Telomeres are key structural elements for the protection and maintenance of linear chromosomes, and they function to prevent recognition of chromosomal ends as DNA double-stranded breaks. Loss of telomere capping function brought about by telomerase deficiency and gradual erosion of telomere ends or by experimental disruption of higher-order telomere structure culminates in the fusion of defective telomeres and/or the activation of DNA damage checkpoints. Previous work has implicated the nonhomologous end-joining (NHEJ) DNA repair pathway as a critical mediator of these biological processes. Here, employing the telomerasedeficient mouse model, we tested whether the NHEJ component DNA-dependent protein kinase catalytic subunit (DNA-PKcs) was required for fusion of eroded/dysfunctional telomere ends and the telomere checkpoint responses. In late-generation mTerc ؊/؊ DNA-PKcs ؊/؊ cells and tissues, chromosomal end-to-end fusions and anaphase bridges were readily evident. Notably, nullizygosity for DNA Ligase4 (Lig4)-an additional crucial NHEJ component-was also permissive for chromosome fusions in mTerc ؊/؊ cells, indicating that, in contrast to results seen with experimental disruption of telomere structure, telomere dysfunction in the context of gradual telomere erosion can engage additional DNA repair pathways. Furthermore, we found that DNAPKcs deficiency does not reduce apoptosis, tissue atrophy, or p53 activation in late-generation mTerc ؊/؊ tissues but rather moderately exacerbates germ cell apoptosis and testicular degeneration. Thus, our studies indicate that the NHEJ components, DNA-PKcs and Lig4, are not required for fusion of critically shortened telomeric ends and that DNA-PKcs is not required for sensing and executing the telomere checkpoint response, findings consistent with the consensus view of the limited role of DNA-PKcs in DNA damage signaling in general.Telomeres are key structural elements for the protection and maintenance of linear chromosomes that are comprised of a series of repetitive DNA sequence elements (TTAGGG in humans) and an array of sequence-specific and -nonspecific DNA binding proteins that create a higher-order chromatin structure (21). Telomeres serve various cellular functions, including the prevention of recognition of the linear end as a DNA double-strand break (DSB) (20,49,85); the modulation of local chromatin structure, which influences the expression of those genes proximal to chromosome ends (5, 66, 67); and the regulation of telomere maintenance enzymes and their accessibility (21). The last function is crucial, given the end replication problem that plagues conventional DNA synthesis (65,90). Telomere sequences can be added by telomerase, a specialized reverse transcriptase that adds telomere repeat DNA to the ends of chromosomes, thereby restoring sequences lost after RNA primer removal and end processing following DNA replication (7,53). Human cells in culture that divide in the absence of telomerase experience telomere attrition on the order of 50 to 100 bp per ce...

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Background and study aims Per-oral endoscopic myotomy (POEM) is associated with a short-term clinical response of 82 % to 100 % in treatment of patients with achalasia. Data are limited on the long-term durability of the clinical response in these patients. The aim of this study was to determine the long-term outcomes of patients undergoing POEM for management of achalasia. Methods This was a retrospective multicenter cohort study of consecutive patients who underwent POEM for management of achalasia. Patients had a minimum of 4 years follow-up. Clinical response was defined by an Eckardt score ≤ 3. Results A total of 146 patients were included from 11 academic medical centers. Mean (± SD) age was 49.8 (± 16) years and 79 (54 %) were female. The most common type of achalasia was type II, seen in 70 (47.9 %) patients, followed by type I seen in 41 (28.1 %) patients. Prior treatments included: pneumatic dilation in 29 (19.9 %), botulinum toxin injection in 13 (8.9 %) and Heller myotomy in seven patients (4.8 %). Eight adverse events occurred (6 mucosotomies, 2 pneumothorax) in eight patients (5.5 %). Median follow-up duration was 55 months (IQR 49.9–60.6). Clinical response was observed in 139 (95.2 %) patients at follow-up of ≥ 48 months. Symptomatic reflux after POEM was seen in 45 (32.1 %) patients, while 35.3 % of patients were using daily PPI at 48 months post POEM. Reflux esophagitis was noted in 16.8 % of patients who underwent endoscopy. Conclusion POEM is a durable and safe procedure with an acceptably low adverse event rate and an excellent long-term clinical response.

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In this retrospective study, endoscopic revision provided significantly greater weight loss compared to medical management alone. Results show that revision can help resolve obesity-related comorbidities. Analysis of intraoperative factors suggests that pouch reduction at time of stoma revision may improve weight loss.

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INTRODUCTION: Health literacy and health inequity have emerged as significant issues facing the medical community. Despite in-depth explanations and language translation services, many patients fail to comprehend medical concepts and proposed surgical treatments. Our study aimed to evaluate how an instructional course on digital drawing would impact the likelihood of medical students to utilize medical illustrations in inpatient encounters.METHODS: "Draw Your Way Through Medicine" is an elective course in digital medical illustration. The nine-week course hosted weekly virtual lectures for medical students which combined instruction on digital drawing concepts with direct training on depicting specific surgical procedures. Students completed preand post-course surveys which utilized a 1 to 5 Likert scale and included both multiple-choice and free-response questions. Statistical analysis was performed using paired t-tests.RESULTS: 36 students enrolled in the course, 27 completed the pre-course survey while 21 completed pre-and post-course surveys. Participants reported a strong perceived value in drawing as a communication tool (4.57), especially in the clinical context (4.76). After course completion, enrollees felt that a digital drawing platform could enhance patient satisfaction (4.71). Students' comfort level with drawing improved after course completion (3.14 to 3.48, p¼0.27), specifically towards creating medical visuals (2.24 to 3.67, p<0.01). Qualitative responses echoed the perceived value for implementing digital drawing as a clinical communication tool. CONCLUSION:The introduction of a digital drawing course showed considerable value in improving medical students' confidence in generating medical illustrations. Future research should work to gauge the impact of digital illustration in the clinical setting.

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