Background
Neutrophil CD64 is widely described as an accurate biomarker for the diagnosis of infection in patients with septic syndrome. We performed a systematic review and meta-analysis to evaluate ...the diagnostic accuracy of neutrophil CD64, comparing it with C-reactive protein (CRP) and procalcitonin (PCT) for the diagnosis of infection in adult patients with septic syndrome, based on sepsis-2 criteria. We searched the PubMed and Embase databases and Google Scholar. Original studies reporting the performance of neutrophil CD64 for sepsis diagnosis in adult patients were retained. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and hierarchical summary receiver operating characteristic (SROC) curve were calculated.
Results
We included 14 studies (2471 patients) from 2006 to 2017 in the meta-analysis. The pooled sensitivity and specificity of neutrophil CD64 for diagnosing infection in adult patients with septic syndrome were 0.87 (95% CI 0.80–0.92) and 0.89 (95% CI 0.82–0.93), respectively. The area under the SROC curve and the DOR were 0.94 (95% CI 0.92–0.96) and 53 (95% CI 22–128), respectively. There was significant heterogeneity between the studies included. Subgroup analyses showed that this heterogeneity was due to differences in sample size and the proportions of patients with sepsis included in the studies. Six studies (927 patients) compared neutrophil CD64 and CRP determinations, and six studies (744 patients) compared neutrophil CD64 and PCT determinations. The area under the SROC curve was larger for neutrophil CD64 than for CRP (0.89 95% CI 0.87–0.92 vs. 0.84 95% CI 0.80–0.88,
P
< 0.05) or PCT (0.89 95% CI 0.84–0.95 vs. 0.84 95% CI 0.79–0.89,
P
< 0.05).
Conclusions
In adult patients with septic syndrome, neutrophil CD64 levels are an excellent biomarker with moderate accuracy outperforming both CRP and PCT determinations.
Sparsentan is a dual endothelin/angiotensin II receptor antagonist indicated to reduce proteinuria in patients with primary IgA nephropathy at high risk of disease progression. In vitro data indicate ...that sparsentan is likely to inhibit or induce various CYP enzymes at therapeutic concentrations. Sparsentan as a victim and perpetrator of CYP3A4 mediated drug–drug interactions (DDIs) has been assessed clinically. A mechanistic, bottom‐up, physiologically‐based pharmacokinetic (PK) model for sparsentan was developed based on in vitro data of drug solubility, formulation dissolution and particle size, drug permeability, inhibition and induction of metabolic enzymes, and P‐glycoprotein (P‐gp) driven efflux. The model was verified using clinical PK data from healthy adult volunteers administered single and multiple doses in the fasted and fed states for a wide range of sparsentan doses. The model was also verified by simulation of clinically observed DDIs. The verified model was then used to test various DDI simulations of sparsentan as a perpetrator and victim of CYP3A4 using an expanded set of inducers and inhibitors with varying potency. Additional perpetrator and victim DDI simulations were performed using probes for CYP2C9 and CYP2C19. Simulations were conducted to predict the effect of complete inhibition of P‐gp inhibition on sparsentan absorption and clearance. The predictive simulations indicated that exposure of sparsentan could increase greater than two‐fold if co‐administered with a strong CYP3A4 inhibitor, such as itraconazole. Other potential DDI interactions as victim or perpetrator were all within two‐fold of control. The effect of complete P‐gp inhibition on sparsentan PK was negligible.
Physiologically‐based pharmacokinetic (PBPK) modeling is being increasingly used in drug development to avoid unnecessary clinical drug–drug interaction (DDI) studies and inform drug labels. Thus, ...regulatory agencies are recommending, or indeed requesting, more rigorous demonstration of the prediction accuracy of PBPK platforms in the area of their intended use. We describe a framework for qualification of the Simcyp Simulator with respect to competitive and mechanism‐based inhibition (MBI) of CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5. Initially, a DDI matrix, consisting of a range of weak, moderate, and strong inhibitors and substrates with varying fraction metabolized by specific CYP enzymes that were susceptible to different degrees of inhibition, were identified. Simulations were run with 123 clinical DDI studies involving competitive inhibition and 78 clinical DDI studies involving MBI. For competitive inhibition, the overall prediction accuracy was good with an average fold error (AFE) of 0.91 and 0.92 for changes in the maximum plasma concentration (Cmax) and area under the plasma concentration (AUC) time profile, respectively, as a consequence of the DDI. For MBI, an AFE of 1.03 was determined for both Cmax and AUC. The prediction accuracy was generally comparable across all CYP enzymes, irrespective of the isozyme and mechanism of inhibition. These findings provide confidence in application of the Simcyp Simulator (V19 R1) for assessment of the DDI potential of drugs in development either as inhibitors or victim drugs of CYP‐mediated interactions. The approach described herein and the identified DDI matrix can be used to qualify subsequent versions of the platform.
Microbiota plays an important role in regulating immune responses associated with atopic diseases. We sought to evaluate relationships among airway microbiota, serum IgE levels, allergic ...sensitization and their relevance to rhinitis and asthma. Microbial characterization was performed using Illumina-based 16S rRNA gene sequencing of 87 throat swabs collected from children with asthma (n = 32) and rhinitis (n = 23), and from healthy controls (n = 32). Data analysis was performed using QIIME (Quantitative Insights Into Microbial Ecology) v1.8. Significantly higher abundance of Proteobacteria was found in children with rhinitis than in the healthy controls (20.1% vs. 16.1%, P = 0.009). Bacterial species richness (Chao1 index) and diversity (Shannon index) were significantly reduced in children with mite sensitization but not in those with food or IgE sensitization. Compared with healthy children without mite sensitization, the mite-sensitized children with rhinitis and asthma showed significantly lower Chao1 and Shannon indices. Moraxella and Leptotrichia species were significantly found in the interaction of mite sensitization with rhinitis and asthma respectively. Airway microbial diversity appears to be inversely associated with sensitization to house dust mites. A modulation between airway dysbiosis and responses to allergens may potentially cause susceptibility to rhinitis and asthma in early childhood.
Taiwan experienced two waves of imported infections with Coronavirus Disease 2019 (COVID-19). This study aimed at investigating the genomic variation of severe acute respiratory syndrome coronavirus ...2 (SARS-CoV-2) in Taiwan and compared their evolutionary trajectories with the global strains. We performed culture and full-genome sequencing of SARS-CoV-2 strains followed by phylogenetic analysis. A 382-nucleotides deletion in open reading frame 8 (ORF8) was found in a Taiwanese strain isolated from a patient on February 4, 2020 who had a travel history to Wuhan. Patients in the first wave also included several sporadic, local transmission cases. Genomes of 5 strains sequenced from clustered infections were classified into a new clade with ORF1ab-V378I mutation, in addition to 3 dominant clades ORF8-L84S, ORF3a-G251V and S-D614G. This highlighted clade also included some strains isolated from patients who had a travel history to Turkey and Iran. The second wave mostly resulted from patients who had a travel history to Europe and Americas. All Taiwanese viruses were classified into various clades. Genomic surveillance of SARS-CoV-2 in Taiwan revealed a new ORF8-deletion mutant and a virus clade that may be associated with infections in the Middle East, which contributed to a better understanding of the global SARS-CoV-2 transmission dynamics.
...there is a need for an alternative CYP inducer due to 1-methyl-4-nitrosopiperazine (MNP) impurity exceeding the acceptable limit in rifampin products. 1 The US Food and Drug Administration (FDA) ...advised against using rifampin products with MNP impurity above 0.16 ppm in healthy volunteers. 1 Here, we compared phenytoin, phenobarbital, efavirenz, and carbamazepine as alternative CYP3A4 inducers using a physiologically-based pharmacokinetic (PBPK) approach. PBPK SIMULATION TRIAL DESIGN PBPK simulations were performed using the Simcyp human population-based simulator (version 20) to compare induction potentials between rifampin (600 mg q.d.) and the proposed inducers, including phenytoin (300 mg q.d.), phenobarbital (100 mg q.d.), efavirenz (600 mg q.d.), and carbamazepine (100 mg b.i.d. on days 1–2, 200 mg b.i.d. on days 3–4, and 300 mg b.i.d. on days 5–14). PBPK SIMULATION RESULTS Based on the simulated midazolam DDI-to-control geometric mean ratios (GMRs) of AUC0–24h and Cmax, carbamazepine was determined to be the strongest CYP3A4 inducer second to rifampin (AUC GMR 90% confidence intervals = 0.208 0.194, 0.224 vs. 0.0709 0.0628, 0.0800; Cmax GMR = 0.259 0.244, 0.274 vs. 0.107 0.0952, 0.121), which is followed by phenytoin (AUC GMR = 0.224 0.203, 0.248; Cmax GMR = 0.284 0.260, 0.310), phenobarbital (AUC GMR = 0.225 0.209, 0.243; Cmax GMR = 0.295 0.276, 0.314), and efavirenz (AUC GMR = 0.302 0.282, 0.324; Cmax GMR = 0.415 0.392, 0.440; Figure 1a). ...even at the highest dose levels simulated (i.e., 600 mg b.i.d. regimen 5 for carbamazepine or 450 mg q.d. for phenytoin), the induction was still lower than that after rifampin 600 mg q.d. Caution has to be taken when using carbamazepine and phenytoin at these dose levels as the risk of adverse side effects increases.
Early recognition and rapid initiation of high-quality cardiopulmonary resuscitation (CPR) are key to maximising chances of achieving successful return of spontaneous circulation in patients with ...out-of-hospital cardiac arrests (OHCAs), as well as improving patient outcomes both inside and outside hospital. Mechanical chest compression devices such as the LUCAS-2 have been developed to assist rescuers in providing consistent, high-quality compressions, even during transportation. However, providing uninterrupted and effective compressions with LUCAS-2 during transportation down stairwells and in tight spaces in a non-supine position is relatively impossible. In this study, we proposed adaptations to the LUCAS-2 to allow its use during transportation down stairwells and examined its effectiveness in providing high-quality CPR to simulated OHCA patients. 20 volunteer emergency medical technicians were randomised into 10 pairs, each undergoing 2 simulation runs per experimental arm (LUCAS-2 versus control) with a loaded Resusci Anne First Aid full body manikin weighing 60 kg. Quality of CPR compressions performed was measured using the CPRmeter placed on the sternum of the manikin. The respective times taken for each phase of the simulation protocol were recorded. Fisher's exact tests were used to analyse categorical variables and median test to analyse continuous variables. The LUCAS-2 group required a longer time (~ 35 s) to prepare the patient prior to transport (p < 0.0001) and arrive at the ambulance (p < 0.0001) compared to the control group. The CPR quality in terms of depth and rate for the overall resuscitation period did not differ significantly between the LUCAS-2 group and control group, though there was a reduction in both parameters when evaluating the device's automated compressions during transport. Nevertheless, the application of the LUCAS-2 device yielded a significantly higher chest compression fraction of 0.76 (p < 0.0001). Our novel adaptations to the LUCAS-2 device allow for uninterrupted compressions in patients being transported down stairwells, thus yielding better chest compression fractions for the overall resuscitation period. Whether potentially improved post-OHCA survival rates may be achieved requires confirmation in a real-world scenario study.
Abnormal formation of girth weld is a major threat to the safe operation of pipelines, which may lead to serious accidents. Therefore, regular inspection and maintenance of girth weld are essential ...for accident prevention and energy security. This paper presents a novel method for inspecting abnormal girth weld formation in oil and gas pipelines using alternating excitation detection technology. The method is based on the analysis of the microscopic magnetic variations in the welded area under alternating magnetic fields. An internal inspection probe and electronic system for detecting abnormal girth weld formation were designed and developed. The system’s capability to identify misalignment, undercutting, root concavity, and abnormal formation height of girth weld was tested by numerical simulation and experimental study. The results show that the detection system can effectively identify a minimum misalignment of 0.5 mm at a lift-off height of 15 mm. The proposed method offers several advantages, such as rapid response, low cost, non-contact operation, and high sensitivity to surface flaws in ferromagnetic pipelines.
To investigate the effect of Er:YAG laser treatment on lipopolysaccharide (LPS) clearance and fibroblast adhesion on titanium disks. Grade IV titanium discs (n = 216) were used and allocated to 6 ...groups. Group 1 was the negative control without Porphyromonas gingivalis inoculation. Discs in Groups 2-6 were incubated with P. gingivalis to form a biofilm. Group 3 received 0.12% chlorhexidine irrigation and Group 4 received titanium curettage to remove the biofilm. Group 5 was treated with Er:YAG laser irradiation and Group 6 was treated with titanium curettage plus Er:YAG laser irradiation. The contact angle and surface roughness were measured after the various treatments. The surface microstructure and residual bacteria were examined using scanning electron microscopy and confocal laser scanning microscopy, respectively. Residual LPS was examined using a limulus amoebocyte lysate assay and human gingival fibroblast adhesion was quantified using fluorescent microscopy. Curettage plus Er:YAG laser irradiation was the most effective method for removing bacteria and LPS. No significant difference in the amount of fibroblast adhesion was found between the control and Group 6. Combined use of Er:YAG laser irradiation and curettage optimizes LPS clearance and fibroblast adhesion on titanium discs.
PDF
