Assessment of pan-immune-inflammation value as a novel marker of proliferative diabetic retinopathy stage.

Purpose Diabetic macular edema (DME) is a major cause of vision loss in all stages of diabetic retinopathy (DR). However, there is limited recognition of aqueous humor (AH) proteome profiles of DME patients at different DR stages. In this study, we aimed to investigate the AH proteome changes between DME patients at the nonproliferative diabetic retinopathy (NPDR) stage and those at the proliferative diabetic retinopathy (PDR) stage. Methods A label-free data-independent acquisition based liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis was performed to profile the abundances of AH proteins in 73 eyes from DME patients at different DR stages. Enzyme-linked immunosorbent assay (ELISA) was used to confirm the proteomics results with AH samples from non-diabetic patients and DME patients at the NPDR or PDR stage. Results LC-MS/MS results showed significantly changed expression of 308 proteins between DME patients in the NPDR and PDR groups. Compared to the NPDR group, the proteins relatively up-regulated in the PDR group are involved in the immune system and/or negative regulation of the cell cycle, while proteins relatively down-regulated in the PDR group are associated with the vascular endothelial growth factor receptor (VEGFR) pathway and/or metabolism. ELISA results further verified the proteomic result of down-regulated expression of the immune-associated protein cystatin C (CST3) in the PDR group compared to that in the NPDR and non-diabetic groups. Conclusions In this study, we reported for the first time the decreased abundances of AH proteins associated with the VEGFR pathway and both down- and up-regulated expression of AH proteins associated with the immune system in the PDR group compared to that in the NPDR group. Furthermore, we found negative correlations of immune-associated protein, CST3 concentration in AH with DR severity and central retinal thickness, suggesting CST3 as a promising target independent of the VEGFR pathway in DME-involved DR treatment.

To investigate systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) levels in patients with type 2 diabetes at different stages of diabetic retinopathy (DR). This retrospective study included 141 patients with type 2 diabetes mellitus (DM): 45 without diabetic retinopathy (NDR), 47 with non-proliferative diabetic retinopathy (NPDR), and 49 with proliferative diabetic retinopathy (PDR). Complete blood counts were obtained, and NLR, PLR, and SII were calculated. The study analysed the ability of inflammatory markers to predict DR using receiver operating characteristic (ROC) curves. The relationships between DR stages and SII, PLR, and NLP were assessed using multivariate logistic regression. The average NLR, PLR, and SII were higher in the PDR group than in the NPDR group (P=0.011, 0.043, 0.009, respectively); higher in the NPDR group than in the NDR group (P<0.001 for all); and higher in the PDR group than in the NDR group (P<0.001 for all). In the ROC curve analysis, the NLR, PLR, and SII were significant predictors of DR (P<0.001 for all). The highest area under the curve (AUC) was for the PLR (0.929 for PLR, 0.925 for SII, and 0.821 for NLR). Multivariate regression analysis indicated that NLR, PLR, and SII were statistically significantly positive and independent predictors for the DR stages in patients with DM [odds ratio (OR)=1.122, 95% confidence interval (CI): 0.200-2.043, P<0.05; OR=0.038, 95%CI: 0.018-0.058, P<0.05; OR=0.007, 95%CI: 0.001-0.01, P<0.05, respectively). The NLR, PLR, and SII may be used as predictors of DR.

Objective To investigate the expression and clinical significance of miR-126 and vascular endothelial growth factor (VEGF) in proliferative diabetic retinopathy (PDR). Methods 226 cases of diabetic retinopathy (DR) patients admitted in our hospital were studied, including 110 cases of PDR (group PDR), 116 non proliferative diabetic retinopathy (NPDR) (group NPDR). 80 patients with diabetes mellitus without retinopathy (NDR) were enrolled in DR group at the same period, another 80 healthy subjects (control group) were selected as control group. The plasma miR-126 level of all subjects was detected by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR). The enzyme linked im-munosorbent assay (ELISA) method was used to detect plasma VEGF level. The clinical diagnostic value of miR-126 and VEGF in PDR patients was further analyzed. Results Plasma levels of miR-126 in PDR group, NPDR group and NDR group were lower than those in control group (P<0.05), PDR group was lower than NPDR group and NDR group (P<0.05); plasma levels of VEGF in PDR group, NPDR group and NDR group were higher than those in control group (P<0.05), PDR group was higher than NPDR group and NDR group (P<0.05). Total cholesterol (TC), triglyceride (TG) and glycated hemoglobin (HbA1c) in PDR group were higher than those in NPDR group and NDR group (P<0.05), low density lipoprotein cholesterol (LDL-C) in PDR group, NPDR group and NDR group were higher than those in control group (P<0.05), and LDL-C in PDR group was higher than that in NPDR group and NDR group (P<0.05). High density lipoprotein cholesterol (HDL-C) in PDR group and NDR group was lower than that in control group (P<0.05), C-reactive protein (CRP) in PDR group, NPDR group and NDR group was higher than that in control group (P<0.05); plasma miR-126 levels in PDR group were negatively correlated with TC, LDL-C, CRP and HbA1c (P<0.05), but positively correlated with HDL-C (P<0.05), and no correlation with TG; the plasma levels of VEGF in PDR patients were positively correlated with TC, TG, LDL-C, CRP and HbA1c (P<0.05), but negatively correlated with the expressions of miR-126 (r=-0.573, P=0.000); the AUC of miR-126 was 0.861, and when the cut-off value was <0.64, the diagnostic sensitivity and specificity were 82.50% , 83.64%; the area under curve (AUC) of VEGF was 0.889, and when the cut-off value was <7.000, the sensitivity and specificity of diagnosis were 82.73%, 86.25%; 0.847 for the AUC of HbA1c, and the sensitivity and specificity 81.82%, 87.50% respectively. Conclusions Plasma miR-126 is low-expressed and VEGF is high-expressed in PDR patients, there is a negative correlation between the two indexes. They may be involved in the course of PDR through abnormal lipid metabolism and inflammatory reaction and may be a potential biomarker for early diagnosis of PDR. Key words: Diabetic retinopathy/BL; MicroRNAs/BL; Vascular endothelial growth factors/BL

Introduction: Diabetic retinopathy (DR) remains a visually debilitating disease and is commonly classified according to its severity as non-proliferative DR (NPDR) or proliferative DR (PDR). Those suffering from PDR tend to have worse vascular complications and prognosis. Platelets exposed by vasculopathy caused by DR maybe activated to try to maintain haemostasis. This activity can be illustrated by the mean platelet component (MPC). Therefore, by MPC monitoring we may be able to predict the progression from NPDR into PDR.Purpose: To investigate the difference of MPC in patients with NPDR and PDR.Study design: Cross-sectional.Materials and methods: This study involved 71 DR patients. Preliminary data regarding the patients’ demographic characteristics, diabetes history, related diseases, medication history, and general eye examination were recorded. Fundus photographs were taken after dilating eyedrops and DR was graded by an ophthalmologist. The patients were grouped into NPDR and PDR. Mean platelet component was analyzed using the automatic hematology analyzer ADVIA 120.Results: Mean platelet component (MPC) was 26.69 g/dl (± 1.79) and 25.52 g/dl (± 1.20) in the NPDR and PDR group, respectively (p = 0.002), but was not clinically significant. In depth analysis into the DR grades differed significantly between mild NPDR and high-risk PDR (p = 0.015), and moderate NPDR and high-risk PDR (p = 0.024). Using our definition of mild DR (mild and moderate NPDR) and severe DR (high-risk and advanced PDR), there was a significant difference with mean MPC of 27.01 g/dl (± 1.64) and 25.31 g/dl (± 1.22), respectively (p = 0.001). The proportion of activated platelets was also higher in severe DR. Negative correlations were found between MPC with duration of DM (r = -0.333; p = 0.004) and MPC with systolic blood pressure (r = -0.241; p = 0.043).Conclusion: There was a significant difference in MPC between NPDR and PDR, but the results should be interpreted carefully. Further analysis between the mild and severe form of DR strengthened this finding.

Retinal and Corneal Neurodegeneration and Their Association with Systemic Signs of Peripheral Neuropathy in Type 2 Diabetes

Monitoring the openness of the major temporal arcade (MTA) and how it changes over time could facilitate diagnosis and treatment of proliferative diabetic retinopathy (PDR). We present methods for user-guided semiautomated modeling and measurement of the openness of the MTA based on Gabor filters for the detection of retinal vessels, morphological image processing, and a form of the generalized Hough transform for the detection of parabolas. The methods, implemented via a graphical user interface, were tested with retinal fundus images of 11 normal individuals and 11 patients with PDR in the present pilot study on potential clinical application. A method of arcade angle measurement was used for comparative analysis. The results using the openness parameters of single- and dual-parabolic models as well as the arcade angle measurements indicate areas under the receiver operating characteristics of A z = 0.87, 0.82, and 0.80, respectively. The proposed methods are expected to facilitate quantitative analysis of the architecture of the MTA, as well as assist in detection and diagnosis of PDR.

The use of systemic immune inflammatory index as a predictor for nematodes infections in horses

This study aimed to evaluate the risk of proliferative diabetic retinopathy (DR) in the fellow eye of an eye with existing proliferative DR. Our DR screening programme database listed 1513 diabetes patients alive at the time of the study. Seventy-six had proliferative DR in one or both eyes. In 28 of the 76 (37%) diabetes patients, proliferative DR was diagnosed in both eyes at the same examination. Another 28 patients developed proliferative DR in the second eye within 5 years of its diagnosis in the first eye, bringing the total number of diabetes patients with proliferative DR in both eyes at 5 years to 56 (74%). Almost all the diabetes patients eventually developed proliferative DR in the second eye. The median duration of diabetes before the development of proliferative retinopathy was 19 years for type 1 and 14 years for type 2 diabetes. Proliferative DR is a bilateral disease. Diabetes patients with proliferative DR in one eye are at high risk of developing neovascularization in the second eye and close follow-up is recommended.

The systemic immune inflammation index (SII), based on lymphocyte, neutrophil, and platelet counts, has been shown to be an independent indicator of no-reflow phenomenon during percutaneous intervention. However, the relationship between SII and no-reflow phenomenon (NRP) that develops after the procedure of saphenous vein grafts is unknown. In this study, we aimed to investigate the relationship between no-reflow phenomenon and SII during percutaneous intervention on saphenous vein grafts. A total of 133 patients who underwent percutaneous intervention for saphenous vein grafts due to acute coronary syndrome between 2019 and 2022 were included in this study. The receiver-operating characteristics (ROC) curve was used to determine the cut-off value of SII to predict the no-reflow. The multivariate regression was used to analyse the correlation between no-reflow and SII. The median value of SII was significantly higher in patients with no-reflow in comparison with normal reperfusion (543 (447, 717) vs. 861 (642, 1272), p < 0.001). The optimal threshold for SII in predicting the no-reflow phenomenon was 613, with sensitivity and specificity of 84% and 66%, respectively. The area under the ROC curve (AUC) was 0.80 (95% CI: 0.73-0.89, p < 0.001). In multivariate analysis, SII ≥ 613 showed an independent predictive value for the no-reflow (OR = 4.02, 95% CI: 1.40-11.57, p < 0.001). Our results showed that high SII levels were independently associated with the development of no-reflow phenomenon in patients presenting with acute coronary syndrome and undergoing percutaneous intervention to the SVG.

Objective To observe the serum vascular endothelial growth factor (VEGF), apelin and heme oxygenase-1 (HO-1) levels in patients with type 2 diabetes mellitus (T2DM) and to explore their their relationship with diabetic retinopathy (DR). Methods A total of 208 patients with T2DM and 50 healthy subjects (control group) from the Central Hospital of Western Hainan during January 2014 and December 2017 were selected in this study. Vision, slit lamp microscope, indirect ophthalmoscope and FFA examinations were performed on all the subjects. According to the results of the examinations combined with the DR clinical staging criteria, the patients were divided into non-DR (NDR) group, non-proliferative DR (NPDR) group, and proliferative DR (PDR) group, with 72, 76 and 60 patients in each, respectively. The clinical data of each group were recorded, and the levels of fasting blood glucose (FPG), HbA1c, total cholesterol (TC), three acylglycerol (TG), high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), VEGF, apelin and HO-1 were detected in each group. The receiver operating characteristic curve (ROC) were used to analyze the value of VEGF, apelin and HO-1 in predicting the occurrence of PDR. Correlation analysis of serum VEGF, Apelin and HO-1 with clinical parameters in PDR patients by Pearson correlation analysis. Results The level of VEGF (56.82±10.16 vs 91.74±22.83, 140.15±36.40, 195.28±42.26 pg/ml) and apelin (2.95±0.53 vs 4.68±0.74, 7.25±1.13, 10.16±1.35 ng/ml) in PDR group were significantly higher than those in NPDR, NDR and control groups (F=17.306, 21.814; P<0.05). The level of HO-1 (50.37±10.14 vs 43.58±8.16, 30.25±6.28, 22.60±4.72 mmol/L) in PDR group was significantly lower than those in NPDR, NDR and control groups (F=15.827, P<0.05). The ROC curve analysis showed that the best cut-off values of serum VEGF, apelin and HO-1 were 162.50 pg/ml, 8.30 ng/ml, 27.13 mmol/L, and the three combined to predict PDR of AUC (95%CI) was 0.906 (0.849−0.962), and their sensitivity (90.3%) and specificity (83%) were better. The correlation analysis showed that the VEGF, apelin and HO-1 of PDR patients were correlated with the course of diabetes (r=0.382, 0.416, −0.36; P<0.05), FPG (r=0.438, 0.460, −0.397; P<0.05) and HbAlc (r=0.375, 0.478, −0.405; P<0.05), and the serum VEGF were correlated with apelin and HO-1 (r=0.793, −0.594; P<0.01). Conclusion Elevated serum VEGF and apelin levels and reduced HO-1 levels are associated with the progression of DR, and the three combination helps predict the occurrence of PDR. Key words: Diabetic retinopathy/etiology; Diabetes mellitus, type 2; Vascular endothelial growth factors; Receptors, angiotensin; Heme oxygenase-1

Diabetic retinopathy is an important cause of visual loss. Laser photocoagulation preserves vision in diabetic retinopathy but is currently used at the stage of proliferative diabetic retinopathy (PDR). The primary aim was to assess the clinical effectiveness and cost-effectiveness of pan-retinal photocoagulation (PRP) given at the non-proliferative stage of diabetic retinopathy (NPDR) compared with waiting until the high-risk PDR (HR-PDR) stage was reached. There have been recent advances in laser photocoagulation techniques, and in the use of laser treatments combined with anti-vascular endothelial growth factor (VEGF) drugs or injected steroids. Our secondary questions were: (1) If PRP were to be used in NPDR, which form of laser treatment should be used? and (2) Is adjuvant therapy with intravitreal drugs clinically effective and cost-effective in PRP? Randomised controlled trials (RCTs) for efficacy but other designs also used. MEDLINE and EMBASE to February 2014, Web of Science. Systematic review and economic modelling. The Early Treatment Diabetic Retinopathy Study (ETDRS), published in 1991, was the only trial designed to determine the best time to initiate PRP. It randomised one eye of 3711 patients with mild-to-severe NPDR or early PDR to early photocoagulation, and the other to deferral of PRP until HR-PDR developed. The risk of severe visual loss after 5 years for eyes assigned to PRP for NPDR or early PDR compared with deferral of PRP was reduced by 23% (relative risk 0.77, 99% confidence interval 0.56 to 1.06). However, the ETDRS did not provide results separately for NPDR and early PDR. In economic modelling, the base case found that early PRP could be more effective and less costly than deferred PRP. Sensitivity analyses gave similar results, with early PRP continuing to dominate or having low incremental cost-effectiveness ratio. However, there are substantial uncertainties. For our secondary aims we found 12 trials of lasers in DR, with 982 patients in total, ranging from 40 to 150. Most were in PDR but five included some patients with severe NPDR. Three compared multi-spot pattern lasers against argon laser. RCTs comparing laser applied in a lighter manner (less-intensive burns) with conventional methods (more intense burns) reported little difference in efficacy but fewer adverse effects. One RCT suggested that selective laser treatment targeting only ischaemic areas was effective. Observational studies showed that the most important adverse effect of PRP was macular oedema (MO), which can cause visual impairment, usually temporary. Ten trials of laser and anti-VEGF or steroid drug combinations were consistent in reporting a reduction in risk of PRP-induced MO. The current evidence is insufficient to recommend PRP for severe NPDR. There is, as yet, no convincing evidence that modern laser systems are more effective than the argon laser used in ETDRS, but they appear to have fewer adverse effects. We recommend a trial of PRP for severe NPDR and early PDR compared with deferring PRP till the HR-PDR stage. The trial would use modern laser technologies, and investigate the value adjuvant prophylactic anti-VEGF or steroid drugs. This study is registered as PROSPERO CRD42013005408. The National Institute for Health Research Health Technology Assessment programme.

Objective To investigate the correlations between the systemic immune inflammatory index (SII) and prognosis of patients with gallbladder cancer. Methods From April 2005 to January 2019, patients with gallbladder cancer underwent surgical treatment in the Department of Hepatobiliary and Pancreatic Surgery, Affiliated Tumor Hospital of Zhengzhou University were followed up and their SII values were analyzed. The receiver operating characteristic curve (ROC) was used to determine the best clinical boundary value of SII. According to the boundary value, patients were divided into two groups: low SII and high SII. Survival curves were drawn by Kaplan-Meier method. The overall survival time of the two groups was analyzed, and univariate analysis of postoperative survival was performed using log-rank test. Cox regression proportional hazard model was used for multivariate analysis of clinical prognosis. Results A total of 312 patients were included, including 120 males and 192 females, aged 30.0 to 86.0 (61.5±9.9) years. The best clinical cut off value of preoperative SII was determined by ROC curve to be 510.42. A total of 312 patients with gallbladder cancer were divided into low SII group (SII≤510.42) and high SII group (SII>510.42). Kaplan-Meier survival curve was used to analyze the 1, 3 and 5-year survival rates of gallbladder cancer patients in low SII group and high SII group after operation. The survival rates were 65.7%, 39.6% and 30.2%, and 27.9%, 12.0% and 9.6% respectively. The median survival time was 25 months (95% CI: 16.9-33.1) and 9 months (95% CI: 8.1-9.9), respectively. The survival rate of gallbladder cancer patients in low SII group was better. There were significant differences of the overall survival rate between the two groups (P 510.42 (HR=0.086, 95% CI: 0.032-0.289) was a risk factor for overall survival of gallbladder cancer patients. Cox multivariate analysis confirmed that preoperative SII (HR=2.649, 95% CI: 1.981-3.543) was an independent risk factor for overall survival of gallbladder cancer patients. Conclusions SII can be used as an independent prognostic factor to predict the prognosis of patients with gallbladder cancer. The higher the preoperative SII, the worse the prognosis of patients with gallbladder cancer. Key words: Gallbladder neoplasms; Systemic immune-inflammation index; Prognostic facts

To investigate the content of serum microRNA-126 (miR-126) and its role in screening retinal endothelial injury and early diagnosis of proliferative diabetic retinopathy. The study included 184 serum samples, 59 samples from healthy individuals, 44 samples from diabetes mellitus (DM) patients without diabetic retinopathy (NDR), 42 from non-proliferative diabetic retinopathy (NPDR) patients and 39 samples from proliferative diabetic retinopathy (PDR) patients. The expression of miR-126 was evaluated using a real-time quantitative polymerase chain reaction. The serum content of miR-126 declined as the damage degree in the retina. There was significant difference between the two retinopathy groups (P<0.001). No difference was observed in miR-126 content between healthy individuals and NDR patients (P>0.05). Receiver operating characteristic curve (ROC) analyses indicated that serum miR-126 had significant diagnostic value for PDR. It yielded an area under the curve (AUC) of ROC of 0.976 with 81.21% sensitivity and 90.34% specificity in discriminating PDR from healthy controls, and an AUC of ROC of 0.919 with 84.75% sensitivity and 94.41% specificity in discriminating NDR and NPDR from healthy controls. When the diagnostic threshold was greater than or equal to 8.43, there was an increase in the possibility of NPDR. When the content of miR-126 was less than or equal to 5.02, the possibility of the occurrence of PDR increased. Serum miR-126 can serve as a non-invasive biomarker for screening retinal endothelial injury and early diagnosis PDR.

Systemic Immune-Inflammation (SII) index predicts poor outcome after spontaneous supratentorial intracerebral hemorrhage

Background The pathogenesis of cardiovascular diseases (CVD) is sustained by persistent low-grade systemic inflammation. Lipid deposition, atherosclerotic plaque formation, toll-like receptor activation, leukocyte infiltration and secretion of pro-inflammatory mediators collectively promote chronic low-grade inflammation which drives CVD-progression. Despite the well-described inflammatory processes in CVD, its perioperative clinical significance in cardiac surgery is ill-defined. Aim To evaluate the association between the preoperative chronic inflammation and postoperative outcome. We hypothesized that an elevated systemic inflammation predisposes patients to adverse postoperative outcome. Methods A retrospective analysis of 1251 consecutive adults undergoing cardiac surgery between July 2018 and Dec 2019. We used the systemic-immune-inflammation index (SII) as a marker for chronic inflammation and was calculated as follows: “platelet counts x (Neutrophil/Lymphocyte ratio)”. A Receiver Operating Characteristic (ROC) curve was generated by plotting the SII values for in-hospital mortality cases vs successfully discharged patients, the Wilcoxon estimate of area under ROC curve = 0.67; an optimum cut-off point of 647 (sensitivity = 0.72, specificity = 0.59) was chosen to classify patients with an elevated inflammatory status. We used the Fisher's exact test to assess whether the preoperative SII was related with adverse outcome. Finally, we included the SII in a multivariable logistic regression controlling for 11 established cardiac surgery mortality risk-factors. Results The median age was 65 years (range 18–88), 361 (29%) were females. The mean ACEF II operative mortality was 3.49%. The median SII before surgery was 576 (IQR 402 - 855). In comparison, the SII of a healthy control non-surgical cohort (N=60) was 434 (IQR 290–559), median difference = 142 [CI95% 84 to 223), p&amp;lt;0.0001. Sub-group analysis revealed that patients who passed away during hospitalisation were admitted with a significantly higher preoperative SII (= 824), median difference 255 [CI95% 143–388], p&amp;lt;0.0001, compared to those patients who were successfully discharged, SII = 569. Contrary to patients with low-grade systemic inflammation (= SII &amp;lt;647), we observed that patients with an elevated SII (≥647) were more likely to have difficulties coming off-pump, Odds Ratio (OR) 1.73, p=0.007; to experience an infection, OR 1.94, p&amp;lt;0.001, or death during postoperative hospitalisation, OR 3.46, p&amp;lt;0.0001. Multivariable logistic regression revealed that an SII ≥647 is an independent risk factor for in-hospital mortality, adjusted OR 2.67, p=0.004. Conclusion A high SII (≥647) is independently associated with postoperative morbidity and mortality following cardiac surgery. The SII may support clinical decision making and stratification of high-risk patients undergoing cardiac surgery. Funding Acknowledgement Type of funding source: None