The pharmacokinetics/pharmacodynamics of ceftazidime/avibactam for central nervous system infections caused by carbapenem-resistant Gram-negatives: a prospective study.

OBJECTIVES: To describe the pharmacokinetics/pharmacodynamics (PK/PD) of ceftazidime/avibactam in critically ill patients with CNS infections. METHODS: A prospective study of critically ill patients with CNS infections who were treated with ceftazidime/avibactam and the steady-state concentration (Css) of ceftazidime/avibactam in serum and/or CSF was conducted between August 2020 and May 2023. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of ceftazidime/avibactam was evaluated. RESULTS: Seven patients were finally included. The ceftazidime/avibactam target attainment in plasma was optimal for three, quasi-optimal for one and suboptimal for three. In three patients with CSF drug concentrations measured, ceftazidime/avibactam target attainment in CSF was 100% (3/3), which was optimal. The AUCCSF/serum values were 0.59, 0.44 and 0.35 for ceftazidime and 0.57, 0.53 and 0.51 for avibactam. Of the seven patients, 100% (7/7) were treated effectively, 71.4% (5/7) achieved microbiological eradication, 85.7% (6/7) survived and 14.3% (1/7) did not survive. CONCLUSIONS: The limited clinical data suggest that ceftazidime/avibactam is effective in the treatment of CNS infections caused by MDR Gram-negative bacilli (MDR-GNB), can achieve the ideal drug concentration of CSF, and has good blood-brain barrier penetration.

Serum trough concentration threshold and risk factors of cefoperazone-induced coagulopathy in critically ill patients: A retrospective case-control study.

PURPOSE: To analyze the risk factors influencing the development of cefoperazone-induced coagulopathy in critically ill patients and determine the threshold of serum trough concentration. METHODS: A retrospective case-control study was conducted in the intensive care unit patients treated with cefoperazone, and it was approved by the Ethical Committee of Drum Tower Hospital affiliated with the Medical School of Nanjing University (NO.2023-158-01). Patients were divided into the normal group and coagulopathy group based on prothrombin time. The clinical characteristics of the two groups were compared using univariate analysis. The serum concentration threshold and influencing factors of cefoperazone-induced coagulopathy in critically ill patients were analyzed using the receiver operating characteristic curve and multivariate logistic regression analysis. RESULTS: A total of 113 patients were included, and cefoperazone-induced coagulopathy occurred in 39 patients, with an incidence of 34.5%. These patients experienced significant prothrombin time prolongation around day 6 (median) after cefoperazone application. The serum trough concentration threshold of cefoperazone-induced coagulopathy in critically ill patients was 87.765 mg/l. Multivariate logistic regression analysis revealed that the APACHE II score (p = 0.034), prophylactic use of vitamin K1 (p < 0.001), hepatic impairment (p = 0.014), and Cmin ≥ 87.765 mg/l (p = 0.005) were associated with cefoperazone-induced coagulopathy. CONCLUSION: Cefoperazone-induced coagulopathy usually occurs on the 6th day of cefoperazone use in critically ill patients. The risk will increase in patients with an APACHE II score > 25, hepatic impairment, and cefoperazone Cmin ≥ 87.765 mg/l. Vitamin K1 is effective in preventing this adverse reaction.

A descriptive pharmacokinetic/pharmacodynamic analysis of ceftazidime-avibactam in a case series of critically ill patients with augmented renal clearance.

To describe the pharmacokinetics/pharmacodynamics (PK/PD) of a 2 h infusion of ceftazidime-avibactam (CAZ-AVI) in critically ill patients with augmented renal clearance (ARC). A retrospective review of all critically ill patients with ARC who were treated with CAZ-AVI between August 2020 and May 2023 was conducted. Patients whose 12-h creatinine clearance prior to CAZ-AVI treatment and steady-state concentration (Css) of CAZ-AVI were both monitored were enrolled. The free fraction (fCss) of CAZ-AVI was calculated from Css. The joint PK/PD targets of CAZ-AVI were considered optimal when a Css/minimum inhibitory concentration (MIC) ratio for CAZ ≥4 (equivalent to 100% fT > 4 MIC) and a Css/CT ratio of AVI >1 (equivalent to 100% fT > CT 4.0 mg/L) were reached simultaneously, quasioptimal when only one of the two targets was reached, and suboptimal when neither target was reached. The relationship between PK/PD goal achievement, microbial eradication and the clinical efficacy of CAZ-AVI was evaluated. Four patients were included. Only one patient achieved optimal joint PK/PD targets, while the other three reached suboptimal targets. The patient with optimal PK/PD targets achieved microbiological eradication, while the other three patients did not, but all four patients achieved good clinical efficacy. Standard dosages may not enable most critically ill patients with ARC to reach the optimal joint PK/PD targets of CAZ-AVI. Optimal drug dose adjustment of CAZ-AVI in ARC patients requires dynamic drug concentration monitoring.

Ruthenium-Catalyzed Aminocarbonylation with Isocyanates Through Weak Coordinating Groups.

Introducing amide functional groups under mild conditions has growing importance owing to the prevalence of such moiety in biologically active molecules. Herein, we disclose a mild protocol for the directed ruthenium-catalyzed C-H aminocarbonylation with isocyanates as the amidating agents developed through high-throughput experimentation (HTE). The redox-neutral and base-free reaction is guided by weakly Lewis basic functional groups, including anilides, lactams and carbamates to access anthranilamide derivatives. The synthetic utility of this transformation is reflected by large-scale synthesis and late-stage functionalization.

Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification.

Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C-H activations, these arene functionalizations generally require directing groups to enable the C-H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C-H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C-H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C-H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C-H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.

A Large-Scale Survey on Perceived Risk, Risk Emotions and Humanistic Care Needs Among Nurses During the Covid-19 Pandemic.

Purpose: The purpose of this study is to understand the risk perception, risk emotions and humanistic care needs of nursing staff during the Novel Coronavirus 2019 (Covid-19) pandemic. Methods: A cross-sectional survey was conducted on the perceived risk, risk emotions and humanistic care needs of 35,068 nurses in 18 cities of the Henan Province, China.We collected a total of 35,188 questionnaires, of which 35,068 were effectively returned, with an effective return rate of 99.7%. The collected data were summarized and statistically analyzed using Excel 97 2003 and IBM SPSS software. Results: Nurses' risk perceptions and emotions vary during the covid-19 pandemic. In order to provide nurses with targeted psychological intervention to prevent nurses from suffering from unhealthy mental states.The results show that the total score of the nurses' risk perceptions of Covid-19 was 3.66 ± 0.39, the highest score of nurses' risk perception part is 5 points, and ≥3 points represent high risk and 88.3% of nurses believed that the Covid-19 risk was high. There were significant differences in the nurses' total perceived risk scores for Covid-19 based on gender, age, prior contact with patients with suspected or confirmed Covid-19 and previous participation in other similar public health emergencies (P < 0.050). Of the nurses included in the study, 44.8% had some level of fear relating to Covid-19 and 35.7% were able to remain calm and objective. There were significant differences in the total scores for risk emotions relating to Covid-19 based on gender, age and prior contact with patients with suspected or confirmed Covid-19 (P < 0.050). Of the nurses included in the study, 84.8% were willing to receive humanistic care and 77.6% of these expected to be provided with humanistic care by institutions in the healthcare sector. Conclusion: Nurses with different basic data have different risk cognition and risk emotions. Different psychological needs should be considered, and targeted multi-sectoral psychological intervention services should be provided to help prevent nurses from developing unhealthy psychological states.

Ruthenium-Catalyzed Remote Difunctionalization of Nonactivated Alkenes for Double meta-C(sp2 )-H/C-6(sp3 )-H Functionalization.

Twofold distal C-H functionalization was accomplished by difunctionalization of nonactivated alkenes to provide rapid access to multifunctionalized molecules. The multicomponent ruthenium-catalyzed remote 1,n-difunctionalization (n=6,7) of nonactivated alkenes with fluoroalkyl halides and heteroarenes in a modular manner is reported. The meta-C(sp2 )-H/C-6(sp3 )-H distal functionalization featured mild conditions, unique selectivity, and broad substrate scope with a domino process for twofold remote C(sp2 )-H/C(sp3 )-H activation of the sequential formation of three different carbon-centered radicals. A plausible mechanism was proposed based on detailed experimental and computational studies.

Enantioselective electrochemical cobalt-catalyzed aryl C-H activation reactions.

Enantioselective redox transformations typically rely on costly transition metals as catalysts and often stoichiometric amounts of chemical redox agents as well. Electrocatalysis represents a more sustainable alternative, in particular through the use of the hydrogen evolution reaction (HER) in place of a chemical oxidant. In this work, we describe strategies for HER-coupled enantioselective aryl carbon-hydrogen bond (C-H) activation reactions using cobalt in place of a precious metal catalyst for the asymmetric oxidation. Thus, highly enantioselective carbon-hydrogen and nitrogen-hydrogen (C-H and N-H) annulations of carboxylic amides were achieved, which gave access to point and axially chiral compounds. Furthermore, the cobalt-mediated electrocatalysis enabled the preparation of various phosphorus (P)-stereogenic compounds by selective desymmetrization through dehydrogenative C-H activation reactions.

Electrochemical Rearrangement for Remote Functionalizations of Unactivated Alkenes.

An electrochemical strategy for the dual functionalizations of unactivated alkenes through an intramolecular migration process was realized in the absence of sacrificial chemical oxidants and noble-metal catalysts under mild reaction conditions. The electrochemistry enabled a (hetero)aryl migration while providing access to alkenyl/alkynyl-migration products. Thus, electricity was employed for the formation of functionalized fluoroalkyl radicals through activation of C-H/C-Br bonds from fluorinated esters. Thereby, we obtained a variety of di and mono-fluorinated alkyl products with good functional group tolerance as well as chemo, and regioselectivities. Likewise, defluorinative allylation of α-carbonyl alkyl bromides proved viable. The reaction mechanism was established by experiments and computations.

Remote C-H Glycosylation by Ruthenium(II) Catalysis: Modular Assembly of meta-C-Aryl Glycosides.

The prevalence of C-aryl glycosides in biologically active natural products and approved drugs has long motivated the development of efficient strategies for their selective synthesis. Cross-couplings have been frequently used, but largely relied on palladium catalyst with prefunctionalized substrates, while ruthenium-catalyzed C-aryl glycoside preparation has thus far proven elusive. Herein, we disclose a versatile ruthenium(II)-catalyzed meta-C-H glycosylation to access meta-C-aryl glycosides from readily available glycosyl halide donors. The robustness of the ruthenium catalysis was reflected by mild reaction conditions, outstanding levels of anomeric selectivity and exclusive meta-site-selectivity.

Analysis and Review of the Countermeasures Required for Medical Staff's Cognition of Relevant Laws and Regulations in the Coronavirus 2019 Context.

Background: Novel coronavirus 2019 (COVID-19) infections are highly contagious and have spread worldwide. Healthcare workers must understand the laws and regulations related to major public health emergencies to work effectively within this environment. Through investigation and analysis, a review was conducted to help gain a better understanding of a Level-1 response to public health events and the relevant laws and regulations applicable to medical staff. Based on the results, this study formulated measures for working in the current COVID-19 healthcare context. Methods: A total of 42,490 medical personnel in 18 cities in Henan Province (China) were reviewed and analysed using the convenience sampling method. A questionnaire was employed to address two areas of cognitive status quo (25 items), ie, "general information" and "major public events and rules of the law". Results: More than 90% of medical staff had a good understanding related to knowledge about prevention and control in the pandemic context, as well as their due diligence and legal responsibility for controlling the pandemic and preventing others from being infected. However, 3.47-32.61% of medical staff still had a minimal understanding of a Level-1 response to public health events and its relevant laws and regulations. Conclusion: The response to public health events required strengthening at all levels through promotion and education, by implementing an optimised treatment system and establishing an improved legal mechanism for the treatment of major conditions, such as hierarchical, stratified and triaged infectious diseases.

A Novel DNA Repair Gene Signature for Immune Checkpoint Inhibitor-Based Therapy in Gastric Cancer.

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responding to immunotherapy. The relationships between tumor DNA damage response, patient immune system and immunotherapy have recently attracted attention. Accumulating evidence suggests that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsive to immunotherapies, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of the DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of patients with gastric adenocarcinoma, using publicly available datasets. The results demonstrated that DRGS high score patients showed significantly better therapeutic outcomes for ICB compared to DRGS low score patients (p < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocyte infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival, as compared to the low-score patients. Results obtained from HPA and IHC supported significant dysregulation of the genes in DRGS in gastric cancer tissues, and a positive correlation in protein expression between DRGS and PD-L1. Therefore, the DRGS scoring system may have implications in tailoring immunotherapy in gastric cancers. A preprint has previously been published (Yuan et al., 2021).

Foliar application of SiO2 and ZnO nanoparticles affected polycyclic aromatic hydrocarbons uptake of Amaranth (Amaranthus tricolor L.): A metabolomics and typical statistical analysis.

Nano-enabled foliar-application could be an ideal strategy for advancing agricultural productivity. However, it remains largely unknown whether they inhibit or promote the uptake of pollutants. Here, we systematically examined how foliar applying SiO2 nanoparticles (nSiO2) and ZnO nanoparticles (nZnO) (20 nm, 100 mg·L-1), influence polycyclic aromatic hydrocarbons (PAHs) uptake in 4-week-old amaranth (Amaranthus tricolor L.). Results showed that foliar application of nSiO2 or nZnO enhanced amaranth biomass by 20.2-26.4% but decreased PAHs bioaccumulation in leaves by 20.4-54.9% after 7-d incubation. Changes regarding amino acid-related pathways (alanine/aspartate/glutamate metabolism and arginine biosynthesis) and energy maintenance pathways (TCA cycle) were observed in amaranth leaves after foliar application of nSiO2 and nZnO. Specific PLS-DA analyses with total PAHs uptake as the biological endpoint showed that the contents of PAHs positively correlated with valine (R2 = 0.799) and tyrosine (R2 = 0.789), but negatively correlated with D-tagatose (R2 = 0.805) and L-gulonolactone (R2 = 0.877), indicating greater oxidant stress under higher PAHs level. We propose that mechanisms of declined uptake of PAHs involve the biomass-dependent dilute effect and activation of biological response against PAHs accumulation. These findings provide a prospective vision on how nano-enabled foliar-application alleviates PAH-enriched environmental burden while producing higher-yield agricultural products, especially for low toxic and biocompatible nSiO2.

Ruthenaelectro-catalyzed C-H acyloxylation for late-stage tyrosine and oligopeptide diversification.

Ruthenaelectro(ii/iv)-catalyzed intermolecular C-H acyloxylations of phenols have been developed by guidance of experimental, CV and computational insights. The use of electricity bypassed the need for stoichiometric chemical oxidants. The sustainable electrocatalysis strategy was characterized by ample scope, and its unique robustness enabled the late-stage C-H diversification of tyrosine-derived peptides.

Rhodaelectro-Catalyzed peri-Selective Direct Alkenylations with Weak O-Coordination Enabled by the Hydrogen Evolution Reaction (HER).

Direct C-H functionalizations by electrocatalysis is dominated by strongly coordinating N(sp2 )-directing groups. In sharp contrast, direct electrocatalytic transformations of weakly-coordinating phenols remain underdeveloped. Herein, electrooxidative peri C-H alkenylations of challenging 1-naphthols were achieved by versatile rhodium(III) catalysis via user-friendly constant current electrolysis. The rhodaelectrocatalysis employed readily-available alkenes and a protic reaction medium and features ample scope, good functional group tolerance and high site- and stereoselectivity. The strategy was successfully applied to high-value, nitrogen-containing heterocycles, thereby providing direct access to uncommon heterocyclic motifs based on the dihydropyranoquinoline skeleton.

Electrooxidative o-carborane chalcogenations without directing groups: cage activation by copper catalysis at room temperature.

Copper-catalyzed electrochemical direct chalcogenations of o-carboranes was established at room temperature. Thereby, a series of cage C-sulfenylated and C-selenylated o-carboranes anchored with valuable functional groups was accessed with high levels of position- and chemo-selectivity control. The cupraelectrocatalysis provided efficient means to activate otherwise inert cage C-H bonds for the late-stage diversification of o-carboranes.

Enantioselective palladaelectro-catalyzed C-H olefinations and allylations for N-C axial chirality.

Enantioselective palladaelectro-catalyzed C-H alkenylations and allylations were achieved with easily-accessible amino acids as transient directing groups. This strategy provided access to highly enantiomerically-enriched N-C axially chiral scaffolds under exceedingly mild conditions. The synthetic utility of our strategy was demonstrated by a variety of alkenes, while the versatility of our approach was reflected by atroposelective C-H allylations. Computational studies provided insights into a facile C-H activation by a seven-membered palladacycle.

FHOD1 is upregulated in gastric cancer and promotes the proliferation and invasion of gastric cancer cells.

Gastric cancer (GC) is one of the main causes of cancer-associated morbidity and mortality worldwide. The present study aimed to investigate the role of the gene encoding formin homology 2 domain containing 1 (FHOD1) protein in GC development. Data from The Cancer Genome Atlas were firstly analyzed, and immunohistochemistry was conducted on GC tissues. The results demonstrated that FHOD1 expression in GC tissues was significantly increased compared with adjacent non-tumor tissues. Furthermore, the expression level of FHOD1 was negatively associated with the overall survival of patients with GC. For the functional studies, lentivirus-mediated short hairpin RNA against FHOD1 and FHOD1-overexpression vectors were constructed to knockdown and overexpress the expression level of FHOD1 in human GC cell lines, respectively. The results indicated that FHOD1 knockdown inhibited the proliferation, colony formation and migratory and invasive abilities of GC cells. Conversely, overexpression of FHOD1 in GC cells promoted soft-agar colony formation and migratory and invasive abilities. In addition, it was demonstrated that genes of which expression levels were correlated with FHOD1 were enriched in the Gene Ontology term of 'extracellular matrix (ECM) structural constituent', suggesting that FHOD1 may serve an important role in the regulation of ECM. In conclusion, the present study demonstrated that FHOD1 may exert an oncogenic role in cultured GC cells and be inversely associated with the overall survival of patients with GC.

Naloxone Protects against Lipopolysaccharide-Induced Neuroinflammation and Microglial Activation via Inhibiting ATP-Sensitive Potassium Channel.

AIM: The aim of this study was to evaluate the anti-inflammatory effects and underlying mechanism of naloxone on lipopolysaccharide- (LPS-) induced neuronal inflammation and microglial activation. METHODS: LPS-treated microglial BV-2 cells and mice were used to investigate the anti-inflammatory effects of naloxone. RESULTS: The results showed that naloxone dose-dependently promoted cell proliferation in LPS-induced BV-2 cells, downregulated the expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and proinflammatory enzymes iNOS and COX-2 as well as the expression of free radical molecule NO, and reduced the expression of Iba-1-positive microglia in LPS-stimulated BV-2 cells and mouse brain. Moreover, naloxone improved LPS-induced behavior degeneration in mice. Mechanically, naloxone inhibited LPS-induced activation in the ATP-sensitive potassium (KATP) channel. However, the presence of glibenclamide (Glib), an antagonist of KATP channel, ameliorated the suppressive effects of naloxone on inflammation and microglial activation. CONCLUSION: Naloxone prevented LPS-induced neuroinflammation and microglial activation partially through the KATP channel. These findings might highlight the potential of naloxone in neuroinflammation therapy.