Age-Related Changes in Upper Airway Anatomy Via Ultrasonography in Pediatric Patients.

PURPOSE: Ultrasonography is a portable, noninvasive tool that may be used to evaluate the upper airway. The purpose of our study was to present a systematic approach to identify salient features of the pediatric airway and determine whether ultrasonography can identify anatomical changes that occur with growth and development. METHODS: We present a prospective, observational trial where patients included were between 1 day and 10 years of age presenting for elective surgery who had no known history of unfavorable airway pathology. We sequentially obtained 5 ultrasound views under anesthesia: (1) sagittal sternal notch view of the trachea, (2) sagittal longitudinal view of trachea (LT), (3) axial view at the level of the vocal cords (AVC), (4) axial view at the level of the cricoid membrane (AC), and (5) sagittal longitudinal submental space view (SM). A broadband linear array transducer was used to identify airway structures and perform measurements. RESULTS: Eighty-four percent of enrolled patients underwent airway imaging and were analyzed using multiple regression and Spearman correlation (ρ). In view 1, tracheal diameter via sagittal sternal notch view was immeasurable because of air disturbance. In the LT view, the distance from the skin to the cricothyroid membrane (LT1) did not statistically increase with age in days (P = 0.06); however, the distance from the cricoid to thyroid cartilage (LT2) did correlate to age (P < 0.001; 99% confidence interval [CI], 1.8 × 10-5, 7.7 × 10-5; ρ = 0.77, P = 0.001). We found a statistically significant relationship between age and the distance between the anterior and posterior commissures (AVC2; P < 0.001; 99% CI, 1.0 × 10-4, 1.7 × 10-4; ρ = 0.80, P < 0.001), the distance from the skin to the posterior commissure (AVC3; P < 0.001; 99% CI, 9.6 × 10-5, 2.0 × 10-4; ρ = 0.73, P < 0.001), the distance to the cricoid cartilage (AC; P < 0.001; 99% CI, 2.0 × 10-5, 7.7 × 10-5; ρ = 0.66, P < 0.001), and the distance from the tongue base to the soft palate (SM2; P < 0.001; 9% CI, 1.8 × 10-4, 3.9 × 10-4; ρ = 0.85, P < 0.001). There were no significant relationships between age and AVC1 (P = 0.16) and SM1 (P = 0.44). CONCLUSIONS: Airway ultrasound is a feasible tool to evaluate the pediatric airway in children younger than 10 years; however, the detection of age-related changes of certain structures is limited to select measurements.

Low-acuity emergency department use among patients in different primary care models in Hamilton and Ontario.

Jurisdictions such as Hamilton, Ontario, where most primary care practices participate in patient enrolment models with enhanced after-hours access, may demonstrate overall improved health equity outcomes. Non-urgent Emergency Department (ED) use has been suggested as an indicator of primary care access; however, the impact of primary care access on ED use is uncertain and likely varies by patient and contextual factors. This population-based, retrospective study investigated whether or not different primary care models were associated with different rates of non-urgent ED visits in Hamilton, a city with relatively high neighbourhood marginalization, compared to the rest of Ontario from 2014/2015 to 2017/2018. In Ontario, enrolment capitation-based practices had more non-urgent ED visits than non-enrolment fee-for-service practices. In Hamilton, where most of the city's family physicians are in enrolment capitation-based practices, differences between models were minimal. The influence of primary care reforms may differ depending on how they are distributed within regions.

Exploring role clarity in interorganizational spread and scale-up initiatives: the 'INSPIRED' COPD collaborative.

BACKGROUND: Role clarification is consistently documented as a challenging process for inter professional healthcare teams, despite being a core tenet of interprofessional collaboration. This paper explores the role clarification process in two previously unexplored contexts: i) in the dissemination phase of a quality improvement (QI) program, and ii) as part of interorganizational partnerships for the care of chronic disease patients. METHODS: A secondary analysis using asynchronous purposive coding was conducted on an innovative pan-Canadian Chronic Obstructive Pulmonary Disease QI program. RESULTS: Our study reveals that the iterative structure of QI initiatives in the spread phase can offer numerous unique benefits to role clarification, with the potential challenge of time commitment. In addition, the role clarification process within interorganizational partnerships proved to be relatively well-structured, characterized by three phases: relationship conceptualization or early contact, familiarization, and finally, role division. Common strategies in the last stage included the establishment of working groups and new information-sharing networks. CONCLUSION: This article characterizes some ways in which providers and organizational partners negotiate their roles in a changing professional environment. As the movement towards integrated care continues, issues of role clarity are assuming increasing importance in healthcare contexts, and understanding role dynamics can provide valuable insight into the optimization of QI initiatives.

Managing greenhouse gas emissions in the terminal year of life in an overwhelmed health system: a paradigm shift for people and our planet.

Health care contributes 4·4% of global net carbon emissions. Hospitals are resource-intensive settings, using a large amount of supplies in patient care and have high energy, ventilation, and heating needs. This Viewpoint investigates emissions related to health care in a patient's last year of life. End of life (EOL) is a period when health-care use and associated emissions production increases exponentially due primarily to hospital admissions, which are often at odds with patients' values and preferences. Potential solutions detailed within this Viewpoint are facilitating advanced care plans with patients to ensure their EOL wishes are clear, beginning palliative care interventions earlier when treating a life-limiting illness, deprescribing unnecessary medications because medications and their supply chains make up a significant portion of health-care emissions, and, enhancing access to low-intensity community care settings (eg, hospices) within the last year of life if home care is not available. Our analysis was done using Canadian data, but the findings can be applied to other high-income countries.

Genetics and Pharmacogenetics of Atrial Fibrillation: A Mechanistic Perspective.

The heritability of atrial fibrillation (AF) is well established. Over the last decade genetic architecture of AF has been unraveled by genome-wide association studies and family-based studies. However, the translation of these genetic discoveries has lagged owing to an incomplete understanding of the pathogenic mechanisms underlying the genetic variants, challenges in classifying variants of uncertain significance (VUS), and limitations of existing disease models. We review the mechanistic insight provided by basic science studies regarding AF mechanisms, recent developments in high-throughput classification of VUS, and advances in bioengineered cardiac models for developing personalized therapy for AF.

Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs; however, patient responses remain highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield phenotypically immature cells and are not easily scalable for high-throughput screening. Here, primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within multiwell plates to engineer patterned iPSC-aCM and atrial fibroblast coculture (PC) that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks compared to conventional mono-/coculture. PC displayed greater sensitivity for detecting drug efficacy than monoculture and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a mutated sodium channel. Overall, PC is useful for elucidating cell signaling in the atria, drug screening, and modeling AF.

Modulation of NOX2 causes obesity-mediated atrial fibrillation.

Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase II (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knock-out (KO) mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.

Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility.

Developmental causes of the most common arrhythmia, atrial fibrillation (AF), are poorly defined, with compensation potentially masking arrhythmic risk. Here, we delete 9 amino acids (Δ9) within a conserved domain of the giant protein titin's A-band in zebrafish and human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that ttna Δ9/Δ9 zebrafish embryos' cardiac morphology is perturbed and accompanied by reduced functional output, but ventricular function recovers within days. Despite normal ventricular function, ttna Δ9/Δ9 adults exhibit AF and atrial myopathy, which are recapitulated in TTN Δ9/Δ9-hiPSC-aCMs. Additionally, action potential is shortened and slow delayed rectifier potassium current (I Ks) is increased due to aberrant atrial natriuretic peptide (ANP) levels. Strikingly, suppression of I Ks in both models prevents AF and improves atrial contractility. Thus, a small internal deletion in titin causes developmental abnormalities that increase the risk of AF via ion channel remodeling, with implications for patients who harbor disease-causing variants in sarcomeric proteins.

Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC-derived atrial fibrillation model.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can model heritable arrhythmias to personalize therapies for individual patients. Although atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality, current platforms to generate iPSC-atrial (a) CMs are inadequate for modeling AF. We applied a combinatorial engineering approach, which integrated multiple physiological cues, including metabolic conditioning and electrical stimulation, to generate mature iPSC-aCMs. Using the patient's own atrial tissue as a gold standard benchmark, we assessed the electrophysiological, structural, metabolic, and molecular maturation of iPSC-aCMs. Unbiased transcriptomic analysis and inference from gene regulatory networks identified key gene expression pathways and transcription factors mediating atrial development and maturation. Only mature iPSC-aCMs generated from patients with heritable AF carrying the non-ion channel gene (NPPA) mutation showed enhanced expression and function of a cardiac potassium channel and revealed mitochondrial electron transport chain dysfunction. Collectively, we propose that ion channel remodeling in conjunction with metabolic defects created an electrophysiological substrate for AF. Overall, our electro-metabolic approach generated mature human iPSC-aCMs that unmasked the underlying mechanism of the first non-ion channel gene, NPPA, that causes AF. Our maturation approach will allow for the investigation of the molecular underpinnings of heritable AF and the development of personalized therapies.

Bioengineering approaches to mature induced pluripotent stem cell-derived atrial cardiomyocytes to model atrial fibrillation.

Induced pluripotent stem cells (iPSCs) serve as a robust platform to model several human arrhythmia syndromes including atrial fibrillation (AF). However, the structural, molecular, functional, and electrophysiological parameters of patient-specific iPSC-derived atrial cardiomyocytes (iPSC-aCMs) do not fully recapitulate the mature phenotype of their human adult counterparts. The use of physiologically inspired microenvironmental cues, such as postnatal factors, metabolic conditioning, extracellular matrix (ECM) modulation, electrical and mechanical stimulation, co-culture with non-parenchymal cells, and 3D culture techniques can help mimic natural atrial development and induce a more mature adult phenotype in iPSC-aCMs. Such advances will not only elucidate the underlying pathophysiological mechanisms of AF, but also identify and assess novel mechanism-based therapies towards supporting a more 'personalized' (i.e. patient-specific) approach to pharmacologic therapy of AF.

Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation.

Mutations in SCN5A, encoding the cardiac sodium channel, are linked with familial atrial fibrillation (AF) but the underlying pathophysiologic mechanisms and implications for therapy remain unclear. To characterize the pathogenesis of AF-linked SCN5A mutations, we generated patient-specific induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) from two kindreds carrying SCN5A mutations (E428K and N470K) and isogenic controls using CRISPR-Cas9 gene editing. We showed that mutant AF iPSC-aCMs exhibited spontaneous arrhythmogenic activity with beat-to-beat irregularity, prolonged action potential duration, and triggered-like beats. Single-cell recording revealed enhanced late sodium currents (INa,L) in AF iPSC-aCMs that were absent in a heterologous expression model. Gene expression profiling of AF iPSC-aCMs showed differential expression of the nitric oxide (NO)-mediated signaling pathway underlying enhanced INa,L. We showed that patient-specific AF iPSC-aCMs exhibited striking in vitro electrophysiological phenotype of AF-linked SCN5A mutations, and transcriptomic analyses supported that the NO signaling pathway modulated the INa,L and triggered AF.

Dietary soy isoflavones increased hepatic protein disulfide isomerase content and suppressed its enzymatic activity in rats.

Protein disulfide isomerase (PDI) is a multifunctional protein and plays important roles in protein folding, triglyceride transfer, insulin degradation, and thyroid hormone transportation. This study examined the modulation of PDI expression by soy consumption using rat as a model. Sprague-Dawley male and female rats at 50 days (d) of age were fed diets containing either 20% casein or alcohol-washed soy protein isolate (SPI, containing 50 mg isoflavones (ISFs)/kg diet) or SPI plus ISF (250 mg/kg diet) and mated at age of 120 d. The offspring (F1) were fed the same diets as their parents. Addition of ISF to SPI diet markedly increased PDI protein content in the liver and testis of the adult rats compared with the casein or SPI diet. PDI mRNA abundance in the liver and protein content in the brain, thyroid, heart, and uterus were unchanged by the diets. Two-dimensional Western blot showed that the rats fed diets containing SPI had a diminished hepatic PDI protein with an isoelectric point (pI) of 6.12, a dephosphorylated form, compared with the rats fed diets containing either casein or SPI with supplemental ISF. Soy ISF added into SPI diet remarkably suppressed hepatic PDI activity of the rats compared with the casein diet. Moreover, soy ISF dose-dependently increased PDI and thyroid hormone receptor (TR) ß protein content, whereas reduced TR DNA binding ability in human hepatocytes. Overall, this study shows that soy ISF increased hepatic PDI protein content, but addition of ISF into SPI diet inhibited its enzymatic activities and this effect may be mediated through a post-transcriptional mechanism.