Compensating losses in polariton propagation with synthesized complex frequency excitation.

Surface plasmon polaritons and phonon polaritons offer a means of surpassing the diffraction limit of conventional optics and facilitate efficient energy storage, local field enhancement and highsensitivity sensing, benefiting from their subwavelength confinement of light. Unfortunately, losses severely limit the propagation decay length, thus restricting the practical use of polaritons. While optimizing the fabrication technique can help circumvent the scattering loss of imperfect structures, the intrinsic absorption channel leading to heat production cannot be eliminated. Here, we utilize synthetic optical excitation of complex frequency with virtual gain, synthesized by combining the measurements made at multiple real frequencies, to compensate losses in the propagations of phonon polaritons with dramatically enhanced propagation distance. The concept of synthetic complex frequency excitation represents a viable solution to the loss problem for various applications including photonic circuits, waveguiding and plasmonic/phononic structured illumination microscopy.

Platelet Membrane-Coated Curcumin-PLGA Nanoparticles Promote Astrocyte-Neuron Transdifferentiation for Intracerebral Hemorrhage Treatment.

Intracerebral hemorrhage (ICH) is a hemorrhagic disease with high mortality and disability rates. Curcumin is a promising drug for ICH treatment due to its multiple biological activities, but its application is limited by its poor watersolubility and instability. Herein, platelet membrane-coated curcumin polylactic-co-glycolic acid (PLGA) nanoparticles (PCNPs) are prepared to achieve significantly improved solubility, stability, and sustained release of curcumin. Fourier transform infrared spectra and X-ray diffraction assays indicate good encapsulation of curcumin within nanoparticles. Moreover, it is revealed for the first time that curcumin-loaded nanoparticles can not only suppress hemin-induced astrocyte proliferation but also induce astrocytes into neuron-like cells in vitro. PCNPs are used to treat rat ICH by tail vein injection, using in situ administration as control. The results show that PCNPs are more effective than curcumin-PLGA nanoparticles in concentrating on hemorrhagic lesions, inhibiting inflammation, suppressing astrogliosis, promoting neurogenesis, and improving motor functions. The treatment efficacy of intravenously administered PCNPs is comparable to that of in situ administration, indicating a good targeting effect of PCNPs on the hemorrhage site. This study provides a potent treatment for hemorrhagic injuries and a promising solution for efficient delivery of water-insoluble drugs using composite materials of macromolecules and cell membranes.

Cyclophilin 37 maintains electron transport via the cytochrome b6/f complex under high light in Arabidopsis.

Plants have evolved multiple mechanisms to cope with diverse types of light stress, particularly the regulation of the electron transport chain (ETC). Under high light (HL) conditions, the balance of electron flux in the ETC is disturbed, which leads to the overaccumulation of reactive oxygen species (ROS) and results in photodamage and photoinhibition. The cytochrome (Cyt) b6/f complex, which coordinates electron transfer between photosystems I and II (PSI and PSII), plays an essential role in regulating the ETC and initiating photoprotection. However, how the Cyt b6/f complex is maintained under HL conditions remains unclear. Here, we report that the activity of the Cyt b6/f complex is sustained by thylakoid-localized cyclophilin 37 (CYP37) in Arabidopsis (Arabidopsis thaliana). Compared with wild-type plants, cyp37 mutants displayed an imbalance in electron transport from Cyt b6/f to PSI under HL stress, which led to increased ROS accumulation, decreased anthocyanin biosynthesis, and increased chlorophyll degradation. Surprisingly, CYP37's role in regulating ETC balance was independent of photosynthesis control, which was indicated by a higher Y (ND), an indicator of P700 oxidation in PSI. Furthermore, the interaction between CYP37 and photosynthetic electron transfer A (PetA), a subunit of the Cyt b6/f complex, suggests that the central function of CYP37 is to maintain Cyt b6/f complex activity rather than to serve as an assembly factor. Our study provides insights into how plants balance electron flow between PSII and PSI via Cyt b6/f complex under HL.

Sodium Butyrate Ameliorates Postoperative Delirium by Regulating Gut Microbiota Dysbiosis to Inhibit Astrocyte Activation in Aged Mice.

Postoperative delirium (POD) is a common complication in elderly surgical patients, with limited targeted interventions due to incomplete understanding of its pathophysiological mechanisms. Central nervous system (CNS) inflammation, involving glial cell activation, particularly astrocytes, is considered crucial in POD development. Butyrate, a four-carbon fatty acid, has shown protective effects in CNS diseases, but its potential in mitigating POD remains unclear. This study aimed to investigate the impact of sodium butyrate on POD in aged mice. Behavioral tests, including open field, Y maze, and food burying tests, demonstrated that sodium butyrate preconditioning ameliorated laparotomy-induced delirium in aged mice. Pre-treatment with sodium butyrate inhibited astrocyte activation in the hippocampus, reduced interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) expression levels, and protected hippocampal neurons. Furthermore, the study revealed a connection between gut microbiota regulation and central neuroprotective effects mediated by astrocyte activation inhibition. Sodium butyrate improved the intestinal morphological barrier by rebalancing gut microbiota, inhibiting Proteobacteria and Actinobacteria, reducing Allobaculum and Bacteroides abundance, and increasing Oscillospira abundance. This regulation decreased gut permeability, limiting the entry of toxic substances into the bloodstream, thereby reducing inflammation spread and astrocyte overactivation, leading to central anti-inflammatory effects. In conclusion, sodium butyrate may ameliorate POD by inhibiting astrocyte-mediated neuroinflammation through gut microbiota rebalancing.

Photovoltaic-enhanced water splitting properties of low-temperature-synthesized BiVO4 photoanode films.

The fabrication of photoelectrodes on indium tin oxide (ITO) glass at low temperatures poses a significant challenge due to the inherent instability of ITO at reduced temperatures, while the inexpensive production of high-functionality photoanode technology is a critical determinant facilitating large-scale photovoltaic conversion in water splitting. In this work, highly efficient BiVO4 (BVO) photoanodes with different thicknesses were grown on ITO glass at a low temperature by the sol-gel spin coating method. Pure BVO photoanode, enriched with nanostructures, exhibits a current density of 2.25 mA cm-2 (@1.23 V vs. RHE) under AM-1.5G illumination. The photovoltaic effect induces a continual oxygen evolution reaction at zero bias voltage on the photoanode, resulting in a photocurrent density of 0.04 mA cm-2 at zero bias. This study not only evaluates the feasibility of the large-scale fabrication of a photoanode from economic considerations but also presents potential for water splitting properties of the BVO photoanode.

HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells.

Currently, platinum agents remain the mainstay of chemotherapy for ovarian cancer (OC). However, cisplatin (DDP) resistance is a major reason for chemotherapy failure. Thus, it is extremely important to elucidate the mechanism of resistance to DDP. Here, we establish two DDP-resistant ovarian cancer cell lines and find that caseinolytic protease P (CLPP) level is significantly downregulated in DDP-resistant cell lines compared to wild-type ovarian cancer cell lines (SK-OV-3 and OVcar3). Next, we investigate the functions of CLPP in DDP-resistant and wild-type ovarian cancer cells using various assays, including cell counting kit-8 assay, western blot analysis, immunofluorescence staining, and detection of reactive oxygen species (ROS) and apoptosis. Our results show that CLPP knockdown significantly increases the half maximal inhibitory concentration (IC 50) and mitophagy of wild-type SK-OV-3 and OVcar3 cells, while CLPP overexpression reduces the IC 50 values and mitophagy of DDP-resistant SK-OV-3 and OVcar3 cells. Next, we perform database predictions and confirmation experiments, which show that heat shock protein family A member 8 (HSPA8) regulates CLPP protein stability. The dynamic effects of the HSPA8/CLPP axis in ovarian cancer cells are also examined. HSPA8 increases mitophagy and the IC 50 values of SK-OV-3 and OVcar3 cells but inhibits their ROS production and apoptosis. In addition, CLPP partly reverses the effects induced by HSPA8 in SK-OV-3 and OVcar3 cells. In conclusion, CLPP increases DDP resistance in ovarian cancer by inhibiting mitophagy and promoting cellular stress. Meanwhile, HSPA8 promotes the degradation of CLPP protein by regulating its stability.

Clinical outcomes of endodontic microsurgery in complicated cases with large or through-and-through lesions: a retrospective longitudinal study.

OBJECTIVES: To investigate the clinical outcomes of endodontic microsurgery in complicated cases presenting with large or through-and-through lesions. MATERIALS AND METHODS: We retrospectively collected and analyzed preoperative, intraoperative, and follow-up data from 143 complicated cases that underwent endodontic microsurgery. Clinical outcomes were assessed in terms of tooth survival and surgery success. Cox regression analysis was used to evaluate the survival rate and identify associated risk factors. Additionally, the success rate was compared across different postoperative periods, and potential factors contributing to surgical failure were identified through binary logistic regression. RESULTS: The overall survival and success rates were 93.0% and 91.7%, respectively. The Cox regression model identified four risk factors affecting tooth survival, including apicoectomy of four teeth (HR = 35.488; P = 0.0002), an open apex observed on preoperative radiographs (HR = 6.300; P = 0.025), the performance of guided tissue regeneration technique (HR = 8.846; P = 0.028), and a palatal surgical approach (HR = 8.685; P = 0.030). The success rate demonstrated an initial increase in the early postoperative period (from 0.5 to 2 years; P = 5.8124e-30), followed by stabilization (from 2 to 9 years; P = 0.298). Surgery success rate significantly declined when apicoectomy involved four teeth (OR = 109.412; P = 0.002). CONCLUSIONS: Endodontic microsurgery demonstrates satisfactory outcomes in complicated cases, maintaining a stable success rate after two years. However, tooth survival and surgery success are significantly compromised when apicoectomy involves four teeth. Factors such as guided tissue regeneration, an open apex, and the palatal surgical approach are associated with an increased risk of tooth extraction. CLINICAL RELEVANCE: Despite achieving acceptable outcomes in complicated cases, endodontic microsurgery is adversely affected by the apicoectomy of four teeth.

The Interaction between Iron Cyanide and Lead Ions in Pyrite Flotation.

Despite being a major cyanide species in the process water, it is unclear how iron cyanide influences pyritic gold ore flotation as well as how lead ions influence pyritic gold ore flotation in the presence of iron cyanide. This study aims at revealing the interaction of Fe(CN)63- and lead ions in pyrite flotation to investigate the strong depressing effect of Fe(CN)63- on pyritic gold ore flotation and the significant activating effect of lead ions on pyritic gold ore flotation in the presence of Fe(CN)63- using flotation, zeta potential measurement and surface analysis methods. The flotation results showed that upon 5 × 10-5 mol/L Fe(CN)63- addition, pyrite recovery drastically decreased from about 51.3% to 8.6%, while the subsequent addition of 9.5 × 10-4 mol/L lead ions significantly activated pyrite with the recovery increasing from 8.6% to 91%, which demonstrated that Fe(CN)63- strongly depressed pyrite flotation, while lead ions completely activated pyrite in the presence of Fe(CN)63-. Zeta potential measurement, surface analysis using Cryogenic X-ray photoelectron spectroscopy (Cryo-XPS) and electrochemical impedance spectroscopy (EIS) revealed that Fe(CN)63- depression was attributed to the chemical adsorption of Fe(CN)63- on iron sites of pyrite as Prussian Blue (Fe[Fe(CN)6]); however, this hydrophilic layer could be covered totally by lead ions which adsorbed on as lead hydroxide/oxide through electrostatic interactions, which resulted in the significant activation effect of lead ions. The results from this study will lead to improved flotation of gold associated with pyrite in gold flotation plants.

Association between muscular tissue desaturation and acute kidney injury in older patients undergoing major abdominal surgery: a prospective cohort study.

PURPOSE: Present study was designed to investigate the association between muscular tissue desaturation and acute kidney injury (AKI) in older patients undergoing major abdominal surgery. METHOD: A total of 253 patients (≥ 65 years old) who underwent abdominal surgery with expected duration ≥ 2 h were enrolled. Muscular tissue oxygen saturation (SmtO2) was monitored at quadriceps and bilateral flanks during surgery. Muscular desaturation was defined as SmtO2 < 90% baseline lasting for > 60 s. The primary outcome was the incidence of AKI within postoperative 7 days. The association between muscular desaturation and AKI was analyzed by multivariable logistic regression model. The secondary outcomes indicated the other complications within postoperative 30 days. RESULTS: Among 236 patients, 44 (18.6%) of them developed AKI. The incidence of muscular desaturation at quadriceps was 28.8% (68/236). Patients with muscular desaturation had higher incidence of AKI than those without desaturation (27.9% [19/68], vs. 14.9% [25/168], P = 0.020). After adjustment of confounders, multivariable analysis showed that muscular desaturation at quadriceps was significantly associated with an increased risk of AKI (OR = 2.84, 95% CI 1.21-6.67, P = 0.016). Muscular desaturations at left and right flank were also associated with an increased risk of AKI (OR = 6.38, 95% CI 1.78-22.89, P = 0.004; OR = 8.90, 95% CI 1.42-45.63; P = 0.019, respectively). Furthermore, patients with muscular desaturation may have a higher risk of pulmonary complications, sepsis and stroke at 30-day follow-up. CONCLUSION: Muscular desaturation was associated with postoperative AKI in older patients undergoing major abdominal surgery which may serve as a predictor of AKI.

Learning Causes of Functional Dynamic Targets: Screening and Local Methods.

This paper addresses the challenge of identifying causes for functional dynamic targets, which are functions of various variables over time. We develop screening and local learning methods to learn the direct causes of the target, as well as all indirect causes up to a given distance. We first discuss the modeling of the functional dynamic target. Then, we propose a screening method to select the variables that are significantly correlated with the target. On this basis, we introduce an algorithm that combines screening and structural learning techniques to uncover the causal structure among the target and its causes. To tackle the distance effect, where long causal paths weaken correlation, we propose a local method to discover the direct causes of the target in these significant variables and further sequentially find all indirect causes up to a given distance. We show theoretically that our proposed methods can learn the causes correctly under some regular assumptions. Experiments based on synthetic data also show that the proposed methods perform well in learning the causes of the target.

Dissolved organic matter accelerates microbial degradation of 17 alpha-ethinylestradiol in the presence of iron mineral.

Dissolved organic matter (DOM) and iron minerals widely existing in the natural aquatic environment can mediate the migration and transformation of organic pollutants. However, the mechanism of interaction between DOM and iron minerals in the microbial degradation of pollutants deserves further investigation. In this study, the mechanism of 17 alpha-ethinylestradiol (EE2) biodegradation mediated by humic acid (HA) and three kinds of iron minerals (goethite, magnetite, and pyrite) was investigated. The results found that HA and iron minerals significantly accelerated the biodegradation process of EE2, and the highest degradation efficiency of EE2 (48%) was observed in the HA-mediated microbial system with pyrite under aerobic conditions. Furthermore, it had been demonstrated that hydroxyl radicals (HO•) was the main active substance responsible for the microbial degradation of EE2. HO• is primarily generated through the reaction between hydrogen peroxide secreted by microorganisms and Fe(II), with aerobic conditions being more conducive. The presence of iron minerals and HA could change the microbial communities in the EE2 biodegradation system. These findings provide new information for exploring the migration and transformation of pollutants by microorganisms in iron-rich environments.

GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice.

BACKGROUND: Temporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. Phagocytic activity of microglia is essential for clearing apoptotic neuronal debris, allowing for repair and regeneration. Our previous research has shown that gasdermin D (GSDMD)-mediated pyroptosis is involved in the pathogenesis of TLE. However, whether GSDMD-mediated pyroptosis influences the accumulation of apoptotic neurons remains unclear. Therefore, the present study was designed to investigate whether phagocytic activity of microglia is involved in GSDMD-mediated pyroptosis and the pathogenesis of TLE. METHODS: To establish a TLE model, an intra-amygdala injection of kainic acid (KA) was performed. The Racine score and local field potential (LFP) recordings were used to assess seizure severity. Neuronal death in the bilateral hippocampus was assessed by Nissl staining and TUNEL staining. Microglial morphology and phagocytic activity were detected by immunofluorescence and verified by lipopolysaccharide (LPS) and the P2Y12R agonist 2MeSADP. RESULTS: GSDMD knockdown augmented the accumulation of apoptotic neurons and seizure susceptibility in TLE mice. Microglia activated and transition to the M1 type with increased pro-inflammatory cytokines. Furthermore, GSDMD knockdown attenuated the migration and phagocytic activity of microglia. Of note, LPS-activated microglia attenuated seizure susceptibility and the accumulation of apoptotic neurons in TLE after GSDMD knockdown. A P2Y12R selective agonist, 2MeSADP, enhanced the migration and phagocytic activity of microglia. CONCLUSIONS: Our results demonstrate that GSDMD knockdown exacerbates seizure susceptibility and the accumulation of apoptotic neurons by attenuating phagocytic activity of microglia. These findings suggest that GSDMD plays a protective role against KA-induced seizure susceptibility.

tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.

RATIONALE: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation. OBJECTIVE: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke. METHODS AND RESULTS: Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. CONCLUSIONS: Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.

Saliva - a new opportunity for fluid biopsy.

Saliva is a complex biological fluid with a variety of biomolecules, such as DNA, RNA, proteins, metabolites and microbiota, which can be used for the screening and diagnosis of many diseases. In addition, saliva has the characteristics of simple collection, non-invasive and convenient storage, which gives it the potential to replace blood as a new main body of fluid biopsy, and it is an excellent biological diagnostic fluid. This review integrates recent studies and summarizes the research contents of salivaomics and the research progress of saliva in early diagnosis of oral and systemic diseases. This review aims to explore the value and prospect of saliva diagnosis in clinical application.

Molecular mechanism of paraquat-induced ferroptosis leading to pulmonary fibrosis mediated by Keap1/Nrf2 signaling pathway.

Paraquat (PQ) is a widely used and highly toxic pesticide that is often actively ingested and causes pulmonary fibrosis in patients. Ferroptosis is a regulated form of non-apoptotic cell death associated with iron-dependent lipid peroxidation. Previous studies have shown that ferroptosis is involved in the occurrence and development of acute lung injury (ALI). In this study, a model rat with inflammatory response, oxidative stress, lipid peroxidation, and pulmonary fibrosis was successfully established by PQ administration. The occurrence of ferroptosis in PQ model rats was confirmed by TUNEL staining, iron ion detection, and Ferroptosis related biomarkers detection. Western blotting (WB) and real-time PCR (RT-PCR) showed that the expression of Keap1 was significantly up-regulated and the expression of Nrf2 was significantly down-regulated in the lung tissue of PQ rats. Further transcriptomics and proteomics confirmed: (1) Enrichment of molecular processes related to iron ion binding; (2) Keap1 may promote Nrf2 ubiquitination and lead to Nrf2 degradation; (3) There is functional enrichment in ferroptosis related pathways. Our results suggest that PQ can regulate Keap1/Nrf2 signaling pathway, leading to increased lipid peroxidation and abnormal iron uptake, thereby inducing iron death and exacerbating the progression of pulmonary fibrosis. Our study provides new insights into PQ-induced pulmonary fibrosis.

Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3.

Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-ß. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.

Effectiveness of Progressive Resistance Training in Parkinson's Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: The aim of this study was to systematically explore progressive resistance training (PRT) effects in Parkinson's disease (PD). METHODS: Eligible literature was systematically searched from five electronic databases (PubMed, Web of Science, Ovid, Wanfang, and China National Knowledge Infrastructure) from their inception to February 2022. Included studies were selected based on strict eligibility criteria. RevMan 5.3 software was used for statistical analysis. RESULTS: A total of 14 studies with 761 PD patients were selected for eligibility in this systematic review and meta-analysis. A total of 383 performed trunk or upper or lower extremity PRT and 378 underwent balance training, modified fitness counts, or did not change their lifestyle. The results demonstrated positive PRT effect on freezing of gait (standardized mean difference [SMD] = -0.55, 95% CI = -0.95 to -0.16, p = 0.006), muscular strength (SMD = 1.9, 95% CI = 0.55-3.24, p = 0.006), and quality of life (SMD = -0.86, 95% CI = -1.66 to -0.06, p = 0.04) in adults with PD compared with other training programmes but not for gait velocity, stride length, timed up and go test, and Berg Balance Scale. CONCLUSIONS: This meta-analysis revealed that PRT had positive effects on freezing of gait, muscle strength, and improved quality of life during rehabilitation in PD patients.

Improved LC-MS/MS method for the simultaneous quantification of tacrolimus and cyclosporine A in human blood and application to therapeutic drug monitoring.

In order to facilitate therapeutic drug monitoring of tacrolimus and cyclosporine A in clinical practice, a simple, rapid, robust, sensitive and specific LC-MS/MS assay was developed and validated for the simultaneous determination of tacrolimus and cyclosporine A in human whole blood. Erythrocytes were destroyed using internal standard solution with 10% (w/v) zinc sulfate in water. The analytes were extracted from 100 µl of whole blood by protein precipitation with acetonitrile. Chromatographic separation was conducted on a Kinetex PFP column (60°C) by a gradient elution with a flow rate of 0.450 ml/min in 2.5 min. Quantitative analysis was performed using electrospray ionization and multiple reaction monitoring in positive ionization mode. The method was fully validated as per current guidelines on bioanalytical methodologies of the US Food and Drug Administration and European Medicines Agency. The method developed was applied successfully in analyzing clinical samples from patients administered tacrolimus or cyclosporine A. The sample treatment procedure was rationalized and improved to fulfill the complete target extraction. The chromatography conditions were optimized to achieve rapid and accurate quantification of both analytes. This method may be beneficial as a constructive input for the therapeutic drug monitoring of tacrolimus and cyclosporine A in obtaining individualized therapy.

The effects of polyethylene microplastics on the growth, reproduction, metabolic enzymes, and metabolomics of earthworms Eisenia fetida.

The existing data regarding the effects of polyethylene (PE) microplastics (MPs) smaller than 5 mm in size on earthworms are insufficient to fully comprehend their toxicity. In this study, earthworms Eisenia fetida were exposed to artificially added PE at a concentration ranging from 0.05 to 20 g/kg soil (0.005%-2%) for 60 days to determine the concentration range causing negative effects on earthworms and to uncover the potential toxic mechanisms. The individual growth, reproduction, and metabolic enzyme activities, including phase I enzymes (cytochrome P450 [CYP] 1A2, 2B6, 2C9, and 3A4), and phase II metabolic enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione sulfotransferase (GST)), and metabolomics were measured. The observed variations in responses of multiple cross-scale endpoints indicated that individual indices are less responsive to PE MPs than metabolic enzymes or metabolomics. Despite the absence of significant alterations in growth inhibition based on body weight, PE MPs at concentrations equal to or exceeding 2.5 g/kg were found to exert a toxic effect on earthworms, which was evidenced by significant changes in metabolic enzyme activities (CYP1A2, 2B6, 2C9, and 3A4, SOD, CAT, and GST) and important small molecule metabolites screened based on metabolomics, likely due to the bioaccumulation of PE. The toxicity of PE MPs to earthworms is inferred to be associated with neurotoxicity, oxidative damage, decreased detoxification capacity, energy metabolism imbalance, and impaired amino acid and purine metabolism due to bioaccumulation. The findings of this study will enhance our understanding of the molecular toxicity mechanisms of PE MPs and contribute to a more accurate assessment of the ecological risks posed by PE MPs in soil.

Heparin anticoagulation versus regional citrate anticoagulation for membrane therapeutic plasma exchange in patients with increased bleeding risk.

Background Heparin anticoagulation (HA) is commonly employed for membrane therapeutic plasma exchange (mTPE). However, for patients with increased bleeding risk, there were controversial opinions on the use of HA versus regional citrate anticoagulation (RCA) for mTPE. Our present study aimed to evaluate the efficacy and safety of HA vs. RCA for mTPE in patients with increased bleeding risk.Methods Patients with increased bleeding risk who underwent mTPE between 2014 and 2021 in our center were screened. Observations of anticoagulation efficacy and safety were used as the study endpoints.Results A total of 108 patients with 368 mTPE sessions were included. Of the included patients, 38 and 70 received HA and RCA mTPE, respectively. There was no significant difference in the clotting of extracorporeal circuits between the HA and RCA groups (4.1% vs. 4.4%, p = 0.605). More bleeding episodes were observed in the HA group compared to the RCA group (16.4% vs. 4.4% mTPE sessions, p < 0.001). The frequency of postoperative transfusion within 24 h (11% vs. 3.4%, p = 0.007) was significantly different in the HA and RCA group. Anticoagulation strategy (HA vs. RCA; OR 5.659, 95%CI 2.266-14.129; p < 0.001), and mean arterial pressure (prior treatment, OR 1.052, 95%CI 1.019-1.086; p = 0.002) were independent risk factors of bleeding episodes. At the end of mTPE treatment, the incidence of metabolic alkalosis (16.7% vs. 54.1%, p = 0.027) and hypocalcemia (41.7% vs. 89.2%, p = 0.001) was significantly different in the HA (n = 5, 12 sessions) and RCA (n = 22, 74 sessions) groups, respectively.Conclusion RCA is as effective as HA for mTPE. However, for patients with increased bleeding risk, RCA is associated with a lower risk of bleeding, compared with HA. With careful monitoring and timely adjustment, RCA most likely is a safe and effective anticoagulation option for mTPE in patients with increased bleeding risk.