Epidemiological characteristics of New Delhi Metallo-ß-Lactamase-producing Enterobacteriaceae in the Fourth hospital of Hebei Medical University.

The epidemiological characteristics of New Delhi Metallo-ß-Lactamase-Producing (NDM) Enterobacteriaceae were analyzed to provide theoretical support for clarifying the distribution characteristics of carbapenem-resistant Enterobacteriaceae (CRE) in the hospital environment and early identification of susceptible patients. From January 2017 to December 2021,42 strains of NDM-producing Enterobacteriaceae were gathered from the Fourth Hospital of Hebei Medical University, primarily Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. The micro broth dilution method combined with the Kirby-Bauer method was used to determine the minimal inhibitory concentrations (MICs) of antibiotics. The carbapenem phenotype was detected by the modified carbapenem inactivation method (mCIM) and EDTA carbapenem inactivation method (eCIM). Carbapenem genotypes were detected by colloidal gold immunochromatography and real-time fluorescence PCR. The results of antimicrobial susceptibility testing showed that all NDM-producing Enterobacteriaceae were multiple antibiotic resistant, but the sensitivity rate to amikacin was high. Invasive surgery prior to culture, the use of excessive amounts of different antibiotics, the use of glucocorticoids, and ICU hospitalization were clinical characteristics of NDM-producing Enterobacteriaceae infection. Molecular typing of NDM-producing Escherichia coli and Klebsiella pneumoniae was carried out by Multilocus Sequence Typing (MLST), and the phylogenetic trees were constructed. Eight sequence types (STs) and two NDM variants were detected in 11 strains of Klebsiella pneumoniae, primarily ST17, and NDM-1. A total of 8 STs and 4 NDM variants were detected in 16 strains of Escherichia coli, mainly ST410, ST167, and NDM-5. For high-risk patients who have CRE infection, CRE screening should be done as soon as feasible to adopt prompt and efficient intervention measures to prevent outbreaks in the hospital.

Randomized clinical trials towards a single-visit cure for chronic hepatitis C: Oral GSK2878175 and injectable RG-101 in chronic hepatitis C patients and long-acting injectable GSK2878175 in healthy participants.

Single-visit cures for chronic hepatitis C are lacking. We conducted two clinical studies towards the goal of developing a regimen for single-visit cure. In a randomized, open-label, Phase 2 study (RG101-04), investigators enrolled 26 adult chronic hepatitis C patients to evaluate safety and efficacy of single subcutaneous injection of RG-101 (4 mg/kg) and daily oral tablets of GSK2878175 (20 mg) for 6, 9 or 12 weeks. In another randomized, double-blind, single dose Phase 1 study (RG101-06), investigators enrolled 18 healthy men to assess safety and PK of GSK2878175 long-acting injectable at 100, 200 or 400 mg. In RG101-04, SVR48 rates were 50%, 56% and 89%, for the 6, 9 and 12 weeks treatment arms, respectively. All AEs were mild or moderate in severity (≤Grade 2). In RG101-06 at 400 mg, the mean duration of GSK2878175 plasma levels above in vitro therapeutic concentrations for GT1b was 41 days. All AEs were Grade 2 or less. In conclusion, single injection of RG-101 combined with 12 weeks of GSK2878175 oral tablets was generally well tolerated and resulted in high SVR rates in chronic hepatitis C patients. Single injections of GSK2878175 long-acting injectable were also well tolerated; however, higher doses would be required if used in combination with RG-101 to achieve the SVR rates observed in the oral combination study to enable a single-visit curative regimen.

The effects of active acupuncture and placebo acupuncture on insomnia patients: a randomized controlled trial.

The purpose of this study was to observe and compare the clinical efficacy of active acupuncture and placebo acupuncture in the treatment of insomnia and mood disorders. 96 patients with insomnia in Chengdu were randomly divided into two groups (1:1). The active acupuncture group (AA group n = 48) received the tube of Park sham device with deep needle insertion. The placebo acupuncture group (PA group n = 48) received the tube of Park sham device with a retractable needle shaft and a blunt tip. The same acupuncture points and treatment cycles were used in both groups. The overall score for the Pittsburgh Sleep Quality Index (PSQI) is the primary outcome. Secondary outcomes recorded sleep rate, self-reported depression scale (SDS), self-assessment anxiety scale (SAS), the 'six component' scores of PSQI, and 'Deqi' scale scores. Eventually, 90 patients completed the study. After 2 weeks of treatment, the total score of PSQI in the AA group was 4.6 ± 2.4 and in the PA group was 12.9 ± 1.8 (ES = 3.91, p < .1). The SAS, SDS score in the AA group were 39.9 ± 5.6/39.9 ± 5.9 and in the PA group were 59.7 ± 6.1/61.2 ± 4.4 (ES = 3.38/4.9, p < .1). The sleep rate were 93.8% and 25.0% (p < .1). During the 1 month follow-up period, the PSQI total score in the AA group (5.2 ± 1.9) was superior to the PA group (13.1 ± 1.8) (ES = 4.27, p < .1). The SAS, SDS score in the AA group were 40.4 ± 5.1/42.7 ± 6.6 and in the PA group were 63.7 ± 6.6/63.5 ± 4.8 (ES = 3.95/3.60, p < .1). Throughout the study period, the 'six component' scores of PSQI in the AA group was superior to the PA group (each p < .1). Except for tingling and cooling, other acupuncture sensations were significant differences (each p < .1). Compared to the placebo acupuncture, active acupuncture can significantly improve insomnia, and clinical efficacy is maintained for at least 6 weeks.

Fast and Selective Removal of Aqueous Uranium by a K+-Activated Robust Zeolitic Sulfide with Wide pH Resistance.

For the nuclear industry, uranium is not only an important strategic resource but also a serious global contaminant with radiotoxicity and high chemotoxicity. It is very important to efficiently capture uranium from complex aqueous solutions for further treatment and disposal of nuclear wastes. Herein, we first demonstrate the suitability of a three-dimensional (3D) water-stable K+-exchanged zeolitic sulfide, namely K@GaSnS-1, for the remediation of radioactive and toxic uranium by ion exchange. In comparison to the pristine compound GaSnS-1, the K+-activated porous sulfide K@GaSnS-1 exhibits faster [UO2]2+ ion uptake kinetics, following the pseudo-second-order adsorption model. Further studies indicate that K@GaSnS-1 shows high exchange capacity (qmU = 147.6 mg/g) and wide pH resistance (pH 2.75-10.87). In particular, it can efficiently capture [UO2]2+ ion even when excessive amounts of Na+, K+, Mg2+, and Ca2+ ions are present. The highest distribution coefficient value Kd, signifying the affinity and selectivity for [UO2]2+ ion, reaches as high as 1.24 × 104 mL/g. More importantly, the uranium in corresponding exchanged samples can be facilely and effectively eluted by a low-cost and eco-friendly method. These merits of K@GaSnS-1 make it promising for the effective and selective removal of uranium from complex contaminated water.

Magnolol and Honokiol Attenuate Apoptosis of Enterotoxigenic Escherichia Coli-Induced Intestinal Epithelium by Maintaining Secretion and Absorption Homeostasis and Protecting Mucosal Integrity.

BACKGROUND The cortex of Magnolia officinalis has long been used as an element of traditional Chinese medicine for the treatment of anxiety, chronic bronchitis, and gastrointestinal dysfunction. This study aimed to elucidate the underlying mechanism of its functional ingredients (magnolol and honokiol) in modifying the secretion and absorption homeostasis and protecting mucosal integrity in an Enterotoxigenic Escherichia coli (ETEC)-induced diarrhea mouse model. MATERIAL AND METHODS This study established a diarrhea mouse model infected by ETEC at a dosage of 0.02 ml/g live body weight (BW) in vivo. Magnolol or honokiol was followed by an intraperitoneal administration at dosages of 100, 300, and 500 mg/kg BW according to a 3×3 factorial arrangement. The useful biomarkers for evaluating the integrity of intestinal tract and histologic injury were analyzed and morphological development (including villus height, crypt depth, and ratio of villus height to crypt depth) and the expressions of inflammatory cytokines were determined by real-time PCR. RESULTS The results showed that magnolol and honokiol (500 mg/kg BW) reduced the concentrations of NO, DAO, and DLA, and iNOS activity, and the mRNA expressions of the interferon gamma (IFN-γ) and interleukin 10 (IL-10), and inhibited intestinal epithelial cell apoptosis. Magnolol and honokiol (300 mg/kg BW) elongated the villus height and crypt depth and decreased the number of goblet cells and the ratio of villus height to crypt depth. CONCLUSIONS The current results indicate that magnolol and honokiol enhance the intestinal anti-inflammatory capacities, elongate the villus height and crypt depth, and reduce goblet cell numbers to inhibit the intestinal epithelium apoptosis and effectively protect the intestinal mucosa. These results show that magnolol and honokiol protect the intestinal mucosal integrity and regulate gastrointestinal dysfunction.

Investigation of metabolism and disposition of GSK1322322, a peptidase deformylase inhibitor, in healthy humans using the entero-test for biliary sampling.

GSK1322322 (N-((R)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N-hydroxy-formamide) is an antibiotic in development by GlaxoSmithKline. In this study, we investigated the metabolism and disposition of [(14)C]GSK1322322 in healthy humans and demonstrated the utility of the Entero-Test in a human radiolabel study. We successfully collected bile from five men using this easy-to-use device after single i.v. (1000 mg) or oral administration (1200 mg in a solution) of [(14)C]GSK1322322. GSK1322322 had low plasma clearance (23.6 liters/hour) with a terminal elimination half-life of ∼4 hours after i.v. administration. After oral administration, GSK1322322 was readily and almost completely absorbed (time of maximal concentration of 0.5 hour; bioavailability 97%). GSK1322322 predominated in the systemic circulation (>64% of total plasma radioactivity). An O-glucuronide of GSK1322322 (M9) circulated at levels between 10% and 15% of plasma radioactivity and was pharmacologically inactive. Humans eliminated the radioactive dose in urine and feces at equal proportions after both i.v. and oral doses (∼45%-48% each). Urine contained mostly unchanged GSK1322322, accounting for 30% of the dose. Bile contained mostly M9, indicating that glucuronidation was likely a major pathway in humans (up to 30% of total dose). In contrast, M9 was found in low amounts in feces, indicating its instability in the gastrointestinal tract. Therefore, without the Entero-Test bile data, the contribution of glucuronidation would have been notably underestimated. An unusual N-dehydroxylated metabolite (a secondary amide) of GSK1322322 was observed primarily in the feces and was most likely formed by gut microbes.

[Assessing drug targeting of Yougui Pill, Zuogui Pill, and their disassembled prescriptions using infrared thermography].

OBJECTIVE: To dynamically assess drug targeting of Yougui Pill (YP) and Zuogui Pill (ZP) using infrared thermography. METHODS: In this self-control experiment, five healthy volunteers were recruited. By using infrared thermography 10 to 11 thermal images of different body locations were taken from each participant after they took warm water, YP, ZP, and their dissembled prescriptions at 30, 70, 100, 130, and 160 min, respectively. The heat values in the lower quadrant abdomen, uterus, Du channel, and Shenque (CV8) were statistically analyzed after scanning for 125 times. RESULTS: Administration of YP and its disassembled prescriptions enhanced the heat value of the locations of the Du channel and Shenque (CV8), but did no enhance the heat value of the lower quadrant abdomen at 30 min. Administration of ZP and its disassembled prescriptions reduced the heat value in the locations of the lower quadrant abdomen, uterus, Du channel, and Shenque (CV8) at each time point. CONCLUSION: The drug targeting of ZP and YP focused on the locations of the Du channel and Shenque (CV8), not on the locations of the lower quadrant abdomen or uterus.

Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer.

1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. 2. In this two-part study, we investigated the metabolism, disposition of [(14)C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer. 3. In part A, three men each received a single oral dose of [(14)C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose). 4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5-28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.

Metabolite Profiling of External and Internal Petals in Three Different Colors of Tea Flowers (Camellia sinensis) Using Widely Targeted Metabolomics.

The flower is the reproductive organ of the tea plant, while it is also processed into different kinds of products and thus of great significance to be utilized. In this study, the non-volatile secondary metabolites in the internal and external petals of white, white and pink, and pink tea flowers were studied using a widely targeted metabolomics method with ultra-high liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A total of 429 metabolites were identified, including 195 flavonoids, 121 phenolic acids, 40 alkaloids, 29 lignans and coumarins, 19 tannins, 17 terpenoids, and 8 other metabolites. The metabolites in the internal and external petals of different colored flowers showed great changes in flavonoids. Most flavonoids and all tannins in the internal petals were higher compared with the external petals. Some phenolic acids were more accumulated in the external petals, while others showed opposite trends. The pink tea flower contained more flavonoids, alkaloids, lignans, coumarins, terpenoids, and tannins compared with white tea flowers. In addition, cyanidin-3-O-glucoside was more accumulated in the external petals of the pink flower, indicating that anthocyanin may be the main reason for the color difference between the pink and white tea flower. The enriched metabolic pathways of different colored flowers were involved in flavonoid biosynthesis, glycine, serine and threonine metabolism, glycerophospholipid metabolism, and phenylpropanoid biosynthesis. The findings of this study broaden the current understanding of non-volatile compound changes in tea plants. It is also helpful to lay a theoretical foundation for integrated applications of tea flowers.

Intolerance of uncertainty fuels preservice teachers' smartphone dependence through rumination and anxiety during the COVID-19 pandemic: A cross-sectional study.

Objectives: We aimed to explore the relationship among intolerance of uncertainty (IU), rumination, anxiety, and smartphone dependence (SPD) in preservice teachers during the COVID-19 pandemic. Methods: Two cross-sectional studies were conducted with Chinese preservice teachers, using questionnaires on IU, rumination, anxiety, and SPD. Data were analyzed using AMOS 24.0 and SPSS 25.0, and the mediating mechanism was tested using the macro program Model 6. Study 1 recruited participants who were forcibly sequestered in a university due to an anti-epidemic policy during the COVID-19 crisis. Study 2 was surveyed online from different universities to replicate and enhance the reliability of Study 1 finding. Results: Study 1 (N = 553, Mage = 20.8 ± 2.3, 30.0% female) and Study 2 (N = 1610, Mage = 21.1 ± 2.1, 51.4% female) both found that IU affected SPD through the independent mediators of rumination and anxiety, as well as the chain mediation of rumination→ anxiety. In Study 1, the indirect effect of IU on SPD was significant through rumination (ß = 0.16, 95% CI [0.03, 0.06]), anxiety (ß = 0.11, 95% CI [0.03, 0.06]), and the chain mediation (ß = 0.02, 95% CI [0.01, 0.04]); in Study 2, the indirect effect of IU on SPD was significant through rumination (ß = 0.08, 95% CI [0.05, 0.11]), anxiety (ß = 0.10, 95% CI [0.08, 0.13]), and the chain mediation (ß = 0.02, 95% CI [0.02, 0.03]). Conclusion: Two cross-sectional studies found that preservice teachers' SPD is indirectly connected to IU, mediated by rumination and anxiety, and weakly mediated by the chain mediation of rumination and anxiety. Our findings may help educators understand the impact of anti-epidemic policies on preservice teachers and possible inclusive later interventions.

Pyroptosis Provides New Strategies for the Treatment of Cancer.

Cancer is an important cause of death worldwide. The main types of cancer treatment are still surgery, chemotherapy and radiotherapy, and immunotherapy is becoming an important cancer treatment. Pyroptosis is a type of programmed cell death that accompanies an inflammatory response. This paper reviews the recent research progress in pyroptosis in tumors. Pyroptosis has been observed since 1986 and until recently has been recognized as programmed cell death mediated by GSDM family proteins. The molecular pathway of pyroptosis depends on the inflammasome-mediated caspase-1/GSDMD pathway, which is the canonical pathway, and the caspase-4/5/11/GSDMD pathway, which is the noncanonical pathway. Other pathways include caspase3/GSDME. Pyroptosis is a double-edged sword that is closely related to the tumor immune microenvironment. On the one hand, pyroptosis produces a chronic inflammatory environment, promotes the transition of normal cells to tumor cells, helps tumor cells achieve immune escape, and promotes tumor growth and metastasis. On the other hand, some tumor cell treatments can induce pyroptosis, which is a nonapoptotic form of cell death. Additionally, pyroptosis releases inflammatory molecules that promote lymphocyte recruitment and enhance the immune system's ability to kill tumor cells. With the advent of immunotherapy, pyroptosis has been shown to enhance the antitumor efficacy of immune checkpoint inhibitors. Some antineoplastic agents, such as chemotherapeutic agents, can also exert antineoplastic effects through the pyroptosis pathway. Pyroptosis, which is a programmed cell death mode, has been the focus of research in recent years, and the relationship between pyroptosis, tumors and tumor immunity has attracted attention, but there are still some questions to be answered regarding the specific mechanism. Further study of pyroptosis would aid in developing new antitumor therapies and has great clinical prospects.

Acupuncture for Uremic Pruritus: A Systematic Review and Meta-Analysis.

Uremic pruritus (UP) is a chronic disease that can seriously affect the quality of life of dialysis patients. Acupuncture is a non-medication therapy that has been used to treat pruritus disorders. This systematic review aimed to evaluate the efficacy and safety of acupuncture for the treatment of UP. A total of nine Chinese and English databases were searched from their inception to December 31, 2021, and 214 studies were retrieved. Finally, seven randomized controlled trials (n=504) were included in the meta-analysis performed using RevMan V.5.3. Results included effective rate, recurrence rates, and adverse events. Compared with conventional treatment, acupuncture was more effective in treating UP (risk ratio [RR]=1.28, 95% confidence interval [CI]=1.09 to 1.50, P=0.003). The results were consistent after sensitivity analysis (RR=1.38, 95% CI=1.21 to 1.57, P<0.00001). In subgroup analysis, the efficacy rates of acupuncture and medications (oral and topical) were comparable (RR=1.20, 95% CI=0.98 to 1.47, P=0.07). Acupuncture combined with hemodialysis was more effective than hemodialysis alone in relieving pruritus (RR=1.42, 95% CI=1.18 to 1.72, P=0.0002). Adverse events were reported in only three studies, including one case of hyperphosphatemia in the medications group (RR=0.29, 95% CI=0.01 to 7.06, P=0.45). None of the studies reported recurrence rates. In conclusion, acupuncture is a safe treatment modality for patients with UP receiving hemodialysis that can effectively improve UP symptoms, and acupuncture in combination with hemodialysis has more efficacy than hemodialysis alone in improving the UP symptoms.

Exploring the clinical efficacy and mechanism of high-position colon dialysis combined with Traditional Chinese Medicine retention enema in real-world patients with stage 3-5 chronic kidney disease (non-dialysis) based on the theory of the Gut-Kidney axis.

Background: With societal and economic development, the annual incidence of chronic kidney disease (CKD) is increasing. Current treatments for CKD are limited, and once patients progress to the uraemic stage, it places a significant economic burden on families and society. Based on the "gut-kidney axis" theory and real-world research, this study aims to evaluate the clinical efficacy, safety, and potential mechanism of high-position colon dialysis combined with traditional Chinese medicine (TCM) retention enema in treating stage 3-5 chronic kidney disease (non-dialysis). Additionally, it seeks to identify new therapeutic targets and approaches for CKD treatment. Methods: The TCM decoction was analyzed using Ultra-Performance Liquid Chromatography-Quadrupole-Orbitrap-High Resolution Mass Spectrometry (UPLC-Q-Orbitrap-HRMS). Participants meeting the inclusion criteria were divided into a control group (n = 153) and a treatment group (n = 159) based on their preferences and physicians' recommendations. Both groups adhered to a high-quality low-protein, low-salt, low-phosphorus, and low-fat diet supplemented with essential amino acids, and were monitored for blood pressure, blood glucose, and blood lipids. The treatment group received high-position colon dialysis combined with TCM retention enemas (administered at least 12 times every other day). Results: Thirteen compounds were identified from the herbs by UPLC-Q-Orbitrap-HRMS. The CKD3-5 treatment group exhibited improvements in blood biochemistry and other laboratory indices, with significant enhancements in renal function-related indices for CKD4 and CKD5 stages (p < 0.05). Following treatment, indoxyl sulfate (IS), endotoxin, and D-lactic acid levels decreased to a certain extent in both groups, with a statistically significant difference observed within the treatment group (p < 0.05). The treatment group displayed a significant reduction in aerobic bacterial colonies, an increase in anaerobic bacterial colonies, a decrease in Escherichia coli colonies, and an increase in Bifidobacterium and Lactobacillus colonies (p < 0.05). No significant changes in colony numbers were observed in the control group. Conclusion: High-position colon dialysis combined with TCM retention enema may serve as an adjuvant treatment for CKD4-5 (non-dialysis), and its mechanism may be related to the reduction of uraemic toxins, improvement of intestinal mucosal barrier function, and regulation of intestinal microecology. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2200062852.

Acupuncture for gastrointestinal urticaria: A protocol for systematic review and network meta-analysis.

Introduction: The purpose of this review is to evaluate the effectiveness and safety of acupuncture in the treatment of patients with gastrointestinal urticaria (GU) and to provide a clinician's guide to GU treatment options. Methods and analysis: We plan to search multiple databases (i.e., PubMed, EMBASE, Springer, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and Wanfang Database) for studies published before September 1, 2022. We will electronically search for all relevant studies concerning clinical acupuncture treatments of GU, including unpublished conference articles and other gray literature. The language limit of this systematic review is Chinese and English. Any reports of clinical randomized controlled trials of acupuncture for the treatment of GU will be included in the study. Two researchers will perform independent data extraction to increase the quality of the data extraction. The primary outcome was the Urticaria Activity Score 7 (UAS7). Abdominal visual analog scale (VAS) for abdominal pain, dermatological life quality index (DLQI), the total effective rate, recurrence rate, and occurrence of adverse events were secondary outcomes. We will use RevMan V.5.3 statistical software for pairwise meta-analysis and ADDIS V.1.16.8 software for Bayesian network meta-analysis. If feasible, meta-regression and subgroup analyses will also be performed to address the potential causes of inconsistency and heterogeneity. We will conduct a GRADE assessment of the quality of evidence for the interventions included in this review. Discussion: This study may validate acupuncture as an alternative therapy for the effective treatment of GU. Trial registration number: PROSPERO CRD42022333977.

The effects of acupuncture on clinical efficacy and steady-state visual evoked potentials in insomnia patients with emotional disorders: A randomized single-blind sham-controlled trial.

The aim of this study was to observe the clinical effects and brain electrical potential changes following acupuncture in the treatment of insomnia patients with mood disorders. Ninety patients with insomnia who met the inclusion criteria were randomly divided into the active acupuncture group (AA group, n = 44) and sham acupuncture group (SA group, n = 46) at a ratio of 1:1. The primary outcome was the total score of the Pittsburgh Sleep Quality Index (PSQI), and the secondary outcomes were the total effective rate, Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) scores, and values of steady-state visual evoked potentials (SSVEP). The two groups received acupuncture or sham acupuncture 10 times (2 weeks). Finally, the total PSQI scores of the AA group and SA group were significantly different (p < 0.05) at 2 weeks (6.11 ± 2.33 vs. 10.37 ± 4.73), 6 weeks (6.27 ± 1.39 vs. 11.93 ± 3.07), 18 weeks (6.32 ± 2.84 vs. 11.78 ± 2.95) and 42 weeks (8.05 ± 3.14 vs. 12.54 ± 2.81). Further analysis found that AA group patients received acupuncture treatment at any age after the same effect (p > 0.05). The SAS and SDS scores of the AA group were also significantly different from those of the SA group at each assessment time point (p < 0.05). The total effective rate of the AA group was 81.82%, while that of the SA group was 30.43% (p < 0.05). There was no significant difference between the AA group and SA group only in the brain potential of the parietal lobe (F4), left temporal lobe (C3) and right temporal lobe (T8) (P > 0.05), but there was a significant difference between other brain regions (P < 0.05). In addition, correlation analysis showed that there was a certain positive correlation between the total PSQI score, SAS score, efficacy level, and SSVEP value in the AA group as follows: C4 and the total PSQI score (r = 0.595, P = 0.041), F3 and SAS score (r = 0.604, P = 0.037), FPz and efficiency level of the frontal lobe (r = 0.581, P = 0.048), and O2 and efficiency level of the occipital lobe (r = 0.704, P = 0.011). Therefore, acupuncture have a good clinical effect on patients with insomnia and emotional disorders and have a significant regulatory effect on abnormally excited brain potentials.

Functional connectivity impairment of thalamus-cerebellum-scratching neural circuits in pruritus of chronic spontaneous urticaria.

Pruritus of chronic spontaneous urticaria (CSU) is one of the most common and irritating sensations that severely affects the quality of life. However, the changes in the functional connectivity (FC) between thalamic subregions and other brain regions have not been fully elucidated. This study aimed to explore the potential changes in brain neural circuits by focusing on various subregions of the thalamus in patients with CSU pruritus to contribute to the understanding of chronic pruritus from the perspective of central mechanisms. A total of 56 patients with CSU and 30 healthy controls (HCs) completed the data analysis. Urticaria Activity Score 7 (UAS7), pruritus visual analog score (VAS-P), Dermatological Life Quality Index (DLQI), and immunoglobulin E (IgE) values were collected to assess clinical symptoms. Seed-based resting-state functional connectivity (rs-FC) analysis was used to assess relevant changes in the neural circuits of the brain. Compared to HCs, seeds within the caudal temporal thalamus (cTtha) on the right side of patients with CSU showed increased rs-FC with the cerebellum anterior lobe (CAL). Seeds within the lateral prefrontal thalamus (lPFtha) on the right side showed increased rs-FC with both CAL and pons, while those within the medial prefrontal thalamus (mPFtha) on the right side showed increased rs-FC with both CAL and the dorsal lateral prefrontal cortex (dlPFC) on the right side. Seeds within the posterior parietal thalamus (PPtha) on the right side showed increased rs-FC with the cerebellum posterior lobe (CPL) on the left side. The UAS7 values and IgE levels were positively correlated with the rs-FC of the right dlPFC. Our results suggest that patients with CSU may exhibit stronger rs-FC alterations between certain thalamic subregions and other brain regions. These changes affect areas of the brain involved in sensorimotor and scratching. Trial registration number: [http://www.chictr.org.cn], identifier [ChiCTR1900022994].

Metabolism of [(14)C]GSK977779 in rats and its implication with the observed covalent binding.

GSK977779 is a potent HM74a agonist evaluated for the treatment of dyslipidemia. The disposition and metabolism of [(14)C]GSK977779 (67.6 µmol/kg p.o.) was studied in male and female rats. The compound was well absorbed and its primary route of elimination was in the feces. Based on metabolite profiling of plasma extracts and urine and bile samples, it was demonstrated that GSK977779 was extensively metabolized in the rat by N-dealkylation, mono- and dioxygenation, reductive and oxidative cleavage of the 1,2,4-oxadiazole ring, and conjugative pathways. After plasma extraction high amounts of nonextractable radioactivity were observed, which were more pronounced in female rats. Size-exclusion chromatography and SDS gel electrophoresis indicated that the majority of the nonextractable radioactivity was covalently bound to plasma proteins. Solubilization of the plasma protein pellet followed by high-performance liquid chromatography and mass spectrometry suggested that a carboxylic acid metabolite derived from oxadiazole ring cleavage may be responsible for the observed covalent binding of the radioactivity to rat plasma proteins.

Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects.

The metabolism and disposition of eltrombopag, the first-in-class small molecule human thrombopoietin receptor agonist, were studied in six healthy men after a single oral administration of a solution dose of [(14)C]eltrombopag (75 mg, 100 µCi). Eltrombopag was well tolerated. The drug was quickly absorbed and was the predominant circulating component in plasma (accounting for 63% of the total plasma radioactivity). A mono-oxygenation metabolite (M1) and acyl glucuronides (M2) of eltrombopag were minor circulating components. The predominant route of elimination of radioactivity was fecal (58.9%). Feces contained approximately 20% of dose as glutathione-related conjugates (M5, M6, and M7) and another 20% as unchanged eltrombopag. The glutathione conjugates were probably detoxification products of a p-imine methide intermediate formed by metabolism of M1, which arises through cytochrome P450-dependent processes. Low levels of covalently bound drug-related intermediates to plasma proteins, which could result from the reaction of the imine methide or acyl glucuronide conjugates with proteins, were detected. The bound material contributes to the longer plasma elimination half-life of radioactivity. Renal elimination of conjugates of hydrazine cleavage metabolites (mostly as M3 and M4) accounted for 31% of the radiodose, with no unchanged eltrombopag detected in urine.

Investigations of hydrazine cleavage of eltrombopag in humans.

After oral administration to humans, eltrombopag undergoes extensive cleavage of its hydrazine linkage to metabolites, which are exclusively eliminated in urine. In vitro, the cleavage pathway was not detected in systems using cytochrome P450 enzymes, renal or hepatic microsomes, or hepatocytes but was readily evident after anaerobic incubation with rodent cecal contents or human fecal homogenate. Antibiotic treatment in vitro and in vivo inhibited eltrombopag cleavage, further indicating that cleavage is via gut microbes. Antibiotic treatment did not alter the systemic exposure of eltrombopag in mice. Oral and intravenous pharmacokinetic characterization in the mice with one of the cleavage products indicated that it was readily absorbed, conjugated, and eliminated in urine, consistent with its fate after oral administration of eltrombopag. Variation in this microbial pathway, for example by antibiotic cotherapy, is unlikely to be clinically significant.

Genome-level diversification of eight ancient tea populations in the Guizhou and Yunnan regions identifies candidate genes for core agronomic traits.

The ancient tea plant, as a precious natural resource and source of tea plant genetic diversity, is of great value for studying the evolutionary mechanism, diversification, and domestication of plants. The overall genetic diversity among ancient tea plants and the genetic changes that occurred during natural selection remain poorly understood. Here, we report the genome resequencing of eight different groups consisting of 120 ancient tea plants: six groups from Guizhou Province and two groups from Yunnan Province. Based on the 8,082,370 identified high-quality SNPs, we constructed phylogenetic relationships, assessed population structure, and performed genome-wide association studies (GWAS). Our phylogenetic analysis showed that the 120 ancient tea plants were mainly clustered into three groups and five single branches, which is consistent with the results of principal component analysis (PCA). Ancient tea plants were further divided into seven subpopulations based on genetic structure analysis. Moreover, it was found that the variation in ancient tea plants was not reduced by pressure from the external natural environment or artificial breeding (nonsynonymous/synonymous = 1.05). By integrating GWAS, selection signals, and gene function prediction, four candidate genes were significantly associated with three leaf traits, and two candidate genes were significantly associated with plant type. These candidate genes can be used for further functional characterization and genetic improvement of tea plants.