Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial.

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation.

BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).

Barriers to Implementation of Teleretinal Diabetic Retinopathy Screening Programs Across the University of California.

Aim: To describe barriers to implementation of diabetic retinopathy (DR) teleretinal screening programs and artificial intelligence (AI) integration at the University of California (UC). Methods: Institutional representatives from UC Los Angeles, San Diego, San Francisco, Irvine, and Davis were surveyed for the year of their program's initiation, active status at the time of survey (December 2021), number of primary care clinics involved, screening image quality, types of eye providers, image interpretation turnaround time, and billing codes used. Representatives were asked to rate perceptions toward barriers to teleretinal DR screening and AI implementation using a 5-point Likert scale. Results: Four UC campuses had active DR teleretinal screening programs at the time of survey and screened between 246 and 2,123 patients at 1-6 clinics per campus. Sites reported variation between poor-quality photos (<5% to 15%) and average image interpretation time (1-5 days). Patient education, resource availability, and infrastructural support were identified as barriers to DR teleretinal screening. Cost and integration into existing technology infrastructures were identified as barriers to AI integration in DR screening. Conclusions: Despite the potential to increase access to care, there remain several barriers to widespread implementation of DR teleretinal screening. More research is needed to develop best practices to overcome these barriers.

Surgical and anesthetic influences of the oculocardiac reflex in adults and children during strabismus surgery.

One of the most common untoward occurrences during strabismus surgery at all ages is the oculocardiac reflex. Although typically easily treated, the sudden bradycardia or cardiac arrest may add a few gray hairs to ophthalmologists and anesthesiologists alike as it can be potentially fatal. This updated review of the literature and novel detailed treatment algorithm may prevent patient morbidity and mortality through proper recognition of at-risk patients and rapid treatment through proper communication between surgical and anesthesia physicians/providers.

Whole-body CD8+ T cell visualization before and during cancer immunotherapy: a phase 1/2 trial.

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8+ T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8+ T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer 89ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed 89ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection (n = 38, median patient maximum standard uptake value (SUVmax) 5.2, IQI 4.0-7.4). Higher SUVmax was associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8+ T cell distribution and pharmacodynamics within and between patients. In conclusion, 89ZED88082A can characterize the complex dynamics of CD8+ T cells in the context of ICIs, and may inform immunotherapeutic treatments.

Clinical Decision Support to Address Racial Disparities in Hypertension Control in an Integrated Delivery System: Evaluation of a Natural Experiment.

INTRODUCTION: Effective, equity-promoting interventions implemented by health care systems are needed to address health care disparities and population-level health disparities. We evaluated the impact of a clinical decision support tool to improve evidence-based thiazide diuretic prescribing among Black patients to address racial disparities in hypertension control. METHODS: We employed an interrupted time series design and qualitative interviews to evaluate the implementation of the tool. Our primary outcome measure was the monthly rate of thiazide use among eligible patients before and after implementation of the tool (January 2013-December 2016). We modeled month-to-month changes in thiazide use for Black and White patients, overall, and by sex and medical center racial composition. We conducted key informant interviews to identify modifiable facilitators and barriers to implementation of the tool across medical centers. RESULTS: Of the 318,720 patients, 15.5% were Black. We observed no change in thiazide use or blood pressure control following the implementation of the tool in either racial subgroup. There was a slight but statistically significant reduction (2.32 percentage points, p < 0.01) in thiazide use among Black patients following the removal the tool that was not observed among White patients. Factors affecting the tool's implementation included physician and pharmacist resistance to thiazide use and a lack of ongoing promotion of the tool. DISCUSSION: The clinical decision support tool was insufficient to change prescribing practices and improve blood pressure control among Black patients. CONCLUSIONS: Future interventions should consider physician attitudes about thiazide prescribing and the importance of multilevel approaches to address hypertension disparities.

Rate of visual field decay in glaucomatous eyes with acquired pits of the optic nerve.

BACKGROUND: To evaluate the relationship between the presence of an acquired pit of the optic nerve (APON) and the rate of visual field (VF) decay in primary open-angle glaucoma (POAG). METHODS: Consecutive patients with POAG were screened for APON by three glaucoma specialists. A control group of POAG eyes without APON were matched with the APON group for factors such as age, gender, baseline intraocular pressure and baseline mean deviation (MD). The pointwise rate of change (PRC) was used for pointwise comparisons between the two groups. MD rate, Visual Field Index (VFI) rate and Glaucoma Rate Index (GRI) were used for global rate comparisons. We compared the proportions of eyes progressing in the groups with event-based guided progression analysis (GPA), MD, VFI and GRI criteria. RESULTS: Mean (SD) PRC was faster in the APON group -1.00 (±2.57) %/year compared with the control group -0.25 (±2.19) %/year; p<0.001. MD rate (-0.22 (±0.27) dB/year vs 0.03 (±0.41) dB/year; p=0.009), VFI rate (-0.81 (±0.86) %/year vs -0.05 (±1.0) %/year; p=0.04) and GRI (-12.27 (±16.27) vs -3.75 (±10.6); p=0.052) were all faster in the APON group compared with controls. The proportion of progressing eyes with GPA, MD, VFI and GRI was not significantly different between the two groups (p>0.1). CONCLUSIONS: The presence of APON in patients with POAG is associated with focal, fast rates of VF decay. Identification of patients with APON should alert clinicians to the possibility of a fast rate of functional progression and to consider appropriately aggressive treatment of their glaucoma.

High-Dose Methotrexate in Pediatric Acute Lymphoblastic Leukemia: Predictors of Delayed Clearance and the Effect of Increased Hydration Rate on Methotrexate Clearance.

Objectives High-dose methotrexate (HDMTX) is an important chemotherapeutic agent in the treatment of many cancers. Identification of the predictors of poor clearance during HDMTX infusions could advance the introduction of improved supportive care to prevent toxicities and reduce hospital length of stay. The purpose of this study was to identify relationships between patient physical characteristics and HDMTX clearance in the treatment of pediatric acute lymphoblastic leukemia (ALL). At our hospital, patients who have delayed methotrexate (MTX) clearance during a cycle of HDMTX receive an increased rate of hydration with subsequent cycles. This increase in hydration rate was examined for its potential to mitigate predictors of poor clearance and to prevent nephrotoxicity. Methods This study retrospectively examined the treatment records of 87 pediatric patients diagnosed with ALL who were treated on or according to Children's Oncology Group (COG) protocols AALL0232, AALL0434, AALL1131, and AALL1231. Each patient received four cycles of HDMTX (5 g/m2 over 24 hours) at two-week intervals. Patients received either 125 ml/m2/hour (standard) or 200 ml/m2/hour (delayed clearance protocol) hydration before, with, and after each infusion. MTX levels taken at 24-, 42-, and 48-hour time points were used as an indirect measure of drug clearance. Two-tailed inference for ordinary least squares regression and both heteroskedastic and paired two-tailed t-tests were performed to identify physical characteristics associated with delayed MTX clearance and the effects of hydration rate on MTX clearance, respectively. Results Patient age and body surface area (BSA) were found to have statistically significant (p<0.05) positive associations with the serum MTX levels at 24, 42, and 48 hours in cycle 1. Age and BSA were significant only at the 24-hour time point in cycles 2 and 4. Weight alone was not associated with delayed MTX clearance. For patients who had delayed MTX clearance once and thus received the delayed clearance protocol in subsequent cycles, increasing the hydration rate from 125 to 200 ml/m2/hour was associated with a statistically significant decrease in average MTX levels as well as serum creatinine levels at the 24-, 42-, and 48-hour time points. Once patients with delayed clearance received the 200 ml/m2/hour rate of hydration, the history of prior poor clearance lost its predictive value for serum MTX levels and delayed clearance. Conclusions These results suggest that patient age and BSA are significant predictors of MTX clearance if all patients receive the same rate of hydration. Age and BSA affect the distribution phase of MTX kinetics, with downstream effects in the elimination phase. Increased hydration mitigates the effects of these physical characteristics on the elimination phase kinetics by improving renal elimination of MTX, causing a loss of significance of age and BSA as predictors of MTX levels in subsequent cycles at the 42- and 48-hour time points, but with less effect at 24 hours. Thus, hyperhydration regimens prior to cycle 1 of HDMTX could be considered for patients presenting with risk factors of advanced age or high BSA to avoid delayed clearance.

Pointwise Methods to Measure Long-term Visual Field Progression in Glaucoma.

Importance: Rates of visual field (VF) progression vary among patients with glaucoma. Knowing the rate of progression of individual patients would allow appropriately aggressive therapy for patients with high rates of visual loss and protect those with low rates from unnecessary therapy. Objective: To compare 3 pointwise methods of estimating the rate of VF progression in glaucoma. Design, Setting, and Participants: This retrospective, observational cohort study included 729 eyes of 567 consecutive patients with primary open-angle glaucoma who had at least 6 reliable VFs and at least 3 years of follow-up. One hundred seventy-six patients (257 eyes) were treated at a tertiary glaucoma center; in addition, data were collected from 391 participants (472 eyes) in the Advanced Glaucoma Intervention Study. Data were collected from May 1988 to November 2004 and analyzed from October 2018 to February 2019. Exposures: Estimates of VF progression were measured with guided progression analysis (GPA), pointwise linear regression (PLR), and the glaucoma rate index (GRI). A subgroup analysis was performed in a subset of patients with likely VF progression and likely VF stability. Main Outcomes and Measures: Proportion of VF series detected as progressing, estimates of false-positive proportions, time to detect progression, and agreement among measures. Results: Among the 567 patients included in the analysis, mean (SD) age was 65.6 (9.7) years, 300 (52.9%) were female, and 295 (52.0%) were white. The median baseline mean deviation was -6.7 (interquartile range [IQR], -11.6 to -3.5) dB; the median follow-up time, 8.9 (IQR, 7.3-10.4) years. The proportion of eyes labeled as progressing was 27.7% according to the GPA, 33.5% according to the PLR, and 52.9% according to the GRI; pairwise differences for GRI vs PLR were 20% (95% CI, 17%-23%); for GRI vs GPA, 25% (95% CI, 22%-29%); and for PLR vs GPA, 6% (95% CI, 3%-9%; P < .001 for all comparisons, McNemar test). The shortest median time to progression was with the GRI (8.8 [IQR, 2.4-10.5 years), compared with the GPA and PLR (both >16 years). The hazard ratio of VF progression for GRI vs PLR (reference) was 11.3 (95% CI, 9.2-13.7); for GRI vs GPA (reference), 18.1 (95% CI, 14.5-22.6); and for PLR vs GPA (reference), 1.5 (95% CI, 1.3-1.9; P < .001 for all comparisons, Cox proportional hazards regression). These results held in the subgroup with likely progression; the proportions of progressing eyes were 73.7% (115 of 156) for GPA, 81.4% (127 of 156) for PLR, and 92.9% (145 of 156) for GRI. Pairwise difference for GRI vs PLR was 11.5% (95% CI, 7.4%-17.6%; P < .001, McNemar test); for GRI vs GPA, 19.2% (95% CI, 12.6%-26.4%; P < .001, McNemar test); and for PLR vs GPA, 7.7% (95% CI, 0.3%-15.7%; P = .08, McNemar test). Conclusions and Relevance: These results suggest GRI can detect long-term VF progression in glaucoma earlier than PLR or GPA. Validation with prospective designs may strengthen the generalizability and value of this method.

Population pharmacokinetic analysis of high-dose methotrexate in pediatric and adult oncology patients.

PURPOSE: High-dose methotrexate (HD-MTX) is widely used in pediatric and adult oncology treatment regimens. This study aimed to develop a population pharmacokinetic model to characterize pediatric and adult MTX exposure across various disease types and dosing regimens, and to evaluate exposure-toxicity relationships. METHODS: MTX pharmacokinetic data from pediatric and adult patients were collected. A population pharmacokinetic model was developed to determine the effects of age, liver function, renal function, and demographics on MTX disposition. The final model was used in Monte Carlo simulations to generate expected exposures for different dosing regimens. The association of toxicity, determined through chart review, and MTX area under the curve (AUC) was modeled using logistic regression. RESULTS: The analysis included 5116 MTX concentrations from 320 patients (135 adult, age 19-79 years; 185 pediatric, age 0.6-19 years). Estimated glomerular filtration rate (eGFR) and treatment cycle number were independent predictors of clearance (CL). CL varied 2.1-fold over the range of study eGFR values and increased 14% for treatment cycle numbers greater than 7. Higher MTX AUC was associated with higher risk of nephrotoxicity in adults, and neurotoxicity and hepatotoxicity in pediatrics. CONCLUSIONS: This study represents one of the most comprehensive evaluations of HD-MTX PK across a wide range of ages and disease types. After accounting for differences in renal function, age did not impact CL, although toxicity patterns differed by age. The model allows for early identification of patients with slowed MTX clearance and at higher risk of toxicity.

Outcomes of Combined Ahmed Glaucoma Valve and Trabeculectomy Revision With Adjunctive Antimetabolite.

PURPOSE: Evaluate the intraocular pressure (IOP) control in combined Ahmed Glaucoma Valve (AGV) implantation and trabeculectomy revision with adjunctive antimetabolite compared with AGV alone in patients who failed prior trabeculectomy. METHODS: Consecutive cases of combined AGV implantation and trabeculectomy revision with adjunctive antimetabolite (combined group) after January 3, 2014 were case-matched to cases of AGV implantation alone (AGV-alone group) before January 3, 2014. Primary outcome measures were qualified success with stratified IOP targets based on criteria: (A) IOP≤18 mm Hg and 20% IOP reduction; (B) IOP≤15 mm Hg and 25% IOP reduction; (C) IOP≤12 mm Hg and 30% IOP reduction, and hypertensive phase (HP) rate. Secondary outcome measures were 1-year postoperative IOP and number of glaucoma medications and complications. RESULTS: Twenty eyes (20 patients) in each group were included. Cumulative success for combined group and AGV-alone group at 1-year were: 74.0% versus 59.2% (criterion A, P=0.221), 61.9% versus 49.5% (B, P=0.183), and 54.2% versus 30.0% (C, P=0.033), respectively. In total, 50% (10 eyes) in the AGV-alone group developed HP compared with 15% (3 eyes) in the combined group (P=0.041). At 1-year follow-up, combined group had statistically significantly lower IOP than AGV-alone group (10.1±4.4, 13.3±2.9 mm Hg, respectively; P=0.028). There were no cases of bleb-related infections, choroidal effusion or hemorrhage, persistent hypotony, or hypotony maculopathy in either group. CONCLUSIONS: Combining AGV implantation with trabeculectomy revision with antimetabolite was associated with better tonometric success compared with AGV implantation alone in patients with previously failed trabeculectomy, particularly when a low IOP target (≤12 mm Hg) is required. Revised trabeculectomy may provide complimentary outflow facility to AGV.

Less Pulsatile Levodopa Therapy (6 Doses Daily) Is Associated with a Reduced Incidence of Dyskinesia.

OBJECTIVE: To evaluate whether less pulsatile levodopa therapy (LPT) can reduce the development of levodopa-induced dyskinesia (LID). METHODS: This is a retrospective cohort study of patients with Parkinson's disease at the movement disorders clinic of Medstar Washington Hospital Center. The study was not blinded or randomized. Patients were seen between August 2002 and August 2018. During these years, we treated patients with less pulsatile (6 doses daily) levodopa treatment to reduce LID. Occurrence of LID was recorded. RESULTS: Ninety-five patients with Parkinson's disease taking levodopa were divided into two groups: 1) patients who were initially managed on LPT or who switched from traditional therapy (TT) (n = 61) (mean disease duration: 7.7 ± 4.8 years, mean levodopa duration: 5.6 ± 4.5 years and mean observation time: 4.3 ± 3.4 years), and 2) patients on TT throughout the observation period or until they developed dyskinesia (n = 34) (mean disease duration: 8.3 ± 3.8 years, mean levodopa duration: 6.2 ± 4.2 years and mean observation time: 4.1 ± 3.4 years). Three of the 61 LPT patients developed dyskinesia during the observation period. One of the patients developed dyskinesia after being switched to pulsatile doses by another doctor. In the other two, dyskinesia was minimal. In contrast to this 4.9% cumulative incidence, dyskinesia occurred in 50% (17/34) of TT patients, an incidence similar to that in published data (p < 0.001). CONCLUSION: Less pulsatile levodopa with 6 daily doses was associated with a low incidence of LID. Further study of this method of treatment is warranted.

Severe Neuropathic Pain With Concomitant Administration of Vincristine and Posaconazole.

Vincristine is a chemotherapeutic agent with a potential toxicity of sensorimotor peripheral neuropathy. Patients receiving chemotherapy are in an immunocompromised state and may require antifungal agents. Triazole antifungals are known inhibitors of cytochrome P450 (CYP) enzymes. Vincristine is a known CYP3A4 and CYP3A5 substrate, and concomitant administration with fluconazole or voriconazole has been reported to increase vincristine toxicity and peripheral neuropathy, but there is limited literature on posaconazole in this regard. This 5-year-old girl with pre-B-cell acute lymphoblastic leukemia received vincristine while receiving posaconazole for a mucormycosis infection and developed unexpectedly severe peripheral neuropathy. After recovery, the child continued on mucormycosis prophylaxis with posaconazole with instructions to hold for 2 days before and on the day of vincristine administration. This case illustrates the potentiating effect that posaconazole had on vincristine-associated neurotoxicity, and our approach to mitigating that negative interaction.

A Phenotype of Primary Open-angle Glaucoma With Systemic Vasospasm.

PURPOSE: Primary open-angle glaucoma (POAG) patients constitute a heterogenous group. Identification of phenotypic subtypes among these patients may provide a deeper understanding of the disease and aid associations with genotypes. We describe a phenotype of POAG patients associated with a constellation of systemic disorders; patients with this phenotype seem to be vulnerable to optic nerve damage at low intraocular pressures. MATERIALS AND METHODS: In this retrospective study, we evaluated the medical records of active Jules Stein Eye Institute glaucoma patients from January 1996 to 2017 and included subjects with POAG, acquired pits of the optic nerve (APON), and at least one of the following: systolic blood pressure persistently ≤100 mm Hg, history of migraine headaches or migraine variant, and the Raynaud syndrome. RESULTS: Of 87 patients (125 eyes) with APON, 37 patients (55 eyes) met the study criteria. In total, 34 patients were female (92%). The median age at the time of diagnosis was 55 years. Nineteen patients (73%) had low systolic blood pressures, same number had Raynaud syndrome, and 25 (68%) had a history of migraine. CONCLUSIONS: We describe a POAG subtype with APON and systemic vascular instability, predominantly female in their sixth decade of life who demonstrate progressive glaucomatous visual field damage at low intraocular pressure. We suggest that this clinical picture represents an important phenotype of POAG, and that identification and further study of it will help guide diagnosis and development of individualized treatments.

Latanoprost-induced Skin Depigmentation.

Latanoprost, and other prostaglandin analogs, have been previously associated with increased pigmentary reactions on the periocular skin. Here, we present a patient with paradoxical depigmentation of periocular skin within 1 year of latanoprost use in both eyes. This report is the first to document such an association, and clinicians should be aware of this adverse effect and monitor for signs accordingly.

Expert Evaluation of Visual Field Decay in Glaucoma Correlates With the Fast Component of Visual Field Loss.

PURPOSE: To compare the assessment of serial visual fields (VFs) based on subjective expert evaluation with the fast and slow VF component rates determined with pointwise exponential regression (PER) and pointwise linear regression (PLR). MATERIALS AND METHODS: A total of 5272 VF examinations from 376 eyes diagnosed with open-angle glaucoma were included. Three glaucoma specialists assessed each VF qualitatively to evaluate progression status and the qualitative rate of progression. The rates of VF decay were determined with PER and PLR at each VF location, which were ranked according to the regression coefficient and partitioned into 2 groups (fast and slow). A mean rate for the fast and slow partitions was obtained based on the average of the regression coefficients in each partition. κ-values were used to measure the agreement among the experts and the PER and PLR algorithms. RESULTS: The average baseline VF mean deviation for the study sample was -6.6 (±5.9) dB. The agreement of the likelihood of progression among the dichotomized experts' score and PER was moderate (κ=0.41, P<0.01) and fair (κ=0.39, P<0.01) for PLR. The agreement of the likelihood of progression among the 3 dichotomized experts' scores was fair (κ=0.22, P<0.01). The agreement of the area of worsening among the dichotomized experts' score and PER and PLR were both moderate (κ=0.48, P<0.01; κ=0.46, P<0.01). The eyes flagged by experts as having "fast" progression rates had a higher average rates of decay for PER and PLR at -2.7 (±4.1) %/year and -0.8 (±1.2) dB/year; eyes flagged as "slow" had lower rates of decay at -0.3 (±1.5) %/year and -0.1 (±0.5) dB/year. CONCLUSIONS: Expert qualitative evaluation of field series for change and rate of change correlate more closely with the fast component than with the slow component of VF decay.

Warfarin Use and Increased Mortality in End-Stage Renal Disease.

BACKGROUND: Controversy exists regarding the benefits and risks of warfarin therapy in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. In this study, we assessed mortality and cardiovascular outcomes associated with warfarin treatment in patients with stages 3-5 CKD and ESRD admitted to the University of California-Irvine Medical Center. METHODS: In a retrospective matched cohort study, we identified 59 adult patients with stages 3-6 CKD initiated on warfarin during the period 2011-2013, and 144 patients with stages 3-6 CKD who had indications for anticoagulation therapy but were not initiated on warfarin. All-cause mortality risk associated with warfarin treatment was estimated using Cox proportional hazard regression analysis, and the risk of significant bleeding and major adverse cardiovascular events were analyzed with Poisson regression analysis. Adjustment models were used to account for age, gender, diabetes mellitus, use of antiplatelet agents, and preexisting cardiovascular disease, and stratified by pre-dialysis CKD stages 3-5 vs. ESRD. FINDINGS: During 5.8 years of follow-up, unadjusted mortality risk was higher in CKD patients on warfarin therapy (hazard ratio [HR] 2.34 with 95% CI 1.25-4.39; p < 0.01). After multivariate adjustment and stratification by CKD stage, the mortality risk remained significant in ESRD patients receiving warfarin (HR 6.62 with 95% CI 2.56-17.16; p < 0.001). Furthermore, adjusted rates of significant bleeding (incident rate ratio, IRR 3.57 with 95% CI 1.51-8.45; p < 0.01) and myocardial infarction (IRR 4.20 with 95% CI 1.78-9.91; p < 0.01) were higher among warfarin users. No differences in rates of ischemic or hemorrhagic strokes were found between the 2 groups. CONCLUSIONS: Warfarin use was associated with several-fold higher risk of death, bleeding, and myocardial infarction in dialysis patients. If additional studies suggest similar associations, the use of warfarin in dialysis patients warrants immediate reconsideration.

Vision retention in early versus delayed glaucoma surgical intervention in patients with Boston Keratoprosthesis type 1.

IMPORTANCE: The loss of vision following Boston Keratoprosthesis (BKPro) surgery due to glaucoma occurs at a high frequency as diagnosis and management of glaucoma after this procedure pose challenges. OBJECTIVE: To compare visual outcomes in patients undergoing Boston Keratoprosthesis surgery with and without prior or concurrent glaucoma surgery. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, observational cohort study of patients who underwent Boston Type I Keratoprosthesis surgery. 19 eyes of 18 patients who had undergone BKPro and met the inclusion criteria were identified. Twelve eyes received BKPro with prior or concurrent glaucoma surgery (Group 1), and seven eyes were identified undergoing BKPro surgery without prior or concurrent glaucoma surgery (Group 2). MAIN OUTCOMES AND MEASURES: Main outcome included best corrected visual acuity at each follow up. RESULTS: In Group 1, mean best corrected visual acuity (BCVA) within a year of BKPro surgery was 20/100 (range 20/40 to Count Fingers (CF); n = 12) and mean BCVA at 1 year from BKPro surgery was 20/115 (range 20/30 to CF; n = 12). 7 out of 12 patients retained or had improved BCVA at 1 year follow up after BKPro implantation, and 5 out of 12 patients had mild BCVA worsening. In Group 2, the mean BCVA within a year of BKPro surgery was 20/140 (ranging from 20/25 to hand motion vision (HM); n = 7) and mean BCVA at 1 year from BKPro surgery was Count Fingers (range 20/60 to Light Perception (LP); n = 6). 4 out of 6 patients lost significant vision at one year after BKPro. CONCLUSIONS AND RELEVANCE: BKPro patients with early glaucoma surgical intervention retained vision significantly better compared to patients with late or no intervention. Our preliminary findings support the recommendation for concurrent or pre-emptive glaucoma surgical intervention in patients undergoing BKPro implantation.

Population Health Management for Diabetes: Health Care System-Level Approaches for Improving Quality and Addressing Disparities.

PURPOSE OF REVIEW: Population care approaches for diabetes have the potential to improve the quality of care and decrease diabetes-related mortality and morbidity. Population care strategies are particularly relevant as accountable care organizations (ACOs), patient-centered medical homes (PCMH), and integrated delivery systems are increasingly focused on managing chronic disease care at the health system level. This review outlines the key elements of population care approaches for diabetes in the current health care environment. RECENT FINDINGS: Population care approaches proactively identify diabetes patients through disease registries and electronic health record data and utilize multidisciplinary care teams, personalized provider feedback, and decision support tools to target and care for patients at risk for poor outcomes. Existing evidence suggests that these strategies can improve care outcomes and potentially ameliorate existing race/ethnic disparities in health care. However, such strategies may be less effective for patients who are disengaged from the health care system. As population care for diabetes continues to evolve, future initiatives should consider ways to tailor population care to meet individual patient needs, while leveraging improvements in clinical information systems and care integration to optimally manage and prevent diabetes in the future.