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Background Non-negative matrix factorization (NMF) is a technique widely used in various fields, including artificial intelligence (AI), signal processing and bioinformatics. However existing algorithms and R packages cannot be applied to large matrices due to their slow convergence or to matrices with missing entries. Besides, most NMF research focuses only on blind decompositions: decomposition without utilizing prior knowledge. Finally, the lack of well-validated methodology for choosing the rank hyperparameters also raises concern on derived results. Results We adopt the idea of sequential coordinate-wise descent to NMF to increase the convergence rate. We demonstrate that NMF can handle missing values naturally and this property leads to a novel method to determine the rank hyperparameter. Further, we demonstrate some novel applications of NMF and show how to use masking to inject prior knowledge and desirable properties to achieve a more meaningful decomposition. Conclusions We show through complexity analysis and experiments that our implementation converges faster than well-known methods. We also show that using NMF for tumour content deconvolution can achieve results similar to existing methods like ISOpure. Our proposed missing value imputation is more accurate than conventional methods like multiple imputation and comparable to missForest while achieving significantly better computational efficiency. Finally, we argue that the suggested rank tuning method based on missing value imputation is theoretically superior to existing methods. All algorithms are implemented in the R package NNLM, which is freely available on CRAN and Github.

Immune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC. A tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression. Of 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36-0.94, p = 0.031; HR 0.46, 95%CI 0.26-0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50-0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%). PD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation.

Proliferative diabetic retinopathy (PDR) remains a leading cause of blindness despite progress in screening and treatment. Recently, the Warburg effect, a metabolic alteration affecting amino acid (AA) metabolism in proliferating cells, has drawn attention regarding its role in PDR. This study aimed to investigate the impact of the Warburg effect on AA metabolism in human retinal endothelial cells (HRECs) subjected to PDR-associated risk factors and validate the findings in patients with PDR. In vitro experiments exposed HRECs to high glucose (HG) and/or hypoxia (Hyp), known inducers of the Warburg effect. The HG + Hyp group of HRECs exhibited significant differences in non-essential AAs with aliphatic non-polar side chains, mainly driven by elevated glycine concentrations. Pathway enrichment analysis revealed several glycine metabolism-related pathways significantly altered due to the Warburg effect induced by HG + Hyp. Crucially, vitreous humor samples from PDR patients displayed higher glycine levels compared to non-diabetic and diabetic patients without PDR. The odds ratio for PDR patients with glycine levels above the cut-off of 0.0836 µM was 28 ( p  = 0.03) compared to non-PDR controls. In conclusion, this study provides mechanistic insights into how a specific Warburg effect subtype contributes to glycine accumulation in PDR and supports glycine's potential as a biomarker for PDR pathogenesis.

While great progress has been made in screening methods and therapies for proliferative diabetic retinopathy (PDR), it is still a major cause of blindness. Rapidly dividing cells reprogram their metabolism toward hyperglycolysis (the Warburg effect), a process recently implicated in angiogenesis. In this study, we sought to investigate nucleotide metabolism in human retinal endothelial cells (HRECs) under high glucose (HG) and hypoxia (Hyp), both key risk factors in PDR and known to induce the Warburg effect, and to validate these findings in patients with PDR. HRECs were cultured under normal conditions and then exposed to HG, Hyp, or both. Metabolomic profiling was performed using liquid chromatography-mass spectrometry (LC-MS/MS) to quantify nucleotide-related metabolites. In parallel, proteomic analysis was conducted to assess proteins involved in nucleotide metabolism. To validate the findings, vitreous samples from patients with PDR and non-PDR controls were analyzed. Receiver operating characteristic (ROC) analysis was then applied to evaluate the diagnostic potential of nucleotide metabolites in PDR. HG and Hyp in HRECs caused selective disruptions in nucleotide metabolism, marked by significant accumulation of D-ribose-5-phosphate, a glycolytic precursor for both purines and pyrimidines, as well as nucleoside mono- and diphosphates (NMPs, NDPs), particularly adenosine mono- and diphosphates (AMP and ADP), without global changes in total nucleotide pools. This accumulation was also observed in vitreous samples from patients with PDR. ROC analysis identified AMP+ADP levels >0.0062 µM as a potential diagnostic biomarker for PDR with 87.5% specificity. Proteomic profiling revealed dysregulation of key enzymes regulating nucleotide homeostasis, including reduced expression of mitochondrial nucleoside diphosphate kinase (NME4), increased levels of cytosolic adenylate kinase (AK1), and upregulation of multiple enzymes involved in and salvage nucleotide biosynthesis. Notably, expression of ribonucleotide reductase catalytic subunit M (RRM2), which converts NDPs to deoxynucleotides (dNDPs) for DNA synthesis, was also elevated. Exposure to HG and Hyp, key risk factors for PDR, disrupts nucleotide homeostasis in HRECs, with enhanced glycolytic flux fueling nucleotide precursor production and altered kinase expression favoring the accumulation of nucleoside mono- and diphosphates over triphosphates. The corresponding increase in AMP and ADP in PDR vitreous highlights their potential as biomarkers and underscores the central role of nucleotide metabolism in PDR pathogenesis.

Here we describe a patient with atypical presentation of autosomal dominant vitreoretinochoroidopathy (ADVIRC) with a novel missense mutation in BEST1 gene and briefly review reported ADVIRC-associated genetic mutations. The patient is a 71-year-old African American female who presented with progressively worsening blurry vision bilaterally over the course of 40 years, with significant deterioration in both peripheral and central vision in the past five years. Her anterior segment exam was unremarkable. Fundoscopic examination showed confluent, demarcated areas of pigmentary chorioretinal atrophy in the mid-periphery of the retina with sparing of the macula in both eyes. Optical coherence tomography (OCT) of the lesions revealed flattening of the fovea with an elevation of the inner retinal structures and outer plexiform layer, and peripheral retinal thinning and loss of retinal structures with choroid hyperreflectivity, consistent with peripheral chorioretinal atrophy. Genetic testing identified a heterozygous c.830C>T, p.(T277M) mutation located on exon 7 of the BEST1 gene. This patient represents an atypical presentation of ADVIRC with more posterior involvement, and this case is associated with a novel missense mutation in the BEST1 gene.

BACKGROUND AND OBJECTIVE:To evaluate the efficacy of systemic prostaglandin E1 (PGE1) infusion within the first 24 hours of acute central retinal artery occlusion (CRAO). PATIENTS AND METHODS:Best corrected visual acuity (BCVA) was analyzed in a case series of six eyes from six patients (mean age: 69.33 years) with acute CRAO who were treated with twice-daily intravenous infusion of 40 μg PGE1. Therapy continued until the patient no longer experienced visual acuity improvements for 24 hours. RESULTS:Average time to presentation was 8.33 hours (range: 2 to 12 hours). The logMAR BCVA at presentation was 2.73. BCVA at the final visit 1 month after initial presentation was 1.48 (P = .025). All patients experienced vision improvement. No systemic adverse events were experienced. CONCLUSION:Intravenous PGE1 infusion resulted in significant visual improvement in patients presenting with acute CRAO and is well tolerated with few adverse effects.[Ophthalmic Surg Lasers Imaging Retina. 2019;50:S5–S8.]

To evaluate the ocular presentation, treatment, and clinical course of graft-versus-host disease (GVHD). Retrospective case series. Two hundred and forty-nine patients with systemic GVHD were included in the study. Ocular and systemic data were collected from 2003 to 2013. Mortality, visual acuity, and response of ocular symptoms. Sixty-four patients had ocular manifestations (25.7%). At presentation, the mean age was 44.5 years and mean latency was 16.4 months. The most common presentations were keratoconjunctivitis sicca, cataract, blepharitis, ocular hypertension, and filamentary keratitis. Visual acuity at presentation was 20/49; at the worst point in the disease was 20/115; and at most recent visit was 20/63. When topical anti-inflammatory drops were used in addition to tears, 54.3% of patients' ocular symptoms stabilized. When autologous serum was used in addition, 80% stabilized. The overall 10-year mortality of GVHD was 29.7%. For those with ocular involvement, it was 21.9%. Systemic GVHD has a high mortality rate, but ocular involvement does not suggest a worse prognosis. The main ocular presentations were keratoconjunctivitis sicca, cataracts, and ocular hypertension. Dry eyes in this population were very severe with overall worsening in visual acuity. However, with a step-wise approach involving topical anti-inflammatory medications and autologous serum tears, ocular symptoms do improve. It is important to monitor these patients closely, as they are prone to serious ocular complications such as corneal perforation and endophthalmitis.

To analyze visual outcomes and accuracy of intraocular lens (IOL) calculation formulas in predicting postoperative outcomes in patients undergoing flanged intrascleral IOL fixation. Case Series. Twenty-three patients who had undergone secondary IOL placement using flanged intrascleral fixation technique. Retrospective chart review. Corrected distance visual acuity (CDVA) and postoperative spherical equivalent based on manifest refraction. Visual acuity improved from 20/577 to 20/58. Overall, the actual refraction was 0.06 D more myopic than predicted. Holladay 2, Sanders Retzlaff Kraff/Theoretical (SRK/T) and Barrett Universal II resulted in mild myopic surprise (-0.55, -0.18 and -0.20 D). Haigis and Hill-RBF (Radial Basis Function) resulted in mild hyperopic surprise (+0.28 and +0.28 D). Hoffer Q and Holladay 1 were the most accurate (-0.02D and -0.08 D). Flanged intrascleral IOL fixation improved vision even in patients with other posterior segment pathologies. The effective lens positioning is likely similar to in-the-bag positioning. Hoffer Q and Holladay 1 formulas with in-the-bag calculations were the most accurate.

To evaluate surgeon performance and intraoperative complication rates of cataract surgery after resumption of elective surgeries following the operating room (OR) shutdown from the coronavirus disease 2019 (COVID-19) pandemic. Subjective surgical experience is also evaluated. This is a retrospective comparative study which analyzes cataract surgeries performed at an inner city, tertiary academic center. Cataract surgeries were categorized into Pre-Shutdown (January 1-March 18, 2020), and Post-Shutdown, for all cases which occurred after surgeries resumed (May 11-July 31, 2020). No cases were performed between March 19 and May 10, 2020. Patients undergoing combined cataract and minimally invasive glaucoma surgery (MIGS) were included, but MIGS complications were not counted as cataract complications. No other combined cataract-other ophthalmic surgeries were included. A survey was used to gather subjective surgeon experience. A total of 480 cases (n=306 Pre-Shutdown and n=174 Post-Shutdown) were analyzed. Although there was a higher frequency of complex cataract surgeries performed Post-Shutdown (5.2% vs 21.3%; p<0.00001), complication rates before versus after the shutdown were not statistically significant (9.2% vs 10.3%; p=0.75). Phacoemulsification was the step of cataract surgery in which residents were most concerned about when returning to the OR. After the surgical hiatus due to COVID-19, significantly more complex cataract surgeries were reported and surgeons reported higher general anxiety level when first returning to the OR. Increased anxiety did not lead to higher surgical complications. This study provides a framework to understand surgical expectations and outcomes for patients whose surgeons faced a prolonged two-month hiatus from cataract surgery.

To evaluate the outcomes of scleral-fixated intraocular lenses (IOLs) implanted using either Yamane technique or Gore-Tex suture fixation, in comparison to intracapsular lens fixation, and to assess the efficacy of various lens formulas in achieving predicted refractive targets. This study included 45 eyes from 44 patients with scleral-fixated IOLs, comprising 37 Yamane eyes and 8 Gore-Tex eyes. Preoperative refractive predictions from various formulae were compared with final postoperative refraction. Outcomes assessed included effective lens position (ELP), postoperative predictive error, and changes in visual acuity. The ELP of scleral-fixated IOLs was compared with that of intracapsular IOLs in fellow eyes. Average ELP for Yamane IOLs was 0.62 mm more posterior relative to intracapsular IOLs but was not significantly different for Gore-Tex IOLs. Average postoperative logMAR acuity change was significant at -1.30 (p=4.5x10 ) and -1.65 (p=5x10 ) for Yamane and Gore-Tex eyes, respectively. Mean prediction error for Yamane eyes was +0.29±1.3 D, -0.53±0.40 D, +0.80±1.4 D, and +0.43±1.4 D using Barrett Universal II, Holladay, Hill-RBF, and Hoffer QST formulas, respectively. Mean prediction error for Gore-Tex eyes was -0.37±1.24 D and +0.53±1.19 D using Barrett Universal II and Holladay formulas, respectively. Different scleral fixation techniques result in variations in ELP compared to intracapsular IOL placement. In our hands, when using the Yamane technique, surgeons should aim for a myopic refractive target to offset hyperopic errors when employing the Barrett Universal II, Hill-RBF, or Hoffer QST formulas, and a hyperopic target when using the Holladay formula. For Gore-Tex IOLs, a slightly hyperopic target is recommended to counter myopic error when using the Barrett Universal II formula, whereas a slightly myopic target is advised with the Holladay formula to offset hyperopic error. A limitation of our study is the small sample size for patients who underwent Gore-Tex suture fixation.