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Background and Study Aims: Long-time follow-up of sigmoidoscopy screening trials has shown reduced incidence and mortality of colorectal cancer (CRC), but inadequate bowel cleansing may hamper efficacy. The aim of this study was to assess the impact of bowel cleansing quality in sigmoidoscopy screening., Patients and Methods: Individuals 50 to 74 years old who had a screening sigmoidoscopy in a population-based Norwegian, randomized trial between 2012 and 2019, were included in this cross-sectional study. The bowel cleansing quality was categorised as excellent, good, partly poor, or poor. The effect of bowel cleansing quality on adenoma detection rate (ADR) and referral to colonoscopy was evaluated by fitting multivariable logistic regression models., Results: 35,710 individuals were included. The bowel cleansing at sigmoidoscopy was excellent in 20,934 (58.6%) individuals, good in 6580 (18.4%), partly poor in 7097 (19.9%) and poor in 1099 (3.1%). The corresponding ADRs were 17.0%, 16.6%, 14.5%, and 13.0%. Compared to participants with excellent bowel cleansing, those with poor bowel cleansing had an odds ratio for adenoma detection of 0.66 (95% confidence interval 0.55-0.79). We found substantial differences in the assessment of bowel cleansing quality among endoscopists., Conclusions: Inadequate bowel cleansing reduces the efficacy of sigmoidoscopy screening, by lowering ADR. A validated rating scale and improved bowel preparation are needed to make sigmoidoscopy an appropriate screening method., Trial registration Clinicaltrials.gov (NCT01538550).

Introduction: The effectiveness of multiple-choice questions (MCQs) in dental education is pivotal to student performance and knowledge advancement. However, their optimal implementation requires exploration to enhance the benefits., Materials and Methods: An educational tool incorporating MCQs was administered from the 5th to the 10th semester in a dental curriculum. The students filled out a questionnaire after the MCQ, which was linked to the learning management system. Four cohorts of four semesters generated 2300 data points analysed by Spearmen correlation and mixed model regression analysis., Results: Demonstrated a significant correlation between early exam preparation and improved student performance. Independent study hours and lecture attendance emerged as significant predictors, accounting for approximately 10.27% of the variance in student performance on MCQs. While the number of MCQs taken showed an inverse relationship with study hours, the perceived clarity of these questions positively correlated with academic achievement., Conclusion: MCQs have proven effective in enhancing student learning and knowledge within the discipline. Our analysis underscores the important role of independent study and consistent lecture attendance in positively influencing MCQ scores. The study provides valuable insights into using MCQs as a practical tool for dental student learning. Moreover, the clarity of assessment tools, such as MCQs, remains pivotal in influencing student outcomes. This study underscores the multifaceted nature of learning experiences in dental education and the importance of bridging the gap between student expectations and actual performance., (© 2024 The Authors. European Journal of Dental Education published by John Wiley & Sons Ltd.)

Telomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fill-in synthesis of the C-rich strand by Polα/primase. At telomeres, Polα/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CST-Polα/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Polα/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Polα/primase into an active state that completes telomere replication through fill-in synthesis., Competing Interests: Declaration of interests T.R.C. is a member of the SAB of Storm Therapeutics, Eikon Therapeutics, and SomaLogic, Inc., (Published by Elsevier Inc.)

Programmed telomere shortening limits tumorigenesis through the induction of replicative senescence. Here we address three long-standing questions concerning senescence. First, we show that the ATM kinase is solely responsible for the induction of replicative senescence. Senescence was delayed by ATM inhibition (ATMi) or overexpression of TRF2, the shelterin subunit dedicated to ATM repression. In contrast, there was no evidence for ATR signaling contributing to replicative senescence even when ATMi was combined with ATR inhibition. Second, we show ATMi can induce apparently normal cell divisions in a subset of senescent cells, indicating that senescence can be reversed. Third, we show that the extended replicative life span at low (physiological) oxygen is due to diminished ATM activity. At low oxygen, cells show a decreased ATM response to dysfunctional telomeres and genome-wide DSBs compared to 20% oxygen. As this effect could be reversed by NAC, the attenuated response of ATM to critically short telomeres and the resulting extended life span at low oxygen is likely due to ROS-induced formation of cysteine disulfide-bridges that crosslink ATM dimers into a form that is not activated by DSBs. These findings show how primary human cells detect shortened telomeres and reveal the molecular mechanism underlying the telomere tumor suppressor pathway.

Deep learning has achieved immense success in computer vision and has the potential to help physicians analyze visual content for disease and other abnormalities. However, the current state of deep learning is very much a black box, making medical professionals skeptical about integrating these methods into clinical practice. Several methods have been proposed to shed some light on these black boxes, but there is no consensus on the opinion of medical doctors that will consume these explanations. This paper presents a study asking medical professionals about their opinion of current state-of-the-art explainable artificial intelligence methods when applied to a gastrointestinal disease detection use case. We compare two different categories of explanation methods, intrinsic and extrinsic, and gauge their opinion of the current value of these explanations. The results indicate that intrinsic explanations are preferred and that physicians see value in the explanations. Based on the feedback collected in our study, future explanations of medical deep neural networks can be tailored to the needs and expectations of doctors. Hopefully, this will contribute to solving the issue of black box medical systems and lead to successful implementation of this powerful technology in the clinic., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Sravanthi Parasa: Consultant Covidien LP; Medical advisory board of Fujifilms Pål Halvorsen: Board member of Augere Medical. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Hicks et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The complex formed by Ku70/80 and DNA-PKcs (DNA-PK) promotes the synapsis and the joining of double strand breaks (DSBs) during canonical non-homologous end joining (c-NHEJ). In c-NHEJ during V(D)J recombination, DNA-PK promotes the processing of the ends and the opening of the DNA hairpins by recruiting and/or activating the nuclease Artemis/DCLRE1C/SNM1C. Paradoxically, DNA-PK is also required to prevent the fusions of newly replicated leading-end telomeres. Here, we describe the role for DNA-PK in controlling Apollo/DCLRE1B/SNM1B, the nuclease that resects leading-end telomeres. We show that the telomeric function of Apollo requires DNA-PKcs's kinase activity and the binding of Apollo to DNA-PK. Furthermore, AlphaFold-Multimer predicts that Apollo's nuclease domain has extensive additional interactions with DNA-PKcs, and comparison to the cryo-EM structure of Artemis bound to DNA-PK phosphorylated on the ABCDE/Thr2609 cluster suggests that DNA-PK can similarly grant Apollo access to the DNA end. In agreement, the telomeric function of DNA-PK requires the ABCDE/Thr2609 cluster. These data reveal that resection of leading-end telomeres is regulated by DNA-PK through its binding to Apollo and its (auto)phosphorylation-dependent positioning of Apollo at the DNA end, analogous but not identical to DNA-PK dependent regulation of Artemis at hairpins., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: The aim of this study was to investigate how students perceive the benefit of participating in a teacher-organised session providing feedback on exams, termed post-exam feedback, in two dental hygienist programmes., Methods: The study was based on interviews with 22 participants, including 18 students and 4 faculty teachers. The data were approached on the basis of thematic analysis, allowing us to generate insights on how the participants reflected on their participation in the post-exam feedback sessions and how they perceived this arrangement as learners., Results: The findings from the study suggest that motivated students consider post-exam feedback to be beneficial in clearing up uncertainties and deepening their understanding of issues not fully understood during the exam, as well as supporting their further learning. Less motivated students mainly consider post-exam feedback to be relevant for students who do not pass the exams., Conclusions: Organised in a student-centred way and with attentiveness to student learning preferences, the results suggest that post-exam feedback can be valuable for enhancing assessment and supporting student learning related to exams., (© 2023 The Authors. European Journal of Dental Education published by John Wiley & Sons Ltd.)

Telomerase adds G-rich telomeric repeats to the 3' ends of telomeres 1 , counteracting telomere shortening caused by loss of telomeric 3' overhangs during leading-strand DNA synthesis ('the end-replication problem' 2 ). Here we report a second end-replication problem that originates from the incomplete duplication of the C-rich telomeric repeat strand (C-strand) by lagging-strand DNA synthesis. This problem is resolved by fill-in synthesis mediated by polymerase α-primase bound to Ctc1-Stn1-Ten1 (CST-Polα-primase). In vitro, priming for lagging-strand DNA replication does not occur on the 3' overhang and lagging-strand synthesis stops in a zone of approximately 150 nucleotides (nt) more than 26 nt from the end of the template. Consistent with the in vitro data, lagging-end telomeres of cells lacking CST-Polα-primase lost 50-60 nt of telomeric CCCTAA repeats per population doubling. The C-strands of leading-end telomeres shortened by around 100 nt per population doubling, reflecting the generation of 3' overhangs through resection. The measured overall C-strand shortening in the absence of CST-Polα-primase fill-in is consistent with the combined effects of incomplete lagging-strand synthesis and 5' resection at the leading ends. We conclude that canonical DNA replication creates two telomere end-replication problems that require telomerase to maintain the G-rich strand and CST-Polα-primase to maintain the C-strand., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Telomerase, the enzyme that maintains telomeres at natural chromosome ends, should be repressed at double-strand breaks (DSBs), where neotelomere formation can cause terminal truncations. We developed an assay to detect neotelomere formation at Cas9- or I-SceI-induced DSBs in human cells. Telomerase added telomeric repeats to DSBs, leading to interstitial telomeric repeat insertions or the formation of functional neotelomeres accompanied by terminal deletions. The threat that telomerase poses to genome integrity was minimized by ataxia telangiectasia and Rad3-related (ATR) kinase signaling, which inhibited telomerase at resected DSBs. In addition to acting at resected DSBs, telomerase used the extruded strand in the Cas9 enzyme-product complex as a primer for neotelomere formation. We propose that although neotelomere formation is detrimental in normal human cells, it may allow cancer cells to escape from breakage-fusion-bridge cycles.

Objective: Colorectal cancer (CRC) has a significant role in cancer-related mortality. Colonoscopy, combined with adenoma removal, has proven effective in reducing CRC incidence. However, suboptimal colonoscopy quality often leads to missed polyps. The impact of artificial intelligence (AI) on adenoma and polyp detection rate (ADR, PDR) is yet to be established., Design: We conducted a randomised controlled trial at Sahlgrenska University Hospital in Sweden. Patients underwent colonoscopy with or without the assistance of AI (AI-C or conventional colonoscopy (CC)). Examinations were performed with two different AI systems, that is, Fujifilm CADEye and Medtronic GI Genius. The primary outcome was ADR., Results: Among 286 patients, 240 underwent analysis (average age: 66 years). The ADR was 42% for all patients, and no significant difference emerged between AI-C and CC groups (41% vs 43%). The overall PDR was 61%, with a trend towards higher PDR in the AI-C group. Subgroup analysis revealed higher detection rates for sessile serrated lesions (SSL) with AI assistance (AI-C 22%, CC 11%, p=0.004). No difference was noticed in the detection of polyps or adenomas per colonoscopy. Examinations were most often performed by experienced endoscopists, 78% (n=86 AI-C, 100 CC)., Conclusion: Amidst the ongoing AI integration, ADR did not improve with AI. Particularly noteworthy is the enhanced detection rates for SSL by AI assistance, especially since they pose a risk for postcolonoscopy CRC. The integration of AI into standard colonoscopy practice warrants further investigation and the development of improved software might be necessary before enforcing its mandatory implementation., Trial Registration Number: NCT05178095., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Polyps are well-known cancer precursors identified by colonoscopy. However, variability in their size, appearance, and location makes the detection of polyps challenging. Moreover, colonoscopy surveillance and removal of polyps are highly operator-dependent procedures and occur in a highly complex organ topology. There exists a high missed detection rate and incomplete removal of colonic polyps. To assist in clinical procedures and reduce missed rates, automated methods for detecting and segmenting polyps using machine learning have been achieved in past years. However, the major drawback in most of these methods is their ability to generalise to out-of-sample unseen datasets from different centres, populations, modalities, and acquisition systems. To test this hypothesis rigorously, we, together with expert gastroenterologists, curated a multi-centre and multi-population dataset acquired from six different colonoscopy systems and challenged the computational expert teams to develop robust automated detection and segmentation methods in a crowd-sourcing Endoscopic computer vision challenge. This work put forward rigorous generalisability tests and assesses the usability of devised deep learning methods in dynamic and actual clinical colonoscopy procedures. We analyse the results of four top performing teams for the detection task and five top performing teams for the segmentation task. Our analyses demonstrate that the top-ranking teams concentrated mainly on accuracy over the real-time performance required for clinical applicability. We further dissect the devised methods and provide an experiment-based hypothesis that reveals the need for improved generalisability to tackle diversity present in multi-centre datasets and routine clinical procedures., (© 2024. The Author(s).)

Labor migration policies within the European Union and its Member States typically address two conflictive labor market policy goals. They aim to attract and retain foreign workers in a situation of labor shortage, while at the same time protecting the national workforce from additional labor market competition. The balancing of these two goals is commonly resolved in favor of nationals and with fewer rights for migrant workers. It is precisely this nexus between migrant rights and the protection of the national workforce that is central to the understudied question of whether and under what conditions migrant workers from third countries (i.e. non-EU countries) may change their employer to quit low-quality work or exploitative employment, or for career reasons. Building on scholarly discussions on employer dependency and bureaucratic complexity as general sources of migrant precarity, as well as on international and EU law on the rights of migrant workers, this article presents three policy variations of the right to change employers currently in place in the European context. Thereby we fill a gap in the literature on labor migration, labor market regulation, and migrant workers' rights. To illustrate the mixed ambitions of EU institutions to reduce migrant precarity the article then presents and critically discusses the high-level negotiations over the recast of the EU Single Permit Directive 2011/98 that were centered around the right to change employers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 De Lange and Falkenhain.)

Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure., (© 2023. The Author(s).)