Identification of diabetic retinopathy classification using machine learning algorithms on clinical data and optical coherence tomography angiography.

BACKGROUND: To apply machine learning (ML) algorithms to perform multiclass diabetic retinopathy (DR) classification using both clinical data and optical coherence tomography angiography (OCTA). METHODS: In this cross-sectional observational study, clinical data and OCTA parameters from 203 diabetic patients (203 eye) were used to establish the ML models, and those from 169 diabetic patients (169 eye) were used for independent external validation. The random forest, gradient boosting machine (GBM), deep learning and logistic regression algorithms were used to identify the presence of DR, referable DR (RDR) and vision-threatening DR (VTDR). Four different variable patterns based on clinical data and OCTA variables were examined. The algorithms' performance were evaluated using receiver operating characteristic curves and the area under the curve (AUC) was used to assess predictive accuracy. RESULTS: The random forest algorithm on OCTA+clinical data-based variables and OCTA+non-laboratory factor-based variables provided the higher AUC values for DR, RDR and VTDR. The GBM algorithm produced similar results, albeit with slightly lower AUC values. Leading predictors of DR status included vessel density, retinal thickness and GCC thickness, as well as the body mass index, waist-to-hip ratio and glucose-lowering treatment. CONCLUSIONS: ML-based multiclass DR classification using OCTA and clinical data can provide reliable assistance for screening, referral, and management DR populations.

Jagged1-Notch1 Signaling Pathway Induces M1 Microglia to Disrupt the Barrier Function of Retinal Microvascular Endothelial Cells.

PURPOSE: Microglia-related inflammation is closely linked to the pathogenesis of retinal diseases. The primary objective of this research was to investigate the impact and mechanism of M1 phenotype microglia on the barrier function of retina microvascular endothelial cells. METHODS: Quantitative polymerase chain reactions and western blot techniques were utilized to analysis the mRNA and protein expressions of M1 and M2 markers of human microglial clone 3 cell line (HMC3), as well as the levels of Notch ligands and receptors under the intervention of lipopolysaccharide (LPS) or interleukin (IL)-4. ELISA was utilized to detect the pro-inflammatory and anti-inflammatory cytokines from HMC3 cells. The cellular tight junction and apoptosis of human retinal microvascular endothelial cells (HRMECs) were assessed by western blot and fluorescein isothiocyanate-dextran permeability assay. The inhibitors of Notch1 and RNA interference (RNAi) targeting Jagged1 were used to assess their contribution to the barrier function of vascular endothelial cells. RESULTS: Inducible nitric oxide synthase (iNOS) and IL-1ß were considerably elevated in LPS-treated HMC3, while CD206 and Arg-1 markedly elevated under IL-4 stimulation. The conditioned medium derived from LPS-treated HMC3 cells promoted permeability, diminished the expression of zonula occludens-1 and Occludin, and elevated the expression of Cleaved caspase-3 in HRMECs. RNAi targeting Jagged1 or Notch1 inhibitor could block M1 HMC3 polarization and maintain barrier function of HRMECs. CONCLUSION: Our findings suggest that Jagged1-Notch1 signaling pathway induces M1 microglial cells to disrupt the barrier function of HRMECs, which may lead to retinal diseases.

Associations of concomitant retinopathy and depression with mortality in a nationally representative population.

OBJECTIVE: To evaluate the interaction effects between retinopathy and depression on mortality risks in genral population and subpopulation with diabetes. METHODS: Prospective analyses were conducted on data from the National Health and Nutrition Examination Surveys study. Associations of retinopathy, depression and their interaction with all-cause, cardiovascular disease (CVD)-specific, cancer-specific and other-specific mortality risk were estimated using Kaplan-Meier curves and multivariate Cox proportional hazards models. RESULTS: Among 5367 participants, the weighted prevalence of retinopathy and depression was 9.6 % and 7.1 %, respectively. After a follow-up period of 12.1 years, 1295 deaths (17.3 %) occurred. Retinopathy was associated with an increased risk of all-cause (hazard ratio [HR]; 95 % confidence interval [CI]) (1.47; 1.27-1.71), CVD-specific (1.87; 1.45-2.41), and other-specific (1.43; 1.14-1.79) mortality. Similar relationship was observed between depression and all-cause mortality (1.24; 1.02-1.52). Retinopathy and depression had a positive multiplicative and additive interaction effect on all-cause (Pinteraction = 0.015; relative excess risk of interaction [RERI] 1.30; 95 % CI 0.15-2.45) and CVD-specific mortality (Pinteraction = 0.042; RERI 2.65; 95 % CI -0.12-5.42). Concomitant retinopathy and depression was more markedly associated with all-cause (2.86; 1.91-4.28), CVD-specific (4.70; 2.57-8.62), and other-specific mortality risks (2.18; 1.14-4.15) compared to those without retinopathy and depression. These associations were more pronounced in the diabetic participants. CONCLUSIONS: The co-occurrence of retinopathy and depression increases the risk of all-cause and CVD-specific mortality among middle-aged and older adults in the United States, especially in population with diabetes. Focus on diabetic patients and active evaluation and intervention of retinopathy with depression may improve their quality of life and mortality outcomes.

Ray-transfer functions for camera simulation of 3D scenes with hidden lens design.

Combining image sensor simulation tools with physically based ray tracing enables the design and evaluation (soft prototyping) of novel imaging systems. These methods can also synthesize physically accurate, labeled images for machine learning applications. One practical limitation of soft prototyping has been simulating the optics precisely: lens manufacturers generally prefer to keep lens design confidential. We present a pragmatic solution to this problem using a black box lens model in Zemax; such models provide necessary optical information while preserving the lens designer's intellectual property. First, we describe and provide software to construct a polynomial ray transfer function that characterizes how rays entering the lens at any position and angle subsequently exit the lens. We implement the ray-transfer calculation as a camera model in PBRT and confirm that the PBRT ray-transfer calculations match the Zemax lens calculations for edge spread functions and relative illumination.

[Effects of mid-palatal suture opening and midfacial bony structure changes induced by maxillary skeletal expansion in adults].

PURPOSE: To analyze the opening of mid-palatal suture, transverse changes in dental and dentoalveolar measurements and shift of midfacial bony structures induced by maxillary skeletal expansion (MSE) with cone-beam CT (CBCT), and to evaluate the effect of maxillary skeletal expansion and its influence on adjacent bony structures in adults. METHODS: The study sample consisted of 12 adult patients with maxillary transverse deficiency (4 males, 8 females) at a mean age of (21.17±4.13) years old. All patients were treated with MSE. After treatment, the posterior crossbite was corrected, and the width of the maxillary arch was achieved the optimal width. Pre- and post-treatment CBCT exams were taken before and after MSE treatment. Multiplanar coronal and axial slices obtained from CBCT images were used to measure the changes in transverse widths, angular changes and tooth inclination with Dolphin Imaging 11.9. SPSS 26.0 software package was used for statistical analysis. RESULTS: After MSE treatment, the anterior nasal spine width increased by (2.38±1.01) mm, posterior nasal spine width increased by (2.25±1.08) mm (P<0.01). The inter-crown and inter-apex distance at the first molar increased by (5.56±1.38) mm and (4.14±1.29) mm, respectively (P<0.01). No significant difference was seen in terms of tooth inclination of the first molar(P>0.05). Pterygoid process angle, pterygoid process width, anterior inter-maxillary distance, upper and lower inter-zygomatic distance were significantly larger after treatment (P<0.01), while the inter-temporal distance and bilateral zygomaticomaxillary angle remained unchanged(P>0.05). CONCLUSIONS: MSE has a favorable effect in adult patients with parallel skeletal expansion of the mid-palatal suture achieved after expansion. The teeth present with certain buccal inclination but show no significant movement relative to the alveolar bone. The midfacial bony structures also shift in three-dimensional under the effect of the expansion force.

Simulations of fluorescence imaging in the oral cavity.

We describe an end-to-end image systems simulation that models a device capable of measuring fluorescence in the oral cavity. Our software includes a 3D model of the oral cavity and excitation-emission matrices of endogenous fluorophores that predict the spectral radiance of oral mucosal tissue. The predicted radiance is transformed by a model of the optics and image sensor to generate expected sensor image values. We compare simulated and real camera data from tongues in healthy individuals and show that the camera sensor chromaticity values can be used to quantify the fluorescence from porphyrins relative to the bulk fluorescence from multiple fluorophores (elastin, NADH, FAD, and collagen). Validation of the simulations supports the use of soft-prototyping in guiding system design for fluorescence imaging.

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events.

OBJECTIVE: We aimed to retrospectively analyze the toxicity profiles and predictors of immune-related adverse events (irAEs) as well as the correlation between irAEs and the clinical efficacy of multi-type immune checkpoint inhibitors (ICIs) in patients with advanced pan-cancer in a real-world setting. METHODS: We retrospectively analyzed data from 105 patients with advanced pan-cancer treated with multi-type ICIs at the First Hospital of Jilin University between January 1, 2016 and August 1, 2020. We used logistic regression analyses to investigate the associations of irAEs with clinical baseline characteristics, blood count parameters, and biochemical indicators during treatment. Receiver operating characteristic curves were used to determine cutoff values for parameters and area under the curve values. KaplanMeier and Cox multivariate regression analyses were performed to estimate the relationships of baseline characteristics and irAEs with progression-free survival (PFS) and overall survival (OS). RESULTS: A lower relative lymphocyte count (cutoff = 28.5%), higher albumin level (cutoff = 39.05 g/L), and higher absolute eosinophil count (AEC) (cutoff = 0.175 × 109/L) were significantly associated with the occurrence of irAEs, among which a higher AEC (cutoff = 0.205 × 109/L) was strongly associated with skin-related irAEs [odds ratios (ORs) = 0.163, P = 0.004]. Moreover, a higher lactate dehydrogenase level (cutoff = 237.5 U/L) was an independent predictor of irAEs of grade ≥ 3 (OR = 0.083, P = 0.023). In immune cell subgroup analysis, a lower absolute count of CD8+CD28- suppressor T cells (OR = 0.806; 95% confidence interval: 0.643-1.011; P = 0.062), which are regulatory T lymphocytes, was associated with the occurrence of irAEs, although the difference was not statistically significant. Furthermore, a higher percentage of CD19+ B cells was associated with the occurrence of irAEs of grade ≥ 3 (P = 0.02) and grade ≥ 2 (P = 0.051). In addition, patients with any grade of irAE had a significantly high PFS (8.37 vs. 3.77 months, hazard ratios (HR) = 2.02, P = 0.0038) and OS (24.77 vs. 13.83 months, HR = 1.84; P = 0.024). CONCLUSIONS: This retrospective study reports clinical profile data for irAEs in unselected patients in a real-world setting and explored some parameters that may be potential predictive markers of the occurrence, type, or grade of irAEs in clinical practice. Evidence of a correlation between safety and efficacy may facilitate a complete assessment of the risk-benefit ratio for patients treated with ICIs.

Clinical Progress of PD-1/L1 Inhibitors in Breast Cancer Immunotherapy.

Breast cancer is a major killer of women's health worldwide. While breast cancer is thought to have lower immunogenicity compared with other solid tumors, combination therapy is able to improve the immunogenicity of the tumor and sensitize breast cancer cells to immunotherapy. Immunotherapy represented by immune checkpoint inhibitors (ICIs) has been largely explored in the field of breast cancer, including both early and advanced disease. Immunotherapy for triple-negative breast cancer (TNBC) has been the most studied, and the PD-L1 inhibitor atezolizumab combined with nab-paclitaxel has been used in the first-line treatment of TNBC. Immunotherapeutic data for human epidermal growth factor receptor-positive and hormone receptor-positive breast cancer are also accumulating. This review summarizes the clinical trial data of ICIs or ICI-containing therapies in different types and stages of breast cancer.

[Analysis of the changes of inflammatory cytokine levels in patients with critical coronavirus disease 2019 undergoing invasive mechanical ventilation].

OBJECTIVE: To investigate the relationship between the changes of inflammatory cytokine levels and prognosis of patients with critical coronavirus disease 2019 (COVID-19) undergoing invasive mechanical ventilation (IMV). METHODS: A retrospective study was conducted. The clinical date of critical COVID-19 patients undergoing IMV who were hospitalized in Wuhan Union Hospital, Tongji Medical College of Huazhong University of Science and Technology from February 4th to March 25th in 2020 were collected. At the same time, the inflammatory cytokine levels including interleukins (IL-2, IL-4, IL-6, IL-10) and tumor necrosis factor-α (TNF-α) at 48 hours before IMV and 48 hours after IMV of all the patients, as well as the 48 hours after weaning or right before death were recorded. Multivariate unconditional Logistic regression analysis was used to screen the independent risk factors of death during hospitalization. RESULTS: Among the 43 patients, 13 patients improved and 30 died. Compared with the survival group, the patients in the non-survival group were older (years old: 67.6±7.3 vs. 58.5±11.9, P < 0.05), with higher rates of hypertension, diabetes and coronary heart disease (53.3% vs. 15.4%, 63.3% vs. 23.1%, 26.7% vs. 0%, all P < 0.05), and the time from onset to admission to hospital, admission to ICU and IMV were longer (days: it was 9.17±5.00 vs. 5.07±2.49, 17.10±7.11 vs. 12.23±5.05, and 17.90±7.46 vs. 12.61±5.60, respectively, all P < 0.05). The IL-6 and TNF-α levels on 48 hours after IMV in the non-survival patients increased significantly as compared with those before 48 hours and the surviving patients. Especially, the IL-6 levels increased significantly as compared with those at 48 hours after IMV and 48 hours after weaning in the surviving patients [ng/L: 800.00 (194.25, 2 000.00) vs. 22.03 (6.66, 28.21), 3 204.00 (1 264.88, 5 000.00) vs. 5.00 (3.98, 12.27), both P < 0.01]. The IL-10 level before death in the non-survival patients increased significantly as compared with that at 48 hours after weaning in the surviving patients [ng/L: 55.89 (26.07, 100.14) vs. 3.53 (2.76, 12.36), P < 0.05]. There were no significant differences in the levels of IL-2 and IL-4 between the two groups at every time point. The variables of age, basic diseases, the IL-6 level after IMV were included in the multivariate unconditional Logistic regression analysis, which showed that age [odds ratio (OR) = 0.821, 95% confidence interval (95%CI) was 0.695-0.968], hypertension (OR = 0.027, 95%CI was 0.002-0.378), diabetes mellitus (OR = 0.054, 95%CI was 0.005-0.611), coronary heart disease (OR = 0.042, 95%CI was 0.002-0.968) and the IL-6 level after IMV (OR = 0.902, 95%CI was 0.819-0.994) were independent risk factors for death during hospitalization in patients with critical COVID-19 undergoing IMV (all P < 0.05). CONCLUSIONS: The levels of inflammatory cytokine including IL-6, IL-10, and TNF-α increased significantly with aggravation in critical COVID-19 patients undergoing IMV, especially IL-6. IL-6 was an independent risk factor for death of critical COVID-19 patients undergoing IMV.

Atractylodin ameliorates lipopolysaccharide and d-galactosamine-induced acute liver failure via the suppression of inflammation and oxidative stress.

Atractylodin (ACD) possesses versatile biological and pharmacological activities, including antibacterial, anti-inflammatory and hepatoprotective properties. However, the protective effects of ACD on lipopolysaccharide (LPS) and d-galactosamine (GalN)-induced acute liver failure (ALF) as well as the underlying molecular mechanisms remain unclear. In this study, our findings showed that ACD treatment could reduce the high lethality rate; decrease the serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST), monocyte chemoattractant protein (MCP)-1, interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α), and ameliorate the pathological hepatic damage of ALF. Furthermore, ACD pretreatment inhibited toll like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), the mitogen-activated protein kinase (MAPK) and NOD-like receptor protein-3 (NLRP3) activation pathway. Moreover, our research showed that ACD could dramatically increase superoxide dismutase (SOD) and glutathione (GSH) production, and reduce COX-2, inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS) and malondialdehyde (MDA) production through upregulating the expression of the anti-oxidative enzymes heme oxygenase-1 (HO-1) and quinone (NQO1), which were related to the induction of nuclear transcription factor 2 (Nrf2) nuclear translocation. These results indicated that ACD exhibited anti-inflammatory activity, which was associated with the inhibition of inflammatory mediator production via the downregulation of the NLRP3 inflammasome and TLR4-NF-κB/-MAPK signaling pathways, and the antioxidative effects of ACD were connected with GSH and SOD activation through upregulation of the Nrf2-mediated signaling pathways.

Research progress on immunotherapy for breast cancer / 中国肿瘤生物治疗杂志

@# 乳腺癌是中国女性最常见的恶性肿瘤，传统治疗方法存在一定副作用，而免疫治疗为攻克乳腺癌提供了新途径，尤以 晚期乳腺癌及三阴性乳腺癌（triple-negative breast cancer, TNBC）患者的PD-1/PD-L1抑制剂治疗最具发展前景。随着乳腺癌免疫 治疗相关临床试验的开展， 以HER2/nue疫苗、MUC-1疫苗等为代表的肿瘤疫苗已观察到可以改善患者的无病生存期（DFS）和总 生存期（OS）。曲妥珠单抗、帕妥珠单抗、T-DM1、MM-111等单克隆抗体也显示出较好疗效，CIK、TIL、CAR-T等过继性细胞治疗 具有较强的肿瘤杀伤能力且安全性良好，而抗PD-1/PD-L1抗体、 抗CTLA-4抗体、 抗LAG-3抗体等免疫负调控抑制剂能够抑制肿 瘤逃逸，为乳腺癌的治疗提供了新策略，这些突破性的成果推动了乳腺癌治疗实现“个体化”的进程。

Contact Selectivity Engineering in a 2 µm Thick Ultrathin c-Si Solar Cell Using Transition-Metal Oxides Achieving an Efficiency of 10.8.

In this paper, the integration of metal oxides as carrier-selective contacts for ultrathin crystalline silicon (c-Si) solar cells is demonstrated which results in an ∼13% relative improvement in efficiency. The improvement in efficiency originates from the suppression of the contact recombination current due to the band offset asymmetry of these oxides with Si. First, an ultrathin c-Si solar cell having a total thickness of 2 µm is shown to have >10% efficiency without any light-trapping scheme. This is achieved by the integration of nickel oxide (NiOx) as a hole-selective contact interlayer material, which has a low valence band offset and high conduction band offset with Si. Second, we show a champion cell efficiency of 10.8% with the additional integration of titanium oxide (TiOx), a well-known material for an electron-selective contact interlayer. Key parameters including Voc and Jsc also show different degrees of enhancement if single (NiOx only) or double (both NiOx and TiOx) carrier-selective contacts are integrated. The fabrication process for TiOx and NiOx layer integration is scalable and shows good compatibility with the device.

[Lymph node metastasis and prognostic analysis of 354 cases of T1 breast cancer].

OBJECTIVE: To analyze the characteristics of lymph node metastasis and prognosis in patients with T1 breast cancer. METHODS: The clinicopathological data of 354 patients with T1 breast cancer after standard treatment from March 2007 to September 2011 were collected to analyze the relationship between the clinical characteristics of T1 breast cancer, lymph node metastasis and prognostic features. RESULTS: In the 354 patients with T1 breast cancer, 105 patients (29.7%) had lymph node metastasis, among them 73 cases (69.5%) had 1-3 lymph node metastasis, and 32 cases (30.5%) had more than 4 lymph node metastasis. The lymph node metastasis rate was 8.3% in T1a patients, 39.7% in T1b patients, and 30.4% in T1c cases (P = 0.005). Pairwise comparison showed that the difference of lymph node metastasis rate between T1a, T1b and T1c patients was statistically significant (P = 0.001 and P = 0.006, respectively). The difference of lymph node metastasis rates in T1b and T1c patients was statistically insignificant (P = 0.171). In the 354 patients of T1 breast cancer, 92 patients had vascular tumor thrombi and their lymph node metastasis rate was 71.7%, while the lymph node metastasis rate in 262 patients without vascular tumor thrombus was 14.9% (P < 0.001). The median follow-up was 49 months (range 27-81 months). 12 patients developed recurrence, and 3 patients died, one of them died of cerebrovascular accident. The 4-year disease-free survival for all patients was 96.6%, and the 4-year overall survival rate was 99.2%. CONCLUSIONS: There is a correlation between vascular tumor thrombus, tumor size and lymph node metastasis rate. The lymph node metastasis rate is lower in T1a patients and relatively higher in T1b/c patients. Compared with patients without vascular tumor thrombus, the T1 breast cancer patients with vascular tumor thrombi have a higher lymph node metastasis rate. Generally speaking, there is a still good prognosis in patients with T1 breast cancer.

Comparison of immunohistochemistry with fluorescence in situ hybridization in determining the human epidermal growth factor receptor 2 status of breast cancer specimens: a multicenter study of 3,149 Chinese patients.

BACKGROUND: Accurate detection of human epidermal growth factor receptor 2 (HER2) expression and gene amplification is crucial for the application of HER2-specific therapy and for evaluating the response of patients with breast cancer. A uniform and standard procedure of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) needs to be established for evaluating the HER2 status in breast cancer tissues for the treatment of patients with real HER2-positive tumors. The present multicenter study was aimed to examine the HER2 status in breast cancer specimens from Chinese patients using both IHC and FISH methods. METHODS: A multicenter study was performed on the HER2 status in 3 149 breast cancer specimens from different ethnic populations and areas in China by IHC and FISH assays. The potential association of HER2 status with demographic and clinical characteristics was analyzed. RESULTS: The positive rates for HER2 over-expression and HER2 amplification were 23.3% and 27.5% in this study, respectively. The concordance between IHC and FISH was 71.2% (κ = 0.494, P < 0.001). Furthermore, 72.9% of specimens with IHC 2+ were negative to FISH. The discordance rates among laboratories were from 5% to 28% for IHC and 1% to 16% for FISH. HER2 amplification was associated significantly with advanced tumor stage (III or IV, P = 0.002), large tumor size (>5 cm, P = 0.002), moderate and poor histological grades (P < 0.0001), post-menopause (P < 0.0001), ER-PR- (P = 0.002), and having ≥ 4 lymph nodes affected (P < 0.0001) in this population. The positive rates of HER2 amplification in specimens from Man and Hui Chinese were significantly higher than that in other Chinese populations. There are slightly higher positive rates of HER2 expression and amplification in Chinese patients with breast cancer. CONCLUSION: These findings may provide new insights into understanding the epidemiological features of HER2 expression and amplification, and may be valuable for clinical practice.