[Traditional Chinese medicine and active ingredients regulate M1/M2 macrophage polarization balance to treat chronic obstructive pulmonary disease: a review].

Chronic obstructive pulmonary disease(COPD) is a progressive lung dysfunction(disease) caused by long-term inhalation of toxic particles, especially smoking. The continued exposure to harmful substances triggers an abnormal inflammatory response, which causes permanent damage to the respiratory system, ultimately leading to irreversible pathological changes. Lung macrophages(LMs) are key innate immune effectors involved in the recognition, phagocytosis, and clearance of pathogens, as well as in the processing of inhaled hazardous particulate matter(e. g., cigarette smoke and particulate matter). LMs are polarized toward the M1 or M2 phenotype in response to the activation of inflammatory mediators to exert pro-/anti-inflammatory effects, respectively, thus being involved in the pulmonary parenchymal damage(emphysema) and repair(airway remodeling) throughout the process of COPD.In addition, they are responsible for phagocytosis and clearance of apoptotic or necrotic tissue cells, which helps to maintain the stability of the microenvironment in the lungs of COPD patients. Modern studies have revealed that macrophage polarization plays a pivotal role in the pathogenesis and development of COPD and is considered a potential target for treating COPD because of its ability to reduce airway inflammation, inhibit tissue remodeling, and combat oxidative stress. In recent years, traditional Chinese medicine(TCM) and its active ingredients have become a hot area in the treatment of COPD by targeting the balance of M1/M2 macrophage polarization. TCM and its active ingredients can intervene in the inflammatory response to promote the repair of the lung tissue in the patients with COPD. This paper reviews the research achievements of TCM and its active ingredients in this field in recent years,aiming to provide a scientific basis and strong support for the precise diagnosis and treatment of COPD.

A DNA machine-based magnetic resonance imaging nanoprobe for in vivo microRNA detection.

In situ monitoring microRNA (miRNA) expression in vivo holds immense potential for directly visualizing the occurrence and progression of tumors. However, the significant barrier to developing a probe that can overcome the low abundance of miRNAs while providing an output signal with unlimited tissue penetration depth remains formidable. In this study, we developed a DNA machine-based magnetic resonance imaging nanoprobe (MRINP) for amplified detection of miR-21 in vivo. The MRINP was constructed with superparamagnetic Fe3O4 nanoparticles (NPs), paramagnetic Gd-DOTA complexes, and miR-21-activated DNA machines; the DNA machine was composed of hairpin DNAzyme (HD) strands serving as the DNAzyme walker and hairpin substrate (HS) strands serving as the track. Once uptake into tumor cells, the intracellular miR-21 specifically recognized and hybridized with the HD strand, restoring the activity of DNAzyme. Subsequently, the DNAzyme walker autonomously traveled on the surface of MRINP, and each step movement of the DNAzyme walker resulted in the cleavage of its substrate strands and the ensued release of the Gd-DOTA complex-labeled oligonucleotides, turning on the T1 signal of Gd-DOTA complexes for in situ imaging of miR-21 in tumor-bearing mice. This strategy would offer a promising approach for mapping tumor-specific biomarkers in vivo with unlimited penetration depth.

Endophytic Colletotrichum fructicola KL19 and Its Derived SeNPs Mitigate Cd-Stress-Associated Damages in Spinacia oleracea L.

The application of nanotechnology in agriculture has received much attention in order to improve crop yield, quality and food safety. In the present study, a Cd-tolerant endophytic fungus Colletotrichum fructicola KL19 was first ever reported to produce SeNPs, and the production conditions were optimized using the Box-Behnken design in the Response Surface Methodology (RSM-BBD), achieving a peak yield of 1.06 mM under optimal conditions of 2.62 g/20 mL biomass, 4.56 mM Na2SeO3, and pH 6.25. Following this, the properties of the biogenic SeNPs were elucidated by using TEM, DLS, and FTIR, in which the 144.8 nm spherical-shaped SeNPs were stabilized by different functional groups with a negative zeta potential of -18.3 mV. Furthermore, strain KL19 and SeNPs (0, 5, 10, 20 and 50 mg/L) were inoculated in the root zone of small-leaf spinach (Spinacia oleracea L.) seedlings grown in the soil with 33.74 mg/kg Cd under controlled conditions for seven weeks. Impressively, compared with Cd stress alone, the strain KL19 and 5 mg/L SeNPs treatments significantly (p < 0.05) exhibited a reduction in Cd contents (0.62 and 0.50 folds) within the aboveground parts of spinach plants and promoted plants' growth by improving the leaf count (0.92 and 1.36 folds), fresh weight (2.94 and 3.46 folds), root dry weight (4.00 and 5.60 folds) and root length (0.14 and 0.51 folds), boosting total chlorophyll synthesis (0.38 and 0.45 folds), enhancing antioxidant enzymes (SOD, POD) activities, and reducing the contents of reactive oxygen species (MDA, H2O2) in small-leaf spinach under Cd stress. Overall, this study revealed that utilizing endophytic fungus C. fructicola or its derived SeNPs could mitigate reactive oxygen species generation by enhancing antioxidant enzyme activity as well as diminish the absorption and accumulation of Cd in small-leaf spinach, promoting plant growth under Cd stress.

The kynurenine pathway regulated by intestinal innate lymphoid cells mediates postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) expression and activity, which shifts intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.

Coarse-Fine Nested Network for Weakly Supervised Group Activity Recognition.

Weakly supervised group activity recognition (WSGAR) aims at identifying the overall behavior of multiple persons without any fine-grained supervision information (including individual position and action label). Traditional methods usually adopt a person-to-whole way: detect persons via off-the-shelf detectors, obtain person-level features, and integrate into the group-level features for training the classifier. However, these methods are unflexible due to serious reliance on the quality of detectors. To get rid of the detector, recent works learn several prototype tokens from noisy grid features with learnable weights directly, which treat all the local visual information equally and bring in redundant and ambiguous information to some extent. To this end, we propose a novel coarse-fine nested network (CFNN) to coarsely localize the key visual patches of activity and further finely learn the local features, as well as the global features. Specifically, we design a nested interactor (NI) to progressively model the spatiotemporal interactions of the learnable global token. According to the cue of spatial interaction in NI, we localize several key visual patches via a new coarse-grained spatial localizer (CSL). Then, we finally encode these localized visual patches with the help of global spatiotemporal dependency via a new fine-grained spatiotemporal selector (FSS). Extensive experiments on Volleyball and NBA datasets demonstrate the effectiveness of the proposed CFNN compared with the existing competitive methods. Code is available at: https://github.com/gexiaojingshelby/CFNN.

Achieving Controllable Thermochromic Fluorescence via Synergistic Intramolecular Charge Transfer and Molecular Packing.

Thermochromic fluorescent materials (TFMs) have attracted significant attention due to their unique fluorescent colorimetric response to temperature. However, existing TFMs still suffer from weak stimulus responsiveness, broad temperature response ranges, uncontrollable emission color changes, and low quantum yields. In this study, we address these issues by designing and synthesizing three diketone-boron complexes with distinct emission wavelengths (NWPU-(2-4)). Utilizing a molecular engineering strategy to manipulate intramolecular charge transfer transitions and molecular packing modes, our synthesized complexes exhibit efficient fluorescence emission in both solution and solid states. Moreover, their emission wavelengths are highly sensitive to environmental polarity. By incorporating these compounds into thermosensitive matrices of long-chain alkanes, we produced TFMs with varied fluorescence emission peak variation ranges. Notably, the TFM based on NWPU-4, owing to its strong charge transfer transitions and dense J-aggregate packing configuration, not only exhibits intense fluorescence emission spanning the deep red to near-infrared spectrum but also displays a remarkable 90 nm broad range of thermochromic properties. Ultimately, it was successfully applied to programmable, thermally controlled, multi-level information encryption.

Development and validation of a UPLC-MS/MS method for rapid and simultaneous quantification of BPI-460372 and its metabolites BPI-460444 and BPI-460456 in human plasma.

In cancer development and progression, the Hippo signaling pathway functions. The transcriptional enhanced associate domain (TEAD) stands out as a pivotal transcription factor within this pathway, and the suppression of TEAD represents a promising approach for cancer treatment. The primary aim of the study was to establish an analytical method for the concurrent quantification of a novel TEAD target inhibitor, BPI-460372, and its principal metabolites, BPI-460444 and BPI-460456, in human plasma. The chromatographic separation utilized a XSelect™ HSS C18 column (2.1 × 100 mm, 2.5 µm), while quantification was conducted on a SCIEX API 4000 mass spectrometer. 22 plasma samples were tested via the developed method. The calibration curve for BPI-460372 exhibited linearity from 2 to 2000 ng/mL, while its metabolites BPI-460444 and BPI-460456 had linearity between 1 and 1000 ng/mL (r > 0.99). The precision (RSD) was ≤ 17.1 %, and the accuracy (RE) fell within the range of -17.7 % to 15.0 %, all meeting acceptance criteria. The matrix effect was from 101.0 % to 105.8 %. The extraction recovery of analytes fell within the range of 96.8 % to 104.1 % with an RSD of less than 7.4 %. The developed method was effectively utilized in an advanced solid tumor patient, and the concentration trends of the three analytes in plasma were found to be largely consistent. The established analytical method showed great sensitivity, simplicity, accuracy, and reliability for the rapid and simultaneous analysis of the TEAD target inhibitor BPI-460372, alongside its major metabolites BPI-460444 and BPI-460456 in human plasma. This analytical method provided essential support for future clinical investigations and pharmacokinetic analysis.

Ab Initio Simulation of Liquid Water without Artificial High Temperature.

Comprehending the structure and dynamics of water is crucial in various fields, such as water desalination, ion separation, electrocatalysis, and biochemical processes. While reported works show that the ab initio molecular dynamics (AIMD) can accurately portray water's structure, the artificial high temperature (AHT) from 120 to 30 K is needed to mimic the quantum nature of hydrogen-bond network from GGA, metaGGA to hybrid functionals. The AHT proves to be an inadequate approach for systems involving aqueous multiphase mixtures, such as water-solid interfaces and aqueous solutions. This is due to the activation of additional phonons in other phases, which can lead to an overestimation of the dynamics of nearby water molecules. In this work, we find that the regularized SCAN (rSCAN) functional effectively captures both the structure and dynamics of liquid water at ambient conditions without AHT. Moreover, rSCAN closely matches experimental results for the hydration structures of alkali, alkali earth, and halide ions. We anticipate that the versatile and accurate rSCAN functional will emerge as a key tool based on ab initio simulation for investigating chemical processes in aqueous environments.

Paospora carinifang n. gen., n. sp. (Microsporidia: Spragueidae), a parasite of the ridgetail white prawn, Palaemon carinicauda.

A new microsporidian disease of the pond-reared ridgetail white prawn, Palaemon carinicauda, was found in China. Light microscopy, pathology, and scanning electron microscopy showed that the parasite infected the host's skeletal muscle tissue and formed spherical sporophorous vesicles (SPOVs). Electron microscopy revealed that its merogonic life stages developed in direct contact with the host cytoplasm. The sporogonic life stages underwent octosporoblastic sporogony with the formation of eight uninucleate spores in each SPOV. Fresh SPOVs were 5.4 ± 0.55 µm in diameter. The octospores were oval and measured 2.3 × 1.5 µm (fresh) and 1.96 × 1.17 µm (fixed). The isofilar polar filament was coiled with 9-10 turns and arranged in two rows. Phylogenetic analysis based on the SSU rRNA gene suggests that this microsporidium has close affinities with members of the genera Potaspora and Apotaspora, but represents an independent generic taxon. We therefore propose the establishment of a new genus and species (Paospora carinifang n. gen., n. sp.) within the family Spragueidae. We also propose a taxonomic revision to transfer Potaspora macrobrachium to this new genus and reclassify it as Paospora macrobrachium comb. nov.

The third-order nonlinear optical responses of zinc porphyrin oligomers: Cycles vs linear chains.

Porphyrins are widely used as potential nonlinear optical (NLO) materials because of their highly delocalized π electrons and feasible synthesis and functionalization with broad biological applications. A variety of linear and cyclic porphyrin derivatives have been synthesized, and the correlation between their structures and NLO properties awaits being disclosed. In this work, the electronic structures and third-order NLO properties of linear and cyclic butadiyne-linked zinc porphyrin oligomers have been studied by quantum chemical methods and sum-over-states model. The static second hyperpolarizability (<γ0>) increases exponentially with the number of zinc porphyrin units ([<γ0>n] = 0.67[<γ0>1]n2.63, n = 2 âˆ¼ 6) in linear π-conjugated oligomers, and the <γ0> of the linear hexamer is about 74 times that of the monomer. Such enhancement of <γ0> in linear oligomers originates from closely-lying frontier molecular orbitals available for low energy electron excitations and strong charge transfer-based excitations across porphyrins. The <γ0>s of cyclic porphyrins are lower than that of the linear hexamer, though the interaction between the ring and the ligand enhances the <γ0> of some cyclic zinc porphyrin complexes. The large two-photon absorption cross sections confer on these zinc porphyrin derivatives excellent candidates for two-photon absorption applications.

The full-length genomic sequence of the HLA-G*01:19 allele.

Full genomic sequence shows HLA-G*01:19 differs from HLA-G*01:04:01:01 only at position 99 in exon 2.

Blockage of the NLRP3 inflammasome by MCC950 inhibits migration and invasion in adenomyosis.

RESEARCH QUESTION: Does the NOD-like receptor protein 3 (NLRP3) inflammasome have an effect in adenomyosis? DESIGN: Fresh-frozen endometrial tissues and paraffin specimens were obtained from endometrial tissues from patients with adenomyosis and controls. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were applied to assess expression of the NLRP3 inflammasome components. Primary eutopic endometrial stromal cells were isolated from the uteri of patients with adenomyosis. After NLRP3 was knocked down using small interfering RNA, proliferation, invasion and epithelial-mesenchymal transition (EMT) were evaluated using EdU, CCK8, transwell assays and western blot. Importantly, a mouse model of adenomyosis was established to evaluate the effects of the NLRP3 inhibitor MCC950 on the formation of adenomyosis. RESULTS: Expression of the NLRP3 inflammasome components was elevated in the ectopic or eutopic endometrium of patients with adenomyosis. NLRP3 knockdown inhibited migration, invasion and EMT in endometrial cells and primary endometrial cells (P < 0.0001). MCC950, which blocks the NLRP3 inflammasome, reduced migration and invasion of endometrial cells (P < 0.01) and primary endometrial cells (P < 0.0001) considerably. Importantly, in the mouse model of adenomyosis, MCC950 had a mitigating effect on the severity of adenomyosis (P < 0.01). CONCLUSIONS: NLRP3 was found to enhance migration, invasion and EMT of human endometrial cells in adenomyosis. Notably, the NLRP3 inhibitor MCC950 reduced migration and invasion of endometrial cells effectively. Furthermore, in the mouse model of adenomyosis, MCC950 exhibited a therapeutic effect by alleviating the severity of adenomyosis.

Comparison of percutaneous microwave/radiofrequency ablation liver partition and portal vein embolization versus transarterial chemoembolization and portal vein embolization for planned hepatectomy with insufficient future liver remnant.

BACKGROUND: In China, both percutaneous microwave/radiofrequency ablation liver partition plus portal vein embolization (PALPP) and transarterial chemoembolization (TACE) plus portal vein embolization (PVE) have been utilized in planned hepatectomy. However, there is a lack of comparative studies on the effectiveness of these two techniques for cases with insufficient future liver remnant (FLR). METHODS: Patients were categorized into either the PALPP group or the TACE + PVE group. Clinical data, including FLR growth rate, complications, secondary resection rate, and overall survival rate, were compared and analyzed for both groups retrospectively. RESULTS: Between December 2014 and October 2021, a total of 29 patients underwent TACE + PVE (n = 12) and PALPP (n = 17). In the TACE + PVE group, 7 patients successfully underwent two-stage hepatectomy, while in the PALPP group, 13 patients underwent the procedure (two-stage resection rate: 58.3% vs. 76.5%, P = 0.42). There were no significant differences in postoperative complications of one-stage procedures (11.8% vs. 8.3%, P > 0.05) and second-stage resection complication (0% vs. 46.2%, P = 0.05) between the TACE + PVE and PALPP groups. However, the PALPP group demonstrated a shorter time to FLR volume growth for second-stage resection (18.5 days vs. 66 days, P = 0.001) and KGR (58.5 ml/week vs. 7.7 ml/week, P = 0.001). CONCLUSIONS: Compared with TACE + PVE, PALPP results in a more significant increase in FLR volume and a higher rate of two-stage resection without increasing postoperative complications.

Inhibition of TRAF6 alleviates secondary brain injury by reducing neuronal pyroptosis after intracerebral hemorrhage.

Secondary brain injury (SBI) is one of the main causes of high mortality and disability rates following intracerebral hemorrhage (ICH). TRAF6 plays a crucial role in the process of pyroptosis, and modulating its expression may present a novel therapeutic strategy for mitigating brain injury. This study aims to explore the mechanisms of TRAF6 in pyroptosis after ICH. C57BL/6J mice were used to establish the ICH model. Brain was collected at different time points for q-PCR and western blot to detect the level of TRAF6. After the C25-140 (the TRAF6 inhibitor) was administrated, the mice were divided into four groups. Then, the neurological deficit, brain water content, and blood-brain barrier (BBB) ​​damage were detected. Immunofluorescence and western blot were used to detect the level of pyroptosis proteins, and enzyme-linked immunosorbent assay (ELISA) and q-PCR were used to detect the levels of IL-18 and IL-1ß. TRAF6 expression was upregulated after ICH and was mainly expressed in neurons. Inhibition of TRAF6 expression with C25-140 alleviated neurological deficits and reduced brain edema after ICH. In addition, inhibition of TRAF6 also reduced the expression of pyroptosis inflammasomes such as GSDMD, NLRP3, and ASC, as well as neurological damage caused by IL-18 and IL-1ß after ICH. TRAF6 regulates neuronal pyroptosis in SBI after ICH. Inhibition of TRAF6 may be a potential target for alleviating inflammatory damage after ICH.

Gallbladder cancer masquerading as xanthogranulomatous cholecystitis: a case report and literature review.

Xanthogranulomatous cholecystitis (XGC) is a rare type of cholecystitis that, despite being benign poses diagnostic challenges due to its low prevalence and need for consensus on diagnostic criteria. Consequently, distinguishing XGC from gallbladder cancer (GBC) is challenging, leading to clinical misdiagnoses. This article presents a case where a patient initially diagnosed with GBC was later found to have XGC.

Unconventional Luminescence Polymer with Color-Tunability based on Solvent-induced Electrostatic Potential Distribution of Fluorophore.

Tuning the full-color emission of polymers holds significant promise. However, preparing unconventional luminescence polymers with color-tunability in dilute solution and understanding the relationship between non-covalent interactions and luminescent behavior remains a great challenge. We report two emitters (P1 and P2) incorporating tetracoordinate boron. The P1 with non-conjugated D-π-A structure, exhibited red delayed fluorescence at 645 nm with quantum yield of 9.15% in aggregates. Notably, the emission wavelength of P1 can be tuned from 418 to 588 nm at different solvent. Similarly, the emission wavelength of P2 can also be adjusted by manipulating the interactions between the solvent and fluorophore. Experimental characterization and theoretical calculations indicate that the B←N bond and electronic interactions between solvent and fluorophore significantly regulate the equilibrium the electrostatic potential (ESP) and the intramolecular O···O interactions of P1, thereby modulating its emission wavelength. Additionally, these polymers showed excellent potential in fluoride ions detection. This work provides new insights into the complex effects of intermolecular interactions on luminescent properties.

Latent profile analysis of nurses' moral courage: a professional values perspective.

INTRODUCTION: Nurses' moral courage (NMC) enhances care quality and patient safety. Nurses' professional values promote ethical adherence, moral obligation fulfillment, and compliance to prevent ethical violations. It is necessary to explore the current status and influencing factors of moral courage from the perspective of professional values. AIM: To investigate the current situation of nurses' moral courage, analyze the latent profiles of nurses' moral courage, and explore the influencing factors from the perspective of professional values. RESEARCH DESIGN: A cross-sectional design was employed. PARTICIPANTS AND RESEARCH CONTEXT: Data were collected through convenient sampling at a tertiary hospital during May 2023 in Wuhan, Hubei province, China. A self-designed web-based questionnaire consisting of demographic characteristics, the Chinese Nurses' Professional Values Scale-Revised Version (NPVS-R-CV) and the Nurses' Moral Courage Scale (NMCS) were used for the cross-sectional survey. Latent profile analysis was conducted using the results of 3 explicit indexes of NMCS, and multivariate logistic regression was used to analyze the influencing factors of NMC. ETHICAL CONSIDERATIONS: Research ethics approval (with the code of TJ- IRB 20220543) was obtained from Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. FINDINGS: This study included 966 nurses, predominantly female and under 30 years old, with 91.10% holding a bachelor's degree. Latent profile analysis identified three moral courage profiles: low-level (31.5%), medium-level (47.2%), and high-level (21.3%). Multivariate logistic regression analysis showed significant positive correlations between professional values and moral courage, with head nurses being significantly more likely to exhibit high moral courage (OR = 3.586, p = 0.013). CONCLUSIONS: The moral courage of nurses can be classified into 3 subgroups. Nurses' professional values positively correlate with moral courage, with head nurses showing significantly higher levels of moral courage. Strengthening professional values through training can enhance ethical behavior in nursing, potentially improving patient care and safety.

The anthraquinone derivative KA-4s reduces energy metabolism and enhances the sensitivity of ovarian cancer cells to cisplatin.

Ovarian cancer is the leading cause of death from female gynecological cancers. Cisplatin (DDP) is a first-line drug for ovarian cancer treatment. Due to DDP resistance, there is an urgent need for novel therapeutic drugs with improved antitumor activity. AMPK-mediated metabolic regulatory pathways are related to tumor drug resistance. Our study aimed to determine the relationship between reversing DDP resistance with the anthraquinone derivative KA-4s and regulating AMPK energy metabolism in ovarian cancer. The results showed that KA-4s inhibited the proliferation of ovarian cancer cells. The combination of KA-4s with DDP effectively promoted drug-resistant ovarian cancer cell apoptosis and inhibited cell migration and invasion. Moreover, KA-4s decreased the intracellular ATP level and increased the calcium ion level, leading to AMPK phosphorylation. Further studies suggested that the AMPK signaling pathway may be involved in the mechanism through which KA-4s reduce drug resistance. KA-4s inhibited mitochondrial respiration and glycolysis; downregulated the glucose metabolism-related proteins GLUT1 and GLUT4; the lipid metabolism-related proteins SREBP1 and SCD1; and the drug resistance-related proteins P-gp, MRP1, and LRP. The inhibitory effect of KA-4s on GLUT1 was confirmed by the application of the GLUT1 inhibitor BAY-876. KA-4s combined with DDP significantly increased the expression of p-AMPK and reduced the expression of P-gp. In a xenograft model of ovarian cancer, treatment with KA-4s combined with DDP reduced energy metabolism and drug resistance, inducing tumor apoptosis. Consequently, KA-4s might be evaluated as a new agent for enhancing the chemotherapeutic efficacy of treatment for ovarian cancer.

Homocysteine Metabolism, Subclinical Myocardial Injury, and Cardiovascular Mortality in the General Population.

Background: Homocysteine (Hcy) is a recognized cardiovascular disease (CVD) risk factor linked with atherosclerosis. However, the association between Hcy and myocardial injury is little known. Objectives: This study aimed to examine the associations between Hcy metabolism, subclinical myocardial injury, and cardiovascular mortality. Methods: We included 10,871 participants without diagnosed CVD. Generalized linear regression was used to investigate the relationship between Hcy-related indicators (plasma total Hcy [tHcy], vitamin B12, and folate) and myocardial injury biomarkers (high-sensitivity troponin T [hs-cTnT], high-sensitivity troponin I [hs-cTnI] measured using 3 assays [Abbott, Siemens, and Ortho], and N-terminal pro-B-type natriuretic peptide [NT-proBNP]). Results: Among 10,871 participants, the weighted mean levels for tHcy, folate, and vitamin B12 were 8.58 µmol/L, 32.43 nmol/L, and 447.08 pmol/L, respectively. Plasma tHcy levels were positively associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP, whereas folate and vitamin B12 were not inversely related to myocardial injury biomarkers. Multivariable-adjusted odds ratios for elevated hs-cTnT (19 ng/L) and NT-proBNP (125 pg/mL) per doubling of tHcy were 2.80 (95% CI: 1.17-6.73; P < 0.001) and 1.58 (95% CI: 1.20-2.08; P < 0.001), respectively. The associations of tHcy levels with elevated hs-cTnI (Abbott: 28 ng/L; Siemens: 46.5 ng/L; Ortho: 11 ng/L) were consistent. Indirect effects of tHcy on cardiovascular mortality risk via hs-cTnT and NT-proBNP explained up to 26.6% and 12.3% of the total effect, respectively. Conclusions: Plasma tHcy, not folate or vitamin B12, is significantly associated with elevated hs-cTnT, hs-cTnI, and NT-proBNP in adults without CVD. Subclinical myocardial injury may substantially mediate Hcy-related cardiovascular mortality risk.

A Phase I Clinical Study: Evaluation of Safety, Tolerability, and Population Pharmacokinetic-Pharmacodynamic Target Attainment Analysis of Etimicin Sulfate Among Healthy Chinese Participants.

BACKGROUND: This phase I clinical study aimed to assess the safety, tolerability, and population pharmacokinetic-pharmacodynamics (PK-PD) target attainment analysis of etimicin sulfate in healthy participants, and to provide scientific reference for further development of clinical breakpoints. METHODS: A total of 24 healthy Chinese subjects were enrolled in this study and received an etimicin sulfate infusion. A population PK model was constructed for the estimation of the PK profiles of etimicin sulfate. The area under the concentration-time curve divided by the minimum inhibitory concentration (AUC0-24h/MIC) and the peak concentration divided by the MIC (Cmax/MIC) were selected as the PK/PD indices. The probability of target attainment (PTA) was calculated for each designed dosing regimen using Monte Carlo simulations. The minimum MIC value with a PTA ≥ 90% for each regimen was considered as the PK/PD cutoff values. RESULTS: Etimicin sulfate demonstrated safety, tolerability, and predictable PK characteristics. No deaths or serious adverse events were reported. Seven treatment-emergent adverse events (TEAEs) were reported by five participants; all TEAEs were minor and were rapidly relieved. A two-compartment model was developed and validated for describing the PK features of etimicin sulfate among Chinese healthy participants. The diagnostic goodness-of-fit plots and visual predictive check plots showed that this developed model could describe these data well. CONCLUSIONS: The PTA results showed that etimicin sulfate provided clinical improvement against strains with an MIC of 0.5-1 mg/L and below, and antibacterial effect against strains with an MIC of 0.25 mg/L and below. However, etimicin sulfate had limited clinical efficacy for clinical isolates with MIC values > 1 mg/L.