Genetic Analyses of Enamel Hypoplasia in Multiethnic Cohorts.

Enamel hypoplasia causes reduction in the thickness of affected enamel and is one of the most common dental anomalies. This defect is caused by environmental and/or genetic factors that interfere with tooth formation, emphasizing the importance of investigating enamel hypoplasia on an epidemiological and genetic level. A genome-wide association of enamel hypoplasia was performed in multiple cohorts, overall comprising 7,159 individuals ranging in age from 7-82 years. Mixed-models were used to test for genetic association while simultaneously accounting for relatedness and genetic population structure. Meta-analysis was then performed. More than 5 million single-nucleotide polymorphisms were tested in individual cohorts. Analyses of the individual cohorts and meta-analysis identified association signals close to genome-wide significance (P < 510-8), and many suggestive association signals (510-8 < P < 510-6) near genes with plausible roles in tooth/enamel development. The strongest association signal (P = 1.5710-9) was observed near BMP2K in one of the individual cohorts. Additional suggestive signals were observed near genes with plausible roles in tooth development in the meta-analysis, such as SLC4A4 which can influence enamel hypoplasia. Additional human genetic studies are needed to replicate these results and functional studies in model systems are needed to validate our findings.

Association between cumulative social risk, particulate matter environmental pollutant exposure, and cardiovascular disease risk.

BACKGROUND: Long-term exposure to pollution has been shown to increase risk of cardiovascular disease (CVD) and mortality, and may contribute to the increased risk of CVD among individuals with higher social risk. METHODS: Data from the community-based Heart Strategies Concentrating on Risk Evaluation (HeartSCORE) study were used to quantify Cumulative Social Risk (CSR) by assigning a score of 1 for the presence of each of 4 social risk factors: racial minority, single living, low income, and low educational status. 1-year average air pollution exposure to PM2.5 was estimated using land-use regression models. Associations with clinical outcomes were assessed using Cox models, adjusting for traditional CVD risk factors. The primary clinical outcome was combined all-cause mortality and nonfatal CVD events. RESULTS: Data were available on 1933 participants (mean age 59 years, 66% female, 44% Black). In a median follow up time of 8.3 years, 137 primary clinical outcome events occurred. PM2.5 exposure increased with higher CSR score. PM2.5 was independently associated with clinical outcome (adjusted hazard ratio [HR]: 1.19 [95% CI: 1.00, 1.41]). Participants with ≥2 CSR factors had an adjusted HR of 2.34 (1.48-3.68) compared to those with CSR = 0. The association was attenuated after accounting for PM2.5 (HR: 2.16; [1.34, 3.49]). Mediation analyses indicate that PM2.5 explained 13% of the risk of clinical outcome in individuals with CSR score ≥ 2. CONCLUSION: In a community-based cohort study, we found that the association of increasing CSR with higher CVD and mortality risks is partially accounted for by exposure to PM2.5 environmental pollutants.

Particulate Matter Air Pollution and Racial Differences in Cardiovascular Disease Risk.

OBJECTIVE: We aimed to assess racial differences in air pollution exposures to ambient fine particulate matter (particles with median aerodynamic diameter <2.5 µm [PM2.5]) and black carbon (BC) and their association with cardiovascular disease (CVD) risk factors, arterial endothelial function, incident CVD events, and all-cause mortality. APPROACH AND RESULTS: Data from the HeartSCORE study (Heart Strategies Concentrating on Risk Evaluation) were used to estimate 1-year average air pollution exposure to PM2.5 and BC using land use regression models. Correlates of PM2.5 and BC were assessed using linear regression models. Associations with clinical outcomes were determined using Cox proportional hazards models, adjusting for traditional CVD risk factors. Data were available on 1717 participants (66% women; 45% blacks; 59±8 years). Blacks had significantly higher exposure to PM2.5 (mean 16.1±0.75 versus 15.7±0.73µg/m3; P=0.001) and BC (1.19±0.11 versus 1.16±0.13abs; P=0.001) compared with whites. Exposure to PM2.5, but not BC, was independently associated with higher blood glucose and worse arterial endothelial function. PM2.5 was associated with a higher risk of incident CVD events and all-cause mortality combined for median follow-up of 8.3 years. Blacks had 1.45 (95% CI, 1.00-2.09) higher risk of combined CVD events and all-cause mortality than whites in models adjusted for relevant covariates. This association was modestly attenuated with adjustment for PM2.5. CONCLUSIONS: PM2.5 exposure was associated with elevated blood glucose, worse endothelial function, and incident CVD events and all-cause mortality. Blacks had a higher rate of incident CVD events and all-cause mortality than whites that was only partly explained by higher exposure to PM2.5.

Association of obstructive sleep apnea with microvascular endothelial dysfunction and subclinical coronary artery disease in a community-based population.

Studies have reported an association between obstructive sleep apnea (OSA) and cardiovascular disease (CVD) morbidity and mortality. Proposed mechanisms include endothelial dysfunction and atherosclerosis. We aimed to investigate the associations of OSA with endothelial dysfunction and subclinical atherosclerotic coronary artery disease (CAD), and assess the impact of race on these associations. We used data from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study, a community-based prospective cohort with approximately equal representation of black and white participants. OSA severity was measured in 765 individuals using the apnea-hypopnea index (AHI). Endothelial dysfunction was measured using the Endo-PAT device, expressed as Framingham reactive hyperemia index (F_RHI). Coronary artery calcium (CAC), a marker of subclinical CAD, was quantified by electron beam computed tomography. There were 498 (65%) female participants, 282 (37%) black individuals, and 204 (26%) participants with moderate/severe OSA (AHI ≥15). In univariate models, moderate/severe OSA was associated with lower F_RHI and higher CAC, as well as several traditional CVD risk factors including older age, male sex, hypertension, diabetes, higher body mass index, and lower high-density lipoprotein cholesterol levels. In a multivariable model, individuals with moderate/severe OSA had 10% lower F_RHI and 35% higher CAC, which did not reach statistical significance ( p=0.08 for both comparisons). There was no significant interaction of race on the association of OSA with F_RHI or CAC ( p-value >0.1 for all comparisons). In a community-based cohort comprised of black and white participants, moderate/severe OSA was modestly associated with endothelial dysfunction and subclinical atherosclerotic CAD. These associations did not vary by race.

Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries.

A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus. Linear models were used to test for genetic association, while adjusting for sex, age and components of ancestry. SNPs in and near PKD2 showed significant evidence of association in individual samples of black adults (rs17013735, P-value=0.0009) and white adults (rs11938025; P-value=0.0005; rs2725270, P-value=0.003). Meta-analyses across black adult samples recapitulated the association with rs17013735 (P-value=0.003), which occurs at low frequency in non-African populations, possibly explaining the race specificity of the effect. In addition to race-specific associations, we also observed evidence of gene-by-fluoride exposure interaction effects in white adults for SNP rs2725233 upstream of PKD2 (P=0.002). Our results show evidence of regional replication, though no single variant clearly accounted for the original GWAS signal. Therefore, while we interpret our results as strengthening the hypothesis that chromosome 4q21 may impact dental caries, additional work is needed.

Differences in Hospital Risk-standardized Mortality Rates for Acute Myocardial Infarction When Assessed Using Transferred and Nontransferred Patients.

BACKGROUND: One in 5 patients with acute myocardial infarction (AMI) are transferred between hospitals. However, current hospital performance measures based on AMI mortality exclude these patients from the evaluation of referral hospitals. OBJECTIVE: To determine the relationship between risk-standardized mortality for transferred and nontransferred patients at referral hospitals. RESEARCH DESIGN: This is a retrospective cohort study. SUBJECTS: Fee-for-service Medicare claims from 2011 for patients hospitalized with a primary diagnosis of AMI, at hospitals admitting at least 15 patients in transfer. MEASURES: Hospital-specific risk-standardized 30-day mortality rates (RSMRs) for 2 groups of patients: those admitted through transfer from another hospital, and those natively admitted without a preceding or subsequent interhospital transfer. RESULTS: There were 304 hospitals admitting at least 15 patients in transfer. These hospitals cared for 77,711 natively admitted patients (median, 254; interquartile range, 162-321), and 11,829 patients admitted in transfer (median, 26; interquartile range, 19-46). Risk-standardized mortality rates were higher for natively admitted patients than for those admitted in transfer (mean, 11.5%±1.2% vs. 7.2%±1.1%). There was weak correlation between hospital performance as assessed by RSMR for patients natively admitted versus those admitted in transfer (Pearson r=0.24, P<0.001); when performance was arrayed by quartile, 102 hospitals (33.6%) differed at least 2 quartiles of performance across the 2 patient groups. CONCLUSIONS: For Medicare patients with AMI, hospital-specific RSMRs for natively admitted patients are only weakly associated with RSMRs for patients transferred in from another hospital. Current AMI performance metrics may fail to provide guidance about hospital quality for transferred patients.

Association of cumulative social risk with mortality and adverse cardiovascular disease outcomes.

BACKGROUND: Quantifying the cumulative effect of social risk factors on cardiovascular disease (CVD) risk can help to better understand the sources of disparities in health outcomes. METHOD AND RESULTS: Data from the Heart Strategies Concentrating on Risk Evaluation (HeartSCORE) study were used to create an index of cumulative social risk (CSR) and quantify its association with incident CVD and all-cause mortality. CSR was defined by assigning a score of 1 for the presence of each of 4 social factors: i) racial minority status (Black race), ii) single living status, iii) low income, and iv) low educational level. Hazard ratios (HRs) were computed using Cox-regression models, adjusted for CVD risk factors. Over a median follow-up period of 8.3 years, 127 incident events were observed. The incidence of the primary outcome for subgroups of participants with 0, 1, and ≥2 CSR scores was 5.31 (95% CI, 3.40-7.22), 10.32 (7.16-13.49) and 17.80 (12.94-22.67) per 1000 person-years, respectively. Individuals with CSR score of 1 had an adjusted HR of 1.85 (1.15-2.97) for incident primary outcomes, compared to those with score of 0. The corresponding HR for individuals with CSR score of 2 or more was 2.58 (1.60-4.17). CONCLUSION: An accumulation of social risk factors independently increased the likelihood of CVD events and deaths in a cohort of White and Black individuals.

Renal Protection Using Remote Ischemic Peri-Conditioning During Inter-Facility Helicopter Transport of Patients With ST-Segment Elevation Myocardial Infarction: A Retrospective Study.

OBJECTIVE: To assess the impact of remote ischemic peri-conditioning (RIPC) during inter-facility air medical transport of ST-segment elevation myocardial infarction (STEMI) patients on the incidence of acute kidney injury (AKI) following primary percutaneous coronary intervention (pPCI). BACKGROUND: STEMI patients who receive pPCI have an increased risk of AKI for which there is no well-defined prophylactic therapy in the setting of emergent pPCI. METHODS: Using the ACTION Registry-GWTG, we evaluated the impact of RIPC applied during inter-facility helicopter transport of STEMI patients from non-PCI capable hospitals to 2 PCI-hospitals in the United States between March, 2013 and September, 2015 on the incidence of AKI following pPCI. AKI was defined as ≥0.3 mg/dL increase in creatinine within 48-72 hours after pPCI. RESULTS: Patients who received RIPC (n = 127), compared to those who did not (n = 92), were less likely to have AKI (11 of 127 patients [8.7%] vs. 17 of 92 patients [18.5%]; adjusted odds ratio = 0.32, 95% CI 0.12-0.85, P = 0.023) and all-cause in-hospital mortality (2 of 127 patients [1.6%] vs. 7 of 92 patients [7.6%]; adjusted odds ratio = 0.14, 95% CI 0.02-0.86, P = 0.034) after adjusting for socio-demographic and clinical characteristics. There was no difference in hospital length of stay (3 days [interquartile range, 2-4] vs. 3 days [interquartile range, 2-5], P = 0.357) between the 2 groups. CONCLUSION: RIPC applied during inter-facility helicopter transport of STEMI patients for pPCI is associated with lower incidence of AKI and in-hospital mortality. The use of RIPC for renal protection in STEMI patients warrants further in depth investigation.

Effect of Two Work-to-Rest Ratios on Cardiovascular, Thermal, and Perceptual Responses During Fire Suppression and Recovery.

OBJECTIVE: Fire suppression is a physically demanding occupation that often results in significant heat stress and hypohydration. Guidelines for the number of work intervals allowed before a structured recovery were consensus derived and have not been tested. METHODS: Apparently healthy firefighters were recruited for this field study. Subjects were assigned to two or three bouts of live fire training prior to 20 minutes of structured recovery to provide rehydration and cooling. After recovery, the subjects completed a timed test of firefighting skills. RESULTS: Extending the fire suppression interval from two to three work periods before a structured recovery period increased core temperature and the time required to perform a high intensity circuit of firefighting skills immediately following recovery. A mild hypotension was noted during recovery but the groups did not differ for blood pressure, heart rate, or firefighter perception of thermal strain or exertion. CONCLUSIONS: This is the first study to examine the physiologic effects of structural firefighting work intervals on recovery and subsequent performance. Both groups experienced maximal cardiovascular strain during fire suppression but extending the work interval worsened heat stress and negatively affected certain aspects of performance immediately following the recovery period.

Pilot Study Examining the Effects of Atropine on Performance during Uncompensable Heat Stress.

UNLABELLED: In many operational scenarios, hypohydration can be corrected with oral rehydration following the work interval. Although rare, there are potential situations that require extended intervals of uncompensable heat stress exposure while working in personal protective equipment (PPE). Under these conditions, retention of body water may be valuable to preserve work capacity and reduce cardiovascular strain. We conducted a pilot study comparing intramuscular atropine sulfate versus saline placebo to establish the safety profile of the protocol and to provide pilot data for future investigations. Five, healthy, heat-acclimated subjects completed this crossover design laboratory study. Each subject performed up to one hour of exertion in a hot environment while wearing a chemical resistant coverall. Atropine sulfate (0.02 mg/kg) or an equivalent volume of sterile saline was administered by intramuscular injection. Core temperature, heart rate, perceptual measures, and changes in body mass were measured. All five subjects completed the acclimation period and both protocols. No adverse events occurred, and no pharmacologically induced delirium was identified. Change in body mass was less following exercise influenced by atropine sulfate (p = 0.002). Exertion time tended to be longer in the atropine sulfate arm (p = 0.08). Other measures appeared similar between groups. Intramuscular atropine sulfate reduced sweating and tended to increase the work interval under uncompensable heat stress when compared to saline placebo. Heart rate and temperature changes during exertion were similar in both conditions suggesting that the influence of an anticholinergic agent on thermoregulation may be minimal during uncompensable heat stress. KEY WORDS: thermoregulation; cholinolytic; anticholinergic; reaction time.

Effects of enamel matrix genes on dental caries are moderated by fluoride exposures.

Dental caries (tooth decay) is the most common chronic disease, worldwide, affecting most children and adults. Though dental caries is highly heritable, few caries-related genes have been discovered. We investigated whether 18 genetic variants in the group of non-amelogenin enamel matrix genes (AMBN, ENAM, TUFT1, and TFIP11) were associated with dental caries experience in 13 age- and race-stratified samples from six parent studies (N = 3,600). Linear regression was used to model genetic associations and test gene-by-fluoride interaction effects for two sources of fluoride: daily tooth brushing and home water fluoride concentration. Meta-analysis was used to combine results across five child and eight adult samples. We observed the statistically significant association of rs2337359 upstream of TUFT1 with dental caries experience via meta-analysis across adult samples (p < 0.002) and the suggestive association for multiple variants in TFIP11 across child samples (p < 0.05). Moreover, we discovered two genetic variants (rs2337359 upstream of TUFT1 and missense rs7439186 in AMBN) involved in gene-by-fluoride interactions. For each interaction, participants with the risk allele/genotype exhibited greater dental caries experience only if they were not exposed to the source of fluoride. Altogether, these results confirm that variation in enamel matrix genes contributes to individual differences in dental caries liability, and demonstrate that the effects of these genes may be moderated by protective fluoride exposures. In short, genes may exert greater influence on dental caries in unprotected environments, or equivalently, the protective effects of fluoride may obviate the effects of genetic risk alleles.

Effect of aspirin on acute changes in peripheral arterial stiffness and endothelial function following exertional heat stress in firefighters: The factorial group results of the Enhanced Firefighter Rehab Trial.

Peripheral arterial stiffness and endothelial function, which are independent predictors of cardiac events, are abnormal in firefighters. We examined the effects of aspirin on peripheral arterial stiffness and endothelial function in firefighters. Fifty-two firefighters were randomized to receive daily 81 mg aspirin or placebo for 14 days before treadmill exercise in thermal protection clothing, and a single dose of 325 mg aspirin or placebo immediately following exertion. Peripheral arterial augmentation index adjusted for a heart rate of 75 (AI75) and reactive hyperemia index (RHI) were determined immediately before, and 30, 60, and 90 minutes after exertion. Low-dose aspirin was associated with lower AI75 (-15.25±9.25 vs -8.08±10.70, p=0.014) but not RHI. On repeated measures analysis, treatment with low-dose aspirin before, but not single-dose aspirin after exertion, was associated with lower AI75 following exertional heat stress (p=0.018). Low-dose aspirin improved peripheral arterial stiffness and wave reflection but not endothelial function in firefighters.

The effects of ice slurry ingestion before exertion in Wildland firefighting gear.

PURPOSE: To investigate the effect of ice slurry ingestion precooling on body core temperature (Tc) during exertion in wildland firefighting garments in uncompensable heat stress. METHODS: On two separate trials, 10 males ingested 7.5 g·kg(-1) of either an ice slurry (0.1°C) or control beverage (20°C) during seated rest for 30 minutes prior to simulating the U.S. Forest Service Pack Test on a treadmill in wildland firefighting garments in a hot environment (38.8 ± 1.2°C, 17.5 ± 1.4% relative humidity). Deep gastric temperature, mean skin temperature (Tsk), and heart rate (HR) were recorded. Ratings of perceived exertion, thermal sensation, comfort, and sweating were assessed. RESULTS: Compared with ingestion of a temperate beverage, precooling with ice slurry before exertion in a hot environment reduced Tc during the first 30 minutes of the exercise bout. Exercise time and distance completed were not different between treatments. Skin temperature, heart rate, and perceptual responses rose in both conditions during exercise but did not differ by condition. CONCLUSION: Pretreatment with ice slurry prior to exertion in wildland firefighting garments results in a modest reduction in Tc during the first 30 minutes of exercise when compared to pretreatment with control beverage but the ice slurry precooling advantage did not persist throughout the 45-minute exercise protocol.

A randomized controlled trial of aspirin and exertional heat stress activation of platelets in firefighters during exertion in thermal protective clothing.

PURPOSE: Platelet aggregation is enhanced in firefighters following short bouts of work in thermal protective clothing (TPC). We sought to determine if aspirin therapy before and/or following exertion in TPC prevents platelet activation. METHODS: In a double-blind, placebo-controlled study, 102 firefighters were randomized to receive daily therapy (81 mg aspirin or placebo) for 14 days before and a single dose (325 mg aspirin or placebo) following exercise in TPC resulting in four potential assignments: aspirin before and after exercise (AA), placebo before and after exercise (PP), aspirin before and placebo after exercise (AP), and placebo before and aspirin after exercise (PA). Platelet closure time (PCT) was measured with a platelet function analyzer before the 2-week treatment, after the 2 week treatment period, immediately after exercise, and 30, 60, and 90 minutes later. RESULTS: Baseline PCT did not differ between groups. PCT changed over time in all four groups (p < 0.001) rising to a median of >300 seconds [IQR 99, 300] in AA and >300 [92, 300] in AP prior to exercise. Following exercise, median PCT decreased to in all groups. Median PCT returned to >300 seconds 30 minutes later in AA and AP and rose to 300 seconds in PA 60 minutes after exercise. CONCLUSIONS: Daily aspirin therapy blunts platelet activation during exertional heat stress and single-dose aspirin therapy following exertional heat stress reduces platelet activation within 60 minutes.

Statin utilization and cardiovascular outcomes in a real-world primary prevention cohort of older adults.

Background: Statins are a cost-effective therapy for prevention of atherosclerotic cardiovascular disease (ASCVD). Guidelines on statins for primary prevention are unclear for older adults (>75 years). Objective: Investigate statin utility in older adults without ASCVD events, by risk stratifying in a large healthcare network. Methods: We included 8,114 older adults, without CAD, PVD or ischemic stroke. Statin utilization based on ACC/AHA 10-year ASCVD risk calculation, was evaluated in intermediate (7.5%-19.9%) and high-risk patients (≥ 20%); and categorized using low and 'moderate or high' intensity statins with a follow up period of ∼7 years. Cox regression models were used to calculate hazard ratios for incident ASCVD and mortality across risk categories stratified by statin utilization. Data was adjusted for competing risk using Elixhauser Comorbidity Index. Results: Compared with those on moderate or high intensity statins, high-risk older patients not on any statin had a significantly increased risk of MI [HR 1.51 (1.17-1.95); p<0.01], stroke [HR 1.47 (1.14-1.90); p<0.01] and all-cause mortality [HR 1.37 (1.19-1.58); p<0.001] in models adjusted for Elixhauser Comorbidity Index. When comparing the no statin group versus the moderate or high intensity statin group in the intermediate risk cohort, although a trend for increased risk was seen, it did not meet statistical significance thresholds for MI, stroke or all-cause mortality. Conclusion: Lack of statin use was associated with increased cardiovascular events and mortality in high-risk older adults. Given the benefits appreciated, statin use may need to be strongly considered for primary ASCVD prevention among high-risk older adults. Future studies will assess the risk-benefit ratio of statin intervention in older adults.

Apolipoprotein E and Alzheimer's disease pathology in African American older adults.

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and ß-amyloid (Aß) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aß or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aß PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aß in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aß (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aß differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets.

The effect of prolonged light intensity exercise in the heat on executive function.

OBJECTIVE: When people are involved in outdoor activities, it is important to be able to assess a situation and make rational decisions. The goal of this study is to determine the effects of 90 minutes of light-intensity exercise in a hot environment on executive functioning capabilities of healthy individuals. METHODS: In this prospective laboratory study, 40 healthy male and female subjects 18 to 45 years of age performed treadmill exercise while wearing athletic clothing and a backpack in either a hot or temperate environment. Vital signs, core and skin temperature, and perceptual measures (thermal sensation, sweating, comfort, and perceived exertion) were measured before, during, and after the treadmill test. Cognitive function was measured before and after the treadmill test using the Wisconsin Card Sorting Test (WCST) and a Psychomotor Vigilance Test (PVT). RESULTS: Subjects in the hot condition reached a similar core temp of 38.2° ± 0.5°C vs 37.7° ± 0.3°C (P = .325) in the temperate group but had a higher heart rate (P < .001) and skin temperature (P < .001). Hot and normal temperature groups did not differ in their PVT performance. There were more correct responses (P < .001), fewer errors (P < .001), and more conceptual responses (P = .001) on the WCST after exertion in both the hot room and normal temperature room conditions. Perseverations and perseverative errors (P = .002) decreased in both groups after exertion. CONCLUSIONS: Conditions of mild heat stress coupled with modest rehydration and short hiking treks do not appear to negatively affect executive function or vigilance.

Cardiovascular Disease and Alzheimer's Disease: The Heart-Brain Axis.

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality in aging adults across the United States. Prior studies indicate that the presence of atherosclerosis, the pathogenic basis of CVD, is linked with dementias. Alzheimer's disease (AD) and AD-related dementias are a major public health challenge in the United States. Recent studies indicate that ≈3.7 million Americans ≥65 years of age had clinical AD in 2017, with projected increases to 9.3 million by 2060. Treatment options for AD remain limited. Development of disease-modifying therapies are challenging due, in part, to the long preclinical window of AD. The preclinical incubation period of AD starts in midlife, providing a critical window for identification and optimization of AD risk factors. Studies link AD with CVD risk factors such as hypertension, inflammation, and dyslipidemia. Both AD and CVD are progressive diseases with decades-long development periods. CVD can clinically manifest several years earlier than AD, making CVD and its risk factors a potential predictor of future AD. The current review focuses on the state of literature on molecular and metabolic pathways modulating the heart-brain axis underlying the potential association of midlife CVD risk factors and their effect on AD and related dementias. Further, we explore potential CVD/dementia preventive strategies during the window of opportunity in midlife and the future of research in the field in the multiomics and novel biomarker use era.

Leveraging CTSA hubs for rapid, large-scale, high-impact research: A case study during a global public health emergency.

As the COVID-19 pandemic took hold in the USA in early 2020, it became clear that knowledge of the prevalence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among asymptomatic individuals could inform public health policy decisions and provide insight into the impact of the infection on vulnerable populations. Two Clinical and Translational Science Award (CTSA) Hubs and the National Institutes of Health (NIH) set forth to conduct a national seroprevalence survey to assess the infection's rate of spread. This partnership was able to quickly design and launch the project by leveraging established research capacities, prior experiences in large-scale, multisite studies and a highly skilled workforce of CTSA hubs and unique experimental capabilities at the NIH to conduct a diverse prospective, longitudinal observational cohort of 11,382 participants who provided biospecimens and participant-reported health and behavior data. The study was completed in 16 months and benefitted from transdisciplinary teamwork, information technology innovations, multimodal communication strategies, and scientific partnership for rigor in design and analytic methods. The lessons learned by the rapid implementation and dissemination of this national study is valuable in guiding future multisite projects as well as preparation for other public health emergencies and pandemics.