Digital Health Interventions for Cardiac Rehabilitation: Systematic Literature Review.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite strong evidence supporting the benefits of cardiac rehabilitation (CR), over 80% of eligible patients do not participate in CR. Digital health technologies (ie, the delivery of care using the internet, wearable devices, and mobile apps) have the potential to address the challenges associated with traditional facility-based CR programs, but little is known about the comprehensiveness of these interventions to serve as digital approaches to CR. Overall, there is a lack of a systematic evaluation of the current literature on digital interventions for CR. OBJECTIVE: The objective of this systematic literature review is to provide an in-depth analysis of the potential of digital health technologies to address the challenges associated with traditional CR. Through this review, we aim to summarize the current literature on digital interventions for CR, identify the key components of CR that have been successfully addressed through digital interventions, and describe the gaps in research that need to be addressed for sustainable and scalable digital CR interventions. METHODS: Our strategy for identifying the primary literature pertaining to CR with digital solutions (defined as technology employed to deliver remote care beyond the use of the telephone) included a consultation with an expert in the field of digital CR and searches of the PubMed (MEDLINE), Embase, CINAHL, and Cochrane databases for original studies published from January 1990 to October 2018. RESULTS: Our search returned 31 eligible studies, of which 22 were randomized controlled trials. The reviewed CR interventions primarily targeted physical activity counseling (31/31, 100%), baseline assessment (30/31, 97%), and exercise training (27/31, 87%). The most commonly used modalities were smartphones or mobile devices (20/31, 65%), web-based portals (18/31, 58%), and email-SMS (11/31, 35%). Approximately one-third of the studies addressed the CR core components of nutrition counseling, psychological management, and weight management. In contrast, less than a third of the studies addressed other CR core components, including the management of lipids, diabetes, smoking cessation, and blood pressure. CONCLUSIONS: Digital technologies have the potential to increase access and participation in CR by mitigating the challenges associated with traditional, facility-based CR. However, previously evaluated interventions primarily focused on physical activity counseling and exercise training. Thus, further research is required with more comprehensive CR interventions and long-term follow-up to understand the clinical impact of digital interventions.

Progress in Understanding, Diagnosing, and Managing Cardiac Complications of Systemic Sclerosis.

PURPOSE OF THE REVIEW: Systemic sclerosis (scleroderma) is a complex autoimmune disease that commonly involves the cardiovascular system. Even if often subclinical, cardiac involvement is considered a poor prognostic factor as it is a leading cause of death in scleroderma patients. We review the cardiac manifestations of scleroderma, the diagnostic methods useful in detection, and current advances in therapeutic management. RECENT FINDINGS: Beside the routine exams for the assessment of cardiac status (including EKG, standard echocardiography, provocative tests) novel techniques such as myocardial strain imaging on echocardiography, cardiac magnetic resonance imaging, invasive hemodynamic assessment, and endomyocardial biopsy have been demonstrated to be useful in understanding the cardiac alterations that typically affect scleroderma patients. Recent application of novel cardiac detection strategies is providing increased insight into the breadth and pathogenesis of cardiac complications of scleroderma. Further studies coupling exercise provocation, invasive and imaging assessment, and mechanistic studies in scleroderma cardiac tissue are needed to develop the optimal approach to early detection of cardiac disease in scleroderma and targeted therapies.

Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model.

RATIONALE: After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile. OBJECTIVE: To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility. METHODS AND RESULTS: Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01). CONCLUSIONS: The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

Preclinical Models for Translational Investigations of Left Ventricular Assist Device-Associated von Willebrand Factor Degradation.

Evidence suggests a major role for von Willebrand factor (vWF) in left ventricular assist device (LVAD)-associated bleeding. However, the mechanisms of vWF degradation during LVAD support are not well understood. We developed: (i) a simple and inexpensive vortexer model; and (ii) a translational LVAD mock circulatory loop to perform preclinical investigations of LVAD-associated vWF degradation. Whole blood was obtained from LVAD patients (n = 8) and normal humans (n = 15). Experimental groups included: (i) blood from continuous-flow LVAD patients (baseline vs. post-LVAD, n = 8); (ii) blood from normal humans (baseline vs. 4 h in vitro laboratory vortexer, ∼ 2400 rpm, shear stress ∼175 dyne/cm(2) , n = 8); and (iii) blood from normal humans (baseline vs. 12 h HeartMate II mock circulatory loop, 10 000 rpm, n = 7). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblotting. Blood from LVAD patients, blood exposed to in vitro supraphysiologic shear stress, and blood circulated through an LVAD mock circulatory loop demonstrated a similar profile of decreased large vWF multimers and increased vWF degradation fragments. A laboratory vortexer and an LVAD mock circulatory loop reproduced the pathologic degradation of vWF that occurs during LVAD support. Both models are appropriate for preclinical studies of LVAD-associated vWF degradation.

Bioengineered stromal cell-derived factor-1α analogue delivered as an angiogenic therapy significantly restores viscoelastic material properties of infarcted cardiac muscle.

Ischemic heart disease is a major health problem worldwide, and current therapies fail to address microrevascularization. Previously, our group demonstrated that the sustained release of novel engineered stromal cell-derived factor 1-a analogue (ESA) limits infarct spreading, collagen deposition, improves cardiac function by promoting angiogenesis in the region surrounding the infarct, and restores the tensile properties of infarcted myocardium. In this study, using a well-established rat model of ischemic cardiomyopathy, we describe a novel and innovative method for analyzing the viscoelastic properties of infarcted myocardium. Our results demonstrate that, compared with a saline control group, animals treated with ESA have significantly improved myocardial relaxation rates, while reducing the transition strain, leading to restoration of left ventricular mechanics.

LncRNA MALAT1 Regulates Hyperglycemia Induced EMT in Keratinocyte via miR-205.

Epithelial-to-mesenchymal transition (EMT) is critical to cutaneous wound healing. When skin is injured, EMT activates and mobilizes keratinocytes toward the wound bed, therefore enabling re-epithelialization. This process becomes dysregulated in patients with diabetes mellitus (DM). Long non-coding RNAs (lncRNAs) regulate many biological processes. LncRNA-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) influences numerous cellular processes, including EMT. The objective of the current study is to explore the role of MALAT1 in hyperglycemia (HG)-induced EMT. The expression of MALAT1 was found to be significantly upregulated, while the expression of miR-205 was downregulated in diabetic wounds and high-glucose-treated HaCaT cells. The initiation of EMT in HaCaT cells from hyperglycemia was confirmed by a morphological change, the increased expression of CDH2, KRT10, and ACTA2, and the downregulation of CDH1. The knockdown of MALAT1 was achieved by transfecting a small interfering RNA (SiRNA). MALAT1 and miR-205 were found to modulate HG-induced EMT. MALAT1 silencing or miR-205 overexpression appears to attenuate hyperglycemia-induced EMT. Mechanistically, MALAT1 affects HG-induced EMT through binding to miR-205 and therefore inducing ZEB1, a critical transcription factor for EMT. In summary, lncRNA MALAT1 is involved in the hyperglycemia-induced EMT of human HaCaT cells. This provides a new perspective on the pathogenesis of diabetic wounds.

Paracrine-mediated rejuvenation of aged mesenchymal stem cells is associated with downregulation of the autophagy-lysosomal pathway.

Age-related differences in stem-cell potency contribute to variable outcomes in clinical stem cell trials. To help understand the effect of age on stem cell potency, bone marrow-derived mesenchymal stem cells (MSCs) were isolated from young (6 weeks) and old (18-24 months) mice. HUVEC tubule formation (TF) induced by the old and young MSCs and ELISA of conditioned media were compared to one another, and to old MSCs after 7 d in indirect co-culture with young MSCs. Old MSCs induced less TF than did young (1.56 ± 0.11 vs 2.38 ± 0.17, p = 0.0003) and released lower amounts of VEGF (p = 0.009) and IGF1 (p = 0.037). After 7 d in co-culture with young MSCs, TF by the old MSCs significantly improved (to 2.09 ± 0.18 from 1.56 ± 0.11; p = 0.013), and was no longer different compared to TF from young MSCs (2.09 ± 0.18 vs 2.38 ± 0.17; p = 0.27). RNA seq of old MSCs, young MSCs, and old MSCs following co-culture with young MSCs revealed that the age-related differences were broadly modified by co-culture, with the most significant changes associated with lysosomal pathways. These results indicate that the age-associated decreased paracrine-mediated effects of old MSCs are improved following indirect co-culture with young MSC. The observed effect is associated with broad transcriptional modification, suggesting potential targets to both assess and improve the therapeutic potency of stem cells from older patients.

Scan path during change-detection visual search.

When observing a particular image or object, one's perception depends upon prior expectations, memory, and cognitive abilities. It is hypothesized that cognitive processing in the form of top-down or bottom-up processing could be determined via analysis of the eye fixation scan path. To assess the variations in scan paths, 7 subjects underwent 5 change-detection trials. During each trial, they were presented with a specific set of images via a MATLAB program, in which the original image alternated with a modified image consisting of a single change. An open-source program called GazeRecorder was used to track the subject's eye movements and to record the eye fixations. The scan path was then analyzed through the use of a 4 by 4 grid pattern superimposed on the image to determine the subject's eye fixation distribution pattern in terms of Boxes Viewed and Concentration within a single area. It was determined that higher Concentration was positively correlated with faster Detection Speed (R = 0.84), while higher number of Boxes Viewed was negatively correlated with Detection Speed (R = -0.71). Among the subjects, the more optimal scan paths were found in those with a balance between Concentration and Boxes Viewed, as subjects with a more balanced approach had the greatest Accuracy (p = 0.02). This indicates an optimal scan path involves both top-down and bottom-up processing to more efficiently identify a change. Moreover, the methodology developed in this study could be used in the home or clinic for quantitative assessment of improvement following therapy in patients with neurological deficits.

Correction: Strategies for the Successful Implementation of a Novel iPhone Loaner System (iShare) in mHealth Interventions: Prospective Study.

[This corrects the article DOI: 10.2196/16391.].

Mobile health application platform 'Corrie' personalises and empowers the heart attack recovery patient experience in the hospital and at home for an underserved heart attack survivor.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide with an estimated 17.5 million deaths annually, according to the World Health Organization (WHO). CVD prevention efforts have the potential to prevent the majority of these deaths by supporting guideline-directed medical therapy (GDMT) and lifestyle modification. Mobile health (mHealth) has the potential to address this gap, but has limited evaluation in clinical studies to date. We present the case of a middle-aged patient of low socioeconomic status, with multiple comorbidities, and no prior smartphone experience, who suffered an acute myocardial infarction (MI) and was given the Corrie intervention while hospitalised. The patient demonstrated improvement in lifestyle modification, adherence to GDMT and post-MI recovery through 2.4 years follow-up. This case supports (1) the potential of mHealth interventions to enhance patient experience and outcomes, (2) intuitive design for adoption and improvement in end user experience and (3) the capability of mHealth to reach and empower underserved patients.

Biomechanics of the golf swing using OpenSim.

A study was conducted to investigate the underlying mechanisms involved in the dynamics of body motions during the golf swing. A series of model simulation programs were developed in OpenSim to control the characteristics of the biomechanical model of the body. The resultant model parameters were put in an Excel file, which allowed these parameters to be modified. OpenSim model simulation run was paused at various points of the golf swing and screenshots were taken. MATLAB was used to find the positional value of the center of clubface for each screenshot and the Euclidean distances of the clubhead position between poses. A series of simulation trials were then conducted using various time increments between the poses in order to calculate the clubhead velocities. Three of these trials were selected to illustrate the swing patterns of players of varying skill levels ranging from basic beginner to highly-skilled. These simulations using OpenSim can serve as a platform for understanding the dynamics of body motions in sports and biomedicine.

Strategies for the Successful Implementation of a Novel iPhone Loaner System (iShare) in mHealth Interventions: Prospective Study.

BACKGROUND: As smartphone ownership continues to rise, health care systems and technology companies are driven to develop mobile health (mHealth) interventions as both diagnostic and therapeutic tools. An important consideration during mHealth intervention development is how to achieve health equity despite demographic differences in smartphone ownership. One solution is through the recirculation of loaner smartphones; however, best practices for implementing such programs to optimize security, privacy, scalability, and convenience for participants are not well defined. OBJECTIVE: In this tutorial, we describe how we implemented our novel Corrie iShare program, a 30-day loaner iPhone and smartwatch recirculation program, as part of a multi-center mHealth intervention to improve recovery and access to guideline-directed therapy following acute myocardial infarction. METHODS: We conducted a prospective study utilizing a smartphone app and leveraged iOS enterprise features as well as cellular data service to automate recirculation. RESULTS: Our configuration protocol was shortened from 1 hour to 10 minutes. Of 200 participants, 92 (46.0%) did not own an iPhone and would have been excluded from the study without iShare. Among iShare participants, 72% (66/92) returned their loaned smartphones. CONCLUSIONS: The Corrie iShare program demonstrates the potential for a sustainable and scalable mHealth loaner program, enabling broader population reach while optimizing user experience. Implementation may face institutional constraints and software limitations. Consideration should be given to optimizing loaner returns.

Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction.

Aims: Previous studies have demonstrated improved cardiac function following myocardial infarction (MI) after administration of endothelial progenitor cells (EPCs) into ischaemic myocardium. A growing body of literature supports paracrine effectors, including extracellular vesicles (EVs), as the main mediators of the therapeutic benefits of EPCs. The direct use of paracrine factors is an attractive strategy that harnesses the effects of cell therapy without concerns of cell engraftment or viability. We aim to reproduce the beneficial effects of EPC treatment through delivery of EPC-derived EVs within a shear-thinning gel (STG) for precise localization and sustained delivery. Methods and results: EVs were harvested from EPCs isolated from adult male Rattus norvegicus (Wistar) rats and characterized by electron microscopy, nanoparticle tracking analysis (NTA), and mass spectrometry. EVs were incorporated into the STG and injected at the border zone in rat models of MI. Haemodynamic function, angiogenesis, and myocardial remodelling were analyzed in five groups: phosphate buffered saline (PBS) control, STG control, EVs in PBS, EVs in STG, and EPCs in STG. Electron microscopy and NTA of EVs showed uniform particles of 50-200 nm. EV content analysis revealed several key angiogenic mediators. EV uptake by endothelial cells was confirmed and followed by robust therapeutic angiogenesis. In vivo animal experiments demonstrated that delivery of EVs within the STG resulted in increased peri-infarct vascular proliferation, preservation of ventricular geometry, and improved haemodynamic function post-MI. Conclusions: EPC-derived EVs delivered into ischaemic myocardium via an injectable hydrogel enhanced peri-infarct angiogenesis and myocardial haemodynamics in a rat model of MI. The STG greatly increased therapeutic efficiency and efficacy of EV-mediated myocardial preservation.

Incremental retinal-defocus theory of myopia development--schematic analysis and computer simulation.

Previous theories of myopia development involved subtle and complex processes such as the sensing and analyzing of chromatic aberration, spherical aberration, spatial gradient of blur, or spatial frequency content of the retinal image, but they have not been able to explain satisfactorily the diverse experimental results reported in the literature. On the other hand, our newly proposed incremental retinal-defocus theory (IRDT) has been able to explain all of these results. This theory is based on a relatively simple and direct mechanism for the regulation of ocular growth. It states that a time-averaged decrease in retinal-image defocus area decreases the rate of release of retinal neuromodulators, which decreases the rate of retinal proteoglycan synthesis with an associated decrease in scleral structural integrity. This increases the rate of scleral growth, and in turn the eye's axial length, which leads to myopia. Our schematic analysis has provided a clear explanation for the eye's ability to grow in the appropriate direction under a wide range of experimental conditions. In addition, the theory has been able to explain how repeated cycles of nearwork-induced transient myopia leads to repeated periods of decreased retinal-image defocus, whose cumulative effect over an extended period of time results in an increase in axial growth that leads to permanent myopia. Thus, this unifying theory forms the basis for understanding the underlying retinal and scleral mechanisms of myopia development.

Drowsy driver mobile application: Development of a novel scleral-area detection method.

A reliable and practical app for mobile devices was developed to detect driver drowsiness. It consisted of two main components: a Haar cascade classifier, provided by a computer vision framework called OpenCV, for face/eye detection; and a dedicated JAVA software code for image processing that was applied over a masked region circumscribing the eye. A binary threshold was performed over the masked region to provide a quantitative measure of the number of white pixels in the sclera, which represented the state of eye opening. A continuously low white-pixel count would indicate drowsiness, thereby triggering an alarm to alert the driver. This system was successfully implemented on: (1) a static face image, (2) two subjects under laboratory conditions, and (3) a subject in a vehicle environment.

Normal human cell proteins that interact with the adenovirus type 5 E1B 55kDa protein.

Several of the functions of the human adenovirus type 5 E1B 55kDa protein are fulfilled via the virus-specific E3 ubiquitin ligase it forms with the viral E4 Orf6 protein and several cellular proteins. Important substrates of this enzyme have not been identified, and other functions, including repression of transcription of interferon-sensitive genes, do not require the ligase. We therefore used immunoaffinity purification and liquid chromatography-mass spectrometry of lysates of normal human cells infected in parallel with HAdV-C5 and E1B 55kDa protein-null mutant viruses to identify specifically E1B 55kDa-associated proteins. The resulting set of >90 E1B-associated proteins contained the great majority identified previously, and was enriched for those associated with the ubiquitin-proteasome system, RNA metabolism and the cell cycle. We also report very severe inhibition of viral genome replication when cells were exposed to both specific or non-specific siRNAs and interferon prior to infection.

Eye growth and myopia development: Unifying theory and Matlab model.

The aim of this article is to present an updated unifying theory of the mechanisms underlying eye growth and myopia development. A series of model simulation programs were developed to illustrate the mechanism of eye growth regulation and myopia development. Two fundamental processes are presumed to govern the relationship between physiological optics and eye growth: genetically pre-programmed signaling and blur feedback. Cornea/lens is considered to have only a genetically pre-programmed component, whereas eye growth is considered to have both a genetically pre-programmed and a blur feedback component. Moreover, based on the Incremental Retinal-Defocus Theory (IRDT), the rate of change of blur size provides the direction for blur-driven regulation. The various factors affecting eye growth are shown in 5 simulations: (1 - unregulated eye growth): blur feedback is rendered ineffective, as in the case of form deprivation, so there is only genetically pre-programmed eye growth, generally resulting in myopia; (2 - regulated eye growth): blur feedback regulation demonstrates the emmetropization process, with abnormally excessive or reduced eye growth leading to myopia and hyperopia, respectively; (3 - repeated near-far viewing): simulation of large-to-small change in blur size as seen in the accommodative stimulus/response function, and via IRDT as well as nearwork-induced transient myopia (NITM), leading to the development of myopia; (4 - neurochemical bulk flow and diffusion): release of dopamine from the inner plexiform layer of the retina, and the subsequent diffusion and relay of neurochemical cascade show that a decrease in dopamine results in a reduction of proteoglycan synthesis rate, which leads to myopia; (5 - Simulink model): model of genetically pre-programmed signaling and blur feedback components that allows for different input functions to simulate experimental manipulations that result in hyperopia, emmetropia, and myopia. These model simulation programs (available upon request) can provide a useful tutorial for the general scientist and serve as a quantitative tool for researchers in eye growth and myopia.

In Vivo Anastomosis and Perfusion of a Three-Dimensionally-Printed Construct Containing Microchannel Networks.

The field of tissue engineering has advanced the development of increasingly biocompatible materials to mimic the extracellular matrix of vascularized tissue. However, a majority of studies instead rely on a multiday inosculation between engineered vessels and host vasculature rather than the direct connection of engineered microvascular networks with host vasculature. We have previously demonstrated that the rapid casting of three-dimensionally-printed (3D) sacrificial carbohydrate glass is an expeditious and a reliable method of creating scaffolds with 3D microvessel networks. Here, we describe a new surgical technique to directly connect host femoral arteries to patterned microvessel networks. Vessel networks were connected in vivo in a rat femoral artery graft model. We utilized laser Doppler imaging to monitor hind limb ischemia for several hours after implantation and thus measured the vascular patency of implants that were anastomosed to the femoral artery. This study may provide a method to overcome the challenge of rapid oxygen and nutrient delivery to engineered vascularized tissues implanted in vivo.

Minimally invasive mitral valve surgery is associated with equivalent cost and shorter hospital stay when compared with traditional sternotomy.

OBJECTIVE: Mitral valve surgery is increasingly performed through minimally invasive approaches. There are limited data regarding the cost of minimally invasive mitral valve surgery. Moreover, there are no data on the specific costs associated with mitral valve surgery. We undertook this study to compare the costs (total and subcomponent) of minimally invasive mitral valve surgery relative to traditional sternotomy. METHODS: All isolated mitral valve repairs performed in our health system from March 2012 through September 2013 were analyzed. To ensure like sets of patients, only those patients who underwent isolated mitral valve repairs with preoperative Society of Thoracic Surgeons scores of less than 4 were included in this study. A total of 159 patients were identified (sternotomy, 68; mini, 91). Total incurred direct cost was obtained from hospital financial records. RESULTS: Analysis demonstrated no difference in total cost (operative and postoperative) of mitral valve repair between mini and sternotomy ($25,515 ± $7598 vs $26,049 ± $11,737; P = .74). Operative costs were higher for the mini cohort, whereas postoperative costs were significantly lower. Postoperative intensive care unit and total hospital stays were both significantly shorter for the mini cohort. There were no differences in postoperative complications or survival between groups. CONCLUSIONS: Minimally invasive mitral valve surgery can be performed with overall equivalent cost and shorter hospital stay relative to traditional sternotomy. There is greater operative cost associated with minimally invasive mitral valve surgery that is offset by shorter intensive care unit and hospital stays.

HBV polymerase overexpression due to large core gene deletion enhances hepatoma cell growth by binding inhibition of microRNA-100.

Different types of hepatitis B virus (HBV) core gene deletion mutants were identified in chronic hepatitis B patients. However, their clinical roles in different stages of natural chronic HBV infection remained unclear. To address this issue, HBV core genes were sequenced in three gender- and age-matched patient groups diagnosed as chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC), respectively. Functional analysis of the identified mutants was performed. A novel type of large-fragment core gene deletion (LFCD) was identified exclusively in HCC patients and significantly associated with unfavorable postoperative survival. The presence of LFCDs resulted in generation of precore-polymerase fusion protein or brought the polymerase reading frame under direct control of HBV precore/core promoter, leading to its over-expression. Enhanced cell proliferation and increased tumorigenicity in nude mice were found in hepatoma cells expressing LFCDs. Because of the epsilon-binding ability of HBV polymerase, we hypothesized that the over-expressed polymerase carrying aberrant amino-terminal sequence could bind to cellular microRNAs. Screening of a panel of microRNAs revealed physical association of a precore-polymerase fusion protein with microRNA-100. A binding inhibition effect on microRNA-100 by the precore-polymerase fusion protein with up-regulation of its target, polo-like kinase 1 (PLK1), was discovered. The binding inhibition and growth promoting effects could be reversed by overexpressing microRNA-100. Together, HCC patients carrying hepatitis B large-fragment core gene deletion mutants had an unfavorable postoperative prognosis. The growth promoting effect was partly due to polymerase overexpression, leading to binding inhibition of microRNA-100 and up-regulation of PLK1.