Analysis of residual disease in periocular basal cell carcinoma following hedgehog pathway inhibition: Follow up to the VISORB trial.

Basal cell carcinoma (BCC) is a common skin cancer caused by deregulated hedgehog signaling. BCC is often curable surgically; however, for orbital and periocular BCCs (opBCC), surgical excision may put visual function at risk. Our recent clinical trial highlighted the utility of vismodegib for preserving visual organs in opBCC patients: 67% of patients displayed a complete response histologically. However, further analysis of excision samples uncovered keratin positive, hedgehog active (Gli1 positive), proliferative micro-tumors. Sequencing of pre-treatment tumors revealed resistance conferring mutations present at low frequency. In addition, one patient with a low-frequency SMO W535L mutation recurred two years post study despite no clinical evidence of residual disease. Sequencing of this recurrent tumor revealed an enrichment for the SMO W535L mutation, revealing that vismodegib treatment enriched for resistant cells undetectable by traditional histology. In the age of targeted therapies, linking molecular genetic analysis to prospective clinical trials may be necessary to provide mechanistic understanding of clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02436408.

Augmenting Kalman Filter Machine Learning Models with Data from OCT to Predict Future Visual Field Loss: An Analysis Using Data from the African Descent and Glaucoma Evaluation Study and the Diagnostic Innovation in Glaucoma Study.

Purpose: To assess whether the predictive accuracy of machine learning algorithms using Kalman filtering for forecasting future values of global indices on perimetry can be enhanced by adding global retinal nerve fiber layer (RNFL) data and whether model performance is influenced by the racial composition of the training and testing sets. Design: Retrospective, longitudinal cohort study. Participants: Patients with open-angle glaucoma (OAG) or glaucoma suspects enrolled in the African Descent and Glaucoma Evaluation Study or Diagnostic Innovation in Glaucoma Study. Methods: We developed a Kalman filter (KF) with tonometry and perimetry data (KF-TP) and another KF with tonometry, perimetry, and global RNFL data (KF-TPO), comparing these models with one another and with 2 linear regression (LR) models for predicting mean deviation (MD) and pattern standard deviation values 36 months into the future for patients with OAG and glaucoma suspects. We also compared KF model performance when trained on individuals of European and African descent and tested on patients of the same versus the other race. Main Outcome Measures: Predictive accuracy (percentage of MD values forecasted within the 95% repeatability interval) differences among the models. Results: Among 362 eligible patients, the mean ± standard deviation age at baseline was 71.3 ± 10.4 years; 196 patients (54.1%) were women; 202 patients (55.8%) were of European descent, and 139 (38.4%) were of African descent. Among patients with OAG (n = 296), the predictive accuracy for 36 months in the future was higher for the KF models (73.5% for KF-TP, 71.2% for KF-TPO) than for the LR models (57.5%, 58.0%). Predictive accuracy did not differ significantly between KF-TP and KF-TPO (P = 0.20). If the races of the training and testing set patients were aligned (versus nonaligned), the mean absolute prediction error of future MD improved 0.39 dB for KF-TP and 0.48 dB for KF-TPO. Conclusions: Adding global RNFL data to existing KFs minimally improved their predictive accuracy. Although KFs attained better predictive accuracy when the races of the training and testing sets were aligned, these improvements were modest. These findings will help to guide implementation of KFs in clinical practice.

Cumulative Endogenous Estrogen Exposure Is Associated With Postmenopausal Fracture Risk: The Women's Health Initiative Study.

We aimed to evaluate the relationship between cumulative endogenous estrogen exposure and fracture risk in 150,682 postmenopausal women (aged 50 to 79 years at baseline) who participated in the Women's Health Initiative. We hypothesized that characteristics indicating lower cumulative endogenous estrogen exposure would be associated with increased fracture risk. We determined ages at menarche and menopause as well as history of irregular menses from baseline questionnaires and calculated years of endogenous estrogen exposure from ages at menarche and menopause. Incident clinical fractures were self-reported over an average 16.7 years of follow-up. We used multivariable proportional hazards models to assess the associations between the estrogen-related variables and incidence of any clinical fracture. In fully adjusted models, those with the fewest years of endogenous estrogen exposure (<30) had an 11% higher risk of developing central body fractures and a 9% higher risk of lower extremity fractures than women with 36 to 40 years of endogenous estrogen exposure (the reference category). In contrast, women with the most years of endogenous estrogen exposure (more than 45 years) had a 9% lower risk of lower extremity fractures than the reference category. Women with irregular (not monthly) menstrual cycles were 7% to 8% more likely to experience lower extremity fractures than women with regular monthly cycles. Our findings support the hypothesis that characteristics signifying lower cumulative endogenous estrogen exposure are associated with higher fracture risk. © 2022 American Society for Bone and Mineral Research (ASBMR).

Oral Microbiome Is Associated With Incident Hypertension Among Postmenopausal Women.

Background Oral microbiota are thought to influence blood pressure (BP) regulation. However, epidemiological data supporting this hypothesis are limited. We examined associations between oral microbiota, BP, and incident hypertension in postmenopausal women. Methods and Results Baseline (1997-2001) examinations were completed on 1215 women (mean age, 63 years) during which subgingival plaque was collected, BP was measured, and medical and lifestyle histories and medication inventory were obtained. Microbiome composition of subgingival plaque was measured using 16S ribosomal RNA gene amplicon sequencing. Baseline measured BP was defined as normotensive (systolic <120 mm Hg and diastolic <80 mm Hg, no BP medication use; n=429); elevated (systolic ≥120 mm Hg or diastolic ≥80 mm Hg, no medication use; n=306); or prevalent treated hypertension (history of physician diagnosis treated with medications; n=480). Incident hypertension (375 cases among 735 without baseline treated hypertension) was defined as newly physician-diagnosed hypertension treated with medication reported on annual health surveys (mean follow-up, 10.4 years). Cross-sectional analysis identified 47 bacterial species (of 245 total) that differed significantly according to baseline BP status (P<0.05). Prospective analysis identified 15 baseline bacterial species significantly (P<0.05) associated with incident hypertension: 10 positively (age-adjusted hazard ratios [HRs], 1.10-1.16 per SD in bacterial abundance) and 5 inversely (HRs, 0.82-0.91) associated. Associations were materially unchanged after further adjustment for demographic, clinical, and lifestyle factors; were similar when analysis was restricted to the normotensive group; and were of consistent magnitudes between strata of baseline age, smoking, body mass index, and BP categories. Conclusions Specific oral bacteria are associated with baseline BP status and risk of hypertension development among postmenopausal women. Research to confirm these observations and elucidate mechanisms is needed.

Predicting rapid progression phases in glaucoma using a soft voting ensemble classifier exploiting Kalman filtering.

In managing patients with chronic diseases, such as open angle glaucoma (OAG), the case treated in this paper, medical tests capture the disease phase (e.g. regression, stability, progression, etc.) the patient is currently in. When medical tests have low residual variability (e.g. empirical difference between the patient's true and recorded value is small) they can effectively, without the use of sophisticated methods, identify the patient's current disease phase; however, when medical tests have moderate to high residual variability this may not be the case. This paper presents a framework for handling the latter case. The framework presented integrates the outputs of interacting multiple model Kalman filtering with supervised learning classification. The purpose of this integration is to estimate the true values of patients' disease metrics by allowing for rapid and non-rapid phases; and dynamically adapting to changes in these values over time. We apply our framework to classifying whether a patient with OAG will experience rapid progression over the next two or three years from the time of classification. The performance (AUC) of our model increased by approximately 7% (increased from 0.752 to 0.819) when the Kalman filtering results were incorporated as additional features in the supervised learning model. These results suggest the combination of filters and statistical learning methods in clinical health has significant benefits. Although this paper applies our methodology to OAG, the methodology developed is applicable to other chronic conditions.

Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial.

BACKGROUND: Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular BCC (opBCC). MATERIALS AND METHODS: In this open-label, nonrandomized phase IV trial, we enrolled patients with globe- and lacrimal drainage system-threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists. RESULTS: In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1-15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2-4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1-91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins. CONCLUSION: Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408. IMPLICATIONS FOR PRACTICE: Use of the antihedgehog inhibitor vismodegib resulted in preservation of end-organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end-organ preservation.

Plasma 25-Hydroxyvitamin D Concentrations and Serum and Salivary C-Reactive Protein in the Osteoporosis and Periodontal Disease Study.

Vitamin D has been hypothesized to play an important role in preventing the development and progression of periodontal disease, but the underlying immune modulatory mechanisms remain understudied. We examined the cross-sectional association between biomarkers of vitamin D status and C-reactive protein (CRP) among postmenopausal women aged 53-81 years. Linear regression was used to examine the association between plasma 25-hydroxyvitamin D (25[OH]D) concentrations, a biomarker of vitamin D status, and both salivary and serum CRP concentrations in 567 women from the Buffalo Osteoporosis and Periodontal Disease (OsteoPerio) Study (1997-2000). CRP concentrations were measured with multiplex arrays and transformed for normality using the natural log. Concentrations above and below the limit of detection were included in analysis as right- and left-censored observations. An inverse association was observed between 25(OH)D and salivary CRP in a model adjusted for age, smoking status, frequency of tooth brushing and flossing, and hormone therapy use (-7.56% difference in salivary CRP concentrations per 10 nmol/L increase in 25(OH)D, 95% CI: -12.78 to -2.03). Further adjustment for percent body fat attenuated this association (-2.48%, 95% CI: -7.88 to 3.24). No significant associations were found between 25(OH)D and serum CRP. Plasma vitamin D concentrations were not associated with salivary or serum CRP concentrations in this cohort of postmenopausal women.

The association between serum inflammatory biomarkers and incident hypertension among postmenopausal women in the Buffalo OsteoPerio Study.

Several serum inflammatory biomarkers have been associated with blood pressure and hypertension prevalence in cross-sectional studies. Few of these associations have been evaluated prospectively. We examined associations for 10 serum inflammatory biomarkers with incident hypertension among 471 postmenopausal women (mean age = 65) in the Buffalo OsteoPerio Study. Concentrations of C-reactive protein, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, adiponectin, and leptin were measured using multiplexed sandwich immunoassays on fasting serum samples collected at baseline (1997-2001). Incident hypertension (195 cases) was defined as physician-diagnosed hypertension and treatment with medication identified on annual mailed health surveys during follow-up (mean 10 years). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) between log-transformed biomarkers (per 1-SD) and hypertension. When adjusted for age, leptin was significantly associated with hypertension risk (HR = 1.55, 95% CI: 1.04, 2.29), however, the association was attenuated and not significant after adjustment for demographic and lifestyle factors, including BMI. Significant (P < 0.10) interactions were observed for smoking (never, ever) with CRP (HR: never, 1.31; ever, 0.91; P = 0.06) and MCP-1 (HR: never, 0.59; ever, 5.11; P = 0.004); for BMI (<25, ≥25) with MCP-1(HR: <25, 3.45; ≥25, 0.95; P = 0.07); for systolic BP with IL-10 (HR: <120, 0.85; 120-139, 1.11; P = 0.07); and for diastolic BP with MCP-1 (HR: <80, 1.29; 80-89, 0.84; P = 0.03) and with adiponectin (HR: <80, 0.86; 80-89, 1.50; P = 0.03). This study adds needed understanding on prospective associations between several serum inflammatory biomarkers and hypertension risk in older postmenopausal women, among whom hypertension burden is substantial.

Subgingival microbiome is associated with alveolar bone loss measured 5 years later in postmenopausal women.

BACKGROUND: The aim of this study was to quantify the association between subgingival microbiota and periodontal disease progression in older women, for which limited published data exist. METHODS: A total of 1016 postmenopausal women, aged 53 to 81 years, completed baseline (1997 to 2001) and 5-year (2002 to 2006) dental exams that included probing depth, clinical attachment level, gingival bleeding, and radiographic alveolar crestal height (ACH). Baseline microbiota were measured in subgingival plaque using 16S rRNA sequencing. Associations between 52 microbiota we previously found statistically significantly associated with clinical periodontal disease at baseline, were examined with disease progression. The traditional Socransky microbiota complexes also were evaluated. Side-by-side radiograph comparisons were used to define progression as ≥2 teeth with ≥1 mm ACH loss or ≥1 new tooth loss to periodontitis. The association between baseline centered log(2) ratio transformed microbial relative abundances and 5-year periodontal disease progression was measured with generalized linear models. RESULTS: Of 36 microbiota we previously showed were elevated in moderate/severe disease at baseline, 24 had statistically significantly higher baseline mean relative abundance in progressing compared with non-progressing women (P < .05, all); which included all Socransky red bacteria (P. gingivalis, T. forsythia, T. denticola). Of 16 microbiota elevated in none/mild disease at baseline, five had statistically significantly lower baseline abundance in non-progressing compared with progressing women (P < 0.05, all), including one Socransky yellow bacteria (S. oralis). When adjusted for baseline age, socioeconomic status, and self-rated general health status, odds ratios for 5-year progression ranged from 1.18 to 1.51 (per 1-standard deviation increment in relative abundance) for microbiota statistically significantly (P < 0.05) positively associated with progression, and from 0.77 to 0.82 for those statistically significantly (P < 0.05) inversely associated with progression. These associations were similar when stratified on baseline levels of pocket depth, gingival bleeding, ACH, and smoking status. CONCLUSIONS: These prospective results affirm clearly that subgingival microbiota are measurably elevated several years prior to progression of alveolar bone loss, and include antecedent elevations in previously undocumented taxa additional to known Socransky pathogenic complexes.

Walking Volume and Speed Are Inversely Associated With Incidence of Treated Hypertension in Postmenopausal Women.

Few studies have evaluated hypertension incidence in relation to walking, which is a common physical activity among adults. We examined the association between walking and hypertension incidence in 83 435 postmenopausal women who at baseline were aged 50 to 79 years, without known hypertension, heart failure, coronary heart disease, or stroke, and reported the ability to walk at least one block without assistance. Walking volume (metabolic equivalent hours per week) and speed (miles per hour) were assessed by questionnaire. Incident physician-diagnosed hypertension treated with medication was ascertained through annual questionnaires. During a mean 11-year follow-up, 38 230 hypertension cases were identified. After adjustment for covariates including nonwalking activities, a significant inverse association with hypertension was observed across categories of baseline walking volume (0 [referent], >0-3.5, 3.6-7.5, and >7.5 metabolic equivalent hours per week), hazard ratio: 1.00 (referent), 0.98, 0.95, 0.89; trend P<0.001. Faster walking speeds (<2, 2-3, 3-4, and >4 miles per hour) also were associated with lower hypertension risk, hazard ratio: 1.00 (referent), 1.07, 0.95, 0.86, 0.79; trend P<0.001. Further adjustment for walking duration (h/wk) had little impact on the association for walking speed (hazard ratio: 1.00 [referent], 1.08, 0.96, 0.86, 0.77; trend P<0.001). Significant inverse associations for walking volume and speed persisted after additional control for baseline blood pressure. Results for time-varying walking were comparable to those for baseline exposures. This study showed that walking at guideline-recommended volumes (>7.5 metabolic equivalent hours per week) and at faster speeds (≥2 miles per hour) is associated with lower hypertension risk in postmenopausal women. Walking should be encouraged as part of hypertension prevention in older adults.

Association of Dietary Magnesium Intake with Fatal Coronary Heart Disease and Sudden Cardiac Death.

Background: Postmenopausal women represent the highest population-based burden of cardiovascular disease, including sudden cardiac death (SCD). Our understanding of the etiology and risk factors contributing to fatal coronary heart disease (CHD) and SCD, particularly among women, is limited. This study examines the association between dietary magnesium intake and fatal CHD and SCD. Materials and Methods: We examined 153,569 postmenopausal women who participated in the Women's Health Initiative recruited between 1993 and 1998. Magnesium intake at baseline was assessed using a validated food frequency questionnaire, adjusting for energy via the residual method. Fatal CHD and SCD were identified over an average follow-up of 10.5 years. Results: For every standard deviation increase in magnesium intake, there was statistically significant risk reduction, after adjustment for confounders, of 7% for fatal CHD (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.89-0.97), and 18% risk reduction for SCD (HR 0.82, 95% CI 0.58-1.15) the latter of which did not reach statistical significance. In age-adjusted quartile analysis, women with the lowest magnesium intake (189 mg/day) had the greatest risk for fatal CHD (HR 1.54, 95% CI 1.40-1.69) and SCD (HR 1.70, 95% CI 0.94-3.07). This association was attenuated in the fully adjusted model, with HRs of 1.19 (95% CI 1.06-1.34) for CHD and 1.24 (95% CI 0.58-2.65) for SCD for the lowest quartile of magnesium intake. Conclusions: This study provides evidence of a potential inverse association between dietary magnesium and fatal CHD and a trend of magnesium with SCD in postmenopausal women. Future studies should confirm this association and consider clinical trials to test whether magnesium supplementation could reduce fatal CHD in high-risk individuals.

Serum Vitamin D Deficiency Is an Independent Risk Factor for Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) is an inflammatory orbitopathy with significant impact on visual function and quality of life. Although studies have shown that patients who are deficient in vitamin D are more likely to develop autoimmune conditions, there are no studies demonstrating a definitive correlation between serum 25-hydroxyvitamin D (25(OH)D) deficiency and an increased risk of TED. METHODS: This retrospective case-control study compared serum 25(OH)D levels among 4 groups: 1) Graves disease (GD) patients with TED (n = 89); 2) GD patients without TED (n = 89); and healthy control patients matched to 3) the TED group (n = 356); and 4) the GD group (n = 356). The authors compared 25(OH)D level in the TED group measured within 1 year of TED diagnosis to the most recently measured 25(OH)D level in the GD group using Student t test of the log transformation of serum levels. Linear regression was used to control for other risk factors. Thyroid eye disease patients and GD patients were compared separately to their matched healthy control patients with linear mixed models. RESULTS: Thyroid eye disease patients displayed significantly lower serum 25(OH)D levels than GD patients (24.8 ± 13.2 ng/ml vs. 29.4 ± 13.3 ng/ml; p = 0.006). Controlling for smoking status and previous radioactive iodine treatment did not affect this statistically significant difference. CONCLUSIONS: Low serum vitamin D is associated with TED diagnosis. Assessing and supplementing vitamin D levels may be an important addition to the early management of GD patients. Future research should include longitudinal studies and prospective clinical trials to further explore the mechanism responsible for the observed association.Thyroid eye disease is an inflammatory orbitopathy associated with Graves disease. Vitamin D is a known immune system regulator. The authors show that vitamin D deficiency is associated with the development of thyroid eye disease.

Composition and diversity of the subgingival microbiome and its relationship with age in postmenopausal women: an epidemiologic investigation.

BACKGROUND: The extent to which the composition and diversity of the oral microbiome varies with age is not clearly understood. METHODS: The 16S rRNA gene of subgingival plaque in 1219 women, aged 53-81 years, was sequenced and its taxonomy annotated against the Human Oral Microbiome Database (v.14.5). Composition of the subgingival microbiome was described in terms of centered log(2)-ratio (CLR) transformed OTU values, relative abundance, and prevalence. Correlations between microbiota abundance and age were evelauted using Pearson Product Moment correlations. P-values were corrected for multiple testing using the Bonferroni method. RESULTS: Of the 267 species identified overall, Veillonella dispar was the most abundant bacteria when described by CLR OTU (mean 8.3) or relative abundance (mean 8.9%); whereas Streptococcus oralis, Veillonella dispar and Veillonella parvula were most prevalent (100%, all) when described as being present at any amount. Linear correlations between age and several CLR OTUs (Pearson r = - 0.18 to 0.18), of which 82 (31%) achieved statistical significance (P < 0.05). The correlations lost significance following Bonferroni correction. Twelve species that differed across age groups (each corrected P < 0.05); 5 (42%) were higher in women ages 50-59 compared to ≥70 (corrected P < 0.05), and 7 (48%) were higher in women 70 years and older. CONCLUSIONS: We identified associations between several bacterial species and age across the age range of postmenopausal women studied. Understanding the functions of these bacteria could identify intervention targets to enhance oral health in later life.

Is the Oral Microbiome Associated with Blood Pressure in Older Women?

INTRODUCTION: A possible role of the oral microbiome, specifically oral nitrate reducing flora, in blood pressure (BP) homeostasis, if proven etiologic in nature, could lead to novel mechanism-based therapy to improve hypertension prevention and control. AIM: This cross-sectional study characterized and compared the oral microbiome between four study groups based on BP status among 446 postmenopausal women aged 53-82 years. METHODS: Three study groups were not taking hypertension medication and were separated based on BP, as follows: normal BP (systolic < 120 and diastolic < 80; N = 179), elevated BP/Stage I hypertension (systolic 120-139 or diastolic 80-90; N = 106), Stage II hypertension (systolic > 140 or diastolic > 90; N = 42). The forth group consisted of anyone taking hypertension medications, regardless of BP (N = 119). Subgingival microbiome composition was determined using 16S rRNA sequencing with the Illumina MiSeq platform. Kruskal-Wallis tests were used to compare species-level relative abundance of bacterial operational taxonomic units across the four groups. RESULTS: Sixty-five bacterial species demonstrated significant differences in relative abundance in women with elevated BP or using hypertension medication as compared to those with normal BP. After correction for multiple testing, two species, Prevotella oral (species 317) and Streptococcus oralis, remained significant and were lower in abundance among women taking antihypertension medications compared to those with normal BP (corrected P < 0.05). CONCLUSIONS: These data provide novel description of oral subgingival bacteria grouped according to BP status. Additional larger studies including functional analysis and prospective designs will help further assess the potential role of the oral microbiome in BP regulation and hypertension.

Serum 25-Hydroxyvitamin D Concentrations and Incidence of Age-Related Macular Degeneration: The Atherosclerosis Risk in Communities Study.

Purpose: To investigate the association between serum 25-hydroxyvitamin D (25[OH]D) concentrations at visit 2 (1990-1992) and the 18-year incidence of age-related macular degeneration (AMD) between visit 3 (1993-1995) and visit 5 (2011-2013). Methods: This prospective analysis was conducted in a subset of participants (n = 1225) from the Atherosclerosis Risk in Communities Study. We evaluated the incidence of any, early, and late AMD from visit 3 to 5. The 25(OH)D concentrations were assessed in 2012-2013 by using stored serum from visit 2. Retinal fundus photographs taken at both visits were graded side by side to determine the incidence of AMD. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for incident AMD outcomes during 18 years of follow-up (1993-1995 to 2011-2013) by tertile of 25(OH)D adjusted for age, race, and smoking status. P for linear trend was estimated by using continuous 25(OH)D concentrations. Sensitivity analyses applied inverse probability weights to account for selection to have eye photographs, death, and loss to follow-up. Results: There was a decreased odds of any incident AMD (n = 139) and large, soft drusen (n = 80) in 25(OH)D tertile 3 versus 1, with OR (95% CI) = 0.57 (0.36-0.90), P trend = 0.11 and with 0.52 (0.28-0.93), P trend = 0.18, respectively. Applying sampling weights attenuated these results to 0.66 (0.38-1.16), P trend = 0.32 (any incident AMD) and 0.54 (0.27-1.09), P trend = 0.36 (large, soft drusen), respectively, suggesting these associations may be biased by loss to follow-up and sampling for retinal photographs at visit 5. No statistically significant results were observed with pigmentary abnormalities (n = 46) or incident late AMD (n = 26). Conclusions: High 25(OH)D concentrations, approximately >70 nM, may be associated with decreased odds of incident early AMD.

Orbital Septum Fibrosis in Congenital Ptosis Correlates With Eyelid Function: A Clinicopathologic Study.

PURPOSE: Congenital ptosis can threaten visual function and is usually treated with surgical correction. This study tests the hypothesis that congenital ptosis involves not only the levator muscle but also the orbital septum, which may tether the eyelid in the primary position. METHODS: A retrospective chart review was performed on 30 patients (41 eyelids) with congenital ptosis who underwent surgical correction that included partial septum excision. Histologic analysis was performed by a masked pediatric pathologist, with grading of septal tissue disorganization and fibrosis based on standard histologic criteria. An independent comparison of histologic grading with clinical ptosis measures was then performed. RESULTS: Fifteen eyelids demonstrated significant septal fibrosis, 19 were mild, and 7 were not fibrotic. Thirty-six eyelids demonstrated histologic disorganization. Mildly fibrotic eyelids were found to have reduced preoperative levator function than those that were not fibrotic (2.84 ± 1.92 vs. 9.57 ± 4.76 mm; p < 0.0001). Samples that demonstrated significant fibrosis were also found to have reduced preoperative levator function (4.67 ± 2.12 vs. 9.57 ± 4.76 mm; p = 0.0007). Histologically disorganized samples were also found to have a lower preoperative levator function (9.50 ± 6.04 vs. 3.99 ± 2.49; p = 0.0052). CONCLUSIONS: Orbital septae in patients with congenital ptosis demonstrate histologic disorganization and fibrosis. When decreased levator function is observed clinically, septal fibrosis and/or disorganization is likely present. These observations suggest that debulking the fibrotic septum during congenital ptosis surgery may improve outcomes by releasing the eyelid from its congenitally tethered position, improving eyelid elasticity.

Cohort profile: the Buffalo OsteoPerio microbiome prospective cohort study.

PURPOSE: The Buffalo Osteoporosis and Periodontal Disease (OsteoPerio) study is a prospective cohort study focused on the relationship between the microbiome and oral and systemic health outcomes in postmenopausal women. The cohort was established to examine how the oral microbiome is affected by (and how it affects) periodontal disease presence, severity and progression and to characterise the relationship between the microbiome, lifestyle habits and systemic disease outcomes. PARTICIPANTS: Participants (n=1342) were postmenopausal women who were participating in the Women's Health Initiative observational study at the Buffalo, New York clinical centre. There were 1026 participants at the 5-year follow-up visit and 518 at the 15-year visit. FINDINGS TO DATE: Data collected include questionnaires, anthropometric measures, serum blood and saliva samples. At each clinic visit, participants completed a comprehensive oral examination to measure oral health and the oral microbiome. Preliminary findings have contributed to our understanding of risk factors for periodontal disease and the relationship between the oral microbiome and periodontal disease. FUTURE PLANS: The novel microbiome data collected on a large sample of participants at three time points will be used to answer a variety of research questions focused on temporal changes in the microbiome and the relationship between the oral microbiome and oral and systemic disease outcomes. Little is currently known about the relationship between the oral microbiome and health outcomes in older adults; data from the OsteoPerio cohort will fill this gap. Microbiome samples are currently being analysed using next-generation sequencing technology with an anticipated completion date of late 2018.

Substantial Differences in the Subgingival Microbiome Measured by 16S Metagenomics According to Periodontitis Status in Older Women.

Aging invokes physiological changes, such as immunosenescence and inflammation, that could increase host susceptibility to oral microbiome shifts that enable periodontitis progression in later life. At present, there is a dearth of studies specifically evaluating the oral microbiome and periodontitis in older adults. We used high-throughput untargeted sequencing methods and functional metagenomic analyses to assess and compare the subgingival biofilm of postmenopausal women (mean age 71 years) according to periodontitis status. Subgingival plaque samples were obtained from 15 postmenopausal women with no periodontitis, and from 15 women with severe periodontitis, determined by probing measures. The 16S rRNA gene (V1⁻V3 region) was sequenced on the 454 FLX platform. The PICRUSt technique was used to provide information on what the potential functional characteristics of microbiota might be in healthy, compared with diseased, periodontium. The subgingival microbiome associated with periodontitis showed clear differences to that associated with health. Of the 464 species identified, 22.8% had elevated abundance in disease, while only 6.3% had elevated abundance in health. Among the 12 most prevalent organisms in periodontitis, one-half have previously been recognized as periodontal pathogens by other investigators. The subgingival microbiome in periodontitis contained genes that could code for specific activities, including microbial mobility, synthesis of endotoxin, and proteolytic degradation. The healthy microbiome included genes that could code for sustaining microbial life, including encoding for transporters, glycolysis, gluconeogenesis, the Krebs cycle, and protein kinases. In the present study on postmenopausal women, aged 60 and older, the subgingival microbiome differed in composition and potential function between those with and without periodontitis. Studies of functional gene expression, such as transcriptomics, are needed to definitively identify the molecules carrying out functions associated with pathogenic subgingival complexes. This, in turn, could lead to identification of targets for enhanced management of periodontitis and, possibly, other diseases, in later life.

Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study.

OBJECTIVE: To determine the association between use of vaginal estrogen and risk of a global index event (GIE), defined as time to first occurrence of coronary heart disease (CHD), invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death from any cause. METHODS: For this prospective observational cohort study, we used data from participants of the Women's Health Initiative Observational Study, who were recruited at 40 US clinical centers, aged 50 to 79 years at baseline and did not use systemic estrogen therapy during follow-up (n = 45,663, median follow-up 7.2 years). We collected data regarding incident CHD, invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, death, and self-reported use of vaginal estrogen (cream, tablet). We used Cox proportional-hazards regression models to adjust for covariates. RESULTS: Among women with an intact uterus, the risks of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, and pulmonary embolism/deep vein thrombosis were not significantly different between vaginal estrogen users and nonusers, whereas the risks of CHD, fracture, all-cause mortality, and GIE were lower in users than in nonusers (GIE adjusted hazard ratio 0.68, 95% confidence interval 0.55-0.86). Among hysterectomized women, the risks of each of the individual GIE components and of the overall GIE were not significantly different in users versus nonusers of vaginal estrogen (GIE adjusted hazard ratio 0.94, 95% confidence interval 0.70-1.26). CONCLUSIONS: The risks of cardiovascular disease and cancer were not elevated among postmenopausal women using vaginal estrogens, providing reassurance about the safety of treatment.

History of Periodontitis Diagnosis and Edentulism as Predictors of Cardiovascular Disease, Stroke, and Mortality in Postmenopausal Women.

BACKGROUND: Few studies have reported associations between periodontitis and cardiovascular disease (CVD) risk in older women, which is the objective of the present investigation. METHODS AND RESULTS: Participants were 57 001 postmenopausal women ages 55 to 89 years (mean 68 years; >85% 60 and older) who were enrolled (1993-1998) in the Women's Health Initiative Observational Study, and were without known CVD when history of periodontitis and edentulism was assessed by questionnaire at study Year-5 (1998-2003). There were 3589 incident CVD events and 3816 total deaths during a mean follow-up of 6.7 years. In multivariable analysis, periodontitis was not associated with CVD events, but was associated with higher total mortality (hazard ratio (HR)=1.12, 95% CI: 1.05-1.21). Edentulism was associated with higher age- and smoking-adjusted risks of CVD (HR=1.42, 95% CI: 1.27-1.59) and mortality (HR=1.47, 95% CI: 1.32-1.63). Further adjustment eliminated the association with CVD, but mortality remained significantly increased (HR=1.17, 95% CI: 1.02-1.33). Stratification on age, race-ethnicity, smoking, and diabetes mellitus yielded comparable results; however, edentulism was more strongly associated with CVD in women reporting ≥1 dental visit (HR=1.57) compared with <1 visit (HR 1.03, interaction P=0.004) annually. CONCLUSIONS: In community-dwelling older women, edentulism was associated with increased risks of CVD and total mortality, and presence of periodontitis, which is more prevalent than edentulism, was associated with 17% higher mortality rate. These findings suggest that improving periodontal condition of the general population could reduce overall mortality.