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Due to their physiological relevance, multicellular 3D spheroids are actively replacing standard 2D monolayer cultures. How spheroids are formed through the assembly of individual cells in natural fibrous environments that include a mix of diameters and architectures in vivo remains unknown. Here, we demonstrate that the spontaneous assembly of human vasa vasorum-derived pericytes in 3D spheroids depends on the fiber diameter and network architecture. A parallel arrangement of suspended fibers of all tested diameters (200, 500, and 800 nm) leads to the formation of spheroids, while on crosshatch networks, spheroid assembly on larger diameters is absent. The design of fibrous networks of a mix of diameters and architectures leads to the patterning of spheroids in desired locations. Fiber remodeling in parallel arrangements serves as force sensors providing mechanical insights into the assembly dynamics of spheroids and subsequent cell sprouting from spheroids. Translocation and merger of spheroids occur predominantly on parallel fiber networks, while on crosshatch networks, a cellular exchange is observed between spheroids connected with remodeled fibers. Rho kinase inhibition by Y27632 and subsequent wash-off leads to spheroid disintegration and reassembly, thus, highlighting the role of cell contractility in the assembly and integrity of 3D spheroids. Overall, using extracellular mimicking fiber networks of varying diameters and architectures, we report new insights into the 3D dynamics of spheroids which may inform pericyte’s role in vasculogenesis, and (patho)physiological angiogenesis

OBJECTIVE We sought to evaluate the feasibility and safety of carotid access transcatheter aortic valve replacement (TAVR) by performing a meta-analysis of published cases. BACKGROUND Several case series and regional data have provided initial basis for carotid access TAVR in patients with prohibitive femoral approach. We performed this meta-analysis to provide further evidence of feasibility and safety of carotid TAVR. METHODS We searched PubMed, EMBASE, CINAHL, and Cochrane CENTRAL for any study on carotid access TAVR involving ⩾5 patients since inception till March 1, 2020. Random-effects model was used to compute overall effects. The outcomes analyzed were all-cause mortality, Transient ischemic attack (TIA)/stroke, need for permanent pacemaker (PPM) implantation, pericardial tamponade, access site complications, major bleeding, and length of stay. RESULTS There was a total of 17 retrospective studies (n = 2082) with a median follow-up of 1 month. Mean age of the patient was 80 years. Mean Euroscore and STS scores were 15 ± 6.2 and 7.9 ± 3.3, respectively. The procedural success rate was 99%. The rate of all-cause mortality was 6.7% (range 4.6-9.7%, p

Improvements in health indexes over last few decades have been accompanied by escalating health care costs, with spending on health in the near-term projected to be nearly 20% ([1][1]). All major stakeholders agree that this growth in health care spending requires moderation to ensure sustainable

Phrenic and hypoglossal nerve pacing therapies have shown benefit in sleep apnea. We sought to analyze the role of pacing therapies in sleep apnea and their impact on heart failure. A comprehensive literature search in PubMed and Google Scholar from inception to August 5, 2019, was performed. A meta-analysis was performed using fixed effects model to calculate mean difference (MD) with 95% confidence interval (CI). Six studies were eligible and included 626 patients, of whom 334 were in the control arm and 393 were in the experimental arm. Phrenic nerve pacing (MD − 23.20 events/h, 95% CI − 27.96 to − 18.44, p

There are paucity of data on gender-based differences in the effect of thrombocytopenia and coronary heart disease (CHD) towards development of acute coronary syndrome (ACS). We used National Inpatient Sample (NIS) database of the United States to assess the gender-based differences in the association of thrombocytopenia with CHD and the impact of thrombocytopenia on mortality, length of stay and hospitalization costs on ACS subgroup of CHD. Our analysis found that thrombocytopenia was associated with increased odds of CHD on univariate (odds ratio [OR] 1.31 (95% CI 1.30–1.32) p

Objectives This study aimed to investigate the feasibility and safety of left atrial appendage occlusion (LAAO) procedures in patients with persistent left atrial appendage (LAA) thrombus. Background The left atrial appendage (LAA) is the most common site of thrombus formation in patients with nonvalvular atrial fibrillation (AF). Oral anticoagulation (OAC) is used to prevent and treat AF-related thrombus. However, a significant proportion of patients may not be eligible for long-term OAC therapy. In many cases, OAC may fail to resolve the thrombus. Left atrial appendage occlusion (LAAO) may be a potential option in such cases. Major LAAO studies have excluded patients with LAA thrombus, and it is not known whether LAAO procedures in the presence of LAA thrombus is feasible and safe. Methods This was a systematic review of patient-level data of all published cases of LAAO in the presence of LAA thrombus. Results There was a total of 58 patients included in the study. Most of the patients had a distally located thrombus in the LAA. All cases underwent successful implantation of LAAO devices with some procedural modifications. Amulet was the most commonly used device (50%). A cerebral protection device was used in 17 (29%) patients, and procedural transesophageal echocardiography was used in most of the cases. One stroke (1.7%) and 2 (3.4%) device-related thromboses were noted during the mean follow-up of 3.4 ± 7 months. Conclusions Percutaneous LAAO procedures appear to be feasible in patients with a distally located persistent LAA thrombus when performed by experienced operators with some technical modifications. Further studies are required to determine the long-term safety and efficacy of this approach.

The use of rotational atherectomy (RA) in percutaneous coronary intervention (PCI) of acute coronary syndrome (ACS) is considered relatively contraindicated. There have been several observational studies showing RA use in ACS, however, no systemic studies have been undertaken. We sought to evaluate the feasibility and outcomes of RA PCI in ACS by performing a meta-analysis.We searched PUBMED, EMBASE, CINAHL, and Cochrane Central Register of Clinical Trials for any studies that evaluated the role of RA PCI in ACS. The outcomes analyzed were all-cause mortality, cardiac mortality, short and long-term major adverse cardiac events (MACE), procedural complications and cardiac perforations.There was a total of 8 retrospective studies with a total population of 1237 with a median follow up of 23 months. The median age of the included patient was 73. Angiographic success rate was 97.4%. The rate of all-cause mortality and cardiac mortality were 5% (range 1-12%, p0.001, IOur results show that RA PCI is feasible in ACS with comparable procedural complications and short-term MACE, but with a higher long-term MACE rate compared to RA PCI in routine cases.

Locus control regions (LCRs), cis-acting, noncoding regulatory elements with strong transcription-enhancing activity, are conserved in sequence and organization, and exhibit strict gene-specific expression. LCRs have been reported and studied in several mammalian gene systems, signifying that they play an important role in eukaryotic gene expression control. Their highly regulated, stable, and precise levels of expression have made them a strong candidate for use in gene therapy vectors. In this study, we attempted to determine the unique signatures of human LCRs by analyzing a data set of LCR sequences for the presence of motifs through systematic bioinformatics approach. Using web-based regulatory sequence analysis tools (RSAT), motif-based analysis was performed. Detected significant motifs were analyzed further for their identity using Tomtom tool. RSAT analysis revealed that significant motifs are existent within the LCRs. Identity analysis using Tomtom showed that detected significant motifs were comparable with known transcription factor (TF) binding sites and the top scoring motifs belong to zinc finger-containing proteins, an important group of proteins involved in a variety of cellular activities. Correspondence to segment of known motif indicates the biological relevance of the detected motifs. Motif-based analysis is valuable for analyzing the various characteristics of sequences, notably TF binding models in this study. Owning to their unique expression control abilities, LCRs form an important component of integrating vectors, therefore identification of unique signatures present within LCR sequences will be instrumental in the design of new generation of regulatory elements containing LCR sequences.

Case studies reporting real-world experiences with survey falsification are uncommon. In this article, we document the experience of a panel survey in India that produced TV viewing estimates (“TV ratings”) where external parties were illegitimately trying to influence respondents’ behavior. The usual method to detect possible falsifications was that of analysts poring through data to find suspicious viewing patterns. Here, we develop a method using multilevel models and illustrate its use in the detection of an actual incident. We report how the model-based method was used to direct on-ground investigations that ultimately supported our analytic inferences. The model-based method offers four advantages over the usual method. First, by approximating an interpenetrated sample, the model simultaneously controls for several household characteristics. Second, Empirical Best Linear Unbiased Predictors (EBLUPs) of random effects can be examined separately at both the household and interviewer level, thus suggesting where further investigation efforts should be directed. Third, the method is faster and more objective than the usual method. Fourth, the method is easily implemented and can provide regular quality control for survey organizations.

CRISPR/Cas9, once discovered as an adaptive immune system in bacteria, has emerged as a disruptive technology in the field of genetic engineering. Technological advancements in the recent past has enhanced the applicability of CRISPR/Cas9 tool for gene editing, gene therapies, developmental studies and mutational analysis in various model organisms. Zebrafish, one of the excellent animal models, is preferred for conducting CRISPR/Cas9 studies to assess the functional implication of specific genes of interest. CRISPR/Cas9 mediated gene editing techniques, such as, knock-out and knock-in approaches, provide evidences to identify the role of different genes through loss-of-function studies. Also, CRISPR/Cas9 has been proved to be an efficient tool for designing disease models for gene expression studies based on phenotypic screening. The present chapter provides an overview of CRISPR/Cas9 mechanism, different strategies for DNA modifications and gene function analysis, highlighting the translational applications for future prospects, such as screening of drug toxicity and efficacy.

Antiplatelet agents are the standard of practice in the management of atherosclerosis and acute coronary syndrome. In contrast to the available antiplatelet agents, vorapaxar represents a novel mechanism of action. It is an antagonist of the platelet protease-activated receptor-1 and inhibits thrombin-induced and thrombin receptor agonist peptide-induced platelet aggregation. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50) trial led to the approval of vorapaxar by the Food and Drug Administration and European Medicines Agency for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral arterial disease. TRA 2°P-TIMI 50 trial showed that the use of vorapaxar (2.5 mg once/daily) in addition to standard dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor was effective in the secondary prevention of recurrent thrombotic events among patients with previous atherothrombosis, particularly in patients with prior MI; at the expense of an increase in major bleeding. Another recently published Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor (VORA-PRATIC) study showed that among post-MI patients treated with potent P2Y12 inhibitors (prasugrel or ticagrelor), vorapaxar reduced platelet-driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin. The current review summarizes an up-to-date literature on pharmacokinetics, pharmacodynamics, and clinical efficacy of vorapaxar and proposes future directions of research.

The emergence of Next Generation Sequencing (NGS), such as DNA, RNA and other small RNA sequencing technologies, gave rise to a huge amount of raw data on a massive scale. To analyse that data and to obtain the biological interpretation as a challenging act, advancements in computational biology and bioinformatics applications emerged as the need of the hour. RNAseq accounts for exploration of comprehensive expression profile of genes and quantifies the presence of RNA content in the biological sample. In addition to this, RNAseq also provides information for alternative splice variants, novel gene identification, differentially expressing genes, etc. The workflow for RNAseq data analysis requires quality check of the data, mapping onto a reference genome/transcriptome, read quantification, differential expression analysis and functional annotation. Various tools and softwares with different algorithms have been developed to provide biological understanding of the data and to meet the demands of the analyst. An overview of the tools and softwares has been provided in the chapter that can be exploited to analyse the data for different investigations. Also, a glimpse of other RNAseq techniques such as single cell RNAseq and small RNA sequencing has been discussed as an introduction to newer forms of RNA sequencing.

CRISPR/Cas9, once discovered as an adaptive immune system in bacteria, has emerged as a disruptive technology in the field of genetic engineering. Technological advancements in the recent past has enhanced the applicability of CRISPR/Cas9 tool for gene editing, gene therapies, developmental studies and mutational analysis in various model organisms. Zebrafish, one of the excellent animal models, is preferred for conducting CRISPR/Cas9 studies to assess the functional implication of specific genes of interest. CRISPR/Cas9 mediated gene editing techniques, such as, knock-out and knock-in approaches, provide evidences to identify the role of different genes through loss-of-function studies. Also, CRISPR/Cas9 has been proved to be an efficient tool for designing disease models for gene expression studies based on phenotypic screening. The present chapter provides an overview of CRISPR/Cas9 mechanism, different strategies for DNA modifications and gene function analysis, highlighting the translational applications for future prospects, such as screening of drug toxicity and efficacy.

Coding sequences, making up only a very small percentage of human genome, have been relatively well studied than regulatory sequences. Hence, importance of majority of the elements and sequences that control the regulation and expression of protein-coding genes remains unknown. To realize the role of regulatory sequences in health and diseases, structural and regulatory information needs to be transcribed from them to be incorporated with the protein-coding counterpart. This will certainly provide an opportunity to realize the information generated from non-coding sequences in basic and clinical research. With advancements in computational biology and bioinformatics tools and techniques, web-based bioinformatics tools provide ample opportunities to study regulatory elements which help understand their biological relevance especially when their dysregulation can result in disease. Analysis of regulatory sequences via powerful online approaches has given a boost to comparative genomics studies enabling accurate annotations of sequences under study. This chapter provides a bird’s eye view of web-based online approaches for analysing regulatory sequences in mammalian genomes. As our knowledge on involvement of regulatory regions in diseases in increasing, it is only rationale to develop additional sophisticated user-friendly bioinformatics tools to analyse the regulatory sequences for the identification of unique regions or novel variants potentially involved in the pathogenesis of disease.

Background: We have recently shown that PTSD/TBI takes an especially devastating toll on America’s veterans and their families with mental, physical and financial ramifications and poor clinical outcomes (Thakur et al. Epidemiology (Sunnyvale) 2018; 8:353). Patients with PTSD were found to have higher rates of cardiovascular symptoms, hospitalizations and mortality. Whereas electrocardiographic abnormalities, arrhythmias and ventricular dysfunction have been reported in patients with TBI. Association of PTSD/TBI with Myocardial Infarction (MI) is not well studied; the objective of this study was to examine the relationship between PTSD/TBI and MI in a large patient population. Methods: This retrospective study used national data from Veterans Administrations Informatics and Computing Infrastructure (VINCI). Propensity score analysis was performed to obtain matched pairs of (1) Non-PTSD/TBI vs. PTSD (2) Non-PTSD/TBI vs. TBI. Confounding variables used for matching were patients’ demographics and co-morbidities. Cox proportional hazard regression analysis was conducted on matched pairs to determine the relationship between PTSD, TBI and incidence of MI. Kaplan-Meier curves were plotted to compare the time to development of incident MI among the groups. Relationships between variables were examined using chi-square tests, t-tests and non-parametric tests. Results: The risk of new-onset MI was significantly higher for patients with PTSD/TBI when compared with their counterparts without PTSD/TBI. Risk of MI with TBI (HR=2.687, CI 2.546-2.835, P Conclusion: There is a significant increase in the incidence of MI in patients with a diagnosis of PTSD or TBI. Further studies are needed to formulate clinical guidelines to risk stratify and intervene to help reduce the incidence of MI in this patient population.

Background: Electrophysiological procedures such as epicardial ventricular tachycardia ablation and Lariat left atrial appendage ligation that involve the epicardial space are typically associated with significant postoperative pain due to mechanical irritation and associated inflammation. There is an unmet need for an effective pain management strategy in this group of patients. We studied how this impacts patient comfort and duration of hospitalization and other associated comorbidities related to pericardial access. Methods: This is a multicenter retrospective study including 104 patients who underwent epicardial ventricular tachycardia ablation and Lariat left atrial appendage exclusion. We compared 53 patients who received postprocedural intrapericardial liposomal bupivacaine (LB)+oral colchicine (LB group) and 51 patients who received colchicine alone (non-LB group) between January 2015 and March 2018. Results: LB was associated with significant lowering of median pain scale at 6 hours (1.0 [0–2.0] versus 8.0 [6.0–8.0], P P P Conclusions: Addition of intrapericardial postprocedural LB to oral colchicine in patients undergoing epicardial access during ventricular tachycardia ablation or Lariat procedure is associated with significantly decreased numeric pain score up to 48 hours compared with colchicine alone. It is also associated with significantly shorter length of hospital stay without an increase in the risk of adverse events.

This case is about a young man with no significant medical history who presents with significant premature ventricular contractions (PVC) and severe heart failure. His workup revealed intense myocardial inflammation in PET scan with negative coronary angiogram. Endomyocardial biopsy proved it to be giant cell myocarditis. Patient was treated with immunosuppressive therapy including cyclosporine, rituximab and steroid together with guideline-directed medical therapy for heart failure. This resulted in marked improvement with near resolution of inflammation and normalization of ejection fraction and significant marked improvement in PVC burden.

Patients with long standing persistent atrial fibrillation who have failed prior ablations and anti-arrhythmic drugs are often treated with surgical ablation. There is wide inter-institution and inter-individual variation in surgical procedure in terms of creation of lesion and ablation. We describe a 70-year old gentleman who had long-standing atrial fibrillation and has failed prior multiple antiarrhythmic medications as well as ablation. He successfully underwent thoracoscopic surgical ablation and became arrhythmia free for 6 months when he was seen to develop atrial tachycardia (AT). Existing data on post-surgical AF ablation suggests wide variability in the locations of AT circuits in both atriums probably reflecting disparate arrhythmia substrate and difference in surgical ablation techniques. In our case, activation site was demonstrated on the posterior wall with earliest activation between mitral annulus and left inferior pulmonary vein. Focal ablation of the activation site terminated the tachycardia in our patient.

Atrial fibrillation and flutter are well-known causes of stroke. Whether other atrial arrhythmias categorized as paroxysmal supraventricular tachycardia (PSVT) are associated with stroke is less clear. We aimed to evaluate the association of PSVT with ischemic and embolic stroke and its impact on short-term outcomes in hospitalized stroke patients. National Inpatient Sample database of the USA was used to assess the association of PSVT with ischemic stroke. Atrial fibrillation and flutter were excluded to minimize the confounding effects. The association of PSVT with stroke was evaluated using univariate and multivariate analysis. Subgroup analyses by gender, age, and stroke type were also performed. PSVT was associated with increased odds of overall ischemic stroke in univariate [OR 1.18 (95% CI 1.09–1.27) p < 0.001] analysis. No such association was observed in multivariate analysis (OR 1.06 (95% CI 0.98–1.14) p = 0.1) or with subgroup analysis by gender and age. However, PSVT was associated with embolic stroke in both univariate (OR 2.01 (95%CI 1.67–2.43, p < 0.001) and multivariate analysis (OR 1.7 (95%CI 1.4–2.14) p < 0.001) as well as in subgroup analyses by gender and age. Furthermore, the presence of PSVT was associated with increased mortality in embolic stroke (OR 4.11, CI 2.29 to 7.39, p < 0.001) and increased total hospital cost and length of hospital stay in all stroke types. PSVT is independently associated with higher prevalence of embolic stroke but not with overall ischemic stroke. Patients with embolic stroke in the presence of PSVT have worse in-hospital outcomes with increased mortality.

A 75-year old female with atrial fibrillation/tachycardia with history of failed previous antiarrhythmic therapy and ablations was found to have atrial tachycardia originating from left atrial appendage. Endocardial ablation of the arrhythmogenic area resulted in success for a short-term period with recurrence at 4-month post-ablation. An underrecognized site of focal atrial tachycardia, AT originating from LAA is often seen during atrial fibrillation ablation. Endocardial ablation of LAA tachycardia involves several challenges. After recurrence with endocardial ablation, we decided to pursue LARIAT suture ligation for her left atrial appendage that abolished the tachycardia.

Background Transradial access (TRA) is preferred for coronary angiography (CA) or percutaneous coronary intervention due to reduced access-related complications, and mortality especially for patients with ST elevation myocardial infarction. Radial artery occlusion (RAO) is a known complication of TRA, and precludes its use as a future access site, conduit for coronary artery bypass grafting or for hemodialysis fistula placement. Although a standard dose (SD) heparin of 5000 Units is used during TRA, the risks of RAO and hematoma compared to lower dose (LD) remain unclear. To compare the risks of RAO and hematoma using SD vs. LD heparin after CA through TRA, we performed a meta-analysis of randomized controlled trials (RCT). Methods We searched PubMed, EMBASE, CINAHL and CENTRAL for RCTs since inception through 06/30/2017 and used random effects model for analysis. The outcomes analyzed were RAO, hematoma formation and radial artery compression time (RACT). Results We identified a total of 6 RCTs with a total of 2239 patients. SD heparin resulted in a trend toward a lower risk of RAO [4.2% vs. 10.7%; risk ratio (RR): 0.40, 95% confidence interval (CI): 0.16–1.0; P = 0.05], a trend toward increased risk of hematoma [2.2% vs. 1.1%; 1.83 (0.91–3.66); P = 0.09], and a longer duration of RACT [mean difference: 9.64 min (4.01–15.28); P = 0.0008] compared to LD. Conclusions The current meta-analysis showed a trend towards reduction in the risk of RAO with the use of standard dose heparin. Larger randomized trials should explore the appropriate dosing of heparin to prevent radial artery occlusion.

The benefit of optical coherence tomography (OCT) guidance in percutaneous coronary intervention (PCI) is unclear. We aimed to assess the incremental value of adding OCT to coronary angiography in PCI by meta-analytic technique. We searched PubMed, EMBASE, Cochrane, Scopus and relevant references for randomized studies (inception through January 5, 2018 without language restrictions) and performed meta-analysis using random effects model. Major adverse cardiac events (MACE), all-cause mortality, myocardial infarction, target vessel revascularization, stent thrombosis, fluoroscopic time, contrast volume, and procedural side effects were the measured outcomes. Five randomized studies with a total population of 931 were analyzed. There was no difference in MACE between angiography plus OCT and angiography alone arms (2.5 vs. 2.0% OR 1.26; 95% CI 0.40–3.99; P = 0.69; I2 = 5%). Two groups were not different in terms of all-cause mortality (0.2 vs. 0% OR 3.03; 95% CI 0.12–75; P = 0.5; I2 = not applicable), myocardial infarction (1 vs. 0.2% OR 2.21; 95% CI 0.39–12.49; P = 0.3; I2 = 0%), target vessel revascularization (1.6 vs. 1.2% OR 1.36; 95% CI 0.4–4.4; P = 0.6; I2 = 0%), and stent thrombosis (0.2 vs. 0.5% OR 0.7; 95% CI 0.11–4.51; P = 0.7; I2 = 0%). OCT group had significantly higher fluoroscopic time and contrast volume. Our meta-analysis shows that the addition of OCT to angiography for PCI guidance is not associated with lower MACE, all-cause mortality, myocardial infarction, target vessel revascularization, or stent thrombosis. It is associated with longer fluoroscopic time and higher contrast volume.

Background Traditionally the right ventricular (RV) pacing lead is placed in the RV apex in cardiac resynchronization therapy (CRT). It is not clear whether nonapical placement of the RV lead is associated with a better response to CRT. We aimed to perform a meta‐analysis of all randomized controlled trials (RCTs) that compared apical and nonapical RV lead placement in CRT. Methods We searched PubMed, EMBASE, Cochrane, Scopus, and relevant references for studies and performed meta‐analysis using random effects model. Our main outcome measures were all‐cause mortality, composite of death and heart failure hospitalization, improvement in ejection fraction (EF), left ventricle end‐diastolic volume (LVEDV), left ventricle end‐systolic volume (LVESV), and adverse events. Results Seven RCTs with a total population of 1641 patients (1199 apical and 492 nonapical) were included in our meta‐analysis. There was no difference in all‐cause mortality (5% vs 4.3%, odds ratio (OR) = 0.86; 95% confidence interval (CI) 0.45‐1.64; P = .65; I 2 = 11%) and a composite of death and heart failure hospitalization (14.2% vs 12.9%, OR = 0.92; 95% CI: 0.61‐1.38; P = .68; I 2 = 0) between apical and nonapical groups. No difference in improvement in EF (Weighted mean difference (WMD) = 0.37; 95% CI: −2.75‐3.48; P = .82; I 2 = 68%), change in LVEDV (WMD = 3.67; 95% CI: −4.86‐12.20; P = .40; I 2 = 89%) and LVESV (WMD = −1.20; 95% CI: −4.32‐1.91; P = .45; I 2 = 0) were noted between apical and nonapical groups. Proportion of patients achieving >15% improvement in EF was similar in both groups (OR = 0.85; 95% CI: 0.62‐1.16; P = .31; I 2 = 0). Conclusion In patients with CRT, nonapical RV pacing is not associated with improved clinical and echocardiographic outcomes compared with RV apical pacing.

BACKGROUND Long-term aspirin use in cardiovascular disease prevention may result in gastrointestinal bleeding. Although proton pump inhibitors (PPI) have been shown to reduce the risks of peptic ulcers and dyspeptic symptoms in long-term aspirin users in the randomized controlled trials, there are safety concerns about the long-term use of PPI. STUDY QUESTION What is the safety and efficacy of PPI in patients using aspirin in long term for prevention of cardiovascular diseases and stroke? METHODS We searched MEDLINE, EMBASE, CENTRAL, CINAHL, ProQuest, and relevant references from inception through February 2015, and used random-effects model for meta-analysis. RESULTS A total of 10 publications from 9 studies (n = 6382) were included in the meta-analysis. Compared with control, PPI reduced the risks of peptic ulcers [risk ratio (RR): 0.19; 95% confidence interval: 0.13-0.26; P < 0.00001], gastric ulcers [0.24 (0.16-0.35); P < 0.00001], duodenal ulcers [0.12 (0.05-0.29); P < 0.00001], bleeding ulcers [0.22 (0.10-0.51); P = 0.0004], and erosive esophagitis [0.14 (0.07-0.28); P < 0.00001]. PPI increased the resolution of epigastric pain [1.13 (1.03-1.25); P = 0.01], heartburn [1.24 (1.18-1.31); P < 0.00001], and regurgitation [1.26 (1.13-1.40); P < 0.0001], but did not increase the risks of all-cause mortality [1.72 (0.61-4.87); P = 0.31], cardiovascular mortality [1.80 (0.59-5.44); P = 0.30], nonfatal myocardial infarction/ischemia [0.56 (0.22-1.41); P = 0.22], ischemic stroke/transient ischemic attack [1.09 (0.34-3.53); P = 0.89] and other adverse events. CONCLUSIONS The PPI seems to be effective in preventing peptic ulcers and erosive esophagitis and in resolution of dyspeptic symptoms without increasing adverse events, cardiac risks or mortality in long-term aspirin users.

B-cell translocation gene 3 (BTG3), recognized as a member of an antiproliferative B-cell translocation gene/Transducer of ErbB2 (BTG/Tob) gene family, is a downstream target of p53 and is induced upon genotoxic stress in a p53 and Checkpoint kinase 1 (CHK1), a vital checkpoint kinase which contributes significantly in cell survival and cell cycle checkpoints, dependent manner. Post-translational modifications of CHK1 (phosphorylation and ubiquitination) facilitated by interaction with BTG3 have been observed suggesting their possible role in tumorigenesis, although the underlying mechanisms are unclear. Methylation, as one of the types of post-translational modifications, is a critical event during cell cycle checkpoint controls and DNA damage repair. Here, for the first time, it is reported that overexpression of BTG3 vividly enhances the methylation of CHK1. Expression of CHK1 was detected in a cancer cell line in this study. This work also reveals the significant role of the kinase domain of CHK1 for BTG3 facilitated methylation as BTG3 overexpression only promoted the methylation of wild type CHK1 but failed to promote the methylation of CHK1 mutants which were impaired for their kinase domain. This novel finding would therefore greatly enhance our understanding of the mechanisms underlying interactions between important cancer biomarkers.

Intracardiac echocardiography (ICE) is increasingly common among periprocedural imaging modalities used during complex cardiac procedures. We sought to perform a meta-analysis comparing transesophageal echocardiography (TEE) and ICE in endocardial left atrial appendage occlusion (LAAO). We searched PubMed and Google Scholar regarding abstracts and manuscripts using keywords: atrial fibrillation, left atrial appendage occlusion, Watchman, Amplatzer Cardiac Plug, Amulet, intracardiac echocardiography, and transesophageal echocardiography from their inception to July 12, 2019. Data extraction was performed using standard form for the following: title, year of publication, sample size, comorbid conditions, LAAO device, type of pre-procedural imaging, intraprocedural imaging, and clinical outcomes including the following: acute procedural success, fluoroscopy, and total procedure time and complications. A total of 42 relevant studies were screened resulting in inclusion of 8 observational studies comparing TEE and ICE in endocardial LAAO. Outcomes assessed including procedural success (RR 1.00, 95% CI (0.97–1.03, p = 0.98)), complications (RR 0.77, 95% CI (0.52 to 1.15, p = 0.20)), fluoroscopy time (mean difference − 0.40, 95% CI (−3.12–2.32, p = 0.77)), and procedural time (mean difference − 8.02, 95% CI (−22.81 to 6.76, p = 0.29)) were found to be similar between both groups. While TEE is the gold standard for perioperative imaging with LAAO, ICE is a feasible and safe alternative that reduces exposure to general anesthesia and associated potential risks.

Leadless pacemaker (LP) extraction is a relatively new field with limited operator experience. We sought to report a comparison of retrieval process for Nanostim vs Micra transcatheter LPs. The list of retrievals for the Micra transcatheter pacemaker system (TPS) was obtained from Medtronic whereas Nanostim data was obtained from centers that participated in the Leadless II study. Details of retrieval such as indication, days post implantation, complications, and post procedure device management were obtained from the manufacturer database for each site, and any missing details were obtained from individual operators. Extractions performed on the same day were labeled as “Early” and thereafter were labeled as “Late.” A total of 113 retrievals were attempted (73 in Nanostim and 40 in Micra TPS). The most common reasons for retrieval were battery advisory and inadequate pacing threshold (n = 16) for Nanostim and Micra, respectively. Success rate in Nanostim group was around 90% (66/73) compared with 100% in Micra group (p = 0.049). Late retrieval occurred in 50% of Micra TPS cases (20/40) compared with 100% of Nanostim LP cases. Median time to extraction was 46 days for Micra TPS and 256 days for Nanostim LP (p

Left atrial (LA) strain and strain rate (SR) analysis by two-dimensional speckle tracking echocardiography is a novel way of LA function assessment. From prior study, we know that LA appendage closure with LARIAT appears to improve LA function. The purpose of this study was to assess the impact of LAA closure via Watchman device on LA function via strain and volumetric analyses using two-dimensional speckle tracking echocardiography (2D-STE). Twenty-five patients who underwent Watchman device implantation (WDI) were included. LA function parameters (volumetric, strain indices) were calculated from apical four chamber views with the reference point set at QRS using 2D-STE before and after WDI. LA expansion index, strain and strain rate during ventricular systole represent LA reservoir function. Passive emptying fraction, strain and strain rate during early ventricular diastole represent LA conduit function. Mean age was 76 ± 6.9 years with 60% males. There was significant improvement in conduit function (LA passive emptying fraction; post 28.6 (21.9–35.9) vs pre 21.0 (13.8–34.7), p = 0.032), reservoir function (LA expansion index; post 75.3 (52.3–98.0) vs pre 58.1 (37.8–85.2), p = 0.026), and booster function (LA active emptying fraction; post 13.3 (9.7–29.9) vs pre 12.6 (8.8–25.5), p = 0.04) by volumetric indices. No significant improvement was noted with strain indices in conduit function (SRe; post − 0.56 (0.43–0.93) vs pre − 0.58 (0.46–0.87); p = 0.518) and reservoir function (SRs; post + 0.58 (0.28–0.40) vs pre + 0.52 (0.35–0.86); p = 0.851). WDI resulted in discrepancy of volumetric and strain indices in LA function assessment.

Endocardial LAAO has been increasingly utilized in atrial fibrillation (AF) patients who are not suitable for long term oral anticoagulation. While overall procedural complications have decreased, rare complications like contiguous vessel and valve injury may be more frequently seen in the future with increase in the procedure volume. We performed a systematic search using predefined terms which reviewed all cases published in literature of contiguous vessel (pulmonary artery, pulmonary vein and left circumflex artery) and mitral valve injury caused by LAAO devices. Our results showed that Amplatzer Cardiac Plug (ACP) and Amplatzer Amulet devices were the most commonly used devices. Pulmonary artery perforation was the most commonly seen collateral vessel injury associated with LAAO. Close proximity of left atrial appendage to pulmonary artery was noted in all cases of pulmonary artery injury. Pulmonary artery injury commonly manifests as pericardial tamponade with hemodynamic collapse and is often fatal. Most common denominator of all the reviewed cases was the presence of an oversized LAAO device. In conclusion, collateral vessels and valve injury can be seen after LAAO mostly with double lobe devices such as ACP or Amulet. Increased awareness by the operators along with proper imaging and investigations could potentially mitigate such rare complications associated with LAAO.

Transseptal puncture is a routinely performed interventional cardiology procedure for an array of cardiac diseases. We aimed to review the current status of available devices and techniques of transseptal puncture with consideration to specific interventions. Except for a few modifications, devices for transseptal puncture technique has not changed much compared to when it was first described almost 60 years ago. For difficult transseptal puncture, a few newer techniques such as radio frequency needle puncture system have been used but there is lack of robust clinical study. Advanced imaging, such as intracardiac echocardiography and transesophageal echocardiography, has been found to make transseptal puncture safer. A new transseptal approach that incorporates 3D non-fluoroscopic catheter tracking systems has shown promising results in two human studies. While various modifications in the transseptal technique tailored to the specific interventions have improved procedural safety, further improvement in existing devices focusing on distinct procedure might be needed in the future.

Background Direct current cardioversion (DCCV) is a common rhythm control strategy in patients with symptomatic atrial fibrillation or flutter. There is no long-term data regarding the safety of DCCV in patients with endocardial left atrial appendage occlusion (LAAO) devices. Objectives The purpose of this study was to assess the feasibility and safety of DCCV in patients with an LAAO device. Methods This multicenter retrospective study included 148 patients with an LAAO device who underwent DCCV for symptomatic atrial fibrillation or atrial flutter. Results The average age of the included patients was 72 ± 7 years and 59% were men. All patients (100%) had a transesophageal echocardiogram prior to DCCV. Device-related thrombus was seen in 2.7%. They were all successfully treated with oral anticoagulation (OAC) and were able to undergo DCCV after 6 to 8 weeks. DCCV restored sinus rhythm in all patients. None of the patients had DCCV-related thromboembolic complications. A total of 22% of patients were newly started on OAC after DCCV. There was no difference in DCCV-related complications between patients treated with or without OAC post-DCCV. Patients receiving OAC post-DCCV were found to undergo cardioversion at an earlier time after implantation (3.6 months [interquartile range (IQR): 0.7 to 8.6 months] vs. 8.6 months [IQR: 2.5 to 13.3 months]; p = 0.003). Three transient ischemic attacks, unrelated to DCCV, were found during follow-up. During a median follow-up of 12.8 months (IQR: 11.8 to 14.2 months), no device or left atrial thrombosis, device dislodgement, or a new device leak were observed. One patient died during follow-up due to noncardiac cause. Conclusions DCCV is feasible in high-risk AF patients with an LAAO device without the need for oral anticoagulation if pre-procedural transesophageal echocardiography shows good device position, absence of device-related thrombus, and peridevice leak of ≤5 mm. The preliminary results are encouraging, but further large studies are warranted to establish safety.

Left atrial appendage occlusion (LAAO) is a promising alternative for stroke risk reduction in patients with non-valvular atrial fibrillation who are not suitable for long-term oral anticoagulation (OAC). Current practice mandates use of post-procedural OAC for 45 days after WatchmanTM placement during which complete device endothelialization is expected to occur. However, most of the evidence supporting this strategy stem from animal studies. Incomplete device endothelialization are often encountered after 6-weeks of procedure and its therapeutic implications are less clear. Here, we present two cases of incomplete endothelialization after 1.5- and 2-year of Watchman implantation. In one of the cases, we believe that an eccentric mitral regurgitation jet caused shearing force on the Watchman device and impeded with normal endothelialization. In the other case, we found a device related thrombus possibly favored by prothrombotic environment created by lack of endothelialization. Further studies are warranted to find predictors and better diagnostic tool of LAAO endothelialization.

BackgroundTriple therapy (TT) that includes oral anticoagulation and dual antiplatelet therapy is recommended in patients who are on chronic anticoagulation and undergo percutaneous coronary intervention (PCI). The randomized clinical trials (RCTs) comparing the effectiveness and safety of TT compared to double therapy (DT), which consists of an oral anticoagulation and one of the P2Y12 inhibitors, have shown increased risk of bleeding; however, none of the individual studies were powered to show a difference in ischemic outcomes. To compare the clinical outcomes of TT and DT, we performed this meta-analysis of RCTs.MethodsElectronic search of PubMed, EMBASE and Cochrane CENTRAL databases was performed for RCTs comparing TT and DT in patients who were on oral anticoagulation (Vitamin K antagonist or non-vitamin K antagonist oral anticoagulant) who underwent PCI. All-cause and cardiovascular mortality, myocardial infarction (MI), stroke, stent thrombosis (ST) and TIMI major and minor bleeding were the major outcomes.ResultsAn analysis of 5 trials including 10,592 total patients showed that TT, compared to DT, resulted in non-significant difference in risk of all-cause [odds ratio (OR); 1.14;95% confidence interval (CI):(0.80–1.63); P = 0.46) and cardiovascular mortality [1.43(0.58–3.36); P = 0.44], MI [0.88 (0.64–1.21); P = 0.42], stroke [1.10(0.75–1.62); P = 0.63] and ST [0.82(0.46–1.45); P = 0.49]. TT, compared to DT resulted in higher risk of TIMI major bleeding [1.61(1.09–2.37); P = 0.02], TIMI minor bleeding [1.85(1.23–2.79); P = 0.003] and TIMI major and minor bleeding [1.81 (1.38–2.38); P 2 = 52%].ConclusionCompared to DT, the patients receiving TT are at a higher risk of major and minor bleeding with no survival benefit or impact on thrombotic outcomes.

It is not clear whether additional empiric superior vena cava isolation (SVCI) to pulmonary vein isolation (PVI) results in low recurrences of atrial fibrillation. We aimed to perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated role of empiric SVCI in atrial fibrillation ablation. We searched PubMed, EMBASE, Cochrane, Scopus, and relevant references for RCTs (inception April 15, 2016 without language restrictions) and performed meta-analysis using random effects model. Recurrence rates of atrial fibrillations, procedural times, fluoroscopic times, and adverse events were the measured outcomes. Three RCTs with a total population of 526 were analyzed. There was no difference in the recurrence rate between PVI plus SVCI versus PVI alone when comparison was made across all types of AF (39 vs 60; odds ratio 0.68; 95 % CI 0.43–1.07; P = 0.73; I 2 = 0 %). When analysis was restricted only to paroxysmal AF, there was a trend towards low recurrence rate in combination group without statistical significance (19 vs 35, OR 0.54; 95 % CI 0.29–1.00; P = 0.05; I 2 = 0). Similarly, no difference was noted between two groups in procedural (weighted mean difference [WMD] 10.12; 95 % CI −9.84 to 30.08; P = 0.32; I 2 = 85 %) and fluoroscopic time (WMD 4.66; 95 % CI −0.92 to 10.25; P = 0.1; I 2 = 94). Adverse events were similar in both groups. Empiric SVCI does not provide additional benefit to PVI alone for atrial fibrillation ablation.

IL-17 has a role in inflammation in RA, and its levels in joints correlate with disease severity. Multiple RCTs have been performed to study effects of anti-IL-17 agents. The objective of this study was to perform a systematic review and meta-analysis to analyze the efficacy and safety of anti-IL-17 agents in the management of RA. This work is based on a systematic review of studies retrieved by a sensitive search strategy in PubMed, EMBASE and Cochrane CENTRAL from inception through 9/7/15. Study selection criteria were the following: adult patients (age ≥ 18 years) with RAs, random selection of patients for anti-IL-17 therapy and treatment response compared to placebo. We performed systematic literature review per PRISMA guideline and two investigators independently selected seven randomized clinical trials (RCTs) for meta-analysis. We used random effect model calculating odds ratio (OR) and 95 % confidence interval (CI) to measure the efficacy with ACR20/50/70 responses and the safety with adverse events. Seven studies with total of 1226 patients including 905 in anti-IL-17 group and 321 in placebo were included in the meta-analysis. Anti-IL-17 was effective in achieving ACR20 and ACR50 compared to placebo (OR 2.47, 95 % CI 1.29–4.72, P = 0.006, I 2 77 % and OR 2.94, 95 % CI 1.37–6.28, P = 0.005, I 2 64 %, respectively). Data analysis for ACR70 showed a favorable trend toward anti-IL-17 (OR 2.62, 95 % CI 1–6.89, P = 0.05, I 2 15 %). Subgroup analysis of ACR20 for individual anti-IL-17 agents showed that ixekizumab was more effective than placebo, while secukinumab showed a trend toward achieving the ACR20 response. However, brodalumab was not effective compared to placebo. Safety analysis did not show increased risk of any or serious adverse effects by anti-IL-17 compared to placebo (OR 1.23, 95 % CI 0.94–1.61, P = 0.13, I 2 = 0 % and OR 1.28, 95 % CI 0.57–2.88, P = 0.55, I 2 = 0 %, respectively). This meta-analysis concludes that anti-IL-17 is effective in the treatment of RA without increased risk of any or serious adverse effects; however, the results are limited by significant heterogeneity and small duration of studies.

Viral vectors based gene therapy is often compromised by adverse immunological reactions raising safety concerns. Hence, improved design and development of non-viral vectors with strong regulatory regions is desired. We describe the design of a non-viral mammalian expression vector in which the primary transgene (a truncated dystrophin gene linked with Duchenne muscular dystrophy (DMD)) named microdystrophin delR4-R23/delCT (MD1) is under the transcriptional control of elements of desmin locus control region (DES-LCR). The designed vector, named as DES-LCR/MD1-EGFP, was constructed by cloning two fragments into the pBluescript backbone. Fragment 1 contains DES-LCR enhancer and DES-LCR promoter region while fragment 2 contains MD1 transgene and reporter EGFP (enhanced green fluorescent protein) gene separated by linker P2A (2A peptide). This vector design provides a framework for strong regulation with non-viral features. This design forms the foundation for application in conditions linked to multisystem diseases.