METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The impact of maternal pertussis vaccination recommendation on infant pertussis incidence and mortality in the USA: an interrupted time series analysis.

BACKGROUND: Pertussis is a contagious respiratory disease. Maternal tetanus-diphtheria-acellular pertussis vaccination during pregnancy has been recommended by the United States Centres for Disease Control (US CDC) Advisory Committee on Immunization Practices (ACIP) for unvaccinated pregnant women since October 2011 to prevent infection among infants; in 2012, ACIP extended this recommendation to every pregnancy, regardless of previous vaccination status. The population-level effect of these recommendations on infant pertussis is unknown. This study aimed to examine the impact of the 2011/2012 ACIP pertussis recommendation on pertussis incidence and mortality among US infants. METHODS: We used monthly data on pertussis deaths among infants aged <1 year between January 2005 and December 2017 in the CDC Death Data and yearly infant pertussis incidence data from the CDC National Notifiable Disease Surveillance System to perform an interrupted time series analysis, accounting for the passage of the Affordable Care Act. RESULTS: This study included 156 months of data. A potential decline in trend in infant pertussis incidence was noted during the post-recommendations period. No appreciable differences in trend were found in population-level infant pertussis mortality after the guideline changes in both adjusted and unadjusted models. Results were similar for all mortality sensitivity analyses. CONCLUSIONS: The 2011/2012 ACIP maternal pertussis vaccination recommendations were not associated with a population-level change in the trend in mortality, but were potentially associated with a decrease in incidence in the USA between 2005 and 2017.

Aqueous Fluid Transcriptome Profiling Differentiates Between Non-Neovascular and Neovascular AMD.

Purpose: Early and intermediate non-neovascular AMD (NN-AMD) has the potential to progress to either advanced NN-AMD with geographic atrophy, or to neovascular AMD (N-AMD) with CNV. This exploratory study performed an unbiased analysis of aqueous humor transcriptome in patients with early or intermediate NN-AMD vs. treatment-naïve N-AMD to determine the feasibility of using this method in future studies investigating pathways and triggers for conversion from one form to another. Methods: Aqueous humor samples were obtained from 20 patients with early or intermediate NN-AMD and 20 patients with untreated N-AMD, graded on clinical examination and optical coherence tomography. Transcriptome profiles were generated using next-generation sequencing methods optimized for ocular samples. Top-ranked transcripts were compared between groups, and pathway enrichment analysis was performed. Results: Seventy-eight differentially expressed transcripts were identified. Unsupervised clustering of differentially expressed transcripts was able to successfully differentiate between the two groups based on aqueous transcriptome alone. Pathway analysis highlighted changes in expression of genes associated with mitochondrial respiration, oxidative stress, ubiquitination, and neurogenesis between the two groups. Conclusions: This pilot study compared the aqueous fluid transcriptome of patients with early or intermediate NN-AMD and untreated N-AMD. Differences in transcripts and transcriptome pathways identified in the aqueous of patients with early or intermediate NN-AMD compared with patients with N-AMD are consistent with those previously implicated in the pathogenesis of these distinct AMD subtypes. The findings from this exploratory study warrant further investigation using a larger, prospective study design, with the inclusion of a control group of eyes without AMD.

Racial and ethnic differences in foveal avascular zone in diabetic and nondiabetic eyes revealed by optical coherence tomography angiography.

PURPOSE: The purpose of this study was to examine whether racial and ethnic differences in retinal microvasculature are detectable with quantitative measures derived from optical coherence tomography angiography (OCTA). METHODS: OCTA scans and fundus photography were obtained in 447 eyes from 271 patients with and without diabetes between April and October 2018. Fundus photos were graded by the hospital reading center for diabetic retinopathy (DR) severity. Eight OCTA parameters relating to the foveal avascular zone (FAZ), superficial vascular perfusion, and deep vascular perfusion were analyzed for significant differences between race and ethnicity groups, self-reported by patients and organized according to National Center for Health Statistics groupings. Multiple regression was then used to adjust estimates for possible confounding by age, gender, hypertension, and last hemoglobin A1c level. RESULTS: Significant differences in FAZ area were found between white and non-white patients. After adjustment, the differences between white and all non-white groups were statistically significant (p<0.05) among patients with mild to moderate DR. In those without diabetes, the Hispanic and Asian groups had significantly larger FAZ areas (p<0.005) than NH white patients. In those with mild to moderate non-proliferative diabetic retinopathy (NPDR), NH Black, Hispanic, and Asian patients also had significantly larger FAZ areas than NH white patients (p<0.005). CONCLUSION: Significant differences in FAZ area exist among different racial and ethnic groups. These results highlight the importance of considering and further studying race and ethnicity in OCTA analyses of the retinal microvasculature.

Sex-Based Analysis of Potential Inflammation-Related Protein Biomarkers in the Aqueous Humor of Patients With Diabetes Mellitus.

Purpose: To investigate whether men have higher inflammatory protein biomarker concentrations in their aqueous humor (AH) compared with women in groups of patients with varying levels of diabetic disease. Methods: This cross-sectional study included AH specimens from 59 adult patients comprised of three groups: no diabetes mellitus (DM), DM without diabetic retinopathy (DR), and DM with proliferative diabetic retinopathy (PDR). Protein biomarker concentration values were quantified using a commercial proximity extension assay-based technique. Results: Intersex comparisons of concentration values for each protein biomarker revealed no discoveries in patients with no DM or with PDR. In contrast, 24 discoveries were detected in patients with DM without DR. The mean concentration value for all 24 protein biomarkers was higher in men compared with women. Of these 24 proteins, 12 demonstrated a significant association with sex on multivariate linear regression analysis. The ß coefficient results demonstrated a positive association between male sex and concentration value for all 12 of these proteins. Conclusions: Higher AH concentration levels of several potential biomarkers, including chemokines, proteases, proteins involved in programmed cell death, and a T-cell surface protein, were detected in men with DM with no DR. These findings suggest that men may have a more inflammatory disease phenotype compared with women in this group of patients. Translational Relevance: The findings of this study help explain differences in epidemiologic patterns of diabetic retinopathy development between men and women.

Comparative Analysis of Multiplex Platforms for Detecting Vitreous Biomarkers in Diabetic Retinopathy.

Purpose: To evaluate the feasibility of using the Proximity Extension Assay (PEA) platform to detect biomarkers in vitreous and to compare the findings with results obtained with an electrochemiluminescent (ECL) sandwich immunoassay. Methods: Vitreous samples from patients with proliferative diabetic retinopathy (PDR) and non-diabetic controls were tested using two different proteomics platforms. Forty-one assays were completed with the ECL platform and 459 with the PEA platform. Spearman's rank correlation coefficient (rs ) was used to determine the direction and strength of the relationship between protein levels detected by both platforms. Results: Three hundred sixty-six PEA assays detected the tested protein in at least 25% of samples, and the difference in protein abundance between PDR and controls was statistically significant for 262 assays. Seventeen ECL assays yielded a detection rate ≥ 25%, and the difference in protein concentration between PDR and controls was statistically significant for 13 proteins. There was a subset of proteins that were detected by both platforms, and for those the Spearman's correlation coefficient was higher than 0.8. Conclusions: PEA is suitable for the analysis of vitreous samples, showing a strong correlation with the ECL platform. The detection rate of PEA panels was higher than the panels tested with ECL. The levels of several proinflammatory and angiogenic cytokines were significantly higher in PDR vitreous compared to controls. Translational Relevance: This study provides new information on the yields of small-volume assays that can detect proteins of interest in ocular specimens, and it identifies patterns of cytokine dysregulation in PDR.

Discordant vascular parameter measurements in diabetic and non-diabetic eyes detected by different optical coherence tomography angiography devices.

PURPOSE: To compare quantitative changes in macular parameters in diabetic patients detected by two optical coherence tomography angiography (OCTA) instruments. METHODS: 80 phakic eyes were classified as no diabetes, diabetes without diabetic retinopathy (DR), mild non-proliferative diabetic retinopathy (NPDR), and severe NPDR or proliferative DR (PDR). OCTA was performed using devices from two manufacturers (Zeiss and Heidelberg). Superficial and deeper vascular skeleton density (SVSD, DVSD), superficial and deeper vessel area density (SVAD, DVAD), choriocapillaris flow voids (CCFV), and choroidal flow voids (CFV) were calculated. Inter-device comparisons were performed using the size comparison index (SCI) and the discrepancy index (DI). RESULTS: The two devices were inconsistent in SVSD, DVSD, DVAD, CCFV and CFV parameters (all P < 0.05). In addition, the SCI was positive for DVAD (all P < 0.001) and negative for SVSD, DVSD, CCFV and CFV in all groups (all P <0.001), except for DVSD in severe NPDR or PDR. The discrepancy index was not significantly different among groups for SVD, SPD, DVD, DPD and CFV (all P> 0.05). The mean DI of CCFV was statistically different between the four groups (P < 0.001). CONCLUSIONS: The two instruments were largely inconsistent in the measurement of macular parameters relevant to DR. The choice of imaging device can impact OCTA analytics and should be taken into account when drawing conclusions about DR-related changes.

Correlation of Aqueous, Vitreous, and Plasma Cytokine Levels in Patients With Proliferative Diabetic Retinopathy.

Purpose: To investigate the relationship between proangiogenic and inflammatory cytokines in concurrent vitreous, aqueous, and plasma samples from patients with proliferative diabetic retinopathy (PDR). Methods: Vitreous, aqueous, and plasma samples were analyzed using multiplex immunoassay for 10 PDR-related cytokines (IL-6, IL-8, TNF-α, monocyte chemoattractant protein-1 [MCP-1], macrophage inflammatory protein-1ß [MIP-1ß], VEGF receptor 1 [Flt-1], placental growth factor [PlGF], VEGF-A, VEGF-C, VEGF-D). A total of 17 patients with PDR and 7 controls were included. The primary outcome was correlation of cytokines in vitreous, aqueous, and plasma. The secondary outcome was the comparison of cytokine levels in controls and diabetics with and without recent anti-VEGF injection. Results: The following factors were elevated in diabetics compared with controls: vitreous IL-6, IL-8, TNF-α, MCP-1, MIP-1ß, PlGF, and VEGF-A; and aqueous IL-6, IL-8, PlGF, and VEGF-C (all P < 0.05). Vitreous and aqueous IL-8, PlGF, and VEGF-A were significantly correlated in patients with PDR (all P < 0.05). Plasma cytokines were not correlated with those in vitreous and aqueous (all P > 0.05). Vitreous and aqueous IL-6, IL-8, TNF-α, PlGF, and VEGF-A differed among controls and diabetics with and without recent anti-VEGF injection (all P < 0.05). In one-to-one comparisons, aqueous VEGF-A levels were lower in diabetic patients who had recent anti-VEGF injection compared with those who did not (P = 0.01). Conclusions: In this proof-of-concept study, IL-8, VEGF-A, and PlGF demonstrated a strong correlation in vitreous and aqueous of patients with PDR. The aqueous may serve as a proxy for vitreous for some cytokines involved in PDR. Recent anti-VEGF injections decreased VEGF-A levels in aqueous, but did not significantly affect other cytokines, suggesting a role for other targeted therapies in PDR management.

OCT Angiography Assessment of Retinal Microvascular Changes in Diabetic Eyes in an Urban Safety-Net Hospital.

PURPOSE: To determine whether quantitative OCT angiography (OCTA) parameters can be used to distinguish among eyes at various stages of diabetic retinopathy (DR) in an urban safety-net hospital population. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Three hundred twenty-nine eyes from 329 patients were included in this study: 90 nondiabetic patients, 170 diabetic patients without DR, 57 diabetic patients with mild to moderate nonproliferative DR (NPDR), and 12 diabetic patients with severe NPDR to proliferative DR. METHODS: Patients underwent OCTA imaging and ultra-widefield fundus photography at Zuckerberg San Francisco General Hospital and Trauma Center between April and October 2018. For participants with diabetes, imaging was classified according to DR severity by a telemedicine reading center. Eight OCTA parameters were analyzed. Perfusion density and vessel length density (VD) were examined from both the superficial capillary plexus (SCP) and deep capillary plexus. The other 4 parameters were examined only from the SCP. Total extrafoveal avascular area (tEAA) was based on the area of absent capillary vessels. Foveal avascular zone (FAZ)-related metrics consisted of FAZ area, FAZ circularity index, and FAZ acircularity index. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC) for OCTA parameters to distinguish among groups according to DR severity. RESULTS: All OCTA parameters demonstrated a significant relationship with DR severity (P < 0.05). No significant difference was found when comparing nondiabetic participants versus diabetic participants without retinopathy. The FAZ area was the only metric that demonstrated a significant difference between genders: mean of 0.29±0.12 mm2 in men and 0.34±0.13 mm2 in women (P < 0.001). Receiver operating characteristic curve analyses showed that tEAA had the highest AUC when comparing various stages of the disease. CONCLUSIONS: In this urban, public hospital population, quantification of retinal vascular findings with OCTA imaging was a useful means of distinguishing patients according to DR severity. Because these results were similar to those of other tertiary referral centers, it would be reasonable to perform further DR-related OCTA studies in this population and expect generalizable results.

Dexamethasone Intravitreal Implant Injection in Eyes with Comorbid Hypotony.

PURPOSE: To evaluate outcomes in patients with hypotony treated with intravitreal dexamethasone implant (Ozurdex). DESIGN: Retrospective cohort study. PARTICIPANTS: Thirteen patients (15 eyes) that received a total of 99 dexamethasone implant injections on occasions at which the intraocular pressure was low, meeting the definition of statistical hypotony. METHODS: The medical records of 13 patients (15 consecutive eyes) receiving 1 or more intravitreal dexamethasone implants between December 2014 and April 2017 were reviewed retrospectively. Hypotony was defined as intraocular pressure less than 6.5 mmHg. The indications for intravitreal dexamethasone implant injection were intermediate or posterior uveitis (86.7%), diabetic macular edema (13.3%), and/or cystoid macular edema (6.7%). MAIN OUTCOME MEASURES: The primary outcome measures were safety outcomes and best visual acuity within 6 months of the final intravitreal dexamethasone implant injection in a hypotonous eye. RESULTS: In 15 eyes (13 patients), 99 injections were administered to eyes under circumstances of hypotony. Uveitic cystoid macular edema or diabetic macular edema was reduced after treatment in all cases. No complications were noted during the injection procedure. Three complications were noted in 2 patients after injection. Pseudophakodonesis and mild vitreous hemorrhage immediately after injection were noted in 1 patient, and a case of delayed-onset vitreous hemorrhage with pigment release was noted in another. All 3 complications resolved without intervention. The primary end point of this study-mean visual acuity-was stable over the follow-up period. In patients with hypotony whose intraocular pressure normalized during the follow-up period, this was attributable to management of glaucoma surgery-related complications rather than an effect of the intravitreal dexamethasone implant. CONCLUSIONS: Intravitreal dexamethasone implant injection is a reasonable treatment option for patients with comorbid hypotony in whom clinical findings warrant treatment with a sustained-delivery intravitreal steroid implant. Further studies, including imaging of zonules before and after intravitreal dexamethasone implant injection in a hypotonous eye, could help define risks to intraocular lens stability with this procedure.