AbstractGlaucoma affects approximately 80 million individuals worldwide, a condition for which current treatment options are inadequate. The primary risk factor for glaucoma is elevated intraocular pressure. Intraocular pressure is determined by the balance between the secretion and outflow of aqueous humor. Here we show that using the RNA interference tool CasRx based on shH10 adenovirus-associated virus can reduce the expression of the aqueous humor circulation related genes Rock1 and Rock2, as well as aquaporin 1 and β2 adrenergic receptor in female mice. This significantly reduced intraocular pressure in female mice and provided protection to the retina ganglion cells, ultimately delaying disease progression. In addition, we elucidated the mechanisms by which the knockdown of Rock1 and Rock2, or aquaporin 1 and β2 adrenergic receptor in female mice, reduces the intraocular pressure and secures the retina ganglion cells by single-cell sequencing.

Corneal neovascularization (CNV) is a common clinical finding seen in a range of eye diseases. Current therapeutic approaches to treat corneal angiogenesis, in which vascular endothelial growth factor (VEGF) A plays a central role, can cause a variety of adverse side effects. The technology of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 can edit VEGFA gene to suppress its expression. CRISPR offers a novel opportunity to treat CNV. This study shows that depletion of VEGFA with a novel CRISPR/Cas9 system inhibits proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Importantly, subconjunctival injection of this dual AAV-SpCas9/sgRNA-VEGFA system is demonstrated which blocks suture-induced expression of VEGFA, CD31, and α-smooth muscle actin as well as corneal neovascularization in mice. This study has established a strong foundation for the treatment of corneal neovascularization via a gene editing approach for the first time.

Dry eye disease (DED) is a widespread ophthalmic illness that inflicts massive economic and medical burdens on society. Although oxidative stress is closely associated with the onset of DED, barely any quantities of antioxidants are clinically available owing to low efficiency, toxicity, and poor bioavailability. Cerium-based nanozymes possess promising enzyme-mimetic activities in scavenging reactive oxygen species (ROS). Moreover, the ultra-small metal-organic frameworks (MOFs) have the potential for more efficient drug delivery, ROS elimination, and therapeutic efficacy. However, the development of ultra-small cerium-based MOFs (Ce-MOFs) is limited to a small minority due to challenges in the synthetic process and stability. By simply adjusting raw ingredients concentrations, three types of Ce-MOFs with distinct particle sizes are synthesized: Ce-MOF 1 (213 nm), Ce-MOF 2 (36 nm), and Ce-MOF 3 (2 nm). In comparison, the obtained ultra-small Ce-MOF 3 exhibited superior ROS scavenging and antioxidant capacity, decreased cytotoxicity, and excellent ocular penetration. Therapeutically, Ce-MOF 3 is demonstrated to be highly efficient in alleviating DED by suppressing oxidative stress and inflammation, boosting corneal epithelial repair, and facilitating tear secretion recovery. The novel ultra-small Ce-MOF 3 may serve as a promising alternative treatment for DED and other ROS-related disorders when combined with ocular biocompatibility. By simply adjusting the concentrations of raw ingredients, the cerium-based metal-organic frameworks (Ce-MOFs) nanozymes with ultra-small particle size (2-3 nm) are first synthesized. In comparison, the obtained ultra-small Ce-MOFs nanozymes exhibited superior antioxidative capacity and decreased cytotoxicity. Therapeutically, the novel Ce-MOFs nanozymes are demonstrated to be a highly efficient and promising therapeutic candidate for dry eye disease treatment.image

BackgroundThe neutrophil-lymphocyte ratio (NLR) is a simple marker of systemic inflammatory responses. The present study aims to evaluate the prognostic significance of the NLR on admission day in predicting outcomes for patients with upper gastrointestinal bleeding (UGIB), which is a prevalent medical emergency.Methods726 patients who were admitted to our clinic between January 2019 and December 2022 diagnosed with UGIB, and who underwent necessary examinations, were included in the study. The patients’ Glasgow-Blatchford Score (GBS), Full Rockall Score (FRS), and NLR levels were calculated at the first admission. Outcomes were defined as in-hospital mortality, need for blood transfusion, surgical treatment and endoscopic therapy. Patients were categorized into four groups using NLR quartile levels to compare their clinical characteristics, Glasgow Blatchford Score, Full Rockall Score levels, and prognosis. Secondary, we modified FRS and GBS by adding NLR, respectively. We used area under the receiver operating characteristic curve (AUROC) to assess the accuracy of risk prediction for NLR, NLR-GBS, and NLR-FRS improved models.ResultsOf 726 patients, 6% died in hospital, 23.9% received endoscopic interventon, 4.8% received surgical treatment, and 46.4% received transfusion therapy. Multifactorial logistic regression showed that a high level of NLR was a risk factor for death in patients with UGIB (p = 0.028). NLR, GBS, FRS, NLR-GBS, and NLR-FRS have sufficient accuracy in predicting inpatient mortality, endoscopic treatment, and transfusion treatment, and the differences are statistically significant (p < 0.05). In the comprehensive prediction of adverse outcomes, NLR-GBS has the highest AUROC, and in predicting inpatient mortality, NLR-FRS has the highest AUROC.ConclusionFor UGIB patients, a high NLR was strongly associated with high risk UGIB. Combined testing with the GBS and FRS can achieve good predictive results, which is valuable in guiding the pre-screening and triage of emergency nursing care and clinical treatment to ensure that patients receive rapid and effective treatment and improve the quality of care.

Importance Optical coherence tomography angiography (OCTA) has been widely applied into children, however, few studies have assessed the repeatability and reproducibility of papillary and peripapillary VD in healthy children. Objective To assess the precision of papillary and peripapillary vascular density (VD) measurements using optical coherence tomography angiography (OCTA) and analyze the effects of the signal strength index (SSI) and axial length (AL) on precision estimates. Design, setting, and participants This was a prospective observational study. Seventy-eight children aged 6–16 years underwent 4.5 × 4.5 mm OCTA (RTVue XR Avanti) disc scans: two scans by one examiner (repeatability) and two additional scans by another examiner (reproducibility). Within-subject standard deviation (Sw), test-retest reproducibility (TRT), within-subject coefficient of variation (CoV), intraclass correlation coefficient (ICC), and Bland–Altman analysis were performed. Main outcomes and measures In repeatability measurement, the fluctuation ranges (minimum to maximum) of VD between intraexaminer A/B in Sw, TRT, CoV, and ICC were (1.05–2.17)% / (1.16–2.32)%, (2.9–6)% / (3.21–6.44)%, (1.9–4.47)% / (2.08–5)%, and (0.588–0.783)% / (0.633–0.803)%, respectively. In reproducibility measurement, the fluctuation ranges of VD in Sw, TRT, CoV, and ICC were 1.11–2.13%, 3.07–5.91%, 1.99–4.41%, and 0.644–0.777%, respectively. VD was negatively correlated with SSI in most sectors of the peripapillary (e.g., inferior nasal, temporal inferior, temporal superior, superior temporal, and superior nasal). AL was positively correlated with inferior temporal VD and negatively correlated with superior nasal VD. Conclusion and relevance Optical coherence tomography angiography showed moderate-to-good repeatability and reproducibility for papillary and peripapillary perfusion measurements in healthy children. The SSI value affects most of the peripapillary VD, while AL affects only the temporal inferior and nasal superior peripapillary VD.

AbstractBackgroundPrimary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin’s B-cell lymphoma which normally treated by high-dose methotrexate (HD-MTX)-based chemotherapy. However, such treatment cannot always guarantee a good prognosis (GP) outcome while suffering several side effects. Thus, biomarkers or biomarker-based models that can predict PCNSL patient prognosis would be beneficial.MethodsWe first collected 48 patients with PCNSL and applied HPLC-MS/MS-based metabolomic analysis on such retrospective PCNSL patient samples. We then selected the highly dysregulated metabolites to build a logical regression model that can distinguish the survival time length by a scoring standard. Finally, we validated the logical regression model on a 33-patient prospective PCNSL cohort.ResultsSix metabolic features were selected from the cerebrospinal fluid (CSF) that can form a logical regression model to distinguish the patients with relatively GP (Z score ≤0.06) from the discovery cohort. We applied the metabolic marker-based model to a prospective recruited PCNSL patient cohort for further validation, and the model preformed nicely on such a validation cohort (AUC = 0.745).ConclusionsWe developed a logical regression model based on metabolic markers in CSF that can effectively predict PCNSL patient prognosis before the HD-MTX-based chemotherapy treatments.