Intrinsic and Extrinsic Contributors to the Cardiac Benefits of Exercise.

Among its many cardiovascular benefits, exercise training improves heart function and protects the heart against age-related decline, pathological stress, and injury. Here, we focus on cardiac benefits with an emphasis on more recent updates to our understanding. While the cardiomyocyte continues to play a central role as both a target and effector of exercise's benefits, there is a growing recognition of the important roles of other, noncardiomyocyte lineages and pathways, including some that lie outside the heart itself. We review what is known about mediators of exercise's benefits-both those intrinsic to the heart (at the level of cardiomyocytes, fibroblasts, or vascular cells) and those that are systemic (including metabolism, inflammation, the microbiome, and aging)-highlighting what is known about the molecular mechanisms responsible.

Unlocking the dark matter: noncoding RNAs and RNA modifications in cardiac aging.

Cardiac aging is a multifaceted process that encompasses structural and functional alterations culminating in heart failure. As the elderly population continues to expand, there is a growing urgent need for interventions to combat age-related cardiac functional decline. Noncoding RNAs have emerged as critical regulators of cellular and biochemical processes underlying cardiac disease. This review summarizes our current understanding of how noncoding RNAs function in the heart during aging, with particular emphasis on mechanisms of RNA modification that control their activity. Targeting noncoding RNAs as potential novel therapeutics in cardiac aging is also discussed.

Intraoperative Use of Phenylephrine versus Ephedrine and Postoperative Delirium: A Multicenter Retrospective Cohort Study.

BACKGROUND: The treatment of intraoperative hypotension with phenylephrine may impair cerebral perfusion through vasoconstriction, which has been linked to postoperative delirium. The hypothesis was that intraoperative administration of phenylephrine, compared to ephedrine, is associated with higher odds of postoperative delirium. METHODS: A total of 103,094 hospitalized adults undergoing general anesthesia for noncardiac, non-neurosurgical procedures between 2008 and 2020 at two tertiary academic healthcare networks in Massachusetts were included in this multicenter hospital registry study. The primary exposure was the administration of phenylephrine versus ephedrine during surgery, and the primary outcome was postoperative delirium within 7 days. Multivariable logistic regression analyses adjusted for a priori defined confounding variables including patient demographics, comorbidities, and procedural factors including magnitude of intraoperative hypotension were applied. RESULTS: Between the two healthcare networks, 78,982 (76.6%) patients received phenylephrine, and 24,112 (23.4%) patients received ephedrine during surgery; 770 patients (0.8%) developed delirium within 7 days. The median (interquartile range) total intraoperative dose of phenylephrine was 1.0 (0.2 to 3.3) mg and 10.0 (10.0 to 20.0) mg for ephedrine. In adjusted analyses, the administration of phenylephrine, compared to ephedrine, was associated with higher odds of developing postoperative delirium within 7 days (adjusted odds ratio, 1.35; 95% CI, 1.06 to 1.71; and adjusted absolute risk difference, 0.2%; 95% CI, 0.1 to 0.3%; P = 0.015). A keyword and manual chart review-based approach in a subset of 45,465 patients further validated these findings (delirium incidence, 3.2%; adjusted odds ratio, 1.88; 95% CI, 1.49 to 2.37; P < 0.001). Fractional polynomial regression analysis further indicated a dose-dependent effect of phenylephrine (adjusted coefficient, 0.08; 95% CI, 0.02 to 0.14; P = 0.013, per each µg/kg increase in the cumulative phenylephrine dose). CONCLUSIONS: The administration of phenylephrine compared to ephedrine during general anesthesia was associated with higher odds of developing postoperative delirium. Based on these data, clinical trials are warranted to determine whether favoring ephedrine over phenylephrine for treatment of intraoperative hypotension can reduce delirium after surgery.

Beyond cardiomyocytes: Cellular diversity in the heart's response to exercise.

Cardiomyocytes comprise ∼70% to 85% of the total volume of the adult mammalian heart but only about 25% to 35% of its total number of cells. Advances in single cell and single nuclei RNA sequencing have greatly facilitated investigation into and increased appreciation of the potential functions of non-cardiomyocytes in the heart. While much of this work has focused on the relationship between non-cardiomyocytes, disease, and the heart's response to pathological stress, it will also be important to understand the roles that these cells play in the healthy heart, cardiac homeostasis, and the response to physiological stress such as exercise. The present review summarizes recent research highlighting dynamic changes in non-cardiomyocytes in response to the physiological stress of exercise. Of particular interest are changes in fibrotic pathways, the cardiac vasculature, and immune or inflammatory cells. In many instances, limited data are available about how specific lineages change in response to exercise or whether the changes observed are functionally important, underscoring the need for further research.

Factors Influencing Physician Assistant Student Attrition Rates.

INTRODUCTION: The aim of this study was to assess factors that influence student well-being and attrition and to compare faculty perceptions to the realities of student experience. METHODS: Three anonymous online surveys were distributed, one for each group of currently enrolled students, faculty/staff, and attritted students. RESULTS: Faculty estimated that an average of 12.8% of PA students in their program have considered dropping out in the past 6 months, while 22.9% of students self-reported considering dropping out in the past 6 months. The most frequently cited factors for considering dropping out were mental health and lack of connection to the program. Mental health was the highest cited reason for having taken or having considered taking a leave of absence. DISCUSSION: Faculty perceptions in this study were incongruent with the actual situations of their students. Mental health issues and a lack of connection to programs were the largest influencers of attrition.

The Relationship Between Pedagogy and Changes in Students' Learning Styles in Physician Assistant Education.

INTRODUCTION: The purpose of this study was to examine the relationship between instructional pedagogy and changes in physician assistant (PA) students' learning styles during a 2-year master's program. METHODS: Two parallel curricular tracks were established in the didactic year, one using problem-based learning (PBL) and the other lecture-based learning (LBL) for 6 years. Kolb's Learning Style Inventory (LSI) was administered to both groups at matriculation and at the end of the first and second years. Multivariate analyses, including logarithmic transformations of LSI data because of its ipsative nature, were conducted to evaluate differences and changes in students' learning style. RESULTS: A majority of students changed learning styles during the program. Despite considerable movement within and between learning styles, the percentage distribution of LBL students' learning styles changed little during the program, whereas there was a significant increase in PBL students having a Convergent learning style after 2 years. PBL students preferred more transformation than prehension in information processing than LBL students. About a third of LBL students, compared to a fifth of PBL students, had reverted to close to their matriculation learning style by the end of the clinical year. DISCUSSION: Primary care physicians and PAs tend to have a Convergent learning style. Little movement towards this learning style was seen with LBL students, whereas a significant increase in the number of PBL students had adopted this learning style by the end of the program.

Plasma Proteomics of COVID-19-Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics.

To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFß signaling, and ADAMTS13, the von Willebrand Factor-cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

Preliminary Study of Serum Biomarkers Associated With Delirium After Major Cardiac Surgery.

OBJECTIVES: The objective of this study was to identify novel serum biomarkers specific to postoperative delirium after major cardiac surgery to provide insight into the pathologic processes involved in delirium and its sequelae. DESIGN: Nested, case-control study. SETTING: Cardiac surgical intensive care unit in a single-site hospital setting. PARTICIPANTS: The study comprised 24 older adults (aged >60 years) undergoing major cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a positive screen for delirium from postoperative days one through three based on criteria included in the long form of the Confusion Assessment Method. A multiplexed proteomic approach was applied using proximity extension assays to identify and quantify proteins found in serum collected on the day of surgery and postoperative day one in delirious and nondelirious patient cohorts. An increase in serum fibroblast growth factor (FGF)-21 levels was identified in the delirious cohort from a presurgery baseline of (mean ± standard deviation) 5.0 ± 1.1 log2 abundance (95% confidence interval [CI], 4.3-5.7) to 6.7 ± 1.6 log2 abundance (95% CI, 5.7-7.7; p = 0.01) postsurgery. A similar increase was identified in FGF-23 from a presurgery baseline of 1.7 ± 1.3 log2 abundance (95% CI, 0.8-2.5) to 3.4 ± 2.2 log2 abundance (95% CI, 2.0-4.8; p = 0.06) postsurgery. An increase in interleukin-6 serum levels also was identified in the delirious cohort from a presurgery baseline of 3.8 ± 1.1 log2 abundance (95% CI, 3.1-4.5) to 8.7 ± 1.9 log2 abundance (95% CI, 7.5-9.9; p < 0.0001) postsurgery. However, the increase in interleukin-6 serum levels of the nondelirious cohort also met the study's threshold for statistical significance (p < 0.0001). Finally, an increase in monocyte chemotactic protein-3 serum levels was identified in the delirious cohort from a presurgery baseline of 4.1 ± 0.9 log2 abundance (95% CI, 3.6-4.7) to 6.1 ± 2.0 log2 abundance (95% CI, 4.8-7; p = 0.009) postsurgery. CONCLUSIONS: FGF-21, FGF-23, interleukin-6, and monocyte chemotactic protein-3 serum levels were increased postoperatively in patients who developed delirium after major cardiac surgery. This study identified two members of the FGF family as potential putative systemic biomarkers for postoperative delirium after cardiac surgery, suggesting a possible role for metabolic recovery in the pathophysiologic mechanisms underlying neurocognitive dysfunction.

Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium.

Background: Postoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD. Methods: Serum and whole blood samples were collected before CPB (n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1-3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay. Results: Cardiac surgery with CPB resulted in a significant (padj < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3',5'-cyclic phosphodiesterase A (PDE3A). Conclusions: Cardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms.

Plasma Proteomics of COVID-19 Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics.

Cardiovascular complications are common in COVID-19 and strongly associated with disease severity and mortality. However, the mechanisms driving cardiac injury and failure in COVID-19 are largely unknown. We performed plasma proteomics on 80 COVID-19 patients and controls, grouped according to disease severity and cardiac involvement. Findings were validated in 305 independent COVID-19 patients and investigated in an animal model. Here we show that senescence-associated secretory proteins, markers of biological aging, strongly associate with disease severity and cardiac involvement even in age-matched cohorts. FSTL3, an indicator of Activin/TGFß signaling, was the most significantly upregulated protein associated with the heart failure biomarker, NTproBNP (ß = 0.4;p adj =4.6x10 - 7 ), while ADAMTS13, a vWF-cleaving protease whose loss-of-function causes microvascular thrombosis, was the most downregulated protein associated with myocardial injury (ß=-0.4;p adj =8x10 - 7 ). Mendelian randomization supported a causal role for ADAMTS13 in myocardial injury. These data provide important new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

The Effect of the Coronavirus Pandemic on Physician Assistant Educators.

PURPOSE: The coronavirus (COVID-19) pandemic has presented physician assistant (PA) educators with unprecedented challenges in delivering content remotely with minimal time to develop new pedagogical strategies. We surveyed faculty about their experience during the early weeks of adapting to these new instructional techniques. METHODS: An anonymous quantitative and qualitative survey was distributed to all individuals registered by programs as Physician Assistant Education Association members. RESULTS: The survey response rate was 22.3% (667/2991) with 32% of program directors (PD), and 23.7% of faculty reporting they had taught online synchronous content prior to COVID-19 adaptations. Prior experience with technology was associated with significantly lower levels of faculty stress during the pivot to online instruction. A majority of the respondents felt educational quality had remained consistent despite the transition to online teaching, and a majority of both faculty and program directors anticipate only minor changes to program structure once they are able to return to traditional classroom learning. Concerns about technology were most commonly cited as stressors and as causes of decreased quality of instruction. CONCLUSION: Educational challenges and stress during the pandemic were most prominently associated with unfamiliar technology. It remains to be seen what changes persist when the pandemic subsides.

Targeting Age-Related Pathways in Heart Failure.

During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.

The Magic Touch: A Case Report of How Smartphone Fingerprint Technology Was Utilized to Establish a Last Known Well Time for Recanalization Treatment in a Patient With Acute Ischemic Stroke.

Tissue plasminogen activator (tPA) is currently a standard of care for acute stroke patients. One of the necessary criteria in determining eligibility for tPA is the last known well (LKW) time. The LKW time is unfortunately often difficult to obtain accurately if no witness is available, thus posing as an obstacle for acute recanalization therapy. We present the case of a patient who arrived unresponsive with an unwitnessed onset of symptoms concerning for an acute stroke. An LKW time was able to be successfully established by using her fingerprint to unlock her phone and discover a coherent text sent a few hours prior. Patient was able to receive intravenous (IV) tPA and demonstrated remarkable recovery. The use of fingerprint ID to unlock the patient's phone raises the concern of breach of privacy and whether involuntary smartphone searches apply to the emergency code of conduct outlined by the FDA. Smartphone applications, such as Apple iOS "Medical ID" argues for maximal utilization of smartphone technology for emergent medical conditions. Utilization of smartphone technology can potentially serve a potential solution, but the question remains as to whether this practice would be deemed to be ethically appropriate under the policy of implied informed consent under emergent conditions.

The Rise of Technology: Testing the Limits of Curriculum Innovation.

Medical training programs are being pulled between the desire to make content engaging and personalized and the necessity to deliver copious amounts of detailed information rapidly. This project replaced traditional lectures with a virtual 3D cardiac model (ShareCare YOU) in attempts to boost student engagement while maintaining academic rigor.

Charting the Course for Online Physician Assistant Education.

The move to online learning has become one of the most challenging events in physician assistant (PA) education; however, new advances in online technology now make it possible to deliver an entire PA didactic curriculum online. The blending of the latest innovations in online technology with a problem-based learning (PBL) curriculum enables programs to engage students using the Socratic method online while providing feedback in real time. While this novel approach to learning is still being evaluated as data is continually collected, preliminary results indicate online technology can be successfully implemented in a blended PA education curriculum.

Delta oscillations phase limit neural activity during sevoflurane anesthesia.

Understanding anesthetic mechanisms with the goal of producing anesthetic states with limited systemic side effects is a major objective of neuroscience research in anesthesiology. Coherent frontal alpha oscillations have been postulated as a mechanism of sevoflurane general anesthesia. This postulate remains unproven. Therefore, we performed a single-site, randomized, cross-over, high-density electroencephalogram study of sevoflurane and sevoflurane-plus-ketamine general anesthesia in 12 healthy subjects. Data were analyzed with multitaper spectral, global coherence, cross-frequency coupling, and phase-dependent methods. Our results suggest that coherent alpha oscillations are not fundamental for maintaining sevoflurane general anesthesia. Taken together, our results suggest that subanesthetic and general anesthetic sevoflurane brain states emerge from impaired information processing instantiated by a delta-higher frequency phase-amplitude coupling syntax. These results provide fundamental new insights into the neural circuit mechanisms of sevoflurane anesthesia and suggest that anesthetic states may be produced by extracranial perturbations that cause delta-higher frequency phase-amplitude interactions.