Metabolomics identifies and validates serum androstenedione as novel biomarker for diagnosing primary angle closure glaucoma and predicting the visual field progression.

Background: Primary angle closure glaucoma (PACG) is the leading cause of irreversible blindness in Asia, and no reliable, effective diagnostic, and predictive biomarkers are used in clinical routines. A growing body of evidence shows metabolic alterations in patients with glaucoma. We aimed to develop and validate potential metabolite biomarkers to diagnose and predict the visual field progression of PACG. Methods: Here, we used a five-phase (discovery phase, validation phase 1, validation phase 2, supplementary phase, and cohort phase) multicenter (EENT hospital, Shanghai Xuhui Central Hospital), cross-sectional, prospective cohort study designed to perform widely targeted metabolomics and chemiluminescence immunoassay to determine candidate biomarkers. Five machine learning (random forest, support vector machine, lasso, K-nearest neighbor, and GaussianNaive Bayes [NB]) approaches were used to identify an optimal algorithm. The discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC). Calibration was assessed by Hosmer-Lemeshow tests and calibration plots. Results: Studied serum samples were collected from 616 participants, and 1464 metabolites were identified. Machine learning algorithm determines that androstenedione exhibited excellent discrimination and acceptable calibration in discriminating PACG across the discovery phase (discovery set 1, AUCs=1.0 [95% CI, 1.00-1.00]; discovery set 2, AUCs = 0.85 [95% CI, 0.80-0.90]) and validation phases (internal validation, AUCs = 0.86 [95% CI, 0.81-0.91]; external validation, AUCs = 0.87 [95% CI, 0.80-0.95]). Androstenedione also exhibited a higher AUC (0.92-0.98) to discriminate the severity of PACG. In the supplemental phase, serum androstenedione levels were consistent with those in aqueous humor (r=0.82, p=0.038) and significantly (p=0.021) decreased after treatment. Further, cohort phase demonstrates that higher baseline androstenedione levels (hazard ratio = 2.71 [95% CI: 1.199-6.104], p=0.017) were associated with faster visual field progression. Conclusions: Our study identifies serum androstenedione as a potential biomarker for diagnosing PACG and indicating visual field progression. Funding: This work was supported by Youth Medical Talents - Clinical Laboratory Practitioner Program (2022-65), the National Natural Science Foundation of China (82302582), Shanghai Municipal Health Commission Project (20224Y0317), and Higher Education Industry-Academic-Research Innovation Fund of China (2023JQ006).

Association between Serum Total Bilirubin Level and Patients with Primary Open-Angle Glaucoma in China: A Cross-Sectional, Case-Control Study.

Objective: To investigate the relationship between peripheral blood total bilirubin (TBIL) levels and the risk of primary open-angle glaucoma (POAG). Methods: This study was a cross-sectional, case-control study design. Between April 2021 and January 2022, 198 POAG patients and 205 healthy subjects were recruited from the EENT Hospital of Fudan University. Their clinical information (intraocular pressure, central corneal thickness, vertical cup-disk ratios (VCDR), and axial length) and demographic data were collected. Serum levels of TBIL were measured in enzymes using a Roche C702 biochemical analyzer. The POAG subgroups were classified by gender and VCDR: mild (VCDR ≤ 0.64), moderate (VCDR ≤ 0.85), and severe (VCDR > 0.85). Univariate and multivariate logistic regression analyses were performed. Results: The level of TBIL (11.58 ± 5.16 µmol/L) in the POAG group was higher than that in the control group (10.18 ± 3.38 µmol/L; p < 0.05). In the male subgroup, TBIL was also significantly higher than in the normal control group; TBIL levels were lower in the mild subgroup (10.82 ± 4.48 µmol/L), followed by the moderate subgroup (12.00 ± 5.55 µmol/L) and the severe subgroup (14.47 ± 5.45 µmol/L). The results of the multivariate logistic regression analysis showed that high TBIL levels were a risk factor for male POAG, at 1.126 (95% CI 1.009-1.256). Pearson's analysis revealed that TBIL was positively correlated with intraocular pressure (r = 0.134, p = 0.012), VCDR (r = 0.142, p = 0.046), anterior chamber depth (r = 0.190, p = 0.014), and axial length (r = 0.179, p = 0.019) in the patients. However, no statistical difference (p < 0.05) was observed in the female patients with POAG. Conclusion: The results showed that high levels of TBIL may be related to the pathogenesis of POAG and that the severity of the disease is positively correlated, especially in male patients.

Serum complement component 3, complement component 4 and complement component 1q levels predict progressive visual field loss in older women with primary angle closure glaucoma.

AIM: To evaluate the association between serum levels of complement component (C) 3, C4 and C1q and visual field (VF) loss in patients with primary angle closure glaucoma (PACG). METHODS: In this prospective cohort study, a total of 308 patients with PACG were included. The patients were followed up every 6 months (at least 2 years), with clinical examination and VF testing. Based on their sex and age, the subjects were stratified into male and female subgroups, and by age at <60 and ≥60 years per subgroup. RESULTS: One hundred twenty-three (39.94%) patients showed glaucoma VF progression. The serum levels of C3, C4 and C1q were significantly lower (p<0.05) in the progression group compared with the non-progression group in the ≥60 years female subgroup. In female patients with age ≥60 years, (1) lower levels of baseline C3 (HR=0.98, p<0.001), C4 (HR=0.96, p=0.01) and C1q levels (HR=0.99, p=0.003) were associated with a greater risk of VF progression; (2) patients with lower C3 levels had significantly (p<0.05) higher rates of VF loss progression, similar to those with lower C4 and lower C1q levels; and (3) the generalised additive model revealed a negative correlation between baseline C3 (p<0.001), C4 (p<0.001) and C1q (p<0.001) levels with the risk of VF progression. No statistical significance was observed in the male (<60 and ≥60 years) and female (<60 years) subgroups. CONCLUSION: Decreased C3, C4 and C1q levels at baseline were significantly associated with a greater risk of VF loss progression only in older women with PACG.

Association between Serum Potassium with Risk of Onset and Visual Field Progression in Patients with Primary Angle Close Glaucoma: A Cross-Sectional and Prospective Cohort Study.

Evidence suggests that ion metabolism may be associated with oxidative stress in the ocular tissue in glaucoma patients. This study is aimed at determining whether serum ion levels are associated with the onset and/or visual field (VF) progression of PACG. A total of 265 PACG and 166 healthy subjects were included in the cross-sectional study. Meanwhile, 265 subjects with PACG were followed up every six months for at least two years in the cohort study. All subjects were evaluated for serum concentrations of ions (calcium, phosphorus, potassium (K+), sodium, and chlorine) and underwent VF examination. Logistic regression analysis was performed to assess the risk factors for PACG. Cox regression analyses and Kaplan-Meier survival analyses were performed to identify factors associated with VF progression in PACG subjects. In the cross-sectional study, the K+ level (4.31 ± 0.39 mmol/L) was significantly higher in the PACG group than in the normal group (4.16 ± 0.35 mmol/L, P < 0.001). Multiple logistic regression showed that the increased K+ level was a risk factor of PACG (OR = 2.94, 95%CI = 1.63-5.32, P < 0.001). In the cohort study, there were 105 PACG subjects with progression and 160 PACG subjects without progression. The progression group had significantly higher baseline serum K+ levels (4.41 ± 0.37 mmol/L) than the no progression group (4.25 ± 0.39 mmol/L) (P = 0.002). The increased level of K+ at baseline was associated with faster VF progression (HR = 2.07, 95%CI = 1.23-3.46, P = 0.006). PACG subjects with higher baseline K+ levels had significantly lower VF nonprogression rates (51.94%) than subjects with lower K+ levels (68.38%, log-rank test P = 0.01). This study found that increased serum K+ level is a risk factor of PACG and is associated with faster VF progression in PACG, which might result from its influence on the oxidative stress process.

Association Between Increased Lipid Profiles and Risk of Diabetic Retinopathy in a Population-Based Case-Control Study.

Purpose: We aimed to investigate the association between lipid profiles and diabetic retinopathy (DR). Patients and Methods: This case-control study, which was conducted between November 2019 and August 2021, comprised 309 patients with DR, 186 patients with diabetes mellitus, and 172 healthy controls. Serum cholesterol (CHOL), triglyceride (TRIG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (SDLDL-C), apolipoprotein A (APOA), APOB, APOE and lipoprotein (a)(LPA) levels were assessed. Patients were divided into two groups according to median age and glycated hemoglobin (HbA1c) level. Linear and logistic regression analyses were performed to assess the association between lipid levels and DR. Results: CHOL, TRIG, HDL-C, APOB, APOE, and SDLDL-C levels were significantly higher in the DR group than in the healthy control group, and TRIG levels were lower in the DR group than in the DM group (P < 0.05), especially in the ≤57-year-old and the HbA1c ≤7.2% subgroups. Linear regression analyses showed that CHOL, TRIG, APOA, APOB, APOE, and SDLDL-C levels were associated with HbA1c levels. Multivariable logistic regression analyses indicated that CHOL (odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.112-1.566), TRIG (OR = 1.269, 95% CI = 1.030-1.563), HDL-C (OR = 43.744, 95% CI = 17.12-111.769), APOB (OR = 7.037, 95% CI = 3.370-14.695), APOE (OR = 1.057, 95% CI = 1.038-1.077), and SDLDL-C (OR = 14.719, 95% CI = 8.304-26.088) levels were risk factors for DR (P < 0.05). Conclusion: Increased lipid levels were risk factors for DR, and lipid level control should be strengthened, especially in younger adults or in patients with HbA1c ≤7.2%.

Platelet Parameters and Their Relationships With the Thickness of the Retinal Nerve Fiber Layer and Ganglion Cell Complex in Primary Open-Angle Glaucoma.

Objective: Glaucoma is a neurodegenerative disease of the visual system. Platelet parameters are correlated with visual field mean deviation (MD) in glaucoma, but there is a lack of relative data on their relationship with structural changes in the retina. This study aimed to explore the relationship between platelet parameters and retinal nerve fiber layer (RNEL), ganglion cell complex (GCC) thickness, and cup/disk area ratio, evaluated by optical coherence tomography (OCT) in primary open-angle glaucoma (POAG). Methods: A total of 118 consecutive patients with POAG and 120 age- and sex-matched control subjects were included in this retrospective study. Demographic data, platelet parameters in blood tests, visual field, and OCT results were evaluated. The RNFL was divided into the temporal, superior, nasal, and inferior quadrants. Based on the visual field MD, the patients were stratified into mild (MD ≤ 6.0 dB), moderate (6 dB < MD ≤ 12 dB), and severe (MD > 12.0 dB) subgroups. Results: Patients with POAG had significantly lower platelet (PLT) levels and significantly higher platelet distribution width (PDW) and mean platelet volume (MPV) levels than controls. As the visual field MD increased, structural evaluation by OCT identified loss of disk rim area, average GCC thickness, and average RNFL thickness (all P < 0.001), as well as increased PDW (P < 0.001) and MPV (P = 0.004) levels in patients with POAG. The Spearman's rank correlation analysis showed that PDW levels were significantly correlated with OCT parameters such as RNFL thickness (r = -0.370, P < 0.001), GCC thickness (r = -0.294, P = 0.001), and cup/disk area ratio (r = 0.322, P < 0.001), as well as visual field MD (r = 0.607, P < 0.001) and mean sensitivity (MS) (r = -0.570, P < 0.001). Significantly correlations were also found between MPV and RNFL thickness (r = -0.321, P < 0.001), GCC thickness (r = -0.194, P = 0.041), and cup/disk area ratio (r = 0.237, P = 0.010). All the quadrants showed similar negative correlations between PDW, MPV, and RNFL thickness. The multiple linear regression analyses showed significant association between PDW and RNFL thickness (ß = -0.331, P < 0.001), PDW and GCC thickness (ß = -0.288, P = 0.002), MPV and RNFL thickness (ß = -0.313, P = 0.001), and MPV and GCC thickness (ß = -0.188, P = 0.048). Conclusion: This study found significantly negative association between PDW, MPV levels and RNFL, GCC thickness, as well as positive association between PDW, MPV levels, and cup/disk area ratio in patients with POAG, suggesting that platelet activation may contribute to glaucomatous optic neuropathy.

Association of Serum Complement C1q and C3 Level with Age-Related Macular Degeneration in Women.

PURPOSE: To investigate the association between serum complement components and age-related macular degeneration (AMD). PATIENTS AND METHODS: A total of 118 AMD patients and age- and sex-matched 106 control subjects were included. Demographic data and the level of serum complement component (C)1q, C3 and C4 were evaluated. Based on sex, the subjects were stratified into male and female subgroups. RESULTS: The level of C1q (226.31±45.33mg/dL) was significantly higher and C3 (121.14±15.76mg/dL) was significantly lower than that in control group (200.03±38.54mg/dL) (128.42±19.81mg/dL) in the female AMD patients (p = 0.005, p = 0.045). Logistic regression showed that increased C1q (OR = 1.132, p = 0.016) and decreased C3 (OR = 0.960, p = 0.048) were independent risk factors for female AMD patients. No statistical significance was observed in the male. CONCLUSION: Increased C1q and decreased C3 were associated with increased risk of AMD, suggesting that the complement classical pathway probably be involved in AMD, especially in female.

Association of systemic inflammation indices with visual field loss progression in patients with primary angle-closure glaucoma: potential biomarkers for 3P medical approaches.

RELEVANCE: Accumulating evidence suggests a dysfunction of the para-inflammation in the retinal ganglion cell layer and the optic nerve head in patients with glaucoma. Currently, circulating blood platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR) are regarded as novel indicators of systemic inflammation. Biomarkers allow early identification of patients with visual field (VF) loss progression and timely implementation of replacement therapies. OBJECTIVE: This study aimed to investigate whether higher inflammatory indices (PLR, NLR, and LMR) were associated with VF loss progression in patients with primary angle-closure glaucoma (PACG) for the predictive diagnostics, targeted prevention, and personalization of medical services. METHODS: This prospective cohort study followed up 277 patients with PACG for at least 24 months, with clinical examination and VF testing every 6 months. Inflammatory cell quantification, including platelets, neutrophils, lymphocytes, and monocytes, was measured using the Sysmex XN-A1 automated inflammatory cells quantification system. Three systemic inflammatory indices, PLR, NLR, and LMR, were determined on the basis of baseline neutrophil, lymphocyte, monocyte, and platelet counts in patients with PACG. The risk factors for PACG were analyzed using logistic regression, Cox proportional hazards regression, and the Kaplan-Meier curve. RESULTS: Our results revealed that 111 (40.07%) patients showed VF loss progression. The PLR was significantly higher (P = 0.046) in the progression group than in the non-progression group. A higher PLR (OR 1.05, 95% CI 1.01-1.08, P = 0.004) was a risk factor for PACG progression. In multivariate analyses, PLR independently predicted VF loss progression (HR 1.01, 95% CI 1.00-1.01, P = 0.04). Kaplan-Meier curve analysis showed that higher PLR indicated significantly higher rates of VF loss progression (66.91% vs. 52.90%, P = 0.03). Comparable results were observed in the male and female subgroups. CONCLUSION: Our findings revealed the significant association between a high PLR and a greater risk of VF loss progression in patients with PACG. PLR may be highly recommended as a novel predictive/diagnostic tool for the assessment of VF loss progression from the perspectives of predictive, preventive, and personalized medicine in vulnerable populations and for individual screening. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00260-3.

Association Between Serum Lipid Levels and Patients With Primary Angle-Closure Glaucoma in China: A Cross Sectional, Case-Control Study.

Objective: To evaluate the serum lipid levels of patients with primary angle-closure glaucoma (PACG) and to investigate the relationship between serum lipid levels and PACG. Methods: In this cross-sectional, case-control study, a total of 320 PACG subjects and 242 age- and sex-matched control subjects were recruited. Serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (SDLDL-C), triglyceride (TRIG), and cholesterol (CHOL) levels were measured using enzymatic colorimetry. Serum apolipoprotein A (APOA), apolipoprotein B (APOB), apolipoprotein E (APOE), and lipoprotein(a) (LPa) levels were measured by immunoturbidimetry. Results: The serum LDL-C, TRIG, HDL-C, APOE, LPa, CHOL, APOB, and APOA levels were significantly higher (p < 0.05) in the PACG group than in the control group. Multiple liner regression analyses revealed that there was a statistically correlation between HDL-C levels and mean deviation MD (B = 0.389, P = 0.002, 95% confidence interval [CI] = -1.249 to -0.624); LDL-C levels and MD (B = 0.190, P = 0.019, 95% CI = -5.632 to -1.306); and CHOL levels and MD (B = 0.364, P = 0.27, 95% CI = -7.727 to -1.839). Logistic regression analyses showed that high serum HDL-C (odds ratio [OR] = 11.01, 95% CI = 5.616-21.587), LDL-C (OR = 1.330, 95% CI = 1.079-1.640), SDLDL-C (OR = 1.007, 95% CI = 1.005-1.008), APOA (OR = 13.621, 95% CI = 7.251-25.591), APOB (OR = 2.243, 95% CI = 1.060-4.732), LPa (OR = 0.999, 95% CI = 0.998-1.00), and CHOL (OR = 1.131, 95% CI = 1.005-1.326) levels were significantly associated with PACG. Conclusions: High serum HDL-C, LDL-C, APOA, APOB, LPa, and CHOL levels were associated with PACG.

Association Between Sex Hormones and Visual Field Progression in Women With Primary Open Angle Glaucoma: A Cross-Sectional and Prospective Cohort Study.

Purpose: We evaluated the level of sex hormones in female patients with primary open angle glaucoma (POAG) to determine whether they are associated with the onset and/or progression of POAG. Methods: The cross-sectional study enrolled 63 women with POAG and 56 healthy women as normal control subjects. Furthermore, 57 women with POAG were included and followed-up for at least 2 years in the cohort study. All subjects were evaluated for serum concentration of sex hormones [prolactin (PRL), luteinizing hormone (LH), testosterone (TESTO), follicle-stimulating hormone (FSH), progesterone (PROG), and estrogen (E2)] and underwent visual field (VF) examination. In the cross-sectional study, Spearman analysis, linear regression analysis, and logistic regression analysis were performed to assess risk factors for POAG in women. In the cohort study, Cox regression analyses and Kaplan-Meier survival analysis were performed to identify factors associated with VF progression in women with POAG. Results: In the cross-sectional study, the level of E2 was significantly lower in the POAG group than in the normal group (p < 0.05). Multiple logistic regression showed that the decreased level of E2 was a risk factor of POAG (OR = 0.27, 95% CI = 0.09-0.78, p < 0.05), especially in premenopausal subjects. In the cohort study, there were 29 non-progression subjects and 28 progression subjects. Patients in the progression group had significantly lower levels of E2 than those in the no progression group (p < 0.01). The decreased level of E2 at baseline was associated with POAG progression (HR = 0.08, 95% CI = 0.02-0.46, p < 0.05), especially in premenopausal subjects. Patients with POAG and with lower baseline E2 levels had significantly lower VF non-progression rates than patients with higher E2 levels (log-rank test p < 0.001), especially premenopausal subjects (log-rank test p < 0.05). Additionally, logistic regression analyses, Cox regression analyses, and Kaplan-Meier survival analysis showed that PROG, LH, FSH, and TESTO were risk factors of POAG and/or significantly associated with POAG progression. Conclusion: A decreased E2 level is a POAG risk factor and is associated with VF progression in women with POAG, especially in premenopausal subjects. Additionally, other sex hormones (PROG, LH, FSH, and TESTO) might also play a role in POAG pathogenesis.

Exploring the Demographics and Clinical Characteristics Related to the Expression of Angiotensin-Converting Enzyme 2, a Receptor of SARS-CoV-2.

Objective: Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, and has rapidly spread throughout the world. It has been reported that angiotensin-converting enzyme 2 (ACE2) is one of the major cellular entry receptors of SARS-CoV-2; thus, high ACE2 expression may increase susceptibility to infection. Therefore, we analyzed the expression of ACE2 in the blood to identify the individuals who may be susceptible to infection. Methods: In total, 229 subjects were enrolled in this study, and reverse transcription-quantitative polymerase chain reaction and ELISA assay was used to identify the level of ACE2 mRNA expression and ACE2 protein level in the blood. Demographic and clinical characteristics, including age, gender, weight, height, smoking habits, drinking habits, diabetes, and hypertension, were obtained using a face-to-face questionnaire. Independent Student's t-test, Pearson's linear correlation, logistic regression analysis, and multiple linear regression correlation were performed to assess the association between these factors and the expression of ACE2. Results: Higher level of ACE2 was observed in females, older subjects, subjects with hypertension, subjects with a cardiocerebrovascular disease, male smokers, and subjects with cancer (p < 0.05) than in other subjects. Multiple linear regression analysis showed that there is a statistically significant correlation between being a female and ACE2 expression (ß = 0.550, p < 0.001), between older age and ACE2 expression (ß = 0.197, p = 0.003), between smoking and ACE2 expression (ß = 0.163, p = 0.037), and between cancer and ACE2 expression (ß = 0.265, p < 0.001). Logistic regression analysis revealed that female subjects (odds ratio [OR] = 2.255, 95% confidence interval [CI] = 1.770-2.872), subjects with hypertension (OR = 1.264, 95% CI = 1.075-1.486), subjects with a cardiocerebrovascular disease (OR = 1.271, 95% CI = 1.023-1.579), subjects with cancer (OR = 1.695, 95% CI = 1.253-2.293), and subjects above 60 years of age (OR = 3.097, 95% CI = 1.078-8.896) are at an increased risk of infection due to their high expression of ACE2. Conclusion: The level of ACE2 is higher in females, older subjects, smokers, and subjects with cancer than in other subjects, indicating that some of which are at higher risk for the severe forms of COVID-19 when they are exposed to the SARS-Cov-2.

Relationship between Oxidative Stress Biomarkers and Visual Field Progression in Patients with Primary Angle Closure Glaucoma.

PURPOSE: To investigate the serum changes of oxidative stress markers and the relationship between these factors and visual field (VF) progression in patients with primary angle closure glaucoma (PACG). METHODS: A case-control and a prospective cohort study. A total of 94 patients with PACG and 89 normal controls were enrolled. Furthermore, 94 PACG subjects were followed up for at least two years (once every six months). All participants were evaluated for serum levels of superoxide dismutase (SOD), total antioxidant status (TAS), hydrogen peroxide (H2O2), malondialdehyde (MDA), glutathione peroxidase, glutathione reductase, and detailed eye and systematic examination. Binary logistic regression analysis and Cox regression analysis were performed. RESULTS: The serum levels of SOD and TAS in the PACG group were significantly lower than those in the control group (p < 0.001). Meanwhile, PACG subjects had significantly higher levels of MDA and H2O2 than the normal control subjects (p < 0.001). Serum levels of TAS (OR = 0.773, 95%CI = 0.349 - 0.714, p < 0.001), SOD (OR = 0.975, 95%CI = 0.955 - 0.995, p < 0.001), MDA (OR = 1.155, 95%CI = 1.080 - 1.235, p < 0.001), and H2O2 (OR = 1.216, 95%CI = 1.142 - 1.295, p < 0.001) were independent risk/protective factors for PACG. TAS levels (HR = 0.041, 95%CI = 0.008-0.218, p < 0.001), SOD levels (HR = 0.983, 95%CI = 0.971-0.994, p = 0.003), and MDA levels (HR = 1.010, 95%CI = 1.001-1.018, p = 0.015) at baseline were associated with visual field progression. Kaplan-Meier curves reveal that patients with TAS < 0.95/SOD < 143/MDA > 12 had a significantly higher percentage of PACG progression (p < 0.05). CONCLUSIONS: Decreased levels of TAS and SOD as well as increased levels of MDA at baseline were associated with VF progression in patients with PACG. These findings suggest that oxidative stress was involved in the onset and development of PACG.

Association Between 17-ß-Estradiol and Interleukin-8 and Visual Field Progression in Postmenopausal Women with Primary Angle Closure Glaucoma.

PURPOSE: To investigate an association between sex hormones and inflammatory cytokines, and to determine whether baseline 17-ß-estradiol (E2) and interleukin-8 (IL-8) are associated with visual field (VF) progression in postmenopausal women with primary angle closure glaucoma (PACG). DESIGN: A prospective cross-sectional and cohort study. PARTICIPANTS: The cross-sectional study enrolled 200 postmenopausal women with PACG and 151 healthy postmenopausal women as normal control subjects. A total of 105 postmenopausal women with PACG were included and followed up for ≥2 years in the cohort study. METHODS: All participants were evaluated for levels of baseline sex hormones (follicle-stimulating hormone, prolactin, progesterone, testosterone, luteinizing hormone, and E2) and inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, IL-10, and C-reactive protein) and underwent VF examinations. The cross-sectional study was conducted to establish risk factors for postmenopausal women with PACG using logistic regression analysis. The cohort study was designed to identify factors that could be used to predict VF progression in postmenopausal women with PACG using multivariate Cox regression analyses. The main outcome measures included factors associated with VF progression over time. RESULTS: Decreased E2 (odds ratio 0.88 [95% confidence interval {CI} 0.78-0.99], P = .007) and increased IL-8 (odds ratio 1.12 [95% CI 1.01-1.23], P < .001) levels were risk factors in postmenopausal women with PACG. A significant negative correlation was observed between IL-8 levels and E2 (r = -0.21, P = .02). Multivariable regression analyses revealed a significant correlation between E2 levels and visual field mean deviation (MD) (B = -0.16, P = .04 [95% CI -.09 to -.003) and between IL-8 levels and MD (B = 0.36, P < .001 [95% CI 0.01-0.02]). During follow-up, 48 (45.71%) patients showed VF progression. Lower baseline E2 (hazard ratio 0.85 [95% CI 0.82-0.88], P = .04) and higher baseline IL-8 levels (hazard ratio 1.01 [95% CI 1.00-1.02], P = .004) were associated with progression of glaucoma. Patients with lower E2 levels had a significantly higher rate of PACG progression (log-rank test P < .001), similar to those with higher IL-8 levels (log-rank test P = .04). CONCLUSIONS: Decreased E2 and increased IL-8 levels at baseline are significant predictors of VF progression in postmenopausal women with PACG.

Relationship between ocular biometry and severity of primary angle-closure glaucoma: relevance for predictive, preventive, and personalized medicine.

BACKGROUND: Several ocular factors have been identified for primary angle-closure glaucoma (PACG), such as a small cornea, elevated intraocular pressure (IOP), shallow anterior chamber, and short axial length (AL). However, the relationship between the severity of PACG and various ocular parameters [IOP, anterior chamber depth, AL, central corneal thickness] is not fully understood. METHODS: A 7-year cross-sectional study. A total of 2254 eyes of 1312 PACG patients (females = 856 [1479 eyes] and males = 456 [775 eyes]) were included. A detailed eye examination was performed. The participants were categorized into gender subgroups followed by subdivision into three different severity groups according to their mean deviation (MD) of the visual fields results as follows: mild (MD ≤ 6 dB), moderate (MD 6-12 dB), and severe (MD > 12 dB) PACG. The associations of ocular biometry with severity of PACG were analyzed using paired Student's t test, multivariate linear regression, and logistic regression analysis. RESULTS: There was a significant positive correlation between the MD and AL in the female subgroup (B = 0.663, p = 0.001, 95%CI = 1.070 to 1.255) but not in the male subgroup. Increased AL levels (mild [OR = 1], moderate [OR = 1.047, p = 0.062, 95%CI = 0.947 to 2.462], and severe [OR = 1.274, p < 0.001, 95%CI = 1.114 to 1.457]) were only associated with the severity of PACG in females. Paired Student's t tests showed that the long AL female eyes have a higher MD value than in the short AL female eyes (mean difference = 3.09, t = 6.846, p < 0.001) in the same subjects, but not in the male subgroup (p = 0.648). CONCLUSIONS: The AL was positively and significantly related to the severity of PACG in female but not male subjects. This finding refers to the PACG pathogenesis and suggests the use of AL assessment in glaucoma monitoring, diagnosis, and progression. This may contribute to further development of personalized strategies in preventive medicine.

Pretreatment Serum Uric Acid as an Efficient Predictor of Prognosis in Men with Laryngeal Squamous Cell Cancer: A Retrospective Cohort Study.

PURPOSE: Uric acid (UA) is a major antioxidant molecule that has been hypothesized to have a protective effect against cancer-induced oxidative damage. The aim of the present study was to investigate whether preoperative levels of serum UA are associated with the prognosis of laryngeal squamous cell cancer (LSCC). METHODS: A total of 814 male LSCC patients (followed up for five years) and 814 normal control subjects were enrolled from January 2007 to December 2011. The rates of total mortality and cancer mortality were 23.46% and 21.36%, respectively. The prevalence of overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) was analysed using the Kaplan-Meier method. Univariate and multivariate Cox regression models were evaluated to identify UA as a prognostic factor. RESULTS: The serum UA and UA/Cr (creatinine) ratio levels were significantly reduced (P < 0.001 for both) in the LSCC group compared with the control group. The applied multivariate Cox regression model analysis found that low levels of UA and the UA/Cr ratio were independent poor prognostic factors for OS (UA (HR (95% CI) = 1.458 (1.095-1.942)), UA/Cr ratio (HR (95% CI) = 1.337 (1.004-1.780))), DFS (UA (HR (95% CI) = 1.504 (1.131-2.001)), UA/Cr ratio (HR (95% CI) = 1.376 (1.030-1.839))), and CSS (UA (HR (95% CI) = 1.494 (1.109-2.012)), UA/Cr ratio (HR (95% CI) = 1.420 (1.049-1.923))). The patients with high UA (>0.310 mmol/l) and UA/Cr ratio (>3.97) experienced five more years of OS, DFS, and CSS than did patients with low UA (<0.310 mmol/l) and UA/Cr ratio (<3.97) levels. CONCLUSION: High preoperative UA serum levels were identified as an independent prognostic factor associated with improved clinical outcomes among LSCC patients.

Uric Acid Provides Protective Role in Red Blood Cells by Antioxidant Defense: A Hypothetical Analysis.

Uric acid (UA) is a major antioxidant molecule in the human blood, and it has been linked with cell longevity. However, it is unclear whether serum UA levels are associated with red blood cell (RBC) indexes. This cross-sectional study included 10,759 Chinese subjects, recruited from the Shanghai Xuhui Central Hospital from January 2014 to December 2017. The participants were categorized into gender groups and then further divided into three different subgroups according to their UA reference range as follows: low (male (UA < 0.202 mmol/l), female (UA < 0.143 mmol/l)), normal (male (0.417 mmol/l > UA ≥ 0.202 mmol/l), female (0.339 mmol/l > UA ≥ 0.143 mmol/l)), and high (male (UA ≥ 0.417 mmol/l), female (UA ≥ 0.339 mmol/l)). The associations of UA levels with RBC parameters were analyzed using 1-way ANOVA, Pearson correlations, and multivariate linear regression. The levels of mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, RBCs, and hemoglobin were lowest in the low UA group, followed by the normal UA group and high UA group (p < 0.001). Pearson analysis showed that there was a statistically significant correlation between UA levels with mean corpuscular hemoglobin, mean corpuscular hemoglobin concentrations, mean corpuscular volumes, RBC counts, and hemoglobin (p < 0.05). Multiple linear regression analysis suggested that there were statistically significant positive correlations between UA levels and RBC counts (B = 0.245, p < 0.001, 95% CI = 0.003 to 0.092), as well as UA levels and hemoglobin concentrations (B = 0.138, p < 0.001, 95% CI = 0.002 to 0.082). Furthermore, similar results were observed in both the male and female subgroups. The serum UA levels may be independently associated with RBC parameters, regardless of sex, and UA may protect RBCs owing to its antioxidant effect.

Association between Pretreatment Serum Uric Acid Levels and Progression of Newly Diagnosed Primary Angle-Closure Glaucoma: A Prospective Cohort Study.

PURPOSE: Increased evidence reveals that uric acid (UA) may have an important neuroprotective effect through its antioxidant properties. The aim of the present study was to investigate the relationship between pretreatment serum UA levels and the progression of newly diagnosed primary angle-closure glaucoma (PACG). METHODS: This prospective observational cohort study included 64 patients with newly diagnosed PACG who were followed up for a mean period of 12.77 months (range: 3-28 months). All subjects underwent a complete ophthalmological examination during the baseline and final follow-up visits, together with the acquisition of blood samples for UA measurements. During the follow-up period, the progression of PACG was defined as a clinical diagnosis of medically uncontrolled intraocular pressure and a loss of visual field with a mean deviation of >1 dB/year. Univariable and multivariable Cox regression models were used to investigate the association between baseline serum UA levels and the progression of PACG. The cumulative probability of progression of glaucoma was analyzed using the Kaplan-Meier method. RESULTS: During follow-up, 32 subjects were defined as progressive PACG, among whom baseline UA values were significantly higher in nonprogressing subjects than in progressing subjects (0.314 ± 0.069 mmol/l versus [vs.] 0.258 ± 0.069 mmol/l, respectively; P = 0.002). Similar results were also observed in male and female subgroups (P < 0.05). In a multivariable model, a decreased baseline serum UA level was associated with an increased risk for progressing PACG: both in male (hazard ratio [HR] 6.088 [95% confidence interval (CI) 1.163-31.8638]; P = 0.032) and female subjects (HR 3.565 [95% CI 1.131-11.236]; P = 0.030). Subjects with high UA levels demonstrated higher cumulative probabilities of nonprogressing PACG than those with low UA levels (male [16.67% vs. 80.00%; P = 0.0084] and female [29.41% vs. 68.00%; P = 0.0182]). CONCLUSION: An association between high baseline serum UA levels and a decreased risk for progressing PACG was found. This primary finding suggests that high serum UA levels may have a protective role against PACG and could slow disease progression.

Association of serum uric acid levels with primary open-angle glaucoma: a 5-year case-control study.

PURPOSE: It has been hypothesised that uric acid (UA) has a protective effect against oxidative damage in the central nervous system. Therefore, we investigated serum UA concentrations in patients with primary open-angle glaucoma (POAG) and explored the relationship between serum UA concentration and glaucoma severity. METHODS: This prospective, cross-sectional, case-control study was conducted in 163 POAG patients and 103 normal controls. Clinical and demographic information was obtained from the medical data platform of the Eye & ENT Hospital of Fudan University, Shanghai, China. The POAG patients were categorised into mild [median deviation (MD) ≤ 6.00 dB], moderate (MD > 6 Db-≥12 dB) and severe (MD > 12 dB) subgroups, based on their visual field MD results. RESULTS: The level of serum UA in the POAG group (0.321 ± 0.084 mmol/l) was approximately 12.77% lower (p < 0.001) than that of the control group (0.362 ± 0.053 mmol/l). The UA/creatinine (Cr) ratio was approximately 14.99% lower (p < 0.001) in patients with POAG (4.47 ± 1.15), compared with the control group (5.14 ± 1.05). The mean level of UA was lowest in the severe POAG group, followed by the moderate POAG group, and the mild POAG group (p < 0.001). A similar trend was observed when UA levels were compared between the POAG and control groups in males. Multivariate regression analyses showed a significant negative correlation between UA and vertical cup-disc ratio (B = -0.320, p = 0.034), and UA and MD (B = -0.441, p = 0.031) in males. CONCLUSION: Primary open-angle glaucoma patients have lower UA levels; however, a negative association between UA levels and disease severity was evident in male patients.

Decreased Serum Levels of Complement C3 Reflect Complement System Dysregulation in Patients With Primary Open-angle Glaucoma: Results From a Pilot Study.

PURPOSE: To evaluate the serum complement component (C)3 concentration in patients with primary open-angle glaucoma (POAG) and to investigate the association between C3 levels and POAG severity. MATERIALS AND METHODS: This study enrolled 190 consecutive POAG patients and 204 normal control subjects. A detailed eye and systematic examination, including intraocular pressure, gonioscopy, fundus photography, A-scan ultrasound, visual field testing, electrocardiograms, x-rays, liver function, renal function, infectious disease, etc., and measurement of serum C3 concentration by immunoturbidimetry, was performed. The subgroups were classified according to age (17 to 29, 30 to 49, 50 to 69, 70+ y), sex, and visual field: mild (MD≤6 dB), moderate (6 dB12 dB) glaucoma. RESULTS: The serum C3 level of the POAG (95.63±17.71 mg/dL) was ∼20.93% lower than that of the control group (115.65±22.19 mg/dL) (P<0.001). A similar result was observed when serum levels of C3 were compared between the POAG and control groups with respect to age and sex. The mean serum C3 level was lowest in the severe POAG group (85.18±19.62 mg/dL), followed by the moderate POAG group (96.62±12.63 mg/dL) and the mild POAG group (110.44±14.89 mg/dL) (P<0.001). Multiple logistic regression analyses revealed a significant correlation between the C3 levels and the vertical cup-disc ratio (B=-0.373, P=0.026), C3 levels and MD (B=-0.546, P=0.001). Logistic regression analyses revealed that serum C3 levels were associated (odds ratio=0.939, 95% CI=0.901-0.979, P=0.003) with severity of POAG. CONCLUSIONS: The POAG patients had decreased C3 levels, which were further negatively associated with POAG severity, suggesting the involvement of C3 in the pathomechanisms of POAG.

Association between serum lipids concentration and patients with age-related cataract in China: a cross-sectional, case-control study.

OBJECTIVE: Obesity and a high-fat diet have been found to be associated with an increased risk of age-related cataract (ARC). Thus, this study aimed to investigate whether serum lipid levels are associated with the incidence of ARC. DESIGN: Cross-sectional, case-control study. SETTING: EyeandENT Hospital of Fudan University, Shanghai, China. PARTICIPANTS: A total of 219 ARC (male=94, female=125) subjects and 218 (male=110, female=118) normal control subjects were recruited in this study. OUTCOME MEASURES: A detailed eye and systematic examination was performed. Serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and cholesterol (CHO) levels were measured by enzymatic colorimetry, and serum apolipoprotein A (APOA) and apoB (APOB) levels were measured by immunoturbidimetry. The subgroups were classified according to gender and types of disease (cortical, nuclear and posterior subcapsular cataract). Logistic regression analyses were performed to identify the association between serum lipid levels and ARC. RESULTS: The serum LDL-C, TG, CHO and APOA levels were significantly higher (p<0.05) in the ARC group than in the control group. A similar result was observed when the serum lipid concentrations were compared between the ARC and control groups both in male and female subgroups. A higher proportion of individuals in the ARC group had higher LDL-C, TG, CHO and APOA levels (fold=3.45, 17.37, 3.27 and11.91, respectively; p<0.0001 in all cases) than in the control group. Results of the logistic regression analyses revealed that high LDL-C (ORs=1.897, 95% CI 0.960 to 3.678) and TG (OR=1.854, 95% CI 1.232 to 2.791) were the independent risk factors for ARC. CONCLUSION: The serum LDL-C and TG levels were demonstrated to be independent risk factors for ARC.