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Objective There is substantial variability in the effectiveness of group lifestyle interventions for weight loss. We examined associations between intervention weight loss counselors and participant weight loss and program engagement in a structured lifestyle intervention. Methods Data were from 575 adults (87% female, 51 (12) years, baseline BMI: 32.4 (7.2) kg/m2) in an 11-week structured group lifestyle program. Participants self-enrolled in groups led by 11 weight loss counselors based on meeting times. All weight loss counselors received the same training. Linear mixed models were used to evaluate counselor predictors of participant percent (%) weight loss and program engagement (weight reporting throughout 11 weeks). Results Of the 575 participants, 415 (72%) defined as complete reporters, i.e. reported weight weekly, lost a mean 7.3% weight (range: +3.1% to 16.2%). Participant weight loss differed between weight loss counselors (p = 0.003), and adjusted mean participant weight loss by weight loss counselor ranged from 6% to 9%. Weight loss was greater for weight loss counselors with a graduate degree in nutrition than weight loss counselors with another graduate degree (8.3% versus 6.4%, p = 0.05), but was not different between weight loss counselors with and without graduate degrees. Higher counselor BMI was associated with higher participant weight loss (p = 0.005). Conclusions These results demonstrate the potential for quantitatively important effects of weight loss counselor characteristics on participant success and engagement in structured lifestyle interventions, indicating a need for research in this area.

Introduction Effective, standardized, and easily accessible weight management programs are urgently needed for military beneficiaries. Videoconference interventions have the potential for widespread scaling, and can provide both real time interaction and flexibility in delivery times regardless of location, but there is little information on their effectiveness and acceptability. Materials and Methods This study as part of a larger weight loss trial describes the videoconference adaption of Group Lifestyle Balance (GLB) program, a community group-based Diabetes Prevention Program intervention, and provides a comparison of weight loss and meeting attendance between in-person and videoconference delivery modes over 12 weeks in adult family members of military service members. Forty-three participants were enrolled from two military installations and received either the videoconference-adapted or an in-person GLB program in a non-randomized trial design. Differences in program attendance and percent weight lost at 12 weeks were compared by independent samples t-tests and nonparametric methods. Group differences in the percentage of weight lost over the 12-week period were analyzed using a linear mixed model. Results All GLB intervention components were successfully delivered by videoconference with minor adaptations for the different delivery mechanism. Participant retention was 70% and 96% in the in-person and videoconference groups, respectively (p = 0.04). Completing participants in both groups lost a significant percent body weight over the 12 week intervention (p < 0.001) and there was no difference in percent body weight after 12 weeks of intervention (6.2 ± 3.2% and 5.3 ± 3.4% for in-person and videoconference at 12 weeks, respectively; p = 0.60). Conclusion This study describes the first videoconference adaption of the GLB program for use in military families. Attrition was lower in the videoconference group, and there were a similar levels of weight loss in both groups regardless of delivery modality. Videoconference weight loss interventions are effective and feasible for scaling to support healthy weight management in military as well as civilian populations.

OBJECTIVES: Emerging evidence suggests that anti-inflammatory dietary patterns may improve depression, stress, and quality of life. Similar benefits are observed during weight loss interventions; however, the effect of combining these dietary patterns with weight loss is not clear. We evaluated the association between dietary inflammation and measures of psychological health in female military dependents with overweight and obesity during a behavioral weight loss intervention. METHODS: Participants (n = 120) received a 6-month intervention recommending dietary patterns with an anti-inflammatory profile. An energy-adjusted dietary inflammatory index (DII) score was calculated from 28 food components collected using 3 interviewer-administered multiple-pass 24-hour recalls at each study time point. A negative score indicates a lower-inflammatory dietary pattern, and a positive score indicates a pro-inflammatory pattern. Self-reported symptoms of depression, stress, general health, vitality, and psychological quality of life were measured by validated questionnaires. Multivariable linear mixed models were used to assess the association between 6-month changes in DII and each outcome and were adjusted for age, ethnicity, military rank of spouse, body weight, and physical activity. RESULTS: On average, females were 42.2 ± 11.8 years old with a body mass index of 34.9 ± 6.4 kg/m(2). The average DII score was 0.07 (range: −4.3, 3.0) at baseline. Six-month improvements in DII scores (i.e., for a 1-unit reduction) were associated with fewer self-reported symptoms of depression (β: −0.87; 95% confidence interval: −1.43, −0.31; P = 0.003) and stress (−0.85; −1.44, −0.26; P = 0.005), as well as higher general health (0.57; 0.23, 0.91; P = 0.001), vitality (0.45; 0.12, 0.77; P = 0.008), and psychological quality of life (0.33; 0.11, 0.55; P = 0.004). No significant associations between weight loss or physical activity and any outcome were observed in these models that included the DII. CONCLUSIONS: Anti-inflammatory dietary patterns are associated with beneficial effects on a range of psychological health and wellbeing measures independent of weight loss. FUNDING SOURCES: Jean Mayer USDA Human Nutrition Research Center on Aging Doctoral Scholarship; Department of Defense (DoD) grant W81XWH-14–2-0005 (SBR). Author views do not reflect official DoD or Army policy.

OBJECTIVES: There is persistent controversy over the extent to which different components of energy expenditure disproportionately decrease after weight loss and contribute to weight regain through decreased energy requirements. We conducted a secondary analysis of the CALERIE I study to test the hypothesis that decreased resting metabolic rate (RMR) and energy expenditure for physical activity (EEPA) after a 6-month calorie restriction intervention would predict weight regain at 12 months, with a greater decrease in RMR than EEPA. METHODS: Participants (n = 46) received all food and energy-containing beverages for 6 months. Outcome measures included total energy expenditure by doubly labeled water, RMR by indirect calorimetry, and body composition by BOD POD. Predictions for RMR and EEPA were derived from baseline linear regression models including age, sex, fat mass, and fat free mass. Baseline regression coefficients were used to calculate the predicted RMR and EEPA at 6 months. Residuals were calculated as the difference between measured and predicted values and were adjusted for body weight. The presence of metabolic adaptation was evaluated by a paired t-test comparing measured and predicted RMR at 6 months. Differences between 6-month RMR and EEPA residuals were evaluated by the same method. Linear regression was used to assess the association between 6-month residuals and weight loss maintenance (% weight change, 6 to 12 months). RESULTS: Mean weight loss was 6.9% at 6 months with 2.1% regain from 6 to 12 months. No adaptation in RMR was observed at 6 months (mean residual: 19 kcal; 95% confidence interval: −9, 48; P = 0.18). However, significant adaptation was observed in EEPA (mean residual: −199 kcal; −126, −272; P

The amount of time spent in poor health at the end of life is increasing. This narrative review summarizes consistent evidence indicating that healthy dietary patterns and maintenance of a healthy weight in the years leading to old age are associated with broad prevention of all the archetypal diseases and impairments associated with aging including: noncommunicable diseases, sarcopenia, cognitive decline and dementia, osteoporosis, age-related macular degeneration, diabetic retinopathy, hearing loss, obstructive sleep apnea, urinary incontinence, and constipation. In addition, randomized clinical trials show that disease-specific nutrition interventions can attenuate progression-and in some cases effectively treat-many established aging-associated conditions. However, middle-aged and older adults are vulnerable to unhealthy dietary patterns, and typically consume diets with inadequate servings of healthy food groups and essential nutrients, along with an abundance of energy-dense but nutrient-weak foods that contribute to obesity. However, based on menu examples, diets that are nutrient-dense, plant-based, and with a moderately low glycemic load are better equipped to meet the nutritional needs of many older adults than current recommendations in US Dietary Guidelines. These summary findings indicate that healthy nutrition is more important for healthy aging than generally recognized. Improved public health messaging about nutrition and aging, combined with routine screening and medical referrals for age-related conditions that can be treated with a nutrition prescription, should form core components of a national nutrition roadmap to reduce the epidemic of unhealthy aging.

BACKGROUND Lifestyle interventions are the first-line treatment for obesity, but participant weight loss is typically low. OBJECTIVES We evaluated the efficacy of an alternative lifestyle intervention [Healthy Weight for Living (HWL)] compared with a modified Diabetes Prevention Program (m-DPP). HWL was based on a revised health behavior change model emphasizing hunger management and the development of healthy food preferences. m-DPP was a standard Diabetes Prevention Program implemented with counselor time matched to HWL. Participants were adult dependents of military personnel and had overweight or obesity. METHODS Participants were randomly assigned to HWL (n = 121) or m-DPP (n = 117), delivered primarily by group videoconference with additional midweek emails. The primary outcome was 12-mo weight change. Secondary outcomes included 6-mo changes in cardiometabolic risk factors and diet. Intention-to-treat (ITT) and complete case (CC) analyses were performed using linear mixed models. RESULTS Retention did not differ between groups (72% and 66% for HWL and m-DPP at 12 mo, respectively; P = 0.30). Mean ± SE adjusted 12-mo weight loss in the ITT cohort was 7.46 ± 0.85 kg for HWL and 7.32 ± 0.87 kg for m-DPP (P = 0.91); in the CC cohort, it was 7.83 ± 0.82 kg for HWL and 6.86 ± 0.88 kg for m-DPP (P = 0.43). Thirty-eight percent of HWL and 30% of m-DPP completers achieved ≥10% weight loss (P = 0.32). Improvements in systolic blood pressure, LDL cholesterol, triglycerides, fasting glucose, general health, sleep, and mood were similar across groups; improvements in diastolic blood pressure were greater in m-DPP. Adjusted group mean reductions in energy intake were not significantly different between groups, but HWL participants were more adherent to their dietary prescription for lower glycemic index and high fiber and protein (P = 0.05 to

Renan Rodrigues,1 Myrna Serapião Dos Santos,1,2 Rachel E Silver,3 Mauro Campos,1,2 Rachel LR Gomes1,2 1Department of Ophthalmology, Federal University of Sao Paulo, Sao Paulo, Brazil; 2Cataract Department, Hospital de Olhos Paulista, Sao Paulo, Brazil; 3Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA Purpose: To evaluate anatomical differences between laser (VICTUS) and manual constructed phacoemulsification incisions.Setting: Study was conducted at the Hospital de Olhos Paulista, Sao Paulo, Brazil.Design: This is a prospective, observational, consecutive nonrandomized cohort.Patients and methods: Sixteen patients (18 eyes) had phacoemulsification surgery, nine eyes had manual incisions and nine eyes had femtosecond incisions. All incisions were performed by the same surgeon. All incisions were evaluated at the 1st and 30th postoperative day with anterior segment optical coherence tomography to evaluate anatomical features. Inclusion criterion was presence of low visual acuity due to cataract. Exclusion criteria were other ocular pathologies, previous trauma, or corneal wound healing disease, as any intra or postoperative complication. Three different corneal specialists analyzed wound architecture features (epithelial or endothelial gap, incision edema, number of planes, Descemet’s detachment, and loss of wound sealing) at both visits. ImageJ (National Institutes of Health) software was also used to analyze anatomical features of incisions.Results: Almost all incisions had edema at the first postoperative day. All femto incisions were triplanar, as intended, unlike manual incisions, which showed two uniplanar incisions (P=0.009). All laser incisions presented partial loss of wound sealing, while five keratome incisions had no loss of wound sealing at the first postoperative day (P=0.03).Conclusion: These findings support the hypothesis that laser constructed incisions are more precisely constructed than manual, although corneal wound healing was similar between the two groups at the 30th postoperative day, with a tendency to a faster anatomical improvement in the keratome group. Keywords: phacoemulsification, cataract, femtosecond laser, optical coherence tomography, cornea&nbsp

OBJECTIVES: Self-monitoring daily dietary intake is recommended for weight loss, weight maintenance, and healthy eating. However, current tracking methods are often burdensome and result in short-term use. We conducted a pilot study to evaluate the accuracy of a new application designed to self-monitor dietary intake using natural spoken language (COCO; The Conversational Calorie Counter). METHODS: A total of 14 participants were recruited for the pilot study. They were instructed to record daily dietary intake using the COCO application for at least five consecutive days. Two unscheduled 24-hour dietary recalls were conducted between day 3 and day 5 as the reference method for evaluating total energy intake (TEI). The two-day energy estimates were averaged for each assessment method. Pearson's correlation coefficient was used to assess the validity of the COCO application. Estimates of TEI from COCO were compared to the 24-hour dietary recall by a paired samples t-test. RESULTS: Participants were primarily female (86%), with an average body mass index of 22.2 ± 1.8 kg/m(2) (mean ± standard deviation). On average, participants consumed three daily meals and recorded dietary intake for six days using the COCO application. The average TEI was 1782 ± 773 kcal for all recorded days (range: 4 to 10). The mean TEI measured by 24-hour dietary recall was 1791 ± 862 kcal, and mean TEI measured by COCO for the corresponding days was 1818 ± 916 kcal. We observed a significant correlation between the assessment methods (r = 0.58; P = 0.03), and there was no significant difference in TEI estimates from COCO compared to the 24-hour recall (P = 0.90). CONCLUSIONS: These results suggest that natural spoken language technology can be used in applications that facilitate self-monitoring of food intake to support weight management and the prevention of noncommunicable diseases. The significant correlation between estimates of TEI from COCO and the 24-hour dietary recall indicates the potential validity of this novel approach for capturing dietary data and assessing energy intake. FUNDING SOURCES: Sponsored by the National Institutes of Health (R21HL118347), the U.S. Department of Agriculture with Tufts University (58–1950-4–003), Quanta Computing, Inc., and the Department of Defense (National Defense Science Engineering Graduate Fellowship Program).

Purpose There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but no prospective studies have explored the impact of vitamin D. We evaluated the association between vitamin D intake and progression to advanced AMD. Methods Among 2146 participants (3965 eyes), 541 (777 eyes) progressed from early or intermediate AMD to advanced disease (mean follow-up: 9.4 years) based on ocular imaging. Nutrients were log transformed and calorie adjusted. Survival analysis was used to assess associations between incident advanced disease and vitamin D intake. Neovascular disease (NV) and geographic atrophy (GA) were evaluated separately. Combined effects of dietary vitamin D and calcium were assessed based on high or low consumption of each nutrient. Results There was a lower risk of progression to advanced AMD in the highest versus lowest quintile of dietary vitamin D intake after adjustment for demographic, behavioral, ocular, and nutritional factors (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.43-0.83; P trend = 0.0007). Similar results were observed for NV (HR: 0.59; 95% CI: 0.39-0.89; P trend = 0.005) but not GA (HR: 0.83; 95% CI: 0.53-1.30; P trend = 0.35). A protective effect was observed for advanced AMD among participants with high vitamin D and low calcium compared to the group with low levels for each nutrient (HR: 0.67; 95% CI: 0.50-0.88; P = 0.005). When supplement use was considered, the effect was in the protective direction but was not significant. Conclusions A diet rich in vitamin D may prevent or delay progression to advanced AMD, especially NV. Additional exploration is needed to elucidate the potential protective role of vitamin D and its contribution to reducing visual loss.

Background/aims The Age-Related Eye Disease Study (AREDS) reported the beneficial impact of antioxidant and zinc supplements on the risk of progression to advanced stages of age-related macular degeneration (AMD). We evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD. Methods Among 4124 eyes (2317 subjects with a genetic specimen), 882 progressed from no AMD, early or intermediate AMD to overall advanced disease, including geographic atrophy (GA) and neovascular disease (NV) over the course of the clinical trial. Survival analysis using individual eyes as the unit of analysis was used to assess the effect of supplementation on AMD outcomes, with adjustment for demographic, environmental, ocular and genetic covariates. Interaction effects between supplement groups and individual complement factor H (CFH) Y402H and age-related maculopathy susceptibility 2 ( ARMS2 ) genotypes, and composite genetic risk groups combining the number of risk alleles for both loci, were evaluated for their association with progression. Results Among antioxidant and zinc supplement users compared with the placebo group, subjects with a non-risk genotype for CFH (TT) had a lower risk of progression to advanced AMD (HR: 0.55, 95% CI 0.32 to 0.95, p=0.033). No significant treatment effect was apparent among subjects who were homozygous for the CFH risk allele (CC). A protective effect was observed among high-risk ARMS2 (TT) carriers (HR: 0.52, 95% CI 0.33 to 0.82, p=0.005). Similar results were seen for the NV subtype but not GA. Conclusions The effectiveness of antioxidant and zinc supplementation appears to differ by genotype. Further study is needed to determine the biological basis for this interaction. Trial registration number NCT00594672, pre-results.

Calorie restriction (CR) is a promising strategy to attenuate age-related disease risk. Higher protein diets enhance satiety but may also impair metabolic health and accelerate aging. The effect of higher protein intake on adherence to CR and cardiometabolic markers of healthspan remains unknown. We used the Geometric Framework for Nutrition to examine the association between diet composition and 1) CR adherence; and 2) cardiometabolic risk factors during a 2-year intervention. The CR group consumed higher percentage energy from protein and lower fat at 12 months compared to baseline (logit % protein=0.1; 95% CI=0.05, 0.15; logit % fat= -0.12; CI=-0.29, -0.18). Higher protein intake over the 2-year intervention was associated with higher adherence to CR. No effect of diet composition on cardiometabolic risk factors was observed. These findings suggest that dietary protein plays a critical role in adherence to CR with no adverse effects on cardiometabolic markers of healthspan. Part of a symposium sponsored by the Nutrition Interest Group.

ObjectiveTo assess the effects of food supplementation on improving working memory and additional measures including cerebral blood flow in children at risk of undernutrition.DesignRandomized controlled trial.Setting10 villages in Guinea-Bissau.Participants1059 children aged 15 months to 7 years; children younger than 4 were the primary population.InterventionsSupervised isocaloric servings (≈1300 kJ, five mornings each week, 23 weeks) of a new food supplement (NEWSUP, high in plant polyphenols and omega 3 fatty acids, within a wide variety and high fortification of micronutrients, and a high protein content), or a fortified blended food (FBF) used in nutrition programs, or a control meal (traditional rice breakfast).Main outcome measurementsThe primary outcome was working memory, a core executive function predicting long term academic achievement. Additional outcomes were hemoglobin concentration, growth, body composition, and index of cerebral blood flow (CBFi). In addition to an intention-to-treat analysis, a predefined per protocol analysis was conducted in children who consumed at least 75% of the supplement (820/925, 89%). The primary outcome was assessed by a multivariable Poisson model; other outcomes were assessed by multivariable linear mixed models.ResultsAmong children younger than 4, randomization to NEWSUP increased working memory compared with the control meal (rate ratio 1.20, 95% confidence interval 1.02 to 1.41, P=0.03), with a larger effect in the per protocol population (1.25, 1.06 to 1.47, P=0.009). NEWSUP also increased hemoglobin concentration among children with anemia (adjusted mean difference 0.65 g/dL, 95% confidence interval 0.23 to 1.07, P=0.003) compared with the control meal, decreased body mass index z score gain (−0.23, −0.43 to −0.02, P=0.03), and increased lean tissue accretion (2.98 cm2, 0.04 to 5.92, P=0.046) with less fat (−5.82 cm2, −11.28 to −0.36, P=0.04) compared with FBF. Additionally, NEWSUP increased CBFi compared with the control meal and FBF in both age groups combined (1.14 mm2/s×10−8, 0.10 to 2.23, P=0.04 for both comparisons). Among children aged 4 and older, NEWSUP had no significant effect on working memory or anemia, but increased lean tissue compared with FBF (4.31 cm2, 0.34 to 8.28, P=0.03).ConclusionsChildhood undernutrition is associated with long term impairment in cognition. Contrary to current understanding, supplementary feeding for 23 weeks could improve executive function, brain health, and nutritional status in vulnerable young children living in low income countries. Further research is needed to optimize nutritional prescriptions for regenerative improvements in cognitive function, and to test effectiveness in other vulnerable groups.Trial registrationClinicalTrials.gov NCT03017209.

OBJECTIVES: Anti-inflammatory diets have been suggested to improve psychological health. This research evaluated the combined effects of consuming an anti-inflammatory diet and caloric restriction (CR) on changes in perceived stress and health-related quality of life in a healthy, non-obese population. METHODS: We conducted a secondary analysis of the publicly available CALERIE data. Participants were randomized to a 2 year CR intervention (n = 143) or an ad libitum Control group (n = 75) and self-selected their dietary intake. An energy-adjusted dietary inflammatory index (DII) was calculated based on 28 components from self-reported food records. Self-reported stress and general health outcomes were measured using validated questionnaires. Linear mixed models were used to assess changes in each outcome from baseline to 12 and 24 months. Models were adjusted for age, sex, baseline outcome measure, change in body fat, and a treatment by DII interaction term. RESULTS: On average, participants were 38.1 ± 7.2 years old with a BMI of 25.1 ± 1.7 kg/m(2). Baseline characteristics, including the DII, stress, and general health, did not differ with randomization. There was no significant association between temporal changes in DII and changes in stress or general health in the CR or Control groups. On average, both groups tended to report higher stress at 12 months; however, there was no difference in perceived stress between groups (adjusted mean difference [MD]: 0.5; 95% confidence interval [CI]: −0.4, 1.5; P = 0.25). There was an improvement in reported general health in the CR group at 12 months (MD: 4.1; 95% CI: 2.2, 6.0; P

Gluten-free (GF) eating patterns are frequently perceived to be healthier than gluten-containing (GC) ones, but there has been very little research to evaluate this viewpoint. The effect of GF eating patterns on dietary composition was assessed using two independent approaches. One approach compared macronutrients and typical shortfall nutrients between MyPlate example menus developed with either GC or equivalent GF foods. In this analysis, the GF menus were significantly lower in protein, magnesium, potassium, vitamin E, folate, and sodium (p = 0.002&ndash, 0.03), with suggestive trends towards lower calcium and higher fat (p = 0.06&ndash, 0.08). The second approach was a meta-analysis of seven studies comparing information on the nutrient intakes of adults with celiac disease following a GF diet with control subjects eating a GC diet, and differences were evaluated using paired t-tests or Wilcoxon Signed rank tests. In this analysis, consuming a GF diet was associated with higher energy and fat intakes, and lower fiber and folate intakes compared to controls (p &lt, 0.001 to p = 0.03). After adjusting for heterogeneity and accounting for the large mean effect size (&minus, 0.88 &plusmn, 0.09), the lower fiber remained significant (p &lt, 0.001). These combined analyses indicate that GF diets are not nutritionally superior except for sodium, and in several respects are actually worse.

OBJECTIVES: Undernutrition is prevalent among young children worldwide and is associated with impaired cognition and reduced educational attainment. We conducted a randomized controlled trial to test the effect of a novel supplementary food (regenerative nutrition for enhanced wellness-cognition; RENEW-C) compared to traditional feeding practices on cognitive function, cerebral blood flow and oxygen metabolism in rural Guinea-Bissau. METHODS: Children aged 15 months to 7 years (n = 1059) were randomized to receive isocaloric quantities of RENEW-C (a highly-fortified cocoa-based bar), a USAID fortified blended food (FBF) or a Control food (rice cooked with oil, replicating a traditional breakfast). The primary outcome was executive function. Secondary outcomes included a cerebral blood flow index (CBF(i)) and cerebral metabolic rate of oxygen (CMRO(2)) measured by Frequency-Domain Near-Infrared Spectroscopy and Diffusion Correlation Spectroscopy (FDNIRS-DCS, MetaOx, ISS Inc.). Six-month changes for RENEW-C and FBF versus Controls were assessed by multivariable linear mixed models adjusted for age, sex, baseline measurement, and study cohort. RESULTS: Improvements in executive function (0.38; 95% CI: 0.10, 0.71; P = 0.02) were observed for RENEW-C compared to Controls in the predefined study focus (children 75% their supplement). There was no significant effect of RENEW-C in children ≥ 4 years. No benefit of the FBF was observed in either age group. In addition, changes in CBF(i) and CMRO(2) in RENEW-C children were greater than in Controls in both ventrolateral prefrontal cortical regions (P = 0.03 and P = 0.04 for left and right, respectively) and greater than FBF in the left ventrolateral (P = 0.05) and left dorsolateral (P = 0.03) prefrontal cortices. CONCLUSIONS: Compared with traditional feeding practices, the RENEW-C supplement consumption was correlated with a marked improvement in executive function among children

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 50 years of age in industrialized countries.1 Despite its high prevalence, the cause of AMD remains largely unknown. Clinically and histologically, AMD is generally classified as nonexudative or dry AMD, of which geographic atrophy (GA) is the severe form, and exudative or neovascular AMD. Dry AMD progresses more slowly and is characterized by drusen, geographic or focal atrophy of the retinal pigment epithelium (RPE), and photoreceptor dysfunction and degeneration. The advanced exudative form, neovascular AMD, can develop after early and intermediate dry AMD.2 The key feature of the advanced subtype is choroidal neovascularization (CNV), the growth of new blood vessels from the choroid into the region underlying the RPE or extending into the subretinal space. Emerging evidence supports the association between chronic inflammation and AMD. Penfold et al.3 described inflammatory cells (macrophages, lymphocytes, and mast cells) in human AMD choroids. More recent findings suggest a role for immunologic processes in AMD pathogenesis, including recruitment of macrophages,4 involvement of systemic inflammatory processes,5–7 complement activation,8–12 and microglial activation and accumulation.13 Historically, macrophages have been observed at sites of CNV in patients with AMD,14,15 and CD68+ macrophages were detected in rapidly progressive fibrovascular AMD membranes.16 Grossniklaus et al.17 evaluated human CNV and observed that macrophages express proangiogenic vascular endothelial growth factor (VEGF) and suggested that they directly promote CNV.18 Macrophage populations are simplistically divided into phenotypes M1 and M2. Phenotype M1 is proinflammatory and causes tissue injury, whereas M2 phenotype is pro-angiogenic and promotes tissue repair.19 In the laser-induced mouse CNV model with scar, M2 macrophages were recruited to the site of laser injury20,21; however, M1 macrophages were identified in the subretinal space when mice were immunized with carboxyethylpyrrole), an immune response-initiated model of AMD.22,23 Determination of M1 and M2 macrophages in a human is not as straightforward as it is in mouse. In the present study, we chose to localize all macrophages with the monocyte marker ionized calcium-binding adapter molecule 1 (IBA1) and determine if they were activated using an antibody to human leukocyte antigen-antigen D-related (HLA-DR), a subunit of major histocompatibility complex (MHC) class II. The present study aimed to quantify the number, distribution, and activation of choroidal macrophages in choroidal whole mounts from aged control eyes and in eyes from patients with clinically documented early and intermediate AMD, as well as two advanced subtypes, neovascular AMD and GA. The presence of macrophages was related to changes in choriocapillaris (CC) and CNV.

Age-related macular degeneration (AMD) is a multifactorial disease with genetic and environmental factors contributing to risk. Histopathologic changes underlying AMD are not fully understood, particularly the relationship between choriocapillaris (CC) dysfunction and phenotypic variability of this disease.To examine histopathologic changes in the CC of eyes with clinically documented AMD.The study was designed in 2011. Tissues were collected post mortem (2012-2016), and histopathological images were obtained from participants enrolled in AMD studies since 1988. Clinical records and images were collected from participants as standard protocol. Eyes without AMD (n = 4) and eyes with early (n = 9), intermediate (n = 5), and advanced stages of AMD (geographic atrophy, n = 5; neovascular disease, n = 13) were evaluated. Choroidal vasculature was labeled using Ulex europaeus agglutinin lectin and examined using confocal microscopy.A standardized classification system was applied to determine AMD stage. Ocular records and images were reviewed and histopathologic analyses performed. Viability of the choroidal vasculature was analyzed for each AMD stage.All participants were white. Fourteen were male, and 16 were female. The mean age was 90.5 years among AMD patients and 88.5 years among control participants. Submacular CC dropout without retinal pigment eipthelial (RPE) loss was observed in all cases with early stages of AMD. Higher vascular area loss for each AMD stage was observed compared with control participants: 20.5% in early AMD (95% CI, 11.2%-40.2%; P .001), 12.5% in intermediate AMD (95% CI, 2.9%-21.4%; P = .01), 39.0% loss in GA (95% CI, 32.1%-45.4%; P .001), and 38.2% loss in neovascular disease where RPE remained intact (95% CI, 27.7%-47.9%; P .001). Hypercellular, apparent neovascular buds were adjacent to areas of CC loss in 22.2% of eyes with early AMD and 40% of eyes with intermediate AMD.Retinal pigment epithelial atrophy preceded CC loss in geographic atrophy, but CC loss occurred in the absence of RPE atrophy in 2 of 9 eyes with early-stage AMD. Given the cross-sectional nature of this study and the small number of eyes evaluated, definitive conclusions regarding this progression cannot be determined with certainty. We speculate that neovascular buds may be a precursor to neovascular disease. Hypoxic RPE resulting from reduced blood supply might upregulate production of vascular endothelial growth factor, providing the stimulus for neovascular disease.

The era of personalized medicine and targeted therapies is emerging in many areas of medicine. In ophthalmology, the disease age-related macular degeneration (AMD) stands alone in having several environmental and genetic risk factors with confirmed, combined high impact on its development and progression. The combination of demographic, behavioral, and genetic factors can achieve a high predictive value for progression to advanced stages of disease approaching 90%, unlike any other disease.1–,5 We developed genetic risk algorithms in 2006,6 subsequently adding nongenetic markers7 and more common genetic variants,2–,4,8 then recently validated these risk models in an independent study cohort.5 More genetic loci in a 9 gene model, including the strongly related rare variant in the gene CFH (R1210C),9 and common loci RAD51B and COL8A1,10,11 enhanced predictability for transition from early and intermediate stages to advanced disease.12 Knowledge about the genetic underpinnings of AMD continues to expand. New, rare genetic variants have been discovered in case-control association studies in the genes C313–,15 and C9,13 as well as a burden of several rare variants in CFI.13 While these variants are uncommon, they have a stronger impact on the development of the disease individually compared with the low to moderate impact of the 20 or more common variants associated with AMD. Given that previous analyses were based on cross-sectional analyses of prevalent cases, and that progression of disease over time can have different underlying predictors, we conducted longitudinal analyses to determine the impact of these new rare variants on transition to the late stages of AMD resulting in visual loss over time. We also assessed the independent association of these new variants on progression, controlling for other genetic and nongenetic predictors. Building upon our previous algorithms, we developed and assessed a new risk prediction model for progression of AMD (rPPMD) and evaluated the degree to which AMD progression could be attributed to its various components: environmental, ocular, and genetic. In order to lay the groundwork to disseminate these predictive models for clinical use, we developed a software framework and analytics components in the form of an online browser-based calculator (seddonamdriskscore.org, available in the public domain) to demonstrate its use with various subject risk profiles. The rPPMD software components are also designed to be adapted as a stand-alone application for a personal computer or mobile devices such as smartphones and tablets.