citrate prevention group compared with those in caffeine citrate treatment group. CONCLUSIONS: Prevention usage of caffeine citrate in preterm infants with apnea could reduce the level of cytokine profile and the incidence of BPD.

Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants.

Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.

Pilot Study of Model-Based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection.

Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. A target area under the concentration-time curve from 0 to 24 h (AUC0-24) of 40 to 50 µg · h/ml is recommended. The standard dose has resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization for this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach. The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC0-24 to ensure its efficacy. A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC0-24 after being given the standard dose. For all the subtherapeutic patients (achieving <80% of the target AUC) (n = 5), a model-based dosage adjustment was performed using the Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased by 28.6% to 60.0% in these five patients, and all adapted AUC0-24 values achieved the target (range, 48.6 to 66.1 µg · h/ml). The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. The population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinically feasible method to adapt the ganciclovir dose in neonatal clinical practice. (This study has been registered at ClinicalTrials.gov under registration no. NCT03113344.).

A microscale HPLC-UV method for the determination of latamoxef in plasma: An adapted method for therapeutic drug monitoring in neonates.

Latamoxef, a broad-spectrum anti-bacterial agent of the ß-lactam antibiotics, is used off-label in treatment of neonatal sepsis. Large inter-individual variability and uncertainty of treatment make therapeutic drug monitoring (TDM) useful to optimize antimicrobial therapy. The objective of this study was to develop and validate a simple, selective and reliable HPLC method for the determination of latamoxef in small volumes of plasma, which could be used in neonatal TDM. After a simple protein precipitation, analytes were separated with liquid chromatography and quantified by UV detection, with tinidazole as the internal standard. The calibration range was linear from 3.0 to 60.0 µg/mL. Intra- and inter-day precisions were < 7.2%. The acceptance criteria of accuracy (between 85 and 115%, 120% for lower limit of quantification) were met in all cases. A plasma volume of 50 µL was required to achieve the limit of quantification of 3.0 µg/mL. The TDM results showed a large variability in trough concentrations. A large number of patients were underdosed, highlighting the unmet need for TDM to optimize latamoxef therapy in neonates.

Cardiac computed tomography angiography-derived pulmonary vein volumetry as a predictor for atrial fibrillation recurrence after catheter ablation.

Background: There is an increasing evidence that pulmonary vein (PV) enlargement is associated with atrial fibrillation (AF); however, the predictive value of PV enlargement in AF recurrence remains unclear. This study sought to evaluate whether PV volume quantification derived from cardiac computed tomographic angiography (CCTA) could serve as a predictive indicator of the success of the catheter ablation (CA) procedure. Methods: The data of 160 patients diagnosed with AF who underwent both CCTA and CA treatments from January to June 2020 were retrospectively examined; the CCTA was conducted before the CA surgery. The study focused on documenting the PV structure, and the volume of the PV and left atrium (LA). The clinical, CCTA, and echocardiographic predictors of the recurrence and no-recurrence groups were compared. A multivariable logistic regression analysis was performed to adjust for confounders. Receiver operating characteristic (ROC) curves were analyzed to assess the predictive performance of the predictors of AF recurrence. Results: Of the 160 patients [55.6% male, 62.00 (55.25-68.00) years, 23.1% with persistent AF], 45 (28.1%) experienced AF recurrence within a one-year period. Notably, patients with AF recurrence had elevated CHADS2 scores (P=0.020) and increased LA and PV volumes (P<0.05). Patients with persistent AF (n=37) had significantly larger LA volume indexes (P<0.001) than those with paroxysmal AF, but there was no difference between the two groups in terms of the PV maximum volume index (P=0.200). Moreover, the PV maximum volume index [odds ratio (OR): 1.244, 95% confidence interval (CI): 1.008-1.536, P=0.042] and the LA minimum volume index (OR: 1.026, 95% CI: 1.001-1.052, P=0.038) were found to be significant predictors of AF recurrence. The ROC curves revealed that the PV maximum volume index threshold for predicting AF recurrence was 7.13 mL/m2, with a sensitivity of 84.4% and a specificity of 34.8% [area under the curve (AUC): 0.635, 95% CI: 0.540-0.730, P=0.008], and the LA minimum volume index threshold for predicting AF recurrence was 46.16 mL/m2, with a sensitivity of 88.9% and a specificity of 31.3% (AUC: 0.629, 95% CI: 0.534-0.723, P=0.012). A sub-analysis of patients with a lower left atrial dimension (LAD ≤38 mm in females, LAD ≤40 mm in males, n=120) demonstrated that the PV maximum volume index was a noteworthy indicator of AF recurrence (OR: 1.443: 95% CI: 1.145-1.820, P=0.002). Conversely, no significant correlation between AF recurrence and the LA volume index was found. The AUC value for the PV maximum volume index predictive of recurrent AF was 0.680 (95% CI: 0.577-0.781, P=0.003), with a sensitivity of 75.8%, specificity of 54%, and the cut-off value of the maximum AUC was 7.89 mL/m2. Conclusions: PV volume, derived from CCTA, may help to predict the recurrence of AF after CA, and is superior to the LA size in patients with less pronounced LA enlargement.

The Associations of Vitamin D Level with Metabolic Syndrome and Its Components Among Adult Population: Evidence from National Health and Nutrition Examination Survey 2017-2018.

Background and Purpose: Vitamin D can both stimulate and inhibit adipogenesis, indicating that associations of the vitamin D level with some metabolic disorders may be nonlinear. This cross-sectional study aims to explore potential nonlinear associations of the 25-hydroxy vitamin D [25(OH)D] level with metabolic syndrome (MetS) and its components. Methods: Adults without previously diagnosed specific noncommunicable disease were selected from the National Health and Nutrition Examination Survey 2017-2018 (n = 870). Their demographic, physical, and laboratory data were obtained. The associations of serum 25(OH)D with MetS and its components were analyzed using logistic regression. Restricted cubic spline was applied to flexibly model the nonlinear association if the nonlinearity test was statistically significant. Results: The 25(OH)D level was inversely associated with risk of MetS [adjusted odds ratio (OR) = 0.986; 95% confidence interval (CI) = 0.978-0.993] and most MetS components, but not with the risk of raised triglycerides (adjusted OR = 0.996; 95% CI = 0.988-1.005). The association of serum 25(OH)D with central obesity risk was significantly nonlinear (P for the nonlinearity test: 0.037). The OR for risk of central obesity decreased rapidly with increase in serum 25(OH)D concentration until the concentration reached 50 nmol/L, and then, the intensity of decrease in OR slowed down. Conclusions: Vitamin D is inversely associated with MetS, but not all MetS components. A nonlinear association between the vitamin D level and risk of central obesity has been found for the first time among the adult population, which reflects the complex roles of vitamin D in lipid metabolism. Although vitamin D deficiency (<50 nmol/L) was defined to avoid abnormal calcium and phosphorus metabolism, preventing its deficiency may also be beneficial for reduction of central obesity risk.

Aluminum surface defect detection method based on a lightweight YOLOv4 network.

Deep learning is currently being used to automate surface defect detection in aluminum. The common target detection models based on neural networks often have a large number of parameters and a slow detection speed, which is not conducive to real-time detection. Therefore, this paper proposes a lightweight aluminum surface defect detection model, M2-BL-YOLOv4, based on the YOLOv4 algorithm. First, in the YOLOv4 model, the complex CSPDarkNet53 backbone network was modified into an inverted residual structure, which greatly reduced the number of parameters in the model and increased the detection speed. Second, a new feature fusion network, BiFPN-Lite, is designed to improve the fusion ability of the network and further improve its detection accuracy. The final results show that the mean average precision of the improved lightweight YOLOv4 algorithm in the aluminum surface defect test set reaches 93.5%, the number of model parameters is reduced to 60% of the original, and the number of frames per second (FPS) detected is 52.99, which increases the detection speed by 30%. The efficient detection of aluminum surface defects is realized.

Perspectives on miRNAs directly targeting BDNF for cancer diagnosis and treatment (Review).

MicroRNA (miRNA), a non­coding single­stranded RNA molecule with a length of 21­25 nucleotides transcripts, has been identified to play important roles in tumorigenesis and shows great potential applications in cancer diagnosis, prognosis and therapy. Brain derived neurotrophic factor (BDNF) is a member of the nerve growth factor family and usually serves as a biomarker in neurological and neuropsychiatric diseases for diagnosis and treatment by regulating its high­affinity receptor TrkB (Tyrosine Kinase Receptor B). Abnormal expression of BDNF is also closely related to the development of cancer, cancer­related pain and depression. However, little significant progress has been made in the application of BDNF in cancers. Recent studies have shown that the expression of BDNF is directly regulated by a cluster of miRNAs. This review concluded and discussed the role and mechanism of miRNAs targeting BDNF in cancers, and provided novel insights into the diagnosis and therapy of cancer in the future.

Multi-objective optimization of water distribution networks based on non-dominated sequencing genetic algorithm.

Due to the conflict between reducing cost and improving water supply performance, how to select the appropriate pipe diameter is a current challenge. In this paper, the problem is transformed into a multi-objective optimization problem, and the evolutionary genetic optimization algorithm is used to solve the problem to determine the optimal selection of pipe diameter in the pipe network. To solve this problem, the evolutionary genetic algorithm was coupled with EPANET hydraulic simulation software in Python environment. The results show that NSGA-II and NSGA-III perform better in two typical case tests. Moreover, the increase of the objective functions will lead to an increase in the amount of data in the optimal solution set, and will affect the optimal value of each objective function. That shows that the balance between the economy and reliability of water supply can be successfully found by coupling the hydraulic model and the multi-objective optimization algorithm, which can provide an auxiliary decision for enterprises.

Developmental Population Pharmacokinetics-Pharmacodynamics of Meropenem in Chinese Neonates and Young Infants: Dosing Recommendations for Late-Onset Sepsis.

The pharmacokinetic (PK) studies of meropenem in Chinese newborns with late-onset sepsis (LOS) are still lacking. Causative pathogens of LOS and their susceptibility patterns in China differ from the data abroad. We, therefore, conducted a developmental population pharmacokinetic−pharmacodynamic analysis in Chinese newborns with the goal to optimize meropenem dosing regimens for LOS therapy. An opportunistic sampling strategy was used to collect meropenem samples, followed by model building and validation. A Monte Carlo simulation was performed to show the probability of target attainment (PTA) for various dosages. The information from 78 newborns (postmenstrual age: 27.4−46.1 weeks) was compiled and had a good fit to a 1-compartment model that had first order elimination. The median (range) values of estimated weight−normalized volume of distribution (V)and clearance (CL) were 0.60 (0.51−0.69) L/kg and 0.16 (0.04−0.51) L/h/kg, respectively. Covariate analysis revealed that postnatal age (PNA), gestational age (GA) and current weight (CW) were the most important factors in describing meropenem PK. Simulation results showed for LOS with a minimal inhibitory concentration (MIC) of 8 mg/L, the doses of 30 mg/kg 3 times daily (TID) as a 1-h infusion for newborns with GA ≤ 37 weeks and 40 mg/kg TID as a 3-h infusion for those with GA > 37 weeks were optimal, with PTA of 71.71% and 75.08%, respectively. In conclusion, we proposed an evidence-based dosing regimen of meropenem for LOS in Chinese newborns by using the population pharmacokinetic−pharmacodynamic analysis, based on domestic common pathogens and their susceptibility patterns.

Room-Temperature Fabrication of p-Type SnO Semiconductors Using Ion-Beam-Assisted Deposition.

Over the past decade, SnO has been considered a promising p-type oxide semiconductor. However, achieving high mobility in the fabrication of p-type SnO films is still highly dependent on the post-annealing procedure, which is often used to make SnO, due to its metastable nature, readily convertible to SnO2 and/or intermediate phases. This paper demonstrates a fully room-temperature fabrication of p-type SnOx thin films using ion-beam-assisted deposition. This technique offers independent control between ion density, via the ion-gun anode current and oxygen flow rate, and ion energy, via the ion-gun anode voltage, thus being able to optimize the optical band gap and the hole mobility of the SnO films to reach 2.70 eV and 7.89 cm2 V-1 s-1, respectively, without the need for annealing. Remarkably, this is the highest mobility reported for p-type SnO films whose fabrication was carried out entirely at room temperature. Using first-principles calculations, we rationalize that the high mobility is associated with the fine-tuning of the Sn-rich-related defects and lattice densification, obtained by controlling the density and energy of the oxygen ions, both of which optimize the spatial overlap of the valence bands to form a continuous conduction path for the holes. Moreover, due to the absence of the annealing process, the Raman spectra reveal no significant signatures of microcrystal formation in the films. This behavior contrasts with the case involving the air-annealing procedure, where a complex interaction occurs between the formation of SnO microcrystals and the formation of SnOx intermediate phases. This interplay results in variations in grain texture within the film, leading to a lower optimum Hall mobility of only 5.17 cm2 V-1 s-1. Finally, we demonstrate the rectification characteristics of all-fabricated-at-room-temperature SnOx-based p-n devices to confirm the viability of the p-type SnOx films.

Assessing Plasma Levels of α-Synuclein and Neurofilament Light Chain by Different Blood Preparation Methods.

The potential biomarkers of Parkinson's disease are α-synuclein and neurofilament light chain (NFL). However, inconsistent preanalytical preparation of plasma could lead to variations in levels of these biomarkers. Different types of potassium salts of EDTA and different centrifugation temperatures during plasma preparation may affect the results of α-synuclein and NFL measurements. In this study, we prepared plasma from eight patients with Parkinson's disease (PD) and seven healthy controls (HCs) by using di- and tri-potassium (K2- and K3-) EDTA tubes and recruited a separated cohort with 42 PD patients and 40 HCs for plasma samples prepared from whole blood by centrifugation at room temperature and 4°C, respectively, in K2-EDTA tubes. The plasma levels of α-synuclein and NFL in K2- and K3-EDTA were similar. However, the levels of α-synuclein in the plasma prepared at 4°C (101.57 ± 43.43 fg/ml) were significantly lower compared with those at room temperature (181.23 ± 196.31 fg/ml, P < 0.001). Room temperature preparation demonstrated elevated plasma levels of α-synuclein in PD patients (256.6 ± 50.2 fg/ml) compared with the HCs (102.1 ± 0.66 fg/ml, P < 0.001), whereas this increase in PD was not present by preparation at 4°C. Both plasma preparations at room temperature and 4°C demonstrated consistent results of NFL, which are increased in PD patients compared with HCs. Our findings confirmed that K2- and K3-EDTA tubes were interchangeable for analyzing plasma levels of α-synuclein and NFL. Centrifugation at 4°C during plasma preparation generates considerable reduction and variation of α-synuclein level that might hinder the detection of α-synuclein level changes in PD.

Feasibility of using bimetallic Au-Ag nanoparticles for organic light-emitting devices.

Matching the resonant wavelength of plasmonic nanoparticles (NPs) and the emission band of organic materials is critical for achieving optimal plasmon-enhanced luminescence in organic light-emitting devices (OLEDs). However, the spectral matching is often unsatisfactory because the interior architecture of OLEDs limits the dimensions of the NPs to support the desired wavelength adjustment. In this article, we proposed a design strategy via AuxAg1-x alloy NPs to enable resonance tuning while preserving the size of the NP to suit the OLED design requirements. The bimetallic NPs, especially for x < 0.6, not only add one more degree of freedom to vary the plasmon wavelength but also provide the benefits of higher scattering and more intense and outspread electric fields over a broader spectrum compared to Au monometallic NPs. These features allow smaller NPs, which are more compatible with OLED interiors, to scatter electric fields more efficiently and increase the density of molecules interacting with the NP plasmons. In the presence of a nearby dipole emitter, the bimetallic NPs can simultaneously increase radiative enhancement and suppress non-radiative losses, which are advantageous for increasing the quantum yield and luminescence efficiency of the emitter. These improvements are associated with lower intraband and interband activities resulting from the higher molar fraction of Ag in the alloy NPs. We provided composition mappings to achieve enhanced luminescence for specified wavelengths at fixed NP sizes. Finally, we theoretically demonstrated that the bimetallic NPs could improve the light-extraction efficiency of OLEDs better than Au monometallic NPs. This work provides essential guidance to enable versatile plasmon-enhanced applications with predefined nanostructural geometries and wavelengths to match the device requirements.

Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial.

Early-onset neonatal sepsis (EONS), a bacterial infection that occurs within 72 h after birth, is associated with high likelihood of neonatal mortality. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has been brought back into empirical EONS treatment in recent years. In the preliminary work, we established a population pharmacokinetics (PPK) model for latamoxef in Chinese neonates. Moreover, in order to better guide clinical treatment, we conducted dose simulation and found that ascending administration frequency could improve the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval (70% fT > MIC). Accordingly, this study is aimed to compare the 70% fT > MIC, efficacy and safety between conventional regimen and PPK model regimen for rational use of latamoxef in EONS treatment. A single-blind, multicenter randomized controlled trial (RCT) for latamoxef will be conducted in Chinese EONS patients. Neonates (≤3 days of age, expected number = 114) admitted to the hospital with the diagnosis of EONS and fulfilling inclusion and exclusion criteria will be randomized (ratio of 1:1) to either a conventional regimen (30 mg/kg q12h) or model regimen (20 mg/kg q8h) latamoxef treatment group for at least 3 days. Primary outcome measure will be 70% fT > MIC and secondary outcome indicators will be the latamoxef treatment failure, duration of antibiotic therapy, changes of white blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT), blood culture results during administration and incidence of adverse event (AE)s. Assessments will be made at baseline, initial stage of latamoxef treatment (18-72 h) and before the end of latamoxef treatment. Ethical approval of our clinical trial has been granted by the ethics committee of the Beijing Children's Hospital (ID: 2020-13-1). Written informed consent will be obtained from the parents of the participants. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR 2000040064).It is hoped that our study will provide a clinical basis for the rational clinical use of latamoxef in EONS treatment.

Population pharmacokinetics-pharmacodynamics of ceftazidime in neonates and young infants: Dosing optimization for neonatal sepsis.

Ceftazidime is a third-generation cephalosporin with high activity against many pathogens. But the ambiguity and diversity of the dosing regimens in neonates and young infants impair access to effective treatment. Thus, we conducted a population pharmacokinetic study of ceftazidime in this vulnerable population and recommended a model-based dosage regimen to optimize sepsis therapy. Totally 146 neonates and young infants (gestational age (GA): 36-43.4 weeks, postnatal age (PNA): 1-81 days, current weight (CW): 900-4500 g) were enrolled based on inclusion and exclusion criteria. Ceftazidime bloods samples (203) were obtained using the opportunistic sampling strategy and determined by the high-performance liquid chromatography. The population pharmacokinetic-pharmacodynamic analysis was conducted by nonlinear mixed effects model (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic data. Covariate analysis showed the significance of GA, PNA, and CW on developmental pharmacokinetics. Monte Carlo simulation was performed based on above covariates and minimum inhibitory concentration (MIC). In the newborns with PNA ≤ 3 days (MIC=8 mg/L), the dose regimen was 25 mg/kg twice daily (BID). For the newborns with PNA > 3 days (MIC=16 mg/L), the optimal dose was 30 mg/kg three times daily (TID) for those with GA ≤ 37 weeks and 40 mg/kg TID for those with GA > 37 weeks. Overall, on the basis of the developmental population pharmacokinetic-pharmacodynamic analysis covering the whole range of neonates and young infants, the evidence-based ceftazidime dosage regimens were proposed to optimize neonatal early-onset and late-onset sepsis therapy.

Enhanced Plasmonic Biosensor Utilizing Paired Antibody and Label-Free Fe3O4 Nanoparticles for Highly Sensitive and Selective Detection of Parkinson's α-Synuclein in Serum.

Parkinson's disease (PD) is an acute and progressive neurodegenerative disorder, and diagnosis of the disease at its earliest stage is of paramount importance to improve the life expectancy of patients. α-Synuclein (α-syn) is a potential biomarker for the early diagnosis of PD, and there is a great need to develop a biosensing platform that precisely detects α-syn in human body fluids. Herein, we developed a surface plasmon resonance (SPR) biosensor based on the label-free iron oxide nanoparticles (Fe3O4 NPs) and paired antibody for the highly sensitive and selective detection of α-syn in serum samples. The sensitivity of the SPR platform is enhanced significantly by directly depositing Fe3O4 NPs on the Au surface at a high density to increase the decay length of the evanescent field on the Au film. Moreover, the utilization of rabbit-type monoclonal antibody (α-syn-RmAb) immobilized on Au films allows the SPR platform to have a high affinity-selectivity binding performance compared to mouse-type monoclonal antibodies as a common bioreceptor for capturing α-syn molecules. As a result, the current platform has a detection limit of 5.6 fg/mL, which is 20,000-fold lower than that of commercial ELISA. The improved sensor chip can also be easily regenerated to repeat the α-syn measurement with the same sensitivity. Furthermore, the SPR sensor was applied to the direct analysis of α-syn in serum samples. By using a format of paired α-syn-RmAb, the SPR sensor provides a recovery rate in the range from 94.5% to 104.3% to detect the α-syn in diluted serum samples precisely. This work demonstrates a highly sensitive and selective quantification approach to detect α-syn in human biofluids and paves the way for the future development in the early diagnosis of PD.

Drug Clearance in Neonates: A Combination of Population Pharmacokinetic Modelling and Machine Learning Approaches to Improve Individual Prediction.

BACKGROUND: Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data. OBJECTIVE: The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates. METHODS: Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods. RESULTS: The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods. CONCLUSION: A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data.