Beyond Repair Foci: DNA Double-Strand Break Repair in Euchromatic and Heterochromatic Compartments Analyzed by Transmission Electron Microscopy

DNA double-strand breaks (DSBs) generated by ionizing radiation pose a serious threat to the preservation of genetic and epigenetic information. The known importance of local chromatin configuration in DSB repair raises the question of whether breaks in different chromatin environments are recognized and repaired by the same repair machinery and with similar efficiency. An essential step in DSB processing by non-homologous end joining is the high-affinity binding of Ku70-Ku80 and DNA-PKcs to double-stranded DNA ends that holds the ends in physical proximity for subsequent repair.Using transmission electron microscopy to localize gold-labeled pKu70 and pDNA-PKcs within nuclear ultrastructure, we monitored the formation and repair of actual DSBs within euchromatin (electron-lucent) and heterochromatin (electron-dense) in cortical neurons of irradiated mouse brain.While DNA lesions in euchromatin (characterized by two pKu70-gold beads, reflecting the Ku70-Ku80 heterodimer) are promptly sensed and rejoined, DNA packaging in heterochromatin appears to retard DSB processing, due to the time needed to unravel higher-order chromatin structures. Complex pKu70-clusters formed in heterochromatin (consisting of 4 or ≥ 6 gold beads) may represent multiple breaks in close proximity caused by ionizing radiation of highly-compacted DNA. All pKu70-clusters disappeared within 72 hours post-irradiation, indicating efficient DSB rejoining. However, persistent 53BP1 clusters in heterochromatin (comprising ≥ 10 gold beads), occasionally co-localizing with γH2AX, but not pKu70 or pDNA-PKcs, may reflect incomplete or incorrect restoration of chromatin structure rather than persistently unrepaired DNA damage.Higher-order organization of chromatin determines the accessibility of DNA lesions to repair complexes, defining how readily DSBs are detected and processed. DNA lesions in heterochromatin appear to be more complex, with multiple breaks in spatial vicinity inducing severe chromatin disruptions. Imperfect restoration of chromatin configurations may leave DSB-induced epigenetic memory of damage with potentially pathological repercussions

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

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

Identifying observational studies of surgical interventions in MEDLINE and EMBASE

Background: Health technology as sessments of surgical interventions frequently require the inclusion of non-randomised evidence. Literature search strategies employed to identify this evidence often exclude a methodological component because of uncertainty surrounding the use of appropriate search terms. This can result in the retrieval of a large number of irrelevant records. Methodological filters would help to minimise this, making literature searching more efficient. Methods: An objective approach was employed to develop MEDLINE and EMBASE filters, using a reference standard derived from screening the results of an electronic literature search that contained only subject-related terms. Candidate terms for MEDLINE (N = 37) and EMBASE (N =35) were derived from examination of the records of the reference standard. The filters were validated on two sets of studies that had been included in previous health technology assessments. Results: The final filters were highly sensitive (MEDLINE 99.5%, EMBASE 100%, MEDLINE/EMBASE combined 100%) with precision ranging between 16.7% – 21.1%, specificity 35.3% – 43.5%, and a reduction in retrievals of over 30%. Against the validation standards, the individual filtersretrieved 85.2% – 100% of records. In combination, however, the MEDLINE and EMBASE filters retrieved 100% against both validation standards with a reduction in retrieved records of 28.4% and 30.1% Conclusion: The MEDLINE and EMBASE filters were highly sensitive and substantially reduced the number of records retrieved, indicating that they are useful tools for efficient literature searching.Publisher PDFPeer reviewe