Progression of Age-Related Macular Degeneration Among Individuals Homozygous for Risk Alleles on Chromosome 1 (CFH-CFHR5) or Chromosome 10 (ARMS2/HTRA1) or Both

Importance: Age-related macular degeneration (AMD) is a common cause of irreversible vision loss among individuals older than 50 years. Although considerable advances have been made in our understanding of AMD genetics, the differential effects of major associated loci on disease manifestation and progression may not be well characterized. Objective: To elucidate the specific associations of the 2 most common genetic risk loci for AMD, the CFH-CFHR5 locus on chromosome 1q32 (Chr1) and the ARMS2/HTRA1 locus on chromosome 10q26 (Chr10)-independent of one another and in combination-with time to conversion to late-stage disease and to visual acuity loss. Design, Setting, and Participants: This case series study included 502 individuals who were homozygous for risk variants at both Chr1 and Chr10 (termed Chr1&10-risk) or at either Chr1 (Chr1-risk) or Chr10 (Chr10-risk) and who had enrolled in Genetic and Molecular Studies of Eye Diseases at the Sharon Eccles Steele Center for Translational Medicine between September 2009 and March 2020. Multimodal imaging data were reviewed for AMD staging, including grading of incomplete and complete retinal pigment epithelium and outer retinal atrophy. Main Outcomes and Measures: Hazard ratios and survival times for conversion to any late-stage AMD, atrophic or neovascular, and associated vision loss of 2 or more lines. Results: In total, 317 participants in the Chr1-risk group (median [IQR] age at first visit, 75.6 [69.5-81.7] years; 193 women [60.9%]), 93 participants in the Chr10-risk group (median [IQR] age at first visit, 77.5 [72.2-84.2] years; 62 women [66.7%]), and 92 participants in the Chr1&10-risk group (median [IQR] age at first visit, 71.7 [68.0-76.3] years; 62 women [67.4%]) were included in the analyses. After adjusting for age and AMD grade at first visit, compared with 257 participants in the Chr1-risk group, 56 participants in the Chr1&10-risk group (factor of 3.3 [95% CI, 1.6-6.8]; P < .001) and 58 participants in the Chr10-risk group (factor of 2.6 [95% CI, 1.3-5.2]; P = .007) were more likely to convert to a late-stage phenotype during follow-up. This difference was mostly associated with conversion to macular neovascularization, which occurred earlier in participants with Chr1&10-risk and Chr10-risk. Eyes in the Chr1&10-risk group (median [IQR] survival, 5.7 [2.1-11.1] years) were 2.1 (95% CI, 1.1-3.9; P = .03) times as likely and eyes in the Chr10-risk group (median [IQR] survival, 6.3 [2.7-11.3] years) were 1.8 (95% CI, 1.0-3.1; P = .05) times as likely to experience a visual acuity loss of 2 or more lines compared with eyes of the Chr1-risk group (median [IQR] survival, 9.4 [4.1-* (asterisk indicates event rate did not reach 75%)] years). Conclusions and Relevance: These findings suggest differential associations of the 2 major AMD-related risk loci with structural and functional disease progression and suggest distinct underlying biological mechanisms associated with these 2 loci. These genotype-phenotype associations may warrant consideration when designing and interpreting AMD research studies and clinical trials

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10&nbsp;years; 78.2% included were male with a median age of 37&nbsp;years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Long-term Outcomes of Adding Lutein/Zeaxanthin and omega-3 Fatty Acids to the AREDS Supplements on Age-Related Macular Degeneration Progression AREDS2 Report 28

IMPORTANCE After the Age-Related Eye Disease Study 2 (ARED52) study, the beta carotene component was replaced by lutein/zeaxanthin for the development of the revised AREDS supplement. However, it is unknown if the increased risk of lung cancer observed in those assigned beta carotene persists beyond the conclusion of the AREDS2 trial and if there is a benefit of adding lutein/zeaxanthin to the original AREDS supplement that can be observed with long-term follow-up. OBJECTIVE To assess 10-year risk of developing lung cancer and late age-related macular degeneration (AMD). DESIGN, SETTING, AND PARTICIPANTS This was a multicenter epidemiologic follow-up study of the AREDS2 clinical trial, conducted from December 1, 2012, to December 31, 2018. Included in the analysis were participants with bilateral or unilateral intermediate AMD for an additional 5 years after clinical trial. Eyes/participants were censored at the time of late AMD development, death, or loss to follow-up. Data were analyzed from November 2019 to March 2022. INTERVENTIONS During the clinical trial, participants were randomly assigned primarily to lutein/zeaxanthin and/or omega-3 fatty acids or placebo and secondarily to no beta carotene vs beta carotene and low vs high doses of zinc. In the epidemiologic follow-up study, all participants received AREDS2 supplements with lutein/zeaxanthin, vitamins C and E, and zinc plus copper. Outcomes were assessed at 6-month telephone calls. Analyses of AMD progression and lung cancer development were conducted using proportional hazards regression and logistic regression, respectively. MAIN OUTCOMES AND MEASURES Self-reported lung cancer and late AMD validated with medical records. RESULTS This study included 3882 participants (mean [SD] baseline age, 72.0 [7.7] years; 2240 women [57.7%]) and 6351 eyes. At 10 years, the odds ratio (OR) of having lung cancer was 1.82 (95% CI, 1.06-3.12; P = .02) for those randomly assigned to beta carotene and 1.15 (95% CI, 0.79-1.66; P = .46) for lutein/zeaxanthin. The hazard ratio (HR) for progression to late AMD comparing lutein/zeaxanthin with no lutein/zeaxanthin was 0.91(95% CI, 0.84-0.99; P = .02) and comparing omega-3 fatty acids with no omega-3 fatty acids was 1.01(95% CI, 0.93-1.09; P = .91). When the lutein/zeaxanthin main effects analysis was restricted to those randomly assigned to beta carotene, the HR was 0.80 (95% CI, 0.68-0.92; P = .002). A direct analysis of lutein/zeaxanthin vs beta carotene showed the HR for late AMD was 0.85 (95% CI, 0.73-0.98; P = .02). The HR for low vs high zinc was 1.04 (95% CI, 0.94-1.14; P = .49), and the HR for no beta carotene vs beta carotene was 1.04 (95% CI, 0.94-1.15; P = .48). CONCLUSIONS AND RELEVANCE Results of this long-term epidemiologic follow-up study of the AREDS2 cohort suggest that lutein/zeaxanthin was an appropriate replacement for beta carotene in AREDS2 supplements. Beta carotene usage nearly doubled the risk of lung cancer, whereas there was no statistically significant increased risk with lutein/zeaxanthin. When compared with beta carotene, lutein/zeaxanthin had a potential beneficial association with late AMD progression

Complement component C5a Promotes Expression of IL-22 and IL-17 from Human T cells and its Implication in Age-related Macular Degeneration

<p>Abstract</p> <p>Background</p> <p>Age related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Recent studies have demonstrated a strong genetic association between AMD and complement factor H (CFH), the down-regulatory factor of complement activation. Elevated levels of complement activating molecules including complement component 5a (C5a) have been found in the serum of AMD patients. Our aim is to study whether C5a can impact human T cells and its implication in AMD.</p> <p>Methods</p> <p>Human peripheral blood mononuclear cells (PBMCs) were isolated from the blood of exudative form of AMD patients using a Ficoll gradient centrifugation protocol. Intracellular staining and enzyme-linked immunosorbent assays were used to measure protein expression. Apoptotic cells were detected by staining of cells with the annexin-V and TUNEL technology and analyzed by a FACS Caliber flow cytometer. SNP genotyping was analyzed by TaqMan genotyping assay using the Real-time PCR system 7500.</p> <p>Results</p> <p>We show that C5a promotes interleukin (IL)-22 and IL-17 expression by human CD4⁺T cells. This effect is dependent on B7, IL-1β and IL-6 expression from monocytes. We have also found that C5a could protect human CD4⁺cells from undergoing apoptosis. Importantly, consistent with a role of C5a in promoting IL-22 and IL-17 expression, significant elevation in IL-22 and IL-17 levels was found in AMD patients as compared to non-AMD controls.</p> <p>Conclusions</p> <p>Our results support the notion that C5a may be one of the factors contributing to the elevated serum IL-22 and IL-17 levels in AMD patients. The possible involvement of IL-22 and IL-17 in the inflammation that contributes to AMD may herald a new approach to treat AMD.</p

Elevated CD1c(+) Myeloid Dendritic Cell Proportions Associate With Clinical Activity and Predict Disease Reactivation in Noninfectious Uveitis

PURPOSE. To test the association between elevated proportions of CD1c(+) myeloid dendritic cells (mDCs) and disease activation/reactivation in noninfectious uveitis. METHODS. Noninfectious uveitis patients (n = 89) and healthy controls (n = 111) were recruited. The proportion of CD1c(+) mDCs in the total dendritic cell (DC) population of peripheral blood was measured by flow cytometry (CD1c(+) mDCs gated on Lineage 1(+)HLADR(+) DCs). Disease activity was assessed per Standardization of Uveitis Nomenclature criteria. Uveitis reactivation was ascribed to clinically quiescent patients who developed reactivation of intraocular inflammation within 6 months. RESULTS. The proportions of CD1c(+) mDCs were increased in noninfectious uveitis patients, especially in active disease, compared to healthy controls. This CD1c(+) mDC elevation was not associated with underlying systemic diseases, anatomic locations of uveitis, medications, or demographic factors. Longitudinal data showed that the dynamics of CD1c(+) mDC levels were correlated with disease activity. The average proportion of CD1c(+) mDCs in active uveitis patients was 60% so we set this as the cutoff between high and low CD1c(+) mDC levels. Although 74% of quiescent patients had low proportions of CD1c(+) mDCs, 26% still had high proportions. Quiescent patients with high CD1c(+) mDC proportions showed increased risk of disease reactivation, compared to quiescent patients with low CD1c(+) mDC proportions. CONCLUSIONS. Increased proportions of CD1c(+) mDCs were associated with clinical activity, and quiescent patients with elevated CD1c(+) mDCs were more likely to undergo reactivation. This suggests that CD1c(+) mDC proportion may be a potential biomarker for assessing clinical activation and reactivation in noninfectious uveitis.National Institutes of Health (NIH)/National Eye Institute (NEI) NIH Medical Research Scholars Program Pan-American Ophthalmological Foundation/Retina Research Foundation CONICY

Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 (AREDS2) Randomized Clinical Trial

Determining whether adding lutein + zeaxanthin, DHA + EPA, or both to the Age-Related Eye Disease Study (AREDS) formulation decreases the risk of developing advanced age-related macular degeneration (AMD) and evaluating the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation are discussed. Result shows that addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation

Secondary Analyses of the Effects of Lutein/Zeaxanthin on Age-Related Macular Degeneration Progression

The Age-Related Eye Disease Study (AREDS) formulation for treatment of age-related macular degeneration contains vitamins C, E, beta-carotene and zinc with copper. Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk of lung cancer from beta-carotene in smokers and former smokers. As previously reported in a secondary analysis, AREDS2 participants taking lutein/zeaxanthin with or without omega-3 long-chain polyunsaturated fatty 3 acids had a slightly lower progression rate to late AMD than participants not taking lutein/zeaxanthin. OBJECTIVE: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTS: AREDS2, a multicenter, double-masked randomized trial, of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% had bilateral large drusen and 34% had large drusen and late AMD in one eye. INTERVENTIONS: In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to one of the following four groups: placebo, lutein/zeaxanthin (10mg/2mg), omega-3 long-chain polyunsaturated fatty 3 acids (1.0 g), or the combination. MAIN OUTCOME MEASURES: Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS: In exploratory analysis of lutein/zeaxanthin vs. no lutein/zeaxanthin, the HR the development of late AMD was 0.90 (95% CI: 0.82–0.99), p=0.04. Exploratory analyses of direct comparison of lutein/zeaxanthin vs. beta-carotene showed HRs: 0.82 (95% CI: 0.69–0.96), p=0.02 for development of late AMD, 0.78 (95% CI: 0.64–0.94) p=0.01 for development of neovascular AMD, and 0.94 (95% CI: 0.70–1.26), p=0.67 for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs. beta-carotenes showed HRs: 0.76 (95% CI: 0.61–0.96) p=0.02 for progression to late AMD; 0.65 (95% CI: 0.49–0.85) p=0.002 for neovascular AMD; and 0.98 (95% CI: 0.69–1.39) p=0.91 for central geographic atrophy. CONCLUSION AND RELEVANCE: The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta-carotene in the AREDS type supplements

Hypomethylation of the IL17RC Promoter Associates with Age-Related Macular Degeneration

SummaryAge-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Although recent studies have demonstrated strong genetic associations between AMD and SNPs in a number of genes, other modes of regulation are also likely to play a role in the etiology of this disease. We identified a significantly decreased level of methylation on the IL17RC promoter in AMD patients. Furthermore, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and messenger RNA in peripheral blood as well as in the affected retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis