Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study)

Background: Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications. The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas. Methods/design. Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma 3 cm, located between 115 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane i

Functional regulation of FEN1 nuclease and its link to cancer

Flap endonuclease-1 (FEN1) is a member of the Rad2 structure-specific nuclease family. FEN1 possesses FEN, 5′-exonuclease and gap-endonuclease activities. The multiple nuclease activities of FEN1 allow it to participate in numerous DNA metabolic pathways, including Okazaki fragment maturation, stalled replication fork rescue, telomere maintenance, long-patch base excision repair and apoptotic DNA fragmentation. Here, we summarize the distinct roles of the different nuclease activities of FEN1 in these pathways. Recent biochemical and genetic studies indicate that FEN1 interacts with more than 30 proteins and undergoes post-translational modifications. We discuss how FEN1 is regulated via these mechanisms. Moreover, FEN1 interacts with five distinct groups of DNA metabolic proteins, allowing the nuclease to be recruited to a specific DNA metabolic complex, such as the DNA replication machinery for RNA primer removal or the DNA degradosome for apoptotic DNA fragmentation. Some FEN1 interaction partners also stimulate FEN1 nuclease activities to further ensure efficient action in processing of different DNA structures. Post-translational modifications, on the other hand, may be critical to regulate protein–protein interactions and cellular localizations of FEN1. Lastly, we also review the biological significance of FEN1 as a tumor suppressor, with an emphasis on studies of human mutations and mouse models

Super Resolution Microscopy Reveals that Caveolin-1 Is Required for Spatial Organization of CRFB1 and Subsequent Antiviral Signaling in Zebrafish

10.1371/journal.pone.0068759PLoS ONE87-POLN

Natural Vacuum Alignment from Group Theory: The Minimal Case

Discrete flavour symmetries have been proven successful in explaining the leptonic flavour structure. To account for the observed mixing pattern, the flavour symmetry has to be broken to different subgroups in the charged and neutral lepton sector. However, cross-couplings via non-trivial contractions in the scalar potential force the group to break to the same subgroup. We present a solution to this problem by extending the flavour group in such a way that it preserves the flavour structure, but leads to an 'accidental' symmetry in the flavon potential. We have searched for symmetry groups up to order 1000, which forbid all dangerous cross-couplings and extend one of the interesting groups A4, T7, S4, T' or \Delta(27). We have found a number of candidate groups and present a model based on one of the smallest extension of A4, namely Q8 \rtimes A4. We show that the most general non-supersymmetric potential allows for the correct vacuum alignment. We investigate the effects of higher dimensional operators on the vacuum configuration and mixing angles, and give a see-saw-like UV completion. Finally, we discuss the supersymmetrization of the model. Additionally, we release the Mathematica package "Discrete" providing various useful tools for model building such as easily calculating invariants of discrete groups and flavon potentials.Comment: 33 pages, 7 figures; references added, minor changes, matches version published in JHE

Blood coagulation and beyond: position paper from the fourth Maastricht consensus conference on thrombosis

The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ- specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/ or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of- the- art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i. e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID- 19-associated coagulopathy is revisited.Nephrolog

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Bilateral vocal fold injection with autologous fat in patients with vocal fold atrophy with or without sulcus

Otorhinolaryngolog

Bilateral medialization thyroplasty in patients with vocal fold atrophy with or without sulcus

Purpose To evaluate voice outcome after bilateral medialization thyroplasty in patients with non-paralytic glottic insufficiency due to vocal fold atrophy with or without sulcus. Methods Retrospective cohort study on 29 patients undergoing bilateral medialization thyroplasty for vocal fold atrophy (14 procedures) or atrophy with sulcus (15 procedures) between October 2012 and November 2017. Voice data were collected and analyzed for the preoperative and the 3- and 12-month postoperative time point according to a standardized protocol, including Voice Handicap Index (VHI)-30 and perceptual, acoustic and aerodynamic parameters. Failure rate was based on number of revisions within 12 months and non-relevant improvement (= 15 points) and statistically significant improvement (p < 0.0001) in the VHI-30 (preoperative: 55.8 points; postoperative at 12 months: 30.9 points). Fundamental frequency for male subjects decreased significantly from 175 to 159 Hz (p = 0.0001). The pre- and post-operative grade of dysphonia was significantly lower in patients with atrophy compared to atrophy and sulcus (mean difference 0.70, p = 0.017). Conclusion Bilateral medialization thyroplasty is a valid treatment option for patients with atrophy with or without sulcus. Outcomes are comparable to other methods reported in literature. However, there is a great need for larger, prospective studies with long-term follow-up to gain more insight into the comparative voice outcomes for the different forms of surgery for patients with glottic incompetence due to atrophy with or without sulcus