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971.
Left ventricular deformation at rest predicts exercise‐induced elevation in pulmonary artery wedge pressure in patients with unexplained dyspnoea 下载免费PDF全文
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Challenges in Patient Enrollment and Retention in Clinical Studies for Alcoholic Hepatitis: Experience of the TREAT Consortium 下载免费PDF全文
Megan Comerford Spencer Lourens Suthat Liangpunsakul Naga P. Chalasani Arun J. Sanyal Vijay H. Shah Patrick S. Kamath Puneet Puri Barry P. Katz Svetlana Radaeva David W. Crabb 《Alcoholism, clinical and experimental research》2017,41(12):2000-2006
The TREAT Consortium has carried out clinical studies on alcoholic hepatitis (AH) for over 4 years. We encountered problems with participant recruitment, retention, and eligibility for specific protocols. To improve our ability to carry out such trials, we reviewed recruitment screening logs, end of study logs, and surveyed study coordinators to learn the reasons for missing patients, why patients declined enrollment, and the number of patients eligible for treatment trials. Associations of the recruited subjects’ demographics with their adherence to follow‐up appointments were examined. Three hundred eight‐seven patients (AH and heavy drinking controls) were enrolled in the observational study, and 55 AH patients were recruited into treatment trials. About half of patients identified with AH could not be recruited; no specific reason could be determined for about two‐thirds of these. Among the patients who gave a reason for not participating, the most common reasons were feeling too sick to participate, desire to concentrate on abstinence, and lack of interest in research. Approximately a quarter of the AH patients met eligibility criteria for treatment trials for moderate or severe AH and we were able to recruit half to two‐thirds of those eligible. Approximately 35% of participants in the observational study returned for both 6‐ and 12‐month follow‐up visits. We did not identify biopsychosocial or demographic correlates of retention in the study. This analysis revealed that attempts at recruitment into trials for AH miss some subjects because of structural issues surrounding their hospital admission, and encounter a high rate of patient refusal to participate. Nonetheless, more than half of the patients who met the eligibility criteria for moderate or severe AH were entered into clinical trials. Retention rates for the observational study are relatively low. These findings need to be accounted for in clinical trial design and power analysis. 相似文献
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Han S. Lim Mélèze Hocini Remi Dubois Arnaud Denis Nicolas Derval Stephan Zellerhoff Seigo Yamashita Benjamin Berte Saagar Mahida Yuki Komatsu Matthew Daly Laurence Jesel Carole Pomier Valentin Meillet Sana Amraoui Ashok J. Shah Hubert Cochet Frédéric Sacher Michel Haïssaguerre 《Journal of the American College of Cardiology》2017,69(10):1257-1269
Background
The underlying mechanisms sustaining human persistent atrial fibrillation (PsAF) is poorly understood.Objectives
This study sought to investigate the complexity and distribution of AF drivers in PsAF of varying durations.Methods
Of 135 consecutive patients with PsAF, 105 patients referred for de novo ablation of PsAF were prospectively recruited. Patients were divided into 3 groups according to AF duration: PsAF presenting in sinus rhythm (AF induced), PsAF <12 months, and PsAF >12 months. Patients wore a 252-electrode vest for body surface mapping. Localized drivers (re-entrant or focal) were identified using phase-mapping algorithms.Results
In this patient cohort, the most prominent re-entrant driver regions included the pulmonary vein (PV) regions and inferoposterior left atrial wall. Focal drivers were observed in 1 or both PV regions in 75% of patients. Comparing between the 3 groups, with longer AF duration AF complexity increased, reflected by increased number of re-entrant rotations (p < 0.05), number of re-entrant rotations and focal events (p < 0.05), and number of regions harboring re-entrant (p < 0.01) and focal (p < 0.05) drivers. With increased AF duration, a higher proportion of patients had multiple extra-PV driver regions, specifically in the inferoposterior left atrium (p < 0.01), superior right atrium (p < 0.05), and inferior right atrium (p < 0.05). Procedural AF termination was achieved in 70% of patients, but decreased with longer AF duration.Conclusions
The complexity of AF drivers increases with prolonged AF duration. Re-entrant and focal drivers are predominantly located in the PV antral and adjacent regions. However, with longer AF duration, multiple drivers are distributed at extra-PV sites. AF termination rate declines as patients progress to longstanding PsAF, underscoring the importance of early intervention. 相似文献974.
Matthew C. Konerman Joshua C. Greenberg Theodore J. Kolias James R. Corbett Ravi V. Shah Venkatesh L. Murthy Scott L. Hummel 《Journal of cardiac failure》2018,24(2):90-100
Introduction
Coronary microvascular dysfunction (MVD) may contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Using myocardial flow reserve (MFR) measured by positron emission tomography (PET) as an assessment of microvascular function, we hypothesized that abnormal MFR is associated with LV diastolic dysfunction (DD) and reduced LV and LA strain in patients with risk factors for HFpEF and normal epicardial perfusion on cardiac PET.Methods and Results
Retrospective study of patients without heart failure who underwent cardiac rubidium-82 PET and echocardiography. Global MFR was calculated as the ratio of global stress to rest myocardial blood flow. Echocardiographic measures of diastolic function were recorded. Global longitudinal LA and LV strain were measured with a 2-dimensional speckle-tracking technique. Relationships among MFR and echocardiographic measures were assessed with linear regression, analysis of variance, and test for trend. Seventy-three patients (age 64 ± 11 years, 52% male) were identified with no epicardial perfusion defect on cardiac PET and an ejection fraction ≥50%. Decreased MFR was associated with LV DD (P = .02) and increased E/e', an estimation of LV filling pressure (low E/e' [<8] vs. high E/e' [>15], P < .001). MFR was associated with LA strain independent of age, gender, and common comorbidities (adjusted β = 2.6% per unit MFR, P = 0.046); however, MFR was only marginally related to LV strain.Conclusions
In patients with risk factors for HFpEF, MVD assessed with MFR was associated with DD, increased estimated LV filling pressure, and abnormal LA strain. 相似文献975.
Simone Romano Robert M. Judd Raymond J. Kim Han W. Kim Igor Klem John F. Heitner Dipan J. Shah Jennifer Jue Brent E. White Raksha Indorkar Chetan Shenoy Afshin Farzaneh-Far 《JACC: Cardiovascular Imaging》2018,11(10):1419-1429
Objectives
The aim of this study was to evaluate the prognostic value of cardiac magnetic resonance (CMR) feature-tracking–derived global longitudinal strain (GLS) in a large multicenter population of patients with ischemic and nonischemic dilated cardiomyopathy.Background
Direct assessment of myocardial fiber deformation with GLS using echocardiography or CMR feature tracking has shown promise in providing prognostic information incremental to ejection fraction (EF) in single-center studies. Given the growing use of CMR for assessing persons with left ventricular (LV) dysfunction, we hypothesized that feature-tracking–derived GLS may provide independent prognostic information in a multicenter population of patients with ischemic and nonischemic dilated cardiomyopathy.Methods
Consecutive patients at 4 U.S. medical centers undergoing CMR with EF <50% and ischemic or nonischemic dilated cardiomyopathy were included in this study. Feature-tracking GLS was calculated from 3 long-axis cine-views. The primary endpoint was all-cause death. Cox proportional hazards regression modeling was used to examine the association between GLS and death. Incremental prognostic value of GLS was assessed in nested models.Results
Of the 1,012 patients in this study, 133 died during median follow-up of 4.4 years. By Kaplan-Meier analysis, the risk of death increased significantly with worsening GLS tertiles (log-rank p < 0.0001). Each 1% worsening in GLS was associated with an 89.1% increased risk of death after adjustment for clinical and imaging risk factors including EF and late gadolinium enhancement (LGE) (hazard ratio [HR]:1.891 per %; p < 0.001). Addition of GLS in this model resulted in significant improvement in the C-statistic (0.628 to 0.867; p < 0.0001). Continuous net reclassification improvement (NRI) was 1.148 (95% confidence interval: 0.996 to 1.318). GLS was independently associated with death after adjustment for clinical and imaging risk factors (including EF and late gadolinium enhancement) in both ischemic (HR: 1.942 per %; p < 0.001) and nonischemic dilated cardiomyopathy subgroups (HR: 2.101 per %; p < 0.001).Conclusions
CMR feature-tracking–derived GLS is a powerful independent predictor of mortality in a multicenter population of patients with ischemic or nonischemic dilated cardiomyopathy, incremental to common clinical and CMR risk factors including EF and LGE. 相似文献976.
Validation of the HFA‐PEFF score for the diagnosis of heart failure with preserved ejection fraction
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Shiv Shah Caldon Jayson Esdaille Maumita Bhattacharjee Ho-Man Kan Cato T. Laurencin 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(2)
Stem cells are of great interest in tissue regeneration due to their ability to modulate the local microenvironment by secreting bioactive factors (collectively, secretome). However, secretome delivery through conditioned media still requires time-consuming cell isolation and maintenance and also may contain factors antagonistic to targeted tissue regeneration. We have therefore engineered a synthetic artificial stem cell (SASC) system which mimics the paracrine effect of the stem cell secretome and provides tailorability of the composition for targeted tissue regeneration. We report the first of many applications of the SASC system we have formulated to treat osteoarthritis (OA). Choosing growth factors important to chondrogenesis and encapsulating respective recombinant proteins in poly (lactic-coglycolic acid) 85:15 (PLGA) we fabricated the SASC system. We compared the antiinflammatory and chondroprotective effects of SASC to that of adipose-derived stem cells (ADSCs) using in vitro interleukin 1B-induced and in vivo collagenase-induced osteoarthritis rodent models. We have designed SASC as an injectable therapy with controlled release of the formulated secretome. In vitro, SASC showed significant antiinflammatory and chondroprotective effects as seen by the up-regulation of SOX9 and reduction of nitric oxide, ADAMTS5, and PRG4 genes compared to ADSCs. In vivo, treatment with SASC and ADSCs significantly attenuated cartilage degeneration and improved the biomechanical properties of the articular cartilage in comparison to OA control. This SASC system demonstrates the feasibility of developing a completely synthetic, tailorable stem cell secretome which reinforces the possibility of developing a new therapeutic strategy that provides better control over targeted tissue engineering applications.Stem cell science has become an essential component of regenerative engineering and has the potential to revolutionize healing outcomes once clinical translation is achieved (1). Regenerative engineering utilizes a transdisciplinary approach and is defined by the convergence of advanced material science, stem cell sciences, physics, developmental biology, and clinical translation to regenerative complex tissues and organs (2, 3). Mesenchymal stem cells, which are a multipotent cell type, possess the ability to self-renew and differentiate into various lineages such as adipocytes, bone, cartilage, muscle, skin, and tendon and have been used in preclinical studies to regenerate these respective and other connective tissues (4, 5). In addition to their differentiation ability, stem cells also have the ability to secrete bioactive factors during differentiation which will further drive repair and regeneration (6, 7) As a result, the role of stem cells as progenitor cells with associated bioactive factors is becoming increasingly important as a strategy to harness the regenerative potential of the tissues within the body (8).Stem cell therapy focuses on the delivery of cells to facilitate tissue repair and regeneration by a combination of antiinflammatory, immunomodulatory properties and multipotent differentiation capacity. However, in order to be used in a clinical setting, they must be isolated from human tissue and require constant growth and passage in in vitro culture environments. In addition, studies have reported that cells are at risk for undergoing spontaneous alterations in behavior and properties while being cultured (9). Contamination is also a risk due to improper technique or nonsterile conditions. Other limitations and challenges that should be considered when developing stem cell therapies include immune compatibility and rejection reactions, formation of malignant tumors due to uncontrolled proliferation, and transmission of infectious processes (10, 11).Following these concerns and further reportedly negligible levels of stem cell engraftment into the diseased tissue (12), more recent studies are highlighting the fact that the collection of paracrine factors secreted by stem cells (known as the secretome) is the main enforcer of therapeutics effects. Cell-free alternatives that utilize paracrine factors in a similar fashion have recently been considered (13–16). Secretome has been proposed as a cell-free alternative to cell therapy to overcome the limitations and associated risks with stem cell therapeutics. The secretome is defined as a set of biological factors and molecules that are secreted into the extracellular matrix (ECM) which play an essential role in a wide range of biological processes, including homeostasis, immunomodulation, inflammation, angiogenesis, and ECM organization (17). The functions of the secretome can be broken into four main functions: angiogenesis, antiapoptosis, antifibrosis, and antiinflammation (17). Various secreted proteins make up the cell secretome and can include growth factors, angiogenic factors, cytokines, chemokines, and extracellular vesicles for transport of lipids and proteins. The composition of the secretome is highly dynamic and is based on the cell type and microenvironment which it will be used in, allowing for greater design flexibility and versatility for use in a wide array of tissues (17, 18). The paracrine effect exhibited by the secretome has been shown to be very effective in regenerating different tissues (12) with several logistical advantages for use in a clinical setting such as longer shelf lives, availability, and scalability (19, 20).While the secretome provides many advantages over cell-based therapy, it shares many similar translational challenges, including time-consuming cell maintenance to obtain conditioned media and compositional sensitivity to the cell microenvironment. Stem cells secrete a mixture of biological factors in a controlled, sequential, and combinatorial fashion to exhibit the paracrine effect which has recently been shown to be a key driver for the regenerative process. To date, there has been no study conducted which attempts to mimic the paracrine functions of the stem cell. While single growth factor treatment may not be effective for complete regeneration, controlled delivery of a mixture of factors is needed to truly mimic cellular paracrine functions. Therefore, we have engineered the synthetic artificial stem cell (SASC). With the added ability to tailor the formulation for targeted tissues, SASC has the potential to be used in different systems by providing potent immunomodulatory and regenerative effects.In the present study, we aimed at developing the first SASC system to attenuate osteoarthritis (OA) progression by tailoring factors abundant in the stromal stem cell secretome that have specifically an anabolic, chondroprotective, and/or antiinflammatory effect in the joint (21–23). Katagiri et al. (23) found insulin-like growth factor (IGF) and transforming growth factor (TGF)-β1 to be important chondrogenic factors in bone marrow–derived stem cell conditioned media. Others have also reported the importance of fibroblast growth factor (FGF)-18 in chondrogenesis (specifically signaling through anabolic receptor FGFR3) (24–26) and of human growth hormone (HGH) (a proliferative factor which also signals for IGF1) (27, 28). As a pilot SASC composition, IGF1, TGF-β1, FGF-18, and HGH were combined at concentrations similar to conditioned media and delivered using a poly (lactic-coglycolic acid) (PLGA) 85:15 matrix. The antiinflammatory and chondroprotective effects of SASC have been evaluated in comparison with the current treatment standard, adipose-derived stem cells (ADSCs) (5), in both in vitro and in vivo OA models (Fig. 1). Furthermore, biomechanical outcomes of SASC treatment were also evaluated in vivo.Open in a separate windowFig. 1.A graphical summary of coculture in vitro (A) and rodent collagenase-induced in vivo (B) models. Figure made in Biorender. 相似文献