Citations

The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in BNIP3 expression and its consequences in PE-stressed ACM, AAV9.dn-FX3a delivery in an experimental model of HFpEF decreased BNIP3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/role-of-foxo3a-in-heart-failure/ .

Objective: Symptomatic thumb carpometacarpal (CMC) joint osteoarthritis is common. Early data support selective strengthening of the first dorsal interosseous (FDI) and opponens pollicis (OP) muscles for conservative management with improvement in pain and functional outcomes scores. There are limited biomechanical studies to support such strengthening programs. The purpose of these studies was to quantify the kinematics and joint kinetics at the thumb CMC joint during simulated pinch with selective activation of the FDI and OP muscles. The first study was completed with all ligamentous attachments of the CMC joint intact. The second study was completed with all CMC ligaments released. Hypothesis: Our hypothesis was that increased loads in the FDI and OP result in effects to the joint kinematics and reduce subluxation. Results: Our results from both studies show the OP and FDI act synergistically to center the first metacarpal on the trapezium and reduce subluxation during simulated pinch. The OP is the predominant corrective force but tends to overcorrect if unopposed. The FDI tempers the action of OP and contributes to improved CMC congruency. Conclusion: Our conclusion is these biomechanical data support selective thenar muscle re-education and strengthening programs for conservative management of thumb CMC joint osteoarthritis and pain.

Abstract Rationale Despite significant advances in knowledge of the genetic architecture of asthma, specific contributors to the variability in the burden between populations remain uncovered. Objectives To identify additional genetic susceptibility factors of asthma in European American and African American populations. Methods A phenotyping algorithm mining electronic medical records was developed and validated to recruit cases with asthma and control subjects from the Electronic Medical Records and Genomics network. Genome-wide association analyses were performed in pediatric and adult asthma cases and control subjects with European American and African American ancestry followed by metaanalysis. Nominally significant results were reanalyzed conditioning on allergy status. Measurements and Main Results The validation of the algorithm yielded an average of 95.8% positive predictive values for both cases and control subjects. The algorithm accrued 21,644 subjects (65.83% European American and 34.17% African American). We identified four novel population-specific associations with asthma after metaanalyses: loci 6p21.31, 9p21.2, and 10q21.3 in the European American population, and the PTGES gene in African Americans. TEK at 9p21.2, which encodes TIE2, has been shown to be involved in remodeling the airway wall in asthma, and the association remained significant after conditioning by allergy. PTGES, which encodes the prostaglandin E synthase, has also been linked to asthma, where deficient prostaglandin E2 synthesis has been associated with airway remodeling. Conclusions This study adds to understanding of the genetic architecture of asthma in European Americans and African Americans and reinforces the need to study populations of diverse ethnic backgrounds to identify shared and unique genetic predictors of asthma.

Abstract Van Iterson, EH, Fitzgerald, JS, Dietz, CC, Snyder, EM, and Peterson, BJ. Reliability of triaxial accelerometry for measuring load in men's collegiate ice hockey. J Strength Cond Res 31(5): 1305–1312, 2017—Wearable microsensor technology incorporating triaxial accelerometry is used to quantify an index of mechanical stress associated with sport-specific movements termed PlayerLoad. The test-retest reliability of PlayerLoad in the environmental setting of ice hockey is unknown. The primary aim of this study was to quantify the test-retest reliability of PlayerLoad in ice hockey players during performance of tasks simulating game conditions. Division I collegiate male ice hockey players ( N = 8) wore Catapult Optimeye S5 monitors during repeat performance of 9 ice hockey tasks simulating game conditions. Ordered ice hockey tasks during repeated bouts included acceleration (forward or backward), 60% top-speed, top-speed (forward or backward), repeated shift circuit, ice coasting, slap shot, and bench sitting. Coefficient of variation (CV), intraclass correlation coefficient (ICC), and minimum difference (MD) were used to assess PlayerLoad reliability. Test-retest CVs and ICCs of PlayerLoad were as follows: 8.6% and 0.54 for forward acceleration, 13.8% and 0.78 for backward acceleration, 2.2% and 0.96 for 60% top-speed, 7.5% and 0.79 for forward top-speed, 2.8% and 0.96 for backward top-speed, 26.6% and 0.95 for repeated shift test, 3.9% and 0.68 for slap shot, 3.7% and 0.98 for coasting, and 4.1% and 0.98 for bench sitting, respectively. Raw differences between bouts were not significant for ice hockey tasks ( p > 0.05). For each task, between-bout raw differences were lower vs. MD: 0.06 vs. 0.35 (forward acceleration), 0.07 vs. 0.36 (backward acceleration), 0.00 vs. 0.06 (60% top-speed), 0.03 vs. 0.20 (forward top-speed), 0.02 vs. 0.09 (backward top-speed), 0.18 vs. 0.64 (repeated shift test), 0.02 vs. 0.10 (slap shot), 0.00 vs. 0.10 (coasting), and 0.01 vs. 0.11 (bench sitting), respectively. These data suggest that PlayerLoad demonstrates moderate-to-large test-retest reliability in the environmental setting of male Division I collegiate ice hockey. Without previously testing reliability, these data are important as PlayerLoad is routinely quantified in male collegiate ice hockey to assess on ice physical activity.

AbstractFor many people the emergency department (ED) is the first point of access to healthcare for acute needs and a recurring location for many with chronic healthcare needs. While the ED is well placed to identify unmet needs it can also be a net that people slip through when faced with uncoordinated and expensive healthcare challenges. Thus the ED has a responsibility to set patients on a safe and meaningful care trajectory, which can only be done in consultation and partnership with the patients themselves. The purpose of this article is to present crucial aspects of patient engagement that are essential for future research to foster an environment of colearning and respect that encourages ongoing involvement by patients, families, and staff.

AbstractDecision aids are evidenced‐based tools designed to increase patient understanding of medical options and possible outcomes, facilitate conversation between patients and clinicians, and improve patient engagement. Decision aids have been used for shared decision making (SDM) interventions outside of the ED setting for more than a decade. Their use in the ED has only recently begun to be studied. This article provides background on this topic and the conclusions of the 2016 Academic Emergency Medicine consensus conference SDM in practice work group regarding “Shared Decision Making in the Emergency Department: Development of a Policy‐Relevant, Patient‐Centered Research Agenda.” The goal was to determine a prioritized research agenda for the development and testing of SDM interventions for use in emergency care that was most important to patients, clinicians, caregivers, and other key stakeholders. Using the nominal group technique, the consensus working group proposed prioritized research questions in six key domains: 1) content (i.e., clinical scenario or decision area), 2) level of evidence available, 3) tool design strategies, 4) risk communication, 5) stakeholders, and 6) outcomes.

Objectives: Approximately half of ICU admissions are comprised of patients older than 65 years old. Mild cognitive impairment is a common disorder affecting 10–20% of patients in the same age group. A need exists for exploring mild cognitive impairment and risk of critical illness. As mild cognitive impairment may be a contributor to poorer overall health or be a result of it, we sought to determine whether the presence of mild cognitive impairment independently increases the risk of critical illness admissions. Design: Data from the Mayo Clinic Study of Aging were analyzed. All study participants underwent prospective comprehensive cognitive testing and expert panel consensus diagnosis of both cognitive function and clinical state at baseline and subsequent visits. Comparisons were made between those with normal cognitive function and mild cognitive impairment regarding baseline health and frequency of critical illness. Setting: Single-center population-based cohort out of Olmsted County, MN. Participants: All individuals 70–89 years old were screened for prospective enrollment in the Mayo Clinic Study of Aging. Patients with preexisting dementia and ICU admission within 3 years of entry to the study were excluded from this analysis. Interventions: None. Measurements and Main Results: Of 2,425 patients analyzed from the Mayo Clinic Study of Aging, 1,734 patients (71%) were included in the current study. Clinical factors associated with baseline mild cognitive impairment included age, male gender, stroke, and poorer health self-rating. Using a Cox regression model adjusting for these and a priori variables of baseline health, the presence of mild cognitive impairment remained a significant predictor of ICU admission (hazard ratio, 1.50 [1.15–1.96]; p = 0.003). Conclusions and Relevance: The presence of mild cognitive impairment is independently associated with increased critical illness admission. Further prospective studies are needed to analyze the impact of critical illness on cognitive function.

Abstract Diagnostic testing is an integral component of patient evaluation in the emergency department ( ED ). Emergency clinicians frequently use diagnostic testing to more confidently exclude “worst‐case” diagnoses rather than to determine the most likely etiology for a presenting complaint. Increased utilization of diagnostic testing has not been associated with reductions in disease‐related mortality but has led to increased overall healthcare costs and other unintended consequences (e.g., incidental findings requiring further workup, unnecessary exposure to ionizing radiation or potentially nephrotoxic contrast). Shared decision making ( SDM ) presents an opportunity for clinicians to discuss the benefits and harms associated with diagnostic testing with patients to more closely tailor testing to patient risk. This article introduces the challenges and opportunities associated with incorporating SDM into emergency care by summarizing the conclusions of the diagnostic testing group at the 2016 Academic Emergency Medicine Consensus Conference on SDM . Three primary domains emerged: 1) characteristics of a condition or test appropriate for SDM , 2) critical elements of and potential barriers to SDM discussions on diagnostic testing, and 3) financial aspects of SDM applied to diagnostic testing. The most critical research questions to improve engagement of patients in their acute care diagnostic decisions were determined by consensus.

AbstractShared decision making in emergency medicine has the potential to improve the quality, safety, and outcomes of emergency department (ED) patients. Given that the ED is the gateway to care for patients with a variety of illnesses and injuries and the safety net for patients otherwise unable to access care, shared decision making in the ED is relevant to numerous disciplines and the interests of the United States (U.S.) public. On May 10, 2016 the 16th annual Academic Emergency Medicine (AEM) consensus conference, “Shared Decision Making: Development of a Policy‐Relevant Patient‐Centered Research Agenda” was held in New Orleans, Louisiana. During this one‐day conference clinicians, researchers, policy‐makers, patient and caregiver representatives, funding agency representatives, trainees, and content experts across many areas of medicine interacted to define high priority areas for research in 1 of 6 domains: 1) diagnostic testing; 2) policy, 3) dissemination/implementation and education, 4) development and testing of shared decision making approaches and tools in practice, 5) palliative care and geriatrics, and 6) vulnerable populations and limited health literacy. This manuscript describes the current state of shared decision making in the ED context, provides an overview of the conference planning process, the aims of the conference, the focus of each respective breakout session, the roles of patient and caregiver representatives and an overview of the conference agenda. The results of this conference published in this issue of AEM provide an essential summary of the future research priorities for shared decision making to increase quality of care and patient‐centered outcomes.

SAGE-Journals-Accessible-Video-Player 10.1089/vid.2016.0030.M1 sj-vid-1-vid-10.1089_vid.2016.0030