Life's Essential 8 Cardiovascular Health Score and Cardiorespiratory Fitness in the Community.

BACKGROUND: The relation of cardiorespiratory fitness (CRF) to lifestyle behaviors and factors linked with cardiovascular health remains unclear. We aimed to understand how the American Heart Association's Life's Essential 8 (LE8) score (and its changes over time) relate to CRF and complementary exercise measures in community-dwelling adults. METHODS AND RESULTS: Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise testing for direct quantification of peak oxygen uptake (V̇O2). A 100-point LE8 score was constructed as the average across 8 factors: diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure. We related total LE8 score, score components, and change in LE8 score over 8 years with peak V̇O2 (log-transformed) and complementary CRF measures. In age- and sex-adjusted linear models (N=1838, age 54±9 years, 54% women, LE8 score 76±12), a higher LE8 score was associated favorably with peak V̇O2, ventilatory efficiency, resting heart rate, and blood pressure response to exercise (all P<0.0001). A clinically meaningful 5-point higher LE8 score was associated with a 6.0% greater peak V̇O2 (≈1.4 mL/kg per minute at sample mean). All LE8 components were significantly associated with peak V̇O2 in models adjusted for age and sex, but blood lipids, diet, and sleep health were no longer statistically significant after adjustment for all LE8 components. Over an ≈8-year interval, a 5-unit increase in LE8 score was associated with a 3.7% higher peak V̇O2 (P<0.0001). CONCLUSIONS: Higher LE8 score and improvement in LE8 over time was associated with greater CRF, highlighting the importance of the LE8 factors in maintaining CRF.

Psychedelic Drug Microdosing Practices: A Qualitative Online Exploration.

"Microdosing," defined as the consumption of small, sub-hallucinogenic quantities of psychedelic drugs, has gained recent popularity. Microdosing is a relatively new concept, therefore no scientific recommendations exist on how to prepare and consume microdoses. Many consumers obtain microdosing information online. Few studies have investigated the content of this information; thus, the present study aimed to do so by collecting a large set of online microdosing information. A qualitative approach was taken to compile and characterize online microdosing information. Medical databases, video websites, online forums, drug-specific websites and forums, search engines, and social media websites were searched. A total of 174 unique resources were found, detailing the types of substances, preparation methods, doses, schedules, and safety strategies used by people who microdose. Future research is recommended to further explore how people prepare microdoses through in-person interviews and sample collection.

Omics-driven investigation of the biology underlying intrinsic submaximal working capacity and its trainability.

Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity.NEW & NOTEWORTHY Multi-omics and in silico explorations of the genes and underlying biology of submaximal exercise capacity and its response to 20 wk of endurance training were undertaken. Prioritized genes were identified: 13 genes for variation in submaximal exercise capacity in the sedentary state and 5 genes for the response level to endurance training, with no overlap between them. Genes and pathways associated with submaximal exercise capacity in the sedentary state are different from those underlying trainability.

Comparative review of airway anesthesia and sedation methods for awake intubation.

PURPOSE OF REVIEW: Successful awake intubation hinges upon adequate airway anesthesia and sedation for patient comfort. This review will summarize relevant anatomy and regional anesthesia techniques to achieve airway anesthesia, and compare various airway anesthesia and sedation regimens. RECENT FINDINGS: Overall, nerve blocks consistently provided superior airway anesthesia, shorter time to intubation, higher patient comfort, and higher postintubation patient satisfaction. Additionally, ultrasound guidance can further provide benefit by reducing the amount of local anesthetic administered, leading to denser blockade, and proving invaluable in challenging clinical situations. Regarding sedation methods, numerous studies supported the use of dexmedetomidine, with or without the addition of supplemental sedation, such as midazolam, ketamine, or opioids. SUMMARY: Emerging evidence has indicated that nerve blocks for airway anesthesia may be superior to other methods of topicalization. Additionally, dexmedetomidine can be useful, both as monotherapy and with supplemental sedatives, to safely provide anxiolysis for the patient and increase success. However, it is crucial to note that the method of airway anesthesia and sedation regimen should be adapted to each patient and clinical situation, and knowledge of multiple techniques and sedation regimens can best equip anesthesiologists to do so.

Plasma Proteomic Kinetics in Response to Acute Exercise.

Regular exercise has many favorable effects on human health, which may be mediated in part by the release of circulating bioactive factors during each bout of exercise. Limited data exist regarding the kinetic responses of plasma proteins during and after acute exercise. Proteomic profiling of 4163 proteins was performed using a large-scale, affinity-based platform in 75 middle-aged adults who were referred for treadmill exercise stress testing. Plasma proteins were quantified at baseline, peak exercise, and 1-h postexercise, and those with significant changes at both exercise timepoints were further examined for their associations with cardiometabolic traits and change with aerobic exercise training in the Health, Risk Factors, Exercise Training and Genetics Family Study, a 20-week exercise intervention study. A total of 765 proteins changed (false discovery rate < 0.05) at peak exercise compared to baseline, and 128 proteins changed (false discovery rate < 0.05) at 1-h postexercise. The 56 proteins that changed at both timepoints included midkine, brain-derived neurotrophic factor, metalloproteinase inhibitor 4, and coiled-coil domain-containing protein 126 and were enriched for secreted proteins. The majority had concordant direction of change at both timepoints. Across all proteins assayed, gene set enrichment analysis showed increased abundance of coagulation-related proteins at 1-h postexercise. Forty-five proteins were associated with at least one measure of adiposity, lipids, glucose homeostasis, or cardiorespiratory fitness in Health, Risk Factors, Exercise Training and Genetics Family Study, and 20 proteins changed with aerobic exercise training. We identified hundreds of novel proteins that change during acute exercise, most of which resolved by 1 h into recovery. Proteins with sustained changes during exercise and recovery may be of particular interest as circulating biomarkers and pathways for further investigation in cardiometabolic diseases. These data will contribute to a biochemical roadmap of acute exercise that will be publicly available for the entire scientific community.

Plasma proteomic changes in response to exercise training are associated with cardiorespiratory fitness adaptations.

Regular exercise leads to widespread salutary effects, and there is increasing recognition that exercise-stimulated circulating proteins can impart health benefits. Despite this, limited data exist regarding the plasma proteomic changes that occur in response to regular exercise. Here, we perform large-scale plasma proteomic profiling in 654 healthy human study participants before and after a supervised, 20-week endurance exercise training intervention. We identify hundreds of circulating proteins that are modulated, many of which are known to be secreted. We highlight proteins involved in angiogenesis, iron homeostasis, and the extracellular matrix, many of which are novel, including training-induced increases in fibroblast activation protein (FAP), a membrane-bound and circulating protein relevant in body-composition homeostasis. We relate protein changes to training-induced maximal oxygen uptake adaptations and validate our top findings in an external exercise cohort. Furthermore, we show that FAP is positively associated with survival in 3 separate, population-based cohorts.

Purification and biochemical analysis of native AMPA receptors from three different mammalian species.

The majority of fast, excitatory synaptic transmission in the central nervous system (CNS) is mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which are glutamate-activated ion channels integral to synaptic plasticity, motor coordination, learning, and memory. Native AMPARs are multiprotein assemblies comprised of a tetrameric receptor core that co-assembles with a broad range of peripheral auxiliary proteins which shape subcellular localization and signaling properties of the resulting complexes. Structure determination of AMPARs has traditionally relied on recombinant expression systems; however, these methods are not well suited to elucidate the diverse array of AMPAR assemblies that are differentially expressed in mammalian brains. While recent studies of native receptor complexes have advanced our understanding of endogenous assemblies, receptors thus far have only been isolated from rodent brain tissue. Here, we employed an immunoaffinity purification strategy to isolate native AMPARs from the brains of three different mammals-pigs, sheep, and cows. Compared to rodents, pigs, sheep, and cows are ungulate mammals, animals with closer genomic identity with humans. Here we determined the molecular size, overall yield, and purity of native AMPARs isolated from these three mammals, thereby demonstrating that structural determination and biochemical analysis is possible from a clade of mammals evolutionarily distinct from rodents.

Mandibular Ramus: An Indicator for Gender Determination.

Background The goal of this study is to use digital orthopantomographs (OPGs) to find out the role the mandibular ramus plays in figuring out a person's gender. Methodology Six hundred digital OPGs of patients, aged 21 to 50 years of either gender, fulfilling the exclusion and inclusion criteria, were randomly selected from the department archives exclusively for this digital retrospective study. All the scans were anonymized before the analysis. A total of seven measurements (in mm) were performed on OPGs, namely, minimum and maximum widths of the ramus, minimum and maximum condylar heights, maximum height of the ramus and coronoid, gonial angle bilaterally, and bigonial width. The data obtained was statistically analyzed using IBM SPSS Statistics for Windows, Version 21.0. (IBM Corp., Armonk, NY, USA), by a stepwise discriminant functional analysis for gender determination. Results Linear measurements, including maximum and minimum widths of the ramus, maximum height of the condyle, height of the ramus, and coronoid and bigonial width, revealed more values in males than in females. However, the gonial angle showed higher average values in females than in males. Moreover, all seven parameters showed statistically insignificant age-related changes. Conclusions The mandibular ramus showed high sexual dimorphism, and its analysis on OPG can be a valuable aid in the determination of gender in the fields of forensic odontology and anthropology.

Plasma Proteomic Risk Markers of Incident Type 2 Diabetes Reflect Physiologically Distinct Components of Glucose-Insulin Homeostasis.

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including ß-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk. ARTICLE HIGHLIGHTS: Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Orthostatic and Exercise Intolerance in Recreational and Competitive Athletes With Long COVID.

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (PASC) infection is particularly concerning to athletes who place a high premium on cardiovascular performance and competition. This initial case series shows the overlap between PASC and orthostatic intolerance in athletes, reveals the diagnostic challenges, and highlights the role of graded exercise training in this population. (Level of Difficulty: Advanced.).

Exercise, Physical Activity, and Cardiometabolic Health: Pathophysiologic Insights.

Physical activity and its sustained and purposeful performance-exercise-promote a broad and diverse set of metabolic and cardiovascular health benefits. Regular exercise is the most effective way to improve cardiorespiratory fitness, a measure of one's global cardiovascular, pulmonary and metabolic health, and one of the strongest predictors of future health risk. Here, we describe how exercise affects individual organ systems related to cardiometabolic health, including the promotion of insulin and glucose homeostasis through improved efficiency in skeletal muscle glucose utilization and enhanced insulin sensitivity; beneficial changes in body composition and adiposity; and improved cardiac mechanics and vascular health. We subsequently identify knowledge gaps that remain in exercise science, including heterogeneity in exercise responsiveness. While the application of molecular profiling technologies in exercise science has begun to illuminate the biochemical pathways that govern exercise-induced health promotion, much of this work has focused on individual organ systems and applied single platforms. New insights into exercise-induced secreted small molecules and proteins that impart their effects in distant organs ("exerkines") highlight the need for an integrated approach towards the study of exercise and its global effects; efforts that are ongoing.

Exercise, Physical Activity, and Cardiometabolic Health: Insights into the Prevention and Treatment of Cardiometabolic Diseases.

Physical activity (PA) and exercise are widely recognized as essential components of primary and secondary cardiovascular disease (CVD) prevention efforts and are emphasized in the health promotion guidelines of numerous professional societies and committees. The protean benefits of PA and exercise extend across the spectrum of CVD, and include the improvement and reduction of risk factors and events for atherosclerotic CVD (ASCVD), cardiometabolic disease, heart failure, and atrial fibrillation (AF), respectively. Here, we highlight recent insights into the salutary effects of PA and exercise on the primary and secondary prevention of ASCVD, including their beneficial effects on both traditional and nontraditional risk mediators; exercise "prescriptions" for ASCVD; the role of PA regular exercise in the prevention and treatment of heart failure; and the relationships between, PA, exercise, and AF. While our understanding of the relationship between exercise and CVD has evolved considerably, several key questions remain including the association between extreme volumes of exercise and subclinical ASCVD and its risk; high-intensity exercise and resistance (strength) training as complementary modalities to continuous aerobic exercise; and dose- and intensity-dependent associations between exercise and AF. Recent advances in molecular profiling technologies (ie, genomics, transcriptomics, proteomics, and metabolomics) have begun to shed light on interindividual variation in cardiometabolic responses to PA and exercise and may provide new opportunities for clinical prediction in addition to mechanistic insights.

Midazolam-Induced Hiccups Reversed by Flumazenil: A Case Report.

Hiccups are a common phenomenon experienced by many people and are usually short-lived with spontaneous resolution of symptoms. Certain anesthetic medications have been associated with the development of hiccups, though the underlying pathophysiology and reflex arcs remain poorly understood. We describe a patient who developed hiccups lasting 9 days following an orthopedic surgery and again developed hiccups during a subsequent surgery after only having received midazolam; flumazenil administration led to sustained cessation of his hiccup symptoms immediately.

Risk Prediction in Cardiogenic Shock: Current State of Knowledge, Challenges and Opportunities.

Cardiogenic shock (CS) is a condition associated with high mortality rates in which prognostication is uncertain for a variety of reasons, including its myriad causes, its rapidly evolving clinical course and the plethora of established and emerging therapies for the condition. A number of validated risk scores are available for CS prognostication; however, many of these are tedious to use, are designed for application in a variety of populations and fail to incorporate contemporary hemodynamic parameters and contemporary mechanical circulatory support interventions that can affect outcomes. It is important to separate patients with CS who may recover with conservative pharmacological therapies from those in who may require advanced therapies to survive; it is equally important to identify quickly those who will succumb despite any therapy. An ideal risk-prediction model would balance incorporation of key hemodynamic parameters while still allowing dynamic use in multiple scenarios, from aiding with early decision making to device weaning. Herein, we discuss currently available CS risk scores, perform a detailed analysis of the variables in each of these scores that are most predictive of CS outcomes and explore a framework for the development of novel risk scores that consider emerging therapies and paradigms for this challenging clinical entity.

Flavonoids in the Treatment of Neuropathic Pain.

PURPOSE OF REVIEW: Chronic pain continues to present a large burden to the US healthcare system. Neuropathic pain, a common class of chronic pain, remains particularly difficult to treat despite extensive research efforts. Current pharmacologic regimens exert limited efficacy and wide, potentially dangerous side effect profiles. This review provides a comprehensive, preclinical evaluation of the literature regarding the role of flavonoids in the treatment of neuropathic pain. RECENT FINDINGS: Flavonoids are naturally occurring compounds, found in plants and various dietary sources, which may have potential benefit in neuropathic pain. Numerous animal-model studies have demonstrated this benefit, including reversal of hyperalgesia and allodynia. Flavonoids have also exhibited an anti-inflammatory effect relevant to neuropathic pain, as evidenced by the reduction in multiple pro-inflammatory mediators, such as TNF-α, NF-κB, IL-1ß, and IL-6. Flavonoids represent a potentially new treatment modality for neuropathic pain in preclinical models, though human clinical evidence is yet to be explored at this time.

Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition.

AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus1. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes2. Thus far, extensive studies of recombinant AMPA receptor-auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor-auxiliary subunit complexes. The GluA1-GluA2, GluA1-GluA2-GluA3 and GluA2-GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2-SynDIG4 non-stochastically positioned at the B'/D' and A'/C' positions, respectively. We further demonstrate how the receptor-TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.

Current and Potential Applications of Wearables in Sports Cardiology.

Purpose of the review: Commercial wearable biosensors are commonly used among athletes and highly active individuals, although their value in sports cardiology is not well established. In this review, we discuss the evidence for the current applications of wearables and provide our outlook for promising future directions of this emerging field. Recent findings: The integration of routine assessment of physiological parameters, activity data, and features such as electrocardiogram recording has generated excitement over a role for wearables to help diagnose and monitor cardiovascular disease. Presently, however, there are significant challenges limiting their routine clinical use. While studies suggest that wearable-derived data may help guide training, evidence for the use of wearables in guiding exercise regimens for individuals with cardiovascular disease is lacking. Further, there is a paucity of data to demonstrate its efficacy in detecting exercise-related arrhythmias or conditions associated with sudden cardiac death. Further technological developments may lead to a greater potential for wearables to aid in sports cardiology practice. Summary: The ability to collect vast amounts of physiological information can help athletes personalize training regimens. However, interpretation of these data and separating the signal from the noise are paramount, especially when used in a clinical setting. While there are currently no standardized approaches for the use of wearable-derived data in sports cardiology, we outline three domains in which they could guide the care of athletes in the future: (1) optimizing athletic performance (2) guiding exercise in athletes with known cardiovascular disease, and (3) screening for cardiovascular disease.

Parameters of cardiac symptoms in young athletes using the Heartbytes database.

Introduction: To determine clinical parameters that are related to abnormal cardiac symptoms in physically active youth. Methods: We used Simon's Heart Heartbytes National Youth Cardiac Registry to collect data from adolescent athletes in southeastern Pennsylvania. We collected age, race/ethnicity, abnormal cardiac symptoms, medical history, medication use, caffeine intake, and family history. We obtained height, weight, blood pressure, cardiac murmur findings, and ECGs. Echocardiogram was obtained if necessary. Binary logistic regression analysis was performed to identify independent associations between abnormal cardiac symptoms and collected variables. The odds ratio (OR), 95% confidence interval (95% CI), and p-values were used as statistical values. Results: Of the 887 athletes (543 males and 344 females, age = 16.9 ± 2.1 years, height = 166.9 ± 11.4 cm, weight = 62.0 ± 16.0 kg), 186 (21%) had abnormal cardiac symptoms including chest pain, passing out, difficulty breathing, extreme fatigue, and heart race. There was an independent association between abnormal symptoms and a past medical history (OR: 4.77, 95%CI: 3.18, 7.17, p = 0.001) and medication use (OR: 1.74, 95%CI: 1.08, 2.79, p = 0.022). In medical history, young athletes with asthma showed a greater propensity of abnormal cardiac symptoms (48.9%) compared to young athletes without (14.0%, p = 0.001). Additionally, young athletes with anxiety or depression demonstrated a higher proportion of abnormal cardiac symptoms (48.9%) than those without (19.5%, p = 0.001). Although the association between the presence of abnormal symptoms and African-American race (OR: 2.04, 95%CI: 0.96, 4.35, p = 0.065) and average daily consumption of at least 2 caffeine drinks (OR: 2.08, 95%CI: 0.86, 5.02, p = 0.103) were not significant, there was a trend to reach the a priori significance level. Conclusions: This study identified several clinical parameters that are associated with symptoms suggestive of abnormal cardiac conditions. Larger studies need to be done to better sort out the clinical history that may contribute to false positives to further reduce false positives at heart screenings.