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Abstract Background Self-assembly of the amyloid-β peptide (Aβ) has been implicated in the pathogenesis of Alzheimer's disease (AD). As a result, synthetic molecules capable of inhibiting Aβ self-assembly could serve as therapeutic agents and endogenous molecules that modulate Aβ self-assembly may influence disease progression. However, increasing evidence implicating a principal pathogenic role for small soluble Aβ aggregates warns that inhibition at intermediate stages of Aβ self-assembly may prove detrimental. Here, we explore the inhibition of Aβ1–40 self-assembly by serum albumin, the most abundant plasma protein, and the influence of this inhibition on Aβ1–40 activation of endothelial cells for monocyte adhesion. Results It is demonstrated that serum albumin is capable of inhibiting in a dose-dependent manner both the formation of Aβ1–40 aggregates from monomeric peptide and the ongoing growth of Aβ1–40 fibrils. Inhibition of fibrillar Aβ1–40 aggregate growth is observed at substoichiometric concentrations, suggesting that serum albumin recognizes aggregated forms of the peptide to prevent monomer addition. Inhibition of Aβ1–40 monomer aggregation is observed down to stoichiometric ratios with partial inhibition leading to an increase in the population of small soluble aggregates. Such partial inhibition of Aβ1–40 aggregation leads to an increase in the ability of resulting aggregates to activate endothelial cells for adhesion of monocytes. In contrast, Aβ1–40 activation of endothelial cells for monocyte adhesion is reduced when more complete inhibition is observed. Conclusion These results demonstrate that inhibitors of Aβ self-assembly have the potential to trap small soluble aggregates resulting in an elevation rather than a reduction of cellular responses. These findings provide further support that small soluble aggregates possess high levels of physiological activity and underscore the importance of resolving the effect of Aβ aggregation inhibitors on aggregate size.

Introduction: National data on dental caries and dental service use among immigrant children in U.S. are limited. It is not known whether race/ethnicity would interact with immigration status to increase these disparities. Using a nationally representative sample, this study assessed the interaction effects of immigrant generation status and race/ethnicity on dental caries and dental visits among children in the U.S., Methods: Data were from the 2020 and 2021 National Survey of Children's Health. All data were self-reported by parents/guardians. The 2 outcomes were (1) dental caries (yes/no) in the past 12 months and (2) preventive dental visits (yes/no) in the past 12 months. Racial/ethnic groups included non-Hispanic White, Black, Hispanics, and Asian Americans. The analytical sample included 66,167 children aged 2-17 years, including 1,243 first-generation immigrant children; 11,017 second-generation immigrant children; and 53,907 nonimmigrant children. Study authors ran separate multiple logistic regression models for the 2 outcome variables. All analyses accounted for the survey design of National Survey of Children's Health., Results: First-generation immigrant children were more likely to have dental caries than nonimmigrant children (AOR=1.44). The interaction of race/ethnicity and immigrant generation status was significant ( p =0.04) in the preventive dental visits model, indicating increased challenges in getting dental visits among minority immigrant children in comparison with that among non-Hispanic White immigrant children, especially among first-generation immigrant children of Asian Americans (AOR=0.41) and non-Hispanic Black immigrant children (AOR=0.37)., Conclusions: First-generation immigrant children were less likely to see a dentist and more likely to have dental caries than nonimmigrants. Moreover, first-generation immigrant children from minority racial/ethnic groups were the least likely to seek dental services. To further reduce disparities in oral health and dental use among children in the U.S., culturally sensitive health promotion is warranted to improve oral health literacy and reduce barriers to dental care for immigrants, especially immigrant children of the minority groups., (© 2024 The Author(s).)

Background: Examination of serial cross-sectional national surveys from a representative sample of the population can identify patterns and help support policy development., Methods: The authors used data from the National Health Interview Survey on US adults reporting a dental visit in the past 12 months to examine trends from 1997 through 2019. Groups analyzed were based on sociodemographic factors including residence in a metropolitan statistical area, race and ethnicity, family income level, and geographic region., Results: Over the 23-year period, the authors found differences for family income level, living in a rural (nonmetropolitan vs metropolitan) area, race and ethnicity, and geographic region (P < .0001). When stratified by family income, racial disparities have diminished. Gaps in dental service use are long-standing for rural nonmetropolitan communities., Conclusions: Relative to urban locales, rural communities experienced persistent disparities in the use of the oral health care delivery system throughout the 23 years measured. Strategies to create innovative models of care are needed to address oral health needs in underserved rural communities., Practical Implications: Policy is needed to foster a shift toward population health that will incentivize a health care system that reduces financial barriers and enhances health outcomes for adult oral health, especially for rural areas., Competing Interests: Disclosures None of the authors reported any disclosures., (Copyright © 2024 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Objectives: This project examined patterns of adult patient management using a caries risk assessment (CRA) protocol at East Carolina University, School of Dental Medicine. Usage of the CRA protocol from 2014 to 2019 was assessed. Non-operative anti-caries treatments were measured against caries risk status (high, moderate, low, or none). Steps to improve the appropriate management of patients based on caries risk are presented to align with accreditation standards for predoctoral education programs., Methods: The CRA protocol is based on the Caries Management by Risk Assessment approach. Risk-based patterns for two non-operative interventions were examined: (1) prescriptions for 0.12% chlorhexidine gluconate (CHX) mouth rinse and (2) prescriptions for 5000 ppm fluoride toothpaste (PreviDent 5000 [PreviDent]). Statistical analyses included chi-square tests and logistic regression., Results: Over the study period only 16.4% of adult patients had completed the CRA form. Among 29,411 patients from nine community sites, treatment rates for PreviDent were 18.7% among high-risk patients, 11.6% for moderate-risk adults, and 6.4% for low-risk adults (p < 0.01). Treatment rates for CHX were 23.0%, 22.6%, and 17.1%, respectively (p < 0.05). Patients without a CRA status were least likely to receive any anti-caries treatments, indicating that CRA status affects clinical, non-operative care., Conclusions: Patterns for prescription of PreviDent and CHX are consistent with CRA status. Future efforts to improve usage of the CRA protocol using faculty calibration, tracking with quality improvement tools, and reassessment. Training in the community-based educational setting is enhanced through data-based tracking to assure evidence-based decision making., (© 2023 The Authors. Journal of Dental Education published by Wiley Periodicals LLC on behalf of American Dental Education Association.)

Background: This study aimed to identify the most common types of nontraumatic dental conditions (NTDCs) before and during the COVID-19 pandemic and assess the variations in the most common NTDCs by patient age groups and rural or urban locations and the impact of COVID-19 on emergency department (ED) visits for NTDCs in North Carolina., Methods: The authors conducted a retrospective data analysis of ED data from the North Carolina Disease Event Tracking and Epidemiology Collection Tool. The authors estimated the proportions of NTDCs of all ED visits in 2019 and 2021 and ranked the proportions of the major categories of NTDCs by age groups and rural or urban locations. They used a multiple logistic regression model to assess the impact of COVID-19 on NTDCs., Results: By the first diagnosis, the proportion of NTDCs dropped from 1.1% in 2019 to 0.99% in 2021 (P < .001). Caries was specified as the third most common NTDC. Oral infection was the top NTDC among young (≤ 17 years) and older patients (≥ 65 years). No significant differences were found in NTDCs between rural and urban areas (P = .68). Children younger than 2 years (adjusted odds ratio, 4.36) and adults aged 18 through 44 years (adjusted odds ratio, 4.54) were more likely to visit the ED for NTDCs than those 75 years and older., Conclusions: The proportion of NTDCs seen at the ED was lower during the COVID-19 pandemic in 2021 than in 2019. The common NTDCs varied by age group but were similar in rural and urban areas. The most common NTDCs were related to toothache, oral infection, and caries., Practical Implications: More efforts are needed to reduce ED visits for NTDCs., Competing Interests: Disclosures None of the authors reported any disclosures., (Copyright © 2024 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the patterns of specific dental service utilization among the various sociodemographic groups in North Carolina served by the East Carolina University School of Dental Medicine (ECU SoDM)., Design: This was a descriptive study utilizing self-reported patients' sociodemographic information, payment method history, and CDT codes of procedures performed. Deidentified clinical data recorded for 26 710 patients and 534 983 procedures from 2011 to 2020 were extracted from a centralized axiUm database. Data were analyzed using IBM SPSS Statistics, version 25.0. Cross-tabulations between dental service utilizations, patients' demographics, and payment method were performed using chi-square analysis., Setting: Nine dental clinic sites across the state of North Carolina., Participants: In total, 26 710 adults 23 years to older than 65 years were included in the sample for this study., Main Outcome Measures: In total, 534 983 procedure codes completed for the eligible patients were cross-tabulated with payment method., Results: Payment method was significantly related to individual characteristics including location of service, age, race, ethnicity, and untreated decay ( P < .001). Payment method is associated with the dental service type utilized by an individual ( P < .001). Patients who received Medicaid benefits were more likely to receive restorative procedures, removable prosthetics, or oral surgery. Despite NC Medicaid covering preventive procedures, patients who received Medicaid benefits showed lower utilization of preventive procedures than expected. Privately insured or self-paying individuals demonstrated a greater variety of service option utilization, as well as more frequent usage of more specialized procedure options such as endodontics, periodontics, fixed prosthodontics, and implants., Conclusions: Payment method was found to be related to patients' demographics and type of dental service utilized. Adults older than 65 years demonstrated a higher proportion of self-payment for dental care, indicating a lack of payment options for this population. In the interest of providing care for underserved populations in North Carolina, policy makers should consider expanding dental coverage for adults older than 65 years., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc.)

Hierarchical control is often thought to dissect a complex task space into isolated subspaces in order to eliminate interference. Yet, there is also evidence from serial-order control tasks that our cognitive system can make use of abstract relationships between different parts (chunks) of a sequence. Past evidence in this regard was limited to situations with ordered stimuli (e.g., numbers or positions) that may have aided the detection of relationships and allowed gradual learning and hypothesis testing. Therefore, we used a modified task-span paradigm (with no ordered elements between tasks) in which participants performed memorized sequences of tasks that were encoded in terms of separate chunks of three tasks each. To allow examination of learning effects, each sequence was "cycled" through repeatedly. Importantly, we compared sequences whose chunks were governed by a common, abstract grammar with sequences whose chunks were governed by different grammars. Experiment 1 examined the effect of relationships between shared-element chunks (e.g., ABB-BAA vs. ABB-BAB), Experiment 2 and 3 between different-element chunks (e.g., ABA-CDC vs. ABA-CCD), and Experiment 4 examined second-order relationships (e.g., ABA-ABB--CDC-CDD vs. ABA-ABB--CDC-CCD). Robust evidence in favor of beneficial effects of abstract inter-chunk relationships was obtained across all four experiments. Importantly, these effects were at least as strong in initial cycles of performing a given sequence as during later cycles, suggesting that the cognitive system operates with an "expectation of abstract relationships," rather than benefitting from them through gradual learning. We discuss the implications of these results for models of hierarchical control., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Medicare beneficiaries in rural areas may face challenges in access to dental care. This study assessed rural-urban differences in the use of dental services and dental procedures by Medicare beneficiaries., Methods: We obtained data from the 2018 Medicare Current Beneficiary Survey cost and use files. Outcome variables examined in this study were (1) dental visits (yes/no), whether the Medicare beneficiary had ≥1 dental visit in the past year, and (2) dental procedures-preventive (yes/no), restorative (yes/no), and surgical procedures (yes/no)-whether the beneficiary had the procedure in a dental visit. The independent variable was the beneficiary's residence (rural vs urban). We used multiple logistic regression to analyze data and accounted for the survey design of the Medicare Current Beneficiary Survey. The analytic sample included 7377 respondents aged ≥65 years., Results: Approximately 57.0% (95% CI, 54.9%-59.0%) and 46.4% (95% CI, 41.6%-51.2%) of Medicare beneficiaries in urban and rural communities in the United States had a dental visit in 2018, respectively. Rural beneficiaries were significantly less likely than their urban counterparts to have preventive procedures (adjusted odds ratio = 0.51; 95% CI, 0.36-0.72) but significantly more likely to have restorative procedures (adjusted odds ratio = 1.30; 95% CI, 1.05-1.62)., Conclusion: We found significant disparities in use of dental services by Medicare beneficiaries in rural communities. When Medicare beneficiaries in rural areas used dental care, they were less likely than beneficiaries in urban areas to have preventive procedures but more likely to have restorative procedures, suggesting a greater burden of oral health needs among them. Policy research is needed to identify models that can incentivize prevention and improve access to dental care for Medicare beneficiaries in rural communities.

Most task spaces require a hierarchical structure, where decisions on one level are contingent on previous decisions made on one or more higher levels. While it is a truism that increasing the number of hierarchical levels makes it harder to solve a given task, the exact nature of this "number-of-levels" effect is not clear. On the one hand, processing costs might be strictly "local," incurred only when higher-level settings need to be updated, while otherwise lower-level decisions are insulated from the presence of higher-level settings (local updating costs with ballistic control). On the other hand, maintaining and integrating more complex hierarchical structures could require overall greater representational resources, negatively affecting each individual decision within the represented task space (global integration/maintenance costs). Further, navigation through hierarchical structures can be guided either through prompts in the environment (cue-based), or through sequential plans (serial-order based), with potentially distinct maintenance and updating demands. In two experiments, we assessed performance as a function of hierarchical level and format (serial-order vs. cue-based). Model comparisons showed that the pattern of costs in the serial-order format was consistent with a global maintenance/integration account. In contrast, in the cue-based format, costs arose at updating points and when one additional relevant level beyond the current decision was relevant, while additional levels produced no further costs. This overall constellation of costs can be explained by assuming that each decision requires checking the immediately relevant higher-level context for that decision. For cue-based control, this context involves the "next-level-up" rule, whereas in the serial-order format, each trial requires updating of the current position within the sequence, which in turn requires integration across all relevant hierarchical levels., 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 © 2023 Elsevier Inc. All rights reserved.)

Background: Although there has been a slight increase in dental professionals since 2011, 98 of North Carolina's 100 counties are designated as Dental Health Professional Shortage Areas by the Heath Resources and Service Administration. This shortage significantly increases disparities and access to primary and specialized oral health care. Also, dental professionals in these remote locations may feel the access and referrals to oral and maxillofacial pathologists cumbersome. In 2020, the COVID-19 pandemic prompted an inevitable surge in the use of digital technology due to the social distancing norms and lockdowns, which forced dental education institutions and practitioners to adjust to new ways of meeting, teaching, and providing dental care. In the present manuscript, we report our institutional experience delivering specialized dental care in rural areas., Materials and Methods: We conducted a retrospective case series of diagnosis, management, and outcomes of patients who underwent synchronous or asynchronous virtual and remote examination of oral lesions at ECU School of Dental Medicine and one satellite clinic over seven years. For those cases that concluded on surgical sampling, the clinical impressions, differential diagnoses, and the final diagnosis were compared to assess the accuracy of the clinical exam through teledentistry., Results: The total study population consisted of 71 patients. Most of the remote consultations were done asynchronously. Also, most virtual clinical consultations were initiated due to clinical suspicion of malignancy and infectious/reactive conditions, accounting for 42% and 25.3% of all encounters., Conclusions: The presented data suggest how teledentistry can support clinical practice in rural areas to achieve optimal care for the patient in rural or remote communities. Also, it significantly decreases the travel required, the number of appointments, and increases the speed of diagnosis. Teledentistry is an excellent tool available to all clinicians and can dramatically aid in diagnosing oral mucosa lesions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Flores-Hidalgo, Collie, King, Grant, Beasley, Moss and Tempel.)

Objectives: Previous meta-analyses have mainly focused on studies conducted in endemic fluorosis areas with relatively high fluoride concentrations. These are impoverished rural communities in China, India, and Iran, and the findings cannot be generalised to developed countries. Therefore, we investigated the association between fluoride concentrations relevant to community water fluoridation and children's cognition measured with IQ scores by synthesising effect sizes reported in observational studies., Methods: A previous meta-analysis and the National Toxicology Program database that included a search of multiple databases and the authors' search of PubMed, Google Scholar, and Mendeley provided the data. Cross-sectional and cohort studies examining the association between fluoride and children's cognition and intelligence scores were selected. Two reviewers abstracted data using standard procedures. We performed three meta-analyses to synthesise the effects using the random effects models., Results: Eight studies of standardized mean difference in IQ scores from non-endemic fluorosis areas found no statistically significant difference between recommended and lower levels of fluoride (standardized mean difference = 0.07; 95% confidence interval: -0.02, 0.17; I 2  = 0%), and no significant fluctuation in IQ scores across the differences in fluoride concentrations by non-linear modeling with restricted cubic spline (P = 0.21). Meta-analyses of children's and maternal spot urinary fluoride associated pooled regression coefficients (Beta children  = 0.16; 95% confidence interval: -0.40, 0.73; P = 0.57; I 2  = 0%, Beta maternal  = -0.92; 95% CI: -3.29, 1.46; P = 0.45; I 2  = 72%) were not statistically significant. Further regression analysis by standardizing absolute mean IQ scores from lower fluoride areas did not show a relationship between F concentration and IQ scores (Model Likelihood-ratio test: P-value = 0.34.) CONCLUSIONS: These meta-analyses show that fluoride exposure relevant to community water fluoridation is not associated with lower IQ scores in children. However, the reported association observed at higher fluoride levels in endemic areas requires further investigation., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Motivation: Native top-down proteomics (nTDP) integrates native mass spectrometry (nMS) with top-down proteomics (TDP) to provide comprehensive analysis of protein complexes together with proteoform identification and characterization. Despite significant advances in nMS and TDP software developments, a unified and user-friendly software package for analysis of nTDP data remains lacking., Results: We have developed MASH Native to provide a unified solution for nTDP to process complex datasets with database searching capabilities in a user-friendly interface. MASH Native supports various data formats and incorporates multiple options for deconvolution, database searching, and spectral summing to provide a "one-stop shop" for characterizing both native protein complexes and proteoforms., Availability and Implementation: The MASH Native app, video tutorials, written tutorials, and additional documentation are freely available for download at https://labs.wisc.edu/gelab/MASH&#95;Explorer/MASHSoftware.php. All data files shown in user tutorials are included with the MASH Native software in the download .zip file., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: To assess disparities in preventive dental service use in four major racial/ethnic groups and assess whether racial/ethnic and income-related disparities among children were reduced from 2016 to 2020., Methods: Data were from the 2016 and 2020 National Survey of Children's Health (NSCH). The outcomes of interest were having dental sealants, fluoride treatment, and dental caries in the past 12 months. Racial/ethnic groups included non-Hispanic (NH) whites, blacks, Hispanics, Asians, and others. Family income level was categorized as below or above the 200% federal poverty level (low-income vs. high-income). Children ages 2-17 were included (N = 161,539). All data were self-reported by parents/guardians. We estimated the trends of racial/ethnic disparities in having fluoride treatment, dental sealants, and dental caries from 2016 to 2020 and tested two 2-way interactions (i.e., year by race/ethnicity, year by income) and one 3-way interaction (year by income by race/ethnicity) to assess the change in disparities from 2016 to 2020., Results: Overall, no significant trends in receipt of fluoride treatment, dental sealants, or having dental caries were found from 2016 to 2020 among the racial/ethnic groups, except for a decreasing trend in dental sealants for Asian American children (p = 0.03). Overall, NH white children were more likely to have received preventive dental services than children from minority groups (all p < 0.05); Asian American children (AOR = 1.31) were more likely to have dental caries than NH white children., Conclusion: Disparities in receipt of evidence-based preventive services by children persisted. Continuous efforts are needed to promote the use of preventive dental services among children of minority populations., (© 2023 American Association of Public Health Dentistry.)

Background: Population studies consistently demonstrate a greater prevalence of chronic diseases, including oral diseases, among underrepresented minorities. This retrospective study aimed to measure and describe the prevalence and extent of periodontitis among adults seeking dental care within an academic practice-based network in rural North Carolina., Methods: This study used de-identified electronic health record (EHR) data from 2011 to 2017 of adult dentate patients (aged ≥30 years) seeking dental care who received a comprehensive periodontal examination at one of nine networked clinical centers. Periodontitis prevalence was calculated using CDC/AAP case definitions, along with extent (%) scores for periodontal parameters. Comparisons focused on age, sex, race, ethnicity, tobacco use, diabetes status, payer or insurance status, plaque scores, and the number of teeth., Results: EHR data for 10,544 adult patients (60.5% female) indicated 79.8% had some form of periodontitis. This patient population was diverse: 22.6% Black, 4.4% American Indian, and 53.8% White, with 4.8% self-identified as Hispanic. Patients 50 years and older showed greater mean extent scores for clinical attachment levels relative to patients 30 to 49 years. Males exhibited greater periodontitis than females (p = 0.001). Blacks showed significantly (p < 0.001) greater periodontitis prevalence relative to Whites. Hispanics also showed a greater prevalence of periodontitis (p < 0.001) relative to non-Hispanics. Significantly greater periodontitis was also noted for tobacco users (p < 0.001) but not for diabetes or payer status. A multiple logistic regression analysis of periodontitis prevalence confirmed significant associations for periodontitis for age, sex, race, ethnicity, tobacco use, high plaque scores, and the number of teeth (p < 0.001), but not diabetes or payer status., Conclusions: The data document that racial and ethnic inequalities in periodontal health occur within the population of adults residing in rural communities in North Carolina and seeking dental care., (© 2022 The Authors. Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

Objectives: To assess the association between sugar from sugar-sweetened beverages (SSBs) and untreated decay in permanent teeth and calculate the cost burden of sugar from SSBs on untreated decay in US adults., Methods: Cross-sectional data from the 2013-2014 and 2015-2016 cycles of the National Health and Nutrition Examination Survey (NHANES) were analysed in 2020 (n = 9001 adults aged ≥20). Multivariable analyses assessed sugar intake from SSB consumption with the presence of untreated decay in permanent teeth and number of untreated decayed teeth. Population attributable risk was used to estimate the cost burden arising from SSBs on untreated decay in US adults., Results: One fourth (25.1%) of US adults had untreated dental decay, and higher prevalence was observed among those with low income, low education and race/ethnicity of non-Hispanic Black. Overall, 53% of adults reported no intake of SSBs. For the remaining 47%, the median 24-h intake was 46.8 g of sugar from SSBs. The adjusted prevalence ratio (PR) for untreated decay was 1.3 (95% confidence interval [CI] 1.1-1.5) for consumption of 46.8 g or more of sugar from SSBs compared to those reporting no sugar from SSBs. Number of untreated decayed teeth increased with sugar intake from SSBs from lowest to highest tertile: 0.1, (p = .35); 0.4, (p = .006); and 0.6, (p < .001). The cost burden of untreated decay attributable to SSBs in US adults is estimated conservatively at $1.6 billion USD., Conclusions: Community level interventions directed at sugar from SSBs are justified to address disparities in the burden of untreated dental decay., (© 2021 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

We tested the hypothesis that there is an age-related deficit in the recovery from interruptions. This hypothesis is based on the idea that it is more difficult for old than for young adults to establish a focused state after working memory has been "opened up" through an interruption. Old ( N = 95) and young adults ( N = 94) performed competing nondominant and dominant primary tasks (selecting either exogenously or endogenously cued targets) in alternating, single-task blocks that were occasionally interrupted through trials with unrelated math tasks. As predicted, after interruptions, older adults showed increased and prolonged recovery costs, as well as generally larger endogenous/exogenous and conflict effects in blocks that contained interruptions. Individual differences in working memory (WM) capacity did not produce comparable results, suggesting that the interruption-based deficits were specific to aging. In addition, the theoretically important, paradoxical cost asymmetry (i.e., larger interruption costs for the dominant exogenous than for the nondominant endogenous task) was stronger in old than in young adults. These results provide novel insights about the interplay between WM and long-term memory during task control, as well as the origin of age differences in task-set selection. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Objective: Animal models of atherosclerosis are used extensively to interrogate molecular mechanisms in serial fashion. We tested whether a novel systems biology approach to integration of preclinical data identifies novel pathways and regulators in human disease. Approach and Results: Of 716 articles published in ATVB from 1995 to 2019 using the apolipoprotein E knockout mouse to study atherosclerosis, data were extracted from 360 unique studies in which a gene was experimentally perturbed to impact plaque size or composition and analyzed using Ingenuity Pathway Analysis software. TREM1 (triggering receptor expressed on myeloid cells) signaling and LXR/RXR (liver X receptor/retinoid X receptor) activation were identified as the top atherosclerosis-associated pathways in mice (both P <1.93×10 - 4 , TREM1 implicated early and LXR/RXR in late atherogenesis). The top upstream regulatory network in mice (sc-58125, a COX2 inhibitor) linked 64.0% of the genes into a single network. The pathways and networks identified in mice were interrogated by testing for associations between the genetically predicted gene expression of each mouse pathway-identified human homolog with clinical atherosclerosis in a cohort of 88 660 human subjects. Homologous human pathways and networks were significantly enriched for gene-atherosclerosis associations (empirical P <0.01 for TREM1 and LXR/RXR pathways and COX2 network). This included 12(60.0%) TREM1 pathway genes, 15(53.6%) LXR/RXR pathway genes, and 67(49.3%) COX2 network genes. Mouse analyses predicted, and human study validated, the strong association of COX2 expression ( PTGS2 ) with increased likelihood of atherosclerosis (odds ratio, 1.68 per SD of genetically predicted gene expression; P =1.07×10 - 6 )., Conclusions: PRESCIANT (Preclinical Science Integration and Translation) leverages published preclinical investigations to identify high-confidence pathways, networks, and regulators of human disease.

Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex., Approach and Results: We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity., Conclusions: These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation.

Purpose: In response to COVID-19, dental educators have been tasked with maintaining the quality of education while reducing cost, increasing efficiency, and leveraging technology., Methods: This collaborative, multisite virtual health policy course used the Staged Self-Directed Learning Model (SSDL) to lead a diverse group of students studying health policy. Twelve Core sessions were offered with three additional sessions in August or December for a total of 15 total synchronous Zoom sessions that covered policy issues on supply, demand, and need for dental care., Results: Twenty-eight students, seven lead instructors, and two course directors from six schools reported positive feedback on the course format, use of technology and the SSDL model, and breadth of topics presented. Participation by universities in four states with differing health policies stimulated virtual classroom discussions., Conclusion: In conclusion, collaborative interinstitutional virtual teaching and learning is cost effective, efficient, and engaging for students. This model has the potential to continue even when institutions are no longer affected by COVID-19., (© 2021 American Dental Education Association.)

Purpose: School-based oral health programs (SBOHPs) provide opportunities to address oral health inequities by providing convenient access points for care. No published guidelines on SBOHP implementation existed. Our work describes how philanthropic, public, and academic organizations partnered to support dental safety net providers with designing comprehensive SBOHPs in North and South Carolina., Description: A multi-sector leadership team was established to manage a new SBOHP philanthropic-funded grant program organized into two phases, Readiness and Implementation, with the former a 6-month planning period in preparation of the latter. Readiness included technical assistance (TA) delivered through coaching and 15 online learning modules organized in four domains: operations, finance, enabling services, and impact. Organizations could apply for implementation grants after successful TA completion. Process evaluation was used including a Readiness Stoplight Report for tracking progression., Assessment: Ten Readiness grantees completed the TA. A variety of models resulted, including mobile, portable and fixed clinics. Descriptive analysis was conducted on the readiness stoplight reports. Components of the operation and finance domains required were the most time-intensive, specifically the development of policy manuals, production goals, and financial performance tracking., Conclusion: The program's structure resulted in (a) a two-state learning community, (b) SBOHP practice and policy alignment, and (c) coordinated program distribution. TA improvements are planned to account for COVID-19 threats, including school closures, space limitations, and transmission fears. Telehealth, non-aerosolizing procedures, and improved scheduling and communication can address concerns. Organizations considering SBOHPs should explore similar recommendations to navigate adverse circumstances., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abnormalities that characterize pulmonary arterial hypertension include impairment in the structure and function of pulmonary vascular endothelial and smooth muscle cells. Aldosterone levels are elevated in human pulmonary arterial hypertension and in experimental pulmonary hypertension, while inhibition of the aldosterone-binding mineralocorticoid receptor attenuates pulmonary hypertension in multiple animal models. We explored the role of mineralocorticoid receptor in endothelial and smooth muscle cells in using cell-specific mineralocorticoid receptor knockout mice exposed to sugen/hypoxia-induced pulmonary hypertension. Treatment with the mineralocorticoid receptor inhibitor spironolactone significantly reduced right ventricular systolic pressure. However, this is not reproduced by selective mineralocorticoid receptor deletion in smooth muscle cells or endothelial cells. Similarly, spironolactone attenuated the increase in right ventricular cardiomyocyte area independent of vascular mineralocorticoid receptor with no effect on right ventricular weight or interstitial fibrosis. Right ventricular perivascular fibrosis was significantly decreased by spironolactone and this was reproduced by specific deletion of mineralocorticoid receptor from endothelial cells. Endothelial cell-mineralocorticoid receptor deletion attenuated the sugen/hypoxia-induced increase in the leukocyte-adhesion molecule, E-selectin, and collagen IIIA1 in the right ventricle. Spironolactone also significantly reduced pulmonary arteriolar muscularization, independent of endothelial cell-mineralocorticoid receptor or smooth muscle cell-mineralocorticoid receptor. Finally, the degree of pulmonary perivascular inflammation was attenuated by mineralocorticoid receptor antagonism and was fully reproduced by smooth muscle cell-specific mineralocorticoid receptor deletion. These studies demonstrate that in the sugen/hypoxia pulmonary hypertension model, systemic-mineralocorticoid receptor blockade significantly attenuates the disease and that mineralocorticoid receptor has cell-specific effects, with endothelial cell-mineralocorticoid receptor contributing to right ventricular perivascular fibrosis and smooth muscle cell-mineralocorticoid receptor participating in pulmonary vascular inflammation. As mineralocorticoid receptor antagonists are being investigated to treat pulmonary arterial hypertension, these findings support novel mechanisms and potential mineralocorticoid receptor targets that mediate therapeutic benefits in patients., (© The Author(s) 2021.)

Purpose: To assess rural-urban differences in dental service use and procedures and to explore the interaction effects of individual- and county-level factors on having dental service use and procedures., Methods: Data were from the 2016 Medical Expenditure Panel Survey (MEPS). We assessed rural-urban differences in 3 outcome variables: number of dental visits (1, 2, or 3+ visits), preventive care procedures (Yes/No), and treatment procedures (Yes/No). The study sample included 8,199 adults ≥ 18 years of age who reported at least 1 dental visit in the past year. Sampling weights embedded in MEPS were incorporated into all the analyses., Findings: A significant interaction between residential location and race/ethnicity (P = .030) suggested limited access to dental visits for minority groups, especially for blacks in the more rural areas. Adults from a more rural area were less likely to have received a preventive procedure (AOR = 0.55, 95% CI: 0.35-0.87) than those from an urban area. Adults of racial/ethnic minority groups, with lower SES, and without dental insurance were less likely to have received a preventive procedure (all P < .01) but were more likely to have received a treatment procedure (all P < .05)., Conclusions: The study showed rural adults were less likely to have received preventive dental procedures than their urban counterparts. Racial/ethnic minority groups living in a more rural area had even more limited access to dental services. Innovative service delivery models that integrate telehealth and community-based case management may contribute to addressing these gaps in rural communities., (© 2020 National Rural Health Association.)

Background: Mineralocorticoid receptor (MR) antagonists decrease heart failure (HF) hospitalization and mortality, but the mechanisms are unknown. Preclinical studies reveal that the benefits on cardiac remodeling and dysfunction are not completely explained by inhibition of MR in cardiomyocytes, fibroblasts, or endothelial cells. The role of MR in smooth muscle cells (SMCs) in HF has never been explored., Methods: Male mice with inducible deletion of MR from SMCs (SMC-MR-knockout) and their MR-intact littermates were exposed to HF induced by 27-gauge transverse aortic constriction versus sham surgery. HF phenotypes and mechanisms were measured 4 weeks later using cardiac ultrasound, intracardiac pressure measurements, exercise testing, histology, cardiac gene expression, and leukocyte flow cytometry., Results: Deletion of MR from SMC attenuated transverse aortic constriction-induced HF with statistically significant improvements in ejection fraction, cardiac stiffness, chamber dimensions, intracardiac pressure, pulmonary edema, and exercise capacity. Mechanistically, SMC-MR-knockout protected from adverse cardiac remodeling as evidenced by decreased cardiomyocyte hypertrophy and fetal gene expression, interstitial and perivascular fibrosis, and inflammatory and fibrotic gene expression. Exposure to pressure overload resulted in a statistically significant decline in cardiac capillary density and coronary flow reserve in MR-intact mice. These vascular parameters were improved in SMC-MR-knockout mice compared with MR-intact littermates exposed to transverse aortic constriction., Conclusions: These results provide a novel paradigm by which MR inhibition may be beneficial in HF by blocking MR in SMC, thereby improving cardiac blood supply in the setting of pressure overload-induced hypertrophy, which in turn mitigates the adverse cardiac remodeling that contributes to HF progression and symptoms.

Introduction: Dental Readiness Classifications (DRCs) enable the Military Health System to prioritize dental care in garrison, minimizing dental emergencies and mission degradation during deployments. Over half (52.4%) of 2008 military recruits presented with high-priority urgent needs classified as DRC3 upon initial dental examination and 18.1% required extensive treatment, needing 7 or more restorations, in order to achieve operational dental readiness. The purpose of this study is to identify risk indicators for urgent and extensive dental treatment needs in current U.S. Air Force (USAF) recruits so that Dental Corps leadership can target interventions to maximize oral health, prioritize resources, and reduce health expenditures in this patient population., Materials and Methods: A secondary data analysis was performed of deidentified survey and clinical exam data from the 2018 to 2019 USAF Recruit Oral Health Surveillance study conducted at Lackland Air Force Base from February 2018 to February 2019. Select demographic and self-reported variables were analyzed with two outcome variables: urgent (DRC3) and urgent and extensive (DRC3 + 7) dental treatment needs. Univariate log binomial regression was performed to determine relative risk of DRC3 and DRC3 + 7 by independent variable. The Uniformed Services University of the Health Sciences institutional review board approved the study as an exempt protocol., Results: Among the 1,335 recruits studied, the overall prevalence of urgent dental needs was 21.5%, whereas 5.5% of participants had both urgent and extensive needs. The study group included participants who were mostly male (69%), were non-Hispanic white (60%), aged 17 to 19 years (48%), were high school educated (47%), had private dental insurance coverage (50%) and self-reported: no need for dental care in the past year (65%), excellent or good condition of teeth (63%), were toothbrushing more than once a day (58%), and had daily consumption of one to three servings of sugary beverages (62%) and foods (69%). Statistically significant differences in relative risk for DRC3 were found for all independent variables except gender and education level. Risk indicators significant for DRC3 and DRC3 + 7 were aged 25 to 29 years; Other and Black race/ethnicity; Medicaid insurance; uninsured; self-reported fair, poor, or unsure current condition of teeth; and past year needed care but did not go (P < .05). The majority of DRC3 and DRC3 + 7 cases were in the small subset of recruits who self-reported fair, poor, or unknown current condition of teeth or need for dental care in the past year without a dental visit., Conclusions: Among USAF recruits, oral health disparities are observed in certain groups. The study findings can inform targeted utilization of resources and interventions to efficiently optimize oral health and operational dental readiness and decrease dental expenditures. Additionally, a two-question screening tool is proposed to facilitate priority assignment for dental examination during boot camp. This tool has the potential to correctly identify nearly 90% of those with urgent and extensive dental treatment needs at half the typical workload., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Dental care utilization for low income pregnant women is met with challenges in the traditional dentist-centered model of care. County-level measures provide insights for policy and roles for stakeholders that extend beyond the dentist-patient relationship. We examined county-level data to generate hypotheses about factors that influence utilization of dental services in North Carolina's Medicaid for Pregnant Women (MPW) program., Methods: County-level Medicaid utilization data for dental services for 2014-2016 were pooled to get mean county estimates of dental utilization in the MPW program. Descriptive statistics and multivariate regression models of dental utilization and county-level measures are presented. Data used were collected by NC Child and the Robert Wood Johnson Foundation's County Health Rankings Reports. USDA Economic Research Service data were used to categorize counties in terms of Farming, Recreation, Persistent Poverty, and metro/non-metro status using Rural Urban Continuum Codes., Results: Dental utilization ranged from 1-26% with a median of 8.5% across the 100 counties of North Carolina. Strong patterns linking utilization of dental services in the MPW program to contextual social measures of well-being emerged, specifically, increased reporting of child abuse and neglect, elevated infant mortality, poor quality of life, and worse ranking in years of potential life lost. Counties with persistent poverty had lower rates of dental utilization., Conclusions: Utilization of dental services in the MPW program is generally low. Patterns identify the potential for enhancing community-clinical linkages to improve birth outcomes and care coordination for pregnant women to enhance dental utilization in this population. Dental coverage in the Medicaid program in most states is administered separately from medical coverage. The separation of the funding mechanisms adds a further layer of complexity to care integration. Efforts to enhance dental care for pregnant women in the Medicaid program may benefit from policy that aligns incentives for care coordination within the community. Policy that extends the window of eligibility for dental benefits to 24 months after the birth of the child will help women complete the dental treatment that is needed. This also leverages the value of care coordination for community stakeholders from diverse child health sectors.

Theoretical considerations and results from individual differences studies suggest that working memory and conflict resolution are interrelated functions. Yet, there is little direct evidence suggesting that they actually share common cognitive resources. To study how overcoming conflict influences the maintenance of working memory representations and vice versa, we conducted 4 experiments using a dual-task paradigm in which both working memory load and level of conflict were independently manipulated. Participants performed an auditory Stroop task ("high" or "low" spoken in high/low pitch), which was presented during the retention period of a visual change detection task (Experiments 1-4) or simultaneously with the working memory encoding phase (Experiment 2-4). Across the 4 experiments, we found no consistent interaction between level of conflict and working memory load on working memory performance, although there was evidence in 2 of the 4 experiments for a small effect on auditory Stroop accuracy (but not on response times). These findings present at best weak evidence for the hypothesis that the maintenance of task goals in working memory is critical for successful conflict resolution. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Introduction: The objectives of this study were to describe trends of children being given dental checkup advice by primary care providers (PCPs) and having dental visits and to assess factors associated with being given dental checkup advice and having a dental visit., Methods: Data were from the annual, cross-sectional Medical Expenditure Panel Survey (MEPS) from 2001 to 2016. The sample included 126,773 children ages 2-17 years. We used predictive margins to estimate the probability of being given dental checkup advice and having a dental visit. We examined time trends of the proportion of children being given dental checkup advice from PCPs, as well as trends in the proportion of children having a dental visit from 2001 to 2016. Multiple logistic regression was used to assess the association between being given dental checkup advice and having a dental visit., Results: Overall, the proportion of children being given dental checkup advice increased from 31.4% in 2001 to 51.8% in 2016 (Trend P < 0.001). No significant increasing trend was found for having a dental visit among those being given dental checkup advice (Trend P > 0.05). Children being given dental checkup advice were more likely to have a dental visit (AOR = 1.54, P < 0.001)., Conclusions: Although there was an increase in the proportion of children being given advice to have dental checkups by PCPs from 2001 to 2016, there was no significant increase in having a dental visit among children being given the advice. More research is needed to better understand how dental care advice from a PCP can effectively motivate and facilitate dental care for children., (© 2020 American Association of Public Health Dentistry.)

Cardiovascular disease remains the leading cause of death for both men and women. The observation that premenopausal women are protected from cardiovascular disease relative to age-matched men, and that this protection is lost with menopause, has led to extensive study of the role of sex steroid hormones in the pathogenesis of cardiovascular disease. However, the molecular basis for sex differences in cardiovascular disease is still not fully understood, limiting the ability to tailor therapies to male and female patients. Therefore, there is a growing need to investigate molecular pathways outside of traditional sex hormone signaling to fully understand sex differences in cardiovascular disease. Emerging evidence points to the mineralocorticoid receptor (MR), a steroid hormone receptor activated by the adrenal hormone aldosterone, as one such mediator of cardiovascular disease risk, potentially serving as a sex-dependent link between cardiovascular risk factors and disease. Enhanced activation of the MR by aldosterone is associated with increased risk of cardiovascular disease. Emerging evidence implicates the MR specifically within the endothelial cells lining the blood vessels in mediating some of the sex differences observed in cardiovascular pathology. This review summarizes the available clinical and preclinical literature concerning the role of the MR in the pathophysiology of endothelial dysfunction, hypertension, atherosclerosis, and heart failure, with a special emphasis on sex differences in the role of endothelial-specific MR in these pathologies. The available data regarding the molecular mechanisms by which endothelial-specific MR may contribute to sex differences in cardiovascular disease is also summarized. A paradigm emerges from synthesis of the literature in which endothelial-specific MR regulates vascular function in a sex-dependent manner in response to cardiovascular risk factors to contribute to disease. Limitations in this field include the relative paucity of women in clinical trials and, until recently, the nearly exclusive use of male animals in preclinical investigations. Enhanced understanding of the sex-specific roles of endothelial MR could lead to novel mechanistic insights underlying sex differences in cardiovascular disease incidence and outcomes and could identify additional therapeutic targets to effectively treat cardiovascular disease in men and women., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: MR (mineralocorticoid receptor) activation is associated with cardiovascular ischemia in humans. This study explores the role of the MR in atherosclerotic mice of both sexes and identifies a sex-specific role for endothelial cell (EC)-MR in vascular inflammation. Approach and Results: In the AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9) mouse atherosclerosis model, MR inhibition attenuated vascular inflammation in males but not females. Further studies comparing male and female littermates with intact MR or EC-MR deletion revealed that although EC-MR deletion did not affect plaque size in either sex, it reduced aortic arch inflammation specifically in male mice as measured by flow cytometry. Moreover, MR-intact females had larger plaques but were protected from vascular inflammation compared with males. Intravital microscopy of the mesenteric vasculature demonstrated that EC-MR deletion attenuated TNFα (tumor necrosis factor α)-induced leukocyte slow rolling and adhesion in males, while females exhibited fewer leukocyte-endothelial interactions with no additional effect of EC-MR deletion. These effects corresponded with decreased TNFα-induced expression of the endothelial adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and E-selectin in males with EC-MR deletion compared with MR-intact males and females of both genotypes. These observations were also consistent with MR and estrogen regulation of ICAM-1 transcription and E-selectin expression in primary cultured mouse ECs and human umbilical vein ECs., Conclusions: In male mice, EC-MR deletion attenuates leukocyte-endothelial interactions, plaque inflammation, and expression of E-selectin and ICAM-1, providing a potential mechanism by which the MR promotes vascular inflammation. In females, plaque inflammation and leukocyte-endothelial interactions are decreased relative to males and EC-MR deletion is not protective.

Objective: The debate over use of race as a proxy for genetic risk of disease continues, but little is known about how primary care providers (nurse practitioners and general internal medicine physicians) currently use race in their clinical practice. Our study investigates primary care providers' use of race in clinical practice., Methods: Survey data from three cross-sectional parent studies were used. A total of 178 nurse practitioners (NPs) and 759 general internal medicine physicians were included. The outcome of interest was the Racial Attributes in Clinical Evaluation (RACE) scale, which measures explicit use of race in clinical decision-making. Predictor variables included the Genetic Variation Knowledge Assessment Index (GKAI), which measures the providers' knowledge of human genetic variation., Results: In the final multivariable model, NPs had an average RACE score that was 1.60 points higher than the physicians' score (P=.03). The GKAI score was not significantly associated with the RACE outcome in the final model (P=.67)., Conclusions: Physicians had more knowledge of genetic variation and used patients' race less in the clinical decision-making process than NPs. We speculate that these differences may be related to differences in discipline-specific clinical training and approaches to clinical care. Further exploration of these differences is needed, including examination of physicians' and NPs' beliefs about race, how they use race in disease screening and treatment, and if the use of race is contributing to health care disparities., Competing Interests: Competing Interests: None declared.

Objective: Elevated levels of the hormone aldosterone are associated with increased risk of myocardial infarction and stroke in humans and increased progression and inflammation of atherosclerotic plaques in animal models. Aldosterone acts through the mineralocorticoid receptor (MR) which is expressed in vascular smooth muscle cells (SMCs) where it promotes SMC calcification and chemokine secretion in vitro . The objective of this study is to explore the role of the MR specifically in SMCs in the progression of atherosclerosis and the associated vascular inflammation in vivo in the apolipoprotein E knockout (ApoE -/- ) mouse model. Methods and Results: Male ApoE -/- mice were bred with mice in which MR could be deleted specifically from SMCs by tamoxifen injection. The resulting atheroprone SMC-MR-KO mice were compared to their MR-Intact littermates after high fat diet (HFD) feeding for 8 or 16 weeks or normal diet for 12 months. Body weight, tail cuff blood pressure, heart and spleen weight, and serum levels of glucose, cholesterol, and aldosterone were measured for all mice at the end of the treatment period. Serial histologic sections of the aortic root were stained with Oil Red O to assess plaque size, lipid content, and necrotic core area; with PicroSirius Red for quantification of collagen content; by immunofluorescent staining with anti-Mac2/Galectin-3 and anti-smooth muscle α-actin antibodies to assess inflammation and SMC marker expression; and with Von Kossa stain to detect plaque calcification. In the 16-week HFD study, these analyses were also performed in sections from the brachiocephalic artery. Flow cytometry of cell suspensions derived from the aortic arch was also performed to quantify vascular inflammation after 8 and 16 weeks of HFD. Deletion of the MR specifically from SMCs did not significantly change plaque size, lipid content, necrotic core, collagen content, inflammatory staining, actin staining, or calcification, nor were there differences in the extent of vascular inflammation between MR-Intact and SMC-MR-KO mice in the three experiments. Conclusion: SMC-MR does not directly contribute to the formation, progression, or inflammation of atherosclerotic plaques in the ApoE -/- mouse model of atherosclerosis. This indicates that the MR in non-SMCs mediates the pro-atherogenic effects of MR activation.

Stiffening of the vasculature with aging is a strong predictor of adverse cardiovascular events, independent of all other risk factors including blood pressure, yet no therapies target this process. MRs (mineralocorticoid receptors) in smooth muscle cells (SMCs) have been implicated in the regulation of vascular fibrosis but have not been explored in vascular aging. Comparing SMC-MR-deleted male mice to MR-intact littermates at 3, 12, and 18 months of age, we demonstrated that aging-associated vascular stiffening and fibrosis are mitigated by MR deletion in SMCs. Progression of cardiac stiffness and fibrosis and the decline in exercise capacity with aging were also mitigated by MR deletion in SMC. Vascular gene expression profiling analysis revealed that MR deletion in SMC is associated with recruitment of a distinct antifibrotic vascular gene expression program with aging. Moreover, long-term pharmacological inhibition of MR in aged mice prevented the progression of vascular fibrosis and stiffness and induced a similar antifibrotic vascular gene program. Finally, in a small trial in elderly male humans, short-term MR antagonism produced an antifibrotic signature of circulating biomarkers similar to that observed in the vasculature of SMC-MR-deleted mice. These findings suggest that SMC-MR contributes to vascular stiffening with aging and is a potential therapeutic target to prevent the progression of aging-associated vascular fibrosis and stiffness., (© 2018 American Heart Association, Inc.)

Objectives: There are reports showing higher prevalence of enamel fluorosis among African-American children. This study was conducted to assess whether the effect of water fluoride level on enamel fluorosis is different among different race/ethnicity groups among US school children., Methods: Data from the National Survey of Oral Health of US School Children 1986-1987 were analyzed to determine the prevalence of enamel fluorosis among 7-17 year-old children. The association between race/ethnicity and enamel fluorosis was examined using logistic regression modeling after controlling for potential confounders age, gender, water fluoridation, other sources of fluoride, and region of residence., Results: The prevalence of very mild to severe enamel fluorosis was 20.8 (95% CI, 15.4, 26.3) and 25.7 (95% CI, 15.0, 36.5) percent among non-Hispanic White and non-Hispanic Black children, respectively. Neither the adjusted odds ratio of 1.3 (0.8, 2.0) for the non-Hispanic Black group nor the interaction effect between non-Hispanic Black and water fluoridation were statistically significant., Conclusions: Enamel fluorosis was not associated with race/ethnicity. Our analysis suggests that exposure to similar levels of fluoride in the water does not appear to place certain race/ethnic groups at a higher risk for developing enamel fluorosis, and lowering the optimal range of drinking water fluoride to a single value of 0.7 ppm will provide a level of protection against enamel fluorosis that will benefit all race/ethnicity groups., (© 2017 American Association of Public Health Dentistry.)

Background: The incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (MR) activation, we tested the hypothesis that MR in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors., Methods and Results: Male and female endothelial cell-specific MR knockout mice and MR-intact littermates were randomized to high-fat-diet-induced obesity or obesity with hyperlipidemia induced by adeno-associated virus-based vector targeting transfer of the mutant stable form (DY mutation) of the human PCSK9 (proprotein convertase subtilisin/kexin type 9) gene and compared with control diet. Female but not male mice were sensitive to obesity-induced endothelial dysfunction, whereas endothelial function was impaired in obese hyperlipidemic males and females. In males, obesity or hyperlipidemia decreased the nitric oxide component of vasodilation without altering superoxide production or endothelial nitric oxide synthase expression or phosphorylation. Decreased nitric oxide content in obese males was overcome by enhanced endothelium-derived hyperpolarization-mediated relaxation along with increased SK3 expression. Conversely, in females, endothelium-derived hyperpolarization was significantly impaired by obesity with lower IK1 expression and by hyperlipidemia with lower IK1 and SK3 expression, loss of H 2 O 2 -mediated vasodilation, and increased superoxide production. Endothelial cell-MR deletion prevented endothelial dysfunction induced by risk factors only in females. Rather than restoring endothelium-derived hyperpolarization in females, endothelial cell-MR deletion enhanced nitric oxide and prevented hyperlipidemia-induced oxidative stress., Conclusions: These data reveal distinct mechanisms driving resistance vessel dysfunction in males versus females and suggest that personalized treatments are needed to prevent the progression of vascular disease in the setting of obesity, depending on both the sex and the metabolic profile of each patient., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia., (© 2017 American Heart Association, Inc.)

Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 (ICAM-1). Recently, we reported that ICAM-1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction (TAC). Whether MR specifically in endothelial cells (EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs (EC-MR -/- ) and wild-type littermate controls (EC-MR +/+ ). MR was specifically deleted in heart EC, and in EC-containing tissues, but not in leukocytes of TAC EC-MR -/- mice. While EC-MR -/- TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNF α and the endothelin receptors in the LV as compared to EC-MR +/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM-1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC-MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Objective: Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression., Methods and Results: Apolipoprotein-E (ApoE) -/- mice fed an atherogenic diet and treated with aldosterone for 4weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE -/- /ICAM-1 -/- ) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1., Conclusions: Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To examine nurses' self-reported use of race in clinical evaluation., Design: This cross-sectional study analyzed data collected from three separate studies using the Genetics and Genomics in Nursing Practice Survey, which includes items about use of race and genomic information in nursing practice. The Racial Attributes in Clinical Evaluation (RACE) scale was used to measure explicit clinical use of race among nurses from across the United States., Methods: Multivariate regression analysis was used to examine associations between RACE score and individual-level characteristics and beliefs in 5,733 registered nurses., Findings: Analysis revealed significant relationships between RACE score and nurses' race and ethnicity, educational level, and views on the clinical importance of patient demographic characteristics. Asian nurses reported RACE scores 1.41 points higher than White nurses (p < .001), and Black nurses reported RACE scores 0.55 points higher than White nurses (p < .05). Compared to diploma-level nurses, the baccalaureate-level nurses reported 0.69 points higher RACE scores (p < .05), master's-level nurses reported 1.63 points higher RACE scores (p < .001), and doctorate-level nurses reported 1.77 points higher RACE scores (p < .01). In terms of clinical importance of patient characteristics, patient race and ethnicity corresponded to a 0.54-point increase in RACE score (p < .001), patient genes to a 0.21-point increase in RACE score (p < .001), patient family history to a 0.15-point increase in RACE score (p < .01), and patient age to a 0.19-point increase in RACE score (p < .001)., Conclusions: Higher reported use of race among minority nurses may be due, in part, to differential levels of racial self-awareness. A relatively linear positive relationship between level of nursing degree nursing education and use of race suggests that a stronger foundation of knowledge about genetic ancestry, population genetics and the concept "race" and genetic ancestry may increase in clinical decision making could allow nurses to more appropriately use of race in clinical care. Integrating patient demographic characteristics into clinical decisions is an important component of nursing practice., Clinical Relevance: Registered nurses provide care for diverse racial and ethnic patient populations and stand on the front line of clinical care, making them essential for reducing racial and ethnic disparities in healthcare delivery. Exploring registered nurses' individual-level characteristics and clinical use of race may provide a more comprehensive understanding of specific training needs and inform nursing education and practice., (© 2016 Sigma Theta Tau International.)

Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.

Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality.

Objectives: The objectives of this study are to determine the effect of fluoride exposure on permanent tooth eruption patterns as well as to understand its effect on caries attack rate by accounting for the number of erupted tooth surfaces., Methods: We analyzed data from the 1986-1987 National Survey of Oral Health of US Schoolchildren to determine the mean number of erupted permanent teeth and permanent first molars according to fluoride level in drinking water. The analysis included 13,348 children aged 5-17 years with a history of single residence. We also estimated the attack rate (decayed, missing, and filled surfaces/surfaces at risk) for fluoride deficient, suboptimal, and optimally fluoridated areas adjusting for covariates. Multivariable statistical analyses were performed to control for potential confounders., Results: By age 7, almost all permanent first molars had erupted. The adjusted mean number of erupted permanent first molars per child were 3.81, 3.67, and 3.92 in areas with <0.3, 0.3-<0.7, and 0.7-1.2 ppm of fluoride, respectively. The adjusted caries attack rate in the first permanent molars among 5- to 17-year-old children was 93, 81, and 78 per 1,000 surfaces in fluoride deficient, suboptimal, and optimally fluoridated areas, respectively (P < 0.0001). This pattern of higher first molar attack rate among children in the fluoride-deficient communities was also observed in all erupted teeth., Conclusion: Exposure to fluoride in drinking water did not delay the eruption of permanent teeth. The observed difference in dental caries experience among children exposed to different fluoride levels could not be explained by the timing of eruption of permanent teeth., (© 2014 American Association of Public Health Dentistry.)