Model-Informed Dose Selection for a Novel Human Immunoglobulin G4 Derived Monoclonal Antibody Targeting Proprotein Convertase Kwashiorkor Type 9: Insights from Population Pharmacokinetics-Pharmacodynamics and Systems Pharmacology.

Monoclonal antibody drugs targeting proprotein convertase kwashiorkor type 9 (PCSK9) have recently demonstrated remarkable success in lipid-lowering therapies. Specifically, antibodies derived from immunoglobulin G1 (IgG1, alirocumab) and IgG2 (evolocumab) have been successfully utilized for this purpose. Recently, a novel recombinant fully human anti-PCSK9 monoclonal antibody, originally derived from IgG4 and designated as SAL003, was developed. This study aimed to explore the pharmacokinetics, efficacy, and safety of SAL003 in both single and multiple administrations. The investigation included both healthy individuals and individuals with hyperlipidemia. To comprehensively grasp the pharmacokinetic (PK) and pharmacodynamic (PD) attributes of SAL003, this study employed population PK-PD (popPK-PD) and mechanistic systems pharmacology (MSP) modeling. These models were employed for predicting low-density lipoprotein cholesterol (LDLc) concentrations and appropriate dosages across diverse potential clinical scenarios. The research results indicated that SAL003 demonstrated comparable pharmacokinetic properties to evolocumab, exhibited notable effectiveness in reducing lipid levels, and was confirmed to be safe and well-tolerated in both healthy individuals and individuals with hyperlipidemia. Notably, SAL003 displayed differing effectiveness between patients and healthy populations. This discrepancy was observed in the popPK-PD model, with a positive population influence on Emax, and the MSP model, indicating elevated PCSK9 clearance and LDLr-related LDLc clearance in the healthy group. Simulation results from the popPK-PD and MSP models indicated a dosage of 140 mg of Q4W and 420 mg of Q8W for phase II/III clinical trials. Reducing the drug dose or extending the dosing intervals may result in treatment failure. Additionally, the simultaneous use of statins led to elevated PCSK9 levels and intensified fluctuations in steady-state LDLc levels during SAL003 treatment.

Photocatalytic microbial disinfection under indoor conditions: Prospects and challenges of near IR-photoactive materials.

The accumulation of microbes especially in the air and in water bodies is causing the major disease outbreaks. Indoor environment remediation methods are necessary today to clean up these microbes. Among the remediation methods available, in situ generation of highly reactive and oxidizing radical species by advanced oxidation processes (AOPs) inactivate most of the microbes unselectively. Of these AOPs, photocatalytic microbial disinfection especially under indoor conditions is of great interest to maintain microbe-free indoor environment. For efficient microbes' inactivation under indoor conditions, the near IR and IR response of the photocatalysts must be improved. Though the photocatalytic disinfection of microbes using semiconductor-based photocatalysts has been extensively investigated, most of the photocatalysts that have been investigated are either weekly responsive or totally not irresponsive to IR photons due to inappropriate bandgap energies. Several strategies have been investigated to enhance the light harvesting properties of semiconductor based photocatalysts under indoor conditions and make them active to near IR and IR radiations. This review summarizes the recent progress in the field of materials for photocatalysts employed for microbial removal in indoor environments over the past decade as well as outlines key perspectives to enlighten future researches. The paper details the fundamentals of photocatalysis and basic properties of photocatalytic materials in the disinfection of common microbes under indoor conditions. The applications of photocatalytic materials in the disinfection of microbes in indoor environmental conditions are discussed and reviewed. Finally, the remaining challenges and future strategies/prospects in the design and synthesis of IR (and near IR) responsive photocatalysts are discussed.

Acinetobacter baumannii outer membrane protein A induces autophagy in bone marrow-derived dendritic cells involving the PI3K/mTOR pathway.

BACKGROUND: Outer membrane protein A (OmpA) is the major virulence factor of Acinetobacter baumannii and plays a wide role in the pathogenesis and antimicrobial resistance of A. baumannii. Dendritic cells (DCs) are the most effective antigen-presenting cells and play a crucial role in regulating the immune response to multiple antigens and immune sentries. We aimed to study the role and molecular mechanisms of OmpA-induced mouse bone marrow-derived dendritic cells (BMDCs) autophagy in the immune response of A. baumannii. METHODS: First, purified A. baumannii OmpA was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blot. OmpA effect on BMDCs viability was evaluated by MTT assay. BMDCs were pretreated with autophagy inhibitor chloroquine or transfected with overexpression plasmids (oe-NC or oe-PI3K). Then BMDCs apoptosis, inflammatory cytokines, protein kinase B (PI3K)/mammalian target of rapamycin (mTOR) pathway, and autophagy-related factors levels were evaluated. RESULTS: SDS-PAGE and western blot verified the successful purification of OmpA. BMDCs viability repressed gradually with the increase of OmpA concentration. OmpA treatment of BMDCs led to apoptosis and inflammation in BMDCs. OmpA caused incomplete autophagy in BMDCs, and light chain 3 (LC3), Beclin1, P62, and LC3II/I levels were significantly elevated with the increase of the time and concentration of OmpA treatment. Chloroquine reversed OmpA effects on autophagy in BMDCs, that was, LC3, Beclin1, and LC3II/I levels were reduced, while P62 level was elevated. Furthermore, chloroquine reversed OmpA effects on apoptosis and inflammation in BMDCs. PI3K/mTOR pathway-related factor expression was affected by OmpA treatment of BMDCs. After overexpression of PI3K, these effects were reversed. CONCLUSIONS: A. baumannii OmpA induced autophagy in BMDCs involving the PI3K/mTOR pathway. Our study may provide a novel therapeutic target and theoretical basis for treating infections caused by A. baumannii.

Bioequivalence of Levocetirizine Hydrochloride Granules (Kangzhitai) in Healthy Subjects.

Objective: Levocetirizine hydrochloride is the R-enantiomer of cetirizine, which is a new-generation histamine H1 receptor antagonist with high safety, selectivity, and affinity. As a high-efficiency non-sedating antihistamine, levocetirizine hydrochloride has been widely used in the clinical treatment of skin, respiratory, and eye allergies. However, the bioavailability of levocetirizine hydrochloride granules remains to be determined. The study examined the relative bioavailability of the test drug (levocetirizine hydrochloride granules (Kangzhitai®)) and determined whether Kangzhitai® was bioequivalent to the reference drug (levocetirizine (Xyzal®)) in healthy individuals. Methods: Twenty eligible healthy male subjects were randomly divided into two groups. Group one received 5 mg of Kangzhitai®, followed by a 10-day wash-out period and 5 mg of Xyzal® on day 11. Group two received the same doses but in a reverse sequence. The subjects fasted for 12 h, and blood samples were collected before (blank) and after administration. The plasma concentration of Kangzhitai® was determined by HPLC-MS-MS. Pharmacokinetic parameters were analyzed using DAS 2.0 software. Results: The main pharmacokinetic parameters Cmax, Tmax, T1/2, AUC0-48, and AUC0-∞ of the Xyzal® and Kangzhitai® groups were as follows: (218.4 ± 46.4) µg/L vs. (213.6 ± 39.3) µg/L, (0.73 ± 0.32)/h vs. (0.75±0.3)/h, (9.2 ± 2.0) h vs. (8.9 ± 2.7) h, (1594.0 ± 337.2) µg·h/L vs. (1652.6 ± 383.5) µg·h/L, and (1683.2 ± 338.5) µg·h/L vs. (1753.7 ± 445.4) µg·h/L. The two-one-sided t tests of Cmax, AUC0-48, and AUC0-∞ showed that th and t1 were both higher than one-sided t0.05. The 90% confidence intervals (CI) for AUC0-48 and AUC0-∞ of Kangzhitai® did not exceed 80%-125% of AUC0-48 and AUC0-∞ of Xyzal®. The 90% CI for the Cmax of Kangzhitai® did not exceed 70%-143% of the Cmax of Xyzal®. There was no significant difference in Tmax between the two drugs. The relative bioavailability (F, assessed by AUC0-48) of Kangzhitai® vs. Xyzal® was 104.4±18.5%. No adverse events occurred during the drug administration. Conclusion: The results indicated that there was no significant difference in absorption between Kangzhitai® and Xyzal®, which confirmed the bioequivalence of the two drugs.

Clinical Characteristics of Chlamydia psittaci Pneumonia Confirmed by Metagenomic Next-Generation Sequencing.

BACKGROUND: Chlamydia psittaci pneumonia has atypical clinical manifestations and the diagnosis may be missed by traditional methods of microbiological diagnosis. METHODS: Twelve cases of Chlamydia psittaci pneumonia diagnosed by metagenomic next-generation sequencing (mNGS) in Huizhou Central People's Hospital in China between January 2020 and August 2021 were reviewed and analyzed, retrospectively, using hospital records, the clinical characteristics, treatment, and prognosis. RESULTS: Ten of the 12 cases (83%) were associated with a definite history of bird/poultry contact. Common symptoms included high fever, cough, fatigue, anorexia (12/12, 100%), dyspnea (11/12, 92%), and changes in the level of consciousness and headache (5/12, 42%). There was a marked increase in C-reactive protein and D-dimer levels, but white blood cells and neutrophils were normal or slightly increased. Nine patients (75%) had liver enzyme abnormalities, and six (50%) had cardiac insufficiency and myocardial injury. There was no correlation between the mNGS sequence number of Chlamydia psittaci and the pneumonia severity. The chest imaging manifestations were mainly large areas of consolidation, predominantly in the lower lung lobes. Monotherapies or combinations of doxycycline, moxifloxacin/levofloxacin, and azithromycin were effective for treating Chlamydia psittaci pneumonia. CONCLUSIONS: The use of mNGS increases the probability of diagnosing Chlamydia psittaci pneumonia, and good prognosis can be achieved with timely use of appropriate antibiotics.

Omadacycline for the Treatment of Severe Chlamydia psittaci Pneumonia Complicated with Multiple Organ Failure: A Case Report.

Psittacosis is a rare zoonotic disease caused by Chlamydia psittaci infection, and tetracyclines are the preferred treatment. Omadacycline is a novel tetracycline that has a strong in vitro antibacterial activity against atypical pathogens, including C. psittaci; however, clinical data for its usage are lacking. We report a patient with severe C. psittaci-induced pneumonia presenting with a high fever, muscle aches, severe hepatic and renal insufficiency, and acute respiratory failure requiring tracheal intubation and mechanical ventilation. The condition was diagnosed using metagenomic next-generation sequencing. The patient was discharged after treatment with omadacycline. The findings of this study suggest that metagenomic next-generation sequencing is valuable for the rapid and accurate diagnosis of psittacosis. With its good safety profile and no requirement for dose adjustment in special populations, omadacycline is a new option for the treatment of severe C. psittaci pneumonia. However, additional case reports are needed to support this conclusion.

Insight into the Evolution of Ordered Mesoporous sp2 Carbonaceous Material Derived from Self-Assembly of a Block Copolymer.

Block-copolymer-derived ordered mesoporous carbon (OMC) materials have great potential in many applications, such as adsorption, catalysis, and energy conversions; however, their formation process and the kinetic mechanism remain unclear. Herein, a N-doped OMC (N-OMC) with sp2-bonded C atoms is developed via self-assembly of the polystyrene-block-poly(4-vinyl pyridine) block copolymer. By correlating the external morphologies with the internal chemical states, the formation process can be concluded as follows: (1) pore evolution via polystyrene domain degradation and (2) regularization and graphitization of the residual carbon via the removal of sp3 C atoms. In addition, the thickness of the N-OMC shows a power function relationship with the spin-coating rate, and the N content can be incredibly increased up to 26.34 at. % in an NH3 carbonization atmosphere. With the as-prepared N-OMC as the support for loading of the pseudo-atomic-scale Pt (Pt/N-OMC), a high electrochemical active surface area value of 99.64 m2·g-1 and a half-wave potential (E1/2) of 0.850 VRHE are achieved, showing great potential in developing single-atom electrocatalysts.

Population Pharmacokinetic Modelling for Nifedipine to Evaluate the Effect of Parathyroid Hormone on CYP3A in Patients with Chronic Kidney Disease.

Purpose: Parathyroid hormone (PTH) can induce the downregulation of CYP3A in chronic kidney disease (CKD). Nevertheless, the effect of PTH on CYP3A-mediated clearance pathways from a clinical perspective remains unclear. Methods: This study employed population pharmacokinetic (PopPK) modeling to delineate potential changes in CYP3A activity in patients with CKD. Pharmacokinetic data for nifedipine, a typical CYP3A substrate, as well as covariate information, were prospectively collected from 157 patients with a total of 612 concentrations. PopPK data analysis was performed using a nonlinear mixed-effects model. Results: The pharmacokinetics of nifedipine were optimally described according to a one-compartment model with zero-order absorption and first-order elimination. The estimated population parameters (and interindividual variability) were apparent clearance (CL/F) 49.61 L/h (58.33%) and apparent volume of distribution (V/F) 2300.26 L (45.62%), and the PTH level negatively correlated with CL/F. In comparison with the reference level, it was observed that the dosage of nifedipine should be reduced with the maximum boundary value of PTH, after a Monte Carlo simulation. Conclusion: This study provides insight into the effects of PTH on CYP3A-mediated clearance pathways. Moreover, PTH could be used as a guide for the appropriate administration of CYP3A eliminated drugs in patients with CKD.

Pharmacokinetics effects of chuanxiong rhizoma on warfarin in pseudo germ-free rats.

Aim: In China, warfarin is usually prescribed with Chuanxiong Rhizoma for treating thromboembolism diseases. However, the reason for their combination is still being determined. The present study explored the pharmacokinetics interactions of warfarin, Chuanxiong Rhizoma, and gut microbiota in the rat model of middle cerebral artery occlusion (MCAO). Methods: A total of 48 rats were randomly divided into six groups: MCAO rats orally administered warfarin (W group), pseudo germ-free MCAO rats orally administered warfarin (W-f group), MCAO rats co-administered Chuanxiong Rhizoma and warfarin (C + W group), pseudo germ-free MCAO rats co-administered Chuanxiong Rhizoma and warfarin (C + W-f group), MCAO rats co-administered warfarin and senkyunolide I (S + W group); pseudo germ-free MCAO rats co-administered warfarin and senkyunolide I (S + W-f group). After treatment, all animals' blood and stool samples were collected at different time points. The stool samples were used for 16S rRNA sequencing analysis. Ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was established to quantify warfarin, internal standards, and the main bioactive components of Chuanxiong in blood samples. The main pharmacokinetics parameters of warfarin were calculated by DAS 2.1.1 software. Results: The relative abundance of Allobaculum and Dubosiella in the pseudo germ-free groups (W-f, C + W-f, S + W-f) was lower than that in the other three groups (W, C + W, S + W). The relative abundance of Lactobacillus in the W-f group was higher than that of the W group, while the relative abundance of Akkermansia decreased. The relative abundance of Ruminococcaceae_UCG-014 and Ruminococcaceae_NK4A214_group in the S + W-f group was lower than in the S + W group. Compared to the W group, the AUC0-t and Cmax of warfarin in the W-f group increased significantly to 51.26% and 34.58%, respectively. The AUC0-t and Cmax in the C + W group promoted 71.20% and 65.75% more than the W group. Compared to the W group, the AUC0-t and Cmax increased to 64.98% and 64.39% in the S + W group. Conclusion: Chuanxiong Rhizoma and senkyunolide I (the most abundant metabolites of Chuanxiong Rhizoma aqueous extract) might affect the pharmacokinetics features of warfarin in MCAO rats through, at least partly, gut microbiota.

Case Report: Chlamydia psittaci pneumonia complicated by Guillain-Barré syndrome detected using metagenomic next-generation sequencing.

Psittacosis and Guillain-Barré syndrome are both rare clinical diseases with low incidence, and their combination has rarely been reported. Here, we report a case of Chlamydia psittaci pneumonia combined with Guillain-Barré syndrome. The patient initially presented with high fever, difficulty breathing, and fatigue. Chest computerised tomography indicated large consolidation opacities in both lungs. Metagenomic next-generation sequencing clearly identified the pathogen as C. psittaci. The patient's fever subsided after targeted antibiotic treatment, but difficulty breathing and fatigue worsened, and the patient developed symmetric limb numbness and weakness. Lumbar puncture, electrophysiological examination, and clinical characteristics were suggestive of Guillain-Barré syndrome, and the symptoms improved after treatment with human immunoglobulin. The results of this study suggest that metagenomic next-generation sequencing is useful for the rapid diagnosis of pulmonary infectious agents. Psittacosis is closely associated with the development of Guillain-Barré syndrome; however, more cases are needed to support this conclusion, and early targeted antibiotic treatment, immunotherapy, and basic supportive treatment are essential for improving outcomes.

External evaluation of published population pharmacokinetic models of polymyxin B.

OBJECTIVES: Several population pharmacokinetics (popPK) models for polymyxin B have been constructed to optimize therapeutic regimens. However, their predictive performance remains unclear when extrapolated to different clinical centers. Therefore, this study aimed to evaluate the predictive ability of polymyxin B popPK models. METHODS: A literature search was conducted, and the predictive performance was determined for each selected model using an independent dataset of 20 patients (92 concentrations) from the Third Xiangya Hospital. Prediction- and simulation-based diagnostics were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. RESULTS: Eight published studies were evaluated. In prediction-based diagnostics, the prediction error within ± 30% was over 50% in two models. In simulation-based diagnostics, the prediction- and variability-corrected visual predictive check (pvcVPC) showed satisfactory predictivity in three models, while the normalized prediction distribution error (NPDE) tests indicated model misspecification in all models. Bayesian forecasting demonstrated a substantially improvement in the model predictability even with one prior observation. CONCLUSION: Not all published models were satisfactory in prediction- and simulation-based diagnostics; however, Bayesian forecasting improved the predictability considerably with priors, which can be applied to guide polymyxin B dosing recommendations and adjustments for clinicians.

Subjective strain of care experienced by pulmonary and critical care medical nurses when caring for patients with delirium: a cross-sectional study.

BACKGROUND: Delirium, a disorder of consciousness, often occurs for a period of time during hospitalisation. It is characterised by a disturbance of attention or awareness. Hyperactive delirium may lead to accidental removal of medical equipment, while hypoactive delirium may inhibit patients from participating in nursing interventions, medical treatment, and physical therapy. However, there are limited relevant studies of the strain of care of nurses in China when caring for patients with delirium. This study, thus, aimed to investigate the subjective level of the strain of care experienced by pulmonary and critical care nurses when caring for patients with delirium. METHODS: This was a descriptive, cross-sectional study. A survey was conducted with 100 nurses in the Chinese pulmonary and critical care medical (PCCM) department in 2018. The Strain of Care for Delirium Index (SCDI) was used to measure nurses' strain of care. Participants were instructed to rate the degree of perceived difficulty in managing patients who displayed the behaviours listed in the SCDI, on a scale from 1 (quite easy) to 4 (very difficult). The mean ± standard deviation (SD) scores of the ranked difficulty scores were calculated. RESULTS: In our sample, 47 % of the nurses had received delirium-related training previously. The three wards with the highest strain of care scores when caring for patients with delirium were the chronic obstructive pulmonary disease ward (3.29 ± 0.72), interstitial lung disease ward (3.11 ± 1.31), and respiratory intensive care unit (3.02 ± 0.78). The three types of patient behaviours associated with the highest degree of nursing strain of care were being uncooperative and difficult to manage (3.37 ± 0.84), pulling out tubes and tearing out dressings (3.33 ± 0.98), and irritability (3.22 ± 0.95). CONCLUSIONS: This study is the first to focus on nurses' subjective strain of care when caring for patients with delirium in PCCM departments in China. The findings suggest the need to pay more attention to the working status of Chinese nurses. Further trials with large samples assessing relevant outcomes of patients with delirium are warranted.

Oncogenic role of epithelial cell transforming sequence 2 in lung adenocarcinoma cells.

[This retracts the article DOI: 10.3892/etm.2016.3584.].

[Analysis of clinical features of 16 cases with Chlamydia psittaci pneumonia].

OBJECTIVE: To analyze the clinical characteristics of Chlamydia psittaci pneumonia and to investigate the correlation between serum inflammatory biomarkers and severity of the disease. METHODS: Sixteen patients with Chlamydia psittaci pneumonia admitted to the Huizhou Municipal Central Hospital from January 2020 to July 2021 were selected as the study subjects, including 10 severe cases and 6 mild cases. Clinical data were collected and analyzed, such as baseline characteristics, clinical symptoms, laboratory inspection and chest imaging manifestations. RESULTS: (1) Thirteen Chlamydia psittaci pneumonia were associated with a definite bird or poultry contact history. Common symptoms included high fever, chill, cough, fatigue, and anorexia (16 cases), dyspnoea (12 cases), and other systemic symptoms. (2) Laboratory test results showed normal white blood cell count (WBC, 10 cases), decreased lymphocyte count (LYM, 13 cases), increased high sensitive C-reactive protein (hs-CRP, 16 cases), D-dimer (15 cases), lactate dehydrogenase (LDH, 13 cases), aspartate aminotransferase (AST, 16 cases) and alanine aminotransferase (ALT, 12 cases) levels, however, the albumin (Alb, 15 cases) lever was decreased. The numbers of CD3+ T cells and CD4+ T cells decreased in 10 patients. (3) The levels of D-dimer, interleukins (IL-2, IL-6, IL-10) in severe Chlamydia psittaci pneumonia were significantly higher than those in mild Chlamydia psittaci pneumonia [D-dimer (µg/L): 10 257±4 203 vs. 1 085±642, IL-2 (ng/L): 1.1 (0.8, 1.7) vs. 0.3 (0.1, 0.7), IL-6 (ng/L): 315 (182, 505) vs. 75 (18, 131), IL-10 (ng/L): 7.0±4.1 vs. 2.3±0.7], but the LYM was lower (×109/L: 0.4±0.1 vs. 1.1±0.4), with significant differences (all P < 0.05). (4) Chest imaging manifestations were exudative lesions and large consolidation of lungs. Large consolidation of both lungs can occur in some critically ill patients. CONCLUSIONS: Chlamydia psittaci pneumonia is mainly associated with a bird or poultry contact history. The clinical manifestations usually present high fever, dyspnea, normal or slightly increased leucocytes, and lung consolidation. The levels of LYM, D-dimer, IL-2, IL-6 and IL-10 in serum are expected to predict the severity of the Chlamydia psittaci pneumonia.

Cross-infection of adenovirus among medical staff: A warning from the intensive care unit in a tertiary care teaching hospital in China.

RATIONALE: In 2019, a small HAdV55-associated outbreak of adenovirus infection occurred among the intensive care unit (ICU) staff in Xiangya Hospital of Central South University in Hunan Province, China, during the treatment of a patient. OBJECTIVE: To investigate the characteristics of a nosocomial adenovirus outbreak in an ICU. METHODS: We evaluated all the patients treated and the medical staff working in the ICU from August 1 to September 4, 2019. We further performed an epidemiological and molecular analysis for this outbreak from patient to healthcare workers and between healthcare workers. After the outbreak, we adopted exposure prevention and droplet prevention measures based on standard precautions. MEASUREMENTS AND MAIN RESULTS: Between August 1 and August 27, 2019, 27 cases of human adenovirus cross-infection were reported in our institution. Among the cases, eleven were doctors (41%), eleven were nurses (41%), three were respiratory therapists (11%), and two were caregivers (7%). The attack rate was 28.4%, and the fatality rate was 0. The results showed that contact with the index case, lack of hand hygiene or gloving adherence were risk factors for infection after adenovirus exposure. After taking specific precautions, no new cases of infection have appeared since August 27. CONCLUSIONS: Our results show that HAdV55 in a single patient had strong transmission potential in an intensive care unit with adequate facilities and standardized operation. We provide convincing evidence indicating that attention could be highlighted on the role of standard and specific precautions for controlling the spread of adenovirus in ICUs.

Dose investigation of imrecoxib in patients with renal insufficiency based on modelling and simulation.

OBJECTIVE: Imrecoxib is a new moderately selective cyclooxygenase-2 (COX-2) inhibitor. A previous study has shown that drug exposure differs significantly in renally impaired patients. We aim to describe the population pharmacokinetics (PPK) of imrecoxib (M0) and its two metabolites (M1, M2) to provide a theoretical basis for investigating imrecoxib doses for renally impaired patients. METHODS: Using PPK analysis, 24 patients with 257 different plasma concentrations were studied. Of these, 12 had severe renal impairment and 12 had normal renal function. The dose regimen was simulated based on the final model to compare the ratio (Cu,ss/IC50) of the average unbound concentration at steady state (Cu,ss) to the half-maximal inhibitory concentration (IC50) of COX-2. RESULTS: Imrecoxib and its metabolite concentrations were satisfactorily described by a two-compartment with first-order transit absorption model for imrecoxib and a one-compartment model for its metabolites. Renal function was a significant binary covariate. Scenarios of '75 mg q12h' and '50 mg q8h' in renally impaired patients had similar Cu,ss/IC50 values with a '100 mg q12h' regimen in subjects with normal renal function. CONCLUSION: A PPK model of imrecoxib and its two metabolites is presented. The renal insufficiency regimen should be reduced to '75 mg q12h' or '50 mg q8h'.

Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

BACKGROUND: Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. METHODS: We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were ≥18 years of age, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range of the international normalized ratio during the first 12 weeks after starting warfarin therapy. RESULTS: A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher percentage of time in the therapeutic range than the control group (58.8% versus 53.2% [95% CI of group difference, 1.1-10.2]; P=0.01). The genotype-guided dosing group also achieved the target international normalized ratio sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher percentage of time in the therapeutic range during the first 12 weeks compared with the control group (60.8% versus 48.9% [95% CI, 1.1-24.4]). The incidence of adverse events was low in both groups. CONCLUSIONS: The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02211326.

Synthesis of Ordered Pt Nanocube Arrays Directed by Block Copolymer Nanotemplate and Their Potential on Ethanol Oxidation Reaction.

In this work, well-ordered platinum (Pt) nanocubes (NCs), with precise control on the size and the spatial arrangement, are synthesized from a microemulsion overgrowth in a block copolymer (BC) nanotemplate. The nanovials on this self-assembled BC template serve as microreactors for the reduction of the HCl/H2PtCl6 precursor and direct the ordered periodic arrangement of the reduced Pt nanoparticles (NPs). As the content of HCl increases from 0% to 25%, the Pt NPs evolve from quasi-spheres to NCs, for which the density functional theory (DFT) computation reveals that the different adsorption energies of Cl and HCl dominate this morphology transition. For their potential application in fuel cells, the electrochemical catalysis of the Pt NCs demonstrates a 2.8-fold mass activity in contrast to the commercial JM 40% catalyst at the same Pt loading in ethanol oxidation reaction (EOR) and a good stability of 2.2% ECSA loss over 10 000 CV cycling.

Long non-coding RNA MALAT1 sponges miR-149 to promote inflammatory responses of LPS-induced acute lung injury by targeting MyD88.

Acute lung injury (ALI) caused by sepsis occurs early and the condition is severe, and is also an important reason for accelerating the death of patients. Increasing evidence has identified long non-coding RNA (lncRNA) metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) as a regulator of ALI. However, the potential mechanism underlying MALAT1 on ALI still needs further identification. To explore the mechanisms of gene regulation expression mediated by MALAT1 through miR-149/MyD88 in lung injury inflammation, we constructed a lung injury inflammatory model using the lipopolysaccharides (LPS)-induced method and quantificated the cytokines and signaling cascade molecules as well as miR-149. The MALAT1, myeloid differentiation factor 88 (MyD88), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 levels were significantly increased, and the nuclear factor-κB (NF-κB) pathway was activated, but the miR-149 level was decreased in the LPS-induced ALI model. miR-149 directly targeted both lncRNA MALAT1 and the MyD88 gene. Knockdown of MALAT1 down-regulated the levels of MyD88, TNF-α, IL-1ß, and IL-6, and inhibited the NF-κB pathway. However, MALAT1 knockdown up-regulated the expression of miR-149. Overexpression of miR-149 down-regulated MyD88, TNF-α, IL-1ß, and IL-6 levels, and inhibited the NF-κB pathway. MALAT1 acts as a pro-inflammatory factor in ALI via the miR-149/MyD88/NF-κB axis and is therefore a potential novel therapeutic target for ALI treatment.