Arsenite-induced drug-drug interactions in rats.

Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for CYPs3A2, 2C6, 2D2, 2C11, 1A2, and 2E1, were selected as model drugs for the pharmacokinetic study. Significant decreases in AUCs of probe substrates were observed in rats after consecutive 30 day exposure to As at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little changes in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, in vivo study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. Significance Statement Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. In this study, we found that P450 enzyme probe drug exposure was reduced in arsenic-exposed animals (AUCs) and the intestinal absorption of the drug was reduced in the animals. Subacute arsenic exposure tends to cause damage to intestinal function, which leads to reduced drug absorption.

Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo.

Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.

Transcriptome and Metabolome Analyses Provide Insight into the Glucose-Induced Adipogenesis in Porcine Adipocytes.

Glucose is a major energy substrate for porcine adipocytes and also serves as a regulatory signal for adipogenesis and lipid metabolism. In this study, we combined transcriptome and metabolome analyses to reveal the underlying regulatory mechanisms of high glucose (HG) on adipogenesis by comparing differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) identified in porcine adipocytes. Results showed that HG (20 mmol/L) significantly increased fat accumulation in porcine adipocytes compared to low glucose (LG, 5 mmol/L). A total of 843 DEGs and 365 DAMs were identified. Functional enrichment analyses of DEGs found that multiple pathways were related to adipogenesis, lipid metabolism, and immune-inflammatory responses. PPARγ, C/EBPα, ChREBP, and FOS were identified as the key hub genes through module 3 analysis, and PPARγ acted as a central regulator by linking genes involved in lipid metabolism and immune-inflammatory responses. Gene-metabolite networks found that PPARγ-13-HODE was the most important interaction relationship. These results revealed that PPARγ could mediate the cross-talk between adipogenesis and the immune-inflammatory response during adipocyte maturation. This work provides a comprehensive view of the regulatory mechanisms of glucose on adipogenesis in porcine adipocytes.

H. pylori infection and osteoporosis: a large-scale observational and mendelian randomization study.

PURPOSE: There is controversy concerning the relationship between Helicobacter pylori (H. pylori) infection and osteoporosis. This study is to examine the causal relationship between H. pylori infection and osteoporosis and to analyze the potential mechanism underlying the relationship. METHODS: The clinical data of H. pylori infection and bone mineral density from patients or physical examiner with good general condition in our hospital between September 2019 and September 2020 were retrospectively collected. The relationship between H. pylori infection and osteoporosis was compared and analyzed, using logistic regression to examine the potential mechanism underlying the association. To investigate the causal effects of H. pylori infection and osteoporosis, we conducted a two-sample bidirectional Mendelian randomization (MR) analysis. RESULTS: A total of 470 patients were positive for H. pylori, with a detection rate of 52.22%. It was found that age, SBP, FPG, DBP, ALB, LDL-C, hs-CRP, and OC were positively correlated with osteoporosis, while negative correlations were observed with BMI, LYM, ALB, TP, TG, HDL-C, SCr, UA, and VitD. After stratified analysis of sex and age, it was found that there was a significant correlation between H. pylori infection and osteoporosis. The levels of SBP, ALP, FPG, LDL-C, hs-CRP, and OC in both H. pylori-positive group and osteoporosis group were higher than those in the H. pylori-negative group while the levels of BMI, ALB, TP, HDL-C, SCr, UA, and VitD in the positive group were significantly lower than those in the negative group. Logistic regression analyses with gender and age showed that ALB, FPG, HDL-C, and VitD were common risk factors for osteoporosis and H. pylori infection. In the MR analysis, the IVW results found a positive effect of H. pylori infection on osteoporosis (OR = 1.0017, 95% CI: 1.0002-1.0033, P = 0.0217). Regarding the reverse direction analysis, there was insufficient evidence to prove the causal effects of osteoporosis on H. pylori infection. CONCLUSION: Our study provides evidence for causal effects of H. pylori infection on osteoporosis. H. pylori may affect osteoporosis through serum albumin, high-density lipoprotein, fasting blood glucose and vitamin D.

High-quality chromosome-level genome assembly and multi-omics analysis of rosemary (Salvia rosmarinus) reveals new insights into the environmental and genome adaptation.

High-quality genome of rosemary (Salvia rosmarinus) represents a valuable resource and tool for understanding genome evolution and environmental adaptation as well as its genetic improvement. However, the existing rosemary genome did not provide insights into the relationship between antioxidant components and environmental adaptability. In this study, by employing Nanopore sequencing and Hi-C technologies, a total of 1.17 Gb (97.96%) genome sequences were mapped to 12 chromosomes with 46 121 protein-coding genes and 1265 non-coding RNA genes. Comparative genome analysis reveals that rosemary had a closely genetic relationship with Salvia splendens and Salvia miltiorrhiza, and it diverged from them approximately 33.7 million years ago (MYA), and one whole-genome duplication occurred around 28.3 MYA in rosemary genome. Among all identified rosemary genes, 1918 gene families were expanded, 35 of which are involved in the biosynthesis of antioxidant components. These expanded gene families enhance the ability of rosemary adaptation to adverse environments. Multi-omics (integrated transcriptome and metabolome) analysis showed the tissue-specific distribution of antioxidant components related to environmental adaptation. During the drought, heat and salt stress treatments, 36 genes in the biosynthesis pathways of carnosic acid, rosmarinic acid and flavonoids were up-regulated, illustrating the important role of these antioxidant components in responding to abiotic stresses by adjusting ROS homeostasis. Moreover, cooperating with the photosynthesis, substance and energy metabolism, protein and ion balance, the collaborative system maintained cell stability and improved the ability of rosemary against harsh environment. This study provides a genomic data platform for gene discovery and precision breeding in rosemary. Our results also provide new insights into the adaptive evolution of rosemary and the contribution of antioxidant components in resistance to harsh environments.

Mechanism-Based Inactivation of CYP2D6 by Phellopterin and Related Drug-Drug Interaction with Metoprolol.

Phellopterin (PLP) is a linear furanocoumarin widely found in citrus fruits and herbal medicines. The study aims to comprehensively investigate the mechanism of inhibition of CYP2D6 enzyme activity by PLP and its alteration of metoprolol pharmacokinetics. PLP was found to irreversibly inhibit CYP2D6 in time-, concentration-, and nicotinamide adenine dinucleotide phosphate-dependent manners. Coincubation with quinidine, which is a competitive inhibitor of CYP2D6, attenuated this time-dependent inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse the PLP-induced CYP2D6 inactivation. GSH trapping experiments provided strong evidence that PLP metabolic activation produces epoxide or γ-ketoaldehyde intermediates. In addition, pretreatment with PLP resulted in significant increases in Cmax and area under curve of plasma metoprolol in rats.

Characterization and fine mapping analysis of a major stable QTL qKnps-4A for kernel number per spike in wheat.

KEY MESSAGE: A major stable QTL for kernel number per spike was narrowed down to a 2.19-Mb region containing two potential candidate genes, and its effects on yield-related traits were characterized. Kernel number per spike (KNPS) in wheat is a key yield component. Dissection and characterization of major stable quantitative trait loci (QTLs) for KNPS would be of considerable value for the genetic improvement of yield potential using molecular breeding technology. We had previously reported a major stable QTL controlling KNPS, qKnps-4A. In the current study, primary fine-mapping analysis, based on the primary mapping population, located qKnps-4A to an interval of approximately 6.8-Mb from 649.0 to 655.8 Mb on chromosome 4A refering to 'Kenong 9204' genome. Further fine-mapping analysis based on a secondary mapping population narrowed qKnps-4A to an approximately 2.19-Mb interval from 653.72 to 655.91 Mb. Transcriptome sequencing, gene function annotation analysis and homologous gene related reports showed that TraesKN4A01HG38570 and TraesKN4A01HG38590 were most likely to be candidate genes of qKnps-4A. Phenotypic analysis based on paired near-isogenic lines in the target region showed that qKnps-4A increased KNPS mainly by increasing the number of central florets per spike. We also evaluated the effects of qKnps-4A on other yield-related traits. Moreover, we dissected the QTL cluster of qKnps-4A and qTkw-4A and proved that the phenotypic effects were probably due to close linkage of two or more genes rather than pleiotropic effects of a single gene. This study provides molecular marker resource for wheat molecular breeding designed to improve yield potential, and lay the foundation for gene functional analysis of qKnps-4A.

Recent Advances in Mass Spectrometry-Based Spatially Resolved Molecular Imaging of Drug Disposition and Metabolomics.

Mass spectrometric imaging is a nontargeted, tag-free, high-throughput, and highly responsive analytical approach. The highly accurate molecular visualization detection technology enables qualitative and quantitative analyses of biologic tissues or cells scanned by mass spectrometry in situ, extracting known and unknown multiple compounds, and simultaneously assessing relative contents of targeting molecules by monitoring their molecular ions and pinpointing the spatial locations of those molecules distributed. Five mass spectrometric imaging techniques and their characteristics are introduced in the review, including matrix-assisted laser desorption ionization mass spectrometry, secondary ion mass spectrometry, desorption electrospray ionization mass spectrometry, laser ablation electrospray ionization mass spectrometry, and laser ablation inductively coupled plasma mass spectrometry. The mass spectrometry-based techniques provide the possibility for spatial metabolomics with the capability of high throughput and precision detection. The approaches have been widely employed to spatially image not only metabolome of endogenous amino acids, peptides, proteins, neurotransmitters, and lipids but also the disposition of exogenous chemicals, such as pharmaceutical agents, environmental pollutants, toxicants, natural products, and heavy metals. The techniques also provide us with spatial distribution imaging of analytes in single cells, tissue microregions, organs, and whole animals. SIGNIFICANCE STATEMENT: The review article includes an overview of five commonly used mass spectrometers for spatial imaging and describes the advantages and disadvantages of each. Examples of the technology applications cover drug disposition, diseases, and omics. Technical aspects of relative and absolute quantification by mass spectrometric imaging and challenges for future new applications are discussed as well. The reviewed knowledge may benefit the development of new drugs and provide a better understanding of biochemical processes related to physiology and diseases.

Esophageal cancer-related gene 4 inhibits gastric cancer growth and metastasis by upregulating Krüppel-like factor 2 expression.

Background: There are a large number of people suffering from gastric cancer (GC) worldwide, so the study of biomarkers for GC is urgently needed. This study aimed to investigate the role of esophageal cancer-related gene 4 (ECRG4) in the growth, metastasis, and prognosis of GC and the possible underlying mechanism. Methods: The expression of ECRG4 was detected in GC tissues by quantitative polymerase chain reaction (PCR), Western blot, and immunohistochemistry. The relationships between ECRG4 expression and clinicopathological parameters of patients with GC were statistically analyzed, and Kaplan-Meier prognosis and survival curves of the patients were plotted. ECRG4 was overexpressed in the human gastric adenocarcinoma cell line (AGS) and human GC cell line 27 (HGC27), and the in vivo effects of ECRG4 overexpression on the growth, invasion, and metastasis of GC were analyzed and verified in nude mice. To identify the downstream transcription factors potentially regulated by ECRG4, ribonucleic acid (RNA) sequencing and differential gene expression analysis were performed on ECRG4-overexpressing cells. Quantitative PCR, Western blot, and immunohistochemistry were used to detect the expression of the downstream transcription factors targeted by ECRG4 in GC. Results: The ECRG4 mRNA and protein expression levels were low in GC tissues and were associated with a poor prognosis. Least absolute shrinkage and selection operator (LASSO) Cox regression and Kaplan-Meier survival analyses showed that patients with low ECRG4 expression had worse prognosis and survival. Overexpression of ECRG4 inhibited the proliferation, metastasis, and invasion of GC cells. RNA sequencing analysis showed that overexpression of ECRG4 induced the upregulation of Krüppel-like factor 2. Conclusions: Our findings show that ECRG4 promotes GC progression via Krüppel-like factor 2 signaling and highlight ECRG4 as a potential GC biomarker and therapeutic target.

CYP2C19 gene polymorphism in Ningxia.

BACKGROUND: Poor metabolizer (PM) status of CYP2C19 can be a predisposing factor for developing gastric cancer in H. pylori-infected patients. It is unclear whether PM status of CYP2C19 can also be a potential factor for H.pylori infection in healthy people. METHODS: We used high-throughput sequencing to detect single nucleotide polymorphisms (SNPs) at just three loci, rs4244285 (CYP2C19*2), rs4986893 (CYP2C19*3) and rs12248560 (CYP2C19*17), to identify the exact CYP2C19 alleles corresponding to the mutated sites. We determined CYP2C19 genotypes of 1050 subjects from 5 cities of Ningxia from September 2019 to September 2020 and evaluated the potential correlation between H.pylori and CYP2C19 gene polymorphisms. Clinical data were analyzed using χ2 tests. RESULTS: The frequency of CYP2C19*17 in Hui (3.7%) was higher as compared to Han (1.4%) in Ningxia (p = 0.001). The frequency of CYP2C19*1/*17 of Hui (4.7%) was higher as compared to Han (1.6%) in Ningxia (p = 0.004). The frequency of CYP2C19*3/*17 of Hui (1%) was higher as compared to Han (0%) in Ningxia (p = 0.023). The frequencies of alleles (p = 0.142) and genotypes (p = 0.928) were not found to be significantly different among the different BMI groups. The frequencies of four alleles between H. pylori positive and negative groups were not found to be statistically different (p = 0.794). The frequencies of the different genotypes between H. pylori positive and negative groups were not statistically different (p = 0.974), and no statistical difference was observed between the different metabolic phenotypes (p = 0.494). CONCLUSION: There were regional differences observed in CYP2C19*17 distribution in Ningxia. The frequency of CYP2C19*17 in Hui was higher than in Han of Ningxia. No significant relationship was found between CYP2C19 gene polymorphism and susceptibility to H. pylori infection.

Krüppel-Like Factor 2 Is a Gastric Cancer Suppressor and Prognostic Biomarker.

Gastric cancer (GC) is a common digestive tract tumor. Due to its complex pathogenesis, current diagnostic and therapeutic effects remain unsatisfactory. Studies have shown that KLF2, as a tumor suppressor, is downregulated in many human cancers, but its relationship and role with GC remain unclear. In the present study, KLF2 mRNA levels were significantly lower in GC compared to adjacent normal tissues, as analyzed by bioinformatics and RT-qPCR, and correlated with gene mutations. Tissue microarrays combined with immunohistochemical techniques showed downregulation of KLF2 protein expression in GC tissue, which was negatively correlated with patient age, T stage, and overall survival. Further functional experiments showed that knockdown of KLF2 significantly promoted the growth, proliferation, migration, and invasion of HGC-27 and AGS GC cells. In conclusion, low KLF2 expression in GC is associated with poor patient prognosis and contributes to the malignant biological behavior of GC cells. Therefore, KLF2 may serve as a prognostic biomarker and therapeutic target in GC.

Nonlinear Vibration Control Experimental System Design of a Flexible Arm Using Interactive Actuations from Shape Memory Alloy.

The flexible arm easily vibrates due to its thin structural characteristics, which affect the operation accuracy, so reducing the vibration of the flexible arm is a significant issue. Smart materials are very widely used in the research topic of vibration suppression. Considering the hysteresis characteristic of the smart materials, based on previous simulation research, this paper proposes an experimental system design of nonlinear vibration control by using the interactive actuation from shape memory alloy (SMA) for a flexible arm. The experiment system was an interactive actuator-sensor-controller combination. The vibration suppression strategy was integrated with an operator-based vibration controller, a designed integral compensator and the designed n-times feedback loop. In detail, a nonlinear vibration controller based on operator theory was designed to guarantee the robust stability of the flexible arm. An integral compensator based on an estimation mechanism was designed to optimally reduce the displacement of the flexible arm. Obtaining the desired tracking performance of the flexible arm was a further step, by increasing the n-times feedback loop. From the three experimental cases, when the vibration controller was integrated with the designed integral compensator, the vibration displacement of the flexible arm was much reduced compared to that without the integral compensator. Increasing the number of n-times feedback loops improves the tracking performance. The desired vibration control performance can be satisfied when n tends to infinity. The conventional PD controller stabilizes the vibration displacement after the 7th vibration waveform, while the vibration displacement approaches zero after the 4th vibration waveform using the proposed vibration control method, which is proved to be faster and more effective in controlling the flexible arm's vibration. The experimental cases verify the effectiveness of the proposed interactive actuation vibration control approach. It is observed from the experimental results that the vibration displacement of the flexible arm becomes almost zero within less time and with lower input power, compared with a traditional controller.

Biphenylene network as sodium ion battery anode material.

Sodium ion batteries possess several advantages for large-scale energy storage, such as low cost and enhanced safety. However, graphite or other anode materials are not satisfactory because the large radius of Na+ hinders their embedding and removal in the charge and discharge processes. Recently, a biphenylene network (BPN), a two-dimensional (2D) carbon allotrope, has been synthesized. In this paper, we reveal the potential possibility of BPN as a Na storage material. The theoretical results indicate the advantages of BPN as a sodium battery anode. The maximum specific capacity (413 mA h g-1) is larger than that of the graphite-Li system (372 mA h g-1). With low Na+ diffusion barrier (<0.6 eV) and small volume expansion in the charging process (∼26%), BPN presents superiority to the graphite-Na system. Our findings show new insights into Na storage in BPN and provide guidance for the use of a BPN anode in sodium ion batteries.

Evaluating and predicting the correlations of hepatic concentration and pyrrole-protein adduction with hepatotoxicity induced by retrorsine based on pharmacokinetic/pharmacodynamic model.

Retrosine (RTS) is a pyrrolozidine alkaloid and a known hepatotoxin that widely exist in nature. The mechanisms involved in toxic action of pyrrolizidine alkaloids need further investigation. The objective of the present study was to evaluate the correlation of RTS hepatotoxicity with hepatic RTS concentration and pyrrole-protein adduction. Mice were intragastrically treated with RTS alone or RTS and ketoconazole (KTZ) simultaneously. Sera and liver tissues were collected at various time points after administration, followed by the determination of changes in serum transaminase activity, hepatic RTS concentration and pyrrole-protein adduction. The correlation of RTS hepatotoxicity with hepatic RTS concentration and hepatic pyrrole-protein adduction were examined by use of Sigmoid-Emax PK/PD models. Dose-dependent hepatotoxicity, hepatic RTS concentration and pyrrole-protein adduction were observed in the animals, which could be modulated by co-treatment with KTZ. The fit parameters indicated pyrrole-protein adduction was more closely related with liver injury than hepatic RTS concentration. Similar correlation was observed in mice given low-dose of RTS for 4 consecutive days. RTS hepatotoxicity is correlated with hepatic pyrrole-protein adduction derived from RTS rather than hepatic RTS concentration. The observed protein modification would be a good indicator to predict the hepatoxicity of RTS at low dose.

Overexpression of TaLBD16-4D alters plant architecture and heading date in transgenic wheat.

Lateral organ boundaries domain (LBD) proteins, a class of plant-specific transcription factors with a special domain of lateral organ boundaries (LOB), play essential roles in plant growth and development. However, there is little known about the functions of these genes in wheat to date. Our previous study demonstrated that TaLBD16-4D is conducive to increasing lateral root number in wheat. In the present work, we further examined important agronomical traits of the aerial part of transgenic wheat overexpressing TaLBD16-4D. Interestingly, it was revealed that overexpressing TaLBD16-4D could lead to early heading and multiple alterations of plant architecture, including decreased plant height, increased flag leaf size and stem diameter, reduced spike length and tillering number, improved spike density and grain width, and decreased grain length. Moreover, auxin-responsive experiments demonstrated that the expression of TaLBD16-4D in wild-type (WT) wheat plants showed a significant upregulation through 2,4-D treatment. TaLBD16-4D-overexpression lines displayed a hyposensitivity to 2,4-D treatment and reduced shoot gravitropic response. The expressions of a set of auxin-responsive genes were markedly different between WT and transgenic plants. In addition, overexpressing TaLBD16-4D affected the transcript levels of flowering-related genes (TaGI, TaCO1, TaHd1, TaVRN1, TaVRN2, and TaFT1). Notably, the expression of TaGI, TaCO1, TaHd1, TaVRN1, and TaFT1 displayed significant upregulation under IAA treatment. Collectively, our observations indicated that overexpressing TaLBD16-4D could affect aerial architecture and heading time possibly though participating in the auxin pathway.

Large-scale analysis of protein crotonylation reveals its diverse functions in Pinellia ternata.

BACKGROUND: Pinellia ternata is an important traditional medicine in China, and its growth is regulated by the transcriptome or proteome. Lysine crotonylation, a newly identified and important type of posttranslational modification, plays a key role in many aspects of cell metabolism. However, little is known about its functions in Pinellia ternata. RESULTS: In this study, we generated a global crotonylome analysis of Pinellia ternata and examined its overlap with lysine succinylation. A total of 2106 crotonylated sites matched on 1006 proteins overlapping in three independent tests were identified, and we found three specific amino acids surrounding crotonylation sites in Pinellia ternata: KcrF, K***Y**Kcr and Kcr****R. Gene Ontology (GO) and KEGG pathway enrichment analyses showed that two crucial alkaloid biosynthesis-related enzymes and many stress-related proteins were also highly crotonylated. Furthermore, several enzymes participating in carbohydrate metabolism pathways were found to exhibit both lysine crotonylation and succinylation modifications. CONCLUSIONS: These results indicate that lysine crotonylation performs important functions in many biological processes in Pinellia ternata, especially in the biosynthesis of alkaloids, and some metabolic pathways are simultaneously regulated by lysine crotonylation and succinylation.

Selective CO2 reduction on topological Chern magnet TbMn6Sn6.

As a new type of topological magnet, TbMn6Sn6 has a planar Mn kagome lattice with out-of-plane magnetic moments. Previous studies have found spin-polarized Chern gapped Dirac fermions in TbMn6Sn6, which are advantageous to topological catalysis. In this study, we theoretically demonstrate that the TbMn6Sn6 (001) surface is favorable for CO2 reduction. The stability of different surface types is investigated, and then the reaction paths of CO2 reduction on the surfaces are revealed to prove that the product is selective. This work reveals the effect of magnetic topological materials on CO2 reduction.

A Survey of Helicobacter pylori Antibiotic-Resistant Genotypes and Strain Lineages by Whole-Genome Sequencing in China.

Antibiotic resistance is the most important factor leading to failed Helicobacter pylori eradication therapy, and personalized treatment based on antibiotic susceptibility is becoming increasingly important. To strengthen the understanding of antibiotic genotypic resistance of H. pylori and identify new antibiotic resistance loci, in this study, we identified phenotypic resistance information for 60 clinical isolates and compared the concordance of phenotypic and genotypic resistance using whole-genome sequencing (WGS). Clarithromycin and levofloxacin genotypic resistance was in almost perfect concordance with phenotypic resistance, with kappa coefficients of 0.867 and 0.833, respectively. All strains with the R16H/C mutation and truncation in rdxA were metronidazole resistant, with 100% specificity. For other genes of concern, at least one phenotypically sensitive strain had a previous mutation related to antibiotic resistance. Moreover, we found that the A1378G mutation of HP0399 and the A149G mutation of FabH might contribute to tetracycline resistance and multidrug resistance, respectively. Overall, the inference of resistance to clarithromycin and levofloxacin from genotypic resistance is reliable, and WGS has been very helpful in discovering novel H. pylori resistance loci. In addition, WGS has also enhanced our study of strain lineages, providing new ways to understand resistance information and mechanisms.

Comparison of the Dual Therapy of Ilaprazole-Amoxicillin and the Bismuth Quadruple Therapy of Ilaprazole-Amoxicillin-Furazolidone-Bismuth Glycyrrhizinate for Eradication of Helicobacter pylori.

Objective: The present study aims to compare the safety and efficacy of an amoxicillin/ilaprazole regimen with a bismuth quadruple regimen as the first-line treatment for eradicating Helicobacter pylori (H. pylori) infection. Methods: This was an open-label, randomized, single-center study involving 450 patients with untreated H. pylori infection who were randomly assigned to an Ilaprazole-amoxicillin-furazolidone-bismuth glycyrrhizinate (IAFB) quadruple therapy group for 14 days, a bismuth quadruple therapy group for 10 days, or Ilaprazole-amoxicillin (IA) dual therapy group for 14 days. The 13C urea breath test determined that H. pylori had been eliminated 4-6 weeks after treatment. For patients who failed the first treatment, mucosal tissues (two gastric antrum and one gastric body) were taken under gastroscope for the culture of H. pylori, drug sensitivity, the CYP2C19 gene, and globular degeneration. Results: In the intention-to-treat analysis, the eradication rates of H. pylori in the IAFB-14-day group, the IAFB-10-day group, and the IA-14-day group were 84.0, 79.3, and 88.0%, respectively. In the per-protocol analysis, the eradication rates in the three groups were 94.7, 87.5, and 93.0%, respectively. The resistance rates of patients who failed H. pylori eradication were 68.9% (22/32) for amoxicillin, 90.6% (29/32) for clarithromycin, 68.9% (22/32) for metronidazole, and 87.5% (28/32) for levofloxacin, and the extensive metabolizers of CYP2C19 polymorphism were 59.3% (19/32), the intermediate metabolizers were 34.4% (11/32), and the poor metabolizers were 6.3% (2/32). Conclusion: For newly treated patients with H. pylori infection in China, the efficacy of IA therapy for 14 days was similar to IAFB quadruple therapy for 10 or 14 days with better compliance and less cost. Therefore, these therapies can be considered first-line regimens for empirical treatment. Clinical Trial Registration: [http://www.chictr.org.cn/searchproj.aspx], identifier [ChiCTR2100052308].

Nomogram for Postoperative Headache in Adult Patients Undergoing Elective Cardiac Surgery.

Background Postoperative headache (POH) is frequent after cardiac surgery; however, few studies on risk factors for POH exist. The aims of the current study were to explore risk factors related to POH after elective cardiac surgery and to establish a predictive system. Methods and Results Adult patients undergoing elective open-heart surgery under cardiopulmonary bypass from 2016 to 2020 in 4 cardiac centers were retrospectively included. Two thirds of the patients were randomly allocated to a training set and one third to a validation set. Predictors for POH were selected by univariate and multivariate analysis. POH developed in 3154 of the 13 440 included patients (23.5%) and the overall mortality rate was 2.3%. Eight independent risk factors for POH after elective cardiac surgery were identified, including female sex, younger age, smoking history, chronic headache history, hypertension, lower left ventricular ejection fraction, longer cardiopulmonary bypass time, and more intraoperative transfusion of red blood cells. A nomogram based on the multivariate model was constructed, with reasonable calibration and discrimination, and was well validated. Decision curve analysis revealed good clinical utility. Finally, 3 risk intervals were divided to better facilitate clinical application. Conclusions A nomogram model for POH after elective cardiac surgery was developed and validated using 8 predictors, which may have potential application value in clinical risk assessment, decision-making, and individualized treatment associated with POH.