Platelet Membrane-Coated r-SAK Improves Thrombolytic Efficacy by Targeting Thrombus.

Thrombolytic therapy is one of the most effective treatments for thrombus dissolution and recanalization of blocked vessels in thrombotic diseases. However, the application of the thrombolytic strategy has been limited due to unsatisfactory thrombolytic efficacy, relatively higher bleeding complications, and consequently restricted indications. Recombinant staphylokinase (r-SAK) is a third-generation thrombolytic agent produced by genetic engineering technology, which exhibits a better thrombolytic efficacy than urokinase and recombinant streptokinase. Inspired by the natural affinity of platelets in hemostasis and pathological thrombosis, we developed a platelet membrane (PM)-coated r-SAK (PM-r-SAK). Results from animal experiments and human in vitro studies showed that the PM-r-SAK had a thrombolytic efficacy equal to or better than its 4-fold dose of r-SAK. In a totally occluded rabbit femoral artery thrombosis model, the PM-r-SAK significantly shortened the initial recanalization time compared to the same dose and 4-fold dose of r-SAK. Regarding the recanalized vessels, the PM-r-SAK prolonged the time of reperfusion compared to the same dose and 4-fold dose of r-SAK, though the differences were not significant. An in vitro thrombolytic experiment demonstrated that the thrombolytic efficacy of PM-r-SAK could be inhibited by platelet-poor plasma from patients taking aspirin and ticagrelor. PM coating significantly improves the thrombolytic efficacy of r-SAK, which is related to the thrombus-targeting activity of the PM-r-SAK and can be inhibited by aspirin- and ticagrelor-treated plasma.

Impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease patients complicated with end-stage renal disease.

It is controversial whether hemodialysis affects the efficacy of the antiplatelet agents. We aimed to investigate the impact of hemodialysis on efficacies of the antiplatelet agents in coronary artery disease (CAD) patients complicated with end-stage renal disease (ESRD). 86 CAD patients complicated with ESRD requiring hemodialysis were consecutively enrolled. After 5-day treatment with aspirin and clopidogrel or ticagrelor, the platelet aggregations induced by arachidonic acid (PLAA) or adenosine diphosphate (PLADP), and the P2Y12 reaction unit (PRU) were measured before and after hemodialysis. The propensity matching score method was adopted to generate a control group with normal renal function from 2439 CAD patients. In patients taking aspirin, the PLAA remained unchanged after hemodialysis. In patients taking clopidogrel, the PLADP (37.26 ± 17.04 vs. 31.77 ± 16.09, p = 0.029) and corresponding clopidogrel resistance (CR) rate (23 [48.9%] vs. 14 [29.8%], p = 0.022) significantly decreased after hemodialysis, though PRU remained unchanged. Subgroup analysis indicated that PLADP significantly decreased while using polysulfone membrane (36.8 ± 17.9 vs. 31.1 ± 14.5, p = 0.024). In patients taking ticagrelor, PLADP, and PRU remained unchanged after hemodialysis. ESRD patients had higher incidences of aspirin resistance (AR) and CR compared to those with normal renal function (AR: 16.1% vs. 0%, p = 0.001; CR: 48.4% vs. 24.8%, p = 0.024). Hemodialysis does not have negative effect on the efficacies of aspirin, clopidogrel and ticagrelor in ESRD patients with CAD. ESRD patients have higher incidences of AR and CR compared with those with normal renal function.Trial registration ClinicalTrials.gov Identifier: NCT03330223, first registered January 4, 2018.

Single Bolus r-SAK Before Primary PCI for ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: It is uncertain whether adjunctive thrombolysis is beneficial for patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) within 120 minutes of presentation. This study was to determine whether in patients presenting with ST-segment-elevation myocardial infarction a single bolus recombinant staphylokinase (r-SAK) before timely PCI leads to improved patency of the infarct-related artery and reduces the infarct size. METHODS: This is an open-label, prospective, multicenter, randomized study. We enrolled patients aged 18 to 75 years who were within 12 hours of symptom onset of ST-segment-elevation myocardial infarction and expected to undergo PCI within 120 minutes. Patients were administered loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive 5 mg bolus of r-SAK or normal saline intravenously before PCI. The primary end point was Thrombolysis in Myocardial Infarction flow grade 2 to 3 or grade 3 in the infarct-related artery 60 minutes after thrombolysis. The infarct size was detected by cardiac magnetic resonance 5 days after randomization. The safety end point was major bleeding (Bleeding Academic Research Consortium ≥3) during 30-day follow-up. RESULTS: A total of 283 patients were screened from 8 centers and 200 were randomized (median age, 58.5 years; 14% female). The median symptom to thrombolysis time was 252.5 (interquartile range, 142.8-423.8) minutes and thrombolysis to coronary arteriography was 50.0 (interquartile range, 37.0-66.0) minutes. Patients randomized to r-SAK compared with normal saline more often had Thrombolysis in Myocardial Infarction flow grade 2 to 3 (69.0% versus 29.0%; P<0.001) and Thrombolysis in Myocardial Infarction flow grade 3 (51.0% versus 18.0%; P<0.001) and had smaller infarct size (21.91±10.84% versus 26.85±12.37%; P=0.016). There was no increase in major bleeding (r-SAK, 1.0% versus control, 3.0%; P=0.616). CONCLUSIONS: A single bolus r-SAK before primary PCI for ST-segment-elevation myocardial infarction improves infarct-related artery patency and reduces infarct size without increasing major bleeding. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05023681.

Aortic calcification accelerates cardiac dysfunction via inducing apoptosis of cardiomyocytes.

Vascular calcification (VC) is a known predictor of cardiovascular events in patients with atherosclerosis and chronic renal disease. However, the exact relationship between VC and cardiovascular mortality remains unclear. Herein, we investigated the underlying mechanisms between VC progression, arterial stiffness, and cardiac dysfunction. C57BL/6 mice were administered intraperitoneally vitamin D3 (VD3) at a dosage of 35×104 IU/day for 14 days. At day 42, VC extent, artery elasticity, carotid artery blood flow, aorta pulse propagation velocity, cardiac function, and pathological changes were evaluated. Heart apoptosis was detected using TUNEL and immunohistochemistry staining. In vitro, rat cardiomyocytes H9C2 were exposed to media from calcified rat vascular smooth muscle cells (VSMCs) cultured in calcification medium, and then H9C2 apoptosis and gene expression related to cardiac function were assessed. VD3-treated mice displayed a significant aortic calcification, increased pulse propagation velocity of aortae, and reduced cardiac function. Aortae showed increased calcification and elastolysis, with increased heart apoptosis. Hearts demonstrated higher levels of ANP, BNP, MMP2, and lower levels of bcl2/bax. Moreover, calcified rat VSMC media induced H9C2 apoptosis and upregulated genes expression linked to cardiac dysfunction. Our data provide evidence that VC accelerates cardiac dysfunction, partially by inducing cardiomyocytes apoptosis.

Efficient biosynthesis of creatine by whole-cell catalysis from guanidinoacetic acid in Corynebacterium glutamicum.

Creatine is a naturally occurring derivative of an amino acid commonly utilized in functional foods and pharmaceuticals. Nevertheless, the current industrial synthesis of creatine relies on chemical processes, which may hinder its utilization in certain applications. Therefore, a biological approach was devised that employs whole-cell biocatalysis in the bacterium Corynebacterium glutamicum, which is considered safe for use in food production, to produce safe-for-consumption creatine. The objective of this study was to identify a guanidinoacetate N-methyltransferase (GAMT) with superior catalytic activity for creatine production. Through employing whole-cell biocatalysis, a gamt gene from Mus caroli (Mcgamt) was cloned and expressed in C. glutamicum ATCC 13032, resulting in a creatine titer of 3.37 g/L. Additionally, the study employed a promoter screening strategy that utilized nine native strong promoters in C. glutamicum to enhance the expression level of GAMT. The highest titer was achieved using the P1676 promoter, reaching 4.14 g/L. The conditions of whole-cell biocatalysis were further optimized, resulting in a creatine titer of 5.42 g/L. This is the first report of successful secretory creatine expression in C. glutamicum, which provides a safer and eco-friendly approach for the industrial production of creatine.

Mitigating life-cycle environmental impacts and increasing net ecosystem economic benefits via optimized fertilization combined with lime in pomelo production in Southeast China.

Excessive fertilization is acknowledged as a significant driver of heightened environmental pollution and soil acidification in agricultural production. Combining fertilizer optimization with soil acidity amendment can effectively achieve sustainable crop production in China, especially in Southeast China. However, there is a lack of long-term studies assessing the environmental and economic sustainability of combining fertilizer optimization with soil acidity amendment strategies, especially in fruit production. A four-year field experiment was conducted to explore pomelo yield, fruit quality, and environmental and economic performance in three treatments, e.g., local farmer practices (FP), optimized NPK fertilizer application (OPT), and OPT with lime (OPT+L). The results showed that the OPT+L treatment exhibited the highest pomelo yield and fruit quality among the three treatments. The OPT treatment had the lowest net greenhouse gas (GHG) emissions among the three treatments, which were 90.1 % and 42.6 % lower than those in FP and OPT+L, respectively. It is essential to note that GHG emissions associated with lime production constitute 40.7 % of the total emissions from fertilizer production. The OPT+L treatment reduced reactive nitrogen (Nr) emissions and phosphorus (P) losses, compared to FP and OPT. Moreover, the OPT+L treatment increased the net ecosystem economic benefit by 220.3 % and 20.3 % compared with the FP and OPT treatments, respectively. Overall, the OPT and OPT+L treatments underscore the potential to achieve environmentally friendly and economically sustainable pomelo production. Our study provides science-based evidence to achieve better environmental and economic performance in pomelo production through optimized NPK fertilization and alleviating soil acidification by lime.

Diagnostic Performance and Safety of a Novel Ferumoxytol-Enhanced Coronary Magnetic Resonance Angiography.

BACKGROUND: Currently, noninvasive arteriography for the diagnosis of coronary artery disease is clinically limited to the computed tomography scanning, where patients have to be exposed to the radiation and risks associated with iodinated contrast. We aimed to investigate the diagnostic performance and safety of a novel ferumoxytol-enhanced coronary magnetic resonance angiography (CMRA) in patients with suspected coronary artery disease. METHODS: Thirty patients, 19 males, with a median age of 63 years old, and 17 with renal insufficiency, who were scheduled for invasive coronary angiography, were enrolled. Ferumoxytol was administered intravenously with a dose of 3 mg/kg during CMRA. Images were acquired with an ECG-triggered, navigator-gated, inversion recovery-prepared 3D fast low-angle shot sequence, and the image quality was assessed by a 4-point scale. Eighteen-segment coronary artery model was adopted to evaluate the visibility of the coronary arteries, and the image quality and stenosis were evaluated in nine segments. The diagnostic performance of CMRA is described as sensitivity, specificity, positive and negative predictive values, and accuracy with the invasive coronary angiography results as reference. The patients' vital signs were monitored during CMRA, and their hepatic and renal functions were followed up for 3 months to evaluate the safety of ferumoxytol. RESULTS: Two hundred fifty-two of the 270 study segments were identified by CMRA, and their quality score reached 3.6±0.7. Referring to the invasive coronary angiography results, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ferumoxytol-enhanced CMRA reached 100.0%, 66.7%, 92.3%, 100.0%, and 93.3% respectively in patient-based analysis; 91.4%, 90.9%, 86.5%, 94.3%, and 91.1%, respectively in vessel-based analysis; and 92.3%, 96.7%, 83.7%, 98.6%, and 96.0%, respectively in segment-based analysis. No ferumoxytol-related adverse event was observed during the 3-month follow-up. CONCLUSIONS: Ferumoxytol-enhanced CMRA demonstrated good diagnostic performance and excellent safety in the diagnosis of significant coronary stenosis, providing an alternative to coronary computed tomography angiography for the diagnosis of coronary artery disease. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05032937.

Efficacy and safety of a bolus of half-dose r-SAK prior to primary PCI in ST-elevation myocardial infarction: Rationale and design of the OPTIMA-6 trial.

BACKGROUND: Time to reperfusion is the key to the treatment of patients with ST-elevation myocardial infarction (STEMI). It is uncertain whether adjunctive thrombolytic therapy combined with contemporary antiplatelet agent ticagrelor improves outcomes as administered prior to primary percutaneous coronary intervention (PCI) expected to be performed within 120 minutes. METHODS: OPTIMA-6 is a multicenter, randomized, double-blind, placebo-controlled, and superiority trial to evaluate the efficacy of a bolus of half-dose recombinant staphylokinase (r-SAK) vs placebo prior to timely primary PCI in patients with STEMI. Enrollment began in April 2023 and is expected to enroll 2,260 patients at approximately 50 centers. Patients with acute STEMI presenting ≤12 hours of symptom onset and expected to undergo primary PCI within 120 minutes but more than 30 minutes are to be randomized to a bolus of half-dose r-SAK or placebo. All recruited patients will be mandatory to take aspirin and ticagrelor and receive a bolus of loading dose heparin before the thrombolytic therapy. The primary efficacy endpoint is major adverse cardiovascular events (MACE) within 90 days, and the MACE is defined as a composite of all-cause death, reinfarction, unplanned target vessel revascularization, heart failure or cardiogenic shock, and major ventricular arrhythmia. The primary safety endpoints are major bleeding events (BARC 3, 5) within 90 days. CONCLUSIONS: OPTIMA-6 will reveal the efficacy and safety of a contemporary facilitated PCI with a bolus of half-dose r-SAK in combination with ticagrelor in patients with STEMI.

Rationale and design of the optimal antithrombotic treatment for acute coronary syndrome patients with concomitant atrial fibrillation and implanted with new-generation drug-eluting stent: OPtimal management of anTIthroMbotic Agents (OPTIMA)-4 trial.

BACKGROUND: About 5%-15% of acute coronary syndrome (ACS) patients undergoing stent implantation have concomitant atrial fibrillation and need both antiplatelet and anticoagulant therapies. The optimal antithrombotic regimen remains uncertain in this scenario. HYPOTHESIS: A multicenter randomized controlled trial (OPtimal management of anTIthroMbotic Agents [OPTIMA]-4) is designed to test the hypothesis that, for ACS patients with concomitant nonvalvular atrial fibrillation (NVAF) and having low-to-moderate risk of bleeding, clopidogrel is comparable in efficacy but superior in safety compared to ticagrelor while being used in combination with dabigatran after new-generation drug-eluting stent (DES) implantation. METHODS: ACS patients who have low-to-moderate risk of bleeding (e.g., HAS-BLED score ≤ 2) and require anticoagulation therapy (CHA2 DS2 -VASc score ≥ 2) will be recruited after implantation of new-generation DES. A total of 1472 eligible patients will be randomly assigned to receive a 12-month dual antithrombotic treatment of either clopidogrel 75 mg daily or ticagrelor 90 mg twice daily in combination with dabigatran 110 mg twice daily. Participants will be followed up for 12 months after randomization. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, unplanned revascularization, ischemic stroke, and systemic thromboembolism. The primary safety endpoint is set as major bleeding or clinically relevant nonmajor bleeding defined by the International Society of Thrombosis and Hemostasis. The enrollment and follow-up have been launched. RESULTS: The first enrollment occurred on March 12, 2018. The recruitment is anticipated to be completed before December 31, 2024. CONCLUSIONS: The OPTIMA-4 trial offers an opportunity to assess the optimal dual antithrombotic regimen in ACS patients with concomitant NVAF after the implantation of new-generation DES.

Quantitative assessment of selective degradation behavior of etoxazole in different classes of organisms by compound-specific isotope analysis.

In this paper, the stereoselective degradation and quantitative identification of chiral pesticide etoxazole in organisms with different classes of organisms (soil, chlorella algal fluid and mice) were carried out by compound-specific isotope analysis (CSIA). The degradation behavior and stable isotope fractionation effect of etoxazole in soil, chlorella and mice were investigated. The R-etoxazole degraded faster than S-etoxazole in different classes of organisms. The metabolites M1, M2 and M3 were detected in all three substrates. Biodegradation is the main factor for the change of stable isotope ratio of chiral pesticide etoxazole. Furthermore, the relationship between fractionation value of carbon isotope and residual concentration of etoxazole is established by Rayleigh equation, and the biodegradation rate of etoxazole could be calculated by using CSIA without measuring the concentration of etoxazole. Therefore, the use of CSIA can accurately assess the degradation behavior of pesticide pollution in the environment and provide a certain scientific evidence and technical support in the process of environmental remediation.

Interleukin-29 Accelerates Vascular Calcification via JAK2/STAT3/BMP2 Signaling.

Background Vascular calcification (VC), associated with enhanced cardiovascular morbidity and mortality, is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells. Inflammation promotes VC initiation and progression. Interleukin (IL)-29, a newly discovered member of type III interferon, has recently been implicated in the pathogenesis of autoimmune diseases. Here we evaluated the role of IL-29 in the VC process and underlying inflammatory mechanisms. Methods and Results The mRNA expression of IL-29 was significantly increased and positively associated with an increase in BMP2 (bone morphogenetic protein 2) mRNA level in calcified carotid arteries from patients with coronary artery disease or chronic kidney disease. IL-29 and BMP2 proteins are colocalized in human calcified arteries. IL-29 binding to its specific receptor IL-28Rα (IL-28 receptor α) (IL-29/IL-28Rα) inhibited the proliferation of rat vascular smooth muscle cells without altering cell apoptosis or migration. IL-29 promoted the calcification of rat vascular smooth muscle cells and their osteogenic transdifferentiation in vitro as well as the rat aortic ring calcification ex vivo, induced by the calcification medium or osteogenic medium. The procalcification effect of IL-29 was reduced by pharmacological inhibition of IL-29/IL-28Rα binding as well as suppression of janus kinase 2/signal transducer and activator of transcription pathway activation, accompanied by decreased BMP2 expression in the cultured rat vascular smooth muscle cells. Conclusions These results suggest an important role of IL-29 in VC development, at least partly, via activating the janus kinase 2/signal transducer and activator of transcription 3 signaling. Inhibition of IL-29 or its specific receptor, IL-28Rα, may provide a novel strategy to reduce VC in patients with vascular diseases.

Effects of ilaprazole on the steady-state pharmacodynamics of clopidogrel in healthy volunteers: An open-label randomized crossover study.

Background: Previous studies have suggested that proton pump inhibitors could impair the antiplatelet effect of clopidogrel. It is uncertain whether ilaprazole affects the antiplatelet effect of clopidogrel. This study aimed to determine the drug-drug interaction between ilaprazole and clopidogrel. Methods: A randomized crossover trial of 40 healthy subjects was performed. Clopidogrel was administered alone or in combination with ilaprazole for 7 days. The maximal platelet aggregation (MPA) to 5 µmol/L adenosine diphosphate was measured by light transmission aggregometry and the platelet reactivity index (PRI) was determined by vasodilator-stimulated phosphoprotein P2Y12 assay. High on-treatment platelet reactivity (HOPR) was defined as a MPA of >40%. The inhibition of platelet aggregation (IPA) and PRI in the two phases were compared between two regimens after the last dosing. Results: IPA was comparable between the two regimens at 0, 10 and 24 h (p > 0.05), but higher at 4 h in the clopidogrel alone regimen compared with that in the combined treatment regimen (75.66 ± 18.44% vs. 70.18 ± 17.67%, p = 0.031). The inhibition of PRI was comparable between the two regimens at 0 and 24 h. There were no significant differences in the area under the time-IPA% curve (AUC) or the incidence of HOPR at all time-points between the two regimens. Conclusion: In healthy subjects, ilaprazole has limited effect on the pharmacodynamics of clopidogrel and it may not be clinically relevant. Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR2000031482].

Impact of Insulin Receptor Substrate-1 rs956115 and CYP2C19 rs4244285 Genotypes on Clinical Outcome of Patients Undergoing Percutaneous Coronary Intervention.

Background Insulin receptor substrate-1 (IRS-1) rs956115 is associated with vascular risk in patients with coronary artery disease and concomitant diabetes. CYP2C19*2 (rs4244285) modulates clopidogrel response and predicts the outcome of coronary artery disease. This study was designed to explore the association between IRS-1, CYP2C19*2 genotypes, platelet reactivity, and 1-year outcome in patients with coronary artery disease undergoing percutaneous coronary intervention. Methods and Results Genotyping was performed using an improved multiplex ligation detection reaction technique. Platelet aggregation was assessed by light transmission aggregometry. Major adverse cardiovascular events were defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. A total of 2213 consecutive patients were screened and 1614 were recruited. At 1 month, patients with IRS-1 CG genotype had significantly lower levels of ADP-induced platelet aggregation compared with patients with CC homozygotes. Patients with IRS-1 CG or GG genotype had a 2.09-fold higher risk of major adverse cardiovascular events compared with those with CC homozygotes (95% CI, 1.04-4.19; P=0.0376). By comparison, patients with CYP2C19*2 GA or AA genotype had higher ADP-induced platelet aggregation compared with patients with GG homozygotes. Although there was no significant difference in risk of major adverse cardiovascular events between patients with GA/AA and GG genotypes, patients with GA genotype had a 2.19-fold higher risk than those with GG homozygotes (95% CI, 1.13-4.24; P=0.0200). No interaction between IRS-1 and CYP2C19*2 genotypes was observed. Conclusions In patients following percutaneous coronary intervention, IRS-1 GG/CG and CYP2C19*2 GA genotypes were associated with 2.09- and 2.19-fold increased cardiovascular risk, respectively, at 1-year follow-up. The association between IRS-1 genotypes and major adverse cardiovascular events appeared to be independent of known clinical predictors. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01968499.

Use of handheld electrocardiograph (SnapECG) for the remote monitoring of arrhythmias.

Objective: To investigate the value of a SnapECG monitoring in diagnosing arrhythmias compared with the conventional management. Methods: In the first phase, the SnapECG and 12-lead electrocardiogram (ECG) were simultaneously adopted to detect arrhythmias in 439 hospitalized patients. The accuracies of the SnapECG in detecting different arrhythmias were assessed. In the second phase, 62 patients with palpitations were randomized to receive the SnapECG monitoring or conventional management for 3 months. The diagnosis rate, time of diagnosis, episodes before diagnosis, associated expenses, and scores of the modified European Heart Rhythm Association (EHRA), Self-rating Anxiety Scale (SAS), and the 36-item short-form health survey questionnaire (SF-36) were compared between groups. Results: In the first phase, the SnapECG monitoring showed a sensitivity of 83.55% and specificity of 96.79% in identifying tachyarrhythmias, and a sensitivity of 95.29% and specificity of 97.54% in identifying bradyarrhythmias. In the second phase, 1642 ECGs were recorded by the SnapECG, among which 290 abnormal ECGs were identified. Compared with the conventional management, the SnapECG monitoring increased the diagnosis rate of symptomatic arrhythmias (70.97% vs. 19.35%, P < 0.05), shortened the time of diagnosis (48.26 ± 36.78 days vs. 71.45 ± 30.01 days, P < 0.05) and consequently reduced the episodes of symptomatic arrhythmias prior to establishing diagnosis. The scores of modified EHRA, SAS, SF-36 significantly improved at 3-month compared with their baseline levels in the SnapECG group. Conclusions: Remote monitoring with the SnapECG can achieve early diagnosis of symptomatic arrhythmias. However, its sensitivity in identifying P-wave-related arrhythmias warrants further improvement.

Physiological Essence of Magnesium in Plants and Its Widespread Deficiency in the Farming System of China.

Magnesium (Mg) is an essential nutrient for a wide array of fundamental physiological and biochemical processes in plants. It largely involves chlorophyll synthesis, production, transportation, and utilization of photoassimilates, enzyme activation, and protein synthesis. As a multifaceted result of the introduction of high-yielding fertilizer-responsive cultivars, intensive cropping without replenishment of Mg, soil acidification, and exchangeable Mg (Ex-Mg) leaching, Mg has become a limiting nutrient for optimum crop production. However, little literature is available to better understand distinct responses of plants to Mg deficiency, the geographical distribution of soil Ex-Mg, and the degree of Mg deficiency. Here, we summarize the current state of knowledge of key plant responses to Mg availability and, as far as possible, highlight spatial Mg distribution and the magnitude of Mg deficiency in different cultivated regions of the world with a special focus on China. In particular, ~55% of arable lands in China are revealed Mg-deficient (< 120 mg kg-1 soil Ex-Mg), and Mg deficiency literally becomes increasingly severe from northern (227-488 mg kg-1) to southern (32-89 mg kg-1) China. Mg deficiency primarily traced back to higher depletion of soil Ex-Mg by fruits, vegetables, sugarcane, tubers, tea, and tobacco cultivated in tropical and subtropical climate zones. Further, each unit decline in soil pH from neutral reduced ~2-fold soil Ex-Mg. This article underscores the physiological importance of Mg, potential risks associated with Mg deficiency, and accordingly, to optimize fertilization strategies for higher crop productivity and better quality.

Association of serum creatinine with aortic arch calcification in middle-aged and elderly adults: an observational cross-sectional study from China.

BACKGROUND AND AIMS: Vascular calcification (VC) is a strong predictor of cardiovascular events and all-cause mortality in cardiovascular diseases (CVD). Renal dysfunction is closely related to VC. Serum creatinine, as an important indicator of renal function in chronic kidney disease (CKD), is closely associated with increased VC. Here, to explore the potential role of serum creatinine in CVD, we examined the association between serum creatinine level and aortic arch calcification (AAC) presence in a larger general population. METHODS: A total of 9067 participants aged > 45 years were included in this study. All participants underwent postero-anterior chest X-ray examination to diagnose AAC. According to the distribution characteristics, serum creatinine levels in male and female were divided into tertiles respectively. Univariate and multivariate logistic regression analysis were used to analyze the association between aortic calcification and serum creatinine. RESULTS: Participants included 3776 men and 5291 women, and 611 and 990 AAC were detected, respectively. Serum creatinine level in the female AAC group was significantly higher than that in the non-AAC group (p < 0.001), while there was no significant difference in male serum creatinine between the two groups (p = 0.241). After logistic regression analysis excluded confounding factors, with the first tertile of serum creatinine as the reference, multivariable-adjusted ORs and 95% CIs of the second and the highest tertile of female and male were 1.045 (0.856-1.276), 1.263 (1.036-1.539); 0.953 (0.761-1.193), 0.948 (0.741-1.198), respectively. CONCLUSION: Elevated serum creatinine levels are independently associated with higher AAC incidence in female aged > 45 years old. Measuring serum creatinine levels may assist the early screening individuals at high risk of developing CVD. And higher attention should be given to female's serum creatinine levels in daily clinical practice.

Simultaneous determination of clopidogrel, 2-oxo-clopidogrel, and the thiol metabolite of clopidogrel in human plasma by LC-MS/MS.

Clopidogrel is a pro-drug which needs two-step metabolism to produce the active thiol metabolite. This study aimed to explore an efficient method to simultaneously determine the plasma clopidogrel, 2-oxo-clopidogrel (2-Oxo-CLP), and the clopidogrel active metabolite (CAM). A high-throughput liquid chromatography tandem mass spectrometry (LC-MS/MS) was therefore developed. The analytes were extracted from plasma by using methyl tert-butyl ether (MTBE). Chromatographic separation was performed on a C18 column under an isocratic elution, accompanied with acetonitrile and deionized water containing 0.1% formic acid. After optimizing the condition of LC-MS/MS, a stable linearity was observed in the standard curves over the concentration ranges of 0.05 to 50.0 ng/mL for clopidogrel, 0.5 to 50.0 ng/mL for 2-Oxo-CLP, and 0.5 to 100 ng/mL for clopidogrel active metabolite derivative (CAMD). The retention time was 4.78 minutes, 3.79 minutes, 3.59 minutes, and 4.82 minutes for clopidogrel, 2-Oxo-CLP, CAMD, and internal standard, respectively. Both the relative standard deviation and the relative error were within the requirement of operating criteria. No significant degradation of clopidogrel, 2-Oxo-CLP, and CAMD occurred under different storage conditions. This method was successfully validated in 3 patients with coronary artery disease. The results showed that the current LC-MS/MS method was efficient for simultaneously detecting clopidogrel, 2-Oxo-CLP, and CAM with fine linearity, accuracy, precision, and stability.

Predictive Value of Globulin to Prealbumin Ratio for 3-Month Functional Outcomes in Acute Ischemic Stroke Patients.

Objective: We aimed to evaluate and compare the association between globulin to albumin ratio (GAR) and globulin to prealbumin ratio (GPR) and 3-month functional prognosis of acute ischemic stroke (AIS) patients receiving intravenous thrombolysis therapy. Methods: 234 AIS patients undergoing intravenous thrombolysis were retrospectively enrolled with acute ischemic stroke from February 2016 to October 2019. Blood sample was collected within 24 h after admission. Poor outcome was defined as the modified Rankin Scale (mRS) ≥ 3 and a favorable outcome as mRS < 3. Severe stroke was defined as the National Institutes of Health Stroke Scale (NIHSS) score > 10 on admission. Student's t-test, Mann-Whitney U test, Chi-square test, logistics' regression analysis, and receiver operating characteristic (ROC) analysis were performed. Results: Patients with poor functional outcome had higher GAR and GPR levels compared with favorable functional group (p = 0.001, p < 0.001, respectively). Severe stroke was also associated with these two increasing variables. After adjustment for confounding factors, multivariate logistic regression analysis indicated that GPR was an independent indicator predictor of AIS. Conclusions: The 24 h GPR level can predict the 3-month functional outcome in AIS patients accepting recombinant tissue plasminogen activator (r-tPA) intravenous thrombosis.