Genomic hallmarks of localized, non-indolent prostate cancer.

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Optimization and expansion of non-negative matrix factorization.

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.

BPG: Seamless, automated and interactive visualization of scientific data.

BACKGROUND: We introduce BPG, a framework for generating publication-quality, highly-customizable plots in the R statistical environment. RESULTS: This open-source package includes multiple methods of displaying high-dimensional datasets and facilitates generation of complex multi-panel figures, making it suitable for complex datasets. A web-based interactive tool allows online figure customization, from which R code can be downloaded for integration with computational pipelines. CONCLUSION: BPG provides a new approach for linking interactive and scripted data visualization and is available at http://labs.oicr.on.ca/boutros-lab/software/bpg or via CRAN at https://cran.r-project.org/web/packages/BoutrosLab.plotting.general.

A Crowdsourcing Approach to Developing and Assessing Prediction Algorithms for AML Prognosis.

Acute Myeloid Leukemia (AML) is a fatal hematological cancer. The genetic abnormalities underlying AML are extremely heterogeneous among patients, making prognosis and treatment selection very difficult. While clinical proteomics data has the potential to improve prognosis accuracy, thus far, the quantitative means to do so have yet to be developed. Here we report the results and insights gained from the DREAM 9 Acute Myeloid Prediction Outcome Prediction Challenge (AML-OPC), a crowdsourcing effort designed to promote the development of quantitative methods for AML prognosis prediction. We identify the most accurate and robust models in predicting patient response to therapy, remission duration, and overall survival. We further investigate patient response to therapy, a clinically actionable prediction, and find that patients that are classified as resistant to therapy are harder to predict than responsive patients across the 31 models submitted to the challenge. The top two performing models, which held a high sensitivity to these patients, substantially utilized the proteomics data to make predictions. Using these models, we also identify which signaling proteins were useful in predicting patient therapeutic response.

Advancements of vitreoretinal surgical machines.

PURPOSE OF REVIEW: This article reviews current advancements in vitreoretinal surgical machines. RECENT FINDINGS: The most recent advancement in vitreoretinal surgical machines include 27-gauge vitrectomy probes, new cutter designs, higher cut rate, improved intraocular pressure control, new endoillumination technologies, and combined anterior/posterior segment capabilities. SUMMARY: With recent advancements in vitreoretinal surgical machines, surgical incisions have become less traumatic and fluidics control has led to a more controlled posterior segment vitrectomy.

Ab Interno Ahmed Glaucoma Valve Plugs In An Eye With Persistent Hypotony.

PURPOSE: This case report aims to describe a new method for increasing intraocular pressure (IOP) in patients with acute hypotony resulting from uveitis flare-ups and preexisting glaucoma drainage devices. The temporary glaucoma tube plug method described is effective and safe. METHODS: This case report presents a 47-year-old female patient with a history of chronic panuveitis and secondary glaucoma, who had 2 previously implanted Ahmed glaucoma valves. The patient developed panuveitis flare-up and persistent hypotony. A novel method of ab interno plugging of the glaucoma tubes using 2-0 prolene suture plugs was performed. Following treatment, the IOP increased successfully and remained within the normal range. CONCLUSION: The temporary ab interno glaucoma tube plug method effectively increased IOP in a patient with 2 preimplanted Ahmed glaucoma valves with persistent low IOP due to uveitis.

Surgically Induced Scleritis Associated With Suture Hypersensitivity Following Strabismus Surgery.

A 67-year-old woman with history of mild suture hyper-sensitivity presented with localized scleritis after strabismus surgery. After infection was ruled out, the patient was prescribed topical and systemic non-steroidal anti-inflammatory drugs and systemic steroids, which led to full clinical resolution. [J Pediatr Ophthalmol Strabismus. 2024;61(1):e4-e6.].

Rahnella Aquatilis Endophthalmitis after Intravitreal Injection in an Immunocompetent Patient.

PURPOSE: To present a novel case of exogenous Rahnella aquatilis endophthalmitis following an intravitreal injection. METHODS: Case report. RESULTS: A 74-year-old male presented with acute progressive vision loss and pain in the left eye, 5 days after an intravitreal injection for diabetic macular edema. The patient was diagnosed with exogenous endophthalmitis and empirically treated with intravitreal injections of vancomycin and ceftazidime as well as topical and oral ciprofloxacin. In follow up two days later, the patient was treated with preoperative povidone-iodine followed by prompt vitrectomy with additional vancomycin and ceftazidime due to pharmacy sterile hood issues that delayed antibiotic availability. Microbiological cultures and two mass spectrometry identification tests confirmed the diagnosis of exogenous Rahnella aquatilis endophthalmitis. Despite the presence of scattered retinal hemorrhagic infarcts involving the macula and subsequent full-thickness atrophic macular holes seen in follow up, the patient achieved a favorable anatomical and functional outcome of BCVA 20/80 at 1 year of follow-up. CONCLUSION: This case highlights the occurrence of exogenous Rahnella aquatilis endophthalmitis following an intravitreal injection for diabetic macular edema. Prompt diagnosis and treatment produced a favorable outcome relative to other typical Gram-negative Enterobacteriaceae organisms.

Recalcitrant Fusarium Fungal Endophthalmitis: Novel Surgical Technique Combining Vitrectomy with Intralesional Injection of Voriconazole and Povidone Iodine.

PURPOSE: To show the feasibility while comparing functional and anatomical outcomes of vitrectomy combined with intralesional injection of voriconazole and povidone iodine for recalcitrant fusarium fungal endophthalmitis. METHODS: In a noncomparative interventional case, vitrectomy combined with intralesional injection of voriconazole and povidone iodine was performed in a single patient. RESULTS: Following vitrectomy and intralesional injection, our patient's fungal endophthalmitis stabilized and vision improved to 20/25. He did not require further intravitreal injections or vitrectomy. CONCLUSIONS: Vitrectomy and intralesional injection for the treatment of refractory filamentary fungal endophthalmitis proved to be safe and effective for this case.

Acute macular infarctions in pediatric patients with hemoglobin SS disease.

Purpose: To report two cases of symptomatic posterior pole arterial occlusions in patients with hemoglobin SS disease. Observations: Two teenage patients with hemoglobin SS disease presented with visual distortions, and on dilated fundus examination and testing, they were found to have arterial occlusions involving the posterior pole. The patients were evaluated for stroke with head imaging and received exchange transfusion by hematology. Conclusions and Importance: This case series reports the unusual findings of arterial occlusions in the posterior pole resulting in areas of retinal whitening and ischemia in patients with HbSS. While sickle cell retinopathy is typically considered a peripheral retinal disease, these findings underscore the importance of vigilance when examining patients with sickle cell disease.

A Case of Retinal Atherosclerotic Oxalosis due to Hyperoxaluria in a Patient with Short Gut Syndrome.

PURPOSE: To describe a severe case of crystalline retinopathy secondary to hyperoxaluria from short gut syndrome. METHODS: Case report. RESULTS: A 62-year-old Caucasian female with short gut syndrome and end-stage renal disease from renal oxalosis presented with chronic bilateral vision loss. She had previously been treated for presumed occlusive vasculitis. Visual acuity on initial exam was 20/400 OD and 20/100 OS with an afferent pupillary defect of the right eye.Exam revealed attenuated retinal vasculature and diffuse crystalline infiltration of retinal arterial lumens and throughout the retinas bilaterally. Optical coherence tomography revealed inner retinal atrophy with crystalline deposition in the inner retinal layers. Fluorescein angiography demonstrated delayed vascular filling and dropout consistent with severe ischemic vasculopathy. It was concluded that the short-gut syndrome led to over-absorption of oxalate with subsequent hyperoxaluria leading to retinal atherosclerotic oxalosis. CONCLUSION: Retinal calcium oxalate deposits due to hyperoxaluria have been previously noted; however, this degree of severe retinal vascular infiltration has not been described. Our patient was receiving hemodialysis, which is associated with high rebound increases in systemic oxalate concentrations. It is important to keep hyperoxaluria in mind as a potential cause of retinopathy in patients with end-stage renal disease presenting with vision loss.

Intraoperative Complication Rates in Cataract Surgery After Resuming Surgery Following the COVID-19 Shutdown.

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.

Intraocular Lens Formula Comparison of Flanged Intrascleral Intraocular Lens Fixation with Double Needle Technique.

Purpose: To analyze visual outcomes and accuracy of intraocular lens (IOL) calculation formulas in predicting postoperative outcomes in patients undergoing flanged intrascleral IOL fixation. Design: Case Series. Subjects: Twenty-three patients who had undergone secondary IOL placement using flanged intrascleral fixation technique. Methods: Retrospective chart review. Main Outcome Measures: Corrected distance visual acuity (CDVA) and postoperative spherical equivalent based on manifest refraction. Results: 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). Conclusion: 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.

The Warburg effect alters amino acid homeostasis in human retinal endothelial cells: implication for proliferative diabetic retinopathy.

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.

Individual versus collective fibroblast spreading and migration: regulation by matrix composition in 3D culture.

Extracellular matrix (ECM) supplies both physical and chemical signals to cells and provides a substrate through which fibroblasts migrate during wound repair. To directly assess how ECM composition regulates this process, we used a nested 3D matrix model in which cell-populated collagen buttons were embedded in cell-free collagen or fibrin matrices. Time-lapse microscopy was used to record the dynamic pattern of cell migration into the outer matrices, and 3D confocal imaging was used to assess cell connectivity and cytoskeletal organization. Corneal fibroblasts stimulated with PDGF migrated more rapidly into collagen as compared to fibrin. In addition, the pattern of fibroblast migration into fibrin and collagen ECMs was strikingly different. Corneal fibroblasts migrating into collagen matrices developed dendritic processes and moved independently, whereas cells migrating into fibrin matrices had a more fusiform morphology and formed an interconnected meshwork. A similar pattern was observed when using dermal fibroblasts, suggesting that this response is not unique to corneal cells. We next cultured corneal fibroblasts within and on top of standard collagen and fibrin matrices to assess the impact of ECM composition on the cell spreading response. Similar differences in cell morphology and connectivity were observed ­ cells remained separated on collagen but coalesced into clusters on fibrin. Cadherin was localized to junctions between interconnected cells, whereas fibronectin was present both between cells and at the tips of extending cell processes. Cells on fibrin matrices also developed more prominent stress fibers than those on collagen matrices. Importantly, these spreading and migration patterns were consistently observed on both rigid and compliant substrates, thus differences in ECM mechanical stiffness were not the underlying cause. Overall, these results demonstrate for the first time that ECM protein composition alone (collagen vs. fibrin) can induce a switch from individual to collective fibroblast spreading and migration in 3D culture. Similar processes may also influence cell behavior during wound healing, development, tumor invasion and repopulation of engineered tissues.

Plasmapheresis as a viable treatment option for scleritis.

Purpose: We describe a case and our experience with using plasmapheresis as a treatment for scleritis. Observations: Treating relapsing autoimmune scleritis can be challenging when it inadequately responds to traditional therapy. Our patient could not receive non-steroidal anti-inflammatory therapy for her scleritis due to recent gastrointestinal surgery and previously failed multiple steroid sparing treatments due to intolerance. There was good initial control with high dose oral prednisone, however, the steroid could not be tapered to a safe dosage (<10 mg per day) without relapse. Therefore, we opted to treat our patient with plasmapheresis. Conclusions and Importance: After undergoing plasmapheresis, our patient experienced total resolution of symptoms with corresponding clinical resolution of scleritis. Plasmapheresis derives great benefit by filtering circulating immune complexes. Although rarely used, plasmapheresis can be effective in treating non-infectious scleritis.

Pleiotropy of a Stickler syndrome genotype.

PURPOSE: To report a case of pleiotropy in the COL2A1 gene typically associated with Stickler Syndrome Type 1. OBSERVATIONS: A patient with a confirmed mutation of the COL2A1 gene presented with an isolated retinitis pigmentosa phenotype. CONCLUSIONS: The mutated COL2A1 gene in Stickler Syndrome Type 1 represents a site of pleiotropy, highlighting a change in phenotype across the same genotype potentially due to tissue alternative splicing.

Autosomal Dominant Vitreoretinochoroidopathy With a Novel BEST1 Mutation and a Review of Reported Mutations.

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.

CASE OF TORPEDO MACULOPATHY WITH TWO DISTINCT ZONES OF THE RETINAL PIGMENT EPITHELIUM.

BACKGROUND/PURPOSE: To report a case of torpedo maculopathy with two distinct zones of the retinal pigment epithelium visualized on optical coherence tomography. METHODS: Observational case report. RESULTS: A 6-year-old female presented for a routine examination. Visual acuity was 20/20 bilaterally. Dilated fundus examination was normal in the right eye. Dilated fundus examination of the left eye showed a wedge-shaped area of hypopigmentation in the temporal macula. Optical coherence tomography macula of the left eye showed outer retinal cavitation with segmentation of the foveal retinal pigment epithelium into a superficial fluffy zone and a deeper hyperreflective zone. CONCLUSION: This case helps contribute to the growing body of the torpedo maculopathy literature that may reveal different stages of the same disease evolving over time.