Association of Age-adjusted Charlson Comorbidity Index With Orbital Fungal Disease Outcomes.

PURPOSE: To determine whether the age-adjusted Charlson comorbidity index (age-CCI) in sino-orbital fungal disease patients correlates with disease-specific mortality. METHODS: Hospital billing systems at 2 academic institutions were queried for patients with ICD-9, ICD-10, and CPT codes used in fungal disease who also had orbital disease and significant visual loss. Thirty-two patients at Institution A and 18 patients at Institution B met the inclusion criteria of microbiologic or pathologic confirmation of fungal infection and completion of inpatient ophthalmology evaluation. Patients without radiographic abnormality in the sinus or orbit were excluded. Demographic, diagnostic, treatment, and outcome variables were recorded. Our primary outcome was death due to fungal disease. RESULTS: Of the 50 medical records examined, 44 patients met the criteria for fungal-related death outcome on multivariate analysis. The regression coefficient for age-CCI and fungal-related mortality was 0.242 (95% CI, 0.012-0.779) with a p value of 0.038. CONCLUSIONS: Age-CCI is significantly associated with fungal-related mortality. This relationship remains significant when controlling for 5 covariates of fungal organism phylum, presence or absence of CNS disease, exenteration, local treatment use, and presence or absence of an immunosuppressive diagnosis. Age-CCI shows promise as a clinical and research tool in the evaluation of invasive fungal disease involving the orbit.

Case Report: Significant Complications of Cosmetic Iris Implantation.

SIGNIFICANCE: The complications of cosmetic iris implantation may result in irreversible vision loss. Patients who obtain these implants against general medical consensus may present to providers when sequelae develop. In symptomatic patients, providers must recognize the imminent risk to vision and mitigate further ocular damage. PURPOSE: This is an observational clinical case report of a patient with significant, progressive, vision-threatening ocular pathology from prior cosmetic iris implantation, despite medical and surgical efforts to preserve vision. CASE REPORT: A 35-year-old HIV-positive man with a history of cosmetic iris implants in India 16 months prior was referred to our center. He had a history of 4 months of steroid-refractory uveitis and secondary glaucoma, with IOP measurements of more than 50 mmHg in the outpatient setting. Slit-lamp examination revealed ciliary flush, pannus formation, corneal edema, and keratic precipitates. Optical coherence tomography suggested possible retinal nerve fiber layer loss in the left eye. He was diagnosed with uveitis and glaucoma, and after a short course of IOP-lowering medication, the implants were removed sequentially. Post-operatively, his course was complicated by IOP elevation, cataract development, and corneal decompensation. This led to bilateral Ahmed tube placement, Descemet's stripping endothelial keratoplasty of the right eye, and pending cataract surgery because of now-dense bilateral cataracts. CONCLUSIONS: This case emphasizes the vision-threatening dangers of cosmetic iris implantation. It also demonstrates that sequelae may persist and develop despite implant removal and anticipatory management. Providers managing similar patients should carefully monitor for disease progression and maintain a low threshold for referral and/or decisive surgical intervention.

Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis.

During catalysis by liver alcohol dehydrogenase (ADH), a water bound to the catalytic zinc is replaced by the oxygen of the substrates. The mechanism might involve a pentacoordinated zinc or a double-displacement reaction with participation by a nearby glutamate residue, as suggested by studies of human ADH3, yeast ADH1, and some other tetrameric ADHs. Zinc coordination and participation of water in the enzyme mechanism were investigated by X-ray crystallography. The apoenzyme and its complex with adenosine 5'-diphosphoribose have an open protein conformation with the catalytic zinc in one position, tetracoordinated by Cys-46, His-67, Cys-174, and a water molecule. The bidentate chelators 2,2'-bipyridine and 1,10-phenanthroline displace the water and form a pentacoordinated zinc. The enzyme-NADH complex has a closed conformation similar to that of ternary complexes with coenzyme and substrate analogues; the coordination of the catalytic zinc is similar to that found in the apoenzyme, except that a minor, alternative position for the catalytic zinc is ∼1.3 Šfrom the major position and closer to Glu-68, which could form the alternative coordination to the catalytic zinc. Complexes with NADH and N-1-methylhexylformamide or N-benzylformamide (or with NAD+ and fluoro alcohols) have the classical tetracoordinated zinc, and no water is bound to the zinc or the nicotinamide rings. The major forms of the enzyme in the mechanism have a tetracoordinated zinc, where the carboxylate group of Glu-68 could participate in the exchange of water and substrates on the zinc. Hydride transfer in the Michaelis complexes does not involve a nearby water.

Longer-term Baerveldt to Trabectome glaucoma surgery comparison using propensity score matching.

PURPOSE: To apply propensity score matching to compare Baerveldt glaucoma drainage implant (BGI) to Trabectome-mediated ab interno trabeculectomy (AIT). Recent data suggests that AIT can produce results similar to BGI which is traditionally reserved for more severe glaucoma. METHODS: BGI and AIT patients with at least 1 year of follow-up were included. The primary outcome measures were intraocular pressure (IOP), number of glaucoma medications, and a Glaucoma Index (GI) score. GI reflected glaucoma severity based on visual field, the number of preoperative medications, and preoperative IOP. Score matching used a genetic algorithm consisting of age, gender, type of glaucoma, concurrent phacoemulsification, baseline number of medications, and baseline IOP. Patients with neovascular glaucoma, with prior glaucoma surgery, or without a close match were excluded. RESULTS: Of 353 patients, 30 AIT patients were matched to 29 BGI patients. Baseline characteristics including, IOP, the number of glaucoma medications, type of glaucoma, the degree of VF loss and GI were not significantly different between AIT and BGI. BGI had a preoperative IOP of 21.6 ± 6.3 mmHg compared to 21.5 ± 7.4 for AIT on 2.8 ± 1.1 medications and 2.5 ± 2.3 respectively. At 30 months, the mean IOP was 15.0 ± 3.9 mmHg for AIT versus 15.0 ± 5.7 mmHg for BGI (p > 0.05), while the number of drops was 1.5 ± 1.3 for AIT (change: p = 0.001) versus 2.4 ± 1.2 for BGI (change: p = 0.17; AIT vs BGI: 0.007). Success, defined as IOP < 21 mmHg, < 20% reduction and no reoperation, was achieved at 1 year in 56% of AIT versus 55% of BGI (p > 0.05) and 50% versus 52% at 2.5 years. CONCLUSIONS: A propensity score matched comparison of AIT and BGI demonstrated a similar IOP reduction through 1 year. AIT required fewer medications.

Gap Analysis of Glaucoma Examination Concept Representations within Standard Systemized Nomenclature of Medicine - Clinical Terms.

OBJECTIVE/PURPOSE: Standardization of eye care data is important for clinical interoperability and research. We aimed to address gaps in the representations of glaucoma examination concepts within Systemized Nomenclature of Medicine - Clinical Terms (SNOMED-CT), the preferred terminology of the American Academy of Ophthalmology. DESIGN: Study of data elements. METHODS: Structured eye examination data fields from 2 electronic health records (EHR) systems (Epic Systems and Medisoft) were compared against existing SNOMED-CT codes for concepts representing glaucoma examination findings. Glaucoma specialists from multiple institutions were surveyed to identify high-priority gaps in representation, which were discussed among the SNOMED International Eye Care Clinical Reference Group. Proposals for new codes to address the gaps were formulated and submitted for inclusion in SNOMED-CT. MAIN OUTCOME MEASURES: Gaps in SNOMED-CT glaucoma examination concept representations. RESULTS: We identified several gaps in SNOMED-CT regarding glaucoma examination concepts. A survey of glaucoma specialists identified high-priority data elements within the categories of tonometry and gonioscopy. For tonometry, there was consensus that we need to define new codes related to maximum intraocular pressure (IOP) and target IOP and delineate all methods of measuring IOP. These new codes were proposed and successfully added to SNOMED-CT for future use. Regarding gonioscopy, the current terminology did not include the ability to denote the gonioscopic grading system used (e.g., Shaffer or Spaeth), degree of angle pigmentation, iris configuration (except for plateau iris), and iris approach. There was also no ability to specify eye laterality or angle quadrant for gonioscopic findings. We proposed a framework for representing gonioscopic findings as observable entities in SNOMED-CT. CONCLUSION: There are existing gaps in the standardized representation of findings related to tonometry and gonioscopy within SNOMED-CT. These are important areas for evaluating clinical outcomes and enabling secondary use of EHR data for glaucoma research. This international multi-institutional collaborative process enabled identification of gaps, prioritization, and development of data standards to address these gaps. Addressing these gaps and augmenting SNOMED-CT coverage of glaucoma examination findings could enhance clinical documentation and future research efforts related to glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with BRAF-Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation.

RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development.

Evaluation of Virtual Reality Perimetry and Standard Automated Perimetry in Normal Children.

Purpose: The Olleyes VisuALL-K is a pediatric videogame-based static threshold perimeter using a virtual reality headset. We determined normal threshold sensitivities for the 24-2 test locations using the virtual reality perimetry (VRP) and also tested patients on the Humphrey Field Analyzer (HFA). Patient satisfaction for the two instruments was compared. Methods: This exploratory study tested 50 normal pediatric participants aged 8 to 17 years on the HFA and VRP. The main outcome measure was threshold sensitivity at the 24-2 test locations for the two instruments. Results: The mean participant age was 13.0 ± 2.6 years; 50% were female. The threshold values for VRP are reported as measured on the device and after conversion to an HFA-equivalent scale. Age-adjusted thresholds showed a mean sensitivity of 31.8 ± 1.1 dB (46.1 ± dB HFA equivalent) diminution from the maximum light intensity in the VRP and 31.0 ± 1.5 dB diminution from the maximum light intensity in the HFA; interparticipant variability in mean threshold sensitivity was 2.7 ± 0.4 dB for the VRP and 2.7 ± 0.6 dB for the HFA. The HFA demonstrated decreased threshold sensitivity with increasing eccentricity, whereas the VRP threshold did not seem to vary with eccentricity. Mild age effects on threshold sensitivity were seen in the VRP and the HFA (R2 = 0.11, P < 0.001 and R2 = 0.05, P < 0.05, respectively). The mean time to completion for VRP and HFA was 7.6 ± 1.5 and 5.3 ± 0.9 min/eye, respectively (P < 0.0001). Patient satisfaction scores favored VRP (P < 0.01) despite the longer test duration. Conclusions: The Olleyes game-based VRP and HFA can be used to map out the peripheral vision in normal children. The VRP has a higher patient satisfaction when used in children than the HFA. The portability of the test allows it to be performed in a myriad of environments, lending a flexibility that can benefit this population. Translational Relevance: This virtual reality perimetry device provides an alternative to the Humphrey Field Analyzer for children.

SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy.

Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit. SIGNIFICANCE: PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda, p. 1762. This article is highlighted in the In This Issue feature, p. 1749.

Proteomic analysis of vitreous biopsy techniques.

PURPOSE: To compare vitreous biopsy methods using analysis platforms used in proteomics biomarker discovery. METHODS: Vitreous biopsies from 10 eyes were collected sequentially using a 23-gauge needle and a 23-gauge vitreous cutter instrument. Paired specimens were evaluated by UV absorbance spectroscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: The total protein concentration obtained with a needle and vitrectomy instrument biopsy averaged 1.10 mg/mL (standard error of the mean = 0.35) and 1.13 mg/mL (standard error of the mean = 0.25), respectively. In eight eyes with low or medium viscidity, there was a very high correlation (R = 0.934) between the biopsy methods. When data from 2 eyes with high viscidity vitreous were included, the correlation was reduced (R = 0.704). The molecular weight protein sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles of paired needle and vitreous cutter samples were similar, except for a minority of pairs with single band intensity variance. Using LC-MS/MS, equivalent peptides were identified with similar frequencies (R ≥ 0.90) in paired samples. CONCLUSION: Proteins and peptides collected from vitreous needle biopsies are nearly equivalent to those obtained from a vitreous cutter instrument. This study suggests both techniques may be used for most proteomic and biomarker discovery studies of vitreoretinal diseases, although a minority of proteins and peptides may differ in concentration.

Presentation and outcomes of orbital cellulitis caused by Group F Streptococcus.

PURPOSE: To compare the presentation and outcomes of patients with orbital cellulitis requiring surgical intervention caused by the Group F Streptococcus (GFS) versus other bacteria. We hypothesize that patients with GFS infections have a more severe presentation and worse clinical outcomes compared to infections by other bacteria. METHODS: After Institutional Review Board approval at a large academic institutional center, 70 patients with culture-positive orbital cellulitis who required surgical intervention were identified. Clinical examinations before and after surgery as well as preoperative imaging with computed tomography and/or magnetic resonance imaging were reviewed. The study measures were preoperative and postoperative vision, motility, involved sinus disease, complications, and total hospital length of stay. Multiple imputation was used for missing data. Characteristics of patients were compared using Chi-square and Wilcoxon rank-sum. RESULTS: Nineteen patients (27%) had positive cultures for GFS and 51 patients (73%) had positive cultures for other bacterial species. There was no significant difference in visual acuity, motility, or inflammatory markers in patients with GFS compared to other patients. Patients with GFS were noted to have more sinus involvement on presentation compared to patients with other bacterial infections (P = 0.007). CONCLUSION: GFS associated orbital cellulitis is associated with significantly more sinus involvement, but has similar outcomes as orbital cellulitis from other bacterial species.