Clinical characteristics and prognosis of non-APAP drug-induced acute liver failure: a large multicenter cohort study.

BACKGROUND: There is growing recognition of natural history, complications, and outcomes of patients who develop non-acetaminophen (APAP) drug-induced acute liver failure (ALF). To clarify high-risk factors and develop a nomogram model to predict transplant-free survival (TFS) in patients with non-APAP drug-induced ALF. METHODS: Patients with non-APAP drug-induced ALF from 5 participating centers were retrospectively analyzed. The primary endpoint was 21-day TFS. Total sample size was 482 patients. RESULTS: Regarding causative agents, the most common implicated drugs were herbal and dietary supplements (HDS) (57.0%). The hepatocellular type (R ≥ 5) was the main liver injury pattern (69.0%). International normalized ratio, hepatic encephalopathy grades, the use of vasopressor, N-acetylcysteine, or artificial liver support system were associated with TFS and incorporated to construct a nomogram model (drug-induced acute liver failure-5, DIALF-5). The AUROC of DIALF-5 for 7-day, 21-day, 60-day, and 90-day TFS in the internal cohort were 0.886, 0.915, 0.920, and 0.912, respectively. Moreover, the AUROC of DIALF-5 for 21-day TFS had the highest AUROC, which was significantly higher than 0.725 of MELD and 0.519 of KCC (p < 0.05), numerically higher than 0.905 of ALFSG-PI but without statistical difference (p > 0.05). These results were successfully validated in the external cohort (147 patients). CONCLUSIONS: Based on easily identifiable clinical data, the novel DIALF-5 model was developed to predict transplant-free survival in non-APAP drug-induced ALF, which was superior to KCC, MELD and had a similar prediction performance to ALFSG-PI but is more convenient, which can directly calculate TFS at multiple time points.

The Value of Sports and Functional Exercise on Preventing Falls in Elderly Patients with Cognitive Impairment: A Systematic Review and Meta-Analysis.

Objective: To explore the value of sports and functional exercises in preventing falls in elderly patients with cognitive impairment. Methods: PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, VIP, Wanfang Database, and China Biomedical Literature Database (CBM), from inception to January 2023, were used to search the randomized controlled trials (RCTs) of sports and functional exercises in elderly patients with cognitive impairment. Two independent researchers extracted the data and evaluated the quality of the included literature. RevMan5.4 software was adopted for data analysis. Results: The results indicated that exercise combined with functional exercise could noticeably enhance the fall effect score and shorten the Timed Up and Go Test (TUGT) time of elderly patients with cognitive impairment compared to simple drug treatment (P < .05). Our results showed that the exercise combined with functional exercise can noticeably prolong the standing time of elderly patients with cognitive impairment upon monocular eye closure. Our results also showed that exercise combined with functional exercise can noticeably improve the fear of falls in elderly patients with cognitive impairment. Conclusion: Sports and functional exercise intervention can promote the balance ability and fall self-efficacy of elderly patients with cognitive impairment and have a positive effect on enhancing patients' fear of falls. The findings need to be further verified and methodological quality needs to be improved. In addition, longer intervention times are required to verify the findings.

Phosphorus limitation induced by nitrogen addition changed soil microbial community structure in a subtropical Pinus taiwanensis forest.

Soil microorganisms play an important role in the biogeochemical cycles of terrestrial ecosystems. How-ever, it is still unclear how the amount and duration of nitrogen (N) addition affect soil microbial community structure and whether there is a correlation between the changes in microbial community structure and their nutrient limi-tation status. In this study, we conducted an N addition experiment in a subtropical Pinus taiwanensis forest to simulate N deposition with three treatments: control (CK, 0 kg N·hm-2·a-1), low N (LN, 40 kg N·hm-2·a-1), and high N (HN, 80 kg N·hm-2·a-1). Basic soil physicochemical properties, phospholipid fatty acids content, and carbon (C), N and phosphorus (P) acquisition enzyme activities were measured after one and three years of N addition. The relative nutrient limitation status of soil microorganisms was analyzed using ecological enzyme stoichiometry. The results showed that one-year N addition did not affect soil microbial community structure. Three-year LN treatment significantly increased the contents of Gram-positive bacteria (G+), Gram-negative bacteria (G-), actinomycetes (ACT), and total phospholipid fatty acids (TPLFA), whereas three-year HN treatment did not significantly affect soil microbial community, indicating that bacteria and ACT might be more sensitive to N addition. Nitrogen addition exacerbated soil C and P limitation. Phosphorus limitation was the optimal explanatory factor for the changes in soil microbial community structure. It suggested that P limitation induced by N addition might be more beneficial for the growth of certain oligotrophic bacteria (e.g. G+) and the microorganisms participating in the P cycling (e.g. ACT), with consequences on soil microbial community structure of subtropical Pinus taiwanensis forest.

[Suitable harvest period of Aurantii Fructus based on UPLC-Q-TOF-MS metabolomics].

The types of secondary metabolites of Aurantii Fructus samples from GAP base in different harvest periods were detected by UPLC-Q-TOF-MS metabolomics, and the differential metabolites were screened out by multivariate statistical analysis. The variation of the content of differential metabolites with different harvest periods was analyzed, and the correlation analysis was carried out on the differential metabolites to determine the suitable harvest period for different components. Sixteen differential metabolites were obtained. With the delay of harvest time, the content of flavonoid glycosides, including naringin, neohesperidin, poncirin, narirutin, and hesperidin, gradually decreased. It is suggested that the suitable harvest period for raw materials of Aurantii Fructus with flavonoids as active components is from July 18 to July 25(within one week before and after the Great heat). The content of nobiletin, tangeretin, natsudaidain, 7-hydroxyl-4',3,5,6,8-pentamethoxyflavone, sinensetin, isosinensetin, 5,6,7,4'-tetramethoxyflavone, and isomeranzin decreased first, then increased, and finally decreased. It is suggested that the suitable harvest time for raw materials of Aurantii Fructus with these components as the active components is July 18. The content changes of meranzin, limonin, and 3,5,6,7,8,3',4'-heptamethoxyflavone have their characteristics. According to the conditions of actual production, it is suggested that the suitable harvest time is June 27, July 11, and July 25, respectively. The results showed that there were differences in the content of chemical components of Aurantii Fructus in different harvest periods, and the suitable harvest period should be determined according to the differences in chemical component content. This study is expected to provide a scientific basis for the purchase of raw materials of Aurantii Fructus for Chinese patent medicines with different effects.

[Soil enzyme stoichiometry revealed the changes of soil microbial carbon and phosphorus limitation along an elevational gradient in a Pinus taiwanensis forest of Wuyi Mountains, Southeast China]. / åœŸå£¤é ¶è®¡é‡æ­ç¤ºäº†æ­¦å¤·å±±é»„å±±æ¾æž—åœŸå£¤å¾®ç”Ÿç‰©æ²¿æµ·æ‹”æ¢¯åº¦çš„ç¢³ç£·é™åˆ¶å˜åŒ–.

Understanding changes in soil enzyme activities and ecoenzymatic stoichiometry is important for assessing soil nutrient availability and microbial nutrient limitation in mountain ecosystems. However, the variations of soil microbial nutrient limitation across elevational gradients and its driving factors in subtropical mountain forests are still unclear. In this study, we measured soil properties, microbial biomass, and enzyme activities related to carbon (C), nitrogen (N), and phosphorus (P) cycling in Pinus taiwanensis forests at different altitudes of Wuyi Mountains. By analyzing the enzyme stoichiometric ratio, vector length (VL), and vector angle (VA), the relative energy and nutrient limitation of soil microorganisms and its key regulatory factors were explored. The results showed that ß-glucosaminidase (BG) activities increased along the elevational gradient, while the activities of ß-N-acetyl glucosaminidase (NAG), leucine aminopeptidase (LAP), acid phosphatase (AcP) and (NAG+LAP)/microbial biomass carbon (MBC) and AcP/MBC showed the opposite trend. Enzyme C/N, enzyme C/P, enzyme N/P, and VL were enhanced with increasing elevation, while VA decreased, indicating a higher degree of microbial P limitation at low elevation and higher C limitation at high elevation. In addition, our results suggested that dissolved organic carbon and microbial biomass phosphorus are critical factors affecting the relative energy and nutrient limitation of soil microorganisms at different elevations. The results would provide a theoretical basis for the responses of soil carbon, nitrogen, and phosphorus availability as well as the relative limitation of microbial energy and nutrition to elevational gradients, and improve our understanding of soil biogeochemical cycle process in subtropical montane forest ecosystems.

Integrated transcriptomic and metabolomic analyses revealed the molecular mechanism of terpenoid formation for salicylic acid resistance in Pulsatilla chinensis callus.

As a kind of traditional Chinese medicine, Pulsatilla chinensis (Bunge) Regel is well known for its anti-inflammation and anti-cancer activities, which are attributed to its active components including total saponins and monomers. To clarify the synthesis and metabolism mechanisms of class components in callus terpenes of P. chinensis, a certain concentration of salicylic acid (SA) hormone elicitor was added to the callus before being analysed by transcriptomic and metabolomic techniques. Results showed that the content of Pulsatilla saponin B4 in the callus suspension culture was significantly increased up to 1.99% with the addition of SA. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes were mainly enriched in 122 metabolic pathways, such as terpenoid metabolism-related pathways: terpenoid skeleton synthesis pathway, monoterpenoid biosynthesis pathways, diterpenoid biosynthesis pathways, and ubiquinone and other terpenoid-quinone biosynthesis pathways. A total of 31 differentially accumulated metabolites were obtained from four differential groups. Amongst 21 kinds of known chemical components in P. chinensis, deoxyloganic acid was the only monoterpenoid; the others are triterpenoids. In summary, this study found that SA elicitors can affect the metabolic changes of terpenoids in P. chinensis callus, which provided a basis for analysing the genetic regulation of terpenoid components of leucons.

[Regulation Effect of Myeloid Leukemia No.1 Chinese Herb Medicine Prescription Combined with Chemotherapy on Th17 Cells in Bone Marrow of Patients with Acute Myeloid Leukemia].

OBJECTIVE: To explore the regulation effect of myeloid leukemia No.1 Chinese herb medicine prescription combined with chemotherapy on Th17 cells in bone marrow fluid of AML patients, so as to provide guidance for improving AML treatment effect and patients' long-term survival. METHODS: Seventy patients with AML who were hospitalized in Department of Hematology, Wuwei People's Hospital from April 2017 to August 2019 were selected and enrolled in AML group, 25 healthy volunteers were selected and enrolled in control group; then according to therapeutic regimen, AML patients were divided into 2 groups: combined therapy group (myeloid leukemia NO.1 Chinese herb medicine prescription combined with chemotherapy) and non-combined therapy group (chemotherapy alone). Flow cytometry was used to detect the ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells in bone marrow fluid, and ELISA was used to detect the vascular endothelial growth factor (VEGF) and interleukin-17 (IL-17) concentrations in bone marrow fluid. Statistical analysis was performed on the data with SPSS 22.0. RESULTS: The ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells, VEGF and IL-17 concentration in newly diagnosed and relapsed AML patients were significantly higher than those in the normal control group (P<0.001); while those in CR and DFS stage patients were significantly lower than those in newly diagnosed and relapsed patients (P<0.001), and the ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells, VEGF and IL-17 concentration in DFS patients with AML were not significantly different from those in the control group (P>0.05). The ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells, VEGF and IL-17 concentration in CR stage of AML patients treated with chemotherapy alone were significantly higher than those in the control group (P<0.05), but there was no difference between combined therapy group and the control group; the ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells, the concentration of VEGF and IL-17 in CR stage of AML patients treated with chemotherapy alone were higher than those of patients treated with combined therapy regimen (P<0.05). AML patients treated with combined therapy regimen had a significantly higher complete remission rate compared with patients received chemotherapy alone (P<0.05), but the recurrence rate was significantly lower (P<0.05). CONCLUSION: Th17 cells expression in bone marrow of newly diagnoses and relapsed AML patients significantly increase, and decrease significantly after treatment. Myeloid leukemia No.1 Chinese herb prescription combined with chemotherapy can significantly increase the CR rate and reduce the RL rate for AML.

[Nutrient resorption patterns of Phragmites australis leaves and its response to soil moisture in Yangguan wetland, Dunhuang, Northwest China]. / æ•¦ç Œé˜³å ³æ¹¿åœ°èŠ¦è‹‡å¶ç‰‡å »åˆ†é‡å¸æ”¶æ¨¡å¼åŠå ¶å¯¹åœŸå£¤æ°´åˆ†çš„å“åº”.

Nutrient resorption of leaves is an important nutrient conservation mechanism for plants in nutrient-poor habitats. Understanding the responses of leaf nutrient resorption to soil moisture is helpful to reveal the adaptation strategies of plants to the environment. In this study, the dominant plant in the Yangguang wetland of Dunhuang Phragmites australis was used as research material, to explore nitrogen and phosphorus resorption patterns of P. australis leaves and their responses to soil moisture under different moisture regimes, i.e. high (33.5%±1.9%), medium (26.4%±1.3%) and low (11.3%±1.5%). The results showed that: 1) With the decreases of soil moisture, soil N concentration decreased significantly, and N concentrations in mature and senescent leaves increased significantly, the P concentration in mature and senescent leaves as well as in soil did not change. 2) N resorption efficiency of leaves under high moisture condition was 76.1%, which was significantly higher than the medium (65.5%) and low (62.5%) moisture conditions. P resorption efficiency varied among different moisture conditions. 3) The N concentrations of mature and senescent leaves were negatively correlated with N resorption efficiency. There was no significant correlation between P concentration and P resorption efficiency in mature leaves, but the P concentration of senescent leaves was negatively correlated with P resorption efficiency of leaves. As a result, water scarcity is not conducive to leaf N resorption.

Probiotics for vulvovaginal candidiasis in non-pregnant women.

BACKGROUND: Vulvovaginal candidiasis (VVC) is estimated to be the second most common form of infection after bacterial vaginosis. The ability of probiotics in maintaining and recovering the normal vaginal microbiota, and their potential ability to resist Candidas give rise to the concept of using probiotics for the treatment of VVC. OBJECTIVES: To assess the effectiveness and safety of probiotics for the treatment of vulvovaginal candidiasis in non-pregnant women. SEARCH METHODS: We searched the following databases to October 2017: Sexually Transmitted Infections Cochrane Review Group's Specialized Register, CENTRAL, MEDLINE, Embase and eight other databases. We searched in following international resources: World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, Web of Science and OpenGrey. We checked specialty journals, reference lists of published articles and conference proceedings. We collected information from pharmaceutical companies and experts in the field. SELECTION CRITERIA: Randomized controlled trials (RCT) using probiotics, alone or as adjuvants to conventional antifungal drugs, to treat VVC in non-pregnant women. Trials recruiting women with recurrent VVC, coinfection with other vulvovaginal infections, diabetes mellitus, immunosuppressive disorders or taking immunosuppressant medication were ineligible for inclusion. Probiotics were included if they were made from single or multiple species and in any preparation type/dosage/route of administration. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and quality and extracted data. We resolved any disagreements through consensus. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Ten RCTs (1656 participants) met our inclusion criteria, and pharmaceutical industry funded none of these trials. All trials used probiotics as adjuvant therapy to antifungal drugs. Probiotics increased the rate of short-term clinical cure (risk ratio (RR) 1.14, 95% confidence interval (CI) 1.05 to 1.24, 695 participants, 5 studies, low quality evidence) and mycological cure (RR 1.06, 95% CI 1.02 to 1.10, 969 participants, 7 studies, low quality evidence) and decreased relapse rate at one month (RR 0.34, 95% CI 0.17 to 0.68, 388 participants, 3 studies, very low quality evidence). However, this effect did not translate into a higher frequency of long-term clinical cure (one month after treatment: RR 1.07, 95% CI 0.86 to 1.33, 172 participants, 1 study, very low quality evidence; three months after treatment: RR 1.30, 95% CI 1.00 to 1.70, 172 participants, one study, very low quality evidence) or mycological cure (one month after treatment: RR 1.26, 95% CI 0.93 to 1.71, 627 participants, 3 studies, very low quality evidence; three months after treatment: RR 1.16, 95% CI 1.00 to 1.35, 172 participants, one study, very low quality evidence). Probiotics use did not increase the frequency of serious (RR 0.80, 95% CI 0.22 to 2.94; 440 participants, 2 studies, low quality evidence). We found no eligible RCTs for outcomes as time to first relapse, need for additional treatment at the end of therapy, patient satisfaction and cost effectiveness. AUTHORS' CONCLUSIONS: Low and very low quality evidence shows that, compared with conventional treatment, the use of probiotics as an adjuvant therapy could increases the rate of short-term clinical and mycological cure and decrease the relapse rate at one month but this did not translate into a higher frequency of long-term clinical or mycological cure. Probiotics use does not seem to increase the frequency of serious or non-serious adverse events. There is a need for well-designed RCTs with standardized methodologies, longer follow-up and larger sample size.

Improved artificial pathway for biosynthesis of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) with high C6-monomer composition from fructose in Ralstonia eutropha.

Poly((R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate) [P(3HB-co-3HHx)], a flexible and practical kind of polyhydroxyalkanoates, is generally produced from plant oils and fatty acids by several wild and recombinant bacteria. This study established an improved artificial pathway for the biosynthesis of P(3HB-co-3HHx) with high 3HHx composition from structurally unrelated fructose in Ralstonia eutropha. Depression of (R)-specific reduction of acetoacetyl-CoA by the deletion of phaB1 was an effective modification for formation of the C6-monomer unit from fructose driven by crotonyl-CoA carboxylase/reductase (Ccr). Co-overexpression of phaJ4a, which encodes medium-chain-length (R)-enoyl-CoA hydratase, with ccr promoted the incorporation of both 3HB and 3HHx units. Further introduction of emdMm, a synthetic gene encoding ethylmalonyl-CoA decarboxylase derived from mouse, was remarkably effective for P(3HB-co-3HHx) biosynthesis, probably by converting ethylmalonyl-CoA generated by the reductive carboxylase activity of Ccr back into butyryl-CoA. A high cellular content of P(3HB-co-3HHx) composed of 22mol% 3HHx could be produced from fructose by the engineered strain of R. eutropha with ΔphaB1 genotype expressing ccr, phaJ4a, and emd.

Pharmacophore modeling and hybrid virtual screening for the discovery of novel IκB kinase 2 (IKK2) inhibitors.

IKK2 (IκB kinase 2) inhibitors have been identified as potential drug candidates in the treatment of various immune/inflammatory disorders as well as cancer. So far more than one hundred small molecule inhibitors against IKK2 have been reported publicly. In this investigation, pharmacophore modeling was carried out to clarify the essential structure-activity relationship for the known IKK2 inhibitors. One of the established pharmacophore hypotheses, namely Hypo8, which has the best prediction ability to an external test data set, was suggested as a template for virtual screening. Evaluation of the performances of Hypo8 and a hybrid method (Hypo81docking) in virtual screening indicated that the use of the hybrid virtual screening considerably increased the hit rate and enrichment factor. The hybrid method was therefore adopted for screening several commercially available chemical databases, including Specs, NCI, Maybridge and Chinese Nature Product Database (CNPD), for novel potent IKK2 inhibitors. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. Finally some of the final hit compounds were selected and suggested for further experimental investigations.

Discovery of novel Pim-1 kinase inhibitors by a hierarchical multistage virtual screening approach based on SVM model, pharmacophore, and molecular docking.

In this investigation, we describe the discovery of novel potent Pim-1 inhibitors by employing a proposed hierarchical multistage virtual screening (VS) approach, which is based on support vector machine-based (SVM-based VS or SB-VS), pharmacophore-based VS (PB-VS), and docking-based VS (DB-VS) methods. In this approach, the three VS methods are applied in an increasing order of complexity so that the first filter (SB-VS) is fast and simple, while successive ones (PB-VS and DB-VS) are more time-consuming but are applied only to a small subset of the entire database. Evaluation of this approach indicates that it can be used to screen a large chemical library rapidly with a high hit rate and a high enrichment factor. This approach was then applied to screen several large chemical libraries, including PubChem, Specs, and Enamine as well as an in-house database. From the final hits, 47 compounds were selected for further in vitro Pim-1 inhibitory assay, and 15 compounds show nanomolar level or low micromolar inhibition potency against Pim-1. In particular, four of them were found to have new scaffolds which have potential for the chemical development of Pim-1 inhibitors.

Integrin αvß3-targeted gold nanoshells augment tumor vasculature-specific imaging and therapy.

PURPOSE: Gold nanoshells (NSs) have already shown great promise as photothermal actuators for cancer therapy. Integrin αvß3 is a marker that is specifically and preferentially overexpressed on multiple tumor types and on angiogenic tumor neovasculature. Active targeting of NSs to integrin αvß3 offers the potential to increase accumulation preferentially in tumors and thereby enhance therapy efficacy. METHODS: Enzyme-linked immunosorbent assay (ELISA) and cell binding assay were used to study the in vitro binding affinities of the targeted nanoconjugate NS-RGDfK. In vivo biodistribution and tumor specificity were analyzed using 64Cu-radiolabeled untargeted and targeted NSs in live nude rats bearing head and neck squamous cell carcinoma (HNSCC) xenografts. The potential thermal therapy applications of NS-RGDfK were evaluated by subablative thermal therapy of tumor xenografts using untargeted and targeted NSs. RESULTS: ELISA and cell binding assay confirmed the binding affinity of NS-RGDfK to integrin αvß3. Positron emission tomography/computed tomography imaging suggested that tumor targeting is improved by conjugation of NSs to cyclo(RGDfK) and peaks at ~20 hours postinjection. In the subablative thermal therapy study, greater biological effectiveness of targeted NSs was implied by the greater degree of tumor necrosis. CONCLUSION: The results presented in this paper set the stage for the advancement of integrin αvß3-targeted NSs as therapeutic nanoconstructs for effective cancer therapy.

[The feasibility of application of reverse docking method to the selectivity studies of protein kinase inhibitors].

This investigation is to explore the feasibility of applying reverse docking method to the selectivity studies of protein kinase inhibitors. Firstly, a database that consists of 422 protein kinase structures was established through collecting the reported crystal structures or homology modeling. Then a reverse docking based method of protein kinase target screening was established, followed by the optimization of related parameters and scoring functions. Finally, seven typical selective kinase inhibitors were used to test the established method. The results show that the selective targets of these inhibitors have relatively high scoring function values (ranking in the first 35% of the tested kinase targets according to the scoring function values). This implies that the reverse docking method can be applied to the virtual screening of kinase targets and further to the selectivity studies of protein kinase inhibitors.

Hepatitis B virus inhibiting constituents from Herpetospermum caudigerum.

From the ethanol extract of the seeds of Herpetospermum caudigerum wall, one new lignan compound 1, was isolated and characterized along with three known compounds 2, 3 and 4. The structure elucidation of the isolated new compound was performed on the basis of spectroscopic and chemical evidence. The structures of known compounds were determined by comparison of spectral data and physical data with those previously reported. The activity inhibiting hepatitis b virus was evaluated. Preliminary studies showed that compound 1 and 2 displayed promising inhibitory potential against hepatitis b virus.