Citations

Background and Aims: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the biliary epithelium with limited therapeutic options and poor long-term survival rates. To address the limitations of CCA treatment, we investigated cell-targeted nanovesicles as a delivery platform for transcriptome-targeting therapeutics. Approach and Results: Milk-derived nanovesicles were loaded with short interfering RNAs targeting Yes-associated protein (YAP), the downstream effector of the Hippo pathway; LCK, an upstream regulator of YAP; and tafazzin, a protein critical for the integrity of the inner mitochondrial membrane. These transcriptome-targeting nanovesicles were decorated with a lipid-coupled RNA aptamer to epithelial cell adhesion molecule, including a tracking fluorophore. In vitro studies were conducted using multiple CCA cell lines. In vivo studies were performed using C57BL/6 and non-obese diabetic/severe combined immunodeficient mice to evaluate delivery and efficacy in both an immunocompetent syngeneic murine and a patient-derived xenograft model. We demonstrated that transcriptome-targeting nanovesicles were selectively taken up by liver tumor cells, which was augmented by the incorporation of a targeting aptamer, and that milk-derived nanovesicles loaded with short interfering RNA effectively downregulated target gene expression, both in vitro and in vivo. Downstream effects of target gene inhibition were observed, including downregulation of YAP-TEAD target genes and an increase in reactive oxygen species production at the mitochondrial level. Administration of transcriptome-targeting nanovesicles targeting YAP, LCK, and tafazzin inhibited CCA growth and further synergized with chemotherapy in 2 preclinical CCA models. Conclusions: Herein, we show that aptamer-directed, nanovesicle-mediated targeting of YAP, LCK, and tafazzin potentiates chemosensitivity in 2 CCA models when delivered using aptamer-guided milk-derived nanovesicles.

This cohort study conducted among Minnesota children diagnosed with adrenoleukodystrophy through newborn screening examines correlation of C26:0 lysophosphatidylcholine (C26LPC) with clinical phenotype over 5 years and recommends adjusting early childhood surveillance regimens in children with lower C26LPC levels.

In this study, we propose a new mathematical model able to quantify C-peptide secretion and β-cell responsivity in response to a glucagon bolus in individuals without and with type 2 diabetes. We show that individuals with type 2 diabetes exhibit reduced β-cell responsivity to glucagon.

Background: The calf muscle pump is an understudied contributor to venous return from the lower extremity. This study aimed to determine if calf pump function (CPF) is independently associated with the severity of chronic venous disease classified by CEAP (Clinical-Etiology-Anatomy-Pathophysiology). Methods: The Mayo Clinic Vascular Laboratory database was analyzed from January 2015 through September 2023. Ambulatory adults who underwent venous air plethysmography were included. Venous plethysmography assessed the severity of venous incompetence, and CPF was measured as ejection fraction (EF) per leg. The clinical component (C0 through C6) of the CEAP score was evaluated for each extremity at the time of the study. Results: A total of 7760 limbs from 3733 patients were analyzed. The mean age was 62 years, with 62% women. Venous obstruction was detected in 3.2% of limbs. Venous incompetence severity was categorized as normal (44%), mild (26%), moderate (19%), and severe (10%). A significant trend of reduced CPF was observed with higher CEAP scores ( p < 0.001). Multivariable logistic regression, adjusted for age, sex, degree of venous incompetence, and obstruction showed reduced CPF was a significant predictor (odds ratio 1.84, CI: 1.5–2.2) of active/prior ulcer (C5 or C6). In contrast to more severely reduced CPF, mildly reduced CPF (EF 40–49%) was not associated with active/prior ulcers. Conclusion: This large contemporary study demonstrates that decreased CPF is associated with worse chronic venous disease. Importantly, we demonstrate for the first time that CPF is independently associated with active/prior venous ulcers after accounting for other venous physiologic parameters and demographics.

Background: Mycobacterium chelonae is a ubiquitous, rapidly growing, nontuberculous mycobacteria that primarily affects immunocompromised patients. The most common presentation is an atypical, chronic skin and soft tissue infection. Due to its high resistance rate, early diagnosis based on clinical suspicion, risk factor assessment, and exposure history is crucial for initiating appropriate multi-drug treatment. Methods: We report two cases of M. chelonae skin and soft tissue infections, one presenting with localized disease and the other with disseminated involvement. One case had a specific exposure to fish-related activities, a risk factor more commonly associated with Mycobacterium marinum infections rather than M. chelonae. Results: One of the cases involved osteomyelitis and tenosynovitis which are rare presentations of M. chelonae infection. While the limbs are the most commonly affected sites in disseminated M. chelonae infections, involvement of the lower extremities, as seen in one of our cases, is rarely reported. Treatment posed challenges due to antibiotic resistance and patient tolerance. However, in both cases where follow up was possible, prolonged multi-drug therapy led to complete resolution of the lesions. Conclusions: These cases highlight the importance of considering M. chelonae in chronic skin and soft tissue infections, especially in patient with relevant exposures or immunosupression. Uncommon presentations require a high index of suspicion. Given the challenges of treatment resistance and patient tolerance, prolonged multi-drug therapy remains essential for successful outcomes.

Abstract Background Cholangitis is a well-described adverse event (AE) following endoscopic retrograde cholangiopancreatography (ERCP) that is associated with significant morbidity and mortality. Despite this, contemporary characterization of this AE using high-quality prospective data is incomplete. Aims In this study we describe post-ERCP cholangitis incidence, risk factors, and outcomes in a large, international multicenter population of patients undergoing ERCP. Methods We analyzed prospective data from nine centers in Canada, USA, and Europe between 2018-2024 with 30-day follow-up. The primary outcome was post-ERCP cholangitis, defined as (1) temperature &lt;36.0°C or &gt;38.0°C or white blood cells &lt;4 x109/L or &gt;10x109/L, (2) accompanying rise in bilirubin or transaminases to &gt;1.5 times the upper limit of normal or any increase compared to pre-procedure, and (3) emergency department visit or hospital admission and/or prolongation of existing admission. Multivariable logistic regression was performed to identify risk factors, with results presented as odds ratios (OR) with associated 95% confidence intervals. Outcomes following cholangitis were also described. Results Post-ERCP cholangitis occurred following 134 (1.7%) of 8,119 ERCPs (mean onset of symptoms 2.0 days). Repeat ERCP was required in 53.7% of these cases. Mortality attributed to cholangitis occurred in 8.2% of incident cases. Male sex (OR 1.48, 1.02-2.19), longer procedural time (OR 1.01, 1.00-1.02 per additional minute) and presence of a biliary stricture (OR 3.24, 1.98-5.30) were all independent risk factors for post-ERCP cholangitis, while placement of a biliary stent (OR 0.59, 0.36-0.95), and biliary sphincterotomy (OR 0.59 0.39-0.87) were both protective against post-ERCP cholangitis. Conclusions Post-ERCP cholangitis is common and associated with high mortality rates. Adequate pre-procedural counseling and early recognition is advised, especially in patients at increased risk. Funding Agencies None

Abstract Background Training with virtual reality (VR) simulation is increasingly used for health professions training to allow novices to practice in a learner-centered, risk-free environment. This review was performed to evaluate the effectiveness of VR simulation training in gastrointestinal endoscopy. Aims To determine whether virtual reality simulation training can supplement and/or replace early conventional endoscopy training in diagnostic endoscopy for health professions trainees with limited or no prior endoscopic experience. Methods We searched 17 databases from inception until October 18, 2023. We included randomised and quasi-randomised trials that compared VR simulation training with no training, conventional training, another form of simulation training, or an alternative method of VR training. We screened and abstracted data through Cochrane methodology. The primary outcome was composite score of competency. Secondary outcomes were procedure completion, procedure time, adverse events, patient discomfort, global rating of competency, and mucosal visualization. We calculated risk ratio for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) for continuous outcomes with 95% CI. We used GRADE to assess the certainty of evidence. Results We included 20 trials (500 participants; 3975 endoscopic procedures). There was insufficient evidence to determine the effect of VR training on composite score of competency compared to no training or conventional training. VR training was advantageous over no training based for independent procedure completion (RR 1.62, 95% CI 1.15 to 2.26; moderate certainty evidence), overall rating of performance (mean difference [MD] 0.45, 95 %CI 0.15 - 0.75, very low certainty evidence), and mucosal visualization (MD 0.60, 95 %CI 0.20 - 1.00, very low certainty evidence). VR training resulted in fewer independent procedure completions compared to conventional training (RR = 0.45, 95 %CI 0.27 - 0.74, low certainty evidence). We found no differences between VR training and no training or conventional training for other outcomes. Based on qualitative analysis, we found no significant differences between VR training and other forms of simulation training. VR curricula based in educational theory provided benefit with respect to composite score of competency, compared with unstructured curricula. Based on qualitative analysis, we found no significant differences between VR training and other forms of simulation training. VR curricula based in educational theory provided benefit with respect to composite score of competency, compared with unstructured curricula. Conclusions VR simulation training in endoscopy can supplement conventional endoscopy training and provides benefit compared to no training. Risk of bias summary Funding Agencies None

Abstract Background Real-time endoscopic optical diagnosis involves detailed visualization of the digestive mucosal and microvascular pattern, allowing for prediction of histology. This is advantageous as it can guide endoscopic resection decisions, surgical referrals and provide cost savings to histopathology. There is, however, no standardized or widely implemented curriculum for endoscopists or trainees to learn optical diagnosis skills. Aims To evaluate the impact of a course for the optical diagnosis of esophageal squamous cell carcinoma (ESCC), early gastric cancer (EGC), Barrett’s esophagus (BE), and colorectal polyps Methods 19 gastroenterology trainees were invited to the 2-day course in Kingston, Canada. Number of procedures previously performed was recorded. The impact of the course on lesion diagnosis accuracy was evaluated using a pre-test, immediate post-test, and delayed post-test administered 6 weeks after the course. A repeated measures ANOVA was performed to compare the mean score (%) between the three tests. Results 13 trainees completed all the tests (Table 1). Mean score % values for the overall tests and test scores for esophageal, gastric, and colon lesions were summarized on Table 1. The repeated measures ANOVA determined that the mean score % had a statistically significant difference between the three tests (F (2,24)=5.63, P=0.01). Pairwise comparisons revealed that there was a statistically significant increase in mean scores between pre- and post-tests (13.86 (95% confidence interval (CI) of 4.36 to 23.33), p&lt;0.01) with no significant difference between post and delayed post-tests (8.46 (95% CI of -0.12 to 17.04), p&gt;0.05) (Figure 1). The mean correct % from the delayed post-test was higher than the pre-test but there was no statistical significance (5.39 (95% CI of -3.72 to 14.49), p&gt;0.05). Conclusions This novel optical diagnosis course improved trainee accuracy in diagnosing ESCC, EGC, BE and colorectal polyps. Learning retention was evident, with no significant score difference between immediate and delayed post-tests. This study was limited by the low sample size and low number of test items. Further investigation is required to validate the course for international trainees and explore its clinical transferability. Demography and Mean Score % Figure 1. Mean score %. (*) denotes p&lt;0.05. Funding Agencies None