Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population.

Multiple treatment options exist for children with epilepsy, including surgery, dietary therapies, neurostimulation, and antiseizure medications (ASMs). ASMs are the first line of therapy, and more than 30 ASMs have U.S. Food and Drug Administration (FDA) approval for the treatment of various epilepsy and seizure types in children. Given the extensive FDA approval of ASMs in children, it is crucial to consider how the physiological and developmental changes throughout childhood may impact drug disposition. Various sources of pharmacokinetic (PK) variability from different extrinsic and intrinsic factors such as patients' size, age, drug-drug interactions, and drug formulation could result in suboptimal dosing of ASMs. Barriers exist to conducting clinical pharmacological studies in neonates, infants, and children due to ethical and practical reasons, limiting available data to fully characterize these drugs' disposition and better elucidate sources of PK variability. Modeling and simulation offer ways to circumvent traditional and intensive clinical pharmacology methods to address gaps in epilepsy and seizure management in children. This review discusses various physiological and developmental changes that influence the PK and pharmacodynamic (PD) variability of ASMs in children, and several key ASMs will be discussed in detail. We will also review novel trial designs in younger pediatric populations, highlight the role of extrapolation of efficacy in epilepsy, and the use of physiologically based PK modeling as a tool to investigate sources of PK/PD variability in children. Finally, we will conclude with current challenges and future directions for optimizing the efficacy and safety of these drugs across the pediatric age spectrum.

Zeolitic Pickering Emulsifier with Intrinsic Amphiphilicity.

The formation of oil-in-water Pickering emulsions stabilized by lamellar zeolite MWW (International Zeolite Association, three-letters code) emulsifier without surface grafting is investigated. The crucial emulsification factors are the oligolayer morphology and amphiphilicity developed upon acidic treatment (NH4+ exchange/calcination, HNO3 treatment). In contrast with the readily available/abundant hydrophilic ≡Si-OH group in layer MWW, the lipophilicity generated by strong acid sites is another key to the success of emulsification. Hydrocarbon-strong acid site interaction is long known in petrochemistry and superacid research. However, to the best of our knowledge, this interaction was first introduced to gain lipophilicity in emulsion formation. Finally, the Pd-loaded acidic form of the MWW zeolite successfully stabilized the toluene/H2O emulsion system. The biphasic interfacial nitroarene hydrogenation demonstrated excellent catalytic performance. Overall, this work provided not only a new kind of intrinsic solid to emulsify the organic-aqueous biphase system but also a new mechanism to generate lipophilicity. Both are important for the applications and designs of Pickering emulsion materials.

Loss of SARM1 ameliorates secondary thalamic neurodegeneration after cerebral infarction.

Ischemic stroke causes secondary neurodegeneration in the thalamus ipsilateral to the infarction site and impedes neurological recovery. Axonal degeneration of thalamocortical fibers and autophagy overactivation are involved in thalamic neurodegeneration after ischemic stroke. However, the molecular mechanisms underlying thalamic neurodegeneration remain unclear. Sterile /Armadillo/Toll-Interleukin receptor homology domain protein (SARM1) can induce Wallerian degeneration. Herein, we aimed to investigate the role of SARM1 in thalamic neurodegeneration and autophagy activation after photothrombotic infarction. Neurological deficits measured using modified neurological severity scores and adhesive-removal test were ameliorated in Sarm1-/- mice after photothrombotic infarction. Compared with wild-type mice, Sarm1-/- mice exhibited unaltered infarct volume; however, there were markedly reduced neuronal death and gliosis in the ipsilateral thalamus. In parallel, autophagy activation was attenuated in the thalamus of Sarm1-/- mice after cerebral infarction. Thalamic Sarm1 re-expression in Sarm1-/- mice increased thalamic neurodegeneration and promoted autophagy activation. Auotophagic inhibitor 3-methyladenine partially alleviated thalamic damage induced by SARM1. Moreover, autophagic initiation through rapamycin treatment aggravated post-stroke neuronal death and gliosis in Sarm1-/- mice. Taken together, SARM1 contributes to secondary thalamic neurodegeneration after cerebral infarction, at least partly through autophagy inhibition. SARM1 deficiency is a potential therapeutic strategy for secondary thalamic neurodegeneration and functional deficits after stroke.

The Structure and Function of the Glycocalyx and Its Connection With Blood-Brain Barrier.

The vascular endothelial glycocalyx is a dense, bush-like structure that is synthesized and secreted by endothelial cells and evenly distributed on the surface of vascular endothelial cells. The blood-brain barrier (BBB) is mainly composed of pericytes endothelial cells, glycocalyx, basement membranes, and astrocytes. The glycocalyx in the BBB plays an indispensable role in many important physiological functions, including vascular permeability, inflammation, blood coagulation, and the synthesis of nitric oxide. Damage to the fragile glycocalyx can lead to increased permeability of the BBB, tissue edema, glial cell activation, up-regulation of inflammatory chemokines expression, and ultimately brain tissue damage, leading to increased mortality. This article reviews the important role that glycocalyx plays in the physiological function of the BBB. The review may provide some basis for the research direction of neurological diseases and a theoretical basis for the diagnosis and treatment of neurological diseases.

Chinese Herbal Medicine for the Treatment of Children and Adolescents With Refractory Mycoplasma Pneumoniae Pneumonia: A Systematic Review and a Meta-Analysis.

Objectives: Chinese herb medicine (CHM) is one of the most popular complementary and alternative therapies, which has been widely used to treat Refractory Mycoplasma Pneumoniae Pneumonia (RMPP). However, the effect and safety of CHM remain controversial. Hence, we conducted this meta-analysis to evaluate whether CHM combination therapy could bring benefits to children and adolescents with RMPP. Methods: Seven databases were used for data searching through November 11, 2020 following the PRISMA checklist generally. Review Manager 5.3, Trial sequential analysis 0.9.5.10 Beta software and Stata16.0 were applied to perform data analyses. Mean difference or risk ratio was adopted to express the results, where a 95% confidence interval (CI) was applied. Results: In general, this research enrolled 17 trials with 1,451 participants. The overall pooled results indicated that CHM was beneficial for children and adolescents with RMPP by improving the clinical efficacy rate [RR = 1.20, 95% CI (1.15, 1.25), p < 0.00001], shortening antipyretic time [MD = -2.60, 95% CI (-3.06, -2.13), p < 0.00001], cough disappearance time [MD = -2.77, 95% CI (-3.12, -2.42), p < 0.00001], lung rale disappearance time [MD = -2.65, 95% CI (-3.15, -2.15), p < 0.00001], lung X-ray infiltrates disappearance time [MD = -2.75, 95% CI (-3.33, -2.17), p < 0.00001], reducing TNF-α level [MD = -5.49, 95% CI (-7.21, -3.77), p < 0.00001]. Moreover, subgroup results suggested that removing heat-phlegm and toxicity therapy had more advantages in shortening antipyretic time, cough disappearance time, lung X-ray infiltrates disappearance time and reducing TNF-α level. Meanwhile promoting blood circulation therapy seemed to be better at relieving lung rale. However, regarding adverse events, the two groups displayed no statistical difference [RR = 0.97, 95% CI (0.60, 1.57), p = 0.91]. Conclusion: Despite of the apparently positive results in relieving clinical symptoms, physical signs and reducing inflammation, it is premature to confirm the efficacy of CHM in treating RMPP because of the limitation of quality and the number of the included studies. More large-scale, double-blind, well-designed, randomized controlled trials are needed in future research.

Copper decorated with nanoporous gold by galvanic displacement acts as an efficient electrocatalyst for the electrochemical reduction of CO2.

The reduction of carbon dioxide (CO2) is recognized as a key component in the synthesis of renewable carbon-containing fuels. Herein, we report on nanoporous gold (NPAu) decorated with copper atoms for the efficient electrochemical reduction of CO2. A facile and green galvanic displacement technique was developed to incorporate Cu onto the surface of the nanoporous gold-zinc (NPAuZn) electrode. The effect of zinc on the morphology and electrochemical performance of the formed NPAuCu electrodes for CO2 reduction was systematically investigated. The NPAuCu electrode exhibited 16.9 and 2.86 times higher current density than those of polycrystalline gold and NPAuZn at -0.60 V (vs. RHE) in a 0.1 M CO2-saturated NaHCO3 solution, respectively. A far higher faradaic efficiency was achieved at the NPAuCu electrode for the electrochemical reduction of CO2 to CO, CH4 and HCOOH. The facile synthesis of the NPAuCu electrode demonstrated in the present study can be employed as a promising strategy in the development of high-performance electrocatalysts for energy and environmental applications.

The embedding of fluorescent N-methyl-9-acridone into a topological new layered aluminophosphate SYSU-2 by one-pot synthesis.

A layered aluminophosphate |C14H11NO|2[Al4(HPO4)4F4(H2O)2] (denoted as SYSU-2) with a new topology has been hydrothermally synthesized with N-methyl-9-acridone (NMA) as the organic structure-directing agent. Single-crystal X-ray diffraction analysis reveals that SYSU-2 crystallizes in a triclinic space group P1[combining macron], with the inorganic sheets stacked in an AA sequence. Hydrogen bonds are responsible for the neutral inorganic-organic layer connection. The layer structure of SYSU-2 is constructed by alternating AlO4F2 octahedra and PO4 tetrahedra. The topological analysis of SYSU-2 indicates an independent topology. The NMA layers are self-assembled with π-π interaction. SYSU-2 crystals show interesting dual-band emission fluorescence properties compared with NMA crystals. Under 406 nm UV irradiation, SYSU-2 crystals emit yellow light with two emission bands at 477 and 566 nm, while NMA crystals emit blue light with only one band at 473 nm. The differences may be derived from the difference of stacking orders and distance of NMA molecule layers between the two crystals.

Silicon Forms a Rich Diversity of Aliphatic Polyol Complexes in Aqueous Solution.

A detailed examination of aqueous Si complexation by alditols and aldonic acids was conducted using high-sensitivity 29Si NMR spectroscopy of isotopically enriched solutions combined with theoretical modeling. Contrary to previous thinking, we have established that aliphatic polyols do not require a threo pair of hydroxy groups to form hypercoordinated Si complexes, although formation constants may be orders of magnitude higher if they are present. Thirteen distinctly different molecular assemblages containing 4-, 5-, or 6-coordinate Si centers have been identified, with significant concentrations of 5-coordinate Si bis-ligand complex being detected even under biologically relevant solution conditions.

Highly boosted gas diffusion for enhanced electrocatalytic reduction of N2 to NH3 on 3D hollow Co-MoS2 nanostructures.

Transition metal chalcogenide MoS2 catalysts are highly selective for the electrochemical reduction of dinitrogen (N2) to ammonia (NH3) in aqueous electrolytes. However, due to the low solubility of N2 in water, limited N2 diffusion and mass transport have heavily restricted the yield and the faradaic efficiency (FE). Here, we have demonstrated a highly efficacious assembled gas diffusion cathode with hollow Co-MoS2/N@C nanostructures to significantly improve the electrochemical reduction of N2 to NH3. Our results revealed that the synthesized Co-MoS2 heterojunctions with abundant graphitic N groups exhibited a superb NH3 yield of 129.93 µg h-1 mgcat-1 and a high faradaic efficiency of 11.21% at -0.4 V vs. the reversible hydrogen electrode (RHE), as well as excellent selectivity and stability. The strategy described in this study offers new inspiration to design high-performance electrocatalyst assemblies for the sustainable environmental and energy applications.

Synthesis and Electrochemical Study of Mesoporous Nickel-Cobalt Oxides for Efficient Oxygen Reduction.

Development of a cost-effective and efficient electrocatalyst for the sluggish oxygen reduction reaction (ORR) is a crucial challenge for clean energy technologies. In this study, we have synthesized various Ni and Co oxide (NCO) nanomaterials via a facile coprecipitation, followed by the calcination method. The morphology of the formed NCO nanomaterials was controlled by varying the percentage of the Ni and Co precursors, leading to the formation of a template-free mesoporous spinel phase structure of Ni xCo3- xO4. It was found that the number of the octahedral site cations and the defect sites with lower oxygen in the spinel oxides can be tunable by taking appropriate ratios of the Ni and Co precursors. The optimized NCO nanomaterial exhibits superior electrocatalytic activity compared to the mono-metal oxides of NiO and Co3O4 with over 3 times higher current density and ∼0.250 V lower onset potential toward ORR in a 0.1 M KOH solution. Scanning electrochemical microscopy was utilized in mapping the activity of the catalyst and monitoring the ORR products, further confirming that a four-electron transfer pathway was facilitated by the NCO nanomaterial. Moreover, the developed mesoporous NCO nanomaterial exhibits a high methanol tolerance capability and long-term stability when compared to the commercial state-of-the-art Pt/C electrocatalyst. The improvement of the catalytic activity and stability of this advanced NCO nanomaterial toward ORR may be attributed to the facile accessible mesoporous structure, and the abundance of octahedral site cations and defective oxygen sites.

Unique copper and reduced graphene oxide nanocomposite toward the efficient electrochemical reduction of carbon dioxide.

The electrochemical reduction of CO2 to useful chemicals and fuels has garnered a keen and broad interest. Herein, we report a unique nanocomposite consisting of Cu nanoparticles (NPs) and reduced graphene oxide (rGO) supported on a Cu substrate with a high catalytic activity for CO2 reduction. The nanocomposite was optimized in terms of the composition of Cu NPs and rGO as well as the overall amount. A gas chromatograph was employed to analyze the gaseous products, whereas a chemical oxygen demand (COD) method was proposed and utilized to quantify the overall liquid products. The optimized nanocomposite could effectively reduce CO2 to CO, HCOOH and CH4 with a Faradaic efficiency (FE) of 76.6% at -0.4 V (vs. RHE) in a CO2 saturated NaHCO3 solution. The remarkable catalytic activity, high FE, and excellent stability make this Cu-rGO nanocomposite promising for the electrochemical reduction of CO2 to value-added products to address the pressing environmental and energy challenges.

A rapid and high-throughput microplate spectrophotometric method for field measurement of nitrate in seawater and freshwater.

The well-known zinc-cadmium reduction method is frequently used for determination of nitrate. However, this method is seldom to be applied on field research of nitrate due to the long time consuming and large sample volume demand. Here, we reported a modified zinc-cadmium reduction method (MZCRM) for measurement of nitrate at natural-abundance level in both seawater and freshwater. The main improvements of MZCRM include using small volume disposable tubes for reaction, a vortex apparatus for shaking to increase reduction rate, and a microplate reader for high-throughput spectrophotometric measurements. Considering salt effect, two salinity sections (5~10 psu and 20~35 psu) were set up for more accurate determination of nitrate in low and high salinity condition respectively. Under optimized experimental conditions, the reduction rates were stabilized on 72% and 63% on the salinity of 5 and 20 psu respectively. The lowest detection limit for nitrate was 0.5 µM and was linear up to 100 µM (RSDs was 4.8%). Environmental samples assay demonstrated that MZCRM was well consistent with conventional zinc-cadmium reduction method. In total, this modified method improved accuracy and efficiency of operations greatly, and would be realized a rapid and high-throughput determination of nitrate in field analysis of nitrate with low cost.

Comparative analysis of two 16S rRNA gene-based PCR primer sets provides insight into the diversity distribution patterns of anammox bacteria in different environments.

Due to the high divergence among 16S rRNA genes of anammox bacteria, different diversity pattern of the community could be resulted from using different primer set. In this study, the efficiencies and specificities of two commonly used sets, Amx368F/Amx820R and Brod541F/Amx820R, were evaluated by exploring the diversity characteristics of anammox bacteria in sediments from marine, estuary, and freshwater wetland. Statistical analysis indicated that the base mispairing rate between bases on 16S rRNA gene sequences retrieved by Amx368F/Amx820R and their corresponding ones on primer Brod541F was quite high, suggesting the different efficiency and specificity of Amx368F/Amx820R and Brod541F/Amx820R. Further experimental results demonstrated that multiple genera of anammox bacteria, including Ca. Scalindua, Ca. Brocadia, and Ca. Kuenenia, were able to be detected by Amx368F/Amx820R, but only Ca. Scalindua could be retrieved by Brod541F/Amx820R. Moreover, the phylogenetic clusters of Ca. Scalindua by Amx368F/Amx820R were different completely from those by Brod541F/Amx820R, presenting a significant complementary effect. By joint application of these two primer sets, the diversity distribution patterns of anammox bacteria in different environments were analyzed. Almost all retrieved sequences from marine sediments belonged to Ca. Scalindua. Sequences from freshwater wetland were affiliated to Ca. Brocadia and two new clusters, while high diversity of anammox bacteria was found in estuary, including Ca. Scalindua, Ca. Brocadia, and Ca. Kuenenia, corresponding to the river-sea intersection environmental feature. In total, these two prime sets have different characteristic for anammox bacteria detecting from environmental samples, and their combined application could achieve better diversity display of anammox community.

Electrochemical determination of methylglyoxal as a biomarker in human plasma.

A novel electrochemical approach for the quantitative analysis of methylglyoxal as a biomarker in human plasma has been developed. An electrochemical sensor employing a single walled carbon nanotube modified glassy carbon electrode for the sensitive detection of methylglyoxal is delineated for the first time using square wave voltammetry. This modified electrode exhibits potent and sustained electron-mediating behavior and a well-defined reduction peak in response to methylglyoxal was observed. Under optimized experimental conditions, a wide linear dynamic range, from 0.1 to 100 µM, and high sensitivity of 76.3 nA µM⁻¹ were achieved for the detection of methylglyoxal. The interfering effect of common coexisting metabolites in human whole blood has also been investigated. The developed assay was shown to be specific and sensitive for the analysis of plasma levels of methylglyoxal in healthy volunteer and diabetic patients.

One-step synthesis of N- and F-codoped mesoporous TiO2 photocatalysts with high visible light activity.

We report on a novel approach to the synthesis of N- and F-codoped mesoporous TiO2 photocatalysts via a reproducible, rapid and single-step combustion method. TiF4 was used as the precursor to provide the source of Ti and F, while urea was used as the fuel as well as the source of the N dopant. The as-synthesized samples were characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), x-ray photoelectron spectroscopy (XPS) and UV-vis spectroscopy. The specific surface areas of the samples were determined using a Quantachrome Nova 2200 for the N2 adsorption/desorption under liquid-nitrogen temperature. Our studies show that the fabricated N- and F-codoped TiO2 photocatalysts have mesoporous structure and a very large specific surface area (155.3 m(2) g(-1)) and that the codoping of N and F significantly narrows the TiO2 bandgap energy from 3.2 to 2.45 eV. We further studied the photocatalytic activity of the synthesized N- and F-codoped mesoporous TiO2 through the decomposition of acetic acid, showing that the N- and F-codoped mesoporous TiO2 catalyst fabricated in this study exhibits superb photocatalytic activity and visible light response compared to one of the best commercially available TiO2 photocatalysts, P25.