Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.

Elimination of Toxic Microsatellite Repeat Expansion RNA by RNA-Targeting Cas9.

Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington's disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for diagnostic and therapeutic purposes. Here, we describe the development of a programmable CRISPR system capable of specifically visualizing and eliminating these toxic RNAs. We observe specific targeting and efficient elimination of microsatellite repeat expansion RNAs both when exogenously expressed and in patient cells. Importantly, RNA-targeting Cas9 (RCas9) reverses hallmark features of disease including elimination of RNA foci among all conditions studied (DM1, DM2, C9-ALS, polyglutamine diseases), reduction of polyglutamine protein products, relocalization of repeat-bound proteins to resemble healthy controls, and efficient reversal of DM1-associated splicing abnormalities in patient myotubes. Finally, we report a truncated RCas9 system compatible with adeno-associated viral packaging. This effort highlights the potential of RCas9 for human therapeutics.

Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTGexp) disorder caused by expression of CUGexp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUGexp-associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.

Prognostic value of left atrial strain in aortic stenosis: A systematic review.

PURPOSE: Aortic stenosis (AS) is a common valvular heart disease with high morbidity and mortality. Recently, the association between peak atrial longitudinal strain (PALS) and AS clinical outcomes has been identified. This systematic review evaluates the prognostic value of PALS for adverse events in AS. METHODS: We performed a systematic literature review to identify clinical studies that evaluated Speckle-Tracking Echocardiography (STE)-derived PALS to predict adverse outcomes in patients with AS. We excluded studies that compared echocardiography to computed tomography and studies that focused on diseases other than AS. RESULTS: We included 18 studies reporting on 2660 patients. Patients with symptomatic AS had decreased PALS when compared to patients with asymptomatic AS. Patients with AS who had adverse events had decreased PALS when compared to patients with AS with no events. Each unit increase of PALS was independently associated with decreased risk for the primary endpoint. PALS cut-off values were associated with increased risk for the primary endpoint. CONCLUSION: This systematic review suggests PALS as an independent predictor for cardiovascular events in patients with AS and highlights the importance of evaluating LA mechanics for AS prognosis.

Echocardiographic parameters associated with less reverse left ventricular remodeling after transcatheter aortic valve implant in subjects with prosthesis patient mismatch.

BACKGROUND: Transaortic valve implant (TAVI) is the treatment of choice for severe aortic stenosis (AS). Some patients develop prosthesis patient mismatch (PPM) after TAVI. It is challenging to determine which patients are at risk for clinical deterioration. METHODS: We retrospectively measured echocardiographic parameters of left ventricular (LV) morphology and function, prosthetic aortic valve effective orifice area (iEOA) and hemodynamics in 313 patients before and 1 year after TAVI. Our objective was to compare the change in echocardiographic parameters associated with left ventricular reverse modeling in subjects with and without PPM. Our secondary objective was to evaluate echo parameters associated with PPM and the relationship to patient functional status and survival post-TAVI. RESULTS: We found that 82 (26.2%) of subjects had moderate and 37 (11.8%) had severe PPM post-TAVI. There was less relative improvement in LVEF with PPM (1.9 ± 21.3% vs. 8.2 + 30.1%, p = .045). LV GLS also exhibited less relative improvement in those with PPM (13.4 + 34.1% vs. 30.9 + 73.3%, p = .012). NYHA functional class improved in 84.3% of subjects by one grade or more. Echocardiographic markers of PPM were worse in those without improvement in NYHA class (mean AT/ET was .29 vs. .27, p = .05; DVI was .46 vs. .51, p = .021; and iEOA was .8 cm/m2 vs. .9 cm/m2 , p = .025). There was no association with PPM and survival. CONCLUSIONS: There was no improvement in LVEF and less improvement in LV GLS in those with PPM post-TAVI. Echocardiographic markers of PPM were present in those with lack of improvement in NYHA functional class.

Relationship between left atrial reservoir strain, volumes, and geometry: Insights from simple theoretical model.

BACKGROUND: Left atrial (LA) volume is related to LA reservoir strain (LASR ), but the relationship is not fully resolved. We sought to model the relationship between LA end-diastolic and end-systolic volumes (LAEDV and LAESV) and LASR based on a geometrical approach to exploit the relationship between LASR and volume. METHODS: Modeling the LA as a hemisphere with radius r, LASR was recognized to vary linearly with r and LA volume with r3 . Expanding this cubic relation as a Taylor series resulted in a simple linear equation: LAESV/LAEDV = 1 + 3 × LASR . To validate this, 52 transthoracic echocardiograms were analyzed from 18 patients who underwent transcatheter edge-to-edge repair (TEER) with MitraClip with serial assessment pre-procedure, 1 month post-clip, and 12 months post-TEER. Linear regression was performed to compare the geometric equation to a statistical model created by a line of best fit to relate LAESV/LAEDV to LASR . RESULTS: The statistical and geometric model both resulted in a strong correlation (r = .8, p < .001, respectively). The slope of the line in the statistical model was 3.3, which was statistically indistinguishable from the expected slope of 3 based on the geometric model (Figure 2A). Using the geometric model to compare the measured versus calculated LAESV/LAEDV also resulted in a strong correlation (r = .8, p < .001)(Figure 2B). CONCLUSION: We describe the relationship between LA volume and strain mathematically by considering the geometry of the LA. This model enhances our understanding of the interaction between atrial strain and volume. Further research is necessary to validate this using 3D atrial volumes in a broader cohort of subjects.

HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy.

Studies on myotonic dystrophy type 1 (DM1) have led to the RNA-mediated disease model for hereditary disorders caused by noncoding microsatellite expansions. This model proposes that DM1 disease manifestations are caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions (CUGexp) leading to decreased muscleblind-like, but increased CUGBP1/ETR3-like factor 1 (CELF1), alternative splicing activities. Here, we test this model in vivo, using the mouse HSALR poly(CUG) model for DM1 and recombinant adeno-associated virus (rAAV)-mediated transduction of specific splicing factors. Surprisingly, systemic overexpression of HNRNPA1, not previously linked to DM1, also shifted DM1-relevant splicing targets to fetal isoforms, resulting in more severe muscle weakness/myopathy as early as 4 to 6 wk posttransduction, whereas rAAV controls were unaffected. Overexpression of HNRNPA1 promotes fetal exon inclusion of representative DM1-relevant splicing targets in differentiated myoblasts, and HITS-CLIP of rAAV-mycHnrnpa1-injected muscle revealed direct interactions of HNRNPA1 with these targets in vivo. Similar to CELF1, HNRNPA1 protein levels decrease during postnatal development, but are elevated in both regenerating mouse muscle and DM1 skeletal muscle. Our studies suggest that CUGexp RNA triggers abnormal expression of multiple nuclear RNA binding proteins, including CELF1 and HNRNPA1, that antagonize MBNL activity to promote fetal splicing patterns.

The Emerging Role of Artificial Intelligence in Valvular Heart Disease.

Valvular heart disease (VHD) is a morbid condition in which timely identification and evidence-based treatments can lead to improved outcomes. Artificial intelligence broadly refers to the ability for computers to perform tasks and problem solve like the human mind. Studies applying AI to VHD have used a variety of structured (eg, sociodemographic, clinical) and unstructured (eg, electrocardiogram, phonocardiogram, and echocardiograms) and machine learning modeling approaches. Additional researches in diverse populations, including prospective clinical trials, are needed to evaluate the effectiveness and value of AI-enabled medical technologies in clinical care for patients with VHD.

Valvular regurgitation flow jet assessment using in vitro 4D flow MRI: Implication for mitral regurgitation.

PURPOSE: The purpose of this study was to evaluate the accuracy of four-dimensional (4D) flow MRI for direct assessment of peak velocity, flow volume, and momentum of a mitral regurgitation (MR) flow jets using an in vitro pulsatile jet flow phantom. We systematically investigated the impact of spatial resolution and quantification location along the jet on flow quantities with Doppler ultrasound as a reference for peak velocity. METHODS: Four-dimensional flow MRI data of a pulsatile jet through a circular, elliptical, and 3D-printed patient-specific MR orifice model was acquired with varying spatial resolution (1.5-5 mm isotropic voxel). Flow rate and momentum of the jet were quantified at various axial distances (x = 0-50 mm) and integrated over time to calculate Voljet and MTIjet . In vivo assessment of Voljet and MTIjet was performed on 3 MR patients. RESULTS: Peak velocities were comparable to Doppler ultrasound (3% error, 1.5 mm voxel), but underestimated with decreasing spatial resolution (-40% error, 5 mm voxel). Voljet was similar to regurgitant volume (RVol) within 5 mm, and then increased linearly with the axial distance (19%/cm) because of flow entrainment. MTIjet remained steady throughout the jet (2%/cm) as theoretically predicted. Four and 9 voxels across the jet were required to measure flow volume and momentum-time-integral within 10% error, respectively. CONCLUSION: Four-dimensional flow MRI detected accurate peak velocity, flow rate, and momentum for in vitro MR-mimicking flow jets. Spatial resolution significantly impacted flow quantitation, which otherwise followed predictions of flow entrainment and momentum conservation. This study provides important preliminary information for accurate in vivo MR assessment using 4D flow MRI.

Advances in Machine Learning Approaches to Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) represents a prototypical cardiovascular condition in which machine learning may improve targeted therapies and mechanistic understanding of pathogenesis. Machine learning, which involves algorithms that learn from data, has the potential to guide precision medicine approaches for complex clinical syndromes such as HFpEF. It is therefore important to understand the potential utility and common pitfalls of machine learning so that it can be applied and interpreted appropriately. Although machine learning holds considerable promise for HFpEF, it is subject to several potential pitfalls, which are important factors to consider when interpreting machine learning studies.

Strain echocardiography to describe left ventricular function pre- and postexercise in elite basketball athletes: A feasibility study.

BACKGROUND: Elite athletes show structural cardiac changes as an adaptation to exercise. Studies examining strain in athletes have largely analyzed images at rest only. There is little data available regarding the change in strain with exercise. Our objectives were: to investigate the feasibility of strain analysis in athletes at peak exercise, to determine the normal range of left ventricular (LV) global longitudinal strain (GLS) within this population postexercise, to describe how LV GLS changes with exercise, and to determine whether any clinical characteristics correlate with the change in GLS that occurs with exercise. METHODS: We conducted a cross-sectional study on elite athletes who participated in the 2016-2018 National Basketball Association Draft Combines. Echocardiograms were obtained at rest and after completing a treadmill stress test to maximal exertion or completion of Bruce protocol. Primary outcomes included GLS obtained at rest and peak exercise. Secondary outcome was the change in GLS between rest and exercise. Univariate relationships between various clinical characteristics and our secondary outcome were analyzed. RESULTS: Our final cohort (n = 111) was all male and 92/111 (82.9%) were African American. Mean GLS magnitude increased in response to exercise (-17.6 ± 1.8 vs -19.2 ± 2.6, P < .0001). Lower resting heart rates (r = .22, P = .02) and lower heart rates at peak exercise (r = .21, P = .03) correlated with the increase in LV GLS from exercise. CONCLUSIONS: Strain imaging is technically feasible to obtain among elite basketball athletes at peak exercise. Normative strain response to exercise from this study may help identify abnormal responses to exercise in athletes.

Temporal trends in right heart strain in patients undergoing pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension.

BACKGROUND: Pulmonary thromboendarterectomy (PTE) is a curative procedure for chronic thromboembolic pulmonary hypertension (CTEPH). Right ventricular free wall strain (RV FWS) and right atrial strain (RAS) are not well studied in a CTEPH population. We sought to determine temporal trends in RAS and RV FWS in patients post-PTE. METHODS: 28 patients undergoing PTE for CTEPH were prospectively enrolled in a surgical database. Comprehensive echocardiographic assessment of the right heart was performed including RV FWS, right atrial volume, and the three components of RAS: reservoir, conduit, and booster strain. RESULTS: Patients undergoing PTE demonstrated improvement in NYHA functional class (P < 0.001). Hemodynamic assessment showed improvement in mean pulmonary artery pressure from 49.7 ± 8.5 mm Hg to 23.9 ± 6.5 mm Hg (P < 0.001) and pulmonary vascular resistance decreased from 7.8 ± 3.2 wu to 2.4 ± 1.3 wu (P < 0.001). Tricuspid annular plane systolic excursion (TAPSE) and lateral S` declined immediately post-op. RV FWS improved from -14.4 ± 4% to -19 ± 3.4% post-op and -21.2 ± 4.7% at long-term follow-up (P < 0.001). Improvement in RV FWS post-op was driven primarily by increases in the apical and mid segments. RA volume declined significantly during the study period. RA reservoir and conduit strain improved after PTE. CONCLUSION: Patients undergoing PTE for CTEPH had significant improvement in right heart hemodynamics immediately post-op. Traditional echo metrics of RV performance including TAPSE and lateral S` did not improve. RV FWS improved, which was driven by changes in the apical and mid segments. This highlights that RV FWS is a viable and useful metric to follow in CTEPH patients post-PTE.

Tissue Doppler Imaging (E/e') and Pulmonary Capillary Wedge Pressure in Patients With Severe Aortic Stenosis.

OBJECTIVE: Although American and European consensus statements advocate using the ratio of the transmitral E velocity and tissue Doppler early diastolic mitral annular velocity (E/e') in the assessment of left-sided heart filling pressures, recent reports have questioned the reliability of this ratio to predict left atrial pressures in a variety of disease states. The authors hypothesized that there is a clinically significant correlation between E/e' and pulmonary capillary wedge pressure (PCWP) in patients with severe aortic stenosis. DESIGN: Retrospective cohort study. PARTICIPANTS: The study comprised 733 consecutive patients with severe aortic stenosis who underwent transcatheter aortic valve replacement for severe aortic stenosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PCWP and E/e'ave (average of the lateral and medial annulus tissue Doppler velocities) were measured with a pulmonary artery catheter and transthoracic echocardiography during preprocedural evaluation. Patients were grouped by left ventricular ejection fraction (LVEF) ≥50% and LVEF <50%. Spearman rank correlation, analysis of variance, and t and chi-square tests were used to analyze the data. Seventy-nine patients met the inclusion criteria. There was no significant correlation between E/e'ave and PCWP (n = 79, Spearman r = 0.096; p = 0.3994). This correlation did not improve when ventricular function was considered (LVEF <50%: n = 11, Spearman r = -0.097; p = 0.776 and LVEF ≥50%: n = 68, Spearman r = 0.116; p = 0.345). There was no statistically significant difference in mean PCWP between each range of E/e'ave. CONCLUSION: A clinically relevant relationship between E/e' and PCWP was not observed in patients with severe aortic stenosis.

Intron retention induced by microsatellite expansions as a disease biomarker.

Expansions of simple sequence repeats, or microsatellites, have been linked to ∼30 neurological-neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite sequence and repeat length diversity is more prominent in introns with eight different trinucleotide to hexanucleotide repeats, causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal dystrophy (FECD), and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we test the hypothesis that these GC-rich intronic microsatellite expansions selectively trigger host intron retention (IR). Using DM2, FECD, and C9-ALS/FTD as examples, we demonstrate that retention is readily detectable in affected tissues and peripheral blood lymphocytes and conclude that IR screening constitutes a rapid and inexpensive biomarker for intronic repeat expansion disease.

Echocardiographic evidence of left ventricular untwisting-filling interplay.

BACKGROUND: Left ventricular untwisting generates an early diastolic intraventricular pressure gradient (DIVPG) than can be quantified by echocardiography. We sought to confirm the quantitative relationship between peak untwisting rate and peak DIVPG in a large adult population. METHODS: From our echocardiographic database, we retrieved all the echocardiograms with a normal left ventricular ejection fraction, for whom color Doppler M-Mode interrogation of mitral inflow was available, and left ventricular untwisting rate was measurable using speckle tracking. Standard indices of left ventricular early diastolic function were assessed by Doppler (peaks E, e' and Vp) and speckle tracking (peak strain rate Esr). Load dependency of DIVPG and untwisting rate was evaluated using a passive leg raising maneuver. RESULTS: We included 154 subjects, aged between 18 to 77 years old, 63% were male. Test-retest reliability for color Doppler-derived DIVPG measurements was good, the intraclass correlation coefficients were 0.97 [0.91-0.99] and 0.97 [0.67-0.99] for intra- and inter-observer reproducibility, respectively. Peak DIVPG was positively correlated with peak untwisting rate (r = 0.73, P <  0.001). On multivariate analysis, peak DIVPG was the only diastolic parameter that was independently associated with untwisting rate. Age and gender were the clinical predictive factors for peak untwisting rate, whereas only age was independently associated with peak DIVPG. Untwisting rate and DIVPG were both load-dependent, without affecting their relationship. CONCLUSIONS: Color Doppler-derived peak DIVPG was quantitatively and independently associated with peak untwisting rate. It thus provides a reliable flow-based index of early left ventricular diastolic function.

MBNL splicing activity depends on RNA binding site structural context.

Muscleblind-like (MBNL) proteins are conserved RNA-binding factors involved in alternative splicing (AS) regulation during development. While AS is controlled by distribution of MBNL paralogs and isoforms, the affinity of these proteins for specific RNA-binding regions and their location within transcripts, it is currently unclear how RNA structure impacts MBNL-mediated AS regulation. Here, we defined the RNA structural determinants affecting MBNL-dependent AS activity using both cellular and biochemical assays. While enhanced inclusion of MBNL-regulated alternative exons is controlled by the arrangement and number of MBNL binding sites within unstructured RNA, when these sites are embedded in a RNA hairpin MBNL binds preferentially to one side of stem region. Surprisingly, binding of MBNL proteins to RNA targets did not entirely correlate with AS efficiency. Moreover, comparison of MBNL proteins revealed structure-dependent competitive behavior between the paralogs. Our results showed that the structure of targeted RNAs is a prevalent component of the mechanism of alternative splicing regulation by MBNLs.

Multimodality imaging to guide transcatheter treatment of severe degenerative tricuspid regurgitation with tricuspid valve-in-ring implantation and paravalvular leak closure.

Tricuspid valve (TV) degeneration after surgical repair with an annuloplasty ring is problematic as redo operation carries high mortality. This can be addressed with transcatheter therapies to implant a valve within in prior ring (tricuspid valve-in-ring). When an incomplete ring is present, paravalvular leak is commonly encountered after tricuspid valve-in-ring (TViR) implant; however, this can be addressed with paravalvular leak closure devices. Multimodality imaging including cardiac computed tomography and three-dimensional (3D) transesophageal echocardiography (TEE) are important for successful TViR implant. We report a case of tricuspid regurgitation after tricuspid repair with an incomplete annuloplasty ring and subsequent paravalvular leak closure.

Emergency medicine practice environment and impact on concert examination performance.

OBJECTIVE: The ABEM ConCert Examination is a summative examination that ABEM-certified physicians are required to pass once in every 10-year cycle to maintain certification. This study was undertaken to identify practice settings of emergency physicians, and to determine if there was a difference in performance on the 2017 ConCert between physicians of differing practice types and settings. METHODS: This was a mixed methods cross sectional-study, using a post-examination survey and test performance data. All physicians taking the 2017 ConCert Examination who completed three survey questions pertaining to practice type, practice locations, and teaching were included. These three questions address different aspects of academia: self-identification, an academic setting, and whether the physician teaches. RESULTS: Among 2796 test administrations of the 2017 ConCert Examination, 2693 (96.3%) completed the three survey questions about practice environment. The majority (N = 2054; 76.3%) self-identified as primarily being a community physician, 528 (19.6%) as academic, and 111 (4.1%) as other. The average ConCert Examination score for community physicians was 83.5 (95% CI, 83.3-83.8); the academic group was 84.8 (95% CI, 84.3-85.3); and the other group was 82.3 (95% CI, 81.1-83.6). After controlling for initial ability as measured by the Qualifying Examination score, there was no significant difference in performance between academic and community physicians (p = .10). CONCLUSIONS: Academic emergency physicians and community emergency physicians scored similarly on the ConCert. Working at a community teaching hospital was associated with higher examination performance. Teaching medical learners, especially non-emergency medicine residents, was also associated with better examination performance.

A Prospective Pilot Study of Pocket-Carried Ultrasound Pre- and Postdischarge Inferior Vena Cava Assessment for Prediction of Heart Failure Rehospitalization.

BACKGROUND: Rehospitalization for heart failure (HF) is common, and subclinical congestion may be present at discharge. Larger inferior vena cava (IVC) size and lower collapsibility at discharge assessed via bedside ultrasound are predictive of rehospitalization; however, the utility of IVC assessment with the use of pocket-carried ultrasound (PCUS) during the transition from discharge to the posthospitalization follow-up visit (FU) has not been investigated. METHODS AND RESULTS: IVCmax and IVCmin were measured with the use of PCUS, and the collapsibility index (IVCCI = [IVCmax - IVCmin]/IVCmax) was determined. The primary outcome was 90-day rehospitalization or death. We prospectively enrolled 49 adults (71 ± 13 years of age, 51% male, 47% black, 43% preserved ejection fraction) hospitalized for HF. Nineteen patients (39%) experienced the outcome. Within the rehospitalized group, discharge and FU mean IVCmax were both >2.1 cm (2.2 ± 0.5 and 2.2 ± 0.7) and IVCCIs <50% (44 ± 20% and 45 ± 24%). Within those not rehospitalized, FU IVCmax was ≤2.1 cm (2.1 ± 0.6 and 1.9 ± 0.6; P = .038) and IVCCI >50% at both time points (55 ± 25% and 62 ± 19%; P = NS). FU IVCCI below an optimal cutoff of 42% had modest discrimination alone (c-statistic = 0.73). FU IVCCI <42% was associated with a greater hazard of the outcome independent of admission log B-type natriuretic peptide (adjusted hazard ratio = 6.8; 95% confidence interval 2.4-19.0; P < .001). CONCLUSIONS: Posthospitalization IVCCI assessment with PCUS predicts HF rehospitalization and may identify patients in need of intervention.

High hospital research participation and improved colorectal cancer survival outcomes: a population-based study.

OBJECTIVE: In 2001, the National Institute for Health Research Cancer Research Network (NCRN) was established, leading to a rapid increase in clinical research activity across the English NHS. Using colorectal cancer (CRC) as an example, we test the hypothesis that high, sustained hospital-level participation in interventional clinical trials improves outcomes for all patients with CRC managed in those research-intensive hospitals. DESIGN: Data for patients diagnosed with CRC in England in 2001-2008 (n=209 968) were linked with data on accrual to NCRN CRC studies (n=30 998). Hospital Trusts were categorised by the proportion of patients accrued to interventional studies annually. Multivariable models investigated the relationship between 30-day postoperative mortality and 5-year survival and the level and duration of study participation. RESULTS: Most of the Trusts achieving high participation were district general hospitals and the effects were not limited to cancer 'centres of excellence', although such centres do make substantial contributions. Patients treated in Trusts with high research participation (≥16%) in their year of diagnosis had lower postoperative mortality (p<0.001) and improved survival (p<0.001) after adjustment for casemix and hospital-level variables. The effects increased with sustained research participation, with a reduction in postoperative mortality of 1.5% (6.5%-5%, p<2.2×10-6) and an improvement in survival (p<10-19; 5-year difference: 3.8% (41.0%-44.8%)) comparing high participation for ≥4 years with 0 years. CONCLUSIONS: There is a strong independent association between survival and participation in interventional clinical studies for all patients with CRC treated in the hospital study participants. Improvement precedes and increases with the level and years of sustained participation.