Downregulation of IL-11 regulates the TGFß/ERK1/2 signaling pathway to inhibit articular capsule fibrosis and alleviate post-traumatic articular capsule contracture.

BACKGROUND: Post-traumatic capsular contracture is a common complication of joint injury and surgery. Post-traumatic capsular contracture is associated with fibrosis characterized by excessive differentiation and proliferation of myofibroblasts and abnormal secretion and accumulation of extracellular matrix. Previous studies have suggested that IL11 plays a role in myocardial fibrosis. We thus hypothesized that IL11 may play a fibrotic role during capsular contracture, in order to discover new targets for preventing joint capsule contracture METHODS: We constructed a post-traumatic contracture model by excessively extending the knee joint and fixing the joint in the flexion position, and a post-traumatic joint capsule contracture model was constructed in the wild-type, IL11-/-, IL11R -/-, α-SMA-cre-IL11fl/fl, α-SMA-cre-IL11Rfl/fl mouse strain, with wild-type mice without any treatment of the knee joint as the control group. Fibrotic markers and the expression of IL11 and IL11R in knee joint tissue were detected in each group of mice. The NIH3T3 cell line was used for in vitro analyses. The expression of fibrosis markers, IL11, TGFß and ERK1/2 were detected by western blot, ELISA and RT-qPCR. RESULTS: Inhibition of IL11 inhibited ERK1/2 phosphorylation, reduced the secretion of collagen in the joint capsule, and inhibited the excessive differentiation and proliferation of myofibroblasts in the post-traumatic joint capsule contracture, thus alleviating the joint capsule contracture and obtaining better joint mobility. CONCLUSION: Downregulation of IL11 in traumatic joint capsule contracture inhibits ERK1/2 phosphorylation, thus significantly relieving joint capsule contracture. Our findings indicate the TGFß/IL11/ERK1/2 axis is an important pathway for the differentiation of fibroblasts into myofibroblasts. Anti-IL11 treatment is an effective means to prevent traumatic joint capsule contracture.

Transition from electromagnetically-induced transparency to absorption in a single microresonator.

Electromagnetically induced transparency (EIT) and absorption (EIA) are two phenomena that can be observed in whispering-gallery-mode (WGM) optical microresonators. Transition from EIT to EIA has potential applications in optical switching, filtering and sensing. In this paper an observation of the transition from EIT to EIA in a single WGM microresonator is presented. A fiber taper is used to couple light into and out of a sausage-like microresonator (SLM) that contains two coupled optical modes with significantly different quality factors. By stretching the SLM axially the resonance frequencies of the two coupled modes are tuned to the same, a transition from EIT to EIA is then observed in the transmission spectra when the fiber taper is moved closer to the SLM. It is the special spatial distribution of the optical modes of the SLM that provide a theoretical basis for the observation.

FIVE-YEAR INCIDENCE OF FELLOW EYE NEOVASCULAR INVOLVEMENT IN AGE-RELATED MACULAR DEGENERATION AND POLYPOIDAL CHOROIDAL VASCULOPATHY IN AN ASIAN POPULATION.

PURPOSE: To assess 5-year cumulative incidence and risk factors of fellow eye involvement in Asian neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy. METHODS: In a prospective cohort study of Asian nAMD and polypoidal choroidal vasculopathy, the fellow eyes were evaluated for exudation. The 5-year incidence of exudation was compared between nAMD and polypoidal choroidal vasculopathy. RESULTS: A total of 488 patients were studied. The 5-year incidence of exudation in fellow eyes was 16.2% (95% confidence interval: 12.0-20.2). Polypoidal choroidal vasculopathy compared with nAMD in the first eye was associated with lower fellow eye progression (9.8% [95% confidence interval: 5.1-14.3]) vs. 22.9% [95% confidence interval: 15.8-29.3], P < 0.01). Drusen (hazards ratio 2.11 [95% confidence interval: 1.10-4.06]), shallow irregular retinal pigment epithelium elevation (2.86 [1.58-5.18]), and pigment epithelial detachment (3.01 [1.27-7.17]) were associated with greater progression. A combination of soft drusens and subretinal drusenoid deposits, and specific pigment epithelial detachment subtypes (multilobular, and sharp peaked) were associated with progression. Pigment epithelial detachment, shallow irregular retinal pigment epithelium elevation, and new subretinal hyperreflective material occurred at 10.4 ± 4.2 months, 11.1 ± 6.0 months, and 6.9 ± 4.3 months, respectively, before exudation. CONCLUSION: The 5-year incidence of fellow eye involvement in Asian nAMD is lower than among Caucasians because of a higher polypoidal choroidal vasculopathy prevalence. Drusens, shallow irregular retinal pigment epithelium elevation, and pigment epithelial detachment are risk factors for fellow eye progression.

CHOROIDAL VASCULAR ALTERATIONS IN AGE-RELATED MACULAR DEGENERATION AND POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To evaluate morphologic alterations in choroidal veins in eyes with typical neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: A retrospective review of baseline indocyanine green angiography in eyes with typical nAMD and PCV. We evaluated Haller layer veins in the early-phase indocyanine green angiography (before 2 minutes) for 1) macular anastomosis, 2) dilated Haller veins, and 3) focal variation in vessel caliber by at least 50% from the narrowest to largest diameters. RESULTS: We included 70 patients with gradable indocyanine green angiography for the prespecified features in the study eye (36 typical nAMD and 34 PCV) and 59 fellow eyes. The median subfoveal choroidal thickness was 167 µm versus 219 µm, P = 0.08, in the presenting eyes in typical nAMD and PCV, respectively. Macular anastomosis was common in both typical nAMD and PCV (presenting eyes 58.3% vs. 58.8%. P = 0.97; fellow eyes 65.5% vs. 63.3%, P = 0.86). Dilated Haller veins were numerically less common in typical nAMD than PCV (presenting eyes 52.8% vs. 67.6%, P = 0.21; fellow eyes 65.5% vs. 70.0%, P = 0.71), while vascular caliber variation was numerically more common in typical nAMD than PCV (presenting eyes 72.2% vs. 63.8%, P = 0.45; fellow eyes 69.0% vs. 56.7%, P = 0.33). The presence of all three features was more common in the presenting eyes with PCV compared with typical nAMD (35.3% vs. 13.9%, P = 0.03). In a multivariable analysis, every increase of 100 µm of CT conferred a 2.75 risk of having all three features present. CONCLUSION: Choroidal vascular remodeling is common in both tAMD and PCV but may be driven by different stimuli.

PATTERN AND CHARACTERISTICS OF DRUSEN SUBTYPES IN CHINESE AND INDIAN POPULATIONS IN SINGAPORE.

PURPOSE: To report the pattern and characteristics of drusen subtypes in Asian populations and the association with choroidal thickness. METHODS: This is the cross-sectional analysis of the population-based cohort study. Two thousand three hundred and fifty-three eyes of 1,336 Chinese and Indian participants aged older than 50 years, eyes with best-corrected visual acuity better than 20/60, and without other retinal diseases were recruited. Pachydrusen, reticular pseudodrusen, soft and hard drusen were graded on both color fundus photographs, and optical coherence tomography imaging with automated segmentation yielding and measurements of choroidal thickness. RESULTS: Nine hundred and fifty-five Chinese and 381 Indians were included in the final analysis. The pattern of pachydrusen, soft drusen, hard drusen, and reticular pseudodrusen was 14.0%, 3.7%, 12.5%, and 0.2%, respectively. Mean choroidal thickness was the thickest in eyes with pachydrusen (298.3 µm; 95% confidence interval: 290.5-306.1), then eyes with hard (298.1 µm; 95% confidence interval: 290.6-305.5) and soft drusen (293.7 µm; 95% confidence interval: 281.9-305.4) and thinnest in eyes without drusen (284.6 µm; 95% confidence interval: 280.5-288.7). Systemic associations of the various drusen subtypes also differed. CONCLUSION: Patterns, characterization and choroidal thickness of drusen subtypes, and their associations provide insights into the Asian phenotypic spectrum of age-related macular degeneration and the underlying pathogenesis.

Repair and Mechanism of Oligopeptide SEP-3 on Oxidative Stress Liver Injury Induced by Sleep Deprivation in Mice.

To investigate the effects of bonito oligopeptide SEP-3 on the repair of liver damage and regulation of liver biorhythm in sleep-deprived mice (SDM), C57BL/6 male mice were subjected to sleep deprivation by modified multi-platform water environment method, and were given different doses of bonito oligopeptide SEP-3 in groups. To determine the liver organ index, liver tissue-related apoptotic protein levels, Wnt/ß-Catenin pathway-related protein expression levels, serum alanine transaminase (ALT), glutamicum transaminase (AST), glucocorticoid (GC), and adrenocorticotropin (ACTH) content in each group of mice, four time points were selected to examine the mRNA expression levels of circadian clock-related genes in mouse liver tissue. The results showed that low, medium, and high doses of SEP-3 significantly increased SDM, ALT, and AST (p < 0.05), and medium and high doses of SEP-3 significantly reduced SDM liver index and GC and ACTH. As SEP-3 increased the apoptotic protein and Wnt/ß-Catenin pathway, mRNA expression gradually tended to normal (p < 0.05). This suggests that sleep deprivation can cause excessive oxidative stress in mice, which can lead to liver damage. Additionally, oligopeptide SEP-3 achieves the repair of liver damage by inhibiting SDM hepatocyte apoptosis, activating liver Wnt/ß-Catenin pathway, and promoting hepatocyte proliferation and migration, and suggests that oligopeptide SEP-3 is closely related to repair of liver damage by regulating the biological rhythm of SDM disorder.

Development and validation of machine learning models for nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) had become the most prevalent liver disease worldwide. Early diagnosis could effectively reduce NAFLD-related morbidity and mortality. This study aimed to combine the risk factors to develop and validate a novel model for predicting NAFLD. METHODS: We enrolled 578 participants completing abdominal ultrasound into the training set. The least absolute shrinkage and selection operator (LASSO) regression combined with random forest (RF) was conducted to screen significant predictors for NAFLD risk. Five machine learning models including logistic regression (LR), RF, extreme gradient boosting (XGBoost), gradient boosting machine (GBM), and support vector machine (SVM) were developed. To further improve model performance, we conducted hyperparameter tuning with train function in Python package 'sklearn'. We included 131 participants completing magnetic resonance imaging into the testing set for external validation. RESULTS: There were 329 participants with NAFLD and 249 without in the training set, while 96 with NAFLD and 35 without were in the testing set. Visceral adiposity index, abdominal circumference, body mass index, alanine aminotransferase (ALT), ALT/AST (aspartate aminotransferase), age, high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride (TG) were important predictors for NAFLD risk. The area under curve (AUC) of LR, RF, XGBoost, GBM, SVM were 0.915 [95% confidence interval (CI): 0.886-0.937], 0.907 (95% CI: 0.856-0.938), 0.928 (95% CI: 0.873-0.944), 0.924 (95% CI: 0.875-0.939), and 0.900 (95% CI: 0.883-0.913), respectively. XGBoost model presented the best predictive performance, and its AUC was enhanced to 0.938 (95% CI: 0.870-0.950) with further parameter tuning. CONCLUSIONS: This study developed and validated five novel machine learning models for NAFLD prediction, among which XGBoost presented the best performance and was considered a reliable reference for early identification of high-risk patients with NAFLD in clinical practice.

The Porous Structure of Peripheral Nerve Guidance Conduits: Features, Fabrication, and Implications for Peripheral Nerve Regeneration.

Porous structure is an important three-dimensional morphological feature of the peripheral nerve guidance conduit (NGC), which permits the infiltration of cells, nutrients, and molecular signals and the discharge of metabolic waste. Porous structures with precisely customized pore sizes, porosities, and connectivities are being used to construct fully permeable, semi-permeable, and asymmetric peripheral NGCs for the replacement of traditional nerve autografts in the treatment of long-segment peripheral nerve injury. In this review, the features of porous structures and the classification of NGCs based on these characteristics are discussed. Common methods for constructing 3D porous NGCs in current research are described, as well as the pore characteristics and the parameters used to tune the pores. The effects of the porous structure on the physical properties of NGCs, including biodegradation, mechanical performance, and permeability, were analyzed. Pore structure affects the biological behavior of Schwann cells, macrophages, fibroblasts, and vascular endothelial cells during peripheral nerve regeneration. The construction of ideal porous structures is a significant advancement in the regeneration of peripheral nerve tissue engineering materials. The purpose of this review is to generalize, summarize, and analyze methods for the preparation of porous NGCs and their biological functions in promoting peripheral nerve regeneration to guide the development of medical nerve repair materials.

The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation.

The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1ß production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1ß resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.

OPTICAL COHERENCE TOMOGRAPHY FEATURES OF POLYPOIDAL LESION CLOSURE IN POLYPOIDAL CHOROIDAL VASCULOPATHY TREATED WITH AFLIBERCEPT.

PURPOSE: To evaluate whether optical coherence tomography (OCT) can determine polypoidal lesion (PL) perfusion in polypoidal choroidal vasculopathy eyes after 12 months of aflibercept monotherapy. Polypoidal lesion perfusion status, assessed by indocyanine green angiography, is an important anatomical outcome in polypoidal choroidal vasculopathy management. METHODS: Post hoc data from a prospective randomized, open-label, study in eyes with polypoidal choroidal vasculopathy undergoing monotherapy with aflibercept evaluated PL perfusion status based on indocyanine green angiography (gold standard) and OCT features from baseline to 12 months. RESULTS: Individual PLs (110 in total) from 48 eyes (48 patients) showed at 12 months; 57/110 PLs (51.8%) were closed on indocyanine green angiography. At 12 months, eyes with closed PLs were more likely to have the following OCT features: 1) no subretinal fluid (67.1% vs. 32.9%), 2) smaller pigment epithelial detachment height (67.2 [±43.8] vs. 189.2 [±104.9] µm), 3) densely hyperreflective pigment epithelial detachment contents (84.0% vs. 16.0%), 4) an absence of a hyperreflective ring(64.0% vs. 36.0%), and a 5) indistinct overlying retinal pigment epithelial (71.4% vs. 28.6%) (all P < 0.05). The three highest performing OCT features that differentiated perfused from closed PLs were (1), (3), and (4) (area under the receiver operating characteristic curve 0.85, 0.73, and 0.70, respectively). A combination of these three features achieved an area under the receiver operating characteristic curve of 0.90. CONCLUSION: Polypoidal lesion closure, an important anatomical treatment outcome in polypoidal choroidal vasculopathy typically defined by indocyanine green angiography, can be accurately detected by specific OCT features.

PULSATILE FILLING OF DILATED CHOROIDAL VESSELS IN MACULAR WATERSHED ZONES.

PURPOSE: To describe pulsatile filling of dilated choroidal veins in the watershed zones and propose an alteration in choroidal perfusion pressure. METHODS: Retrospective review of original and digital subtraction indocyanine green angiography. RESULTS: We observed pulsating blood flow within choroidal vein segments in the posterior pole in 14 eyes (diagnosis of polypoidal choroidal vasculopathy, central serous chorioretinopathy, or neovascular age-related macular degeneration). Pulsating dye front was observed in single or multiple large choroidal vein(s) in a location that is ordinarily a watershed zone between the segmental areas of venous drainage, and vessels proximal and distal were often dilated. The pulsatile venous segments filled more slowly than the neighboring veins. In digital subtraction indocyanine green angiography, the dye front advanced in an incremental fashion or oscillated in a back-and-forth manner during several cardiac cycles during the filling of these larger choroidal veins. With indocyanine green angiography, we observed dilated choroidal veins that violated the macula watershed zone, localized bulbous dilations, and arteriole-over-vein crossings with apparent compression. CONCLUSION: These novel observations suggest the pressure gradient for flow in the affected veins varied from low gradients when the filling was slow to high gradients when the filling was faster. The vessels violated the physiological watershed zone and seem to function as anastomoses between the ordinarily segmented venous drainage of the choroid. The dilated segments may result in pooling of venous blood as part of venous outflow abnormalities that may be operative in these diseases.

POLYPOIDAL CHOROIDAL VASCULOPATHY FEATURES VARY ACCORDING TO SUBFOVEAL CHOROIDAL THICKNESS.

PURPOSE: To evaluate associations between choroidal thickness and features of polypoidal choroidal vasculopathy (PCV) lesions based on multimodal imaging. METHODS: This cross-sectional analysis included treatment-naive PCV eyes from a prospectively recruited observational cohort. Associations between of subfoveal choroidal thickness (SFCT) and qualitative and quantitative morphologic features of PCV lesions on color fundus photographs, indocyanine green and fluorescein angiography, and spectral-domain optical coherence tomography were evaluated. RESULTS: We included 100 eyes with indocyanine green angiography-proven PCV. Subfoveal choroidal thickness showed a bimodal distribution with peaks at 170 µm and 350 µm. There was a significant linear increase in the total lesion area (P-trend = 0.028) and the polypoidal lesion area (P-trend = 0.030 and P-continuous = 0.037) with increasing SFCT. Pairwise comparisons between quartiles showed that the total lesion area (4.20 ± 2.61 vs. 2.89 ± 1.43 mm2, P = 0.024) and the polypoidal lesion area (1.03 ± 1.01 vs. 0.59 ± 0.45 mm2, P = 0.042) are significantly larger in eyes in Q4 (SFCT ≥ 350 µm) than eyes in Q1 (SFCT ≤ 170 µm). Although there was no significant linear trend relating SFCT to best-corrected visual acuity, pairwise comparisons showed that eyes in Q4 (SFCT ≥ 350 µm) have significantly worse vision (0.85 ± 0.63 vs. 0.55 ± 0.27 logMAR, P = 0.030) than eyes in Q2 (SFCT 170-260 µm). CONCLUSION: Total lesion areas and polypoidal lesion areas tend to be larger in eyes with increasing SFCT. Choroidal background may influence the phenotype or progression pattern of PCV.

Association between retinal thickness variation and visual acuity change in neovascular age-related macular degeneration.

BACKGROUND: To assess the association between variation in retinal central subfield thickness (CSFT) with best-corrected visual acuity (BCVA) change in patients receiving vascular endothelial growth factor (VEGF) inhibitor therapy for neovascular age-related macular degeneration (nAMD). METHODS: CSFT measurements were obtained from 141 eyes (total 1300 scans). SD of CSFT was calculated. The eyes were categorised into CSFT variation tertiles. Multiple linear regression was used to examine the association between the CSFT tertiles and BCVA change at 12 mo, adjusting for differences in baseline demographic and clinical characteristics. RESULTS: At 12 mo, the mean BCVA of the high CSFT variation group (50.6 letters) was significantly lower than the low and moderate CSFT variation groups (57.5 and 59.8 letters, respectively), P = .02. The adjusted mean BCVA gains were +1.7, +7.2, and +7.8 letters in the high, moderate and low CSFT variation groups, respectively (P = .03). CONCLUSIONS: A greater variation in retinal thickness during VEGF inhibitor therapy for nAMD is associated with a less favourable visual outcome. CSFT stability is useful in prognosticating visual outcomes in VEGF inhibitor therapy for nAMD.

Preclinical and clinical studies of photobiomodulation therapy for macular oedema.

AIMS/HYPOTHESIS: Diabetic macular oedema (DME) is the leading cause of visual impairment in people with diabetes. Intravitreal injections of vascular endothelial growth factor inhibitors or corticosteroids prevent loss of vision by reducing DME, but the injections must be given frequently and usually for years. Here we report laboratory and clinical studies on the safety and efficacy of 670 nm photobiomodulation (PBM) for treatment of centre-involving DME. METHODS: The therapeutic effect of PBM delivered via a light-emitting diode (LED) device was tested in transgenic mice in which induced Müller cell disruption led to photoreceptor degeneration and retinal vascular leakage. We also developed a purpose-built 670 nm retinal laser for PBM to treat DME in humans. The effect of laser-delivered PBM on improving mitochondrial function and protecting against oxidative stress was studied in cultured rat Müller cells and its safety was studied in pigmented and non-pigmented rat eyes. We then used the retinal laser to perform PBM in an open-label, dose-escalation Phase IIa clinical trial involving 21 patients with centre-involving DME. Patients received 12 sessions of PBM over 5 weeks for 90 s per treatment at a setting of 25, 100 or 200 mW/cm2 for the three sequential cohorts of 6-8 patients each. Patients were recruited from the Sydney Eye Hospital, over the age of 18 and had centre-involving DME with central macular thickness (CMT) of >300 µm with visual acuity of 75-35 Log minimum angle of resolution (logMAR) letters (Snellen visual acuity equivalent of 20/30-20/200). The objective of this trial was to assess the safety and efficacy of laser-delivered PBM at 2 and 6 months. The primary efficacy outcome was change in CMT at 2 and 6 months. RESULTS: LED-delivered PBM enhanced photoreceptor mitochondrial membrane potential, protected Müller cells and photoreceptors from damage and reduced retinal vascular leakage resulting from induced Müller cell disruption in transgenic mice. PBM delivered via the retinal laser enhanced mitochondrial function and protected against oxidative stress in cultured Müller cells. Laser-delivered PBM did not damage the retina in pigmented rat eyes at 100 mW/cm2. The completed clinical trial found a significant reduction in CMT at 2 months by 59 ± 46 µm (p = 0.03 at 200 mW/cm2) and significant reduction at all three settings at 6 months (25 mW/cm2: 53 ± 24 µm, p = 0.04; 100 mW/cm2: 129 ± 51 µm, p < 0.01; 200 mW/cm2: 114 ± 60 µm, p < 0.01). Laser-delivered PBM was well tolerated in humans at settings up to 200 mW/cm2 with no significant side effects. CONCLUSIONS/INTERPRETATION: PBM results in anatomical improvement of DME over 6 months and may represent a safe and non-invasive treatment. Further testing is warranted in randomised clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02181400 Graphical abstract.

PREVALENCE AND RISK FACTORS FOR THE DEVELOPMENT OF PHYSICIAN-GRADED SUBRETINAL FIBROSIS IN EYES TREATED FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess the prevalence and incidence of and risk factors for subretinal fibrosis (SRFi) in eyes with neovascular age-related macular degeneration (nAMD) that underwent vascular endothelial growth factor inhibitor treatment for up to 10 years. METHODS: A cross-sectional and longitudinal analysis was performed on data from a neovascular age-related macular degeneration registry. The presence and location of SRFi were graded by the treating practitioner. Visual acuity, lesion characteristics (type, morphology, and activity), and treatment administered at each visit was recorded. RESULTS: The prevalence of SRFi in 2,914 eyes rose from 20.4% at year interval 0-1 to 40.7% at year interval 9 to 10. The incidence in 1,950 eyes was 14.3% at baseline and 26.3% at 24 months. Independent characteristics associated with SRFi included poorer baseline vision (adjusted odds ratio 5.33 [95% confidence interval 4.66-7.61] for visual acuity ≤35 letters vs. visual acuity ≥70 letters, P < 0.01), baseline lesion size (adjusted odds ratio 1.08 [95% confidence interval 1.08-1.14] per 1000 µm, P = 0.03), lesion type (adjusted odds ratio 1.42 [95% confidence interval 1.17-1.72] for predominantly classic vs. occult lesions, P = 0.02), and proportion of active visits (adjusted odds ratio 1.58 [95% confidence interval 1.25-2.01] for the group with the highest level of activity vs. the lowest level of activity, P < 0.01). CONCLUSION: Subretinal fibrosis was found in 40% of eyes after 10 years of treatment. High rates of lesion activity, predominantly classic lesions, poor baseline vision, and larger lesion size seem to be independent risk factors for SRFi.

Interfering cellular lactate homeostasis overcomes Taxol resistance of breast cancer cells through the microRNA-124-mediated lactate transporter (MCT1) inhibition.

BACKGROUND: Breast cancer, the most common invasive cancer of women, is a malignant neoplasm and the second main cause of cancer death. Resistance to paclitaxel (Taxol), one of the frequently used chemotherapy agents for breast cancer, presents a major clinical challenge. Recent studies revealed that metabolic alterations of cancer cells play important roles in chemo-resistance. MATERIALS AND METHODS: In this study, Human breast cancer cells, BT474, SKBR3 and MCF7 were used to study the causal relationship between the lactate exporter, MCT1 (SLC16A1)-modulated glucose metabolism and Taxol resistance of breast cancer cells. Taxol resistant breast cancer cells were established. The intracellular lactate and extracellular lactate levels as well glucose uptake and oxygen consumption were measured. MicroRNA-124 expressions were detected by qRT-PCR from both breast cancer patient samples and breast cancer cells. Target of miR-124 was predicted and verified by Western blot and luciferase assay. An xenograft mice model was established and evaluated for the in vivo tumor therapeutic effects of MCT1 inhibitor plus microRNA-124 treatments. RESULTS: Low toxic Taxol treatments promoted cellular glucose metabolism and intracellular lactate accumulation with upregulated lactate dehydrogenase-A (LDHA) and MCT1 expressions. By establishing Taxol resistant breast cancer cell line, we found Taxol resistant cells exhibit upregulated LDHA and MCT1 expressions. Furthermore, glucose consumption, lactate production and intracellular ATP were elevated in Taxol resistant MCF7 cells compared with their parental cells. The miR-124, a tumor suppressive miRNA, was significantly downregulated in Taxol resistant cells. Luciferase assay and q-RT-PCR showed MCT1 is a direct target of miR-124 in both breast cancer cell lines and patient specimens. Moreover, co-treatment of breast cancer cells with either MCT1 inhibitor or miR-124 plus Taxol led to synergistically cytotoxic effects. Importantly, based on in vitro and in vivo results, inhibition of MCT1 significantly sensitized Taxol resistant cells. Finally, rescue experiments showed restoration of MCT1 in miR-124 overexpressing cells promoted Taxol resistance. CONCLUSIONS: This study reveals a possible role of miRNA-214-mediated Taxol resistance, contributing to identify novel therapeutic targets against chemoresistant breast cancers.

CHARACTERIZATION OF THE CHOROIDAL VASCULATURE IN MYOPIC MACULOPATHY WITH OPTICAL COHERENCE TOMOGRAPHIC ANGIOGRAPHY.

PURPOSE: To characterize the choriocapillaris (CC) in highly myopic eyes with myopic maculopathy, using optical coherence tomographic angiography. METHODS: Prospective, clinic-based study of 42 eyes of 38 patients with high myopia (≤-6 diopters and axial length ≥26.5 mm). Myopic maculopathy was graded from fundus photographs according to the Meta-Analysis for Pathologic Myopia classification. Macular 3 × 3 mm en face optical coherence tomographic angiographic images were obtained with swept-source optical coherence tomographic angiography and graded for CC flow impairment as follows: 1) intact CC, 2) focal (<1 mm), and 3) extensive (>1 mm). RESULTS: Of the 42 eyes, 17 (39.5%) had tessellated fundus, 20 (46.5%) had diffuse, and 6 (14.0%) had patchy atrophy. Choriocapillaris flow impairment was observed in all eyes with diffuse and patchy atrophy. Even in eyes with tessellated fundus only, CC signal voids were seen in 3 eyes (17.6%). With increasingly severe myopic maculopathy, the pattern of CC flow impairment changed from predominantly focal to predominantly extensive. CONCLUSION: Choriocapillaris flow impairment was observed in many highly myopic eyes, even in those with mild fundus changes, and worsened with increasing severity of myopic maculopathy. Longitudinal studies are needed to assess whether CC flow impairment predicts the risk of myopic maculopathy progression.

Chronic wound assessment and infection detection method.

BACKGROUND: Numerous patients suffer from chronic wounds and wound infections nowadays. Until now, the care for wounds after surgery still remain a tedious and challenging work for the medical personnel and patients. As a result, with the help of the hand-held mobile devices, there is high demand for the development of a series of algorithms and related methods for wound infection early detection and wound self monitoring. METHODS: This research proposed an automated way to perform (1) wound image segmentation and (2) wound infection assessment after surgical operations. The first part describes an edge-based self-adaptive threshold detection image segmentation method to exclude nonwounded areas from the original images. The second part describes a wound infection assessment method based on machine learning approach. In this method, the extraction of feature points from the suture area and an optimal clustering method based on unimodal Rosin threshold algorithm that divides feature points into clusters are introduced. These clusters are then merged into several regions of interest (ROIs), each of which is regarded as a suture site. Notably, a support vector machine (SVM) can automatically interpret infections on these detected suture site. RESULTS: For (1) wound image segmentation, boundary-based evaluation were applied on 100 images with gold standard set up by three physicians. Overall, it achieves 76.44% true positive rate and 89.04% accuracy value. For (2) wound infection assessment, the results from a retrospective study using confirmed wound pictures from three physicians for the following four symptoms are presented: (1) Swelling, (2) Granulation, (3) Infection, and (4) Tissue Necrosis. Through cross-validation of 134 wound images, for anomaly detection, our classifiers achieved 87.31% accuracy value; for symptom assessment, our classifiers achieved 83.58% accuracy value. CONCLUSIONS: This augmentation mechanism has been demonstrated reliable enough to reduce the need for face-to-face diagnoses. To facilitate the use of this method and analytical framework, an automatic wound interpretation app and an accompanying website were developed. TRIAL REGISTRATION: 201505164RIND , 201803108RSB .

COMPARISON OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHIC CHANGES AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY ALONE OR IN COMBINATION WITH PHOTODYNAMIC THERAPY IN POLYPOIDAL CHOROIDAL VASCULOPATHY.

PURPOSE: To compare changes in optical coherence tomography angiography in eyes with polypoidal choroidal vasculopathy after treatment with anti-vascular endothelial growth factor monotherapy or combined with photodynamic therapy. METHODS: This is a longitudinal case-controlled study. The authors performed optical coherence tomography angiography at baseline and Month 3 in patients with treatment-naive polypoidal choroidal vasculopathy undergoing monotherapy (n = 10) or combination therapy (n = 13). We analyzed flow signal within the outer retina and choriocapillaris using automated segmentation. The authors analyzed the presence of pachyvessels using a 10.4-µm segment through Haller layer. The changes in each layer were compared between treatments. RESULTS: At Month 3, both groups showed similar improvement in best-corrected visual acuity and central retinal thickness. However, flow signal within the polypoidal choroidal vasculopathy complex was decreased in more eyes after combination therapy than after monotherapy (84.6% vs. 40.0%, P = 0.04). Patchy reduction in flow signal within the choriocapillaris layer was noted in 15.4% and 10.0% after combination therapy and monotherapy, respectively (P = 0.61). Significant reduction in pachyvessel caliber was seen only after combination therapy but not after monotherapy (75.0% vs. 0.0%, P = 0.01). CONCLUSION: Longitudinal optical coherence tomography angiography demonstrates more significant reduction in lesion flow and pachyvessels in the short term after combination therapy than after monotherapy, although visual and structural OCT showed similar improvement.

The Use of Vascular Endothelial Growth Factor Inhibitors and Complementary Treatment Options in Polypoidal Choroidal Vasculopathy: A Subtype of Neovascular Age-Related Macular Degeneration.

Polypoidal choroidal vasculopathy (PCV) is a subtype of neovascular age-related macular degeneration (AMD; nAMD) which occurs more commonly in Asian populations as compared to Caucasians. PCV and nAMD share pathological mechanisms, including pathological expression of vascular endothelial growth factor (VEGF). The advent of anti-vascular endothelial growth factor (VEGF) revolutionized the treatment of nAMD. Despite being a subtype of nAMD, PCV responds less well to VEGF inhibitors; thus, photodynamic therapy (PDT) in combination with anti-VEGF treatment may be considered. This review aims to summarize the current evidence for the treatment of PCV, especially whether VEGF inhibitors should be used alone or in combination with PDT.