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Study Design: Retrospective cohort study., Objectives: To evaluate the predictive value of D-dimer/fibrinogen (D/F) ratio for deep vein thrombosis (DVT) in patients with traumatic spinal cord injury (SCI)., Setting: Department of Rehabilitation Medicine Center, West China Hospital, Sichuan University., Methods: SCI patients within 24 h of trauma were consecutively enrolled. DVT was diagnosed by DUS examination during hospitalization. Multivariable logistic regression analysis was performed to determine the relationship between D/F ratio and DVT. Stratified logistic regression analysis was performed to identify effect modifiers. The receiver operating characteristic (ROC) curve was conducted to assess the predictive value of D/F ratio., Results: A total of 284 patients with SCI were included, of whom 106 (37.3%) developed DVT. D/F ratio was positively correlated with DVT (OR 1.17, 95% confidence interval [CI] 1.04-1.31, p = 0.009). Patients in the upper D/F ratio tertile (3.15-18.27) had a higher risk of DVT than patients in the lower tertile (0.08-0.97) after adjustment for potential confounders (OR 6.01, 95% CI 2.24-16.15, p < 0.001). The risk of DVT increased stepwise across D/F ratio tertiles (p for trend = 0.003). The area under the ROC curve (AUC) was 0.758 (95% CI 0.704-0.806). There was a significant interaction between D/F ratio and neurological level of injury (p for interaction = 0.003) and the association between D/F ratio and DVT remained significant only in patients with cervical injury., Conclusions: A higher D/F ratio was independently associated with a higher risk of DVT in a dose-dependent manner in patients with cervical SCI., (© 2023. The Author(s), under exclusive licence to International Spinal Cord Society.)

Understanding the electric double layer (EDL) of the metal electrode-electrolyte interface is essential to electrochemistry and relevant disciplines. In this study, potential-dependent electrode Sum Frequency Generation (SFG) intensities of polycrystalline gold electrodes in HClO4 and H2SO4 electrolytes were thoroughly analyzed. The potential of zero charges (PZC) of the electrodes was -0.06 and 0.38 V in HClO4 and H2SO4, respectively, determined from differential capacity curves. Without specific adsorption, the total SFG intensity was dominated by the contribution from the Au surface and increased similar to that of the visible (VIS) wavelength scanning, which pushed the SFG process closer to the double resonant condition in HClO4. However, the EDL contributed about 30% SFG signal with specific adsorption in H2SO4. Below PZC, the total SFG intensity was dominated by the Au surface contribution and increased with potential at a similar slope in these two electrolytes. Around PZC, as the EDL structure became less ordered and the electric field changed direction, there would be no EDL SFG contribution. Above PZC, the total SFG intensity increased much more rapidly with potential in H2SO4 than in HClO4, which suggested that the EDL SFG contribution kept increasing with more specific adsorbed surface ions from H2SO4., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Objectives: The New Chinese Diabetes Risk Score (NCDRS) is a noninvasive tool to assess the risk of type 2 diabetes mellitus (T2DM) in the Chinese population. Our study aimed to evaluate the performance of the NCDRS in predicting T2DM risk with a large cohort. Methods: The NCDRS was calculated, and participants were categorized into groups by optimal cutoff or quartiles. Hazard ratios (HRs) and 95% confidential intervals (CIs) in Cox proportional hazards models were used to estimate the association between the baseline NCDRS and the risk of T2DM. The performance of the NCDRS was assessed by the area under the curve (AUC). Results: The T2DM risk was significantly increased in participants with NCDRS ≥25 (HR = 2.12, 95% CI 1.88-2.39) compared with NCDRS <25 after adjusting for potential confounders. T2DM risk also showed a significant increasing trend from the lowest to the highest quartile of NCDRS. The AUC was 0.777 (95% CI 0.640-0.786) with a cutoff of 25.50. Conclusion: The NCDRS had a significant positive association with T2DM risk, and the NCDRS is valid for T2DM screening in China., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2023 Chen, She, Dai, Wang, Tao, Huang, Xu, Lou, Hu, Li and Wang.)

Metabolic defects increase the risk of skeletal muscle diseases, and muscle impairment might worsen metabolic disruption, leading to a vicious cycle. Both brown adipose tissue (BAT) and skeletal muscle play important roles in non-shivering thermogenesis to regulate energy homeostasis. BAT regulates body temperature, systemic metabolism, and seretion of batokines that have positive or negative impacts on skeletal muscle. Conversely, muscle can secrete myokines that regulate BAT function. This review explained the crosstalk between BAT and skeletal muscle, and then discussed the batokines and highlighted their impact on skeletal muscle under physiological conditions. BAT is now considered a potential therapeutic target for obesity and diabetes treatment. Moreover, manipulation of BAT may be an attractive approach for the treatment of muscle weakness by correcting metabolic deficits. Therefore, exploring BAT as a potential treatment for sarcopenia could be a promising avenue for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Hu, Wang and Wang.)

Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis, but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity, we proposed a "two-step approach" that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC 50  = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC 50  = 4.56 μmol/L) and the positive control gefitinib (IC 50  = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK. Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes, thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5, a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Study Design: Retrospective cohort study., Objectives: To investigate the association between neutrophil percentage-to-albumin ratio (NPAR) and pneumonia in patients with SCI., Setting: Department of Rehabilitation Medicine Center, West China Hospital, Sichuan University., Methods: SCI patients admitted to West China Hospital within 24 h of injury were consecutively enrolled. Blood samples were collected on admission. Pneumonia was diagnosed based on chest radiography and clinician records of patient symptoms and laboratory tests. Multivariable logistic regression analysis was performed to determine the relationship between NPAR and pneumonia. Receiver operating characteristic (ROC) curves were generated to assess the predictive value of NPAR., Results: A total of 264 SCI patients were included, of whom 65 (24.6%) developed pneumonia. NPAR was positively correlated with pneumonia (OR 2.66, 95% CI, 1.06-6.71, p = 0.038). Patients in the upper NPAR tertile (2.35-3.71) had a higher risk of pneumonia than patients in the lower tertile (1.66-2.12) after adjustment for potential confounders (OR 2.55, 95% CI, 1.05-6.19, p = 0.039). The risk of pneumonia increased stepwise across NPAR tertiles (p for trend = 0.031). The optimal cutoff value of NPAR for predicting pneumonia was 2.17 with a sensitivity of 0.82 and a specificity of 0.50. There was a significant interaction between NPAR and neurological level of injury (p for interaction = 0.034), with no significant association between NPAR and pneumonia in patients with cervical SCI., Conclusions: A higher NPAR was independently associated with higher risk of pneumonia in a dose-dependent manner in patients with non-cervical SCI., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Rate control is a cornerstone of atrial fibrillation treatment. Barium titanate nanoparticles (BTNPs) are piezoelectric nanomaterials that can generate local electromagnetic fields under ultrasound activation, stimulating nearby neuronal tissue. This study aimed to modulate the inferior right ganglionated plexus (IRGP) of the heart and reduce the ventricular rate during rapid atrial pacing (RAP)-induced atrial fibrillation using ultrasound-mediated BTNPs. Adult male beagles were randomly divided into a phosphate-buffered saline (PBS) group ( n = 6) and a BTNP group ( n = 6). PBS or nanoparticles were injected into the IRGP of both groups before RAP. The biological safety of the material was evaluated according to electrophysiology recordings, thermal effects and level of inflammation. Compared to the PBS group, the BaTiO 3 piezoelectric nanoparticle group had reduced ventricular rates in the sinus rhythm and atrial fibrillation models after stimulating the IRGP by applying ultrasound. In addition, transient stimulation by BTNPs did not lead to sustained neuronal excitation in the IRGP. The activation of the BTNPs did not induce inflammation or thermal damage effects in the IRGP. Ultrasound-mediated BTNP neuromodulation can significantly reduce the ventricular rate by stimulating the IRGP. Thus, ultrasound-mediated BTNP neuromodulation is a potential therapy for atrial fibrillation rate control.

Objectives: Clinical outcomes following myocardial ischemia-reperfusion (I/R) injury are strongly related to the intensity and duration of inflammation. The splenic nerve (SpN) is indispensable for the anti-inflammatory reflex. This study aimed to investigate whether splenic nerve stimulation (SpNS) plays a cardioprotective role in myocardial I/R injury and the potential underlying mechanism., Methods: Sprague-Dawley rats were randomly divided into four groups: sham group, I/R group, SpNS group, and I/R plus SpNS group. The highest SpNS intensity that did not influence heart rate was identified, and SpNS at this intensity was used as the subthreshold stimulus. Continuous subthreshold SpNS was applied for 1 h before ligation of the left coronary artery for 45 min. After 72 h of reperfusion, samples were collected for analysis., Results: SpN activity and splenic concentrations of cholinergic anti-inflammatory pathway (CAP)-related neurotransmitters were significantly increased by SpNS. The infarct size, oxidative stress, sympathetic tone, and the levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, were significantly reduced in rats subjected to subthreshold SpNS after myocardial I/R injury compared with those subjected to I/R injury alone., Conclusions: Subthreshold SpNS ameliorates myocardial damage, the inflammatory response, and cardiac remodelling induced by myocardial I/R injury via neuroimmunomodulation of proinflammatory factor levels. SpNS is a potential therapeutic strategy for the treatment of myocardial I/R injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In patients with cardiovascular diseases, it is reported that the triglyceride-glucose index (TGI) potentially indicates prognosis. However, the results are controversial. Moreover, whether age has an impact on the predictive value of TGI remains unclear., Methods: Participants with cardiovascular diseases were enrolled using the China Health and Retirement Longitudinal Study (CHARLS) registry. TGI was calculated as ln (triglyceride×glucose/2). The survival status was recorded every 2 years in the follow-up waves. Multivariate regression analysis was carried out to determine the relationship between TGI levels and long-term all-cause mortality in patients grouped by different age. Patients younger than 65 years old were regarded as middle-aged group. Otherwise, they were classified as old group., Results: In total, 2923 patients with cardiovascular diseases and baseline blood test results were included. After 7 years of follow-up, 242 (8.91%) patients died. Cox regression analysis revealed that higher TGI levels were associated with a higher risk of long-term all-cause mortality in middle-aged participants (hazard ratio [HR], 3.64; 95% confidence interval [CI] 1.44-9.22, P = 0.006) but not in old participants (HR 1.20, 95% CI 0.62-2.32, P = 0.594, P for interaction = 0.017), after adjusting physical activity and other factors. Kaplan-Meier estimate analysis and restricted cubic spline curves showed similar results., Conclusion: TGI was a promising marker for predicting all-cause mortality in middle-aged patients after cardiovascular diseases. Patients younger than 65 years old who have a higher level of TGI may develop a higher risk of all-cause mortality, and they are encouraged to control vascular risk factors and take more physical activity to improve their prognosis. Additionally, whether intervention in regulating TGI levels is beneficial for the prognosis of these patients needs further investigation., (© 2022. The Author(s).)

Aims: PDK1 is one of the key enzymes in the glucose metabolism pathway, which is abnormally high expressed in breast cancer tissues and can promote tumor proliferation and metastasis. PDK1 and the PDHC/PDK axis are important targets for regulating glucose metabolism and anti-tumor activity. In this study, we evaluated the anti-tumor activities of a series of semi-synthesized shikonin (SK) derivatives against human breast cancer cells., Main Methods: The anti-proliferation activity of SK derivatives against human breast cancer cell lines was tested by CCK-8 and EdU assay. Flow cytometry was utilized to evaluate cell apoptosis, reactive oxygen species and cell cycle distribution. Cell migration ability was determined by wound healing and trans-well assay. PDK1 targeting effect was confirmed by western bolting, molecular docking, bio-layer interferometry and PDK1 enzyme activity assay. Nude-mouse transplanted tumor model was used to evaluate their anti-tumor effect in vivo., Key Findings: Findings revealed that SK derivatives had good anti-proliferation ability against MDA-MB-231 cell. They induced cell apoptosis by regulating the mitochondrial apoptosis and death receptor pathway. They also inhibited cell migration by suppressing EMT progression. Molecular docking, PDK1 affinity and enzyme activity demonstrated their PDK1 targeting. In vivo antitumor experiment showed that E2 could significantly inhibit tumor growth with lower side-effect on mice than SK., Significance: In conclusion, the novel SK derivatives E2 and E5 inhibited tumor glycolysis by targeting PDK1 and ultimately induced apoptosis. Our data demonstrated that E2 would be a good lead compound for the treatment of human TNBC as a novel PDK1 inhibitor., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2022. Published by Elsevier Inc.)

The seepage is completed under the control of the action. There is a definite relationship between the seepage and its controlling factors. The recharge flow, seepage flow and water level change are unified. In this paper, the exact and complete relationship among seepage flow, recharge flow and water level change is discussed in detail through field observation and repeated tests, and a new equation for clarifying seepage flow law and water level change law is established, it provides more accurate, more convenient and more reliable theoretical basis for solving the problem of seepage flow. At the same time, through the study of seepage movement law, it is found that the method of parameter introduction has some disadvantages, and then a new method is established to study the law of seepage movement., (© 2022. The Author(s).)

The BAHD acyltransferase family is a unique class of plant proteins that acylates plant metabolites and participates in plant secondary metabolic processes. However, the BAHD members in Lithospermum erythrorhizon remain unknown and uncharacterized. Although the heterologously expressed L. erythrorhizon BAHD family member LeSAT1 in Escherichia coli has been shown to catalyze the conversion of shikonin to acetylshikonin in vitro, its in vivo role remains unknown. In this study, the characterization, evolution, expression patterns, and gene function of LeBAHDs in L. erythrorhizon were explored by bioinformatics and transgenic analysis. We totally identified 73 LeBAHDs in the reference genome of L. erythrorhizon . All LeBAHDs were phylogenetically classified into five clades likely to perform different functions, and were mainly expanded by dispersed and WGD/segmental duplication. The in vivo functional investigation of the key member LeBAHD1/LeSAT1 revealed that overexpression of LeBAHD1 in hairy roots significantly increased the content of acetylshikonin as well as the conversion rate of shikonin to acetylshikonin, whereas the CRISPR/Cas9-based knockout of LeBAHD1 in hairy roots displayed the opposite trend. Our results not only confirm the in vivo function of LeBAHD1/LeSAT1 in the biosynthesis of acetylshikonin, but also provide new insights for the biosynthetic pathway of shikonin and its derivatives.

This study aimed to evaluate the potential associations of dietary BCAAs (isoleucine, leucine, and valine) with physical function in the elderly Chinese population. A validated semiquantitative food frequency questionnaire and anthropometric and physical function measurements were used to collect data. We modeled trends in physical function indicators for BCAA quartiles using multivariate linear regression models. Among 4336 (43.97% men) participants aged 72.73 ± 5.48 years, a higher dietary intake of BCAAs was positively associated with increased handgrip strength (all p trends < 0.001), shorter times for 4-m fast walking (all p trends < 0.001) and repeated chair rises (all p trends < 0.001). No linear association was found between subtypes of amino acids and any physical functions (all p trends > 0.05). Individuals in the highest quartiles of BCAA intake had a reduced risk of developing low muscle strength, and the multiadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for women and men were 0.50 (0.38−0.65) and 0.67 (0.50−0.91), respectively. Similarly, higher BCAA consumption was associated with a lower risk of developing low physical performance (4-m walking speed: OR = 0.68 [0.50−0.93]; repeated chair rises: OR = 0.66 [0.54−0.81]). Higher dietary BCAA intake might be beneficial for physical function in the elderly population.

Sarcopenia is a progressive skeletal muscle disease that occurs most commonly in the elderly population, contributing to increased costs and hospitalization. Exercise and nutritional therapy have been proven to be effective for sarcopenia, and some drugs can also alleviate declines in muscle mass and function due to sarcopenia. However, there is no specific pharmacological treatment for sarcopenia at present. This review will mainly discuss the relationship between inflammaging and sarcopenia. The increased secretion of proinflammatory cytokines with aging may be because of cellular senescence, immunosenescence, alterations in adipose tissue, damage-associated molecular patterns (DAMPs), and gut microbes due to aging. These sources of inflammaging can impact the sarcopenia process through direct or indirect pathways. Conversely, sarcopenia can also aggravate the process of inflammaging, creating a vicious cycle. Targeting sources of inflammaging can influence muscle function, which could be considered a therapeutic target for sarcopenia. Moreover, not only proinflammatory cytokines but also anti-inflammatory cytokines can influence muscle and inflammation and participate in the progression of sarcopenia. This review focuses on the effects of TNF-α, IL-6, and IL-10, which can be detected in plasma. Therefore, clearing chronic inflammation by targeting proinflammatory cytokines (TNF-α, IL-1, IL-6) and the inflammatory pathway (JAK/STAT, autophagy, NF-κB) may be effective in treating sarcopenia., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: Neutrophils and albumin are associated with outcomes in patients with acute ischemic stroke (AIS). We aimed to explore the association between the neutrophil percentage-to-albumin ratio (NPAR), a novel marker of inflammation and oxidative stress, and the 3-month functional outcome in AIS patients with reperfusion therapy., Methods: This single-center, retrospective cohort study consecutively enrolled AIS patients with reperfusion therapy. Neutrophils and albumin were collected on admission. The primary outcome was a poor functional outcome, which was defined as a modified Rankin scale score of 3-6 at 3 months., Results: A total of 647 patients with AIS who received reperfusion therapy were analyzed. The mean age was 68.9 ± 13.9 years, and 358 (55.3%) of the patients were men. The median NPAR was 1.89 (interquartile range [IQR] 1.64-2.09). The percentage of patients with a 3-month poor functional outcome was 57.0% (369/647). NPAR was positively associated with a poor functional outcome (odds ratio [ OR ] 2.76, 95% CI : 1.52-5.03, p = 0.001). When patients were classified into tertiles, patients in the upper tertile (2.03-7.59) had a higher risk of poor outcome than patients in the lower tertile after adjusting for potential confounders (0.78-1.73) ( OR 2.10, 95% CI : 1.28-3.42, p = 0.003). The risk of poor outcome increased with NPAR tertiles ( p -trend = 0.003). The optimal cut-off value of the NPAR for predicting a poor outcome was 1.72, with a sensitivity of 0.75, and a specificity of 0.43., Conclusion: Neutrophil percentage-to-albumin ratio was significantly associated with 3-month poor functional outcomes in patients with AIS who received reperfusion therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cui, Wang, Zhu, Li, Yang, Wang, Zhang, Shang and Wu.)

Aims: This study was conducted to evaluate 35 natural flavonoids for their in vitro susceptibility against E. coli (ATCC 25922), Ps. aeruginosa (ATCC 27853), B. subtilis (ATCC 530) and Staph. aureus (ATCC 6538) in search of a potential broad-spectrum antibiotic., Methods and Results: Glabridin, a natural isoflavonoid isolated from Glycyrrhiza glabra L., was identified to be highly active with a MIC of 8-16 μg ml -1 against Staph. aureus, B. subtilis and E. coli. By the results of the docking simulation, we located the potential targets of glabridin as DNA gyrase and dihydrofolate reductase (DHFR). The subsequent DNA gyrase inhibition assays (glabridin: IC 50  = 0.8516 μmol L -1 , ciprofloxacin: IC 50  = 0.04697 μmol L -1 ), DHFR inhibition assays (glabridin: inhibition ratio = 29%, methotrexate: inhibition ratio = 45% under 100 μmol L -1 treatment) and TUNEL confirmed that glabridin acted as DNA gyrase inhibitor and DHFR mild inhibitor, exerting bactericidal activity by blocking bacterial nucleic acid synthesis. CCK-8 and in silico calculations were also conducted to verify the low cytotoxicity and acceptable druggability of glabridin., Conclusion: These findings suggest that glabridin represents the prototypical member of an exciting structural class of natural antimicrobial agents., Significance and Impact of the Study: This study reports a novel mechanism of bactericidal activity of glabridin against Staph. aureus., (© 2022 Society for Applied Microbiology.)

Newly formed plant allopolyploids usually have meiosis defect, resulting in chromosomal instability manifested as variation in chromosome number and/or structure. However, not all nascent allopolyploids are equally unstable. The wheat group ( Aegilops/Triticum ) contains 13 diploid species with distinct genome types. Many of these species can be artificially hybridized to produce viable but sterile inter-specific/intergeneric F1 hybrids, which can generate fertile synthetic allotetraploid wheats after whole genome doubling. Compared with synthetic allotetraploid wheats that contain genome combinations of AADD and S*S*DD (S* refers to related S genomes of a different species), those containing an S*S*AA genome are significantly more stable. However, robustness of the relative stability of S*S*AA genomes is unknown, nor are the phenotypic and fitness consequences during occurrences of secondary chromosomal instability. Here, we report a specific lineage originated from a single individual plant of a relatively stable synthetic allotetraploid wheat with genomes S l S l AA (S l and A subgenomes were from Ae. longissima and T. urartu , respectively) that showed a high degree of transgenerational chromosomal instability. Both numerical chromosome variation (NCV) and structural chromosome variation (SCV) occurred widely. While substantial differences in frequencies of both NCV and SCV were detected across the different chromosomes, only NCV frequencies were significantly different between the two subgenomes. We found that NCVs and SCVs occurred primarily due to perturbed meiosis, allowing formation of multivalents and univalents as well as homoeologous exchanges. Thus, the combination of NCVs and SCVs affected multiple phenotypic traits, particularly those related to reproductive fitness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lv, Wang, Wang, Wang, Zhao, Wang, Aslam, Han and Liu.)

Background: This study aimed at investigating the relationships between Platelet-Lymphocyte ratio (PLR) and Neutrophil-Lymphocyte ratio (NLR) and their dynamic changes (∆PLR, ∆NLR) with type 2 diabetes mellitus (T2DM) in a Chinese cohort study., Methods: This study recruited 41,439 individuals who were diagnosed without T2DM at first health examination and completed at least one follow-up. The relationships between NLR, PLR, ∆PLR, ∆NLR and T2DM risk were analyzed using the Cox regression model with corresponding Hazard Ratios (HRs) and 95% Confidence Intervals (CIs)., Results: PLR exhibited significant correlation with T2DM risk in a linear reverse dose-response pattern, the corresponding HRs and 95% CIs were 0.81 (0.72, 0.90), 0.71 (0.63, 0.80) and 0.56 (0.49, 0.64) respectively ( P trend < 0.001) for Q2, Q3 and Q4 vs Q1 after adjusting for age, gender, BMI, TG, TC, HDL-C, FPG, ALT, AST, heart rate, smoking, family history of diabetes, and alcohol consumption at baseline in Model 3. The significance remained in subgroups of women, <45 years, ≥45 years, BMI ≥ 24, with fatty liver disease, without fatty liver disease and normotension. Comparing with the largest decrease group of NLR (∆NLR < -0.32), the risk of T2DM increased for -0.003 ≤ ∆NLR < 0.31 (HR 1.17, 95% CI 1.01-1.36) and ∆NLR ≥ 0.31 (HR 1.23, 95% CI 1.06-1.43)., Conclusions: Higher PLR could reduce the risk of T2DM. Larger increase of NLR could increase T2DM risk.

Background: Postinterventional cerebral hyperdensities are common on non-contrast-enhanced computed tomography (CT) after endovascular thrombectomy in patients with acute ischemic stroke, which may reflect blood-brain barrier damage. The disruption of the blood-brain barrier may lead to malignant brain edema. The relationship between the extent of postinterventional cerebral hyperdensities and malignant brain edema is unclear., Methods: Patients with middle cerebral artery territory infarction and successful recanalization were consecutively enrolled. Postinterventional non-contrast-enhanced CT was performed to evaluate postinterventional cerebral hyperdensities within 24 h after endovascular thrombectomy. On the basis of the areas of the Alberta Stroke Program Early CT Score, we devised the Hyperdensity on CT Score to evaluate the extent of postinterventional cerebral hyperdensities. The primary outcome was malignant brain edema, defined as the development of clinical signs of herniation (including a decrease in consciousness and/or anisocoria), accompanied by imaging evidence of brain swelling. The component of postinterventional cerebral hyperdensities was divided into contrast staining and hemorrhage on the basis of persistency., Results: Three hundred sixty patients were included (50.6% male, mean age 67.9 years), of whom 247 (68.6%) developed postinterventional cerebral hyperdensities and 66 (18.3%) developed malignant brain edema. After adjustment for confounders, including the component of postinterventional cerebral hyperdensities, the extent of postinterventional cerebral hyperdensities assessed by the Hyperdensity on CT Score was significantly associated with malignant brain edema (odds ratio 1.46, 95% confidence interval 1.20-1.77, p < 0.001). A Hyperdensity on CT Score greater than 3 had a sensitivity of 0.73 and a specificity of 0.87 for predicting malignant brain edema., Conclusions: The extent of postinterventional cerebral hyperdensities on postinterventional non-contrast-enhanced CT was associated with malignant brain edema. The Hyperdensity on CT Score could be used to predict malignant brain edema regardless of the component of postinterventional cerebral hyperdensities., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Sugar not only is an important biomacromolecule that plays important roles in plant growth, development, and biotic and abiotic stress tolerance but also provides a skeleton for other macromolecules, such as proteins and nucleic acids. Sugar transporter proteins (STPs) play essential roles in plant sugar transport and ultimately affect the abovementioned life processes. However, the evolutionary dynamics of this important gene family in Brassicaceae crops are still largely unknown, and the functional differentiation of radish STP genes remains unclear., Results: In the present study, a comparative genomic study of STP genes in five representative Brassicaceae crops was conducted, and a total of 25, 25, 28, 36 and 49 STP genes were individually identified in Raphanus sativus (Rs), Brassica oleracea (Bo), B. rapa (Br), B. napus (Bn) and B. juncea (Bj), which were divided into four clades by phylogenetic analysis. The number of STP genes was no direct correlation with genome size and the total number of coding genes in Brassicaceae crops, and their physical and chemical properties showed no significant difference. Expression analysis showed that radish STP genes play vital roles not only in flower and seedpod development but also under heavy metal (cadmium, chromium and lead), NaCl and PEG-6000 stresses, Agrobacterium tumefaciens infection, and exogenous sugar treatment. RsSTP13.2 was significantly upregulated in the resistant radish cultivar by A. tumefaciens infection and induced by heavy metal, NaCl and PEG-6000 stress, indicating that it is involved in resistance to both biotic and abiotic stress in radish., Conclusions: The present study provides insights into the evolutionary patterns of the STP gene family in Brassicaceae genomes and provides a theoretical basis for future functional analysis of STP genes in Brassicaceae crops., (© 2022. The Author(s).)

Objective: This study examined the functional outcomes and safety of endovascular treatment (EVT) in acute ischemic stroke (AIS) patients owing to large vessel occlusion of the anterior circulation, presented during a late-time window (6-24 hours after last seen well (LSW)) in a real-world practice., Methods: This was a retrospective analysis from a bi-center prospective cohort. According to the stroke treatment, patients with continuous Alberta Stroke Plan Early Aspect score (ASPECTS) ≥6 on non-contrast CT (NCCT) and moderate to good collateral state on CT angiography (CTA) were divided into EVT group and standard medical treatment (SMT) group. The primary outcome was the rate of functional independence (90-day mRS ≤2). Safety outcomes were the occurrence of symptomatic intracranial hemorrhage (sICH) and the 90-day mortality., Results: Among the 288 enrolled patients (53.5% male, median age 64 years), there were 167 patients in the EVT group and 121 in the SMT group. After multivariable adjustments for potential confounders, EVT was associated with functional independence (adjusted OR: 3.052; 95% confidence interval (CI): 1.553-5.997; p = 0.001). In the PSM cohort, 44.2% (42/95) of patients in the EVT group versus 18.9% (18/95) in the SMT group achieved functional independence (OR: 3.39, 95% CI: 1.763-6.517), and there was a significant difference favoring EVT over the SMT in the overall distribution of mRS (OR: 2.170, 95% CI: 1.302-3.618) at 90 days. The rate of sICH did not differ between the EVT and SMT groups (10.5% vs 8.4%, p = 0.804) nor did 90-day mortality (18.9% vs 22.1%, p = 0.719). No interaction was found in p-values with statistical significance in subgroup analysis., Conclusion: This real-world experience suggests that EVT for late-presenting stroke patients, based on small core on NCCT and moderate to good collaterals on CTA, is associated with better outcomes than SMT alone, with no increase in sICH and 90-day mortality rates., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Yang et al.)

Background and Purpose: Blood pressure in the days following endovascular thrombectomy (EVT) can influence functional outcomes of patients who have suffered an acute ischemic stroke, but whether the same is true of blood pressure during the first few hours after EVT is unclear., Methods: Several blood pressure parameters were retrospectively analyzed in acute ischemic stroke patients who underwent EVT at West China Hospital from March 2016 to December 2019. Baseline blood pressure, speed of blood pressure reduction, postoperative blood pressure, degree of blood pressure reduction, and quality of blood pressure management were evaluated during the first 24 h after EVT. We explored whether these parameters during different time windows correlated significantly with patients' modified Rankin Scale (mRS) score at 90 days., Results: Analysis of 163 patients showed that poor functional outcome (mRS scores 3-6) correlated significantly with higher postoperative blood pressure and worse blood pressure management during the first 6 h after EVT. Postoperative systolic blood pressure at 37 min after EVT was significantly higher in patients with poor outcome (141 mmHg) than in those with good outcome (mRS scores 0-2; 122 mmHg, p = 0.006), and systolic pressure >136 mmHg at this time point was associated with a significantly higher risk of poor outcome, before and after adjusting for other risk factors (adjusted OR 0.395, 95% CI 0.20-0.79)., Conclusions: Among acute ischemic patients who successfully undergo recanalization, adequate blood pressure management during the first 30-40 min after EVT may be important for ensuring good 90-day functional outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Cui, Zhu, Wang, Wang, Yang, Li, Hu and Wu.)

Background and Aims: The purpose of this study is to explore the relationship between Chinese visceral adipose index (CVAI) and the risk of coronary heart disease (CHD) in Chinese through a large cohort study., Methods and Results: This study included 42,165 adults who were without CHD at baseline and who completed at least one annual follow-up between 2009 and 2016. We used the Cox proportional hazards model to estimate Hazard Ratios (HRs) and 95% Confidence Intervals (CIs) for the association between CVAI and risk of CHD. During the median follow-up of 3.36 years (154,808 person years), 520 participants developed CHD, including 374 males and 146 females. Compared with the first quartile of CVAI, the risk of CHD was significantly increased in the fourth quartile of CVAI in multivariate model (HR [95% CI]: 9.92 [5.45, 18.04], P < 0.001). Sensitivity analysis by excluding incident CHD developed in the first two years of follow-up reinforced our results. Gender stratification analyses showed that the relationship between CVAI and CHD risk was higher in males than that in females. The restricted cubic spline showed a non-linear dose-response relationship between CVAI and CHD risk. In addition, CVAI was associated with CHD risk in the subgroups of participants without T2DM, without hypertension, and without fatty liver., Conclusion: CVAI was significantly associated with the risk of CHD. Individuals should keep CVAI at normal level to prevent CHD., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Elevated admission glucose and hemoglobin A1c (HbA1c) levels have been suggested to be associated with 90-day functional outcomes in acute ischemic stroke (AIS) patients with endovascular thrombectomy (EVT). However, whether the prognostic significance of admission glucose and that of HbA1c have a joint effect on patients with intravascular thrombolysis (IVT) and/or EVT remains unclear. This study aimed to explore the association between admission glucose combined with HbA1c and outcomes in patients with reperfusion therapy., Methods: Consecutive AIS patients treated with IVT and/or EVT between 2 January 2018 and 27 February 2021 in West China hospital were enrolled. Admission glucose and HbA1c levels were measured at admission. Participants were divided into four groups according to admission glucose level (categorical variable: <7.8 and ≥7.8 mmol/L) and HbA1c level (categorical variable: <6.5% and ≥6.5%): normal glucose and normal HbA1c (NGNA), normal glucose and high HbA1c (NGHA), high glucose and normal HbA1c (HGNA), and high glucose and high HbA1c (HGHA). The primary outcome was an unfavorable functional outcome defined as a modified Rankin Scale (mRS) ≥ 3. The secondary outcome was all-cause mortality at 90 days., Results: A total of 519 patients (mean age, 69.0 ± 13.4 years; 53.8% males) were included. Patients in the HGHA group had a significantly increased risk of unfavorable functional outcome (OR, 1.81; 95%CI, 1.01-3.23) and mortality (OR, 1.75; 95%CI, 1.01-3.06) at 90 days compared with those in the NGNA group after adjustment for confounders. There was no significant association between NGHA (OR, 0.43; 95%CI, 0.12-1.53) or HGNA (OR, 1.46; 95%CI, 0.84-2.56) and outcomes compared to the NGNA group., Conclusion: The combination of high admission glucose and high HbA1c level was significantly associated with unfavorable functional outcome and mortality at 90 days in AIS patients with reperfusion therapy.

Background/objective: Systemic immune-inflammation index (SII) is a novel inflammatory factor, which may be involved in the destruction of the blood-brain barrier (BBB) after acute ischemic stroke (AIS); however, the association between SII and symptomatic intracranial hemorrhage (sICH) in AIS patients undergoing endovascular treatment (EVT) remains unclear., Methods: Patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO) who underwent EVT were consecutively enrolled. Blood samples were collected in the emergency room and SII was calculated by neutrophils × platelets/lymphocytes. Participants were categorized into tertiles according to admission SII. The main outcome was defined as the occurrence of sICH, following the European Cooperative Acute Stroke Study III (ECASS-III) criteria., Results: A total of 379 AIS-LVO patients with EVT were enrolled (median age = 71 years, 52.5% males). The median baseline National Institutes of Health Stroke Scale (NIHSS) score was 15 (IQR, 12-18). The median of SII was 820.9 × 109/L (IQR, 473.1-1345.2). Forty-three (11.3%) patients developed sICH. SII was found to be independently associated with sICH after EVT (adjusted odd ratio (OR) = 1.005 (per 10 units increase); 95% confidence interval (CI): 1.002-1.008; p = 0.002). Compared to patients in the lowest SII tertile, patients in the highest tertile had a higher risk of sICH (adj-OR 3.379; 95% CI 1.302-8.768; p = 0.012). The risk of sICH increased with the increase of SII in a dose-dependent manner (p for trend = 0.004). There was no interaction between potential modifiers and SII on sICH., Conclusion: Admission SII is positively associated with sICH in AIS-LVO patients treated with EVT. These results need to be confirmed in future studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Low-density lipoprotein cholesterol (LDL-C) can increase cardiovascular risk. However, the association between LDL-C change and functional outcomes in acute ischemic stroke (AIS) patients who underwent reperfusion therapy remains unclear., Methods: Patients who received reperfusion therapy were consecutively enrolled. LDL-C measurement was conducted at the emergency department immediately after admission and during hospitalization. The change of LDL-C level (ΔLDL-C) was calculated by subtracting the lowest LDL-C among all measurements during hospitalization from the admission LDL-C. Poor functional outcome was defined as modified Rankin Scale (mRS) > 2 at 90 days., Results: A total of 432 patients were enrolled (mean age 69.2 ± 13.5 years, 54.6 % males). The mean LDL-C level at admission was 2.55 ± 0.93 mmol/L. The median ΔLDL-C level was 0.43 mmol/L (IQR 0.08-0.94 mmol/L). A total of 263 (60.9 %) patients had poor functional outcomes at 90 days. There was no significant association between admission LDL-C level and functional outcome (OR 0.99, 95 % CI 0.77-1.27, p = 0.904). ΔLDL-C level was positively associated with poor functional outcome (OR 1.80, 95 % CI 1,12-2.91, p = 0.016). When patients were divided into tertiles according to ΔLDL-C, those in the upper tertile (T3, 0.80-3.98 mmol/L) were positively associated with poor functional outcomes compared to patients in the lower tertile (T1, -0.91-0.13 mmol/L) (OR 2.56, 95 % CI 1.22-5.36, p = 0.013). The risk of poor functional outcome increased significantly with ΔLDL-C tertile (P-trend = 0.010)., Conclusions: In AIS patients who underwent reperfusion therapy, the decrease in LDL-C level during hospitalization was significantly associated with poor functional outcomes at 90 days., (© 2021. The Author(s).)

Background: Epidemiological studies have suggested that adipsin and visfatin are associated with the development of type 2 diabetes. This is the first study to investigate the effects of supplementation with purified anthocyanins on serum adipsin and visfatin in patients with prediabetes or newly diagnosed diabetes., Methods: A total of 160 participants with prediabetes or newly diagnosed diabetes (40-75 years old) were given 320 mg anthocyanins or placebo daily for 12 weeks in a randomized trial. Serum adipsin, serum visfatin, lipids and glycated hemoglobin A1c (HbA1c) were measured. The areas under the curve (AUCs) for glucose, insulin and C-peptide were determined before-and after-treatment by a standard 3-h 75 g oral glucose tolerance test (OGTT)., Results: Relatively significant increases in serum adipsin (net change 0.15 µg/mL [0.03, 0.27], p = 0.018) and decreases in visfatin (-3.5 ng/mL [-6.69, -0.31], p = 0.032) were observed between the anthocyanins and placebo groups. We also observed significant improvements in HbA1c (-0.11% [-0.22, -0.11], p = 0.033), apolipoprotein A-1 (apo A-1) (0.12 g/L [0.03, 0.21], p = 0.012) and apolipoprotein B (apo B) (-0.07 g/L [-0.14, -0.01], p = 0.033) in response to the anthocyanins intervention., Conclusion: Purified anthocyanins supplementation for 12 weeks increased serum adipsin and decreased serum visfatin in patients with prediabetes or newly diagnosed diabetes. Trial registration ClinicalTrials.gov, identifier: NCT02689765.

Background: DNA methylation was considered to play an important role in hypertension. However, the direct association between dihydrofolate reductase ( DHFR ) promoter methylation and hypertension remains unclear. We thus aimed to investigate the relationship between DNA methylation of DHFR promoter and hypertension., Materials and Methods: A total of 371 hypertensive patients (diastolic blood pressure ≥90 mmHg and/or systolic blood pressure ≥140 mmHg or a history of antihypertensive treatment) and 320 age- and sex-matched healthy controls from the Hypertension Management Information System in Nanshan Community Health Service Centers were included in this case-control study. Quantitative methylation-specific polymerase chain reaction was used to measure the level of DHFR promoter methylation, which was presented as the percentage of methylated reference (PMR). A multivariate logistic regression model was used to explore the risk of DHFR promoter methylation., Results: Our results indicated that the level of DHFR promoter methylation was higher in hypertensive patients (median PMR, 34.32%; interquartile range, 11.34-119.60) than in healthy controls (median PMR, 18.45%; interquartile range, 8.16-35.40) ( P < 0.001). Multivariable analysis showed that the risk of DHFR promoter hypermethylation was significantly higher in hypertensive patients than in healthy controls (odds ratio = 3.94, 95% confidence interval = 2.56-6.02, P < 0.001). Furthermore, hypermethylation was positively associated with sex, high blood homocysteine levels, and alcohol drinking. In particular, the area under the receiver operating characteristic curve was 0.688 (0.585-0.668) for the male hypertensive patients, suggesting the potential diagnostic value of DHFR promoter methylation in male hypertension., Conclusion: Our results demonstrated that DHFR promoter hypermethylation is positively associated with the risk of hypertension in Chinese., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Journal of Research in Medical Sciences.)

Background: The association of ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL-C ratio) change trajectory with risk of type 2 diabetes mellitus (T2DM) remains unknown. The aim of this study was to evaluate the association between risk of T2DM and TG/HDL-C ratio change trajectory., Methods: A total of 18 444 participants aged 18-80 years old were included in this cohort study. Linear regression and quadratic regression models were used to determine the TG/HDL-C ratio change trajectory. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between TG/HDL-C ratio change trajectory and probability of T2DM., Results: T2DM developed in 714 participants during a median follow-up of 5.74 years (92 076.23 person-years of follow-up). After adjusting for baseline potential confounders, odds of T2DM were greater for participants with the increasing, U-shape, bell-shape, and other shape change vs decreasing change (adjusted OR [aOR] 2.01, 95% CI 1.42-2.81; 1.56, 1.15-2.13; 1.60, 1.17-2.20; and 1.49, 1.13-2.00, respectively). The results were robust in the sensitivity analyses on excluding baseline participants with T2DM. Moreover, the associations remained significant with male sex, age <60 years and body mass index <24 kg/m 2 ., Conclusions: This retrospective study revealed increased probability of T2DM with increasing, U-shape, bell-shape, and other-shape TG/HDL-C ratio change trajectories, especially with male sex, age <60 years and body mass index <24 kg/m 2 ., (© 2020 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Epidemiological studies have suggested that adiponectin is associated with the development of insulin resistance and type 2 diabetes. This study first examined the effect of purified anthocyanins, a group of dietary flavonoids, on serum adiponectin in patients with prediabetes and newly diagnosed diabetes., Methods: A total of 160 patients with prediabetes (n = 90) or newly diagnosed diabetes (n = 70) were randomly assigned to either the anthocyanins group or the placebo group for 12 weeks of intervention. Serum adiponectin, a set of biomarkers related to glucolipid metabolism, anthropometric parameters, dietary intake and physical activity were measured before and after intervention., Results: Anthocyanins increased serum adiponectin compared with placebo (net change 0.46 µg/mL, 95% CI [0.03, 0.90], p  = 0.038) in the subjects with newly diagnosed diabetes. No significant difference in the change in adiponectin was observed between the two groups either in the overall subjects (0.02 µg/mL [- 0.32, 0.36], p  = 0.906) or in prediabetes (- 0.35 µg/mL [- 0.85, 0.16], p  = 0.174). Anthocyanins also decreased fasting glucose (- 0.5 mmol/L [- 1, - 0.04], p  = 0.035) in the subjects with newly diagnosed diabetes, but no such change was observed in those with prediabetes., Conclusions: Anthocyanins supplementation for 12 weeks improved serum adiponectin and fasting glucose in patients with newly diagnosed diabetes, but not in patients with prediabetes., Trial Registration: ClinicalTrials.gov, NCT02689765. Registered on 6 February 2016, https://clinicaltrials.gov/ct2/show/NCT02689765., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background and Purpose: We aimed to use novel whole-brain vessel-wall magnetic resonance imaging (WB-VWI) to investigate the association between plaque distribution of middle cerebral artery (MCA) and morphological changes of the lenticulostriate arteries (LSAs) in single subcortical infarctions., Methods: Forty single subcortical infarction patients with no relevant MCA disease on magnetic resonance angiography were prospectively enrolled. Plaque location in the MCA was dichotomized as proximal (located adjacent to the LSA origin) or distal (located distal to the LSA origin) on whole-brain vessel-wall magnetic resonance imaging. The MCAs with proximal plaques were divided into the symptomatic and asymptomatic side, and asymptomatic side MCAs without proximal plaques were the control group. The morphological characteristics of the LSAs and features of proximal plaques were analyzed., Results: A total of 71 MCAs in 40 patients were analyzed (31 on the symptomatic side, 22 on the asymptomatic side, and 18 in the control group). Superior-wall plaques of MCAs were observed more frequently on the symptomatic side than the asymptomatic side (45.2% versus 9.1%, P =0.005). The wall area index, plaque burden, and remodeling index did not differ significantly between the symptomatic and asymptomatic side. The number of LSA branches was smaller ( P =0.011) in the symptomatic side (5.48±1.88) compared with the control group (6.83±1.92). The symptomatic side exhibited shorter average length of the LSAs (23.23±3.44 versus 25.75±3.76 mm, P =0.025) and shorter average distance of the LSAs (16.47±3.11 versus 21.53±4.76 mm, P <0.001) compared with the asymptomatic side., Conclusions: Superiorly distributed MCA plaques at the LSA origin are closely associated with morphological changes of the LSA in symptomatic MCAs, suggesting that the distribution, rather than the inherent features of plaques, determines the occurrence of single subcortical infarctions. Our findings provide insight into the etiologic mechanism of branch atheromatous disease in single subcortical infarctions.

Background: The discordance of the low-density lipoprotein cholesterol-to-high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with alterative lipid parameters may explain the inconsistent association of CIMT with the LDL-C/HDL-C ratio. Therefore, this study aimed to explore the associations between LDL-C/HDL-C ratio discordance with alternative lipid parameters and elevated carotid intima-media thickness (CIMT) risk in a large cohort in Beijing, China., Methods: In total, 13,612 adults who didn't have elevated CIMT at baseline and who participated in at least one follow-up of annual examination between 2009 and 2016 were included in this cohort study. A multivariable Cox regression model was utilized to evaluate the associations of discordance of the LDL-C/HDL-C ratio with TC, TGs, LDL-C and HDL-C with elevated CIMT risk., Results: During 37,999 person-years of follow-up, 2004 individuals (1274 men and 730 women) developed elevated CIMT. Among individuals with normal TC and TGs, 16.6 and 15.2% individuals had a discordantly high LDL-C/HDL-C ratio, respectively, and the risk of elevated CIMT increased by 1.54 (95% CI 1.33, 1.77) and 1.53 (95% CI 1.33, 1.76), respectively, comparing to individuals with a concordantly low LDL-C/HDL-C ratio. A high LDL-C/HDL-C ratio could significantly increase elevated CIMT risk regardless of discordance/concordance with LDL-C and HDL-C (P < 0.001). A low LDL-C/HDL-C ratio with discordantly normal HDL-C and high LDL-C (13.2% of individuals) had a 32% (HR = 1.32, 95% CI 1.11, 1.57) higher risk of elevated CIMT than concordantly low LDL-C and normal HDL-C. Sensitivity analysis by excluding CIMT developed in the first 2 years follow-up further confirmed the above results., Conclusions: A high LDL-C/HDL-C ratio could significantly increase elevated CIMT risk regardless of discordance/concordance with TC, TGs, LDL-C and HDL-C Even a low LDL-C/HDL-C ratio with discordantly high LDL-C and normal HDL-C could also significantly increase CIMT risk. Individuals should maintain both the LDL-C/HDL-C ratio and LDL-C at normal levels to prevent elevated CIMT.

The N 6 -Methyladenosine (m 6 A) modification plays an important role in many biological processes, especially tumor development. However, little is still known about how it affects colorectal cancer (CRC) carcinogenesis. Here, we first systematically investigate the association of variants related to m 6 A modification with the CRC risk in 1,062 CRC cases and 2,184 controls by using our exome-wide association data and followed by two replication sets including 7,341 CRC cases and 7,902 controls. The variant rs8100241 located in ANKLE1 was significantly associated with CRC risk (odds ratio = 0.88, 95% confidence interval = 0.84-0.92, p = 4.85 × 10 -8 ) in 8,403 cases and 10,086 controls. This variant was previously identified to be associated with the susceptibility of breast cancer with BRCA1 mutation triple negative breast cancer. Further functional analysis indicated that overexpression of the rs8100241[A] allele significantly increased the ANKLE1 m 6 A level and facilitated the ANKLE1 protein expression compared to that of rs8100241[G] allele. We further found the ANKLE1 m 6 A modification was catalyzed by the "writer" complex (METTL3, METTL14, or WTAP) and recognized by the "reader" YTHDF1. Mechanistically, we found that the ANKLE1 functions as a potential tumor suppressor that inhibits cell proliferation and facilitates the genomic stability. An elevated frequency of micronucleated cells, increased cell proliferation, and colony formation ability were observed when ANKLE1 knockdown. Our study illustrated that the germline missense variant can increase CRC risk by influencing ANKLE1 m 6 A level, highlighting a clinical potential of variants-associated m 6 A modification as a risk marker for CRC prevention., (© 2019 UICC.)

Background: The prevalence of central obesity is constantly increasing, and visceral fat is associated with increased production of inflammatory factors and metabolic risk factors. Lutein might retard the development of metabolic disease through its antioxidant and anti-inflammatory properties. Furthermore, epidemiological studies have associated higher dietary intake and serum levels of lutein with decreased adiposity. However, few randomised controlled trials have shown the effects of lutein supplementation on inflammatory biomarkers and metabolic risk factors, especially in adults with central obesity., Methods: This study will be conducted as a double-blind, parallel placebo-controlled clinical trial in which 120 people who have central obesity, are 18 to 60 years old and are willing to provide informed consent will be randomly assigned to the intervention or placebo group in a 1:1 ratio according to sex, age and waist circumference. The intervention group will receive 10 mg daily lutein supplementation for 12 weeks to explore the effect of lutein supplementation on serum lutein, glycaemic and lipid profiles, inflammatory factors and body composition. Two populations (intention-to-treat population and per-protocol population) will be used in the data analyses., Discussion: Our findings from this trial will contribute to the knowledge of the association between lutein supplementation and inflammatory biomarkers and metabolic risk factors in people with central obesity and will offer a possibility for the prevention of inflammatory diseases., Trial Registration: Chinese Clinical Trial Registry: ChiCTR1800018098. Registered on 30 August 2018.

Background and Purpose: The relationship between neutrophil to lymphocyte ratio (NLR) and prognosis after acute ischemic stroke (AIS) remains controversial. The aim of this cohort study and systematic review was to ascertain the association of admission NLR with major clinical poor outcomes after AIS., Methods: We analyzed data from Chengdu stroke registry and performed a systematic review for previous literature. The outcomes were hemorrhagic transformation (HT), parenchymal hematoma (PH), symptomatic intracranial hemorrhage (sICH), 3-month death or disability (modified Rankin Scale≥3), and 3-month death. Odds ratios (ORs) and 95% confidence intervals (CIs) of NLR as a continuous and categorical variable and poor outcomes were pooled separately. We also calculated the predictive accuracy of admission NLR in different outcomes., Results: We included 808 patients from registry database and 9563 patients from previous studies. Our registry data showed that NLR ≥5 was associated with HT (OR 2.03, 95%CI 1.19-3.46), PH (OR 2.54, 95%CI 1.20-5.35) and 3-month death (OR 5.55, 95%CI 1.41-21.89); meta-analysis with our data and other observational studies indicated that higher NLR was associated with HT (OR 1.99, 95% CI 1.45-2.73), sICH (OR 2.22, 95% CI 1.60-3.09), 3-month death or disability (OR 1.68, 95% CI 1.18-2.38), and 3-month death (OR 2.79, 95% CI 1.57, 4.94). NLR had the highest predictive accuracy for 3-month death., Conclusions: Higher NLR is positively associated with the risk of HT and 3-month death after stroke. Considering the limited predictive ability of a single biomarker, more studies should validate the role of NLR in prognostic models., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The effect of the blood urea nitrogen (BUN) to creatinine (Cr) ratio (henceforth BUN/Cr) on haemorrhagic transformation (HT) of acute ischaemic stroke (AIS) patients is unclear., Methods: AIS patients in the West China Hospital, Sichuan University, Chengdu, China, admitted within seven days from stroke onset (2012-2016) were included in the study. Baseline data, including BUN and Cr levels, were collected. The outcome was defined as HT during hospitalization., Results: In this study, 1738 participants with an average age of 62.7 ± 14.0 years were included. After adjusting potential confounders (age, blood platelet, albumin, stroke severity, triglycerides and low-density lipoprotein [LDL]), multivariate logistic regression analyses indicated that BUN/Cr is independently associated with HT. The nonlinear relation between BUN/Cr and HT was explored in a dose-dependent manner, with an apparent inflection point of 30.71. On the left and right sides of the inflection point, the odds ratio (OR) and 95% confidence interval (CI) were 1.05 (1.02-1.08) and 0.96 (0.88-1.05), respectively. Interaction between BUN/Cr and diabetes mellitus (DM) and HT (P for interaction = 0.0395) was noted. BUN/Cr showed positive correlation with HT in DM patients (OR = 1.07; 95% CI: [1.02, 1.12]) but no significant relationship with HT in patients without DM., Conclusion: BUN/Cr is significantly associated with HT in AIS patients in a linear fashion, with an apparent cut point demarcating the HT difference. When the patients have DM, BUN/Cr is positively correlated with HT. These results support a revision in how we anticipate the prognosis for AIS patients.

Objectives: Cystathionine β-synthase is a major enzyme in the metabolism of plasma homocysteine. Hyperhomocysteinemia is positively associated with hypertension and stroke. The present study was performed to examine the possible effects of Cystathionine β-synthase promoter methylation on the development of hypertension and stroke., Methods: Using quantitative methylation-specific PCR, we determined the Cystathionine β-synthase methylation levels in 218 healthy individuals and 132 and 243 age- and gender-matched stroke and hypertensive patients, respectively. The relative changes in Cystathionine β-synthase promoter methylation were analyzed using the 2-ΔΔCt method. The percent of the methylated reference of Cystathionine β-synthase was used to represent the Cystathionine β-synthase promoter methylation levels., Results: In this study, the Cystathionine β-synthase promoter methylation levels of hypertensive and stroke participants were both higher than that of the healthy individuals (median percentages of the methylated reference were 50.61%, 38.05% and 30.53%, respectively, all p<0.001). Multivariable analysis showed that Cystathionine β-synthase promoter hypermethylation increased the risk of hypertension [odds ratio, OR (95% confidence interval, CI)=1.035 (1.025-1.045)] and stroke [OR (95% CI)=1.015 (1.003-1.028)]. The area under the curve of Cystathionine β-synthase promoter methylation was 0.844 (95% CI: 0.796-0.892) in male patients with hypertension and 0.722 (95% CI: 0.653-0.799) in male patients with stroke., Conclusion: Cystathionine β-synthase promoter hypermethylation increases the risk of hypertension and stroke, especially in male patients.

Objective: Hypertension and hyperhomocysteinemia are both stroke risk factors. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) plays a vital role in one-carbon metabolism via encoding a protein with three distinct enzymatic activities (methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formate-tetrahydrofolate ligase). We aimed to elucidate the association between MTHFD1 promoter methylation and stroke in a Chinese population with primary hypertension., Methods: Quantitative methylation-specific PCR was used to quantify MTHFD1 methylation levels in 243 hypertensive controls and 138 matched patients with stroke (also with primary hypertension). A luciferase reporter gene assay was performed to investigate the possible regulatory function of the MTHFD1 promoter., Results: Methylation of the MTHFD1 promoter was significantly higher in hypertensive controls than in patients with stroke (median [interquartile range]: 10.16[6.61-14.00] vs. 5.41[3.15-7.53], P <0.001). The median level of homocysteine (Hcy) was 15.50 μmol/L in patients with stroke, which was higher than the (homocysteine) Hcy level of 14.40 μmol/L in the hypertensive controls ( P =0.010). The diagnostic value of MTHFD1 methylation for stroke was also examined. The area under the curve was 0.789(0.743-0.836), and the sensitivity and specificity were 79.7% and 67.1%, respectively. A significant inverse correlation was observed between MTHFD1 methylation level and Hcy ( r s =-0.110, P =0.031). Subsequently, a significant gene regulatory function of the MTHFD1 promoter was discovered using a dual-luciferase reporter assay., Conclusions: Our findings suggest a significant association between hypomethylation of the MTHFD1 promoter and stroke in Chinese hypertensive populations., (© 2019 by the Association of Clinical Scientists, Inc.)

Aims: Hyperhomocysteinemia (HHcy) is known to increase the risk of many diseases. Factors influencing HHcy in healthy and hypertensive subjects remain under-researched., Methods: A large population-based study was conducted in 60 communities from Shenzhen, China. Responses to standardized questions on lifestyle factors and blood samples were collected from all participants after a 12-h overnight fast. Multiple linear and multivariate logistic regressions were used to explore risk factors for HHcy. Results were then compared to those from a systematic review of English-language articles listed in Pubmed, EBSCOhost, Web of Science, Embase and Cochrane libraries that investigated HHcy risk factors in healthy and hypertensive subjects., Results: A total of 1586 healthy (Male/Female = 642/944) and 5935 hypertensive subjects (Male/Female = 2928/3007) participated in our population-based study. In logistic regression analyses, age, BMI and creatinine (Cr) were risk factors, while being female, fruit intake and physical activity were protective factors for HHcy in healthy subjects. In hypertensive subjects, seven [age, smoking, salt intake, systolic blood pressure (SBP), uric acid, triglycerides (TG), and Cr] and four [female, fruit intake, total cholesterol (TC), and glucose] factors were associated with higher and lower HHcy respectively. The review of 71 studies revealed that potential risk factors for Hcy included nutritional, physiologic, lifestyle habits, ethnicity, genetics, interactions between gene-environment, gene-gene, gene-nutritional, environment-environment, nutritional-nutritional., Conclusion: Our study indicates the potential importance of increasing folic acid and vitamin B supplementation, daily fruit and vegetable intake, regular exercise and refraining from tobacco smoking and alcohol consumption as preventive strategies for Hcy., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objectives:: The aim of this study was to compare the expression levels of serum miRNAs in diabetic retinopathy and type 2 diabetes mellitus., Methods:: Serum miRNA expression profiles from diabetic retinopathy cases (type 2 diabetes mellitus patients with diabetic retinopathy) and type 2 diabetes mellitus controls (type 2 diabetes mellitus patients without diabetic retinopathy) were examined by miRNA-specific microarray analysis. Quantitative real-time polymerase chain reaction was used to validate the significantly differentially expressed serum miRNAs from the microarray analysis of 45 diabetic retinopathy cases and 45 age-, sex-, body mass index- and duration-of-diabetes-matched type 2 diabetes mellitus controls. The relative changes in serum miRNA expression levels were analyzed using the 2-ΔΔCt method., Results:: A total of 5 diabetic retinopathy cases and 5 type 2 diabetes mellitus controls were included in the miRNA-specific microarray analysis. The serum levels of miR-3939 and miR-1910-3p differed significantly between the two groups in the screening stage; however, quantitative real-time polymerase chain reaction did not reveal significant differences in miRNA expression for 45 diabetic retinopathy cases and their matched type 2 diabetes mellitus controls., Conclusion:: Our findings indicate that miR-3939 and miR-1910-3p may not play important roles in the development of diabetic retinopathy; however, studies with a larger sample size are needed to confirm our findings.

Objective: To analyze the association between homocysteine (Hcy) and stroke in hypertensive patients., Methods: This was a prospective cohort study conducted in 60 communities in Nanshan District, Shenzhen. Totally 5 488 patients with hypertension were included at baseline survey and followed for an average of 2.7 years. At the end of follow-up, 327 (5.96%) subjects were missing with unknown reasons. Hcy was detected by enzymatic cycling method. Head CT, MRI, cerebral angiography and transcranial Doppler ultrasound were performed in the patients. Stroke was defined based on the International Classification of Diseases (ICD10 coding I60-I64)., Results: After an average of 2.7-year follow-up, 197 developed new stroke. The incidence rate was 3.82%. Subjects whose Hcy levels were within the highest quartile (Q4) had higher risk to develop stroke compared with those whose Hey levels were within the lowest quartile (Q1). The HR (95% CI) were 7.4 (3.2-13.2) in total with 7.5(3.0-19.5) in men and 7.7 (2.7-22.1) in women after adjustment of age, sex, education, smoking, alcohol drinking, and BMI, physical activity, diabetes, depression, family history of stroke or coronary heart disease, years of hypertension, antihypertensive drugs, folic acid, systolic blood pressure, TC, glucose and TG. For every 5 µmol/L increase in Hcy, the HR (95% CI) of stroke increased 1.15-fold (1.09-1.21) in total subjects with 1.15 (1.08-1.21) in men and 1.19 (1.04-1.35) in women, respectively. No significant interactions on stroke could be found between Hcy and the above stratified factors., Conclusion: Elevated Hcy levels were associated with stroke in hypertensive patients.

The potential effects of the interactions between DNA methylation (CpG1 and CpG2-5 methylation levels) of the α-adducin (ADD1) gene promoter and ADD1 tagSNPs (tag single-nucleotide polymorphisms) or the environmental factors on essential hypertension (EH) risk have not been clarified. Thus, we performed an age- and gender-matched case-control study to investigate the association between ADD1 tagSNPs and EH. A total of 1020 subjects with EH and 1020 normotensive subjects were genotyped by melting temperature shift technology. Logistic regression was used to assess the associations of ADD1 tagSNPs, environmental factors and EH. The generalized multifactor dimensionality reduction (GMDR) method was applied to explore the potential interactions. Under additive, dominant and recessive models, no significant associations were evidenced between EH and rs3755885, rs2071694, rs4963 or rs3775067 with the complete data set or the gender-stratified analysis after adjusting for triglycerides, body mass index and alcohol consumption. However, we observed a significant association between rs4961 and EH under the dominant model after Bonferroni correction when adjusting for confounding factors in the entire sample (odds ratio (OR)=0.64, 95% confidence interval (CI)=0.50-0.83, P=0.001). In GMDR, the two-factor interaction model of alcohol consumption and DNA methylation (CpG1 methylation) was the best model, with a maximum cross-validation consistency of 9/10 and testing balance accuracy of 0.63 (P=0.01). Our results indicate that the SNP rs4961 has a protective role in the development of EH. In conclusion, the interactions between alcohol consumption and DNA methylation (CpG1 methylation) of the ADD1 gene promoter have a significant role in modifying EH susceptibility.

Background and Objectives: There is only limited available evidence of a relationship between total plasma homocysteine (tHcy) levels and type 2 diabetes in hypertensive subjects., Methods and Study Design: A total of 5,935 Chinese essentially hypertensive subjects were recruited by cluster sampling from 60 communities. The cases had diabetes, whereas the controls did not. Anthropometric indices and biochemical parameters were assessed using standard procedures. A multivariable analysis was performed to analyze the association of tHcy and type 2 diabetes susceptibility in hypertensive subjects., Results: The 5,241 controls (women/men: 2,716/2,625) and 594 cases (women/men: 291/303) were recruited consecutively. The level of tHcy was dose- dependently associated with type 2 diabetes in the hypertensive women subjects. After controlling for corresponding confounding factors, a significant trend was only noted in the women subjects, with odds ratios per 5 μmol/L tHcy of 1.11 (95% confidence interval (CI), 1.07-1.16) in the crude model, 1.05 (95% CI, 1.01-1.11) in model 1, and 1.07 (95% CI, 1.02-1.13) in model 2. However, no significant result was found for levels of tHcy>or=15 μmol/L vs <15 μmol/L in the men, women and all hypertensive subjects., Conclusions: When the level of tHcy was divided into quartiles, tHcy was positively associated with type 2 diabetes in hypertensive women subjects. However, when the level of tHcy was separated into hyperhomocysteinemic (>or=15 μmol/L) and normal (<15 μmol/L), no significant results were observed.

Background: Controversy remains for the association between hepatocyte nuclear factor 4α (HNF-4α) P2 promoter polymorphism rs1884613 and type 2 diabetes (T2D). There was no association test of this polymorphism with prediabetes and T2D in the Chinese population. Moreover, an updated meta-analysis in various ethnic groups is needed to establish the contribution of rs1884613 to T2D risk., Methods: Using the Sequenom MassARRAY platform approach, we genotyped rs1884613 of HNF-4α in the P2 promoter region among 490 T2D patients, 471 individuals with prediabetes, and 575 healthy controls. All the individuals were recruited from 16 community health service centers in Nanshan district in Shenzhen province. Using STATA 11.0 software, meta-analysis was performed to summarize the overall contribution of rs1884613 to T2D risk., Results: Polymorphism rs1884613 was associated with genetic susceptibility to prediabetes in the whole samples (OR = 1.40, 95% CI = 1.16-1.68, P = 0.0001) and the female subgrouped samples (OR = 1.48, 95% CI = 1.14-1.92, P = 0.003) after adjusting for age and body mass index (BMI). In contrast, there was no association of rs1884613 with T2D in the whole samples and male in our case-control study and meta-analysis., Conclusions: Our results suggest that rs1884613 contributes to susceptibility to prediabetes, whereas this polymorphism may not play an important role in the development of T2D.