How Medication Adherence Affects Disease Management in Veterans with Glaucoma: Lessons Learned from a Clinical Trial.

INTRODUCTION: We conducted a secondary, real-world clinical assessment of a randomized controlled trial to determine how a glaucoma medication adherence intervention impacted the clinical outcomes of participants at 12 months post-randomization. Participants included veterans at a VA eye clinic with medically treated glaucoma who reported poor adherence and their companions, if applicable. METHODS: The treatment group received a glaucoma education session with drop administration instruction and virtual reminders from a "smart bottle" (AdhereTech) for their eye drops. The control group received a general eye health class and the smart bottle with the reminder function turned off. Medical chart extraction determined if participants in each group experienced visual field progression, additional glaucoma medications, or a recommendation for surgery or laser due to inadequate intraocular pressure control over the 12 months following randomization. The main outcome measure was disease progression, defined as visual field progression or escalation of glaucoma therapy, in the 12 months following randomization. RESULTS: Thirty-six versus 32% of the intervention (n = 100) versus control (n = 100) groups, respectively, experienced disease intensification. There was no difference between the intervention and control groups in terms of intensification (intervention vs. control group odds ratio: 1.20; 95% confidence interval: [0.67, 2.15]), including when age, race, and disease severity were accounted for in the logistic regression model. Those whose study dates included time during the COVID-19 pandemic were evenly distributed between groups. CONCLUSIONS: A multifaceted intervention that improved medication adherence for glaucoma for 6 months did not affect the clinical outcomes measured at 12 months post-randomization. Twelve months may not be long enough to see the clinical effect of this intervention or more than 6 months of intervention are needed.

Concurrent Identification and Characterization of Protein Structure and Continuous Internal Dynamics with REDCRAFT.

Internal dynamics of proteins can play a critical role in the biological function of some proteins. Several well documented instances have been reported such as MBP, DHFR, hTS, DGCR8, and NSP1 of the SARS-CoV family of viruses. Despite the importance of internal dynamics of proteins, there currently are very few approaches that allow for meaningful separation of internal dynamics from structural aspects using experimental data. Here we present a computational approach named REDCRAFT that allows for concurrent characterization of protein structure and dynamics. Here, we have subjected DHFR (PDB-ID 1RX2), a 159-residue protein, to a fictitious, mixed mode model of internal dynamics. In this simulation, DHFR was segmented into 7 regions where 4 of the fragments were fixed with respect to each other, two regions underwent rigid-body dynamics, and one region experienced uncorrelated and melting event. The two dynamical and rigid-body segments experienced an average orientational modification of 7° and 12° respectively. Observable RDC data for backbone C'-N, N-HN, and C'-HN were generated from 102 uniformly sampled frames that described the molecular trajectory. The structure calculation of DHFR with REDCRAFT by using traditional Ramachandran restraint produced a structure with 29 Å of structural difference measured over the backbone atoms (bb-rmsd) over the entire length of the protein and an average bb-rmsd of more than 4.7 Å over each of the dynamical fragments. The same exercise repeated with context-specific dihedral restraints generated by PDBMine produced a structure with bb-rmsd of 21 Å over the entire length of the protein but with bb-rmsd of less than 3 Å over each of the fragments. Finally, utilization of the Dynamic Profile generated by REDCRAFT allowed for the identification of different dynamical regions of the protein and the recovery of individual fragments with bb-rmsd of less than 1 Å. Following the recovery of the fragments, our assembly procedure of domains (larger segments consisting of multiple fragments with a common dynamical profile) correctly assembled the four fragments that are rigid with respect to each other, categorized the two domains that underwent rigid-body dynamics, and identified one dynamical region for which no conserved structure could be defined. In conclusion, our approach was successful in identifying the dynamical domains, recovery of structure where it is meaningful, and relative assembly of the domains when possible.

Improved Glaucoma Medication Adherence in a Randomized Controlled Trial.

PURPOSE: To test the effectiveness of an intervention designed to improve glaucoma medication adherence. DESIGN: Randomized, controlled trial at a Veterans Affairs (VA) eye clinic. PARTICIPANTS: Veterans with medically treated glaucoma who reported poor adherence and their companions if applicable. METHODS: Participants, and their companions if applicable, were randomized to receive an intervention to improve medication adherence that included glaucoma education, personalized disease management suggestions, and a reminder aid, or the control arm that received education regarding general eye health. MAIN OUTCOME MEASURES: The average proportion of prescribed glaucoma medication doses taken on schedule over the 6 months after randomization according to an electronic monitor between participants in the 2 arms. RESULTS: The mean proportion of prescribed doses taken on schedule was higher in the intervention group compared with controls (0.85 vs. 0.62, P < 0.0001). The difference in proportions between the 2 groups did not vary in regressions models adjusted for companion status, frequency of dosing, and race. The longitudinal model indicated that the intervention group had significantly higher adherence during the first month after randomization and continued to stay higher through 6 months (month by treatment interaction, P = 0.003). CONCLUSIONS: A multifaceted intervention can help improve glaucoma medication adherence.

Estimated Glomerular Filtration Rate Variability in Patients With Heart Failure and Chronic Kidney Disease.

BACKGROUND: Greater variability in the estimated glomerular filtration rate (eGFR) is associated with higher mortality in patients with chronic kidney disease (CKD). Heart failure (HF) is common in CKD and may increase variability through changes in hemodynamic and volume regulation. We sought to determine if patients with vs without HF have higher kidney function variability in CKD, and to define the association with mortality. METHODS AND RESULTS: Patients undergoing coronary angiography from 2003 to 2013 with an eGFR of less than 60 mL/min/1.73 m2 were evaluated from the Duke Databank for Cardiovascular Disease. Variability in the eGFR, measured as the coefficient of variation (CV) of residuals from the regression of eGFR vs time, was calculated spanning 3 months to 2 years after catheterization. Mortality was assessed 2 to 7 years after catheterization. Patients were grouped into 3 HF phenotypes: HF with reduced ejection fraction, HF with preserved ejection, and no HF. Regression was used to evaluate associations between HF phenotypes and variability in the eGFR and between variability in the eGFR and mortality rate with stratification by HF phenotype. Among 3767 participants, the median eGFR at baseline was 45 mL/min/1.73 m2 (interquartile range 33-53 mL/min/1.73 m2), and longitudinal measures of eGFR over 21 months had within-patient residual variability (CV) of 14% (9%-20%). In adjusted analyses, variability in the eGFR was greater in those with HF with preserved ejection (n = 695, CV difference 0.98%, 95% confidence interval 0.14%-1.81%) or HF with reduced ejection fraction (n = 800, CV difference 2.51%, 95% confidence interval 1.66%-3.37%) relative to no HF (n = 2272). In 3068 participants eligible for mortality analysis, the presence of HF and greater variability in the eGFR were each associated independently with higher mortality, but there was no evidence of interaction between variability in the eGFR and any HF phenotype (all P for interaction ≥.49). CONCLUSIONS: Variability in the eGFR is greater in patients with HF and associated with mortality. Prediction algorithms and classification schemes should consider not only static, but also dynamic eGFR variability in HF and CKD prognostication.

Randomized controlled trial of an education-based intervention to improve medication adherence: Design considerations in the medication adherence in glaucoma to improve care study.

BACKGROUND: Glaucoma treatment requires patients to follow daily, often times complex, eye drop regimens, but adherence is poor for many patients, putting them at risk for irreversible vision loss. A comprehensive approach is needed to address the challenges in the self-management of glaucoma. The purpose of this study is to improve glaucoma medication adherence in Veterans with medically treated glaucoma using an education-based intervention. METHODS/DESIGN: This study is a single-site randomized controlled trial enrolling 200 Veterans and their companions, if companions are involved in their care. It has two arms: an intervention group and a control group. Participants in the intervention group receive an educational session with a non-physician interventionist and are provided with an AdhereTech smart bottle with the reminder functions activated. The control group is designed as an attention control such that they have a session on general eye health and are provided with a smart bottle but without the reminder functions activated. The primary outcome is the proportion of prescribed doses taken on schedule over 6 months following randomization according to the smart bottle. Secondary outcomes include intensification of glaucoma treatment, cost of intervention delivery, and cost-effectiveness of the intervention over 12 months. DISCUSSION: The education-based intervention that we are testing is comprehensive in scope, to encompass a variety of barriers to adherence that glaucoma patients encounter, but personalized to address issues facing individual patients. Particular attention was given to feasibility in the real-world setting, as the high throughput of patients and lack of reimbursement for educational encounters in ophthalmology would limit implementation of a resource-intensive intervention.

The Association of an Upper Extremity Functional Survey and Glaucoma Medication Administration Success.

Purpose/Aim: To determine if an upper extremity functional survey may identify which patients will have eye drop administration difficulty. Materials and Methods: Participants with glaucoma treated at a Veterans Affairs Eye Clinic who did not self-report 100% medication adherence were enrolled in a cross-sectional study. Participants were scored on their observed ability to place a drop into the eye (accuracy) and express no more than one drop from the bottle (efficiency). Successful execution of both of these conditions was defined as good drop technique. Participants also completed the QuickDASH, a validated upper extremity functional survey, with higher scores indicating worse disability. We hypothesized participants with lower QuickDASH scores would have an increased probability of observed success with drop administration measures. Diagnoses of upper extremity co-morbidities were abstracted from participants' medical records and clustered into diagnostic groups of either neurologic or musculoskeletal etiologies. Results: When observed, 80 of 94 participants displayed successful accuracy, 58 of 94 participants displayed successful efficiency, and 50 of 94 participants displayed good drop technique. Accuracy with eye drop performance was not related to QuickDASH scores (odds ratio (OR) [probability of successful administration per 10-point decrease in QuickDASH score]: 1.14, 95% CI: 0.89-1.45, p = .29). Success with drop administration efficiency was strongly associated with QuickDASH score (OR: 1.27, 95% CI: 1.04-1.54, p = .02), as was good drop technique (OR: 1.28, 95% CI: 1.05-1.56, p = .01), with lower (better) QuickDASH scores associated with better drop technique. There were no associations between upper extremity neurologic or musculoskeletal co-morbidities and observed good drop technique. The presence of either a neurologic or musculoskeletal upper extremity co-morbidity in a participant's medical record was associated with a higher QuickDASH score. Conclusions: The QuickDASH survey may identify patients with eye drop administration difficulties so this population receives focused drop technique education and management strategies. Abbreviations: CPRS: Computerized Patient Records System; MSK: musculoskeletal; UE: upper extremity; VA: Veterans Affairs.

Medical Management of Heart Failure With Reduced Ejection Fraction in Patients With Advanced Renal Disease.

Large randomized clinical trials (RCT) supporting guidelines for the management of heart failure with reduced ejection fraction (HFrEF) have typically excluded patients with advanced chronic kidney disease (CKD). Patients with concomitant advanced CKD and HFrEF experience poor cardiovascular outcomes and mortality relative to either disease in isolation and have been shown to consistently receive lower rates of HFrEF guideline-directed medical therapy (GDMT). This review evaluated recent evidence for the use of GDMT in patients with HFrEF and advanced CKD approaching dialysis from RCTs and observational cohorts. The authors also discuss the limitations and challenges inherent in the evidence for GDMT in this population, and offer guidance to clinicians for proper clinical use and future research directions.

The Relationship of Self-Report and Medication Possession With Glaucoma Medication Administration Success.

PURPOSE: Many glaucoma eye drop users cannot successfully self-administer drops, and observing patients' drop technique can be time-consuming. We sought to examine the association of patient self-reported efficacy of eye drop technique and medication possession data as potential surrogate measures for actual drop administration success. PATIENTS AND METHODS: In total, 137 adults with medically treated glaucoma were enrolled from a University eye clinic (n=54) or a Veteran Affairs (VA) eye clinic (n=83). All participants were asked, "How confident are you that you can get the medication into your eye?" Medication possession ratio (MPR), defined as the amount of eye drop available divided by the amount prescribed, was calculated for VA study site participants for 6 months. The main outcome was the correct eye drop technique, defined as the ability to get drops into the eye and to put only 1 drop into the eye at a time. RESULTS: Among 117 participants who were "very confident" they could administer eye drops correctly, 95 participants (81%) displayed the correct drop technique. Of those who reported being less than "very confident" (n=18), 11 participants (61%) displayed correct drop technique (the Fisher exact test, P=0.07). For the VA sample, 20 participants with MPR<1.2, 20 participants with MPR=1.2 to 1.8, and 23 participants with MPR>1.8 displayed correct eye drop technique (the Fisher exact test, P=0.18). CONCLUSIONS: Self-reported administration success and MPR are not strongly associated with successful eye drop administration. Thus, direct observation of patients' drop instillation may be the most effective means of determining patient efficacy.

Pulmonary Th17 Antifungal Immunity Is Regulated by the Gut Microbiome.

Commensal microbiota are critical for the development of local immune responses. In this article, we show that gut microbiota can regulate CD4 T cell polarization during pulmonary fungal infections. Vancomycin drinking water significantly decreased lung Th17 cell numbers during acute infection, demonstrating that Gram-positive commensals contribute to systemic inflammation. We next tested a role for RegIIIγ, an IL-22-inducible antimicrobial protein with specificity for Gram-positive bacteria. Following infection, increased accumulation of Th17 cells in the lungs of RegIIIγ(-/-) and Il22(-/-) mice was associated with intestinal segmented filamentous bacteria (SFB) colonization. Although gastrointestinal delivery of rRegIIIγ decreased lung inflammatory gene expression and protected Il22(-/-) mice from weight loss during infection, it had no direct effect on SFB colonization, fungal clearance, or lung Th17 immunity. We further show that vancomycin only decreased lung IL-17 production in mice colonized with SFB. To determine the link between gut microbiota and lung immunity, serum-transfer experiments revealed that IL-1R ligands increase the accumulation of lung Th17 cells. These data suggest that intestinal microbiota, including SFB, can regulate pulmonary adaptive immune responses.