Incident glaucoma and ocular hypertension after periocular and intravitreal steroid injections: a claims-based analysis.

BACKGROUND/AIMS: This study aims to determine the incidence and risk of open-angle glaucoma or ocular hypertension (OHT) following ocular steroid injections using healthcare claims data. METHODS: We retrospectively reviewed deidentified insurance claims data from the IBM MarketScan Database to identify 19 156 adult patients with no prior history of glaucoma who received ocular steroid injections between 2011 and 2020. Patient demographics and steroid treatment characteristics were collected. Postinjection glaucoma/OHT development was defined as a new diagnosis of glaucoma/OHT, initiation of glaucoma drops, and/or surgical or laser glaucoma treatment. Cox proportional hazards models were used to determine the risk of glaucoma/OHT development within 5 years after first steroid injection. RESULTS: Overall, 3932 (20.5%) patients were diagnosed with new glaucoma/OHT, 3345 (17.5%) started glaucoma drops and 435 (2.27%) required a laser or surgical glaucoma procedure within 5 years of first steroid injection. Triamcinolone subconjunctival injections were associated with a lower risk of glaucoma/OHT development than retrobulbar or intravitreal steroid injections (p<0.001, HR 0.68, 95% CI 0.59 to 0.79), whereas the 0.59 mg fluocinolone acetonide intravitreal implant had the highest risk of glaucoma/OHT development (p=0.001, HR 2.01, 95% CI 1.34 to 3.02). The risk of glaucoma/OHT development was also higher for patients receiving multiple steroid injections (p<0.001), with the largest increase in risk occurring after three total steroid injections. CONCLUSION: Patients receiving ocular steroid injections are at risk of developing glaucoma/OHT, even with no prior glaucoma/OHT diagnosis or treatment. Patients should be closely monitored for the development of glaucoma following ocular steroid injections, particularly in the setting of intravitreal and/or repeated steroid administration.

The Use of ChatGPT to Assist in Diagnosing Glaucoma Based on Clinical Case Reports.

INTRODUCTION: The purpose of this study was to evaluate the capabilities of large language models such as Chat Generative Pretrained Transformer (ChatGPT) to diagnose glaucoma based on specific clinical case descriptions with comparison to the performance of senior ophthalmology resident trainees. METHODS: We selected 11 cases with primary and secondary glaucoma from a publicly accessible online database of case reports. A total of four cases had primary glaucoma including open-angle, juvenile, normal-tension, and angle-closure glaucoma, while seven cases had secondary glaucoma including pseudo-exfoliation, pigment dispersion glaucoma, glaucomatocyclitic crisis, aphakic, neovascular, aqueous misdirection, and inflammatory glaucoma. We input the text of each case detail into ChatGPT and asked for provisional and differential diagnoses. We then presented the details of 11 cases to three senior ophthalmology residents and recorded their provisional and differential diagnoses. We finally evaluated the responses based on the correct diagnoses and evaluated agreements. RESULTS: The provisional diagnosis based on ChatGPT was correct in eight out of 11 (72.7%) cases and three ophthalmology residents were correct in six (54.5%), eight (72.7%), and eight (72.7%) cases, respectively. The agreement between ChatGPT and the first, second, and third ophthalmology residents were 9, 7, and 7, respectively. CONCLUSIONS: The accuracy of ChatGPT in diagnosing patients with primary and secondary glaucoma, using specific case examples, was similar or better than senior ophthalmology residents. With further development, ChatGPT may have the potential to be used in clinical care settings, such as primary care offices, for triaging and in eye care clinical practices to provide objective and quick diagnoses of patients with glaucoma.

Preclinical Pharmacokinetic Profile of Topical Ophthalmic and Intravenous Delivery of QLS-101, a Novel ATP-Sensitive Potassium Channel Opening Ocular Hypotensive Agent.

Purpose: To evaluate the pharmacokinetic profiles of the ocular hypotensive agent QLS-101, a novel ATP-sensitive potassium channel opening prodrug, and its active moiety levcromakalim, following topical ophthalmic and intravenous dosing of normotensive rabbits and dogs. Methods: Dutch belted rabbits (n = 85) and beagle dogs (n = 32) were dosed with QLS-101 (0.16-3.2 mg/eye/dose) or formulation buffer for 28 days. Pharmacokinetic profiles of QLS-101 and levcromakalim were evaluated in ocular tissues and blood by LC-MS/MS. Tolerability was assessed by clinical and ophthalmic examinations. Maximum systemic tolerated dose was evaluated in beagle dogs (n = 2) following intravenous bolus administrations of QLS-101 (0.05 to 5 mg/kg). Results: Plasma analysis following topical dosing of QLS-101 (0.8-3.2 mg/eye/dose) for 28 days indicated an elimination half-life (T1/2) of 5.50-8.82 h and a corresponding time (Tmax) range of 2-12 h in rabbits, and a T1/2 of 3.32-6.18 h with a Tmax range of 1-2 h in dogs. Maximum tissue concentration (Cmax) values ranged from 54.8-540 (day 1) to 50.5-777 ng/mL (day 28) in rabbits, and 36.5-166 (day 1) to 47.0-147 ng/mL (day 28) in dogs. Levcromakalim plasma T1/2 and Tmax were similar to QLS-101, while Cmax was consistently lower. Topical ophthalmic delivery of QLS-101 was well tolerated in both species, with sporadic mild ocular hyperemia noted in the group treated with the highest concentration (3.2 mg/eye/dose). Following topical ophthalmic dosing, QLS-101 and levcromakalim were found primarily in the cornea, sclera, and conjunctiva. Maximum tolerated dose was determined to be 3 mg/kg. Conclusions: QLS-101 was converted to its active moiety levcromakalim and showed characteristic absorption, distribution, and safety profiles of a well-tolerated prodrug.

Abdominal aortic aneurysm and exfoliation syndrome in Utah.

PURPOSE: A pilot study of electronic medical records (EMR) in Utah was undertaken to investigate exfoliation syndrome and exfoliation glaucoma (XFS/XFG) in abdominal aortic aneurysm (AAA) patients. In a subsequent retrospective cohort study of Utah XFS/XFG patients and population controls, the risk of AAA was examined. METHODS: EMR of a statewide healthcare population were obtained from the Utah Population Database (UPDB) which links decades of medical records with Utah demographic and vital records data. In a pilot study, 7167 patients ages ≥40 years identified with AAA diagnosed from 1996 to 2015, based on International Classification of Diseases (ICD) version 9/10 codes, were included. A univariable hazards model was used to determine the risk of XFS/XFG in AAA patients. An XFS/XFG outcome based on ICD 9/10 codes in AAA patients and in 5:1 sex- and age-matched non-AAA controls was determined. A retrospective cohort of 3412 XFS/XFG patients ages ≥50 years diagnosed from 1996 to 2020 and 10 227 3:1 sex- and age-matched controls who underwent ≥1 dilated eye examination(s) were recently identified and updated diagnoses of AAA were obtained. Multivariable logistic regression was used to estimate AAA risk in XFS/XFG patients compared with controls. In a subset of XFS/XFG patients, chart reviews were conducted to confirm clinically diagnosed AAA. RESULTS: In the AAA pilot, 20 patients (0.3%) and 118 controls (0.3%) developed XFS/XFG, respectively. We observed no increased risk of XFS/XFG in AAA patients compared with non-AAA-matched controls (HR = 0.99, 95% CI 0.6-1.6). Among XFS/XFG study patients and controls, 122 patients (3.6%) and 376 controls (3.7%) had an AAA diagnosis. We likewise observed no increased risk of AAA in XFS/XFG patients (OR = 0.97, 95% CI 0.8-1.2). In 14 XFS/XFG patients with an ICD 9/10 diagnosis of AAA who underwent chart review, a clinical diagnosis of AAA was confirmed in 9 patients (64.3%). CONCLUSION: Our findings do not support an association between AAA and XFS/XFG.

Abdominal aortic aneurysm and exfoliation syndrome: A literature review comparing single site findings.

Several studies have suggested a possible relationship between exfoliation syndrome (XFS) and abdominal aortic aneurysm (AAA). A systematic literature review was undertaken to investigate this potential association. The systematic literature review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clear definitions of XFS and AAA were used to identify eligible studies via an unrestricted search of the PubMed interface from 1979 to October 31st, 2021. After review, 876 citations were gathered and evaluated for inclusion, from which 22 articles were included. Of these 22, 16 were excluded because they did not assess the relationship between AAA and XFS or provide primary data. Ultimately, six studies were included in this literature review. Half of the studies explored AAA prevalence in a population with or without XFS, and the other half explored the opposite. Three studies supported XFS as a risk factor for the development of AAA, and the other three found this relationship to be inconclusive. This systematic review revealed inconsistent results regarding an association between AAA and XFS. A large database study including XFS and AAA patients would be useful in further determining if an association does in fact exist.

Exfoliation Syndrome and Exfoliation Glaucoma in the Navajo Nation.

(1) Background: Exfoliation syndrome (XFS) is a common cause of secondary open angle glaucoma. In 1971, Faulkner et al. estimated the prevalence of XFS among 50 Navajo Nation residents as 38%. Given that XFS can cause irreversible blindness secondary to glaucoma (XFG), this study aims to identify the current prevalence of XFS among Navajo Nation residents within the Four Corners region of the U.S. (2) Methods: A retrospective chart review was conducted from 2016 to 2021 for patients aged 18 and older. All patients with XFS or XFG diagnosed by slit lamp exam were identified through chart review. (3) Results: Of the 1152 patient charts available for review, eight patients (11 eyes) were diagnosed with XFS with three patients (4 eyes) demonstrating concomitant XFG. Within this XFS population, 50% of the patients identified as male, with a mean age of 73 years. The overall prevalence of XFS was 0.7% and the overall prevalence of XFG was found to be 0.26%. The rate of XFG among patients with XFS was 37.5%. (4) Conclusion: Compared to Faulkner's study of Navajo Nation residents in 1971, our findings show a considerably lower prevalence of XFS at 0.7%. We present the largest study to date of XFS among this population.

The utility of home tonometry for peri-interventional decision-making in glaucoma surgery: Case series.

Purpose: To describe twelve cases in which home intraocular pressure (IOP) monitoring complimented clinical decision-making in glaucoma management. Observations: Home IOP monitoring elucidated peaks and amplitudes of variation that were not captured by in-clinic IOP measurements during the pre- or post-interventional period. Conclusions & Importance: Home monitoring can establish pre-treatment IOP patterns that are not evident during in-clinic measurements. Home monitoring can also demonstrate response to treatment more quickly than in-clinic monitoring, and provide more information about nyctohemoral fluctuations than is ascertained by in-clinic tonometry.

Head and Neck Region Dermatological Ultraviolet-Related Cancers are Associated with Exfoliation Syndrome in a Clinic-Based Population.

OBJECTIVE: We assessed the relationship between ultraviolet (UV)-associated dermatological carcinomas (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) and exfoliation syndrome (XFS) or exfoliation glaucoma (XFG). DESIGN: Case-control study. PARTICIPANTS: Between 2019 and 2021, 321 participants and control subjects (XFS or XFG = 98; primary open-angle glaucoma [POAG] = 117; controls = 106; ages 50-90 years) were recruited. METHODS: A cross-sectional survey assessing medical history, maximum known intraocular pressure, cup-to-disc ratio, Humphrey visual field 24-2, the propensity to tan or burn in early life, history of BCC or SCC, and XFS or XFG diagnosis. The multivariable models adjusted for age, sex, medical history, eye color, hair color, and likeliness of tanning versus burning at a young age. MAIN OUTCOME MEASURES: History of diagnosed XFS or XFG. RESULTS: Any history of BCC or SCC in the head and neck region was associated with a 2-fold higher risk of having XFS or XFG versus having POAG or being a control subject (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.04-3.89) in a multivariable-adjusted analysis. We observed a dose-response association in which the chance of having XFS or XFG increased by 67% per head and neck BCC or SCC occurrence (OR, 1.67; 95% CI, 1.09-2.56). When we excluded POAG participants, head and neck BCC or SCC was associated with a 2.8-fold higher risk of XFS or XFG (OR, 2.80; 95% CI, 1.12-7.02), and each additional occurrence had a 2-fold higher risk of XFS or XFG (OR, 1.97; 95% CI, 1.09-3.58). The association between head and neck region BCC or SCC and POAG compared with the control subjects was null (OR, 1.42; 95% CI, 0.58-3.48). With BCC or SCC located anywhere on the body, there was a nonsignificantly higher risk of having XFS or XFG compared with having POAG or being a control subject (OR, 1.65; 95% CI, 0.88-3.09). CONCLUSIONS: Head and neck region BCCs or SCCs are associated with a higher risk of having XFS or XFG. These findings support prior evidence that head and neck UV exposure may be a risk factor for XFS.

Ocular Hypotensive Properties and Biochemical Profile of QLS-101, a Novel ATP-Sensitive Potassium (KATP) Channel Opening Prodrug.

Purpose: To characterize the ocular hypotensive and pharmacological properties of QLS-101, a novel ATP-sensitive potassium (KATP) channel opening prodrug. Methods: Ocular hypotensive properties of QLS-101 were evaluated by measuring IOP with a handheld rebound tonometer after daily topical ocular instillation of 0.2% (n = 5) or 0.4% QLS-101 (n = 10) in C57BL/6J mice. KATP channel specificity was characterized in HEK-293 cells stably expressing human Kir6.2/SUR2B subunits and assessed for off-target interactions using a receptor binding screen. Conversion of QLS-101 prodrug to its active moiety, levcromakalim, was evaluated in vitro using human ocular tissues and plasma samples and after incubation with human phosphatase enzymes (2.0 nM-1.0 µM). Results: C57BL/6J mice treated once daily with 0.2% QLS-101 exhibited significant (P < 0.01) IOP reductions of 2.1 ± 0.4 mmHg after five days; however, a daily attenuation of the effect was noted by 23h post-dose. By comparison, treatment with 0.4% QLS-101 lowered IOP by 4.8 ± 0.7 mm Hg (P < 0.0001) which was sustained for 24 hours. Unlike levcromakalim, QLS-101 failed to induce KATP channel activity in HEK-Kir6.2/SUR2B cells consistent with its development as a prodrug. No off-target receptor effects were detected with either compound. In vitro ocular tissue conversion of QLS-101 prodrug was identified in human iris, ciliary body, trabecular meshwork, and sclera. Alkaline phosphatase was found to convert QLS-101 (mean Km = 630 µM, kcat = 15 min-1) to levcromakalim. Conclusions: QLS-101 is a novel KATP channel opening prodrug that when converted to levcromakalim shows 24-hour IOP lowering after once-daily topical ocular administration.

Exfoliation Syndrome in Baja Verapaz Guatemala: A Cross-Sectional Study and Review of the Literature.

There are little epidemiologic data on exfoliation syndrome (XFS) or exfoliation glaucoma (XFG) in Guatemala, especially in the underserved Baja Verapaz region. This observational study assessing XFS/XFG and demographic factors of this region aims to better understand unique exogenous and endogenous risk factors associated with XFS/XFG in Guatemala. During Moran Eye Center's global outreach medical eye camps from 2016-2017, 181 patients age 15 years and older presented for complete eye exams. These individuals were screened for eye disease and evaluated for possible surgical interventions that could occur during the camps to improve eyesight. During the dilated exams, XFS was noted as missing or present. Of those 181, 10 had insufficient data and 18 lacked a definitive diagnosis of XFS or XFG, resulting in 153 evaluable patients; 46 XFS and 9 XFG were identified. Age, gender, hometown, ancestry (languages spoken by parents and grandparents), past medical history, family medical history, and occupational data (only 2017 trip) were obtained for each patient. The most common occupations of these individuals were farming and housekeeping. Higher rates of XFS/XFG were noted in individuals of rural compared to urban settings and Mayan speaking people compared with Spanish speakers. Based on this subset of patients, with various ocular pathologies being evaluated during medical eye outreach camps, the prevalence of XFS/XFG appeared to be 36%, a high prevalence compared to other world populations. Location and higher altitude, along with a farming occupation, may contribute to XFS development and subsequent progression to XFG. To our knowledge, this is the largest study looking at the epidemiology of XFS/XFG in the Baja Verapaz region of Guatemala for those over the age of 15 years seeking eye exams and interventions.

Risk of atrial fibrillation is increased in patients with exfoliation syndrome: the Utah project on exfoliation syndrome (UPEXS).

PURPOSE: Exfoliation syndrome, a systemic disorder with ocular manifestations, is associated with lysyl oxidase-like gene variants. Along with transforming growth factor beta-1, lysyl oxidase-like 1 is a key enzyme in stabilizing extracellular matrix and remodelling collagen/elastin. Given the role that transforming growth factor beta-1, lysyl oxidase-like gene variants and fibrosis play in atrial fibrillation, an association with exfoliation syndrome was investigated. METHODS: An exfoliation syndrome cohort of 2803 patients and an atrial fibrillation cohort of 43 694 patients aged 60-90 years at disease onset were identified using the Utah Population Database (1996-2015). Conditional logistic regression was used to estimate risk of atrial fibrillation in exfoliation syndrome patients and risk of exfoliation syndrome in atrial fibrillation patients compared with respective 5:1 sex- and age-matched control cohorts. Kaplan-Meier curves were examined to assess survival in atrial fibrillation patients by exfoliation syndrome status. RESULTS: Exfoliation syndrome patients had a 21% greater risk (95% CI 1.06-1.37; p < 0.0001) of atrial fibrillation. This was more pronounced in exfoliation syndrome patients with no hypertension history, who exhibited a 52% increased atrial fibrillation risk (95% CI 1.27-1.82; p < 0.0001). Atrial fibrillation patients exhibited a 20% increased risk of exfoliation syndrome (95% CI 1.07-1.35; p = 0.003), while atrial fibrillation patients with no hypertension had a 72% higher exfoliation risk (95% CI 1.45-2.03; p < 0.0001). Atrial fibrillation patients with exfoliation syndrome had a higher estimated probability of survival (alive at study end or at last follow-up) compared with patients with no exfoliation history (p < 0.0001, log-rank test). CONCLUSIONS: Exfoliation syndrome patients were at a statistically significant increased risk of atrial fibrillation. Similarly, atrial fibrillation patients were at a statistically significant higher risk of exfoliation, particularly when hypertension history was absent.

Reversible HER2 antibody-drug conjugate-induced ocular toxicity.

PURPOSE: To report 3 cases of reversible epitheliopathy induced by A166-a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. METHODS: Advanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. RESULTS: After ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. CONCLUSION: A166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.

Summary of Utah Project on Exfoliation Syndrome (UPEXS): using a large database to identify systemic comorbidities.

The purpose of the Utah Project on Exfoliation Syndrome (UPEXS) is to identify associations between exfoliation syndrome (XFS) and other diseases that share the commonality of abnormalities in elastin and Lysyl Oxidase-Like 1 gene regulation. The UPEXS is unique because it uses the Utah Population Database, which is linked to the Utah genealogy, that contains a compilation of large pedigrees of most families in the state of Utah that go back multiple generations (3 to ≥11). The health and medical records of these family members are linked to vital records and can be used effectively in studies focused on genetic disorders like XFS, where familial clustering of a disorder is a trend. There is increasing evidence that patients with XFS have a higher risk of certain systemic disorders that reflect the systemic tissue abnormalities of XFS. Epidemiological studies focused on patients with XFS have shown that there is an increased risk of these individuals developing other pathologies that have abnormalities in extracellular matrix metabolism and repair. UPEXS has focused on suspected comorbidities that involve abnormalities in elastin maintenance, a protein that plays a role in the makeup of the extracellular matrix. In this paper, the results from the analysis of chronic obstructive pulmonary disease, inguinal hernias, pelvic organ prolapse, obstructive sleep apnoea and atrial fibrillation are summarised along with the utility of using such a large dataset.

Intraocular Pressure Elevation Following Intravitreal Anti-VEGF Injections: Short- and Long-term Considerations.

Published studies agree that transient intraocular pressure (IOP) spikes are common after intravitreal injections of anti-vascular endothelial growth factor agents. Currently, there is no standard of care guiding if and when to prevent these IOP spikes. Furthermore, there are challenges in determining the impact of postinjection IOP elevation on the health of the retinal ganglion cells, particularly given the often-existing comorbidities of retinal and glaucoma pathology. This review highlights the current literature regarding both acute and chronic postinjection IOP elevations and discusses management of postinjection IOP elevation, especially in patients at high risk for glaucomatous damage.

Association between Obstructive Sleep Apnea and Exfoliation Syndrome: The Utah Project on Exfoliation Syndrome.

PURPOSE: Exfoliation syndrome (XFS), the most common recognizable cause of open-angle glaucoma worldwide, is a systemic disorder with genetic predisposition due to variations in lysyl oxidase-like 1 (LOXL1) function, leading to altered elastin matrices in ocular and systemic tissues. Obstructive sleep apnea (OSA) is a highly prevalent disorder also involving elastic tissue dysfunction and is associated with glaucoma. Because of the similarities between the disorders, we sought to uncover any relationship in the prevalence of these diagnoses. DESIGN: Case-control, retrospective cohort study. PARTICIPANTS: A cohort of 81 735 patients diagnosed with OSA at ages 50 to 90 years was identified from medical records from 1996 to 2017 in the Utah Population Database. Case subjects were matched to random controls on sex and birth year in a 4:1 ratio. METHODS: International Classification of Diseases, Ninth Revision (ICD-9) codes or their Tenth Revision equivalent were used to define a diagnosis of OSA (ICD-9 327.23) and a diagnosis of XFS (ICD-9 365.52 and 366.11). Conditional logistic regression odds ratios (ORs) accounting for individual matching on sex and birth year were used to estimate the risk of XFS in patients with OSA. Models included adjustment for race, obesity, tobacco use, hypertension (HTN), atrial fibrillation (AF), and chronic obstructive pulmonary disease (COPD). MAIN OUTCOME MEASURE: Whether patients with OSA have an increased risk of diagnosis of XFS compared with controls without OSA. RESULTS: There was an increased risk of an XFS diagnosis in patients with OSA compared with non-OSA controls (OR, 1.27; 95% confidence interval [CI], 1.02-1.59; P = 0.03). In a stratification of patients by HTN diagnosis history, patients with OSA and HTN exhibited an increased risk of XFS compared with non-OSA controls with HTN (OR, 2.67; 95% CI, 2.06-3.46; P < 0.0001). CONCLUSIONS: Patients with OSA may be at an increased risk of XFS compared with patients without OSA, particularly in patients with a history of HTN.

Special Commentary: Using Clinical Decision Support Systems to Bring Predictive Models to the Glaucoma Clinic.

Advances in the field of predictive modeling using artificial intelligence and machine learning have the potential to improve clinical care and outcomes, but only if the results of these models are presented appropriately to clinicians at the time they make decisions for individual patients. Clinical decision support (CDS) systems could be used to accomplish this. Modern CDS systems are computer-based tools designed to improve clinician decision making for individual patients. However, not all CDS systems are effective. Four principles that have been shown in other medical fields to be important for successful CDS system implementation are (1) integration into clinician workflow, (2) user-centered interface design, (3) evaluation of CDS systems and rules, and (4) standards-based development so the tools can be deployed across health systems.