Pre- and Postnatal Maturation are Important for Fentanyl Exposure in Preterm and Term Newborns : A Pooled Population Pharmacokinetic Study

Publisher Copyright: © 2021, The Author(s).Background and Objective Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individualize dosing. Methods We pooled data from two previous studies on 164 newborns with a median gestational age of 29.0 weeks (range 23.9-42.3), birthweight of 1055 g (range 390-4245), and postnatal age (PNA) of 1 day (range 0-68). In total, 673 plasma samples upon bolus dosing (69 patients; median dose 2.1 mu g/kg, median 2 boluses per patient) or continuous infusions (95 patients; median dose 1.1 mu g/kg/h for 30 h) with and without boluses were used for population pharmacokinetic modeling in NONMEM(R) 7.4. Results Clearance in neonates with birthweight of 2000 and 3000 g was 2.8- and 5.0-fold the clearance in a neonate with birthweight of 1000 g, respectively. Fentanyl clearance at PNA of 7, 14, and 21 days was 2.7-fold, 3.8-fold, and 4.6-fold the clearance at 1 day, respectively. Bodyweight-based dosing resulted in large differences in fentanyl concentrations. Depending on PNA and birthweight, fentanyl concentrations increased slowly after the start of therapy for both intermittent boluses and continuous infusion and reached a maximum concentration at 12-48 h. Conclusions As both prenatal and postnatal maturation are important for fentanyl exposure, we propose a birthweight- and PNA-based dosage regimen. To provide rapid analgesia in the first 24 h of treatment, additional loading doses need to be considered.Peer reviewe

Maturation of Paracetamol Elimination Routes in Preterm Neonates Born Below 32 Weeks of Gestation

Purpose: Despite being off-label, intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates. Here we aim to quantify the maturation of paracetamol elimination pathways in preterm neonates born below 32 weeks of gestation. Methods: Datasets after single dose (rich data) or multiple doses (sparse data) of intravenous PCM dose (median (range)) 9 (3–25) mg/kg were pooled, containing 534 plasma and 44 urine samples of PCM and metabolites (PCM–glucuronide, PCM–sulfate, PCM–cysteine, and PCM–mercapturate) from 143 preterm neonates (gestational age 27.7 (24.0–31.9) weeks, birthweight 985 (462–1,925) g, postnatal age (PNA) 5 (0–30) days, current weight 1,012 (462–1,959) g. Population pharmacokinetic analysis was performed using NONMEM® 7.4. Results: For a typical preterm neonate (birthweight 985 g; PNA 5 days), PCM clearance was 0.137 L/h, with glucuronidation, sulfation, oxidation and unchanged renal clearance accounting for 5.3%, 73.7%, 16.3% and 4.6%, respectively. Maturational changes in total PCM clearance and its elimination pathways were best described by birthweight and PNA. Between 500–1,500 g birthweight, total PCM clearance increases by 169%, with glucuronidation, sulfation and oxidation clearance increasing by 347%, 164% and 164%. From 1–30 days PNA for 985 g birthweight neonate, total PCM clearance increases by 167%, with clearance via glucuronidation and oxidation increasing by 551%, and sulfation by 69%. Conclusion: Birthweight and PNA are the most important predictors for maturational changes in paracetamol clearance and its glucuronidation, sulfation and oxidation. As a result, dosing based on bodyweight alone will not lead to consistent paracetamol concentrations among preterm neonates.</p

A Computer Aided Grading System for Subjective Tests

Computer aided tests replace traditional written answers on paper sheets with electronic records. For subjective tests, computers are not able to do all grading jobs, due to limited comprehensive ability of computers. Subjective answers need be reviewed by different graders in order to improve justice. We propose a distributed computational model for grading electronic subjective answers. Answer data are divided into numerous independent data cells. Computational resources are automatically allocated by the system to do grading jobs and independently report grading results to the system. Since the grading results may vary slightly or magnificently, we assign computational factors to data cells and computational resources to minimize the variation. In addition, rules are defined to obtain a final result. We successfully apply the proposed model in our grading system in computer aided spoken English tests. 1

Quinoa bran insoluble dietary fiber-zinc chelate mediates intestinal flora structure to regulate glucose and lipid metabolism in obese rats

Insoluble dietary fiber (IDF) and ZnSO4·7H2O were chelated to obtain the IDF-Zn. The Zn ion content was as high as 31.25 mg/g, which is a good source of Zn-rich products. The effects of IDF-Zn on metabolism and blood lipid levels were investigated in obese rats. Results showed that compared to IDF and organic Zn (ZnSO4·7H2O), IDF-Zn can significantly reduce the body weight, the levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol in serum, improve liver abnormal lipid sedimentation, oxidation stress state, and enhance the immunity of obese rats. Through 16S rRNA results, IDF-Zn intervention decreased the ratio of Firmicutes/Bacteroidetes and increased the abundance of probiotics (such as Lactobacillus, Muribaculaceae, and Bacteroides), and decreased the abundance of cellulolytic bacteria (such as Romboutsia and Clostridia-UCG-014). These results suggest that IDF-Zn can adjust intestinal flora structure of high-fat diet rats, promote liver health, reduce lipid deposits, and ultimately positively impact glucolipid metabolism

Exosomes and osteosarcoma drug resistance

Osteosarcoma (OS) is a primary malignant tumor of bone characterized by the formation of bone tissue or immature bone by tumor cells. Because of its multi-drug resistance, even with the improvement of chemotherapy and the use of targeted drugs, the survival rate of osteosarcoma (OS) is still less than 60%, and it is easy to metastasize, which is a difficulty for many clinicians and researchers. In recent years, with the continuous research on exosomes, it has been found that exosomes play a role in the diagnosis, treatment and chemotherapy resistance of osteosarcoma due to their unique properties. Exosomes can reduce the intracellular accumulation of chemotherapeutic drugs by mediating drug efflux, thus inducing chemotherapeutic resistance in OS cells. Exosomal goods (including miRNA and functional proteins) carried by exosomes also show great potential in affecting the drug resistance of OS. In addition, miRNA carried by exosomes and exosomes exist widely in tumor cells and can reflect the characteristics of parent cells, so it can also be used as a biomarker of OS. At the same time, the development of nanomedicine has given a new hope for the treatment of OS. Exosomes are regarded as good natural nano-carriers by researchers because of their excellent targeted transport capacity and low toxicity, which will play an important role in the field of OS therapy in the future. This paper reviews the internal relationship between exosomes and OS chemotherapy resistance, discusses the broad prospects of exosomes in the field of diagnosis and treatment of OS, and puts forward some suggestions for the study of the mechanism of OS chemotherapy resistance

Oridonin Attenuates Myocardial Ischemia/Reperfusion Injury via Downregulating Oxidative Stress and NLRP3 Inflammasome Pathway in Mice

Oridonin (ORI), the major pharmacological component extracted from a traditional Chinese medicine, possesses a beneficial effect on myocardial ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanism by which ORI effects take place is not completely known. Thus, whether ORI works via downregulating oxidative stress and nod-like receptor protein-3 (NLRP3) inflammasome pathway was investigated in this study. Mice underwent surgery to induce myocardial I/R injury, and some were administered ORI (10 mg/kg/day) pretreatment, while others were not. The myocardial enzymes’ levels, infarct area, and inflammatory injury were measured. The activation situation of oxidative stress and NLRP3 inflammasome was also detected. We found that ORI pretreatment significantly alleviated CK-MB and cTnI levels and infarct size induced by I/R. ORI mitigated the inflammatory injury by decreasing the pathological damage and lowering TNF-α, IL-1β, and IL-18 levels. Moreover, the SOD1 and eNOS levels were significantly increased by ORI, while MDA and iNOS levels were relatively decreased. The oxidative stress was reversed using ORI pretreatment. Importantly, NLRP3 inflammasome pathway was also inhibited by ORI, as reflected by the lower protein levels of NLRP3, caspase-1, and IL-1β. In conclusion, ORI alleviates myocardial injury induced by I/R via inhibiting the oxidative stress and NLRP3 inflammasome pathway

Different gut microbial types were found in captive striped hamsters

Background Typing analysis has become a popular approach to categorize individual differences in studies of animal gut microbial communities. However, previous definitions of gut microbial types were more understood as a passive reaction process to different external interferences, as most studies involve diverse environmental variables. We wondered whether distinct gut microbial types can also occur in animals under the same external environment. Moreover, the role of host sex in shaping gut microbiota has been widely reported; thus, the current study preliminarily explores the effects of sex on potential different microbial types. Methods Here, adult striped hamsters Cricetulus barabensis of different sexes were housed under the same controlled laboratory conditions, and their fecal samples were collected after two months to assess the gut microbiota by 16S rRNA sequencing. Results The gut microbiota of captive striped hamsters naturally separated into two types at the amplicon sequence variant (ASV) level. There was a significant difference in the Shannon index among these two types. A receiver operating characteristic (ROC) curve showed that the top 30 ASVs could effectively distinguish each type. Linear discriminant analysis of effect size (LEfSe) showed enrichment of the genera Lactobacillus, Treponema and Pygmaiobacter in one gut microbial type and enrichment of the genera Turicibacter and Ruminiclostridium in the other. The former type had higher carbohydrate metabolism ability, while the latter harbored a more complex co-occurrence network and higher amino acid metabolism ability. The gut microbial types were not associated with sex; however, we did find sex differences in the relative abundances of certain bacterial taxa, including some type-specific sex variations. Conclusions Although captive animals live in a unified environment, their gut bacteria can still differentiate into distinct types, but the sex of the hosts may not play an important role in the typing process of small-scale captive animal communities. The relevant driving factors as well as other potential types need to be further investigated to better understand host-microbe interactions