Regulation of the RhoA exchange factor GEF-H1 by pro-fibrotic stimuli through a positive feedback loop involving RhoA, MRTF and Sp1.

RhoA and its effectors, the transcriptional coactivators Myocardin-Related Transcription Factor (MRTF) and Serum Response Factor (SRF), control epithelial phenotype and are indispensable for profibrotic epithelial reprogramming during fibrogenesis. Context-dependent control of RhoA and fibrosis-associated changes in its regulators, however, remain incompletely characterized. We previously identified the guanine nucleotide exchange factor GEF-H1 as a central mediator of RhoA activation in renal tubular cells exposed to inflammatory or fibrotic stimuli. Here we found that GEF-H1 expression and phosphorylation were strongly elevated in two animal models of fibrosis. In the Unilateral Ureteral Obstruction mouse kidney fibrosis model, GEF-H1 was upregulated predominantly in the tubular compartment. GEF-H1 was also elevated and phosphorylated in a rat pulmonary artery banding model of right ventricular fibrosis. Prolonged stimulation of LLC-PK1 tubular cells with tumor necrosis factor-α or transforming growth factor ß1 increased GEF-H1 expression and activated a luciferase-coupled GEF-H1 promoter. Knockdown and overexpression studies revealed that these effects were mediated by RhoA, cytoskeleton remodeling and MRTF, indicative of a positive feed-back cycle. Indeed, silencing endogenous GEF-H1 attenuated activation of the GEF-H1 promoter. Importantly, inhibition of MRTF using CCG-1423 prevented GEF-H1 upregulation in both animal models. MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. Since the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.

Biventricular responses to exercise and their relation to cardiorespiratory fitness in pediatric pulmonary hypertension.

Despite exercise intolerance being predictive of outcomes in pulmonary arterial hypertension (PAH), its underlying cardiac mechanisms are not well described. The aim of the study was to explore the biventricular response to exercise and its associations with cardiorespiratory fitness in children with PAH. Participants underwent incremental cardio-pulmonary exercise testing and simultaneous exercise echocardiography on a recumbent cycle ergometer. Linear mixed models were used to assess cardiac function variance and associations between cardiac and metabolic parameters during exercise. Eleven participants were included with a mean age 13.4 ±2.9 years. Right ventricle (RV) systolic pressure (RVsp) increased from a mean of 59 ±25 mmHg at rest to 130 ±40 mmHg at peak exercise (p<0.001), while RV fractional area change (RV-FAC) and RV free wall longitudinal strain (RVFW-Sl) worsened (35.2% vs 27%, p=0.09 and -16.6% vs -14.6%, p=0.1, respectively). At low and moderate intensity exercise, RVsp was positively associated with stroke volume and O2 pulse (p<0.1). At high intensity exercise RV-FAC, RVFW-Sl and left ventricular longitudinal strain were positively associated with oxygen uptake and O2 pulse (p<0.1), while stroke volume decreased towards peak (p=0.04). In children with PAH, the increase of pulmonary pressure alone does not limit peak exercise, but rather the concomitant reduced RV functional reserve, resulting in RV-PA uncoupling, worsening of inter-ventricular interaction and LV dysfunction. A better mechanistic understanding of PAH exercise physiopathology can inform stress testing and cardiac rehabilitation in this population.

Left ventricular remodelling in rheumatic heart disease - trends over time and implications for follow-up in childhood.

BACKGROUND: Rheumatic heart disease (RHD) is the most common form of acquired heart disease worldwide. In RHD, volume loading from mitral regurgitation leads to left ventricular (LV) dilatation, increased wall stress, and ultimately LV dysfunction. Improved understanding of LV dynamics may contribute to refined timing of intervention. We aimed to characterize and compare left ventricular remodelling between rheumatic heart disease (RHD) severity groups by way of serial echocardiographic assessment of volumes and function in children. METHODS: Children with RHD referred to Perth Children's Hospital (formally Princess Margaret Hospital) (1987-2020) were reviewed. Patients with longitudinal pre-operative echocardiograms at diagnosis, approximately 12 months and at most recent follow-up, were included and stratified into RHD severity groups. Left ventricular (LV) echocardiographic parameters were assessed. Adjusted linear mixed effect models were used to compare interval changes. RESULTS: 146 patients (median age 10 years, IQR 6-14 years) with available longitudinal echocardiograms were analysed. Eighty-five (58.2%) patients had mild, 33 (22.6%) moderate and 28 (19.2%) severe RHD at diagnosis. Mean duration of follow-up was 4.6 years from the initial diagnosis. Severe RHD patients had significantly increased end-systolic volumes (ESV) and end-diastolic volumes (EDV) compared to mild/moderate groups at diagnosis (severe versus mild EDV mean difference 27.05 ml/m2, p < 0.001, severe versus moderate EDV mean difference 14.95 ml/m2, p = 0.006). Mild and moderate groups experienced no significant progression of changes in volume measures. In severe RHD, LV dilatation worsened over time. All groups had preserved cardiac function. CONCLUSIONS: In mild and moderate RHD, the lack of progression of valvular regurgitation and ventricular dimensions suggest a stable longer-term course. Significant LV remodelling occurred at baseline in severe RHD with progression of LV dilatation over time. LV function was preserved across all groups. Our findings may guide clinicians in deciding the frequency and timing of follow-up and may be of clinical utility during further reiterations of the Australia and New Zealand RHD Guidelines.

The dynamics of integration and integrated care: An exploratory study of physician organizations.

BACKGROUND: Substantial variation exists in how well health care is integrated, even across similarly structured organizations, yet research about what physician organizations (POs) do that enables or inhibits integrated care is limited. PURPOSE: The aim of this study was to explore the dynamics that enable POs to integrate care. METHODOLOGY/APPROACH: We ranked a stratified sample of POs according to patient perceptions of integrated care, as measured in a survey. We interviewed professionals, patients, and family members in 10 higher and 3 lower ranked POs about the process of caring for patients with complex conditions. We derived integration-related themes from the interview data and quantified their prevalence. Using a quasi-statistical approach, we explored relationships among themes and their associations with patient perceptions of integrated care. RESULTS: From 6,104 coded references, we derived a set of themes representing integration perspectives, integration engagement mechanisms, and integration failures. POs experienced frequent integration failures. Higher ranked POs experienced these failures less often because of a combination of functional, interpersonal, and stakeholder engagement mechanisms, which appear to complement one another. Integration perspectives, including both people-oriented and systems-oriented mindsets, appear to play a role in generating these integration dynamics. CONCLUSION: Delivering integrated care depends on a PO's ability to limit integration failures, keeping provider attention focused on patients. Building on the attention-based view, we present a framework suggesting that this ability is a function of both integration perspectives and integration engagement mechanisms. PRACTICE IMPLICATIONS: POs interested in delivering more integrated care should employ a variety of complementary integration engagement mechanisms and facilitate these efforts by nurturing both people-oriented and system-oriented mindsets among PO decision-makers.

Reversal of right ventricular pressure loading improves biventricular function independent of fibrosis in a rabbit model of pulmonary artery banding.

Right ventricular (RV) pressure loading leads to RV and left ventricular (LV) dysfunction through RV hypertrophy, dilatation and fibrosis. Relief of RV pressure load improves RV function. However, the impact and mechanisms on biventricular reverse-remodelling and function are only partially characterized. We evaluated the impact of RV pressure overload relief on biventricular remodelling and function in a rabbit model of reversible pulmonary artery banding (PAB). Rabbits were randomized to three groups: (1) Sham-operated controls (n = 7); (2) PAB (NDef, n = 7); (3) PAB followed by band deflation (Def, n = 5). Sham and NDef animals were sacrificed at 6 weeks after PAB surgery. Def animals underwent PAB deflation at 6 weeks and sacrifice at 9 weeks. Biventricular geometry, function, haemodynamics, hypertrophy and fibrosis were compared between groups using echocardiography, magnetic resonance imaging, high-fidelity pressure-tipped catheters and histology. RV pressure loading caused RV dilatation, systolic dysfunction, myocyte hypertrophy and LV compression which improved after PAB deflation. RV end-diastolic pressure (RVEDP) decreased after PAB deflation, although remaining elevated vs. Sham. LV end-diastolic pressure (LVEDP) was unchanged following PAB deflation. RV and LV collagen volumes in the NDef and Def group were increased vs. Sham, whereas RV and LV collagen volumes were similar between NDef and Def groups. RV myocyte hypertrophy (r = 0.75, P < 0.001) but not collagen volume was related to RVEDP. LV myocyte hypertrophy (r = 0.58, P = 0.016) and collagen volume (r = 0.56, P = 0.031) correlated with LVEDP. In conclusion, relief of RV pressure overload improves RV and LV geometry, hypertrophy and function independent of fibrosis. The long-term implications of persistent fibrosis and increased biventricular filling pressures, even after pressure load relief, need further study. KEY POINTS: Right ventricular (RV) pressure loading in a pulmonary artery banding rabbit model is associated with RV dilatation, left ventricular (LV) compression; biventricular myocyte hypertrophy, fibrosis and dysfunction. The mechanisms and impact of RV pressure load relief on biventricular remodelling and function has not been extensively studied. Relief of RV pressure overload improves biventricular geometry in conjunction with improved RV myocyte hypertrophy and function independent of reduced fibrosis. These findings raise questions as to the importance of fibrosis as a therapeutic target.

Primary Care Nurse Practitioner Work Environments and Hospitalizations and ED Use Among Chronically Ill Medicare Beneficiaries.

BACKGROUND: Nurse practitioners (NPs) play a critical role in delivering primary care, particularly to chronically ill elderly. Yet, many NPs practice in poor work environments which may affect patient outcomes. OBJECTIVE: We investigated the relationship between NP work environments in primary care practices and hospitalizations and emergency department (ED) use among chronically ill elderly. RESEARCH DESIGN: We used a cross-sectional design to collect survey data from NPs about their practices. The survey data were merged with Medicare claims data. SUBJECTS: In total, 979 primary care practices employing NPs and delivering care to chronically ill Medicare beneficiaries (n=452,931) from 6 US states were included. MEASURES: NPs completed the Nurse Practitioner-Primary Care Organizational Climate Questionnaire-a valid and reliable measure for work environment. Data on hospitalizations and ED use was obtained from Medicare claims. We used Cox regression models to estimate risk ratios. RESULTS: After controlling for covariates, we found statistically significant associations between practice-level NP work environment and 3 outcomes: Ambulatory Care Sensitive (ACS) ED visits, all-cause ED visits, and all-cause hospitalizations. With a 1-unit increase in the work environment score, the risk of an ACS-ED visit decreased by 4.4% [risk ratio (RR)=0.956; 99% confidence interval (CI): 0.918-0.995; P=0.004], an ED visit by 3.5% (RR=0.965; 99% CI: 0.933-0.997; P=0.005), and a hospitalization by 4.0% (RR=0.960;99% CI: 0.928-0.993; P=0.002). There was no relationship between NP work environment and ACS hospitalizations. CONCLUSION: Favorable NP work environments are associated with lower hospital and ED utilization. Practice managers should focus on NP work environments in quality improvement strategies.

Development of High-Risk Geriatric Polypharmacy Electronic Clinical Quality Measures and a Pilot Test of EHR Nudges Based on These Measures.

BACKGROUND: Inappropriate polypharmacy, prevalent among older patients, is associated with substantial harms. OBJECTIVE: To develop measures of high-risk polypharmacy and pilot test novel electronic health record (EHR)-based nudges grounded in behavioral science to promote deprescribing. DESIGN: We developed and validated seven measures, then conducted a three-arm pilot from February to May 2019. PARTICIPANTS: Validation used data from 78,880 patients from a single large health system. Six physicians were pre-pilot test environment users. Sixty-nine physicians participated in the pilot. MAIN MEASURES: Rate of high-risk polypharmacy among patients aged 65 years or older. High-risk polypharmacy was defined as being prescribed ≥5 medications and satisfying ≥1 of the following high-risk criteria: drugs that increase fall risk among patients with fall history; drug-drug interactions that increase fall risk; thiazolidinedione, NSAID, or non-dihydropyridine calcium channel blocker in heart failure; and glyburide, glimepiride, or NSAID in chronic kidney disease. INTERVENTIONS: Physicians received EHR alerts when renewing or prescribing certain high-risk medications when criteria were met. One practice received a "commitment nudge" that offered a chance to commit to addressing high-risk polypharmacy at the next visit. One practice received a "justification nudge" that asked for a reason when high-risk polypharmacy was present. One practice received both. KEY RESULTS: Among 55,107 patients 65 and older prescribed 5 or more medications, 6256 (7.9%) had one or more high-risk criteria. During the pilot, the mean (SD) number of nudges per physician per week was 1.7 (0.4) for commitment, 0.8 (0.5) for justification, and 1.9 (0.5) for both interventions. Physicians requested to be reminded to address high-risk polypharmacy for 236/833 (28.3%) of the commitment nudges and acknowledged 441 of 460 (95.9%) of justification nudges, providing a text response for 187 (40.7%). CONCLUSIONS: EHR-based measures and nudges addressing high-risk polypharmacy were feasible to develop and implement, and warrant further testing.

Effect of Peer Benchmarking on Specialist Electronic Consult Performance in a Los Angeles Safety-Net: a Cluster Randomized Trial.

BACKGROUND: Since the advent of COVID-19, accelerated adoption of systems that reduce face-to-face encounters has outpaced training and best practices. Electronic consultations (eConsults), structured communications between PCPs and specialists regarding a case, have been effective in reducing face-to-face specialist encounters. As the health system rapidly adapts to multiple new practices and communication tools, new mechanisms to measure and improve performance in this context are needed. OBJECTIVE: To test whether feedback comparing physicians to top performing peers using co-specialists' ratings improves performance. DESIGN: Cluster-randomized controlled trial PARTICIPANTS: Eighty facility-specialty clusters and 214 clinicians INTERVENTION: Providers in the feedback arms were sent messages that announced their membership in an elite group of "Top Performers" or provided actionable recommendations with feedback for providers that were "Not Top Performers." MAIN MEASURES: The primary outcomes were changes in peer ratings in the following performance dimensions after feedback was received: (1) elicitation of information from primary care practitioners; (2) adherence to institutional clinical guidelines; (3) agreement with peer's medical decision-making; (4) educational value; (5) relationship building. KEY RESULTS: Specialists showed significant improvements on 3 of the 5 consultation performance dimensions: medical decision-making (odds ratio 1.52, 95% confidence interval 1.08-2.14, p<.05), educational value (1.86, 1.17-2.96) and relationship building (1.63, 1.13-2.35) (both p<.01). CONCLUSIONS: The pandemic has shed light on clinicians' commitment to professionalism and service as we rapidly adapt to changing paradigms. Interventions that appeal to professional norms can help improve the efficacy of new systems of practice. We show that specialists' performance can be measured and improved with feedback using aspirational norms. TRIAL REGISTRATION: clinicaltrials.gov NCT03784950.

The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding.

BACKGROUND: Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored. HYPOTHESIS: We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle. METHODS: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. RESULTS: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05). SIGNIFICANCE: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

Impaired right and left ventricular function and relaxation induced by pulmonary regurgitation are not reversed by tardive antifibrosis treatment.

Pulmonary regurgitation (PR) after repair of tetralogy of Fallot (rTOF) is associated with progressive right (RV) and left (LV) ventricular dysfunction and fibrosis. However, angiotensin II receptor blockade therapy has shown mixed and often disappointing results. The aim of this study was to serially assess changes in biventricular remodeling, dysfunction, and interactions in a rat model of isolated severe PR and to study the effects of angiotensin II receptor blockade. PR was induced in Sprague-Dawley rats by leaflet laceration. Shams (n = 6) were compared with PR (n = 5) and PR + losartan treatment (n = 6). In the treatment group, oral losartan (50 mg·kg-1·day-1) was started 6 wk after PR induction and continued for 6 wk until the terminal experiment. In all groups, serial echocardiography was performed every 2 wk until the terminal experiment where biventricular myocardium was harvested and analyzed for fibrosis. PR and PR + losartan rats experienced early progressive RV dilatation by 2 wk which then stabilized. RV systolic dysfunction occurred from 4 wk after insult and gradually progressed. In PR rats, RV dilatation caused diastolic LV compression and impaired relaxation. PR rats developed increased RV fibrosis compared with shams. Although losartan decreased RV fibrosis, RV dilatation and dysfunction were not improved. This suggests that RV dilatation is an early consequence of PR and affects LV relaxation. RV dysfunction may progress independent of further remodeling. Reduced RV fibrosis was not associated with improved RV function and may not be a viable therapeutic target in rTOF with predominant RV volume loading.NEW & NOTEWORTHY The time-course of RV dilatation and the mechanisms of biventricular dysfunction caused by PR have not been well characterized and the effect of losartan in volume-overloaded RV remains controversial. Our findings suggest that severe PR induces early onset of RV dilatation and dysfunction with little progression after the first 4 wk. The RV dilatation distorts LV geometry with associated impaired LV relaxation. Losartan reduced RV fibrosis but did not reverse RV dilatation and dysfunction.

Association between genetic variants in the HIF1A-VEGF pathway and left ventricular regional myocardial deformation in patients with hypertrophic cardiomyopathy.

BACKGROUND: Information on genetic etiology of pediatric hypertrophic cardiomyopathy (HCM) rarely aids in risk stratification and prediction of disease onset. Little data exist on the association between genetic modifiers and phenotypic expression of myocardial performance, hampering an individual precision medicine approach. METHODS: Single-nucleotide polymorphism genotyping for six previously established disease risk alleles in the hypoxia-inducible factor-1α-vascular endothelial growth factor pathway was performed in a pediatric cohort with HCM. Findings were correlated with echocardiographic parameters of systolic and diastolic myocardial deformation measured by two-dimensional (2-D) speckle-tracking strain. RESULTS: Twenty-five children (6.1 ± 4.5 years; 69% male) with phenotypic and genotypic (60%) HCM were included. Out of six risk alleles tested, one, VEGF1 963GG, showed an association with reduced regional systolic and diastolic left ventricular (LV) myocardial deformation. Moreover, LV average and segmental systolic and diastolic strain and strain rate were significantly reduced, as assessed by the standardized difference, in patients harboring the risk allele. CONCLUSIONS: This is the first study to identify an association between a risk allele in the VEGF pathway and regional LV myocardial function, with the VEGF1 963GG allele associated with reduced LV systolic and diastolic myocardial performance. While studies are needed to link this information to adverse clinical outcomes, this knowledge may help in risk stratification and patient management in HCM. IMPACT: Risk allele in the VEGF gene impacts on LV myocardial deformation phenotype in children with HCM. LV 2-D strain is significantly reduced in patients with risk allele compared to non-risk allele patients within HCM patient groups. Describes that deficiencies in LV myocardial performance in children with HCM are associated with a previously identified risk allele in the angiogenic transcription factor VEGF. First study to identify an association between a risk allele in the VEGF pathway and regional LV myocardial deformation measured by 2-D strain in children with HCM.

Getting Value From Electronic Health Records: Research Needed to Improve Practice.

Electronic health records (EHRs) are now widely adopted in the United States, but health systems have barely begun using them to deliver high-value care. More directed and rigorous research is needed to fulfill the promise of EHRs to not only store information but also support the delivery of better care. This article describes 4 potential benefits of EHR-based research: improving clinical decisions, supporting triage decisions, enabling collaboration among the care team (including patients), and increasing productivity via automation of tasks. Six recommendations are made for conducting and reporting research to catalyze value creation: develop interventions systematically by using user-centered design and a building-block approach; assess value in terms of cost, quality, outcomes, and work required of providers and patients; consider the time horizon for the intervention; test best practices for implementation in a range of real-world contexts; assess subtleties of behavior change tools used to improve high-value behaviors; and report the intervention in enough detail that it can be replicated, including context. Just as research played a critical role in developing early EHR prototypes and demonstrating their value to justify dissemination, research will continue to be essential in the next phase: expanding EHR-based interventions and maximizing their role in creating value.

Factors Influencing Physician Practices' Adoption of Behavioral Health Integration in the United States: A Qualitative Study.

BACKGROUND: Behavioral health integration is uncommon among U.S. physician practices despite recent policy changes that may encourage its adoption. OBJECTIVE: To describe factors influencing physician practices' implementation of behavioral health integration. DESIGN: Semistructured interviews with leaders and clinicians from physician practices that adopted behavioral health integration, supplemented by contextual interviews with experts and vendors in behavioral health integration. SETTING: 30 physician practices, sampled for diversity on specialty, size, affiliation with parent organizations, geographic location, and behavioral health integration model (collaborative or co-located). PARTICIPANTS: 47 physician practice leaders and clinicians, 20 experts, and 5 vendors. MEASUREMENTS: Qualitative analysis (cyclical coding) of interview transcripts. RESULTS: Four overarching factors affecting physician practices' implementation of behavioral health integration were identified. First, practices' motivations for integrating behavioral health care included expanding access to behavioral health services, improving other clinicians' abilities to respond to patients' behavioral health needs, and enhancing practice reputation. Second, practices tailored their implementation of behavioral health integration to local resources, financial incentives, and patient populations. Third, barriers to behavioral health integration included cultural differences and incomplete information flow between behavioral and nonbehavioral health clinicians and billing difficulties. Fourth, practices described the advantages and disadvantages of both fee-for-service and alternative payment models, and few reported positive financial returns. LIMITATION: The practice sample was not nationally representative and excluded practices that did not implement or sustain behavioral health integration, potentially limiting generalizability. CONCLUSION: Practices currently using behavioral health integration face cultural, informational, and financial barriers to implementing and sustaining behavioral health integration. Tailored, context-specific technical support to guide practices' implementation and payment models that improve the business case for practices may enhance the dissemination and long-term sustainability of behavioral health integration. PRIMARY FUNDING SOURCE: American Medical Association and The Commonwealth Fund.

Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension.

The potential benefit of heart rate reduction (HRR), independent of ß-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg/kg/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure-volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca++ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell-derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH/PAB rats. RV systolic-elastance (control, 121 ± 116; MCT, 49 ± 36 vs. MCT+IVA, 120 ± 54; PAB, 70 ± 20 vs. PAB+IVA, 168 ± 76; SUHX, 86 ± 56 vs. SUHX +IVA, 218 ± 111; all P < 0.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6 ± 1%; MCT, 13.4 ± 6.5 vs. MCT+IVA, 6.7 ± 2.6%; PAB, 11.4 ± 4.5 vs. PAB+IVA, 6.4 ± 5.1%; SUHX, 10 ± 4.6 vs. SUHX+IVA, 3.9 ± 2.2%; all P < 0.001) were improved by IVA versus controls. IVA had a dose-response effect on induced pluripotent stem cell-derived cardiomyocytes beat rate by delaying Ca++ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of ß-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.

Implementation of Medical Homes in Federally Qualified Health Centers.

BACKGROUND: From 2011 through 2014, the Federally Qualified Health Center Advanced Primary Care Practice Demonstration provided care management fees and technical assistance to a nationwide sample of 503 federally qualified health centers to help them achieve the highest (level 3) medical-home recognition by the National Committee for Quality Assurance, a designation that requires the implementation of processes to improve access, continuity, and coordination. METHODS: We examined the achievement of medical-home recognition and used Medicare claims and beneficiary surveys to measure utilization of services, quality of care, patients' experiences, and Medicare expenditures in demonstration sites versus comparison sites. Using difference-in-differences analyses, we compared changes in outcomes in the two groups of sites during a 3-year period. RESULTS: Level 3 medical-home recognition was awarded to 70% of demonstration sites and to 11% of comparison sites. Although the number of visits to federally qualified health centers decreased in the two groups, smaller reductions among demonstration sites than among comparison sites led to a relative increase of 83 visits per 1000 beneficiaries per year at demonstration sites (P<0.001). Similar trends explained the higher performance of demonstration sites with respect to annual eye examinations and nephropathy tests (P<0.001 for both comparisons); there were no significant differences with respect to three other process measures. Demonstration sites had larger increases than comparison sites in emergency department visits (30.3 more per 1000 beneficiaries per year, P<0.001), inpatient admissions (5.7 more per 1000 beneficiaries per year, P=0.02), and Medicare Part B expenditures ($37 more per beneficiary per year, P=0.02). Demonstration-site participation was not associated with relative improvements in most measures of patients' experiences. CONCLUSIONS: Demonstration sites had higher rates of medical-home recognition and smaller decreases in the number of patients' visits to federally qualified health centers than did comparison sites, findings that may reflect better access to primary care relative to comparison sites. Demonstration sites had larger increases in emergency department visits, inpatient admissions, and Medicare Part B expenditures. (Funded by the Centers for Medicare and Medicaid Services.).

Relation between right ventricular wall stress, fibrosis, and function in right ventricular pressure loading.

Right ventricle (RV) pressure loading can lead to RV fibrosis and dysfunction. We previously found increased RV, septal hinge-point and left ventricle (LV) fibrosis in experimental RV pressure loading. However, the relation of RV wall stress to biventricular fibrosis and dysfunction is incompletely defined. Rabbits underwent progressive pulmonary artery banding (PAB) over 3 wk with hemodynamics, echocardiography, and myocardial samples obtained at a terminal experiment at 6 wk. An additional group received PAB and treatment with an endothelin receptor antagonist. The endocardial and epicardial borders of short-axis echo images were traced and analyzed with invasive pressures to yield regional end-diastolic (ED) and end-systolic (ES) wall stress. To increase clinical translation, computer model-derived wall stress was compared with Laplace wall stress. The relation of wall stress with fibrosis (picrosirius red staining) and ventricular function was analyzed. ED wall stress in all regions and RV and LV free-wall ES wall stress were increased in PAB rabbits versus sham animals. Laplace wall stress correlated well with computational models. In PAB, fibrosis was highest in the RV free wall, then septal hinge regions, and lowest in the septum and LV free wall. Fibrosis was moderately related to ED (r = 0.47, P = 0.0011), but not ES wall stress. RV ED wall stress was strongly related to echo indexes of function (strain rate: r = 0.71, P = 0.048; E', r = -0.75, P = 0.0077; tricuspid annular plane systolic excursion: r = 0.85, P = 0.0038) and RV fractional area change (r = 0.77, P = 0.027). ED, more than ES, wall stress is related moderately to fibrosis and strongly to function in experimental RV pressure loading, especially at the septal hinge-point regions, where fibrosis is prominent. This suggests that wall stress partially links RV pressure loading, fibrosis, and dysfunction and may be useful to follow clinically.NEW & NOTEWORTHY Biventricular fibrosis and dysfunction impact outcomes in RV pressure loading, but their relation to wall stress is poorly defined. Using a pulmonary artery band rabbit model, we entered echocardiography and catheter data into a computer model to yield regional end-diastolic (EDWS) and end-systolic (ESWS) wall stress. EDWS, more than ESWS, correlated with fibrosis and dysfunction, especially at the fibrosis-intense septal hinge-point regions. Thus, wall stress may be clinically useful in linking RV pressure loading to regional fibrosis and dysfunction.

Assessing Cancer Patient Experience of Care in Outpatient Oncology Practices in the United States.

INTRODUCTION: Cancer patients' experience of care is an important component of quality that has not previously been used for comparing performance. We administered a new patient experience survey to cancer patients receiving outpatient chemotherapy treatment. We examined its measures for sensitivity to adjustment for case-mix and response tendency (level of general optimism/pessimism) and reliability for making performance comparisons between practices. METHODS: We surveyed 2304 cancer patients who received chemotherapy at 23 medical oncology practices in Southeastern Pennsylvania, receiving 715 responses (response rate 31%; 14 practices had 10 or more responses). We aggregated patient responses to calculate practice-level scores on 5 predefined composites: Affective Communication, Shared Decision-Making, Patient Self-Management, Exchanging Information, and Access. We then ranked the practices on each composite before and after adjustment for standard case-mix variables and supplemental adjustment for response tendency (measured via the Life Orientation Test-Revised). We calculated the reliability of practice scores on each composite using hierarchical linear models and calculated minimum sample sizes necessary to achieve reliabilities exceeding 0.7. RESULTS: After adjusting responses for case-mix and converting to a 0-100 scale, composite scores ranged from 77 for the Patient Self-Management composite to 92 for the Access composite. Adjustment for response tendency had an impact on practice rankings only for the Shared Decision-Making composite. The number of responses necessary to create reliable practice-level measurements ranged from 17 (Access composite) to 96 (Affective Communication composite). CONCLUSIONS: Patient experiences at oncology practices can be measured reliably using reasonable sample sizes. Standard case-mix adjustment is adequate for making comparisons on most composites.

Physician-Nurse Practitioner Teamwork in Primary Care Practices in New York: A Cross-Sectional Survey.

BACKGROUND: Primary care practices increasingly rely on the growing workforce of nurse practitioners (NPs) to meet primary care demand. Understanding teamwork between NPs and physicians in primary care practices is critically important. OBJECTIVE: We assessed teamwork between NPs and physicians practicing within the same primary care practice and determined how teamwork affects their job satisfaction, intent to leave their current job, and quality of care. DESIGN: A cross-sectional survey design was used to collect data from both NPs and physicians in New York State in 2017. PARTICIPANTS: 584 participants (398 NPs and 186 physicians) from 476 primary care practices completed the survey yielding a 27% response rate for NPs and 12% for physicians. MAIN MEASURES: The survey tool contained validated measures of teamwork and three outcomes: job satisfaction, intent to leave, and perceived quality of care. Simple and multi-level multivariable regression models were built. KEY RESULTS: Most participants (76%) were either moderately satisfied or very satisfied with their job (NP sample: 75%; physician sample: 77%) and about 10% intended to leave their current job (NP sample: 11%; physician sample: 9%). The average perceived quality of care was the same across NP and physician samples with a mean of 8.5 on a 11 point scale. After controlling for confounders, a higher organizational-level teamwork score was associated with higher job satisfaction (cumulative OR: 3.00; 95% CI: 1.85-4.88), lower odds of intent to leave (OR: 0.25; 95% CI: 0.09-0.74), and higher perceived quality of care (b=1.00; 95% CI: 0.77-1.23). CONCLUSIONS: This study produced evidence about NP-physician teamwork in primary care practices. We found the vast majority of NPs and physicians reported favorable teamwork, and that teamwork affects clinician job satisfaction and intent to leave as well as perceived quality of care in their practices.

Clinician-Level Variation in Three Measures Representing Overuse Based on the American Geriatrics Society Choosing Wisely Statement.

IMPORTANCE: The extent of clinician-level variation in the overuse of testing or treatment in older adults is not well understood. OBJECTIVE: To examine clinician-level variation for three new measures of potentially inappropriate use of medical services in older adults. DESIGN: Retrospective analysis of overall means and clinician-level variation in performance on three new measures. SUBJECTS: Adults aged 65 years and older who had office visits with outpatient primary or immediate care clinicians within a single academic medical center health system between July 1, 2016, and June 30, 2017. MEASURES: Two electronic clinical quality measures representing potentially inappropriate use of medical services in older adults: prostate-specific antigen testing against guidelines (PSA) in men aged 76 and older; urinalysis or urine culture for non-specific reasons in women aged 65 and older; and one intermediate outcome measure: hemoglobin A1c less than 7.0 in adults aged 75 and older with diabetes mellitus treated with insulin or oral hypoglycemic medication. RESULTS: Sixty-nine clinicians and 2009 patients contributed observations to the PSA measure, 144 clinicians and 5933 patients contributed to the urinalysis/urine culture measure, and 42 clinicians and 665 patients contributed to the diabetes measure. Meaningful clinician-level performance variation was greatest for the PSA measure (intraclass correlation coefficient [ICC] = 0.27), followed by the urinalysis/urine culture measure (ICC = 0.18), and the diabetes measure (ICC = 0.024). The range of possible overuse across clinician quartiles was 8-54% for the PSA measure, 3-35% for the urinalysis/urine culture measure, and 13-49% for the diabetes measure. The odds ratios of overuse in the highest quartile compared with the lowest for the PSA, urinalysis/urine culture, and diabetes measures were 99.3 (95% CI 43 to 228), 15.7 (10 to 24), and 6.0 (3.3 to 11), respectively. CONCLUSIONS: Within the same health system, rates of potential overuse in elderly patients varied greatly across clinicians, particularly for the process measures examined.

Nomograms of Fetal Right Ventricular Fractional Area Change by 2D Echocardiography.

OBJECTIVES: Fetal right ventricular (RV) function assessment is challenging due to the RV geometry and limitations of in utero assessment. Postnatally, 2D echocardiographic RV fractional area change (FAC) is used to assess RV global systolic function by calculating the percentage of change in RV area from systole to diastole. Reports on FAC are scarce in prenatal life, and nomograms throughout pregnancy are not available. Our aims were (1) to study prenatal RV FAC feasibility and reproducibility and (2) to construct nomograms for RV FAC and end-diastolic (ED) and end-systolic (ES) RV areas from 18 to 41 weeks of gestation. METHODS: Prospective cohort study including 602 low-risk singleton pregnancies undergoing a fetal echocardiography from 18 to 41 weeks of gestation. RV ED and ES areas were measured following standard recommendations for ventricular dimensions and establishing strict landmarks to identify the different phases of the cardiac cycle. RV FAC was calculated as: ([ED area - ES area]/ED area) × 100. RV FAC intra- and inter-observer reproducibility was evaluated in 45 fetuses by calculating the intraclass correlation coefficient (ICC). Parametric regressions were tested to model each parameter against gestational age (GA) and estimated fetal weight (EFW). RESULTS: RV areas and FAC were successfully obtained in ∼99% of fetuses with acceptable reproducibility throughout gestation (RV ED area inter-observer ICC [95% CI] 0.96 [0.93-0.98], RV ES area 0.97 [0.94-0.98], and FAC 0.69 [0.44-0.83]). Nomograms were constructed for RV ED and ES areas and FAC. RV areas showed a quadratic and logarithmic increase with GA and EFW, respectively. In contrast, RV FAC showed a slight quadratic decrease throughout gestation (mean RV FAC ranged from 36% at 18 weeks of gestation [10-90th centiles: 25-47%, respectively] to 29% at 41 weeks [10-90th centiles: 18-40%, respectively]). The best models for RV areas and FAC were a second-degree polynomial. CONCLUSIONS: RV FAC is a feasible and reproducible parameter to assess RV global systolic function in fetal life. We provide reference ranges adjusted by GA and EFW that can be used as normal references for the assessment of RV function in prenatal conditions.