Association of central arterial stiffness with atrial myopathy: the Atherosclerosis Risk in Communities (ARIC) study.

Atrial myopathy-defined as abnormal left atrial (LA) size and function-is associated with an increased risk of atrial fibrillation, heart failure, and dementia. Central arterial stiffness is associated with increased atrial afterload and fibrosis and may be a risk factor for atrial myopathy. We examined the association of carotid-femoral pulse wave velocity (cfPWV) with LA function and assessed potential causal relationships. We included 2825 Atherosclerosis Risk in Communities (ARIC) study participants from Visit 5 (2011-2013). cfPWV was related to echocardiographic LA function continuously per 1-SD and categorically in quartiles. Mendelian randomization (MR) analysis was performed using U.K. Biobank-derived genetic variants associated with arterial stiffness index and cardiac magnetic resonance measures of LA function. When analyzed per SD increment (297.6 cm/s), higher cfPWV was significantly associated with lower LA reservoir and conduit strain (ß = -0.53%, 95% CI [-0.81, -0.25] and ß = -0.46%, 95% CI [-0.68, -0.25], respectively) after adjusting for demographics, clinical characteristics, systolic blood pressure, and left ventricular (LV) morphology and function. In MR analyses there was a non-significant inverse association of arterial stiffness index with LA total, passive, and active emptying fractions. Higher cfPWV is associated with lower LA reservoir and conduit strain, independent of systolic blood pressure and LV morphology and function. No evidence for a causal relationship between arterial stiffness index and alterations in LA function was found. Future studies should examine the prospective association of central arterial stiffness with LA function alterations.

Protocol for a Study Investigating Context-Specific Sedentary Behaviors and Cardiometabolic Health in College-Based Young Adults (CONTEXT-SB).

Background: Sedentary behavior (SB) is detrimental to cardiometabolic disease (CMD) risk, which can begin in young adulthood. To devise effective SB-CMD interventions in young adults, it is important to understand which context-specific sedentary behaviors (CS-SB) are most detrimental for CMD risk, the lifestyle behaviors that co-exist with CS-SBs, and the socioecological predictors of CS-SB. Methods: This longitudinal observational study will recruit 500 college-aged (18-24 years) individuals. Two laboratory visits will occur, spaced 12 months apart, where a composite CMD risk score (e.g., arterial stiffness, metabolic and inflammatory biomarkers, heart rate variability, and body composition) will be calculated, and questionnaires to measure lifestyle behaviors and different levels of the socioecological model will be administered. After each visit, total SB (activPAL) and CS-SB (television, transportation, academic/ occupational, leisure computer, "other"; ecological momentary assessment) will be measured across seven days. Discussion: It is hypothesized that certain CS-SB will show stronger associations with CMD risk, compared to T-SB, even after accounting for coexisting lifestyle behaviors. It is expected that a range of intra-individual, inter-individual, and physical environment socioecological factors will predict CS-SB. The findings from this study will support the development of an evidence-based, multi-level intervention to target SB reduction and mitigate CMD risk in CBYA.

Should regression calibration or multiple imputation be used when calibrating different devices in a longitudinal study?

In longitudinal studies, the devices used to measure exposures can change from visit to visit. Calibration studies, wherein a subset of participants is measured using both devices at follow-up, may be used to assess between-device differences (i.e., errors). Then, statistical methods are needed to adjust for between-device differences and the missing measurement data that often appear in calibration studies. Regression calibration and multiple imputation are two possible methods. We compared both methods in linear regression with a simulation study, considering various real-world scenarios for a longitudinal study of pulse wave velocity. Regression calibration and multiple imputation were both essentially unbiased, but correctly estimating the standard errors posed challenges. Multiple imputation with predicted mean matching produced close agreement with the empirical standard error. Fully stochastic multiple imputation underestimated the standard error by up to 50%, and regression calibration with bootstrapped standard errors performed slightly better than fully stochastic multiple imputation. Regression calibration was slightly more efficient than either multiple imputation method. The results suggest use of multiple imputation with predictive mean matching over fully stochastic imputation or regression calibration in longitudinal studies where a new device at follow-up might be error-prone compared to the device used at baseline.

Contralateral differences in ankle SBP and pulse wave velocity: associations with incident heart failure and mortality.

BACKGROUND: Contralateral differences in brachial SBP are indicative of underlaying cardiovascular issues. OBJECTIVES: To examine the association of contralateral differences in ankle SBP, brachial-ankle pulse wave velocity (baPWV), and heart-ankle pulse wave velocity (haPWV) with incident heart failure and all-cause and cardiovascular mortality. METHODS: Cox proportional-hazards models were used to calculate hazard ratios and 95% confidence intervals (95% CIs) in 5077 participants (75 ±â€Š5 years) of the Atherosclerosis Risk in Communities study. RESULTS: Over a mean follow-up of 7.5 ±â€Š2.2 years, there were 457 heart failure events, 1275 all-cause and 363 cardiovascular deaths. Interankle SBP difference of at least 10 mmHg [hazard ratio = 1.12; confidence interval (CI) 1.00-1.28], at least 15 mmHg (hazard ratio = 1.21; CI 1.03-1.43), contralateral difference in baPWV more than 240 cm/s (hazard ratio = 1.22; CI 1.02-1.46), and haPWV more than 80 cm/s (hazard ratio = 1.24; CI 1.04-1.48) were each independently associated with all-cause mortality after adjustment for confounders. Contralateral differences in ankle SBP of at least 15 mmHg (hazard ratio = 1.56; CI 1.17-2.09), and haPWV more than 80 cm/s (hazard ratio = 1.42; CI 1.03-1.96) were both independently associated with cardiovascular mortality. Unadjusted analysis revealed that those with contralateral differences in ankle SBP of at least 10 and at least 15 mmHg, baPWV more than 240, and haPWV more than 80 cm/s had higher risks of heart failure (all P  < 0.05). CONCLUSION: These results underscore the significance of evaluating contralateral differences in ankle SBP and PWV as potential markers of increased mortality risk among older adults.

Standardization and clinical applications of retinal imaging biomarkers for cardiovascular disease: a Roadmap from an NHLBI workshop.

The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemic diseases. The National Heart, Lung, and Blood Institute conducted a workshop in October 2022 to examine this concept. On the basis of the discussions at that workshop, this Roadmap describes current knowledge gaps and new research opportunities to evaluate the relationships between the eye (in particular, retinal biomarkers) and the risk of cardiovascular diseases, including coronary artery disease, heart failure, stroke, hypertension and vascular dementia. Identified gaps include the need to simplify and standardize the capture of high-quality images of the eye by non-ophthalmic health workers and to conduct longitudinal studies using multidisciplinary networks of diverse at-risk populations with improved implementation and methods to protect participant and dataset privacy. Other gaps include improving the measurement of structural and functional retinal biomarkers, determining the relationship between microvascular and macrovascular risk factors, improving multimodal imaging 'pipelines', and integrating advanced imaging with 'omics', lifestyle factors, primary care data and radiological reports, by using artificial intelligence technology to improve the identification of individual-level risk. Future research on retinal microvascular disease and retinal biomarkers might additionally provide insights into the temporal development of microvascular disease across other systemic vascular beds.

Graphene Multiplexed Sensor for Point-of-Need Viral Wastewater-Based Epidemiology.

Wastewater-based epidemiology (WBE) can help mitigate the spread of respiratory infections through the early detection of viruses, pathogens, and other biomarkers in human waste. The need for sample collection, shipping, and testing facilities drives up the cost of WBE and hinders its use for rapid detection and isolation in environments with small populations and in low-resource settings. Given the ubiquitousness and regular outbreaks of respiratory syncytial virus, SARS-CoV-2, and various influenza strains, there is a rising need for a low-cost and easy-to-use biosensing platform to detect these viruses locally before outbreaks can occur and monitor their progression. To this end, we have developed an easy-to-use, cost-effective, multiplexed platform able to detect viral loads in wastewater with several orders of magnitude lower limit of detection than that of mass spectrometry. This is enabled by wafer-scale production and aptamers preattached with linker molecules, producing 44 chips at once. Each chip can simultaneously detect four target analytes using 20 transistors segregated into four sets of five for each analyte to allow for immediate statistical analysis. We show our platform's ability to rapidly detect three virus proteins (SARS-CoV-2, RSV, and Influenza A) and a population normalization molecule (caffeine) in wastewater. Going forward, turning these devices into hand-held systems would enable wastewater epidemiology in low-resource settings and be instrumental for rapid, local outbreak prevention.

Air pollution impacts from warehousing in the United States uncovered with satellite data.

Regulators, environmental advocates, and community groups in the United States (U.S.) are concerned about air pollution associated with the proliferating e-commerce and warehousing industries. Nationwide datasets of warehouse locations, traffic, and satellite observations of the traffic-related pollutant nitrogen dioxide (NO2) provide a unique capability to evaluate the air quality and environmental equity impacts of these geographically-dispersed emission sources. Here, we show that the nearly 150,000 warehouses in the U.S. worsen local traffic-related air pollution with an average near-warehouse NO2 enhancement of nearly 20% and are disproportionately located in marginalized and minoritized communities. Near-warehouse truck traffic and NO2 significantly increase as warehouse density and the number of warehouse loading docks and parking spaces increase. Increased satellite-observed NO2 near warehouses underscores the need for indirect source rules, incentives for replacing old trucks, and corporate commitments towards electrification. Future ground-based monitoring campaigns may help track impacts of individual or small clusters of facilities.

Polycystic Ovary Syndrome, Metabolic Syndrome, and Inflammation in the Hispanic Community Health Study/Study of Latinos.

CONTEXT: Polycystic Ovary Syndrome (PCOS) is a multifaceted endocrine disorder with reproductive and metabolic dysregulation. PCOS has been associated with inflammation and Metabolic Syndrome (MetS); however, the moderating effects of inflammation as measured by C-reactive protein (CRP) and menopause on the PCOS-MetS association have not been studied in Hispanic/Latinas with PCOS who have a higher metabolic burden. OBJECTIVE: We studied the cross-sectional association between PCOS and (i) MetS in 7316 females of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), (ii) subcomponents of MetS including impaired fasting glucose (IFG) and elevated triglycerides (TGL), and (iii) effect modification by menopausal status and CRP. DESIGN: HCHS/SOL is a multicenter, longitudinal, and observational study of US Hispanic/Latinos. Our study sample included females from Visit 2 with self-reported PCOS and MetS (ages 23-82 years). RESULTS: PCOS (prevalence=18.8%) was significantly associated with MetS prevalence (OR=1.41[95% confidence interval: 1.13-1.76]), IFG and TGL (OR=1.42[1.18-1.72], OR=1.48[1.20-1.83] respectively). We observed effect modification by menopausal status (ORpre=1.46, pint=0.02; ORpost=1.34, pint=0.06) and CRP (ORelevated=1.41, pint=0.04; ORnormal=1.26, pint=0.16) on the PCOS-MetS association. We also observed a super-additive interaction between CRP and PCOS, adjusting for which resulted in an attenuated effect of PCOS on MetS (OR=1.29[0.93-1.78]). CONCLUSIONS: Hispanic/Latino females with PCOS had higher odds of MetS, IFG, and elevated TGL, than their peers without PCOS. Interaction analyses revealed that the odds of MetS are higher among PCOS females who have pre-menopausal status or high inflammation. Interventions in Hispanic/Latinas should target these outcomes for effective management of the disease.

Sex and Age Differences in Atypical Chief Complaints for Acute Decompensated Heart Failure in Emergency Department Visits.

Objectives: Around one million United States emergency department (ED) visits annually are due to acute decompensated heart failure (ADHF) symptoms. Characterizing ED symptom presentation of ADHF patients may improve clinical care, yet sex and age differences in ED chief complaints have not been thoroughly investigated. This paper aims to describe differences in chief complaints and comorbid conditions for ED patients with a ADHF diagnosis, stratified by sex and age. Methods: Retrospective analysis of adults presenting to North Carolina EDs in NC DETECT, a statewide syndromic surveillance system, between 2010 and 2016 with a diagnosis of ADHF. Frequencies of chief complaint categories for ED visits and comorbid conditions, stratified by sex and age, were evaluated and standardized differences computed. Results: Top chief complaints were dyspnea (19.1%), chest pain (13.5%), and other respiratory complaints (13.4%). In the 18-44 age group, females when compared to males reported more nausea/vomiting (6.7% versus 4.1%) and headache (4.2% versus 2.0%). In those 45-64 and 65+ years old, complaints were similar by sex. When stratified by age group alone, the 18-44 and 45-64 age groups had more complaints of chest pain, whereas balance issues, weakness, and confusion were more common in the 65+ age group. Conclusion: Sex and age differences in atypical ADHF symptoms were seen in in ED patients with ADHF. Characterizing variation of ADHF symptoms in ED patients can inform the identification of ED patients with ADHF and the management of ADHF-related symptoms.

Potential corporate uses of polygenic indexes: Starting a conversation about the associated ethics and policy issues.

Some commercial firms currently sell polygenic indexes (PGIs) to individual consumers, despite their relatively low predictive power. It might be tempting to assume that because the predictive power of many PGIs is so modest, other sorts of firms-such as those selling insurance and financial services-will not be interested in using PGIs for their own purposes. We argue to the contrary. We build this argument in two ways. First, we offer a very simple model, rooted in economic theory, of a profit-maximizing firm that can gain information about a single consumer's genome. We use the model to show that, depending on the specific economic environment, a firm would be willing to pay for statistically noisy PGIs, even if they allow for only a small reduction in uncertainty. Second, we describe two plausible scenarios in which these different kinds of firms could conceivably use PGIs to maximize profits. Finally, we briefly discuss some of the associated ethics and policy issues. They deserve more attention, which is unlikely to be given until it is first recognized that firms whose services affect a large swath of the public will indeed have incentives to use PGIs.

Designing user-centered decision support systems for climate disasters: What information do communities and rescue responders need during floods?

Flooding events are the most common natural hazard globally, resulting in vast destruction and loss of life. An effective flood emergency response is necessary to lessen the negative impacts of flood disasters. However, disaster management and response efforts face a complex scenario. Simultaneously, regular citizens attempt to navigate the various sources of information being distributed and determine their best course of action. One thing is evident across all disaster scenarios: having accurate information and clear communication between citizens and rescue personnel is critical. This research aims to identify the diverse needs of two groups, rescue operators and citizens, during flood disaster events by investigating the sources and types of information they rely on and information that would improve their responses in the future. This information can improve the design and implementation of existing and future spatial decision support systems (SDSSs) during flooding events. This research identifies information characteristics crucial for rescue operators and everyday citizens' response and possible evacuation to flooding events by qualitatively coding survey responses from rescue responders and the public. The results show that including local input in SDSS development is crucial for improving higher-resolution flood risk quantification models. Doing so democratizes data collection and analysis, creates transparency and trust between people and governments, and leads to transformative solutions for the broader scientific community.

PIPETS: A statistically robust, gene-annotation agnostic analysis method to study bacterial termination using 3'-end sequencing.

We present PIPETS, an R package available on Bioconductor that provides a novel analysis approach to study 3'-end sequencing data. PIPETS statistically robust, gene-annotation agnostic methodology identified more significant 3'-end termination signal across a wider range of genomic contexts than existing analysis tools. PIPETS provides a broadly applicable platform to compare data sets across different organisms.

Divergent antibody recognition profiles are generated by protective mRNA vaccines against Marburg and Ravn viruses.

The first-ever recent Marburg virus (MARV) outbreak in Ghana, West Africa and Equatorial Guinea has refocused efforts towards the development of therapeutics since no vaccine or treatment has been approved. mRNA vaccines were proven successful in a pandemic-response to severe acute respiratory syndrome coronavirus-2, making it an appealing vaccine platform to target highly pathogenic emerging viruses. Here, 1-methyl-pseudouridine-modified mRNA vaccines formulated in lipid nanoparticles (LNP) were developed against MARV and the closely-related Ravn virus (RAVV), which were based on sequences of the glycoproteins (GP) of the two viruses. Vaccination of guinea pigs with both vaccines elicited robust binding and neutralizing antibodies and conferred complete protection against virus replication, disease and death. The study characterized antibody responses to identify disparities in the binding and functional profiles between the two viruses and regions in GP that are broadly reactive. For the first time, the glycan cap is highlighted as an immunoreactive site for marburgviruses, inducing both binding and neutralizing antibody responses that are dependent on the virus. Profiling the antibody responses against the two viruses provided an insight into how antigenic differences may affect the response towards conserved GP regions which would otherwise be predicted to be cross-reactive and has implications for the future design of broadly protective vaccines. The results support the use of mRNA-LNPs against pathogens of high consequence.

Thyroid Hormones and Diabetes in Euthyroid Hispanic/Latino Adults of Diverse Backgrounds: HCHS/SOL.

Context: Previous studies have demonstrated associations of endogenous thyroid hormones with diabetes; less is known about stages of diabetes development at which they are operative, mechanisms of associations, and the role of the hypothalamic-pituitary-thyroid axis. Objective: This study examined associations of thyroid hormones with incident prediabetes and diabetes and with changes in glycemic traits in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the largest cohort of Hispanic/Latino adults with diverse backgrounds in the United States. Methods: The study includes 592 postmenopausal euthyroid women and 868 euthyroid men aged 45 to 74 years without diabetes at baseline participating in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Baseline hormones included thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (T3), and indices calculated from thyroid hormones evaluating pituitary sensitivity to thyroid hormone. Transitions to diabetes and prediabetes, and changes in glycemic traits determined at the 6-year follow-up visit, were examined using multivariable Poisson and linear regressions. Results: Among women, T3 (incident rate ratio [IRR] = 1.65; 95% CI, 1.22-2.24; P = .001) and TSH (IRR = 2.09; 95% CI, 1.01-4.33; P = .047) were positively, while FT4 (IRR = 0.59; 95% CI, 0.39-0.88; P = .011) was inversely, associated with transition from prediabetes to diabetes. Among men, the T3/FT4 ratio was positively associated with transition from normoglycemia to prediabetes but not from prediabetes to diabetes. Indices measuring sensitivity of the pituitary to thyroid hormone suggested increased sensitivity in men who transitioned from prediabetes to diabetes. Conclusion: Positive associations in women of T3 and TSH and inverse associations of FT4, as well as inverse associations of thyroid indices in men with transition from prediabetes to diabetes, but not from normoglycemia to diabetes, suggest decreased pituitary sensitivity to thyroid hormones in women and increased sensitivity in men later in the development of diabetes.

RNA cis-regulators are important for Streptococcus pneumoniae in vivo success.

Bacteria have evolved complex transcriptional regulatory networks, as well as many diverse regulatory strategies at the RNA level, to enable more efficient use of metabolic resources and a rapid response to changing conditions. However, most RNA-based regulatory mechanisms are not well conserved across different bacterial species despite controlling genes important for virulence or essential biosynthetic processes. Here, we characterize the activity of, and assess the fitness benefit conferred by, twelve cis-acting regulatory RNAs (including several riboswitches and a T-box), in the opportunistic pathogen Streptococcus pneumoniae TIGR4. By evaluating native locus mutants of each regulator that result in constitutively active or repressed expression, we establish that growth defects in planktonic culture are associated with constitutive repression of gene expression, while constitutive activation of gene expression is rarely deleterious. In contrast, in mouse nasal carriage and pneumonia models, strains with either constitutively active and repressed gene expression are significantly less fit than matched control strains. Furthermore, two RNA-regulated pathways, FMN synthesis/transport and pyrimidine synthesis/transport display exceptional sensitivity to mis-regulation or constitutive gene repression in both planktonic culture and in vivo environments. Thus, despite lack of obvious phenotypes associated with constitutive gene expression in vitro, the fitness benefit conferred on bacteria via fine-tuned metabolic regulation through cis-acting regulatory RNAs is substantial in vivo, and therefore easily sufficient to drive the evolution and maintenance of diverse RNA regulatory mechanisms.

Comparison of Clinical Decision Support Tools to Improve Pediatric Lipid Screening.

OBJECTIVE: To test whether different clinical decision support tools increase clinician orders and patient completions relative to standard practice and each other. STUDY DESIGN: A pragmatic, patient-randomized clinical trial in the electronic health record was conducted between October 2019 and April 2020 at Geisinger Health System in Pennsylvania, with 4 arms: care gap-a passive listing recommending screening; alert-a panel promoting and enabling lipid screen orders; both; and a standard practice-no guideline-based notification-control arm. Data were analyzed for 13 346 9- to 11-year-old patients seen within Geisinger primary care, cardiology, urgent care, or nutrition clinics, or who had an endocrinology visit. Principal outcomes were lipid screening orders by clinicians and completions by patients within 1 week of orders. RESULTS: Active (care gap and/or alert) vs control arm patients were significantly more likely (P < .05) to have lipid screening tests ordered and completed, with ORs ranging from 1.67 (95% CI 1.28-2.19) to 5.73 (95% CI 4.46-7.36) for orders and 1.54 (95% CI 1.04-2.27) to 2.90 (95% CI 2.02-4.15) for completions. Alerts, with or without care gaps listed, outperformed care gaps alone on orders, with odds ratios ranging from 2.92 (95% CI 2.32-3.66) to 3.43 (95% CI 2.73-4.29). CONCLUSIONS: Electronic alerts can increase lipid screening orders and completions, suggesting clinical decision support can improve guideline-concordant screening. The study also highlights electronic record-based patient randomization as a way to determine relative effectiveness of support tools. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04118348.

Coronary artery calcium as a marker of healthy and unhealthy aging in adults aged 75 and older: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND AIMS: Coronary artery calcium (CAC) is validated for risk prediction among middle-aged adults, but there is limited research exploring implications of CAC among older adults. We used data from the Atherosclerosis Risk in Communities (ARIC) study to evaluate the association of CAC with domains of healthy and unhealthy aging in adults aged ≥75 years. METHODS: We included 2,290 participants aged ≥75 years free of known coronary heart disease who underwent CAC scoring at study visit 7. We examined the cross-sectional association of CAC = 0, 1-999 (reference), and ≥1000 with seven domains of aging: cognitive function, hearing, ankle-brachial index (ABI), pulse-wave velocity (PWV), forced vital capacity (FVC), physical functioning, and grip strength. RESULTS: The mean age was 80.5 ± 4.3 years, 38.6% male, and 77.7% White. 10.3% had CAC = 0 and 19.2% had CAC≥1000. Individuals with CAC = 0 had the lowest while those with CAC≥1000 had the highest proportion with dementia (2% vs 8%), hearing impairment (46% vs 67%), low ABI (3% vs 18%), high PWV (27% vs 41%), reduced FVC (34% vs 42%), impaired grip strength (66% vs 74%), and mean composite abnormal aging score (2.6 vs 3.7). Participants with CAC = 0 were less likely to have abnormal ABI (aOR:0.15, 95%CI:0.07-0.34), high PWV (aOR:0.57, 95%CI:0.41-0.80), and reduced FVC (aOR:0.69, 95%CI:0.50-0.96). Conversely, participants with CAC≥1000 were more likely to have low ABI (aOR:1.74, 95%CI:1.27-2.39), high PWV (aOR:1.52, 95%CI:1.15-2.00), impaired physical functioning (aOR:1.35, 95%CI:1.05-1.73), and impaired grip strength (aOR:1.46, 95%CI:1.08-1.99). CONCLUSIONS: Our findings highlight CAC as a simple measure broadly associated with biological aging, with clinical and research implications for estimating the physical and physiological aging trajectory of older individuals.

Association of Segment-Specific Pulse Wave Velocity With Vascular Calcification: The ARIC (Atherosclerosis Risk in Communities) Study.

BACKGROUND: Pulse wave velocity (PWV) is a noninvasive measure of arterial stiffness and predictor of cardiovascular disease. However, the association between PWV and vascular calcification across different vascular beds has not been fully investigated. This study aimed to quantify the association between PWV and multiterritory calcification and to explore whether PWV can identify individuals with vascular calcification beyond traditional risk factors. METHODS AND RESULTS: Among 1351 older adults (mean age, 79.2 years [SD, 4.1]) from the ARIC (Atherosclerosis Risk in Communities) study, we measured segment-specific PWVs: heart-carotid, heart-femoral, carotid-femoral, heart-ankle, brachial-ankle, and femoral-ankle. Dependent variables were high calcium score (≥75th percentile of Agatston score) across different vascular beds: coronary arteries, aortic valve ring, aortic valve, mitral valve, ascending aorta, and descending aorta. Quartiles of carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV were significantly associated with coronary artery calcium (eg, adjusted odds ratio [OR] for the highest versus lowest quartile of carotid-femoral PWV, 1.84 [95% CI, 1.24-2.74]). Overall, PWVs were most strongly associated with descending aorta calcification, with significant results for carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV (eg, adjusted OR for the highest versus lowest quartile of carotid-femoral PWV, 3.99 [95% CI, 2.61-6.17]). In contrast, femoral-ankle PWV was inversely associated with descending aorta calcification. Some PWVs improved the discrimination of coronary artery calcium and descending aorta calcification beyond traditional risk factors. CONCLUSIONS: The associations of PWV with vascular calcification varied substantially across segments, with descending aorta calcification most closely linked to PWVs. Our study suggests that some PWVs, especially carotid-femoral PWV, are helpful to identify individuals with coronary artery calcium and descending aorta calcification.

New Imidazodiazepine Analogue, 5-(8-Bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole, Provides a Simplified Synthetic Scheme, High Oral Plasma and Brain Exposures, and Produces Antiseizure Efficacy in Mice, and Antiepileptogenic Activity in Neural Networks in Brain Slices from a Patient with Mesial Temporal Lobe Epilepsy.

KRM-II-81 (1) is an imidazodiazepine GABAA receptor (GABAAR) potentiator with broad antiseizure efficacy and a low sedative burden. A brominated analogue, DS-II-73 (5), was synthesized and pharmacologically characterized as a potential backup compound as KRM-II-81 moves forward into development. The synthesis from 2-amino-5-bromophenyl)(pyridin-2yl)methanone (6) was processed in five steps with an overall yield of 38% and without the need for a palladium catalyst. GABAAR binding occurred with a Ki of 150 nM, and only 3 of 41 screened binding sites produced inhibition ≥50% at 10 µM, and the potency to induce cytotoxicity was ≥240 mM. DS-II-73 was selective for α2/3/5- over that of α1-containing GABAARs. Oral exposure of plasma and brain of rats was more than sufficient to functionally impact GABAARs. Tonic convulsions in mice and lethality induced by pentylenetetrazol were suppressed by DS-II-73 after oral administration and latencies to clonic and tonic seizures were prolonged. Cortical slice preparations from a patient with pharmacoresistant epilepsy (mesial temporal lobe) showed decreases in the frequency of local field potentials by DS-II-73. As with KRM-II-81, the motor-impairing effects of DS-II-73 were low compared to diazepam. Molecular docking studies of DS-II-73 with the α1ß3γ2L-configured GABAAR showed low interaction with α1His102 that is suggested as a potential molecular mechanism for its low sedative side effects. These findings support the viability of DS-II-73 as a backup molecule for its ethynyl analogue, KRM-II-81, with the human tissue data providing translational credibility.