Temporal trends and lesion sets for persistent atrial fibrillation ablation: a meta-analysis with trial sequential analysis and meta-regression

BACKGROUND: Ablation for persistent atrial fibrillation (PsAF) has been performed for over 20 years, although success rates have remained modest. Several adjunctive lesion sets have been studied but none have become standard of practice. We sought to describe how the efficacy of ablation for PsAF has evolved in this time period with a focus on the effect of adjunctive ablation strategies. METHODS: Databases were searched for prospective studies of PsAF ablation. We performed meta-regression and trial sequential analysis. RESULTS: A total of 99 studies (15 424 patients) were included. Ablation for PsAF achieved the primary outcome (freedom of atrial fibrillation/atrial tachycardia rate at 12 months follow-up) in 48.2% (5% CI, 44.0-52.3). Meta-regression showed freedom from atrial arrhythmia at 12 months has improved over time, while procedure time and fluoroscopy time have significantly reduced. Through the use of cumulative meta-analyses and trial sequential analysis, we show that some ablation strategies may initially seem promising, but after several randomized controlled trials may be found to be ineffective. Trial sequential analysis showed that complex fractionated atrial electrogram ablation is ineffective and further study of this treatment would be futile, while posterior wall isolation currently does not have sufficient evidence for routine use in PsAF ablation. CONCLUSIONS: Overall success rates from PsAF ablation and procedure/fluoroscopy times have improved over time. However, no adjunctive lesion set, in addition to pulmonary vein isolation, has been conclusively demonstrated to be beneficial. Through the use of trial sequential analysis, we highlight the importance of adequately powered randomized controlled trials, to avoid reaching premature conclusions, before widespread adoption of novel therapies

Inhibition of HCV 3a genotype entry through Host CD81 and HCV E2 antibodies

<p>Abstract</p> <p>Background</p> <p>HCV causes acute and chronic hepatitis which can eventually lead to permanent liver damage hepatocellular carcinoma and death. HCV glycoproteins play an important role in HCV entry by binding with CD81 receptors. Hence inhibition of virus at entry step is an important target to identify antiviral drugs against HCV.</p> <p>Methods and result</p> <p>The present study elaborated the role of CD81 and HCV glycoprotein E2 in HCV entry using retroviral pseudo-particles of 3a local genotype. Our results demonstrated that HCV specific antibody E2 and host antibody CD81 showed dose- dependent inhibition of HCV entry. HCV E2 antibody showed 50% reduction at a concentration of 1.5 ± 1 μg while CD81 exhibited 50% reduction at a concentration of 0.8 ± 1 μg. In addition, data obtained with HCVpp were also confirmed with the infection of whole virus of HCV genotype 3a in liver cells.</p> <p>Conclusion</p> <p>Our data suggest that HCV specific E2 and host CD81 antibodies reduce HCVpp entry and full length viral particle and combination of host and HCV specific antibodies showed synergistic effect in reducing the viral titer.</p

siRNAs: Potential therapeutic agents against Hepatitis C Virus

Hepatitis C virus is a major cause of chronic liver diseases which can lead to permanent liver damage, hepatocellular carcinoma and death. The presently available treatment with interferon plus ribavirin, has limited benefits due to adverse side effects such as anemia, depression and "flu-like" symptoms. Needless to mention, the effectiveness of interferon therapy is predominantly, if not exclusively, limited to virus type 3a and 3b whereas in Europe and North America the majority of viral type is 1a and 2a. Due to the limited efficiency of current therapy, RNA interference (RNAi) a novel regulatory and powerful silencing approach for molecular therapeutics through a sequence-specific RNA degradation process represents an alternative option. Several reports have indicated the efficiency and specificity of synthetic and vector based siRNAs inhibiting HCV replication. In the present review, we focused that combination of siRNAs against virus and host genes will be a better option to treat HC

The SR-BI Partner PDZK1 Facilitates Hepatitis C Virus Entry

Entry of hepatitis C virus (HCV) into hepatocytes is a multi-step process that involves a number of different host cell factors. Following initial engagement with glycosaminoglycans and the low-density lipoprotein receptor, it is thought that HCV entry proceeds via interactions with the tetraspanin CD81, scavenger receptor class B type I (SR-BI), and the tight-junction proteins claudin-1 (CLDN1) and occludin (OCLN), culminating in clathrin-dependent endocytosis of HCV particles and their pH-dependent fusion with endosomal membranes. Physiologically, SR-BI is the major receptor for high-density lipoproteins (HDL) in the liver, where its expression is primarily controlled at the post-transcriptional level by its interaction with the scaffold protein PDZK1. However, the importance of interaction with PDZK1 to the involvement of SR-BI in HCV entry is unclear. Here we demonstrate that stable shRNA-knockdown of PDZK1 expression in human hepatoma cells significantly reduces their susceptibility to HCV infection, and that this effect can be reversed by overexpression of full length PDZK1 but not the first PDZ domain of PDZK1 alone. Furthermore, we found that overexpression of a green fluorescent protein chimera of the cytoplasmic carboxy-terminus of SR-BI (amino acids 479–509) in Huh-7 cells resulted in its interaction with PDZK1 and a reduced susceptibility to HCV infection. In contrast a similar chimera lacking the final amino acid of SR-BI (amino acids 479–508) failed to interact with PDZK1 and did not inhibit HCV infection. Taken together these results indicate an indirect involvement of PDZK1 in HCV entry via its ability to interact with SR-BI and enhance its activity as an HCV entry factor

Outcome reporting in randomised controlled trials and meta-analyses of appendicitis treatments in children: a systematic review

Background: Acute appendicitis is the most common surgical emergency in children. Despite this, there is no core outcome set (COS) described for randomised controlled trials (RCTs) in children with appendicitis and hence no consensus regarding outcome selection, definition and reporting. We aimed to identify outcomes currently reported in studies of paediatric appendicitis. / Methods: Using a defined, sensitive search strategy, we identified RCTs and systematic reviews (SRs) of treatment interventions in children with appendicitis. Included studies were all in English and investigated the effect of one or more treatment interventions in children with acute appendicitis or undergoing appendicectomy for presumed acute appendicitis. Studies were reviewed and data extracted by two reviewers. Primary (if defined) and all other outcomes were recorded and assigned to the core areas ‘Death’, ‘Pathophysiological Manifestations’, ‘Life Impact’, ‘Resource Use’ and ‘Adverse Events’, using OMERACT Filter 2.0. / Results: A total of 63 studies met the inclusion criteria reporting outcomes from 51 RCTs and nine SRs. Only 25 RCTs and four SRs defined a primary outcome. A total of 115 unique and different outcomes were identified. RCTs reported a median of nine outcomes each (range 1 to 14). The most frequently reported outcomes were wound infection (43 RCTs, nine SRs), intra-peritoneal abscess (41 RCTs, seven SRs) and length of stay (35 RCTs, six SRs) yet all three were reported in just 25 RCTs and five SRs. Common outcomes had multiple different definitions or were frequently not defined. Although outcomes were reported within all core areas, just one RCT and no SR reported outcomes for all core areas. Outcomes assigned to the ‘Death’ and ‘Life Impact’ core areas were reported least frequently (in six and 15 RCTs respectively). / Conclusions: There is a wide heterogeneity in the selection and definition of outcomes in paediatric appendicitis, and little overlap in outcomes used across studies. A paucity of studies report patient relevant outcomes within the ‘Life Impact’ core area. These factors preclude meaningful evidence synthesis, and pose challenges to designing prospective clinical trials and cohort studies. The development of a COS for paediatric appendicitis is warranted

Binary Black Hole Mergers in the first Advanced LIGO Observing Run

The first observational run of the Advanced LIGO detectors, from September 12, 2015 to January 19, 2016, saw the first detections of gravitational waves from binary black hole mergers. In this paper we present full results from a search for binary black hole merger signals with total masses up to $100 M_\odot$ and detailed implications from our observations of these systems. Our search, based on general-relativistic models of gravitational wave signals from binary black hole systems, unambiguously identified two signals, GW150914 and GW151226, with a significance of greater than $5\sigma$ over the observing period. It also identified a third possible signal, LVT151012, with substantially lower significance, which has a 87% probability of being of astrophysical origin. We provide detailed estimates of the parameters of the observed systems. Both GW150914 and GW151226 provide an unprecedented opportunity to study the two-body motion of a compact-object binary in the large velocity, highly nonlinear regime. We do not observe any deviations from general relativity, and place improved empirical bounds on several high-order post-Newtonian coefficients. From our observations we infer stellar-mass binary black hole merger rates lying in the range $9-240 \mathrm{Gpc}^{-3} \mathrm{yr}^{-1}$. These observations are beginning to inform astrophysical predictions of binary black hole formation rates, and indicate that future observing runs of the Advanced detector network will yield many more gravitational wave detections