Physiological and biochemical characteristics of the carbon ion beam irradiation-generated mutant strain Clostridium butyricum FZM 240 in vitro and in vivo.

Clostridium butyricum (C. butyricum) represents a new generation of probiotics, which is beneficial because of its good tolerance and ability to produce beneficial metabolites, such as short-chain fatty acids and enzymes; however, its low enzyme activity limits its probiotic efficacy. In this study, a mutant strain, C. butyricum FZM 240 was obtained using carbon ion beam irradiation, which exhibited greatly improved enzyme production and tolerance. The highest filter paper, endoglucanase, and amylase activities produced by C. butyricum FZM 240 were 125.69 U/mL, 225.82 U/ mL, and 252.28 U/mL, which were 2.58, 1.95, and 2.21-fold higher, respectively, than those of the original strain. The survival rate of the strain increased by 11.40 % and 5.60 % after incubation at 90 °C for 5 min and with simulated gastric fluid at pH 2.5 for 2 h, respectively, compared with that of the original strain. Whole-genome resequencing and quantitative real-time PCR(qRT-PCR) analysis showed that the expression of genes related to enzyme synthesis (GE000348, GE001963 and GE003123) and tolerance (GE001114) was significantly up-regulated, while that of genes related to acid metabolism (GE003450) was significantly down-regulated. On this basis, homology modeling and functional prediction of the proteins encoded by the mutated genes were performed. According to the results, the properties related to the efficacy of C. butyricum as a probiotic were significantly enhanced by carbon ion beam irradiation, which is a novel strategy for the application of Clostridium spp. as feed additives.

What influences newly graduated registered nurses' intention to leave the nursing profession? An integrative review.

BACKGROUND: Newly graduated registered nurses leaving the nursing profession in the early stages of their career have enormous financial and time implications for nursing organizations and affect the quality of nursing care. OBJECTIVE: To identify the factors influencing newly graduated registered nurses' intention to leave the nursing profession over the past 10 years. METHODS: The framework developed by Whittemore and Knafl was used to conduct this integrative review. An electronic search was conducted for English articles to identify research studies published between 2011-2022 using the following databases of PubMed, MEDLINE, CINAHL, PsycINFO, and Scopus. Eligible publications were critically reviewed and scored using the Critical Appraisal Skills Program Checklist and the Center for Evidence-Based Management appraisal. RESULTS: Twenty-one studies were analyzed. The main factors affecting newly graduated registered nurses' intention to leave the nursing profession included demographic factors (age, educational level, year of experience, professional title, employment status, health status, shift, hospital location and size), supervisor and peer support, challenges in the workplace, cognitive and affective response to work, work environment (collegial nurse-physician relations, insufficient staffing level, person-work environment fit), gender stereotypes, autonomous motivation, role models, and resilience. CONCLUSIONS: The factors affecting newly graduated registered nurses' intention to leave the nursing profession are multifaceted and should receive continuous attention from nurse managers. The findings provide more comprehensive for nurse administrators to develop intervention strategies to mitigate newly graduated registered nurses' turnover intention.

Adapting the endoplasmic reticulum proteostasis rescues epilepsy-associated NMDA receptor variants.

The GRIN genes encoding N-methyl-D-aspartate receptor (NMDAR) subunits are remarkably intolerant to variation. Many pathogenic NMDAR variants result in their protein misfolding, inefficient assembly, reduced surface expression, and impaired function on neuronal membrane, causing neurological disorders including epilepsy and intellectual disability. Here, we investigated the proteostasis maintenance of NMDARs containing epilepsy-associated variations in the GluN2A subunit, including M705V and A727T. In the transfected HEK293T cells, we showed that the two variants were targeted to the proteasome for degradation and had reduced functional surface expression. We demonstrated that the application of BIX, a known small molecule activator of an HSP70 family chaperone BiP (binding immunoglobulin protein) in the endoplasmic reticulum (ER), dose-dependently enhanced the functional surface expression of the M705V and A727T variants in HEK293T cells. Moreover, BIX (10 µM) increased the surface protein levels of the M705V variant in human iPSC-derived neurons. We revealed that BIX promoted folding, inhibited degradation, and enhanced anterograde trafficking of the M705V variant by modest activation of the IRE1 pathway of the unfolded protein response. Our results suggest that adapting the ER proteostasis network restores the folding, trafficking, and function of pathogenic NMDAR variants, representing a potential treatment for neurological disorders resulting from NMDAR dysfunction.

Pathogenicity Prediction of GABAA Receptor Missense Variants.

Variants in the genes encoding the subunits of gamma-aminobutyric acid type A (GABAA) receptors are associated with epilepsy. To date, over 1000 clinical variants have been identified in these genes. However, the majority of these variants lack functional studies and their clinical significance is uncertain although accumulating evidence indicates that proteostasis deficiency is the major disease-causing mechanism for GABAA receptor variants. Here, we apply two state-of-the-art modeling tools, namely AlphaMissense, which uses an artificial intelligence-based approach based on AlphaFold structures, and Rhapsody, which integrates sequence evolution and known structure-based data, to predict the pathogenicity of saturating missense variants in genes that encode the major subunits of GABAA receptors in the central nervous system, including GABRA1, GABRB2, GABRB3, and GABRG2. Our results demonstrate that the predicted pathogenicity correlates well between AlphaMissense and Rhapsody although AlphaMissense tends to generate higher pathogenic probability. Furthermore, almost all annotated pathogenic variants in the ClinVar clinical database are successfully identified from the prediction, whereas uncertain variants from ClinVar partially due to the lack of experimental data are differentiated into different pathogenicity groups. The pathogenicity prediction of GABAA receptor missense variants provides a resource to the community as well as guidance for future experimental and clinical investigations.

A novel mRNA rabies vaccine as a promising candidate for rabies post-exposure prophylaxis protects animals from different rabies viruses.

Rabies, caused by the rabies virus (RABV), is the most fatal zoonotic disease. It is a neglected tropical disease which remains a major public health problem, causing approximately 59,000 deaths worldwide annually. Despite the existence of effective vaccines, the high incidence of human rabies is mainly linked to tedious vaccine immunisation procedures and the overall high cost of post-exposure prophylaxis. Therefore, it is necessary to develop an effective vaccine that has a simple procedure and is affordable to prevent rabies infection in humans. RABV belongs to the genus Lyssavirus and family Rhabdoviridae. Previous phylogenetic analyses have identified seven major clades of RABV in China (China I-VII), confirmed by analysing nucleotide sequences from both the G and N proteins. This study evaluated the immunogenicity and protective capacity of SYS6008, an mRNA rabies vaccine expressing rabies virus glycoprotein, in mice and cynomolgus macaques. We demonstrated that SYS6008 induced sufficient levels of rabies neutralising antibody (RVNA) in mice. In addition, SYS6008 elicited strong and durable RVNA responses in vaccinated cynomolgus macaques. In the pre-exposure prophylaxis murine model, one or two injections of SYS6008 at 1/10 or 1/30 of dosage provided protection against a challenge with a 30-fold LD50 of rabies virus (China I and II clades). We also demonstrated that in the post-exposure prophylaxis murine model, which was exposed to lethal rabies virus (China I-VII clades) before vaccination, one or two injections of SYS6008 at both 1/10 and 1/30 dosages provided better protection against rabies virus challenge than the immunization by five injections of commercial vaccines at the same dosage. In addition, we proved that SYS6008-induced RVNAs could neutralise RABV from the China I-VII clades. Finally, 1/10 of the dosage of SYS6008 was able to stimulate significant RABV-G specificity in the T cell response. Furthermore, we found that SYS6008 induced high cellular immunity, including RABV-G-specific T cell responses and memory B cells. Our results imply that the SYS6008 rabies vaccine, with a much simpler vaccination procedure, better immunogenicity, and enhanced protective capacity, could be a candidate vaccine for post-exposure prophylaxis of rabies infections.

Pharmacological chaperones restore proteostasis of epilepsy-associated GABAA receptor variants.

Recent advances in genetic diagnosis identified variants in genes encoding GABAA receptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the α1 subunit of GABAA receptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the α1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the α1 variants. Mechanism of action study demonstrated that they enhance the folding and assembly and reduce the degradation of GABAA variants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABAA receptor-specific manner.

Construction of Clostridium tyrobutyricum strain and ionic membrane technology combination pattern for refinery final molasses recovery and butyric acid production.

Introduction: Clostridium tyrobutyricum has considerable prospect in the production of organic acids. Globally, refinery final molasses is rich in sugar and reported to have high levels of accumulation and high emission costs, recognized as an excellent substrate for C. tyrobutyricum fermentation, but there is no suitable method available at present. Methods: In this study, an acid-base treatment combined with a new green membrane treatment technology - a dynamic ion-exchange membrane -was used to pretreat refinery final molasses, so that it could be used for C. tyrobutyricum to produce butyric acid. A high-performance liquid chromatography method was established to determine the conversion of a large amount of sucrose into fermentable sugars (71.88 g/L glucose and 38.06 g/L fructose) in the treated refinery final molasses. The process of sequential filtration with 3, 1, and 0.45 µm-pore diameter dynamic ion-exchange membranes could remove impurities, pigments, and harmful substances from the refinery final molasses, and retain the fermentable sugar. Results and discussion: This means that refinery final molasses from the sugar industry could be utilized as a high-value by-product and used for the growth of C. tyrobutyricum, with industrial feasibility and economic competitiveness. Using the treated refinery final molasses as a carbon source, C. tyrobutyricum was screened by the method of adaptive evolution. The strain with butyric acid yielded 52.54 g/L, and the yield of the six carbon sugar was increased from 0.240 to 0.478 g/g. The results showed that combination of C. tyrobutyricum and ionic membrane technology broke through the bottleneck of its utilization of refinery final molasses. This study provided an innovative idea for the C. tyrobutyricum fermentation to produce butyric acid.

Temporal and spatial evolution and influencing factors of urban ecological total factor productivity in the Yellow River basin under strong sustainable development.

A growing consensus worldwide has indicated the need to protect the ecological environment and achieve sustainable development. Ensuring ecological protection and high-quality development of the Yellow River basin have become China's major national strategy. We reviewed extant literature, summarised government reports and guidance documents on the Yellow River basin, and proposed introducing a strong sustainable development theory into the study of total factor productivity (TFP). The spatial-temporal evolution and influencing factors of urban ecological TFP in the Yellow River basin are of great practical significance. We proposed a new ecological TFP indicator: the modified input-oriented Luenberger productivity indicator (MIL). Using panel data from 78 cities in the Yellow River basin during 2003-2019, we measured the urban ecological TFP. We adopted the geographic information system tool and kernel density estimation to analyse the temporal and spatial evolution of the indicator, as well as its spatial effects and influencing factors, using the global Moran's I index and dynamic spatial Durbin model (SDM). Our results show that, during the sample period, our indicator increased in cities in the region with an average annual growth rate of 0.627%, driven by technological progress. The average annual growth rate in urban areas showed a decreasing distribution of 'downstream-midstream-upstream'. Fiscal decentralisation (FD), industrial structure (IND), financial development (FIN), urbanisation level (URB) and research and development (RD) investment improved growth rates in this and the adjacent regions through direct and indirect effects. However, environmental regulation (ER), opening level (OPEN) of cities and population density (POP) were obstacles to TFP growth.

[Response of Soil Respiration Rates to Soil Temperature and Moisture at Different Soil Depths of Caragana korshinskii Plantation in the Loess-Hilly Region].

It is of great significance to clarify the influence of soil temperature and moisture on soil respiration rate and its characteristics in ecologically fragile regions under the background of climate change for the accurate assessment and prediction of carbon budgets in this region. The average CO2 concentration and soil temperature and moisture at different soil depths (10, 50, and 100 cm) were measured using a CO2 analyzer and temperature and moisture sensors. The soil respiration rate was calculated using Fick's first diffusion coefficient method. The dynamic characteristics of soil temperature, soil moisture, and soil respiration rate in different soil depths were explored, and the response of soil respiration rate to soil temperature and moisture were further analyzed. The results showed that the diurnal variation in soil respiration rate decreased significantly with the increase in soil depth (P<0.05), and the peak time lagged behind. Soil respiration rate in adjacent soil depths (10, 50, and 100 cm) lagged 1 h from top to bottom. The monthly variation in soil respiration rate was a multi-peak curve, in which the maximum soil respiration rates of 10, 50, and 100 cm soil depths were on July 25th, August 6th, and August 10th, reaching 13.96, 2.96, and 1.47 µmol·(m2·s)-1, respectively. The effect of soil temperature on soil respiration rate decreased with the increase in soil depth. Soil temperature at 50 cm and below had no significant effect on soil respiration rate (P>0.05). The fitting index of 10 cm soil depth was the best (R2=0.96), but the fitting indexes of 50 cm and 100 cm soil depths were poor (R2=0.00 and R2=0.01, respectively). The temperature sensitivity coefficient Q10 decreased with the increase in soil depth. Soil moisture in different soil depths had significant effects on soil respiration rate (P<0.05), and the quadratic fitting indicated that 50 cm (R2=0.35)>10 cm (R2=0.22)>100 cm (R2=0.31). The combined effects of soil temperature and moisture in different soil depths could explain 96%, 6%-50%, and 22%-24% of soil respiration rate, respectively. In summary, the effects of soil temperature and moisture at different soil depths of the Caragana korshinskii plantation in the loess-hilly region on soil respiration rate differed. The soil respiration rate of the 10 cm soil depth was affected by the comprehensive effect of soil temperature and moisture; however, the relative contribution of soil temperature was higher, and soil moisture at and below a soil depth of 50 cm was the key factor. These results could help improve predictions on the impact of future climate change on the carbon cycle of terrestrial ecosystems in the region and provide a theoretical basis for greenhouse gas regulation in the future.

Protein quality control of N-methyl-D-aspartate receptors.

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated cation channels that mediate excitatory neurotransmission and are critical for synaptic development and plasticity in the mammalian central nervous system (CNS). Functional NMDARs typically form via the heterotetrameric assembly of GluN1 and GluN2 subunits. Variants within GRIN genes are implicated in various neurodevelopmental and neuropsychiatric disorders. Due to the significance of NMDAR subunit composition for regional and developmental signaling at synapses, properly folded receptors must reach the plasma membrane for their function. This review focuses on the protein quality control of NMDARs. Specifically, we review the quality control mechanisms that ensure receptors are correctly folded and assembled within the endoplasmic reticulum (ER) and trafficked to the plasma membrane. Further, we discuss disease-associated variants that have shown disrupted NMDAR surface expression and function. Finally, we discuss potential targeted pharmacological and therapeutic approaches to ameliorate disease phenotypes by enhancing the expression and surface trafficking of subunits harboring disease-associated variants, thereby increasing their incorporation into functional receptors.

The endoplasmic reticulum membrane complex promotes proteostasis of GABAA receptors.

The endoplasmic reticulum membrane complex (EMC) plays a critical role in the biogenesis of tail-anchored proteins and a subset of multi-pass membrane proteins in the endoplasmic reticulum (ER). However, because of nearly exclusive expression of neurotransmitter-gated ion channels in the central nervous system (CNS), the role of the EMC in their biogenesis is not well understood. In this study, we demonstrated that the EMC positively regulates the surface trafficking and thus function of endogenous γ-aminobutyric acid type A (GABAA) receptors, the primary inhibitory ion channels in the mammalian brain. Moreover, among ten EMC subunits, EMC3 and EMC6 have the most prominent effect, and overexpression of EMC3 or EMC6 is sufficient to restore the function of epilepsy-associated GABAA receptor variants. In addition, EMC3 and EMC6 demonstrate endogenous interactions with major neuroreceptors, which depends on their transmembrane domains, suggesting a general role of the EMC in the biogenesis of neuroreceptors.

Quantitative interactome proteomics identifies a proteostasis network for GABAA receptors.

Gamma-aminobutyric acid type A (GABAA) receptors are the primary inhibitory neurotransmitter-gated ion channels in the mammalian central nervous system. Maintenance of GABAA receptor protein homeostasis (proteostasis) in cells utilizing its interacting proteins is essential for the function of GABAA receptors. However, how the proteostasis network orchestrates GABAA receptor biogenesis in the endoplasmic reticulum is not well understood. Here, we employed a proteomics-based approach to systematically identify the interactomes of GABAA receptors. We carried out a quantitative immunoprecipitation-tandem mass spectrometry analysis utilizing stable isotope labeling by amino acids in cell culture. Furthermore, we performed comparative proteomics by using both WT α1 subunit and a misfolding-prone α1 subunit carrying the A322D variant as the bait proteins. We identified 125 interactors for WT α1-containing receptors, 105 proteins for α1(A322D)-containing receptors, and 54 overlapping proteins within these two interactomes. Our bioinformatics analysis identified potential GABAA receptor proteostasis network components, including chaperones, folding enzymes, trafficking factors, and degradation factors, and we assembled a model of their potential involvement in the cellular folding, degradation, and trafficking pathways for GABAA receptors. In addition, we verified endogenous interactions between α1 subunits and selected interactors by using coimmunoprecipitation in mouse brain homogenates. Moreover, we showed that TRIM21 (tripartite motif containing-21), an E3 ubiquitin ligase, positively regulated the degradation of misfolding-prone α1(A322D) subunits selectively. This study paves the way for understanding the molecular mechanisms as well as fine-tuning of GABAA receptor proteostasis to ameliorate related neurological diseases such as epilepsy.

Downregulation of LRRC19 Is Associated with Poor Prognosis in Colorectal Cancer.

Objective: Colorectal cancer (CRC) is globally one of the most often diagnosed cancers with high mortality rates. This study aimed to explore novel biomarkers for the diagnosis and prognosis of CRC. Methods: We collected 4 datasets about CRC in GEO and sought differentially expressed genes (DEGs) with GEO2R. Leucine-rich repeat-containing protein 19 (LRRC19) expression was assessed through the Oncomine and TIMER database analyses, which was further confirmed by qRT-PCR of CRC samples. We used online survival analysis tools (GEPIA, PrognoScan, and Kaplan-Meier plotter) to examine the prognostic value of LRRC19 in CRC and other malignancies. GO and KEGG enrichment analyses were employed to explore the biological functions of LRRC19. Finally, we conducted network prediction by STRING and further validation on the GEPIA to discover other molecules that might interact with LRRC19. Results: A total of 21 upregulated and 46 downregulated DEGs were identified from the 4 datasets. The TIMER and Oncomine online analyses showed lower mRNA of LRRC19 in CRC tissues compared with adjacent normal tissues, which was validated by qRT-PCR in CRC patient samples. The survival analysis through the GEPIA and PrognoScan websites revealed that low LRRC19 expression was significantly correlated with poor prognosis in CRC patients. The Kaplan-Meier plotter survival analysis indicated that low LRRC19 expression was significantly associated with the disease progression of patients with ovarian cancer, gastric cancer, breast cancer, and lung cancer. The enrichment analysis suggested that low expression of LRRC19 could be involved in the retinol metabolism and the zymogen granule membrane. Through STRING and GEPIA, it was found that LRRC19 is clearly associated with ZCCHC10, MOB3B, IMMP2L, and TRMT11. Conclusion: LRRC19 mRNA was prominently decreased in human CRC tissues and was significantly associated with shorter survival in CRC patients. LRRC19 might serve as a possible target for early diagnosis and prognosis assessment in CRC.

NMR Analysis of Lipid Oxidation in Flaxseed Oil-in-Water Emulsions.

The formation of linolenic (Ln) and linoleic (L) acyl oxidation products during storage of flaxseed oil (FO)-in-water emulsions was monitored using proton nuclear magnetic resonance (1H NMR) spectroscopy, as well as chemical analytical methods and gas chromatography. Emulsions containing 10% FO and 1% Tween 60 were prepared by homogenization and then stored at 37 °C in the dark for 21 days under accelerated oxidation conditions (500 µmol ferrous sulfate). The induction time of the emulsions, after which rapid lipid oxidation was first observed, was 5-7 days, as shown by increases in peroxide values and hydroperoxide concentrations determined by NMR spectroscopy. Analysis of the hexanal and propanal concentrations during storage by HS-SPME-GC indicated that the oxidation of Ln and L acyls in the emulsions occurred simultaneously. The oxidation products originating from the Ln and L acyls were monitored using 1H NMR spectroscopy throughout the oxidation process. These results also showed that the Ln and L acyls oxidized simultaneously, and isomers of hydroperoxy-cyclic hydroperoxides (HCPs), Z,E-conjugated dienic hydroperoxides (ZECDHPs), and E,E-conjugated dienic hydroperoxides (EECDHPs) were the major primary oxidation products. Aldehydes were observed after 7 days, which was taken to be the start of the propagation stage, with the formation of a significant amount of oxygenated α, ß-unsaturated aldehydes (OαßUAs). Based on the concentrations of hydroperoxides originating from the Ln and L acyls, our results suggested that the loss rate of L acyls was parallel to that of Ln acyls. This result was consistent with Ln acyls adopting a tighter packing at the oil-water interface in the emulsions than L acyls. This hypothesis was supported by the NMR relaxation time data. A good correlation between the isomer concentrations of ZECDHPs and HCPs in Ln acyls and between ZECDHPs and EECDHPs in L acyls was shown, with the mole ratios between them being 1.2 and 1.1, respectively. Droplet size and microstructure analyses showed that droplet aggregation occurred from 11 days onwards, which was attributed to polar oxidation products located at the oil droplet surfaces promoting coalescence. Zeta-potential measurements indicated that the droplets became more negative during storage, which was attributed to the accumulation of anionic reaction products at the droplet surfaces.

Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABAA receptors.

BACKGROUND: Genetic variants in the subunits of the gamma-aminobutyric acid type A (GABAA) receptors are implicated in the onset of multiple pathologic conditions including genetic epilepsy. Previous work showed that pathogenic GABAA subunits promote misfolding and inefficient assembly of the GABAA receptors, limiting receptor expression and activity at the plasma membrane. However, GABAA receptors containing variant subunits can retain activity, indicating that enhancing the folding, assembly, and trafficking of these variant receptors offers a potential opportunity to mitigate pathology associated with genetic epilepsy. RESULTS: Here, we demonstrate that pharmacologically enhancing endoplasmic reticulum (ER) proteostasis using small molecule activators of the ATF6 (Activating Transcription Factor 6) signaling arm of the unfolded protein response (UPR) increases the assembly, trafficking, and surface expression of variant GABAA receptors. These improvements are attributed to ATF6-dependent remodeling of the ER proteostasis environment, which increases protein levels of pro-folding ER proteostasis factors including the ER chaperone BiP (Immunoglobulin Binding Protein) and trafficking receptors, such as LMAN1 (Lectin Mannose-Binding 1) and enhances their interactions with GABAA receptors. Importantly, we further show that pharmacologic ATF6 activators increase the activity of GABAA receptors at the cell surface, revealing the potential for this strategy to restore receptor activity to levels that could mitigate disease pathogenesis. CONCLUSIONS: These results indicate that pharmacologic ATF6 activators offer an opportunity to restore GABAA receptor activity in diseases including genetic epilepsy and point to the potential for similar pharmacologic enhancement of ER proteostasis to improve trafficking of other disease-associated variant ion channels implicated in etiologically-diverse diseases.

[Pollution Characteristics and Risk Assessment of Tetracycline Antibiotics in Farmland Soil in Yinchuan].

A total of 43 surface soil samples were collected from Yinchuan farmland and high performance liquid chromatography(HPLC) was used to measure the concentrations of oxytetracycline(OTC), tetracycline(TC), chlortetracycline(CTC), and doxycycline(DOC). The pollution characteristics and spatial distribution of TC were further analyzed using spatial Kriging interpolation, and the ecological risks of OTC, TC, CTC, and DOC in farmland soils were also assessed. Tetracycline antibiotics were detected in all the soil samples at concentrations ranging from 40.68 to 1074.42 µg·kg-1 and an average of 462.24 µg·kg-1. The average proportions were ranked ΣTCs: CTC(69.26%) > OTC(16.34%) > TC(12.86%) > DOC(1.54%), and CTC pollution was the most serious among. The space tended to be high in the middle and low in the periphery, but the concentrations of TC were highest in the northwest. The average contents of ΣTCs in different soils was ranked as follows:vegetable field(596.01 µg·kg-1) > pasture(487.04 µg·kg-1) > cultivated land(437.52µg·kg-1) > garden plot(404.99 µg·kg-1). The average risk values of OTC, TC, CTC, and DOC in farmland soils were 0.14, 0.69, 0.14, and 1.02, respectively. TC and DOC represented a high level of risk in 23.26% and 6.98% of the samples, respectively, which requires particular attention.

Current status of group B Streptococcus infection in neonates: a multicenter prospective study. / 新生儿Bæ—é“¾çƒèŒæ„ŸæŸ“çŽ°çŠ¶çš„å¤šä¸­å¿ƒå‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To investigate the incidence of maternal group B Streptococcus (GBS) colonization and neonatal early-onset GBS disease (GBS-EOD), and to study the factors associated with the development of GBS-EOD in the offspring of pregnant women with GBS colonization. METHODS: A total of 16 384 pregnant women and 16 634 neonates delivered by them were enrolled prospectively who had medical records in Xiamen Maternal and Child Care Hospital, Beijing Obstetrics and Gynecology Hospital of Capital Medical University, and Zhangzhou Zhengxing Hospital from May 1, 2019 to April 30, 2020. Unified GBS screening time, culture method, and indication for intrapartum antibiotic prophylaxis (IAP) were adopted in the three hospitals. The incidence rates of maternal GBS colonization and neonatal GBS-EOD were investigated. A multivariate logistic regression analysis was used to identify the factors associated with the development of GBS-EOD in the offspring of pregnant women with GBS colonization. RESULTS: In these three hospitals, the positive rate of GBS culture among the pregnant women in late pregnancy was 11.29% (1 850/16 384), and the incidence rate of neonatal GBS-EOD was 0.96‰ (16/16 634). The admission rate of live infants born to the GBS-positive pregnant women was higher than that of those born to the GBS-negative ones (P<0.05). The live infants born to the GBS-positive pregnant women had a higher incidence rate of GBS-EOD than those born to the GBS-negative ones [6.38‰ (12/1 881) vs 0.27‰ (4/14 725), P<0.05]. The multivariate logistic regression analysis showed that placental swabs positive for GBS and positive GBS in neonatal gastric juice at birth were independent predictive factors for the development of GBS-EOD (P<0.05), while adequate IAP was a protective factor (P<0.05) in the offspring of pregnant women with GBS colonization. CONCLUSIONS: GBS colonization of pregnant women in late pregnancy has adverse effects on their offspring. It is important to determine prenatal GBS colonization status of pregnant women and administer with adequate IAP based on the indications of IAP to reduce the incidence of neonatal GBS-EOD. Citation.

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.

A Microdose Cocktail to Evaluate Drug Interactions in Patients with Renal Impairment.

Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P-gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (Cmax ), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2-fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed. RIF did not impact MDZ, had a progressively smaller DABI drug-drug interaction (DDI) with increasing RI severity, a similar 3.1-fold to 4.4-fold increase in PTV and RSV AUC in healthy volunteers and patients with RI, and a diminishing DDI with RI severity from 6.1-fold to 4.7-fold for ATV. Endogenous biomarkers of OATP1B (bilirubin, coproporphyrin I/III, and sulfated bile salts) were generally not impacted by RI, and RIF effects on these biomarkers in RI were comparable or larger than those in healthy volunteers. The lack of a trend with RI severity of PTV and several OATP1B biomarkers, suggests that mechanisms beyond RI directly impacting OATP1B activity could also be considered. The DABI, RSV, and ATV data suggest an impact of RI on intestinal P-gp, and potentially BCRP activity. Therefore, DDI data from healthy volunteers may represent a worst-case scenario for clinically derisking P-gp and BCRP substrates in the setting of RI.