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The co-occurrence of glyphosate (GPS), a commonly used organophosphorus herbicide, and cadmium (Cd), a neurotoxic metal, in agricultural environments prompts concerns about their combined toxic effects on ecosystems. This study explores the combined effects of GPS and Cd on the model organism Caenorhabditis elegans (C. elegans), to understand their cumulative effects in organismal living environments. We investigated the interaction between GPS and Cd over 24 hours using a comprehensive approach that included a variety of toxicity endpoints as well as the novel Automated Recognition and Statistics Tool (NCLE) for body bend measurement. Our data show a concentration-dependent interplay in which antagonistic effects at lower concentrations reduce phenotypic damage while synergistic effects emerge at higher concentrations, particularly at GPS's LC50. Transcriptome analysis under antagonistic conditions revealed significant downregulation of Cd toxicity-related genes and identified Y22D7AL.16, which has a C2H2-type zinc finger domain, as a novel gene involved in metal stress response, implying an alternative Cd-resilience mechanism. The expression profile of this gene shows that it plays a larger role in both development and metal stress adaption. These findings highlight the complexities of compound pollutant interactions, emphasizing the importance of including such dynamics in environmental risk assessments and control techniques., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Selecting an appropriate electron donor to enhance nitrogen removal for treating low C/N wastewater in ecological floating beds (EFBs) is controversy. In this study, a systematic and comprehensive evaluation of sodium acetate (EFB-C), sodium thiosulfate (EFB-S) and iron scraps (EFB-Fe) was performed in a 2-year experiment on long-term viability including nitrogen removal and greenhouse gas emissions associated with key molecular biological mechanisms. The results showed that EFB-C (43-85 %) and EFB-S (40-88 %) exhibited superior total nitrogen (TN) removal. Temperature and hydraulic retention time (HRT) have significant impacts on TN removal of EFB-Fe, however, it could reach 86 % under high temperature (30-35 °C) and a long HRT (3 days), and it has lowest N 2 O (0-6.2 mg m -2 d -1 ) and CH 4 (0-5.3 mg m -2 d -1 ) fluxes. Microbial network analysis revealed that the microbes changed from competing to cooperating after adding electron donors. A higher abundance of anammox genera was enriched in EFB-Fe. The Mantel's test and structural equation model provided proof of the differences, which showed that acetate and thiosulfate were similar, whereas Fe 0 was different in the nitrogen removal mechanism. Molecular biology analyses further verified that heterotrophic, autotrophic, and mixotrophic coupled with anammox were the main TN removal pathways for EFB-C, EFB-S, and EFB-Fe, respectively. These findings provide a better understanding of the biological mechanisms for selecting appropriate electron donors for treating low C/N wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To construct evidence-based sensitive quality indicators for patients' rapid rehabilitation care after combined pancreaticoduodenectomy (PD) and to provide a reference for clinical nursing professionals to scientifically evaluate the quality of patients' rehabilitation post-PD., Background: Since PD is associated with higher surgical risk and anastomotic complications, it leads to higher complication rates and longer postoperative recovery cycles. This reiterates the need for rapid recovery of patients after PD; however, the evaluation of sensitive nursing care indicators regarding rapid recovery post-PD has not yet been established to date., Methods: Based on the Donabedian structure-process-result theory model, we used available literature, semi-structured interviews, the Delphi method, and hierarchical analysis to establish a sensitive indicator system for patients' rapid rehabilitation after PD and evaluate the importance of such indicators., Results: There were two rounds of expert correspondence, and the effective recovery rate of the questionnaires of these rounds was 100%. The expert authority coefficients, as well as the Kendall coordination coefficients of the expert opinions, were 0.859 and 0.872 as well as 0.423 and 0.431, with statistically significant differences (p < 0.05), respectively. Consequently, we developed a sensitive quality index system for patients' rapid rehabilitation care after combined PD, including 3 first-level, 12 s-level, and 23 third-level indexes, respectively., Conclusion: The constructed sensitive quality index system developed for patients' rapid rehabilitation nursing care after combined PD is standardized, practical, and aligned with the specialty characteristics. Furthermore, this might help greatly in improving the quality and safety of patients' rapid rehabilitation nursing care after combined PD, standardizing nursing management skills, and enhancing nursing quality., (© 2024. The Author(s).)

The simulated coastal constructed wetlands supplemented with Fe 0 and phragmites australis (P.A) biomass (CW-M) were constructed to improve nitrogen removal under different salinities (0-15‰). Results showed that the denitrification performance of CW-M were improved significantly, with the higher NO 3 - -N removal of 72-94% and lower N 2 O emission flux, when compared with mono-P.A biomass(CW-bio), mono-Fe 0 system (CW-Fe) and control system. The nitrogen removal showed a trend of first increasing (0‰-7‰) and then decreasing (7‰-15‰) with the highest NO 3 - -N removal of 94% and enhanced removal efficiency of 41% in CW-M. Fe 0 and P.A biomass coupling could reduce the stress of salinity on denitrification. Batch experiments have demonstrated that Fe 0 and P.A biomass could mutually stimulate more total organic carbon and total iron (TFe) release as electron donors for denitrification. Meanwhile, appropriate salinity could also promote the release of TFe. The typical heterotrophic denitrifying genera Bacillus and iron autotrophic denitrifying genera Thermomonas have the highest proportion in CW-M, with 21.83% and 0.10%, respectively. Fe 0 and P.A biomass adding simultaneously promoted the carbon and iron metabolism, further enhancing the nitrogen metabolism process. The joint enhancement of autotrophic and heterotrophic denitrification contributes to NO 3 - -N removal in CW-M for treating saline, low C/N wastewater in coastal wetlands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Microplastics (MPs) discharging into constructed wetlands pose risks to these ecosystems. Nevertheless, the perturbation of MPs to different types of macrophytes, which play important roles in purifying pollutants of wetlands, has not been fully elucidated. In this study, polystyrene MPs (PS-MPs) perturbation on nitrogen removal and sensory quality of surface flow constructed wetlands planted with emergent and submerged macrophytes were investigated. PS-MPs enhanced N removal efficiencies temporarily, whereas the N removal rate constants were declined as exposure time was prolonged. The NH 4 + -N removal rate constants declined by 25.78 % and 34.03 % in E and S groups respectively. The NO 3 - -N removal rate constants declined by 22.13 % in the S groups. Denitrifiers including Thiobacillus, Rhodobacter, and Sulfuritalea were stressed. The sensory quality deteriorated after PS-MPs exposure, which was significantly related to changes in Chlorophyll a, particle size distribution, and colored dissolved organic matter. Turbidity in E groups and chroma in S groups were greatly affected by PS-MPs. Overall, under MPs exposure, macrophytes in E groups were more suitable for nitrogen removal, and macrophytes in S groups better purified the turbidity. The study could provide the basis for better allocation of macrophytes in CWs to reduce the purifying risk by PS-MPs disturbance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The effectiveness of medication combined with smartphone-delivered cognitive behavioral therapy for insomnia (CBT-I) has been well verified, but there are few studies on the sequence of remission of insomnia symptoms. This study aims to understand the sequence of symptom improvement and the factors influencing the treatment effectiveness in patients with insomnia., Methods: Smartphone-delivered CBT, as a form of Online CBT, allows for training through mobile devices at any time and place. We utilized the Good Sleep 365 app to conduct a survey, involving 2820 patients who met the baseline inclusion criteria. These patients were assessed using a general demographic questionnaire and the Pittsburgh Sleep Quality Index (PSQI) to evaluate general demographic information and insomnia symptoms, and subsequently underwent CBT training using the Good Sleep 365 app. A total of 1179 patients completed follow-ups at 4 weeks, 8 weeks, 16 weeks, and 24 weeks., Results: At 4 weeks and 8 weeks, the descending order of the reduction rates of PSQI components (excluding component 6: use of sleeping medication) was: sleep latency, subjective sleep quality, sleep efficiency, sleep disturbance, sleep maintenance, and daytime dysfunction. At 16 weeks and 24 weeks, the descending order was subjective sleep quality, sleep latency, sleep efficiency, daytime dysfunction, sleep maintenance, and sleep disturbance. There were significant differences in the reduction rates of PSQI components (excluding component 6: use of sleeping medication) both at the same follow-up times and at different follow-up times (all P<0.05). Multivariable logistic regression analysis showed that patients older than 30 years and those with a college degree or above had better treatment outcomes, whereas those with a disease duration of more than three years had worse outcomes., Conclusion: The sequence of symptom improvement in patients with insomnia changes over time, and age, educational level, and duration of disease are factors influencing treatment outcomes., Competing Interests: The authors declare no competing interests., (© 2024 Wei et al.)

Background: Gut microbiota has been reported to be perturbed by cisplatin and to modulate the nephrotoxicity of chemotherapeutic agents. However, the critical role of toralactone, a bioactive components of Cassia obtusifolia L. seeds, in modulating the gut microbiota in the pathogenesis of cisplatin-induced nephrotoxicity remains to be elucidated., Methods: In this study, we verified the reno-protective effects of toralactone and compared the composition and function of the gut microbiota in the normal, cisplatin-treated and low or high dose of toralactone-treated mice using 16S rDNA gene sequencing. We also investigated the gut microbiota related LPS/TLR4/NF-κB/TNF-α pathway in renal tissue. To elucidate the causal relationship between gut dysbiosis and cisplatin nephrotoxicity, an antibiotic cocktail was administered to deplete the gut microbiota and fecal microbiota transplantation (FMT) was performed prior to cisplatin treatment., Results: The renal histopathology showed that toralactone significantly alleviated cisplatin-induced renal injury. 16S rDNA gene sequencing analysis demonstrated that toralactone treatment effectively reversed cisplatin-induced gut microbiota dysbiosis in mice. FMT from toralactone-treated mice to cisplatin-induced kidney injury mice was observed to have the reno-protective effects, and deletion of gut microbiota by antibiotics was found to negate the reno-protective effect of toralactone. Interestingly, the renal tissue of cisplatin-associated kidney injury mice showed activation of the LPS/TLR4/NF-κB pathway and increase in TNF-α within the renal tissue, whereas toralactone treatment was observed to inhibit the LPS/TLR4/NF-κB/TNF-α pathway., Conclusion: This study elucidated the reno-protective effects for the first time, demonstrating that it exerts its beneficial effects through the gut microbiota, which mediate the LPS/TLR4/NF-κB/TNF-α inflammatory pathway. It may help to develop therapeutic approaches using toralactone and targeted restoration of the gut microbiota., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure-activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potentially improved efficacy and reduced toxicity against tumors. To realize the biosynthesis of the novel aglycone polyethers, the gene clusters and the post-polyketide synthase tailoring pathways for aglycone polyethers endusamycin and lenoremycin are identified and subjected to combinatorial biosynthesis studies, resulting in the creation of a novel aglycone polyether termed End-16, which demonstrates significant potential for treating bladder cancer (BLCA). End-16 demonstrates the ability to suppress the proliferation, migration, invasion, and cellular protrusions formation of BLCA cells, as well as induce cell cycle arrest in the G1 phase in vitro. Notably, End-16 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti-BLCA drug cisplatin in vivo, thereby warranting further preclinical studies. This study highlights the significant potential of integrating combinatorial biosynthesis strategies with rational design to create unnatural products with enhanced pharmacological properties., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Purpose: Voriconazole, a first-line therapeutic agent for chronic pulmonary aspergillosis, is metabolized by the cytochrome 450 enzymes, specifically CYP2C19 and CYP3A4. Rifampicin and rifapentine act as inducers of the cytochrome P450 enzyme. The current study explored the potential drug interactions arising from the co-administration of voriconazole with either rifampicin or rifapentine, as well as the duration of this effect on serum voriconazole levels after discontinuation of rifampicin or rifapentine., Patients and Methods: A retrospective study was conducted in tuberculosis patients with chronic pulmonary aspergillosis. These patients underwent a combination therapy involving voriconazole and rifampicin or rifapentine, or they were treated with voriconazole after discontinuation of rifampicin or rifapentine. The serum concentrations of voriconazole at steady-state were monitored. Data on demographic characteristics and the serum voriconazole levels were used for statistical analyses., Results: A total of 124 serum voriconazole concentrations from 109 patients were included in the study. The average serum concentration of voriconazole fell below the effective therapeutic range in patients treated with both voriconazole and rifampicin or rifapentine. Notably the co-administration of rifapentine led to a substantial (>70%) decrease in serum voriconazole levels in two patients. Moreover, this interfering effect persisted for at least 7 days following rifampicin discontinuation, while it endured for 5 days or more after discontinuation of rifapentine., Conclusion: Concomitant use of voriconazole and rifampicin or rifapentine should be avoided, and it is not recommended to initiate voriconazole therapy within 5 or 7 days after discontinuation of rifapentine or rifampicin. Therapeutic drug monitoring not only provides a basis for the adjustment of clinical dose, but also serves as a valuable tool for identifying drug interactions., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Lu et al.)

Objective: This study aims to investigate the utility of shear wave elastography (SWE) in quantitatively assessing the surrounding tissue hardness of breast masses and its diagnostic significance in distinguishing between benign and malignant masses of varying sizes., Methods: A retrospective analysis was conducted on 60 patients with breast masses diagnosed at our hospital between January 1, 2022, and December 31, 2022. All patients underwent standard breast ultrasound examination and SWE assessment. Masses were categorized based on diameter (≤20mm and >20mm) for comparative analysis. SWE parameters, including maximum shear wave velocity (Max SWV), mean shear wave velocity (Mean SWV), and elasticity ratio (Eratio) of surrounding tissue, were recorded. Histopathological results determined mass nature. SWE parameters were correlated with pathological diagnoses for discrimination analysis., Results: Of all patients, 37 had benign masses, and 23 had malignant masses. Malignant masses exhibited significantly higher Max SWV, Mean SWV, and Eratio in surrounding tissue compared to benign masses (P < .05). Statistically significant differences in SWE parameters were observed between different-sized masses; smaller masses (≤20mm) showed higher SWE parameters in malignant masses compared to benign masses (P < .05). In masses larger than 20mm, though SWE parameters still differed between benign and malignant masses, the significance was less pronounced (P < .05). Receiver operating characteristic (ROC) analysis demonstrated higher diagnostic accuracy of SWE parameters in discriminating malignancy in smaller breast masses., Conclusions: SWE parameters effectively quantify surrounding tissue hardness in breast masses and have diagnostic value in distinguishing between benign and malignant masses of varying sizes, particularly in masses ≤20mm. SWE offers crucial quantitative parameters for the clinical discrimination of breast masses, enhancing diagnostic accuracy and sensitivity. Future studies should expand sample sizes and optimize diagnostic models to enhance SWE's utility further in discriminating breast mass malignancy.

BACKGROUND : Insomnia disorder is associated with an impairment in cognitive performance. Doxepin and zolpidem have been found to be effective in improving sleep. In this study, we aimed to compare the effects of doxepin and zolpidem on sleep structure and executive function in patients with insomnia disorder., Methods: Patients with primary insomnia were randomly assigned to receive doxepin 6 mg/day orally or zolpidem 5-10 mg/day orally. Polysomnography (PSG) and the Pittsburgh Sleep Quality Index (PSQI) were used at baseline and after the 8-week treatment to compare clinical efficacy in the two groups. Safety was assessed using the Treatment Emergent Symptom Scale (TESS). Executive function was evaluated using the Wisconsin sorting card test (WSCT)., Results: Of 120 patients enrolled in the study, 60 participants were assigned to each group. A total of 109 participants (53 in the doxepin group and 56 in the zolpidem group) completed the study. After treatment, the wake after sleep onset (WASO) and total sleep time (TST) values in the doxepin group were 80.3 ± 21.4 min and 378.9 ± 21.9 min, respectively, which were significantly better than those in the zolpidem group (132.9 ± 26.5 min and 333.2 ± 24.2 min, respectively; (P < 0.05)). The sleep onset latency (SOL) value in the zolpidem group (20.3 ± 4.7 min) was significantly better than that in the doxepin group (28.2 ± 5.6 min; P < 0.05). The sleep efficiency (SE) in the doxepin group was 77.8 ± 4.2%, which was significantly better than that in the zolpidem group (68.6 ± 5.0%; P < 0.05). The PSQI score of the doxepin group was 6.1 ± 1.1, which was significantly lower than that in the zolpidem group (7.9 ± 1.9; P < 0.05). The treatment adverse events in the doxepin group was 23.3%, which was significantly higher than that in the zolpidem group (13.3%; P < 0.05). The WSCT showed a significant improvement in persistent errors (PE), random errors (RE), and categories in the two groups after 8-week treatment, and the improvement in RE and the categories was more obvious in the doxepin group (P < 0.05)., Conclusions: Both doxepin and zolpidem were found to be effective in improving sleep quality, but the effects exhibited different patterns. Doxepin improved executive function more effectively than zolpidem in patients with insomnia disorder., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Azvudine is an effective treatment for patients infected with common COVID-19. However, physicians have reported a series of adverse reactions, including multiple cases of liver injury, caused by azvudine in clinical practice. This study assessed the incidence, clinical features, and associated risk factors of liver injury induced by azvudine in real-world settings, offering guidance for safe clinical use., Materials and Methods: This study utilized the Chinese Hospital Pharmacovigilance System (CHPS) to retrospectively analyze the treatment of COVID-19 patients with azvudine at Changsha Central Hospital from December 19, 2022, to June 6, 2023. A case-control study was conducted to analyze the occurrence of azvudine-induced liver injury in COVID-19 patients who triggered a CHPS alert compared to normal COVID-19 patients., Results: Among the total of 2,141 COVID-19 patients, 31 (1.45%) developed azvudine-induced liver injury, which is classified as an occasional adverse reaction. Liver injury was observed in 93.55% of patients between days 4 and 12 of the azvudine treatment, with elevated transaminases as the primary clinical manifestation. Univariate and binary logistic regression analyses indicated that low albumin levels and co-administration of low-molecular-weight heparin were statistically significant risk factors (p < 0.05)., Conclusion: This study represents the first investigation of azvudine-induced liver injury and high-risk patients using the CHPS. The findings provide valuable insights to promote the safety of anti-COVID-19 drugs, serving as an important reference for future drug safety measures.

Considering the unsatisfied denitrification performance of carbon-limited wastewater in iron-based constructed wetlands (ICWs) caused by low electron transfer efficiency of iron substrates, utilization of plant-based conductive materials in-situ for improving the long-term reactivity of iron substrates was proposed to boost the Fe (III)/Fe (II) redox cycle thus enhance the nitrogen elimination. Here, we investigated the effects of withered Iris Pseudacorus biomass and its derived biochar on nitrogen removal for 165 days in ICWs. Results revealed that accumulate TN removal capacity in biochar-added ICW (BC-ICW) increased by 14.7 % compared to biomass-added ICW (BM-ICW), which was mainly attributed to the synergistic strengthening of iron scraps and biochar. The denitrification efficiency of BM-ICW improved by 11.6 % compared to ICWs, while its removal capacity declined with biomass consumption. Autotrophic and heterotrophic denitrifiers were enriched in BM-ICW and BC-ICW, especially biochar increased the abundance of electroactive species (Geobacter and Shewanella, etc.). An active iron cycle exhibited in BC-ICW, which can be confirmed by the presence of more liable iron minerals on iron scraps surface, the lowest Fe (III)/Fe (II) ratio (0.51), and the improved proportions of iron cycling genes (feoABC, korB, fhuF, TC.FEV.OM, etc.). The nitrate removal efficiency was positively correlated with the nitrogen, iron metabolism functional genes and the electron transfer capacity (ETC) of carbon materials (P < 0.05), indicating that redox-active carbon materials addition improved the iron scraps bioavailability by promoting electron transfer, thus enhancing the autotrophic nitrogen removal. Our findings provided a green perspective to better understand the redox properties of plant-based carbon materials in ICWs for deep bioremediation in-situ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Resolvin (Rv) and lipoxin (Lx) play important regulative roles in the development of several inflammation-related diseases. The dysregulation of their metabolic network is believed to be closely related to the occurrence and development of asthma. The Hyssopus Cuspidatus Boriss extract (SXCF) has long been used as a treatment for asthma, while the mechanism of anti-inflammatory and anti-asthma action targeting Rv and Lx has not been thoroughly investigated. In this study, we aimed to investigate the effects of SXCF on Rv, Lx in ovalbumin (OVA)-sensitized asthmatic mice. The changes of Rv, Lx before and after drug administration were analyzed based on high sensitivity chromatography-multiple response monitoring (UHPLC-MRM) analysis and multivariate statistics. The pathology exploration included behavioral changes of mice, IgE in serum, cytokines in BALF, and lung tissue sections stained with H&E. It was found that SXCF significantly modulated the metabolic disturbance of Rv, Lx due to asthma. Its modulation effect was significantly better than that of dexamethasone and rosmarinic acid which is the first-line clinical medicine and the main component of Hyssopus Cuspidatus Boriss, respectively. SXCF is demonstrated to be a potential anti-asthmatic drug with significant disease-modifying effects on OVA-induced asthma. The modulation of Rv and Lx is a possible underlying mechanism of the SXCF effects., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this study, the ecological floating bed supporting with zero-valent iron (ZVI) and plant biomass (EFB-IB) was constructed to improve nitrogen removal from low-polluted water. The effects of ZVI coupling with plant biomass on microbial community structure, metabolic pathways and functional genes were analyzed by metagenomic sequencing, and the mechanism for nitrogen removal was revealed. Results showed that compared with mono-ZVI system (EFB-C), the denitrification efficiencies of EFB-IB were effectively enhanced, with the higher average NO 3 - -N removal efficiencies of 22.60-59.19%. Simultaneously, the average NH 4 + -N removal efficiencies were 73.08-91.10%. Metagenomic analyses showed that EFB-IB enriched microbes that involved in iron cycle, lignocellulosic degradation and nitrogen metabolism. Plant biomass addition simultaneously increased the relative abundances of autotrophic and heterotrophic denitrifying bacteria. Network analysis showed the cooperation between autotrophic and heterotrophic denitrifying bacteria in EFB-IB. Moreover, compared with EFB-C, plant biomass addition increased the relative abundances of genes related to iron cycle, lignocellulose degradation and glycolysis processes, ensuring the production of autotrophic and heterotrophic electron donors. Therefore, the relative abundances of key enzymes and functional genes related to denitrification were higher in EFB-IB, being beneficial to the NO 3 - -N removal. Additionally, the correlation analysis of nitrogen removal and functional genes verified the synergistic mechanism of iron-based autotrophic denitrification and plant biomass-mediated heterotrophic denitrification in EFB-IB. In summary, plant biomass has excellent potential to improve the nitrogen removal of iron-based EFB from low-polluted water., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Research shows the correlation between angiotensin-converting enzyme (ACE) deletion and insertion (D/I) polymorphism and COVID-19 risk; yet, conclusive evidence is still lacking. Thus, a meta-analysis of relevant articles was performed to more accurately estimate the relationship of ACE I/D polymorphism with the risk of COVID-19. Material and Methods . Relevant literature from the PubMed database was systematically reviewed, and odds ratios (ORs) and associated 95% confidence intervals (CIs) were measured. Additionally, the metapackage from Stata version 15.0 was used for statistical analysis., Results: The meta-analysis eventually contained 8 studies, including 1362 COVID-19 cases and 4312 controls. Based on the data, the ACE I/D polymorphism did not show an association with COVID-19 risk (D vs. I: OR = 1.25, 95% CI = 0.96-1.64; DD vs. II: OR = 1.89, 95% CI = 0.95-3.74; DI vs. II: OR = 1.75, 95% CI = 0.92-3.31; dominant model: OR = 1.88, 95% CI = 0.99-3.53; and recessive model: OR = 1.24, 95% CI = 0.81-1.90). Further, subgroup analyses stratified based on case proved that the ACE D allele demonstrated an association with increasing risk of COVID-19 severity (D vs. I: OR = 1.64, 95% CI = 1.01-2.66; DD vs. II: OR = 4.62, 95% CI = 2.57-8.30; DI vs. II: OR = 3.07, 95% CI = 1.75-5.38; dominant model: OR = 3.74, 95% CI = 2.15-6.50; and recessive model: OR = 1.28, 95% CI = 0.46-3.51)., Conclusions: The ACE D allele was clearly related to an enhanced risk of COVID-19 severity. Hence, it is imperative to take into account the influence of genetic factors during the development of future vaccines., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Hu Luoyi et al.)

Korla fragrant pear ( Pyrus sinkiangensis Yü) fruits have a unique flavor and are rich in phenolic acids, flavonoids, amino acids, and other nutrients. At present, the molecular basis of the quality differences among Korla fragrant pear fruits with a convex calyx and rough skin (RS), calyx shedding (SD), and a convex calyx (CV) remains unknown. To analyze the main metabolic components of Korla fragrant pear fruits and compare the antioxidant activities of these three fruits with different qualities, we used nutrient composition analysis and ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based widely targeted metabolomics approaches to analyze the changes in the quality characteristics of the pulp of these three Korla fragrant pear fruits with different appearances. The nutrient composition analysis showed that the fructose and glucose contents were not significantly different, and sucrose and vitamin C contents were significantly higher in SD fruits compared with CV and RS fruits. However, the levels of flavor substances such as titratable acids, total phenols, and total flavonoids were high in the pulp of RS fruits. The metabolomics results identified 1976 metabolites that were clustered into 12 categories, and phenolic acid and flavonoid metabolites were the most abundant. The differentially accumulated metabolites (DAMs) in the fruits with different appearances were screened by multivariate statistical methods, and a total of 595 DAMs were detected. The analysis identified 300 DAMs between the CV and SD fruits, 246 DAMs between the RS and CV fruits, and 405 DAMs between the RS and SD groups. SD fruits contained the most metabolites with a high relative content, especially phenolic acids, lipids, amino acids and derivatives, alkaloids, and organic acids. Compared with CV fruits, flavonoid metabolism was more active in RS fruits, which also had a higher content of flavonoids, whereas the fewest metabolites were found in CV fruits, which also displayed less flavonoid accumulation. KEGG pathway enrichment analysis revealed that the DAMs were mainly enriched in the metabolic pathways of flavone and flavonol biosynthesis, confirming that CV fruits have decreased flavone and flavonol biosynthesis and accumulate fewer flavonoids than RS fruits, which may explain the less bitter and astringent flavor of CV fruits. However, the flavonoid content in RS fruits was very high, which may be one of the reasons why RS fruits have a harder pulp and are less juicy, more slaggy, and less flavorful. Moreover, the analysis of the antioxidant activity showed that during fruit development and maturation, RS fruits had stronger antioxidant activity than SD and CV fruits. These results provide a theoretical basis for improving the fruit quality of Korla fragrant pears and the processing of pear pulp.

Restoration of submerged macrophytes is an efficient way for endogenous nutrient control and aquatic ecological restoration, but slow growth and limited reproduction of submerged macrophytes still exist. In this research, the effect of ferrous on the seed germination and growth of Vallisneria natans (V. natans) were studied through aquatic simulation experiments and its influence on the rhizosphere microbial community was also explored. The seed germination, growth, and physiological and ecological parameters of V. natans were significantly affected by the ferrous treatments. Ferrous concentration above 5.0 mg/L showed significant inhibition of seed germination of V. natans and the best concentration for germination was 0.5 mg/L. During the growth of V. natans, after ferrous was added, a brief period of stress occurred, which then promoted the growth lasting for about 19 days under one addition. The diversity and richness of the rhizospheric microbial were increased after the ferrous addition. However, the function of the rhizospheric microbial community showed no significant difference between different concentrations of ferrous adding in the overlying water. Ferrous addition affected the growth condition of plants (content of CAT, Chl a, Chl b, etc.), thus indirectly affecting the rhizospheric microbial community of V. natans. These impacts on V. natans and rhizosphere microorganisms could generalize to other submerged macrophytes in freshwater ecosystems, particularly which have similar habits. These findings would contribute to the ecological evaluation of ferrous addition or iron-containing water, and provide a reference for submerged macrophytes restoration and ecological restoration in freshwater ecosystems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Linezolid combined with rifampicin has shown excellent clinical outcomes against infection by multi-resistant Gram-positive bacteria. However, several studies have indicated that rifampicin reduces the plasma concentration of linezolid in patients with severe infection. Linezolid has been recommended for the treatment of patients with multidrug-resistant or extensively drug-resistant tuberculosis. However, studies on the interaction between linezolid and rifampicin in patients suffering from tuberculosis with infection are lacking. We evaluated the interaction between linezolid and rifampicin based on therapeutic drug monitoring (TDM). A retrospective analysis was undertaken for patients with tuberculosis and infection who were treated with linezolid and undergoing TDM. Patients were divided into the linezolid group and linezolid + rifampicin group. Data on demographic characteristics, disease, duration of linezolid therapy, and the plasma concentration of linezolid were used for statistical analyses. Eighty-eight patients with tuberculosis and infection were assessed. Values for the peak (C max ) and trough (C min ) concentrations of linezolid in plasma were available for 42 and 46 cases, respectively. Patients in the linezolid group had a significantly higher C max [15.76 (8.07-26.06) vs. 13.18 (7.48-23.64) mg/L, p = 0.048] and C min [8.38 (3.06-16.53) vs. 4.27 (0.45-10.47), p = 0.005] than those in the linezolid + rifampicin group. The plasma concentration of linezolid increased obviously in two patients after rifampicin discontinuation. However, the total efficiency and prevalence of hematologic adverse reactions were not significantly different in the linezolid group and linezolid + rifampin group. The plasma concentration of linezolid decreased upon combination with rifampicin, suggesting that TDM may aid avoidance of subtherapeutic levels of linezolid upon co-treatment with rifampicin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yan, Shi, Hu, Zeng and Lu.)

The artificial tidal wetlands ecosystem was believed to be a useful device in treating saline water, and it played a significant part in global nitrogen cycles. However, limited information is available on nitrogen-cycling pathways and related contributions to nitrogen loss in tidal flow constructed wetlands (TF-CWs) for saline water treatment. This study operated seven experimental tidal flow constructed wetlands to remove nitrogen from saline water at salinities of 0-30‰. Stable and high NH 4 + -N removal efficiency (∼90.3%) was achieved, compared to 4.8-93.4% and 23.5-88.4% for nitrate and total nitrogen (TN), respectively. Microbial analyses revealed the simultaneous occurrence of anaerobic ammonium oxidation (anammox), dissimilatory nitrate reduction to ammonium (DNRA), nitrification and denitrification, contributing to nitrogen (N) loss from the mesocosms. The absolute abundances were 5.54 × 10 3 -8.35 × 10 7 (nitrogen functional genes) and 5.21 × 10 7 -7.99 × 10 9 copies/g (16S rRNA), while the related genera abundances ranged from 1.81% to 10.47% (nitrate reduction) and from 0.29% to 0.97% (nitrification), respectively. Quantitative response relationships showed ammonium transformation were controlled by nxrA, hzsB and amoA, and nitrate removal by nxrA, nosZ and narG. Collectively, TN transformation were determined by narG, nosZ, qnorB, nirS and hzsB through denitrification and anammox pathways. The proportion of nitrogen assimilation by plants was 6.9-23.4%. In summary, these findings would advance our understanding of quantitative molecular mechanisms in TF-CW mesocosms for treating nitrogen pollution that caused algal blooms in estuarine/coastal ecosystems worldwide., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Due to the high exposure toxicity and individual variability of polycyclic aromatic hydrocarbons (PAHs), it is difficult to accurately characterize the actual exposure of exposed individuals through external exposure detection. In this study, the monohydroxyl metabolites of naphthalene, phenanthrene, pyrene, and 9-fluorenone were identified in the urine of low-dose PAH-exposed individuals based on ultra-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS), and their concentrations were monitored for 15 consecutive days after exposure. The results showed that the metabolite concentrations of naphthalene, phenanthrene, and pyrene were basically the same, and all of them reached the maximum value at day 8. In contrast, the metabolite of 9-fluorenone reached its maximum value on day 2. This study showed that the four metabolites were strongly correlated with their parent PAH exposure, with a wide detection window, and their assays were specific, sensitive, and reliable, while the sampling difficulty was low, so the four hydroxylated PAHs may be potential low-dose biomarkers of PAH internal exposure. This study will provide methodological and data support for further health risk studies involving internal exposure to organic pollutants such as PAHs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Steroids are tetracyclic aliphatic compounds, and most of them contain carbonyl groups. The disordered homeostasis of steroids is closely related to the occurrence and progression of various diseases. Due to high structural similarity, low concentrations in vivo, poor ionization efficiency, and interference from endogenous substances, it is very challenging to comprehensively and unambiguously identify endogenous steroids in biological matrix. Herein, an integrated strategy was developed for the characterization of endogenous steroids in serum based on chemical derivatization, ultra-performance liquid chromatography quadrupole Exactive mass spectrometry (UPLC-Q-Exactive-MS/MS), hydrogen/deuterium (H/D) exchange, and a quantitative structure-retention relationship (QSRR) model. To enhance the mass spectrometry (MS) response of carbonyl steroids, the ketonic carbonyl group was derivatized by Girard T (GT). Firstly, the fragmentation rules of derivatized carbonyl steroid standards by GT were summarized. Then, carbonyl steroids in serum were derivatized by GT and identified based on the fragmentation rules or by comparing retention time and MS/MS spectra with those of standards. H/D exchange MS was utilized to distinguish derivatized steroid isomers for the first time. Finally, a QSRR model was constructed to predict the retention time of the unknown steroid derivatives. With this strategy, 93 carbonyl steroids were identified from human serum, and 30 of them were determined to be dicarbonyl steroids by the charge number of characteristic ions and the number of exchangeable hrdrogen or comparing with standards. The QSRR model built by the machine learning algorithms has an excellent regression correlation, thus the accurate structures of 14 carbonyl steroids were determined, among which three steroids were reported for the first time in human serum. This study provides a new analytical method for the comprehensive and reliable identification of carbonyl steroids in biological matrix., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study investigated the nitrogen removal enhanced by combined iron scraps and plant biomass, and its microbial response in the wetland with different plant ages and temperatures. The results showed that older plants benefitted the efficiency and stability of nitrogen removal, which could reach 1.97 ± 0.25 g m -2 d -1 in summer and 0.42 ± 0.12 g m -2 d -1 in winter. Plant age and temperature were the main factors determining the microbial community structure. Compared with temperature, plant ages affected more significantly on relative abundance of microorganisms such as Chloroflexi, Nitrospirae, Bacteroidetes and Cyanobacteria, and functional genera for nitrification (e.g., Nitrospira) and iron reduction (e.g., Geothrix). The absolute abundance of total bacterial 16S rRNA ranged from 5.22 × 10 8 to 2.63 × 10 9 copies g -1 and presented extremely significant negative correlation to plant age, which would lead to a decline in microbial function on information storage and processing. The quantitative relationship further revealed that the ammonia removal was related to 16S rRNA and AOB amoA, while nitrate removal was controlled by 16S rRNA, narG, norB and AOA amoA jointly. These findings suggested that a mature wetland for nitrogen removal enhancement should focus on aging microbes caused by old plants and possible endogenous pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: This study developed a set of competency evaluation indicators for billing nurses in China., Background: In clinical practice, nurses often take up billing responsibilities that are accompanied by certain risks. However, the competency evaluation index system for billing nurses has not been established in China., Methods: This study consisted of two main phases of research design: the first phase included a literature review and semi-structured interviews. Individual semi-structured interviews were conducted with 12 nurses in billing departments and 15 nurse managers in related departments. Concepts distilled from the literature review were linked to the results of the semi-structured interviews; this phase produced the first draft of indicators for assessing the professional competence of nurses in billing departments. In the second phase, two rounds of correspondence were conducted with 20 Chinese nursing experts using the Delphi method to test and evaluate the content of the index. The consensus was defined in advance as a mean score of 4.0 or above, with at least 75% agreement among participants. In this way, the final indicator framework was determined., Results: Using the iceberg model as a theoretical foundation, the literature review identified four main dimensions and associated themes. The semi-structured interviews confirmed all of the themes from the literature review while generating new themes, both of which were incorporated into the first draft of the index. Then two rounds of the Delphi survey were conducted. The positive coefficients of experts in the two rounds were 100% and 95%, respectively, while the authority coefficients were 0.963 and 0.961, respectively. The coefficients of variation were 0.00-0.33 and 0.05-0.24, respectively. The competency evaluation index system for billing nurses consisted of 4 first-level indicators, 16 s-level indicators, and 53 third-level indicators., Conclusion: The competency evaluation index system for billing nurses, which was developed on the basis of the iceberg model, was scientific and applicable., Implications for Nursing Management: The competency assessment index system for billing nurses may provide an effective practical framework for nursing administration to evaluate, train, and assess the competency of billing nurses., (© 2023. The Author(s).)

Three kinds of bioretention were designed to explore the effects of zero-valent iron (ZVI) and biochar on the nitrogen removal performance and to seek a more reasonable packing method in this study. The results showed that the effluent removal rates of nitrate, ammonium and total nitrogen were 53.30 ± 12.68%, 98.41 ± 0.38% and 64.03 ± 8.72% respectively in Bioretention-3 during the rainfall events, while the nitrate concentration decreased gradually with the increase of drying time. According to the batch experiment, it was found that zero-valent iron could release continuously and stably in Bioretention-3 and Bioretention-1 due to the interception effect of biochar on dissolved oxygen. In addition, biochar in soil layer could protect zero-valent iron from excessive oxidation while biochar in the substrate layer could release organic matter to promote heterotrophic denitrification. Microbial community analysis showed that the dominant phyla were Proteobacteria (20.92-40.81%) and Actinobacteriota (9.89-24.54%). The dominant nitrifying genera was Nitrospira while there were also aerobic denitrifying bacteria (Sphingomonas, Bradyrhizobium and Chryseolinea, etc.) in soil layer. In the substrate layer, there was more ferrous iron-mediated autotrophic denitrification process (Thiobacillus, Geobacter and Denitratisoma, etc.) in Bioretention-1 and Bioretention-3 while a larger proportion of Dissimilatory Nitrate Reduction to Ammonium process (DNRA) (Bacillus, Desulfovibrio and Pseudomonas, etc.) in Bioretention-2. In general, this study showed that biochar addition in soil coupled with mixing zero-valent iron and biochar as substrate layer was a more stable and efficient design through various aspects of evidence. It provides a new way for how to use zero-valent iron and biochar to improve nitrogen removal capacity in stormwater management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this study, an iron scrap (IS)-based ecological floating bed was constructed to couple with plant biomass (FeB-EFB) for treating low-polluted water, and the nitrogen removal performance and mechanism were explored. The results showed that the nitrogen could be effectively removed in FeB-EFB, and the nitrate removal efficiency was 29.14 ± 8.06% even at a low temperature (13.9 ± 2.2 °C). After the temperature rose to 20.0 ± 0.9 °C, the denitrification rate was increased by 0.63 ± 0.16-0.81 ± 0.27 g/(m 2 d) due to the synergistic effect of ISs and plant biomass. Plant biomass could promote the ISs release efficiency, while ISs could facilitate plant biomass availability by promoting cellulose decomposition. High-throughput sequencing analysis revealed that the iron-oxidizing bacteria Pseudomonas were the dominant genus in FeB-EFB. Meanwhile, the existence of plant biomass could increase the abundance of iron-related bacteria and enrich heterotrophic and facultative denitrifying bacteria (e.g., Hydrogenophaga, Comamonas) as well, improving iron-mediated denitrification and heterotrophic denitrification simultaneously. Therefore, mixotrophic denitrification improvement played a major role in promoting nitrogen removal of FeB-EFB. These results indicated that coupling iron scraps with plant biomass may be an effective way to improve the nitrogen removal performance of EFB., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Ammonium oxidation coupled to Fe(III) reduction (Feammox) is a newly discovered iron-nitrogen cycle process of microbial catalyzed NH 4 + oxidation coupled with iron reduction. Fe(III) often exists in the form of insoluble iron minerals resulting in reduced microbial availability and low efficiency of Feammox. Electron shuttles(ESs) can be reversibly oxidized and reduced which has the potential to improve Feammox efficiency. This review summarizes the discovery process, electron transfer mechanism, influencing factors and driven microorganisms of Feammox, ang expounds the possibility and potential mechanism of ESs to enhance Feammox efficiency. Based on an in-depth analysis of the current research situation of Feammox for nitrogen removal, the knowledge gaps and future research directions including how to apply ESs enhanced Feammox to promote nitrogen removal in practical wastewater treatment have been highlighted. This review can provide new ideas for the engineering application research of Feammox and strong theoretical support for its development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases (AmpCs)-producing Enterobacteriaceae have been increasingly reported and imposing significant threat to public. Livestock production industry might be the important source for clinically important ESBL-producing Enterobacteriaceae. This study aims to investigate the resistance profile, phenotypic ESBL production, beta-lactamase genes, virulence factors, and plasmid replicon types among 59 Enterobacteriaceae strains isolated from poultry faecal samples in Malaysia's commercial poultry farm. There were 38.7% and 32.3% of Escherichia coli resistant to cefotaxime and cefoxitin, respectively, while Klebsiellaspp. demonstrated resistance rate of 52.6% to both mentioned antimicrobials. Majority of the E. coli isolates carried blaTEM and blaCMY-2 group. blaSHV was the most prevalent gene detected in Klebsiellaspp., followed by blaDHA and blaTEM. Resistance to extended spectrum cephalosporin in our isolates was primarily mediated by plasmid mediated AmpC beta-lactamase such as CMY-2 group and DHA enzyme. The CTX-M genes were found in two ESBL-producing E. coli. IncF, IncI1, and IncN plasmids were most frequently detected in E. coli and Klebsiellaspp. The virulence factor, including EAST1 and pAA were identified at low frequency. This study highlights the poultry as a reservoir of resistance and virulence determinants and prevalence of plasmids in Enterobacteriaceae might drive their dissemination., (© The Author(s) 2022. Published by Oxford University Press on behalf of Applied Microbiology International.)

It has been demonstrated in many studies that angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is related to Henoch-Schonlein purpura nephritis (HSPN) risk in children. However, this conclusion remains controversial. In this study, we systemically retrieved relevant studies in electronic databases such as PUBMED, CNKI, and EMBASE followed by calculation of odds ratios (OR) with 95% confidence intervals (CI). In addition, meta-package in STATA version 12.0 was used. Angiotensin-converting enzyme I/D polymorphism was related to HSPN susceptibility in children (D vs. I: OR 1.47, 95% CI: 1.13-1.93; DD vs. II: OR 2.29, 95% CI: 1.29-4.07; DI vs. II: OR 1.10, 95% CI: 0.82-1.48; dominant model: OR 1.44, 95% CI: 1.09-1.89; recessive model: OR 2.26, 95% CI: 1.67-3.06). In addition, subgroup analysis stratified according to ethnicity indicated a significant relationship between this polymorphism and HSPN susceptibility among Asians and Caucasians. The data extracted from HaploReg indicated that ACE I/D polymorphism was not in linkage disequilibrium with other variants in the ACE gene. The research shows that ACE I/D polymorphism is related to HSPN susceptibility in children.

Background: Chronic obstructive pulmonary disease (COPD) causes organic damage as well as anxiety, depression, fear, and other psychological disorders, which seriously affect the quality of life and prognosis of patients and cause a huge economic burden to the family and society., Objective: The aim of this study was to investigate the correlation between an imbalance of serum Th1/Th2 indicators and psychiatric depression in elderly patients with COPD and analyze its implications for clinical management., Methods: From January 2018 to May 2022, 120 elderly patients with COPD treated at our hospital were categorized into two groups based on the self-rating depression scale (SDS): COPD with depression (SDS score ⩾ 50) and COPD alone (SDS score < 50). Blood gas analysis, pulmonary function, and serum Th1/Th2 index were determined. Receiver operating characteristic (ROC) curves were analyzed to explore the diagnostic value of serum Th1/Th2 ratios for COPD complicated by depression., Results: Compared with the group without depression, the partial pressure of carbon dioxide and COPD assessment test scores were significantly higher, and the oxygenation index, forced expiratory volume in one second (FEV1), and percent predicted FEV1 were significantly lower in the COPD with depression group (P< 0.05). Interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) were significantly higher in the COPD with depression group than in the group without depression (P< 0.05). Logistic regression analysis indicated that the imbalance of serum IL-1β, IL-2, IL-6, IL-8, IL-10, and TNF-α was a risk factor for mental depression in elderly patients with COPD. When comparing prognostic indices, the interval before the first onset of clinically noticeable deterioration (CID-C) in the COPD with depression group was noticeably shorter than that in the COPD without depression group; the incidence of CID-C within 6 months was noticeably higher in the COPD with depression group than in the group without depression., Conclusion: Elderly patients with COPD and depression had reduced pulmonary function and higher serum Th1/Th2 levels, and an imbalance in serum Th1/Th2 indicators was a potential risk factor for depression. Moreover, elderly patients with COPD and depression were at a higher risk of disease progression and had a worse prognosis. Thus, an imbalance in serum Th1/Th2 indicators is a potential prognostic factor for evaluating depression in patients with COPD.

Two-dimensional nanofluidic membranes offer great opportunities for developing efficient and robust devices for ionic/water-nexus energy harvesting. However, low counterion concentration and long pathway through limited ionic flux restrict their output performance. Herein, it is demonstrated that rapid diffusion kinetics can be realized in two-dimensional nanofluidic membranes by introducing in-plane holes across nanosheets, which not only increase counterion concentration but also shorten pathway length through the membranes. Thus, the holey membranes exhibited an enhanced performance relative to the pristine ones in terms of osmotic energy conversion. In particular, a biomimetic multilayered membrane sequentially assembled from pristine and holey sections offers an optimized combination of selectivity and permeability, therefore generating a power density up to 6.78 W m -2 by mixing seawater and river water, superior to the majority of the state-of-the-art lamellar nanofluidic membranes. This work highlights the importance of channel morphologies and presents a general strategy for effectively improving ion transport through lamellar membranes for high-performance nanofluidic devices., (© 2022 Wiley-VCH GmbH.)

This study explored the microbial nitrogen transformation and removal potential in the plant rhizosphere of seven artificial tidal wetlands under different salinity gradients (0-30‰). Molecular biological and stable isotopic analyses revealed the existence of simultaneous anammox (anaerobic ammonium oxidation), nitrification, DNRA (dissimilatory nitrate reduction to ammonium) and denitrification processes, contributing to nitrogen loss in rhizosphere soil. The microbial abundances were 2.87 × 10 3 -9.12 × 10 8 (nitrogen functional genes) and 1.24 × 10 8 -8.43 × 10 9 copies/g (16S rRNA gene), and the relative abundances of dissimilatory nitrate reduction and nitrification genera ranged from 6.75% to 24.41% and from 0.77% to 1.81%, respectively. The bacterial 16S rRNA high-throughput sequencing indicated that Bacillus, Zobellella and Paracoccus had obvious effects on nitrogen removal by heterotrophic nitrifying/aerobic denitrifying process (HN-AD), and autotrophic nitrification (Nitrosomonas, Nitrospira and Nitrospina), conventional denitrification (Bradyrhizobium, Burkholderia and Flavobacterium), anammox (Candidatus Brocadia and Candidatus Scalindua) and DNRA (Clostridium, Desulfovibrio and Photobacterium) organisms co-existed with HN-AD bacteria. The potential activities of DNRA, nitrification, anammox and denitrification were 1.23-9.23, 400.03-755.91, 3.12-35.24 and 30.51-300.04 nmolN 2 ·g -1 ·d -1 , respectively. The denitrification process contributed to 73.59-88.65% of NO x - reduction, compared to 0.71-13.20% and 8.20-15.42% via DNRA and anammox, as 83.83-90.74% of N 2 production was conducted by denitrification, with the rest through anammox. Meanwhile, the nitrification pathway accounted for 95.28-99.23% of NH 4 + oxidation, with the rest completed by anammox bacteria. Collectively, these findings improved our understanding on global nitrogen cycles, and provided a new idea for the removal of contaminants in saline water treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The association between dopamine D3 receptor (DRD3) Ser9Gly polymorphism and treatment response to antipsychotic drugs (APDs) in schizophrenia (SCZ) has been widely reported with inconsistent results, thus we performed an updated meta-analysis to derive a more precise estimation of the relationship. PubMed, Cochrane Library, Medline, Embase, CNKI, Weipu and Wanfang databases were searched for eligible studies published until March 2022. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of the associations in four genetic models. A total of 13 studies with 1769 patients were included in this meta-analysis. Our findings suggested that Ser9Gly polymorphism was significantly associated with treatment response to APDs in SCZ in allele model (Ser vs Gly, OR = 0.72, 95 % CI = 0.58-0.89, P = 0.002), recessive model (Ser/Ser vs Ser/Gly + Gly/Gly, OR = 0.55, 95 % CI = 0.36-0.86, P = 0.008) and co-dominant model (Ser/Ser vs Gly/Gly, OR = 0.57, 95 % CI = 0.33-0.99, P = 0.045) in Caucasians, but not in Asians. meta-regression revealed that the associations were not confounded by mean age, male ratio and treatment duration (P > 0.05). In summary, our results indicated the DRD3 Ser9Gly may influence the efficacy of APDs in specific genetic models, of which Ser allele and Ser/Ser genotype contributed to poor treatment response in Caucasians., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Cholesteryl esters (CEs) are composed of various fatty acyl chains attached to the hydroxyl groups of cholesterol, and abnormalities in their metabolism are related to many diseases. This study aimed to develop an ultrahigh-performance liquid chromatography-quadrupole exactive mass spectrometry (UPLC-Q-Exactive MS) method to identify the CEs in plasma., Methods: First, the MS fragmentation patterns were investigated using seven commercial CE standards. Then, the CEs in plasma were characterized through the accurate mass data of precursor ions and characteristic product ions. A strategy of step-by-step m/z scans in a narrow range was proposed to identify more trace CEs by the full-scan data-dependent MS/MS (ddMS2) mode., Results: A total of 50 CE species consisting of 55 regioisomers were identified in human plasma. Among them, two species were reported for the first time., Conclusion: This study is the most comprehensive identification of CE species in human plasma to date. These results will contribute to the in-depth profiling of CEs in human plasma and provide guidance for animal model selection when studying lipid-related diseases., (© 2022. Huazhong University of Science and Technology.)

Alismatis rhizoma (AR), the dried rhizome of Alisma orientale (Sam) Juzep, is effective in treating hyperlipidemia, but the mechanisms involved require further exploration. This study evaluated the hypolipidemic properties of AR using an integrated strategy combining network pharmacology with metabolomics and lipidomics. Firstly, a hyperlipidemia mouse model induced by a high-fat diet was established to evaluate the therapeutic effects of AR. Secondly, plasma metabolomics and lipidomics were used to identify differential metabolites and lipids, and metabolic pathway analysis was performed using MetaboAnalyst. Thirdly, network pharmacology, based on the metabolic profile of AR in vivo , was used to discover potential therapeutic targets. Finally, key targets were obtained through a compound-target-metabolite network, which was verified by molecular docking and quantitative real-time PCR (qPCR). Biochemistry analysis and histological examinations showed that AR exerted hypolipidemic effects on hyperlipidemic mice. Seventy potential biomarkers for the AR treatment of hyperlipidemia were identified by metabolomics and lipidomics, which were mainly involved in lipid metabolism, energy metabolism and amino acid metabolism. Eighteen potentially active compounds were identified in the plasma of mice after oral administration of AR, which were associated with 83 potential therapeutic targets. The PPAR signaling pathway was considered a crucial signaling pathway of AR against hyperlipidemia by KEGG analysis. The joint analysis showed that 6 upstream key targets were regulated by AR, including ALB, TNF, IL1B, MMP9, PPARA and PPARG. Molecular docking showed that active compounds of AR had high binding affinity with these key targets. qPCR further demonstrated that AR could reverse the mRNA expression of these key targets in hyperlipidemic mice. This study integrates network pharmacology with metabolomics and lipidomics to reveal the regulatory effects of AR on endogenous metabolites and validates key therapeutic targets, and represents the most systematic and in-depth study on the hypolipidemic activity of AR.

Plant biomass can be used as a carbon source to enhance the nitrogen removal effect. Related researches mainly focused on withered biomass, while little on fresh biomass. In this study, batch experiments revealed that the carbon release rate (60.5 mg TOC g -1 ) of fresh biomass was significantly higher than that of withered biomass (44.9 mg TOC g -1 ), while the nitrogen release rate showed the opposite trend. Compared with withered biomass, fresh biomass could release more sugar and less refractory humic acid, which means higher bioavailability. After adding fresh biomass, TN removal rate increased from 18.65% to 51.59%. The TN removal in the wetland adding withered biomass increased from 13.59% to 42.25%. The biomass addition had a slight impact on the effluent sensory quality in the first two days. After adding fresh biomass and withered biomass, the relative abundance of denitrifying bacteria like Flavobacterium and Pseudomonas in the system significantly increased. In general, fresh biomass was more suitable as a denitrification carbon source for surface flow constructed wetlands., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The iron-assisted autotrophic denitrification was plagued by passivation when introduced in surface flow constructed wetlands (SFCWs). Iron‑carbon micro-electrolysis (Fe/C-M/E) could facilitate the transfer of electrons during the utilization of iron. In this study, iron scraps coupling with activated carbon and biochar were applied to explore the effects of carbon materials on autotrophic denitrification. The results showed that TN removal rate in the SFCW with iron scraps and activated carbon (SFCW-IAC) and the SFCW with iron scraps and biochar (SFCW-IBC) were improved by 31.61% ± 8.18% and 14.09% ± 7.15%, and N 2 O fluxes were reduced to 2.73 and 3.12 mg m -2 d -1 , respectively. The greater iron mass loss rate (0.91%) was confirmed in SFCW-IAC. Microbial community analysis reported that autotrophic denitrification and iron related genera were increased. This study proved that activated carbon was more suitable than biochar to Fe/C-M/E for denitrification enhancement and N 2 O emission reduction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Testosterone deficiency can lead to depressive symptoms in humans; however, the causes of this deficiency are incompletely understood. Here, we isolated Mycobacterium neoaurum from the fecal samples of testosterone-deficient patients with depression and showed that this strain could degrade testosterone in vitro. Furthermore, gavaging rats with M. neoaurum reduced their serum and brain testosterone levels and induced depression-like behaviors. We identified the gene encoding 3β-hydroxysteroid dehydrogenase (3β-HSD) as the enzyme causing testosterone degradation. Introducing 3β-HSD into Escherichia coli enhanced its ability to degrade testosterone. Gavaging rats with 3β-HSD-producing E. coli reduced their serum and brain testosterone levels and caused depression-like behaviors. Finally, compared with 16.67% of participants without depression, 42.99% (46/107) of the fecal samples of patients with depression harbored 3β-HSD, and 60.87% (28/46) of these fecal samples expressed 3β-HSD. These results suggest that 3β-HSD expressed by gut microbes may be associated with depressive symptoms due to testosterone degradation., Competing Interests: Declaration of interests The authors applied patents based on this research., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

Associations of serotonin 2A receptor (5-HTR2A) gene polymorphisms with clinical response to atypical antipsychotics (AAPs) treatment in schizophrenia (SCZ) were inconsistent. Thus we conducted a meta-analysis to investigate more reliable estimates. The Cochrane Library, Embase, PubMed, Weipu, CNKI and Wanfang databases were searched for eligible studies published up to September 2021. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in four genetic models. Subgroup analyses were performed by ethnicity and antipsychotic type. Meta-regression was used to evaluate the potential effects of confounding variables. In total, 19 studies were included for the meta-analysis, of which 17 studies containing 2359 patients were identified for T102C polymorphism and 7 studies containing 1408 patients for A-1438G polymorphism. The results showed that A-1438G polymorphism was significantly associated with clinical response to AAPs treatment in SCZ in four genetic models (allele model, A vs. G, OR = 1.87, 95% CI = 1.05-3.33, P = 0.034; recessive model, AA vs. GA + GG: OR = 1.79, 95% CI = 1.17-2.72, P = 0.007; dominant model, AA + GA vs. GG: OR = 3.40, 95% CI = 1.15-10.10, P = 0.027; co-dominant model, AA vs. GG: OR = 3.44, 95% CI = 1.07-11.10, P = 0.039) in Asians, but not in Caucasians. When stratified by antipsychotic type, A-1438G polymorphism was related to the efficacy of olanzapine in recessive model (AA vs. GA + GG, OR = 1.85, 95% CI = 1.18-2.90, P = 0.007), but not in other models. However, neither four genetic models nor subgroup analyses of T102C polymorphism were found any significant associations with AAPs response (P > 0.05). Meta-regression revealed that no association was confounded by mean age, male ratio, treatment duration and illness duration (P > 0.05). The present meta-analysis indicated that 5-HTR2A A-1438G polymorphism, but not T102C polymorphism, was significantly associated with AAPs response in SCZ, especially in Asians and olanzapine-treated patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Agarwood tea derived from Aquilaria malaccensis Lamk is becoming an increasingly popular herbal drink that is said to have multiple health benefits. Co-administration of this tea and clinical used drugs is possible, but it increases the risk of drug-herb interactions., Objective: This in vitro study investigated the inhibitory effects of agarwood tea aqueous extract on the eight major human drug-metabolising cytochrome P450 (CYP) enzyme activities., Methods: High-throughput fluorescence-based Vivid® CYP450 screening kits were employed to obtain the enzyme activities before and after incubation with agarwood tea aqueous extract., Results: Agarwood aqueous extract potently inhibited CYP2C9, CYP2D6, and CYP3A4 activities with Ki values of 5.1, 34.5, and 20.3μg/ml, respectively. The most likely inhibition mode responsible for these inhibitions was non-competitive inhibition. On the other hand, at 1000μg/ml, agarwood tea aqueous extract negligibly inhibited CYP1A2, CYP2B6, CYP2C19, CYP2E1, and CYP3A5 activities., Conclusion: These findings can be used to design additional in vitro investigations using clinical relevant drug substrates for CYP2C9, CYP2D6, and CYP3A4. Subsequently, future studies can be conducted to determine potential interactions between agarwood tea aqueous extract and CYP using in vivo models., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

As a fast, sensitive and selective method, liquid chromatography-tandem high-resolution mass spectrometry (LC-HRMS) has been used for studying the in vivo metabolism of traditional Chinese medicine (TCM). However, the rapid discovery and characterization of metabolites, especially isomers, remain challenging due to their complexity and low concentration in vivo. This study proposed a strategy to improve the structural annotation of prototypes and metabolites through characteristic ions and a quantitative structure-retention relationship (QSRR) model, and Alismatis Rhizoma (AR) triterpenes were used as an example. This strategy consists of four steps. First, based on an in-house database reported previously, prototypes and metabolites in biosamples were preliminarily identified. Second, the candidate structures of prototype compounds and metabolites were determined by characteristic ions, databases or potential metabolic pathways. Then, a QSRR model was established to predict the retention times of the proposed structure. Finally, the structures of unknown prototypes and metabolites were determined by matching experimental retention times with the predicted values. The QSRR model built by the genetic algorithm-multiple linear regression (GA-MLR) has excellent regression correlation (R 2  = 0.9966). Based on this strategy, a total of 118 compounds were identified, including 47 prototypes and 71 metabolites, among which 61 unknown compounds were reasonably characterized. The typical compound identified by this strategy was successfully validated using a triterpene standard. This strategy can improve the annotation confidence of in vivo metabolites of TCM and facilitate further pharmacological research., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The ecological floating bed (EFB) coupled with zero-valent iron (ZVI) is proposed to treat low carbon-to-nitrogen ratio water. However, the application of ZVI is limited by low electron transfer efficiency. Coupling ZVI with carbon materials may improve the performance. In this study, the EFB with ZVI coupled plant biomass (IB-EFB) was established to enhance denitrification performance and compared to the EFB with ZVI coupled activated carbon (IC-EFB). The results showed that higher denitrification rate was observed in IB-EFB (68.8%) than that in IC-EFB (54.40%), which attributed to the synergistic effect of ZVI and plant biomass. Plant biomass also promoted the electron transfer of ZVI which enhanced the Fe(II)-mediated denitrification. High-throughput sequencing analysis revealed that IB-EFB enriched iron-related denitrifying bacteria more effectively than IC-EFB, and obtained high abundance of phototrophic Fe(II)-oxidizing bacteria Rhodopseudomonas (19.26%). Thus coupling ZVI with plant biomass has a potential for enhanced nitrogen removal in EFB., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Rapid eye movement sleep deprivation (REMSD) and fluoxetine affect depression, yet the detailed molecular mechanisms were not clear. Methods: Rat depression chronic unpredictable stress was constructed, and the body weight of rats was measured. The efficacy of REMSD and fluoxetine on the pleasure experience, exploration, and cognition of rats with depression was determined by the Sucrose preference test, the open field test, and Morris water task, respectively. The effects of REMSD and fluoxetine on depression-induced damage and apoptosis in rat hippocampi were detected using hematoxylin-eosin staining and terminal transferase-mediated biotin 2'-deoxyuridine, 5'-triphosphate nick end labeling. A1 adenosine receptor content was measured by immunohistochemistry. Relative expressions of the A1 adenosine receptor, proteins related to apoptosis (B Bcl-2-associated X protein; B-cell lymphoma 2), phosphoinositide 3-kinase, P38 mitogen-activated protein kinase, cFos, and adenosine deaminase RNA specific two were quantified by quantitative real-time polymerase chain reaction and Western blot as needed. Results: Depression decreased rat weight. REMSD combined with fluoxetine increased body weight, prompted rat behavior, alleviated depression-induced damage, attenuated apoptosis, and promoted A1 adenosine receptor level in rat hippocampi. Furthermore, the combined therapy upregulated expressions of A1 adenosine receptor, B-cell lymphoma 2, and phosphoinositide 3-kinase but downregulated those of B-cell lymphoma 2-associated X protein, P38 mitogen-activated protein kinase, cFos, and adenosine deaminase RNA specific 2 in the hippocampi of rats with depression. Conclusion: REMSD combined with fluoxetine protected rats against depression-induced damage and apoptosis in the hippocampus via the A1 adenosine receptor, providing a possible treatment strategy for depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ju, Wang, Yan, Zhu, Hu, Dong and Tan.)

Although a number of studies have been conducted on the association of -1438A/G polymorphism in serotonin 2A receptor (5-HTR2A) gene with anorexia nervosa (AN) and bulimia nervosa (BN), the results remained inconsistent. We thus performed a meta-analysis to clarify the effects of -1438A/G polymorphism on the risk of AN and BN. PubMed, Embase, the Cochrane Library, CNKI, Weipu and Wanfang databases were searched for eligible studies. Pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated to estimate the strength of the association. Subgroup analysis was also performed by ethnicity. In total, 17 studies were included for the meta-analysis, of which 15 studies containing 2028 cases and 2725 controls were used for AN analysis and 7 studies containing 505 cases and 1129 controls for BN analysis. The results showed -1438A/G polymorphism was significantly associated with the risk of AN in four genetic models (allele model, A vs. G: OR = 1.31, 95 % CI = 1.11-1.64, P = 0.003; recessive model, AA vs. GA + GG: OR = 1.69, 95 % CI = 1.28-2.23, P = 0.000; dominant model, AA + GA vs. GG: OR = 1.35, 95 % CI = 1.02-1.79, P = 0.037; co-dominant model, AA vs. GG: OR = 1.94, 95 % CI = 1.29-2.92, P = 0.002) in Caucasians, but not in Asians. We failed to observe a significant association between -1438A/G polymorphism and the risk of BN either in overall or in Caucasian population. The present meta-analysis indicated that A allele and AA genotype of 5-HTR2A -1438A/G polymorphism may contribute to higher risk of AN, especially in Caucasians. However, this polymorphism was not associated with the susceptibility to BN., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Nucleocapsid proteins (NCp) are zinc finger (ZF) proteins, and they play a central role in HIV virus replication, mainly by interacting with nucleic acids. Therefore, they are potential targets for anti-HIV therapy. Natural products have been shown to be able to inhibit HIV, such as turmeric and licorice, which is widely used in traditional Chinese medicine. Liquiritin (LQ), isoliquiritin (ILQ), glycyrrhizic acid (GL), glycyrrhetinic acid (GA) and curcumin (CUR), which were the major active components, were herein chosen to study their interactions with HIV-NCp7 C-terminal zinc finger, aiming to find the potential active compounds and reveal the mechanism involved. The stacking interaction between NCp7 tryptophan and natural compounds was evaluated by fluorescence. To elucidate the binding mode, mass spectrometry was used to characterize the reaction mixture between zinc finger proteins and active compounds. Subsequently, circular dichroism (CD) spectroscopy and molecular docking were used to validate and reveal the binding mode from a structural perspective. The results showed that ILQ has the strongest binding ability among the tested compounds, followed by curcumin, and the interaction between ILQ and the NCp7 zinc finger peptide was mediated by a noncovalent interaction. This study provided a scientific basis for the antiviral activity of turmeric and licorice.

Sphingolipids (SLs) are endogenously bioactive molecules with diverse structures, and its metabolic disorders are involved in the progression of many diseases. In this study, an ultra-performance liquid chromatography quadrupole exactive mass spectrometry (UPLC-Q-Exactive-MS) method was established to comprehensively profile SLs in plasma. First, the fragment patterns of SL standards of each subclass were investigated. Then, the SL species in plasma were characterized based on the fragmentation rules. Finally, a total of 144 endogenous SL species consisting of 216 regioisomers were identified in plasma of human, golden hamster and C57BL/6 mice, which was the most comprehensive identification for SLs in plasma. In addition to the known species, 19 SL species that have never been reported were also identified. The profile of SLs in plasma of human and two rodent species was compared subsequently. It was worth noting that a total of 9 SL molecular species consisting of 11 regioisomers with low abundance were successfully identified in human plasma through comparison among species. Those findings contribute to a deeper understanding of SLs in human plasma and provide scientific basis for the selection of animal model. The established profile of SLs in plasma could be used for screening of lipid biomarkers of various diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Melatonin is a hormone synthesized and secreted by the pineal gland with the effect of regulating sleep rhythm. Circadian and sleep disturbances may be central for understanding the pathophysiology and treatment of depression. Recently, the melatonergic system has been implicated in the pathophysiology and treatment of depression. In this study, we observed the effects of melatonin on depression-like behavior induced by chronic unpredictable mild stress (CUMS) in rats, and its molecular mechanism was explored. Adult male Sprague-Dawley rats were exposed to CUMS for 4 weeks. Melatonin or saline was injected intraperitoneally. Behavioral changes of Sprague-Dawley rats were detected by the open field test, sugar preference test, elevated O maze test and forced swimming test. In addition, the plasma corticosterone level and the expression of endoplasmic reticulum stress-related protein in the hippocampus of rats were measured. Compared with the control group, the CUMS-exposed Sprague-Dawley rats showed depression-like behavior, which was significantly improved by melatonin treatment. Moreover, CUMS induced endoplasmic reticulum stress and JNK phosphorylation in the hippocampus. Melatonin treatment could significantly reverse the endoplasmic reticulum stress and JNK phosphorylation induced by CUMS. These results suggest that melatonin improves depression-like behavior by inhibiting endoplasmic reticulum stress induced by CUMS. This study demonstrates that melatonin can improve depression-like behavior induced by CUMS, which may be related to the inhibition of endoplasmic reticulum stress and JNK phosphorylation in rat hippocampus.

Olanzapine is an atypical antipsychotic drug that has been increasingly used for treatment in schizophrenia. It has been observed that olanzapine responses in schizophrenia patients vary individually, but the reason has not been elucidated. In the study, we aimed to comprehensively explore the relationships between olanzapine responses and genetic polymorphisms of drug metabolizing enzymes, transporters and target receptors, and so as to interpret the reason of good and poor responses of olanzapine. A total of 241 Chinese Han paranoid schizophrenia who treated with olanzapine alone for 4 weeks were recruited. The positive and negative symptom scale (PANSS) was used to evaluate the efficacy of olanzapine. The genetic polymorphisms were detected by improved multiple ligase detection reaction (iMLDR). Multivariate logistic regression analysis suggested that the genetic polymorphisms of CYP1A2 rs762551, UGT1A4 rs2011425, ABCB1 rs1045642, DRD2 rs1799732 and rs1799978, 5-HTR2A rs6311 were significantly associated with olanzapine response. Multifactor dimensionality reduction (MDR) analysis showed that there was a negative interaction between CYP1A2 rs762551, ABCB1 rs1045642, DRD2 rs1799978, 5-HTR2A rs6311 and the interaction model was the optimal model. Our findings could partially explain the different olanzapine outcome and provided evidence for clarifying the predictive indicators of olanzapine response in further., (Copyright © 2020 Elsevier B.V. All rights reserved.)