Multiple Modes of Zinc Binding to Histatin 5 Revealed by Buffer-Independent Thermodynamics.

Histatin 5 (Hist5) is an antimicrobial peptide found in human saliva as part of the innate immune system. Hist5 can bind several metal ions in vitro, and Zn2+ has been shown to function as an inhibitory switch to regulate the peptide's biological activity against the opportunistic fungal pathogen Candida albicans in cell culture. Here, we studied Zn2+ binding to Hist5 at four temperatures from 15 to 37 °C using isothermal titration calorimetry to obtain thermodynamic parameters that were corrected for competing buffer effects. Hist5 bound Zn2+ with a buffer-dependent association constant of ∼105 M-1 and a buffer-independent association constant of ∼6 × 106 M-1 at pH 7.4 and at all temperatures tested. Zn2+ binding was both enthalpically and entropically favorable, with larger entropic contributions at 15 °C and larger enthalpic contributions at 37 °C. Additionally, the Zn:Hist5 binding stoichiometry increased from 1:1 to 2:1 as temperature increased. The enthalpy-entropy compensation and the variable stoichiometry lead us to propose a model in which the Zn-Hist5 complex exists in an equilibrium between two distinct binding modes with different Zn:Hist5 stoichiometries. The in-depth thermodynamic analysis presented herein may help illuminate the biophysical basis for Zn-dependent changes in the antifungal activity of Hist5.

Reductive Amination Revisited: Reduction of Aldimines with Trichlorosilane Catalyzed by Dimethylformamide─Functional Group Tolerance, Scope, and Limitations.

Aldimines, generated in situ from aliphatic, aromatic, and heteroaromatic aldehydes and aliphatic, aromatic, and heteroaromatic primary or secondary amines, can be reduced with trichlorosilane in the presence of dimethylformamide (DMF) as an organocatalyst (≤10 mol %) in toluene or CH2Cl2 at room temperature. The reduction tolerates ketone carbonyls, esters, amides, nitriles, sulfones, sulfonamides, NO2, SF5, and CF3 groups, boronic esters, azides, phosphine oxides, C═C and C≡C bonds, and ferrocenyl nucleus, but sulfoxides and N-oxides are reduced. α,ß-Unsaturated aldimines undergo 1,2-reduction only, leaving the C═C bond intact. N-Monoalkylation of primary amines is attained with a 1:1 aldehyde to amine ratio, whereas excess of the aldehyde (≥2:1) allows second alkylation, giving rise to tertiary amines. Reductive N-alkylation of α-amino acids proceeds without racemization; the resulting products, containing a C≡C bond or N3 group, are suitable for click chemistry. This reaction thus offers advantages over the traditional methods (borohydride reduction or catalytic hydrogenation) in terms of efficiency and chemoselectivity. Solubility of some of the reacting partners appears to be the only limitation. The byproducts generated by the workup with aqueous NaHCO3 (i.e., NaCl and silica) are environmentally benign. As a greener alternative, DMA can be employed as a catalyst instead of DMF.

Management and Outcomes for Neovascular Age-Related Macular Degeneration: Analysis of United States Electronic Health Records.

PURPOSE: To assess anti-vascular endothelial growth factor (VEGF) management patterns and anatomic and visual acuity (VA) outcomes among patients with neovascular age-related macular degeneration (nAMD) in United States clinical practice. DESIGN: Retrospective observational cohort study. PARTICIPANTS: Patients (N = 30 106) initiating intravitreal anti-VEGF treatment for nAMD between October 2009 and November 2016. METHODS: Analysis of longitudinal electronic health records from USRetina. MAIN OUTCOME MEASURES: Number of intravitreal injections, OCT examinations, and fluorescein angiography (FA) examinations per study eye during the first 12 months; corrected VA and central retinal thickness (CRT) at 12 months; and number of ophthalmologist visits, stratified by index anti-VEGF agent. RESULTS: Over the first 12 months, patients made a mean of 8.1 (range, 1-39) ophthalmologist visits, received a mean of 6.0 (range, 1-27) anti-VEGF injections, and underwent 7.2 OCT and 5.3 FA examinations per study eye. For eyes with paired baseline and 12-month readings, mean CRT declined from 320 to 271 µm (mean change, -48 µm), and mean VA increased from 60.3 to 61.0 approximate Early Treatment Diabetic Retinopathy Study (ETDRS) letters (mean change, +0.6 letters). Twelve months after initiating index treatment with bevacizumab, ranibizumab, and aflibercept, 19.3%, 15.8%, and 15.5% of eyes, respectively, showed greater than 10-letter gain, whereas 13.2%, 14.7%, and 14.4% of eyes, respectively, showed greater than 10-letter loss. Mean change from baseline VA at 12 months increased linearly with cumulative anti-VEGF injection count: +1.79 versus -0.95 approximate ETDRS letters for eyes receiving 7 or more injections versus fewer than 7 injections. Similarly, the magnitude of the reduction from baseline CRT at 12 months tended to increase linearly with increasing number of anti-VEGF injections. Multivariate linear regression analysis, adjusted for covariates, indicated a significant association between cumulative number of anti-VEGF injections and change from baseline in VA at 12 months, with each unit increase producing an estimated gain of 0.37 approximate ETDRS letters. CONCLUSIONS: This analysis of combined morphologic and functional outcomes of anti-VEGF therapy, the largest conducted to date in nAMD, identified relatively low anti-VEGF injection frequencies, coupled with moderate anatomic and limited VA improvements, in United States clinical practice.

Real-World Outcomes of Selective Laser Trabeculoplasty in the United Kingdom.

PURPOSE: Selective laser trabeculoplasty (SLT) is a common treatment option for managing glaucoma and ocular hypertension. We assessed the real-world effectiveness of SLT and baseline factors associated with treatment success in the United Kingdom. DESIGN: Retrospective observational study of de-identified electronic medical records (Medisoft Glaucoma module [Medisoft Ltd, Leeds, UK]) from 5 UK ophthalmology teaching centers. PARTICIPANTS: Adult patients undergoing their first recorded SLT. For bilateral SLT (same day), analyses included 1 randomly selected eye. METHODS: Patient demographics, procedure details, and clinical outcomes data were extracted. Factors associated with treatment success were assessed using multivariable Cox regression. MAIN OUTCOME MEASURES: Change from baseline in intraocular pressure (IOP) and glaucoma medication use at 12 to 18 and 24 to 36 months post-SLT. A Kaplan-Meier survival analysis was also conducted. Failure of SLT was defined as any further glaucoma procedure post-SLT or any of the following at 2 consecutive visits: IOP >21 mmHg, IOP reduction <20% from baseline, or increase in glaucoma medications from baseline. RESULTS: A total of 831 SLT-treated eyes (mean baseline IOP 22.0 mmHg) of 831 patients were analyzed. At 12 to 18 and 24 to 36 months post-SLT, respectively, significant reductions in IOP (-4.2 [95% confidence interval {CI}, -4.7 to -3.7] and -3.4 [95% CI, -4.1 to -2.7] mmHg; both P < 0.0001) and significant increases in the number of glaucoma medications (0.13 [95% CI, 0.04-0.23], P = 0.007, and 0.20 [95% CI, 0.06-0.33], P = 0.005) were observed. Survival analysis demonstrated treatment success in 70%, 45%, and 27% of eyes at 6, 12, and 24 months post-SLT, respectively. Higher baseline IOP was strongly associated with treatment success (hazard ratio [HR], 0.67 for baseline IOP >21 mmHg vs. ≤21 mmHg, 95% CI, 0.57-0.80; P < 0.001). Selective laser trabeculoplasty success was not significantly associated with age (P = 0.78), baseline visual field mean deviation (P = 1.00), or concurrent use of IOP-lowering medication (P = 0.52). CONCLUSIONS: Most patients initially responded to SLT, but the majority failed within 1 year. Efficacy of SLT was better in patients with higher baseline IOP but did not differ by glaucoma severity or concurrent use of IOP-lowering medication. These findings may help inform which patients are suitable for SLT therapy.

Structural and Spectroscopic Investigation of Two Plutonium Mellitates.

The aqueous reaction of mellitic acid (H6mell) with 242PuBr3·nH2O forms two plutonium mellitates, 242Pu2(mell)(H2O)9·H2O (Pu-1α) and 242Pu2(mell)(H2O)8·2H2O (Pu-1ß). These compounds are compared to the isomorphous lanthanide mellitates with similar ionic radii via bond length analysis. Both plutonium compounds form three-dimensional metal-organic frameworks, with Pu-1α having two unique metal centers and Pu-1ß having one. All plutonium metal centers exhibit nine-coordinate geometries. Our results show metal-oxygen bond lengths for plutonium significantly shorter than those of the previously reported lanthanum and herein reported cerium analogues, consistent with the nine-coordinate ionic radii. Clear Laporte-forbidden 5f → 5f transitions are observed in the ultraviolet-visible-near-infrared spectra and are assigned to trivalent plutonium. However, there is a distinct color difference between the two plutonium compounds.

Safe and effective use of phototherapy and photochemotherapy in the treatment of psoriasis.

Psoriasis is a chronic, multisystem inflammatory disease, predominantly affecting the skin and joints, which is present in 2-3% of the world's population. Narrow band ultraviolet B (NB-UVB) and Psoralen + ultraviolet A (PUVA) are recognised, effective and, in the case of UVB, economical second-line treatments for psoriasis where topical therapies fail to control the disease or are an impracticable option due to the extent of skin involvement. This article examines the history of phototherapy and photochemotherapy and looks at current phototherapy treatments used for psoriasis. It discusses side effects of treatment and regimens that can be followed to increase effectiveness of treatment and minimise risks. The role of the nurse phototherapist is also discussed.

ASSOCIATION BETWEEN EARLY ANATOMIC RESPONSE TO ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY AND LONG-TERM OUTCOME IN DIABETIC MACULAR EDEMA: An Independent Analysis of Protocol i Study Data.

PURPOSE: This post hoc analysis explores the relationship between early retinal anatomical response and long-term anatomical and visual outcomes with ranibizumab in center-involved diabetic macular edema. METHODS: Eyes randomized to the ranibizumab plus prompt laser and ranibizumab plus deferred laser treatment arms in the Protocol I study were categorized according to their proportional reduction (<20 vs. ≥20%) in central retinal thickness (CRT) after 12 weeks. Adjusted and unadjusted analyses assessed the association between early (Week 12) anatomical response and long-term (Weeks 52 and 156) anatomical and best-corrected visual acuity outcomes. RESULTS: Of 335 study eyes, 118 showed limited (<20%) and 217 showed strong (≥20%) CRT reduction at Week 12. In unadjusted and adjusted analyses, limited early CRT response was negatively and significantly associated with strong CRT response at Weeks 52 and 156. Sensitivity analyses indicated that this association was robust and unrelated to any "floor effect." In unadjusted analyses, a strong early CRT response was associated with greater long-term improvement in best-corrected visual acuity; after controlling for confounders, the association lost statistical significance. CONCLUSION: Early CRT response to ranibizumab is a significant prognostic indicator of medium- to long-term anatomical outcome in center-involved diabetic macular edema.

Adolescent brain activation: dependence on sex, dietary satiation, and restraint.

The study aimed to explore how both sex and dietary restraint impacts brain activation in response to visual food stimuli in young adolescents (12-13 years) under fed and fasted conditions. Food and non-food images were viewed by 15 boys and 14 girls, while functional magnetic resonance images were acquired. The adolescents were either fasted or in a satiated (fed) state following a randomized crossover study design. When satiation state was not considered, girls showed significantly greater brain activity than boys in regions associated with executive function and decision making, working memory, and self-awareness. In contrast, when either fasted or fed states were considered separately, boys showed significantly increased brain activity in regions linked to executive function, self-awareness, and decision making than the girls. When fasted, compared to unrestrained eaters, restrained individuals showed heightened activation in regions connected to executive function and decision making, with areas associated with self-assessment showing increased activity for unrestrained eaters relative to restrained under fed conditions. These findings highlight important differences in adolescent brain activity and support further investigations to gain greater insight into how these differences might evolve with age.

TREATMENT PATTERNS AND 2-YEAR VISION OUTCOMES WITH BEVACIZUMAB IN DIABETIC MACULAR EDEMA: An Analysis From a Large U.S. Integrated Health Care System.

PURPOSE: To assess health care utilization and vision outcomes over 2 years in patients receiving bevacizumab treatment in clinical practice for diabetic macular edema. METHODS: Patients with newly diagnosed diabetic macular edema who received an intravitreal bevacizumab injection within 12 months of initial diagnosis were identified from Kaiser Permanente's 350,000 patients with diabetes mellitus treated between 2008 and 2013. Snellen best-corrected visual acuity (BCVA), number of intravitreal injections, and patient characteristics were abstracted from the electronic record. The main outcome measure was change in BCVA. RESULTS: Three hundred and nine patients met the inclusion criteria and had 2 years of follow-up after their first bevacizumab injection. These patients had a mean of 3.1 injections (range, 1-17) during the 2-year follow-up. Mean BCVA improvement was 5.4 letters at 12 months and 5.3 letters at 24 months. Only 29.8% of patients demonstrated ≥3 lines of vision improvement from baseline, whereas 12.3% had ≥3 lines of vision loss from baseline at 24 months. CONCLUSION: This is the largest U.S. clinical practice-based study of bevacizumab use in diabetic macular edema. Consistent with national studies, the frequency of injection was low. Average BCVA improvement was lower than in anti-vascular endothelial growth factor trials. Significant BCVA improvement was achieved in approximately 30% of patients with newly diagnosed diabetic macular edema.

The effects of a mid-morning snack and moderate-intensity exercise on acute appetite and energy intake in 12-14-year-old adolescents.

Energy intake (EI) and energy expenditure (EE) should not be considered independent entities, but more an inter-connected system. With increased physical activity and reduced snacking initiatives as prevalent Public Health measures, any changes to subsequent EI from these recommendations should be monitored. The aim of this study was to investigate changes in acute EI and appetite over four conditions: (1) a control condition with no snack and no exercise (CON); (2) a snack condition (+1 MJ; SK); (3) a moderate-intensity cycling exercise condition (-1 MJ; EX); and finally (4) both snack and exercise condition (+1 MJ, -1 MJ; EXSK). Acute changes in appetite (visual analogue scale) and lunchtime EI (ad libitum pizza meal) were recorded in twenty boys and eighteen girls (12-13 years). Lunch EI was not significantly different between conditions or sexes (P>0·05). Relative EI was calculated, where the energy manipulation (+1 MJ from the snack or -1 MJ from the exercise) was added to lunchtime EI. Relative EI indicated no significant differences between the sexes (P>0·05); however, in the EX condition, relative EI was significantly lower (P<0·001) compared with all other conditions. Appetite increased significantly over time (P<0·001) and was significantly higher in the CON and EX conditions compared with the SK and EXSK conditions. No significant sex differences were found between conditions. When aiming to evoke an acute energy deficit, increasing EE created a significantly larger relative energy deficit than the removal of the mid-morning snack. Sex was not a confounder to influence EI or appetite between any of the conditions.

The effect of breakfast versus no breakfast on brain activity in adolescents when performing cognitive tasks, as assessed by fMRI.

OBJECTIVES: The study examined the feasibility of utilizing functional magnetic resonance imaging (fMRI) with a group of adolescent boys and girls to assess modifications in cognitive function, dependent upon the nutritional state of the participants. METHODS: Twenty children aged 12-14 years completed two cognitive trials, in a randomized counterbalanced order, one under fasting condition, one after consuming breakfast, during which continuous fMRI data were acquired. RESULTS: Although no statistically significant (P > 0.05) improvement in task performance was determined, significantly higher activation was recorded in the frontal, premotor, and primary visual cortex areas in the breakfast trial relative to the fasting condition. DISCUSSION: Such a finding may have important implications in the examination of the role of diet, and specifically breakfast, in determining children's performance within the school environment.

Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease.

BACKGROUND: Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease. METHODS: We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies. RESULTS: We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E, p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein-protein interactions to intracellular myosin 1E. CONCLUSIONS: COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non-COL4 'podocyte gene' mutations in XLAS when clinical nephropathy is more severe than expected for an individual's age and sex.

'Outcomes of genetic testing in the London MND Center: the importance of achieving timely results and correlations to family history'.

Background: Despite recognition of the importance of genetic factors in the pathogenesis of MND and the increasing availability of genetic testing, testing practice remains highly variable. With the arrival of gene-targeted therapies there is a growing need to promptly identify actionable genetic results and patient death before receipt of results raises ethical dilemmas and limits access to novel therapies. Objective: To identify pathogenic mutations within a London tertiary MND center and their correlation with family history. To record waiting times for genetic results and deaths prior to receipt of results. Methods: In this series of 100 cases, genetic testing was offered to all patients with an MND diagnosis from the tertiary clinic. Data on demographics, disease progression and a detailed family history were taken. Time to receipt of genetic results and patient deaths prior to this were recorded.  Results: Of the 97 patients who accepted testing a genetic cause was identified in 10%, including seven C9orf72 and two positive SOD1 cases. Only three patients with positive genetic findings had a family history of MND, although alternative neurological diagnoses and symptoms in the family were frequently reported. 14% of patients who underwent testing were deceased by the time results were received, including one actionable SOD1 case.  Conclusions: Genetic testing should be made available to all patients who receive an MND diagnosis as family history alone is inadequate to identify potential familial cases. Time to receipt of results remains a significant issue due to the limited life expectancy following diagnosis.

Histatin-5 interacts with cellular copper to promote antifungal activity against Candida albicans.

Histatin-5 (Hist-5) is an antimicrobial peptide found in human saliva that functions to defend the oral cavity from microbial infections, such as those caused by the fungal pathogen Candida albicans (C. albicans). Hist-5 can bind Cu in multiple oxidation states, Cu2+ and Cu+in vitro, and supplemental Cu2+ has been shown to improve the fungicidal activity of the peptide against C. albicans in culture. However, the exact role of Cu on the antifungal activity of Hist-5 and whether direct peptide-Cu interactions occur intracellularly has yet to be fully determined. Here, we used a combination of fluorescence spectroscopy and confocal microscopy experiments to show reversible Cu-dependent quenching of a fluorescent Hist-5 analogue, Hist-5*, indicating a direct interaction between Hist-5 and intracellular Cu. X-ray fluorescence microscopy images revealed peptide-induced changes to cellular Cu distribution and cell-associated Cu content. These data support a model in which Hist-5 can facilitate the hyperaccumulation of Cu in C. albicans and directly interact with Cu intracellularly to increase the fungicidal activity of Hist-5.

Zinc Binding Inhibits Cellular Uptake and Antifungal Activity of Histatin-5 in Candida albicans.

Histatin-5 (Hist-5) is a polycationic, histidine-rich antimicrobial peptide with potent antifungal activity against the opportunistic fungal pathogen Candida albicans. Hist-5 can bind metals in vitro, and metals have been shown to alter the fungicidal activity of the peptide. Previous reports on the effect of Zn2+ on Hist-5 activity have been varied and seemingly contradictory. Here, we present data elucidating the dynamic role Zn2+ plays as an inhibitory switch to regulate Hist-5 fungicidal activity. A novel fluorescently labeled Hist-5 peptide (Hist-5*) was developed to visualize changes in internalization and localization of the peptide as a function of metal availability in the growth medium. Hist-5* was verified for use as a model peptide and retained antifungal activity and mode of action similar to native Hist-5. Cellular growth assays showed that Zn2+ had a concentration-dependent inhibitory effect on Hist-5 antifungal activity. Imaging by confocal microscopy revealed that equimolar concentrations of Zn2+ kept the peptide localized along the cell periphery rather than internalizing, thus preventing cytotoxicity and membrane disruption. However, the Zn-induced decrease in Hist-5 activity and uptake was rescued by decreasing the Zn2+ availability upon addition of a metal chelator EDTA or S100A12, a Zn-binding protein involved in the innate immune response. These results lead us to suggest a model wherein commensal C. albicans may exist in harmony with Hist-5 at concentrations of Zn2+ that inhibit peptide internalization and antifungal activity. Activation of host immune processes that initiate Zn-sequestering mechanisms of nutritional immunity could trigger Hist-5 internalization and cell killing.

The humanistic burden of myasthenia gravis: A systematic literature review.

BACKGROUND/OBJECTIVES: While the clinical manifestations of myasthenia gravis (MG) are well understood, its humanistic impact is not. The objective of this systematic literature review (SLR) was to provide a comprehensive understanding of the humanistic burden of MG with regards to psychological symptoms and health-related quality of life (HRQoL) according to patients and caregivers. METHODS: A systematic search was conducted on December 27, 2019, in MEDLINE and Embase to identify English-language studies that were published from January 1, 2009-December 27, 2019 and presented relevant information on the humanistic burden among adults with MG and their caregivers. Title/abstract and full-text screening was performed by two investigators, with any discrepancies resolved by a third investigator. RESULTS: Sixty-seven publications were included in the SLR. Compared with the general population, patients with MG experienced worse HRQoL. Studies reporting on psychological symptoms of MG, including depression, anxiety, fatigue, and sleep, were heterogeneous in terms of the scales and instruments used to assess patients, as well as the patient populations themselves. However, in general those with more severe symptoms and hospitalization days had worse depression and anxiety, and fatigue and sleep improved with disease remission and/or improvement. Scores were worse for females compared with males and where evaluated, HRQoL scores generally improved following treatment. CONCLUSION: While the literature demonstrates that symptoms associated with MG get better with disease improvement and remission, additional options in efficacious therapy that adequately address the disease-related symptoms and also improve HRQoL may contribute to beneficial outcomes in a greater number of patients with MG.

Comparing Healthcare Resource Utilization and Costs for Patients with Normal Tension Glaucoma Across Levels of Severity: A Retrospective Cohort Study.

PURPOSE: To estimate the healthcare resource utilization (HCRU) and costs for patients with normal tension glaucoma (NTG) as well as their payers across various levels of disease severity. PATIENTS AND METHODS: Our study was a retrospective cohort study of 6330 US NTG patients. Patients were enrolled if they were 40 years or older and had two or more qualifying NTG diagnoses within the enrollment period, October 1st, 2015 to December 31st, 2017. Our analysis was carried out for two cohorts - those with unilateral disease and those with bilateral disease. Baseline demographic and clinical characteristics were assessed for a 12-month pre-index period. The follow up period was 12-months post-index. We employed generalized linear models to model HCRU and costs. RESULTS: Patients with severe, bilateral disease, filled more than two additional prescriptions annually (2.5, p<0.001, 95% CI [2.0, 3.1]) when compared to their mild counterparts and accounted for 111 (p<0.001, 95% CI [83.5, 139.1]) extra days of supply of glaucoma medications. These patients face an adjusted $187 (p<0.001, 95% CI [145, 229]) more out-of-pocket (OOP), and payers an additional $598 (p<0.001, 95% CI [$370, $826]), than their counterparts with a mild diagnosis on an annual basis. Total annual payer costs, on average (SD) for those with severe bilateral NTG were $1175 ($2222). CONCLUSION: Our results suggest that patient and payer burden is significantly greater for those with severe disease compared to those with mild NTG. The excess burden is attributed to additional HCRU and the associated financial burden. Payers experienced a much larger financial burden from patients with severe disease compared to those with mild NTG. Approximately half of the cost differences can be attributed to additional prescription use.

Characteristics and Treatment Patterns of Newly Diagnosed Open-Angle Glaucoma Patients in the United States: An Administrative Database Analysis.

PURPOSE: To characterize newly diagnosed primary open-angle glaucoma (OAG) patients and to describe their treatment journey in United States clinical practice according to the use of topical therapy, laser trabeculoplasty, and surgical procedures. DESIGN: Retrospective claims database study. PARTICIPANTS: Patients with at least 2 diagnoses of OAG 7 days or more apart and within 1 year, with the first (index) diagnosis in 2010, at least 30 months of continuous enrollment before index diagnosis with no OAG diagnosis or medication (exception for ocular hypertension diagnosis), and 48 months of continuous enrollment. METHODS: Analysis of United States healthcare insurance claims database (July 2007-December 2014). MAIN OUTCOME MEASURES: Treatment patterns and ophthalmology visits were evaluated over 48 months in 4 cohorts based on initial therapy after the index diagnosis: (1) drug monotherapy, (2) combination drug therapy, (3) glaucoma procedure, or (4) no claims for treatment. Treatment modification was defined as an addition to or change in drug therapy or procedure. RESULTS: In total, 83.0% of patients (5120/6172) began a drug therapy (69.5%) or underwent a procedure initially (13.5%); topical prostaglandin analogs (n = 2887/5120 [56.4%]) and laser trabeculoplasty (n = 705/5120 [13.8%]) were the most common. During the 4-year follow-up, 58.3% of patients (2109/3620) who began drug monotherapy experienced no further treatment modification. Over this period, 43.8% of patients who began treatment (2242/5120) experienced a treatment modification to the first treatment. Two thirds (1505/2242 [67.1%]) of these patients subsequently underwent a third treatment modification. Ophthalmology visits declined over time regardless of initial therapy, with the greatest decrease among the untreated and first-treatment procedure cohorts. CONCLUSIONS: The high rates of 2 or 3 treatment modifications over the 4-year period suggest an unmet need for glaucoma therapies with durable and predictable actions.

Healthcare Resource Utilization and Costs in Patients with Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PURPOSE: Geographic atrophy (GA) is an advanced form of nonexudative age-related macular degeneration (AMD) that lacks treatment options. With considerable interpatient variability in the rate of GA progression due to lesion characteristics, information characterizing the disease burden is limited. The aim of this study was to describe the healthcare resource utilization (HCRU) and costs associated with increasing severity levels of GA. PATIENTS AND METHODS: A retrospective analysis was conducted using claims data from IQVIA's PharMetrics Plus database. Patients with a prevalent GA diagnosis were identified between October 1, 2016 and June 30, 2017 and classified by disease severity and laterality. Disease-specific HCRU and costs by disease severity were assessed during the 12-month follow-up period, with multivariable analyses performed adjusting for baseline characteristics. RESULTS: A total of 28,773 GA cases were identified (mean age = 68.7; 58.5% female), of which 24% and 76% had unilateral and bilateral GA, respectively, with varying levels of recorded severity (in increasing order): early or intermediate (EI) AMD, GA without subfoveal involvement (GAwoSF), and GA with subfoveal involvement (GAwSF). Patients with greater baseline severity in the bilateral group had a significantly higher number of outpatient (OP) visits per year (1.98 EI AMD; 2.57 for GAwoSF; 2.63 for GAwSF). Increasing disease severity was associated with higher patient-related costs in the outpatient setting (mean [SD] of $82 [$157], $110 [$559] for unilateral EI AMD and GAwSF, respectively, and $56 [$94], $64 [$97], $59 [$85] for bilateral EI AMD, GAwoSF, GAwSF, respectively). Similarly, higher payer-related costs were seen in patients with bilateral GAwSF compared to bilateral EI AMD (mean [SD] $280 [$325]; $198 [$262]). CONCLUSION: Study findings demonstrate that patients, with more severe GA at baseline, experience greater HCRU and costs in the outpatient setting. Further research should explore specific contributing factors to the long-term economic burden of GA.

Development of the Presbyopia Impact and Coping Questionnaire.

INTRODUCTION: Presbyopia is a progressive, age-related visual condition that is characterized by reduced ability to focus on near/close objects, causing impacts on individuals' daily function and health-related quality of life. The Presbyopia Impact and Coping Questionnaire (PICQ) is a new patient-reported outcome (PRO) instrument that assesses presbyopia impact and use of coping behaviors among presbyopic individuals. METHODS: To document the impacts of presbyopia and associated coping behaviors, concept elicitation (CE) interviews were conducted with 20 presbyopic participants. Results from the CE interviews were used to develop draft items for additional testing. Following item generation, the draft PICQ was cognitively debriefed with 20 participants. Data from a phase 2 controlled clinical trial were used for psychometric analyses of the PICQ. The PICQ was administered at site visits throughout a 28-day treatment period. Confirmatory factor analysis (CFA) methods were used to guide the development of the scoring algorithm. The reliability (internal consistency, test-retest), construct validity (convergent and discriminant validity, known-groups methods), and responsiveness (Guyatt's responsiveness statistic [GRS]) of the PICQ scores were evaluated. Finally, anchor-based and distribution-based methods were used to inform thresholds for interpreting meaningful within-patient change. RESULTS: CE interviews identified the important and relevant presbyopia-related impacts and coping behaviors and 22 items were drafted and cognitively debriefed. Following minor revisions and item addition/deletion, a version of the PICQ including 23 items was subjected to psychometric testing. The analysis sample included 151 participants. The CFA established two PICQ domain scores, Coping and Impact, on 0-to-4 scales that demonstrate good model fit (root mean square error of approximation = 0.06, comparative fit index = 0.98, Tucker-Lewis index = 0.98, standardized root mean square = 0.07). Cronbach's alphas for the Coping and Impact scores were 0.89 and 0.84, respectively. Test-retest intraclass correlation coefficients were 0.77 for Coping and 0.67 for Impact. The pattern of results assessing construct validity was acceptable for the PICQ Coping and Impact scores, with the magnitude of correlations and effect sizes generally meeting a priori expectations. The corresponding GRS effect sizes for the PICQ Coping scores were -1.23 (i.e., large) for Patient Global Impression of Change (PGIC) and -0.72 (i.e., medium) for uncorrected near visual acuity (UNVA). The GRS effect sizes for the PICQ Impact scores were -0.60 (i.e., medium) for PGIC and -0.35 (i.e., small) for UNVA. Across three sets of anchor-based analyses for interpreting individual-level change, a responder threshold of -1.00 was identified for both PICQ Coping and PICQ Impact scores. CONCLUSIONS: The totality of evidence from the qualitative and quantitative research establishes that the PICQ scores produced are valid and reliable measures of presbyopia impacts and coping behaviors that are important and relevant for assessing presbyopia treatment outcomes. CLINICALTRIALS. GOV IDENTIFIER: NCT02780115; date of registration May 19, 2016.