Contact force and atrial fibrillation ablation.

Catheters able to measure the force and vector of contact between the catheter tip and myocardium are now available. Pre-clinical work has established that the degree of contact between the radiofrequency ablation catheter and myocardium correlates with the size of the delivered lesion. Excess contact is associated with steam pops and perforation. Catheter contact varies within the left atrium secondary to factors including respiration, location, atrial rhythm and the trans-septal catheter delivery technology used. Compared with procedures performed without contact force (CF)-sensing, the use of this technology has, in some studies, been found to improve complication rates, procedure and fluoroscopy times, and success rates. However, for each of these parameters there are also studies suggesting a lack of difference from the availability of CF data. Nevertheless, CF-sensing technology has been adopted as a standard of care in many institutions. It is likely that use of CF-sensing technology will allow for the optimization of each individual radiofrequency application to maximize efficacy and procedural safety. Recent work has attempted to define what these optimal targets should be, and approaches to do this include assessing for sites of pulmonary vein reconnection after ablation, or comparing the impedance response to ablation. Based on such work, it is apparent that factors including mean CF, force time integral (the area under the force-time curve) and contact stability are important determinants of ablation efficacy. Multicenter prospective randomized data are lacking in this field and required to define the CF parameters required to produce optimal ablation

Countering Social Engineering through Social Media: An Enterprise Security Perspective

The increasing threat of social engineers targeting social media channels to advance their attack effectiveness on company data has seen many organizations introducing initiatives to better understand these vulnerabilities. This paper examines concerns of social engineering through social media within the enterprise and explores countermeasures undertaken to stem ensuing risk. Also included is an analysis of existing social media security policies and guidelines within the public and private sectors.Comment: Proceedings of The 7th International Conference on Computational Collective Intelligence Technologies and Applications (ICCCI 2015), LNAI, Springer, Vol. 9330, pp. 54-6

Assessment of cell proliferation in hydatidiform mole using monoclonal antibody MIB1 to Ki-67 antigen

Aims - To assess the role of Ki67 immunoreactivity in predicting the clinical progress of hydatidiform mole. Methods - Tissue from 87 hydatidiform moles, 11 normal first trimester placentas, 11 normal term placentas and 17 spontaneous abortions were examined for expression of Ki67 antigen, using the monoclonal antibody MIB1. Results - Ki67 immunoreactivity was significantly higher in the tissue from normal first trimester placentas than in that from normal term placentas and spontaneous abortions. Among the 87 patients with hydatidiform moles studied, 20 developed persistent gestational trophoblastic disease and required subsequent treatment. There was no statistically significant difference in the Ki67 index between the 20 patients who developed persistent disease and those who did not. Conclusion-Hydatidiform moles which give rise to persistent trophoblastic disease do not have a higher proliferative rate than those which do not. The Ki67 index is not useful for predicting the prognosis of molar pregnancies.published_or_final_versio

Site-specific Phosphorylation of Histone H3K36 Methyltransferase Set2p and Demethylase Jhd1p is Required for Stress Responses in Saccharomyces cerevisiae

Histone lysine methylation is a key epigenetic modification that regulates eukaryotic transcription. In Saccharomyces cerevisiae, it is controlled by a reduced but evolutionarily conserved suite of methyltransferase (Set1p, Set2p, Dot1p, and Set5p) and demethylase (Jhd1p, Jhd2p, Rph1p, and Gis1p) enzymes. Many of these enzymes are extensively phosphorylated in vivo; however, the functions of almost all phosphosites remain unknown. Here, we comprehensively analyse the phosphoregulation of the yeast histone methylation network by functionally investigating 40 phosphosites on six enzymes. A total of 82 genomically-edited S. cerevisiae strains were generated through mutagenesis of sites to aspartate as a phosphomimetic or alanine as a phosphonull. These phosphosite mutants were screened for changes in native H3K4, H3K36, and H3K79 methylation levels, and for sensitivity to environmental stress conditions. For methyltransferase Set2p, we found that phosphorylation at threonine 127 significantly decreased H3K36 methylation in vivo, and that an N-terminal phosphorylation cluster at serine residues 6, 8, and 10 is required for the diamide stress response. Proteomic analysis of Set2p phosphosite mutants revealed a specific downregulation of membrane-associated proteins and processes, consistent with changes brought about by SET2 deletion and the sensitivity of mutants to diamide. For demethylase Jhd1p, we found that its sole phosphorylation site at serine 44 is required for the cold stress response. This study represents the first systematic investigation into the phosphoregulation of the epigenetic network in any eukaryote, and shows that phosphosites on histone methylation enzymes are required for a normal cellular response to stress in S. cerevisiae

Primary biliary cholangitis has the highest waitlist mortality in patients with cirrhosis and acute on chronic liver failure awaiting liver transplant

Background: Data are sparse on etiology specific outcomes on waitlist (WL) and post-transplant outcomes among patients with acute on chronic liver failure (ACLF). / Methods and results: In a retrospective cohort of 14,774 adults from United network for organ sharing (UNOS) database listed for Liver transplantation (LT) with cirrhosis and ACLF (January 2013–June 2019), 40% were due to alcohol-associated liver disease (ALD), followed by hepatitis C virus (HCV) at 20%, non-alcoholic steatohepatitis (19%), cryptogenic cirrhosis (7%), autoimmune hepatitis (5%), primary sclerosing cholangitis (PSC) at 3%, and 2% each for hepatitis B, primary biliary cholangitis (PBC), and metabolic etiology. Using competing risk analysis, cumulative risk of WL mortality was highest for PBC at 20.5% and lowest for PSC at 13.3%, P < .001. Compared with ALD as reference, WL mortality was higher for PBC (1.45 [1.16–1.82]), and similar for other etiologies, P < .001. Of this cohort, 9650 (65.3%) patients received LT, with 1-year. patient survival of 91.6% for PBC, worst for cryptogenic cirrhosis (89.5%) and best for PSC and ALD (93.4%), P < .001. / Conclusion: Among listed candidates with ACLF, those with PBC have highest WL mortality 1-year. post-transplant survival was excellent among recipients for PBC. If these findings are validated in prospective studies, liver disease etiology should be considered for LT selection among patients in ACLF

Temporal trends in mode, site and stage of presentation with the introduction of colorectal cancer screening: a decade of experience from the West of Scotland

background:  Population colorectal cancer screening programmes have been introduced to reduce cancer-specific mortality through the detection of early-stage disease. The present study aimed to examine the impact of screening introduction in the West of Scotland. methods:  Data on all patients with a diagnosis of colorectal cancer between January 2003 and December 2012 were extracted from a prospectively maintained regional audit database. Changes in mode, site and stage of presentation before, during and after screening introduction were examined. results:  In a population of 2.4 million, over a 10-year period, 14 487 incident cases of colorectal cancer were noted. Of these, 7827 (54%) were males and 7727 (53%) were socioeconomically deprived. In the postscreening era, 18% were diagnosed via the screening programme. There was a reduction in both emergency presentation (20% prescreening vs 13% postscreening, P0.001) and the proportion of rectal cancers (34% prescreening vs 31% pos-screening, P0.001) over the timeframe. Within non-metastatic disease, an increase in the proportion of stage I tumours at diagnosis was noted (17% prescreening vs 28% postscreening, P0.001). conclusions:  Within non-metastatic disease, a shift towards earlier stage at diagnosis has accompanied the introduction of a national screening programme. Such a change should lead to improved outcomes in patients with colorectal cancer

Oxygen-Vacancy Engineering of Cerium-Oxide Nanoparticles for Antioxidant Activity

© 2019 American Chemical Society. To address an important challenge in the engineering of antioxidant nanoparticles, the present work devised a surface-to-bulk migration of oxygen vacancies in the oxygen radical-scavenging cerium-oxide nanoparticles. The study highlights the significance of surface oxygen vacancies in the intended cellular internalization and, subsequently, the radical scavenging activity of the nanoparticles inside the cells. The findings advise future development of therapeutic antioxidant nanomaterials to also include engineering of the particles for enhanced surface defects not only for the accessibility of their oxygen vacancies but also, equally important, rendering them bioavailable for cellular uptake

Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes

This is the final version. Available on open access from Springer via the DOI in this recordData availability: The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.Aims/hypothesis Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31–72 years), followed up for 18–32 years. Methods Peripheral blood samples were obtained from slow progressors (n = 8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes. Results Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells. Conclusions/interpretations We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes.Diabetes UKJDR