Epidemiological and clinical profile of pediatric hepatitis B virus infections in Wuhan: a retrospective cohort study.

BACKGROUND: Hepatitis B virus (HBV) remains a substantial public health safety concern drawing considerable attention in China and globally. The detection of HBV serological markers can enable the assessment of HBV infection and replication status in vivo and evaluate the body's protection against HBV. Therefore, this study aims to identify the epidemiological and clinical characteristics of HBV infection in children to prevent and control HBV infection in Wuhan areas. METHODS: We conducted an extensive retrospective cohort analysis of 115,029 individuals aged 0-18 years who underwent HBV serological markers detection for HBV infection in hospital between 2018 and 2021 using Electrochemiluminescence immunoassay. We generated descriptive statistics and analysed HBV infection's epidemiological and clinical characteristics between different sex and age groups. RESULTS: The overall positive detection rates of HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb in all participants were 0.13%, 79.09%, 0.17%, 2.81%, and 5.82%, respectively. The positive rate of HBeAb and HBcAb in males was significantly lower than that in females (2.64% vs. 3.13%, 5.56% vs. 6.29%) (P < 0.05). Twenty-two distinct HBV serological expression patterns were revealed. Among them, 8 common expression patterns accounted for 99.63%, while the remaining 14 uncommon expression patterns were primarily observed in neonatal patients with HBV infection. There are no significant differences in serological patterns based on sex (P < 0.05). The overall HBV infection detection rate was 5.82% [range 5.68-5.95] and showed a declining yearly trend. The rate in females was higher than that in males 6.29% [6.05, 6.35] vs. 5.56% [5.39, 5.59]. The overall HBV diagnostic rate over 4 years was 0.20% [0.17, 0.22], and the rate declined yearly. The prevalence of acute infection was higher than that of other infection types before 2019, but the incidence of unclassified infection showed a significant upward trend after 2019. CONCLUSIONS: While the overall HBV infection detection rate in children has decreased year by year, the infection rate remains high in children under one year and between 4 and 18 years. This continued prevalence warrants heightened attention and vigilance.

Fibroblast growth factor 21 may be a strong biomarker for renal outcomes: a meta-analysis.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is deemed to play an important role in kidney outcomes, while the association between FGF21 and various kidney diseases remains largely unclear and inconsistent. Therefore, we conducted this meta-analysis to find out the role of FGF21 in various renal diseases. METHODS: The outcome indicator of our study was assessed by the pooled standard mean difference (SMD) with 95% confidence intervals (CIs) which were calculated by random-effect model analysis. The risk of bias was assessed by Non-Randomized Studies of Interventions (ROBINS-I) tool. Funnel plot combined with Egger's and Begg's tests was performed to estimate the publication bias that existed in the study. RESULTS: A total of 28 eligible studies with 19348 participants were included in our research. The agreement between authors reached a kappa-value of 0.88. Overall, the serum FGF21 level was strongly higher in CKD patients (SMD = 0.97 (ng/L); 95% CI, 0.70-1.24 (ng/L)) and the renal outcomes in T2DM patients (SMD = 0.54 (ng/L); 95% CI, 0.39-0.70 (ng/L)) compared with the control group. Consistent with this, the incidence of CKD (OR = 2.56; 95% CI, 1.72-3.81) and the incidence of renal outcomes (OR = 1.63; 95% CI, 1.31-2.01) in T2DM patients was significantly higher in the patients with high FGF21 concentration, indicating that high serum FGF21 level may predict the incidence of CKD and the renal outcomes in T2DM patients. CONCLUSION: Serum FGF21 may be one of the strong predictors for various kidney diseases including the progression of CKD and the hard renal outcomes in type 2 diabetes patients, but more large-scale clinical research are needed to confirm this finding.

Effects of long-term fertilizer practices on rhizosphere soil nitrogen mineralization in the double-cropping rice field.

Nitrogen (N) was an important indictor in change of soil fertility, which was closely related with N mineralization process. However, there is still need to further study on how rhizosphere soil N mineralization in paddy field response to different fertilizer management. Therefore, the influence of long-term (37-years) fertilizer regime on rhizosphere soil N mineralization, ammonification and nitrification rates, and its relationship under the double-cropping paddy field in southern of China were investigated in this study. The field experiment included following fertilizer regimes: inorganic fertilizer alone (MF), rice straw and inorganic fertilizer (RF), 30% organic manure and 70% inorganic fertilizer (OM), and no application of any fertilizer as a control (CK). The result indicated that rhizosphere soil organic carbon (SOC), total N, NO3 -N, and NH4 -N contents in paddy field with OM and RF treatments were increased. The result showed that rhizosphere soil NO2 - -N and mineral N contents with OM and RF treatments were increased, and the order of soil NO2 - -N and mineral N contents with all fertilizer treatments was showed as OM > RF > MF > CK. This result proved that soil aerobic and anaerobic N mineralization rates in paddy field with OM and RF treatments were higher than that of CK and MF treatments. Compared with MF treatment, soil ammonification rate with RF and OM treatments increased by 45.16% and 67.74%, soil nitrification rate with RF and OM treatments increased by 45.71% and 77.14%, respectively. There had significantly positively correlation between soil net mineralization, nitrification rate and SOC, total N contents. As a result, applied with rice straw and organic manure was a good measure to improve soil N mineralization in the double-cropping rice field.

HMGXB4 Targets Sleeping Beauty Transposition to Germinal Stem Cells.

Transposons are parasitic genetic elements that frequently hijack vital cellular processes of their host. HMGXB4 is a known Wnt signaling-regulating HMG-box protein, previously identified as a host-encoded factor of Sleeping Beauty (SB) transposition. Here, we show that HMGXB4 is predominantly maternally expressed, and marks both germinal progenitor and somatic stem cells. SB piggybacks HMGXB4 to activate transposase expression and target transposition to germinal stem cells, thereby potentiating heritable transposon insertions. The HMGXB4 promoter is located within an active chromatin domain, offering multiple looping possibilities with neighboring genomic regions. HMGXB4 is activated by ERK2/MAPK1, ELK1 transcription factors, coordinating pluripotency and self-renewal pathways, but suppressed by the KRAB-ZNF/TRIM28 epigenetic repression machinery, also known to regulate transposable elements. At the post-translational level, SUMOylation regulates HMGXB4, which modulates binding affinity to its protein interaction partners and controls its transcriptional activator function via nucleolar compartmentalization. When expressed, HMGXB4 can participate in nuclear-remodeling protein complexes and transactivate target gene expression in vertebrates. Our study highlights HMGXB4 as an evolutionarily conserved host-encoded factor that assists Tc1/Mariner transposons to target the germline, which was necessary for their fixation and may explain their abundance in vertebrate genomes.

Paneth Cell Alertness to Pathogens Maintained by Vitamin D Receptors.

BACKGROUND AND AIMS: Vitamin D exerts a regulatory role over mucosal immunity via the vitamin D receptor (VDR). Although Paneth cells and their products are known to regulate the commensal and pathogenic microbiota, the role that VDRs in Paneth cells play in these responses is unknown. METHODS: We identified the decreased intestinal VDR significantly correlated with reduction of an inflammatory bowel disease risk gene ATG16L1 and Paneth cell lysozymes in patients with Crohn's disease. We generated Paneth cell-specific VDR knockout (VDRΔPC) mice to investigate the molecular mechanisms. RESULTS: Lysozymes in the Paneth cells were significantly decreased in the VDRΔPC mice. Isolated VDRΔPC Paneth cells exhibited weakened inhibition of pathogenic bacterial growth and displayed reduced autophagic responses. VDRΔPC mice had significantly higher inflammation after Salmonella infections. VDRΔPC mice also showed high susceptibility to small intestinal injury induced by indomethacin, a nonsteroidal anti-inflammatory drug. Co-housing of VDRΔPC and VDRlox mice made the VDRΔPC less vulnerable to dextran sulfate sodium colitis, suggesting the transmission of protective bacterial from the VDRlox mice. Thus, a lack of VDR in Paneth cells leads to impaired antibacterial activities and consequently increased inflammatory responses. Genetically and environmentally regulated VDRs in the Paneth cells may set the threshold for the development of chronic inflammation, as observed in inflammatory bowel diseases. CONCLUSIONS: We provide new insights into the tissue-specific functions of VDRs in maintaining Paneth cell alertness to pathogens in intestinal disorders. Targeting the VDR affects multiple downstream events within Paneth cells that inhibit intestinal inflammation and establish host defense against enteropathogens.

Pharmacokinetics, mass balance, and metabolism of [14C]vicagrel, a novel irreversible P2Y12 inhibitor in humans.

Vicagrel, a novel irreversible P2Y12 receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [14C]vicagrel (120 µCi). Vicagrel absorption was fast (Tmax = 0.625 h), and the mean t1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUCinf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC0-8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.

Female-specific activation of pregnane X receptor mediates sex difference in fetal hepatotoxicity by prenatal monocrotaline exposure.

Pyrrolizidine alkaloids (PAs) are a group of hepatic toxicant widely present in plants. Cytochrome P450 (CYP) 3A plays a key role in metabolic activation of PAs to generate electrophilic metabolites, which is the main cause of hepatotoxicity. We have previously demonstrated the sex difference in developmental toxicity and hepatotoxicity in fetal rats exposed to monocrotaline (MCT), a representative toxic PA. The aim of this study was to explore the underlying mechanism. 20 mg·kg-1·d-1 MCT was intragastrically given to pregnant Wistar rats from gestation day 9 to 20. CYP3As expression and pregnane X receptor (PXR) activation were specifically enhanced in female fetal liver. After MCT treatment, we also observed a significant increase of CYP3As expression in LO2 cells (high PXR level) or hPXR-transfected HepG2 cells (low PXR level). Employing hPXR and CYP3A4 dual-luciferase reporter gene assay, we confirmed the agonism effect of MCT on PXR-dependent transcriptional activity of CYP3A4. Agonism and antagonism of the androgen receptor (AR) either induced or blocked MCT-induced PXR activation, respectively. This study was the first report identifying that MCT served as PXR agonist to induce CYP3A expression. CYP3A induction may increase self-metabolic activation of MCT and subsequently lead to more severe hepatotoxicity in female fetus. While in male, during the intrauterine period, activated AR by testosterone secretion from developing testes represses MCT-induced PXR activation and CYP3A induction, which may partially protect male fetus from MCT-induced hepatotoxicity.

Imbalance of autophagy and apoptosis in intestinal epithelium lacking the vitamin D receptor.

Apoptosis and autophagy are dynamic processes that determine the fate of cells. Vitamin D receptor (VDR) deficiency in the intestine leads to abnormal Paneth cells and impaired autophagy function. Here, we will elucidate the mechanisms of the intestinal epithelial VDR regulation of autophagy and apoptosis. We used in vivo VDRlox and VDR∆IEC mice and ex vivo organoids generated from small intestine and colon tissues. We found that VDR deficiency induced more apoptotic cells and significantly increased cell death in the small intestine and colon of VDR∆IEC mice. The proapoptotic protein B-cell lymphoma 2 (BCL-2) associated X protein (Bax) was enhanced, whereas autophagy related 16 like 1 (ATG16L1) and Beclin-1 were decreased in the intestines of VDRΔIEC mice. Apoptosis induced by Bax reduced autophagy by decreasing Beclin-1. Physical interactions between Beclin-1 and Bcl-2 were increased in the VDR-deficient epithelia from mice. The growth of VDR∆IEC organoids was significantly slower with fewer Paneth cells than that of VDR+/+ organoids. The expression levels of Beclin-1 and lysozyme were decreased in VDR∆IEC organoids. Bacterial endotoxin levels were high in the serum from VDR∆IEC mice and made mice susceptible to colitis. In the organoids and colitis IL-10-/- mice, vitamin D3 treatment increased VDR and ATG16L1 protein expression levels, which activated autophagic responses. In summary, intestinal epithelial VDR regulates autophagy and apoptosis through ATG16L1 and Beclin-1. Our studies provide fundamental insights into the tissue-specific function of VDR in modulating the balance between autophagy and apoptosis.-Lu, R., Zhang, Y.-G., Xia, Y., Sun, J. Imbalance of autophagy and apoptosis in intestinal epithelium lacking the vitamin D receptor.

Identification of a novel fusion gene, TRIM52-RACK1, in oral squamous cell carcinoma.

Gene fusion is caused by the linkage of previously separate genes or sequences. Recently, an increasing number of novel fusion genes have been identified and associated with tumor progression, and several of them have been suggested as promising targets for tumor therapy. However, there are hardly any studies reporting the association of fusion genes with the progression of oral squamous cell carcinoma (OSCC). In this study, we identified a total of 11 fused genes in OSCC cells. We further analyzed the structure of one fused gene, TRIM52-RACK1, and detected its function in tumor progression in vitro. We found that TRIM52-RACK1 was caused by a deletion of 181,257,187-181,247,386 at 5q35.3 and it promoted OSCC cell proliferation, migration, and invasion. Therefore, TRIM52-RACK1 can be a promising target for tumor therapy in OSCC.

Genetic boundaries delineate the potential human pathogen Salmonella bongori into discrete lineages: divergence and speciation.

BACKGROUND: Salmonella bongori infect mainly cold-blooded hosts, but infections by S. bongori in warm-blooded hosts have been reported. We hypothesized that S. bongori might have diverged into distinct phylogenetic lineages, with some being able to infect warm-blooded hosts. RESULTS: To inspect the divergence status of S. bongori, we first completely sequenced the parakeet isolate RKS3044 and compared it with other sequenced S. bongori strains. We found that RKS3044 contained a novel T6SS encoded in a pathogenicity island-like structure, in addition to a T6SS encoded in SPI-22, which is common to all S. bongori strains so far reported. This novel T6SS resembled the SPI-19 T6SS of the warm-blooded host infecting Salmonella Subgroup I lineages. Genomic sequence comparisons revealed different genomic sequence amelioration events among the S. bongori strains, including a unique CTAG tetranucleotide degeneration pattern in RKS3044, suggesting non-overlapping gene pools between RKS3044 and other S. bongori lineages/strains leading to their independent accumulation of genomic variations. We further proved the existence of a clear-cut genetic boundary between RKS3044 and the other S. bongori lineages/strains analyzed in this study. CONCLUSIONS: The warm-blooded host-infecting S. bongori strain RKS3044 has diverged with distinct genomic features from other S. bongori strains, including a novel T6SS encoded in a previously not reported pathogenicity island-like structure and a unique genomic sequence degeneration pattern. These findings alert cautions about the emergence of new pathogens originating from non-pathogenic ancestors by acquiring specific pathogenic traits.

Distinct evolutionary origins of common multi-drug resistance phenotypes in Salmonella typhimurium DT104: a convergent process for adaptation under stress.

Antimicrobial resistance makes pathogenic bacteria hard to control, but little is known about the general processes of resistance gain or loss. Here, we compared distinct S. typhimurium DT104 strains resistant to zero, two, five, or more of the tested antimicrobials. We found that common resistance phenotypes could be encoded by distinct genes, on SGI-1 or plasmid. We also demonstrated close clonality among all the tested non-resistant and differently resistant DT104 strains, demonstrating dynamic acquisition or loss (by total deletion or gradual decaying of multi-drug resistance gene clusters) of the genetic traits. These findings reflect convergent processes to make the bacteria resistant to multiple antimicrobials by acquiring the needed traits from stochastically available origins. When the antimicrobial stress is absent, the resistance genes may be dropped off quickly, so the bacteria can save the cost for maintaining unneeded genes. Therefore, this work reiterates the importance of strictly controlled use of antimicrobials.

Whole genome sequence of Bacillus thuringiensis ATCC 10792 and improved discrimination of Bacillus thuringiensis from Bacillus cereus group based on novel biomarkers.

BACKGROUND: Among the Bacillus cereus group, B. thuringiensis, is one of the most extensively used biological control agent. The present study reports the complete genome and four novel plasmid analysis of the type strain B. thuringiensis ATCC 10792. METHODS: Complete genome sequencing of Bacillus thuringiensis ATCC 10792, assembled using de-novo (v.3.2.0, assembly name MIRA3), Pac-Bio sequencers and Hierarchical Genome Assembly Process software (version 4.1) and real-time polymerase chain reaction (qPCR) is a consistent technique for quantifying gene expression based on specific biomarkers, in addition the efficiency of the primers were analysed based on artificially spiked food samples on lettuce, kimbab and spinach with B. thuringiensis ATCC 10792. RESULTS: Complete genome annotation was performed, and a total of 6269 proteins with 5427594 bps were identified and four novel plasmid (poh2, poh3, poh4, poh5) a total of 134, 131, 96, 21 proteins with 113294; 92,949; 86488; 11332 bps were identified. Six selective genes (lipoprotein-lipo, methyltransferase-MT, S-layer homology domain protein-BC, flagellar motor protein-motB, transcriptional regulator-XRE, crystal protein-cry2) and associated four novel plasmids were investigated along with the characteristics and expression profiles of two housekeeping genes (chaperonin protein-GroEL and topoisomerase enzyme-gyrB). Although from the assessment of 120 strains, both GroEL and gyrB showed 100% specificity towards detection of both B. thuringiensis in artificially spiked vegetable samples. All the eight genes revealed no specificity towards any of the 9 non- Bacillus strains. CONCLUSION: In our study based on the complete genome and plasmid sequence of B. thuringiensis ATCC 10792, among the six discriminating genes, specifically GroEL, gyrB and XRE showed promising results in identifying B. thuringiensis ATCC 10792, and there detection limit was 3.0-9.6 log CFU/g in the food samples respectfully. The key role in control of the predatory biological agent.

New perspectives on Mega plasmid sequence (poh1) in Bacillus thuringiensis ATCC 10792 harbouring antimicrobial, insecticidal and antibiotic resistance genes.

Bacillus thuringiensis promotes the growth of numerous economically important crops. The present study presents the complete genome sequence for a mega plasmid present in the type strain of B. thuringiensis ATCC 10792, a typical spore-forming Gram-positive bacterium with insecticidal activity, and investigates its genetic characteristics. The genome was sequenced and assembled de novo using Pac-Bio sequencers and the Hierarchical Genome Assembly Process, respectively. Further genome annotation was performed, and a total of 489 proteins and a novel mega-plasmid (poh1) with 584,623 bps were identified. The organization of poh1 revealed the genes involved in the insecticidal toxin pathway. The genes responsible for antimicrobial, insecticidal and antibiotic activities were well conserved in poh1, indicating an intimate association with plant hosts. The poh1 plasmid contains the gene encoding a novel crystal protein kinase responsible for production of zeta toxin, which poisons insects and other Gram-negative bacteria through the global inhibition of peptidoglycan synthesis. Lantibiotics are a group of bacteriocins that include the biologically active antimicrobial peptide Paenibacillin. Further, poh1 also contains the genes that encode the gramicidin S prototypical antibiotic peptide and tetracycline resistance protein. In conclusion, the strain-specific genes of B. thuringiensis strain ATCC 10792 were identified through complete genome sequencing and bioinformatics data based on major pathogenic factors that contribute to further studies of the pathogenic mechanism and phenotype analyses.

Correlation between tumor glucose metabolism and multiparametric functional MRI (IVIM and R2*) metrics in cervical carcinoma: Evidence from integrated 18 F-FDG PET/MR.

BACKGROUND: Multiparameter, multimodality 18 F-FDG PET/MRI holds great potential for the diagnosis of cervical cancer based on the correlation between tumor glucose metabolism and imaging parameters. PURPOSE: To characterize the heterogeneity of tumor glucose metabolism by evaluating the correlation between 18 F-FDG uptake parameters and multiparametric functional MRI metrics in cervical carcinoma. STUDY TYPE: Retrospective. POPULATION: Fifty-four patients with cervical carcinoma. FIELD STRENGTH/SEQUENCE: Hybrid PET/MR (3T), multi-b DWI, and R2* mapping. ASSESSMENT: The maximum and mean standardized uptake values (SUVmax and SUVmean , respectively) from PET and functional MRI metrics (D, D*, f, and R2*) were obtained. Cervical carcinoma tissues also underwent HIF-1α, VEGF, and GLUT-1 immunohistochemical staining. STATISTICAL TESTS: Single-factor Spearman rank and Pearson correlation analysis and multiple linear regression (MLR) analysis were applied. RESULTS: R2*, D, and f have different degrees of correlation (moderate, weak, moderately strong correlation, respectively) with SUVmax and SUVmean (r = 0.530 and 0.527, and P < 0.001 for R2*; r = -0.292 and -0.291, and P < 0.05 for D; r = 0.539 and 0.520, and P < 0.001 for f, respectively). Immunohistochemical staining showed that HIF-1α expression has a moderate degree of correlation with R2* (r = 0.491; P < 0.001); GLUT-1 expression was significantly correlated with SUVmax and SUVmean (r = 0.633 and 0.622; P < 0.001), and VEGF expression had a moderately strong correlation with f (r = 0.457; P = 0.001). If SUVmax is the dependent variable, MLR yields an R-squared value after adjustment (adjusted R-squared) = 0.358, and F = 10.833 (P < 0.001), and the fitting linear equation is Y (SUVmax ) = 9.184 + 0.161X1 (R2*)+50.343X2 (f)-4.780 (D). Otherwise, MLR yields the adjusted R-squared = 0.342, and F = 10.187 (P < 0.001), and the linear regression equation is Y (SUVmean ) = 5.925 + 0.102X1 (R2*)+28.029X2 (f)-2.907X3 (D). DATA CONCLUSION: The functional MRI sequence parameters R2*, f, and D can provide information on the hypoxic condition, blood perfusion, and molecular diffusion of the tumor. 18 F-FDG PET/MR multi-imaging technique can be adopted to evaluate the heterogeneity of glucose metabolism in cervical carcinoma. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:1704-1712.

[Whole genome sequencing reveals the distribution of resistance and virulence genes of pathogenic Escherichia coli CCHTP from giant panda].

Pathogenic Escherichia coli (E. coli) is the most common pathogen causing urinary tract infection in animals. We investigated the antibiotic resistance and virulence genes of pathogenic E. coli CCHTP derived from urine with occult blood of the giant panda by whole genome sequencing. The flanking sequencing of resistance and virulence genes in genomic islands were also analyzed. Our results demonstrate that E. coli CCHTP contains different families of antibiotic resistance genes, most of which are efflux pump related genes, including multiple drug resistance efflux pump genes mdfA, emrE, and mdtN. A total of 166 virulence factors and 563 virulence genes were identified, and the most virulence factors and related genes are involved in host cell attachment and invasion processes. Furthermore, sequence analysis of 19 genomic islands revealed that antibiotic and virulence genes are associated with mobile genetic elements (transposon and insertion sequence) in GIs011 and GIs017. These structures can mediate horizontal transfer of antibiotic and virulence genes. Our work described the distribution of antibiotic resistance genes and virulence genes in E. coli CCHTP, which may provide an important guidance for treatment and rational drug use of E. coli CCHTP infection in the giant panda.

Dorzagliatin (HMS5552), a novel dual-acting glucokinase activator, improves glycaemic control and pancreatic ß-cell function in patients with type 2 diabetes: A 28-day treatment study using biomarker-guided patient selection.

AIMS: To investigate the pharmacokinetics and pharmacodynamics of a dual-acting glucokinase activator, dorzagliatin, and its safety, tolerability and effect on pancreatic ß-cell function in Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 24 T2D patients were selected, utilizing a set of predefined clinical biomarkers, and were randomized to receive dorzagliatin 75 mg twice or once daily (BID, QD respectively) for 28 days. Changes in HbA1c and glycaemic parameters from baseline to Day 28 were assessed. In addition, changes in ß-cell function from baseline to Day 32 were evaluated. RESULTS: Significant reductions in HbA1c were observed in both regimens on Day 28 (-0.79%, 75 mg BID; -1.22%, 75 mg QD). Similar trends were found in the following parameters, including reductions from baseline in fasting plasma glucose by 1.20 mmol/L and 1.51 mmol/L, in 2-hour postprandial glucose by 2.48 mmol/L and 5.03 mmol/L, and in glucose AUC0-24 by 18.59% and 20.98%, for the BID and QD groups, respectively. Both regimens resulted in improvement in ß-cell function as measured by steady state HOMA 2 parameter, %B, which increased by 36.31% and 40.59%, and by dynamic state parameter, ΔC30 /ΔG30 , which increased by 24.66% and 167.67%, for the BID and QD groups, respectively. Dorzagliatin was well tolerated in both regimens, with good pharmacokinetic profiles. CONCLUSIONS: Dorzagliatin treatment for 28 days in Chinese T2D patients, selected according to predefined biomarkers, resulted in significant improvement in ß-cell function and glycaemic control. The safety and pharmacokinetic profile of dorzagliatin supports a subsequent Phase II trial design and continued clinical development.

Modeling the effect of pH, water activity, and ethanol concentration on biofilm formation of Staphylococcus aureus.

In this work, the effect of environmental factors on Staphylococcus aureus (ATCC 13150) biofilm formation in tryptic soy broth was investigated under different ranges of pH (3.0-9.5), ethanol concentration (EtOH 0.0-20.0%), and aw (NaCl, 0.866-0.992). Biofilm formation was quantified using the crystal violet staining method and optical density (OD: 590 nm) measurements. Biofilm formation was significantly stronger at pH and aw close to S. aureus optimal growth conditions, while it was high at EtOH around 2.5-3.5%. Data sets from the difference between the OD measurements of the test and control (ΔOD) were fitted to the cardinal parameter model (CPM) and cardinal parameter model with inflection (CPMI) to describe the effect of the environmental factors. The models showed good quality of fit for the experimental data in terms of calculated RMSE, with the latter ranging from 0.276 to 0.455. CPM gave a good quality of fit compared to CPMI for the environmental factors tested. Optimal pH was close to neutral (6.76-6.81) and biofilm formation was possible till pH = 3.81-3.78 for CPM and CPMI, respectively. Optimum EtOH and aw conditions for biofilm formation were in the range of 1.99-2.75 and 0.98-0.97, respectively. Predicted OD values observed using strain 13150 were very closely correlated to the OD values predicted with strain 12600 with R2 of 0.978, 0.991, and 0.947 for pH, EtOH, and aw, respectively. The cultivable bacterial cells within the biofilm were enumerated using standard plate counting and a linear model was applied to correlate the attached biofilm cells to ΔOD of biofilm formation. It was found that the biofilm formation correlated with S. aureus population growth. At 2.5-3.5% of EtOH the maximum population density was lower than that observed at 0.0% of EtOH. As 2.5-3.5% of EtOH initiated a stronger biofilm formation, biofilm formation seems to be induced by ethanol stress. The development of cardinal parameter models to describe the effect environmental factors of importance to biofilm formation, offers a promising predictive microbiology approach to decrypting the S. aureus population growth and survival ability on food processing surfaces.

A multispecialty study of determining the possibility of pregnancy and the documentation of pregnancy status in surgical patients: a cause for concern?

BACKGROUND: Determining the possibility of pregnancy and the documentation of pregnancy status are important considerations in the assessment of females of reproductive age when admitted to hospital. OBJECTIVES: Our aim was to determine the adequacy of the documentation of pregnancy status and possibility of pregnancy across multiple surgical specialties. MATERIALS AND METHODS: A prospective audit of surgical specialties (general, orthopaedics, urology, vascular, maxillofacial, ENT, gynaecology and neurosurgery) within NHS Tayside, in May 2015. RESULTS: A total of 129 females of reproductive age were admitted; 69 (53.5%) elective and 60 (46.5%) emergencies. Eighty-four patients (65%) were asked 'Is there any possibility of pregnancy?' Pregnancy status was documented in 74% of patients. Eleven (8.5%) patients were not asked about possibility of pregnancy and did not have a documented pregnancy status. Documentation of the use of contraception, sexual activity and date of last menstrual period was noted in 53 (41.1%), 31 (24.0%) and 66 (51.2%) patients, respectively. CONCLUSIONS: There is a wide variation in the documentation of pregnancy status and possibility of pregnancy amongst surgical specialties. This was not an issue in gynaecology but is an issue in ENT, maxillofacial, neurosurgery, vascular and general surgery. The reasons are unclear. Documentation of pregnancy status using ßhCG assays should be the gold standard, and national guidelines are required.

Functionalization of N-arylglycine esters: electrocatalytic access to C-C bonds mediated by n-Bu4NI.

An efficient electrocatalytic functionalization of N-arylglycine esters is reported. The protocol proceeds in an undivided cell under constant current conditions employing the simple, cheap and readily available n-Bu4NI as the mediator. In addition, it is demonstrated that the mediated process is superior to the direct electrochemical functionalization.