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The development of photodynamic therapy and anti-vascular endothelial growth factor agents have revolutionized the treatment of retinal diseases, transforming the retina subspecialty by ushering in an age of pharmacological treatments for a wide range of diseases, including age-related macular degeneration (AMD).

Age-related macular degeneration (AMD) remains a leading cause of blindness worldwide. The assessment and management of patients with this condition has evolved in the last decades. In this chapter, current standards for diagnosis, follow-up, and treatment of patients with AMD are reviewed and summarized. Namely, we highlight how current assessment has moved from conventional ophthalmoscopy and fluorescein angiography testing to a multimodal approach, and its important advantages. Alternatives to visual acuity for functional assessment of patients with AMD are also presented. Regarding strategies for follow-up and treatment, we provide specific information for the different stages (i.e., early, intermediate, and late) and forms (for example, choroidal neovascularization and geographic atrophy) of AMD. Specifically, we discuss the relevance and options for self-monitoring and non-pharmacological interventions. Additionally, a summary of the important trials (both on exudative and non-exudative AMD) that have helped inform clinical practice is provided, including data on antiangiogenic agents currently available, and outcomes of the different regimens that have been studied. The influence of advances in imaging on treatment strategies is also discussed.In summary, this chapter is a resource for all clinicians engaged in providing state of the art care for patients with AMD, and can help improve diagnosis, management, and outcomes of individuals with this blinding condition.

Background: Among women with epilepsy, studies regarding changes in seizure frequency during pregnancy have been limited by the lack of an appropriate nonpregnant comparator group to provide data on the natural course of seizure frequency in both groups., Methods: In this prospective, observational, multicenter cohort study, we compared the frequency of seizures during pregnancy through the peripartum period (the first 6 weeks after birth) (epoch 1) with the frequency during the postpartum period (the following 7.5 months after pregnancy) (epoch 2). Nonpregnant women with epilepsy were enrolled as controls and had similar follow-up during an 18-month period. The primary outcome was the percentage of women who had a higher frequency of seizures that impaired awareness during epoch 1 than during epoch 2. We also compared changes in the doses of antiepileptic drugs that were administered in the two groups during the first 9 months of epoch 1., Results: We enrolled 351 pregnant women and 109 controls with epilepsy. Among the 299 pregnant women and 93 controls who had a history of seizures that impaired awareness and who had available data for the two epochs, seizure frequency was higher during epoch 1 than during epoch 2 in 70 pregnant women (23%) and in 23 controls (25%) (odds ratio, 0.93; 95% confidence interval [CI], 0.54 to 1.60). During pregnancy, the dose of an antiepileptic drug was changed at least once in 74% of pregnant women and in 31% of controls (odds ratio, 6.36; 95% CI, 3.82 to 10.59)., Conclusions: Among women with epilepsy, the percentage who had a higher incidence of seizures during pregnancy than during the postpartum period was similar to that in women who were not pregnant during the corresponding epochs. Changes in doses of antiepileptic drugs occurred more frequently in pregnant women than in nonpregnant women during similar time periods. (Funded by the National Institutes of Health; MONEAD ClinicalTrials.gov number, NCT01730170.)., (Copyright © 2020 Massachusetts Medical Society.)

Rationale: Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness in the developed world. Aging, inflammation and complement dysregulation affecting the retinal pigment epithelium (RPE), are considered significant contributors in its pathogenesis and several evidences have linked tumor necrosis factor alpha (TNF-α) and complement component 3 (C3) with AMD. Acadesine, an analog of AMP and an AMP-activated protein kinase (AMPK) activator, has been shown to have cytoprotective effects in human clinical trials as well as having anti-inflammatory and anti-vascular exudative effects in animals. The purpose of this study was to evaluate if acadesine is able to suppress TNF-α induced C3 in RPE cells., Methods: ARPE-19 and human primary RPE cells were cultured and allowed to grow to confluence. TNF-α was used for C3 induction in the presence or absence of acadesine. Small molecule inhibitors and siRNA were used to determine if acadesine exerts its effect via the extracellular or intracellular pathway and to evaluate the importance of AMPK for these effects. The expression level of C3 was determined by immunoblot analysis., Results: Acadesine suppresses TNF-α induced C3 in a dose dependent manner. When we utilized the adenosine receptor inhibitor dipyridamole (DPY) along with acadesine, acadesine's effects were abolished, indicating the necessity of acadesine to enter the cell in order to exert it's action. However, pretreatment with 5-iodotubericidin (5-Iodo), an adenosine kinase (AK) inhibitor, didn't prevent acadesine from decreasing TNF-α induced C3 expression suggesting that acadesine does not exert its effect through AMP conversion and subsequent activation of AMPK. Consistent with this, knockdown of AMPK α catalytic subunit did not affect the inhibitory effect of acadesine on TNF-α upregulation of C3., Conclusions: Our results suggest that acadesine suppresses TNF-α induced C3, likely through an AMPK-independent pathway, and could have potential use in complement over activation diseases., Competing Interests: The authors have declared that no competing interests exist.

Background: Potential safety concerns relative to impaired cognitive function may exist when high folic acid exposures are combined with low vitamin B-12 status., Objectives: We aimed to examine the relation of the coexistence of high folate and low vitamin B-12 status with cognitive function, utilizing various definitions of "high" folate status., Methods: Cross-sectional data from older adults (≥60 y; n = 2420) from the 2011-2014 NHANES were analyzed. High folate status was defined as unmetabolized serum folic acid (UMFA) > 1 nmol/L or serum total folate > 74.1 nmol/L, and low vitamin B-12 status as methylmalonic acid > 271 nmol/L or serum vitamin B-12 < 150 pmol/L. Logistic regression models estimated ORs of scoring low on 1 of 4 cognitive tests: the Digit Symbol Substitution Test (DSST), the Consortium to Establish a Registry for Alzheimer's Disease Delayed Recall (CERAD-DR) and Word Learning tests, and the Animal Fluency test (AF)., Results: A significant interaction was observed relative to scoring low on the DSST (<34; UMFA; P-interaction = 0.0071) and AF (serum folate; P-interaction = 0.0078) for low vitamin B-12 and high folate status. Among those with low vitamin B-12, high UMFA or high serum total folate was associated with higher risk of scoring low on the DSST (OR: 2.16; 95% CI: 1.05, 4.47) and the AF (OR: 1.93; 95% CI: 1.08, 3.45). Among those with "normal" vitamin B-12, higher UMFA or serum total folate was protective on the CERAD-DR. In noninteraction models, when high folate and normal vitamin B-12 status was the reference group, low vitamin B-12 combined with high UMFA was associated with greater risk based on the DSST (<34, OR: 2.87; 95% CI: 1.85, 4.45; <40, OR: 2.22; 95% CI: 1.31, 3.75) and AF (OR: 1.97; 95% CI: 1.30, 2.97); but low vitamin B-12 and lower UMFA (OR: 1.69; 95% CI: 1.16, 2.47) was also significantly associated for DSST < 40 risk., Conclusions: Low vitamin B-12 was associated with cognitive impairment both independently and in an interactive manner with high folate for certain cognitive performance tests among older adults., (Published by Oxford University Press on behalf of the American Society for Nutrition 2020.)

Aging is a complex process with poorly understood genetic mechanisms. Recent studies have sought to classify genes as pro-longevity or anti-longevity using a variety of machine learning algorithms. However, it is not clear which types of features are best for optimizing classification performance and which algorithms are best suited to this task. Further, performance assessments based on held-out test data are lacking. We systematically compare five popular classification algorithms using gene ontology and gene expression datasets as features to predict the pro-longevity versus anti-longevity status of genes for two model organisms (C. elegans and S. cerevisiae) using the GenAge database as ground truth. We find that elastic net penalized logistic regression performs particularly well at this task. Using elastic net, we make novel predictions of pro- and anti-longevity genes that are not currently in the GenAge database., Competing Interests: The authors have declared that no competing interests exist.

Background: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites., Objectives: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites., Methods: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993-1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined., Results: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (-4.00% and -6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration., Conclusions: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas., (Published by Oxford University Press on behalf of the American Society for Nutrition 2020.)

New environmental regulations are mandating cleaner fuels and lower emissions from all maritime operations. Natural gas (NG) is a fuel that enables mariners to meet regulations; however, emissions data from maritime operations with natural gas is limited. We measured emissions of criteria, toxic and greenhouse pollutants from a dual-fuel marine engine running either on diesel fuel or NG as well as engine activity and analyzed the impacts on pollutants, health, and climate change. Results showed that particulate matter (PM), black carbon (BC), nitric oxides (NO x ), and carbon dioxide (CO 2 ) were reduced by about 93%, 97%, 92%, and 18%, respectively when switching from diesel to NG. Reductions of this magnitude provide a valuable tool for the many port communities struggling with meeting air quality standards. While these pollutants were reduced, formaldehyde (HCHO), carbon monoxide (CO) and methane (CH 4 ) increased several-fold. A health risk assessment of exhaust plume focused on when the vessel was stationary, and at-berth showed the diesel plume increased long-term health risk and the NG plume increased short-term health risk. An analysis of greenhouse gases (GHGs) and BC was performed and revealed that, on a hundred year basis, the whole fuel cycle global warming potential (GWP) per kWh including well-to-tank and exhaust was 50% to few times higher than that of diesel at lower engine loads, but that it was similar at 75% load and lower at higher loads. Mitigation strategies for further reducing pollutants from NG exhaust are discussed and showed potential for reducing short-term health risks and climate impacts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

To develop an automated retina layer thickness measurement tool for the ImageJ platform, to quantitate nuclear layers following the retina contour. We developed the ThicknessTool (TT), an automated thickness measurement plugin for the ImageJ platform. To calibrate TT, we created a calibration dataset of mock binary skeletonized mask images with increasing thickness masks and different rotations. Following, we created a training dataset and performed an agreement analysis of thickness measurements between TT and two masked manual observers. Finally, we tested the performance of TT measurements in a validation dataset of retinal detachment images. In the calibration dataset, there were no differences in layer thickness between measured and known thickness masks, with an overall coefficient of variation of 0.00%. Training dataset measurements of immunofluorescence retina nuclear layers disclosed no significant differences between TT and any observer's average outer nuclear layer (ONL) (p = 0.998), inner nuclear layer (INL) (p = 0.807), and ONL/INL ratio (p = 0.944) measurements. Agreement analysis showed that bias between TT vs. observers' mean was lower than between any observers' mean against each other in the ONL (0.77 ± 0.34 µm vs 3.25 ± 0.33 µm) and INL (1.59 ± 0.28 µm vs 2.82 ± 0.36 µm). Validation dataset showed that TT can detect significant and true ONL thinning (p = 0.006), more sensitive than manual measurement capabilities (p = 0.069). ThicknessTool can measure retina nuclear layers thickness in a fast, accurate, and precise manner with multi-platform capabilities. In addition, the TT can be customized to user preferences and is freely available to download.

Breast cancer among males in the United States is rare; approximately 2,300 new cases and 500 associated deaths were reported in 2017, accounting for approximately 1% of all breast cancers.* Risk for male breast cancer increases with increasing age (1), and compared with women, men receive diagnoses later in life and often at a later stage of disease (1). Gradual improvement in breast cancer survival from 1976-1985 to 1996-2005 has been more evident for women than for men (1). Studies examining survival differences among female breast cancer patients observed that non-Hispanic White (White) females had a higher survival than non-Hispanic Black (Black) females (2), but because of the rarity of breast cancer among males, few studies have examined survival differences by race or other factors such as age, stage, and geographic region. CDC's National Program of Cancer Registries (NPCR) † data were used to examine relative survival of males with breast cancer diagnosed during 2007-2016 by race/ethnicity, age group, stage at diagnosis, and U.S. Census region. Among males who received a diagnosis of breast cancer during 2007-2016, 1-year relative survival was 96.1%, and 5-year relative survival was 84.7%. Among characteristics examined, relative survival varied most by stage at diagnosis: the 5-year relative survival for males was higher for cancers diagnosed at localized stage (98.7%) than for those diagnosed at distant stage (25.9%). Evaluation of 1-year and 5-year relative survival among males with breast cancer might help guide health care decisions regarding early detection of male breast cancer and establishing programs to support men at high risk for breast cancer and male breast cancer survivors., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Purpose: This article describes the clinical and multimodal imaging characteristics of subthreshold exudative choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD)., Methods: Among 3773 patients with AMD, 8 eyes (6 patients) were identified with the clinical phenotype of interest. Dilated fundus examinations, color fundus photography, fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and OCT angiography (OCTA) were performed., Results: OCT typically showed a moderately reflective irregular pigment epithelial detachment with overlying subretinal fluid (SRF). Traditional FA did not show leakage and ICGA showed no definitive neovascular network or hot spots. However, OCTA clearly demonstrated a CNV within the pigment epithelial detachment. The majority of our cases (7 of 8) did not receive antivascular endothelial growth factor (anti-VEGF) injections, and visual acuity remained stable over the available follow-up period of I to 10 years., Conclusions: CNV is often associated with SRF and vision loss in AMD, usually requiring frequent anti-VEGF injections. OCTA allowed us to better identify CNV not readily detected on FA and ICGA. Although some have suggested early clinical intervention with anti-VEGF injections in any case with fluid and confirmed CNV on OCTA, we describe a subset of AMD patients with SRF who may be better managed by observation. These cases may represent a more indolent, mature, and stable vascular network., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Maternal obesity during pregnancy can adversely affect adult offspring vascular endothelial function. This study examined whether maternal exercise during pregnancy and lactation mitigates the adverse effects of maternal obesity on offspring vascular endothelial function. Female (C57BL/6N) mice were fed from weaning a control diet (10% kcal fat) or western diet (45% kcal fat) to induce excess adiposity (maternal obesity). After 13 weeks, the female mice were bred and maintained on the diets, with and without access to a running wheel (exercise), throughout breeding, pregnancy, and lactation. Offspring were weaned onto the control or western diet and fed for 13 weeks; male offspring were studied. Maternal exercise prevented the adverse effects of maternal obesity on offspring vascular endothelial function. However, this was dependent on offspring diet and the positive effect of maternal exercise was only observed in offspring fed the western diet. This was accompanied by alterations in aorta and liver one-carbon metabolism, suggesting a role for these pathways in the improved endothelial function observed in the offspring. Obesity and exercise had no effect on endothelial function in the dams but did affect aorta and liver one-carbon metabolism, suggesting the phenotype observed in the offspring may be due to obesity and exercise-induced changes in one-carbon metabolism in the dams. Our findings demonstrate that maternal exercise prevented vascular dysfunction in male offspring from obese dams and is associated with alterations in one-carbon metabolism., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Low circulating 25-hydroxyvitamin D (25OHD) is commonly found in obese individuals and is often attributed to a volume dilution effect of adipose tissue. However, low vitamin D (LD) intake may contribute to the obesity itself. In this study, we examine whether low vitamin D status contributes to increased food intake and weight gain and can be explained by altered brain serotonin metabolism in 8-month-old female C57BL/6J mice. In a first experiment, mice were fed a 45% high-fat diet (HFD) containing different amounts of vitamin D at low (100 IU/kg), normal (1,000 IU/kg) or high (10,000 IU/kg) intake. After 10 weeks, mice fed LD had greater energy intake, weight gain, total and hepatic fat than the higher vitamin D groups (P < .05). In a second experiment, mice were examined for the central serotonin regulation of food intake after a 10% normal-fat diet (NFD) or 45% HFD containing low (100 IU/kg) or normal (1000 IU/kg) vitamin D. After 10 weeks, both HFD and LD diets attenuated circulating 25OHD concentration. Additionally, LD intake lowered cortical serotonin level, regardless of dietary fat intake (P < .05). In the arcuate and raphe nuclei, gene expression of vitamin D 1α-hydroxylase was lower due to LD during HFD feeding (P < .05). Tryptophan hydroxylase-2 and serotonin reuptake transporter gene expression was not altered due to LD. Overall, these findings suggest that a LD diet alters peripheral 25OHD, reduces central serotonin, and may contribute to weight gain in an obesogenic environment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The pathophysiology of sickle cell disease (SCD) includes vasculopathy as well as anaemia. Elevated plasma homocysteine is a risk factor for vascular disease and may be associated with increased risk of vascular complications in SCD patients. In the present study, microvascular characteristics were assessed in the bulbar conjunctiva of 18 paediatric and 18 adult SCD patients, using the non-invasive technique of computer-assisted intravital microscopy. A vasculopathy severity index (SI) was computed to quantify the degree of microvasculopathy in each patient. Plasma homocysteine and several of its determinants [serum folate and vitamin B12, plasma pyridoxal-5'-phosphate (vitamin B6 status) and creatinine (kidney function)] were measured. Age was strongly correlated with microvasculopathy in the SCD patients, with the SI increasing about 0·1 unit per one-year increase in age (P < 0·001). After adjusting for age, gender, B-vitamin status and creatinine, homocysteine concentration was directly correlated with severity index (P < 0·05). Age and homocysteine concentration were independent predictors of microvasculopathy in SCD patients. It remains to be determined whether lowering homocysteine concentrations using appropriate B-vitamin supplements (folate and vitamins B12 and B6) - particularly if started early in life - could ameliorate microvasculopathy and its associated complications in SCD patients., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Folate is essential for DNA synthesis, DNA repair, cell proliferation, development, and morphogenesis. Folic acid (FA) is a nutritional supplement used to fortify human diets., Objectives: We investigated the effects of dietary FA on early mammary gland (MG) development and hyperplasia., Methods: Study 1: nulliparous female FVB wild-type (WT) mice were fed control (Con; 2 mg FA/kg), deficient (Def; 0 mg FA/kg), excess (Ex; 5 mg FA/kg), or super excess (S-Ex; 20 mg FA/kg) diets for 8 wk before mating to WT or heterozygous FVB/N-Tg[mouse mammary tumor virus long terminal repeat (MMTV)-polyomavirus middle T antigen (PyVT)]634Mul/J (MMTV-PyMT+/-) transgenic males. Dams were fed these diets until they weaned WT or MMTV-PyMT+/- pups, which were fed the dam's diet from postnatal day (PND) 21 to 42. Tissues were collected from female progeny at PNDs 1, 21, and 42. Study 2: Con or Def diets were fed to WT intact females and males from PND 21 to 56, or to ovariectomized females from PND 21 to 77; tissues were collected at PND 56 or 77. Growth of all offspring, development of MGs, MG hyperplasia, supramammary lymph nodes, thymus and spleen, cell proliferation, and expression of MG growth factors were measured., Results: Study 1: Ex or S-Ex did not affect postnatal MG development or hyperplasia. The rate of isometric MG growth (PND 1-21) was reduced by 69% in Def female progeny (P < 0.0001). Similarly, hyperplastic growth in MGs of Def MMTV-PyMT+/- offspring was 18% of Con (P < 0.05). The Def diet reduced supramammary lymph node size by 20% (P < 0.0001) and increased MG insulin-like growth factor 2 mRNA by 200% (P < 0.05) and protein by 130%-150% (P < 0.05). Study 2: the Def diet did not affect MG growth, but it did reduce supramammary lymph node size (P < 0.05), spleen weight (P < 0.001), and thymic medulla area (P < 0.05)., Conclusions: In utero and postnatal folate deficiency reduced the isometric development of the MGs and early MG hyperplasia. Postnatal folate deficiency reduced the development of lymphatic tissues., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Purpose: To compare the average intraocular pressure (IOP) among smokers, past smokers, and never smokers using the American Academy of Ophthalmology Intelligent Research in Sight (IRIS®) Registry., Design: Retrospective database study of the IRIS® Registry data., Participants: Intelligent Research in Sight Registry patients who were seen by an eye care provider during 2017., Methods: Patients were divided into current smoker, past smoker, and never smoker categories. The IOP was based on an average measurement, and separate analyses were performed in patients with and without a glaucoma diagnosis based on International Classification of Diseases (Ninth Edition and Tenth Edition) codes. Stratified, descriptive statistics by glaucoma status were determined, and the relationship between smoking and IOP was assessed with a multivariate linear regression model., Main Outcome Measures: Mean IOP., Results: A total of 12 535 013 patients were included. Compared with never smokers, current and past smokers showed a statistically significantly higher IOP by 0.92 mmHg (95% confidence interval [CI], 0.88-0.95 mmHg) and 0.77 mmHg (95% CI, 0.75-0.79 mmHg), respectively, after adjusting for age, gender, glaucoma, age-related macular degeneration, diabetic retinopathy, cataract, glaucoma surgery, cataract surgery, and first-order interactions. In addition, the difference in IOP between current and never smokers was the highest in the fourth decade, regardless of the glaucoma status (glaucoma group, 1.14 mmHg [95% CI, 1.00-1.29 mmHg]; without glaucoma group, 0.68 mmHg [95% CI, 0.65-0.71 mmHg])., Conclusions: Current smokers and past smokers have higher IOP than patients who never smoked. This difference is higher in patients with an underlying glaucoma diagnosis., (Published by Elsevier Inc.)

Purpose: To compare different scan protocols of wide-field swept-source optical coherence tomography angiography (SS-OCTA) for the detection of diabetic retinopathy (DR) lesions., Design: Comparison of diagnostic approaches., Methods: A prospective, observational study was conducted at Massachusetts Eye and Ear from December 2018 to July 2019. Proliferative diabetic retinopathy (PDR), nonproliferative diabetic retinopathy (NPDR), and diabetic patients without DR were included. All patients were imaged using SS-OCTA using the following scan protocol: 3- × 3-mm Angio centered on the fovea; 6- × 6-mm Angio centered on the fovea and the optic disc; 15- × 9-mm Montage; and 12- × 12-mm Angio centered on the fovea and the optic disc. Images were independently evaluated by 2 graders for the presence or absence of DR lesions including microaneurysms, intraretinal microvascular abnormalities, neovascularization, nonperfusion areas, venous looping, and hard exudates. All statistical analyses were performed using commercial software., Results: A total of 176 eyes in 119 participants were included in the study. The detection rate of neovascularization on 6- × 6-mm Angio centered on the fovea was approximately one-half that on 15- × 9-mm Montage (P < .05) imaging. Combining 6- × 6-mm Angio imaging centered on the fovea and the optic disc could increase the rate to approximately two-thirds (P < .05). The 12- × 12-mm Angio imaging centered on the combination of fovea and optic disc had detection rates comparable to those of 15- × 9-mm Montage imaging for all DR lesions (P > .05). For microaneurysms, 6- × 6-mm Angio had better performance than 15- × 9-mm Montage (P < .05)., Conclusions: Wide-field SS-OCTA images were useful in detecting DR lesions. The 12- × 12-mm Angio imaging centered on the fovea and on the optic disc may be an optimal balance between speed and efficacy for evaluation of DR in clinical practice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) provides free cervical cancer screening to low-income women. This study estimated the health benefits gained in terms of life years (LYs) saved and quality-adjusted life years (QALYs) gained if cervical cancer screening by the NBCCEDP increased to reach more eligible women., Methods: Data from Surveillance, Epidemiology, and End Results, NBCCEDP, and Medical Expenditure Panel Surveys were used. LYs saved and QALYs gained/100,000 women were estimated using modeling methods. They were used to predict additional health benefits gained if screening by the NBCCEDP increased from 6.5% up to 10-25% of the eligible women., Results: Overall, per 100,000 women screened by the NBCCEDP, 1,731 LYs were saved and 1,608 QALYs were gained. For white women, 1,926 LYs were saved and 1,780 QALYs were gained/100,000 women screened by the NBCCEDP. For black women, 1,506 LYs were saved and 1,300 QALYs were gained/100,000 women screened. If the proportion of eligible women screened by the NBCCEDP increased to 10-25%, the estimated health benefits would range from 6,626-34,896 LYs saved and 6,153-32,407 QALYs gained., Conclusions: The reported estimates emphasize the value of cervical cancer screening program by extending LE in low-income women. Further, it demonstrates that screening a higher percentage of eligible women in the NBCCEDP may yield more health benefits.

Symbiotic interactions exist within a parasitism to mutualism continuum that is influenced, among others, by genes and context. Dynamics of intracellular invasion, replication, and prevalence may underscore both host survivability and symbiont stability. More infectious symbionts might exert higher corresponding costs to hosts, which could ultimately disadvantage both partners. Here, we quantify infection patterns of diverse Paraburkholderia symbiont genotypes in their amoeba host Dictyostelium discoideum and probe the relationship between these patterns and host outcomes. We exposed D. discoideum to thirteen strains of Paraburkholderia each belonging to one of the three symbiont species found to naturally infect D. discoideum : Paraburkholderia agricolaris, Paraburkholderia hayleyella, and Paraburkholderia bonniea . We quantified the infection prevalence and intracellular density of fluorescently labeled symbionts along with the final host population size using flow cytometry and confocal microscopy. We find that infection phenotypes vary across symbiont strains. Symbionts belonging to the same species generally display similar infection patterns but are interestingly distinct when it comes to host outcomes. This results in final infection loads that do not strongly correlate to final host outcomes, suggesting other genetic factors that are not a direct cause or consequence of symbiont abundance impact host fitness.

We report on the design, fabrication and characterization of subwavelength grating metamaterial waveguides coated with tellurium oxide. The structures are first fabricated using a standard CMOS compatible process on a silicon-on-insulator platform. Amorphous tellurium oxide top cladding material is then deposited via post-process RF magnetron sputtering. The photonic bandstructure is controlled by adjustment of the device geometry, opening a wide range of operating regimes, including subwavelength propagation, slow light and the photonic bandgap, for various wavelength bands within the 1550 nm telecommunications window. Propagation loss of 1.0 ± 0.1 dB/mm is reported for the tellurium oxide-cladded device, compared to 1.5 ± 0.1 dB/mm propagation loss reported for the silicon dioxide-cladded reference structure. This is the first time that a high-index (n > 2) oxide cladding has been demonstrated for subwavelength grating metamaterial waveguides, thus introducing a new material platform for on-chip integrated optics.

Objective: The Program of Active Consumer Engagement in Self-Management in Epilepsy (PACES) is an evidenced-based self-management intervention for adults with epilepsy. Prior randomized controlled trial (RCT) data show that PACES reduces depression and improves self-management, self-efficacy, and quality of life for 6 months postprogram. The objective of this study was to replicate a PACES RCT with key extensions: more diverse patient pool from community-based epilepsy centers; option for telephone-based participation; and longer follow-up (12 months with booster support for intervention group), to examine duration of impact and inform dissemination and implementation., Methods: Participants were adults with chronic epilepsy (n = 101) without serious mental illness or substantive intellectual impairment, recruited from three epilepsy centers. Participants were randomly assigned to intervention or waitlist control groups. Outcomes included the Epilepsy Self-Management Scale (ESMS), Epilepsy Self-Efficacy Scale (ESES), Quality of Life in Epilepsy-31, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7, administered at baseline, postintervention (8 weeks), and 6 and 12 months postintervention. Intervention was an 8-week group of five to eight adults co-led by a psychologist and trained peer with epilepsy that met once per week by teleconference or in person at a hospital for 60-75 minutes. Topics included medical, psychosocial, cognitive, and self-management aspects of epilepsy, as well as community integration and epilepsy-related communication. Treatment group provided program evaluation., Results: PACES participants (n = 49) improved relative to controls (n = 52) on the ESES (P < .022) and overall distress composite (P = .008). At 6 months, PACES participants remained improved on the ESES (P = .008) and composite (P = .001), and were improved on the ESMS (P = .005). At 12 months, PACES participants remained improved on the ESMS (P = .006) and were improved on an overall distress composite of combined measures (P = .018). Attrition was low (<6% in each group), and all program satisfaction ratings exceeded 4.0/5.0., Significance: A consumer-generated epilepsy self-management program with broad psychosocial and medical emphasis can be effectively delivered by telephone or in person and facilitates long-term epilepsy self-management, adjustment, and coping up to 1 year after treatment., (© 2020 International League Against Epilepsy.)

Importance: There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy., Objective: To provide direct, objective information on antiepileptic drug exposure through breast milk., Design, Setting, and Participants: This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks' gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019., Exposures: Antiepileptic drug exposure in infants who were breastfed., Main Outcomes and Measures: The percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle., Results: A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P < .001) but not levetiracetam concentration in infants., Conclusions and Relevance: Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

Objective: To determine the efficacy of DIAM Spinal Stabilization System compared with nonoperative treatment for patients with low back pain and lower lumbar disc degenerative disease., Methods: A single center collected prospective outcomes data on 38 patients randomized to an interspinous device or non-operative treatment for symptomatic lumbar degenerative disc disease with treatment crossover allowed at 6 months., Results: At all postoperative timepoints out to 2-years, statistically significant improvements in ODI and back pain scores were observed with the interspinous device. Clinically significant improvements (ODI >15-point improvement) were seen in 87.5% of DIAM patients at 2-years postoperatively. A high cross-over rate was noted from the non-operative cohort to the operative group (12 of 15) due to continued pain with nonoperative care. Additionally, 80% of patients receiving the DIAM implant reported a >15-point ODI reduction from pre-surgical scores at 2-year follow-up., Conclusion: The DIAM device demonstrates improvement in ODI and Back Pain scores maintained out to a 2-year follow-up timepoint and performed superior to conventional nonoperative treatment regimens commonly used in low back pain., Competing Interests: Dr. Boody has consulting agreements with Medicrea and Medtronic Sofamor Danek as well as grant support from Relievent Medsystems. Dr. Boody's consulting agreement with Medtronic is not related to the device discussed in this manuscript. Dr. Sasso has received royalties from Medtronic Sofamor Danek, unrelated to this work. Dr. Smucker has received honorium in the past and is a principal investigator in research studies for Medtronic Sofamor Danek. Ms. Sasso, Dr. Snowden, and Dr. Miller do not report any conflicts of interest. Indiana Spine Group received research support from Medtronic Sofamor Danek for data collection related to this work, on which Dr. Sasso was the principal investigator., (© 2020 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation.)

Purpose: To evaluate the association between dietary fat intake and the presence of AMD., Methods: Cross-sectional, observational study with cohorts prospectively recruited from the United States and Portugal. AMD was diagnosed based on color fundus photographs with the AREDS classification. A validated food frequency questionnaire was used to calculate the percent energy intake of trans fat, saturated fat, monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA). Odds ratio (OR) and 95% confidence intervals for quintile of amount of FA were calculated. Multiple logistic regression was used to estimate the OR., Results: We included 483 participants, 386 patients with AMD and 97 controls. Higher intake of trans fat was associated with a 2.3-fold higher odds of presence of AMD (P for trend = 0.0156), whereas a higher intake of PUFA (OR, 0.25; P for trend = 0.006) and MUFA (OR, 0.24; P for trend < 0.0001) presented an inverse association. Subgroup analysis showed that higher quintile of trans fat was associated with increased odds of having intermediate AMD (OR, 2.26; P for trend = 0.02); and higher quintile of PUFA and MUFA were inversely associated with intermediate AMD (OR, 0.2 [P for trend = 0.0013]; OR, 0.17 [P for trend < 0.0001]) and advanced AMD (OR, 0.13 [P for trend = 0.02]; OR, 0.26 [P for trend = 0.004]). Additionally, a statistically significant effect modification by country was noted with inverse association between MUFA and AMD being significant (OR, 0.04; P for trend < 0.0001) for the Portugal population only., Conclusions: Our study shows that higher dietary intake of trans fat is associated with the presence of AMD, and a higher intake of PUFA and MUFA is inversely associated with AMD.

Background: Asbestos is an established cause of several cancers, including mesothelioma and ovarian cancer. Incidence of mesothelioma, the sentinel asbestos-associated cancer, varies by state, likely reflecting different levels of asbestos exposure. We hypothesized that states with high mesothelioma incidence may also have high ovarian cancer incidence. Materials and Methods: Using data from the Centers for Disease Control and Prevention National Program for Cancer Registries and the National Cancer Institute Surveillance, Epidemiology, and End Results Program, we examined the geographic co-occurrence of mesothelioma and ovarian cancer incidence rates by U.S. state for 2003-2015. Results: By state, mesothelioma incidence ranged from 0.5 to 1.3 cases per 100,000 persons and ovarian cancer incidence ranged from 9 to 12 cases per 100,000 females. When states were grouped by quartile of mesothelioma incidence, the average ovarian cancer incidence rate was 10% higher in states with the highest mesothelioma incidence than in states with the lowest mesothelioma incidence. Ovarian cancer incidence tended to be higher in states with high mesothelioma incidence (Pearson correlation r  = 0.54; p  < 0.0001). Conclusions: Data from state cancer registries show ovarian cancer incidence was positively correlated with mesothelioma incidence, suggesting asbestos may be a common exposure. The potential for asbestos exposure has declined since the 1970s because fewer products contain asbestos; however, some products, materials, and buildings may still release asbestos and thousands of workers may be exposed. Ensuring that people are protected from exposure to asbestos in their workplaces, homes, schools, and communities may reduce the risk of several cancers.

Background/aims: Microperimetry is a technique that is increasingly used to assess visual function in age-related macular degeneration (AMD). In this study, we aimed to evaluate the relationship between retinal sensitivity measured with macular integrity assessment (MAIA) microperimetry and optical coherence tomography (OCT)-based macular morphology in AMD., Methods: Prospective, cross-sectional study. All participants were imaged with colour fundus photographs used for AMD staging (Age-Related Eye Disease Study scale), spectral-domain OCT (Spectralis, Heidelberg, Germany) and swept-source OCT (Topcon, Japan). Threshold retinal sensitivity of the central 10° diameter circle was assessed with the full-threshold, 37-point protocol of the MAIA microperimetry device (Centervue, Italy). Univariable and multivariable multilevel mixed-effect linear regression models were used for analysis., Results: We included 102 eyes with AMD and 46 control eyes. Multivariable analysis revealed that older age (p<0.0001), advanced AMD stage (p<0.0001) and reduced retinal thickness (p<0.0001) were associated with decreased mean retinal sensitivity. No associations were found between choroidal thickness and retinal sensitivity within the macula. Within the 10° diameter circle of the macula, the presence of ellipsoid disruption, subretinal fluid, atrophy and fibrosis, and outer retinal tubulation on OCT images was also associated with decreased retinal sensitivity (all p<0.05)., Conclusions: There is an association between TRS as determined by MAIA microperimetry and several OCT structural parameters across various stages of AMD. This study highlights the relevance of microperimetry as a functional outcome measure for AMD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammation plays an important role in pathological angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation; however, a comprehensive description of its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1 K45A/K45A mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization, Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis is mediated by caspase activation through a kinase-independent function of RIP1 and RIP3. Mechanistically, infiltrating macrophages are the key target of RIP1 kinase inhibition to attenuate pathological angiogenesis. Inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of proangiogenic M2-like markers but not M1-like markers. Similarly, in vitro, catalytic inhibition of RIP1 down-regulates the expression of M2-like markers in interleukin-4-activated bone marrow-derived macrophages, and this effect is blocked by simultaneous caspase inhibition. Collectively, these results demonstrate a nonnecrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may be a therapeutic target of pathological angiogenesis., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Purpose: To analyze imaging artifacts and segmentation errors with wide-field swept-source optical coherence tomography angiography (SS-OCTA) in diabetic retinopathy (DR)., Methods: We conducted a prospective, observational study at Massachusetts Eye and Ear from December 2018 to March 2019. Proliferative diabetic retinopathy (PDR), nonproliferative diabetic retinopathy (NPDR), diabetic patients with no diabetic retinopathy (DR), and healthy control eyes were included. All patients were imaged with a SS-OCTA and the Montage Angio (15 × 9 mm) was used for analysis. Images were independently evaluated by two graders using the motion artifact score (MAS). All statistical analyses were performed using SPSS 25.0 and R software., Results: One hundred thirty-six eyes in 98 participants with the montage image were included in the study. Patients with more severe stages of DR had higher MAS by trend test analysis ( P < 0.05). The occurrence of segmentation error was 0% in the healthy group, 10.53% in the no DR group, 10.00% in the NPDR group, and 50% in the PDR group. Multivariate regression analysis showed that the severity of DR and dry eye were the major factors affecting MAS ( P < 0.05). There were some modifiable artifacts that could be corrected to improve image quality., Conclusions: Wide field SS-OCTA assesses retinal microvascular changes by noninvasive techniques, yet distinguishing real alterations from artifacts is paramount to accurate interpretations. DR severity and dry eye correlated with MAS., Translational Relevance: Understanding contributing factors and methods to reduce artifacts is critical to routine use and clinical trial with wide-field SS-OCTA., (Copyright 2019 The Authors.)

Purpose: To investigate the choroidal thickness (CT) and choroidal vascular densities (CVD) of patients with macular telangiectasia type 2 (MacTel2) and their association with other multimodal imaging features, using swept-source optical coherence tomography (SS-OCT)., Methods: Prospective, cross-sectional study. Consecutive patients with MacTel2 along with controls without any macular disease were included. Fundus photography, confocal blue reflectance, near-infrared reflectance, autofluorescence, fluorescein angiography, spectral domain OCT and SS-OCT were performed. Images were independently analysed by two graders, and CVD was calculated from binarised en face SS-OCT images. CT was obtained from the SS-OCT platform via built-in automated segmentation. Multilevel mixed-effects models were used for statistical analysis., Results: Thirty-nine eyes of 20 patients with MacTel2 and 29 eyes of 15 control patients were included. Average CT and perifoveal temporal CT did not differ significantly between eyes with MacTel2 and control eyes (p≥0.350), when accounting for confounding factors. Overall and temporal CVD also did not significantly differ between the two groups (p≥0.490)., Conclusion: CT and CVD did not significantly differ between MacTel2 and control eyes in this study using SS-OCT. Even though MacTel2 may include abnormalities involving the choroid, these are likely minor in comparison to the predominant retinal changes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Traditionally, the bioavailability of vitamin B-12 (B12) from in vivo labeled foods was determined by labeling the vitamin with radiocobalt ( 57 Co, 58 Co or 60 Co). This required use of penetrating radioactivity and sometimes used higher doses of B12 than the physiological limit of B12 absorption. The aim of this study was to determine the bioavailability and absorbed B12 from chicken eggs endogenously labeled with 14 C-B12 using accelerator mass spectrometry (AMS). 14 C-B12 was injected intramuscularly into hens to produce eggs enriched in vivo with the 14 C labeled vitamin. The eggs, which provided 1.4 to 2.6 μg of B12 (~1.1 kBq) per serving, were scrambled, cooked and fed to 10 human volunteers. Baseline and post-ingestion blood, urine and stool samples were collected over a one-week period and assessed for 14 C-B12 content using AMS. Bioavailability ranged from 13.2 to 57.7% (mean 30.2 ± 16.4%). Difference among subjects was explained by dose of B12, with percent bioavailability from 2.6 μg only half that from 1.4 μg. The total amount of B12 absorbed was limited to 0.5-0.8 μg (mean 0.55 ± 0.19 μg B12) and was relatively unaffected by the amount consumed. The use of 14 C-B12 offers the only currently available method for quantifying B12 absorption in humans, including food cobalamin absorption. An egg is confirmed as a good source of B12, supplying approximately 20% of the average adult daily requirement (RDA for adults = 2.4 μg/day)., Competing Interests: Miller, Green, and Buchholz hold the following patent: “Assay for Vitamin B12 Absorption and Method of Making Labeled Vitamin B12”, Patent Number: 8,202,507. Garrod, Rossow, Calvert, and Allen, no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Purpose: Magnetoencephalography (MEG) is a noninvasive tool used clinically for presurgical evaluation of patients with medically intractable epilepsy. These recordings require patients to lie still for prolonged periods of time in a magnetically shielded room. Children or uncooperative adults with epilepsy may require sedation to reduce movement artefact and obtain high-quality recordings. Potential challenges related to the use of total intravenous anesthesia in the MEG environment include limited access to the patient's airway, remote location, suppression of cortical activity, and increased patient care expenses. We report our experience with intranasal dexmedetomidine as sedation for intractable epilepsy patients undergoing MEG., Methods: Sleep deprivation occurred the night before MEG testing. Intranasal dexmedetomidine (2 μg/kg) was administered and oxygen saturation, blood pressure, and pulse rate were recorded continuously on a monitor outside the magnetically shielded room. A recording of spontaneous neuromagnetic activity was immediately followed by median nerve electrical stimulation., Results: Twenty-six patients (mean age 12.2 ± 4.2 years) with medically intractable epilepsy were recorded using this protocol. There were no failures of sedation, and although patients experienced transient bradycardia, none required intervention and the recording did not need to be stopped. In all cases, artefact-free MEG recordings were obtained with sufficient interictal discharges available for source analysis., Conclusions: Our experience suggests that intranasal dexmedetomidine is an advantageous sedation option for children and adults with intractable epilepsy who are undergoing MEG. Further research is needed to determine the best ways to apply these methods to younger children and those with developmental disabilities.

Objectives: Patient navigation (PN) services have been shown to improve cancer screening in disparate populations. This study estimates the cost-effectiveness of implementing PN services within the National Breast and Cervical Cancer Early Detection Program (NBCCEDP)., Methods: We adapted a breast cancer simulation model to estimate a population cohort of women aged 40-64 years from the NBCCEDP through their lifetime. We incorporated their screening frequency and screening and diagnostic costs., Results: Within the NBCCEDP, Program with PN (vs. No PN) resulted in a greater number of mammograms per woman (4.23 vs. 4.14), lower lifetime mortality from breast cancer (3.53% vs. 3.61%), and fewer missed diagnostic resolution per woman (0.017 vs. 0.025). The estimated incremental cost-effectiveness ratios for a Program with PN was $32,531 per quality-adjusted life-years relative to Program with No PN., Conclusions: Incorporating PN services within the NBCCEDP may be a cost-effective way of improving adherence to screening and diagnostic resolution for women who have abnormal results from screening mammography. Our study highlights the value of supportive services such as PN in improving the quality of care offered within the NBCCEDP.

Purpose: This article investigates the relationship between visual acuity (VA), total area of geographic atrophy (GA), and percentage of foveal GA., Methods: A multicenter, retrospective, cross-sectional study was conducted of patients with GA due to age-related macular degeneration. Demographics, VA, fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT) images were collected. Using FAF images aided by SD-OCT, fovea-sparing status, GA pattern, total GA size, and percentage of GA covering the foveal area-within a 1.5-mm-diameter circle centered on the fovea centralis-were assessed. Univariable and multiple linear regression analyses were performed., Results: Fifty-four eyes (mean age, 78.7 ± 7.7 years [SD], 60.0% female) were studied. Mean VA was 0.8 ± 0.6 logarithm of the minimum angle of resolution (Snellen equivalent 20/126 ± 20/80), mean total GA 8.8 ± 6.7 mm 2 , and mean percentage of foveal GA was 71.5 ± 30.9%. Of all assessed eyes, 48.2% (n = 26) presented with multifocal GA, and 18.5% (n =10) had foveal sparing. Multiple regression analysis revealed that, controlling for age and GA pattern, the percentage of foveal GA presented a statistically significant association with VA (ß =0.41, P = .004). No significant associations were observed with mean total GA size, while controlling for the same variables (ß=0.010, P = .440)., Conclusions: Percentage of foveal GA was significantly associated with VA impairment, although the same was not verified for total GA area. These findings suggest that percentage of foveal GA may represent a more useful tool for assessing the impact of GA on VA. Further validation is needed in larger cohorts.

Children with autism often need sedation for diagnostic procedures and they are often difficult to sedate. This prospective randomized double-blind control trial evaluates the efficacy and safety using intranasal dexmedetomidine with and without buccal midazolam for sedation in children with autism undergoing computerized tomography and/or auditory brainstem response test. The primary outcome is the proportion of children attaining satisfactory sedation. One hundred and thirty-six children received intranasal dexmedetomidine and 139 received intranasal dexmedetomidine with buccal midazolam for sedation. Combination of intranasal dexmedetomidine and buccal midazolam was associated with higher sedation success when compared to intranasal dexmedetomidine. Since intranasal and buccal sedatives required little cooperation this could be especially useful technique for children with autism or other behavioral conditions.

Purpose: We estimated the costs and effectiveness of state programs in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) based on the type of delivery structure., Methods: Programs were classified into three delivery structures: (1) centralized, (2) decentralized, and (3) mixed. Centralized programs offer clinical services in satellite offices, but all other program activities are performed centrally. Decentralized programs contract with other entities to fully manage and provide screening and diagnostic services and other program activities. Programs with mixed service delivery structures have both centralized and decentralized features. Programmatic costs were averaged over a 3 year period (2006-2007, 2008-2009, and 2009-2010). Effectiveness was defined in terms of the average number of women served over the 3 years. We report costs per woman served by program activity and delivery structure and incremental cost effectiveness by program structure and by breast/cervical services., Results: Average costs per woman served were lowest for mixed program structures (breast = $225, cervical = $216) compared to decentralized (breast = cervical = $276) and centralized program structures (breast = $259, cervical = $251). Compared with decentralized programs, for each additional woman served, centralized programs saved costs of $281 (breast) and $284 (cervical). Compared with decentralized programs, for each additional woman served, mixed programs added an additional $109 cost for breast but saved $1,777 for cervical cancer., Conclusions: Mixed program structures were associated with the lowest screening and diagnostic costs per woman served and had generally favorable incremental costs relative to the other program structures.

Background: Hyperhomocysteinemia is associated with increased cardiovascular disease risk. Whole eggs contain several nutrients known to affect homocysteine regulation, including sulfur amino acids, choline, and B vitamins., Objective: The aim of this study was to determine the effect of whole eggs and egg components (i.e., egg protein and choline) with respect to 1) homocysteine balance and 2) the hepatic expression and activity of betaine-homocysteine S-methyltransferase (BHMT) and cystathionine β-synthase (CBS) in a folate-restricted (FR) rat model of hyperhomocysteinemia., Methods: Male Sprague Dawley rats (n = 48; 6 wk of age) were randomly assigned to a casein-based diet (C; n = 12), a casein-based diet supplemented with choline (C + Cho; 1.3%, wt:wt; n = 12), an egg protein-based diet (EP; n = 12), or a whole egg-based diet (WE; n = 12). At week 2, half of the rats in each of the 4 dietary groups were provided an FR (0 g folic acid/kg) diet and half continued on the folate-sufficient (FS; 0.2 g folic acid/kg) diet for an additional 6 wk. All diets contained 20% (wt:wt) total protein. Serum homocysteine was measured by HPLC and BHMT and CBS expression and activity were evaluated using real-time quantitative polymerase chain reaction, Western blot, and enzyme activity. A 2-factor ANOVA was used for statistical comparisons., Results: Rats fed FR-C exhibited a 53% increase in circulating homocysteine concentrations compared with rats fed FS-C (P < 0.001). In contrast, serum homocysteine did not differ between rats fed FS-C and FR-EP (P = 0.078). Hepatic BHMT activity was increased by 45% and 40% by the EP (P < 0.001) and WE (P = 0.002) diets compared with the C diets, respectively., Conclusions: Dietary intervention with egg protein prevented elevated circulating homocysteine concentrations in a rat model of hyperhomocysteinemia, due in part to upregulation of hepatic BHMT. These data may support the inclusion of egg protein for dietary recommendations targeting hyperhomocysteinemia prevention., (Copyright © American Society for Nutrition 2019.)

Objectives: To estimate awardee-specific costs of delivering breast and cervical cancer screening services in their jurisdiction and to assess potential variation in the cost of key activities across awardees., Methods: We developed the cost assessment tool to collect resource use and cost data from the National Breast and Cervical Cancer Early Detection Program awardees for 3 years between 2006 and 2010 and generated activity-based cost estimates. We estimated awardee-specific cost per woman served for all activities, clinical screening delivery services, screening promotion interventions, and overarching program support activities., Results: The total cost per woman served by the awardees varied greatly from $205 (10th percentile) to $499 (90th percentile). Differences in the average (median) cost per person served for clinical services, health promotion interventions, and overarching support activities ranged from $51 to $125., Conclusions: The cost per woman served varied across awardee and likely reflected underlying differences across awardees in terms of screening infrastructure, population served, and barriers to screening uptake. Collecting information on contextual factors at the awardee, health system, provider, and individual levels may assist in understanding this variation in cost.

Purpose: To estimate the cost-effectiveness of breast cancer screening in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP)., Methods: Using a modified CISNET breast cancer simulation model, we estimated outcomes for women aged 40-64 years associated with three scenarios: breast cancer screening within the NBCCEDP, screening in the absence of the NBCCEDP (no program), and no screening through any program. We report screening outcomes, cost, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and sensitivity analyses results., Results: Compared with no program and no screening, the NBCCEDP lowers breast cancer mortality and improves QALYs, but raises health care costs. Base-case ICER for the program was $51,754/QALY versus no program and $50,223/QALY versus no screening. Probabilistic sensitivity analysis ICER for the program was $56,615/QALY [95% CI $24,069, $134,230/QALY] versus no program and $51,096/QALY gained [95% CI $26,423, $97,315/QALY] versus no screening., Conclusions: On average, breast cancer screening in the NBCCEDP was cost-effective compared with no program or no screening.