Fibroblasts facilitate lymphatic vessel formation in transplanted heart.

Rationale: Lymphangiogenesis plays a critical role in the transplanted heart. The remodeling of lymphatics in the transplanted heart and the source of newly formed lymphatic vessels are still controversial, especially the mechanism of lymphangiogenesis remains limited. Methods: Heart transplantation was performed among BALB/c, C57BL/6J, Cag-Cre, Lyve1-CreERT2;Rosa26-tdTomato and Postn(2A-CreERT2-wpre-pA)1;Rosa26-DTA mice. scRNA-seq, Elisa assay, Western blotting, Q-PCR and immunohistochemical staining were used to identify the cells and cell-cell communications of allograft heart. Cell depletion was applied to in vivo and in vitro experiments. Whole-mount staining and three-dimensional reconstruction depicted the cell distribution within transparent transplanted heart. Results: Genetic lineage tracing mice and scRNA-seq analysis have revealed that these newly formed lymphatic vessels mainly originate from recipient LYVE1+ cells. It was found that LECs primarily interact with activated fibroblasts. Inhibition of lymphatic vessel formation using a VEGFR3 inhibitor resulted in a decreased survival time of transplanted hearts. Furthermore, when activated fibroblasts were ablated in transplanted hearts, there was a significant suppression of lymphatic vessel generation, leading to earlier graft failure. Additional investigations have shown that activated fibroblasts promote tube formation of LECs primarily through the activation of various signaling pathways, including VEGFD/VEGFR3, MDK/NCL, and SEMA3C/NRP2. Interestingly, knockdown of VEGFD and MDK in activated fibroblasts impaired cardiac lymphangiogenesis after heart transplantation. Conclusions: Our study indicates that cardiac lymphangiogenesis primarily originates from recipient cells, and activated fibroblasts play a crucial role in facilitating the generation of lymphatic vessels after heart transplantation. These findings provide valuable insights into potential therapeutic targets for enhancing graft survival.

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).

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.

Pelvic masses after surgery for immature ovarian teratoma: A 10-year experience of Western China.

There are debates on the management of immature ovarian teratoma and its recurrence. This study aimed to report the incidence of pelvic masses after surgery for immature ovarian teratoma and to identify prognostic factors of disease-free survival after surgery, discussing aspects of primary treatment and postoperative management. Data on the diagnosis and treatment of patients with immature teratomas were collected. Follow-up data were acquired from clinic visits and telephone interviews. Disease-free survival was defined as the time interval between the initial surgery for immature ovarian teratoma and the diagnosis of a new pelvic mass. Survival curves were drawn using the Kaplan-Meire method, and multivariate analysis was performed using the Cox proportional hazard regression model using PASW statistics software. The estimated 5-year disease-free survival and overall survival were 74.3% (95%CI 63.9%-84.7%) and 96.5% (95%CI 91.6%-100.0%), respectively. The incidence of growing teratoma syndrome and immature teratoma relapse at a median follow-up of 46 months were 20.0% and 7.7%, respectively. Two patients died of repeated relapses or repeated growing teratoma syndrome. Rupture of initial lesions (RR 4.010, 95%CI 1.035-5.531), lymph node dissection (RR 0.212, 95%CI 0.051-0.887) and adjuvant chemotherapy (RR 0.143, 95%CI 0.024-0.845) were independent prognostic factors for disease-free survival. The development of growing teratoma syndrome is more prevalent than relapse after treatment of immature ovarian teratomas. Lymph node dissection and chemotherapy are recommended to reduce recurrence. Close surveillance and active surgical intervention are important for the diagnosis and appropriate management of new pelvic masses.

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%.

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 of Ocular Surface Diseases With SARS-CoV-2 Infection in Six Districts of China: An Observational Cohort Study.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses is mainly transmitted through respiratory droplets. Notably, some coronavirus disease 2019 (COVID-19) patients have ocular manifestations, including conjunctival hyperaemia, chemosis, epiphora, and increased secretions. However, the association between SARS-CoV-2 and ocular surface diseases is poorly described. Between May 2020 and March 2021, a total of 2, 0157 participants from six districts of China were enrolled. Serum samples were tested for immunoglobulin G and M (IgG and IgM) antibodies against the SARS-CoV-2 spike protein and nucleoprotein using magnetic chemiluminescence enzyme immunoassays. Throat swabs were tested for SARS-CoV-2 RNA using RT-PCR assays in a designated virology laboratory. Fisher exact, χ2 test, and logistic regression analysis were performed. Of 2, 0157 serum samples tested, 1, 755 (8.71%) were from ocular surface diseases, 1, 2550 (62.26%) from no-ocular surface diseases (ocular diseases except ocular surface diseases), 5, 852 (29.03%) from no-ocular diseases. SARS-CoV-2 prevalence for the combined measure was 0.90% (182/2, 0157). Seroprevalence of SARS-CoV-2 was significantly (p<0.05) higher in the population with ocular surface diseases (2.28%, 40/1755) compared with no-ocular surface diseases (0.70%, 88/1, 2550), and no-ocular diseases (0.92%, 54/5, 852). Similar results were also observed with respect to sex, age, time, and districts. Logistic regression analyses revealed that ocular surface diseases [ocular surface diseases vs. no-ocular diseases (p=0.001, OR =1.467, 95% CI=1.174-1.834); ocular surface diseases vs. no-ocular surface diseases (p<0.001, OR =2.170, 95% CI=1.434-3.284)] were associated with increased risk of susceptible to SARS-CoV-2 infection. In a word, there was a significant association between ocular surface disease and SARS-CoV-2 infection. Therefore, increasing awareness of eye protection during the pandemic is necessary, especially for individuals with ocular surface diseases.

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.

Prognostic implication of human papillomavirus types in cervical cancer patients: a systematic review and meta-analysis.

BACKGROUND: To estimate the prognostic relevance of human papillomavirus (HPV) 16 and HPV 18 in patients with cervical cancer. METHOD: We searched PubMed, EMBASE, American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO), CNKI, and Wanfang databases to search primary articles illustrating the survival outcomes in cervical cancer patients with or without HPV 16/18 infection. A meta-analysis was conducted to generate a combined hazard ratio (HR) with 95% confidence intervals (CI) for progression-free survival (PFS), disease free survival (DFS) and overall survival (OS). RESULTS: A total of 13 studies were included. Our meta-analysis revealed that HPV 16 positive did not have any impact on OS (HR, 0.76; 95% CI = 0.37-1.54; P = 0.44). Cervical cancer patiensts infected with HPV 18 had worse OS (HR, 1.66; 95% CI = 1.28-2.17; P = 0.0001), DFS (HR, 2.10; 95% CI = 1.73-2.54; P < 0.0001) and worse PFS (HR, 2.97; 95% CI = 1.69-5.23; P = 0.00012) compared with those not infected with HPV 18. cervical cancer patiensts infected with HPV 18 had worse PFS compared with those infected with HPV 16 ((HR, 1.34; 95% CI = 1.06-1.70; P = 0.01). CONCLUSION: Cervical cancer patients infected with HPV 18 had worse survival compared with cervical cancer patients with HPV 16 infection.

Vitamin D status in endometriosis: a systematic review and meta-analysis.

PURPOSE: No consensus exists on the relationship between vitamin D status and endometriosis. The chief aim of our study was to evaluate the association between serum vitamin D levels and endometriosis. METHODS: We searched for MEDLINE, EMBASE, and China National Knowledge Infrastructure (CNKI) databases for studies elucidated the circulating vitamin D levels in endometriosis. The standardized mean differences (SMDs) or odds ratios (ORs) with their 95% confidence interval (CIs) were calculated to evaluate the association between vitamin D levels and endometriosis. RESULTS: Nine studies were included in this meta-analysis. The pooled results indicated that women with endometriosis had lower vitamin D status than that in controls (SMD - 0.97 ng/mL, 95% CI - 1.80 to - 0.14; p = 0.02), and vitamin D status had a negative correlation with the severity of the disease (stage III-IV vs stage I-II: SMD - 1.33 ng/mL, 95% CI - 2.54 to - 0.12; p = 0.03). Although it was not statistically significantly different, hypovitaminosis D had a tendency to be associated with endometriosis (OR 2.77, 95% CI 0.85-6.08, p = 0.10). Heterogeneity was high among included studies. Subgroup analyses revealed that women with no hormone use had lower vitamin D status when compared with controls (SMD - 1.38 ng/mL, 95% CI - 2.59 to - 0.18; p = 0.02). For studies which sample size < 100, serum vitamin D levels were significantly lower in patients than that in controls (SMD - 0.65 ng/mL, 95% CI - 1.19 to - 0.11; p = 0.02). CONCLUSIONS: Women with endometriosis had lower vitamin D status when compared with controls, and a negative relationship between vitamin D levels and severity of endometriosis was observed. In addition, hypovitaminosis D was a potential risk factor for endometriosis.

Human papillomavirus infection and female infertility: a systematic review and meta-analysis.

There is increasing evidence that human papillomavirus (HPV) infection affects reproductive health and fertility, although its impact on female fertility has not been thoroughly studied. MEDLINE, Embase, CENTRAL, Web of Science, CNKI, Wanfang, VIP and ClinicalTrials.gov databases were systematically searched for relevant articles. A meta-analysis was conducted of 11 studies including 15,450 female subjects that compared HPV prevalence between the infertile and general population, and evaluated the association between HPV positivity and female infertility. Seven case-control studies on 3581 participants reported indiscriminate genotype infections (high-risk/low-risk [HR/LR]-HPV), but the random effects model revealed no association between HPV infection and female infertility (odds ratio [OR] 2.13, 95% confidence interval [CI] 0.97-4.65, P = 0.06). Six studies with a total of 11,869 participants reported HR-HPV infections alone, and the pooled data showed a significant association between HR-HPV infection and female infertility (OR 2.33, 95% CI 1.42-3.83, P = 0.0008). It was concluded that HR-HPV infection is a potential risk factor of female infertility, but not an independent cause. Further prospective studies are needed to assess the exact role of HPV in female infertility.